HRCS2022_ID,FundingOrganisation,FunderAcronym,AwardTitle,AwardAbstract,AwardLayAbstract,RACs,HCs HRCS22_05816,Department of Health and Social Care,NIHR,"'Achieving closure?’ Improving outcomes when care homes close","Care homes for older people are a crucial service, supporting some 400,000 people 24 hours a day/365 days a year. In an era of austerity, care markets are increasingly fragile, and the very logic of a market implies that the risk of failure has to be real for there to be sufficient incentives for providers to deliver appropriate care at the right price. When care homes close –whether through financial problems, care failings or other factors – the received wisdom is that subsequent relocation can be detrimental to the well-being of older residents. Despite this, there is little formal evidence to guide services when undertaking such sensitive work, with local areas reinventing the wheel each time a closure takes place/failing to share learning externally. Building on a previous pilot study of care home closures in Birmingham, this study explores what happens to older people and care staff when homes close, how best to manage closures in a way that minimises negative outcomes for older people and families, and key lessons for Councils as they manage future closures. The study asks: 1.What is the pattern of care home closures nationally, how are they undertaken in different Councils and what do Councils consider best practice when supporting older people at such potentially stressful times? 2.How do older people experience closures, what impact does closure have on health and quality of life, and how can negative impacts be reduced? 3.What impact do closures have on care staff and local care markets, and how can negative impacts be reduced? 4.What are the costs and consequences of closures, and key data required to make this estimation? Can we develop a modelling framework to drive appropriate data collection for future home closure prediction to mitigate adverse outcomes? 5.How can future closures be planned and conducted in a more evidence-based manner, so that outcomes for older people are improved and negative impacts reduced? To answer question the following approaches will be taken: 1.National survey of Directors of Adult Social Services, supplemented by CQC data 2.Four case study sites: Interviews with key stakeholders (commissioners, managers, Healthwatch, broader health partners) Interviews with older people, families, care staff and social work assessors during the closure process Outcomes data (EQ5D, ICECAP-O and outcomes identified in literature on what older people value about care services) at initial assessment, 28-day review and one-year follow-up 3.Survey of care staff (ProQOL) before and after closures, supplemented with individual interviews; interviews with local authorities (commissioners, social workers) and care home providers, supplemented with documentary analysis 4.Preliminary model-based economic evaluation comparing the costs and consequences of alternative pathways of care for residents when homes close (including costs for residents, families, staff and Councils) 5.The study will provide guidance to improve outcomes for older people, supported by key implementation partners, to ensure that future closures are conducted in a more evidence-based manner. This includes a good practice guide for every DASS/CCG/Ambulance Trust in England; an accessible guide for older people/families; and a training video for care staff.","We all want to be cared for with dignity when we are older, and we want the same for our families. Being looked after in a care home is expensive, and we have high expectations of the care delivered. But due to increasing pressures, more and more homes are closing. This can affect the wellbeing of people in care homes and the people that work there. Despite this, there is very little research to guide this important process. If care homes have to close (perhaps because of a financial problem, a problem with the building or due to poor care), we want this to be well managed, so that older people are supported, families are reassured, and care staff are helped to find new work and stay in care roles. While we ve done some initial work in Birmingham, we want to understand more about what happens when care home close and what works best by: Asking Directors of Adult Social Services to complete a survey, providing information about what is happening across England and how they support older people at such potentially stressful times Working in four different areas to explore local closure processes, talking to older people, families, care staff and social workers about their experiences and what would improve these Collecting data on what happens to older people whose homes close to see how their health and wellbeing are affected over time Exploring what happens to low-paid care staff after closures and the impact this has on the care they give and their financial security/future work Exploring the cost implications for residents, family members, staff and wider society Closures can be very upsetting for residents, families and care staff. Because of this, we have built an experienced research team (e.g. our lead is a qualified social worker by background, and has previously been a care assistant). We will also be supported by a Advisory Board of experts who understand what it is like to live in a care home, to work in one, to run one and to close one. This includes national charities such as Age UK, as well as local organisations such as Agewell (a group of older people with lived experience of care services). This Board will help to produce the materials we use in the study (e.g. information sheets/interview questions), help us approach areas where homes are closing and ensure our findings have an impact on policy/practice. We will make a difference by: Developing good practice guidance to inform future closures, and sending this to health and social care leaders across the country Producing a free video for care staff who might not otherwise have access to training materials Producing guidance for older people/families",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_03168,Medical Research Council,MRC,(Epi)genome editing to combat expanded CAG/CTG repeat disorders,"The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Expanded CAG/CTG repeats cause over 13 neurological and neuromuscular disorders, including Huntington disease, myotonic dystrophy, and several spinocerebellar ataxias. They affect 1 in 2000 people worldwide. The diseases are debilitating, often leading to dementia. There is currently no available cure. We aim to develop novel therapeutic avenues and to harness new technologies to detect (i.e., diagnose) and manipulate them. To achieve this, we use a variety of tools, including cutting edge molecular biology and genome engineering techniques, next-generation sequencing, as well as in vitro and in vivo pre-clinical disease models. We focus on: 1) Gene editing and the mechanism of expanded CAG/CTG repeat instability Expanded CAG/CTG repeats are highly unstable somatically, leading to mutation frequencies of 100% in some tissues. The size of the repeat tract determines in large part the severity of the disease. Understanding this mechanism is essential to designing and optimising treatments aimed at contracting the repeat tract. We have recently developed a gene editing-based approach to contract the expanded repeat tract using the CRISPR-Cas9 system. We are currently determining whether this technology can slow, prevent, or reverse the disease phenotypes. Representative reference: Cinesi et al (2016) Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase. Nat Commun, 7, 13272. 2) The role of chromatin structure in the expression of expanded CAG/CTG repeats Expanded CAG/CTG repeats accumulate chromatin marks reminiscent of heterochromatin and are downregulated (but not completely silenced) compared to normal size repeats. In addition, there is genetic and biochemical evidence that expanded repeats require extra factors for efficient expression. Identifying these factors and identifying their mode of action may lead to the development of epigenome editing approaches to combat expanded CAG/CTG repeat disorders. Representative reference: Yang et al (2018) Uncovering the interplay between epigenome editing efficiency and sequence context using a novel inducible targeting system. BioRxiv. 3) Development of tools to manipulate and detect expanded CAG/CTG repeats Determining repeat size for diagnostic purposes and for routine molecular biology applications is laborious. This is because of the repetitive nature and the inherent heterogeneity of the repeat size from cell to cell (i.e., repeat instability). Thus, there is a great need to improve on the current technologies. In addition, such system will help us determine whether any therapies involving contracting the repeat tracts are effective. Representative reference: Malbec et al (2019) µLAS: Sizing of expanded trinucleotide repeats with femtomolar sensitivity in less than 5 minutes. Scientific Reports 9, (1):23.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.2 CELLULAR AND GENE THERAPIES,NEUROLOGICAL HRCS22_06382,Medical Research Council,MRC,"14/150 (12/205 Very Rare Diseases project number 112195): A randomised trial comparing surgical and radiotherapy strategies enabling rational treatment selection for primary Merkel Cell Carcinoma (MCC), a rare virus and immune-related aggressive skin cancer","Merkel cell carcinoma (MCC) is rare but greatly impacts on patients. It starts on skin (the primary), grows fast and often spreads to nearby lymph nodes in the neck, armpit or groin. Spread to other organs is usually fatal. It must be treated effectively or it rapidly regrows. MCC can be treated by surgery and is very sensitive to radiotherapy (RT). _x000D_ We aim to compare treatments for the primary, something not done before. Most specialists remove the primary surgically with 1-3cm of apparently normal skin to reduce the chance of leaving behind satellite tumours. Sometimes RT is used after healing to kill residual cancer. RT can also control MCC if used earlier without prior extensive surgery. Prioritising RT as first treatment may be as effective as or better than prioritising surgery for disease control. _x000D_ This is an 8-year trial for people with primary MCC for whom either surgery or RT are feasible for disease control. It compares these two strategies in preventing cancer regrowth between and including the primary site and the nearby lymph nodes. Patients will be recruited over 5-years by specialist teams across the UK, with informed consent and all getting active treatment. Assessments will be for 2 years: not many MCC recur later. The treatments’ effect on well-being and resource use will be measured. Additional NHS costs will be for the informed consent process, quality control, data and tissue collection and PET scans, but not for treatments as all patients should be treated anyway. Five years recruitment should result sufficiently robust evidence to inform patients and clinicians deciding between treatments. _x000D_ Over the first 3 years, we will invite all new patients with MCC to give data, blood and tumour samples. Many or most will also enter the trial. This wider data collection makes efficient use of resource when studying a rare cancer. Some specialist centres might start recruiting for this wider study while they sort out their treatment pathways for the trial. At 3-years we will have data about the patients (e.g. age, sex, other illnesses), their treatment and a set of biological markers. The markers cover their immunity (whether they have had an illness or treatment suppressing immunity, measurement of white cells called lymphocytes in blood, standard measurements of how lymphocytes work), the cancer’s invasiveness and whether their cancer has been invaded by killer lymphocytes. _x000D_ At 3-years, we will ask if enough people are entering the trial and if it is likely that the trial will deliver a clear comparison between two different treatments, thus benefiting future patients. If not, the trial will close and high quality data about patients, their treatments and the biological markers will be analysed for a relationship to outcomes. If the feasibility phase shows that continuing the trial promises success, the trial will go on to complete 5-years recruitment. We will investigate which of prioritising either radiotherapy versus surgery to treat primary MCC is probably the more effective. We will also explore whether the biological markers of immunity and invasiveness predict the outcome of radiotherapy differently to the outcome of surgery. _x000D_ This project links specialist clinical teams nationwide, is led by a unit experienced in cancer trials for rare populations and uses a tissue bank competent to collect tissue specimens linked to accredited pathology and clinical immunology laboratories to measure the biological markers.","MCC is a rare skin cancer (200-300 cases across the UK annually) of older people, is locally invasive and has high metastatic potential. A paucity of trials means current treatments may be sub-optimal and their selection for individual patients not evidence-based. MCC cells carry integrated Merkel cell polyoma virus (MCPyV). Viral proteins may contribute to oncogenesis and be targets for immunity. Incidence of MCC is higher in immune suppressed states. Infiltration into tumour nodules of CD8+ cytotoxic T cells in MCC specimens associates with better outcome. Radiotherapy (RT) might affect immunity against MCC differently to surgery by exposing antigen presenting cells to immunogenic debris. For a rare cancer currently managed along diverse pathways, it is efficient to build a randomised trial addressing a single aspect of clinical decision-making, set within a wider registration study to maximise collection of clinical data and tissue for translational research, and with a feasibility phase to ensure the trial sits appropriately within real-life clinical pathways. _x000D_ In the UK, management is centred on skin specialist multidisciplinary teams (SSMDT). MCC is sensitive to RT. Many SSMDT treat primary MCC with WLE, sometimes with delayed local RT following graft healing. Earlier use of RT, following biopsy or a limited excision, might result in better local disease control. _x000D_ This is a UK-wide, multi-centre study over 8 years (5 years accrual), for patients with primary MCC considered for radical treatment to achieve durable loco-regional control. Treatment arms are (A) WLE, permitting subsequent adjuvant RT versus (B) prioritising early use of RT for primary MCC following local biopsy or excision but without prior WLE. The primary outcome measurement is time to loco-regional progression. QOL is a key secondary outcome measurement. The sample size derives from probability distributions for correctly identifying the better arm based on an event rate of 20% whereas the trial is not powered to confidently detect a difference between the arms with 5% significance. For example, an observed HR of 0.8 favouring arm A offers a 50% chance that arm A is clearly better than arm B (HR<0.8) and a 92 % chance arm A is roughly equivalent to or better than arm B (HR <1.2). Such data are more informative than current uncontrolled studies for individual decision-making. _x000D_ A critical component is the initial 3-year randomised feasibility study, embedded within registration of all consenting patients newly presenting with MCC, including those not randomised into the trial. This provides a tissue and data bank for future research coordinated by a licensed biorepository linked to CPA-accredited pathology and molecular laboratories. Recognised pathological biomarkers in MCC i.e. tumour viral status and intra-tumoural infiltration by cytotoxic T cells plus standard clinical markers of immune status will be analysed for a relationship with outcome. If the feasibility phase of the trial demonstrates sufficient accrual, and a high probability that the trial will deliver a meaningful comparison between two different treatments, the trial will continue to complete 5-years accrual, with ongoing tissue collection, and a further two years follow up. In that event, data from the feasibility/registration phase will be used to design further analysis of trial patients seeking interaction between immune markers measured at baseline, the randomised treatments and outcome.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,CANCER AND NEOPLASMS HRCS22_11998,British Skin Foundation,,165 V1-V2 sequencing of female genital lichen sclerosus,"DDL will perform the following activities: 1. Nucleic acid isolation 2.165 rRNA ampticon sequencing 3. Data analyses and reporting",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,SKIN HRCS22_05829,Department of Health and Social Care,NIHR,18/37 - Repair of digital nerve injury,"Digital nerves are small nerves that pass along the side of each finger and provide sensation to the fingertips. These nerves can be accidentally cut when handling sharp objects like a knife or broken glass. The NEON study aims to find out whether repairing the nerve surgically (sewing the ends of the cut nerve) is beneficial or even needed. Thoroughly cleaning the cut before closing the skin is a much simpler procedure, and may be satisfactory for patients._x000D_ _x000D_ There is some evidence that both treatments give good results. There is also some evidence that patients may not fully recover the feeling in their injured finger, even after the nerve has been surgically repaired. Research so far has been conflicting and is of varying quality. For example, some studies do not directly compare treatments, or do not ask patients about their views of recovery._x000D_ _x000D_ The best way to find out if surgically repairing digital nerves is appropriate is to conduct a research study. The National Institute for Health Research (NIHR) have commissioned research to address this clinical question. A recent patient/public consultation fully supports the need for more research comparing surgical and non-surgical treatments in hand conditions (http://www.bssh.ac.uk/patients/bssh_james_lind_alliance_partnership.aspx). _x000D_ NEON will compare surgical procedures for digital nerve injury, with and without a nerve repair. 478 patients will have one of these two treatment options by random allocation. Patient questionnaires measuring fingertip sensation and quality of life will assess the benefit of each treatment. Patient recovery in both groups will be checked after the procedure at 6 weeks, 3, 6 and 12 months. Given the cost difference of the procedures and the potential need for further treatment, it will also be important to look into whether surgical repair is a good use of NHS resources. _x000D_ _x000D_ The study is supported by the specialist surgical societies in the UK such as the British Association of Plastic Surgery, the British Society for Surgery of the Hand and the Reconstructive Surgery Trials Network. Patient representatives who have had this injury are part of the study team and are members of the trial steering group._x000D_ _x000D_ The results of our study will be published via the funder’s website and in medical journals. The study team will present the results at association conferences. The study website will present the results and a summary given to participants. To reach the patients and public more widely we will make our results available through public websites like NHS Choices.","Research Question: Does microsurgical nerve repair offer clinical benefit and cost effectiveness (in terms of patient reported hand function, sensory recovery and adverse events) over exploration and washout without microsurgical repair in adult patients with recent traumatic digital nerve injury?_x000D_ _x000D_ Background: Digital nerve injury is common, often sustained through sharp lacerations. Treatment involves specialist referral and direct end to end microsurgical repair of the cut nerve ends in an operating room by a hand surgeon. There is conflicting evidence as to the efficacy and necessity of nerve repair and some evidence that patients have good outcomes even when the nerve is not repaired. The perceived advantage of performing repair is that accurate coaptation of the nerve endings is more likely to result in a better outcome for patients and possibly fewer complications such as neuroma formation. Despite the specialist resources required for this surgical repair procedure there is limited evidence, with regards to patient reported outcome measures or functional improvement, that surgical repair offers significant benefit to patients. A systematic review conducted in 2018 showed most studies were of poor quality and did not consider patient reported outcomes in their conclusions. Only 24% of patients regained what could be considered “normal” sensation. Pooled data in the review indicated there was no evidence that adverse outcome was higher if a nerve was left unrepaired (neuroma rate 4.6% repaired versus 5.0% unrepaired). Where the nerve was not repaired the majority regained protective sensibility and all patients declined further surgery to improve their sensibility suggesting they were satisfied with their outcome._x000D_ _x000D_ Aims & Objectives: The aim is to conduct a randomised trial comparing exploration and washout with microsurgical repair to exploration and washout alone for patients with digital nerve injuries. The primary objective is to ascertain the patient reported clinical efficacy (and effectiveness) of microsurgical repair for patients with digital nerve injuries using the patient-reported Impact of Hand Nerve Disorders (I-HaND) scale assessed at 12 months. Secondary objectives include: Assessing neurosensory and function recovery in both patient groups; comparing complications of surgery and clinically problematic neuroma rates; and providing a basic comparison of costs, QALYs and cost effectiveness between the repair and no repair groups._x000D_ _x000D_ Methods: A multicentre, patient and assessor blinded randomised trial, run over 4 years, with patient questionnaires and clinical follow up over 12 months, and longer-term follow up using routine data._x000D_ _x000D_ Impact & Dissemination: Results will be disseminated via a published funder report, academic journal, and to patients and clinicians through the surgeon societies and patient groups. Administering specific surgical treatment of unknown efficacy or value is problematic for both individual patient well-being and the health service. If surgical repair is not necessary, or less effective, than other forms of treatment then the practice should be changed. There are resource implications for the healthcare system and there may be a risk of complications or unsatisfactory outcome for individual patients if inappropriate practice is continued.",6.4 SURGERY,INJURIES AND ACCIDENTS HRCS22_09423,"Public Health Agency, NI",PHA,2018 Doctoral Fellowship: The effect of dental and salivary gland radiation dose on the occurrence of post-radiotherapy dental disease in patients with head and neck cancer,"Post-radiotherapy head and neck cancer patients are at an increased risk of developing dental caries and periodontal disease due to radiation-related damage to the teeth and salivary glands. To minimise the onset of disease, all patients undergo an oral examination and dental care pre-radiotherapy. Current guidelines advise on aggressive pre-radiotherapy treatment centred around tooth extractions. Post-radiotherapy dental disease may occur rapidly, especially where saliva flow has diminished. Caries, in particular, can be associated with pain, impaired function, and reduced quality of life. Replacement of missing teeth can also prove difficult, as removable dentures can be extremely uncomfortable and may themselves exacerbate dental disease. Presently the relationship between radiation dose, tumour location, and post-radiotherapy dental disease is unknown. Newer radiotherapies have the potential to limit radiation dose to normal tissues, and therefore reduce the amount of damage to structures such as the salivary glands. The aim of this fellowship is to quantify the relationship between dental radiation dose, 'spared' parotid gland radiation dose, tumour location, and post-radiotherapy dental disease. The results will better inform management of pre- and post-radiotherapy head and neck cancer patients by providing information to reduce these side-effects. Participants will be assessed and rendered dentally fit prior to radiotherapy in the School of Dentistry. Patients will be followed-up at 6, 12 and 24 months post-radiotherapy. Data will be collected at each visit including: number of carious teeth, periodontal disease indices, salivary flow, diet, oral hygiene, mouth opening and oral health-related quality of life (QoL). Radiotherapy and individual tissue doses will be prescribed by the Clinical Oncology team. Doses to the teeth and 'spared' parotid gland will be determined using research software (Eclipse, Varian Systems UK). Data analysis will be undertaken using appropriate statistical tests. Economic analysis will evaluate the costs of managing the dental side effects of radiotherapy.",,6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,ORAL AND GASTROINTESTINAL;CANCER AND NEOPLASMS HRCS22_22639,The Academy of Medical Sciences,AMS,3D Printing Imperceptible Orthoses with Biomimetic Geometry and Molecular Structure to Enable Healthy Gait,"This project will develop a novel kind of orthosis that is almost imperceptible yet enables healthy gait in UK and Zambian patients suffering from foot drop and ankle sprain. 20-33% of people suffer from a musculoskeletal condition. Up to 5m people develop foot drop every year due to stroke. Ankle sprain is the most common exercise-related injury. Orthoses are external devices that can significantly ameliorate these conditions by supporting the limbs or spine. Existing orthoses, however, suffer from three limitations: 1) compliance- patients may not wear orthoses due to discomfort; 2) dependency- orthoses prevent muscle use, leading to atrophy; 3) availability- patients in developing countries often cannot access orthoses. 3D printing offers control over geometry, material composition, and processing conditions at every point in an object, potentially leading to better medical devices by enabling them to mimic individual patients’ bodies. 3D printing could also widen access by manufacturing orthoses locally. Existing 3D printed orthoses, though, are uncomfortable because they are bulky, tightly grip limbs, and immobilize joints. Here, novel high stiffness & strength polymers will be integrated with flexible elastomers into computationally-designed architectures that are only tight when necessary and allow free ankle movement while preventing overextension. The resulting orthoses will provide protection, prevent atrophy, and enable healthy gait but be almost imperceptible to the wearer, increasing compliance. The team will work with hospitals in the UK and Zambia to ensure that devices meet local patient needs at appropriate cost and to carry out clinical trials.","This project will develop a new kind of orthosis that is almost imperceptible yet enables healthy walking in UK and Zambian patients suffering from ankle sprain and foot drop (where the forefoot cannot be raised making walking difficult and falls more likely). 20-33% of people suffer from a musculoskeletal condition. Up to 5m people develop foot drop every year due to stroke. Ankle sprain is the most common exercise-related injury. Orthoses are external devices that can make these conditions easier to live with by supporting the limbs or spine. Existing orthoses, however, suffer from three limitations: 1) patients may not wear them due to discomfort, leading to injury; 2) orthoses prevent muscle use, leading it to waste away and making people dependent on the orthosis 3) orthoses are often not available in developing countries. 3D printing enables production of very complex structures, potentially leading to better medical devices by enabling them to mimic patients’ bodies. 3D printing could also widen availability by manufacturing orthoses locally. Existing 3D printed orthoses, though, are uncomfortable because they are bulky, tightly grip limbs, and immobilize joints. Here, new complex orthoses will be 3D printed that are only tight when necessary and allow free ankle movement while preventing overextension. The resulting orthoses will provide protection and allow healthy walking, but be almost imperceptible to the wearer, increasing comfort. The team will work with hospitals in the UK and Zambia to ensure devices meet local patient needs at appropriate cost, and to trial devices with patients.",5.3 MEDICAL DEVICES,MUSCULOSKELETAL HRCS22_22793,The Academy of Medical Sciences,AMS,"A Fluorophore-nanoparticle Composite Designed for the Early Stage Diagnosis of Alzheimer's Disease","The seeming unstoppable rise of Alzheimer's disease (AD) worldwide represents a significant and challenging public health problem. However, early diagnosis of AD can enable improved disease treatments and alleviate significant associated symptoms, thereby, significantly improving a patients outlook and quality of life. Amyloid β-protein (Aβ-protein) is a particularly important biomarker for AD. The pathological features of Alzheimer's disease in the brain are characterized by the deposition of amyloid β-protein in the hippocampus and cortex of the brain, as well as neurofibrillary tangles (NFTs) due to hyperphosphorylation of Tau protein. With this research we plan to develop a near-infrared (NIR) fluorescence imaging tools for the early diagnosis of AD. A nanocarrier approach will be used to selectively release in a controlled manner a NIR imaging probe. The probe will be selectively released from the nanocarrier upon action of enzymes (such as acetylcholinesterase) found in the AD microenvironment. When compared with current diagnostic tools such as single electron emission computed tomography (SPECT) and Positron emission computed tomography (PET) imaging, our approach does not require expensive equipment and can achieve high sensitivity and selectivity. Additionally, in comparison with other optical imaging approaches, the fluorescence of the NIR imaging probe will only be turned on when activated by the AD microenvironment/enzymes, facilitating both high sensitivity and selectivity during deep tissue imaging of the brain. We anticipate that our approach will enable the development of clinically relevant tools for the early diagnosis of AD.","With the advent of aging population, the incidence of neurodegenerative diseases has increased year on year. Among them, Alzheimer's disease (AD) has become one of the major diseases that endanger public health with almost 350 million people worldwide being affected. AD is currently a disease that cannot be prevented and cured, and the clinical drug test failure rate is as high as 90%. While current medications cannot cure AD, they can help alleviate the symptoms and therefore an early diagnosis can significantly benefit the patient’s quality of life. Clinical findings indicate that a certain type of protein is deposited in the brain during the development of AD. Therefore, we aim to image that protein in order to aid the early diagnosis and real-time monitoring of the progression of AD. This project aims to develop a new near-infrared (NIR) imaging probe whose fluorescence can be triggered by the AD microenvironment and enzymes in order to investigate the effects of the deposited protein. Compared with current diagnostic tools, our approach does not require expensive equipment and can achieve high selectivity and sensitivity. We anticipate that our approach will enable the development of clinically relevant tools for the early diagnosis of AD.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,NEUROLOGICAL HRCS22_06966,Department of Health and Social Care,NIHR,A MULTI-centre feasibility study to assess the use of 99m Tc-SestaMIBI SPECT/CT in the diagnosis of kidney tumours (MULTI-MIBI study).,"Research question: Is it feasible to recruit patients to a multi-centre study using 99TcSestamibi (MIBI) scans in the diagnosis of kidney tumours and what components are required for a full-scale multi-centre diagnostic accuracy study? Background: Around 13000 people are diagnosed every year in the UK with a kidney tumour, and the incidence is increasing. The standard of care is surgery, however, up to 30% of kidney tumours are benign, the majority of which are called oncocytomas which do not cause harm and do not need to be removed. Conventional imaging such as CT or MRI cannot distinguish benign from cancerous tumours, and the only pre-surgical diagnostic tool is a tumour biopsy. However, biopsy is under-utilised due to concerns about pain, bleeding and tumour seeding of the biopsy track. This means that a significant proportion of patients lose part or a whole kidney function, and find out afterwards that the tumour was benign and surgery was unnecessary. Recent studies overseas have reported the use of a nuclear medicine scan (MIBI) to differentiate oncocytomas from kidney cancers. We have performed a small single centre study with 20 patients with high histopathology concordance of 95%. Aims and objectives: The study aims to determine whether MIBI can be used in other centres (3-5 hospitals), assess patient and clinician acceptability, refine the inclusion/exclusion criteria, sample size requirements and determine clinician training needs for MIBI scan interpretation in the context of kidney tumours. Methods: A feasibility study with three components: 1. Multi-centre clinical trial to recruit patients with kidney tumours to have a MIBI scan prior to planned surgery of biopsy for diagnostic accuracy analysis. 2. Mixed methods qualitative and quantitative study to assess patient and clinician perception and acceptability of MIBI, training needs of clinicians and determine minimally acceptable criteria for the definitive trial. 3. Early health economic modelling using a decision analytic approach to explore the potential cost-effectiveness of MIBI in the NHS. Timelines for delivery: The study is scheduled to take 24 months; 3 months for regulatory approvals, multi-site study set up and preparatory work, 15 months for recruitment, 3 months for completion of follow up data and 3 months for data analysis and future trial design and funding application. Anticipated impact and dissemination: If MIBI is found to be an effective diagnostic tool in kidney tumours, then it will change clinical practice guidelines. National roll out and adoption will be rapid and facilitated as technology and equipment is already widely available. This will reduce the number of unnecessary kidney surgeries, impacting on quality of life and outcomes for patients with benign kidney tumours as well as reducing surgical waiting list times for those with kidney cancer. There will also be impact on NHS resources, with likely cost savings. Findings will be disseminated at national and international conferences, peer reviewed journals and patient websites such as Kidney Cancer UK, and hospital websites. The study has support from the British Association of Urological Surgeons, Kidney Cancer UK and the British Society of Interventional Radiology.","Background to the research: In the UK, over 13000 people are diagnosed with kidney tumours every year. Most are detected by chance on scans performed for other purposes. Standard treatment is surgical removal of the tumour together with part or the whole kidney, which carries serious risks and reduces overall kidney function. However, not all kidney tumours are cancers and up to 3 in 10 are benign (most are oncocytomas) which do not cause harm and do not need removal. Currently, to tell if a tumour is benign or cancer requires having it surgically removed or having a biopsy. However, a biopsy is still an invasive procedure and most patients experience pain, and bruising, and must stop blood thinning tablets beforehand to reduce the risk of bleeding. Some patients and doctors also worry about cancer spillage from disrupting the tumour during a biopsy. New studies from the USA, Sweden and China show that a type of nuclear medicine scan called sestamibi (MIBI) can distinguish cancer from benign kidney tumours. MIBI scans use very small doses of radio-active tracer and are safe, non-invasive and painless. They are currently used in the NHS for other indications, such as parathyroid and heart scans, and we have successfully performed a small study for patients with kidney tumours in our hospital. Aim: This feasibility study will find out if MIBI scans can be used for patients with kidney tumours, and will also assess patient and clinician acceptability. The results will help design a larger multi-centre study to fully test the effectiveness of these scans in the NHS. Design and methods used: This study will recruit 50 patients from 3-5 hospitals. We will invite people diagnosed with kidney tumours who are planned to have either a biopsy or surgery, to take part in this study and consent to have a MIBI scan. The MIBI scan will be compared to biopsy/surgery results. We will explore the perception, acceptability and experience of MIBI scans through patient and clinician interviews and surveys. Patient and public involvement: We conducted an online pre-study survey of patients, carers and the public hosted by Kidney Cancer UK. Of 152 respondents, 89% would participate in the study. One of our patient representatives is a co-investigator, and has lived experience of kidney surgery for an oncocytoma. Both representatives have helped in drafting the study protocol and plain English summary, and will represent patient views on the trial management committee. Dissemination: The results will be presented at national and international conferences, and published in peer reviewed medical journals. The patient community and carers will be informed of the results through patient education days hosted by KCUK and delivered via social media outlets to the broader public.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_05927,Department of Health and Social Care,NIHR,A Multicentre Study to Investigate a Protocol-Driven Multidisciplinary Service Model to Tackle ‘Spurious Penicillin Allergy’ in Secondary Care (SPACE study),"Background: This research addresses an important problem in health care: the high rate of patients inaccurately diagnosed with penicillin allergy (PenA). More than 1 in 10 patients have a label of PenA in hospitals, meaning they can’t be given penicillins. Currently, patients with a PenA label who have an infection or need antibiotics to prevent infection are treated with non-penicillin antibiotics. These are associated with higher chances of negative consequences: longer hospital stays, higher readmission rates, increased risk of serious infections such as MRSA, wound infections after operations, and resistance to antibiotics, making healthcare very difficult. Also, this is likely to cost the NHS several million pounds each year._x000D_ _x000D_ However, most (9 out of 10) people with a PenA label prove not to actually be allergic when properly tested. Inaccurate PenA labels often happen because side effects and symptoms of infection are mistaken for an allergy. PenA testing involves a careful medical history, review of previous records, allergy skin tests and a ‘penicillin oral challenge’ (giving penicillin by mouth under supervision). This takes several hours, needs a specialist and can only be done in a small number of allergy clinics. Getting rid of incorrect PenA label is called ‘de-labelling’. Because PenA tests are not routinely available to most hospital patients, we have developed a simple method to de-label based on a careful review of the clinical history without the need for skin tests._x000D_ _x000D_ Based on medical history and previous records, patients are grouped as ‘low risk’ or ‘high risk’. Nearly half of ‘PenA’ patients are ’low risk’. Studies suggest that giving penicillin by mouth to ‘low risk’ patients under medical supervision without doing allergy skin tests is safe. This is called a ‘direct’ oral penicillin challenge (DPC). More research is needed to find out how patients, doctors and hospital managers feel about DPC and how best it can be carried out in hospitals. This will help design new allergy testing pathways. _x000D_ _x000D_ Aims: (a)To find out what patients, healthcare workers and managers think about DPC to remove incorrect PenA labels. (b) To design a safe way to start using DPC in hospitals and estimate costs._x000D_ _x000D_ Design and Methods: This study will be carried out in 3 hospitals over 24 months and will need 122 patients from different types of wards including surgical and cancer patients who are at a higher risk of serious infections. Patients with a PenA label will be seen by a pharmacist or a nurse and placed in ‘low risk’ and ‘high risk’ groups. ‘Low risk’ patients will be offered the DPC. ‘High risk’ patients and those declining the DPC will be seen in an allergy clinic for further testing. We will collect information by interviewing patients in ‘low risk’ group and talk to groups of patients, healthcare workers and managers. We will find out how many ‘low risk’ patients are willing to undergo DPC and describe how they get on. We will look at the ways we might offer DPC in hospital and work out what it would cost. _x000D_ _x000D_ Benefits: This study will help to improve antibiotic use in hospitals, improve patient experience and outcomes, reduce rates of serious hospital acquired infections, and save the NHS money. Patients and patient organisations have helped design this study and will be involved in every stage. We will share our findings with all those involved in the care of patients with infections and PenA and beyond.","Research Questions: _x000D_ 1. Can a ‘direct’ oral penicillin challenge (DPC) be safely embedded into routine clinical practice within secondary care to de-label ‘low risk’ patients with a penicillin allergy (PenA) label?_x000D_ 2. Is DPC acceptable to patients and healthcare professionals (HCPs) and managers in secondary care?_x000D_ 3. What are the facilitators and barriers to DPC in secondary care?_x000D_ 4. Is DPC cost-effective?_x000D_ _x000D_ Background: 6% of the population and 15-20% of inpatients carry a PenA label. However, 90-95% of PenA labels are incorrect. PenA labels lead to adverse clinical outcomes such as enhanced risk for serious hospital infections and longer hospital stay and are associated with higher estimated healthcare costs in the order of several million pounds annually. PenA testing is onerous and requires a specialist. There is an unmet need for allergy services in the NHS. Hence, routine inpatient testing is not available. Recent evidence suggests that a DPC (without performing allergy tests) is a safe option in ‘low risk’ patients (those least likely to be allergic based on history). Further research is needed to validate this intervention in routine secondary care practice and explore potential facilitators and barriers to implementation in different settings. _x000D_ _x000D_ Aims: To explore behaviour, attitudes and acceptability of patients, HCPs and managers regarding use of DPC in ‘low risk’ patients and develop treatment pathways and a governance framework. This study will also explore practical issues pertaining to service implementation and delivery and determine potential cost-effectiveness._x000D_ _x000D_ Methods: This study will span over 24 months and involve 3 clinical settings (medical/infectious diseases wards, pre-surgical units and haematology-oncology units) in 3 hospitals. It will involve 3 workstreams (WS): _x000D_ a. WS1: Patients will be stratified into ‘low risk’ and high risk’. ‘Low risk’ patients will undergo a DPC (total n=122). Uptake and safety of DPC will be determined. _x000D_ b. WS2: One-to-one semi-structured interviews with patients will be conducted (10-15 per site subject to saturation checking). Focus group sessions will be held with prescribers, HCPs, clinical leaders and managers at each site. _x000D_ c. WS3: Care pathway mapping for PenA and decision-analytic modelling will be carried out to determine cost-effectiveness of DPC._x000D_ _x000D_ Research team: Comprises a group of highly skilled and experienced multidisciplinary team with a strong track record in PenA, antimicrobial stewardship, behaviour science, implementation and social science, clinical pharmacy, health economics and biostatistics, thus covering all key areas relevant to this research. The applicants have co-designed this proposal with two major patient organisations including Allergy UK and The Sepsis UK Trust alongside patients previously de-labelled for PenA._x000D_ _x000D_ Impact and dissemination: This research has great potential to improve antimicrobial stewardship and quality of care. Greater use of penicillins as first line treatment for infections is likely to improve patient experience, reduce rates of serious hospital acquired infections, antimicrobial resistance and significantly reduce NHS costs. We have embedded strategies to disseminate results of this study to a global audience via regular updates and publications in social media and engagement with patient groups, patient organisations, national and international scientific societies.",7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES,INFECTION HRCS22_19593,Cancer Research UK,CRUK,A Novel Role for PARP Activity During Normal S phase and its Impact on Genome Stability and Cancer,"Background: The poly(ADP-ribose) polymerases (PARPs) comprise a superfamily of enzymes that modify themselves and other proteins with ADP-ribose. Three of these enzymes (PARP1, PARP2 and PARP3) are activated by DNA strand breaks including the archetypal family member, PARP1. Whilst numerous cellular roles have been identified for these enzymes in response to exogenous DNA damage/replication stress, their roles in normal unperturbed cells are unclear. PARP1 and PARP2 are of particular importance in this respect, because simultaneous deletion of both results in embryonic lethality in mouse, indicating that these two enzymes fulfil overlapping and essential role/s. Moreover, small molecule inhibitors of PARP1 are lethal in BRCA1/BRCA2-mutated cancer cells; a property now exploited therapeutically in the clinic. It is thus critical that we identify the roles of PARP activity during normal cell growth, to understand both how genome integrity and cellular viability are maintained and to further develop and exploit inhibitors of this activity in the clinic. To begin to identify the roles of PARP activity during normal cell growth we have identified the sites of endogenous poly(ADP-ribose) in chromatin. Surprisingly, we find that all of the endogenous poly(ADP-ribose) detectable in unperturbed wild-type human cells is localised not at sites of stochastic DNA damage but at sites of DNA replication. This S phase poly(ADP-ribose) does not result from damaged or inappropriate nucleotides incorporated during DNA replication nor does it result from DNA replication fork stress. Rather, based on exciting new data, we propose that the primary role of PARP activity during normal DNA metabolism is as a sensor of unligated Okazaki fragments during normal DNA replication, and as a facilitator of their subsequent repair. Aims: We will, 1. Characterise the novel role we have discovered for PARP activity during normal S phase 2. Address the importance of this role for cell survival and genome stability 3. Define how this role impacts on cancer incidence and treatment Methods: This Programme will employ molecular genetics, molecular biology, biochemistry, and cell biology. How this research will be used: This Programme will identify the role/s of PARP activity during normal S phase that are important for genome stability and cancer prevention, and identify the DNA structures that underpin the clinical sensitivity of specific types of cancer to PARP inhibitor. This work will also identify new cancer genetic backgrounds that are sensitive to PARP inhibitor, extending the clinical utility of this exciting class of anticancer drug.","Background: The poly(ADP-ribose) polymerases (PARPs) comprise a superfamily of enzymes that modify themselves and other proteins with ADP-ribose. Three of these enzymes (PARP1, PARP2 and PARP3) are activated by DNA strand breaks including the archetypal family member, PARP1. Whilst numerous cellular roles have been identified for these enzymes in response to exogenous DNA damage/replication stress, their roles in normal unperturbed cells are unclear. PARP1 and PARP2 are of particular importance in this respect, because simultaneous deletion of both results in embryonic lethality in mouse, indicating that these two enzymes fulfil overlapping and essential role/s. Moreover, small molecule inhibitors of PARP1 are lethal in BRCA1/BRCA2-mutated cancer cells; a property now exploited therapeutically in the clinic. It is thus critical that we identify the roles of PARP activity during normal cell growth, to understand both how genome integrity and cellular viability are maintained and to further develop and exploit inhibitors of this activity in the clinic. To begin to identify the roles of PARP activity during normal cell growth we have identified the sites of endogenous poly(ADP-ribose) in chromatin. Surprisingly, we find that all of the endogenous poly(ADP-ribose) detectable in unperturbed wild-type human cells is localised not at sites of stochastic DNA damage but at sites of DNA replication. This S phase poly(ADP-ribose) does not result from damaged or inappropriate nucleotides incorporated during DNA replication nor does it result from DNA replication fork stress. Rather, based on exciting new data, we propose that the primary role of PARP activity during normal DNA metabolism is as a sensor of unligated Okazaki fragments during normal DNA replication, and as a facilitator of their subsequent repair. Aims: We will, 1. Characterise the novel role we have discovered for PARP activity during normal S phase 2. Address the importance of this role for cell survival and genome stability 3. Define how this role impacts on cancer incidence and treatment Methods: This Programme will employ molecular genetics, molecular biology, biochemistry, and cell biology. How this research will be used: This Programme will identify the role/s of PARP activity during normal S phase that are important for genome stability and cancer prevention, and identify the DNA structures that underpin the clinical sensitivity of specific types of cancer to PARP inhibitor. This work will also identify new cancer genetic backgrounds that are sensitive to PARP inhibitor, extending the clinical utility of this exciting class of anticancer drug.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_23056,The British Academy,,A Study of COVID-19 Social Media Infodemic in the Retail Pharmacy Industry,"The sudden COVID-19 outbreak has forced the retail pharmacy industry to develop new business and operating models to meet unprecedented demands. However, misinformation via social media platforms has created confusion and caused distortions in both market conditions and consumer behaviours. Hence, a large amount of user-generated content on social media needs to be captured, monitored and analysed to gain insight into market requirements and enhance business intelligence. Accordingly, the aim of this research is to develop an analytical framework for organisations to: a) address the diffusion of information about COVID-19 on different social media platforms, b) highlight the most-discussed COVID-19 topics by consumers, and c) to identify the key areas for improvement based on the most urgent needs of customers. The proposed study will focus on the retail pharmacy chains in the UK and help them develop their social media strategies and fight against the impact of COVID-19 pandemic.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,INFECTION HRCS22_02467,Medical Research Council,MRC,A UK/Canada Collaboration on the genetics of long-term diabetes complications and their risk factors among people with type 1 diabetes,"The aim of this collaborative project is to understand the genes and pathways underlying variation in residual beta-cell function as measured by C-peptide levels, age at diabetes onset and glycaemic control in type 1 diabetes (T1D). The purpose is to i) yield insights into the biology of beta-cell function, that will inform the development of new therapies to prevent or reverse T1D, ii) to enable stratification of those with diabetes with respect to predicted rate of C-peptide loss iii) to quantify the likely clinical impact of restoring beta cell function or of changing glycaemic control to a given level. This collaboration will bring together leading researchers from Scotland and Canada; They will combine data from 12,200 people with T1D. The key steps will be: 1) To establish a common analysis plan for conducting genome-wide association studies (GWAS) of these inter-related phenotypes of C-peptide levels, age at onset and HbA1c trajectories. 2)To bring together the cohort specific GWAS results in a meta-analysis thus i)validating previous genotype-phenotype associations for these phenotypes ii)discovering new loci for these traits through a meta-analysis iii) enabling the construction of locus specific and genome wide genotypic scores 3)To use the genotype data in each cohort to compute locus-specific and genome-wide genotypic predictor scores for a range of other phenotypes of interest for which summary GWAS associations statistics are publicly available.4)To use the SNP associations and the genotypic scores to gain greater insight into biological pathways of relevance to beta cell biology and of the causal role of residual beta cell function in complications a number of approaches. 5)These SNP associations and genotypic scores will also be used to i) construct predictive models for C-peptide trajectories ii) quantify the likely impact of restoring beta cell function, or changing glycaemic control, on diabetic complications.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,METABOLIC AND ENDOCRINE HRCS22_08472,Department of Health and Social Care,NIHR,"A bespoke Pharmacist-Clinical Assessment Platform (Ph-CAP) for minor illnesses, designed for and with Community Pharmacists.","GP practices are experiencing significant workload pressures, with declining GP numbers (1,565 fewer than 2015) and rising demand (patient:GP ratios >300 since 2015). This impacts patient care, with 44% struggling for appointments [1,2], creating unnecessary A&E visits: ~40% of 22m A&E attendances are avoidable[3-5]. A key NHS Long Term Plan strategy to meet these capacity challenges is the introduction of Community Pharmacists Consultation Services (CPCS), effectively integrating community pharmacy into urgent care system, by enabling pharmacists to take referrals directly from NHS111 and general practice for minor illness symptoms[6]. The traditional role of the community pharmacist who dispenses prescriptions is evolving, with community pharmacists developing clinical services in addition to dispensing of medication[6]. Over 94% of community pharmacists (10,500 pharmacies) will deliver the service with >12,000 patients being referred weekly for one-to-one consultations[7]. Up to 6% of all GP consultations (20.4m appointments), could be pharmacy managed[8,9]. However, studies assessing advanced pharmacist clinical practice identified lack of confidence in clinical examinations and clinical decision-making as key barriers to change[10,11]. Supporting pharmacists in making clinical assessments is key to ensuring the success of the NHS Community Pharmacist Consultation Service. DemDx has developed and commercialised a Primary Care Clinical Assessment Platform (a revolutionary support tool for primary care Allied Healthcare Professionals), which guides clinical assessment/histories and suggests most appropriate follow-up actions (investigations/referrals). A pharmacy focused Clinical Assessment Platform (Ph-CAP) is urgently needed to provide pharmacists with the support and confidence to work autonomously in their expanding roles. This project will assess the user and market acceptability for Ph-CAP to this new user/provider group (Community Pharmacists). This will include conducting market research to determine whether Ph-CAP could be cost-effective and commercially viable. Project findings will provide the critical evidence required for the business and private funding to develop Ph-CAP for the community pharmacist market.",,7.3 MANAGEMENT AND DECISION MAKING,GENERIC HEALTH RELEVANCE HRCS22_01701,Medical Research Council,MRC,"A cluster randomized trial of an mHealth integrated model of hypertension, diabetes and antenatal care in primary care settings in India and Nepal","Pregnancy-related deaths and diseases pose a substantial burden to India and Nepal. In India, during 2015, nearly 1.2 million perinatal deaths occurred; in Nepal, with its much smaller population, there were 24,000 deaths. Most of these deaths are preventable with better antenatal care (ANC), but unfortunately there is good evidence that recommended interventions are not routinely implemented in the study settings. This project attempts to address this critical gap. The ultimate aim of the project is to enhance antenatal care (ANC), by using a tablet-based electronic decision support system (EDSS) that prompts frontline health workers (FHWs) to provide evidence-based routine ANC, enhances detection and management of two increasingly important conditions impacting pregnancy, namely pregnancy-induced hypertension (PIH) and gestational diabetes (GDM), facilitates record-keeping and reporting, and links across levels of care providers. The research questions are: -Does an mHealth EDSS, provided to FHWs, enhance ANC by improving adherence to national ANC guidelines, and improve the screening, detection, referral and management of GDM and PIH, compared with usual care in primary healthcare settings? -What are the socio-economic, health-system and political factors affecting the implementation of the enhanced ANC? -What is the cost of the enhanced ANC intervention, the change in resource use, and the costs of the intervention relative to the value of the improved health outcomes achieved? The project, taking place in India (Telangana) and Nepal (Kathmandu),will last 36 months. It includes formative research and process evaluation using qualitative methods, and a cluster randomized trial of 88 primary health centres (and those reporting to them). It has a multi-disciplinary team of investigators, coordinated by the Public Health Foundation of India, India, with support from three regional co-ordinating centres in (a) Delhi, (b) Kathmandu and (c) London",,8.1 ORGANISATION AND DELIVERY OF SERVICES,REPRODUCTIVE HEALTH AND CHILDBIRTH;CARDIOVASCULAR;METABOLIC AND ENDOCRINE HRCS22_16153,The Little Princess Trust,,A comprehensive molecular and MR imaging characterization of ependymoma in infants,"Ependymoma is a type of brain tumour that occurs in all age groups. Current treatment includes neurosurgery, followed by radiotherapy (treatment with x-rays), but some scientists argue that chemotherapy (treatment with strong drugs) has a role to play in the treatment of young children with ependymoma. Ependymoma, especially in infants (children younger than three years), constitutes a challenge from many perspectives. Radiotherapy, a key component of postoperative management of ependymoma in children and young people, can have serious long-term side effects. These side effects range from mild learning disabilities to growth impairment and hormone problems. These adverse effects have driven efforts to defer or avoid the use of traditional radiotherapy. Despite all these efforts, infants with ependymoma have poorer outcomes than that of older children. And we want to try and find out why. There is a great need to study the molecular biology of these tumours to understand and identify factors that may contribute to this poor outcome. Attempts to understand the biology of infant ependymoma have been hampered by the lack of data. Thus, our knowledge of tumour biology and what distinguishes infants from other age groups remains very limited. The goal of this project is to delineate the unique biological and imaging characteristics of infant ependymoma. We are gathering samples of ependymoma from infants, planning to perform various molecular experiments and tests on these samples to try and find the different abnormalities. We hope that a better understanding of the biology of infant ependymoma will help to preselect patients who qualify for clinical trials or future combination therapies. It will also help improve the current poor prognosis of these infants with ependymoma.","Ependymoma is a type of brain tumour that occurs in all age groups. Current treatment includes neurosurgery, followed by radiotherapy (treatment with x-rays), but some scientists argue that chemotherapy (treatment with strong drugs) has a role to play in the treatment of young children with ependymoma. Ependymoma, especially in infants (children younger than three years), constitutes a challenge from many perspectives. Radiotherapy, a key component of postoperative management of ependymoma in children and young people, can have serious long-term side effects. These side effects range from mild learning disabilities to growth impairment and hormone problems. These adverse effects have driven efforts to defer or avoid the use of traditional radiotherapy. Despite all these efforts, infants with ependymoma have poorer outcomes than that of older children. And we want to try and find out why. There is a great need to study the molecular biology of these tumours to understand and identify factors that may contribute to this poor outcome. Attempts to understand the biology of infant ependymoma have been hampered by the lack of data. Thus, our knowledge of tumour biology and what distinguishes infants from other age groups remains very limited. The goal of this project is to delineate the unique biological and imaging characteristics of infant ependymoma. We are gathering samples of ependymoma from infants, planning to perform various molecular experiments and tests on these samples to try and find the different abnormalities. We hope that a better understanding of the biology of infant ependymoma will help to preselect patients who qualify for clinical trials or future combination therapies. It will also help improve the current poor prognosis of these infants with ependymoma.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_05658,Department of Health and Social Care,NIHR,A coproduced mixed method evaluation of the NHS England low calorie diet implementation pilot,"WHY IS THIS STUDY NEEDED? Recent studies have shown that for some people who live with overweight or obesity and type 2 diabetes, a low calorie diet can help them lose weight, reduce their risk of heart disease, and put their diabetes into remission. The NHS wants to test whether or not a low calorie diet can be used to support patients in 10 areas in England. Eligible patients in these areas will receive low calorie meal replacement products (e.g. bars, shakes, soups) and ongoing support to help manage their eating. The support aspect will be delivered and tested in three different ways: digital technology, face to face group support, or face to face one to one support._x000D_ THE PROPOSED STUDY THEREFORE AIMS TO UNDERSTAND:_x000D_ - Whether the low calorie diet programme that has been tested in studies, can work as well when delivered by the NHS, in helping patients to lose weight, improve their diabetes &/or reduce their risk of heart disease; _x000D_ - What patients perceive to be the benefits and disadvantages of the programme;_x000D_ - How much it costs the NHS, whether there are any costs to patients, and if so, if this a barrier to them completing the programme; _x000D_ - Which method of support (1:1, group or digital) is more preferable to patients;_x000D_ - What patients and staff involved in the programme think about it;_x000D_ - Whether the programme is being delivered as it is intended (e.g. whether all eligible patients are being invited to receive the programme, whether patients are able to follow it as required, which eligible patients are not using the programme, or are having difficulty following it, and why). _x000D_ - Whether the programme should be made available to every area across England, and if so, are any changes to the programme required before this happens._x000D_ HOW ARE WE GOING TO DO THIS STUDY? Work will be undertaken in several stages:_x000D_ 1. We will talk to NHS staff involved with the programme, and to staff who will be delivering the programme, to ask them for their views about what has worked well, what has not, and why._x000D_ 2. We will ask all patients who have been referred to the programme to complete a short survey to ask for their views about the programme. _x000D_ 3. We will take a detailed look at the lived experiences of a small sample of patients from different backgrounds and areas. This will involve talking to patients and asking them to take photographs or video diaries to document their journey._x000D_ 4. We will look at how much the programme costs to run for the NHS, patients and any supporting organisations, and whether it offers value for money._x000D_ 5. We will look at whether it is feasible to make the programme available across England._x000D_ WHO WILL BE INVOLVED? This study will be carried out by a team of experts in weight management, diabetes and programme evaluation. The team also includes an expert patient panel, who will be involved throughout, in co-designing the study, liaising with patients, collecting data and helping to share the findings. We will also work closely with NHS England who are organising the programme for the 10 areas and collecting data on the patients’ weight and health._x000D_ HOW WILL WE SHARE OUR FINDINGS? We will share learning from this study in a number of different ways. This will include: writing reports for NHS England and academic papers, giving presentations at local and international events, producing short films and illustrated journals describing what we did, what we found and how the findings will be used._x000D_ _x000D_ study website: www.remission.study","Background: An NHS Low Calorie Diet (LCD) delivered via 1:1, group or digital support will be piloted in patients with excess weight and type 2 diabetes. Aim: To coproduce a qualitative & economic evaluation of the NHS LCD pilot, integrated with NHS data to provide an enhanced understanding of the long-term cost effectiveness, implementation, equity & transferability across broad & diverse populations. Research questions & methods: A multi-disciplinary patient-led programme of 5 work packages (WP): WP1 PROJECT MANAGEMENT, COPRODUCTION, PUBLIC AND PATIENT INVOLVEMENT (PPI) & DISSEMINATION: will 1) coordinate project management, PPI, co-production & evaluation reports: integrating WP2-5 with NHS analyses; 2) oversee dissemination: illustrative journals, infographics, website, social media, films, presentations & journal articles. WP2 SERVICE DELIVERY & FIDELITY: will use documentary review, session observations, interviews with NHS support staff & focus groups with providers, to address the following research questions (RQ): RQ1 What are the theoretical principles, behaviour change components, content & mode of delivery of the programme, & how do these vary across sites & providers? RQ2 To what extent does the staff training delivered by each provider address behaviour change theory & content, & how does this vary across sites & providers? RQ3 To what extent is the delivery of the NHS LCD delivered with fidelity to NHS specifications? RQ4 What are provider & NHS support staff experiences of the service & what do they perceive to be key barriers & facilitators to effective delivery & integration into routine care? WP3 PATIENT EXPERIENCE & INEQUITIES: will be undertaken using longitudinal patient surveys, interviews & photovoice. These findings will be integrated with NHS data to address: RQ5 To what extent is the content of the NHS LCD understood & applied by patients? RQ6 Do sociodemographic characteristics influence access, uptake, compliance & success on the NHS LCD, & does this vary across the different delivery models? RQ7 What aspects of the service work & do not work, for whom, in what context & why? RQ8 How can the service be improved in the future, to enhance patient experience, & ensure any inequities are addressed? WP4 ECONOMIC EVALUATION: will use patient-level simulation modelling to estimate long-term cost-effectiveness of the NHS LCD (cost per QALY) to inform commissioning. Micro-costing for each of the delivery models will address: RQ9 What are the costs of delivering the NHS LCD programme from an NHS perspective & how do they a) differ across the different delivery models & b) compare to estimates provided in previous trials? RQ10 What are the costs of the NHS LCD to participants & how do they differ by delivery method & socio-demographics? This & NHS data will also be used in patient-level simulation models to address RQ11: What is the long-term cost-effectiveness of the NHS LCD in terms of cost per QALY & how does this vary by delivery method & patient characteristics?. We will also replicate the methods used in previous trials to address: RQ12 How does the cost & short-term outcome data collected in this study affect the estimates of cost-effectiveness in previous trials? WP5 TRANSFERABILITY ASSESSMENT: will employ a theoretical model for the assessment of transferability to address RQ13: What are the policy implications for wide-spread adoption of the programme? Anticipated delivery timeframe & impact: Nov 20 to Oct 23. Findings will inform national roll out.",8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS,METABOLIC AND ENDOCRINE HRCS22_19600,Wellcome Trust,,"A cross-species, cross-modal approach to computational neuroanatomy","In vivo methods for mapping brain connections are increasingly used in systems neuroscience but are yet to have significant clinical impact. We propose to develop new computational approaches that bridge information from precise but invasive methods in animals to enhance in vivo methods in humans. We translate this framework into clinical care in surgical patients: In Aim 1, we will leverage a unique resource of macaque tracers currently being digitised. We will use state-of-the-art machine learning to automate quantification, and image processing for mapping histology to MRI, to produce a unique resource of macaque ground truth connectivity. In Aim 2, we will develop computational approaches to enable macaque anatomical tracers, alongside multimodal MRI in macaques and humans, to be used to improve the accuracy of methods developed in humans. In Aim 3, we will build end-to-end approaches for connectivity-based functional localisation, and deploy this as a tool to aid pre-surgical planning for localisation of subcortical targets in deep brain stimulation and for localisation of eloquent cortex in tumour surgery.","Some scientists believe that what makes the brain special is its complex web of connections. To understand how the brain works and how it breaks down in disease, we must be able to measure brain connections. This can be done accurately in animals, but even modern tools in humans only give a rudimentary picture of the brain connections. This makes it difficult to trust them in the clinic, where precision is crucial for the success of surgical interventions. My work bridges the gap between animal and human methods. I will use a large collection of data on the brain connections of a close relative of humans, the macaque monkey. This data is being digitised and formatted such that it can be used to make human MRI closer to the precision of animal methods. I will then deploy new algorithms to precisely localise brain areas to be targeted in brain surgery.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,NEUROLOGICAL HRCS22_06787,Health Education England,HEE,A feasibility study examining the use of Mechanical Insufflation-Exsufflation to prevent extubation failure in adult intensive care (The MERIT study),"BackgroundIn the United Kingdom approximately 230,000 adults are admitted to intensive care unit (ITU) each year (ICNARC, 2016) many requiring respiratory support (40-50%), commonly invasive ventilation (40.5%) (ICNARC 2015-16). Most adults successfully extubate in less than 5 days (mean ITU stay 4.8 days) however, 10-40% fail extubation (defined as requiring re-intubation within 48 hours) (ICNARC 2015-2016; Boles et al., 2007; Salam et al., 2004; Glover and Glossop, 2017; Terzi et al., 2018).Extubation failure causes significant problems, which can be associated with a failure to cough effectively. Respiratory physiotherapists use a number of treatment techniques to aid secretion clearance and support coughing; one such device is the Mechanical Insufflation-Exsufflation (MI-E). If this device can improve secretion clearance, used as part of treatment, it may reduce extubation failure. Aims and objectivesTo complete a feasibility study to determine whether it is possible to conduct a larger randomised controlled trial, of implementing MI-E as part of a weaning protocol in an adult ITU setting. MethodsPhase 1 (Year 1): A systematic review of the literature of mechanical insufflation-exsufflation as an airway clearance and/or cough augmentation technique in adult (>18 years) patients. Following up from my recent UK survey, I will explore UK physiotherapists' perceptions and views around current MI-E use within ITU, through semi-structured interviews. Phase 2 (Year 2): A pilot randomised controlled trial feasibility study (n=50) in a single large adult ITU will be undertaken. The study will determine whether it is possible to undertake a larger UK trial, including our ability to recruit and follow-up patients, optimal outcomes and the measurement of these. It will also establish the safety of MI-E in the ITU population. Phase 3 (Year 2 - midyear 3): Concurrently, a qualitative exploration of physiotherapists, patient and family experiences of the MI-E device in an ITU setting and any trial issues that were encountered. This will be by semi-structured interviews. A focus group of adult ITU healthcare professionals will occur to gain further perspective on study findings. Phase 4 (Mid-Year 3)To analyze, write up and actively disseminate study findings. The study will provide information on the safety and feasibility of using MI-E in an ITU population. It will also inform development of a training package tailored to meet the needs of the population (adult ITU physiotherapists) to use the device with both intubated and extubated patients. In addition to conference presentation and publications, dissemination will be achieved with the aid of a study website and Twitter account which will optimize engagement with patients, clinicians and key stakeholders throughout the study.","BackgroundThere are about 230,000 adult intensive care (ITU) admissions each year. Many of these patients require breathing support from a machine and breathing tube. Most adults are successfully removed from the breathing machine (extubation). However 10-40% of patients are unable to breathe by themselves once the tube has been removed and it needs to be put back in. One of the main reasons for this is because the patients are unable to cough well enough to clear mucus from their airway.Having to have the breathing tube put back in leads to worse outcomes for the patient, including prolonging their length of hospital stay and increasing their risk of death.To help with successful extubation, physiotherapists can use a device to help patients cough and clear phlegm from their lungs. The cough device works by blowing air into the patients lungs followed by quickly sucking it out. This device can be used before and after extubation. The cough device has only recently been used in the ITU setting and there are no studies exploring patients and/or healthcare professional's experiences of its use. AimsThe aim of this research is to find out if it is possible to carry out a large study to see whether using a cough device in ITU can help patients be successfully removed from breathing support. Design and methodsThere will be 4 stages:1-Year 1. A detailed review of published work examining the role of the cough device to help patients cough and clear secretions. Interviews with ITU clinicians to explore their thoughts about using the MI-E device with ITU patients.2-Year 2. A small (feasibility) study of 50 patients to see if it is possible to carry out a larger trial of the cough device. The study will tell us whether it is possible to recruit patients and whether they remain in the study. It will also look at the safety of the cough device (most existing safety data is from other hospital settings).Permission (consent) for the study will need to be from family members as patients will still be using the breathing machine when they join the study. Patients will be asked for consent for ongoing study participation once they are able.3- Mid year 2 - mid year 3. Interviews with some of the patients and clinicians involved in the feasibility study will seek their experiences of using the cough device. Separate patient consent will be sought for this. Physiotherapists will be specifically approached for inclusion. Findings will be discussed with groups of professionals from other hospitals to inform future work.4- Mid year 3. Completion of data analysis, write up and dissemination. PPIPatients, carers and a patient support charity 'ICU Steps' have been actively involved in the development of this application through a PPI meeting, informal discussions and reading the plain English summary. The chosen methods reflect these discussions. ICU Steps have agreed to contact patients who have been on ITU and have used a breathing machine to identify at least two people to join the study advisory group. As the study progresses, their views will continue to be sought. DisseminationThere will be a study specific website and social media page. Findings will be submitted to academic journals and professional conferences. ICU Steps have agreed to help share study findings at their regional meetings, and on their website. The patient partners will help to ensure that the findings are accessible to patients. Findings will also be shared with healthcare professionals through newsletters, website articles, presentations at relevant short courses and conferences.",6.3 MEDICAL DEVICES,GENERIC HEALTH RELEVANCE HRCS22_06377,Health Education England,HEE,A feasibility study for a randomised trial to assess prehospital optimal shock energy for defibrillation in cardiac arrest,"BackgroundThe International Liaison Committee on Resuscitation (ILCOR) has identified defibrillation energy levels as a priority area for research (Soar et al, 2015a). In the absence of definitive evidence, UK Ambulance Services employ a range of initial shock energies and differing strategies for subsequent shocks (fixed versus escalating energy). The optimal strategy remains unknown and there is concern that insufficient energy may fail to cardiovert and excess energy may risk myocardial damage (manifest by conversion to a non-perfusing rhythm, refibrillation, or myocardial stunning). Defibrillatory shocks and provision of quality CPR remain the only interventions proven to positively impact outcome. Detailed guidance on characteristics of optimal CPR is now available (Soar et al, 2015b) whereas the evidence base for defibrillation shock energy is still lacking. In 2010, ILCOR guidance changed from three stacked shocks (unseparated by CPR) to a single shock protocol and a greater emphasis on high-quality CPR between shocks. Many defibrillation studies pre-date this change and so are less relevant.If the shock energy is right first time, the resuscitation duration is shortened, and circulation restored more quickly. Amongst witnessed cases, the chance of survival to 30 days decreases with each defibrillation (OR 0.9; 95% CI 0.88-0.92) (Holmen et al, 2017). The duration of the resuscitation attempt, measured from initiation to return of spontaneous circulation (ROSC), also affects neurological outcome. The chance of surviving with good neurological outcome at one month is significantly higher in those achieving ROSC within 5 minutes compared to those who achieve ROSC after more than 31 minutes (AOR 0.04; 95% CI 0.03-0.05) (Matsuyama et al, 2017). It is important to shorten the resuscitation duration by delivering the optimal shock energy on first and subsequent shocks. Research QuestionIs it feasible to conduct a randomised, pragmatic clinical effectiveness trial in UK ambulance services to identify the optimal energy for defibrillation? AimsThe aims of this feasibility study are to explore the following to inform the design and processes in a full randomised controlled trial (RCT): 1. Number of eligible patients and the recruitment rate 2. Acceptability to paramedics of randomisation of the intervention 3. Practicality of obtaining data downloads from defibrillators 4. Practicality of obtaining other outcome data such as mRS scores (a measure of neurological disability) to 30 days post event Timelines for delivery Work package 1 (months 1-12): To ensure that the feasibility study is well informed, I will conduct a systematic review of the literature. Work package 2 (months 13-48): A feasibility study. I aim to recruit 40-60 patients from one ambulance service. I will explore associated difficulties and how to overcome these. Anticipated impact & dissemination The aim of a large RCT would be to improve patient survival rates and decrease myocardial damage, by determining the minimum shock energy required to achieve a successful outcome. Conducting this feasibility study would inform the design of a full trial. Through my supervisors I would keep guideline writing bodies informed of the study. This would facilitate timely integration of results of any future trial.","Background Each year, the UK ambulance services attempt to restart the hearts of 30,000 people who have suffered cardiac arrest (when the heart stops beating). Performance of good chest compressions (CPR) and, where appropriate, delivery of an electric shock to the heart (defibrillation) are the only proven methods of reviving these patients. The purpose of delivering an electric shock is to kick-start the heart back into beating normally. Electric shock machines, known as defibrillators, can deliver a range of electric shock strengths (e.g. low, medium and high). However, we don't presently know the best shock strength to start with and whether subsequent shocks should be increased. Giving an electric shock that is too high risks damaging the heart whilst one that is too low may not restart the heart. Because no one knows what the best shock strength is, UK ambulance services all do something a bit different.When the effects of different treatments are not known, researchers may conduct a clinical trial to find out. Trials of this type are usually large, so it is necessary to first find out whether these tests are possible and anticipate any problems. Conducting a 'feasibility study' helps to ensure that time and money are well spent on a full-scale trial. Aim of the research to conduct a feasibility trial to provide the information needed to design a full clinical trial. to know whether ambulance staff would be prepared to test different shock strengths and how easy it would be to gather information from defibrillators. to find out how easy it would be to collect information about the patients' condition after they have left ambulance service care. Design and methods For the feasibility trial I will: put patients into different groups to receive different shock strategies (either using the same or increasing shock strengths). None of these shock strengths will be any higher or lower than currently used in UK ambulance services. All other treatments and care will be given in the usual way. find out whether ambulance staff follow the shock strategy requested and looking at information recorded by defibrillators to see the actual shock strengths given. use ambulance service records to find out about other care and the patients' condition. find how many patients could have been included by looking at ambulance service 999 call records and compare this to the actual number included to find the 'recruitment rate'. seek information from hospital records to find out what happened to patients in hospital and for the following 30 days. I aim to include 40-60 patients in this feasibility trial. Where I find difficulties, I will explore how I can reduce these difficulties so that the full clinical trial will work. Patient and public involvement Members of South Central Ambulance Service's Patient Forums strongly support this research. They have helped design the research so it is relevant to patients. They provided guidance on how to best communicate information about the trial and how to approach consent. We jointly prepared this lay summary. Going forwards, two members will join a 'Trial Steering Committee' which will closely watch how this project is run. Letting people know the results I will work with our public representatives to let people know about this project. We will speak together at professional meetings and community group meetings. Doctors and other health workers will be told about the results through articles in their professional magazines. I will take advice from our public representatives about good ways to reach large numbers of the public.",6.3 MEDICAL DEVICES,CARDIOVASCULAR HRCS22_22126,"National Centre for the Replacement, Refinement and Reduction of Animals in Research",NC3Rs,A highly sensitive replacement assay for botulinum neurotoxin type B,"The proposed in-vitro assay aims to replace use of animals in the manufacture of pharmaceutical BoNT/B products. BoNT/B product testing involves the most severe levels of animal suffering due to death by slow asphyxiation being the assay endpoint. The LD50 assay also lacks specificity to distinguish between the different BoNTs serotypes, which all cause similar muscular paralysis. With previous NC3Rs support, we engineered a human neuroblastoma SiMa cell line to carry a synthetic VAMP reporter molecule, the target of BoNT/B. We also developed a polyclonal antibody which recognises the BoNT/B-cleaved end of the VAMP reporter molecule. By selecting right capture plates we were able to design a refined ELISA capture assay which can detect the BoNT/B-cleaved VAMP via highly sensitive luminescent reaction. This advance was published in Frontiers in Pharmacology in 2017. To build a robust 3Rs legacy we must now create an assay for easy assimilation into a GMP-compliant environment, allowing widespread adoption by BoNT/B product manufacturers and regulators. In order to achieve this, we must produce monoclonal antibodies that can specifically detect VAMP2 cleaved by BoNT/B and devise a microplate-based assay for reproducible sensitive detection of BoNT/B activity. To make our ELISA assay most compelling, we will improve the sensitivity of our cell lines to further outperform the mouse bioassay by introducing the receptor with the highest known affinity for BoNT/B, mouse synaptotagmin 2 into our engineered cell lines. We will then screen for the most sensitive clones using industrial and in-house pharmaceutical BoNT/B and related BoNT/D. Finally, in partnership with our collaborators we will validate our highly specific and reproducible assay for suitability to test botulinum antitoxins and other pharmaceutical products.",,5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.1 PHARMACEUTICALS,GENERIC HEALTH RELEVANCE HRCS22_02140,Medical Research Council,MRC,A newly discovered protein-coding ORF in enteroviruses: from mechanism to application,"Enteroviruses are common and important mammalian pathogens. Pathology in humans ranges from subclinical to acute flaccid paralysis, myocarditis and meningitis. For nearly 50 years, all the viral proteins were thought to derive from proteolytic processing of a polyprotein encoded in a single open reading frame (ORF) covering most of the ~7.4 kb genome. However, in Nov 2018 we reported that many enteroviruses actually encode an additional, previously unknown protein, UP (Upstream Protein), in a short ORF upstream of the polyprotein ORF (Lulla et al, Nature Microbiol). We showed that UP is expressed in representative members of the major human species Enterovirus A, B and C and that, at least in Enterovirus B, UP facilitates virus growth specifically in gut epithelial cells where membrane-associated UP facilitates virus release at late stages of infection. Despite our published findings, many very important questions remain unanswered such as why do some enteroviruses (particularly poliovirus types 2 and 3) appear to lack UP, how exactly does UP function to facilitate release of virus from membranous compartments, and why is this effect specific to gut epithelia? Having established systems for working with gut epithelial organoids and enteroviruses A, B and C, we are perfectly positioned to properly characterize the UP protein biological function. Our project comprises five main work packages: 1) Bioinformatic analysis - correlation of UP with virus provenance and clinical data 2) Assessing and deciphering the regulation of UP expression 3) Biochemical and functional characterization of the UP protein 4) Biological functionality of UP in human intestinal organoids 5) Physiological role of UP and potential as a vaccine candidate Together these will elucidate the function of the newly discovered UP protein in enterovirus molecular biology and pathogenesis, and lay the groundwork for UP knockout as a possible attenuated virus vaccine strategy.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,INFECTION HRCS22_22990,The Academy of Medical Sciences,AMS,A novel approach to assess malaria mosquito biological age to accelerate the implementation of vector control in endemic settings,"As effective vaccines do not exist for most vector-borne diseases (VBDs), including malaria and dengue, control and prevention of these diseases rely primarily on reducing the arthropod vector populations. The future effectiveness of these public health initiatives is currently at risk, threatened by increased vector abundance following global climate warming and the spread of insecticide resistance. To tackle this emergency, there is urgent need to accelerate the evaluation of new vector control interventions. However, challenges abound. Specifically, there are no appropriate methods to measure mosquito age in vector populations, despite mosquito age being the most important factor that affects disease transmission; indeed, only vectors that live beyond the pathogen’s developmental time can transmit disease. Through this project, I will close this methodological gap by integrating physical chemistry, computing science and medical entomology and develop a rapid and cost-effective tool based on mid-infrared spectroscopy (MIRS) and convolutional neural network (CNN) analysis to determine the age of individuals from three major species of malaria vectors. This technology will be designed to work under different ecological settings, accounting for environmental-dependent ageing rates by predicting mosquito biological age. Specifically, I will: 1.Quantify the effect of temperature on malaria mosquito biological age 2.Develop a CNN-MIRS-based approach to determine biological age in mosquitoes. 3.Validate the new approach on an existing dataset of 40,000 spectra from wild mosquitoes collected in Tanzania and Burkina Faso. The proposed technology has the potential to revolutionize vector surveillance programmes and accelerate the elimination of malaria and other VBDs.","Vector-borne diseases (VBDs) such as malaria are caused by pathogens (such as viruses, bacteria or parasites) transmitted by insects or ticks and kill more than 700,000 people each year. As effective vaccines do not exist for most VBDs, the most effective way to prevent these deaths is to reduce the abundance of older insects, such as mosquitoes, as only old vectors can transmit the disease, having lived long enough to allow the pathogen’s development to the transmissible stage. As mosquitoes are evolving and evading control strategies, new interventions need to be tested and introduced in natural mosquito populations. However, as there are no appropriate methods to measure mosquito age, control programmes often lack the evidence to establish the effectiveness of novel interventions targeted at preventing disease transmission. This project will seek to develop a new technology to measure mosquito age by combining different research disciplines. Specifically, we will rear mosquitoes of different ages under temperature-controlled conditions in the laboratory, then estimate their age using mid-infrared spectroscopy, which is a technique that allows to rapidly measure the chemical composition by quantifying the light absorbed. Finally, we will use methods from artificial intelligence to identify the predictive relationship between mosquito age and their biochemical composition. Ultimately, this project will have positive impacts both on public health in low- and middle-income countries by supporting vector control programmes, and in other areas, such as in Europe, where emerging VBDs pose new health risks, by allowing rapid screening of vector populations to prevent disease transmission.",3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,INFECTION HRCS22_11733,Economic and Social Research Council,ESRC,A novel programme: Agentive here-and-now interaction in persons with dementia,"The primary objective of the research is to develop a novel facilitator-led activity for groups of older people who may have been diagnosed with dementia. The activity offers space for participants to share personal experiences and leads them on to collaborate in the group creation of a narrative. The personal experience is built around an image given to each participant and the participant describing its meaning for them; the group story is based on sharing all the images and agreeing on a possible narrative order that makes sense of them. Personal associations that include sensory memories based on the original image, e.g. music, scents, and tastes, may be carried over into the final, negotiated story. The facilitator collates the details into a multimedia version that can be given to each participant in hard and soft copy forms to keep. Realisation of the primary objective has implications for current NICE (2018) guidance for the assessment, management and support of people living with dementia and their carers: Section 1.4 Interventions to promote cognition, independence and wellbeing, presently 'Consider group reminiscence therapy for people living with mild to moderate dementia' (1.4.3) and 'Consider cognitive rehabilitation or occupational therapy to support functional ability in people living with mild to moderate dementia' (1.4.4). The study findings may provide evidence for upgrading the status of (1.4.4) from consider to offer, as it presently is for group cognitive stimulation therapy for people living with mild to moderate dementia (1.4.2); or to name group story creation in the range of activities that are offered to promote wellbeing and tailored to the person's preferences (4.1.1). The secondary objectives are (1) to involve collaborative partnerships that include people living with dementia, the public, and day centre and care home staff to co-design, test, and evaluate storytelling approaches; (2) to develop a training course in running the activity, targeted at day centre and care home staff who would become workshop facilitators; (3) to build an interactive website to support the facilitators in running the activity face-to-face and online; and (4) to establish a social enterprise start-up that will re-invest profits to update and expand a collection of storyboards and maintain and enhance a web platform for facilitators.","Project summary The principle aim of the research is to develop a group story-telling activity for people living with dementia. The justification for doing so may be found in the contrasting linguistic behaviour of people with dementia when they are reminiscing about episodes in their earlier life and when they are reacting to events in-the-moment. In-the-moment speech appears to be more fluent, supported by shorter turns and shared conversational roles at these points; and agentive, i.e. linguistic directives, first-person declaratives, and other deontic expressions of intent are evident. The person appears to be more animated. Conversely, whilst group reminiscence therapy is suggested for consideration by NICE (2018), some evidence of negative effects in one-to-one reminiscence has been reported, as the speaker becomes aware of the possible contrast between happier past times and their present situation. The proposed activity would achieve a balance between the two conditions, between the natural tendency of people to talk about themselves and the more stimulating interaction enabled in social contexts. Before and after each session, whether in-person or online, participants will complete a situational measurement of their emotional well-being via an adaptation of the CWS (Camic, 2020). The stimulus provided would be a hard-copy image, one per person, from a collection that makes up a storyboard, i.e. it is possible for the images to be placed in an order that invites a narrative. Several orders are possible. Each person would be invited to describe their image, any music it reminded them of, and any associated sensory details, such as tastes, touch, and scents. In the next part of the activity, the participants are invited to agree an order to all the images, perhaps by laying them out on a table top, and collectively building up a story that makes sense of them. This stage involves negotiation and in-the-moment discussion. Afterwards, participants would be given hard and soft copies of the group-authored story to keep. We intend the activity to be available in-person and online to suit participants and conditions. The aim is to provide people living with dementia and, by extension, older people who may feel socially isolated, with opportunities for enjoyable and creative social interaction that builds an end-product. Although one similar commercially available activity called Timeslips exists, it offers single images only, unlike our storyboards. It does not invite participants to name music and other sensory associations with the images, and the participants are not given the completed story at the end. We propose four other initiatives running alongside the development of the activity to further our key objective: ongoing stakeholder involvement in the trialling and development of the activity; a bespoke training course for facilitators interested in using the activity; an interactive website to support the facilitators; and the creation of a Community Interest Company to ensure the activity, training course, and website are self-sustaining. Along with a report of the well-being measurements referred to above, the more conventional research output will be a linguistic analysis of participants' speech in the two parts of the activity. It is hypothesised that speech in the second, group interaction part will be more fluent and agentive. In common with other arts-based activities, associated improvements in well-being are expected. References Camic, P. (2020). Canterbury Wellbeing Scales. https://zenodo.org/record/4063768#.YoZjQqjMKUl NICE. National Institute for Health and Care Excellence (Great Britain). (2018). Dementia: assessment, management and support for people living with dementia and their carers. https://www.nice.org.uk/guidance/ng97",7.1 INDIVIDUAL CARE NEEDS,NEUROLOGICAL HRCS22_06874,Medical Research Council,MRC,A phase II study combining pembrolizumab and olaparib in metastatic pancreatic adenocarcinoma patients with high tumour mutation burden,"Aim of the research_x000D_ To test whether the combination of drugs, pembrolizumab and olaparib, are effective treatment for a specific subgroup of patients with metastatic pancreatic ductal adenocarcinoma (mPDA). _x000D_ _x000D_ Background _x000D_ mPDA is an aggressive form of cancer with very poor outcomes. It is generally treated with traditional chemotherapy, but even with chemotherapy, average life expectancy of patients with mPA is under 1 year. In the search for treatments to improve life expectancy for cancer patients, immunotherapy drugs that boost the immune system, like pembrolizumab, are increasingly being used. Unfortunately, so far, they have not helped people suffering from mPDA. Olaparib works by preventing cancer cells repairing themselves. Combining olaparib with pembrolizumab may be a better way of boosting the immune system. We think that the people most likely to benefit from combining these 2 drugs are those mPDA patients whose tumours contain very high amounts of genetic changes that will help the body’s immune system seek out and kill the cancer cells more easily. These tumours are described as having high mutational burden, or high TMB. High TMB can be identified by examining tumour samples, or biopsies. While currently this is done as part of a national research programme, eventually it is hoped that this will be part of routine care. We plan to identify patients with both mPDA and high TMB and offer them treatment with pembrolizumab plus olaparib in this national clinical trial. _x000D_ _x000D_ Methods_x000D_ Twenty patients with mPDA and high TMB will be invited to take part in this trial. Eligible patients may choose to take part in this trial as their initial treatment, or after conventional chemotherapy. Pembrolizumab is given into the vein once every 3-6 weeks. Olaparib is a tablet taken by mouth twice a day. Treatment duration is for as long as the patient is benefitting, but for a maximum of 2 years. The side effects of both drugs are well known and the treatment is expected to be well tolerated, with about a 1 in 10 chance of unpleasant side effects that can usually be easily managed. _x000D_ We will measure if the treatment works by doing CT scans every 9-12 weeks. We will record any side effects and ask patients to complete quality-of-life surveys. We will also be able to find out what proportion of cancers have high mutation rates and how this reflects the treatment being given. The test to identify high TMB is very expensive and is currently done in a specialist laboratory, but we think we can get the same information more affordably with a simpler test run in local hospital laboratories. We will find out whether this is possible as an added benefit of our trial. Finally, to help understand how the immune system is working in these treated patients, we will seek permission to use any tumour samples collected before starting treatment for our research._x000D_ _x000D_ Patient and Public Involvement_x000D_ Advice has been sought from Patient Advisory Groups, Pancreatic Cancer UK and the Elizabeth Coteman Trust. The National Cancer Research Institute pancreatic cancer workstream patient representative is a named co-applicant._x000D_ _x000D_ Dissemination _x000D_ The trial results will be shared with patients, carers and advocacy groups, as well as NHS commissioners. Trial findings will be published and presented at conferences.","Research Question_x000D_ Does treatment with pembrolizumab plus olaparib improve outcomes for patients with metastatic pancreatic adenocarcinoma (mPDA) and high tumour mutation burden (TMB)? _x000D_ _x000D_ Background_x000D_ Outcomes for patients with mPDA are extremely poor, despite optimal anticancer therapy. Recent breakthroughs with modern immunotherapy reported for many cancer types have not been replicated in mPDA, which is a disease generally characterised by an immunosuppressive microenvironment and low TMB. However, not all PDAs are the same. In a small minority of PDAs, defective DNA damage repair mechanisms exist which generate very high TMB and these patients have the potential to benefit from immunotherapy. Some 2% of PDA patients could be eligible to access the immune checkpoint inhibitor (CPI), pembrolizumab, which was recently approved in the USA to treat cancers with the highest mutation rates caused by defects in DNA mismatch repair genes. However, currently there is no European access to pembrolizumab for this indication. Furthermore, even for the most immunoresponsive cancers, only the minority of treated patients benefit from CPIs, so more effective combination strategies are needed. Pembrolizumab blocks the programmed death-1 receptor on T lymphocytes which unleashes their ability to seek out and kill cancer cells. Emerging evidence suggest that drugs like olaparib, traditionally thought of as DNA repair targeted agents, can enhance response to CPIs. _x000D_ _x000D_ Aims_x000D_ We aim to conduct a single arm prospective trial evaluating pembrolizumab plus olaparib in patients with mPDA and high TMB. The primary outcome is objective response rate (ORR); secondary outcomes are safety, duration of response and progression-free survival; exploratory outcomes are overall survival and additional response biomarkers._x000D_ _x000D_ Methods_x000D_ Patients with high TMB mPDA will be identified via national research and other molecular screening platforms. Eligible patients will be invited to consent to receive treatment as either first or second line therapy for their disease. The regimen is pembrolizumab 200mg IV every 3 weeks plus olaparib 300mg orally twice a day, for as long as there is benefit, but maximum 2 years. Patients continuing beyond 27 weeks can switch to pembrolizumab 400mg IV 6 weekly. Patients will be scanned every 9 weeks for 27 weeks, then and every 12 weeks for the second year, or until disease progression. Thereafter, they will be followed for survival._x000D_ We will collect blood samples before starting treatment, at 9 weeks, then at 1 year or on disease progression, whichever is sooner. We will use pre-treatment tumour samples to explore molecular and immune markers of response_x000D_ We will recruit 20 evaluable patients to assess ORR, with early stopping rules._x000D_ _x000D_ Timelines for delivery_x000D_ Study set up complete: month 9_x000D_ First patient first visit: month 12 _x000D_ Stage 1 interim assessment: month 30 _x000D_ Stage 2 interim assessment: month 40 _x000D_ Stage 3 final ORR assessment: month 54 _x000D_ Final report, close out: month 60_x000D_ _x000D_ Anticipated impact and dissemination_x000D_ This signal-seeking trial will offer the first robust evidence of immunotherapy being an effective treatment strategy for a biomarker-stratified cohort of mPDA patients. A positive outcome will justify an international registration trial. The findings will be presented at conferences, published and shared with patients, carers, advocacy groups and commissioners",5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_07158,Department of Health and Social Care,NIHR,"A prospective observational study to explore the relationship between nuTRition, protein intake ANd muScle mass loss during and after Pediatric Intensive caRE: the TRANSPIRE study","Around 20 000 children are admitted to Paediatric Intensive Care Units (PICU) each year in the UK and Ireland and 13 000 of these stay > 3 days 1. The acuity of PICU patients is also increasing with some children stay for a prolonged period. Despite this, the survival rate for paediatric critical illness is high at >96%1 but their recovery and physical morbidity can be prolonged, so interventions to improve their recovery are vital to improve both child and family outcomes. Muscle wasting is dramatic in critically ill patients (both children and adults) and related to worsened outcomes 2-8. This muscle wasting delays the patient s rehabilitation and prolongs their recovery, due to reduced functional capacity associated with this loss in muscle mass 6. Therefore, we want to examine the relationships between muscle mass loss (measured via non-invasive ultrasound of the muscles) with nutritional intake and inflammatory markers during and after critical illness using standard, readily available bedside equipment. We intend to undertake a prospective observational study to determine the association between muscle mass loss and function, nutrition and protein intake during and after pediatric critical illness over 24 months. We intend to recruit 50 children aged term to 16 years, who stay in PICU >48 hours from a single large mixed general and cardiac PICU (Alder Children s NHS Foundation Trust Liverpool, UK). Our primary and secondary objectives are: Primary: To assess the relationship and determine any correlation between PICU-muscle wasting (assessed on ultrasound) and protein intake during critical illness (from admission to PICU discharge) Secondary: To assess the relationship and determine any correlation between PICU-muscle wasting and energy intake during critical illness (from admission to PICU discharge) To assess the relationship and determine any correlation between PICU-muscle wasting and nitrogen balance during critical illness (from admission to PICU discharge) To describe the relationship between PICU-muscle wasting and inflammatory markers (CRP) that relate to the severity of illness, over the PICU stay To assess and further describe muscle wasting and function changes during PICU admission and from PICU discharge to 3 months after PICU discharge To describe and further quantify risk factors for quantify PICU-muscle wasting To examine and quantify PICU-muscle wasting and muscle function and its impact on short term (Length of ventilation, PICU length of stay, Hospital length of stay) and longer-term outcomes (Functional Status Score (FSS), muscle function recovery (Bayley s motor score, MFM 20 or MFM 32) and Quality of Life (PedsQuAL) at 3 months after PICU discharge. Study findings will be actively disseminated both nationally and internationally, at the annual UK PICU congress (PCCS), the national PICU Study Group (PICS-SG), at European meetings (ESPNIC) and via our study twitter account to both parents/carers and professionals. In addition, at least one paper will be submitted for publication in a high impact journal. From this exploratory study we anticipate that a combined nutrition and rehabilitation intervention may be able to be developed. This would be in collaboration with our colleagues undertaking the NIHR HTA-funded PERMIT Feasibility.","Around 20 000 children are admitted to the peadiatric intensive care unit (PICU) each year in the UK and Ireland and around 13 000 of these stay more than 3 days in intensive care, with some children staying a lot longer. As children s intensive care in the UK has improved in the last decade, almost all children now survive critical illness, but for many, their recovery is prolonged both physically and psychologically. Children on the breathing machine in intensive care lose a lot of weight and muscle very quickly, and this slows down their recovery and can lead to longer stays both in the intensive care and in hospital. In adults in intensive care, research has shown that some of this muscle loss may be able to be lessened by given them a higher protein feed combined with early rehabilitation in intensive care, but in children we still do not know if this weight and muscle loss is modifiable by, and related to the nutrition and the amount of protein they receive This is what we want to find out, as children are not the same as adults, and frequently respond in different ways physiologically. Furthermore, children admitted to intensive care are quite different both in their age range and underlying conditions to those of adults. To do this, we want to look at the children s muscles (by ultrasound, so using gel and running a probe over the muscle, which does not hurt at all) when they first come to intensive care, every few days, when they leave intensive care, when they leave the hospital and 3 months later. We will then see what happens to their muscles and how strong their muscles are, as well how much nutrition and protein they got in intensive care to see if they are related. We will also look at one of the routinely collected daily blood tests during the time the child is in intensive care (called an inflammatory marker) as well as collect information about their age and weight, why they came to intensive care and other important things that might impact on their muscles. We will do this in one intensive care unit, Alder Hey Children s in Liverpool. This large PICU admits around 1200 children every year for lots of different reasons. We have involved one of our past patients (and his faather), who is now 21 years old and who spent around 3 months in our intensive care a few years ago. He and his family say that this (weight loss and weak muscles) was a real problem for him and his recovery, and he believes it is a really important area to investigate.",2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE HRCS22_14688,Barts Charity,,A prospective randomised trial comparing radiofrequency ablation With laparoscopic Adrenalectomy as an alternatiVE treatment for unilateral primary aldosteronism (WAVE),"Background - Primary aldosteronism (PA) is a high-risk form of hypertension characterised by renin-independent hypersecretion of aldosterone. It affects 5-10% of unselected hypertension patients, yet <1% are fully investigated and treated. Approximately half of PA patients have a solitary aldosterone- producing adrenal adenoma (APA) as the underlying cause, making PA the most common surgically-remedial cause of hypertension. The clinical problem - The shortfall in clinical care arises from a combination of 'under-suspicion' through lack of clinical awareness; limited availability of (invasive) investigations to localise the source of aldosterone excess; constrained surgical capacity; and uncertainties about clinical outcomes from (and therefore reluctance to undergo) an abdominal surgical procedure to remove a whole gland as treatment for a benign 1-2cm tumour. Aims - The applicant?s programme of PA research aims to address many of these barriers and develop non- or minimally-invasive investigations and treatments for PA, together with better predictors of outcome that, together, will inform clinical consultations and patient choice. Context of funding request - Recently, the applicant has been awarded a BHF project grant (£500 000) to undertake a randomised study of (routine care) whole adrenalectomy vs selective radiofrequency ablation of the aldosterone-producing adrenal adenoma (APA) in patients with PA. It follows on from their recently-completed NIHR-funded study (MATCH) in which a non-invasive molecular imaging technique was compared with standard adrenal vein sampling as a means to determine the source of excess aldosterone. Funding request - As in MATCH, the applicants are requesting synergistic funding from Barts Charity to augment the information and impact from WAVE. With an MRC-DPFS grant, they have developed an easier-to-use tracer (18-F labelled CETO) than was used in MATCH, which will significantly increase access to molecular imaging in PA. They propose to image all Barts-enrolled WAVE patients with CETO with a view to optimising the accuracy of RFA. Further, the applicants plan for all Barts patients to undergo cardiac MRI further to understand why PA carries excess cardiovascular risk.",,5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,CARDIOVASCULAR;METABOLIC AND ENDOCRINE HRCS22_05649,Department of Health and Social Care,NIHR,"A randomised controlled trial evaluating the effectiveness and cost effectiveness of 'Strengthening Families, Strengthening Communities': a community led parenting programme (TOGETHER)","Aim _x000D_ We aim to assess whether parents who are offered a 13-week group-based parenting programme will feel better in themselves, feel less stressed and generally more able to cope with looking after their families. We will also assess if the programme has any effect on children’s behaviour. _x000D_ _x000D_ Background_x000D_ Childhood is an important stage of life which has long lasting effects into adulthood. Unfortunately many children in modern society experience emotional and behavioural problems which can lead to problems within their family, school and local communities. If these are not dealt with early on, they can get much worse and cause major difficulties for all those involved. Several parenting programmes have been developed and been shown to be helpful to parents and children. However most of these have focused on families with pre-school children, and children with very severe behaviour problems, and have not included many families from Black and ethnic minority groups, and those living in poverty. For over 10 years the Race Equality Foundation, a charity working to promote race equality in the UK, has been organising group-based parenting programmes for families with older children, particularly from minority ethnic communities and those living in poverty. This programme called Strengthening Families, Strengthening Communities has had major success in engaging with these communities across many parts of the country. Although very popular with the families involved, the programme has not yet been fully assessed to show if it is effective in achieving its key goals. This study aims to answer this gap in knowledge. _x000D_ _x000D_ Design _x000D_ Across 7 urban areas of England where ethnically and socially mixed communities live, the parenting programme will be offered to families who either decide themselves that they need help or families referred by professionals for help. 676 parents agreeing to take part in the study will be randomly allocated (like flipping a coin) to either immediately starting the programme or having to wait for a 10-month period before starting it. All the parents agreeing to take part in the study will be interviewed at the start, after the programme has been completed and then 6 months later. A smaller number of parents and staff involved in delivering the programme will also be interviewed about their views and experiences of it._x000D_ _x000D_ Public involvement_x000D_ Parenting is a potentially sensitive and stressful issue. It is therefore vitally important that the public are fully involved in a study which aims to assess the potential value of a parenting programme. A parent and former participant in the programme has agreed to be a co-applicant to assist the team in planning and conducting the study, to ensure parents’ concerns and needs are considered. In addition, 3 parent forums comprising 8-12 parents will be established to provide additional input into all aspects of the study. Two young people's forums will also be set up to provide an opportunity for discussion and interaction with teenagers to assess their views and opinions of the study. _x000D_ _x000D_ Dissemination_x000D_ Given the current high level of research, policy and media interest into the best ways of providing parenting support to families in need, the findings of this study are likely to get a high level of attention. The team will therefore take great care in ensuring that all interested parties including the families involved in the study and their local communities are given information about the results. The PPI co-applicant, parent forums and young people's forums will assist with the dissemination of the study results.","Background_x000D_ Between 10-20% of UK children experience socio-emotional difficulties which can have serious implications for themselves, their families and society. Stark socioeconomic and ethnic inequalities in children’s well-being exist. Giving every child the best start in life is a key strategy to reduce inequalities. Supporting parents to develop effective parenting skills is an important preventive strategy. A range of group-based parenting programmes have been delivered in the UK and evidence from recent reviews showed these can be effective. However most parenting interventions have focused on early childhood (0-5 years) and have failed to engage with families from ethnic minority groups and those living in poverty. A parenting programme for families with children aged up to 18 years (Strengthening Families, Strengthening Communities - SFSC) has been designed by the Race Equality Foundation, a charitable community organisation focused on promoting race equality, and has been delivered across the UK for over 10 years. Small pre-post studies have produced encouraging results but no randomised controlled trials have been undertaken so far. This study aims to address this knowledge gap._x000D_ _x000D_ Aim_x000D_ To assess the effectiveness and cost-effectiveness of the SFSC parenting programme in enhancing parental mental well-being and children’s social and emotional well-being at 6-months follow-up._x000D_ _x000D_ Design_x000D_ This multi-centre waiting list control randomised controlled trial will evaluate the SFSC programme. The study will be conducted in 2 phases. Participants will be randomly allocated to intervention or control arms. Phase 1 will comprise of a 6-month internal pilot to determine the feasibility of the trial. Should progression criteria be met, phase 2 will comprise the main trial. A nested process evaluation will also assess the fidelity and acceptability of the intervention. _x000D_ _x000D_ Setting participants_x000D_ The study will be conducted across 7 urban English areas with ethnically and socially diverse populations where the programme is currently being delivered. Participants (n=676) will be parents of children aged 3-18 years who either self-refer or are referred by health/social care professionals to attend the programme._x000D_ _x000D_ Intervention and comparator_x000D_ Based on social learning theory, the 13-week programme aims to develop parents’ confidence, competence and skills through interactive group based activities. Local authorities in the 7 areas will supply staff, community venues, resources and other costs associated with delivering the intervention through existing contracts. Participants randomised to the control arm will be offered the intervention after approximately a 10-month wait._x000D_ _x000D_ Outcomes_x000D_ The primary outcome will be parental mental well-being (assessed by the Warwick-Edinburgh Mental Well-Being Scale). Secondary outcomes will include child socio-emotional well-being, parenting practices, family relationships, parenting stress, quality of life, and community engagement. Outcomes will be assessed at baseline, post intervention and 6 months follow-up._x000D_ _x000D_ Potential impact_x000D_ If this trial demonstrates beneficial effects on both parental and child outcomes, then the potential impact, both immediate and longer term, is potentially significant. As the intervention focuses in particular on supporting families living in poverty and those from minority ethnic communities, the intervention should also ultimately have a beneficial impact on reducing health inequalities.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,MENTAL HEALTH HRCS22_05498,"Chief Scientist Office, Scotland",CSO,"A randomised, double-blind placebo controlled trial of the effectiveness of the beta-blocker bisoprolol in preventing exacerbations of chronic obstructive pulmonary disease","Chronic obstructive pulmonary disease (COPD) is a long term lung disease that slowly gets worse. Although COPD cannot be cured it can be treated. COPD used to be called chronic bronchitis/emphysema and is strongly linked with smoking. It is common, with about 3 million people being affected in the UK, although only 1.2 million have received a COPD diagnosis. COPD is the fifth leading cause of death in the UK (causing 30,000 deaths each year). Sudden deteriorations, known as exacerbations or “flare ups” shorten life expectancy and reduce peoples’ ability to get on with their lives. COPD costs the NHS £1 billion a year, over half of which is taken up in treating flare ups._x000D_ Beta-blockers are drugs widely used to treat blood pressure and heart disease. Non-heart specialists are very often unwilling to start people with COPD on beta-blockers because older beta-blockers had lung side effects. New evidence shows that newer beta-blockers targeting the heart, eg bisoprolol, are safe in COPD. There is now evidence that people with COPD who take beta-blockers are less likely to have flare ups even if they have no heart problems. This unexpected benefit of beta-blockers has not been tested in patients with COPD who are not known to need beta-blockers. A full randomised controlled trial is now needed to see if starting people with COPD on a beta-blocker reduces flare ups. The proposed trial builds on a COPD trial that has recruited 1560 people in 160 UK centres._x000D_ We will set up a randomised double blind placebo controlled trial to see if adding bisoprolol to usual COPD medicines reduces the number of COPD flare ups and makes patients feel better. We will recruit 1574 patients with COPD who have had flare ups recently (at least two in the last year). Potential participants will be identified from general practice and hospital chest clinics. We will recruit in 160 UK centres. Over 50% of subjects will be recruited from General Practice. Half of the 1574 subjects will take a bisoprolol tablet for a year. The other half will take an identical dummy pill. To work out the best dose of bisoprolol (and dummy pill) for each patient we will slowly build up the dose over 4 weeks whilst checking pulse and blood pressure. This is known to be safe._x000D_ Everyone will be seen 7 times: baseline, 1, 2, 3, 4, 26 and 52 weeks. The dose of bisoprolol (and the dummy pill) will be increased at the 1, 2 and 3 week visits._x000D_ At baseline, 26 and 52 weeks we will see the participants and use simple short questionnaires to count up the number of flare ups, hospital episodes, ability to get on with their lives, side effects and heart problems. Standard breathing tests will be performed to measure how well the lungs are working. We will also count how many times patients have seen a doctor/nurse to see if this reduces NHS costs. We will look at the GP records of those who leave the study early in case there are important reasons for this. _x000D_ Bisoprolol is cheap (4p/day) and if it works it will improve the lives people with COPD and reduce the costs of COPD to the NHS. Our group includes chest doctors, GPs, researchers with experience of running clinical trials as well as a person with COPD.","Design: A randomised double blind placebo controlled clinical trial to determine the clinical and cost effectiveness of adding once daily bisoprolol compared with placebo to reduce exacerbations in patients with COPD at risk of exacerbation._x000D_ Setting: 160 primary and secondary care centres across our existing network that have recruited people with COPD into the TWICS trial._x000D_ Target population: 1574 patients diagnosed with COPD receiving usual NHS care at risk of exacerbating. At least 50% will be identified in primary care._x000D_ Inclusion criteria: 1) Diagnosed COPD (NICE definition: post bronchodilator FEV1<80% predicted, FEV1/FVC<0.7) receiving treatment as per local guidelines; and 2) A history of two or more COPD exacerbations in the previous year treated with oral corticosteroids and/or antibiotics._x000D_ Exclusion criteria: current sole respiratory diagnosis of asthma, any asthma diagnosis before the age of 40 years, heart failure, use of beta-blockers or other heart rate limiting drugs, systolic blood pressure(BP)<100mmHg, heart rate(HR)<60/min, or heart block on ECG._x000D_ Health technology being assessed: The beta (ß1-selective) blocker bisoprolol, to be used in conjunction with usual NHS care and COPD treatment. _x000D_ Allocation: Participants will be randomised 1:1 to once daily oral bisoprolol (maximum dose 5mg od) or placebo for a year. The intervention group will start oral bisoprolol at 1.25mg od with supervised weekly up-titration to maximal tolerated dose or 5mg a day dependent upon symptoms, heart rate, blood pressure and lung function. This dose will continue for the remaining 48 weeks of the trial. The control group will receive an identical oral placebo tablet od, similarly up-titrated and taken for 48 weeks._x000D_ Measurement of costs and outcomes: The primary outcome will be the number of participant reported COPD exacerbations treated with antibiotics and/or OCS during the 1 year treatment period. The primary economic outcome measure will be incremental cost-per-exacerbation avoided and cost-per-QALY gained during the treatment period._x000D_ All outcomes will be assessed blind at baseline, 26 and 52 weeks and will include: patient reported exacerbations, health care utilisation, disease-related health status (CAT test); health related quality of life (EQ-5D-3L); dyspnoea (BDI/TDI); lung function; mortality; adverse events/reactions; cardiac events. Permission to access GP records will be sought to identify exacerbations in those failing to complete the study._x000D_ Sample size: The ECLIPSE study reported a mean (SD) exacerbation rate for such patients of 2.22/yr (1.86). With 669 subjects in each arm, the trial will be able to detect a clinically important 15% reduction in COPD exacerbations (i.e. from an average of 2.22 to 1.89) with 90% power at 5% significance level. Withdrawal from taking study drug is estimated at 15%, making total sample size 1574._x000D_ Timetable: Study duration will be 60 months. Milestones are pre-funding: approvals; Months 1-6: Study set-up authorisations; Months 7-42: recruitment; Months 43-54 follow up; Months 55-60 data analysis, report writing. A 6 month internal pilot is included._x000D_ Recruitment will be for 36 months.. _x000D_ Expertise: An experienced multidisciplinary team comprising chest physicians, general practitioners, clinical trialists, a statistician, a health economist and a COPD patient.",6.1 PHARMACEUTICALS,RESPIRATORY HRCS22_06792,Department of Health and Social Care,NIHR,A risk-based approach to blood pressure for cardiovascular disease prevention,"Background: Although rates of cardiovascular disease have fallen dramatically in recent years, it remains the leading cause of death among men and second leading cause among women in the UK. In UK primary care, patients at risk of disease are routinely identified using cardiovascular disease risk scores, such as QRISK2, which incorporate a number of factors to predict absolute risk of disease over the next ten years. NICE guidelines advocate drug treatment of two main cardiovascular disease risk factors as the focus of the primary preventive strategy in the UK: cholesterol and blood pressure. Eligibility for cholesterol lowering drug treatment is determined by cardiovascular risk, as predicted by QRISK2, rather than levels of cholesterol. Conversely, eligibility for blood pressure lowering drug treatment is determined by a threshold of blood pressure, despite a growing body of international evidence in favour of using cardiovascular risk. A risk-based approach to blood pressure lowering could improve risk stratification and identify those most in need of treatment, and has already been adopted in New Zealand. However, this approach has not yet been adopted in the UK, perhaps due to uncertainties over the overall clinical benefits and harms in the NHS. The research proposed here will address these gaps in knowledge using routinely collected data from the UK NHS and New Zealand.Aim: To prevent cardiovascular disease events through the management of blood pressure reduction by cardiovascular disease risk. Question to be addressed: What would be the impact on patient and population health if blood pressure were managed based on cardiovascular disease risk, rather than the current blood pressure threshold-based approach? Plan of investigation: A range of epidemiological studies will be undertaken to investigate the impact of changing the UK's blood pressure lowering guideline from a blood pressure threshold-based approach to a cardiovascular disease risk-based approach. Two electronic health record sources will be used: (i) the Clinical Practice Research Datalink in the UK, a database holding the longitudinal primary care records of over 4 million current patients, and (ii) PREDICT from New Zealand, a database of over 400,000 patients holding cardiovascular risk factor data and linked to hospitalisation and mortality data.The first study will use CPRD data to quantify and describe the characteristics of patients in the UK who are eligible for blood pressure lowering under the current guideline and compare this to those eligible under a risk-based approach to treatment. The second will use models developed within CPRD data to compare the number of cardiovascular disease events occurring under each approach. The third study will estimate the risk of adverse events resulting from over- or under-treatment with blood pressure lowering, among the groups whose eligibility for treatment would change under a risk-based approach. This will use complementary data from the CPRD and PREDICT. Finally, using PREDICT data, GP and patient adherence to a risk-based guideline will be assessed. Summary of potential benefits to patients and NHS: The analyses planned in this proposal are the first steps in assessing whether a risk-based approach to management of blood pressure would be beneficial for patient and population health in the UK. If the approach resulted in a net decrease in the expected number of cardiovascular disease events, with minimal adverse effects, then NICE should consider recommending this approach in the NHS. This would be beneficial for patient health and would be relevant to a large proportion of the population with high blood pressure or high cardiovascular disease risk. It may also signify important cost savings to the NHS, for which a full cost-effectiveness study would be required.","Although rates of heart attacks and strokes have fallen dramatically in recent years, they remain among the leading causes of death in men and women in the UK. General practitioners identify patients at risk of disease using cardiovascular disease risk scores, which incorporate a number of factors (age, blood pressure, cholesterol, smoking, etc) to predict a person's risk of disease over the next ten years. UK guidelines recommend drug treatment of cholesterol and blood pressure to prevent heart attacks and strokes. Eligibility for cholesterol lowering drug treatment is determined based on a patient's overall disease risk, rather than their cholesterol level. But eligibility for blood pressure lowering drug treatment is determined based on blood pressure itself, even though there is evidence from other countries showing that using a patient's overall disease risk might be better at identifying people most in need of treatment, could reduce the number of heart attacks and strokes, and save money. Using a patient's overall disease risk to guide blood pressure lowering drug treatment is already done in New Zealand. However, this approach has not yet been adopted in the UK because the benefits and risks in the NHS have not been investigated. Given the benefits shown in other countries, it is now crucial to examine the impact of this alternative approach to blood pressure lowering treatment within the NHS and ask whether such an approach would benefit patients in the UK.The aim of this research is therefore to investigate whether managing blood pressure according to a patient's overall cardiovascular disease risk may be more beneficial to patient and public health in the UK than managing based on blood pressure alone. A range of studies will investigate the risks and benefits of managing blood pressure based on cardiovascular risk. Using the largest primary care data source in the UK, this investigation will estimate the number of patients who would be affected by a change in the strategy to manage blood pressure, and the number of heart attacks and strokes that would be expected compared to the current strategy. Given the current UK strategy, data from the UK are not sufficient to measure the harms of a risk-based approach. To ensure that these harms are properly addressed, data will also be used from a setting where blood pressure is already managed according to risk (New Zealand). Possible adverse effects include eye, kidney and heart damage due to untreated high blood pressure, and falls or fractures caused by blood pressures that become too low. Data from New Zealand will also be used to measure whether doctors and patients follow the risk-based approach, which will inform development of a strategy for the UK.Patients from the British Heart Foundation and the Farr Institute's Patient Working Group have discussed the study and contributed to the aims of this research. Their involvement has been central to the development of this application and their participation will continue to influence the investigation. Importantly, these patients will comment on the focus and disease outcomes of the studies, and on materials for distribution to patient groups at the end of the study. The results of these studies will be published in peer-reviewed scientific journals, presented at national and international conferences, and will be considered when the UK blood pressure lowering guidelines are reviewed. Results will be presented to patients and GPs, who will help to develop appropriate materials for distribution to charities and patient groups. These analyses will answer questions relating to a potentially life-saving and cost-saving new approach to the management of blood pressure and could inform the next steps towards implementation of a risk-based approach.",7.3 MANAGEMENT AND DECISION MAKING,CARDIOVASCULAR HRCS22_05066,Department of Health and Social Care,NIHR,"A single-blind, randomised, phase II multi-centre study to determine reactogenicity and immunogenicity of heterologous prime/boost COVID-19 vaccine schedules in adolescents (COMCOV-3)","The successful roll-out of COVID vaccines such as COVID-19 mRNA Vaccine BNT162b2 and the Oxford/AstraZeneca ChAdOx1 nCOV-19 vaccine has saved approximately 60 000 lives in the UK alone up to July 2021. While older age groups and others at most risk of disease have been prioritised in COVID-19 immunisation campaigns, recommendations for immunisation are now being extended to adolescents in many countries including the USA, Israel and Ireland, given the high rates of infection in this age group. The potential benefits (and costs) of extending the UK COVID-19 vaccine immunisation to adolescents in the UK is under active review by the JCVI, and on 4th August 2021 it was announced that a first dose of BNT162b2 was recommended for all 16 to 17 year-olds in the UK, with decisions about the timing and nature of the second dose to be decided. One concern regarding adolescent immunisation is a rare side effect of inflammation of the heart muscle (myocarditis) or lining of the heart (pericarditis), observed at a rate of 67 per million following the second dose of BNT162b2 administered to young men in the USA. The possibility of using alternatives to a full dose of BNT162b2 as the second dose of vaccine are therefore being considered. The use of heterologous prime/boost schedules of COVID-19 vaccines has been studied in COMCOV and COMCOV2, to facilitate flexible immunisation programmes. The COMCOV study showed a schedule with ChAdOx1 nCOV-19 as the first dose, followed by BNT162b2 as the second dose is highly immunogenic and is now deployed routinely in non-elderly populations in Canada and many northern European countries. However, restrictions on the use of ChAdOx1 nCOV-19 in younger adults due to concerns regarding vaccine induced thrombotic thrombocytopenia mean that this would not be a suitable option for a mixed schedule in adolescents. Another potential option for the second dose is NVXCoV2373, which is not yet licensed but under a rolling review from the MHRA. A phase 3 study of NVXCoV2373 showed it to be 89.7% effective at preventing SARS-CoV-2 infection in adults, without any significant safety concerns. A phase 3 study currently underway in the USA (NCT04611802) includes an adolescent cohort (N=3000), in which over 1400 participants have received NVXCoV2373 with no safety concerns raised (Novavax, personal communication). Furthermore, data generated in COMCOV2 has shown that a schedule employing BNT162b2 followed by NVXCoV2373 is no more reactogenic than a homologous BNT162b2/BNT162B2 schedule in participants aged over 50 years. An additional potential approach is use of a half dose vaccine, for either BNT162B2 or an alternative mRNA prodiced by Moderna, which would be expected to be less reactogenic than a full dose and allow greater numbers to be immunised with the available supply of vaccines. Accordingly, this study will determine the side effect profile, and the immune responses, following schedules using BNT162b2 as a first dose, and a second dose administered 8 weeks later of either BNT162b2 (full or half dose), NVXCoV2373 (full dose) or Moderna (half dose).","The successful roll-out of COVID vaccines such as COVID-19 mRNA Vaccine BNT162b2 and the Oxford/AstraZeneca ChAdOx1 nCOV-19 vaccine has saved approximately 60 000 lives in the UK alone up to July 2021. Both of these vaccines are administered as a two-dose regimen, as is the adjuvanted protein COVID-19 vaccine from Novavax, NVXCoV2373, which is under rolling review of the MHRA at the time of writing. The use of heterologous prime/boost (mix and match) schedules of COVID-19 vaccines has already been studied in COMCOV and COMCOV2, and a schedule with ChAdOx1 nCOV-19 as the first dose, followed by BNT162b2 as the second dose has been shown to be highly immunogenic and is now deployed routinely in non-elderly populations in Canada and many northern European countries. Use of heterologous prime/boost schedules could also potentially be of benefit in an adolescent immunisation campaign. The potential benefits (and costs) of extending the UK COVID-19 vaccine immunisation to adolescents in the UK is under active review by the JCVI, and on 4th August 2021 it was announced that a first dose of BNT162b2 was recommended for all 16 to 17-year olds in the UK, with decisions about the timing and nature of the second dose to be decided. One concern regarding adolescent immunisation is a rare side effect of inflammation of the heart muscle (myocarditis) or lining of the heart (pericarditis) that has been observed after the second dose of BNT162b2, especially in young men. Mixed schedules with alternative vaccines used for the second dose, or using half doses of COVID-19 vaccines, could be an alternative that allows protection against COVID-19 while avoiding a second full dose of BNT162b2, and could also help deploy existing stocks of vaccine as effectively as possible. Accordingly, this study will determine the side effect profile, and the immune responses, following schedules using BNT162b2 as a first dose, and a second dose administered 8 weeks later of either BNT162b2 (full or half dose) or NVXCoV2373 (full dose) or an alternative mRNA produced by Moderna (half dose).",3.4 VACCINES,INFECTION HRCS22_06609,Department of Health and Social Care,NIHR,A study of the relationship between inequalities in early child development and subsequent health outcomes in early adolescence to inform policies and interventions to improve health and reduce health inequalities.,"Background Reducing child health inequalities is a global health priority and evidence suggests that early child development is crucial for future wellbeing. Healthy weight and socio-emotional behaviour in early adolescence are known to be predictive of obesity and mental health in adulthood. However the relationship between inequalities in early child development and these early adolescent health consequences remain poorly understood. This project will identify, and quantify the strength of, causal pathways between inequalities in early child development and body weight and socio-emotional behaviour in adolescence. The findings will inform the development of key policies, of cross-sector relevance, needed to effectively reduce health inequalities and increase wellbeing in early adolescence and throughout the subsequent life course. Research Question What are the mediating pathways between inequality in early child development, and body weight and socio-emotional behaviour in adolescence, and where should we intervene in these pathways to improve outcomes and reduce inequalities for adolescents? Objectives For health outcomes of healthy weight and socio-emotional behaviour in early adolescence: Identify what is already known about the pathways linking early child development to these outcomes. Using the Millennium Cohort Study (MCS), elucidate the mediating pathways between inequalities in early child development and these outcomes Quantify the strength of relationships along each mediating pathway. Quantify the potential effect on adolescent health outcomes of targeting interventions along each mediating pathway Identify targets for intervention and policy implications of the above.Methods A comprehensive participatory systematic review (involving a series of workshops with national and local stakeholders across health and education sectors) will synthesise evidence on and develop a conceptual model of the pathways linking early child development (age 3) to health outcomes, and inequalities in, body weight and socio-emotional behaviour in early adolescence (age 11) (Objective1). This model will be used in causal mediation analysis of MCS data (using structural equation modelling) to identify, and quantify the strength of causal pathways (Objectives 2 &3). Estimates from the causal mediation analyses, combined with effect estimates from controlled trials and systematic reviews, will be used to simulate the effects of intervening on the main mediating pathways (Objective 4). Implications for policy will be explored through a second round of participatory engagement with national and local stakeholders, using a deliberative dialogue approach (Objective 5).Timelines Participatory systematic review submitted for publication by the end of year 1. Longitudinal analysis on the mediating pathways complete and papers submitted for publication by end of year 2 Recommendations for policy produced and disseminated from end of year 3.Anticipated impact and dissemination This research will fill a critical evidence gap by providing a comprehensive synthesis and novel conceptual model of the relationship between inequalities in early years development and later health outcomes in early adolescence. It will identify the mediating pathways susceptible to intervention to mitigate the effect of inequalities in early child development on later health consequences. Working closely with policy stakeholders in health and education, recommendations of cross-sectoral relevance will be generated to inform actionable policies to reduce health inequalities.","What is the aim of this study? The aim of this study is to understand how development in children at age 3 (how well children can think and understand as they prepare for school) affects weight and mental health at age 11 (early adolescence). These measures of health in adolescence are important because they predict obesity and mental health in adulthood and are major public health challenges for the NHS. The study will identify what factors are important for supporting children's health as they grow up. Findings will help policymakers decide where to focus support to improve health in early adolescence.Why is this study important? This study is important because poorer children have worse health and development than richer children do and this difference is growing, resulting in inequalities in health. If we are to reduce this difference, we need to understand how development at a young age affects health at a later age. Understanding how factors such as the home environment, parental stress and social circumstances affect children's health as they grow up will identify where and how to provide support. The work could lead to policy changes that have long-term benefits on improving health and future life chances of the most disadvantaged children.How will the research be carried out? This study has three phases: Phase 1I will review literature on how early child development affects weight and mental health in early adolescence. In addition, I will hold workshops to discuss the findings. In the workshops, I will speak with and listen to views from parents, policy makers, local councillors, public health and education practitioners and voluntary sector staff. From the workshops and literature review I will produce a model (a mathematical tool) indicating how early child development affects health.Phase 2I will apply the model produced from phase 1 to a big dataset of 18827 children born across the UK in 2000. This will test the findings from phase 1. It will identify the factors that affect early adolescent health and which of the factors are the most important.Phase 3:I will discuss the factors, identified in phase 2, with similar groups of people I spoke with in phase 1. Together we will make recommendations for policy makers. These recommendations will state how best to support children as they grow up to improve levels of healthy weight and good mental health. Recommendations will also highlight how to reduce the difference in these health outcomes between the richest and poorest children.How will the public be involved in this research? I have developed this research plan with charitable organisations and local authority child health and education leads and parents. I will assemble a more permanent public involvement panel to develop the research project further and: further shape the design of the study; highlight any practical issues with the research plan including the best way of engaging children with research findings; comment upon the language used in documents for the public; and help to promote the findings What will happen to the findings of this research? This research will lead to: An understanding of how early child development affects health in early adolescence An understanding of how to support children to improve levels of healthy weight and good mental health in adolescence Recommendations for policy makers on how to reduce health inequalitiesFindings from each phase of this study will be: Published in academic journals, presented at conferences and developed into visual summaries. Presented to relevant organisations via meetings and updates in newsletters, websites and blogs.","2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",GENERIC HEALTH RELEVANCE HRCS22_19794,Wellcome Trust,,A systems approach for understanding cell surface dynamics in trypanosomes,"The surface membrane and endosomal system of protozoan pathogens directly interfaces with the host; mediated functions including immune evasion, environmental motoring and drug interactions. Recently it has emerged that surface composition and the mechanisms controlling membrane protein turnover in trypanosomatids are highly divergent, and that these processes also are connected with drug interactions. We have clear evidence for complex control based around ubiquitylation, but the roles of many surface proteins remain cryptic. I propose a program of work to integrate, in a system wide manner, how these novel aspects of biology converge to maintain the parasite surface. 1. Examine the mechanisms of ISG and AQP turnover, 2. Evaluate the potential of ISGs for novel anti-trypanosome drug delivery, 3. Assess the essentiality of ISG protein families in vitro and in vivo using genome editing. 4. Refine our understanding of the clathrin and ESCRT sorting systems of trypanosomes to determine how these processes mediate the transport of ISGs, AQPs and the surface proteome in general. Each of these aspects will exploit a combination of state of the art proteomics, super-resolution microscopy and novel genetic tools to understand in greater detail the importance of surface proteins to trypanosome biology, virulence and infectivity.","Infectious organisms exploit many varied approaches to surviving within their hosts, but one of the more spectacular and successful is antigenic variation. This process involves the constant alteration of the surface so that the host immune response is unable to mount a successful response. Significantly, in African trypanosomes this mechanism has become extremely sophisticated and relies on a superabundant surface protein. How this surface is maintained, and importantly, how other proteins are also maintained at the surface, remains incompletely understood. Recent advances have begun to characterise the major players and mechanisms involved, and new and maturing technologies are now available that allow a detailed dissection of this process in a more holistic manner. Here I propose a system wide approach in trypanosomes to understanding the roles of surface molecules and how the surface is maintained. By exploiting methods that allow sampling of the entire trypanosome cell, this allows an integrated, unbiased and comprehensive understanding of the roles of various proteins in maintaining surface composition. The combined outcomes will identify mechanisms that are unique to the parasite, those that represent vulnerable processes and also insights into therapeutic mechanisms.",2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_11737,Economic and Social Research Council,ESRC,AI-enabled Portable Incontinence Management Device,"Our primary target within this project is to create prototypes of an portable incontinance management device while continuously engaging with all the stakeholders. We expect the instrumented sock, and the associate AI algorithm will be ready for clinical validation by the end of the project. The technical aspect of the project will have three distinct sub-themes. -Material design of the sock and the embedded electrodes -Design of the miniaturized stimulation electronics connected to the sock -Development of the associated AI algorithms displayed on a mobile/web application","An overactive bladder is a common medical condition, particularly among the elderly. It leads to urinary incontinence (UI) and influences the quality of life for around 40% of those above 75 (>6million people in UK). People often consider this as a natural progression to old age and do not actively seek any treatment. However, UI is one of the main factors why the elderly lack confidence and give up their independence to move to care homes. Conventional approaches to treat UI, e.g., drugs and bladder-catheterisation have several side effects (e.g., dry-mouth, constipation, confusion). Invasive electrical stimulation of the Tibial nerve (around the ankle) is an established alternative treatment. But a needle electrode inserted into the leg can be painful and distressing. Recently, a non-invasive version of this method has been demonstrated to be successful for older adults. However, it comprises multiple hospital visits per week over a duration of 2 months. Such a long treatment process leads to reduced adherence especially for the frail elderly who have already accepted UI to be a part of their life. We propose an instrumented sock that the user can wear comfortably throughout the day, while electrodes weaved into it will stimulate the tibial nerve when necessary. The stimulation parameters will use an AI-based algorithm (via a smartphone) set by the clinician. The proposed system can be tried by a larger section of the population without surgery or repeated hospital visits. Hence, users will have much greater privacy and flexibility in managing incontinence.",5.3 MEDICAL DEVICES,RENAL AND UROGENITAL HRCS22_03905,Medical Research Council,MRC,AI-powered next-generation imaging biomarkers for dementia,"The vision of this project is to accelerate the translation of next-generation imaging biomarkers of dementia from academic research into real-world impact. The need for advanced biomarkers of dementia has never been greater, as treatment that slows or stops the disease remains elusive. Recent high-profile trial failures underscore the importance of identifying the right participants for trials - those for whom the disease is at an early enough stage to benefit from potential treatments. Biomarkers with higher sensitivity are vital for this endeavour. This project will contribute to this very effort by expediting the process of delivering cutting-edge imaging biomarkers uncovered in academic research to the frontline of therapeutic trials. The project objective will be achieved through a close collaboration between AInostics, an award-winning imaging AI start-up, and University College London (UCL), an international leader in the development of novel imaging biomarkers for dementia and neurodegenerative diseases generally. The close collaboration will be built through the proposed secondment of an early-career imaging researcher, Dr Michele Guerreri, who has recently developed a cutting-edge imaging biomarker sensitive to subtle changes resulting from neurodegeneration. The secondment will give him the ideal opportunity to turn his novel research idea into a viable commercial product, enabling its expedited translation into frontline applications. Crucially, joining the rank of innovation scholars will allow Dr Guerreri the time and space to gain the essential knowledge, and to develop the necessary skills, to successfully operate at the interface of academic research and commercial development in the future. In the long term, this invaluable experience will position him to play a key role in facilitating the interactions between UCL and the UK's vibrant imaging AI sector, expediting the impact of public investment on making UK a healthy and prosperous nation.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,NEUROLOGICAL HRCS22_01026,Medical Research Council,MRC,"AMPA Receptor Biogenesis, Structure and Function","AMPA glutamate receptors (AMPARs) are main mediators of excitatory neurotransmission and are central to synaptic plasticity, a process underlying learning. AMPARs are also essential for brain development and their dysfunction contributes to various neurological diseases, rendering them a potential drug target. Neuronal AMPARs are composed of four pore-forming subunits and different types of auxilliay subunits, that are expressed in diverse, partly overlapping patterns in the brain. The precise composition of the AMPAR comlex is essential for post-synaptic signal processing and determines, signalling properties, trafficking to/from synapses and synaptic nano-positioning of the receptor. Our research aims to: 1) unravel mechanisms underlying gating transitions of major AMPAR signaling complexes at the atomic level, and 2) reveal AMPAR organisation at synapses, at the nanoscale. Our ultimate aim to understand the central role of the AMPAR complex in information storage and learning. In aim 1, we use a combination of cryo-EM, molecular dyamics (MD) simulations and patch-clamp electrophysiology to study gating control of recombinant AMPAR complexes that closely resemble predominant assemblies found in the forebrain. Increased resolution of the ion transduction sector has allowed us to locate traversing cations, as well as study the role of lipids and allosteric modulators. In combination with MD simulations and single-channel recordings, our structural data are expected to generate a detailed understanding of the gating machinery and its regulation by auxiliary subunits. This work is being followed by cryo-EM analysis of native AMPAR extracted from neuronal synapses of select circuitries, permitting us to capture the architecture and complex stoichiometry of synaptic AMPARs. For aim 2, we have shown that the sequence-diverse AMPAR N-terminal domain (NTD), which faces the synaptic cleft, is essential for receptor anchoring at postsynaptic sites and that deletion of the NTD impedes synaptic potentiation. Our data revealed that this domain provides a synaptic anchor positioning the receptor opposite presynaptic glutamate release sites. This organisation is expected to be essential for efficient signal transmission and synaptic potentiation. Inherent to this model is the unique conformational freedom of the modular AMPAR extracellular region, permitting NTD interactions with synaptic cleft proteins, which we are currently identifying in BioID screens. To study the organisation of AMPARs at synapses at the nanoscale, we have implemented 3D-stochastic optical reconstruction microscopy (3D-STORM) together CRISPR/Cas9 tagging of endogenous AMPARs in brain tissue. This set-up will ultimately allow us to follow AMPAR dynamics (and NTD-mediated positioning) at synapses undergoing potentiation with high precision.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,NEUROLOGICAL HRCS22_22811,The Academy of Medical Sciences,AMS,AN ANALYSIS OF PEPTIDE TRAFFICKING AND THE ANTI-TUMOUR IMMUNE RESPONSE IN THE CONTEXT OF IMMUNOTHERAPY IN COLORECTAL CANCER,"Long-term responses to immunotherapy in colorectal cancer patients are variable and poorly understood. The aims of this project are (1) to set up and analyse two new clinical immunotherapy cohorts of CRC patients, (2) elicit the relative importance of tumour biology and host immune response in determining the response to immunotherapy, focussing on intracellular peptide trafficking via golgi vesicle formation and exocytosis, (3) identify the mechanisms of how gene expression changes of these candidate genes/genesets alter tumour profiles or immune cell responses and other aspects of the tumour microenvironment. Immunogenomic approaches, using whole transcriptomic analyses, have recently been developed as a strategy to simultaneously understand tumour biology and the anti-cancer immune responses. There are potential benefits as it allows a quantification of immune cell subtypes in the tumour and their relative levels of activation. From a cancer cell perspective, it enables an accurate measurement of cellular phenotypes, not possible from other techniques. My pilot work has identified that abnormal peptide trafficking following cell proteasome activity links tumour biology to the degree of immune activation. Lower levels of cellular peptide trafficking by the golgi apparatus and vesicle exocytosis lead to poorer immune initiation, through decreased tumour antigen presentation on MHC complexes. These changes in cellular peptide trafficking potentially enable a tumour to inhibit immune initiation and thereby become resistant to immunotherapy. Improved understanding of these processes and how they affect the immunogenomic architecture is the first step to developing more effective immunotherapies for CRC.","The immune system can play an important role in treating and controlling growth of colorectal cancer (CRC). New forms of cancer treatment, called immunotherapy, enable activation of the immune system to treat CRC. They can lead to very good responses in small numbers of patients. Not all patients respond to treatment and these treatments have a number of potentially serious side effects. A number of tests have been devised to try and predict who would do well from treatment, such as the presence of microsatellite instability. However, this test is not very good and many patients with microsatellite instability will still do very poorly from treatment. A new technique called immunogenomics now enables the accurate measurement of the immune system. I have previously found that activation of the immune system is dependent on the tumour cells. Tumour cells grow through the development of mutations and some cancer cells are better able to hide these mutations from the immune system. In this project, I propose to gain a better understand of who could get immunotherapy and why some people do not respond to it. I will use immunogenomic techniques and assess how a cancer cell is able to hide mutations from the immune system. A better understanding of these mechanisms could enable the development of better treatments for CRCs.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_11796,Cancer Research UK,CRUK,ARCADIAN: Phase I study combining the tumour hypoxia modifier atovaquone with radical chemoradiotherapy in locally advanced NSCLC,"Background: Lung cancer is the leading cause of cancer death in the UK with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Radiotherapy treatment (+/- chemotherapy) plays a key role in the management of early and locally advanced disease. Despite significant technical improvements in radiotherapy delivery, clinical outcomes for patients treated with 'curative intent' remain extremely poor. Tumour hypoxia frequently occurs in tumours due to an imbalance in the 'supply and demand' of oxygen. This is recognised as inducing an aggressive tumour phenotype with profound radiation resistance. An emerging strategy to reduce tumour hypoxia is to decrease the oxygen consumption rate (OCR) of cancer cells. We have previously found that the safe and widely used anti-malarial drug atovaquone reduces OCR in vitro. Clinically relevant concentrations of atovaquone rapidly reduce tumour hypoxia in 3D spheroids and tumour xenografts, causing marked radiosensitisation. We subsequently conducted a window of opportunity clinical trial in NSCLC patients prior to surgery. Approximately 14 days of atovaquone treatment reduced tumour hypoxia (measured using FMISO PET-CT) in 11 out of 15 patients with no toxicity. This data supports that atovaquone is able to safely and effectively reduce hypoxia in the clinical setting. Aims: We aim to undertake this phase I, single-arm, open-label, 2-centre trial using the Time-To-Event Continual Reassessment Method (TiTE-CRM) to find the optimal dose of atovaquone in combination with concurrent chemoradiotherapy (CRT) in patients with NSCLC. Also, as a major reason for the lack of success in previous hypoxia modification trials was a failure to utilise biomarkers to select patients with hypoxic tumours, we aim to further develop such biomarkers specifically for this purpose. Methods: Atovaquone will commence 2 weeks prior to CRT, and be continued throughout CRT. The duration of treatment is 8.5 weeks while the follow-up period is 12 weeks. DLTs will be assessed over this period. Biomarker data will be collected at baseline and following 2 weeks of atovaquone treatment (prior to CRT) and will consist of FMISO PET-CT imaging and plasma levels of hypoxia markers. Hypoxia metagene analysis will also be conducted on diagnostic tissue. How results will be used: This study will identify the dose of atovaquone for a subsequent phase II/III trial. Furthermore, the biomarker element of this study will lead to the development of a clear hypoxia-dependant patient selection strategy for the future study and directly inform trial design.","Background: Lung cancer is the leading cause of cancer death in the UK with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Radiotherapy treatment (+/- chemotherapy) plays a key role in the management of early and locally advanced disease. Despite significant technical improvements in radiotherapy delivery, clinical outcomes for patients treated with 'curative intent' remain extremely poor. Tumour hypoxia frequently occurs in tumours due to an imbalance in the 'supply and demand' of oxygen. This is recognised as inducing an aggressive tumour phenotype with profound radiation resistance. An emerging strategy to reduce tumour hypoxia is to decrease the oxygen consumption rate (OCR) of cancer cells. We have previously found that the safe and widely used anti-malarial drug atovaquone reduces OCR in vitro. Clinically relevant concentrations of atovaquone rapidly reduce tumour hypoxia in 3D spheroids and tumour xenografts, causing marked radiosensitisation. We subsequently conducted a window of opportunity clinical trial in NSCLC patients prior to surgery. Approximately 14 days of atovaquone treatment reduced tumour hypoxia (measured using FMISO PET-CT) in 11 out of 15 patients with no toxicity. This data supports that atovaquone is able to safely and effectively reduce hypoxia in the clinical setting. Aims: We aim to undertake this phase I, single-arm, open-label, 2-centre trial using the Time-To-Event Continual Reassessment Method (TiTE-CRM) to find the optimal dose of atovaquone in combination with concurrent chemoradiotherapy (CRT) in patients with NSCLC. Also, as a major reason for the lack of success in previous hypoxia modification trials was a failure to utilise biomarkers to select patients with hypoxic tumours, we aim to further develop such biomarkers specifically for this purpose. Methods: Atovaquone will commence 2 weeks prior to CRT, and be continued throughout CRT. The duration of treatment is 8.5 weeks while the follow-up period is 12 weeks. DLTs will be assessed over this period. Biomarker data will be collected at baseline and following 2 weeks of atovaquone treatment (prior to CRT) and will consist of FMISO PET-CT imaging and plasma levels of hypoxia markers. Hypoxia metagene analysis will also be conducted on diagnostic tissue. How results will be used: This study will identify the dose of atovaquone for a subsequent phase II/III trial. Furthermore, the biomarker element of this study will lead to the development of a clear hypoxia-dependant patient selection strategy for the future study and directly inform trial design.",6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_18359,Cancer Research UK,CRUK,"ASTFOX: A Phase I study of the IAP antagonist, ASTX660, in combination with standard of care FOLFOX chemotherapy in metastatic colorectal cancer","Background: Cytotoxic chemotherapies remain the mainstay of treatment of metastatic colorectal cancer (CRC) with an unmet need to improve treatment given the typical low response rates of chemotherapy in the second line treatment setting. Inhibitor of Apoptosis Proteins (IAPs) are frequently deregulated in cancer, and are a major contributor to chemo-resistance through apoptotic inhibition and pro-survival NF-kappaB signalling. Restoration of apoptotic function through inhibition of IAPs is an attractive therapeutic strategy with additional potential for enhanced cell death through immunomodulation of the tumour microenvironment. ASTX660 is a dual antagonist of both XIAP and cIAP1 and has been evaluated as a single-agent with a recommended phase II monotherapy dose (RP2D) and schedule identified. Our pre-clinical data have shown enhanced cell death in vitro and tumour growth inhibition in vivo following treatment with oxaliplatin/5FU (FOLFOX) chemotherapy and ASTX660. A phase I trial combining ASTX660 and FOLFOX in metastatic CRC is warranted. Patient population: Histologically proven metastatic CRC where FOLFOX chemotherapy would be an appropriate second line treatment option. Additional eligibility criteria include: RECIST measurable and biopsiable disease; adequate organ function and performance status 0-1. Aims: The primary aims are to assess the safety and tolerability and to determine the maximum tolerated dose (MTD) and RP2D of ASTX660 in combination with FOLFOX. The secondary aims are to determine the pharmacokinetics of ASTX660 in combination with FOLFOX and to preliminarily assess the anti-tumour activity of the combination. There are additional exploratory aims which include investigating the effects of combination therapy on changes in apoptotic markers and immune cell infiltrate in tumour biopsies. Methods: Up to 30 patients will be recruited. The mTPI-2 (keyboard design) will be used to find the MTD. The target toxicity rate for the MTD is 0.25, with the acceptable toxicity probability interval of (0.2,0.3). Patients will be enrolled and treated in cohorts of size 3 across five pre-defined dose levels. Patients will receive combination ASTX660 (at cohort-assigned dose) and FOLFOX up to a planned 12 cycles (each of 14 days duration). Use: If this study demonstrates that the combination of ASTX660 and standard care chemotherapy can be delivered safely and is well tolerated by patients with metastatic colorectal cancer, then formal assessment of clinical efficacy will be needed to incorporate this therapy into routine clinical practice. This may be guided by any efficacy signal observed in this study.",,6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_05489,Department of Health and Social Care,NIHR,ATHENA: AmiTritypline for the prevention of post-HErpetic NeuralgiA,"Shingles is caused by the same virus that causes chickenpox. It “sleeps” in the nerve cells for decades. When it “wakes up”, it can make people feel generally unwell, cause tingling or pain in one part of the body, followed a few days later by a rash. The rash can take up to 4 weeks to heal. Antiviral medicine helps reduce initial pain and rash severity._x000D_ _x000D_ Some people can have “nerve pain” months after the shingles rash has gone. Called post-herpetic neuralgia, we don’t have any treatments to prevent this. Patients buy, and GPs prescribe, painkillers such as paracetamol, but they often don’t help. Amitriptyline is an old medicine, originally used at high doses (75-150 mg) to treat depression but now used at low dose for nerve pain. A small study published in 1997 suggested that taking a low dose (25 mg) of amitriptyline early on may help prevent post-herpetic neuralgia. We want to do a larger study to find out if using amitriptyline when the rash first appears really prevents pain later._x000D_ _x000D_ The only way to find this out is by doing a clinical trial. We will recruit 846 people aged >50 years who have been diagnosed by their GP with shingles. We will ask everyone to take tablets nightly for 10 weeks: half will be given amitriptyline and the other half will get placebo (or “dummy”) tablets. Neither patients nor their doctors will be able to choose which group they are in. This will be done by a computerised process called “randomisation” – a bit like rolling dice to decide. This way the results cannot be affected by anyone’s beliefs about amitriptyline. All other care will be the same – this includes GPs prescribing antivirals and painkillers if needed. We will use questionnaires to find out what happens to everyone over the following 12 months, especially whether they still have pain related to shingles at 90 days._x000D_ _x000D_ If starting amitriptyline early on does help, it is a cheap medicine that would prevent prolonged, difficult-to-treat pain for thousands of people. However, amitriptyline commonly causes side-effects such as dizziness, dry mouth and constipation. It can also cause problems when used together with some other tablets. This study is needed so we can be sure that any benefits outweigh any harms._x000D_ _x000D_ We have met with people with experience of shingles, with one person joining us as a co-applicant. We discussed the trial with them, and they identified potential barriers to taking part, such as lack of understanding about the condition; difficulty accessing GP appointments; and wrong information online about the risks of taking amitriptyline. While some people felt that any side-effects were offset by the potential benefits, others wanted more information first. We have carefully considered and addressed these issues in the design of the trial. Patient and Public Involvement will be built into the study set-up, running and sharing of the results._x000D_ _x000D_ We are a group of researchers from three of the UK’s leading primary care research universities. We have expertise in pain, post-herpetic neuralgia and running clinical trials in GP surgeries on skin problems and infections. We are uniquely placed to run the trial that is needed to answer the longstanding and important question of whether early use of amitriptyline in shingles prevents long-term pain.","Background: ~20% of people with Herpes Zoster (HZ, “shingles”) develop post-herpetic neuralgia (PHN). The pain can be difficult to treat and has a substantial impact on the quality of life of those affected. One small trial suggested that amitriptyline used prophylactically at low dose might prevent PHN._x000D_ _x000D_ Aim: To determine the effectiveness of prophylactic low-dose amitriptyline for the prevention of PHN in patients diagnosed with shingles._x000D_ _x000D_ Design: Multi-centre, individually randomised, pragmatic two arm placebo-controlled superiority trial with internal pilot, SWAT and nested qualitative study._x000D_ _x000D_ Setting: ~120 GP surgeries in England._x000D_ _x000D_ Participant recruitment: Adults =50 years, with a clinical diagnosis of HZ._x000D_ _x000D_ Intervention: Amitriptyline 10 mg (or matched placebo tablet), increasing in 10 mg steps over two weeks as tolerated, to 30 mg maximum for 70 days. All participants prescribed an antiviral, as per current clinical practice._x000D_ _x000D_ Masking: Participants, clinicians and researchers will be masked to allocation._x000D_ _x000D_ Primary outcomes: Presence/absence of PHN at 90 days after rash onset (cut-off of =3/10 on numerical rating scale average pain in last 24 hours, Zoster Brief Pain Inventory)._x000D_ _x000D_ Secondary outcomes: Worst/least/current pain; quality of life; mental health; frailty; side-effects and adverse events._x000D_ _x000D_ Sample size: Assuming 20% PHN in control and a relative risk reduction of 45%, with a 20% loss to follow-up, 846 participants will be required to detect a benefit from amitriptyline on a binary outcome for PHN (present/absent) at 90 days, with 90% power._x000D_ _x000D_ Nested qualitative study: We will interview clinicians and patients who do/do not refer/take part and audio-record a sample of consent encounters. The findings will support and optimise the delivery of the trial; and aid interpretation and implementation of the quantitative findings._x000D_ _x000D_ Study Within A Trial: During the internal pilot, GP surgeries will be cluster-randomised (1:1) to evaluate a practice-level education package, designed to facilitate early diagnosis of shingles and recruitment into the study._x000D_ _x000D_ Patient and Public Involvement (PPI): We will ensure meaningful PPI throughout our research, from design to dissemination, supported by a dedicated coordinator and patient co-applicant._x000D_ _x000D_ Dissemination: We will produce traditional academic outputs (reports, presentations and papers) and “actionable” for stakeholders and guideline developers, shared via websites, journals and professional networks._x000D_ _x000D_ Project timetable (months): -6 to 0 contracting, protocol and study materials development; -3 to 3 application/receipt of approvals (ethics, HRA, MHRA); 0 to 6 study database and “pop up” tool development and testing, staff and GP surgery recruitment and training; 7 to 37 participant recruitment and follow-up; 33 to 40 data cleaning, analysis and reporting._x000D_ _x000D_ Research team: We are an experienced group of clinicians and methodologists. We have an excellent track record of successfully delivering high-quality research in this area with expertise in primary care, herpes zoster and infection, pain, dermatology, medicines, health economics, qualitative research and PPI.",6.1 PHARMACEUTICALS,INFECTION HRCS22_05246,Department of Health and Social Care,NIHR,"Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness. The ASTUTE pragmatic randomized controlled trial.","Autoimmune uveitis is a term for several rare eye diseases in which the body’s own immune system causes sight-threatening damage to the light sensitive retina at the back of the eye. Uveitis causes sight loss from inflammation inside the eye, damage to blood vessels in the retina or leakage of fluid into the central, most sensitive area of the retina. Two in 10,000 people are at risk of serious sight loss from uveitis. Usual treatment for autoimmune uveitis involves low dose steroids and one or two other drugs to reduce inflammation. Unfortunately, many patients do not respond to or tolerate usual treatment, or need high dose steroids to control the uveitis. Long term high dose steroids increase the risk of heart attack, stroke, and infection and affect physical and mental health. Adalimumab is an expensive new drug that targets chemicals released by inflamed tissue, neutralizing their damage to the body._x000D_ _x000D_ Two recent studies suggest fortnightly adalimumab is, on average, an effective way to treat uveitis in some patients. However, drugs like adalimumab can have serious side effects and more evidence is required to identify which patients with uveitis benefit the most from adalimumab, both with respect to their vision and quality of life, including treatment side effects._x000D_ _x000D_ This study aims, first, to identify patients who are most likely to benefit from adalimumab. All eligible patients who consent will be given adalimumab for a 16 week trial period, if necessary in combination with low dose of steroids; these patients will include those with impaired vision due to uveitis, requiring high dose steroids to bring the disease under control, and those with better vision but who require high dose steroids to keep the uveitis under control. Over the 16 weeks, doctors will aim to reduce the steroid dose to a low level that should not cause side effects._x000D_ _x000D_ Then, patients who are successfully treated with adalimumab and low dose steroids will enter the main study. They will be given adalimumab or a dummy treatment, in combination with their other medications (including low dose steroids). Chance will determine who receives which treatment and neither patients nor their eye doctors will know. Regular eye examinations, tests and questionnaires will be used to assess how well patients are doing. This part of the study, which will treat and follow up patients for 12 to 30 months, will find out whether adalimumab is better at preventing recurrence of uveitis than the dummy treatment and whether adalimumab is cost -effective compared to the dummy treatment._x000D_ _x000D_ Patients with uveitis have contributed to the study from the start, helping to: design the protocol to ensure it applies to uveitis patients who may benefit; developing and testing a ‘quality of life’ questionnaire about the side effects of medications, impact on work and mood; co-authoring the lay summary; helping to draft the application, providing feedback on the trial design and participating in a national survey to assess support for the study. They will continue to contribute in these ways and provide support to patients, if funding is awarded. The research team includes eye doctors and researchers with expertise in doing eye studies. A registered clinical trials unit, ophthalmology research networks and patient groups will collaborate to conduct the study. The results will be disseminated through NHS England, patient societies and through medical journals.","DESIGN: Phase IV pragmatic placebo-controlled, randomised controlled trial (RCT) with a ‘treatment run-in’ (TRI). After the TRI, responders only (disease remission with <=5mg/day corticosteroid (CS), estimated 50%) will be randomised (1:1) to adalimumab or placebo. An internal pilot (phase 1; 18 months (m) including 6 months (6m) set up) will determine recruitment and responder rates among eligible patients; progression to phase 2 will depend on a) randomising >=80% (n=41) of the target number at this time (n=51), b) having at least 10 sites recruiting to the trial by month 18 and c) <15% of responders at the end of the TRI unwilling to be randomised. The full RCT will evaluate the effectiveness and relative cost-effectiveness of adalimumab vs placebo as add-on therapy to standard care._x000D_ _x000D_ SETTING: UK tertiary centres treating autoimmune non-infectious uveitis (ANIU)._x000D_ _x000D_ TARGET POPULATION: Adults with active (incident) or inactive (prevalent) ANIU, requiring/starting >5mg/day corticosteroid (CS) to induce/maintain remission. _x000D_ _x000D_ Inclusion criteria: Patients with sight threatening ANIU in either or both eyes. ANIU will be diagnosed on the basis of the criteria used to define treatment failure. _x000D_ _x000D_ Exclusion criteria: Untreated or active tuberculosis, uncontrolled glaucoma, multiple sclerosis, HIV positive, hepatitis B or C, Behcet’s disease, heart failure (NYHA III/IV), anti-TNF drug within 90 days, ocular CS implant within 12 months or an intravitreal steroid injection within the previous 3 months, pregnant, allergy or hypersensitivity to adalimumab or any of its excipients._x000D_ _x000D_ HEALTH TECHNOLOGIES BEING ASSESSED: 80mg subcutaneous injection of ImraldiTM (licensed biosimilar for adalimumab) at the start of the TRI, then fortnightly 40mg injections starting one week after the initial dose, up to 16 weeks (end of TRI); after randomisation, fortnightly 40mg injections of drug or placebo to the end of the trial (follow-up 12m to 30m). In the event of treatment failure (TF), open label drug will be restarted as per TRI for 16 weeks and, if a participant responds, allocation will be switched and trial treatment restarted, maintaining masking._x000D_ _x000D_ MEASUREMENT OF OUTCOMES Primary outcome: TF, defined as need for >5mg/day CS to maintain remission (decisions to increase CS made by masked clinicians) or active disease, excluding isolated anterior uveitis and including an increase in cystoid macular oedema. Clinical TF events will be validated by retinal imaging. Follow-up will be censored when all participants have at least 12m follow-up; following participants recruited earlier to the end of the trial will maintain masking and avoid the ethical issue of withdrawing treatment for participants after 12m follow-up. Secondary outcomes include: Patient reported outcomes (visual function, generic, and symptoms of side effects), individual TF components, retinal morphology, adverse events (AEs), changes in employment, NHS resource use and costs._x000D_ _x000D_ COST-EFFECTIVENESS ANALYSIS: The main outcome measure for the economic evaluation will be quality adjusted life years (QALYs), estimated using the EuroQol EQ-5D 5L, administered at every visit. Valuations derived from published UK population tariffs will be assigned. The mean number of QALYs per group and incremental QALYs will be calculated._x000D_ _x000D_ SAMPLE SIZE: Hazard ratios (HRs) in 2 trials of adalimumab to treat active and inactive ANIU were 0.50 and 0.57 respectively. The TRI design should enhance effectiveness and we have set a target HR of 0.5. Assuming that 27% in the placebo group survive free from TF at 12m (estimated from placebo groups of the 2 trials with 40:60 active: inactive disease), 174 participants will allow a HR=0.5 (27% vs 52% survival free from TF at 12 months) to be detected with 90% power and 5% 2-tailed significance, with <=10% loss to follow-up._x000D_ _x000D_ PROJECT TIMETABLE: 48 months comprising 6 months set-up; 23 months recruitment (which includes 4 months TRI and 4 months randomising last recruited participants at end of TRI); minimum 12 months follow-up; 7 months data management, analyses and reporting._x000D_ _x000D_ EXPERTISE IN TEAM: The multidisciplinary team includes ophthalmologists who treat ANIU, a patient with ANIU, an imaging expert, clinical trials researchers with expertise conducting ophthalmic trials and a health economist.",6.1 PHARMACEUTICALS,EYE;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_06268,Department of Health and Social Care,NIHR,"Adapted suicide safety plans to address self harm, suicidal ideation and suicide behaviours in autistic adults: an interventional single arm feasibility trial and external pilot randomised controlled trial","Aims: This study will examine how acceptable and usable adapted Safety Plans (SPs) are for autistic adults who have a history of self-harm and/or suicidal thoughts and behaviours. The findings will also help us to determine the important features to be included in a future study to assess how helpful SPs are. _x000D_ Background: Suicide is a leading cause of premature death for autistic people. Autistic people are 9 times more likely to die by suicide than non-autistic people and 66% of autistic adults report having considered suicide (UK general population rate is 17%). No research has explored suicide prevention strategies for this group. Autistic people need mental health treatments to be adapted to make them more accessible. SPs are a type of intervention to prevent people attempting suicide. They are a simple, cost-effective, potentially life-saving intervention that autistic people could find indispensable in times of crisis. Working with autistic adults we have adapted SPs to make them more suitable for them._x000D_ Design & methods: In Stage 1 we will consult with autistic adults, family members and professionals to refine our adapted SPs and research plan to ensure both are fit for purpose. We will run focus groups with: 1) autistic adults with experience of self-harm; 2) family members of autistic people who have experienced self-harm; 3) service providers who support autistic adults to discuss how the adapted SPs could be utilised in services and what training would be helpful. In this stage we will also work with local authorities, mental health and autism charities to train staff to use the SPs. In Stage 2 we will recruit 10 autistic adults through these organisations, who have experienced self-harm, with support from staff at their service provider they will develop their own SP and we will also ask them to complete some questionnaires about depression, anxiety, self-harm and suicidal thoughts/behaviours. We will ask for feedback on the SPs and the questionnaires and use this information to further refine the SPs and our research procedures. Finally, in Stage 3 we will recruit 70 autistic adults who have experienced self-harm. These autistic adults will be allocated at random, by a computer, to use our SPs (alongside usual care), or receive only usual care. We will follow up these participants one month and six months later and ask them about self harm, depression, anxiety, and suicidal thoughts/behaviours. We will also ask the autistic adults who received the SPs and their support workers (where applicable) if they used the plans and what they thought about them. At the end of the study we will have useful information about whether the adapted SPs are acceptable and usable by autistic adults and whether the procedures are appropriate for a future study to assess how well they work._x000D_ Patient and Public Involvement: Autistic advisers have already guided the development of the SPs through a series of consultations. In the proposed study we will engage autistic people as co-investigators, researchers and members of our steering committee and advisory panel. _x000D_ Dissemination will include a series of reports written in an accessible and inclusive manner for a wide audience; a feedback event; presentations at academic meetings; papers in academic journals; presentations for multidisciplinary teams; articles for professional organisation newsletters.","Research Question: ‘Are Autism Specific Safety Plans to reduce repeat self harm, suicidal ideation and behaviours acceptable and feasible for use with autistic adults and what are the parameters for a future definitive trial?'_x000D_ Background: Suicide prevention is a national priority for UK government policy, and autistic people have recently been identified as a high-risk group in NICE suicide prevention guidelines. Closing the mortality gap between autistic people and the general population is a priority for the Department of Health’s revised “Think Autism Strategy” (2018). Autistic people are a highly disadvantaged group, which has been associated with increased risk of self harm and suicide. Our research, designed in partnership with autistic people, highlights a lack of appropriate support and treatment for autistic people experiencing self-harm, suicidal thoughts and behaviours. No suicide prevention interventions have been developed specifically for autistic people. Hence, it is crucial to address this knowledge gap, and develop appropriate interventions to prevent self-harm and suicide in autistic people. At an engagement event with autistic people, families, practitioners and researchers we identified a suicide prevention intervention for adaptation for use with autistic people, suicide safety plans (SPs). Safety plans are a simple, cost-effective, potentially life-saving intervention that autistic people could find indispensable in times of crisis. We have developed an adapted safety plan for use with autistic adults. We do not yet have systematic data on the use of the SPs. Autistic people experience significant difficulties accessing NHS clinical services and when support is accessed it is often via third sector autism or mental health organisations. Our partners in the current project include third sector organisations where autistic people are most likely to receive support. This will be crucial to explore SPs use in non-NHS settings, where autistic people are most likely to seek support. _x000D_ Aims: to evaluate the feasibility and acceptability of the use of autism adapted safety plans for autistic adults and to undertake an external pilot to explore whether the components of a larger future definitive trial are achievable. _x000D_ Objectives:_x000D_ 1. Refine our autism adapted SPs to ensure they are suitable for use with autistic adults. (Stage One)._x000D_ 2. Conduct an interventional single arm feasibility trial to explore data collection tools/methods & gather information to inform the external pilot Randomised Controlled Trial (RCT) (Stage 2). _x000D_ 3. Conduct an external pilot RCT of adapted SPs + treatment as usual vs. treatment as usual (Stage 3)._x000D_ Methods: Community consultation, single arm interventional feasibility trial, external pilot RCT. _x000D_ Timelines for Delivery: 34 months - Stage One 0-6 months, Stage 2 6-10 months, Stage 3 10-31 months, analysis, write-up & dissemination 31-34 months._x000D_ Anticipated impact and dissemination: Autistic people are significantly more likely to die by self-harm and suicide than the general population. Adapted SPs have significant, scalable and translational potential to close this mortality gap. We will undertake wide dissemination of the findings including reports written in an accessible and inclusive manner for a wide audience; a feedback event; presentations at academic meetings; papers in academic journals & professional newsletters; presentations for multidisciplinary teams.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,MENTAL HEALTH HRCS22_19743,Wellcome Trust,,Adaptive decision templates in the human brain,"Interacting with the surrounding environment depends on our ability to extract meaningful patterns from incoming streams of sensory information. Learning and experience are known to facilitate this skill; yet, we know little about how the brain extracts structure and generalises this knowledge to novel settings. Here, I propose to test the brain mechanisms underlying structure learning using contrasting tasks that involve learning structure in space vs. time at different levels of complexity (simple vs. complex feature contingencies). I will use computational modelling to interrogate the processes involved in learning behaviourally-relevant structures (i.e. decision templates). I will relate this system-level insight to multimodal neuroimaging to provide converging evidence for brain mechanisms that mediate learning specialisation and generalisation. I will exploit high-field imaging to test fine-scale decision templates in the visual cortex. I will combine 7T imaging with human electrophysiology (MEG/EEG) and interventions (TMS) to test for local and larger-scale brain circuits that retune decision templates through feedback and inhibitory interactions. Finally, I will test whether these mechanisms support our ability to generalise previous experience to novel contexts and tasks. This integrated approach will advance our understanding of the brain’s capacity for adaptive and resilient behaviour with implications for promoting lifelong learning.","When immersed in a new environment (e.g. navigating a new city or being surrounded by speakers of an unknown language) we are challenged to make sense of an initially incomprehensible stream of events. At first, it seems like a befuddling cacophony that leaves us completely unprepared for what will happen next. And yet, quite rapidly, the brain finds structure and meaning in the incoming signals, helping us to predict and prepare ourselves for future actions. We have little understanding of how the brain achieves this. Here, I propose to study participants’ ability to learn different types of structure (i.e. regular patterns in clutter or sequences). Using sophisticated algorithms, we will track participants’ ability to extract structure during training. Our goal is to test how these changes in behaviour relate to underlying brain changes. We will use cutting-edge brain imaging methods, to provide complementary evidence for the brain mechanisms that support structure learning. We will test how different brain circuits: i) specialise to support learning of spatial vs. temporal structures, ii) interact to support our ability to generalise knowledge about structure to new contexts. In the longer term, harnessing the brain’s capacity for learning has potential implications for boosting lifelong training.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;NEUROLOGICAL HRCS22_10686,Biotechnology and Biological Sciences Research Council,BBSRC,Added value and resilience,"Food and nutrition security requires safe access to affordable and nutritious food supplies. We aim to enhance grain quality for human health, combat non-communicable diet-related diseases and improve the resilience of wheat production systems to biotic stresses. We will address two topics, with shared objectives across the Desiging Future Wheat BBSRC Strategic Progamme (DFW) and other Rothamsted Research, John Innes Centre, Earlham Institute, Quadram Institute Bioscience and NIAB programmes. Both exploit previous BBSRC investments in germplasm resources and the latest genomic developments, to understand and manipulate the genes and pathways defining wheat grain composition and host resistance/susceptibility to pathogens/pests. We will dissect a range of traits exploiting the germplasm and other resources developed within DFW. These traits include resistance to a range of pathogens and pests (such as rusts, Zymoseptoria, Fusarium, take-all, mildew, eyespot and aphids) and finally the quantity and quality of starch, dietary fibre and minerals in grain.",,3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE HRCS22_14635,Versus Arthritis,,Addressing Child and Adolescent Musculoskeletal Pain: the CAM-Pain Programme,"Musculoskeletal pains, such as back or knee pain, are common throughout the life course, and are a leading cause of disability worldwide. However, musculoskeletal pain research among children and adolescents is scarce. We know very little about how many children visit doctors about musculoskeletal pain, what diagnoses and treatments children get, how many children have persistent pain problems, and what can help doctors identify who will get better and who might not. Professor Kate Dunn and her team will use anonymized national medical health records to answer all of these questions. The researchers will then work with children aged 8 – 18 years, parents, and healthcare professionals to co-develop a support package for children and parents about musculoskeletal pain. They hope that age-appropriate information available as leaflets, cartoons, videos or other formats, will help children and their parents to understand pain and ways of managing it. This self-management support package will be tested and improved with the help of children and parents within a healthcare setting. This award will provide new information on primary care services for musculoskeletal pain (Versus Arthritis Pain Roadmap priority 9), produce a support kit to aid management (priority 7) and, through a life course perspective, work towards the prevention (priority 11) of musculoskeletal pain in children and adolescents (an under-represented group; priority 4). Impact: Children and adolescents with musculoskeletal pain, their families, clinicians, researchers and policymakers will all benefit from the outputs of this award. The data generated in the first part of this project on prevalence, incidence, trends, management, prognosis and prognostic factors for child and adolescent musculoskeletal pain will be of significant value for further research and policy use. The CAM-Pain (Child and Adolescent Musculoskeletal-Pain) support kit will provide much_x0002_needed information and support for an under-served group.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,MUSCULOSKELETAL HRCS22_01851,Medical Research Council,MRC,Adjunctive Ivermectin Mass Drug Administration for Malaria Elimination: A cluster randomized trial,"This trial will be the first to investigate the impact of adjunctive IVM MDA to reduce malaria transmission in a seasonal low-transmission setting. Adjunctive IVM MDA will be compared to DP-only MDA (with treatment daily for three days during the three months of peak malaria transmission (July-September)) in combination with standard programmatic interventions (long-lasting insecticidal nets (LLIN) and intermittent preventative treatment in pregnancy (IPTp)) in a cluster-randomized community-based trial. Primary outcome measures will be population-based Pf prevalence (estimated using ultra-sensitive PCR) and Anopheles gambiae survival (measured using parity). Data on MDA coverage, acceptability and feasibility of the intervention and a cost-effectiveness analysis will be included. We have established field infrastructure on the Bijagós Archipelago (including trained field entomologists and field laboratory technicians) and have detailed recent baseline data on malaria and NTD epidemiology and vector populations on the islands. This island setting provides an unparalleled opportunity to understand transmission and its interruption using a combined MDA strategy through investigating the impact of imported infections (through an expanded community-based CDSAT (case detection screen and treat) intervention in both arms), using serological markers to define transmission dynamics and estimate entomological inoculation rate (EIR) and monitoring the effect of IVM MDA on confined vector populations over time (parity, sporozoite rate, resistance to pyrethroids and IVM and population genomic diversity).",,3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;6.1 PHARMACEUTICALS,INFECTION HRCS22_17948,Diabetes UK,,Adult onset Type 1 Diabetes: Are Slow Progressors and Late Starters examples of immune regulators?,"Approximately half of type 1 diabetes is diagnosed in adults and a recent study of genetic risk suggests that 10% of adult diabetes has an autoimmune aetiology. Could these individuals represent examples of natural immune regulation? For children developing multiple islet autoantibodies, the risk of clinical diabetes is 84% by 15 years old. However, progression from islet autoantibodies to clinical disease can take decades in some individuals. If most childhood cases of autoimmunity develop diabetes by their mid-teens, where do cases of adult type 1 diabetes come from? Are these individuals “Slow Progressors” from childhood islet autoimmunity, or “Late Starters”, with autoimmunity beginning in later life? We have identified 132 “Slow Progressors” from several international studies, but these individuals are too rare to account for all cases of adult type 1 diabetes. This project aims to characterise individuals who seroconvert to islet autoimmunity over the age of 10 years. Humoral immune response, genetic risk, and CD4 T-cell and B-cell activity will be determined in these “Late Starters” and compared between Slow Progressors, controls without diabetes, and patients with diabetes. Research into the heterogeneity of type 1 diabetes could help identify therapeutic targets to slow or prevent disease.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,METABOLIC AND ENDOCRINE HRCS22_07296,Department of Health and Social Care,NIHR,"Advanced image registration for 1View – An augmented reality software platform for inter-operative guidance during Mechanical Thrombectomy (MT's) procedures - Giving Stroke victims a better chance","A stroke is a blood clot or bleed in the brain which can lead to permanent brain damage and death. It is the leading cause of disability and the second leading cause of death worldwide. Over 100,000 people have a stroke in the UK each year, and there are 1.3m stroke survivors in the UK. The number of stroke victims is projected to increase by 60% by 2035. Strokes in the UK currently incur annual costs of £26bn in treatment, rehabilitation, social and unpaid care, and loss of productivity. A common cause of stroke is from a clot that forms within an artery in the brain. Mechanical Thrombectomy (MT) is the newest and most effective treatment. MT is the removal of the blood clot by a tube or catheter, usually inserted into an artery in the groin, and guided through the body into the brain to grab the clot and remove it. However, MTs can be challenging with some lasting up to 5hrs. Despite its effectiveness, MT is currently only performed on 10% of stroke victims suitable for the treatment. This is due to the lack of hospitals that have the specialist equipment, the shortage of trained specialists and the length and difficulty of the procedure itself. The aim of Medical iSight (UK) Limited (MiS) is to develop software (1View) that simplifies and improves the safety and effectiveness of MT. This will be achieved by providing specialist surgeons with highly accurate 3D images of the intricate network of blood vessels in the brain, viewed through Extended Reality headsets (Microsoft s HoloLens), together with guidance as to the optimal route to the clot. The ambition is to shorten the length of procedure by 30%+. Approximately 1200 MTs were performed last year, therefore with 1View another 360 patients could live normal lives post stroke. The software will also allow faster training of specialist surgeons. Approximately 10,000 patients in the UK every year suffer strokes that could be treated by MT. The largest element of stroke cost is the 60% attributed to unpaid care (£15.6bn). This cost excludes the stress and mental health issues experienced by these friends and family carers. In its Long Term Plan (2019) the NHS identified stroke as a clinical priority. The aim is that over the next five years (from 2021) hospitals suitable to treat MT will be increased from the current 8 (all in London) to 30 situated nationwide, so that 90% of stroke victims will have access to Thrombectomy. MiS needs to develop 1View quickly, to coincide with this revitalisation of stroke treatment in the UK, help save lives and reduce care dependency for survivors as well as save much needed NHS funds.","A stroke is a blood clot or bleed in the brain which can lead to permanent brain damage and death. It is the leading cause of disability and the second leading cause of death worldwide. Over 100,000 people have a stroke in the UK each year, and there are 1.3m stroke survivors in the UK. The number of stroke victims is projected to increase by 60% by 2035. Strokes in the UK currently incur annual costs of £26bn in treatment, rehabilitation, social and unpaid care, and loss of productivity. A common cause of stroke is from a clot that forms within an artery in the brain. Mechanical Thrombectomy (MT) is the newest and most effective treatment. MT is the removal of the blood clot by a tube or catheter, usually inserted into an artery in the groin, and guided through the body into the brain to grab the clot and remove it. However, MTs can be challenging with some lasting up to 5hrs. Despite its effectiveness, MT is currently only performed on 10% of stroke victims suitable for the treatment. This is due to the lack of hospitals that have the specialist equipment, the shortage of trained specialists and the length and difficulty of the procedure itself. The aim of Medical iSight (UK) Limited (MiS) is to develop software (1View) that simplifies and improves the safety and effectiveness of MT. This will be achieved by providing specialist surgeons with highly accurate 3D images of the intricate network of blood vessels in the brain, viewed through Extended Reality headsets (Microsoft s HoloLens), together with guidance as to the optimal route to the clot. The ambition is to shorten the length of procedure by 30%+. Approximately 1200 MTs were performed last year, therefore with 1View another 360 patients could live normal lives post stroke. The software will also allow faster training of specialist surgeons. Approximately 10,000 patients in the UK every year suffer strokes that could be treated by MT. The largest element of stroke cost is the 60% attributed to unpaid care (£15.6bn). This cost excludes the stress and mental health issues experienced by these friends and family carers. In its Long Term Plan (2019) the NHS identified stroke as a clinical priority. The aim is that over the next five years (from 2021) hospitals suitable to treat MT will be increased from the current 8 (all in London) to 30 situated nationwide, so that 90% of stroke victims will have access to Thrombectomy. MiS needs to develop 1View quickly, to coincide with this revitalisation of stroke treatment in the UK, help save lives and reduce care dependency for survivors as well as save much needed NHS funds.",5.4 SURGERY,STROKE HRCS22_18675,Wellcome Trust,,Advanced photomanipulation microscopy at the Cambridge Advanced Imaging Centre,"The Cambridge Advanced Imaging Centre (CAIC) is a research facility in the School of Biological Sciences at the University of Cambridge. Since opening in 2013, physical scientists at CAIC have worked with biologists to bring online several new and unique microscopes which are now utlised by over 100 research labs from 16 Departments. While pushing the frontiers of imaging technology, we have identified a critical lack in the ability to perform photomanipulation experiments combined with fast imaging. These experiments include optogenetics, photoactivation, ablation or bleaching specific regions of cells or parts of cells, sometimes deep in tissues, whilst imaging in real time from millimetre to nanometre scales. Research that will benefit from this technology spans multiple departments and a diverse range of groups, including many Wellcome Trust funded researchers. We are requesting resource to develop an advanced microscope capable of a wide range of manipulation and imaging modalities. This technology will require three major components: adaptive optics for fast shaping of light; extensive range of lasers to enable exploitation of existing and emerging fluorophores and the newest generation of spinning disk confocal unit with cameras for fast and and low photon number imaging.","The Cambridge Advanced Imaging Centre (CAIC) is an imaging facility in the School of Biological Sciences at the University of Cambridge. Since it opened in 2013, physicists and computing scientists at CAIC have worked with biologists to develop new and exciting microscopes to enable the fastest and highest resolution imaging possible. Scientists working with CAIC now wish to perform experiments where light is used to perturb or modify specimens being imaged in real-time. Such experiments require exquisite accuracy in manipulation and high speed imaging to observe the effects. Researchers excited about using these tools span a wide range of departments here at Cambridge including Genetics, Zoology and Physiology, Development & Neuroscience. This application requests resource to develop an advanced microscope capable of sculpting light in 2D and 3D for the greatest flexibility in photomanipulation and imaging.",1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),GENERIC HEALTH RELEVANCE HRCS22_06356,Department of Health and Social Care,NIHR,Advancing clinical leadership in healthcare organisations to mobilise evidence into practice. A mixed methods study of clinical leadership in orthopaedic surgery,"Question How can clinical leadership be improved to enhance the use of evidence in orthopaedic surgical practice? Background Variation from best practice in orthopaedic surgery causes inequity, inequality, harm for patients, and has negative consequences for healthcare. My research demonstrates that leadership is a key mechanism through which evidence-based practice(EBP) can be encouraged and knowledge spread across organisations. A knowledge gap exists in how to improve leadership to enhance EBP. This is a barrier to mobilisation of best practice recommendations in orthopaedics. This gap will be filled to understand the optimal methods, conditions and circumstances that influence leaders to enhance EBP. Aim To enhance clinical leadership for evidence-based orthopaedic practice, in order to improve quality of elective arthroplasty care, reduce unjustified variation and therefore save money for the NHS. Objectives Perform realist synthesis to identify the variety of leadership models in surgery and to provide an explanatory analysis of the most effective leadership approaches in the context of practice Sample orthopaedic departments using a retrospective assessment of a range of arthroplasty and hospital performance outcomes to rank and categorise hospitals Undertake interviews with orthopaedic surgeons at various career stages and timepoints to explore relationships between performance, training, clinical leadership and EBP, and any potential improvements Integrate and triangulate data to develop interventions which enhance leadership strategies and training styles to encourage and enable clinicians to improve EBP Pilot empirically grounded leadership interventions to improve EBP of orthopaedic surgeons working in the NHS. Methods Year 1/WP1: Systematically search medical and business databases (Medline,ABI/INFORM,etc) to identify relevant primary research of all study designs. Use prespecified criteria to select and appraise studies using realist synthesis to define context, mechanisms and outcomes of effective leadership. Year 1-2/WP2: Conduct a database analysis of hip and knee arthroplasty 'provider quality indicators' data (risk-adjusted revision & 90-day mortality rates/ODEP implant ratings/quality of life). Clean data, then use STATA SE to conduct hierarchical (multilevel) regression models to explore relationships between outcome measures and overall hospital performance. Year 1-4/WP3: Use constructivist grounded theory to conduct semi-structured longitudinal interviews over 4-years with ~36 early career orthopaedic surgeons to explore context, beliefs and actions regarding leadership and EBP.Year 3/WP4: Conduct semi-structured cross-sectional interviews with ~5-10 national and ~18 hospital orthopaedic leaders. Analyse using constructivist grounded theory to identify similarities, differences and models of leadership practice.Year 4-5/WP5: Integrate data to construct a joint-display matrix of qualitative/quantitative/theoretical findings to inform intervention components. Follow the MRC Framework for Complex Interventions to develop interventions which enhance clinical leadership to improve EBP.Year 5/WP6: Conduct a series of communication and impact activities to share interventions through national workshops with surgeons, orthopaedic communities and hospitals to obtain feedback to co-produce outputs for wider dissemination.Impact The research will improve best practice to overcome the challenges affecting arthroplasty, including inequality in provision, increased demand for treatments, and variation in practice and spending. The fellowship will strive to improve health outcomes and enhance patient wellbeing via the provision of more standardised services across the country.","Aim To demonstrate how clinical leadership can be improved to enhance the use of evidence in orthopaedic practice. Background Evidence-based practice is the foundation of modern medicine, and clinical guidelines are produced to help clinicians use the best evidence when treating patients. However, across the NHS there are differences in how best practice is delivered. In planned NHS joint replacement surgery variation is clear. For example, in 2015, the number of primary hip replacement operations performed in England ranged from 55 to 208 operations per 100,000 people in the population. These differences can lead to unfairness and harm for patients. People suffer from a post code lottery in treatment, as patients in greater need access and receive treatment later than patients in other areas of the country. This project builds on previous research which examined the challenges of using evidence-based guidelines in orthopaedic surgery. The findings suggested that improving how evidence is used throughout the hospital was key to reduce variation. Clinical leadership was an important influencer of practice, and an area for improvement to encourage evidence-based practice in hospitals. This research aims to fill the gap in understanding about how best practice knowledge for joint replacement can be spread across hospitals by promoting and developing the leadership of evidence-based orthopaedic practice.Design and methods The following mixed methods research is planned: Literature review:To identify and understand the different types of clinical leadership which have been characterised in previous surgical research. Database study:To rank, categorise and explore the performance of hospitals according to a range of joint replacement statistics which are collected for all NHS hospitals. This will be used to select a group of nine hospitals to take part in the interview studies. Long term interview study:To interview groups of early career orthopaedic surgeons every nine months over four years to understand how they learn about leadership and the effect that their own leaders have on their evidence-based practice. Short term interview study:To interview clinical leaders in orthopaedic surgery to look for differences and areas of good leadership practice. Additional interviews will be conducted with national orthopaedic leaders to gather a wider NHS perspective on leadership and training. Data comparison and intervention development: To combine all data collected to compare hospital performance ratings with the interview findings in order to explore and explain similarities and differences in the data. Examples demonstrating the impact of leadership on practice variation will be identified. The results will be used to develop leadership interventions which aim to improve the use of evidence-based practice of orthopaedic surgeons working in the NHS. Communication plan:To work with surgeons who take part, and a wider network of clinicians, healthcare users, policymakers and project stakeholders to share and spread the research findings to a larger audience. This will include organisations responsible for medical education in orthopaedics and the training of NHS doctors. Patient and Public Involvement A community of public members who have had joint replacement surgery, arthritis or experience of orthopaedic healthcare services has contributed to planning this research and application. If awarded, its members will be invited to actively take part in the research by attending advisory group meetings, contributing to data analysis, and sharing early research findings across their public involvement networks.Dissemination In addition to the communication plan, a lay summary of the findings will be shared with participants and other NHS hospitals, charities such as Arthritis Research UK, and healthcare organisations responsible for delivering and managing NHS services and for training clinicians. Findings will also be shared through peer-reviewed publications, workshops, social media, national conferences and international collaborations.",7.3 MANAGEMENT AND DECISION MAKING,MUSCULOSKELETAL HRCS22_01738,Medical Research Council,MRC,Affordable near-patient diagnostics to distinguish infectious diseases in the Philippines (AND2ID in Ph),"Infectious diseases are a major cause of morbidity and mortality in the Philippines. Patients may present with fever and a wide range of non-specific symptoms, which are difficult to diagnose without specialist laboratory tests. Dengue is a major public health problem in the Philippines, and is endemic in all regions of the country. Leptospirosis is also endemic and may be misdiagnosed as dengue due to similarity in early clinical manifestations. Current diagnostic tests that rely on culture of pathogens or detection of raised antibody titres can take days to weeks to provide actionable results, and are too slow to guide initial patient management. In the first week of infection, nucleic acid testing (NAT) is the most reliable method to identify the causative agent, but these are expensive and usually require well-resourced laboratories. The aim of this project is to create innovative low cost diagnostics, using local resources and show whether reduction in cost of a diagnostic has an impact on the ability to target treatment (including antibiotics) and lessen the impact of febrile illness on the patient, society and the economy. The project has three steams: (1) Technological Innovation, (2) Clinical study, (3) Economic modelling and will result in - Laboratory evaluation of a new NAT reagent in UK and Philippines - Clinical trial of of the new test in Philippines with impact analysis of the clinical pathway. - Development of an affordable diagnostic NAT platform design with prototype production for trials in a rural clinical site in Philippines for dengue and leptospirosis. - Cost-effectiveness analysis and healthcare economics model of diagnostic platforms. - Impact analysis of diagnostics on patient pathway.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,INFECTION HRCS22_20248,Wellcome Trust,,AlCohol use in HumanitariAN settings: a programme of work to address alcohol and associated adversities among conflict-affected populations in UGanda and UkrainE (CHANGE),"Conflict-affected populations across the world are vulnerable to alcohol misuse and psychosocial distress. This is a direct consequence of exposure to war, violence, and ongoing stressors in their new areas of settlement such as impoverishment, unemployment, and discrimination. Alcohol may be used as strategy to cope with adversities which refugees and internally displaced people might face, and may cause or result from psychosocial distress. Despite the major health, social and economic consequences of alcohol misuse, there is a notable absence of interventions addressing alcohol use disorders (AUD) among conflict-affected populations. This proposal seeks to complement a WHO evidence-based psychological intervention for people living in adversities (“Problem Management Plus” (PM+)) with strategies to reduce alcohol misuse, thereby developing an intervention which prioritises alcohol misuse but also addresses other underlying mental health problems of conflict-affected populations. We will develop our intervention called PM+/AUD through a comprehensive formative research process, and evaluate the final intervention through two independent randomised controlled trials among South Sudanese refugees living in Uganda, and internally displaced persons in Ukraine. Our project will include social science research on implementation and scaling-up, and will produce guidelines for the treatment of AUD among conflict-affected populations.","Research has shown that internally displaced persons and refugees are vulnerable to poor mental health and alcohol misuse leading to harmful drinking patterns and alcohol use disorders. In response to the large number of people with mental health problems in resource poor areas, the World Health Organization has developed a short psychological therapy called Problem Management Plus (PM+). PM+ is a very effective psychological treatment, however, it does not address alcohol misuse, a major problem among conflict-affected populations. Our research group aims to fill this gap and will develop the first evidence-based psychological therapy addressing alcohol misuse for this population group. We will base our alcohol intervention on PM+, and will test and evaluate our new intervention among South Sudanese refugees living in Uganda, and internally displaced persons in Ukraine.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_07873,Department of Health and Social Care,NIHR,"Alpelisib with fulvestrant for HR positive, HER2 negative, PIK3CA positive breast cancer (ID3929)","Breast cancer arises from the tissues of the ducts or lobules of the breast. The cancer is said to be 'advanced' if it has spread to other parts of the body such as the bones, liver, and lungs (metastatic cancer), or if it has grown directly into nearby tissues and cannot be completely removed by surgery._x000D_ _x000D_ In 2017 in England, around 46,109 people were diagnosed with breast cancer.[1] In 2018 there were 9,640 deaths from breast cancer in England.[2] Approximately 13% of women with breast cancer have advanced disease (stage III or IV) in England when they are diagnosed.[3] The 1-year survival rate for adults diagnosed at stage IV (metastatic breast cancer) in England is 66%.[4] Around 35% of people with early or locally advanced disease will progress to metastatic breast cancer in the 10 years following diagnosis.[5]_x000D_ _x000D_ Current treatments for advanced breast cancer aim to relieve symptoms, prolong survival and maintain a good quality of life with minimal adverse events. Treatment depends on whether the cancer cells have particular receptors, the extent of the disease, and previous treatments. Most (80%) breast cancers in are hormone-receptor positive and around two-thirds are oestrogen receptor positive. Human epidermal growth factor receptor 2 (HER2) is present in about 10-15% of breast cancers.[6] Approximately 64% of women with metastatic breast cancer in the UK have hormone-receptor positive, HER2 negative disease.[7] PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutations have been found in 30% to 40% of oestrogen receptor positive, HER2-negative tumours.[8]_x000D_ _x000D_ NICE clinical guideline 81 (CG81) recommends first-line treatment with endocrine therapy for most people with advanced hormone receptor-positive breast cancer. For people whose disease is life-threatening or requires early relief of symptoms, CG81 recommends chemotherapy. The endocrine therapies used in clinical practice in postmenopausal women include aromatase inhibitors (anastrozole and letrozole), or tamoxifen, if aromatase inhibitors are not tolerated or are contraindicated. Women who arepremenopausal or perimenopausal will receive first-line treatment with tamoxifen and ovarian suppression if they have not previously received tamoxifen, while men will receive tamoxifen as a first-line endocrine treatment. NICE technology appraisals 495, 496 and 563 recommend cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors (palbociclib, ribociclib and abemaciclib respectively) in a combination with an aromatase inhibitor for treating hormone receptor positive, HER2-negative, locally advanced or metastatic breast cancer as initial endocrine based therapy in adults. Fulvestrant is not recommended for untreated locally advanced or metastatic oestrogen-receptor positive breast cancer (NICE technology appraisal 503)._x000D_ _x000D_ For people who receive first-line treatment with anastrozole or letrozole, second-line treatment may be either tamoxifen, exemestane, or everolimus and exemestane (NICE technology appraisal 421). NICE technology appraisal 687 recommends ribociclib in combination with fulvestrant as an option for hormone receptor-positive, HER2-negative, advanced breast cancer in people who have had previous endocrine therapy if exemestane plus everolimus is the most appropriate alternative to a CDK 4/6 inhibitor. NICE technology appraisals 579 and 619 recommend abemaciclib and palbociclib respectively in the same population for use within the Cancer Drugs Fund.[a] Subsequent treatment options also include chemotherapy for some people. Fulvestrant monotherapy is not recommended for use following anti-oestrogen therapy, as an alternative to aromatase inhibitors (NICE technology appraisal 239), however, it is sometimes used after exemestane and tamoxifen in people who would otherwise receive chemotherapy._x000D_ _x000D_ References_x000D_ 1 Office for National Statistics (2019) Cancer registration statistics, England, 2017. Accessed January 2020._x000D_ 2 Nomis (2020) Office for National Statistics. Mortality statistics – underlying cause, sex and age: 2018 data. Accessed January 2020._x000D_ 3 Cancer Research UK (2020) Breast cancer incidence statistics: England 2014 data. Accessed January 2020_x000D_ 4 Cancer Research UK (2020) Breast cancer survival statistics: adults diagnosed 2013-2017, followed up to 2018. Accessed January 2020._x000D_ 5 Dewis R and Gribbin J (2009) Breast cancer: diagnosis and treatment, an assessment of need. Cardiff: National Collaborating Centre for Cancer. Accessed August 2018_x000D_ 6.NIHR Evidence Briefing (2017) Alpelisib in combination with fulvestrant for advanced HR positive, HER2-negative breast cancer in men and postmenopausal women. Accessed September 2018._x000D_ 7 NICE (2017) Resource impact report: Palbociclib with an aromatase inhibitor for previously untreated, hormone receptor positive, HER2-negative, locally advanced or metastatic breast cancer (TA495). Accessed September 2018._x000D_ 8 Kratz J, Burkard M, O’Meara T, Pusztai L, Veitch Z, Bedard PL (2018) Incorporating Genomics Into the Care of Patients With Advanced Breast Cancer. American Society of Clinical Oncology. Volume 38, 56-64. Accessed September 2018._x000D_ _x000D_ a Products recommended for use in the Cancer Drugs Fund after 1 April 2016 should not be considered as comparators, or appropriately included in a treatment sequence, in subsequent relevant appraisals. NICE’s position statement.","To appraise the clinical and cost effectiveness of alpelisib within its marketing authorisation for treating advanced hormone-receptor positive, HER2-negative, PIK3CA-mutated breast cancer.",6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_05437,"Chief Scientist Office, Scotland",CSO,"Alpha 2 agonists for sedation to produce Better outcomes from critical illness (A2B Trial): A randomised, parallel-group, allocation concealed, controlled, open, phase 3 pragmatic clinical and cost- effectiveness trial with internal pilot","Many patients in intensive care (ICU) need help to breathe on a breathing machine and need pain killers and sedatives to keep them comfortable and pain free. However, keeping patients too deeply sedated can make their ICU stay longer, can cause ICU confusion (delirium), and afterwards may cause distressing memories. Ideally, we want to keep patients less sedated, but it is difficult to get the balance of sedation and comfort right. _x000D_ _x000D_ For sedation, most ICUs use a drug called 'propofol' that is good at reducing anxiety and making people sleepy, but is not a pain killer, so additional pain killers are needed. There are two other drugs used less often called 'alpha-2 agonists' that have both sedative and pain-killing actions, which may make it easier for patients to be more awake and comfortable on the ventilator. The two drugs are called clonidine and dexmedetomidine ('dex'). _x000D_ _x000D_ We want to know whether starting an alpha2-agonist drug early in ICU can help keep patients more lightly sedated but still comfortable, and whether patients spend less time on the ventilator with these drugs. We also want to know how safe they are and if they can improve important outcomes during ICU stay (like delirium, comfort, and safety) and during recovery (like bad memories, anxiety, and depression). We also want to know if they are value for money._x000D_ _x000D_ Our trial will include 1737 patients needing to be on a ventilator for at least 2 days. Patients will be allocated to one of three groups by chance. One group will receive propofol; one group will receive dexmedetomidine; and one group will receive clonidine. All patients will receive extra pain relief if needed. Nurses and doctors will alter the doses of sedation drugs to try and reduce or stop them, but always aiming to have patients lightly sedated and comfortable. We will compare if patients on dexmedetomidine or clonidine come off the ventilator quicker than those just on propofol. We will also see if there was a difference between the groups in the number of people who experienced delirium in ICU, compare how comfortable people were, and measure if participants memories of being in the ICU differed. _x000D_ _x000D_ Patients who were in the trial will be followed up for 180 days afterwards because we want to compare if there were differences in the after-effects of being ill in ICU between the groups. We will ask patients to complete questionnaires that will assess their memories of the ICU experience at 30 and 90 days after entering the trial. At 90 and 180 days, we will also ask patients to complete questionnaires so that we can detect how they feel about their quality of life or if they suffer from anxiety, depression or stress._x000D_ _x000D_ Alongside this trial, we will be looking at value for money, which is important because clonidine, dexmedetomidine, and propofol costs are quite different. Clonidine, in particular, is relatively inexpensive. We will also find out ICU nurses’ and doctors’ views on how easy or difficult it was to adjust and use the drugs. This will give us valuable practical information that can be shared with other ICUs, particularly if alpha2-agonists are found to be better and other ICUs want to start using them. _x000D_ _x000D_ We have a large experienced team of people guiding this study. They include doctors, nurses, pharmacists, health economists, statisticians, ex-patients and others who have expertise in the study methods. Together they will ensure that the trial runs smoothly, safely and finishes on time.","Design: A randomised, parallel-group, allocation concealed, controlled, open, phase 3 pragmatic clinical and cost- effectiveness trial with internal pilot. Patients will be randomised via a web-based system to one of the intervention groups or a ‘usual care’ control arm in a 1:1:1 ratio._x000D_ Setting: 40-50 Intensive Care Units (ICUs) within NHS hospitals with a patient case mix typical of UK critical care, selected from an established network with a proven track record of successful participation in clinical trials._x000D_ Population: Adult ICU patients within 48 hours of starting mechanical ventilation (MV), expected to require at least 24 hours further MV at randomisation. Exclusions include patients with primary brain injury; post-cardiac arrest; status epilepticus; and peripheral nervous system disease._x000D_ Health technologies being assessed: Alpha2-agonist drugs (either clonidine or dexmedetomidine) by continuous infusion to provide sedation after intubation and initial stabilisation, in combination with opioid drugs as required. For all patients the target will be an awake comfortable patient within the shortest safe time-scale. Weaning from MV will follow current guidelines for frequent reduction in MV support._x000D_ Control group treatment: Continuation of drugs used for intubation and stabilisation on MV (propofol and opioid) by continuous infusion. Sedation targets and weaning procedures will be the same as for the intervention groups._x000D_ Costs and Outcomes: The primary outcome is time to successful extubation (in hours post-randomisation) using an internationally agreed definition. _x000D_ Secondary outcomes in ICU comprise: delirium, time to optimum sedation, mortality, overall sedation quality, ability to communicate with staff, ICU length of stay, pre-defined drug related adverse events. Secondary outcomes during 6 month follow-up comprise: mortality, patients’ recalled experience of ICU stay, anxiety and depression, post-traumatic stress, cognitive function, health-related quality of life._x000D_ The minimum clinically important difference is a mean of 2 days MV. Analyses will compare outcomes for both alpha2-agonist groups with usual care, and also explore the relative clinical and cost effectiveness of the two interventions._x000D_ Health Economic evaluation: We will compare costs and assess within-trial and lifetime cost-effectiveness from an NHS and PSS perspective._x000D_ Process evaluation: We will explore the processes involved in delivering the intervention to identify factors and the mechanisms of their interaction likely impacting on trial outcomes._x000D_ Follow up: Up to 6 months post-randomisation._x000D_ Sample size: 579 per group (1737 in total). Allows 5% drop out or loss to follow-up prior to primary outcome. Sample size is based on simulations using UK patient data from a recent sedation trial._x000D_ Project time frames: After a 3 month set-up period, the internal pilot will run for 6 months. On reaching the pre-defined recruitment milestones, the internal pilot will run seamlessly into the main trial. We will accrue our target sample size in a further 46 months and follow up for 6 months. Analysis will require a further 6 months. Therefore the total project duration is 66 months._x000D_ Expertise: Our team includes intensivists, nurses, pharmacists, geriatrician, trialists, statisticians, a health economist, and PPI applicant. Expertise in ICU trial design/management, sedation trials, delirium, decision-making, process evaluation, ICU outcomes, and economic evaluations.",6.1 PHARMACEUTICALS,GENERIC HEALTH RELEVANCE HRCS22_06232,Department of Health and Social Care,NIHR,"An Integrated Primary Care-based Programme of Pre-pregnancy Care to Improve Pregnancy Outcomes in Women with Type 2 diabetes: A Multi-method Study of Implementation, System Adaptation and Performance","Aims_x000D_ This research will assess new ways to improve access to pre-pregnancy care for women living with Type 2 diabetes and reduce pregnancy complications and costs._x000D_ _x000D_ Background_x000D_ Women with Type 2 diabetes account for over 50% of pregnancies in those with established diabetes. Diabetes pregnancies are risky for both mother and baby - especially if unplanned. If the mother has high sugar levels or is taking medications that are unsafe in pregnancy, the baby may be harmed. The risk of a miscarriage is four times higher and the risks of birth defects and stillbirths are doubled compared to those without diabetes. Half of these women have a caesarean delivery; a quarter of the women have large babies and many babies require special care. Such outcomes are distressing for mothers and result in higher care costs. _x000D_ _x000D_ Most women with Type 2 diabetes do not know these risks. Only 10% of women with Type 2 diabetes receive pre-pregnancy care, which reduces risks by improving blood sugar levels, stopping harmful medications and giving high dose folic acid. Therefore, improving access to pre-pregnancy care for women with Type 2 diabetes is a high priority. _x000D_ _x000D_ We reviewed previous studies on pre-pregnancy care uptake and talked to women and health professionals. A key barrier is the location of pre-pregnancy care in hospitals, rather than in primary care where most women with Type 2 diabetes are seen. Pre-pregnancy care access should improve if it is delivered in a primary care setting. _x000D_ _x000D_ Intervention_x000D_ We have developed a package of primary care-based interventions to ensure that women receive regular reproductive support. The intervention includes:_x000D_ • A clear set of instructions about what care women should receive_x000D_ • Training for health professionals who usually care for women with Type 2 diabetes including clear guidance on what to do and when_x000D_ • Information for women_x000D_ • Recording information about the health of the women and baby at birth (in those who become pregnant) to see if the help made a difference_x000D_ _x000D_ Methods_x000D_ We will assess the impact of the intervention by doing an audit of pre-pregnancy care uptake and pregnancy outcomes at regular intervals in 30 General Practices in areas with high deprivation and with women from different ethnic backgrounds. Using multiple types of data collection, we will audit the uptake of pre-pregnancy care and ask women and health professionals about their experiences in the study. As the study progresses, we will identify how to improve the interventions and how best to implement the interventions in the NHS._x000D_ _x000D_ Patient and Public Involvement_x000D_ Involvement from patients and professionals is central to our work. We have a strong PPI and advisory group with women with Type 2 diabetes, health professionals and representatives from women’s and patient organisations. Our PPI group guided the design of this study and will be part of the study advisory board which will be co-led by our patient co-applicant. _x000D_ _x000D_ We will hold an event with women, health professionals and managers to share what we have learnt and identify if there are any further changes needed, and to make a plan of how our package of care could be used by others who care for women _x000D_ _x000D_ Study outputs and impact_x000D_ At the end of the study we will share our findings widely (including with patients). If successful we will make the interventions and an implementation plan available to the NHS, to improve pregnancy outcomes for this growing population.","Background_x000D_ Women with Type 2 diabetes (T2DM) account over 50% of pregnancies in women with diabetes. These are high risk pregnancies. NICE criteria for diabetes pre-pregnancy care include intensifying glucose control; using high dose folic acid; and stopping medications not safe during pregnancy. Currently less than 10% of T2DM pregnancies achieve these criteria. Effective care models are needed to improve pre-pregnancy care uptake, to reduce adverse pregnancy outcomes and NHS costs._x000D_ _x000D_ Following a review of prior interventions and work with women and health professionals, we have identified an integrated primary-care based programme of intervention to increase pre-pregnancy care uptake. These include practice staff training; electronic decision supports and prompts; care planning tools; a care-pathway; pregnancy awareness materials for women with T2DM; resources for women; and performance monitoring._x000D_ _x000D_ Objectives_x000D_ • Study the impact of intervention components and iteratively optimise their effect on care outcomes._x000D_ • Assess intervention feasibility._x000D_ • Understand organisational factors that mediate intervention implementation and performance._x000D_ • Study behavioural impacts of intervention components on health professionals and women with T2DM._x000D_ • Generate theoretical models for implementing pre-pregnancy care._x000D_ • Undertake preliminary modelling of intervention costs and benefits._x000D_ • Produce an implementation plan for enhancing pre-pregnancy care uptake._x000D_ _x000D_ Methods_x000D_ We will use a multi-method approach based on Complex Adaptive Systems theory to iteratively optimise the intervention’s impact during the study period. We will recruit 30 GP practices with more than 25 women with T2DM of reproductive age (18-45 years) from 2 South London Clinical Commissioning Groups for intervention exposure. This will provide more than 750 women to study, with an estimated incidence of 80-100 pregnancies per year. _x000D_ _x000D_ The study is organised into 4 work-packages:_x000D_ _x000D_ Work-package 1 - Optimising intervention components and preparing them for implementation._x000D_ _x000D_ Work-package 2 - Implementation and optimisation of intervention components using: a clinical audit of processes and outcomes to monitor performance; and a process evaluation considering feasibility and implementation. Performance data will be collected via audits of GP systems, hospital antenatal clinics and pregnancy outcomes. We will use repeat measures to monitor the impact on pre-pregnancy care performance at monthly intervals over 18 months. Performance measures and feasibility data will be reviewed quarterly and interventions boosted or adjusted accordingly. The target for performance is 30% of women meeting NICE pre-pregnancy care criteria. The process evaluation will assess reach, fidelity, delivery and receipt of intervention components; women and health professionals’ experiences; and mechanisms of action._x000D_ _x000D_ Work-package 3 - Findings from work-package 2 will be used to optimise the intervention components and develop an implementation plan._x000D_ _x000D_ Work-package 4 - Study data will be used to estimate intervention cost-benefits; effect uncertainty; and cost-effectiveness._x000D_ _x000D_ Timeline_x000D_ WP1-Months 0-6_x000D_ WP2-Months 7-24_x000D_ WP3-Months 25-30_x000D_ WP4-Months 3-25_x000D_ _x000D_ Impact_x000D_ The primary output from the study will be development of an integrated programme of interventions to improve pre-pregnancy care uptake and reduce the number of costly adverse pregnancy outcomes in women with T2DM.",8.1 ORGANISATION AND DELIVERY OF SERVICES,METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_23114,The British Academy,,An Investigation into Emotional Health in Outer-Space: A Pilot Study,"Astronauts experience poor mental health despite their military grade training. In this project we investigate why poor mental health persists in space-work using a novel combination of critical, social and emotion theory. We focus on emotional health because it is missing from space research as well as the cognate field of systems science which has recognised the importance of emotion. Emotional health is fundamental to mental health and cognitive function. We propose a humanistic, critical examination which investigates the organisational, social, systemic and technical conditions that constrain and enable space travellers’ emotional health. We will conduct primary research comprised of interviews with space programme participants. This project will impact current debates on emotional health in space and also draw implications for mental health in similar extreme environments by developing a group of researchers and stakeholders, publications, knowledge dissemination and outreach events.",,7.1 INDIVIDUAL CARE NEEDS,MENTAL HEALTH HRCS22_07289,Department of Health and Social Care,NIHR,An artificial intelligence disease monitoring tool for patients with brain tumours,"Background Slow growing brain tumours (such as meningiomas or low-grade gliomas) are usually managed with repeated follow up imaging. This is both expensive for the NHS and causes anxiety to the patient who lives knowing their brain tumour may grow. It is not possible to predict speed of growth or really measure this in a clinical setting. Aims and Objectives The aim of this project is to be able to tell patients if their tumour will grow and how quickly. The objective of the project is to develop an AI software prototype for efficient brain tumour monitoring and progression prediction. The prototype will re-align heterogeneous MRI scans, segment the tumour MRI scans, probabilistic tumour progression prediction with reliable uncertainty quantification, and enhanced clinical interpretation. Work plan and methods used There will be three work packages (WP) designed in this project: WP1 will address the challenges of tumour segmentation in heterogeneous clinical datasets, where transferable deep learning models are lacking due to the significant distribution shift of MRI acquired from different scanners. WP2 will focus on the prediction for tumour progression based on the segmented tumour, where the robustness of the prediction model relies on both the dynamic modelling of progression and reliable uncertainty quantification. Explainable AI methodology will also be developed in WP2 to improve clinical interpretation of the proposed AI models. WP3 will work with the NIHR Brain Injury MIC, Cambridge Enterprise and the Office for Translational Research to start commercialising this product and, with PPI involvement, inform future stages of development. Timeline for delivery: This is a one year project to develop a prototype. Anticipated impact and dissemination: By the end of this stage we will have a working prototype and a commercialisation plan that can proceed to acquiring CE marking.","How is this research important? There are many people who live with a slowly-growing brain tumours – such as meningiomas or low-grade gliomas. These tumours are frequently found when they have a brain scan for unrelated problems. Patients will have regular brain scans while living with the knowledge their tumour may grow and cause them problems. Waiting for the results of these scans causes a lot of worry for patients and their families. How will this research help? Currently we don t know which tumours may grow (so need careful watching) and which will not. We want to use artificial intelligence to work out which patients have tumours that are likely to grow. If we could even measure the volume of a tumour and see how it changes over time would be a great help. Even better would be to find those tumours that are high risk of growing before they do. What will we do? Our plan is to take the standard MRI images that we use, enhance them using methods we have already developed. We will then use artificial intelligence to outline the tumour and measure its volume. We plan to study scans that have already been performed on patients, so we know which tumours grew and which did not. This will let us train the computer to work out which patient is at high risk of their tumour growing. How are we involving patients and the public? We hope this study will be the first step of using this method to guide us treating patients. We will hold a workshop to guide our research in the future. We are especially interested asking patients and the public how they would accept decisions about their treatment that come from a computer program. We also wish to understand the best way of showing the results to patients. What we hope we will get from this research By the end of this study we will have a working method to accurately measure tumour volume and predict patients at high risk of tumour growth. We hope we can use this to work out how often and individual patient is scanned – so that those at risk are carefully watched, and those at low risk have less worry.",7.3 MANAGEMENT AND DECISION MAKING,CANCER AND NEOPLASMS HRCS22_21351,Innovate UK,IUK,An innovative cell analytics technology that can increase therapy manufacturing efficiency by 30% and therefore reduce costs for up to 400K UK patients per year,"Cytomos is a UK biotechnology SME with a core project team of Lindsay Fraser (CSO, Head of Research/Programme Manager), Gordon Sharp (CTO, Instrument Development), Tom Clayton (Lead System Architect, Firmware/Software Development) and Sevi Giakoumelou (Project and Research Manager, Research Development). The cost of cell therapy for genetic disorders and rare diseases can be staggering, ranging from £40K to well over £1M, with some treatments continuing for a lifetime. This level of expense can put care out of reach for some populations and has created an immediate and urgent need for more efficient cell and gene therapies to ensure that personalised medicine is not limited by socioeconomic factors. The UK is home to over 12% of the world's clinical trials for cell and gene therapy, and to increase efficiency, the UK's Biomanufacturing Technology Roadmap calls for a 90% reduction in manufacturing costs and an 80% reduction in time by 2030\. Existing cell therapy manufacturing processes use techniques that do not look directly at the cells during manufacture and thus return limited information. To create more effective analytics, Cytomos is developing technology that looks at the details of an individual cell, using electrical fields to create a label-free, scalable solution with automation potential that could benefit up to 400K UK patients per year, addressing healthcare inequality. Cytomos' project will increase cell therapy manufacturing efficiency by 30% and reduce patient costs by up to 20%. A streamlined manufacturing process will reduce environmental impact and further improve availability to patients.",,5.2 CELLULAR AND GENE THERAPIES,GENERIC HEALTH RELEVANCE HRCS22_02621,Medical Research Council,MRC,"An innovative, interdisciplinary platform for the dissection of Pneumocystis, a deadly fungal pathogen of humans","Pneumocystis jirovecii is an opportunistic pathogen causing life-threatening pneumonia in immunocompromised patients and it colonizes the lungs of healthy infants. The worldwide incidence of Pneumocystis pneumonia exceeds 400,000 cases per year with mortality rates of 20 - 80%. This is a serious problem for developing countries where the population of HIV-infected individuals is over 6 times that in developed countries. Challenge: The inability to culture Pneumocystis in vitro despite 3 decades of research makes this pathogen uniquely difficult to study. Diagnosis and treatment of Pneumocystis infections has relied primarily on microscopic detection in respiratory specimens. The lack of in vitro culture methods has been recognized as the major obstacle in Pneumocystis research. Recent genome sequencing has identified a potential explanation for the inability to culture Pneumocystis: it has an extremely reduced genome that lacks essential metabolic pathways. This has prevented growth independently of its mammalian host. Pneumocystis has developed unique dependencies on the host for nutrients as well as highly efficient strategies to evade the host's innate and acquired immune defences. Thus, intimate host-fungus cross-interactions are essential for growth of the pathogen, and simple supplementation of growth media to overcome predicted auxotrophic requirements has not been sufficient to solve the problem. Principal hypothesis: The metabolic issue is more subtle: the pathogen also relies on the host to maintain redox and/or energy homeostasis. Innovative approach to resolve this issue: I will develop an in silico metabolic model of Pneumocystis growth and metabolism based on new genomic data. Outcomes: This work will release a critical bottleneck in Pneumocystis research, and provide major insights into the co-evolution of Pneumocystis pathogens with their mammalian hosts.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),INFECTION HRCS22_02070,Medical Research Council,MRC,An integrated systems-level framework for deciphering multidrug resistant epilepsy.,"Epilepsy is a common, serious neurological disease - it is the 5th most disabling disorder in the WHO's rankings of disability by illness and accounts for 3% of all A&E attendances in the UK NHS. The greatest burden falls on the 20-30% with multidrug resistant epilepsy (MDRE). There has been little progress in improving seizure control in the last 50 years of antiepileptic drug development and none of the current drugs are disease modifying or curative. This absence of progress despite decades of research mandates a new scientific approach. Systems-biological analyses provide powerful techniques for elucidating molecular processes and pathways underlying complex disease. In particular, we have established proof-of-concept for the use of gene regulatory network (regulome) approaches to new drug discovery, including the discovery of novel patented drugs and targets using these approaches. The recent development of methods to assay the transcriptomes of individual cells (single cell RNA-sequencing, scRNA-seq) now offers the opportunity to rapidly accelerate this progress by incorporating cell-type and disease-context specificity to our therapeutic predictions. In this application we start from the hypothesis that connecting genomic liability for MDRE to cellular transcriptomes of the human epileptic brain will identify cell-types and pathways fundamental to the genesis MDRE. Taking an integrative approach, we first evaluate how genomic loci implicated in susceptibility to MDRE map onto specific cell-types, gene networks and functional pathways and then, using knowledge of the cell-types and pathways perturbed in MDRE, we apply a cell-type specific regulome framework to the discovery of new druggable targets for MDRE. Our project has the potential to rapidly advance the discovery of new drugs for treatment resistant epilepsy, and will provide fundamental insights into cell variability and cell-type specific gene expression in the human brain in health and disease.",,5.1 PHARMACEUTICALS,NEUROLOGICAL HRCS22_13302,Borne,,An investigation as to whether transposable element expression drives placental inflammation.,"One risk factor of preterm birth are infections, which can be partly kept at bay by innate immune responses within the placenta. Evidence suggests that it is the inflammation that is triggered by such immune responses that induces preterm birth. Moreover, infections alone cannot account for majority of preterm births. We hypothesize that inflammation could also be triggered by components of our own genome termed transposable elements (TEs). When active, TEs can trigger anti-viral responses that lead to inflammation, as shown previously in cancer and ageing. TEs are normally repressed through a number of so-called epigenetic mechanisms, which prevent those parts of the genome from becoming active. We posit that alterations in epigenetic mechanisms can lead to TE activation and inflammation in the placenta. We will test this hypothesis by using placental cells in culture and removing key components of the epigenetic machinery. We will ask whether these manipulations drive TE activation and consequently an anti-viral-like response. We will also ask if some placental samples from a large collection of pregnancies show concomitant TE activation and inflammation. These experiments aim to build the evidence base for a larger study looking into the potential role of TEs in preterm birth.","One risk factor of preterm birth are infections, which can be partly kept at bay by innate immune responses within the placenta. Evidence suggests that it is the inflammation that is triggered by such immune responses that induces preterm birth. Moreover, infections alone cannot account for majority of preterm births. We hypothesize that inflammation could also be triggered by components of our own genome termed transposable elements (TEs). When active, TEs can trigger anti-viral responses that lead to inflammation, as shown previously in cancer and ageing. TEs are normally repressed through a number of so-called epigenetic mechanisms, which prevent those parts of the genome from becoming active. We posit that alterations in epigenetic mechanisms can lead to TE activation and inflammation in the placenta. We will test this hypothesis by using placental cells in culture and removing key components of the epigenetic machinery. We will ask whether these manipulations drive TE activation and consequently an anti-viral-like response. We will also ask if some placental samples from a large collection of pregnancies show concomitant TE activation and inflammation. These experiments aim to build the evidence base for a larger study looking into the potential role of TEs in preterm birth.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_11768,Economic and Social Research Council,ESRC,An investigation into the experiences of domestic abuse helpline staff and service users during COVID-19 lockdown,"Initial reports illustrate that lockdown measures have been associated with a substantial increase in the prevalence and severity of domestic abuse (DA). However, no research has examined potential changes in the nature of DA or the impact of lockdown on victims and others in the home. This is important to aid in the development of support plans for victims of abuse going forward. Furthermore, in the context of lockdown, DA helplines (including call, text and email services) became an ever more crucial avenue for victim support, in the absence of access to previously available face-to-face or community-based support services. As previous research indicates the potential negative impacts of supporting victims of abuse on the psychological health of helpline staff, this could be exacerbated due to increased service demand during lockdown. It is therefore imperative that research seeks to determine the impact that increased pressure faced by DAHs may have had on helpline staff wellbeing to determine further support and training needs. Findings from this research will aid the UK government and support organisations in developing a plan of action to support both those living with DA and those working at helplines. It will act as a guide when making policy decisions regarding the level and nature of support needed as we navigate through ongoing lockdown threat and emerge from the pandemic. This project aims to identify the impact of COVID-19 lockdown measures on DAH service users and staff. Through three important phases, this research will address these key issues: 1) Identify potential changes in the frequency, severity, and nature of lockdown-related abuse from the perspective of DAH staff and service users. 2) Examine the impact of increased service demand on the psychological health of DAH staff. 3) Examine the impact of lockdown-related abuse on others within the home (children and pets). 4) Examine the impact of lockdown-related abuse on the psychological health of service users. 5) Identify changes required to provide ongoing support for both DAH staff and service users. Aim of Phase 1 (interviews with helpline staff): Provide novel insight into the nature of calls received during lockdown from the perspective of DAH staff regarding: lockdown-related changes in domestic abuse (DA) patterns; factors influencing changes in abuse patterns; commonalities across organisations; and impact of increased service demand on their own psychological health. Importantly, we will identify changes needed to provide ongoing support for DAH staff during and beyond COVID-19. Aim of phase 2 (anonymous online survey with service users): Provide novel insight into the experiences of, and impact of lockdown measures on, service users to determine any lockdown-related changes in abuse experiences. We will examine their perceptions of the impact of COVID restrictions on abuse-related behaviours, access to social support, factors related to others in the home (children, pets), and the impact of these circumstances on their psychological health. Aim of phase 3 (interviews with service users): expand upon their answers in the survey, providing more in-depth insight into their experiences of abuse during lockdown, and provide an indication of ongoing support requirements.","Mobility restrictions enforced by the UK Government in since the beginning of the Covid-19 pandemic in March 2020 have resulted in those vulnerable to domestic abuse being confined in isolation with their abusers, deprived of safe spaces or opportunities for help or support. Domestic abuse helplines saw a substantial increase in the service provision required to support victims of domestic abuse during the last year, in particular, during episodes of 'lockdown'. UK charity Refuge reported a 700% increase in traffic to their support website and a 120% in calls received in April 2020, compared to the previous year. While research begins to emerge on the impact of COVID-19 lockdown measures on rates of domestic abuse, no studies have yet provided insight into the experiences of those living with abusive partners or of the domestic abuse helpline staff required to provide support. Together, these two elements are crucial to understanding the true impact of COVID-19 lockdowns on domestic abuse victims, others within their home, and helpline staff. Through developing an understanding of these impacts, the UK government and support organisations can establish a plan of action to support those living with domestic abuse appropriately as we move in and out of the pandemic. This project will collect data in three phases to address this gap in knowledge. Phase 1 will involve remote interviews with 15 domestic abuse helpline staff. Interview transcripts will be analysed narratively and thematically, identifying patterns in the nature of calls received, impact of increased demand on the wellbeing of domestic abuse helpline staff, and emerging support needs. Simultaneously, data collection phase 2 will occur. Phase 2 will involve a survey distributed to 200 domestic abuse helpline service users investigating the impact of lockdown on the instance and severity of abuse, the impact of/on others in the home and mental health and wellbeing outcomes. Results will be analysed using frequency analysis, inferential statistics and content analysis. In phase 3, 15 service users will be invited to engage in a final wave of remote interviews to provide more in-depth elaboration on survey responses and elicit views regarding ongoing support requirements. We have confirmed involvement from 5 domestic abuse helplines who will facilitate participant recruitment. The three data collection phases in this research are critical to understanding the lived impact of lockdown on domestic abuse helpline staff and service users. This will be vital in the development and refinement of long-term strategies in the UK for improving support provision for victims and ensuring support staff have the tools required to provide adequate support. Findings will be disseminated to policy-makers, practice organisations, academics, and service users through a variety of outputs including policy briefing papers, online workshops, journal articles, and publicly available infographic documents. these will act as a crucial guide for policy decision-making regarding support needs emerging from the pandemic and beyond.","2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;8.1 ORGANISATION AND DELIVERY OF SERVICES",MENTAL HEALTH;INFECTION HRCS22_17148,Wellcome Trust,,An investigation of heat stress in pregnant subsistence farmers,"Climate change is one of the major threats to human life as we know it. The effects of climate change are mostly felt by the poorest in the world and in particular by women. Pregnancy is a vulnerable time for women and when pregnant women are exposed to high temperatures, this can effect pregnancy outcome and lead to premature births, low birth weight infants and stillbirths. The underlying cause that results in these poor outcomes is not known. We will study pregnant subsistence farmers in rural Gambia who are exposed to high temperatures when they work in the field. We will monitor them and their fetuses throughout their work in order to identify factors that can be linked to poor birth outcomes. The results will help to identify those women who are at risk and to understand why some women have problems whilst others do not. We will also test simple sustainable options for relieving heat strain for these women.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,REPRODUCTIVE HEALTH AND CHILDBIRTH;GENERIC HEALTH RELEVANCE HRCS22_16080,Versus Arthritis,,An investigation of multisensory body representation in fibromyalgia and testing a possible intervention,"Fibromyalgia is a debilitating condition characterised by intractable widespread musculoskeletal pain. The causes are unclear but scientific data indicates that aberrant brain processing of bodily signals is linked to a range of chronic pain conditions, and there is some evidence for altered multisensory body representations also in fibromyalgia. A number of recent papers have shown that body illusions, some of them induced via virtual reality, can reduce chronic pain, but none of these have assessed the longevity of pain relief. VR treatment may be particularly suitable for fibromyalgia, given the nature of widespread pain patients experience.To assess this we will test two multisensory full body illusions on patients with fibromyalgia. In the first two years of the project we will investigate whether these full-body illusions can cause sustained reductions in abnormal pain sensations. If we find that the pain-relieving effects of one ~ 2- 5 minute session lasts for at least a day this project would be a first step towards developing a feasible intervention for use by clinicians or by patients at home, and hence be developed as a potential treatment for patients with fibromyalgia. We will also for the first time, explore and quantify the multisensory representation of the body and surrounding space (peripersonal space; PPS) in fibromyalgia, with our final experiment (3) in the third year. We propose that the defensive function and spatial extent of the PPS may be enhanced in fibromyalgia, reflecting adaptation to threats of harm or pain. Hence, we predict that PPS may reflect the sense of vulnerability in patients with fibromyalgia, driven by the fear of threats from the physical or social environment. We will also investigate whether abnormalities in PPS are linked to worse symptoms in fibromyalgia. As a whole, this project will deepen our understanding of how brain representations of the body are altered in fibromyalgia and will test whether these brain representations could be manipulated and targeted by a potential intervention that could help alleviate pain.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL,MUSCULOSKELETAL HRCS22_20634,Wellcome Trust,,Analysis of cytomegalovirus pathogenesis in a human challenge system,"Our research has made major contributions to understanding the natural history and pathogenesis of human cytomegalovirus (HCMV) in allograft recipients. Critically, we have demonstrated that biomarkers can be applied to stratify patients most at risk of HCMV disease and thus inform clinical practice to reduce HCMV end-organ disease. This clinical approach of administration of antivirals to individuals with elevated viraemia above designated levels provides a unique opportunity to gain fundamental insight into disease processes in a human challenge model of HCMV infection. A multi-disciplinary consortium has been recruited to apply next generation DNA sequencing, molecular virology and functional immunological assays to identify virus and host cell determinants of disease susceptibility. Whole genome sequencing of virus in organ donors (live and cadaveric) and recipients will be used to track the source, replication kinetics and evolution of HCMV strains in seronegative and seropositive recipients. We will then define in vitro humoral, cell-mediated immunity and natural killer responses against HCMV that correlate with protective immunity against primary infection, reinfection and reactivation in these patient groups. This approach has the potential to provide unique insights into the natural history and pathogenesis of HCMV and identify innovative therapeutic approaches against it.","Immunosuppressive drugs that prevent the rejection of transplanted organs also reduce immune responses that normally protect patients from virus infections. With previous Wellcome Trust support, we pioneered a way of detecting the most important virus (human cytomegalovirus; HCMV) in the blood to identify those at risk of disease. Based on our research, prompt administration of antiviral drugs at the first detection of HCMV (pre-emptive therapy) was introduced into clinical practice and reduced the serious diseases caused by this virus. These patients all receive the same immunosuppressive drugs, but only some have HCMV detectable in the blood, showing that they have poor immune control of HCMV. This phenotype could be explained if there were genetic differences in some strains of the virus. We will exploit recent changes in contemporary medical practice that mean samples can now be obtained from donors. We have assembled a multidisciplinary team to assess how HCMV evolves after transplant from one person to another and relate the results to measures of how active different components of the immune system are against HCMV. As with our earlier research, we expect the results will explain the phenotypes observed and find immediate practical applications in the management of patients.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM;INFECTION HRCS22_23170,The British Academy,,"Anatomy, acoustics, and the individual: investigating inter-speaker vocal tract variation for forensic speaker comparison","Every person’s vocal tract is unique. Information about its shape is encoded in the speech signal and provides cues for speaker identification. Understanding this encoding is essential for forensic speaker comparison across different speech recordings, but currently there is no direct evidence of how vocal anatomy affects the speech signal. This project addresses the issue with three research questions: which anatomical features contribute most to systematic variation in speech; what is the range of variation of these features within the population; and to what extent are anatomically-derived differences in speech detectable by humans and automatic systems? These questions will be addressed with a novel combination of acoustic modelling and magnetic resonance image analysis. Results will impact forensic casework by highlighting discriminatory features, measuring their impact on listeners, and providing population data. Furthermore, understanding the links between anatomy and acoustics has impact for speech and language therapy and speech synthesis applications.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,EAR HRCS22_19240,Cancer Research UK,CRUK,Aneuploidy is a driver of childhood cancer and a target for novel therapies (co-funded by Children with Cancer UK),"Background. Across the spectrum of childhood cancer therapies, targeting of gene-specific aberrations is being developed to replace current conventional treatments, which although effective, are highly toxic. Non-random whole chromosome aneuploidies are frequent across all childhood cancers and although some aneuploidies and ploidy shifts are established prognostic markers, they rarely co-occur with clinically actionable gene-specific aberrations. Currently there are no therapies designed specifically to counteract the combined effects of multiple cancer driver genes located across intact gained chromosomes. Hypotheses. We hypothesise that (1) common underlying mechanisms drive the formation of aneuploidies across many childhood cancer types; (2) cells attaining the appropriate combination of chromosomal imbalances resulting from aneuploidy will achieve the required level of fitness to propagate and progress to cancer; and (3) that among the gained chromosomes, specific aneuploidy-associated genes orchestrate oncogenic pathways. Methods. Within the Newcastle University Centre for Cancer, we have longstanding expertise in the genetic study of childhood cancer, particularly in acute leukaemia and medulloblastoma. The integration of expertise in chromosome biology and cell division into this project introduces innovative functional cell biology approaches not previously applied to this cancer field. Ground-breaking models of aneuploidy-driven cancer will be created with human artificial chromosomes (HAC) expressing multiple oncogenes. Aims. Our specific aims are: (i) to identify those predisposing genetic factors leading to aneuploidy, (ii) to understand the underlying mechanisms driving the formation of the specific aneuploidies and their contribution to cancer development and (iii) to identify those genes located on the gained chromosomes, which are driving cancer, using genomic, transcriptomic and CRISPR screening data combined with HAC model based positive selection screens. Results will achieve. Understanding of predisposing factors and the mechanisms underlying aneuploidies in this project has potential to further improve risk stratification and early disease detection and may also lead to development of preventative measures. Identification of oncogenes and associated pathways will be key to the discovery of novel therapeutic targets applicable to a high proportion of aneuploidy driven cancers. The novel techniques established will also be applicable to the analysis of aneuploidy involving other chromosomes and malignancies. We are confident that, together, our team’s multi-disciplinary approach can identify novel targets and reduce toxicity related to conventional chemotherapies within these childhood cancers.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_06920,Health Education England,HEE,Anticoagulation in advanced Chronic Kidney Disease- Exploring and Guiding Current Prescribing Practice in the UK,"Patients with chronic kidney disease (CKD) are at increased risk of venous thromboembolism (VTE) and atrial fibrillation (AF). Usual treatment for VTE or AF includes anticoagulant therapy. However, they are also at an increased risk of bleeding making the decision to initiate anticoagulation complex. Unlike the general population there is a lack of evidence to support the benefits and define the risks of anticoagulation in patients with advanced CKD. A dearth of guidance or recommendations for anticoagulation in the nephrology field, from acute anticoagulation to long term prevention, is evident. Patients with CKD do not have access to educational materials to support their decision-making process with a class of medicines defined high-risk . The aim of this research is to develop a practice guideline for anticoagulation prescribing in advanced CKD to support patients and clinicians. There will be four workstreams to this study: Workstream 1- The current evidence base will be identified with a systematic review of the literature relating to anticoagulant prescribing practise in advanced CKD. Appropriate databases and grey literature will be searched. This review will form the basis of a questionnaire of UK prescribing practice which will be developed by the research team and Manchester Kidney Patient Research Advisory Group (MKPRAG) and distributed online via both renal and haematology networks. Workstream 2- Identification of the reasons for variation in anticoagulation prescribing protocols will be identified using a purposive sample of professionals from workstream 1. Telephone interviews using 'think out-loud' methodology case vignettes will allow us to investigate the cognitive processes involved in anticoagulation decision-making and factors affecting treatment choice. Identification of primary care prescribing practice and outcomes will be investigated through retrospective analysis of data from FARSITE, a pre-existing database. A preliminary search identified 1207 patients with CKD and AF where investigation of primary effectiveness (ischemic stroke) and primary safety (major bleeding) will be undertaken using a Cox proportional hazards regression with statistician input. Workstream 3- Exploration of CKD patient's views and experiences of anticoagulation will be undertaken using focus groups with a purposive sample of patients. The focus group topics will be designed with MKPRAG and include information needs of patients when making treatment decisions. Focus groups will be audio-recorded with thematic analysis of the transcripts undertaken by the research team and the MKPRAG.Workstream 4- The Delphi method will be used to develop consensus with experts on best anticoagulant practice in the UK. Statements will be prepared by the research team using findings from workstreams 1, 2 and 3. Pre-defined criteria will determine when consensus has been reached with a maximum of three rounds. Appropriate statements from the consensus will be included. The patient co-applicant, MKPRAG and selected focus group members will work to compile the patient section of the guideline using findings from workstream 3. A Renal Association (RA) guide of best practice for anticoagulation in CKD will be formed by the research team, expert reference group and MKPRAG which will be disseminated via conferences, patient networks and haematology forums.","Blood thinning medications- known as anticoagulants- are high risk medications because under-dosed patients are at risk of blood clots and over-dosed patients are at risk of bleeding, often with fatal consequences. Patients with chronic kidney disease (CKD) are at higher risk of experiencing both clotting and bleeding episodes than those with normal kidney function. There exists a thin line between the risks (bleeding and clots) and benefits (improved survival) of anticoagulation in kidney patients. This makes anticoagulant use in this group of patients more complex. There is strong evidence that patients with CKD have an increased risk of atrial fibrillation (a heart rhythm disturbance) which can lead to stroke. However these patients also have an increased risk of bleeding without any anticoagulation compared to those with normal kidney function. Unfortunately there are still large gaps in what is known about the use of blood thinning drugs in this population. This means that treatment decision is highly variable as it is challenging for health professionals when making anticoagulation decisions to decide what might be best for the patient. Discussions with patients are tough as there is not necessarily enough information available to help them to make an informed decision about their treatment options. There is a lack of knowledge regarding CKD patient perspectives on anticoagulant therapy. We don't know what CKD patients are more concerned by- clots or bleeding- this study aims to explore some of these ideas and perspectives. Patients' knowledge of their medication and medical condition can affect treatment outcomes, and this becomes more critical in patients prescribed oral anticoagulants due to the narrow window of safety of this class of medication, and the potentially devastating sequelae of both under and over treatment. This study aims to identify differences in prescribing and reasons for these differences. The study will undertake a nationwide survey of current practice and follow this up with some in-depth interviews with clinical staff. Patients' views will be sought on anticoagulation to help understand patients' concerns and ideas. All of these parts of the study will then be used to help form the basis of a guideline that will be agreed upon with a group of experts in this field and a group of patients. This document should support both clinicians and patients when making difficult decisions around anticoagulant treatment. Patients and the public will be a key part of this work with a patient co-applicant and support from the Manchester Kidney Patient Research Advisory Group. The patient co-applicant has been involved in the design of the study from the beginning and there will be regular input during the study from the Patient Research Advisory Group. As the research progresses the findings will be presented at scientific conferences with written papers for scientific journals. A summary of findings will be distributed in kidney patient magazines. In addition links available from the research teams' expertise will be used to publicise these findings as extensively as possible.",6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING,RENAL AND UROGENITAL HRCS22_03308,Medical Research Council,MRC,"Antimicrobial Stewardship in Hospitals, Resistance Selection and Transfer in a One Health Context","The "" Antimicrobial Stewardship in Hospitals, Resistance Selection and Transfer in a One Health Context"" (STRESST) project aims to determine the effects of hospital wide antimicrobial stewardship implementation on the levels of antibiotic residues and antimicrobial resistant bacteria leaving the hospital via wastewater. The point of collection of the wastewater will be on the perimeter of the hospital and will represent the boundary between the hospital environment and the wider environment. Once this data has been obtained it will be used to determine the effects on intracellular transposition and intercellular conjugation using state of the art molecular tools and fermenter systems which will enable us to model the chicken caecum. The work will be carried out in five interlinked work packages as follows; 1) hospital wide antimicrobial stewardship implementation at the Queen Elizabeth Central Hospital in Malawi, 2) hospital wastewater sampling before and during antimicrobial stewardship implementation. This will be carried out using bespoke auto-samplers leading to retrieval of the microbiology and determination of concentrations of antibiotic residues. 3) Microbiological and genomic analysis of both susceptible and resistant bacteria to reveal the levels of different antibiotics and antibiotic resistance genes present within the sampled bacteria and 4) conjugation assays to determine the effects of antibiotic residues on intercellular transfer of AMR genes and finally 5) transposition assays to determine the effects of antibiotic residues on intracellular of AMR genes between replicons in the same cell. At the end of the project we will be in a position to demonstrate the effects on AMR downstream of a hospital where robust antimicrobial stewardship interventions have been successfully implemented and highlight hospital wastewater as a site for future engineering solutions to completely remove antibiotic residues.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_17768,Cancer Research UK,CRUK,Apelin Antagonists For The Treatment Of Glioblastoma,"Background Despite invasive surgery followed by radiation and chemotherapy, Grade IV glioblastoma multiforme (GBM) remains the most lethal primary tumour of the central nervous system. To effectively treat this disease, evidence is emerging that attention needs to shift to novel approaches to remove the factors responsible for maintaining tumour growth. GBM malignancy is closely associated with vascularisation and the interaction between glioblastoma-initiating cells, that are similar to neural stem cells, and endothelial cells, where the peptide Apelin, our therapeutic target, is highly expressed. Apelin activates a g protein-coupled receptor and has been implicated as a local mediator of GBM growth (a sustaining endocrine factor). To investigate the role of Apelin in GBM, we have discovered novel antagonists, which selectively block the Apelin receptor. In orthotopic in-vivo models of glioblastoma the antagonists arrest growth of GBM tumours and significantly reduce tumour size. They are synergistic with the current therapy temozolomide and in studies have shown no toxicity. Aims To progress towards a clinical study, we will: 1. Further optimise our novel apelin antagonists for efficacy, safety and metabolic stability 2. Measure important pharmacokinetic and pharmacodynamic properties 3. Validate their therapeutic utility in a second species, where we will measure vascularisation, metabolism and image the GBM upon treatment. 4. Identify a lead compound suitable for progression to pre-clinical evaluation and first in human studies. Methods Compounds are designed (based on knowledge gained from 300 analogs previously synthesized and evaluated in-vitro/in-vivo) utilizing molecular dynamics and structure activity/property calculations. Solid phase peptide synthesis uses standard Fmoc chemistry. Pharmacology studies using human tissue samples, human/rat receptors and in-vivo models will be used to measure affinity, selectivity, receptor bias, PK/PD, safety pharmacology and haemodynamics. Nuclear spin hyperpolarization allows magnetic resonance imaging of injected hyperpolarized 13C labelled cell substrates in-vivo and the kinetics of their metabolic conversion into other cell metabolites. We will use this technique to detect tumour progression and response to treatment of GBM using patient derived xenografts implanted orthotopically in nude rats. T2-weighted MRI will be used to follow changes in tumour size, imaging with hyperpolarized [1-13C]pyruvate to evaluate changes in tumour metabolism and dynamic contrast agent-enhanced MRI changes in tumour perfusion following treatment with apelin antagonists. How the results of this research will be used This will validate a completely new approach to the treatment of GBM. Engagement with CRUK Centre for Drug Development will enable progress into first in human studies.","Background Despite invasive surgery followed by radiation and chemotherapy, Grade IV glioblastoma multiforme (GBM) remains the most lethal primary tumour of the central nervous system. To effectively treat this disease, evidence is emerging that attention needs to shift to novel approaches to remove the factors responsible for maintaining tumour growth. GBM malignancy is closely associated with vascularisation and the interaction between glioblastoma-initiating cells, that are similar to neural stem cells, and endothelial cells, where the peptide Apelin, our therapeutic target, is highly expressed. Apelin activates a g protein-coupled receptor and has been implicated as a local mediator of GBM growth (a sustaining endocrine factor). To investigate the role of Apelin in GBM, we have discovered novel antagonists, which selectively block the Apelin receptor. In orthotopic in-vivo models of glioblastoma the antagonists arrest growth of GBM tumours and significantly reduce tumour size. They are synergistic with the current therapy temozolomide and in studies have shown no toxicity. Aims To progress towards a clinical study, we will: 1. Further optimise our novel apelin antagonists for efficacy, safety and metabolic stability 2. Measure important pharmacokinetic and pharmacodynamic properties 3. Validate their therapeutic utility in a second species, where we will measure vascularisation, metabolism and image the GBM upon treatment. 4. Identify a lead compound suitable for progression to pre-clinical evaluation and first in human studies. Methods Compounds are designed (based on knowledge gained from 300 analogs previously synthesized and evaluated in-vitro/in-vivo) utilizing molecular dynamics and structure activity/property calculations. Solid phase peptide synthesis uses standard Fmoc chemistry. Pharmacology studies using human tissue samples, human/rat receptors and in-vivo models will be used to measure affinity, selectivity, receptor bias, PK/PD, safety pharmacology and haemodynamics. Nuclear spin hyperpolarization allows magnetic resonance imaging of injected hyperpolarized 13C labelled cell substrates in-vivo and the kinetics of their metabolic conversion into other cell metabolites. We will use this technique to detect tumour progression and response to treatment of GBM using patient derived xenografts implanted orthotopically in nude rats. T2-weighted MRI will be used to follow changes in tumour size, imaging with hyperpolarized [1-13C]pyruvate to evaluate changes in tumour metabolism and dynamic contrast agent-enhanced MRI changes in tumour perfusion following treatment with apelin antagonists. How the results of this research will be used This will validate a completely new approach to the treatment of GBM. Engagement with CRUK Centre for Drug Development will enable progress into first in human studies.",5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_20665,Cancer Research UK,CRUK,Application for the Cambridge Member Centre of the CRUK International Cancer Early Detection Alliance,"Background: The earlier detection of cancer would lead to a paradigm shift in cancer patients’ survival and quality of life, with significant economic benefits. The Cancer Research UK International Cancer Early Detection (ICED) Alliance will bring together world-leading UK and US centres of excellence to catalyse a step-change in progress in developing new early detection and intervention strategies. The scientific understanding of the pathogenesis of early cancer is accelerating rapidly and aligning with new technological advances, which generates a growing pipeline of biomarker tests, imaging techniques and risk algorithms that require clinical testing and validation. However, the pathway from experimental proof-of-concept to large scale clinical studies has many challenges. Aims: The Cambridge Member Centre will provide unique and world-leading resources to enable the first-in-human clinical trials for early cancer detection that will establish feasibility, acceptability and cost-effectiveness of new diagnostics and interventions. This shared infrastructure will benefit the ICED Alliance in a standardised, effective approach to accelerate adoption of the most promising approaches for the early detection of cancer towards clinical implementation. Building capacity and training in early detection research and organising networking and engagement events with other Alliance members aims to create a critical mass of research expertise in early detection in the UK. Methods: The Cambridge Member Centre will leverage existing clinical research facilities at Cambridge University Hospital to progress a pipeline of projects from the Alliance through early stage trials. It will build capacity in early detection research in the UK by recruiting clinical staff and senior researchers in clinical trials design and statistics, health economics and by providing regulatory advice. A pre-consented cohort of patients and volunteers will be recruited with longitudinal data and sample capture, for studies on early detection of cancer with the opportunity for recall for testing new technologies. The Centre will support training for the cancer research leaders of tomorrow by recruiting three PhD students and an Academic Clinical Lecturer, as well as initiating an international Summer School in Early Detection and Researcher Exchange Programmes. It will organise networking events in conjunction with the ICED Alliance to promote outreach and to foster new multi-disciplinary scientific collaborations. How the results of this research will be used: Access to clinical infrastructure resource for all ICED Alliance members will result in faster progress of novel early detection strategies through the stages of the development pipeline, improving the opportunity to initiate large-scale, randomised clinical trials.","Background: The earlier detection of cancer would lead to a paradigm shift in cancer patients’ survival and quality of life, with significant economic benefits. The Cancer Research UK International Cancer Early Detection (ICED) Alliance will bring together world-leading UK and US centres of excellence to catalyse a step-change in progress in developing new early detection and intervention strategies. The scientific understanding of the pathogenesis of early cancer is accelerating rapidly and aligning with new technological advances, which generates a growing pipeline of biomarker tests, imaging techniques and risk algorithms that require clinical testing and validation. However, the pathway from experimental proof-of-concept to large scale clinical studies has many challenges. Aims: The Cambridge Member Centre will provide unique and world-leading resources to enable the first-in-human clinical trials for early cancer detection that will establish feasibility, acceptability and cost-effectiveness of new diagnostics and interventions. This shared infrastructure will benefit the ICED Alliance in a standardised, effective approach to accelerate adoption of the most promising approaches for the early detection of cancer towards clinical implementation. Building capacity and training in early detection research and organising networking and engagement events with other Alliance members aims to create a critical mass of research expertise in early detection in the UK. Methods: The Cambridge Member Centre will leverage existing clinical research facilities at Cambridge University Hospital to progress a pipeline of projects from the Alliance through early stage trials. It will build capacity in early detection research in the UK by recruiting clinical staff and senior researchers in clinical trials design and statistics, health economics and by providing regulatory advice. A pre-consented cohort of patients and volunteers will be recruited with longitudinal data and sample capture, for studies on early detection of cancer with the opportunity for recall for testing new technologies. The Centre will support training for the cancer research leaders of tomorrow by recruiting three PhD students and an Academic Clinical Lecturer, as well as initiating an international Summer School in Early Detection and Researcher Exchange Programmes. It will organise networking events in conjunction with the ICED Alliance to promote outreach and to foster new multi-disciplinary scientific collaborations. How the results of this research will be used: Access to clinical infrastructure resource for all ICED Alliance members will result in faster progress of novel early detection strategies through the stages of the development pipeline, improving the opportunity to initiate large-scale, randomised clinical trials.",4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),CANCER AND NEOPLASMS HRCS22_08196,Medical Research Council,MRC,Are gut hormone changes why the long-limb gastric bypass is more effective than the standard-limb gastric bypass in improving type 2 diabetes mellitus? Extended Follow-up,"Obesity is the main cause of the world wide epidemic of diabetes. Weight loss, or ‘bariatric’, surgery produces major and sustained weight loss and is being increasingly used to treat obese diabetic patients. There was initial optimism that these procedures might “cure all diabetes”. However, the gold-standard operation, standard gastric bypass, effectively cures diabetes in only 4 out of 10 patients._x000D_ _x000D_ To design a safer and more successful procedure we need to understand how bariatric surgery works to improve diabetes. Hormones from the gut are released when we eat food. They control how the body uses the food it absorbs. For example they release the sugar-lowering hormone insulin, and also greatly reduce appetite, which is why one feels less hungry after eating a meal. We have discovered that the good effects of bariatric surgery, and in particular the gastric bypass, are mainly due to increased release of gut hormones, reducing patient’s appetite and improving the release of insulin._x000D_ _x000D_ In this project we will be testing a new procedure called the long-limb gastric bypass. It is designed particularly to be better at helping the diabetes in overweight patients, while being as safe as the currently available standard gastric bypass. We now want to show that this new procedure works better than the standard gastric bypass by causing an even bigger increase in the release of gut hormones and thus of insulin. We will take advantage of the fact that we already have a study, funded by the MRC, which examines the direct effect of gut hormones on appetite and insulin release. Using a newly developed technique (mass spectroscopy) we will measure the differences in gut hormone secretion between the new long-limb procedure and the standard gastric bypass far more accurately. In addition we will use a well-tested insulin sensitivity procedure (‘glucose clamp’), both to confirm and to investigate how and why the diabetes is so improved. The measurements we will be making are non-invasive and safe. The only discomfort comes from inserting a cannula to take blood samples._x000D_ _x000D_ Patients who undergo this long-limb gastric bypass procedure should have fewer complications from diabetes, use fewer medications, and have better overall health and quality of life. If we can show that the benefit of the new modified procedure is indeed due to the increased release of gut hormones and insulin, this may lead to improvements in the design of surgical procedures, will better enable us to offer the right patient the right procedure, and will form the basis for designing improved drug treatments for diabetes.","This proposal builds on the MRC grant, MR/K02115X/1, which identifies the importance of enhanced gut hormone release in mediating the weight loss and improvement in carbohydrate metabolism after standard-limb Roux-en-Y gastric bypass surgery (RYGB)._x000D_ _x000D_ The laparoscopic standard-limb RYGB procedure is the “gold-standard” bariatric surgery procedure because of its superior risk/benefit profile. Standard-limb RYGB involves the formation of a small gastric pouch, the formation of a gastric remnant and a biliopancreatic limb which are bypassed by nutrients. Type 2 diabetes mellitus (T2DM) patients after standard-limb RYGB lose ~30% of their body weight. Despite initial optimism that this operation would cause long term remission for the majority of patients with moderate diabetes, disappointingly, <40% achieve euglycaemia without diabetic medications (Brethauer SA et al, Ann Surg 2013)._x000D_ _x000D_ We, and others, have shown that standard-limb RYGB improves glucose control by increasing the immediate post-prandial release of insulin and reducing insulin resistance (Dirksen C et al, Diabetologia 2012). The faster delivery of nutrients to the distal intestine, where gut neuroendocrine L cells are located, stimulates the release of gut hormones (GLP-1, oxyntomodulin, PYY) which suppress appetite and enhance insulin release. These are thought, but not yet conclusively proven, to mediate the enhanced immediate insulin secretion after standard-limb RYGB. We know it is possible to obtain even greater improvement in glycaemic control than standard-limb RYGB by using a longer intestinal bypass, which will further enhance gut hormone release, insulin release, and sensitivity to insulin._x000D_ _x000D_ Long biliopancreatic limb, or long-limb, RYGB is thus a new procedure which produces a greater enhancement of glucose tolerance. Thus a stratified approach may be preferable for treating obese patients with T2DM with more critical impairments of glucose control (Nora et al, Obes Surg 2011). Long-limb RYGB is designed to place nutrients further down the small intestine thus avoiding the severe nutritional complications of older procedures, such as biliopancreatic diversion, whilst more strongly enhancing the release of gut hormones. In matched new cohorts of obese T2DM patients undergoing standard-limb and long-limb RYGB patients we will 1) measure the concentrations of gut hormones after both procedures using the new more specific and accurate technique of mass spectroscopy; 2) measure carbohydrate metabolism using an euglycaemic clamp procedure with isotopic markers; and 3) measure bile acid levels and the gut microbiome, parameters that may contribute to the improved outcome. The gut hormone dose response data established in the existing grant will provide a direct comparator to determine whether the increased gut hormone release expected after long-limb RYGB can explain the greater improvement of glucose tolerance. Identification or refutation of this mechanism as a major contributor to outcome is essential for rational design of these increasingly performed surgical procedures, will inform therapeutic decisions and will aid in future drug development._x000D_ _x000D_ Within a 42 month period we will provide both mechanistic and clinical evidence to support the use of long-limb RYGB, a procedure that may be more effective in improving diabetes than standard-limb RYGB, and provide the rational basis for a stratified approach in bariatric surgery.",5.4 SURGERY;6.4 SURGERY,CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE HRCS22_11573,Economic and Social Research Council,ESRC,Artificial intelligence to create equitable multi-ethnic polygenic risk scores that improve clinical care,"Overall Objective: To develop state-of-the-art artificial intelligence (AI) methods which address the ethnic inequities inherent in genomic medicine and rapidly emerging polygenic risk scores (PRSs). We will subsequently apply these approaches to demonstrate their potential for improved risk prediction and screening of atherosclerotic coronary heart disease (CHD) and hyperlipidemia. Major advances in genomics, combined with machine learning methods in large cohort resources, have enabled the prediction of disease risk through PRSs. The training data for PRSs has been heavily biased toward European ancestries, therefore PRS performance in people of non-European descent is significantly worse. Since a large proportion of individuals in Canada and the UK are of non-European descent, there is a clinical and ethical obligation to work towards the equitable incorporation of PRSs into clinical care to benefit all ancestries. This will require improved PRSs tailored to the ancestries of non-Europeans. Here we propose to develop AI methods to improve PRSs for individuals of non-European descent and begin to test their clinical utility in CHD and hyperlipidemia. This program will therefore provide innovative and cutting-edge interdisciplinary AI research, including new methodologies, software, and translatable tools for the health and biomedical sciences. In order to achieve this overall objective, we have developed specific Aims, each led by a world-class investigator in Canada or the UK. Aim 1: To develop machine learning methods and open source software packages to improve the accuracy of PRSs for CHD and hyperlipidemia for individuals of non-European ancestry (Leaders: van der Shaar, Durand, Inouye, Greenwood). Aim 2: To compare the performance of these ancestry-adapted PRSs in individuals in a diverse set of cohorts, including the East London Genes and Health Study (N = 50,000), the Canadian Longitudinal Study of Aging (N =30,000), the Kadoorie Study (N = 110,000) and the BRAVE study (N = 16,000). (Leaders: Richards, Inouye, Martin) Responsible AI Objective: This proposal is rooted in the development of medical AI tools that respect differences in ancestry and race by improving clinical care in people of non-European ancestry. Therefore, this proposal, if funded, would be an example of research motivated by the Responsible Use of AI. UK/Canada Partnership Objectives: Building on prior collaborations, this program will expand the partnerships between the scientists involved, the students they are training and our end-users, which are the health care systems we aim to improve. Embedded in our program is bilateral training opportunities between the UK and Canada, as well research visits for the investigators. Knowledge Translation Objectives: Collaborating with our four end-users (a large Canadian health care network, Genomics England and Health Data Research UK) and knowledge translation partners (Think Research), we will develop a set of tools to enable future uptake of knowledge within the electronic health record environment of our health care systems. Team: The assembled team has experience leading large-scale, international research programs to completion. We have assembled top expertise in machine learning, genomics, non-European ancestry cohorts and clinical medicine to achieve our project objectives. Training and Data Objectives: Trainees will be embedded in this program from its inception and will partake in bilateral exchanges between our research labs. As we have done previously, we will ensure equitable hiring policies, ensuring gender and minority group balance. Summary: Given the above objectives, our program is well-positioned to realize the mandates of the Canada-UK AI Initiative by implementing Responsible AI to improve the health care of our populations.","Overall Objective: To develop state-of-the-art artificial intelligence (AI) methods which address the ethnic inequities inherent in genomic medicine and rapidly emerging polygenic risk scores (PRSs). We will subsequently apply these approaches to demonstrate improved screening, diagnosis and treatment of common disease. Background: Recent breakthroughs in genomics and machine learning have generated personalized medicine tools that have the potential to improve patient care and health maintenance through PRSs. PRSs are risk predictors, which combine information across the entire genome to predict a person's risk of disease, or whether they have unfavorable disease risk factors, such as high cholesterol levels. While still evolving rapidly, these PRSs are more predictive of susceptibility to disease than many traditional disease risk factors. Since PRSs can predict risk of disease they could be helpful in screening programs, by identifying a group of individuals at such low risk of disease, that screening would be unlikely to be helpful-thereby allowing screening programs to focus on individuals at highest risk. They could also refine diagnosis, by identifying people in the population most likely to have a disease and then targeting required diagnostic testing in those at highest risk. Last, they can also improve disease treatment by identifying individuals most likely to benefit from treatment. While PRSs could help to improve clinical care, they have been largely developed in individuals of European-only ancestry. This is because the large cohorts from which PRSs have been developed consist predominantly of European-ancestry participants. Since genetic make-up varies by ancestry, the performance of these PRSs in non-European ancestries is considerably worse; it is known that not only differences in in genetic risk factors lead to attenuation of performance of PRSs, but also that changes in correlation patterns in our genomes due to distinct population histories decrease predictive accuracy even if the actual genetic risk factors remain the same. This creates several important problems for the roll-out of such tests in the Canadian and UK healthcare environments. This is because approximately 22% of Canada's population and 12% of the UK are visible minorities. Further, these populations can have increased rates of health care utilization. Therefore, use of European-only PRSs could serve to worsen existing health disparities. Canada's Chief Information Officer stated that, ""Using Artificial Intelligence in government means balancing innovation with the ethical and responsible use of emerging technologies."" Using PRSs developed to benefit only the majority group in our societies would not respect these directives and therefore our program will serve to ensure the responsible use of AI. What are our Specific Goals? 1) To develop AI methods and open source software packages to improve the accuracy of PRSs for CHD and hyperlipidemia for individuals of non-European ancestry. 2) To compare the performance of these ancestry-adapted PRSs in individuals in a diverse set of cohorts, representing multiple ancestries in the UK and Canada. The Team: Recruiting leaders across the UK and Canada, we have a depth of expertise in AI methods development, human genetics, clinical medicine, cohort development for minority groups, and statistical genetics. This gender-balanced team involves an appropriate mix of senior and junior investigators. Relevance: Success in this AI-enabled program will allow for the transfer of recent advances in genomic medicine to the citizens of Canada and the UK, regardless of ancestry. The AI methods developed will be widely applicable to other PRSs in development by other groups. As genomics takes root in regular clinician-patient interactions, our set of AI-based tools will ensure that the benefit derived from these advances will be shared by all citizens of our countries.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CARDIOVASCULAR;METABOLIC AND ENDOCRINE HRCS22_15641,Wellcome Trust,,Assessing and optimising the ‘forgiveness’ of tuberculosis drugs for non-adherence to treatment: an interdisciplinary project using pharmacodynamic modelling and wet laboratory approaches,"Tuberculosis is a bacterial disease that affects 10 million people per year globally, with an associated 1.4 million deaths (2019). Current tuberculosis treatment plans are lengthy (minimum of six months) and have extensive side effects, resulting in patients not taking drug doses.  The impact of missing doses on success of a patient’s treatment are poorly known. This is dependent on a treatment drug’s ability to ‘forgive’ (i.e. be robust to) missed doses, which is a function of how long a drug is in the body for and stays at a level where it is working. Recently, new digital technologies that monitor patients have started to give us detailed information about how precisely patients take, or miss, doses of their treatment. This allows us to investigate how these drug taking patterns are affecting patient outcomes. I aim to explore how real-world dose-taking affects the performance of rifampicin, an anti-tuberculosis drug. I will do this by adapting an existing mathematical model, including improving its ability to model how missing doses affects how the bacteria grows through laboratory experiments. I will use the model to assess the impact of missing doses on the performance of rifampicin and whether this could be improved.",,6.1 PHARMACEUTICALS,INFECTION HRCS22_03906,Medical Research Council,MRC,AstraZeneca Secondment for Clinical Pharmacology Training,"The aim of this secondment is to promote knowledge exchange between clinical teams in the NHS, academia and biopharmaceutical sector via cross-sector engagement on early phase clinical trial activity. This will be achieved through a 9-month secondment of a Specialty Training Registrar in Clinical Pharmacology and Therapeutics from Addenbrooke's Hospital into the clinical project team for a Phase 1 or Phase 2a study within the Cardiovascular, Renal and Metabolic group at AstraZeneca (AZ). The secondment will focus on a Phase 2 cirrhosis study with Zibotentan (an endothelin antagonist), in combination with dapagliflozin, in patients with portal hypertension or cirrhosis, an area of unmet clinical need. The secondment will provide training for the secondee in key components of the core syllabus for Clinical Pharmacology, a discipline where there is a national skills shortage. Direct exposure to multiple aspects of the drug development pipeline will also provide a deep understanding of industry drivers in the development of a competitive molecule. In parallel, as a study physician, the secondee will bring significant research exposure, clinical acumen and a specific interest in renal disease which will be valuable to AZ in the context of renal aspects of cardiovascular and hepatic drug development. Overall, this secondment will benefit all parties by promoting transfer of knowledge between sectors. Through direct exposure to the biopharmaceutical industry, it creates an opportunity for the secondee to enhance their professional skills, knowledge and network with opportunities for career development. By focusing on clinical pharmacology, the secondment will boost training in a specialty where there is a national skills shortage and AZ will benefit from the secondee's specialist clinical knowledge. Collectively, these factors align closely with the aims of the UKRI Innovation Scholars programme bringing a range of benefits to the wider biomedical sciences sector.",,5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT),GENERIC HEALTH RELEVANCE HRCS22_08114,Department of Health and Social Care,NIHR,Atosiban versus placebo in the treatment of late threatened preterm birth.APOSTEL VIII study,"Background Preterm birth affects over 60,000 pregnancies annually in the UK (1). It causes more than half of all perinatal deaths and is the leading cause of neonatal morbidity, mostly due to respiratory and gastro-intestinal problems, brain damage and infection (2-4). Overall it is one of the largest single contributors to the Global Burden of Disease (5). Although there are three evidence-based obstetric treatments, namely steroids to promote lung maturity (9), magnesium sulphate to reduce cerebral palsy (10) and delayed cord clamping which reduces perinatal mortality (11), there is no evidence-based prevention. Obstetricians often prescribe uterine relaxants, or tocolytics, to delay birth, but no trial has ever shown that these reduce any substantive adverse outcome compared with placebo or no treatment. The World Health Organisation has recently stated that the use of tocolytics should be re-evaluated. Aim The APOSTEL-8 trial seeks to determine whether the most promising tocolytic agent, the oxytocin antagonist atosiban, reduces adverse baby outcomes. It will test the hypothesis that in women with threatened preterm birth between 30 and 34 weeks, tocolysis with atosiban reduces a composite of poor neonatal outcome (combined morbidity and mortality) compared to placebo. Project plan The present application is for funding to recruit 600 UK participants to the ongoing international multi-centre randomised, double-blind, placebo controlled, APOSTEL-8 trial, led from the Netherlands. Population - Women, aged ≥ 18 years, with threatened preterm birth & gestational age between 30+0 and 33+6 weeks. Threatened preterm birth defined as uterine contractions plus either a cervical length of ≤ 15 mm or a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test), or ruptured membranes Intervention - Atosiban intravenously by a bolus injection of 6.75 mg/0.9 ml in one minute followed by a continuous infusion of 18 mg/hour for 3 hours followed by a continuous infusion of 6 mg/hour for 45 hours. Comparator - Placebo (intravenous normal saline) at the same rate. Outcome - The primary outcome is a composite of perinatal in-hospital mortality or bronchopulmonary dysplasia at 36 weeks postmenstrual age, periventricular leucomalacia > grade 1, intraventricular haemorrhage > grade 2, necrotizing enterocolitis ≥ stage 2, retinopathy of prematurity > grade 2 or needing laser therapy, or culture proven sepsis. Secondary outcome measures include: birth Sample size - The full trial will recruit 1,514 participants (757 in each arm). Assuming 5% drop-out/loss-to follow-up, this is sufficient to show a 40% reduction (10% placebo to 6% atosiban) in the primary endpoint (alpha 0.05; beta 0.2). In the UK part of the trial we propose to recruit in twenty large centres over three years. This amounts to 10 participants per centre per year.","Premature birth is the leading cause of baby death and disability related to pregnancy. Drugs to stop uterine contractions (tocolytics) when a woman is in premature labour are widely used. However, although they delay birth, none have ever been shown to actually improve baby outcomes. They may even do harm if the placenta is not working well, or there is uterine infection, such that the baby would be safer delivered. Previous trials have shown that the safest tocolytic for the mother is a drug called atosiban. This is licensed for use in pregnancy and already used in many hospitals. It is not a new drug. However many other hospitals don t use it, because of the fear that it might do more harm than good. This is why we need a proper research trial to test whether it really improves baby outcomes or not. The trial needs to be randomised to give an unbiased answer. This means that women in preterm labour will be asked to consent to have their treatment chosen at random, like by tossing a coin. Half will be given the drug atosiban, and half will get salt water. Neither the parents, nor the doctors caring for them, will know which treatment they get. Every mother and baby will still get all the other treatments which have been proven effective in previous trials. These include steroids to help the lungs work, magnesium to protect the baby s brain, and delayed cord clamping, which has been shown to improve survival. So no-one will miss out on an effective treatment. Parents of preterm babies, their doctors, and others involved in their care have all indicated that this trial is a priority. The preterm baby charity, BLISS, supports the trial and one of their members is a co-applicant. To give a clear answer the trial needs to be large, 1514 participants, and international. The APOSTEL-8 trial obtained funding and started in 2018 in the Netherlands, but it will take many years to complete in such a small country. The APOSTEL-8 researchers therefore sought help from UK doctors to recruit. At least twenty UK centres are keen to join, and the UK part of the trial has been approved by the UK research ethics committee, and will start soon. However, the funding from the Netherlands is insufficient to cover all the UK costs. The present grant is to fund trial organisation and follow-up for 600 participants in the UK. Separate funding is also being sought for centres from other countries.",6.1 PHARMACEUTICALS,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_01170,Medical Research Council,MRC,Auditory scene analysis in acoustic and electric hearing,"Auditory Scene Analysis (ASA) refers to the perceptual separation of competing sounds. Failure to separate sounds remains the major complaint of people with hearing loss, particularly those whose hearing has been restored by a cochlear implant (CI). We use a combination of behavioural and electrophysiological techniques to a) study the neural basis of ASA in normal-hearing listeners, b) investigate its modulation by cognitive processes such as attention and language processing, c) investigate why it is impaired by CI patients, and d) develop methods for improving ASA and other aspects of hearing by CI users.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,EAR;MENTAL HEALTH;NEUROLOGICAL HRCS22_07891,Department of Health and Social Care,NIHR,Avalglucosidase alfa for treating Pompe disease (ID3737),"Pompe disease, also known as glycogen storage disease type II or acid maltase deficiency is a rare inherited genetic disorder caused by the mutation of the GAA gene which makes an enzyme called acid alpha-glucosidase, resulting in the deficiency of this enzyme. [1] This leads to the progressive accumulation of glycogen, a sugar usually stored in multiple tissues including around the heart, skeletal muscles, respiratory muscles, vascular, gastrointestinal and nervous systems. [1],[2] The signs and symptoms of Pompe disease are directly related to the muscles affected. The respiratory, skeletal and cardiac muscles are most profoundly affected. Other symptoms include pain, mental fatigue and an impact on mental health._x000D_ _x000D_ Pompe disease is classified in two subtypes. The infantile onset which presents within the first months of life and is the most severe form of the disease with rapid progressive cardiomegaly, hepatomegaly, weakness and hypotonia. If untreated, this form is fatal by 1 to 2 years of age. The late onset presents after 1 year of age and is characterised by a progressive myopathy (with little or no cardiac involvement) which can lead to severe morbidity, respiratory failure and early mortality. [3],[4]_x000D_ _x000D_ In 2019 in the EU, Pompe disease was estimated to affect approximately 0.3 in 10,000 people. [5] In 2018 in the EU, the reported birth prevalence was 0.8 per 100,000 people for the infantile onset form and 1.75 per 100,000 for the late-onset form according to European Orphanet data. [6]_x000D_ _x000D_ Current clinical management include enzyme replacement therapy (ERT) with alglucosidase alfa which aims to replace the missing or malfunctioning enzyme. The decision to start treatment is usually based on a set of criteria including confirmed diagnosis and the patient should be symptomatic, have residual skeletal and respiratory muscle function and not have another advanced stage life-threatening condition. [8] Supportive treatment is also needed and can include physiotherapist, occupational therapist, speech therapist and dietetician.[3]_x000D_ _x000D_ References_x000D_ 1. Xu S, Lun Y, Frascella M, Garcia A, Soska R, Nair A, et al. Improved efficacy of a next-generation ERT in murine Pompe disease. JCI Insight. 2019 Mar 7;4(5). Available from:_x000D_ https://www.ncbi.nlm.nih.gov/pubmed/3084388210.1172/jci.insight.125358_x000D_ 2. Lim JA, Sun B, Puertollano R, Raben N. Therapeutic Benefit of Autophagy Modulation in Pompe Disease. Mol Ther. 2018 Jul 5;26(7):1783-96._x000D_ Available from: https://www.ncbi.nlm.nih.gov/pubmed/29804932_x000D_ 3. National Health Service - Cambridge University Hospitals. Pompe. Available from: https://www.cuh.nhs.uk/addenbrookeshospital/services/lysosomal-disorders/disorders/pompe Accessed February 2020_x000D_ 4. Van der Ploeg AT, Reuser AJ. Pompe's disease. Lancet. 2008 Oct 11;372(9646):1342-53. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18929906_x000D_ 5. European Medicines Agency (EMA). Miglustat for the treatment of glycogen storage disease type II (Pompe's disease). Available from:https://www.ema.europa.eu/en/documents/orphandesignation/eu/3/18/2129-public-summary-opinion-orphan-designationmiglustat-treatment-glycogen-storage-disease-type-ii_en.pdf_x000D_ 6. Orphanet – Prevalence and incidence of rare diseases: Bibliographic data. Available from https://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_diseases.pdf Accessed April 2020_x000D_ 7. Association for glyocogen storage disease (AGSD) UK. Available from: https://agsd.org.uk/all-about-gsd/gsd-variants/pompe-disease-gsd2/Accessed February 2020_x000D_ 8. Van der Ploeg AT, Kruijshaar ME, Toscano A, Laforet P, Angelini C, Lachmann RH, et al. European consensus for starting and stopping enzyme replacement therapy in adult patients with Pompe disease: a 10-year experience. Eur J Neurol. 2017 Jun;24(6):768-e31. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28477382",To appraise the clinical and cost effectiveness of avalglucosidase alfa within its marketing authorisation for treating Pompe disease.,6.1 PHARMACEUTICALS,CONGENITAL DISORDERS HRCS22_08686,Department of Health and Social Care,NIHR,Axicabtagene ciloleucel for treating diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma after 2 or more systemic therapies (Cancer Drugs Fund Review of TA559) [ID3980],"Lymphomas are cancers of the lymphatic system, which is a part of the immune system. Lymphomas are divided into Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphomas (NHL) are a diverse group of conditions which are categorised according to the cell type affected (B-cell or T-cell), as well as the clinical features and rate of progression of the disease._x000D_ _x000D_ The most common B-cell lymphomas are follicular lymphoma (FL) which is a slow growing, low grade form of NHL and diffuse large B-cell lymphomas (DLBCL), a fast growing (‘aggressive’), high grade form of NHL. Some FL will transform into high grade DLBCL (transformed high grade FL). Primary mediastinal large B-cell lymphoma (PMBCL) is a rare type of NHL which develops in the mediastinum. The symptoms differ depending on what organ or tissues the lymphoma is affecting. NHL often presents as painless lumps (enlarged lymph nodes) in the neck, armpit or groin but sometimes may start in other parts of the body such as the stomach or bowel (extranodal disease). People may also have loss of appetite, tiredness or night sweats._x000D_ _x000D_ There were around 11,690 new cases of non-Hodgkin lymphoma (NHL) in England in 2015 with 6,322 of these DLBCL[1] . Approximately 3% of lymphomas in the UK are PMBC2L and 10-70% of low grade lymphomas transform into a high grade form[2],[3] Most people diagnosed with DLBCL are 65 or over[4] . 5-year survival rates for DLBCL are around 65-70% for stage 1 and 2 and around 50% at stages 3 and 4 [5] . _x000D_ _x000D_ The most widely used first-line treatment for DLBCL (including transformed follicular lymphoma and primary mediastinal (thymic) large B-cell lymphoma), is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). Sometimes etoposide is added to this regimen. NICE guideline NG52 recommends salvage therapy with rituximab in combination with chemotherapy for relapsed or refractory disease followed by stem cell transplantation. If stem cell transplantation is not suitable chemotherapy or immunotherapy may be used alone. NICE technology appraisal 306 recommends pixantrone monotherapy for people who have multiply relapsed, been treated previously with rituximab and are on the third or fourth line of treatment._x000D_ _x000D_ References_x000D_ 1. Office for National Statistics. Cancer Registration Statistics, England, 2017. Office of National Statistics. Accessed January 2022._x000D_ 2. Low grade NHL. Cancer research UK. Accessed November 2017._x000D_ 3. Diffuse B-cell lymphoma. Lymphoma association. Accessed November 2017._x000D_ 4. Survival for high grade lymphomas. Cancer Research UK. Accessed November 2017.",To appraise the clinical and cost effectiveness of axicabtagene ciloleucel within its marketing authorisation for treating relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after 2 or more lines of systemic therapy.,6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_21598,Innovate UK,IUK,"BRAZZX - Developing a scalable and predictable fermentation process for Brazzein, a new, non-caloric protein sweetener","Calorie gluttony due to sugar over-consumption has led to a worldwide epidemic of obesity and diabetes. The recent statistics highlighting the high propensity of obese and diabetic individuals to require hospitalization and intensive care during COVID infection is a wakeup call for the world to tackle the sugar reduction agenda with renewed urgency. Current non-caloric sweeteners have not met the aims of previous sugar reduction efforts. This is primarily due to the unfavourable sweet taste profile of most of these sweeteners. Moreover, prolonged consumption of some artificial sweeteners has been shown to result in negative health consequences. Consumers demand a non-caloric sweetener that actually tastes like sugar and can be produced on a commercial scale. **Magellan is developing Brazzein as the next generation of non-caloric, natural sweeteners to overcome the limitations of currently available alternatives.** Brazzein is a natural protein molecule that is found in a rare West African fruit and has been consumed by humans and primates for centuries. The sweet taste quality of Brazzein is remarkably similar to tabletop sugar. Moreover, being 1500x sweeter than sugar, one would need to use very little of this sweetener in beverages and food, resulting in negligible calories being consumed. Magellan is developing a scalable and cost effective manufacturing platform for this remarkable natural molecule in order to advance the war against sugar.",,3.3 NUTRITION AND CHEMOPREVENTION,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE;STROKE HRCS22_07526,Department of Health and Social Care,NIHR,BRHUmB: Building a Research Hub for Palliative Care in Birmingham and the West Midlands,"We know that hospice and palliative care services have changed in the past few years in terms of moving care into the home setting. Since the pandemic, hospice in-patient admissions have reduced, some palliative care nursing services have been restricted, and emergency admissions of people in the last year of life are rising. Informal carers and relatives in our patient and public advisory group have raised concerns that ‘the different parts of system do not seem to talk to each other’ and this ‘makes it more difficult to manage on top of the difficulties you already have’, clearly impacting upon the experience for both the person dying and their carers /relatives. What has become clear is that to address these issues we need to coordinate palliative care research and knowledge exchange activities in a better was, not just within palliative health and social care organisations, but across them. _x000D_ _x000D_ In collaboration with our PPI advisory group (made up of people from diverse backgrounds who have experienced supportive care or cared for someone with a terminal condition), we have identified four key ways to achieve better palliative care research and knowledge exchange that will inform health and social care services and ultimately improve care experiences for people who are dying and their relatives and carers. First, we will create a central hub for research at the University of Birmingham called BRHUmB “Building Research Hub for palliative care in Birmingham and the West Midlands”. The hub will bring together a collaborative team of experts, academics, clinicians, stakeholders and patients, carers and public to share expertise in palliative care and palliative care research. In particular, by developing a programme of research to better intervene in palliative care crisis at the end of life it will become an internationally recognised research centre. _x000D_ _x000D_ Second, we recognise that while many in the field of palliative care wish to take part in research, they do not have the necessary knowledge or experience to do so. Therefore, we will instigate a programme of ‘academic buddying’ to share the ‘how to’ with research interested stakeholders and clinicians in palliative care. We will use this time to identify the priorities for palliative care research from the staff and stakeholders working in the different areas of health and social care. _x000D_ _x000D_ Third, we need to explore the priorities for research from key stakeholders (such as hospice managers, team leaders in social care, primary, community and secondary care settings) in different areas in the West Midlands. This is a diverse population in terms of ethnicity, cultural, socio-economic and health needs and so our findings will be useful to researchers and service users around the country. _x000D_ _x000D_ Finally, we will work as one group of academics, clinicians, stakeholders and PPI members to co-design a grant submission for NIHR in 2022 further strengthening the research activity in the area. We will work together to report and present our work which will lead to further research that has been identified by the clinical providers and service users themselves.","Background: The need for palliative care is predicted to increase between 25-42% by 2040 (Etkind et al. 2017) with up to 90% of all people dying in England having palliative care needs (Finucane et al. 2020).The NHS is already seeking to increase generalist and specialist palliative care support, a trend accelerated by Covid-19 but there is a lack of evidence to inform such developments. _x000D_ A particularly challenging aspect of care as death nears is the increased risk of ‘Palliative Care Crisis’; a sudden deterioration which requires an urgent response. Such crises are complex and multifactorial fuelled by the diverse needs of the dying and those close to them. In the absence of sufficient professional and family support, hospital admission (often emergency) is not unusual (Hoare et al. 2019). ‘Palliative Care Crises’ are rarely well managed by single service interventions and the emphasis needs to be on integrated systems of care. To inform such developments, evidence is needed from high quality research conducted with health and social care organisations across different service settings and clinical areas. _x000D_ We propose Building a Research Hub for palliative care in Birmingham and the West Midlands (BRHUmB); a region historically underserved in terms of NIHR funding. The West Midlands is the second most diverse region in the UK in terms of cultural, socio-economic and health and social care needs. It is home to an emergent palliative care research community of academics, clinicians and services users with complex palliative health and social care needs. We seek to better coordinate our collective efforts and build an interdisciplinary, multi-agency research partnership that brings us together to increase patient and staff benefit._x000D_ Aim: To establish BRHUmB as a recognised centre for palliative care research in Birmingham and the West Midlands and develop the region’s international reputation into researching palliative care crisis. _x000D_ Methods: (1) Create a multi-stakeholder hub to link nationally and internationally to other research collaboratives, national bodies and develop our existing patient and public involvement (PPI) group to include wider representation from health and social care; (2) Collaborate with research interested stakeholders and clinicians from across the palliative care field in health and social care through an academic buddying system and outreach activities offering support to research inactive areas and identifying stakeholder membership for BRHUmB Rapid qualitative interviews (n=50) will be conducted with health and social care staff and stakeholders to investigate the research priorities for palliative care integration and co-ordination across different settings (hospital, hospice, community); (3) Consolidate identified research priorities into key themes through a three-round eDelphi study with key stakeholders (n= 50); (4) Co-design the parameters of a programme grant for submission to NIHR with staff, key stakeholders and PPI service users and Co-Produce outputs to disseminate the priorities for palliative care research. _x000D_ Impact: Through BRHUmB we will coordinate a 12-month programme of partnership activities that will embed key research networks in the West Midlands and ensure research capacity in palliative care is able to meet the changing and diverse demands of its population. Outputs will be disseminated through peer reviewed papers, conferences and via social media including the BRHUmB website.",7.2 END OF LIFE CARE,GENERIC HEALTH RELEVANCE HRCS22_01570,Medical Research Council,MRC,BactiVac,"Bacterial infections are major contributors to the global burden of disease among humans and animals in LMICs, hampering development. They are particularly problematic where diagnostic facilities are lacking, and treatments are increasingly compromised by the scourge of antimicrobial resistance. Prevention through vaccination is an efficient and cost-effective strategy, but for many bacterial infections, no suitable vaccine is available. A network that champions bacterial vaccinology has the transforming potential to advance bacterial vaccines for LMICs, save lives and promote economic growth. Such a network does not currently exist and is needed now. The network will complement the active and strong support already present for viral outbreak pathogens through the 'UK Vaccines Network' and WHO 'R&D Roadmap' and 'CEPI' initiatives. BactiVac seeks to redress the current imbalance in global vaccinology, with its vision to facilitate end-to-end LMIC human and animal bacterial vaccine development. It will focus on the transition of promising vaccines from preclinical studies to clinical trials, where many flounder. Bringing together diverse parties with expertise in complementary aspects of bacterial vaccinology and a strong emphasis on LMIC and industry involvement, will help galvanise the community, foster new partnership and disseminate key relevant information. This will be supported by a members directory, website, newsfeeds and annual meetings. Two landscape scoping exercises will assess LMIC priority bacterial diseases for vaccine development and industrial capacities to support translation and clinical development of these vaccines. Catalyst funding will support innovative bacterial vaccine R&D projects and partnerships, and training opportunities to transfer vaccinology skills to LMICs. The network will serves as a global voice for bacterial vaccinology through advocacy initiatives targeting ministries of health and global health policy makers and funders.",,3.4 VACCINES,INFECTION HRCS22_18518,Versus Arthritis,,Balancing co-stimulatory versus co-inhibitory receptors to control the function of Tregs in autoimmunity,"CD4+FOXP3+ Regulatory T cells (Tregs) are crucial for maintaining immune tolerance. However, we still do not fully understand how they keep the immune system in check, or why they fail to function in autoimmune diseases, such as juvenile idiopathic arthritis (JIA). Although modern therapies have improved outcomes in autoimmunity, they are not always effective and often come with severe side effects. A better understanding of how Tregs are altered in autoimmunity will lead to better therapies. T cell activity is dependent on co-receptors, and targeting specific co-receptors is a successful approach for immunotherapy. In preliminary studies I found that Tregs in JIA synovial fluid (SF) express high levels of co-receptors, and that the microenvironment is rich in their ligands. Thus, I hypothesize that altered co-receptor signalling in Tregs could contribute to their dysfunction in autoimmunity. My research will focus on the co-receptor pair CD226 and TIGIT: two co-receptors highly expressed on Tregs but with poorly characterized function in these cells. I will establish signalling, receptor-receptor and receptor-ligand interaction models and study their effects on Treg function. I will generate T cell and Treg lines with specific knockout (CRISPR-Cas) and overexpression (lentiviral) of CD226 and/or TIGIT to delineate receptor-specific roles. I will assess whether Treg signalling via CD226 and TIGIT is altered in autoimmunity by utilizing SF samples from inflamed JIA joints. Additionally, I will assess the impact of mutations in the CD226/TIGIT pathway, or accessory molecules, found in primary immunodeficiencies (PIDs) presenting with autoimmune features. Lastly, I will test whether modulating the CD226/TIGIT pathway in patient-derived Tregs is a suitable therapeutic approach to restore immune-balance in autoimmunity. Determining how Treg function is controlled by co-receptors will increase our understanding of immune tolerance and may lead to new drug targets for JIA and other autoimmune conditions.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_06610,Department of Health and Social Care,NIHR,Balancing the Benefits and Risks of Radiotherapy for Lymphoma,"Background Hodgkin lymphoma (HL) is a malignancy of the lymphatic system that affects approximately 2000 people in the UK annually. More than half of patients are aged under 50 at diagnosis. The prognosis has substantially improved over recent decades. However, there is increasing recognition of the long-term side-effects of treatment, particularly radiotherapy. The optimal use of radiotherapy is therefore under scrutiny. The key to decision making in this context is reliably balancing the benefits and risks.Aims and objectivesMy aim is to develop an online decision support tool that provides individualised estimates of the benefits and risks of radiotherapy used for HL.My objectives are to collate data regarding the benefits and risks of radiotherapy for HL, and to produce a novel dose-response relationship for the risk of stroke. I will also develop methods to estimate radiation doses to organs using pre-chemotherapy PET-CT scans. Data from these studies will be used to formulate statistical models that provide individualised estimates of the benefits and risks of radiotherapy, to be presented as an online decision support tool.MethodsFirstly, I will conduct a systematic review to identify the proportional benefits of radiotherapy from clinical trials, and the relative risks of radiotherapy from epidemiological studies. Secondly, I will perform a population-based cohort study, to determine the absolute rates of HL recurrence and long-term side-effects from radiotherapy. I will investigate whether there is a relationship between the radiation dose received by the carotid arteries and the patient's subsequent risk of stroke using a case-control study nested within a cohort of HL survivors. I will determine correlations between the distribution of HL on pre-chemotherapy PET-CT scans and the radiation dose the organs subsequently receive from radiotherapy.The results of these studies will be used to formulate statistical models that give individualised estimates of the benefits and risks of radiotherapy, based on patient- and disease-specific factors. To enable these estimates to be used in the clinic I will design an online decision support tool, shaped by iterative and formalised qualitative analysis of the views of patients and clinicians.Timelines for deliveryMultiple elements of my work will run concurrently. The systematic review and population-based cohort study will be completed in year 2 to allow development of the statistical models. The studies of stroke risk and radiotherapy dose estimation methods will allow later refinement of the model in year 3. I will commence interviews as part of the decision support tool design in year 1, with surveys in year 2 and focus groups in year 3. The design of the decision support tool will be complete by the end of my fellowship, ready for evaluation in a real-world setting. Anticipated impact and disseminationI will disseminate results at conferences, in peer-reviewed journals and directly with people affected by HL at Lymphoma Action's National Conference and their Lymphoma Matters publication.Ultimately, this research will provide individualised estimates of benefits and risks to facilitate shared decision making regarding radiotherapy that is aligned with an individual's values and preferences.","Background and aimsLymphoma is a cancer of the lymphatic system, which is part of the immune system. In Hodgkin lymphoma, the white blood cells in the lymph nodes become cancerous. It is most commonly detected in the lymph nodes in the neck and chest. People of all ages are diagnosed with Hodgkin lymphoma, but it most commonly affects young adults. Around 2,100 people are diagnosed with Hodgkin lymphoma in the UK every year. The usual treatment for Hodgkin lymphoma is chemotherapy, often followed by radiotherapy. Treatment of Hodgkin lymphoma is usually very successful, and 8 in 10 people are cured. These people normally live long after their treatment has finished. There are over 21,000 survivors of Hodgkin lymphoma alive in the UK today.The radiotherapy used to cure Hodgkin lymphoma can result in serious long-term side-effects. These include heart disease, stroke and other new cancers. However, recent research has shown that if radiotherapy isn't used, the chance of cure is significantly lower.The aim of my research is to understand more about the benefits and risks of radiotherapy used to treat Hodgkin lymphoma, and how these vary between individuals. I plan to develop an online tool to give personalised estimates of the benefits and risks. This information will be used by clinicians together with people affected by Hodgkin lymphoma, to come to a shared decision about whether radiotherapy should be used as part of their treatment. Design and methodsI will collect information on the benefits and risks of radiotherapy from published research studies combined with information that has been routinely collected from all patients treated for Hodgkin lymphoma in England over the last 20 years. I will also conduct research studies myself to produce new information about the risk of stroke after radiotherapy. I will use this information to formulate statistical models that will estimate the benefits and risks of radiotherapy for an individual patient with Hodgkin lymphoma. I will develop an online decision support tool which presents these estimates in a clear, accessible way. I will canvas opinion from a range of people affected by lymphoma, and nurses and doctors treating lymphoma, to develop this tool. This will involve interviews, questionnaires and discussion groups.Patient and public involvementI have set up a Project Advisory Group of four people previously treated for Hodgkin lymphoma. I will meet with them regularly to ensure that the questions we ask are directly relevant to patients, and the work has the impact we believe it can. Our initial meeting highlighted that the decision support tool will need to be used by doctors specialising in chemotherapy as well as those specialising in radiotherapy. The group also suggested it will need to be accompanied by information about the role of radiotherapy, and practical advice for patients on how to manage the anxiety associated with the risk of long-term side-effects, what they can do to minimise the risks, and how the potential side-effects can be monitored for following treatment.Communication of results I will present my research to clinicians at national and international conferences, and will publish them in scientific journals. I will also present at the Lymphoma Action National Conference, which is mostly attended by people affected by lymphoma. The Project Advisory Group has agreed to assist with these presentations. I will communicate my findings to a wider audience of people affected by lymphoma through the Lymphoma Matters publication. The decision support tool will be available as an open-access website that will be freely available for use by clinicians before and during consultations with patients.",6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,CANCER AND NEOPLASMS HRCS22_07715,Department of Health and Social Care,NIHR,Baricitinib for treating severe alopecia areata [ID3979],"Alopecia areata is a chronic, inflammatory, autoimmune condition affecting the hair follicles leading to a sudden onset of hair loss. It does not cause scarring or permanent damage to the hair follicles. It can affect any hair-bearing skin such as the beard, eyebrows, eyelashes, body and limbs. The most common presentation of alopecia areata is small, round or oval patches of baldness on the scalp. Rarely, it may affect the whole scalp (alopecia totalis) or even the entire body and scalp (alopecia universalis). For some people, patchy hair loss may continue over a long period of time, referred to as persistent patchy or chronic alopecia areata. Other types of alopecia areata are characterised by different patterns of hair loss. For example, diffuse alopecia areata is characterised by sudden thinning of the hair all over the scalp, rather than in patches. Alopecia areata ophiasis refers to hair loss from the sides and lower back of the scalp, alopecia areata sisaipho refers to hair loss from the front of the scalp, forehead and rarely the eyebrows while alopecia barbae refers to hair loss in the beard and moustache area. [1],[2] _x000D_ _x000D_ Alopecia areata occurs when hair follicles change from the growth (anagen) phase to the loss (telogen) phase prematurely, but the exact cause is unknown. While there is a genetic predisposition, it can occur at any age, affecting both males and females equally. [2] It is suggested that there may be higher incidence in children and young adults[3] and there may also be a link to social deprivation.[4] In the UK, it is estimated that approximately 0.6% of adults have alopecia areata, [4] of which 7% to 10% may have the severe form[5] and 10 to 50% may have nail involvement. [6] Alopecia areata is also associated with higher rates of atopic and other autoimmune conditions.[4]_x000D_ _x000D_ Alopecia areata is typically diagnosed clinically based on presenting features such as patterns of hair loss, exclamation mark hairs (short, broken hairs tapering proximally) and a positive pull test.[3] Prognosis is unpredictable and varies depending on severity and duration of the condition. Spontaneous remission within one year is seen in up to 80% of people with limited patches of hair loss of less than one year duration.[1] When hair loss becomes extensive, spontaneous re-growth is rare._x000D_ _x000D_ Clinical management depends on the severity of hair loss. If there is evidence of hair regrowth or there is less than 50% hair loss, management may include advice on cosmetic options to camouflage hair loss and watchful waiting. If there is no hair regrowth and more than 50% hair loss, treatment options in primary care may include topical corticosteroids, the only treatment currently licensed for use in alopecia areata. If hair loss does not respond to treatment, people may be referred to a dermatologist. Specialist management depends on disease duration, activity, location, extent, and the person's age and individual preference. It may include local corticosteroid injections or oral corticosteroids, dithranol, contact sensitisation treatment (contact immunotherapy), psoralen plus ultraviolet A light therapy (PUVA), minoxidil, immunosuppressive drugs such as oral azathioprine, ciclosporin, methotrexate and sulfasalazine and prostaglandin analogues such as bimatoprost and latanoprost. [1],[2],[6]_x000D_ _x000D_ References_x000D_ 1. NICE (2018) Clinical Knowledge Summaries Alopecia Areata. Accessed May 2022._x000D_ 2. British Association of Dermatologists (2016) Patient Information Leaflet Alopecia Areata. Accessed May 2022._x000D_ 3. BMJ Best Practice (2021) Alopecia areata. Accessed May 2022._x000D_ 4. Harries M, Macbeth AE, Holmes S, Chiu WS, Gallardo WR, Nijher M, de Lusignan S, Tziotzios C, Messenger AG (2022) The epidemiology of alopecia areata: a population-based cohort study in UK primary care. Br J Dermatol 186(2):257-265._x000D_ 5. Madani S, Shapiro J (2000) Alopecia areata update. J Am Acad Dermatol 42(4):549-66._x000D_ 6. Alopecia UK “What is Alopecia Areata?” Accessed May 2022._x000D_ 7. Alopecia UK “Treatments for Alopecia Areata” Accessed May 2022.",To appraise the clinical and cost effectiveness of baricitinib within its marketing authorisation for treating severe alopecia areata in adults.,6.1 PHARMACEUTICALS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_15985,Barts Charity,,"Bayesian Network Decision Support in managing low back pain: Development, exploration & feasibility","Low back pain (LBP) is common costing the economy £12 billion per year. LBP is also complex to assess, rendering treatment decisions complicated, even for expert clinicians. Delayed care, undesirable pathway variation and sub-optimal outcomes are common. In pre-doctoral work, I developed a promising Intelligent Care Decision System (ICDS), incorporating artificial intelligence, to detect serious spinal pathology. I will further investigate the use of an ICDS to support assessment decision for all LBP based on evidence and clinical reasoning that is then trained by LBP treatment outcomes. In three work programmes, I would: consult patients and clinicians about optimal pathway integration of an ICDS; further develop the ICDS by encoding best practice in a leading spinal triage service; and carry out feasibility studies. Success would yield a tool suitable to improve decision making for LBP by non- experts in the range of digital solutions increasingly being used in out-patient care.",,7.3 MANAGEMENT AND DECISION MAKING,NEUROLOGICAL;MUSCULOSKELETAL HRCS22_19706,Wellcome Trust,,Beyond the pol II CTD: the expanding roles of the pol II CTD modification enzymes,"The multiple Tyr1Ser2Pro3Thr4Ser5Pro6Ser7 repeats within the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II (pol II) undergo reversible phosphorylation during transcription of human protein-coding genes1. The pattern of CTD phosphorylation is controlled by CTD kinases and phosphatases through the transcription cycle, which ensures the sequential recruitment of transcription and RNA processing factors required for correct gene expression. It is now becoming clear that the ""CTD"" modification enzymes have multiple additional targets that may play key roles in transcription, RNA processing and even translation. The exact roles that these kinases and phosphatases play in the cell is therefore not yet well understood. The aim of the proposed research is to understand the precise role(s) that CTD kinases and phosphatases play in transcription and downstream processes through modification of the CTD and other factors, what molecular mechanisms are involved and how their activities are co-ordinated. Towards this goal, I will use state of the art technology to determine the direct effect of loss of CTD kinase or CTD phosphatase activity, identify the targets of the CTD kinases and phosphatases and characterize the molecular interactions underlying the functions of CTD kinases and phosphatases.","The genes contained in our chromosomes direct the production of the components necessary for our cells to function correctly. This is known as ‘expression’ of the gene. To ensure that the appropriate products are made at the right time and in the right place, gene expression is regulated at many steps. Failure of these controls can result in disease. We are investigating the regulation of gene expression at several steps including the first step where the information contained in our genes is copied by a process known as transcription into RNA. We are also investigating what happens to the RNA during and after transcription. The molecular mechanisms controlling these process are not yet completely understood. My aim is to identify the proteins involved in these processes and determine their interactions. Defining the fundamental mechanisms regulating gene expression will help to fully understand the underlying causes of many diseases.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_02769,Medical Research Council,MRC,BioGrOA: Imaging joint biomechanics in growth and osteoarthritis,"Osteoarthritis (OA), characterised by articular cartilage loss, affects almost 9 million people in the UK and is a major financial, social and healthcare burden. Advancing our understanding of the mechanisms underpinning disease aetiology will enable us to deliver new paradigms to identify those at risk of OA, and to deliver personalised interventions to treat patients with OA. Our previous research has identified associations between growth plate cartilage phenotypes and OA development. Further, we have developed new synchrotron X-ray imaging technologies to allow determination of nanoscale mechanical strains in intact joints under loading. Here we will build on this work and for the first time will use a unique integration of approaches and resources in musculoskeletal biology, epidemiology, biomechanics and imaging to examine our hypothesis that: growth plate cartilage dynamics and joint biomechanical functionality are intimately linked. We will apply our new imaging methods to directly test our hypothesis in young, adult and aged OA-prone (STR/Ort mice) and healthy (CBA wild-type mice) intact joints. We will apply loads to murine knee joints and examine the subsequent strain patterns using our unique digital volume correlation code. We will then correlate these to hierarchical anatomical changes in joint structure, which we can now visualise at an unprecedented resolution. Next we will investigate the biomechanical and anatomical implications of microfractures in these joints. Finally, we will interrogate the MRC National Survey of health and development (NSHD) to determine if an association exists between the joint shape and life course longitudinal growth using previously derived measures of height size, tempo and velocity. This work has the potential to improve human health by identifying those at risk of osteoarthritis and by identifying associated imaging biomarkers that predict OA onset and progression.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,MUSCULOSKELETAL HRCS22_19821,Cancer Research UK,CRUK,Biochemical and Cellular Characterisation of Histone Demethylases,"Post-oligomerisation modifications to chromatin are crucially important in transcriptional and epigenetic regulation. Abnormal modification patterns of DNA methylation histones are implicated in the onset and progression of multiple cancers. Small-molecules targeting chromatin modifying enzymes for cancer treatment are in clinical use. Academic and industrial researchers are progressing N-methyl lysine histone demethylases (KDMs) as cancer targets, with orally active compounds being reported; however, progress is limited by incomplete knowledge of KDM functions. Our ongoing CRUK work is exploring JmjC-KDM biochemistry and functions involving modifications to histones/other proteins so informing on roles of epigenetics in cancer and enabling drug discovery. Aims We are carrying out comprehensive functional assignments of human JmjC KDMs /hydroxylases, at biochemical and cellular levels so enabling their roles in cancer to be placed on a sound biochemical basis. Methods WF1. Biochemical characterization and functional assignments of JmjC-KDMs. To inform on roles of epigenetics in cancer and enable drug discovery, we will continue defining biochemical and cellular functions of JmjC-KDMs, building on recent breakthroughs. Areas of focus include (i) dual functionalities of arginine and lysine demethylation/completely novel JmjC catalysed modifications, (ii) KDM mediated acetylation and methylation cross-talk. WF2. Mechanistic studies and enabling development of new generation KDM inhibitors. Due to highly conserved active sites in JmjC-KDMs, achieving inhibitor selectivity is challenging, as evidenced by lack of high-quality chemical functional probes. Using combined chemical, bio-chemical/physical approaches, we will develop new strategies targeting JmjC KDMs involving allosteric/non-catalytic domains/substrate-binding sites, activity modulation (rather than ablation), and structure-based design of non-metal chelating scaffolds. WF3. Investigating the cellular roles of JmjC-KDMs and histone methylation in tumorigenesis/cancer. We will investigate the cellular effects of methylation cross-talk/novel modifications on histones, with respect to roles of KDMs, methyltransferases and acetyltransferases, and analyse links to oncogenic expression profiles. Building on work on transcription factors we will explore cellular roles of JmjC enzymes in ‘epigenetic memory’ and drug resistance. How research results will be used Our functional assignments will be used both by the large research community working on relationships between altered mechanisms of epigenetic regulation and cancer. They will be enabling to academic and pharmaceutical scientists pursuing JmjC-KDMs as cancer targets– an understanding of function is essential both for establishing optimal screens and interpreting the results of inhibitors in cells and animal models/clinical trials. We will work with our network of collaborators to disseminate results for use in studies aimed at validating JmjC enzymes as cancer targets.","Post-oligomerisation modifications to chromatin are crucially important in transcriptional and epigenetic regulation. Abnormal modification patterns of DNA methylation histones are implicated in the onset and progression of multiple cancers. Small-molecules targeting chromatin modifying enzymes for cancer treatment are in clinical use. Academic and industrial researchers are progressing N-methyl lysine histone demethylases (KDMs) as cancer targets, with orally active compounds being reported; however, progress is limited by incomplete knowledge of KDM functions. Our ongoing CRUK work is exploring JmjC-KDM biochemistry and functions involving modifications to histones/other proteins so informing on roles of epigenetics in cancer and enabling drug discovery. Aims We are carrying out comprehensive functional assignments of human JmjC KDMs /hydroxylases, at biochemical and cellular levels so enabling their roles in cancer to be placed on a sound biochemical basis. Methods WF1. Biochemical characterization and functional assignments of JmjC-KDMs. To inform on roles of epigenetics in cancer and enable drug discovery, we will continue defining biochemical and cellular functions of JmjC-KDMs, building on recent breakthroughs. Areas of focus include (i) dual functionalities of arginine and lysine demethylation/completely novel JmjC catalysed modifications, (ii) KDM mediated acetylation and methylation cross-talk. WF2. Mechanistic studies and enabling development of new generation KDM inhibitors. Due to highly conserved active sites in JmjC-KDMs, achieving inhibitor selectivity is challenging, as evidenced by lack of high-quality chemical functional probes. Using combined chemical, bio-chemical/physical approaches, we will develop new strategies targeting JmjC KDMs involving allosteric/non-catalytic domains/substrate-binding sites, activity modulation (rather than ablation), and structure-based design of non-metal chelating scaffolds. WF3. Investigating the cellular roles of JmjC-KDMs and histone methylation in tumorigenesis/cancer. We will investigate the cellular effects of methylation cross-talk/novel modifications on histones, with respect to roles of KDMs, methyltransferases and acetyltransferases, and analyse links to oncogenic expression profiles. Building on work on transcription factors we will explore cellular roles of JmjC enzymes in ‘epigenetic memory’ and drug resistance. How research results will be used Our functional assignments will be used both by the large research community working on relationships between altered mechanisms of epigenetic regulation and cancer. They will be enabling to academic and pharmaceutical scientists pursuing JmjC-KDMs as cancer targets– an understanding of function is essential both for establishing optimal screens and interpreting the results of inhibitors in cells and animal models/clinical trials. We will work with our network of collaborators to disseminate results for use in studies aimed at validating JmjC enzymes as cancer targets.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_05507,Department of Health and Social Care,NIHR,Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection (The BATCH Trial),"WHAT IS THE PROBLEM?_x000D_ Sepsis is defined as the body’s response to infection, which can often be indistinguishable from the response to other insults like burns or surgery. On one hand, giving antibiotics promptly saves lives, but on the other hand, giving antibiotics to people who don’t need them, leads to overuse of antibiotics and antimicrobial resistance. The Department of Health recommends that antibiotics should be given for as short a course as is safe, to prevent antimicrobial resistance._x000D_ Most hospitals in the NHS use a blood test called C-Reactive Protein (CRP) to monitor response to infection, but it is not specific for bacterial infection and shows a delayed response to infection. Procalcitonin is a blood test which is specific for bacterial infection and responds more quickly than CRP, but is not routinely used in the NHS. Studies done mainly in adults shows that using procalcitonin to guide clinicians may reduce the amount of antibiotics used, reduce hospital stay, and is not associated with adverse effects such as hospital re-admission, incomplete treatment of infections, relapse or death. A recent guideline from the National Institute for Health and Care Excellence (NICE) recommends further research on procalcitonin testing to guide antibiotic use in children._x000D_ AIM OF THE RESEARCH_x000D_ In this study, we will conduct a randomised control trial which will compare current management of bacterial sepsis in children (doctors use clinical judgement and may also use CRP to decide on duration of intravenous antibiotics) with procalcitonin-guided management, where the management is identical to current practice, except that doctors have an additional procalcitonin test with advice on how to interpret the result._x000D_ WHAT WILL BE DONE AND WHO WILL BE INVOLVED?_x000D_ Around 12-15 hospitals treating children will participate in the study. Parents will be given information about the study and invited to take part. Children admitted to hospital with bacterial infection and receiving intravenous antibiotics for more than 48 hours will be randomly assigned to one of the two treatment arms. Doctors and patients will know which treatment arm they are in._x000D_ PATIENT AND PUBLIC INVOLVEMENT_x000D_ We have utilised the input of the Patient and Public Involvement (PPI) Manager for the NIHR Alder Hey Clinical Research Facility and Patient and Public Involvement and Engagement Lead for the NIHR Clinical Research Network. In developing the design of this research study we actively sought the input of Liverpool GenerationR Young Person’s Advisory Group (YPAG) coordinated by the PPI Manager. The group consists of nineteen young people aged between twelve and nineteen years old. The group has worked with several researchers exploring the topic of diagnosing and treating sepsis, and expressed a preference for a shorter course of intravenous antibiotics, if it was safe to do so. The group has discussed at length the issues associated with antimicrobial resistance and the need to educate young people and families about the misuse of antibiotics, and felt that findings from this study could be developed into educational materials for patients, families and clinicians._x000D_ HOW WILL THE RESEARCH BENEFIT PATIENTS?_x000D_ If the study shows that procalcitonin-guided management is superior to current practice, it will lead to improved safety and quality of patient care, reductions in the spread of antimicrobial resistance, and reduced time in hospital.","DESIGN: Prospective, individually randomised, two-arm RCT with internal pilot study across 12-15 centres._x000D_ PHASE 1: An internal pilot study to assess the recruitment rates, adherence to intervention, feasibility of individual randomisation, attrition rates, and the proportion of patients in whom we are able to measure both co-primary outcomes. Qualitative process evaluation which aims to improve the trial conduct in Phase 2. Defined stop-go criteria._x000D_ PHASE 2: Two-arm RCT; PCT-guided best practice AMS management versus best practice AMS management alone._x000D_ SETTING: Paediatric wards or PICUs._x000D_ TARGET POPULATION: Hospitalised children <18 years being treated with IV antibiotics for suspected or confirmed bacterial infection._x000D_ HEALTH TECHNOLOGIES BEING ASSESSED: The BATCH trial will assess the use of an additional PCT test in children hospitalised with suspected or confirmed bacterial infection, to guide antimicrobial prescribing decisions[1]. In children randomised to the intervention arm, a PCT test will be performed in the hospital laboratory at baseline and every 1-3 days whilst on on IV antibiotics. Children in the control arm will not have the PCT test performed. _x000D_ OUTCOMES AND SAMPLE SIZE: Co-primary outcomes: IV antibiotics duration (days) and a composite safety outcome comprising: unscheduled admissions/readmissions, re-instating IV antibiotic therapy and mortality. Secondary outcomes include total duration of antibiotics, time to discharge from hospital, health utility and other safety outcomes. A positive conclusion will be both a decrease in IV antibiotic duration AND non-inferiority in safety. Our observational study data showed an admission/re-admission rate of 8.8%. In critically ill patients, 3% re-instated IV antibiotic therapy, and 4% mortality was reported [2],[3]. With some overlaps considered, we estimate around 15% overall rate of our composite safety outcome. Assuming a conservative non-inferiority margin of 5%, a one-sided significance level of 0.05 and 90% power we would need 1748 participants. This will give 99% power to detect antibiotic duration decrease and 90% power to test non-inferiority in safety separately. _x000D_ STATISTICAL ANALYSIS: Our primary analysis of co-primary outcomes will a) compare the duration of days of IV antibiotics to assess the superiority of the intervention; b) compare the rate of the composite safety outcome to assess its non-inferiority in safety. Differences in total duration of antibiotics, time to discharge from hospital, health utility and other safety outcomes will also be compared as secondary outcomes._x000D_ ECONOMIC EVALUATION: A cost-effectiveness analysis will be used to assess possible efficiency gains, and results presented in terms of costs per antibiotic treatment duration and per treatment of unmet primary safety endpoints. Using a NHS perspective, relevant direct medical costs and resource use (in-hospital and community) up to Day 28 will be collected. Health-related quality of life will be measured in children 5 years and older using CHU9D. Descriptive and regression analysis will be used to identify key elements of service use and cost and to explore the potential impact of baseline participant characteristics on the costs and outcomes measures. Differences in each arm will be used for the computation of an incremental cost-effectiveness ratio (ICER), and one way sensitivity analysis performed on key model parameters.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,INFECTION HRCS22_05476,Department of Health and Social Care,NIHR,Biomarker-guided duration of antibiotic treatment in hospitalised patients with moderate or severe sepsis,"Sepsis is a common life-threatening condition that is triggered by infection. In sepsis, the body’s defence mechanisms (immune system) react excessively, resulting in widespread inflammation and swelling. If not treated quickly, sepsis can result in shutdown of vital organs which can result in death. Each year in the UK, about 200,000 people develop sepsis and up to a quarter will die. Previous research indicates that early recognition of sepsis and rapid antibiotic treatments are the most important factors for patient survival. _x000D_ _x000D_ While starting antibiotics for sepsis is crucial, the recommended duration of such treatment is uncertain. The lack of research on when to stop treatment safely can lead to an overuse of antibiotics in this condition. Antibiotic overuse is important because it promotes bacteria that are resistant to antibiotics (so-called antimicrobial resistance), which means that sepsis and, indeed, other infections would become difficult to treat in the future. Shorter courses of antibiotics for a patient with sepsis, if given appropriately, may result in less antibiotic use resulting in fewer side effects, less risk of antibiotic resistance and a reduction in costs. _x000D_ _x000D_ Chemicals circulating in the blood can indicate the level of an infection and how effective the treatment of an infection is. These chemicals are called biomarkers. The two most well researched circulating biomarkers in sepsis are C-reactive protein (CRP) and procalcitonin (PCT). They are both protein chemicals produced by the human body in response to infection and can be readily measured in blood samples using NHS laboratory equipment. Our proposed research is to determine if the duration of antibiotic treatment given to patients with sepsis can be safely reduced following the close, daily monitoring of these biomarkers. A number of studies around the world have shown high levels of both CRP and PCT in the blood of patients with sepsis and that they can fall to low levels during a spell of antibiotics. While these studies suggest that these biomarkers could help determine when to stop antibiotics in sepsis, no studies have been performed to test such strategies for NHS patients. _x000D_ _x000D_ The proposed research will offer 2760 patients with sepsis an opportunity to take part in our study. Patients with sepsis are usually very ill and many will not have the mental capacity to give their views. Under such circumstances, their next-of-kin will be consulted to determine what the patient’s wishes would be. The study seeks to test and compare 3 possible treatment protocols: standard antibiotic treatment course (usually about 7 days), or treatment courses based on the addition of either daily CRP measurement; or daily PCT measurement. Patients will be allocated to only one of the groups at random. All biomarker measurements will be performed on one extra daily blood sample as part of usual care. The results will help provide advice to the patient’s treating team about when to stop antibiotics. To assure patient safety, the final decision to stop antibiotics will rest entirely with the treating team and an independent Monitoring Committee will scrutinise study progress. The study will run over 4 years to allow enough NHS patients throughout the UK to take part so that there is confidence in the results to ensure that any recommendations regarding the duration of antibiotic treatment for sepsis is safe for patients and can be widely achieved.","Design: Multicentre randomised controlled trial with internal pilot. Progression and success criteria (from pilot to main study) will be assessed on (a) recruitment and (b) protocol adherence._x000D_ _x000D_ Setting: UK acute NHS hospitals, including adult surgical, medical and critical care services (including high dependency/intensive care units), with a track record of recruitment to sepsis trials._x000D_ _x000D_ Target population: Hospitalised adults who have been commenced on intravenous antibiotics for sepsis._x000D_ _x000D_ Inclusion criteria: (a) At least 18 years old; (b) receiving intravenous antibiotics for sepsis; (c) No more than 24 hours of systemic antibiotic treatment for present sepsis episode._x000D_ _x000D_ Main exclusions: (a) prolonged antimicrobial therapy mandated; (b) severely immunocompromised; (c) where the treating clinician does not expect survival._x000D_ _x000D_ Health Technology: 3 protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily C-reactive protein (CRP) monitoring; (c) standard care + daily procalcitonin (PCT) monitoring. Standard care will be based on routine sepsis management with associated NHS antibiotic stewardship guidance. We have developed biomarker protocols, based on daily assays, adopting the best evidence from the international guidance for CRP (1) and including NICE guidance (2) for PCT to guide antibiotic discontinuation. _x000D_ _x000D_ Measurement of costs and outcomes: Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; dose of antibiotics; length and level of critical care stay and length of hospital stay. 60-day all-cause mortality rates will also be collected. An assessment of in-trial cost effectiveness will be performed._x000D_ _x000D_ Sample size: A total sample size of 2760 would be able to detect both a mean of 1-day reduction in antibiotic duration (using a mean antibiotic duration of 7 days, a pooled standard deviation of 6 days, 90% power, a significance level of 5%, with a 5% withdrawals rate) and a non-inferiority safety margin of 5% (using a 1-sided significance level of 2.5%, 90% power and 5% withdrawal rate) assuming 28-day mortality is 15%. _x000D_ _x000D_ Project timetable: Total project 48 months (48/12). Set up (6/12), recruitment (30/12), follow up, analysis and reporting (12/12)._x000D_ _x000D_ Expertise in team: A multi-disciplinary team of international experts in sepsis, infectious diseases, microbiology, antibiotic stewardship, clinical chemistry, pharmacy, methodologists, clinicians and patient representatives with a strong track record in large-scale trials in acutely unwell patients. Our team has the support of the Intensive Care Society (UK) and NIHR CRN delivery leadership in Critical Care.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING,INFECTION HRCS22_18747,Wellcome Trust,,Biomedical Research and the Politics of the Human,"The human is a primary reference point for the aims of contemporary biomedical research along with its ethical and political groundings. This project asks: what and who constitutes that human? Despite the many assumptions we may hold about what and who is human, no study has delivered fine-grained empirical research about how scientists, policymakers and regulators approach and define the human across the levels of cells, tissues, and organisms. A series of changes—in biomedicine and in the scholarship on science and society—signal that it is a crucial time to reconsider the meaning and function of the human in the life sciences. Using an inductive qualitative approach, this project offers an ambitious plan for an empirical reorientation with the human in relation to two domains of biomedicine that constitute the project’s work packages: 1) Kidney Organoids: miniature organs grown in petri dishes. 2) Interspecies Mammalian Chimera: injecting human cells into developing pig embryos Based on a theoretical framework that draws together insights from science and technology studies, sociology and legal and political studies, the project is built on detailed empirical observation of the two research domains covering four national case studies in the UK, Spain, Germany and USA.","At the heart of biomedical research is the pursuit of human health. Humans are a primary reference point for the aims of biomedical research, along with its ethical and political groundings. Amidst rapid technological change, my project asks: what and who constitutes this human? To answer this question, I explore the development of human organoids and interspecies chimera. Through national case studies, my project uses a qualitative approach to examine how new technological advances are redrawing the limits and boundaries of the human. We hold many assumptions about what and who is human. But no study has yet investigated empirically just how such designations are made across biomedical research. My project does not set out to prove what the human is (or really should be), but rather to learn what the researchers and diverse stakeholders of contemporary bioscience take it to mean - in times of uncertainty and technological change.","8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_18295,Cancer Research UK,CRUK,Biophysical design of immunomodulatory nanotherapeutics,"The next generation of cancer treatments is expected to be dominated by immunotherapies that direct the body’s own immune system against the cancer. Many immunotherapy drugs are molecules that bind to receptor-proteins on immune cell surfaces, either activating them or inhibiting their activity. Such drugs are invariably single molecules that bind one or at most two of the cell surface-receptor proteins. However recent research has shown that such a single-molecule approach is not a good representation of what happens when immune cells are activated naturally. Rather, we now know that immune cell receptors typically assemble into domains that each contain in the range of 10-200 molecules, called nanoclusters. Nanoclusters play a key role in immune cell signalling, with clear evidence that changes in their size and makeup can control cell activation. Here we will exploit these new insights to develop a new type of immunotherapy drug candidate which is not a single molecule but an artificial nanostructure designed to mimic the natural nanoclusters. This will consist of drug-like molecules anchored to tiny flakes of the material nanographene oxide, with an additional polymer molecule for biocompatibilization. We will test this approach across several types of immune cell that are targets of current cancer therapy. The project will demonstrate that assembling immunotherapy drug molecules into these artificial nanoclusters can enhance their effectiveness in stimulating immune cells, and to identify specific drug molecules where this is most effective leading towards the first generation of these new nanotherapeutics.",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_21772,Innovate UK,IUK,"Biostrain - development of a novel medical device for measuring and stabilising core-muscle imbalances, from lumbar-patients to elite-athletes.","**Public description** Our experienced and proven team is developing Biostrain, a novel medical device to enable clinicians and users to diagnose and treat imbalances in muscle groups known to cause lower-back pain, spinal and hamstring injuries. This groundbreaking new technology will offer major advantages over current techniques, from a wide variety of users from stroke patients to back pain sufferers, to orthopaedic specialists and amateur & elite sports-people. The market-pull for this solution have been proven through rigorous customer discovery. The device is simple to use, and will be developed, manufactured & distributed within the UK in collaboration with proven medical device development partner Lucid Group. Biostrain addresses wider economic and social challenges including UK Industrial Strategy and NHS long-term priorities for preventive healthcare, focus on helping people keep active, reducing susceptibility to debilitating injury. Lower-back-pain increased 12% 1990-2010, particularly in 40-60 year-olds. Resultant production-loss cost were £10,7Bn/year with NHS costs exceeding £2Bn. The project is particularly timely with regard to the Covid pandemic, and the increase in home-working, which is expected to produce an increase in lower back complaints in the coming years, due to poor posture. Lightweight and portability allows for patient home use whilst clinicians can monitor progression via cloud upload. In sports, users will be offered a genuine advantage over any other method of hamstring exercise or monitoring. This will enable sportspeople and clinicians to significantly reduce the risk of hamstring injury, improve recovery for existing injuries, and improve performance & speed in healthy athletes.",,5.3 MEDICAL DEVICES,INJURIES AND ACCIDENTS HRCS22_16095,Wellcome Trust,,Black Health and the Humanities,"The project will establish an interdisciplinary network of researchers with the aim of investigating and bringing to light perspectives from the Black humanities on Black health and wellbeing. Led by the Centre for Black Humanities at the University of Bristol, the project will consist of a series of video conferenced online workshops, symposiums and events, which will: a) create a community of scholars whose research concerns how Black writers, intellectuals, artists, activists and theorists have creatively and critically addressed the psychological and physiological health of black people across the twentieth and twenty-first centuries; b) explore how research in Black humanities might intervene in the current racialized landscape of medicine and health; c) train and develop a new generation of ECR scholars in the theories and methods of Black studies and the medical humanities and in how they insect.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",MENTAL HEALTH;GENERIC HEALTH RELEVANCE HRCS22_02346,Medical Research Council,MRC,Blood-brain barrier dysfunction and risk of dementia following blood-stream infections,"Blood-stream infections (BSI) are common life-threatening infections, a leading cause of sepsis and have a 30-day mortality in excess of 15%. Sepsis-associated encephalopathy is characterised by acute neurological dysfunction in response to extra-cranial, systemic infection - occurring in up to 70% of patients with sepsis. Its mechanisms are poorly understood but there are data to suggest an increased risk of subsequent dementia. Research questions to be answered: 1. What is the relationship between common BSI (Escherichia coli and Staphylococcus aureus) and incident dementia? 2. What are the risk factors for development of dementia following BSI with Escherichia coli and Staphylococcus aureus and do they differ by pathogen? 3. Are Escherichia coli and Staphylococcus aureus BSI associated with increased blood-brain barrier permeability? 4. Are Escherichia coli and Staphylococcus aureus BSI associated with accelerated grey and white matter atrophy? Methods: 1. Public Health Wales Escherichia coli and Staphylococcus aureus BSI data will be linked to routinely collected GP/Hospital patient data using the Secure Anonymised Information Linkage (SAIL) databank. This will take advantage of the newly created dementia e-cohort within SAIL with ~1.2 million people and 130,000 cases of dementia. Survival analysis with a proportional hazards model will then be used to compare time to dementia diagnosis in people who have had BSI compared with those who have not, adjusting for potential confounders. 2. Patients with Escherichia coli and Staphylococcus aureus BSI (n=24) and matched controls (n=12) will be prospectively recruited to a neuroimaging study where MRI scanning (high resolution T1-weighting and dynamic contrast-enhanced) will be performed shortly after and again 12-18 months after blood-stream infection to determine: a. longitudinal rates of atrophy b. blood-brain barrier dysfunction",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION;NEUROLOGICAL HRCS22_21113,Arts and Humanities Research Council,AHRC,Building a Well Communities Research Consortium to address health disparities through Integrated Care Systems,"Community assets such as strong community networks and groups, arts and cultural activities, parks and green spaces have been shown to be associated with a wide range of health and social benefits but there are challenges for heath and care systems to realise these benefits at scale. Not everyone is able to benefit from these types of assets, with those from marginalised groups who often experience poorer health least likely to benefit. This Research Consortium will explore how local health and care systems can better interface with, develop and mobilise community assets to improve health and reduce health disparities in two contrasting geographical contexts. The Consortium will adapt a framework called 'Well Communities' to develop, plan and co-ordinate its activities. Well Communities brings together a range of asset-based community development and co-production approaches that have been tried, tested and refined across more than 40 of the most disadvantaged neighbourhoods in London and are now being transferred into the Northamptonshire context. The Consortium will build on this work to research and develop ways to scale-up, spread and embed such approaches within new Integrated Care Systems (ICSs) within and outside of London. The Well Communities Research Consortium will focus on two broad research questions: 1) What are the drivers of disparities across communities and how can new ICSs interface with, and help develop and mobilise, community assets to help tackle health disparities? 2) How can models designed to support ICSs to interface with community assets be scaled-up, embedded, sustained, and accessed to contribute to improving health outcomes, reducing disparities and creating healthier communities? This case for support is for a nine month project to build our Consortium to fully address the questions above in a subsequent three year research programme. With a focus in particular on arts-based and natural environment assets, a wide range of disciplines and cross-sectoral non-academic partners - who do not usually work together - are needed to successfully design and undertake the research programme and ensure impact. To build the consortium we will use methodologies from the Well Communities framework, including World Café, whole system workshops, participatory systems mapping and arts-based methods. These methods will facilitate engagement and co-production and develop new relationships and partnerships between people with lived experience, researchers, health and care system stakeholders, community and voluntary sector and those working in arts based and natural environment focused groups and organisations.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;7.1 INDIVIDUAL CARE NEEDS",GENERIC HEALTH RELEVANCE HRCS22_15608,Wellcome Trust,,Building a temporal proteomics map of the developing Caenorhabditis elegans nervous system,"The highly specialized neurons that make up the nervous system of an organism develop from a small number of precursor neural cells. This development is driven by a remodelling of the neuronal proteome. Many neurological disorders have been attributed to the dysregulation of genes that are important for the development of neurons. However, a systematic understanding of which genes or proteins control the complex process of neurodevelopment is so far missing. Therefore, we aim to create a precise temporal map of proteome expression changes that occur during neurodevelopment, and systematically identify proteins that regulate this process. We will take advantage of recent advances in proteomics techniques, such as metabolite and proximity labelling mass spectrometry, which enable the study of tissue-specific protein expression in model organisms. We will use this map to identify proteome changes associated with the assembly and maintenance of neural circuits in Caenorhabditis elegans, with focus on microtubule-related proteins. We expect that this will help to understand how the temporal expression of microtubule-related proteins in neurons affect the development and maintenance of neural circuits and facilitate the development of therapies against neurological disorders.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_05623,Department of Health and Social Care,NIHR,"CAMELOT - Continuous rectus sheath Analgesia in eMErgency LaparOTomy: Multi-centre, randomised sham-controlled trial of rectus sheath catheter-delivered local anaesthetic infusion compared with usual care in patients undergoing emergency bowel surgery","BACKGROUND_x000D_ In the UK around 30,000 patients a year undergo an operation called an emergency laparotomy to treat life-threatening conditions. A large vertical cut is made in the abdomen when patients are asleep under general anaesthesia. Good pain relief after surgery will help patients feel better and recover quicker. Because of the high level of pain experienced by many patients, opioid based painkillers such as morphine are often given, using patient-controlled analgesia (PCA) pumps. However, morphine can cause serious side effects such as breathing problems, nausea and vomiting, and delayed bowel movement, which can slow patient recovery. Rectus sheath catheters (RSCs) are a newer way of providing pain relief, where two thin tubes (catheters) are inserted on either side of the wound during the operation. Local anaesthetic is injected slowly into the catheters to numb the nerves and reduce pain for about three days. Small studies suggest that RSCs may provide effective pain relief, reduce the use of morphine, and help patient recovery. Potential disadvantages are that RSCs take time to insert and are expensive. More work is needed to understand whether there are any unwanted effects with RSCs. _x000D_ _x000D_ AIM_x000D_ Our study will find out whether adding RSCs to standard PCA provides better pain relief, fewer side effects and complications, and greater satisfaction for patients undergoing emergency laparotomy. It will also determine whether they are safe and cost-effective._x000D_ _x000D_ METHODS_x000D_ We will recruit 750 patients over three years in 15 hospitals. Patients will be randomly assigned to one of two groups: one group will have RSCs plus standard PCA, and the other will have standard PCA only. In the PCA only group, identical-looking catheters will be attached on the skin surface, but no local anaesthetic will be given. This means that patients will report their pain without knowing which group they are in. We will compare the two groups using the Overall Benefit of Analgesia Score (OBAS). This measures pain scores, opioid side effects and patient satisfaction, and will be completed daily for five days after surgery. We will also compare the speed of patients’ recovery from surgery and look for relevant complications such as breathing problems. We will check for long-term pain six months after surgery, measure NHS costs and impact on patients’ return to activities (e.g. work). _x000D_ _x000D_ PATIENT AND PUBLIC INVOLVEMENT_x000D_ Our patient co-applicant is an important team member and will be supported by a patient advisory group of six individuals with experience of emergency laparotomy as a patient or carer. They emphasised the critical importance of pain management to patients going through this surgery and recommended a patient rating of pain control as the most important measure to use in the trial. They also advised on suitable consent and follow-up processes, and will have ongoing input during the trial. Two patient representatives will contribute to trial oversight as members of a steering committee. _x000D_ _x000D_ DISSEMINATION_x000D_ Study results will be published in research journals and presented at conferences. We will use our close links with key organisations to include the study findings in clinical guidelines. We will also share our findings with participants and the public through patient meetings, newsletters and social media.","BACKGROUND: In the UK over 30,000 patients/year undergo emergency laparotomy surgery. Severe post-operative pain is common after this operation. Small studies suggest that rectus sheath catheters (RSCs) may provide effective pain relief, reduce morphine use and aid recovery, but they have not been investigated in a large randomised controlled trial (RCT)._x000D_ _x000D_ AIM: To compare the clinical and cost-effectiveness of RSC vs. standard analgesia for patients undergoing emergency laparotomy surgery._x000D_ _x000D_ DESIGN: Multi-centre, pragmatic, parallel group, superiority randomised sham-controlled trial with blinding of patients and outcome assessors; an internal pilot phase to determine feasibility of recruitment and protocol adherence; patient follow-up for 6 months._x000D_ _x000D_ SETTING: Acute surgical services in NHS hospitals._x000D_ _x000D_ POPULATION: Adults 18 years or over, undergoing emergency laparotomy surgery via a midline incision and eligible for inclusion in the National Emergency Laparotomy Audit._x000D_ _x000D_ EXCLUSIONS: Clinician or patient refusal, planned epidural anaesthesia, contraindications to RSC including allergy to local anaesthetic (LA), anatomical factors making RSC insertion impossible._x000D_ _x000D_ INTERVENTION: Insertion of RSCs with constant infusion of LA for 72 hours from the end of surgery._x000D_ _x000D_ COMPARATOR: Sham RSCs with inactive infusion device in place for 72 hours from the end of surgery._x000D_ _x000D_ USUAL CARE: All participants will be given standard analgesia including opioid-based patient-controlled analgesia in addition to the RSC/sham RSC._x000D_ _x000D_ OUTCOME MEASURES: _x000D_ Primary: mean Overall Benefit of Analgesia Score (OBAS) on postoperative days 1-5._x000D_ Secondary: Postoperative complications including pulmonary, surgical site infections and intervention complications; time to return of bowel function; time to 1st mobilisation; pain intensity at rest and on movement at 24, 48 and 72 hours; postoperative opioid use; mortality at 30 and 90 days; chronic postoperative pain; health-related quality of life; length of stay in critical care and in hospital; cost effectiveness._x000D_ _x000D_ SAMPLE SIZE: 750 participants (375 per group), which will provide 90% power to detect a 15% relative reduction in mean OBAS assuming a standard deviation (on the logarithmic scale) of 0.65, 5% statistical significance and allowing for 10% missing data._x000D_ _x000D_ ANALYSIS: The primary analyses will be by intention to treat and results will be reported in line with the CONSORT guidelines. The economic evaluation will be conducted from an NHS perspective at 6 months_x000D_ _x000D_ PROJECT TIMETABLE: Target randomisation rate: 2 patients/centre/month across 15 centres. Study duration 56 months: 8-mths set up, 36-mths recruitment (12-mths internal pilot, 24-mths main trial), 6-mths follow-up on all participants; 6-mths analysis and report_x000D_ _x000D_ EXPERTISE: The multidisciplinary team includes patients, anaesthetists, surgeons, pain nurse, statistician, health economist, trialists/methodologists and a UKCRC-registered clinical trials unit._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION: Our national survey has confirmed only limited uptake of RSC into routine emergency laparotomy care. If shown to be superior, we will work closely with our stakeholders to impact clinical guidance and bring RSC into routine practice. Results will be rapidly disseminated through a variety of media, publication in peer-reviewed journals and conference presentations. The CAMELOT patient advisory group will advise on dissemination to relevant patient groups.",6.1 PHARMACEUTICALS;6.4 SURGERY,NEUROLOGICAL HRCS22_01885,Medical Research Council,MRC,CANCER THERAPY USING ANTIBODY-MEDIATED DELIVERY OF ONCOLYTIC VIRUSES,"Antibody-neutralization of viruses is thought to be irreversible. Hence the current perception that anti-viral neutralizing antibodies in patients are a barrier to systemic oncolytic viral therapy. However, our research has discovered that monocytes are able to internalize, process and reactivate antibody-neutralized viruses such that they can then be transmitted to tumour target cells resulting in infection and lysis. We generated reovirus-NAb (reoNAb) complexes by incubating reovirus with a neutralizing volume of human serum. These were loaded onto isolated human monocytes and co-cultured with reovirus-susceptible tumour cells. When loaded onto monocytes, reoNAb complexes induced tumour cell death, whereas free reoNAb complexes were ineffective. Thus the virus was fully neutralized by the serum-derived NAb and unable to infect the target cells directly but when loaded onto monocytes it became effective for target cell killing. We have identified a role for antibody receptor FcgammaRIII in reoNAb uptake by monocytes, but our data suggests other receptors are also involved. This project will use complementary human in vitro and murine in vivo models to investigate the reactivation of antibody-neutralized viruses by monocytes. We will discover whether other oncolytic viruses currently being tested in the clinic are also reactivated by monocytes following antibody neutralization. This will identify those viruses that are applicable for repeat systemic delivery in patients and may also indicate any common viral physiology that would enable prediction of which viruses can be reactivated in this manner. We will also identify other immune cell subsets that are capable of reactivating antibody-neutralized oncolytic viruses and identify the receptors required and we will compare the effect of different antibody isotypes. These investigations will define strategies to improve oncolytic virotherapy in the clinic.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_05213,"Public Health Agency, NI",PHA,CHOICE TRIAL: Changing Habits tO Prevent ChIld CariEs: A Randomized Controlled Trial of a Family-Focused Therapeutic Conversation Delivered by Dental Nurses in Primary Care,"Unfortunately, child tooth decay is a major problem in the UK and many children end up in hospital to have teeth removed due to severe decay. We know the advice and support for parents and carers of these children on how to improve dental health is lacking. Children develop more tooth decay in the future because family routines and lifestyles do not change once the child has recovered from the operation to remove teeth. Many of these families live in deprived communities and face life challenges. Understandably, they can struggle to prioritise oral health and hygiene over other more pressing needs. Families may not be aware of the high sugar content in soft drinks and snacks consumed by their children after school, at grandparents or during weekend activities. They may also not realise the damage that snacking throughout the day can cause to their children’s teeth. _x000D_ _x000D_ We plan to invite parents whose children have tooth decay to visit a local dentist so that they can meet a dental nurse trained in supporting them to change their children’s tooth brushing and dietary habits. We believe that every child should have the opportunity to grow up with a healthy mouth and a bright smile. Children who have healthy smiles have more self-esteem and confidence. This encourages and supports them to have the best possible chance to succeed in life. This study provides families with knowledge and skills to develop healthy tooth brushing habits and an understanding of how healthy eating can prevent child tooth decay._x000D_ _x000D_ Here, we want to explore the benefits of a dental nurse to provide parents with supportive advice and plans, personal to them, to help prevent or reduce future tooth decay. We also want to see if dental practices are the best places to deliver this within local communities. We will identify children with at least one decayed tooth. We will then invite their parent/carer to talk with a dental nurse to learn about how best to prevent tooth decay in the future._x000D_ _x000D_ The study will last up to two years. We plan to ask around 900 parents and children to take part when they attend for a dental check-up with their dentist. Half will be randomly selected to have an initial, supportive conversation with the dental nurse (lasting half an hour) while the other half will not, as they will have their usual dental care. Parents will be asked to come to the dental practice, on one occasion only, to meet with the dental nurse, fill out some questionnaires and learn about how to prevent further tooth decay in their child. The dental nurse will support parents to identify areas of their home life that can be changed and they will set goals that will achieve this. We will ask parents to set two goals of their choice. These goals will usually focus on controlling sugar in the diet and tooth brushing. We know that both can help prevent tooth decay. At the end of this visit, the child will attend the dentist as normal for their check-up. At the end of year one and two, parents will be asked to complete a questionnaire that they will get in the dental practice or by post and return to the study office. At the end of two years, children will have a dental check-up either in the dental practice or in school by the study dentist. _x000D_ _x000D_ Some children may benefit from their parent/carer learning about how to prevent tooth decay, leading to less dental problems in the future. All parents who take part in the study will receive a free oral health pack for their child.","BACKGROUND: Child dental caries remains a significant problem in the UK, with high prevalence in deprived communities. The CHOICE Trial builds on the successful Dental RECUR Trial conducted in secondary care, which showed a significant benefit of the DR-BNI (Dental Recur – Brief Negotiated Interview) intervention for children scheduled for extractions. DR-BNI uses a personalised goal-centred approach to teach parents/guardians how to change habits that lead to tooth decay in favour of health promoting family routines. CHOICE Trial delivers DR-BNI in primary dental care, allowing evaluation of its effectiveness in high risk children at a much earlier stage of the disease._x000D_ _x000D_ AIM: The aim of the trial is to evaluate the effectiveness and cost-effectiveness in NHS primary care of DR-BNI and usual care versus usual care alone, to prevent dental caries in children. _x000D_ _x000D_ PRIMARY OBJECTIVES: Compare the primary outcome (dental caries 2 years’ post-randomisation on any tooth which was caries free or unerupted at baseline) between DR-BNI and usual care versus usual care alone. Compare costs and benefits of DR-BNI and usual care with usual care alone within a cost effectiveness framework._x000D_ _x000D_ SECONDARY OBJECTIVES include comparisons of secondary outcomes, taking account of episodes of dental pain, number of fillings and extractions, and reported oral health behaviours, process evaluation, and exploration of potential mediators (parental self-efficacy and regret/relief) of the effect of intervention on outcome._x000D_ _x000D_ METHODS: 908 children aged 3 to 7 years with at least one decayed tooth, but who do not require dental extractions will be recruited from approximately 40 dental practices in four regions of the UK, and randomised 1:1 to either DR-BNI and usual care, or usual care only. The first 6 months of recruitment will form an internal pilot with stop/go targets. Dental nurses within practices will be trained to deliver the 30-minute intervention based on behaviour change theory and delivered using Motivational Interviewing. Baseline and intermediate clinical data (one year following delivery of the DR-BNI intervention) will be collected from dental practices. Parent reported outcomes will be collected at practices, or by post/telephone if participants do not attend. The primary outcome dental assessment at 2 years will be carried out for all participants by a single trained dentist, either at schools or dental practices. Audio recordings of DR-BNI sessions will be analysed for fidelity and dose using established protocols. _x000D_ _x000D_ TIMELINES FOR DELIVERY: The study will last 54 months including 6 months setup, 18 months recruitment, 24 months follow-up and 6 months analysis and reporting. Participants will remain in the study for two years._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION: Academic outputs will include protocol publication, HTA monograph, and articles both in high impact journals, and publications with wide readership by dental practitioners. Lay summaries and social media campaigns will be used to disseminate to at risk communities. A commissioning policy group will be set up co-chaired by the PPI lead, and results presented and discussed with policy makers in all four UK countries. If effective in primary care, a resource for General Dental Practices to deliver a dental nurse-led motivational interviewing intervention to contribute to an effective caries prevention programme will be made widely available across the UK.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,ORAL AND GASTROINTESTINAL HRCS22_07013,Department of Health and Social Care,NIHR,"CHlorhexidine Or toothpaSte, manual or powered brushing to prEvent pNeumonia complicating stroke (CHOSEN): a 2x2 factorial randomised controlled feasibility trial","Research question: Is a phase 3, randomised controlled trial of guideline oral healthcare (OHC) to prevent stroke-associated pneumonia (SAP) in dysphagic acute stroke patients feasible? Background: 100,000 people in the UK have a stroke each year. Pneumonia is a serious complication, affecting around 1 in 12 patients and increasing their chances of death and disability. Poor oral health increases the risk of developing pneumonia, as bacteria in the mouth can enter the lungs when there are swallowing problems (dysphagia). Poor oral health and dysphagia are common in people with stroke. Improved OHC is therefore a plausible approach to preventing SAP, but ensuring effective OHC in acute stroke patients is challenging. National stroke guidelines for OHC are not evidence-based. We do not know if powered brushes or chlorhexidine dental gel are safe, acceptable or well-tolerated by dysphagic acute stroke patients, or if they confer any benefit over and above manual brushes and toothpaste. Aims and objectives: To determine whether a phase 3, definitive randomised controlled trial of OHC guideline interventions to prevent SAP, supported by staff education and training, is feasible in UK stroke units. To achieve this aim, we will undertake a 2x2 factorial randomised controlled feasibility trial (workstream 1), with a theoretically embedded process evaluation (workstream 2). Objectives are to determine: Can planned recruitment of sites and patients be achieved within the required timescale? What proportion of eligible patients will participate and complete the study? Will participants adhere to the allocated OHC treatments? Are the OHC treatments acceptable to patients, their carers and staff? Are the OHC treatments well-tolerated by patients? What are the facilitators and barriers to delivery of the OHC treatments and the staff education/ training? How appropriate are the outcome measures and can they be collected? Methods: 120 patients with acute stroke and dysphagia within 24 h of onset will be recruited from 4 stroke units in the North West and randomised (1:1:1:1) to one of 4 OHC treatments: Non-foaming toothpaste and manual toothbrush Non-foaming toothpaste and powered toothbrush Chlorhexidine 1% gel and manual toothbrush Chlorhexidine 1% gel and powered toothbrush Stroke unit nursing staff will receive training to deliver the treatments. Assessment of feasibility will include recruitment and set-up of sites, recruitment and retention of participants, adherence to allocated OHC treatment, acceptability and tolerability. Feasibility outcomes will be assessed on a Stop/Review/Go basis to determine progression. We will also record incident SAP, antibiotic doses received, length of stay and independence at 3 months. In the parallel process evaluation we will focus on implementation and fidelity to the OHC, by undertaking focus groups at each site and employing behaviour change techniques to establish an implementation package. Anticipated outcome: Establish whether feasibility progression criteria are met for a phase 3 trial, and whether further piloting is required. Pathway to impact: If feasible, a simple, well-tolerated and effective OHC intervention could have considerable impact on service delivery, resource utilisation and patient outcomes in the NHS.","Aim: We want to find out whether cleaning the mouth after a stroke could reduce the likelihood of getting infections in the lung (pneumonia). Before we can test this in a large clinical trial, we need to conduct a smaller trial to check if our plans are achievable. Background: 100,000 people in the UK have a stroke each year. After a stroke it can be difficult for people to swallow or to keep their teeth and mouth clean. Together, these problems can lead to harmful bacteria building up in the mouth and causing pneumonia. As many people with stroke and swallowing problems suffer from pneumonia we want to know how best to keep their mouths clean when they are in hospital. At this stage, we don t know which approach is best to prevent pneumonia, or even which approach is most suitable for people with stroke. Design and Methods: We will undertake a trial in stroke units at four hospitals. Nurses on the stroke units will receive training in how to deliver our mouth care intervention. 120 stroke patients with swallowing problems will be consented within 24 hours of coming into hospital and divided randomly into one of 4 groups: Toothpaste and manual toothbrush Toothpaste and powered toothbrush Antiseptic gel and manual toothbrush Antiseptic gel and powered toothbrush We will assess whether these mouth care treatments are feasible by looking at how many stroke patients agree to participate, how often they receive the treatment and how many complete the trial. We will see whether the treatments are acceptable by gathering the views of patients, their carers and the nursing staff. We will also collect information about how often pneumonia develops, how long participants stay in hospital, their quality of life and how well they recover. If this trial is positive, it will provide important information for a larger trial to see whether mouth care treatments can actually reduce the chances of pneumonia developing after stroke. Patient and Public Involvement (PPI): Working closely with our stroke PPI group has ensured that the trial design includes the priorities and views of stroke survivors. Stroke survivors will continue to advise the research team at all stages of the trial including trial management, development of participant information documents, staff training and the content of the participant interviews. Dissemination: The study will be publicised to stroke survivors, their carers and healthcare professionals. We will update progress on social media and relevant websites in scientific and lay formats. We will present our findings at meetings for stroke care and oral healthcare, and stroke service-user meetings in collaboration with our PPI partners. We will publish in medical and dental journals and produce a final report to the funders.",6.1 PHARMACEUTICALS,INFECTION;STROKE HRCS22_02429,Medical Research Council,MRC,CLIMB-BIG-DATA: A Cloud Infrastructure for Big-Data Microbial Bioinformatics,"The CLIMB-BIG-DATA partnership will provide a substantial computational resource that will enhance UK capability and infrastructure in microbial bioinformatics, building on our highly successful CLIMB project. Our computational infrastructure will feature an OpenStack cloud architecture with >10000 virtual CPU cores spanning six research organisations (incorporating clouds from the MRC unit Gambia and the Quadram), with access to the CEPH platform to implement object storage. A dedicated web portal Bryn will allow users to gain easy access to their own virtual machines, preconfigured with powerful user-friendly bioinformatics tools. We will add newly requisitioned specialised servers aimed at memory-intensive tasks (e.g. metagenomic assembly) or compute-intensive tasks (e.g. GPU nanopore analyses) and we will add substantial additional storage (>3 petabytes). Other features will include a freely accessible database of relevant workflows, pipelines, scripts, programs, preconfigured virtual machine images and containers, curated to support strategically relevant themed activities; an accreditation-compliant computational infrastructure for linking sensitive human and animal health metadata with microbial sequence data; support for containerisation via the Docker Engine and Singularity; a capability to share VMs, containers, data and software across the entire CLIMB-BIG-DATA infrastructure and with public cloud providers (with cloud bursting on to public clouds, should demand spike on our own infrastructure). We also promise an ambitious and exciting programme of training/community engagement, featuring hackathons, workshops, and modules suitable for a wide range of users from undergraduate students to professional bioinformaticians in the UK and more widely. We will build protocols for demand management and for charging users as we move towards becoming self-sustainable and will also improve integration with public facilities and new potential partner sites.",,1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),INFECTION HRCS22_11614,Economic and Social Research Council,ESRC,CLOSER GCRF Senior Research Associate Post,"This application is for funding from ESRC for a period of three years to fund a post at UCL that supports the development and delivery of plans to position the UK's longitudinal studies to best engage with GCRF opportunities and partners. The post will support cutting-edge research that addresses the challenges faced by developing countries. There are three key elements to this post: 1) To develop a strategic understanding of the issues and opportunities offered by this research, and help plan and execute appropriate subsequent activities to strengthen capacity in this area. 2) To play an active role in CLOSER's UK activities through, for example, research activity, communication and impact or assistance with training and capacity building. 3) To carry out high-quality research based on quantitative analysis of longitudinal studies in a development context. The post holder and their GCRF work will be guided by, and report to, a small steering group of senior academics. They will be a member of the CLOSER team based at UCL's Institute of Education and will managed by CLOSER's Director, Professor Alison Park.","The UK is world leading in the collection, curation, storage and analysis of complex social data, and UCL is one of a small number of UK Research Organisations with broad ranging capability in this area. This post seeks to harness and expand UK expertise through working in partnership with other Research Councils, in-country organisations (e.g. research organisations, UK Department for International Development, policy actors, communities and charities), international organisations (e.g. Organisation for Economic Cooperation and Development, the United Nations, World Bank, US National Institute of Aging) and existing investments (e.g. MRC's existing units, the Wellcome Trust and NIA's existing cohort studies in developing countries) to build capacity for data collection, research and analysis within and between countries and regions to enable better targeted development initiatives. There are three key elements to this post: 1. To develop a strategic understanding of the issues and opportunities offered by this research, and help plan and execute appropriate subsequent activities to strengthen capacity in this area. 2. To play an active role in CLOSER's UK activities through, for example, research activity, communication and impact or assistance with training and capacity building. 3. To carry out high-quality research based on quantitative analysis of longitudinal studies in a development context. The post holder and their GCRF work will be guided by, and report to, a small steering group of senior academics. They will be a member of the CLOSER team based at UCL's Institute of Education and will managed by CLOSER's Director, Professor Alison Park. Some overseas travel will be expected as part of the role.",2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),GENERIC HEALTH RELEVANCE HRCS22_05770,Department of Health and Social Care,NIHR,"CODIFI2: Randomised controlled trial of swab versus tissue sampling for infected diabetic foot ulcers, and comparison of culture versus molecular processing techniques","Up to 1 in 4 people with diabetes will develop a foot ulcer related to their diabetes. Some ulcers become infected with bacteria, leading to pain, redness and delayed ulcer healing. If infection spreads it damages skin and bone in the foot and this can require surgery to remove infected tissues. Doctors, nurses and podiatrists are vigilant for any signs of infection and act quickly to clear the ulcer of infection, including prescribing antibiotics to fight the infection. _x000D_ _x000D_ When infection is suspected the nurse or podiatrist will collect a specimen from the wound to send to a laboratory to identify the bacteria causing the infection. There are two ways to collect a wound sample: collecting wound fluid using a cotton swab (wound swab), or taking a small piece of wound tissue (tissue sample). Swabs are easier and this method is used the most. Many experts and practice guidelines recommend tissue sampling as it is better at collecting harmful bacteria. Previous studies have found tissue samples collect more bacteria than swabs, but also that swabs are less painful. Now that we know tissue samples collect more bacteria, we want to test whether this information helps clinicians make better decisions about which antibiotics to use. We will also see whether this helps clinicians better match the antibiotics to the infection, and so cure the infection and help the ulcer heal more quickly. _x000D_ _x000D_ To make a fair comparison of swab versus tissue sampling we will aim to recruit 730 people with diabetic foot ulcer infection. The nurse or podiatrist will obtain a wound specimen by swab or tissue sample, as allocated by a computer. The doctors, nurses and podiatrists will decide on all aspects of each patient’s care, such as dressings, off-loading and any medications._x000D_ _x000D_ We will follow these patients and collect information on their treatment, the ulcer infection, and the size of the ulcer (until the ulcer heals or 1-2 years later). All samples will be sent to the local laboratory to be grown and tested to see what antibiotics will work. We won’t include people with severe infection, anyone unable to consent or those with very old ulcers (more than 2 years)._x000D_ _x000D_ We will follow-up patients at 4 weeks & at 6 months to see if their ulcer is reducing in size and see patients when their ulcer has healed. We will collect information on the ulcer, their overall health, and the treatments and care they have had for their foot ulcer, using a postal questionnaire and from hospital notes._x000D_ _x000D_ During the CODIFI2 trial we will also study the impact of the letters asking people to complete postal surveys on completion rates. _x000D_ _x000D_ We will take a 2nd wound sample to test for bacteria using genetic 'fingerprinting' techniques that look for bacteria DNA. This will tell us whether these tests find more bacteria than growing them in the laboratory, and if so, would this potentially change antibiotic treatment. The microbiology reports obtained from the molecular techniques will be used to discuss with clinicians in interviews how they would use the detailed information and whether they would replace traditional techniques with the modern methods, or prefer to use both. The information obtained from the molecular techniques will be investigated to see if it helps us predict ulcer healing better than the factors we already know are important (e.g. large ulcers take longer to heal than small ulcers). We will also look at the potential value of future research comparing genetic fingerprinting techniques to detect bacteria, compared with growing the bacteria in the laboratory.","Trial Design: Multi-centre, phase III, parallel group, randomised controlled trial in diabetic foot ulcer infection (DFU), including a 12month internal pilot phase (study 1) & study 2: diagnostic technique agreement study, virtual clinic study, prognostic model development, qualitative study and value of information analysis_x000D_ _x000D_ Setting:UK multi-disciplinary DFU clinics_x000D_ _x000D_ Inclusion criteria:age 18+, Type 1 or 2 diabetes; clinically suspected DFU infection;consent_x000D_ _x000D_ Exclusion criteria:suspected osteomyelitis/severe infection; ulcer duration>2 years;previously randomised_x000D_ _x000D_ *Study 1:Sampling Techniques_x000D_ Randomised (1:1 allocation) to policy of swab or tissue sampling for index & subsequent ulcers, using minimisation algorithm _x000D_ Blinding: Independent clinical assessor to conduct outcome assessments with blinded central photography review of the healing endpoint_x000D_ _x000D_ Technologies being evaluated: _x000D_ Intervention 1:Wound swab with analysis by culture & antibiotic susceptibility (C&S)_x000D_ Intervention 2:Tissue sample with analysis by C&S_x000D_ _x000D_ Primary outcome:Time to healing of index ulcer_x000D_ Secondary outcomes: Compliance with randomisation; healing status at 26 & 52 weeks (& at 104 weeks in people recruited in year1), area change at week 4, time on antibiotics, SAEs (amputation, osteomyelitis, hospital admission) & QoL (Diabetic Foot Ulcer Scale-Short Form & EQ-5D-3L)_x000D_ _x000D_ Health Economic outcomes:Health resource utilisation (incl. antibiotics, cost of health & social services) and QALYs. _x000D_ _x000D_ Follow-up visits: At week 4, 26 and healing. Record review, health resource & QoL at 4/8/12/26/39/52 and (for recruits in first year) 104 weeks_x000D_ _x000D_ Sample Size: 730 participants are required to have 90% power to detect a minimum clinically important difference of 12.5% in the proportion healed at 12 months (centres on 45% healed at 12 months), assuming 2-sided, 5% significance level & 10% loss to follow-up_x000D_ _x000D_ Analysis: Primary analyses on intention-to-treat patient population_x000D_ Primary endpoint analysis: Cox proportional hazards regression model fitted to time to healing with covariates for minimisation factors. Deaths and amputations will be considered competing risks and treatment effect will be estimated with respect to time to death and amputation-free healing. Revascularisation will be considered as a time dependent covariate_x000D_ _x000D_ Health economic analysis: within-trial cost-effectiveness, cost per QALY, using EQ-5D utilities, NHS & PSS costs. Value of information of trial comparing molecular and culture techniques_x000D_ _x000D_ During the trial we will also investigate the impact of modifying letters sent with patient questionnaires improves response rates (a study within a trial). _x000D_ _x000D_ *Study 2:Processing Techniques_x000D_ - A second wound sample (swab in those allocated to swab sampling at randomisation; tissue from those allocated to tissue sampling) will be sent to a central laboratory for molecular testing, thus we will have both swab and tissue samples with analysis by molecular methods and culture. We will compare microbiology results obtained via C&S and molecular methods to assess agreement. _x000D_ - Results from C&S and molecular methods will be presented to clinicians in a ‘virtual clinic’ to ascertain their proposed antibiotic prescribing decision-stop/amend/continue. _x000D_ - We will refine prognostic models of the relationship between clinical data plus bacterial profiles (via molecular methods), and patient outcomes. _x000D_ - We will explore with clinicians the aspects of microbiology reports required to permit molecular techniques to replace, rather than be an adjunct, to culture (e.g. time to results, comprehensiveness)_x000D_ - We will estimate the value of further research aimed at reducing the likely uncertainty surrounding the economic model’s parameters associated with molecular techniques vs plating and culture using a Value of information analysis approach (VOIA).",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,INFECTION;METABOLIC AND ENDOCRINE HRCS22_05736,Department of Health and Social Care,NIHR,COPPER: CO-designing for healthy People and Planet: food Economic policy Research,"The foods that we eat have an impact on our health and the health of the planet. Eating lots of foods rich in sugar, fat and salt and low in whole grains, fruits and vegetables makes us more likely to suffer from diseases like obesity, diabetes, heart disease and certain cancers. People from disadvantaged backgrounds are more likely to suffer from these diseases. Food is also responsible for a third of all greenhouse gas emissions in the UK. If we are to keep ourselves and our planet healthy, we need to change what we eat. Adding subsidies (making foods cheaper) and taxes (making foods more expensive) to our food could help us eat more healthily, and eat foods that are better for the planet. They might also reduce the differences in health that we see between the rich and the poor._x000D_ _x000D_ The aim of our project is to work with the public and policy makers to estimate what impact different taxes and subsidies might have on the foods we eat. We will then work out whether or not that will make us healthier and reduce pollution. We will also work out the impact on how much money households have to spend and on the UK economy as a whole._x000D_ _x000D_ To do this, we will come up with a list of options, such as reforming VAT, taxing sugar and salt in foods, and subsidising fruits and vegetables. We will then run a survey to ask the public what they think of these different options, and compare what the public think to how easy these would be to turn into policies. We will then hold two-day meetings with members of the public, including those from disadvantaged backgrounds, and give them evidence about the foods we eat, the impact they have on our health, environment and economy. Participants will be asked to choose which of the policies from our list of options they think are best. We will then take these options to a meeting with government policy makers, to see which options they would choose._x000D_ _x000D_ We will look at data on people’s shopping patterns to work out what happens to how much food people buy when prices go up and down. We will then build models to work out what changes the taxes and subsidies will have. These ‘models’ are computer simulations – we will use the best evidence available to predict what will happen in different scenarios. First, we will predict how different taxes and subsidies will change what people are buying and eating, and how much it will cost households. We will then model how these changes affect the environment. _x000D_ _x000D_ Raising or lowering food prices will also affect businesses, like food manufacturers and retailers (e.g. supermarkets). We will model how businesses might respond to these policy options. For example, if a tax on sugar were to be introduced, we need to know how a business would change the price of a product. Alternatively they might make different changes, like swapping ingredients in the foods they produce, to avoid paying a tax. We will also predict what impact taxes and subsidies will have on jobs and the UK economy as a whole_x000D_ _x000D_ To estimate what impact all these changes on food prices might have on the NHS, we will use a health model. This will predict the change in body weight, heart disease, diabetes and cancer as a result of changes in the foods that we eat. Throughout the project, we will keep the public involved to make sure that our findings are shared in a clear way.","Background: The food that we eat in the UK impacts on our health and our wallets, with particularly large impacts for the poorer in our society. It also impacts on planetary health and the UK economy. One option to address these challenges is to introduce food taxes and subsidies to incentivise healthy, sustainable food and support low income groups. But taxes and subsidies are politicially difficult to introduce due to concerns over individual agency and stigmatisation. For such policies to be successful, it is vital that they are co-designed with the public and policymakers and their potential impact across multiple outcomes is established. _x000D_ Research questions: What impacts could food taxes and subsidies have on a) the incidence and prevalence of, inequalities in, and consequences for chronic non-communicable diseases? and b) household-level economics, national-level macroeconomics, greenhouse gas emissions, land use, water use and water pollution._x000D_ Aims and objectives: We will co-design tax and subsidy scenarios with public and policymakers, develop a research infrastructure of linked datasets and integrated health, economic and environmental models, estimate the impact of six scenarios and communicate our results with public and policymakers._x000D_ Methods: We will conduct a scoping review of the literature to identify a longlist of scenarios that improve health, reduce health inequalities and/or reduce environmental impact. We will assess public attitudes to the longlist via a survey and discrete choice experiment (DCE) with a representative sample and a low-income household boost. We will hold three deliberative forums with disadvantaged groups where we will present evidence from the survey and DCE alongside information about the health and environmental impact of the food system, the ethics of food taxes and subsidies, and their potential impact on the food industry. Forum participants will rank the longlist of scenarios and we will combine their findings to produce a shortlist of six, which will be refined and ratified at a meeting with public and policymaker representation. We will use household food purchasing data linked with environmental outcome measures to fit a consumer demand model. We will estimate the impact of the scenarios on nutritional quality, price of the diet and environmental outcomes for different income groups. The long-term impact on incidence and prevalence of obesity, diabetes and diet-related diseases, and NHS costs will be modelled using a validated proportional multistate life table model. Our results for health, healthcare costs, and changes in food sales will be used to estimate how the scenarios change GDP, jobs in the food industry and tax revenue using a computable general equilibrium macroeconomic model. _x000D_ Timelines of delivery: Deliberative forums will be held at the end of the first year; data linkage and model infrastucrure and early scenario results will be completed by the end of the second year; full results and dissemination will be completed in year 3._x000D_ Anticipated impact and dissemination: We will work with public and policymaker representatives throughout to ensure our communication strategy is tailored to their needs. We will disseminate our findings through Food Foundation workshops, traditional media and social media. We will circulate policy briefs, and produce result summaries for lay audiences.","8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE HRCS22_20799,Cancer Research UK,CRUK,CRI Unallocated Core Facilities,"Unallocated Core Facilities at the CRUK Cambridge Research Institute. Coded to lab profile.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_19519,Cancer Research UK,CRUK,CRUK/08/032: ARISTOTLE: A phase III trial comparing standard versus novel CRT as pre-operative treatment for MRI defined locally advanced rectal cancer (funded by the Bobby Moore Fund for Cancer Research UK),"Background: Pelvic MRI can identify patients with locally advanced rectal cancer who benefit from pre-operative fluoropyrimidine-based chemoradiation (CRT). Recent phase II studies show that two drug (doublet) CRT results in increased early measures of efficacy with acceptable toxicity. Relevance to cancer: Only 50-60% of patients selected for pre-operative chemoradiation achieve an adequate histologically confirmed tumour free resection margin. 3-year disease-free survival is around 50% for patients who receive standard CRT. There is therefore an urgent need to improve upon this. Specific Aims: The aim of the study is to investigate whether outcomes for patients receiving pre-operative CRT are improved by the addition of irinotecan. Outline plan: The trial is a two arm randomised phase III study comparing capecitabine CRT with irinotecan capecitabine CRT. The primary outcome is disease-free survival, secondary outcomes include local regional failure, overall survival, surgical morbidity, pathological response, toxicity health-related quality of life and resource use. The trial is a two arm study and it is intended to recruit 920 patients over 5 years. Disease-free survival will also be used as an intermediate outcome measure to assess at four different stages whether it is still appropriate to continue randomisation. The trial also offers important translational research opportunities involving radiological, histopathological and molecular approaches.",,6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,CANCER AND NEOPLASMS HRCS22_18067,Cancer Research UK,CRUK,CRUK/11/010 IoN: Is ablative radioiodine Necessary for low risk differentiated thyroid cancer patients - a randomised trial,"Background: Radioactive iodine (RAI) ablation is standard practice along with total thyroidectomy and thyroid stimulating hormone suppression (TSHS) therapy for differentiated thyroid cancer, but all the evidence comes only from observational studies. However, there is a subgroup of patients who have a low risk of recurrence, and there is uncertainty over whether routine RAI ablation is beneficial or represents over-treatment. Furthermore, it has potential side effects including increased risk of second cancers and is associated with significant financial costs to the health service. Aims: To evaluate whether the 5-year recurrence(disease)-free survival rate among patients not given RAI ablation is no worse than those who do have RAI ablation (using cytologically or histologically confirmed structural loco-regional recurrent or residual disease and distant recurrence). Methods: This is a prospective randomised controlled phase III trial. Patients likely to have low risk of recurrence will be randomised to RAI ablation (1.1 GBq) or No ablation following total thyroidectomy. All patients have TSHS therapy and will undergo surveillance with neck ultrasound, stimulated thyroglobulin and standard thyroid function tests. Fifty percent of patients will in addition receive RAI ablation and a post ablation scan as per standard practice. All patients will be followed up every 6 months (from ablation/stimulated Tg timepoint) for 5 years and then as per site local practice thereafter. How the results of this research will be used: The results could have the potential to change clinical practice in the UK and internationally, and mean that these patients could avoid having RAI ablation, which would be of benefit to both patients and a cost saving to sites.",,6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_17909,Cancer Research UK,CRUK,"CRUK/11/051: IRCI 001 - A Phase III randomised trial of gemcitabine plus docetaxel followed by doxorubicin versus observation for uterus limited, high grade uterine leiomyosarcoma (International Rare Cancers Initiative study - IRCI 001)","Background: Uterine leiomyosarcoma (ULMS) is rare but even patients with early-stage disease have a 50-70% chance of relapse/recurrence of disease. Recurrences may be distant or local or both. Adjuvant pelvic radiation can decrease local recurrence rates, but has not been shown to increase overall survival. Previous adjuvant trials have been conducted in a mixed population of sarcomas which may not reflect the potential benefit in ULMS. A recent phase II study of adjuvant gemcitabine plus docetaxel (GT) followed by doxorubicin (D) for women with uterus-limited high grade LMS was conducted by the Sarcoma Alliance for Research through Collaboration (SARC). The result was that 78% of women with uterus-limited LMS treated with adjuvant GT followed by D remain progression-free at 2 years, with median follow-up of 27.3 months which is improved over historical controls. An international rare cancers collaborative has been established to allow a sucessful phase III trial. Aim: To assess whether adjuvantchemotherpay (SARC GT-D regimen) improves survival in high grade uterine LMS. Methods: International 1:1 Randomised phase III clinical trial of GT-D after surgery versus at the point of relapse with primary endpoint of overall survival. Secondary endpoints: whether GT-D imporves recurrence-free survival, evaluate predictors of recurrence and response. Results will be used to determine the future standard of care for patients with ULMS and factors which will determine chemotherapy use and response.",,6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_19326,Cancer Research UK,CRUK,CRUK/12/037: NCRI CLL10 - Phase III trial to assess ibrutinib+R against FCR in newly diagnosed patients with Chronic Lymphocytic Leukaemia (CLL),"Background: Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in the UK. The most effective therapy for CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). FCR is the standard therapy for patients who are fit for relatively intensive therapy. However FCR is associated with significant early and late toxicity mainly with infections, bone marrow suppression, the risk of secondary myelodysplasia and acute myeloid leukaemia. FCR is not curative so all patients will inevitably relapse and most will eventually die from CLL. An understanding of the pathophysiology of CLL is leading to the development of novel therapies and the most promising approach utilizes therapies that target signaling through the B-cell receptor (BCR), which is expressed on CLL cells and leads to CLL cell proliferation. This approach results in impressive responses with minimal toxicity in patients with chemotherapy refractory CLL. Ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase, a critical component of BCR signaling, is one of the leading agents in this new therapeutic class. Aims: The aim of this research is to test whether the cytotoxic chemotherapy component of CLL therapy (i.e. fludarabine and cyclophosphamide), which leads to many of the complications of therapy, can be replaced by targeted therapy with ibrutinib thereby improving responses, duration of remission and survival with reduced toxicity. We will assess the safety and efficacy of ibrutinib in combination with rituximab (IR) in previously untreated patients with CLL compared to the current standard treatment of FCR. Methods: This is a Phase III, multi-centre, randomised, controlled, open, parallel group trial in patients with previously untreated CLL comparing IR with FCR. The principal research question is to assess whether IR is superior to FCR in terms of progression-free survival. Secondary objectives are to assess response rates, overall survival, MRD negativity, CLL growth rates after relapse,safety and toxicity, quality of life and health economics. How the results of this research will be used: The results of the trial will potentially redefine the standard therapy for CLL removing the need for chemotherapy and thereby reducing short and long-term toxicity, reducing relapses and the subsequent development of refractory disease.",,6.1 PHARMACEUTICALS;6.2 CELLULAR AND GENE THERAPIES,CANCER AND NEOPLASMS HRCS22_14348,Cancer Research UK,CRUK,"CRUK/12/040: IELSG 37 - A randomised, open-label, multicentre, two-arm phase III comparative study assessing the role of involved mediastinal radiotherapy after rituximab containing chemotherapy regimens to patients with newly diagnosed primary mediastinal B-Cell lymphoma (PMBL)","Primary mediastinal B-cell lymphoma (PMBL) principally affecting young adults. Initial therapy is critical in PMBL as salvage therapy for recurrence or progressive disease is often of limited efficacy; thus, there is an imperative to cure the disease at the first attempt. A tension however exists between achieving the highest possible cure fraction and minimising long-term toxicity in survivors. Uncertainty exixts as to whether consolidation radiotherapy to the mediastinum is necessary following immunochemotherapy and whether PET scanning can be used to discriminate patients who require radiation therapy from those who do not. This is a prospective international randomised non-inferiority phase III trial. Patients with previously untreated PMBL will be enrolled on the basis of the clinical and local pathologic characteristics of and with consent, be preregistered before the start the chemotherapy. All patients will undergo a pretreatment PET/CT and then go on to receive one of the standard chemotherapy regimens (e.g., CHOP14/21, DA-EPOCH, Mega-CHOP, ACVBP, VACOP-B or MACOP-B) in association with at least 6 courses of Rituximab (R-chemotherapy). The PET/CT scans will be repeated at 5-6 weeks (i.e. day 29-42) after the last R-chemotherapy administration. After mandatory central PET/CT, all patients with a negative-PET/CT scan after completion of R-chemotherapy (either with complete or partial radiological regression of the mediastinal mass), will be randomised to receive consolidation mediastinal involved field radiotherapy (IFRT) (control arm) or observation (experimental arm). IFRT (30 Gy) will commence within 6-8 weeks (i.e. day 36-56) after the last administration of immunochemotherapy. Patients with a partial response and with a positive PET/CT scan will not be randomised and will be treated according the investigator choice (e.g., with IFRT or salvage chemotherapy plus ASCT with or without IFRT). They will be followed for investigator-assessed response to chosen strategy, progression, and survival. All randomised patients will continue participation in the treatment follow-up phase study for 60 months from randomisation. At 10 years from randomisation, long term safety information will be collected. The primary endpoint is 2-year progression free survival following randomisation, with the secondary endpoint of overall survival and long-term safety analysis. The trial is powered to determine a non-inferior outcome in patients not receiving IFRT based on a sample size of 376 patients. The expected proportion of PET negative cases following R-Chemotherapy is 0.5, so at least 752 patients will need to be enrolled. It is expected that this large staudy will define the standard of care for PMBL.",,7.1 INDIVIDUAL CARE NEEDS,CANCER AND NEOPLASMS HRCS22_17763,Cancer Research UK,CRUK,CRUK/13/010: UNIRAD SC - UNIRAD Sample Collection,"Background Although remarkable progress has been made in the treatment of breast cancer, a significant number of patients with ER positive early breast cancer remain at risk of relapse, especially those patients with extensive lymph node involvement (4N+) at diagnosis. The UNIRAD study will investigate whether the addition of everolimus to standard adjuvant endocrine therapy can decrease the rate of disease relapse in patients with ER positive, HER2 negative breast cancer with extensive lymph node involvement. There is significant interest in non-invasive methods of elucidating the biomarkers predicting which patients are at highest risk of relapse and understanding the tumour evolution steps causing it. Aims The translational sub-studies embedded within UNIRAD will investigate the changes to cell free DNA (cfDNA) throughout the trial treatment, as well as the question as to whether cfDNA reflects the primary tumour, or the lymph node metastases, via comparisons with primary, lymph node and recurrent tissue (if available) with the aim of identifying predictive and prognostic changes (Part 1). Primary tumour samples will also be analysed for markers of mTOR activation that may predict response to everolimus treatment and/or disease relapse (Part 2). Methods UNIRAD is a double-blind, multicentre, phase III randomized trial of patients with poor prognosis (4+ involved lymph nodes) ER+ and HER2- primary breast cancer who remain disease-free after 3 years of adjuvant endocrine therapy. The trial is sponsored by a French academic trial group (UNICANCER). Eligible patients will be randomised 1:1 to receive either: everolimus (10mg/day) or placebo (2 tablets/day) added to standard care endocrine therapy for 2 years. The total sample size will be 1984 patients, with approximately 750 patients from the UK. Diagnostic, FFPE tissue samples will be collected from primary, lymph node and future sites of relapse (if applicable) from all UK patients and blood samples at baseline, 4, 12, 18 and 24 months. How results will be used The clinical results of the trial will provide a potential evidence base for the use of everolimus in the treatment of patients with ER positive, HER2 negative early breast cancer who are at high risk of relapse. Correlative science results may identify a subgroup of patients most likely to benefit from such treatment and identify patients with the highest risk of disease relapse.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_20081,Cancer Research UK,CRUK,CRUK/19/016 PEARLS: A phase II/III trial of Primary radiothErapy for Androgen sensitive pRostate cancer patients with Lymph nodeS,"Background Prostate cancer is the most common male cancer in the UK with around 47,000 men diagnosed per year. Around 22% of these men present with disease that has spread outside the prostate. Patients presenting with disease that has spread only to the lymph nodes are likely to represent a favourable subgroup who may be curable with aggressive multi-modality treatment.  Aims The PEARLS trial aims to show that, compared to standard field radiotherapy, extended field radiotherapy covering the prostate, pelvis and para-aortic lymph nodes improves metastasis-free survival (MFS) in prostate cancer patients with involved lymph nodes at presentation. Methods PEARLS is a multi-stage randomised controlled trial. Men with histologically confirmed prostate cancer with radiographically positive nodal disease on PSMA-PET/CT within the pelvis +/- para-aortic region receiving androgen deprivation therapy +/- androgen receptor targeted therapy or docetaxel chemotherapy are eligible. Patients will be randomised (1:1) to standard field intensity modulated radiotherapy (IMRT) (control arm) or extended field IMRT (experimental arm) with stratification by extent of lymph node disease determined by PSMA-PET/CT (pelvic only vs. para-aortic). All participants will receive IMRT given in 20 fractions over 4 weeks. In the control arm, participants will receive 62 Gray (Gy) to the prostate (and 44Gy to the pelvis with integrated boost of 51Gy to the involved lymph nodes for patients with pelvic-node disease only). In the experimental arm participants will receive 62Gy to the prostate and 44Gy to the pelvis and para-aortic region with a 51Gy boost to involved lymph nodes. In the first stage (phase II, n=150) the primary endpoint is acute lower gastrointestinal RTOG grade 2+ toxicity. If unacceptable toxicity is seen in the first 75 participants receiving extended field radiotherapy then recruitment will stop; otherwise the study will continue. In stage 2 (phase III, n=893; inclusive of the patients within phase II) the trial has 85% power (5% 2-sided significance) to detect a hazard ratio of 0.62 for MFS (an increase from 80% to 87% in 5-year MFS) in 714 participants with pelvic lymph node only disease. In selected centres, participants will be asked to donate blood, tissue and stool samples and undergo PSMA-PET/CT imaging for translational research. How the results of this research will be used? Results will contribute to international guidelines for the use of para-aortic radiotherapy in this population and, if positive, will lead to a change in clinical practice.",,6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,CANCER AND NEOPLASMS HRCS22_19640,Cancer Research UK,CRUK,"CRUK/21/010: LOGGIC- Phase III, randomised, international multicentre trial for children and adolescents with low-grade glioma","Background LOGGIC Core and LOGGIC Europe are two studies in the UK, which are part of larger European studies addressing questions in children and young adults (up to 21) with paediatric low grade glioma (pLGG). pLGG is the single most common form of brain/spinal cord tumour. They can occur anywhere in the brain and spinal cord, however the tumours can behave very differently. Some tumours require surgery alone, and others may require many lines of treatment including chemotherapy and radiotherapy. Traditionally pLGG have been treated with chemotherapy as a first line. As of yet we cannot predict which pLGG will grow, nor can we predict how patients will respond to treatment in both the short and long term. Most patients (90%) will survive their tumour, however they may do so at a cost to their neurological function and quality of life. All pLGG are thought to be activated by the MAPK pathway, which is normally used to promote growth and development. MEK inhibitors (MEKi) block this pathway, and have shown effectiveness in control of pLGG in small studies. These small studies in children, in addition to larger studies in adults have shown MEKi to be safe and associated with mild side effects. Aims LOGGIC Core will undertake detailed testing of approximately 500 pLGG in the UK. It will aim to improve diagnostic accuracy and describe groups of pLGG that behave in a similar way. It will also aim to identify markers in the tumour or child that predict response to treatment. LOGGIC Europe will aim to identify the best treatment regimen for pLGG with respect to disease control, improvement of neurological behaviour and/or visual function. Methods All consented pLGG patients will have the first level of molecular testing in the UK. This will inform which treatments or clinical trials are appropriate for the patient. Further detailed testing of the tumour and patient’s blood will be undertaken in Heidelberg (Germany) LOGGIC Europe: All consented patients will be randomised to either vincristine/carboplatin (chemotherapy) or vinblastine (chemotherapy) or trametinib (MEKi). The best treatment will be picked based on disease control, neurological behaviour and vision. Results: The results of LOGGIC Core will allow us to have a comprehensive understanding of the biology of pLGG, and ways to predict the behaviour of patients and these tumours to treatment. LOGGIC Europe will inform us of the best type of treatment for children with pLGG.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_19819,Cancer Research UK,CRUK,CRUK/22/005: Relapsed Follicular lymphoma Randomised trial Against standard ChemoTherapy (REFRACT): A randomised phase II trial of investigator choice standard salvage immuno-chemotherapy versus sequential novel therapy experimental arms,"Background: Follicular lymphoma (FL) is a common subtype of non-Hodgkin lymphoma with an estimated 10-year UK prevalence of 16,000 cases. Most patients have incurable, advanced stage disease that follows a long relapsing/remitting course (rrFL) with progressively shorter remissions despite multiple lines of therapy. Treatment resistance, early progression, and poor survival occurs in 20-25%, whilst increasing numbers experience cumulative complications or treatment resistance after multiple therapies, and eventually exhaust treatment options. Treatment resistance underpins the need for novel therapies and a deeper understanding of the biological determinants of response/resistance to develop personalised approaches. There are no standard treatment pathways, no randomised trials comparing experimental with current therapies, and limited outcome data from current therapy in rrFL. This has created immense difficulties around therapy choice and approval of novel agents. Randomised trials are urgently needed to identify the value of novel agents in treatment pathways. Aims: 1.Identify novel therapies with superior efficacy versus standard treatment based on complete metabolic response (CMR) rates. 2.Identify novel therapies with high efficacy in high-risk FL. 3.Identify therapies with other advantages over standard treatment e.g., safety, quality of life. 4.Prospectively evaluate outcomes for current immunochemotherapy treatment to provide new benchmarks. 5.Evaluate the prognostic value of calculating total metabolic tumour volume via positron emission tomography (PET)-computed tomography (CT) imaging for future risk-adapted treatment approaches. 6.Identify predictive and dynamic biological determinants of treatment response and resistance in FL, including high-risk FL, using advanced molecular techniques. Methods: REFRACT is a prospective, randomised, phase ll platform trial for sequential evaluation of experimental versus standard treatments for rrFL, with embedded translational research into the pathobiology of rrFL. There are 3 treatment rounds; each has a control arm of investigator choice immuno-chemotherapy and an experimental novel treatment arm. Randomisation is 1:1 (experimental:control) in round 1 and 4:1 (experimental:control) in rounds 2 and 3 as the final analysis will use pooled control arm data. This design minimises patient numbers allowing accelerated trial delivery whilst maintaining randomisation to prevent selection bias. Results will be used to: 1.Accelerate onward development of promising novel agents; 2.Inform future trials, treatment pathways, guidelines, and regulatory approvals with unique clarity on the value and place of novel agents and contemporary outcome data for standard immunochemotherapies; 3.Develop novel biomarkers and gain new insights into the pathobiology of treatment response and resistance, and; 4.Provide an efficient trial platform for ongoing comparative evaluation of novel therapies.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_05439,Department of Health and Social Care,NIHR,"CRYOSTAT-2: A multi-centre, randomised, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol (MHP) activation","Every year in the UK, trauma (e.g. car accidents, stabbings) kills 12,500 people, with most of those who die under the age of 45. For the same age group that is more than cancer, HIV/AIDS and heart disease combined. One of the most common causes of death in trauma patients is uncontrolled bleeding. At present, standard treatment for severe bleeding involves rapid infusion of red blood cells and blood components e.g. plasma and platelets in large volumes. Until recently one out of every two people who received a massive blood transfusion (more than 10 pints) would die from their injuries. Two important studies involving bleeding trauma patients have been conducted in the last five years showing that early intervention is more effective after injury and may help save lives._x000D_ _x000D_ Patients who have severe bleeding after injury develop a problem with their clotting system which means that they tend to bleed more. One of the main problems is due to low levels of fibrinogen, a clotting protein normally circulating in the bloodstream. Fibrinogen acts as the ‘glue’ which holds a blood clot together and at low levels, blood clots don’t form properly and bleeding can continue. Cryoprecipitate is a frozen blood component prepared from plasma and rich in fibrinogen. By transfusing cryoprecipitate early to replace fibrinogen levels in bleeding trauma patients) we believe blood clots will be more stable and reduce bleeding.. We hope that this new approach will in turn save lives. _x000D_ _x000D_ We propose to undertake a large research study, called a randomised controlled trial where patients are randomly divided into two groups and treatments are compared: A) standard treatment with normal blood transfusions B) early cryoprecipitate + standard treatment with normal blood transfusions, to see if cryoprecipitate can improve survival in trauma patients with severe bleeding. We are using cryoprecipitate because it contains high levels of fibrinogen, has been used across the UK since the 1960’s and is considered a safe way of increasing a patient’s fibrinogen levels. _x000D_ _x000D_ In UK hospitals, results from a large study across 22 centres show that cryoprecipitate is given on average three hours after injury. We think this is too late and want to give a high dose of cryoprecipitate within 90 minutes of a bleeding trauma patient’s admission to hospital. _x000D_ _x000D_ The majority of patients entered into this clinical trial will be too unwell to agree to participate in the study. Our intention is to use Professional Consultees (doctors who are independent from the research team) or Personal Consultees (relatives) to provide agreement for entering a patient into the study. Patients will then be asked to provide consent to remain in the study when their condition has improved. We have consulted several Patient and Public Involvement groups who understand the need for this method of consent and support this process._x000D_ _x000D_ This study will determine whether or not giving cryoprecipitate treatment reduces death rates. Trauma patients with severe bleeding who are taken to any Major Trauma Centre across the country with be eligible to enter the trial. The Major Trauma Network in England and NHS Blood and Transplant will support the delivery of cryoprecipitate for this study. The results of this study will have the potential to influence the way doctors and nurses all over the world treat trauma patients. We hope this innovative trial will contribute to the advancement of medicine and save many lives.","OBJECTIVE: Determine whether early high-dose fibrinogen supplementation with cryoprecipitate reduces mortality in adult trauma patients with haemorrhagic shock and active bleeding. DESIGN: Multicentre, parallel group randomised controlled clinical trial. SETTING: Major Trauma Centres in England (HTA) and international Level 1 trauma centres (matched funding from Bart’s Charity to support recruitment). TARGET POPULATION: Adult patients suffering major trauma haemorrhage requiring activation of the local major haemorrhage protocol (MHP). EXCLUSION CRITERIA: Transferred from another hospital or injury is thought to be incompatible with life or more than 3 hours elapsed from time of injury. HEALTH TECHNOLOGY BEING ASSESSED: Early cryoprecipitate (3 pools), equivalent to a dose of 6g fibrinogen, in addition to standard of care for resuscitation (MHP). Cryoprecipitate administration will start as soon as possible and within 90 minutes of admission. MEASUREMENT OF COSTS AND OUTCOMES: Primary efficacy outcome is all-cause mortality at 28 days. Secondary efficacy outcomes include: all-cause mortality, & death from bleeding: at 6 and 24 hours and all-cause mortality at 6 months; transfusion requirements: red blood cells (RBC), platelets, fresh frozen plasma (FFP) and cryoprecipitate to 24 hours. Safety assessments include: evaluation of thrombotic events (clinically overt venous thromboembolism or arterial ischaemic event (myocardial infarction, stroke) up to day 28 or discharge from acute care facility. We will evaluate the impact of early cryoprecipitate on Quality of Life (QoL) at discharge and six months following discharge using Glasgow Outcome Scale (GOS) and EQ5D-5L questionnaires. Pre-defined subgroup analysis: mortality according to timing of cryoprecipitate administration. We have considerable experience of the data collection forms based on our feasibility trials, which will be further refined for pragmatic use. SAMPLE SIZE: A total of 1544 patients will be needed, 772 in each treatment group, to detect difference of 7% in mortality (from 26% to 19%) as significant at the 5% significance level, with 90% power. A pilot phase will include the 12 months from when the first patient is randomised. An interim analysis will be carried out after 300 patients have been recruited. PROJECT TIMETABLE INCLUDING RECRUITMENT RATE: Data from the 22 MTCs in England show that MHPs are activated 75-150 times per year, equating to a potential population of at least 1,500 patients per year. We require 25% of this cohort (375 patients per year, 1125 in total) taking into consideration a slower initial recruitment rate in the first six months whilst MTCs become active sites. International recruitment is estimated at 140 patients per year (419 in total) across six Level 1 centres using same accrual rates as England although interested international centres in comparison to English sites have a higher frequency of MHP activation. The pragmatic trial protocol will ensure recruitment targets are met and completed within three years. We believe the recruitment target is within the capacity of the national major trauma system and interested international trauma centres (see letters of support).",6.4 SURGERY,INJURIES AND ACCIDENTS HRCS22_07295,Department of Health and Social Care,NIHR,CYP as One – Investigation in how to further support the community through digital innovation,"With this research, we are trying to find out whether the web-based platform - "CYP as One" - we have created https://www.seftonliverpoolcamhs.com is the following: 1) Is the platform good value for money? 2) What do members of harder to reach communities think of the platform? 3) Is there anything missing from the platform that stakeholders would like, and if so, what is it? 4) Do communities require anything to ensure that they are included as technology plays more of a part in these services? We aim to use this research to develop the platform further to ensure that the views of patients/carers/members of the public are included ensuring that it continues to be a platform for our community developed and designed by the community. Children and young people's mental health services (CYPMHS) at Liverpool and Sefton Clinical Commissioning Groups referrals were paper-based. Paper-based referrals are inefficient and generate delays between appointments, which negatively affects children and young people's (CYP) mental health. Alder Hey Children's NHS Foundation Trust co-created the "CYP as One" with partner agencies to improve mental health services access for children and young people. "CYP as One" went live in May 2021. However, due to COVID-19, we could not involve all of the communities we hoped to. Therefore, we want to do this now to ensure the current product is appropriate for our population and ensure future developments meet the needs of all community members it supports. We must do this now as the number of children and young people whose mental health has been impacted by the pandemic is only increasing. To assess if the online referral systems work better than the paper-based system, we will compare how the platform is working now and how the paper-based system worked previously for the same period of 12 months. We will be comparing health outcomes such as the number of referrals, length of waiting for a first appointment, and staff and patient satisfaction with the process. Furthermore, we will ask a diverse group of young people from underrepresented or disadvantaged communities, what they think about the platform and how it can be improved. We will use that information to further the development of the platform. "CYP as One" was originally co-created via a partnership of agencies, including Health, CYP, parents, and third sector agencies. Building on this work, the project will engage with CYP from diverse communities, including from ethnically diverse backgrounds, digital inequalities and deprivation. At the onset of the project, the co-creation group will be established underpinned by smaller interest-focus groups (e.g. ethnic minority, LGBTQ+). This process will focus on co-producing a platform that will meet the diverse need of the city region. We will ensure that harder-to-reach communities' views are hardcoded into the new platform. The research process and findings will be used to create the blueprint for future versions of the platform incorporating the views of a more diverse community, ensuring those are incorporated into the Integrated Care System (ICS). Our findings will be shared with the partner agencies, CYP and their families. Furthermore, we will share our research with the clinic, and academic communicates via conferences and journal articles.","With this research, we are trying to find out whether the web-based platform - "CYP as One" - we have created https://www.seftonliverpoolcamhs.com is the following: 1) Is the platform good value for money? 2) What do members of harder to reach communities think of the platform? 3) Is there anything missing from the platform that stakeholders would like, and if so, what is it? 4) Do communities require anything to ensure that they are included as technology plays more of a part in these services? We aim to use this research to develop the platform further to ensure that the views of patients/carers/members of the public are included ensuring that it continues to be a platform for our community developed and designed by the community. Children and young people's mental health services (CYPMHS) at Liverpool and Sefton Clinical Commissioning Groups referrals were paper-based. Paper-based referrals are inefficient and generate delays between appointments, which negatively affects children and young people's (CYP) mental health. Alder Hey Children's NHS Foundation Trust co-created the "CYP as One" with partner agencies to improve mental health services access for children and young people. "CYP as One" went live in May 2021. However, due to COVID-19, we could not involve all of the communities we hoped to. Therefore, we want to do this now to ensure the current product is appropriate for our population and ensure future developments meet the needs of all community members it supports. We must do this now as the number of children and young people whose mental health has been impacted by the pandemic is only increasing. To assess if the online referral systems work better than the paper-based system, we will compare how the platform is working now and how the paper-based system worked previously for the same period of 12 months. We will be comparing health outcomes such as the number of referrals, length of waiting for a first appointment, and staff and patient satisfaction with the process. Furthermore, we will ask a diverse group of young people from underrepresented or disadvantaged communities, what they think about the platform and how it can be improved. We will use that information to further the development of the platform. "CYP as One" was originally co-created via a partnership of agencies, including Health, CYP, parents, and third sector agencies. Building on this work, the project will engage with CYP from diverse communities, including from ethnically diverse backgrounds, digital inequalities and deprivation. At the onset of the project, the co-creation group will be established underpinned by smaller interest-focus groups (e.g. ethnic minority, LGBTQ+). This process will focus on co-producing a platform that will meet the diverse need of the city region. We will ensure that harder-to-reach communities' views are hardcoded into the new platform. The research process and findings will be used to create the blueprint for future versions of the platform incorporating the views of a more diverse community, ensuring those are incorporated into the Integrated Care System (ICS). Our findings will be shared with the partner agencies, CYP and their families. Furthermore, we will share our research with the clinic, and academic communicates via conferences and journal articles.",8.1 ORGANISATION AND DELIVERY OF SERVICES,MENTAL HEALTH HRCS22_07106,Department of Health and Social Care,NIHR,CaRi- Heart for predicting cardiac risk in suspected coronary heart disease (CAD) (DAP67),"Coronary artery disease affects around 2.3 million people in the UK. It is caused by a build-up of fatty plaques on the walls of the blood vessels that supply the heart muscle. This can reduce the flow of blood to the heart and result in people experiencing chest pain (angina) especially when they exercise. Over time, the fatty plaques can grow and block more or all of the artery and blood clots can also form, causing blockage. A heart attack happens when the supply of blood to the heart muscle is blocked._x000D_ _x000D_ People who have episodes of chest pain, who’s doctors think that they may have coronary artery disease, can have a type of imaging (CT coronary angiography) which shows whether there is any narrowing of their coronary arteries. When offering treatment, specialist heart doctors are likely to consider a person’s symptoms and other risk factors (such as family history of heart disease, diabetes, and smoking history), as well as how much narrowing of the arteries has occurred, how long is the affected area, the location of the affected area. Medicines, such as statins or aspirin, can be used to reduce the risk of fatty plaques growing or blood clots forming. For more serious disease, procedures may be used to unblock the arteries (angioplasty) or to allow blood to flow round the blockage (bypass)._x000D_ _x000D_ Some people, whose CT coronary angiography imaging results show that they have no or only a small amount of narrowing of their coronary arteries, go on to have heart attacks over the next ten years. For some people this will be because new coronary artery disease has developed during this time. However, it is thought that inflammation of the coronary arteries, which is not detected by CT coronary angiography, can also increase the risk of heart attack._x000D_ CaRi-Heart® is a computer programme that can be used, with CT coronary angiography imaging, to detect inflammation of the coronary arteries. The programme uses information about inflammation of the coronary arteries and other information (such as age, sex, smoking status, diabetes status, cholesterol) to estimate an individual’s risk of dying from a heart attack in the next eight years._x000D_ _x000D_ This assessment will consider whether the information provided by the CaRi-Heart® software has the potential to change how patients are treated so that the numbers of deaths from coronary artery disease are reduced.","The overall aim of this project is to provide a comprehensive summary of all available evidence that may be relevant to the evaluation of CaRi-Heart®, as an adjunctive investigation for assessment of cardiac risk, in people with stable chest pain/suspected CAD, who are undergoing CTCA.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CARDIOVASCULAR HRCS22_07185,Department of Health and Social Care,NIHR,Calibration and utility of ARTEMIS-A: a web application for early identification of mental health difficulties in secondary schools.,"The problem: More young people are experiencing poor mental health, particularly since the Covid-19 pandemic. They struggle to cope in school and socially, while many also have poorer physical health. These negative outcomes can be prevented or reduced if young people at risk are identified and receive the right support promptly. The solution: To help secondary schools identify young people who may need additional support for their mental health, we developed a web application (app) called ARTEMIS-A. The app is a mental health assessment which has been co-produced with school staff and pupils to ensure it is appealing and easy to use. ARTEMIS-A contains 106 questions but uses mathematical calculations (the algorithm) to select just 7-14 questions for each user. Therefore, it only takes 3-5 minutes to complete the ARTEMIS-A assessment. The score is calculated automatically and pupil s report is given immediately, so it is much quicker and easier for schools to use than many standard psychological questionnaires. This project: In this study, we will: (1) Test if ARTEMIS-A can correctly spot young people in need of support; (2) Test is ARTEMIS-A is as good at spotting young people in need of support as a paper-based test (called the DAWBA), which is commonly used by psychologists and psychiatrists; (3) Find out what young people, parents, school staff and mental health professionals think about using ARTEMIS-A in schools. Patient and Public Involvement: We will work with young people and school staff to ensure that outputs are appropriate and meaningful. We will invite two young people into the research team through Leaders-Unlocked. As lay-co-researchers, they will work with us at every stage of the research process with support and training from the research team. We will ask 3-4 members of school staff to advise us on study procedures, review participant materials, and help raise awareness of the study and to help us produce social media content, speak at teacher conferences. Next steps: Once we confirm that ARTEMIS-A correctly spot young people with mental health difficulties and is acceptable to pupils and school staff, we will set up a social enterprise to distribute it to school at the lowest cost.","The problem: More young people are experiencing poor mental health, particularly since the Covid-19 pandemic. They struggle to cope in school and socially, while many also have poorer physical health. These negative outcomes can be prevented or reduced if young people at risk are identified and receive the right support promptly. The solution: To help secondary schools identify young people who may need additional support for their mental health, we developed a web application (app) called ARTEMIS-A. The app is a mental health assessment which has been co-produced with school staff and pupils to ensure it is appealing and easy to use. ARTEMIS-A contains 106 questions but uses mathematical calculations (the algorithm) to select just 7-14 questions for each user. Therefore, it only takes 3-5 minutes to complete the ARTEMIS-A assessment. The score is calculated automatically and pupil s report is given immediately, so it is much quicker and easier for schools to use than many standard psychological questionnaires. This project: In this study, we will: (1) Test if ARTEMIS-A can correctly spot young people in need of support; (2) Test is ARTEMIS-A is as good at spotting young people in need of support as a paper-based test (called the DAWBA), which is commonly used by psychologists and psychiatrists; (3) Find out what young people, parents, school staff and mental health professionals think about using ARTEMIS-A in schools. Patient and Public Involvement: We will work with young people and school staff to ensure that outputs are appropriate and meaningful. We will invite two young people into the research team through Leaders-Unlocked. As lay-co-researchers, they will work with us at every stage of the research process with support and training from the research team. We will ask 3-4 members of school staff to advise us on study procedures, review participant materials, and help raise awareness of the study and to help us produce social media content, speak at teacher conferences. Next steps: Once we confirm that ARTEMIS-A correctly spot young people with mental health difficulties and is acceptable to pupils and school staff, we will set up a social enterprise to distribute it to school at the lowest cost.",7.3 MANAGEMENT AND DECISION MAKING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,MENTAL HEALTH HRCS22_14951,Dunhill Medical Trust,,"Can cognitive tests differentiate Progressive Supranuclear Palsy from Parkinson's Disease?","Progressive Supranuclear Palsy (PSP) or Steele-Richardson-Olszewski syndrome (Steele, Richardson, & Olszewski, 1964) is a degenerative neurological disease that typically affects patients in their sixties and affects between one and five in every 100000 people (Nath et al., 2001). Current diagnostic practice follows the guidelines proposed by Höglinger et al., (2017) which considers paralysis of the eyes, postural instability and akinesia as key diagnostic indicators. However, there is no definitive test for PSP and PSP is often misdiagnosed as Parkinson Disease (Litvan et al., 1996; Willams & Lees 2010). This is highly problematic, because the underlying pathology of PSP is very different to that of PD. Specifically, PSP is unresponsive to dopaminergic medications such as Levodopa (Hajjar & Cooper, 2016), but many patients are prescribed them because PSP is mistaken for PD. Common side effects of these medications include nausea, loss of appetite, constipation, hypotension, headaches & insomnia. The inability to make accurate, early diagnosis of PSP is distressing for the patient carers, exposes patients to medications whose side-effects reduce quality of life and limits the capacity to make adequate care plans. Previous research indicates that patients with PSP may have problems with attention, memory and recognizing emotions (Burrell et al., 2014, Smith & Archibald 2018a,b) that reduces their quality of life (Schragg et al., 2003). These cognitive problems are consistent with theoretical models which propose a tight coupling between the eye-movement system and mental processes such as attention, memory (e.g. Smith & Schenk, 2012; Awh et al., 2006) and emotion recognition (Atkinson & Smithson 2013). Indeed, a handful of small studies have indicated that PSP patients are significantly worse than PD patients at tests of visuospatial attention (Kimmura et al., 1980, Rafal et al., 1988). However, overall the cognitive problems associated with PSP are not well understood, despite being identified as having considerable potential for diagnosis (Burrell et al., 2014). The goal of this project is to test the idea that cognitive tests of visuospatial attention, memory and emotional processing can be used to reliably retrospectively classify individual patients as having PSP or PD. Patients with PSD, PD and controls will complete a battery of computerised tests of attention, memory and emotion recognition in their own homes. Linear discriminant analysis will be applied to establish which tests most accurately classify patients. The results will inform our long-term goal of developing a cheap and effective tool for early diagnosis of PSP.","Progressive Supranuclear Palsy (PSP) is a rare brain disease that typically begins to affect people during their sixties and causes problems with walking, swallowing, speech and eye-movements. Unfortunately, because it is a rare disease doctors often mistakenly diagnose PSP as Parkinson’s disease (PD). Misdiagnosis of this disease is a problem for many reasons. Firstly, the medicines that are effective for treating PD do not work for PSP. They also have unpleasant side effects such as nausea and vomiting, changes to blood pressure, loss of appetite, constipation, hallucinations, headaches & insomnia. Misdiagnosis therefore is both harmful to the patient and wasteful of scarce NHS resources. Secondly, the prognosis for PSP is much worse than that of PD and the disease progresses much more swiftly, so misdiagnosis makes it a lot harder for patients and carers to gain access to the financial support needed to adjust their lifestyle to maximise their quality of life. For example, patients with PSP often require home adaptations and wheelchairs to compensate for their reduced mobility. Finally, inaccurate diagnosis is distressing to patients and carers and leads to unnecessary hospital visits. It is therefore important to develop new ways to effectively diagnose PSP. Existing research, including a pilot study we recently conducted, suggests that people with PSP have particular problems with attention, short term memory and the ability recognize facial emotions which are not experienced by people with Parkinson's disease. These cognitive problems may offer a new and cost-effective way of diagnosing PSP, but the current evidence relies on small studies. We therefore need to conduct a larger study to confirm that cognitive tests reliably differentiate between PSP and PD. We will ask patients to complete a set of computer based tests that measure visual attention, short term memory and their ability to recognize emotions. We will also measure their eye-movements. These tests can be completed using a laptop and a portable eye-tracker, so we can test people in their own homes to make it easier for them to participate. Our goal is to show the scores on these tests can be used to classify individual patients as having either PSP or PD. This research is an essential stepping-stone towards developing an accurate and accessible diagnostic test for PSP.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,NEUROLOGICAL HRCS22_14200,Stroke Association,,Can early specialist orthotic assessment lead to improved rehabilitation outcomes and reduced complications for patients following a stroke? (OTIS),"Background: Delayed orthotic intervention for the lower limb following stroke can negatively impact on stroke survivor’s recovery and contribute to secondary conditions such as contracture. Research is needed to determine the therapeutic value of early orthotic management. Aims: 1. To identify the current evidence base for early orthotic intervention. 2. To reach expert consensus on the content of the early orthotic intervention. 3. To investigate the feasibility of conducting a randomised controlled trial to evaluate early orthotic intervention for stroke survivors. 4. To explore stroke survivor and clinician’s experiences of early orthotic intervention. Methods: A systematic review to determine the evidence base for lower limb orthotic interventions after stroke will be conducted. The results will be reviewed alongside recent national survey findings using a nominal group technique to reach expert consensus on the content of the early orthotic intervention. A feasibility RCT will be conducted with 30 stroke survivors with lower limb weakness or spasticity, randomised to receive usual care or early orthotic intervention. Follow-ups conducted at 2 and 6 months. Qualitative interviews with up-to 15 participants and stroke clinicians to explore their experiences. Expected Outcomes: The study will provide key feasibility outcomes to inform a future definitive study.","Background: Delayed orthotic intervention for the lower limb following stroke can negatively impact on stroke survivor’s recovery and contribute to secondary conditions such as contracture. Research is needed to determine the therapeutic value of early orthotic management. Aims: 1. To identify the current evidence base for early orthotic intervention. 2. To reach expert consensus on the content of the early orthotic intervention. 3. To investigate the feasibility of conducting a randomised controlled trial to evaluate early orthotic intervention for stroke survivors. 4. To explore stroke survivor and clinician’s experiences of early orthotic intervention. Methods: A systematic review to determine the evidence base for lower limb orthotic interventions after stroke will be conducted. The results will be reviewed alongside recent national survey findings using a nominal group technique to reach expert consensus on the content of the early orthotic intervention. A feasibility RCT will be conducted with 30 stroke survivors with lower limb weakness or spasticity, randomised to receive usual care or early orthotic intervention. Follow-ups conducted at 2 and 6 months. Qualitative interviews with up-to 15 participants and stroke clinicians to explore their experiences. Expected Outcomes: The study will provide key feasibility outcomes to inform a future definitive study.",7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES,STROKE;MUSCULOSKELETAL HRCS22_00028,The Francis Crick Institute,Crick,Cancer Metabolism,"The overall aim of my lab is to elucidate the fundamental principles that govern the spatiotemporal regulation of metabolism in mammalian organisms. The ultimate goal is to understand how these mechanisms are perturbed in disease and use this knowledge to design novel pharmacological approaches for cancer therapy and prevention. Towards these goals, research in my lab focuses on three complementary approaches: (1) We use in vivo metabolic tracer studies and metabolic imaging in mouse models of liver regeneration and disease to investigate how metabolic communication between organs is altered during tumorigenesis to support cancer growth. These studies indicate that tumours engage in an intricate metabolic cross-talk between various organs to re-programme metabolism throughout the mammalian body which leads to the use of nutrients not normally implicated in normal organ function. (2) We develop physiologically relevant tissue culture models of cancer that we use for metabolic tracer studies to understand the role of subcellular compartmentalisation in metabolic regulation. This work, complemented by biochemical reconstitution of metabolic pathways in vitro has uncovered new insights into the mechanisms by which metabolic pathways separated in different cellular niches are coordinated and point to a critical role for these mechanisms in supporting cancer cell survival in response to stress. (3) We use computational modelling to predict the allosteric pathways through which metabolites influence protein function and use this information to engineer proteins with altered allosteric properties that can be controlled in a reversible manner through optogenetic methods. As allostery is crucial for the rapid adaptation of metabolic pathways to environmental cues, our studies provide a framework for predicting and designing novel allosteric modulators to interfere with the pathways discovered through directions 1 and 2 in cancer. Overall, since its foundation, our research programme has provided novel insights into less understood aspects of metabolic regulation thereby informing the rational targeting of metabolic pathways that contribute to tumorigenesis. We have also developed a series of mouse models and computational methods that allowed us to investigate regulation mechanisms in glucose metabolism but are broadly applicable to other metabolic pathways.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_19507,Cancer Research UK,CRUK,Cancer Biomarker Centre,"The MCCBS has continually expanded since 2003 to currently >107 staff sited within one operational and six research teams. The proposals begin with an overall introduction and follows with strategy and research documents. The strategy document outlines the original MCCBS concept and the build of a holistic cancer biomarker centre designed to be world leading in support of cancer precision medicine; the Research document is subdivided into five workstreams, two on our focus of lung cancer, that describe past, ongoing and future research. The strategy document reports the MCCBS outputs over the past five years summarising our overall goals and philosophy, our past achievements in both exploratory and regulatory biomarker research and our response to the previous quinquennial review. We describe our approaches to multidisciplinary team work, patient relevant models (mice and cultures) to support treatment selection, and our intellectual input to clinical trial designs and all procedural steps leading from a proposed collaboration through to sample management, biomarker analysis conducted to Good Laboratory Practice standards and data interpretation. We precis highlight exemplars of our research ranging from ctDNA assays for clinical decision making to the development of a visualisation tool to support a virtual molecular tumour board. We describe how the Centre interacts with academics, Pharma and Biotech and how it will develop and expand further in the coming quinquenium including the relocation to the new Paterson Building into the bespoke biomarker centre facility that we have designed. The Research Workstreams capture the scope of our activity that ranges from basic studies of lung cancer biology to biomarker analyses on Phase I –III clinical trials. A common theme running through each workstream is our internationally leading expertise in liquid biopsies. Workstream 1 describes our preclinical and clinical studies of Small Cell Lung Cancer, with Section A focusing on our novel circulating tumour cell patient derived models (CDX) as a platform for translational research. Studies of phenotypic diversity, acquired chemoresistance, experimental medicine collaborations with Biotech and Pharma and mechanisms of metastasis notably particular vasculogenic mimicry are also reported alongside the utility of liquid biopsies. Workstream 2 on Non-Small Cell Lung Cancer, reports our contribution to the national TRACERx consortium on tumour evolution, mapping CTC genomes from surgery to relapse. Our early work and future plans for liquid biopsies to support minimal disease monitoring and early detection are also described. Workstream 3 summarises the Centre’s Clinical Trials and Biomarkers Portfolio (55 trials/studies ongoing or in planning across most tumour types), highlighting our flagship TARGET platform on ctDNA profiling to support clinical decision making at our monthly molecular tumour board to match patient to phase I trials and our progress qualifying circulating biomarkers to optimise use of anti-angiogenic therapies. Workstream 4 describes our enabling biomarker technologies including development of blood and tumour assays based on nucleic acids and cells and proteins, as well as the setup of our new tumour immunology and inflammation monitoring laboratory. Workstream 5 reviews selected ongoing and new collaborations across the Manchester Cancer Research Centre and in national consortia, where our expertise add value to colleagues’ translational and clinical research programs; including melanoma, pancreas cancer, colorectal cancer, cancer of unknown primary, prostate cancer, and neuroendocrine cancers of the upper GI tract.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),CANCER AND NEOPLASMS HRCS22_20997,Cancer Research UK,CRUK,Cancer Research Technology (CRT) Discovery Labs,"CRUK Therapeutic Discovery Laboratories (CRUK-TDL) is the in-house CRUK drug discovery unit with a principal focus on establishing and prosecuting biologically-themed multi-project alliances with industry. Based at the Babraham Research Campus, Cambridge,",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_20988,Cancer Research UK,CRUK,Cancer Research UK City of London Centre,"The ‘Cancer Research UK City of London Centre’ is a powerful collaborative effort, bringing together over 350 cancer researchers from across UCL, QMUL, KCL and The Francis Crick Institute, to form a centre of excellence in cancer biotherapeutics. By uniting our multidisciplinary academic and clinical expertise across the partnership, our aim is to not only significantly impact on the development of biotherapeutics for the treatment of cancer, but revolutionise the way cancer research is conducted in London. Biotherapies delivered as part of a multimodal/combinatorial approach have the potential to dramatically change cancer therapy and management. The Centre will develop innovative biological therapies and diagnostics/stratification strategies to develop novel, potent and selective therapeutic combination approaches. Our platform-based, cross-disciplinary approach will nucleate cancer research activity in biotherapeutics and cancers of unmet need in our Centres and hospitals, and provide a clinical and translational conduit for Crick cancer discovery science. By uniting the population bases across the partnership, our network gives access to important patient cohorts and a referral population of over ten million, which enables excellent academic and commercially-led experimental medicine and rapid clinical uptake of novel tools and approaches. Together the CRUK City of London Centre will foster a unified strategic oncology agenda, feeding directly into the development and deployment of biological therapies as well as allied fields including cancer prevention, evolution/resistance, imaging, and population studies.",,5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.1 PHARMACEUTICALS;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),CANCER AND NEOPLASMS HRCS22_00090,The Francis Crick Institute,Crick,Cancer genomics,"Cancer is caused by somatic changes to the genome. Breakthrough sequencing technologies now enable us to compare the genomes of cancer cells to those of normal cells to base-pair resolution. This in theory allows us to identify all point mutations, small insertions and deletions, genomic rearrangements and copy number changes in a cancer cell, providing a unique opportunity to look at the genes and processes involved in cancer. As genomic changes occur throughout a tumour's lifetime, a cancer's genome is also an archaeological record of its past, allowing a unique view of the tumour's evolutionary history. The Cancer Genomics Group focuses on integrating cancer genomics data across tumour types to gain insight into the genes involved in cancer and into tumour evolution. Contributing to the landscape of cancer genes, we use pan-cancer approaches integrating copy-number data with other mutation classes to identify novel rare tumour suppressor genes. Our analyses are based on leveraging recurrent biallelic inactivation of genes by either homozygous deletions, or by germline deleterious variants combined with loss-of-heterozygosity events. We are developing ""molecular archaeology of cancer"" approaches that use cancer genomes to obtain detailed timelines of cancer development across thousands of cancers and to dissect the subclonal architecture and life history of cancer across cancer types. These analyses are performed within the context of the International Cancer Genome Consortium (ICGC) and its Pan-Cancer Analysis of Whole Genomes (PCAWG) initiative, which enables us to study intra-tumour heterogeneity and the life history of cancers using whole-genome sequences of thousands of tumours. Complementary to these large-scale pan-cancer efforts, we are performing smaller-scale collaborative studies of tumour bulk sequencing, in combination with single-cell and multi-sample sequencing of primary tumours, metastases and circulating and disseminated tumour cells, aiming to characterize intra-tumour heterogeneity in minute detail and to gain insight into tumour evolution and metastasis. As the cancer genome gradually reveals its secrets, we also focus on the next challenge: to understand how genomic changes lead to transcriptomic (and proteomic, interactomic, etc) changes to finally cause cancer. Deep understanding of the cancer transcriptome is confounded by expression signals originating from admixed normal cells. Gene expression analysis by massively parallel sequencing (RNAseq) allows allele-specific expression measurements. It can be shown that, given the fraction of tumour cells, the allele-specific copy number profiles of the tumour cells, and under a few reasonable hypotheses, the expression in tumour cells can be separated from that in normal cells. We are currently developing such bioinformatics approaches to deconvolute the tumour cell transcriptomes from transcriptomes of admixed normal cells, leveraging our experience in deconvoluting genomic signals from different cell populations. In the longer term, we aim to develop integrative ‘omics approaches that study the influence of point mutations, copy number changes and structural variants on transcription at the gene or transcript level and at the transcriptome level, and to apply these approaches in a large-scale pan-cancer setting, to understand the basic principles of cancer development and cancer evolution within and across tumour types.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_01866,Medical Research Council,MRC,Capturing the spatiotemporal diversity of cellular and molecular mechanisms in ALS,"Amyotrophic lateral sclerosis (ALS) is a rapidly progressive selective degeneration of motor neurons (MNs). We desperately need to understand disease mechanisms to guide effective therapy. The hallmark of ALS (>97% of cases) is a nuclear-to-cytoplasmic mislocalization of an RNA binding protein (TDP43). This implicates two possible disease mechanisms: i) cytoplasmic gain-of-function or ii) nuclear loss of TDP43 function. By developing robust directed differentiation paradigms from hiPSCs, we have identified: i) TDP43 nuclear displacement is a primary event in MNs; ii) aberrant intron retention (IR) is the earliest detectable event in MNs; iii) ALS astrocytes (ACs) lose neuroprotective capacity through impaired EphB1-EphrinB1 JAK-STAT signalling and iv) ageing affects ACs > neurons, shifting their regional identity away from areas of primary neurodegeneration. I now propose to: 1) examine regulation and consequences of aberrant IR in MNs; 2) investigate neuronal-subtype vulnerability by comparing MNs to relatively unaffected dorsal spinal interneurons; 3) elucidate how AC regional identity and reactive status influence their established role in ALS and 4) determine how cellular ageing of MNs and ACs contributes to manifestation of ALS. Triangulating molecular mechanisms, cell-type specific contributions and the impact of cellular ageing will allow us to 'zero' in on salient disease mechanisms.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_11615,Economic and Social Research Council,ESRC,"Care leavers' transitions to adulthood in the context of Covid-19: Understanding pathways, experiences and outcomes to improve policy and practice","a)Explore health trajectories, access to and engagement with mainstream and specialist health services, and the strengths and limitations of these arrangements for care leavers in the context of the Covid-19 pandemic; b)Establish what measures different local authorities have put in place to protect and promote the welfare of care leavers during, (and in the aftermath of), the Covid-19 pandemic; c)Explore how young people experience leaving care at 16-18 years of age and how they have negotiated the changes brought about by this transition in the context of Covid-19; d)Obtain care leavers', social workers' and leaving care personal advisors' views on the strengths and limitations of services and (formal and informal) support in the context of Covid-19; e)Examine care leavers' transition pathways and any variations in the journeys that different 'sub-groups' of care leavers follow (with reference to individual characteristics, reasons for entry to care and in-care histories); f)Explore young people's progress and outcomes over time (6-8 months) and any variations between 'sub-groups' according to transition pathways; g)Work in co-production with care leavers, frontline and operational managers to identify measures that might be taken to improve service responses to meet the needs of different 'subgroups' within the leaving care cohort, including those at high risk of poor outcomes.","Care leavers typically leave their foster homes or residential placements at 16-18 years and cannot necessarily rely on receiving as much practical, emotional or family support, once they have moved, as their peers in the general population. Research shows that young people leaving care can feel isolated and abandoned at this time and that they are vulnerable to poor outcomes including poverty, homelessness, mental ill-health and unemployment. The health, social and economic impacts of Covid-19 heighten the challenges they are likely to face at a stage of life that can be difficult in the best of circumstances. The study will involve analysis of quantitative data on around 900 care leavers and in-depth interviews with senior and operational managers from children's services and health on around 50 care leavers and their key workers, (at two time points), to inform understanding of the impact that the Covid-19 has had on the timing of young people's transitions from care, where young people go ('transition pathways'), what services and support they receive, and how they fare. In particular we will focus on understanding the impact that the pandemic has had on the health and wellbeing of care leavers and the strengths and limitations of the mainstream and specialist health services they receive. We will then work together with care leavers and professionals to develop recommendations for policy makers and tools to support best practice.","8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_06938,Health Education England,HEE,"Care of the deceased child after an expected death: understanding how to deliver high quality, equitable services that meet the needs of bereaved parents.","BackgroundAround 3600 children die annually in England and Wales and the majority of these deaths occur either in the neonatal period or due to a life-limiting condition1. Paediatric Palliative Care (PPC) includes the care of these children from diagnosis, through life and into bereavement2. It is recognised that the body of research underpinning PPC is inadequate3, and research relating to the post-death care of children, between the time of death and their funeral is almost non-existent. Most deceased children are cared for either in a mortuary or in a 'cold bedroom' in a children's hospice but increasing numbers of families are choosing to care for their deceased child at home. The effects of bereavement after a child has died are well-documented 4-7. Professionals can have a positive impact on long term grief if they are well trained in supporting parents at this time7-12 , however, staff often do not understand the needs of recently bereaved parents nor do they feel confident to provide support13,14. Aims: To understand the experiences and needs of bereaved parents in the care of their child after an expected death, during the time between the death and the funeral. To influence service provision by informing the choices and care offered to bereaved parents, and to inform education and support for staff providing post-death care.Objectives: To understand the historical, cultural and social context for delivering post-death care to children (a) To identify and describe current practices in the way that post-death care is delivered (b), and the way nursing staff are trained and supported (c). To understand bereaved parents' experiences of, and needs related to, their child's post-death care (d) and nurses' experiences of, and needs related to, providing post-death care to children (e) To develop ways of teaching and supporting staff, including the co-production of digital stories and simulation based education (f)Plan: Work package 1: Scoping of historical, cultural and current social context of the care of children after death and also in regards to the way nurses learn to perform this aspect of care. Scoping of current practice; questionnaires to be sent to bereavement teams in all children's hospitals and hospices in England to identify and describe current practices.Work package 2: In-depth interviews with parents whose child died while receiving care from a tertiary PPC team. Interviews with nurses working in hospitals, community teams and children's hospices. (Total = 25)Work package 3: Co-production of guidance for service provision and education resources, including the creation of 'digital stories', describing parental experiences of post-death care.Summary of potential benefits: This novel study has the potential to powerfully impact the experience and well-being of bereaved parents. This will occur directly by making pragmatic suggestions regarding standardising evidenced based service provision, increasing opportunity for informed decision making and improving professional education. The NHS will benefit from this study by developing resilient staff who understand the value of their role in providing post-death care to children and supporting their parents, reducing emotional distress and 'burnout'12,15.","Background Around twelve children die every day in England and Wales but as professionals we have been relatively slow to understand the needs of bereaved families, partly due to a fear that involving them in research is unethical or harmful. However, it is becoming clearer that many bereaved parents want to take part in research and doing so can be a positive experience for them, and helps to inform service provision. The contact parents have with their child's body after death is influenced by many factors such as culture, religion, views of others and the choices offered to them. Some choose not to see their child's body at all, whereas others spend time with them, washing and dressing them, reading to them, or taking photos. Different practices exist in different places, with some families being offered choices in the care of their child and others receiving no choice. However, the extent of variation between service providers is unclear, and evidence of parents' preferences is lacking. Deceased children may be cared for in a hospital mortuary, a 'cold bedroom' in a hospice or in the family home. Nurses who provide post-death care to children frequently report feeling anxious about knowing what to do and say that a lack of research and understanding about parent's needs makes it challenging to know how to support them. Aims This study aims to understand how to deliver high quality, equitable post-death care to children, that meets the needs of bereaved parents. The focus is on expected death following a child being very unwell, because the needs and experience of their parents are likely to be different from those whose child dies suddenly and unexpectedly. Objectives: To understand the historical, cultural and social context for delivering post-death care to children (a) To identify and describe current practices in the way that post-death care is delivered (b), and the way nursing staff are trained and supported (c). To understand bereaved parents' experiences of, and needs related to, their child's post-death care (d) and nurses experiences of, and needs related to, providing post-death care to children (e) To develop ways of teaching and supporting staff, including the co-production of digital stories as examples of best practice (f)Participants Participants will be parents whose child has died whilst receiving care from the Palliative Care Team at Great Ormond Street Hospital, and nurses who provide post-death care for children working in hospitals, hospices and within family homes. Study design Bereaved parents and professional experts have been consulted and will continue to advise in regards to the purpose, design and ethical issues related to this study. Work Package 1: Bereavement teams in all children's hospitals and hospices in England will be sent a questionnaire to identify current practices and training. Work package 2: 25 parents will be interviewed within the home about their experiences and the decisions they made about the care of their child after death. 15 nurses will also be interviewed, within the clinical setting, about their experiences and training and support needs. Interviews will be in-depth, participant led and sensitively managed. Work package 3: With the support of a bereavement charity, a sample of parents will be invited to make a 'digital story' of their experience of post-death care using photos of their choice (e.g. pictures of where their child was cared for, toys/photos they placed with their child after death, or of significant people). Participants will be offered support following data collection. Sharing the findings The findings will be shared with participants and professionals working throughout the palliative care community and lay audiences via conferences and publications.",7.2 END OF LIFE CARE,GENERIC HEALTH RELEVANCE HRCS22_16378,Wellcome Trust,,"Care, infrastructures and antiblackness: the making of biomedicine in a Sierra Leonean hospital","The research project offers an in-depth analysis of the conflation between biomedical practice, care and antiblackness in the colonial wake. Using historical, geographic and ethnographic methods, it examines how the history of enslavement and colonialism is entangled with notions and practices of Western biomedical care and the spatial organisation of a postcolonial hospital. As a location for this study I have chosen Connaught Hospital in Freetown, Sierra Leone. Situated on Freetown's Northern coast between White Man's Bay and Susan's Bay, this was both the setting for mandatory quarantines for liberated slaves and the site of the British-built Colonial Hospital. Working with Sierra Leonean healthcare staff, I will examine the hold this violent past has on Sierra Leonean conceptions of care and trust in biomedicine. This allows me to 1) explore how biomedicine's conflation with antiblackness shapes biomedical encounters in postcolonial Sierra Leone and 2) examine how biomedical spaces and infrastructures perpetuate feelings of distrust and exclude other forms of care. In doing so I will 1) challenge the traditional geographical remit of Black Studies, 2) study how antiblackness weaves its way through medicine and care and 3) give Fanon's analyses of colonialism, racism and biomedicine a contemporary & geographic dimension.","Background: Medicine and medical racism played an important role in the British colonisation of Sierra Leone and were integral to its administration. One site in particular bore witness to the uses of medicine by colonial officers to administer ideas around racial difference and white superiority. This site, subsequently used to quarantine liberated slaves and build a colonial hospital, is still home to one of Freetown's main hospitals. Approach: A Black Studies framework allows me to research what impact antiblack histories ingrained in this site have on the hospital's contemporary infrastructures and care practices. In doing so I foreground the persistence of antiblackness, its non-linearity and simultaneous intangibility to challenge traditional structural ways of studying health inequalities. Expected impact: The project furthers existing analyses of care, colonialism and African distrust in biomedicine, the sites associated with it and practitioners thereof, and reveals new findings on the relation between racism and medicine.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_06836,Health and Care Research Wales (Welsh Government),,Care-experienced cHildren and young people’s Interventions to improve Mental health and wEllbeing outcomes (CHIMES): Systematic review,"Background: Care-experienced children and young people are individuals who have been placed in care at some point during their life. They are more likely to have poor mental health. This may affect their future, as it increases the risk of poor physical health, being involved in crime and being unemployed. Poor mental health may be the result of a young person’s time in care, but may also be because of the reasons why they have had to come into care._x000D_ _x000D_ There have been efforts to improve the mental health and wellbeing of children and young people who are care-experienced. Some aim to encourage positive mental health and wellbeing. Others offer treatment for those diagnosed with a mental health disorder (e.g. depression or anxiety). There are many different types of programmes. They might look at improving the social and emotional skills of the individual child, or they might try to give support and training to foster carers and residential carers. Some programmes look to change how medical professionals or social workers work with children and young people._x000D_ _x000D_ In the UK it is not clear which programmes are successful as not much research has been done in this area. It is also hard to know if programmes that have worked in other countries could work in the UK._x000D_ _x000D_ Aim: We want to find out which programmes work in different countries and the reasons why they work. This will help us to see what programmes might be successful in the UK._x000D_ We will aim to answer six questions:_x000D_ 1) What types of programmes have been used to improve the mental health and wellbeing of care-experienced children and young people?_x000D_ 2) Have these programmes been successful? _x000D_ 3) What helps these programmes to be delivered well and what are the challenges?_x000D_ 4) Do children and young people, and their carers, like these interventions?_x000D_ 5) From our findings, can we take the most successful parts of the different programmes and build a new programme that might work best?_x000D_ 6) Which programme do different children and young people, and their carers, think is most likely to work in their community?_x000D_ _x000D_ In answering these questions, we hope to have a programme that we can try out in the UK with the aim of improving the mental health and wellbeing of care-experienced children and young people._x000D_ _x000D_ Research method: We will bring together existing research that has tested programmes aiming to improve the mental health and wellbeing of care-experienced children and young people. From this, we should be able to understand what programmes work and how, and also what more research is needed._x000D_ _x000D_ Involving care-experienced children and young people: We will involve care-experienced children and young people. They will advise on all parts of the research and will help us to decide how best to share our findings. The Fostering Network and CASCADE Voices will help us to engage children and young people and carers in our research._x000D_ _x000D_ Sharing our findings: We will share our results through a number of reports, conferences, and online blogs. The Fostering Network will hold two events for foster carers, and care-experienced children and young people, with activities and games to explore what we found out and what to do next. We will also share our findings with the social care sector by hosting a CASCADE ExChange event and meeting with CASCADE Voices, a group of young people who have been in care and now advise on research studies.","Background: Care-experienced children and young people are individuals placed in out-of-home care (e.g. foster, residential or kinship care) or in receipt of statutory home support. This population are at increased risk of mental health conditions. Poor mental health has long-term impacts, including limited physical health, increased involvement in criminality, and higher rates of unemployment. There has been a drive to develop effective interventions, with approaches aiming to promote positive mental health and wellbeing or intervene with diagnosable mental health conditions. Interventions often include clinical guidance, health assessments, training for carers, and mentoring programmes for children and young people. At present there are limits to our understanding of intervention impacts, particularly in the UK context where there are relatively few robust evaluations. Although there are numerous studies elsewhere, it is difficult to know if these can be successfully transferred to the UK as social care and health systems vary. _x000D_ _x000D_ Aims: To systematically review the international evidence to identify effective interventions, understand the contextual contingencies of these effects, and consider the transportability of different approaches to the UK._x000D_ _x000D_ Research Questions: The study will address the following research questions:_x000D_ RQ1: What are the types, theories and outcomes tested in mental health and wellbeing interventions for care-experienced children and young people?_x000D_ RQ2: What are the effects (including inequities and harms) and economic effects of interventions?_x000D_ RQ3: How do contextual characteristics shape implementation factors, and what are key enablers and inhibitors of implementation?_x000D_ RQ4: What is the acceptability of interventions to target populations?_x000D_ RQ5: Can and how might participants, intervention types, components, and outcomes (including inequities and harms) be related in an overarching system-based programme theory? _x000D_ RQ6: Drawing on the findings from RQ1-5, what do stakeholders think is the most feasible and acceptable intervention in the UK that could progress to further outcome or implementation evaluation?_x000D_ _x000D_ Methods: We will conduct a systematic review of prevention and intervention approaches aimed at improving outcomes for care-experienced children and young people (aged up to 25 years). Outcomes are: mental, behavioural or neurodevelopmental disorders; subjective wellbeing; and self-harm, suicidal ideation and suicide. A taxonomy of interventions’ theories of change will be constructed. We will integrate outcome and process findings to understand intervention effectiveness, and how effects might be explained by contextual characteristics, implementation and acceptability. We will seek to develop an overarching candidate theory of change that might best address multiple outcomes, and which could progress to future evaluation within the UK context._x000D_ _x000D_ Impact and Dissemination: The study partner is the Fostering Network. We will undertake dissemination activities in conjunction with the Network, CASCADE Voices and CASCADE ExCHANGE Network. The review will inform identification of a potentially feasible and acceptable intervention, while providing policy-makers and practitioners with direction on what works, which interventions should be disinvested in, and how implementation might be optimised._x000D_ _x000D_ Timeline for Delivery: The study will commence 04/2020 and run for 24 months.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,MENTAL HEALTH HRCS22_00118,The Francis Crick Institute,Crick,Cell Biology of Infection,"Maintenance of appropriate intracellular electrochemical gradients is a fundamental characteristic of cells. This is frequently perturbed by invasive pathogens. Secretory and endocytic compartments are characterised by a moderately acidic and compartment specific pH. The maintenance of the pH of these compartments is important for appropriate posttranslational processing and protein and lipid sorting. We have recently shown that the M2 proton channel of influenza A virus, ionophores and other drugs that raise the pH of vesicles cause accumulation of the autophagy protein LC3 at intracellular membranes. LC3 is commonly used as a marker for autophagy, a catabolic pathway to recycle nutrients during starvation and to degrade large aggregates, damaged organelles and intracellular pathogens. A hallmark of autophagy is the formation of double membrane vesicles called autophagosomes. LC3 becomes covalently associated with phosphatidylethanolamine in both membrane layers of the autophagosome. However, pathways that result in association of lipidated LC3 with single membrane vesicles have also been described, highlighting that LC3 punctae do not always represent autophagosomes. We suggest that IAV-induced LC3-positive intracellular vesicles are not double-membrane autophagosomes, but a highly dynamic single-membrane compartment that exhibits fusion–fission behaviour. Recruitment of the enzyme complex responsible for LC3-lipidation - ATG5-ATG12/ATG16L1- in IAV-induced LC3-lipidation critically depends on the C-terminal WD40 domain of ATG16L1. This domain is dispensable for starvation-induced autophagy. The requirement of this domain for LC3-lipidation in response to the M2 proton channel is shared by ionophores and other drugs that raise the pH of vesicles as well as LC3-assisted phagocytosis. IAV-induced LC3-lipidation therefore differs from canonical autophagy as it targets single membrane vesicles and relies on a distinct ATG16L1 recruitment pathway. To identify genes involved in this process, we have designed sophisticated whole genome CRISPR knock-out screens. These confirm that the LC3 lipidation machinery is required, but not the upstream components of canonical autophagy. Many pathogens cause subtle damage to endomembrane compartments, thereby inhibiting their acidification. We propose that LC3 targeting in this context represents a mechanism for detecting a ‘danger’ signal of erroneously neutral, e.g. possessing a higher pH than appropriate, vesicles.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_00046,The Francis Crick Institute,Crick,Cell biology of host-pathogen interactions in tuberculosis,"To live within eukaryotic cells, M. tuberculosis developed through evolution an impressive set of molecular tools. Many clinical manifestations and problems during treatment of tuberculosis are a direct consequence of a population of intracellular bacilli. Although in vitro and in vivo studies have shed light into some aspects of tuberculosis pathogenesis, we still do not completely understand how M. tuberculosis manages to survive within eukaryotic cells. We believe that a detailed understanding of host-mycobacteria interactions will provide insights not only into the mechanisms usurped by mycobacteria to survive, but also into basic aspects of cellular functions and in the innate immune system. Research in our group focuses on the mechanisms whereby M. tuberculosis arrests phagosome maturation and avoids killing by macrophages and non-phagocytic cells. Towards this goal, we study the intracellular transport of M. tuberculosis in macrophages, epithelial and endothelial cells. We have identified novel factors involved in vesicular trafficking and protein sorting, particularly phago-lysosome fusion, during infection. These proteins are promising candidates for being involved in the lysosomal-mediated killing of M. tuberculosis, as well as in the molecular events linking innate and adaptive immune responses. We are currently characterizing the role played by these proteins during the development of innate and adaptive immune responses.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_02485,Medical Research Council,MRC,"Cell therapy for Huntington's disease: addressing critical knowledge gaps","Cell therapy provides a strategy for treating diseases in which predominant loss of a specific neural cell type is responsible for a substantial element of the functional decline. Huntington's disease (HD) is a devastating, incurable condition, and is a good model for testing cell therapy as loss of striatal medium spiny neurons (MSNs) is a prominent and early feature, and strongly related to functional decline. We have worked on cell therapy for HD for many years. We have developed considerable preclinical knowledge and have started to prepare for clinical translation. The most robust preclinical knowledge is based on rodent foetal allografts, although human foetal cells have shown proof of concept improvements in HD patients. Foetal cells are 'properly' specified through normal development and so provide essential benchmarking, but widespread clinical application will require MSN to be derived from renewable donor sources, such as human embryonic stem cells (hESC-MSNs). Here we address critical questions of hESC-MSNs: (i) Can hESC-MSNs improve function in rodent HD models? We use a sophisticated battery of motor/cognitive tests, first in a widely-used lesion model of HD to comprehensively compare hESC-MSN grafts against the benchmark foetal cells, and second in a transgenic HD rat model; this is a more challenging, but more representative, model of the disease process. (ii) We use a range of approaches to test whether hESC-MSNs make functional synapses with host neurons: slice electrophysiology, DREADDS and rabies transsynaptic tracing. (iii) We will perform scRNAseq to compare hESC-MSNs with their foetal counterparts to assess their degree of heterogeneity, and assess how closely hESC-MSNs and foetal-derived MSNs resemble each other. We will also perform scRNAseq on dissociated mature hESC-MSN and foetal grafts to ask similar questions. This information will guide the route to the clinic as well as guiding the optimisation of next generation donor cells.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.2 CELLULAR AND GENE THERAPIES,NEUROLOGICAL HRCS22_20645,Wellcome Trust,,Cellular mechanisms of viral gene sensing and silencing,"Viruses depend on cellular machinery to express and replicate their genes. Viral RNA must therefore be delivered or generated in the cytosol. Some viruses also deliver genomic DNA into the nucleus, for integration into the host cell genome. The cell’s principal innate defenses are to mount a potent inflammatory response upon sensing cytosolic viral RNA and to repress the transcription of integrated viral DNA. To be effective, these responses must be sensitive, specific and appropriately calibrated to minimize toxicity and autoinflammation. Our overarching goal is to gain a molecular understanding of how the cell recognizes cytosolic viral RNA and how it silences viral gene expression with the necessary sensitivity and specificity. In pursuit of this goal we are applying a complementary set of biophysical, biochemical and cell biological approaches, with a focus on using high-resolution structural information to obtain detailed mechanistic insights with atomic-level detail.  Our key goals are to understand: -how cells distinguish viral from endogenous nucleic acids; -how the immune response against double-stranded RNA is generated and amplified;  -how cells recognize and silence integrated viral DNA; This will provide invaluable insights on fundamental principles of host-pathogen recognition, chromatin regulation and host-virus coevolution.","Viruses deliver their genomes to host cells either as DNA or RNA. The cell’s principal defenses are to mount a potent immune response to viral RNA, and to prevent gene expression from viral DNA. These responses must be finely balanced as their inappropriate activation has been linked to severe autoimmune diseases including Aicardi-Goutières and Singleton-Merten syndromes. To be able to control these responses, we must first define the underlying mechanisms required for activation. We will use a complementary set of approaches to gain a view of how cells interact with viral genomes with unprecedented structural detail. High-resolution structural information has a powerful ability to generate insights into how molecules work and guide the design of potential therapeutics. Our work will establish fundamental principles of how cells calibrate their antiviral responses to prevent virus proliferation without triggering autoimmune responses. We expect to identify new pathogen vulnerabilities and suggest new therapeutic strategies.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_20193,Versus Arthritis,,"Centre for Adolescent Rheumatology Versus Arthritis at University College London (UCL), University College London Hospitals (UCLH) and Great Ormond Street Hospital (GOSH) NHS Trusts","This proposal is to support renewal funding for the Arthritis Research UK Centre for Adolescent Rheumatology at UCL, UCLH and GOSH. Adolescents with inflammatory rheumatological conditions have significant, specific unmet needs, related not only to clinical care and transition between paediatric and adult care settings, but also, of central importance for the Centre, due to lack of knowledge and prior research specific to the biology, disease patterns and treatment responses in this distinct age group. Since 2012 we have built a thriving multidisciplinary Centre, and enabled establishment of a National Network, to address these unmet needs. The Centre has leveraged significant new funding, brought in key expertise through collaborations, and developed in-depth patient involvement. Our goals in the next 5 years are to drive forward research in 4 key areas: Mechanisms of adolescent-related arthritis; Biology of the adolescent immune system in relation to inflammatory disease; Improving health care provision and enabling self-management in young people with inflammatory diseases; The Barbara Ansell National Network for Adolescent Rheumatology. In parallel we will secure the next generation of researchers in this growing area, to ensure sustainability of the Centre, while enhancing patient involvement at every level of Centre activity.",,2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),INFLAMMATORY AND IMMUNE SYSTEM HRCS22_11699,Economic and Social Research Council,ESRC,Centre for Market and Public Organisation to Centre for Evidence-based Public Services,"The main objective of the Centre is to improve the design of public policy interventions and the delivery of public services. Within this, the Centre aims to: - Develop and implement cutting-edge quantitative methods in the area of public policy analysis - Take an interdisciplinary approach in exploiting innovative data - Deliver impact on policy and inform public debate - Develop research capacity by training new cohorts of quantitative researchers The Centre will focus on public policy within four interlinked research themes, plus one over-arching theme on quantitative methods and data development. These are: A) Public services provision and the design of welfare systems B) Education policy C) Health and economic outcomes D) Urban, transport and environmental policy Cross-cutting theme: Data development and econometric methods The objective with regard to Legacy Centre funding is to ensure that our research is translated into policy and user impact within each research theme. Examples are: A) Improving the design of unemployment insurance systems and childcare and parental leave policies. Improving policy-maker and public understanding of the costs and benefits of zero-hours contracts. Improving the design of welfare systems and labour market interventions in low and middle-income countries. B) Improving the evidence base to inform the design of teacher pay schemes, and mechanisms to allocate pupils to schools. Improving school attendance in a low-income country setting using a cost-effective incentive programme. C) Helping policy makers understand the drivers of individuals' dietary choices and how it might be possible to influence behaviour. Providing evidence on the factors influencing contraceptive take-up in a low-income country. D) Increasing understanding of who wins and who loses from transport investment projects, to better inform cost-benefit evaluations. Inform regulatory and competition policy, and airport business models by increasing understanding of how both the airline-side and the retail-side of airports work in tandem.","The Centre addresses research questions covering the provision of public services - education, healthcare and welfare provision, and public policy more broadly. It takes an interdisciplinary approach and its focus is strongly international, analysing policy reforms in the UK and wider Europe, and placing increased focus on public policy in developing economies. The main areas in which we work are: A) Public services provision and the design of welfare systems B) Education policy C) Health and economic outcomes D) Urban, transport and environmental policy In addition, a cross-cutting theme covers data development and econometric methods. Our aim is to provide robust quantitative evidence that is directly useful in policy design, and to advance academic knowledge in these areas. Our approach combines cutting-edge empirical techniques, the development of new data and the leveraging of existing administrative data to better understand how individuals and organisations respond to changes in the policy environment. We aim to use these findings to improve government policy making and advance understanding of individual and firm behaviour. The main activities that we propose to carry out under the Legacy Centre Funding aim to translate our research into policy impact, and to inform the public debate around the effects of government policies and public spending.",3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_10682,Biotechnology and Biological Sciences Research Council,BBSRC,Changes in gut microbe-host interactions and their impact beyond the gut,"The intestinal microbiota is resilient to change, with alterations in community composition and activity occurring as a result of exposure to various environmental factors and insults such as diet, drugs (antibiotics), infection, surgery and lifestyle. Such changes are being increasingly associated with a number of chronic diseases including those affecting organ systems such as the liver, musculoskeletal system and the brain. In particular, there is an increasing appreciation of the role gut microbes play in influencing liver function and central metabolism (the gut-microbiome-liver axis) and brain development and function (the gut-microbiome-brain axis), which may provide future treatments for serious degenerative diseases. Key observations linking the gut microbiome to mental health and chronic age-related neurodegenerative conditions include demonstrating a relationship between diet-related changes in the gut microbiota and altered cognitive flexibility, the ability of key microbial metabolites to influence the physiology of the blood brain barrier, and alterations in neurotransmitter production by gut bacteria. However, the majority of studies to date suffer from being correlative and providing few mechanistic insights. The expertise and track record in commensal microbiology and gut and liver physiology of QIB-based research leaders and in the enteric nervous (ENS) and endocrine (ES) systems provided by our HEI-based partners, provides the skills, expertise and experimental systems required to undertake the mechanistic studies necessary to define the relationship between gut microbes and other organ systems central to human health._x000D__x000D_ Theme 2 will address how changes in microbiota-host interactions in the gut impact on the functionality of other organ systems including the liver and the brain._x000D__x000D_ This theme involves a 360-participant longitudinal population based study of age-associated changes in the intestinal microbiome in elderly individuals stratified according to their risk of developing dementia._x000D__x000D_ _x000D__x000D_ Theme 2 Outputs To provide: _x000D__x000D_ (1) an improved mechanistic understanding of the bidirectional interactions occurring at the mucosal interface in the ageing gut to help develop strategies that_x000D__x000D_ improve intestinal barrier function. _x000D__x000D_ (2) new multiscale models of the dynamics of the gut system and of the microbiota. (3) new, systems-level and mechanistic insights into how ageing influences the_x000D__x000D_ microbiota and its role in endocrine and neuronal signalling pathways. _x000D__x000D_ (4) establish links between the intestinal microbiome and age-associated declines in mental health.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,ORAL AND GASTROINTESTINAL HRCS22_03135,Medical Research Council,MRC,Changing behaviours towards single-use textiles in the operating theatre,"The carbon footprint of the NHS is 4.4% of the total of the UK, and the supply chain accounts for 62% of this. Reuse of medical equipment has been identified as a priority area for carbon reduction. In the UK the market for operating theatre textiles - theatre gowns (worn by the surgical team) and drapes (used to cover the patient and operation site) is dominated by single-use textiles. >60% of gowns and >75% of drapes in the UK are currently single-use. Yet reusable textiles are preferable in almost all important aspects. Over their life-cycle, reusable textiles have 2-3 fold lower carbon than disposable equivalents. They have 4 to 10 fold higher tensile strength, 10 fold lower burst susceptibility and 8 fold lower linting. They have better breathability, aiding temperature regulation for staff and patient. They have lower lifetime financial cost. Over 94 million single use gowns and drapes are purchased each year by the NHS in England, and switching these to reusables could save 66 thousand tonnes of carbon dioxide. We will undertake a 12 month ""action-based"" body of work that will educate and inform decision makers, to help engender a system where reusable textiles become the norm in the NHS. Through interviews with key informants, we will first investigate the potential manifold reasons for continued preference of single use textiles in hospital settings. Informed by those findings we will create a short professional animation to educate and inform, targeted at those involved in decisions about procurement and use of textiles in the operating theatre. We will maximise impact of our intervention by distribution through our exceptional and established network of national and international partners of representative medical bodies in the fields of surgery and healthcare.",,8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_15580,Wellcome Trust,,Characterisation of a novel GBA-L444P BAC transgenic mouse model of Parkinson’s disease.,"Parkinson’s disease (PD) is the second most common neurodegenerative disorder, currently affecting 145,000 people in the UK. It is known that specific mutations in certain genes can increase the risk of developing Parkinson’s disease. One such gene is GBA, which represents the greatest genetic risk factor for developing PD. Despite this, we still don't fully understand how mutations in GBA increase the risk of developing PD and progress is limited by the lack of relevant animal models of GBA-associated PD. The Wade-Martins lab has therefore developed a new mouse model to study GBA-associated PD. These mice harbour a human GBA gene, which contains a mutation called L444P. My project will use biochemical, electrophysiological and behavioural techniques to investigate how disease in these mice progresses with age. I will also assess the effectiveness of potential therapeutic strategies at restoring the function of GBA. The second phase of my project will characterise pathology in stem cell derived dopaminergic neurons from Parkinson’s patients. These neurons also carry the L444P mutation in GBA, which will allow the translation of pathological findings in the mice into human neurons. This project will contribute to the field’s understanding of the pathology of GBA-associated PD.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_05888,Medical Research Council,MRC,ChariotMS - Cladribine to halt deterioration in people with advanced multiple sclerosis,"BACKGROUND. Multiple sclerosis (MS) is a chronic condition of the spinal cord and brain. MS affects over 120,000 people in the UK. It is caused when the immune system does not work well and the coating that protects the nerves (myelin) is damaged. Most people with MS (pwMS) suffer a range of problems such as, arm or leg movement, cognition. If untreated, MS will lead to serious disability within 10 years of onset, with about half of pwMS needing wheelchair assistance within 20 years._x000D_ _x000D_ HEALTH NEED. MS disease modifying treatments (DMTs) to date have only been successful for early MS. They reduce inflammation (swelling), number of relapses and may slow disability. Trials of DMTs for pwMS with more advanced “progressive” disease (pwAMS) are few and there remains a MASSIVE unmet health need. pwAMS who are largely or entirely dependent on a wheelchair value keeping their upper limb function, swallowing, speech, and cognition - vital for their independence. There are no DMTs or trial options for pwAMS._x000D_ _x000D_ WHY THE STUDY IS NEEDED. The ChariotMS trial is built on a strong science background, and cladribine pilot trial data in pwAMS. Results suggest long-term disability in MS may be due to the length of the nerve fibres. Such that, longer nerves, like those to the legs, have a higher chance of being damaged than short nerves, like those to the hands. This leads to earlier loss of lower limb use, while shorter nerves may still be able to be treated. There are also more nerve fibres to the upper limbs than the lower limbs; this may help keep their function for longer. Inflammation is seen in brain tissue from pwAMS under the microscope throughout the disease course. Cladribine is a drug that can pass into the brain and may be able to target brain inflammation and halt the disease._x000D_ _x000D_ Cladribine has been used and licensed for more than 25 years to treat people with hairy cell leukaemia. A tablet form of cladribine (MAVENCLAD®) is now licensed for patients with early (relapsing) MS. We have pilot data that shows cladribine may work for pwAMS. This is exciting as no drugs are available for this patient group._x000D_ _x000D_ AIM ChariotMS will test if cladribine tablets can effectively treat pwAMS compared to a dummy (placebo) drug._x000D_ _x000D_ RESEARCH QUESTION. Does cladribine keep or improve upper limb performance in pwAMS over 24 and 48 months?_x000D_ _x000D_ DESIGN. A national (UK), multi-centre, blinded, dummy drug-versus cladribine trial developed together with pwMS._x000D_ _x000D_ INTERVENTION. Cladribine tablet provided free by the company Merck KGaA._x000D_ _x000D_ CONTROL. Placebo, a “dummy” drug also provided free._x000D_ _x000D_ POPULATION. pwAMS with an Expanded Disability Status Scale (EDSS) of 6.5-8.5 showing lower-limb loss of use, but still upper limb function._x000D_ _x000D_ OUTCOMES. We will test if the treatments work by:_x000D_ _x000D_ PRIMARY. 9-Hole Peg Test (upper limb function) after 24 months follow-up._x000D_ _x000D_ SECONDARY. Cognitive function, fatigue, quality of life, biomarkers and health economics after 24 and 48 months._x000D_ _x000D_ COLLABORATORS. Both the UK MS Society and the National MS Society (US), and Merck KGaA will support funding of ChariotMS. Further funding support, for the MRI proportion of the study, has been awarded by Barts Charity._x000D_ _x000D_ PPI ChariotMS has been co-produced with PPI input, including a pwAMS who has undergone off-label treatment with cladribine (co-applicant of ChariotMS), the UK MS Society, Shift.ms and the MS Trust._x000D_ _x000D_ DISSEMINATION. Alongside traditional outputs (publications), our PPI advisors will produce video info and a plain English trial summary. This will be shared with participants, pwMS and the wider community.","RESEARCH QUESTION Are cladribine tablets 3.5mg/kg over 24 months an effective disease modifying treatment (DMT) to protect upper limb function in people with advanced multiple sclerosis (pwAMS; EDSS 6.5-8.5)._x000D_ BACKGROUND MS is a chronic inflammatory and degenerative disease of the CNS affecting >120,000 people in the UK. Without DMT, majority of people with MS (pwMS) develop significant disability within 10 years of onset; 50% will require a wheelchair by year 20. The resulting cost (>£3 billion/year) is mainly spent on pwAMS. Whilst introduction of DMTs has transformed the management of people with early/relapsing MS (pwRMS), neurologists are mandated to withdraw/withhold DMTs once pwMS reach EDSS >6.5. However, evidence suggests CNS inflammation remains key driver of functional decline beyond this cut-off, and that effective DMT may halt this process. Cladribine is a safe, convenient, highly effective and CNS penetrant DMT for pwRMS given in short courses. It effectively depletes B cells, particularly memory B cells, a likely key mechanism of disease control. Evidence suggesting that (i) a significantly higher number of CNS axons supply upper compared to lower limbs and (ii) longer axons are more vulnerable to the effects of MS than shorter ones corroborate our hypothesis that upper limb function can be protected even beyond EDSS 6.5._x000D_ AIMS To test cladribine tablets 3.5mg/kg over 24 months for safety, efficacy, and cost-effectiveness, and to advance mechanistic understanding in pwAMS._x000D_ PRIMARY CLINICAL OBJECTIVE To establish whether there is efficacy superiority of cladribine over placebo in preventing deterioration of upper limb function in pwAMS at 24 months._x000D_ SECONDARY OBJECTIVES To establish whether there is a difference in _x000D_ SAFETY (AEs/SUSARs; lymphopenia, severe infections, malignancies) and _x000D_ EFFICACY including further clinical indices and “patient reported outcome measures” (PROMS) of upper limb function, cognition, fatigue, and cost-utility from the patients’ and carers’ perspectives, as well as MRI measures of lesion volume and brain atrophy between pwAMS randomised to cladribine tablets versus placebo._x000D_ MECHANISTIC OBJECTIVES To investigate whether in pwAMS any beneficial effect of cladribine on clinical outcomes is mediated by blood/serum biomarkers of inflammation (lymphocyte subsets) and can be predicted through changes in indices of neurodegeneration including serum neurofilament light chain level, MRI detectable grey matter loss and slowly-expanding lesions (as a marker of chronic lesion activity)._x000D_ METHODS Randomised, double-blind, placebo-controlled (1:1) trial cladribine vs placebo. _x000D_ PRIMARY OUTCOME 9-hole peg test (9HPT) speed at 24 months. 9HPT is a simple, sensitive, well established and accepted test of upper limb function among pwMS. To detect a clinically important 15% treatment effect using 9HPT peg speed, adjusting for baseline, with 90% power at 5% significance and 20% drop-out we calculated a sample size of n=200 over 24 months._x000D_ TIMELINES Total project duration 57 month: 9 months set-up; 18 months recruitment across 20 UK centres, 24 months follow-up leaving 6 months for close out, analysis, reporting._x000D_ IMPACT AND DISSEMINATION ChariotMS is the first DMT RCT in pwAMS offering potential for widespread NHS adoption of cladribine thereby addressing significant unmet health/social need. This would have major impact on the lives of pwAMS, their family and carers, and on medical as well as social services since maintaining upper limb function will preserve independence for longer. Results will be published in high-impact journals, meetings, and social media, further catalysed by our strong relationship with the MS Societies, MS Trust, Shift.ms, and the wider community.",5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS,NEUROLOGICAL HRCS22_02973,Medical Research Council,MRC,Checkpoint Inhibitors to Restore Monocyte/Macrophage Function in Liver Failure,"Liver failure is associated with increased susceptibility to infection which leads to multi-organ failure and increased mortality (1,2) . In an animal model of liver failure, innate immune system defects in monocyte/macrophage phagocytic function allowed circulating micro-organisms to disseminate and initiate sepsis (3). Blockade of the immunoregulatory molecule PD-1 restored phagocytosis in a rodent model of acute liver injury and in monocytes from patients with acute liver failure (4). To determine whether PD-1 blockade exerts the desired therapeutic effect in-vivo we will treat patients with acute liver failure (N = 21) or acute decompensation of cirrhosis (N = 51) with the anti-PD-1 antibody, Nivolumab. Monocyte phenotype and phagocytic function will be measured ex-vivo using flow cytometry techniques and differences before and after treatment used to determine whether normal immune function is restored. Safety of anti-PD-1 therapy will be explored in a sentinel cohort of patients treated with a 50% dose of Nivolumab and followed for 6 months. The incidence of infection will be carefully documented in patients with acute decompensation and compared to the expected incidence (35%) to determine whether anti-PD-1 treatment exerts the desired effect on infection rates. Macrophage PD-1 expression was associated with the level of soluble PD-L1 (sPD-L1) in plasma (4). We will therefore measure sPD-L1 in cohorts of patients with acute liver failure or acute decompensation to determine whether this biomarker will predict patients at enhanced risk of sepsis in order to potentially target anti-PD-1 therapy",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_13466,Wellcome Trust,,Checkpoint control of T cell-B cell collaboration in the regulation of autoimmunity,"Productive communication between T cells and B cells is vital for protective immunity, however dysregulation of this process can trigger autoimmunity.  Costimulatory checkpoints limit T cell help for B cells by controlling the differentiation of follicular helper T cells (Tfh), a cellular subset overrepresented in multiple autoimmune diseases. We have found that anti-CTLA-4 antibodies can trigger spontaneous Tfh differentiation in mice. Targeting CTLA-4 with checkpoint inhibitors in cancer patients may therefore induce Tfh, potentially relevant to the autoimmune side-effects seen with these treatments. Despite their escalating clinical burden, the cellular mechanisms underpinning checkpoint-inhibitor induced autoimmunity remain poorly understood. In this proposal I will investigate the hypothesis that induction of Tfh responses is a general feature of autoimmunity, reflecting a loss of costimulatory (checkpoint) control. I will explore how CTLA-4 and PD-1 co-operate to regulate Tfh differentiation, and establish the consequence of a Tfh response for tissue autoimmunity. Insights will be drawn from autoimmune patients treated with CTLA-4-Ig, and cancer patients treated with CTLA-4 antibodies. Building on exciting preliminary data, I will determine whether Tfh populations have value in predicting outcomes in classical autoimmunity as well as in checkpoint-inhibitor induced disease.","Immune cells called T cells and B cells need to work together in harmony to generate effective immune response to clear infection. However if this cellular dialogue is dysregulated, the immune system can attack our own bodies, leading to autoimmune diseases like type 1 diabetes, rheumatoid arthritis and lupus. A particular subset of T cells specialises at communicating with B cells, and these T cells are increased in people with autoimmune diseases. The new drugs we use to fight cancer can cause autoimmune side-effects, and we have found this same type of T cell is increased in response to these drugs. We therefore want to understand how the development of these T cells is controlled and how they contribute to either natural or drug-induced autoimmune disease. Our work may lead to these cells being used as a marker to predict development of these diseases permitting them to be treated earlier.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS HRCS22_20903,Wellcome Trust,,Chemistry in Cells – New Technologies to Probe Complex Biology and Medicine.,"This Programme will provide unique training for a new generation of scientists focusing on the quantification of biologically-important molecular interactions in physiologically-relevant settings. It is currently impossible to accurately and directly quantify interactions of molecules, and their consequences, in the complex physiological settings relevant to diagnosis and treatment of disease. To address this unmet need, we will harness physical science-based approaches to develop technologies that will underpin research across the spectrum of cell biology and biomedical science Scientific goals: • Collaborative research outputs (papers, patents) using innovative approaches to provide new insights into biomedicine. • Adoption of our technologies by the broad biomedical research community to study fundamental biology/diseases including Alzheimer’s, schizophrenia and cancer. We have developed an innovative framework for our training programme, promoting a diverse and positive research culture change that we aim to propagate across Oxford and the UK. Culture-change goals: • Promotion of a positive research culture in Oxford demonstrated by uptake of our practices across the University. • Communication of our strategies via lectures on graduate education and publications in educational journals.  These ambitious goals provide an exceptional basis for a multidisciplinary programme that trains scientist equipped as problem solvers for a diverse range of 21stcentury workplaces.",,1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS HRCS22_06718,Department of Health and Social Care,NIHR,Childhood cancer diagnosis: quantifying national diagnostic intervals and developing professional and public decision support tools for earlier diagnosis.,"BackgroundCancer is the commonest cause of death of children in the UK and many experience long delays to diagnosis. Early diagnosis will reduce morbidity, mortality and treatment burden, improving quality of life into adulthood. An evidence-based national awareness campaign has reduced diagnosis times for children with brain tumours, improving survival and outcomes.This research will quantify diagnostic intervals for children nationally and provide high quality guidance. An accompanying awareness campaign will help reduce diagnostic intervals.Aims1. Assess the UK diagnostic intervals for children diagnosed with all childhood cancers and identify factors associated with diagnostic delays.2. Enhance awareness and recognition of bone and abdominal childhood cancer symptoms amongst the public and Health Care Professionals (HCPs).3. Develop standard operating procedures to apply this methodology to other conditions.Objectives:1. Establish a national cohort study, to determine cancer referral pathways and total diagnostic intervals of incident cases at the 19 principal treatment centres for 4 major childhood cancer types: 1) leukaemias, 2) solid tumours (chest, abdomen, pelvis), 3) head/ neck cancers 4) bone/soft tissue cancers.2. Develop guidance on the recognition, assessment and investigation of paediatric abdominal and bone cancers.3. Develop a standard operating procedure to replicate guidelines and awareness tools for other childhoodcancers. 4. Develop public awareness tools and plan a public and professional awareness campaign to reduce the total diagnostic interval for abdominal and bone cancers.MethodsA prospective national cohort study across all 19 UK Principal Treatment Centres will be conducted. Data will be collected on age at diagnosis, onset of symptoms, first visit to HCP and date and place of diagnosis. Descriptive analysis will be used to characterise the study population. Subgroup analysis of tumour type, age and region will be performed.HCPs and patients will review current evidence base on the presentation of bone and abdominal tumours, answering questions on appropriate investigation and referral timings in a multi-disciplinary workshop. Statements derived from this workshop will be sent to experts in the field using a modified Delphi-consensus process. Consensus will be defined as >70% agreement. This will inform a clinical guideline on the recognition, assessment and investigation of abdominal and bone tumours in children in accordance with AGREE-II criteria which will be sent for stakeholder consultation prior to RCPCH endorsement.To inform the awareness tools and campaign, 3 focus groups will be conducted with general public, cancer survivors and parents. Symptom cards, branding and website content and design will be developed by charity partners using content from the guideline. Anticipated impact and disseminationA detailed dissemination plan for public and professionals will aid widescale dissemination through conferences, journals, social media and advertising. This will enhance awareness of the signs/symptoms of these cancers and promote earlier diagnosis, reducing the diagnostic interval nationally.This research will impact the children and families sadly affected by cancer through earlier diagnosis and better survival and long-term outcomes; healthcare professionals by increasing their confidence in diagnosis and changing practice and the have a large cost benefit for our NHS.","Why is this research needed?Childhood cancer is the commonest cause of death in the UK and many experience long delays to diagnosis. Delayed diagnosis can lead to worse survival for patients and poorer long-term health for survivors. An evidence-based national awareness campaign has halved diagnosis times for children with brain tumours in the UK, improving survival and long-term disabilities.With this research we will understand the time it takes to diagnose children and young people with all cancers across the UK. The research will also start to address delays by developing high quality guidance on bone and abdominal cancers and produce awareness tools for a national awareness campaign to promote earlier diagnosis.What are the important questions that will be answered?How long does it take for children/young people in the UK to be diagnosed with cancer?What factors affect delays in diagnosis?What is the best practice for identifying, investigating and referring children/young people with symptoms suggestive of a bone or abdominal cancer? How will the research be done?1. National cohort study: data will be collected on every child diagnosed with cancer across 19 childhood treatment centres in the UK. Data will be analysed to understand the factors affecting their journey and time to diagnosis.2. Guideline development: a modified-Delphi consensus process will be conducted using statements derived from a workshop of professionals, childhood cancer survivors and parents. This will inform a new clinical guideline advising symptom recognition, and appropriate referrals.3. Awareness tool development: the guideline will be translated into awareness tools including symptom cards and a website to share with the public through an awareness campaign run by our charity partners.4. Focus groups: 3 groups will be run (general public, parents of child with cancer, childhood cancer survivors) to plan strategies for the awareness campaign and understand stakeholder needs. Where will the research take place and who is the research team?The research will take place at the Children's Brain Tumour Research Centre in Nottingham and be led by Dr Shaarna Shanmugavadivel who is a paediatrician and researcher. She is supported by a research group who are experts in early diagnosis of cancer, research design, statistics and developing guidelines.How have patients and public been involved?The idea was peer-reviewed at a Cancer Research UK sandpit event supported by people affected by cancer. Patient advisors have reviewed the project plan and will continue to be involved with the guideline and awareness tool development to ensure they meet the needs of patient and the public. 3 focus groups will be held with patients and the public to inform the awareness campaign.How will the research benefit patients and the NHS?The guideline and awareness tools will improve the confidence of HCPs and the public in spotting bone and abdominal cancer symptoms and promote earlier diagnosis. This will improve the chance of survival, reduce the amount of treatment needed for a cure and reduce long term effects on health into adulthood. It will also save money for the NHS as it costs more to treat advanced disease.How will the results be shared?The results will be translated and shared through a national public and professional awareness campaign called BodySmart in order to reduce the time to diagnosis for children and young people across the UK.Established partnerships with charities and professional bodies including, Children's Cancer and Leukaemia Group (CCLG), Association of Paediatric Emergency Medicine (APEM), Teenage Cancer Trust (TCT) and CLIC Sargent will share results through a plan of action including conferences, journals and social media.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING,CANCER AND NEOPLASMS HRCS22_23104,The British Academy,,Children’s developing understanding of others’ minds across intergroup divides,"The ability to make inferences about the mental states of other people is important for effective and harmonious social interactions. Research has historically focused on investigating the cognitive precursors, trajectory and correlates of this skill in childhood. This project will bridge research areas in developmental and social psychology in a novel line of inquiry to ask whether children are selective in their reasoning about the mental states of others, specifically in intergroup contexts. Experiment 1 will manipulate and test the effect of intergroup competition on children’s mental state inferences using novel groups. Experiment 2 will situate this research question in a society that is historically characterised by intergroup divides and competition - Northern Ireland. The results have the potential to substantially alter the study of children’s mental state understanding to account for the role of socio-cultural processes, and contribute to theories on the origins of intergroup bias.",,1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,MENTAL HEALTH HRCS22_01110,Medical Research Council,MRC,Chromatin and Development,"Our long-term goal is to understand the transcriptional and epigenetic events that underlie the process of mammalian development. In particular, we focus on the parts of the genome made up of transposable elements (TEs): elements known to be historically or currently mobile within our DNA. Significantly less is known about TEs compared to single copy protein-coding genes despite their high abundance in the human genome. This includes during mammalian development, where the role of relaxed TE repression and increased TE expression is not understood. Our previous work has revealed that the TE, LINE1 plays essential functions in controlling gene regulatory networks in the earliest stages of pre-implantation development (Percharde et al., 2018). This is interestingly independent of retrotransposition activity, and distinct from somatic cells, where increased LINE1 expression has been associated with cancer, inflammation, or senescence. These findings highlight how much is still to be learned about TE function in multiple contexts. Our objectives are firstly to investigate how TE expression and regulation has been co-opted for essential processes in mouse and human developmental contexts. Second, we aim to compare and contrast TE regulation in developmental versus disease states to understand how TE mis-regulation occurs and how this contributes to disease. We use a combination of mouse and human somatic and embryonic stem cell lines together with mouse embryo models to explore mechanisms regulating TE expression. Our experimental approach combines both candidate and genome-wide techniques, bioinformatics and CRISPR technology to uncover new TE regulators as well as to directly manipulate TE expression. Overall, we aim to shed light on how TE expression contributes to normal embryo development and uncover mechanisms to explain how and why these elements may contribute to disease.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE HRCS22_00037,The Francis Crick Institute,Crick,Chromatin structure and mobile DNA,"The early phase of the retroviral replication cycle begins with the viral entry via fusion of viral and cellular membranes and culminates with irreversible integration of the viral genetic material into host cell genome. Research in our laboratory focuses on HIV DNA nuclear import, integration and cellular innate defence factors counteracting viral entry. Using X-ray crystallography and cryo-electron microscopy we aim to elucidate molecular mechanisms underlying in these processes. The catalytic events associated with integration are catalysed by an essential viral enzyme, which is structurally and mechanistically related bacterial and eukaryotic transposases. Members of this superfamily are distinguished by the characteristic structural fold, organization of the active site and metal-dependent catalysis. Retroviral integrase acts in the context of a stable synaptic complex, known as the intasome. The latter is the target for integrase strand transfer inhibitors, the only class of HIV integrase antagonists currently approved to treat HIV/AIDS. Over the recent years, using a range of model systems, we determined a collection of high-resolution intasome structures, which explained and illustrated the mechanism of the retroviral integration process. Our structures also revealed the general mode of action of the clinical HIV integrase inhibitors. The brunt of our current efforts is directed towards understanding the structural features specific to HIV/lentiviral integrase and the rules of engagement between the HIV integration machinery and the cellular environment. The two major projects aim to elucidate the structural and functional features of the interface between integrase and chromatin and the identification and the roles of host cell factors during integration. An example of our recent work related to HIV nuclear entry is the series of crystal structures of Transportin 3, the -karyopherin involved in the early steps of HIV replication in addition to its role in nuclear import of cellular Ser/Arg-rich splicing factors. We are currently investigating how Transportin 3 interacts with another important host factor CPSF6. The work related to viral entry currently focusses on the SERINC family of conserved multi-pass transmembrane proteins implicated in restriction of retroviral infection and on the mechanism of viral escape from the control by the cellular defence factors. High resolution structural information obtained in the course of our studies will be of considerable value for antiviral drug development. In particular, we are collaborating with medicinal chemists, whose efforts to develop next-generation HIV integrase inhibitors are informed by our retroviral intasome structures.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,CANCER AND NEOPLASMS;INFECTION HRCS22_02179,Medical Research Council,MRC,Chronic hyperglycaemia and impaired pancreatic beta-cell function.,"Diabetes is a global health problem primarily caused by the inability of pancreatic beta-cells to secrete adequate levels of insulin. However, the molecular mechanisms underlying the progressive failure of beta-cells to response to glucose in type-2 diabetes remain unresolved. Preliminary data reveal that diabetes produces marked impairment of oxidative metabolism and ATP synthesis in islets and beta-cells exposed to diabetes or chronic hyperglycaemia. As a result, insulin secretion is abrogated. The aim of this proposal is to elucidate the molecular mechanisms by which chronic hyperglycaemia impairs beta-cell metabolism. We will (i) determine where the metabolic block occurs and if it can be bypassed by downstream metabolites; (ii) determine if glucose or a metabolite mediates the effects of chronic hyperglycaemia, and identify the key metabolite(s) involved; (iii) investigate if the glucose-induced changes are mediated by reciprocal changes in mTORC1 and AMPK activity, as preliminary data suggest; (iv) determine how high and for how long glucose must be elevated to cause these effects; and (v) explore if reducing metabolic flux can prevent the changes in gene expression and beta-cell metabolism produced by chronic hyperglycaemia. As substantial amounts of glycogen accumulate in diabetic beta-cells, we will also investigate if this is a cause or consequence of the impaired metabolism. Finally, we will determine the extent to which the effects of chronic hyperglycaemia on beta-cell metabolism and insulin secretion can be reversed by: (i) restoration of euglycaemia, both in vivo and in vitro; and (ii) drugs such as metformin. Improved understanding of the proteins and pathways involved in the deleterious effects of chronic hyperglycaemia on beta-cell metabolism is expected to identify new targets for the development of therapeutic drugs designed to preserve beta-cell function and improve insulin secretion in diabetes.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,METABOLIC AND ENDOCRINE HRCS22_19542,Wellcome Trust,,Circuit Mechanisms of Learning and Decision Making,"Decision making concerns every aspect of our lives. Despite substantial progress in understanding the brain regions involved in learning and decision making, the neuronal circuits that govern choice behaviour have remained elusive. This proposal aims at studying precise neuronal circuits underlying learning and decision making. We will focus on frontostriatal neuronal circuits, and how neuromodulators can shape the activity of these circuits during decision making. Our research will take the following complementary directions: A) We will examine defined frontostriatal circuits during a novel decision paradigm that requires integration of perceptual and reward signals in order to investigate the role distinct frontostriatal circuits play in choice behaviour. B) We will focus on dopamine neurons and dopamine recipient structures and examine specialised roles of distinct dopaminergic circuits in learning. C) We will establish how decision uncertainty influences learning, and how dopaminergic circuits regulate learning in uncertain environments. Our group will utilize and develop behavioural, computational, large-scale electrophysiological and imaging tools to study genetically- and anatomically-defined neuronal circuits in behaving mice. These studies will result in a quantitative circuit-level understanding of complex choice behaviour, and will ultimately provide insights into the pathophysiology of diseases compromising cognition.","Decision making concerns every aspect of our lives. Research in neuroscience has identified brain regions which play fundamental roles in choice behaviour. However, it remains unknown how the neuronal circuits embedded in these brain regions regulate learning and decision making. Our team aims to answer this question at the level of individual neurons and the communication pathways among them. We will teach mice to perform a simple decision task. Meanwhile, we will study the electrical activity of cells in the front part of the brain, a critical node for decision making, and dopamine-producing cells, known to be involved in learning. We will go one step further and test if we can influence learning by activating specific cellular communication pathways using novel optical methods. By understanding the cellular foundation of decision making, this research could shed light on why and how the brain begins to dysfunction­ in psychiatric disorders.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_17029,Cancer Research UK,CRUK,City of London AZ-CRUK Clinical Academic Training Award,"The CoL Centre is ideally placed to train and support AZ CRUK CRTFs; as a world class hub in cancer biotherapeutics the Centre’s unique partnerships bring together a wealth of resources in terms of infrastructure, technical expertise, knowledge, networking, collaborations and access to training. The strategic priorities of AZ and CRUK run parallel with the CoL Centre’s research objectives, thus the Centre is ideally placed to host these fellows.",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_21637,Innovate UK,IUK,Clinical Development and Validation of a Novel Optical Facebow based on Deep Learning,"Digital dentistry is the future. Dental patients and dental professionals alike increasingly expect better, more predictable and cost-efficient outcomes for their treatment and incorporating the latest technology is a logical step in achieving those aims. CAD/CAM and the use of 3d scanning and printing is in common use in many industries, but many dentists and dental technicians have been relatively slow to fully adopt this digital approach. The barriers to adoption entry are: in the main, high cost, poor accuracy of the scanning technology and limitations of use for certain more complex, but common dental procedures. 3d scanners, which scan impressions or models of a patient's teeth, are in use in both dental surgeries and dental laboratories and. They can simplify the process of creating dental crowns, bridges, implants and dentures., hHowever, it is a common problem too often thethat scans taken of what is a highly complicated anatomical structure are insufficientlynot accurate enough to work from and consequently result in poor fitting dental work which may lead to failure or future complications. Critically, the inability to accurately record the patient's jaw relationship and relate that to key facial landmarks digitally means that much digital technology has limited applications in more advanced restorative dentistry reconstruction and smile design treatment planning. Overcoming these problems will improve patient experiences, dental health and make a complicated clinical process much more efficientstreamlined. By undertaking this project, Mimetrik Solutions Ltd, a spin-out company incorporated to commercialise the research and development output of the Digital Dentistry Department of the School of Dentistry at the University of Leeds, will seek to solve the issues commonly seen in all the 3d scanning equipment currently available in the marketplace. Building on over ten years' work by world- leading experts in the field, an advanced prototype that has already been tested and validated in a large multi-centre pilot study will be developed further to ensure the device is ready for commercial manufacture so that the benefits it can bring can be accessed by all.",,5.3 MEDICAL DEVICES,ORAL AND GASTROINTESTINAL HRCS22_01293,Medical Research Council,MRC,Clinical Research Studies in the UK and PNG; A: UK Clinical research and B: Kuru field studies in PNG,"Kuru is one of a closely related group of neurodegenerative conditions which affect both humans and animals known as the transmissible spongiform encephalopathies or prion diseases. Animal prion diseases include scrapie, a naturally occurring disease affecting sheep and goats, which has been recognised for over 200 years and is present in many countries world-wide, and the much more recently recognised bovine spongiform encephalopathy (BSE) amongst cattle. The human prion diseases have been traditionally classified into Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Sheinker syndrome (GSS) and kuru. Kuru provides the principal experience of an epidemic human prion disease. It has steadily declined in incidence following the abrupt cessation of its route of transmission, endocannibalism, in Papua New Guinea in the 1950s. The arrival of the novel acquired prion disease, variant CJD, and the unknown prevalence of infection following the extensive dietary exposure to BSE prions in the UK, has led to renewed interest in kuru, particularly with respect to the range of possible incubation periods and the effect of genetic susceptibility factors. That the incubation period of infection acquired by dietary exposure to human prions can exceed 50 years, as found in kuru, suggests the need for caution with respect to predictions of vCJD epidemic size and duration based on the numbers of clinical cases seen to date. Infection of humans with cattle BSE prions involves cross-species, rather than within-species transmission, which would further increase the mean and range of incubation periods. The research activities have seven major aims. (1) Identify and study all remaining kuru patients: document the maximum incubation periods: We have studied the clinical features of recent kuru patients and compared clinical and other diagnostic features with other human prion diseases, notably iatrogenic and variant CJD. Surveillance for new patients is ongoing. (2) Epidemiological analysis of kuru records: Data will be analysed for standard epidemiological variables and differences in geographical area. (3) Document mortuary feast practices and traditional beliefs of the aetiology of kuru by interview of surviving participants and other members of the Fore community: A large number of interviews have been conducted and are being analysed. More interviews are planned to expand the cultural and geographical range of the study and to probe deeper into the details of the mortuary rites. (4) To investigate for any evidence of maternal or other routes of kuru transmission: From the data available we conclude that maternal transmission was not a feature of kuru. The data on mortuary practices do not support a high probability of parenteral transmission. Thus the common route of transmission was undoubtedly oral. (5) Genetic susceptibility: details of laboratory studies are given under Unit Human Molecular Genetics research programme. (6) Peripheral pathogenesis, tissue distribution and investigation of possibility of asymptomatic carriers of kuru: Tissues obtained from a kuru autopsy are under intense investigation. We will interview elderly survivors of the kuru epidemic in all affected linguistic groups to look at factors affecting the transmission of kuru. We aim to obtain autopsies when these older people die to determine whether any were asymptomatic carriers of kuru. (7) Data archive and bibliography: A full inventory will be made of all the kuru and kuru-related files. When the appropriate equipment is available archival and contemporary footage will be combined and edited on digital format for making teaching films on kuru, of varying length and complexity suitable for medical educational purposes.",,"2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",NEUROLOGICAL HRCS22_19354,Cancer Research UK,CRUK,Clinical Training Award Cycle 4 2018,"Clinical Training Award: The Cancer Research UK Cambridge Centre will bring together the diverse strengths of Cambridge to create novel practical applications that will improve the detection and treatment of cancer. The Centre will develop programmes in early detection, and integrative cancer medicine with the aim of developing new therapeutic approaches (http://www.cruk.cam.ac.uk/).",,4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),CANCER AND NEOPLASMS HRCS22_06985,Health Education England,HEE,Clinical and Patient Reported Long-Term Outcomes in Children with Chronic Intestinal Pseudo Obstruction: A UK Multi-Centre Study.,"Background Chronic Intestinal Pseudo-Obstruction (CIPO) affects the nerves, muscles, or both, of the intestine, resembling a physical obstruction in the absence of a true mechanical obstruction. This syndrome represents one of the main cause of intestinal failure in children and is characterised by pain, distended abdomen, incontinence, severe feeding difficulties, high morbidity and mortality. It is reported that 70% of children with severe CIPO require life-long Intravenous (IV) nutrition. Failure of IV Nutrition therapy indicates the need for bowel transplantation, with CIPO accounting for 50% of children/young people (CYP) awaiting bowel transplantation in the UK today. As well as significantly impairing quality of life (QoL) of affected CYP, CIPO results in considerable psychological and emotional burden for both patients and their families. CYP are reported to have significant pain, depression and anxiety, whilst their parents have poor emotional functioning. Current Practice Since 2012, diagnosticservices for CYP with suspected CIPO in the UK have been centralised. NHS England commissioned a National CIPO Diagnostic Service, with the aim of providing timely and accurate diagnosis, enabling early appropriate management strategies in order to change the natural history of the disease. Since April 2012 the service has investigated over 120 children. In a recent small study families stated they are living with fears around 'uncertainty' and 'death' of their child. Consultation with families identified that even when the CYP's health improves, these fears remain. Progress for CYP with CIPO has been made in recent years in the areas of IV Nutrition and transplant. With more CYP being diagnosed, and surviving, it is imperative that QoL is also explored. Long-term outcomes relating to early life interventions are needed now. Clinicians need to be providing the right treatment choices from the start. There is a hypothesis of early surgical intervention (forming a stoma), providing better patient outcomes, which is evidenced with some patients - but there are no long-term larger cohort studies. Research Questions 1. What are the long-term clinical, nutritional, educational and QoL outcomes of children and young people with Chronic Intestinal Pseudo-Obstruction in the UK? 2. Is there a difference in QoL between those with and without a stoma? Research Plan Design: A multi-centre mixed methods cohort study conducted over 4 phases with each phase informing the next. PHASE 1: Qualitative interviews, conducted in clinic or at home, with 15-20 CYP and their parents to understand the factors that impact on their QoL and what outcomes matter to them. Creative methods will be used with younger children. PHASE 2: Themes identified from the interviews will be used to select questionnaires measuring factors of importance which will be used in Phase 3 with the larger cohort. PHASE 3: Follow-up of all 85 CYP diagnosed with CIPO since April 2012, the majority of whom are seen in the collaborating 9 UK paediatric centres. Data will be collected under 4 main domains: Clinical, Nutrition, Education and QoL. Parents/CYP will complete questionnaires assessing areas identified in the interviews and clinical and nutritional data will be collected from the clinical notes. PHASE 4: A dissemination workshop to develop recommendations for practice. Results from this study will provide clinicians with the evidence to support their decisions about treatment pathways. This will result in improvements in mortality and morbidity, and fewer transplant referrals for CYP with CIPO in the UK today. A UK cohort study is needed to provide families with information about treatment and survival. Newly diagnosed families will be able to plan around an up-to-date prognosis. The NHS goals of improving care, reducing variability in patient pathways and increasing efficiency will be addressed for this unique patient group.","Background Chronic Intestinal Pseudo-Obstruction (CIPO) is a rare bowel disease of childhood. It is a condition in which the nerves, muscles, or both, throughout the bowel do not function. Symptoms are pain, bloated abdomen, vomiting, incontinence, and feeding difficulty. Over half the children who have this condition are affected so badly they are unable to process enough food for them to grow or survive, and they present with gut failure; around 50% of children waiting for a bowel transplant in the UK have CIPO. Children with gut failure survive in a similar way to children with renal failure - with a dependency on machines. They are regularly attached to pumps to have Intravenous (IV) Nutrition filtered into their blood. Unfortunately treatment itself is life-threatening. Interviews in 2012 identified that parents feel 'overwhelming sadness' during the diagnostic period. They fear their child will die, and worry about feeding and schooling. In a follow-up study 4 years later the families still expressed fears of death, even if a child's condition had improved. The children themselves worried about schooling, social exclusion and dignity.Current practice The NHS is supporting doctors in the UK to recognise CIPO in children. A centrally based National CIPO Diagnostic Service was commissioned by the NHS in 2012. Paediatricians now have established pathways to follow if they suspect a child/young person has this condition. Paediatric specialists make treatment recommendations, the aims of which are to reduce pain, maximise normal feeding, and prevent further damage to the affected bowel, thus improving survival. The primary and frequently controversial decision is whether to have a bowel operation or not, and when. There is emerging evidence that some children/young people who have an operation for a stoma (artificial opening from the bowel onto the stomach wall) have reduced dependency on IV nutrition, manage oral feeding, get to school, and are surviving. What we need to know is whether this bowel operation has been effective with others, and if there is an optimal time to operate on the next newly diagnosed child. There is reluctance amongst doctors to perform this operation without evidence from a larger group, and families are seeking reassurance that this body-changing surgery will help. Once diagnosed at the national centre, children/young people return to their local hospital for ongoing management. There is no standardised care. Following-up these families could reveal who does better. Doctors across the UK would then have evidence to help future children/young people with CIPO avoid IV nutrition or transplant.Research questions What are the long-term clinical, nutritional and quality of life outcomes of children/young people with CIPO in the UK? Is there a difference in quality of life between those with and without a stoma?Research Plan The study will be conducted over four phases, each phase informing the next. Phase 1: 15-20 children/young people and their parents will be invited to take part in interviews to understand the factors that impact on their quality of life and what matters to them. Interviews will be conducted in clinic or at home. Creative methods (e.g. drawing) will be used with younger children. Phase 2: Themes from the interviews will be identified and will inform the selection of questionnaires to be used in Phase 3 with the larger group of children/young people. Phase 3: We aim to recruit all 85 children/young people with CIPO, diagnosed through the UK service, between 3-9 years ago, with and without stomas. Their progress will be explored in 4 domains, chosen as a result of what parents/CYP have told us is important to them: 1) Medical - hospitalisations, surgery, complications/transplants. 2) Nutrition -h; improvement/deterioration in feeding. 3) Education -h; school attendance and teachers' assessment. 4) Quality of Life -h; measuring what matters to parents and children, as described by them. Visits will be made to families when they attend their regular local hospital outpatient appointment. Phase 4: A workshop will be held with families and staff to tell them the results of the study and develop draft recommendations for changing practice. Currently, we do not know if surgical stomas are helping avoid IV nutrition, or transplant in the long term. Results of this study will help doctors make evidenced-based decisions, improving survival and quality of life for children/young people with CIPO in the UK today. A UK cohort study is needed to provide families with information about treatment and survival. They may be given hope, to replace fear of death, and so can then accurately plan their child's education and future.",6.4 SURGERY,ORAL AND GASTROINTESTINAL HRCS22_09547,Health and Care Research Wales (Welsh Government),,"Clinical and cost effectiveness of an early exercise programme on chronic pain and health-related quality of life following blunt chest wall trauma: A parallel, randomised controlled trial (ELECT2 tri","Background Blunt chest wall trauma (BCWT) accounts for 15% of trauma admissions worldwide.[1] Chronic pain and disability have been reported in 62% and 57% at three months post injury respectively.[2] Physiotherapy is considered a first line treatment for BCWT, however there is little supporting research or universally accepted evidence-based guidance.[3] Standard physiotherapy traditionally involves breathing exercises. Further research is needed to establish best management for addressing chronic pain and health-related quality of life (HRQOL) in patients with BCWT. Research (PICOT) question: In adult patients presenting to hospital with BCWT(P), what is the impact of standard chest physiotherapy and an early exercise programme consisting of simple thoracic and shoulder girdle movements(I), compared with standard chest physiotherapy only(C), on chronic pain prevalence and severity and health-related quality of life(O) at three months post-injury(T). Trial aims: a) Investigate chronic pain prevalence and severity and HRQOL at three months post-injury, using the Brief Pain Inventory (BPI) and EuroQual 5-dimensions, 5-Levels (EQ5D-5L) in adult patients with BCWT who present to hospital, receiving either standard care, or an early exercise programme and standard care. b) Conduct focus groups to investigate the experiences of patients completing the intervention. c) Conduct an analysis of the short-term cost-effectiveness of the exercise programme. Study design: A feasibility study has already been successfully completed testing the methods proposed for this trial.[4] A multi-centre parallel, randomised controlled trial design will be used. Following presentation of our feasibility study results, five sites have agreed to participate in this study. Four sites in Wales and one in England, will recruit patients over a 12 month period. All adult patients with isolated BCWT (defined as any injury ranging from bruising to the chest wall to rib fractures with or without underlying injury to the lung, and no concurrent injuries that preclude completion of the exercise programme), presenting to hospital will be assessed for eligibility to participate. Following recruitment, patients will be randomised (stratified according to number of rib fractures and clinical frailty score) to either the control group receiving standard care only (chest physiotherapy treatment such as breathing exercises and early mobilisation), or the intervention group receiving standard care supplemented with a programme of four thoracic/shoulder girdle exercises (delivered by the physiotherapist who routinely delivers standard care). This programme will be continued by the patient, five repetitions per exercise, three times per day, for 7 days post recruitment. The programme was shown to be safe in our feasibility study, with no adverse events reported.[4] Following randomisation patients will complete BPI and EQ5D-5L surveys at baseline and 3 months post-injury, as shown to be appropriate measures in our feasibility work.[4] Outcomes will include chronic pain prevalence/ severity and HRQOL. Focus groups convened at the end of the trial will assess the acceptability of the programme. Cost-effectiveness will assess whether the programme represents good value for money to the NHS. An improvement in chronic pain or HRQOL will be valuable to the NHS due to a reduction in resource use in primary care, outpatient physiotherapy and chronic pain services.","Why we are doing this: Over 1800 adult patients with rib injuries (ranging from simple bruising to broken ribs with injury to the lung) attended a Welsh hospital in 2018. We know from previous research that chronic pain (known as pain lasting more than three months) and poor health-related quality of life was reported by over one third of patients with a rib injury. Despite this high number of patients with pain, the physiotherapy treatment normally given to patients, has not been tested in a trial. What we hope to discover: Whether an exercise programme delivered by the physiotherapist, consisting of simple trunk and shoulder movements, can reduce the rate of chronic pain and improve health-related quality of life in adult patients presenting to hospital with rib injuries, when compared to no exercise programme. To achieve this, we will: a) Assess how many patients with rib injuries completing a simple exercise programme, report chronic pain, the severity of the pain and their overall self-reported quality of life. This will be compared to patients with rib injuries not completing the exercise programme. b) Explore patients’ opinions of the exercise programme, whether they think it is helpful or not and if not, how it could be improved. c) Assess the short-term cost-effectiveness of including an exercise programme as part of usual clinical practice. How we will do this: We recently completed a feasibility study in which we tested the methods of this proposal.[4] On a small number of patients, we tested a simple exercise programme consisting of four trunk and shoulder movements, that the patients completed for one week, three times per day. In this study, any adult patient with rib injuries (and no other injuries that prevent completion of the exercise programme) who attend one of four hospitals in Wales or one in England, will be put in either the control (receiving usual care only) or treatment group (receiving usual care plus the exercise programme). Both groups will complete a questionnaire booklet when they attend hospital and again three months later. This will allow us to assess whether the exercise programme helps reduce the rate and severity of chronic pain and improve health-related quality of life. We will talk to the patients to gain their opinion of the programme. We will assess whether the exercise programme is cost effective for the NHS. How the public has been involved: Our team of five diverse patient representatives has been part of this work for five years. They have been involved in all aspects of project development and management. They provide an invaluable insight into the patient's perspective in all of our research work. One of these patient representatives has been involved in the design and management of our recent feasibility study related to this proposed full trial. She has also been involved in the completion of this application. She will continue to support and advise on the running of this trial, if our funding application is successful, and will be joined by our other patient representative at that time. How we will tell people about the findings: A series of local and national webinars will be used to achieve a wide clinical audience. We will publish our results in a suitable journal and present at Trauma Conferences. The study's patient representatives will present their involvement experiences at the Involving People Annual Meeting and the bi-annual INVOLVE Conference.",6.7 PHYSICAL;8.2 HEALTH AND WELFARE ECONOMICS,INJURIES AND ACCIDENTS HRCS22_03077,Medical Research Council,MRC,Clonal dynamics and mutational landscape of normal and cancerous tissues in cancer predisposition syndromes,"This study aims to investigate the consequences of TP53 inactivation in malignant transformation, as well as in the development and maintenance of healthy tissues, using tumour and histologically-normal samples from Li-Fraumeni syndrome (LFS) individuals. LFS is a rare familial cancer syndrome caused by heterozygous germline pathogenic variants in TP53, which confer an increased risk of early onset cancer in diverse tissues of origin. Specifically, we will implement a multidisciplinary approach combining spatially-resolved, multi-omic technologies with single-clone and single-molecule resolution to delineate the patterns of mutations and mutational processes, clonal evolution and phylogenetic relationships of cells in LFS individuals. In Work Package (WP) 1 we will analyse samples from diverse histological structures (at least 25) collected post-mortem from ~10 LFS individuals. We will perform laser capture microdissection (LCM) combined with low-input whole-genome sequencing (WGS) on clonal structures, and NanoSeq on non-clonal tissues. The resulting data will allow us to study the consequences of pathogenic TP53 variants on the behaviour of normal cells and clones during life across diverse tissues. In WP2, we will apply WGS on multiple regions extracted using LCM from diverse tumours arising in LFS patients. We will primarily focus on studying the early events triggering the clonal expansion of malignant clones in an LFS background, and will compare the patterns of somatic alterations observed in benign clonal expansions with those leading to malignant transformation in LFS individuals, and in sporadic tumours driven by TP53 inactivation. In WP3, we will perform RNAseq and EMseq (low-input bisulfite sequencing) on the LCM samples collected in WP1 and WP2 to study transcriptional changes and epigenetic modifications in both histologically-normal tissues and tumour samples from LFS individuals.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_05811,Department of Health and Social Care,NIHR,Cluster randomised trial to improve antibiotic prescribing in primary care: individualised knowledge support during consultation for general practitioners and patients,"Antibiotics are medicines that are used to prevent and treat bacterial infections. The world urgently needs to change the way it prescribes and uses antibiotics. Without this urgent action, we are heading for a post-antibiotic era, in which antibiotics no longer work (known as antibiotic resistance) and common infections can once again kill. From earlier studies, we have found that general practitioners (GPs) are as likely to give an antibiotic to patients with very low risk as to those with high risks of complications due to infections. Moreover, not every bacterial infection needs to be treated with an antibiotic as most patients get better naturally. In this project, we aim to change the antibiotic prescribing practices of GPs using two methods: (1) by providing advice (“knowledge support”) during consultation on the best approach to treat the patient with an infection; and (2) by providing regular feedback about their prescribing using online displays (“dashboards”).. The information given on these dashboards will be based on analyses of anonymised patient records from their GP own practice and will show how their antibiotic prescribing compares to that of other practices. In addition to the dashboards, we will also provide GPs in half of the practices taking part in our project with the knowledge support intervention.. The practices will be selected by flipping a coin (a “cluster randomised trial”). The knowledge support given will consist of a display on the GP’s computer while seeing the ill patient. The GP will need to enter answers to standard questions about the patient’s condition (such as presence of fever). Then, in response, the GP will be presented with feedback on the patient’s risk of complications due to the infection without an antibiotic treatment. This estimate of risk is based on analyses in large national research datasets containing anonymised records of patients with similar conditions. The GP will also receive information about how other GPs would treat similar patients (also known as ‘benchmarking’). The GP will also be able to print out a patient information leaflet that gives personal information about the need of being treated with an antibiotic. For example, a 25-year old patient with a sore throat and minimal symptoms, but otherwise healthy, who is consulting their GP would receive information that the risks of developing complications from not taking antibiotics, although not zero, are very low. This patient information leaflet would also contain information about the risks of taking too many antibiotics and of developing resistance to this antibiotic (so it no longer works for future infections). On the other hand, an elderly patient suffering from multiple diseases would receive information about the importance of taking antibiotics. This approach of giving personalised information is in line with previous studies that showed that patients valued written information that was tailored to their individual circumstances and illness, presenting a balance of harm and benefit related to their treatment. The contents of the patient leaflets will be co-designed with members of the public. The GP will be able to ignore this ‘knowledge support’ or decide not to give the leaflet to the patient. The main outcome of interest is whether this ‘knowledge support’ reduces the overall level of antibiotic prescribing without harming patients by not treating with antibiotics.","Antimicrobial resistance is a major threat to public health due to the combination of increasing prevalence of resistant pathogens and diminishing development of new antimicrobial agents. The NHS 2019 Long Term plan states as priority to continue to optimise use, reduce the need for and unintentional exposure to antibiotics. Primary care accounts for 81% of antibiotic prescribing in England. Recent research has found that the likelihood of being treated with antibiotics for a common infection is unrelated to a patient’s risk of infection-related hospital admission. Furthermore, repeated courses of antibiotics, although common practice in primary care, may have limited benefit and be an indicator of adverse outcomes. This project will implement and test a Knowledge Support (KS) infrastructure that provides individualised information to clinician and patient during consultation. This KS would provide real-time, personalised comparative information relevant for the patient’s clinical scenario. By a simply clicking on an icon on their computer screen, clinicians get access to information on “patients like mine” (e.g., the risks of developing clinical complications in similar patients and number-needed-to-treat [NNT] to prevent one hospital admission), tailored recommendations (e.g., best not prescribe amoxicillin given this patient’s frequent prior use), and a patient leaflet that is individualised to the patient. The research question of this project is to evaluate whether individualised KS for General Practitioners (GPs) and patients reduces the level of antibiotic prescribing without increasing the risks of infection-related complications. The KS will be based on the TRANSFoRM infrastructure which activates when the GP enters specific clinical codes into the computer. Symptom information can then be entered along with information on the patient’s medical history and previous antibiotics prescribed. The study design will be a cluster randomised trial comparing two parallel groups of GPs in the UK. In the intervention practices with KS, GPs will be provided with nudging feedback on their individual-level antibiotic` prescribing and their opportunities to improve antibiotic prescribing. The KS activation will be tailored to each individual GP. In collaboration with NICE and Public Health England, this project will develop NNT for infection-related complications and determine possible thresholds for antibiotics across different common infections as well treatment patterns (including incidental and repeated antibiotic use). In addition to NNT, the KS will also provide information on treatment benchmarking (i.e., level of agreement between GPs), which will be developed using the Delphi approach. The personalised patient leaflets will be co-designed with members of the public, including a survey with ranking of different information domains (such as likelihood of the patient developing complications, NNT for antibiotic treatment and possible effects on future resistance). The economic and budget impact of KS will be estimated using incremental cost-effectiveness ratios. A sample size calculation indicates that 124 practices are required (power of 90% for 10% reduction in antibiotic prescribing). This project will implement an exemplar in which insights from advanced analytics of NHS data are made accessible to clinicians and patients when they are making decisions about their care.",7.3 MANAGEMENT AND DECISION MAKING,GENERIC HEALTH RELEVANCE HRCS22_09509,Health and Care Research Wales (Welsh Government),,Co-PaCT study: Development of Co-produced guidance for the care of Patients with blunt Chest wall Trauma: a mixed methods study,"Identifying patients with isolated blunt chest wall trauma (BCWT) who are at high risk of developing delayed complications is a well-recognised complex problem.[1] Morriston Hospital Emergency Department (ED) managed over 1100 patients with BCWT in 2018. Over 1000 of these patients were discharged directly from the ED, which reflects the high volume of patients who are expected to self- manage their injury at home. Of those discharged directly home, 848 patients were instructed to see their General Practitioner (GP) if they experienced problems. In our recent STUMBL Trial, 6% of all trial patients had an unplanned re-attendance at the ED with on-going problems, having been previously discharged home without hospital admission.[1] Decisions regarding care and service innovation primarily focus on efficiency (to reduce number of hospital admissions), rather than patient needs. In this study we propose to gain understanding of the patient experience of being managed at home, and to work with stakeholders to co-produce guidance aimed at improving care of the patient with BCWT. Aim: To co-produce guidance for optimal care for patients with BCWT not requiring admission to hospital; based on current best practice, epidemiological data and stakeholder experience and opinions. Research questions: 1) What is current practice regarding guidance for the management of patients with BCWT who are not admitted to hospital? 2) What is the epidemiology of patients with BCWT who are not admitted to hospital? # Patient characteristics: age, severity of injury, pre-morbid history, risk factors for pulmonary complications. # Management strategies: advice sheets and analgesia provided, provision of follow up. # Outcomes – further ED or Minor Injuries Unit (MIU) contacts, primary care usage, hospital admissions, primary admission diagnosis (on re-attendance), length of stay and mortality 3) What are the patient perspectives of non-admission to hospital? # Patient perspectives on service provided and recovery from BCWT versus initial expectation # Current service models used in clinical decision-making, including follow-up provision # Recommendations for inclusion in the co-produced guidance to improve care for patients with BCWT who are not admitted to hospital Design: A mixed methods study using national anonymized linked routine data and qualitative methods in Swansea Bay University Health Board (SBUHB) (Morriston Hospital ED and Singleton and Neath Port Talbot Hospital MIUs). Plan of investigation: 1. Investigate current UK practice through a survey study, regarding management of BCWT guidance in the community setting 2. Identify patients with BCWT through the Information Department based at Morriston Hospital (who are discharged home from the ED or MIU without hospital admission) and anonymously link to their NHS health data 3. Conduct qualitative focus groups with patients and clinicians in the ED 4. Facilitate co-production workshops with stakeholders 5. Dissemination of co-produced guidance and maximisation of study impact.","Many patients go to A&E for help when they have hurt their ribs. A large proportion of these patients are elderly, frail people who have fallen. Four times more people fall and hurt their ribs, than those who break their hip, but much less is known about the people who hurt their ribs and how best to manage them. If they are sent directly home from A&E, the patient is expected to manage their injury on their own, and this can often mean that the patient needs to go back to A&E or to the GP. If they do get a chest infection or pneumonia, this can lead to a long hospital stay, or can even be fatal. There are currently no standard guidelines that can be used to help care for the patients who are discharged home from A&E. We aim to develop guidelines that can be used to improve the care of patients with rib injuries, who are not admitted to hospital. We will do this by working with these patients and with the clinicians who manage the patients in A&E. What we want to understand: 1) How clinicians in the UK currently manage the patients who are directly discharged from A&E; 2) The similarities and differences between the people who have injured their ribs and been managed at home in the past. We want to know: a) their age, how severe their injury was, did they have a lung disease before they hurt their ribs, what medication they normally take. b) what painkillers they were given by A&E and whether the painkillers helped, what advice (If any written or verbal) they were given in A&E. c) whether they developed a chest infection or their pain was unmanageable, whether they went to their GP or back to A&E, what tablets they were given when they went back, whether they needed to be admitted to hospital and if so, how long they stayed in hospital.",7.3 MANAGEMENT AND DECISION MAKING,INJURIES AND ACCIDENTS HRCS22_09442,"Public Health Agency, NI",PHA,Co-design and feasibility testing of an Holistic Approach for Rehabilitation and Medical OptimisatioN after IntenSivE care (HARMONISE),"Background: People experience a variety of physical, psychological and cognitive complications following discharge home after critical illness. Rehabilitation may be able to address these problems, however there is currently no standard evidenced-based approach for rehabilitation following discharge home after critical illness in the UK, and the level of support people receive depends on where they live. People may also have new clinical needs following ICU admission, including multimorbidity and polypharmacy which are strongly associated with readmission and mortality risk. They may also experience social problems, including unemployment and the need for additional support at home from family or carers. Remote rehabilitation programmes have been shown to be clinically- and cost-effective in settings outside critical illness. However, emerging evidence indicates some people may be unable to participate in a fully remote intervention due to logistical and personal factors. Research questions: Is it possible to 1) co-design a feasible and acceptable personalised multicomponent intervention which addresses rehabilitation, clinical and social needs of patients after critical illness, and 2) deliver the intervention through a hybrid of remote and face-to-face care based on individual patient needs? Methods: Two scoping reviews will inform intervention development by identifying 1) clinical conditions following critical illness which are amenable to treatment (treatable traits) and 2) factors impacting participation in rehabilitation programmes following critical illness. I will then work with patients, relatives and healthcare professionals to co-design a multicomponent intervention, (called HARMONISE) with a personalised hybrid of face-to-face and remote delivery. Using a mixed methods approach, the feasibility and acceptability of the HARMONISE multicomponent intervention will be evaluated. Anticipated impact and dissemination: I will share the findings with patient groups, healthcare professionals, and researchers. If the HARMONISE intervention is feasible and acceptable, it will lead to a trial to evaluate clinical- and cost-effectiveness.",,7.1 INDIVIDUAL CARE NEEDS,GENERIC HEALTH RELEVANCE HRCS22_07211,Department of Health and Social Care,NIHR,Co-design of a tailored intervention to support pressure ulcer prevention behaviours by older patients and their lay carers in community settings (C-PrUP),"Aim To co-design a theoretically-underpinned, healthcare professional (HCP) mediated, tailored intervention to support housebound older patients and their lay carers to adhere to pressure ulcer (PU) prevention behaviours. Objectives Assess current practice and identify adherence/non-adherence with PU prevention guidance with older housebound patients and their lay carers Assess barriers and facilitators to key behaviours that reduce the risk of PU Co-design with patients, lay carers and HCPs an intervention to support patients and lay carers to adhere to best practice in PU prevention Background PUs are localised injuries to the skin and underlying tissues that incur a substantial financial burden on the health service, absorbing approximately 4% of the annual NHS budget. Over 19% of patients receiving care in their own home will suffer from a PU at any time, resulting in increased hospital admissions, morbidity and mortality and decreased quality of life. PU prevention is a priority for patients, carers, HCPs and commissioners. Clinical partners and Patient and Public Involvement and Engagement (PPIE) representatives want to know what can be done differently to reduce incidence. Since HCP visits to housebound patients are increasingly limited, there is greater reliance on self-care and support from lay carers. Methods and timeline This project is Stage 1 of a three-stage research plan. Stage 1 includes two Phases Phase 1 Theoretically informed qualitative interviews to understand barriers and facilitators of adherence to PU prevention behaviours by older housebound patients and their lay carers (Months 1-12). We will investigate what people actually do and why they do what they do. Data will be analysed to identify barriers and facilitators to PU prevention behaviours, and charted against the domains of the Theoretical Domains Framework (TDF). Phase 2 Co-design of a theoretically informed, HCP mediated, tailored intervention to support adherence to PU prevention behaviours (Months 12-18). The TDF domains identified will be used to select appropriate Behaviour Change Techniques (BCTs). The co-design group of patients, lay carers and HCPs will translate BCTs into practical ideas before consensus is reached on modes of delivery. Prototypes will be developed and assessed against established criteria. Anticipated impact and dissemination Impact at this stage is involvement of an underserved community in the co-design of an intervention to reduce the risk of PUs. Dissemination will be through conference presentations, information accessible to patients and the public (including YouTube films and twitter accounts), and a study-specific Twitter and web presence. Subsequent to this project, the trajectory to improved care will be: Stage 2: Feasibility testing and refinement of proposed intervention and feasibility trial (2022-2024) Stage 3: Randomised controlled trial to investigate effectiveness and cost-effectiveness of the intervention (2024-2027). By reducing PU risk, patient comfort, safety and quality of life will improve, as will knowledge, skills and confidence of lay carers. A conservative estimate based on local data suggests that a 5% reduction in severe PUs would mean that 66 individuals would be prevented from needless suffering, with a cost saving of approximately £800,000 in one locality alone.","We aim to change patient and lay carer health behaviours to reduce the risk of pressure ulcer (PU) (often known as a bedsore) development. We will develop a toolkit informed by theory and evidence. Around half a million people in the UK develop a PU each year. PUs reduce health and wellbeing and are costly for the NHS. We will work with older people living at home and their lay carers, an often-underserved group. Our study is important because i) our population is ageing and for most of the time responsibility for PU prevention activities rests with themselves and their family and ii) we do not yet know the best ways to help this group minimise their risk of PU development. We will systematically use the stages of psychological theory which we know are effective in getting people to change embedded health behaviours. Firstly, we will interview adult patients (65 years and over) with limited mobility (often described as being housebound) who are at risk of PUs and their lay carers (unpaid carers, most often family members). We will ask i) what PU prevention advice and information they have been given (e.g. moving around, changing position, healthy eating, checking their skin) and ii) how, why and how much they follow this advice. Secondly, findings from these interviews will inform development of a toolkit to help patients and lay carers follow advice to reduce the risk of PU and change existing health behaviours. We will co-design the toolkit with patients, lay carers and healthcare professionals. It will be adaptable according to patient and lay carer needs. It may include, for example, videos, leaflets and reminders. We know that co-design is most likely to result in a toolkit that is acceptable, fit for purpose and used. The benefits to patients at this stage include: addressing a question that has been identified as important by patients, lay carers, health practitioners and policy makers co-designing an intervention acceptable to end-users, implemented in practice and that supports a personalised/needs-driven provision. Patient and public involvement and engagement (PPIE) has been integral to developing this application and will continue throughout the study. We have visited people who are at risk of PUs, and their lay carers, consulted with the Portsmouth Carers Centre and worked in partnership with PPIE co-applicants who have relevant experience. All agree this is an important research question. They have contributed to study design and how best to be inclusive throughout the study. We will share findings widely through social media, publications, conferences and events, aimed at lay, practitioner and policy maker audiences. Next steps are to test out the toolkit locally and then more widely in a trial to assess its effect.",7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES,SKIN HRCS22_09419,"Public Health Agency, NI",PHA,Co-designing an e-resource to support the resilience of care staff,"The aim of this project is to explore how nurses in care homes developed resilience during the COVID-19 pandemic outbreak and to codesign a digital resource to build future coping and adaptation strategies fostering increasing resilience. We will achieve this through the following objectives: 1. To identify the resilience profile of nurses in care homes following their exposure to the COVID-19 pandemic 2. To codesign an online resource for use by nursing staff in care homes to develop capacity to recover and adapt from adverse situations.3. To deliver and evaluate the online resource in how it promotes resilience of nursing staff in care homes This project is a mixed methods exploratory sequential design1. The project team will undertake a rapid review of the literature2 on interventions that build resilience in nurses to inform the three phases of the study. We also recognise the impact of traumatic events in care homes during the pandemic outbreak and will integrate trauma informed care principles across the three phases of study. Phase 1 will deliver a quantitative survey to 440 care homes across Northern Ireland. Nursing staff will be invited to anonymously complete a demographic questionnaire followed by two validated scales: Resilience Scale RS-253 and Resilience skills in nursing practice4. The findings will contribute to the development of a digital resource to enhance resilience in nurses working in care homes. These questionnaires will be administered via email and sample regional nurse managers, managers, clinical leads and nurses who practice in care home settings. We will work in partnership with the Public Health Agency (NI) to distribute the questionnaires aiming for 150-200 survey responses. Phase 2 will co-design an online resource involving the project team, nurses/nurse managers working in care homes, two practitioners working with mindfulness and yoga therapies and Morrow Communications. An online resource was chosen due to emerging evidence that self-guided internet interventions with multiple sessions might prevent PTSD symptoms in adults following a traumatic event6. As the purpose of the resource is to provide support to nurses working in care homes to cope and adapt in challenging situations over time thus building their resilience, the principles of trauma informed care will be presented as part of the codesign process. To develop the content of this resource, the results of the rapid review of the literature and the resilience questionnaires from the nursing staff in care homes will be used to support the identification of activities best suited to this context. Although to be developed through co-design, it is anticipated 09/09/2020, 18:59 https://outlook.office.com/mail/inbox/id/AAQkADQwOGFmY2Mw…MzMC04N2JhLTE1ZDI1YmQ2YjlkZAAQAA62OoWAUxlBqgZUQAywMp8%3D Page 6 of 17 that the resource will cater for different types of learners using the established VAK learning framework from Neil Fleming5: Visual: e.g 8-12 short videos covering different issues such as avoiding a sedentary lifestyle, how to look after wellbeing, parental mental health, money worries, stress management. This will include peer support by using nurses’ experience and how they coped. Auditory: e.g 8-12 podcast interviews between experts about aspects of resilience such as sleep hygiene, importance of exercise, good nutrition, art of motivation, benefits of mindfulness etc. Kinaesthetic: e.g activities such as mindfulness and yoga (24 sessions over 6 months) and interactive self-help guides as agreed by the codesign group. Phase 3 will evaluate the online digital resource using mixed methods: quantitative data collected from the resource to measure usage and engagement and individual interviews of care home staff who have used the resource to identify the personal benefits if any from the resource. Semi structured interviews with approx 10-12 participants across NI will be held via video conferencing. Quantitative data will be analysed using descriptive statistics. Qualitative data will be managed with NVivo software and analysed using thematic analysis6.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_06179,Department of Health and Social Care,NIHR,Cognitive Behavioural Therapy for the treatment of post-traumatic stress disorder (PTSD) in youth exposed to multiple traumatic stressors: a phase II randomised controlled trial.,"Background Posttraumatic Stress Disorder (PTSD) is a profoundly distressing and disabling psychiatric disorder that markedly impairs educational, social and daily functioning. PTSD is particularly severe, complex and enduring following multiple trauma exposure such as sexual/physical abuse, witnessing domestic violence or community violence. The current NICE-recommended treatment for PTSD in youth is a form of psychological treatment - Trauma Focused Cognitive Behaviour Therapy (TF-CBT). However, the evidence base for TF-CBT in youth exposed to multiple traumatic experiences is limited and there have been no UK randomised controlled trials (RCTs) of interventions for this population. NHS Child and Adolescent Mental Health Services (CAMHS) staff frequently report concern over best practice for this group, and treatment choice is not consistent with the current (albeit limited) evidence base. NICE, as well as recent narrative, systematic and Cochrane reviews, concur that there is an urgent need for further treatment development, supported by clinical trial evidence. The applicant's extensive work with children with PTSD following single incident traumas (traffic accidents, assaults) has led to the development of a TF-CBT protocol - the Triple M model of CBT (CBT-3M) -h; that has now been adapted to be suitable for children with PTSD following exposure to multiple trauma experiences. A case series study supports CBT-3M's strong potential for patient benefit in this population. The current proposal is therefore to conduct an RCT of CBT-3M for young people with PTSD following multiple trauma exposure. Research Objectives The primary objective of Study 1 is to evaluate the effectiveness of CBT-3M, delivered by front-line clinicians in routine settings for the treatment of PTSD in youth exposed to multiple trauma. The secondary objectives of this study are to provide preliminary evaluations of: a) the cost-effectiveness of CBT-3M; b) its mechanisms of action; and c) factors that may limit or facilitate the adoption of CBT-3M within routine care. Study 2 will evaluate how this population is currently treated in CAMHS, and the capacity of CAMHS to implement an evidence-based intervention such as CBT-3M. Plan of investigation Study 1 is a pragmatic, clinic-based RCT that will test the effectiveness of CBT-3M against treatment as usual (TAU). The design is a patient-level, single blind, two-arm, parallel pragmatic randomised controlled trial examining CBT-3M vs. TAU. Participants will be children and adolescents aged 8-17 years who have PTSD following exposure to multiple traumas. We will recruit 120 children and adolescents (60 per arm, 48 if 20% attrition is assumed) from CAMHS in East Anglia. The primary outcome variable will be PTSD severity, as assessed by the child PTSD routine outcome monitoring tool at post-treatment (i.e. 4 months post-randomisation). The secondary outcomes will be PTSD diagnosis, anxiety, depression, quality of life and parent-reported well-being. Embedded quantitative measures will allow for preliminary evaluations of the cost-effectiveness of CBT-3M and mechanisms of action. Qualitative data will be collected from a sub-set of participants receiving CBT-3M, treatment drop outs, parents/carers, clinicians and referrers; these data will identify potential obstacles or facilitators for implementation in routine care. Study 2 will use questionnaire surveys and semi-structured interviews with trial clinicians (from within the trial and UK-representative NHS Trusts), referrers, service managers and commissioners to index the current treatment offered to youth with PTSD following multiple trauma exposure, and the preparedness of NHS services to deliver evidence-based treatments (such as CBT-3M) to this group. Patient Benefit Evaluating an intervention for a population where there is substantive and identified clinical need has a strong potential for patient benefit. The proposal has scope for dramatically improving quality of care and cost-effectiveness for an under-served group, by equipping CAMHS services with an implementable treatment approach.","Background to the research Many tens of thousands of children and young people are growing up in households where they are subjected to sustained abuse and domestic violence, or experience repeated violence in their schools and local communities. The effects of these experiences can be highly damaging and in many cases may lead to life-long mental and physical health problems. Young people who develop post-traumatic stress disorder (PTSD) following these sorts of experiences appear to be particularly vulnerable to significant difficulties. PTSD is a highly disturbing condition that causes significant difficulties for young people and can last for many years. Despite the clear needs of this population, no UK studies have examined how this young people with PTSD following multiple trauma exposure might be treated in the NHS. Previous research by the applicant and his colleagues suggest that a psychological (i.e. talking) therapy called cognitive behavioural therapy (CBT) is a powerful treatment for children and people who have developed PTSD following 'one-off' traumas (e.g. motor vehicle collisions, violence, accidental injuries). This treatment has been carefully developed to target the particular mechanisms that keep PTSD going. However, the existing trials of this intervention have been conducted in highly specialist research clinics by 'expert' therapists, rather than front-line NHS settings. Moreover, these trials have not included young people with PTSD following multiple trauma experiences (e.g. abuse, domestic violence). A recent pilot study conducted by the applicant suggests that this CBT package is acceptable to this population, and delivers significant improvements in PTSD symptoms. Aims of the research The research will involve two studies. The primary aim of Study 1 is to see if a CBT package is an effective treatment for PTSD in young people who have experienced multiple traumatic experiences. In particular, we want to see if this treatment is effective when delivered by front-line NHS clinical staff (e.g. nurses, caseworkers, occupational therapists, family therapists) in normal clinical settings (i.e. Child and Adolescent Mental Health Services or 'CAMHS'). The secondary aims of this study are to ask the following questions: i. Is CBT a cost-effective treatment for PTSD in this group of young people? ii. How does CBT bring about clinical improvement in young people with PTSD? iii. What do young people, their families and CAMHS staff think of this treatment? This will help us to see how CBT might be used to treat PTSD in young people seen in CAMHS services throughout the UK. The aim of Study 2 is to examine how health and social care services are set up and currently care for young people with PTSD following multiple trauma exposure. Design and methods used Study 1 of the proposed Fellowship is a randomised controlled trial comparing a CBT package to 'treatment as usual' (i.e. normal clinical practice) for 8-17 year old young people with PTSD following exposure to multiple traumatic experiences. Young people allocated to receive CBT will receive up to 15 sessions of therapy. The main outcome measure will be the routine questionnaire for assessing PTSD symptoms in children and young people in the NHS, assessed at the end of therapy. Additional questionnaires and interviews will be used to address the secondary aims of the research. In Study 2, CAMHS staff will be surveyed to see how this population of young people are typically cared for, and what skills they currently have to support them. In particular, the views and experiences of referrers, NHS and social staff, service managers and commissioners will be investigated so as to explore how services might be better structured to effectively support young people with PTSD following multiple trauma experiences. Patient and public involvement (PPI) Young people belonging to the PPI group (inspire) of the local mental health trust will attend the Trial Management Group (TMG), serve on the Trial Steering Committee and provide input on how to best share the study findings. The Young People's Mental Health Advisory Group will review trial measures and setup, and help with the dissemination of results. Participants in the recently completed pilot study of this intervention will review the study methodology methods and tools. Local NHS clinicians and third sector representatives (e.g. from domestic violence support groups) will also attend TMG meetings and aid the process of disseminating the study findings. Dissemination In addition to publishing trial findings in peer-reviewed academic journals, study findings will be disseminated through national training workshops, on-line resources (e.g. webinars), guidelines for clinical teams and a report on developing appropriate services (for service managers and commissioners).",6.6 PSYCHOLOGICAL AND BEHAVIOURAL;7.3 MANAGEMENT AND DECISION MAKING,MENTAL HEALTH HRCS22_01577,Medical Research Council,MRC,Communication-centered Parent-mediated treatment for Autism Spectrum Disorder in South Asia (COMPASS).,"Objectives: Phase 3 trial of the clinical and cost-effectiveness of the 'Parent-mediated intervention for Autism Spectrum Disorders in South Asia-Plus' (PASS+) intervention in addition to treatment as usual (TAU) compared to treatment as usual (TAU) alone in India. The study will take the already successfully piloted PASS+ intervention to scale. Design: Two centre, two arm single (rater) blinded random allocation parallel group study of experimental treatment plus TAU against TAU alone. Primary endpoint 9 months, follow-up 15 months. Primary outcome: autism symptom severity (blind-rated Brief Observation of Social Communication Change). Secondary outcomes: include parent-child communication, child adaptation and QoL, parental wellbeing. Primary analysis intention to treat; planned secondary analysis of proposed mediators of treatment effect. Health Economic evaluation will estimate the cost-effectiveness of the intervention from a societal perspective using a QoL index valued to allow calculation of QALYs. Participants: 240 children aged 2 to 9 years with ASD, recruited from Autism clinics in two tertiary government hospitals in New Delhi, India. Treatments: PASS+ is a manualised and piloted adaptation of the UK Pre-school Autism Communication Therapy (PACT), that uses video-feedback with parents to help them enhance social communication in their autistic child. It will be delivered by existing health system frontline workers, in 12 home-based sessions. TAU in the two recruitment centres is delivered through weekly autism clinics, an eclectic mix of behavioural therapy approaches which are delivered once a month delivered by specialists. The duration of therapy is based on the families' ability to follow up, adherence is under 50%. Outcome: Generalizability and policy impact will be maximized through embedding the trial in routine facilities with embedded primary health-care workers, and using our policy influence to disseminate the findings.",,6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_20726,Wellcome Trust,,Community based interventions to improve HIV outcomes in adolescents: a cluster randomised trial in Zimbabwe,"HIV infection is the leading cause of mortality among adolescents in sub-Saharan Africa. Adolescents are the only group in which HIV-associated mortality is rising despite the global scale-up of antiretroviral therapy (ART). Adolescents fare disproportionately poorly across the HIV care continuum compared to other age-groups: the prevalence of undiagnosed HIV is substantially higher, and coverage of and adherence to ART is lower, resulting overall in worse virological outcomes. Current services are thus insufficient for achieving optimal outcomes, and complementary strategies are required to meet the UNAIDS 90-90-90 targets. The aim is to investigate whether a community-based, multi-component intervention incorporating HIV prevention, HIV testing, ART initiation, and ongoing adherence support, can improve virological suppression rates among HIV-infected adolescents in a high HIV prevalence setting The objectives are to: 1. Carry out a cluster-randomised trial in Zimbabwe comparing a) facility level HIV services with b) facility-based services plus the community-based intervention. The primary outcome will be proportion of HIV-infected adolescents in the community with an HIV viral load <1000copies/ml 2. Evaluate the cost and cost-effectiveness of the intervention. 3. To conduct a process evaluation of the intervention’s implementation, to inform components required for sustainability and scalability","HIV is the leading cause of death among adolescents in Africa. There are many reasons for this, including difficulties in getting HIV testing and in taking treatment. Current HIV services, which are mainly delivered in healthcare facilities, are clearly not sufficient, and additional strategies are required to help adolescents living with HIV to get diagnosed, and to support them to take their HIV treatment. The proposed project will evaluate an approach that will incorporate HIV testing, facilitate linkage to HIV treatment services for adolescents (aged 12-20 years) who test HIV-positive, and provide support to improve their capacity to take HIV treatment. The intervention will be delivered in communities in Zimbabwe, which has a high prevalence of HIV, and will complement existing services in health facilities. The study objectives are: 1. To carry out a trial to investigate whether the intervention is effective at improving the proportion of HIV-infected adolescents in the community whose HIV is well-controlled with treatment. 2. To investigate how cost-effective the intervention is in improving the number of years lived in full health by the beneficiaries of the intervention. 3. To carry out a process evaluation to understand how well the intervention is implemented",8.1 ORGANISATION AND DELIVERY OF SERVICES,INFECTION HRCS22_20861,Wellcome Trust,,Complete humanisation of adaptive cellular immunity in the mouse: Vaccine and therapeutic TCR discovery,"Adaptive cell mediated immunity is one of the central components of immunological homeostasis. While the basic mechanisms are conserved the components that encounter antigen are subject to rapid evolutionary change driven by species specific pathogens co-evolving with the host and divergence of the host genome against which antigen receptors are negatively selected. Thus, epitopes that direct protective immunological responses differ between species. Consequently, translation of results obtained from immunisations conducted in model organisms to humans remains a pernicious issue. The long term goals of this proposal are to identify and validate vaccine candidates and discover therapeutic T cell receptors To achieve these goals we will build mice in which all components of adaptive cellular immunity have been humanised, building on the technical success, biological insights and health-care benefits accrued from the construction of a mouse with a complete human immunoglobulin repertoire. We will use this humanised mouse as platform to isolate therapeutic T cell receptors for acute myeloid leukaemia in which the nucleophosmin gene has been mutated. In an independent and parallel work stream we will systematically explore the Plasmodium falciparum genome to identify vaccine candidates protective against the liver stage of the pathogen.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE;INFECTION HRCS22_03068,Medical Research Council,MRC,Comprehensive workplace intervention for cancer prevention in China,"Workplace cancer prevention interventions have been widely conducted in some high-income countries. However, the effective implementation of these evidence-based strategies is lacking in low- and middle-income countries (LMICs). It is an urgent task for LMICs to overcome the implementation barriers to reduce the cancer burden. This research aims to adapt existing strategies of workplace health promotion in the prevention and control of cancer and build a scalable model in China. The research is designed as a stepped wedge cluster randomised controlled trial. We will recruit 15 workplaces with approximately 1500 employees across three low and middle economic cities of China. All the workplaces will be staggered into intervention stage randomly for three steps and will receive a 12-months' intervention and then maintain to the end of the project. The duration of the project is 48 months. A comprehensive workplace intervention package addressing major behaviour risks of cancer for the employees, such as tobacco and alcohol use, unhealthy diet, obesity and lack of physical activity, will be developed and implemented through multilevel involvement strategies covering individual programmes, organizational policies and supportive environment with the support of a mobile application. The primary outcome is the change in modifiable behaviour risk factors of cancer after the intervention. The research will also assess the changes of attendance of employees, the healthcare costs of organizations and the occurrence of cancer of employees in the long term. The comprehensive workplace intervention for cancer prevention in low- and middle-income regions of China, if proven to be effective and cost-effective, will not only provide evidence and recommendations to the national policies on cancer prevention in China, but also have a great potential to be adapted by other LMICs.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,CANCER AND NEOPLASMS HRCS22_01147,Medical Research Council,MRC,Computational models of dynamics in brain networks underlying action selection,"Recent advances in brain computer interfaces open new possibilities of normalizing pathological neural activity underlying symptoms of Parkinson’s disease. For example, patients are now implanted with closed-loop DBS systems including multiple recording and stimulation contacts, allowing the independent control of multiple neural populations. However, to take advantage of this technology, it needs to be understood what patterns of activity are produced during action selection in the healthy brain, because restoring such patterns should be a goal of closed-loop DBS systems. Furthermore, we need to understand how to stimulate with multiple contacts to achieve desired neural dynamics. Such insights are currently missing, so there is a need to develop a theory providing them. The overall aim of the programme is to provide mathematical description of the dynamics of brain networks underlying action selection and to understand how these dynamics can be modified by treatments for disorders affecting the system. The programme has three specific goals that focus on the three neural signals are particularly distorted in Parkinson’s disease. The first goal is to develop a theory of dopamine function in learning and action planning. Understanding its function is important because Parkinson’s disease is caused primarily by the dysfunction and death of neurons releasing dopamine, and medications increasing dopamine level are the most common treatment for Parkinson’s disease and many psychiatric conditions. The second goal is to describe the dynamics of beta oscillations during action planning. These oscillations are thought to be related with the symptoms of Parkinson’s disease, because in Parkinson’s disease the duration of intervals with high beta oscillations is longer when patients are off medications and their movement difficulties are more pronounced. The third goal is to identify control policy supressing tremor for closed-loop DBS with multiple contacts. To achieve these goals, the computational models will be developed based on data gathered in experimental neuroscience and neurology groups within our MRC Unit, and the models will inform development and refinement of interventions, through a collaboration with the neural engineering group.",,1.4 METHODOLOGIES AND MEASUREMENTS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_22082,Innovate UK,IUK,Computer Vision and IoT for Personalised Site Monitoring Analytics in Real-Time (CV-SMART) towards Behaviour-Based Safety,"The ""One Death is too Many"" (Donaghy, 2009) catchphrase for the UK zero-harm agenda shows that no fatal accident is admissible on construction sites. Modern H&S problems can only be solved from a combination of cultural, social and technical perspectives. A lot of work has been done from cultural and social perspectives, but the technical perspective has been massively ignored (particularly the use of digital technologies). There is a need to take a closer look at how social and technical systems overlap, and how the growing overlap influences H&S on construction sites. However, current approaches address the socio-technical overlap of H&S management separately despite the evidence that suggests that the Zero Harm target and H&S best practices cannot be achieved without effective digitisation in addition to appropriate social interventions (NBS, 2018). The consortium will, therefore, leverage state-of-the-art in computer vision and deep learning (convolutional neural networks and recurrent neural networks) to develop a Computer Vision and IoT for Personalised Site Monitoring Analytics in Real-Time (CV-SMART) for behaviour-based safety in confined construction sites. CV-SMART will automatically detect, recognise and track diverse interacting heavy machines, building components, site activities, and site workers in real-time to (i) enforce H&S best practices and (ii) identify H&S risks and unsafe site practices such as failure to wear safety gadgets (helmets, harness, and personal protective equipment PPE), congested work areas, improper movement of heavy equipment, and improper working positions). CV-SMART will provide a digital visualisation platform, which will employ state-of-the-art in advanced visualisation for Intuitive user interaction and reporting. CV-SMART will alert on-site workers, safety managers, and site managers of H&S best practices and impending risks at the forefront of onsite operations with a minimal human intervention using IoT-enabled devices.",,3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,INJURIES AND ACCIDENTS HRCS22_00092,The Francis Crick Institute,Crick,"Control of patterning, growth and apoptosis by developmental signals","My lab investigates how signalling landscapes are established in a developing epithelium and how they are coordinated to control patterning, growth and apoptosis. The signals we are studying include Wnts, TGF-, Hedgehog, EGFR, JNK and steroid hormones. Most of our work uses the Drosophila wing as a model system. Our activities focus on the following specific projects. (1) We study how signalling gradients are formed, paying particular attention to Wnts and TGF-, as they exemplify two classes of morphogens, hydrophobic (Wnts) and water soluble (TGF-). We are devoting significant energy to understand how Wnts, which are appended with palmitoloeate are handed over from secreting to receiving cells. At the same time, we are reconstituting a morphogen gradient from an inert molecule (GFP) to identify, in combination with mathematical modelling, the basic features that allow the spread of morphogens in epithelia. (2) Our studies of Wnts have led us to characterise Notum, a deacylase that inactivate Wnts. In order to identify areas where Notum might be a good drug target, we are studying the phenotype of mice lacking Notum, with a focus on neurodegeneration, blood brain barrier maintenance, bone homeostasis and metabolism. This work is in close collaboration with others who are devising small molecule inhibitors of Notum. (3) We are dissecting (experimentally and through modelling) the signalling network that enable cell fate adjustments during tissue morphogenesis. (4) We study how tissue growth if modulated during development. We are analysing how patterning signals (Wingless, a Wnt and Dpp, a TGF-) control the cellular growth control machinery. To this end, we are developing optogenetic and thermo-sensitive means of controlling signal transduction so that we can identify the immediate early targets that promote growth. In addition, we are investigating whether the activity of these patterning signals might be affected by growth, as this could account for scaling (the coordination of pattern information and tissue size). Tissue growth is not only regulated by patterning signals. It is also modulated by tissue architecture and nutritional status. We are investigating how these pro-growth inputs are coordinated with those from patterning signals. (5) Finally, upon the request of a patient, we are modeling a ribosomopathy in flies and are well on the way to uncover the basis on cellular stress in conditions of inadequate ribosome activity.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_02706,Medical Research Council,MRC,Controlling COVID19 through enhanced population surveillance and intervention (Con-COV): a platform approach,"Con-COV Technical Summary. Background: COVID19 is a rapidly evolving complex issue that requires near real time data, analyses and multidisciplinary team science to devise, implement and evaluate a wide variety of inter- and cross-sectoral interventions in order to minimise population harm. Aims: to integrate multiple sources of data to produce timely and responsive analyses to: 1) provide detailed insight into the evolving pandemic in the general population, vulnerable groups and diverse settings (health care workers, social care workers, care homes and schools); 2) support and undertake evaluations of the effectiveness of adopted counter measures as these evolve; 3) rapidly inform policy and practice decision makers; and 4) communicate effectively with the general public. Methods: We will build on the existing total population 3.2 million Wales Multimorbidity Cohort funded by HDRUK/MRC to create the greatest in-depth COVID19 population study with data enhancements on vulnerable groups and settings, serology and viral genomics, scale the breadth and depth of disciplines involved and support embedded evaluations of countermeasures. Our multi-agency team includes individuals from Welsh Government, Public Health Wales, academics from multiple disciplines and members of the public. Deliverables: Reports on exposure risks, incidence and outcomes to Welsh Government COVID19 Technical Advisory Group (TAG) and onwards to SAGE; share models with multiple UK groups including SPI-M, triallists, and the Royal Society DELVE initiative; and provide evaluations of natural experiments in policy and practice. Timeline: We will report weekly to TAG and monthly to funders, recognising the time-sensitive requirements needed to inform evidence-based control and exit strategies.",,7.3 MANAGEMENT AND DECISION MAKING,INFECTION HRCS22_22944,The Academy of Medical Sciences,AMS,Controlling the protein-protein interactions of telomerase,"This project aims to identify compounds which control the protein-protein interactions (PPIs) in telomerase. This will be achieved by: 1) The preparation of peptides derived from the natural PPI interface and investigation of their telomerase inhibition activity. 2) The synthesis of analogues of these peptides, increasing cell permeability and activity. 3) Implementing peptide directed binding, an efficient method for the generation of small molecule modulators of PPIs. 4) Identifying structural binding modes and design of small molecule leads for preclinical disease models. Telomeres are repeated sequences of DNA which protect the ends of chromosomes. During DNA replication telomeres are incompletely copied, eventually resulting in senescence. Telomerase is the enzyme responsible for increasing telomeric repeats, maintaining cell proliferation. Telomerase is inactive in normal cells as part of the ageing process, but 90% of cancers exploit this system by activating telomerase, creating an environment for limitless cell division. Inhibiting telomerase has demonstrated good efficacy and selectivity in cancer cells. Targeting telomerase has focussed on nucleic acid-protein interactions generating clinical candidates, but few compounds have fulfilled their promise. Telomerase is made up of several proteins, but disrupting the PPIs remains unexplored. Recently, the structure of human telomerase was solved, and mutations of diseases which suffer from dysfunctional telomerase were mapped to the structure. Interestingly, the most common mutations mapped to an 11-amino acid α-helix. This infers that modulation of this interface is evolutionarily designed to prevent telomerase activity, and molecules that can control this interaction should selectively target cancer cells.","A feature of cancer is an ability to grow continuously and uncontrollably, giving tumours immortality. It does this by overriding our natural ageing process. Our DNA has repeating units on the end that protect our DNA code, like the plastic ends of shoelaces, called telomeres. When cells grow and divide the DNA is incompletely copied, shortening the telomeres. As part of a normal ageing process, when the telomeres are shortened too far the DNA unravels, cells can no longer divide, and die. Cancer uses a complex of proteins called telomerase to add telomeres to the end of DNA, giving tumours immortality. This project aims to find molecules that control the interactions of the proteins in the telomerase complex. Protein-protein interactions control many diseases, but are challenging for drugs to affect. Proteins are large molecules and drugs are small, like a Chihuahua trying to keep apart sumo-wrestlers. This project will use a new technique, developed by my research group, to make molecules that control the protein-protein interactions of telomerase. First, peptides, small protein-like molecules that look and act like artificial sumo arms, will be made by copying the natural protein structure. Using peptides as scaffolds, and sections can be replaced with drug pieces to make a drug molecule. These new molecules will break apart the telomerase complex, stopping cancer cells from growing uncontrollably and providing a selective treatment for cancers. This new method is cheaper and faster than current techniques to find drugs for protein-protein interactions, meaning treatment reaches more patients.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_20888,Wellcome Trust,,Core Funding Extension for the Wellcome Centre for Human Genetics,"We are a research community of basic and clinician scientists on an inter-disciplinary hospital campus with extensive outreach to Oxford’s tropical medicine units and global health challenges. Our vision is improving human health by maximising the informativeness of human genetics and disease mechanisms.  We commit to: Responding to clinical need, making discoveries in biology to investigate genome function, translating them to molecular-cellular structures and mechanisms, and investigating impact of variation between individuals and cells, with disease and clinical outcomes. Enabling through technology, using genetics/genomics, bioinformatics, structure determination, computing, and cell/mouse genome editing, underpinned by world-leading core facilities, to understand human physiology and pathology. Data, results, materials, software, and knowhow are made fully accessible.  Translating knowledge to the clinic and, where appropriate, filing patents and establishing partnerships, within the University and wider academic, technology, and biomedical sectors. Promoting a positive research culture and building capacity in people and expertise, for all staff, including enabling early-career researchers to test ideas and flourish with essential support from our core facilities. This extension will enable us to capitalize on, and extend, significant innovations since 2016, developing the next generation of innovative, game-changing technologies, approaches, and researchers, to meet still-existing and emerging threats to health.",,1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),GENERIC HEALTH RELEVANCE HRCS22_09567,Health and Care Research Wales (Welsh Government),,County lines: a co-ordinated Welsh community response to child criminal exploitation,"Background Child criminal exploitation (CCE) has been described as a national priority (Children’s Commissioner, 2019). Much of what is known about CCE relates to county lines, a model of drug supply that has become widespread across the United Kingdom. County lines operate using a dedicated mobile phone number to sell drugs from larger cities to end users living in coastal, rural and market towns. While not all county lines use children, where children are targeted it can affect all ages and ethnicities. This project will contribute to the knowledge base regarding the nature and scale of the problem, what approaches and interventions are most effective and how contextual safeguarding approaches can be used in practice within the Welsh context. Aims The project will examine how children are targeted, recruited and involved in county lines in Wales and what services need to effectively identify, engage and safeguard these children. The research objectives are: 1. How does county lines manifest in Wales? a) How are children targeted and recruited? b) How are children involved in these activities? c) What are the similarities and differences in manifestation across high, medium and low CCE prevalence areas? 2. What approaches and interventions are most effective in the identification and prevention of CCE? a) What are the current barriers services face in engaging with children? b) What changes in practice could facilitate their involvement? 3. How can contextual safeguarding be used in practice across services? a) What factors facilitate contextual safeguarding in everyday practice? b) What are the current barriers to adopting a contextual lens to safeguarding? Plan of investigation An exploratory design is adopted to explore the nature, scale and current responses to CCE with findings used to inform the co-production of a toolkit for professionals. Phase one: Interviews, focus groups and creative participatory methods with young people, parents (YPP) and professionals to obtain an ‘accurate and authentic analysis’ of [the] social reality (MacDonald, 2012) for those affected by CCE. Data will be analysed according to grounded theory principles. Phase two: Drawing on action research principles, a toolkit will be created aimed at developing practice that responds to young people affected by CCE. The project advisory group (PAG) consisting of YPP and professionals from a range of agencies, will engage in collaborative critical reflection of project findings in an emergent process of toolkit design (Koshy et al, 2011). Phase three: Interviews with YPP and professionals regarding toolkit content and delivery. These findings will be used to refine the toolkit and produce the final report. Potential benefits This project would make a significant contribution to what is known about county lines in Wales and what interventions and approaches are most effective. As county lines constantly adapts to evade detection, the exploratory design will enable new patterns and behaviours to be captured. Project outcomes will be informed by YPP affected by CCE and professionals from a range of organisations across all phases: defining the problem (phase one), creating a solution (phase two) and refining the solution (phase three). This follows the Social Services and Well-being (Wales) Act principles of co- production where professionals should work with those in need of care and support to identify solutions.","It is estimated that there are over 100 networks bringing crack cocaine and heroin into Welsh towns (National Crime Agency, 2019). While particularly prevalent in Cardiff, Newport and Swansea, recent police raids have highlighted the presence of county lines in smaller Welsh towns (Evans, 2020). There is evidence of children being exploited by single perpetrators (such as family members), children being brought into Wales by county lines based in England, and children being exploited by gangs in Wales (All-Wales Practice Guide, 2019). Some children may not realise they are being exploited and can present as both victims and perpetrators (Home Office, 2018). This means some children will not seek help, while others feel unable to access help for fear of repercussions from their exploiters (Hudek, 2018). For those that do come to the attention of services, county lines involvement can be perceived as a lifestyle choice which conceals their right to safeguarding until they are 18 years of age (The Children’s Society, 2018). The current lack of effective approaches and strategies means that children may only become known to services when they are at crisis point (Violence and Vulnerability Unit, 2018). The project will examine how children are targeted, recruited and involved in county lines in Wales and what services need to effectively identify, engage and safeguard these children. The research objectives are: 1. How does county lines manifest in Wales? a) How are children targeted and recruited? b) How are children involved in these activities? c) What are the similarities and differences in manifestation across high, medium and low CCE prevalence areas? 2. What approaches and interventions are most effective in the identification and prevention of CCE? a) What are the current barriers services face in engaging with children? b) What changes in practice could facilitate their involvement? 3. How can contextual safeguarding be used in practice across services? a) What factors facilitate contextual safeguarding in everyday practice? b) What are the current barriers to adopting a contextual lens to safeguarding? The project aims to create a toolkit for an effective service response to improve the outcomes for children. The views and experiences of young people, parents and professionals gathered in phase one, will be used to inform design of the toolkit. For phase two, a project advisory group will be assembled consisting of young people, parents and representatives from social care, health, education, police, housing and youth services. The group will advise on toolkit content, mode of delivery and intended audience. Once the toolkit is launched, feedback will be gleaned from young people, parents and professionals so that the toolkit can be refined in phase three. Such engagement across all aspects of the project will ensure that the toolkit is accessible, relevant and appropriate for developing professional skills in working with children and adolescents at risk or involved in child criminal exploitation. It is anticipated that the toolkit may comprise training and/or an online resource. A range of dissemination tools will be used, including newsletters, reports, articles and workshops in order to reach policy makers, child welfare professionals and managers, young people and parents, and academic audiences.","2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",GENERIC HEALTH RELEVANCE HRCS22_20395,Wellcome Trust,,Coupling of transcription with other cellular processes,"The first two steps of gene expression are tightly coupled in both bacteria and eukaryotes, which largely determines outcomes of gene expression. Transcription-translation coupling in bacteria is essential for viability and virulence. Transcription-splicing coupling in eukaryotes is critical for development and differentiation, and its malfunction may lead to disease. However, little is known about the molecular details of these mechanisms, mainly due to the absence of tractable experimental systems. We developed a unique in vitro transcription-translation coupled system, which we will use to investigate interactions of RNA polymerase with ribosome, how transcription regulates initiation of translation, and how ribosome controls RNA polymerase activities, transcription pausing and resolves transcription events that compromise genomic integrity. By using the first in vitro transcription-splicing coupled system, we will study direct interactions of RNA polymerase II with spliceosome ribonucleoprotein particles, how transcription elongation regulates assembly of the spliceosome and alternative splicing, and regulation of elongation by spliceosomal complexes, which is critical for splicing efficiency. In vitro programme will be complemented by new NGS-based techniques and CryoEM analysis of transcription-translation and transcription-splicing coupled complexes.  The results will enrich our understanding of basic molecular processes that underpin many human diseases, and may provide new targets for antibiotics.","The first step of gene expression, transcription, is tightly coupled to the next step. In bacteria, coupling of transcription to translation is essential for survival and virulence, and thus could be a target for antibiotics. In eukaryotes, coupling of transcription and splicing is critical for development and differentiation, and dysregulation of coupling may cause serious diseases. Molecular mechanisms of coupling of these important processes are, currently, beyond reach due to the absence of tractable experimental systems. We have developed a unique in vitro system for studying transcription-translation coupling, and are reconstituting the first in vitro coupled transcription-splicing system. We will use these experimental systems, complemented by novel next-generation-sequencing-based and structural techniques to reveal the details of cross-talk and mutual regulation between these fundamental processes. The results will help understand transcription-translation and transcription-splicing coupling in more mechanistic and global terms, and provide information on new antibiotics targets and mechanisms of disease.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_20741,Cancer Research UK,CRUK,Creating a UK Colorectal Cancer Intelligence Hub - Supported by the Bobby Moore Fund,"Background: High-quality data improve cancer outcomes. Good intelligence underpins patient choice, helping individuals reduce the risk of disease and access the best care. It identifies and quantifies inequalities, improves the cost-effectiveness and quality of services and supports cancer research. Unfortunately, the availability of such high-quality cancer intelligence has been limited; this programme of work seeks to rectify this by robustly linking and analysing multiple routine data sources to enable scrutiny of the performance of the National Health Service (NHS). Aims: The aim is to quantify the characteristics of, and any variation in, colorectal cancer and its management across the UK and so provide the evidence required to guide interventions that will eliminate inequalities and improve survival from the disease. This will be done by 1. Developing an accessible UK COloRECTal cancer Repository (CORECT-R) within which all available routine datasets relevant to colorectal cancer will be linked at a patient level. 2. Pioneering the development and application of appropriate statistical methodologies to analyse the complex data within CORECT-R. 3. Analysing the content of CORECT-R to quantify inequalities and identify processes and procedures associated with best practice and improved patient survival 4. Promoting the use of CORECT-R to inform translational research, clinical trials, and other areas of cancer research. 5. Collaborating with a directly engaged community of patients, charities, data users and policy makers to ensure the resource, and the work it enables, has the highest clinical relevance and impact Methods: The programme will span four areas. Workstream 1 will establish the Programme Advisory Group and engage with all who have a stake in UK colorectal cancer care. Workstream 2 will establish CORECT-R, Workstream 3 will focus on the optimal methods to exploit it and workstream 4 will constitute exemplar projects illustrating what the data will enable. These exemplar projects will focus on supporting earlier diagnosis, quantifying inequalities, optimising treatments and promoting the use of big data to support clinical trials and translational research. How the results of this research will be used: The outputs of the research will be used to reduce inequalities and improve survival from colorectal cancer. Although this programme of work is focused on colorectal cancer, the methods and techniques developed will be directly applicable to other cancer sites and, potentially, other diseases. The programme thus has potential to improve outcomes for all patients in the NHS",,8.1 ORGANISATION AND DELIVERY OF SERVICES;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_00894,Medical Research Council,MRC,Creating a federated cloud-based TRE to facilitate consortium-based research and interoperability between existing institutions/TREs,"Current TREs are generally centred around a thematically consistent group of datasets, owned by a singular institution1. Each has its own computational infrastructure, security arrangements, access management and so on. Researchers need to a) know that the TRE exists, b) know what data is held in it c) have to apply individually per project for access d) have access to their own local, secure environment in which to work with the data. In some cases, d) is not viable due to data sensitivity limiting work to tools provided in the TRE. In all cases, working with data in a TRE is bureaucratically laborious and often scientifically limited, as the ability to work with data sets across TREs, or most importantly, in conjunction with locally collected experimental data, is difficult, or sometimes, impossible. Rather than building another TRE ‘silo’, we will demonstrate a series of components interworking to form a scalable ‘virtual TRE’ or vTRE architecture. This is centred around a multi- cloud ‘data fabric’, built using the commercial SnowflakeTM platform, which offers a powerful toolset for managing security, data sharing and access in a very flexible way. It also has the advantage of extreme scalability, as it is built on the huge resource pools available on AWS, Google and Azure public clouds, allowing for TREs to be easily defined in ‘Infrastructure as Code’ terms, rather than as capitally intensive physical environments. Unlike other cloud-based technologies, SnowflakeTM is unique in being a single data fabric shared between customers, rather than discrete databases which necessitate local access and security controls. Rigid and specific data sharing is enabled and simultaneously makes possible ‘immediate’ access to any approved SnowflakeTM account, with a marketplace to help discovery and public sharing of any appropriate datasets. This work will build an illustrative data environment, enabled to connect the Crick and partners with sample data. Around this data fabric, we will build modular components to demonstrate the principles of creating a stand-alone ‘access-as-a-service’ platform, which any TRE could use to centralise access workflows and requests. This will be connected to an illustrative policy library and provisioning engine to automatically ‘spin up’ pre-defined TRE environments, removing administration whilst ensuring rigour of definition, security and access control.",,2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_23165,The British Academy,,"Creative ageing and social prescribing: Bridging the gap between diverse service users, service providers and policy makers in Wales","Social prescribing is a non-pharmacological approach to supporting people’s health and wellbeing through referrals to meaningful activity such as the arts. In the UK it is a key policy area linked to the personalised healthcare agenda which aims to cut the booming cost of an ageing population. The applications of ‘arts on prescription’ are complex and often exclusive of the communities that need interventions the most. Particularly, when engaging older adults with experiences of social isolation and/or dementia, there are barriers such as digital literacy, access to devices, capacity to consent, cultural and aesthetic preferences. Creative practitioners and service users hold most of the information on impact - it’s a predominantly oral, experiential and private body of knowledge. Ethnographic and participatory approaches are therefore highly suited to document and translate this knowledge to policy makers. This will contribute to cost-effective solutions tailored to the specialised needs of our ageing population.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH;NEUROLOGICAL HRCS22_06573,Department of Health and Social Care,NIHR,Crisis care for people with a diagnosis of ‘personality disorder’: a mixed methods study of outcomes and experiences,"Background: One in 20 people in the UK meet the criteria for a diagnosis of 'personality disorder' or the alternative term Complex Emotional Needs (CEN). People with CEN need good quality care when experiencing a crisis, to relieve suffering, prevent suicide and self-harm. However previous research and feedback from service users suggests current mental health crisis care is not appropriate for this group. There is little research on which to base practice. This is an important gap that has been highlighted by bodies such as NICE and the Royal College of Psychiatrists. Aim:To understand the outcomes and experiences of current models of crisis care for people with a diagnosis of 'personality disorder' or CEN. The aim of the study is to understand the impact on service users using a mixed methods approach. Objectives:1. To review existing literature to establish what is known about outcomes from crisis care for people with a 'personality disorder' diagnosis Investigate and compare outcomes of the three core types of crisis service offered by the NHS for people with a diagnosis of 'personality disorder' Explore the experiences of people with CEN who have used crisis care, the experiences of clinicians delivering care and their views about how services can be improvedMethods:The quantitative and qualitative phases will be conducted using a sequential explanatory design. I will conduct a systematic review of studies reporting outcomes of different types of crisis care for people with a 'personality disorder' diagnosis I will conduct an observational cohort study of anonymised longitudinal electronic health records comparing outcomes for people with a 'personality disorder' diagnosis using the three core models of NHS crisis care. Using survival analysis I will examine associations between the model of crisis care accessed and the time to next crisis. I will also look at associations with self-harm, suicide, and a measure of health and social function. Models will be adjusted to account for differences in individuals referred to each type of service. I will conduct a qualitative study interviewing people with CEN who have used crisis services and convene focus groups of crisis service staff. This will include some people from 'trauma informed' services. I will explore their experiences of crisis care and their views on how care could be improved.Timeline for delivery:0-8 months- perform systematic review and apply to ethics board 6-18 months- observational cohort study 16- 28 months- qualitative study 26-36 months- write up thesis, submit and disseminate Anticipated impact and dissemination:This would be the first piece of research to identify and compare outcomes and experiences of contemporary NHS crisis care specifically for people with CEN. It is thought that crisis care for people with CEN is often inadequate and costly, in part because it fails to meet their needs. This study will provide an evidence base to understand the impact of care that is being delivered in the NHS, to inform further research, commissioning of services, clinical decision making and to initiate service improvement.","Background: One in 20 people in the UK meet the criteria of a 'personality disorder' diagnosis. A person may meet this criteria because of difficulties in the way they relate to themselves and others and with management of emotions. This might be because of trauma or adversity the person experienced in early life. The label can be stigmatising, and some service user groups prefer the term 'Complex Emotional Needs' (CEN) which I will use. People with CEN can experience a crisis in response to overwhelming emotions that can trigger self-harm and suicidal thoughts. In England there are crisis services available, including crisis teams that visit the person at home, crisis houses or admission to hospital. Help in a crisis is very important to reduce suffering and prevent people with CEN harming themselves. However, NHS crisis services were not designed to be tailored to the needs of people with CEN and some service users and clinicians think the crisis care they receive is inadequate. People with CEN have been severely neglected by mental health research. What research we have focuses on longer term therapies. There are very few studies that help us understand what is helpful in a crisis. Concerningly, research in the United States has found that some types of crisis care might be harmful for people with CEN. Given that the NHS provides crisis care to large numbers of people with CEN, we urgently need to understand this better. Aim: This study aims to understand how best to provide care to people with a CEN experiencing a mental health crisis, so that services can be improved to better meet their needs. The study will have three parts: 1) I will review past research to find out what crisis interventions are available and helpful for people with a 'personality disorder' diagnosis 2) I will use anonymous electronic health records of people with a diagnosis of 'personality disorder' in two areas of England to see if the type of crisis service the person uses makes a difference to (a) how long they stay well following a crisis, (b) whether they harm themselves, and (c) how well they can function. This will tell us about the crisis care we provide in the NHS and what impact it has on people with CEN. 3) I will interview people with CEN who have used different crisis services about their experiences and hear their views on how services could be improved. I will hold focus groups of crisis service staff, because the relationship between staff and patient is important in a crisis. A small number of services now offer 'trauma informed care', which recognises that some service users are survivors of trauma. I will recruit some people who have used these services, to think about how these ideas could improve crisis services more widely. I have worked with people with CEN, doctors, nurses and policy makers to design this study. A researcher with CEN will be involved throughout the project. A working group of service users will help decide how the research is run and how to understand the findings. Outcome: This will be the first study to focus on the impact of NHS crisis services on people with CEN. This information is urgently needed so that services can be improved in the NHS and internationally. When the study is finished, I will publish the findings in journals. I will also send out summaries, write blogs and hold an online event for patient groups, NHS England policy makers and crisis care managers to make sure my findings reach people who can improve services.",8.1 ORGANISATION AND DELIVERY OF SERVICES,MENTAL HEALTH HRCS22_19066,Wellcome Trust,,Cryo focussed ion beam scanning electron microscope for correlative functional studies of biological systems in situ by tomography,"Dramatic advances in cryo-electron microscopy (EM) have greatly enhanced macromolecular structure determination. The current frontier is in situ cellular structure determination to understand the machinery of life operating in the native biological environment. Visualising the native structure of cells and tissues by cryo-electron tomography requires the preparation of cryo-samples ~100-600 nanometers in thickness. The vitrified tissue sections must be thin enough to allow penetration by the electron beam, yet thick enough to contain complete structures of biological relevance. Although cells and tissues can be sectioned in the vitreous state by cryo-ultramicrotomy, both section thickness and quality are severely limited by mechanical damage including deformation, non-uniform compression and crevassing. The only available method able to precisely modify the thickness of frozen-hydrated samples and balance these conflicting requirements is focussed ion beam (FIB) milling in a scanning EM. FIB milling provides access to the cell interior, within otherwise unperturbed cellular environments, yielding vitrified lamellae suitable for electron tomography and unaffected by compression forces. Here we request a cryo FIB field emission gun scanning EM (FEG SEM) to produce lamellae targeted to fluorescent features of interest for transfer into a cryo-transmission EM (TEM) for three-dimensional (3D) structure determination by electron tomography.","Current electron microscopes can resolve fine details of cells and molecules, enabling us to observe the machinery of life in operation, revealing mechanisms of action and new therapeutic targets. However, transmission of the electron beam requires samples much thinner than a typical cell. This poses a major challenge, since the goal is to observe cells in their native, frozen-hydrated state. Mechanical cutting of frozen material causes considerable damage, distortion and lacks sufficient volume for three-dimensional modelling. A new approach proffering control and precision has been developed, in which material above and below the layer to be observed is ablated by an ion beam. Although slow, this is the only way to get suitable layers of cells and tissues for high-resolution electron microscopy. This application seeks funding towards a dual-beam scanning electron microscope that will enable us to prepare samples under cryogenic conditions for high-resolution electron tomography of native, cellular structures.",1.3 CHEMICAL AND PHYSICAL SCIENCES;1.4 METHODOLOGIES AND MEASUREMENTS,GENERIC HEALTH RELEVANCE HRCS22_14034,Wellcome Trust,,DNA methylation of different brain cell types in Parkinson’s disease,"Parkinson’s disease is an increasing global concern, affecting one in twenty people by age 85 and costing the NHS more than £1 billion/year. The underlying mechanisms are still almost completely unknown and there are no drugs that can cure the disease. In addition to traditional genetics, recent work in Parkinson’s has focussed on epigenetic variation, in particular DNA methylation in the brain. However, even though different brain cell types are affected by Parkinson’s in different ways, all previous work has only considered bulk brain tissue consisting of a mixture of cell types. For the first time, this project will determine the DNA methylation profile in individual cell types of the prefrontal cortex in both people with Parkinson’s and matched controls. In particular, this will include separate analysis of neurons, oligodendrocytes and other glial cells. This will generate pilot data that will lead to several large (>£1M) follow-up grant applications, including not only studies of DNA methylation, but single-cell-type investigations of other epigenetic marks such as histone modifications and non-coding RNAs. The hope is that this approach will lead to a step change in the mechanistic understanding of Parkinson’s disease, and produce a host of new potential drug targets.","By age 85, one in twenty of us will be affected by Parkinson’s. What is more, the disease will only become more and more common as we continue to live for longer and longer. However, we still know very little about Parkinson’s and there is currently no cure. Although most previous research has looked at how DNA changes cause Parkinson’s, we have recently started to realise that other types of changes (so called “epigenetic” changes) play a crucial role. However, despite this, all previous work in this area has only ever looked at whole brain regions at the same time. In this project, for the first time, I will look at epigenetic changes in Parkinson’s in separate types of cell. I believe this has the potential to revolutionise research into Parkinson’s, leading to much better understanding of the disease and, more excitingly, suggesting new types of drug treatments.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_19118,Cancer Research UK,CRUK,Deciphering inherited susceptibility to childhood cancer (co-funded by Children with Cancer UK),"Background: The identification of cancer-predisposing genes (CPGs) is of increasing importance in paediatric oncology for the diagnosis, treatment, surveillance, family counselling and research. Although many childhood cancers are associated with CPGs the number caused by inherited vs. de novo mutation and the total number of genes which are true CPGs is unknown. Aims: To identify new CPGs and decipher the contribution of inherited predisposition to paediatric cancer. Methods: We will perform family-based genetic analyses of the germline of children with diagnosed with Wilms tumour, Ewing sarcoma, rhadomyosarcoma, glioma, meduloblastoma or Neuroblastoma. Specifically, we shall analyse multiple case families and parent-offspring trios using NGS and array technology. How the results of this research will be used: This work should reveal a striking new landscape of inheritance in childhood cancer and inform personalized and preventive medicine and cancer surveillance programs.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_20425,Cancer Research UK,CRUK,Deciphering the Genomics of Aggressive non-Hodgkin Lymphoma,"Background To unravel the biological basis of aggressive non-Hodgkin lymphomas (aNHL), we and others have performed large mutational profiling studies. These reveal considerable genetic heterogeneity and identify hundreds of recurrent genetic alterations. These mutations are not independently distributed, allowing cases to be clustered into predicted genomic subtypes. Gene expression and survival differences support the concept that these subtypes represent biologically distinct diseases, suggesting optimal treatment may differ between subtypes. There is no shortage of novel, therapeutic agents in development for lymphoma. However, it remains far from clear how these should be targeted to molecular subtypes or individual patients. The large number of theoretical drug combinations, combined with the complex genetic heterogeneity makes it impossible to address these questions by empiric testing in clinical trials. Therefore, we require better preclinical experimental systems to model the effects of mutational repertoires and enable their interrogation. My group has developed a novel experimental system that allows the creation of mutation-customised models of lymphoma, and provides the ability to study many hundreds of mutational combinations simultaneously. Aims 1) Dissect the GNA13 pathway as a potential therapeutic target in aNHL. 2) Perform comprehensive, combinatorial mutant open reading frame (mORF) screening of 1,000 recurrent mutations in human GC B cells ex vivo and in vivo. 3) Combine genetic perturbation and single cell transcriptional profiling of mORF-transduced single cells with a systems biology model to condense genetic heterogeneity into targetable oncogenic pathways. 4) Develop a highly sensitive plasma DNA sequencing assay to capture the evolution of genetic heterogeneity during lymphoma treatment. Methods We will capitalise on a system we developed for ex vivo expansion of primary human B cells in a co-culture designed to mimic the germinal centre microenvironment. Genetic manipulation of lymphoma driver genes allows us to generate immortalised cultures and “synthetic” in vivo models that closely recapitulate aNHL. This will be combined with a lymphoma-specific mutant ORF library and single cell sequencing technologies. How research will be used By understanding how genetic alterations co-operate to drive lymphoma and how mutational profiles evolve during therapy, our results will: 1) Elucidate the molecular basis of recently described genomic subtypes 2) Propose therapeutic stratification for future trials 3) Identify the pathways that should be optimally targeted for individual disease subtypes 4) Determine how we should assess response to treatment at the subclonal level. Results will therefore guide the design and interpretation of the next generation of lymphoma clinical trials.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_23680,Cancer Research UK,CRUK,Deciphering the role of the CCR7/CCL21 chemokine axis in ovarian cancer,"Background: Ovarian cancer (OC) is the deadliest gynaecological malignancy- most patients die within 5 years of diagnosis. New insights into pathogenesis of OC to guide the development of novel therapies are crucial. Chemokines are small cytokines with a defining and conserved cysteine motif which are essential for regulating leukocyte migration, and they form an important part of OC tumour microenvironment. My preliminary data suggested that the most highly expressed chemokine in OC ascites was CCL21. Moreover, high CCL21 (defined as above median expression levels) was significantly associated with poorer survival (Hazard Ratio=2.4, 95%CI 1.28-5.8, p=0.013, log-rank test). Aims: The contribution of CCL21 to pathogenesis in OC has not previously been evaluated. CCL21 is a key regulator of CCR7+ dendritic cells (DCs) and naïve T cells. Specifically, DCs require CCL21 to exit tissues and enter lymph nodes for antigen presentation. The aim of this project to evaluate the effects of the chemokine CCL21 on anti-tumoural responses in OC. My hypothesis is that overexpression of CCL21 induces an immunotolerant tumour microenvironment and leads to poorer survival in OC. Methods: I will first evaluate the expression of CCL21 and its receptor CCR7 in primary tumours and metastases, and their associations with immune cell infiltration, in human OC. Moreover, the ability of ascites with high versus low levels of CCL21 to activate DCs and T cells will be compared. Secondly, I will modify an immunocompetent transplantable murine model of OC (ID8 Trp53-/-), with TP53 deletion consistent with human high-grade serous ovarian carcinoma (the commonest histological OC subtype; ~80-90%). To mimic the elevated ascites CCL21 observed, ID8 Trp53-/- will be transduced with CCL21 and/or ovalbumin, and their influence on tumour-immune microenvironment, cancer progression and survival will be assessed. Thirdly, the relatively ability of adoptively transferred murine CCR7+ DCs to migrate to lymph nodes and OVA-specific T cells to mount adaptive responses will be evaluated. How the results will be used: This pre-clinical study will evaluate CCL21 expression in human tumours and its direct effects on immune cells. I will also modify a new immunocompetent transplantable murine model of OC to mimic the elevated CCL21 observed. Using this new model, I will evaluate the specific effects of CCL21 in OC. If my hypothesis is correct, it would suggest a novel mechanism of tumour immune evasion in OC, and alternative strategies would be needed to promote antigen presentation and anti-cancer immune responses for improving outcomes of OC.","Background: Ovarian cancer (OC) is the deadliest gynaecological malignancy- most patients die within 5 years of diagnosis. New insights into pathogenesis of OC to guide the development of novel therapies are crucial. Chemokines are small cytokines with a defining and conserved cysteine motif which are essential for regulating leukocyte migration, and they form an important part of OC tumour microenvironment. My preliminary data suggested that the most highly expressed chemokine in OC ascites was CCL21. Moreover, high CCL21 (defined as above median expression levels) was significantly associated with poorer survival (Hazard Ratio=2.4, 95%CI 1.28-5.8, p=0.013, log-rank test). Aims: The contribution of CCL21 to pathogenesis in OC has not previously been evaluated. CCL21 is a key regulator of CCR7+ dendritic cells (DCs) and naïve T cells. Specifically, DCs require CCL21 to exit tissues and enter lymph nodes for antigen presentation. The aim of this project to evaluate the effects of the chemokine CCL21 on anti-tumoural responses in OC. My hypothesis is that overexpression of CCL21 induces an immunotolerant tumour microenvironment and leads to poorer survival in OC. Methods: I will first evaluate the expression of CCL21 and its receptor CCR7 in primary tumours and metastases, and their associations with immune cell infiltration, in human OC. Moreover, the ability of ascites with high versus low levels of CCL21 to activate DCs and T cells will be compared. Secondly, I will modify an immunocompetent transplantable murine model of OC (ID8 Trp53-/-), with TP53 deletion consistent with human high-grade serous ovarian carcinoma (the commonest histological OC subtype; ~80-90%). To mimic the elevated ascites CCL21 observed, ID8 Trp53-/- will be transduced with CCL21 and/or ovalbumin, and their influence on tumour-immune microenvironment, cancer progression and survival will be assessed. Thirdly, the relatively ability of adoptively transferred murine CCR7+ DCs to migrate to lymph nodes and OVA-specific T cells to mount adaptive responses will be evaluated. How the results will be used: This pre-clinical study will evaluate CCL21 expression in human tumours and its direct effects on immune cells. I will also modify a new immunocompetent transplantable murine model of OC to mimic the elevated CCL21 observed. Using this new model, I will evaluate the specific effects of CCL21 in OC. If my hypothesis is correct, it would suggest a novel mechanism of tumour immune evasion in OC, and alternative strategies would be needed to promote antigen presentation and anti-cancer immune responses for improving outcomes of OC.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_23113,The British Academy,,Decoding real tool use from visual fMRI response patterns,"The ability of humans to manufacture and use tools is unsurpassed across the animal kingdom, with tool use considered a defining feature of our species. Previous studies that investigate tool use, record brain activity while people view pictures of tools or hands and not when people perform hand movements with tools. But perceiving an image is quite different to acting with a real tool. Recently, we published the first investigation showing that holding an object correctly is represented in brain areas that respond to the sight of hand pictures and not in visual areas that respond to the sight of tool pictures. Here we will investigate whether these visual regions represent specific hand movements during actual tool use. Our work will provide a more realistic understanding of the brain regions involved in tool use, have implications to understanding the impact of brain disease and aid the development of brain-computer interfaces.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,NEUROLOGICAL;MENTAL HEALTH HRCS22_09196,"Chief Scientist Office, Scotland",CSO,Defining a specific IL-22-mediated pathway in regulating eczema,"Eczema is a debilitating condition which has become commoner in the last 30 years. There are several sub-types of eczema, each with varying immunological abnormalities, including atopic eczema, allergic contact dermatitis (ACD), and acute and chronic eczema. Chronic eczema shares some immunological abnormalities with psoriasis. In order to effectively treat patients with eczema in the future, we need a better understanding of the underlying immune abnormalities. Objectives and outcomes: 1: To assess if the Prostaglandin E2/IL22 pathway varies with types of eczema comparing this with psoriasis. Interleukin 22(IL22) is a recently identified functional protein produced by immune cells (T cells), which is closely linked to eczema development. IL22 can be stimulated by another inflammatory chemical called Prostaglandin E2 (PGE2) to cause allergic contact dermatitis (ACD) in a mouse model.1 To establish if this also occurs in human ACD I will take blood samples and skin biopsies from eczema and psoriasis patients and from controls to study these chemicals. 2: Does T cell response to PGE2 differ in eczema patients? PGE2 causes chronic skin inflammation by increasing production of IL22 from T cells. I will study whether the T cell response to PGE2 in eczema patients is by the same signalling pathway as occurs in other systems by studying skin taken at biopsy. 3: What is the sequence of events of activation of the PGE2/IL22 pathway? To study this I will recruit human volunteers in whom I will produce irritant and allergic eczemas, measuring PGE2 and IL22 at various time points. Repeating the experiment I will create two groups, one pre-treated for one week with a non-specific prostaglandin inhibitor (aspirin) and the second with a placebo control. Benefits: If I can identify different pathways according to eczema subtype this would help development of disease-specific treatments with fewer side effects while reducing costs to the health services.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,SKIN HRCS22_02317,Medical Research Council,MRC,Defining and diagnosing neurodegenerative Movement Disorders through integrated analysis of Genetics And neuroPathology (MD-GAP),"The integration of genetics with imaging has led to major insights into brain development and neurodevelopmental disorders. Late onset neurodegenerative disorders are associated with abnormal protein aggregates which define and drive the disease, and so integration with neuropathology is the logical approach to these conditions. We will obtain DNA from ~ 2500 individuals with pathologically defined neurodegenerative movement disorders and ~ 1000 controls. In collaboration with the MRC UK Brain Banks Network (BBN) we will collate initial clinical diagnosis, pathological diagnosis, age at onset, gender and survival. We will collate Braak and Thal pathological stage data reflecting the extent of three major neurodegenerative disease pathologies - tau, alpha-synuclein and amyloid. In a subset of 750 Lewy body disorder spectrum cases we will use digital pathology approaches to quantify the amyloid, tau and alpha-synuclein burden in three important representative areas: frontal cortex, entorhinal cortex and cingulate gyrus. We will genotype each case and control using the Illumina MegaEX / Neurochip v3 single nucleotide variant array. This will provide information on genome wide common variation in individuals with different ancestries; risk variants from genome wide association studies (GWAS) and neurodegenerative rare variants. We will define the genetic drivers of pathology based on candidate gene/transcript analysis, and with hypothesis free GWAS. We will correlate genetic data with clinical data including survival, rate of progression and dementia. We will carry out pathologically defined genome wide association studies, which will be meta-analysed with pathologically defined GWAS from around the world, and use the data to develop polygenic risk tools to enhance diagnostic accuracy. Genetic data will be made available via the BBN database to enable future exploration of the downstream effects of genetic variation by bona fide investigators.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_02929,Medical Research Council,MRC,Defining descending inhibitory pathway functionality in health and disease,"Descending modulatory controls project from the brainstem to the spinal cord to inhibit or facilitate pain sensations. In health the descending pain modulatory system (DPMS), which encompasses a unique form of descending control termed diffuse noxious inhibitory controls (DNIC), may act endogenously to inhibit spinal neuronal processing and thus reduce the final percept of pain. However maladaptive activity in the DPMS has been reported in rodent models of chronic pain and I have published evidence that DNIC pathway expression, quantifiable as a reduction in spinal nociceptive processing upon application of a noxious conditioning stimulus, is dysfunctional in rodent models of chronic pain. For this NIRG application I have collected pilot data to evidence that the DNIC pathway originates in the A5 nucleus and that DNIC expression is negatively impacted by excitation of the locus coeruleus (LC). My working hypothesis is that while the DPMS (LC projection) and DNIC (A5 projection) pathways influence one another in health, they are functionally separate and evolutionarily distinct and that they influence one another differentially in a disease state. If correct, the DPMS and DNIC pathways offer 2 separate therapeutic targets in disease. I have shown that in early stage cancer induced bone pain rats DNIC is dysfunctional. I want to know does the functional relationship between the A5 and LC nuclei change in these animals? I will investigate brainstem reciprocal crosstalk and spinal pharmacological functionality in healthy and early stage CIBP rats in order to potentially reveal a novel underlying mechanism of pain. Altogether, the research proposed in this application will enable me to gain mechanistic insight of pain inhibition pathway malfunction in disease. This insight is crucial for the eventual development of targeted therapeutic strategies that act to boost endogenous descending inhibitory pathway activity.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_18734,Cancer Research UK,CRUK,Defining mechanisms of hormone-dependent cancer disease progression,"Background: Hormone-dependent cancers constitute two of the most common cancer types (ER+ breast and prostate cancer). Treatments that block the driving transcription factors, ER in breast and AR in prostate, have improved survival rates substantially, but treatment resistance is a common clinical problem. The core cell-type defining transcription factors have been identified in primary disease and include pioneer factors such as FOXA1 and a number of co-regulatory proteins and associated transcription factors. Recently, proteomic and genetic screens have linked numerous additional factors with these transcriptional complexes. Aims: The central aim is to define the biological processes and the critical changes that contribute to endocrine-resistant, metastatic disease. This will involve the discovery of genes and proteins involved in breast cancer metastasis, the identification of the role of key pioneer factors in this process and analysis of the role of specific mutations in treatment response and metastasis. We will also explore a hypothesis around the role of FOXA1 in prostate cancer progression. Methods: The proposal builds on a wealth of background information and novel methodological tools, to enable an unbiased and global investigation of the key events that contribute to ER/FOXA1 transcriptional activity in breast cancer and AR/FOXA1 transcriptional activity in prostate cancer. The work will identify key genes and associated proteins that influence tumour progression, it will explore the functional interaction and dynamics between known, but uncharacterised co-regulatory proteins, it will exploit global CRISPR screens and a method we developed called qPLEX-RIME, which permits unbiased discovery of protein interactomes from clinical samples. In addition, the work will exploit a contemporary and clinically relevant in vivo model of luminal breast cancer metastasis. As a community, we have been studying primary breast for decades, but our understanding of the events that drive metastasis are poorly understood. This is in large part because we have been unable to accurately and faithfully model luminal (ER+) breast cancer metastasis and there has been limited access to metastatic samples. The advent of the intraductal tumour engraftment (MIND) system, provides the first reliable and physiologically relevant approach for studying ER+ breast cancer metastasis. How the results will be used: The measurable endpoints of this proposal will be the identification of the critical components in the transcriptional complex, an understanding of the events that drive metastasis, clarity around the impact of specific mutational events on this process and new insight into potential ways of therapeutically intervening in these contexts.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_20117,Sir Jules Thorn Charitable Trust,,Defining new treatment and headache mechanisms in raised intracranial pressure,"The research will also provide the first insight into fundamental headache mechanisms and guide additional approaches to treatment.Furthermore, the results are highly relevant to other conditions of raised brain pressure (traumatic brain injury, hydrocephalus (excess fluid on the brain) and space-flight intracranial hypertension).","Idiopathic intracranial hypertension (IIH) is a debilitating condition characterised by raised intracranial pressure (ICP) and has been overlooked for decades – resulting in no targeted treatments. It causes severe headaches and potential blindness. Predominantly occurring in obese young women, the incidence is rising rapidly in line with the global epidemic of obesity, driving escalating healthcare costs. Patient voice and quality-of-life studies highlight that IIH headaches are the overwhelming long-term disabler, yet mechanisms and potential treatments are not established. My research has established a new target to lower ICP through glucagon-like peptide 1 receptor agonism with Exenatide (an existing diabetic drug). Exciting preliminary data has demonstrated a reduction in ICP and headache in IIH patients. Building on this discovery science, this translational study will evaluate the efficacy of repurposing Exenatide to treat IIH and reduce headaches through a randomised controlled trial that would lead to drug licencing and translation to patient care upon successful completion. Linkedmechanistic evaluation in human and mouse models will interrogate the relationship between ICP, headache mechanisms and therapeutic targeting with Exenatide. Whilst the project focuses on IIH, the research has the potential to uncover treatments for other conditions of raised ICP (hydrocephalus, traumatic brain injury and space-flight intracranial hypertension",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,NEUROLOGICAL HRCS22_15488,Wellcome Trust,,Defining the role of Bacillus subtilis exoproteases during biofilm formation,"Biofilms are communities of microorganisms that attach to surfaces or interfaces which contain one or multiple species and can be beneficial or detrimental for human health. Biofilm formation is tightly regulated by controlling production of exopolysaccharides and extracellular proteins that combine with components including extracellular DNA and extracellular proteases to form a sticky matrix. I am interested in the role of extracellular proteases during biofilm formation. It has been hypothesized that extracellular proteases might be involved in matrix remodelling, cellular dispersal and/or in food acquisition in poor-nutrient conditions. Using the bacterium Bacillus subtilis, I will use biochemical and proteomics approaches to quantify how abundant and how active the extracellular proteases are during biofilm formation. I will also assess if extracellular proteases can be shared among the population and if they confer a selective advantage in certain nutrient environments. By combining live-cell imaging and mathematical modelling, I will also explore how extracellular proteases influence spatial distribution of mixed populations during biofilm formation. The insights garnered with this study will help to understand how exoproteases support biofilm formation in diverse environments and more globally help us to understand why biofilm can be so persistent.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_05893,Department of Health and Social Care,NIHR,Dem Dx Triage Support Platform for Ophthalmology Referrals,"Background A steady increase in the use of Ophthalmology services over the past 2 decades combined with a forecasted shortfall of trained ophthalmologists, make the optimisation of patient triage vital if delivery of care is to be maintained or improved. No globally recognised triaging system for Ophthalmic emergencies yet exists and physician-defined risk stratification is currently considered as gold standard care. Aims and objectives This project aims to train and test machine learning algorithms on Dem Dx s novel Triage Platform and assess how well it supports allied healthcare professionals (AHPs) to perform triage and improve operational efficiency in the Ophthalmology Emergency Department. Methods and timeline for delivery The 24-month project divides broadly in three stages and includes: Stage 1: train and test period for the Triage Platform s ML algorithms using live Electronic Medical Record data from Moorfields Eye Hospital combined with SNOMED CT data input by the triage consultant in Dem Dx. Stage 2: assessment of the Triage Platform s ML algorithms performance, safety and usability when applied by inexperienced healthcare providers in simulated scenarios derived from real cases. Stage 3: multi-centre, prospective, quasi-experimental study to evaluate the accuracy and clinical effectiveness of the triage platform s AI algorithms Anticipated impact and dissemination It is expected that the Dem Dx Triage Platform will increase the efficiency and safety of triage performed by nurses and allied healthcare professionals in ophthalmology services and improve the patient experience by reducing wait and consultation times. The product is also likely to reduce the number of inappropriate referrals to Ophthalmology and promote better integration with tertiary care.","Ophthalmology (the treatment of eye diseases) is the National Health Service s busiest outpatient service, with 7.5 million attendances each year. Currently, two million people in the United Kingdom live with some form of visual impairment and 250 start to lose their sight each day. Two-thirds of eye appointments are for diseases which only occur in the elderly. The Royal College of Ophthalmologists expects a 22% increase of these conditions by 2025 and their work with The Royal College of General Practitioners has shown that 52% of all referrals to specialist eye services are unnecessary. Overall, this means that whilst spending on eye health has almost doubled in the last ten years to £2.3 billion, hospital eye services are struggling with 1 in 8 patients waiting longer than 18 weeks to be seen. Ideally, growing demand for eye care would be met by increasing the number of eye doctors available. However, a recent survey suggests that, in the short term, medical schools were unlikely to be able to provide sufficient new eye doctors to address the current shortfall. Another way of meeting the demand for eye care would be to improve what is known as triage. This is the process by which doctors decide what level of risk a patient s symptoms represent e.g. is this a simple cold or is it a more serious illness like cancer? It is based on a series of judgements made at the time that a patient arrives at a healthcare facility such as a hospital Accident and Emergency department or a GP practice and the outcome of these judgements affect what diagnosis a patient is given, what treatments they are offered and where that care takes place. Research suggests that you can improve the accuracy and speed of this triage process by using computerised Artificial Intelligence software . This project, bringing together a commercial digital health company, DemDx, and Moorfields Hospital (England s leading eye hospital), will develop and test a new technology called Triage Platform to see if it can gather and process information about patients symptoms well enough to support less specialist healthcare staff such as nurses make accurate and safe triage decisions and deal with many of the most common eye problems. This will free-up specialist doctor time for the most urgent or complicated cases. If successful, the Triage Platform could save the NHS between £38-£42million each year and help 350,000-540,000 (mostly elderly) patients gain better access to eye treatment wherever they live, including shorter waiting times to see an eye specialist when that is what they need.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING,EYE HRCS22_06640,Department of Health and Social Care,NIHR,Dental Care Preference Elicitation: An Application to NHS Dental Contract Reform (DEPEND),"Research QuestionWhat do members of the public and dental practitioners value in dental care and does this fit with reform of the NHS dental contract in England? BackgroundThe dental contract between dental practices and NHS England determines how dental practitioners deliver care and how they are reimbursed, but it is not known if the contract provides value for money. Changes to the contract introducing a new care pathway are being tested but its value to the public and dental practitioners and efficiency is unknown. It is important that any new contract uses NHS resources effectively maximising societal welfare and is sustainable. Aims and ObjectivesThis project aims to assess the value of the different elements of dental care to the public and dental practitioners, and use these values to determine if the proposed reforms will provide value for money. The project has several objectives: Identify problems and goals of NHS dental practices Examine the preferences of members of the public in relation to dental care Generate Willingness to Pay (WTP) values using a Discrete Choice Experiment (DCE) for each element of dental care Generate a comprehensive costing of the current dental contract and the proposed contract, using data provided by participating dental practices Estimate the impact the new care pathway has on outcomes in the long term using a Markov Model Establish which elements of dental care provide value for money, using a Cost-Benefit Analysis (CBA)Methods This project will use a mixed methods approach. Qualitative interviews and focus groups will be held with: NHS England dental policy makers and commissioners, public and patient representatives (including those who have experienced care under the proposed contract) and dental practitioners (including those who have delivered care under the proposed contract). The qualitative data will be used to establish scenarios for a Discrete Choice Experiment (DCE), which will be used to assess the value of the different elements of dental care by eliciting a willingness to pay value (WTP) for each scenario. Two DCEs will be designed and completed, one by a sample of public and patient representatives and another by a sample of dental practitioners. A cost-benefit analysis (CBA) using the projected transitions through oral health states established in a Markov model, the WTP values and costs from practices will determine the value of each element of care. These will also be used to determine the value for money of the proposed contract relative to the existing contract. Anticipated Impact and DisseminationThis project will be able to identify the elements of dental care that provide the best value and make recommendations to feed into the ongoing dental contract reform programme. The results will be shared and discussed with those who have informed the research process including those in charge of commissioning dental care and the Dental Contract Reform board In addition, this project results of academic interest which will be presented at several conferences and published in several papers.","TitleDental Care Preference Elicitation: An Application to NHS Dental Contract Reform (DEPEND) The Problem 22 million adults access dental care through NHS dentistry and approximately 4 billion is spent on NHS dentistry. The way dentists deliver NHS care to patients and how dentists are paid is determined by their contract with the NHS. The NHS is currently testing a new contract that will change how dental care is delivered and how dentists are paid. However, little is known about what elements of dental care are important to members of the public. Any changes that do happen may not reflect the preferences of the public and NHS users, who pay for NHS dental care both directly and through taxes. It is important to consider the views of those who pay for and use the care, as well as those who have to deliver it. To date, determining the opinions of dentists or members of the public for different elements of NHS dental care has been limited. There has also been no assessment of the value members of the public or dental practitioners hold for the individual elements of dental care. This means there may be aspects of NHS dental care that do not provide value for money and the money could be better spent elsewhere within NHS dentistry. AimsThis project will assess the values the public and dental practitioners in England hold about the different aspects of NHS dental care. It will examine the public's preferences about each element of dental care by asking how much you would be willing to pay to receive your preferred method of care. Using this information and details about the costs of care, this project will provide an assessment of which elements of dental care provide value for money and if the new contract offers an improvement. Research PlanThe project will be split into three sections that feed into each other. Throughout the project those responsible for the reforms will be informed of the process and results.Research Phase OneI will hold focus groups with members of the public to assess which elements of dental care are important to them. Dental practices, including dentists, dental nurses, hygienists and therapists, will be interviewed about what is important from a practitioner perspective. I will interview NHS Senior managers responsible for making decisions about dental care and the dental contract. Research Phase TwoUsing the information gathered in phase one, I will design a hypothetical choice exercise where members of the public and dental practitioners will make a series of choices between scenarios when delivering or receiving dental care and express an amount they would be willing to pay to obtain their most preferred scenario. This exercise will provide information about what is important about NHS dental care to patients and dental practitioners, what value the different elements hold and how these compare relative to each other. Research Phase ThreeThe willingness to pay values gathered in phase two will enable me to look at the different elements of dental care and see which offer the best value for money, from the perspectives of the public and dental practitioners. Subtracting the cost from the willingness to pay value for each element will do this. Using these values I will be able to identify if the proposed changes to the dental contract offer value for money relative to the existing contract. These results will be shared with NHS England and there will be discussions with policy makers regarding how to incorporate the public and practitioner perspective into decision-making.",8.1 ORGANISATION AND DELIVERY OF SERVICES,ORAL AND GASTROINTESTINAL HRCS22_06891,Department of Health and Social Care,NIHR,Design and evaluation of a novel methodology for stereotactic ablative radiotherapy for lung cancer: reducing treatment side-effects and enabling more patients to benefit from this treatment.,"Research question: Can the volume of non-cancer tissue receiving a high dose of radiotherapy to moving lung tumours be reduced without adversely affecting treatment outcome?Background: SABR is a new treatment option for >1000 lung cancer patients/year. A major advantage is that the success rate of eradication of tumour mass is reported to be >80% for SABR compared with 30% for conventional radiotherapy. In SABR a more focussed, much higher dose is delivered to the tumour than in conventional radiotherapy.Due to the high doses delivered per treatment, SABR needs to be delivered extremely accurately. X-ray imaging is used to ensure the tumour is correctly targeted and to avoid normal, healthy tissue. This is challenging since lung tumours move due to breathing which may vary because breathing cycles are variable in nature particularly in patients with compromised lung function and who may suffer treatment anxiety. In the UK the approach used to account for tumour motion, is to add a margin around the tumour which ensures the tumour is covered in all positions of the breathing cycle, consequently resulting in a large volume of normal tissue receiving a high radiation dose (increasing radiation side-effects such as pneumonitis/breathlessness). An alternative approach which promises significantly smaller high dose volumes of normal tissue whilst still ensuring effective tumour dose, targets the tumour in the middle of the tumour movement range.Aims and Objectives: I will develop a methodology for implementation of the new treatment approach. I will build on international work by making the method easily usable by other NHS hospitals and by developing a method for validation through actual dose measurement.Method: It will be essential to carefully monitor 3D tumour motion during SABR delivery. This will be achieved by measuring the 3D motion of the patient's chest surface during breathing with a novel approach utilising low cost 3D camera technology (used by my supervisor in a different setting). For 30 patients X-ray CT images measuring internal tumour motion will be combined with chest surface measurements to build patient-specific breathing models that correlate external chest motion with tumour motion during SABR delivery. To evaluate this new method I will take advantage of advancements in the design of physical models of the thorax that allow realistic simulation of 3D tumour motion. Detectors positioned in the thorax model will allow measurement of dose delivered to a moving tumour by SABR plans generated for both treatment approaches. Dose measurements will be analysed and used to calculate parameters proven in the literature to have a direct relation to tumour control and normal tissue complication. This will allow both approaches to be compared.Finally I will explore the potential of developing a clinical trial that compares outcomes from the standard and new approach, as a topic of follow-on funding.Anticipated Impact: Fewer patients will develop severe radiation side-effects. SABR will become a treatment option for an increased number of patients (+15%/year) who are currently excluded due to too high doses to healthy lung tissue or adjacent organs.","Aims: To increase the number of patients that benefit from Stereotactic Ablative Radiotherapy (SABR) for lung cancer using new treatment methods that reduce the amount of non-cancer tissue receiving a high radiation dose without effecting treatment outcome.Background: SABR is a treatment for lung cancer which offers major advantages over conventional radiotherapy: a) It is a more precise highly effective treatment with significantly improved treatment outcomes (greater elimination of the cancer cells). b) It is delivered in fewer (3-8) high doses as opposed to many low doses over several weeks. It is favoured by patients, for convenience and reduction of travel costs.Due to the high doses delivered per treatment visit, SABR needs to be delivered extremely accurately to avoid unwanted radiation dose to healthy normal tissue. X-ray imaging is used to ensure this. However, it is complicated by the lung tumour's movement caused by normal breathing which can vary significantly during treatment, particularly in patients with breathing problems (due to their cancer or other diseases) and because they may be anxious. Therefore to avoid missing the tumour, the irradiated volume needs to be larger than the actual tumour.UK standard practice ensures the tumour is targeted by radiation in all positions of the breathing cycle. This results in a lot of normal tissue receiving a high dose which causes side effects (e.g. lung inflammation and breathlessness). To address this, I will design a treatment based on a new approach that targets the tumour at the position it spends most time. This will result in significantly smaller volumes of normal tissue that need to be given a high radiation dose.It would greatly enhance current practice by impacting on current SABR patients since fewer patients would develop severe radiation side-effects. Moreover, SABR would become a viable treatment option for patients who are currently excluded due to too high a risk of complications from unwanted radiation to their healthy tissue.Design and Methods: I will develop a method for safely implementing the new treatment approach. I will build on international work by making the method easily usable by other NHS hospitals and developing necessary testing through dose measurement.To carefully monitor the variability of tumour motion during treatment, a camera will be used to make videos of how the patient's chest moves in 3D. I will draw on my supervisor's experience using this technology to build a complex mathematical model that infers movement of the tumour from movement of the chest. Next, I will take advantage of recent advancements in the design of dummies of the chest and dose detectors. Dose detectors will be positioned inside a dummy to allow measurement of dose delivered to a moving tumour during SABR. I will measure differences between the old and new treatment approach.Finally I will explore the potential development of a clinical trial to start after this project that would compare clinical outcomes between both approaches.Patient and Public Involvement and Dissemination: Patient representatives have already been involved in the writing and development of this proposal. Representatives will participate in bi-annual steering group meetings during which they will provide advice and guidance on patient impact as the study progresses. To ensure the results are disseminated to public and patients, they will be presented through the patient group Independent Cancer Patients' Voice. Additionally, it is planned that this work will produce at least three journal papers alongside presentations at international conferences, and at least one European multidisciplinary meeting.To facilitate early translation to clinical practice, the work will be presented to the UK SABR Consortium, which is responsible for current Lung SABR guidelines.",6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,CANCER AND NEOPLASMS HRCS22_19054,Wellcome Trust,,Designer biology to live image purine metabolism at single-cell resolution,"I recently discovered the function of a previously uncharacterised gene, FAMIN, that is linked to Crohn’s disease, leprosy and arthritis. A multifunctional purine enzyme, FAMIN is the pacesetter for purine recycling and hence determines cellular redox status, pH balance and energy production. Altogether, these control macrophage functions, such as bacterial killing and cytokine production. Importantly, my work has established this therapeutically targetable purine pathway as a direct driver of human inflammatory disease. However, further investigation of this pathway is currently limited by the inability to directly visualise and study purine metabolites in-situ, in real-time, and at single-cell resolution. Thus, the spatiotemporal dynamics of purine metabolism are mostly unknown. Assessing these dynamics will be crucial in understanding how purine dysfunction emerges in individual cells and can influence disease pathogenesis, for example through affecting redox state. Samie Jaffrey has pioneered technology that could overcome this hurdle. His group has generated programmable RNA-biosensors capable of live-imaging metabolites in single cells. I intend to learn these techniques and will engineer bespoke sensors for purine metabolites. I shall use these biosensors to dynamically track purine metabolism, and interrogate how environmental triggers can cause the purine dysfunction seen in numerous pathological contexts including chronic inflammatory diseases.","Cells carefully balance how they metabolise nutrients in order to maintain a healthy state, avoid the build-up of toxic chemicals, and to support essential activities such as responding to infection. Conversely, metabolism is frequently altered in disease processes such as cancer and autoimmunity. I am proposing to learn new methods to create sensors that can live-track metabolite levels in individual cells and will utilise it to study a particularly important group of metabolites known as purines. Purines perform several critical functions. For example, they are required as the building blocks for our DNA and as cofactors for the chemical reactions occurring in our cells. I recently discovered a novel role for purine metabolism in controlling inflammation. I will utilise my biosensors, a much needed addition to the metabolism research toolkit, to directly image purine regulation and better understand its role in preventing diseases such as inflammatory arthritis and Crohn’s disease.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_02809,Medical Research Council,MRC,Detection and sequencing of SARS-CoV-2 derived HLA-I bound antigenic peptides in the blood of COVID-19 patients: mapping the CD8 T cell response.,"The role that CD8 cytotoxic T cells play in the clearance of viral infections cells is well established, and depends upon the recognition of short (typically 9-11 mer) antigenic viral peptide epitopes presented on HLA class I molecules (HLA-I). The design of effective future vaccines, that can induce both classical memory B cell antibody, and CD8 T cell responses therefore requires that we identify, map and include the most antigenic epitopes being presented to CD8 T cells. In this study we will take advantage of the presence in serum and plasma of both soluble HLA-I and extracellular vesicles (EV) expressing HLA-I as a source of the cellular immunopeptidome. Based on our existing recent studies that both cancer cell line derived and patient plasma EV HLA-I contain tumour associated antigenic peptides, we hypothesise that COVID-19 induced inflammation in the lungs will release excess soluble and EV HLA-I into plasma which we can utilise as a simple to access liquid biopsy, to immunoisolate the HLA-I, extract the antigenic peptides and de novo sequence by mass spectrometry. By comparison to the known viral proteome we will rapidly identify viral epitopes across a wide range of HLA-I alleles present in the population. We aim to rapidly process up to 200 patients samples to build a comprehensive map of real viral antigenic epitopes of use for future intelligent vaccine design.",,2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),INFECTION HRCS22_06145,Department of Health and Social Care,NIHR,Developing LifeLight: A contactless vital signs monitor for CVD screening,"Research question: Is Lifelight® technology clinically efficacious and safe? Background: Cardiovascular disease (CVD) is the most common cause of mortality with 28% of UK deaths attributed to it. CVD risk is highly modifiable however steps to reduce CVD risk can only be made if these individuals are detected. The leading risk factor for CVD is hypertension and hence Public Health England aims to diagnose an additional 3.7 million cases of hypertension by 2029. Lifelight® is the world s first contactless method for measuring vital signs, including blood pressure. The contactless and software nature of this CE marked technology means it overcomes issues of conventional methods for measuring vital signs that make hypertension screening unfeasible. Its advantages over traditional methods means it could also be useful for helping people with hypertension to keep their blood pressure at safe levels. Aims and Objectives: Collect clinical data to improve Lifelight® accuracy for measuring blood pressure and other vital signs. Trial primary endpoint is progression of the technology s performance closer to standard-of-care efficacy levels (e.g. automatic blood pressure machine). Collect data and patient feedback and strengthen strategic relationships with NHS and PHE to prepare for real-world implementation. Methods: Prospective multi-centre trial conducted at Portsmouth Hospitals NHS Trust and Barts Health NHS Trust collecting artificial intelligence training and testing data from 10,000 people. Collection of vital sign measurement timing data to assess cost-saving opportunity of CVD screening use case and patient feedback on the concept. Timelines for delivery: 24-month project incorporating a 12-month trial. Anticipated Impact and Dissemination: Project outputs include publications in The Lancet, attendance at major clinical conferences, and health economics model. If future real-world implementation is successful and rolled out nationally, application of the technology for CVD screening and hypertension monitoring could save UK health and social care £210 million over 10 years.","Lifelight® is an app for measuring the pressure in your blood vessels (blood pressure), how fast your heart beats (heart rate), how fast you are breathing (respiratory rate), and how much oxygen you have in your blood (oxygen saturation). These are essential “vital signs”. All you need to do is look at the camera in your smartphone or tablet for 20-40 seconds. Previously, the app has used data from nearly 10,000 people to learn how to measure these vital signs as well as some technologies already used by doctors and nurses. AIMS: Make Lifelight® even better at measuring vital signs, especially for a broader range of people. It is important to make the blood pressure measurements more accurate so that the technology can be used to find people with abnormally high blood pressure who do not already know that they have high blood pressure. Get ready for a future project where Lifelight® can be used to find these people. BACKGROUND: Lifelight® is already available for doctors and nurses to use on their patients. Some changes need to be made so that patients and the public can use the app and so that it can give doctors and nurses the information they need to find people with abnormally high blood pressure in an efficient, effective and economical way. This diagnosis will mean they can give these people the medicines they need so they are less likely to have a heart attack or stroke. WORKPLAN: This 24-month project has 7 work packages (WP): WP1: Collect the data Lifelight® needs to be able to measure high blood pressure more accurately. WP2: Build this new learning into the app. WP3: Make the app available for people with Android or Apple phones or tablets. WP4: Create lots of interest for the app to be used across the country in future. WP5: Get ready for the future project where the app is used to find people with high blood pressure who do not already know they have it. WP6: Make sure the new app meets all necessary regulations. WP7: Make sure the project meets its aims. PPI: 10,000 patients and the public at two hospitals will give the data needed to let the app learn how to measure blood pressure more accurately. Xim will talk with patients, public and people managing the NHS to work out the best way to get Lifelight® into the hands of people most likely to have high blood pressure but who are not aware of it. DISSEMINATION AND OUTCOMES: Xim will let people know about its work by publishing articles in prominent journals and magazines, posting updates on social media, and speaking at conferences.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING,CARDIOVASCULAR HRCS22_15436,Wellcome Trust,,Developing Machine Learning Approaches for Survival Analysis and Patient Stratification in Inherited Cardiac Conditions,"Inherited Cardiac Conditions (ICCs) include a variety of diseases for which the genetic basis and pathogenesis is still majorly unexplained. The clinical outcomes of patients with ICCs are very diverse, rendering diagnosis, prognosis, and accurate therapeutic decisions very challenging. The purpose of this project is to develop machine learning approaches that will be able to explain some of the survival and clinical differences among patients with the same ICC and describe genetic biomarkers responsible. This will enable better patient stratification which will lead to more accurate diagnosis and assessment of therapeutic actions that need to be taken. The modelling approaches will be based on cardiac imaging and genetic data collected from patients across the ICC spectrum and healthy volunteers.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CARDIOVASCULAR HRCS22_16367,Dunhill Medical Trust,,Developing a co-designed systems-level response to safety issues for residents transitioning from hospital to care homes,"Background: Transition from hospital to care home is high in risk, with a third of transitions resulting in adverse events (Kapoor et al., 2019). Common problems include communication failures, (Richardson et al., 2019) medication errors, (Weir et al., 2019) and incorrect documentation (Hellesø et al., 2004). Identifying incidents is difficult; reports do not accurately reflect level of harm (Scott et al., 2019a), care home and hospital organisations have different priorities (Sutton et al., 2016), and health and social care sectors use different definitions of safety (Scott et al., 2017). Consequently integrated care is lacking, and opportunities for organisational, cross-sector learning can be missed (Scott et al., 2017). Moreover, there is a knowledge gap around how care homes collect incident reports. Aims: Develop a better understanding of incident reporting in care homes and co-design a systems-level response to safety issues for patients transitioning from hospital to care home. Methods: Two Workstreams (W) will run in parallel. W1 will consist of a scoping review of types of existing systems for reporting incidents, including policies, technology and types of data captured. Representative stakeholders representing medium to large care home organisations will be involved, leading to the development of a taxonomy of incident reporting in care homes. The taxonomy will be developed using a standardised approach to taxonomy development (Nickerson et al., 2013). W2 will be structured in three Phases (P) with care home organisations. P1 will consist of ≤40 interviews with care home staff to develop a better understanding of their specific internal systems for reporting incidents. P2 will consist of a retrospective documentary analysis of care home data relating to resident transitions, using the knowledge of the systems gained in P1. Data size and sampling will be determined based on potential data size. A validated data extraction form (Scott et al., 2019) will be adapted and revalidated before use. Content analysis (Elo and Kyngäs, 2008) informed by the heuristic of systemic risk factors will be the primary mode of analysis, supported by thematic analysis for emerging themes (Braun and Clarke, 2006). P3 will consist of four validation and co-design workshops to develop a service specification using NHS Improvement's (2018) framework. This will then be mapped against existing systems and recommendations produced. Discussion: Commissioners, providers and regulators will be able to use the co-designed service specification to improve integrated care, leading to a positive impact on the health and care of older people.","When people move from hospital into a care home, it is quite common for something to go wrong with their care that does or could affect their safety. This is called a safety incident. Some examples include medicines being lost or delayed, or important documents containing mistakes or going missing. It is important to find out when and why safety incidents happen so that improvements can be made. Finding this out doesn’t happen enough because care homes and hospitals sometimes have different priorities other than the person’s care. They also have different understandings of what unsafe care means. Hospitals generally think of unsafe care as being a problem with the system that affects everyone, whereas care homes usually think of someone being unsafe because of problems with the care provided to just them. Because of these different approaches, it can be difficult for care homes, hospitals, or even organisations that oversee them, to learn from safety incidents. As such, this study aims to understand how care homes and care home staff report safety incidents when a person moves from hospital to a care home. Using this understanding, we aim to work with care homes and hospitals to jointly design a better way of reporting and learning from safety incidents. The study will be split into two parts that run alongside each other. During the first part (workstream 1), we will review how care homes respond to safety incidents. This will include looking at what policies exist, what technology is used and how reports are captured. This review will be desk-based, combining internet searches, telephone interviews and academic papers. From this, we will create categories of the different systems being used. During the second part (workstream 2), we will work with two care home organisations, one in North East and one in South West England. Each will contain around 30-50 care homes, and will cover all different types of care homes (eg nursing, residential, dementia). We will begin by speaking with up to 40 care home staff to find out how they report incidents. Then we will review the information that the care homes hold, using a method that we have developed and used previously. We will use what we learn to jointly design a new system for learning from safety incidents by hosting four workshops. This new system will be compared with existing systems and recommendations will be made.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_02566,Medical Research Council,MRC,Developing a human pluripotent stem cell-based strategy for treating Hirschsprung disease,"Hirschsprung disease (HSCR) is the consequence of a failure of neural crest-derived enteric neural progenitor cells to colonise the distal gut during embryonic and fetal development. Nevertheless, such progenitors derived from mouse and human postnatal gut have been shown to effectively colonize, and differentiate within, aganglionic gut explants from animal models of HSCR and from affected patients, demonstrating that cell therapy should be a viable option for treatment. However, harvesting sufficient progenitor cells from human gut biopsies poses a significant hurdle which could be overcome by their production from differentiation of human pluripotent stem cells (hPSC). We have established an effective protocol to derive neural crest cells from hPSC in chemically defined, xeno-free conditions, and have shown that these can generate enteric neural progenitors which can colonise long term and efficiently the intestine of animals following transplantation and also produce enteric neurons in vitro. In this project we will establish the preclinical basis for a regenerative medicine approach to treating HSCR by transplantation of hPSC-derived enteric neural progenitors to re-innervate the affected part of the gut. To this end we will assess the ability of our hPSC-derived enteric neuron progenitors to correct for the lack of enteric neurons in both established and novel models of HSCR. We will also identify new specific cell surface markers to improve the isolation of enteric neuron progenitors suitable for transplantation and optimise the protocol for their generation. Finally, we will define the best-performing hPSC cell line for generating such progenitors in order to treat Hirschsprung disease.",,5.2 CELLULAR AND GENE THERAPIES,ORAL AND GASTROINTESTINAL HRCS22_06214,Department of Health and Social Care,NIHR,Developing a model for high quality service design for children and young people with common mental health problems,"The mental health of children and young people (CYP) is a national and international priority, with around one in ten UK CYP having a mental health difficulty that requires professional help. Most of this need lies with CYP experiencing a ‘common’ mental health problem (CMHP). These are commonly occurring problems like anxiety, depression, obsessive-compulsive disorder (OCD), self-harm, psychological trauma, issues relating to gender, sex and sexuality, and problems with emotions and behaviour that are often called ‘personality disorder’. CYP with these problems typically do not need to be admitted to hospital; if they do, it tends to be for a very short time or a very severe form of the problem. _x000D_ _x000D_ More CYP with CMHPs are asking for help (or their parents, carers or teachers are) but it is often difficult to get help because services do not exist, are oversubscribed or depend on where the service user lives. When a service is available and used, it may turn out to be poor quality or unsuitable for the service user._x000D_ _x000D_ We want to explore the services available to these CYP in England & Wales. Most of these services will be community or out-patient services. We want to find out what services exist, how CYP and their families/carers find out about and access these services, what the services actually do, whether they are any good, and whether they offer value for money. _x000D_ _x000D_ Our study has 4 work streams. In Stream 1 we will conduct ‘evidence syntheses’. This involves us looking at the literature on services for CYP with CMHPs. This helps identify what services exist, what CYP and their families like about these services and what seems to work. In Stream 2, we will use a survey and the literature from Stream 1 to try to map all of the available services for CYP with CMHPs in England & Wales. Streams 1 & 2 combined will help us group services according to things they have in common or things they differ on, eg who provides the service (NHS or other), who it is for (a general service for CMHPs or one for a specific condition), how it is delivered (face-to-face, telephone or online, etc), whether appointments are required or whether you can simply drop in._x000D_ _x000D_ In Stream 3, we will pick 8-10 services from our Stream 2 service map and visit each one, talking to 6-8 CYP, 2-3 parents, carers and/or siblings, and 2-3 staff members in each service. We plan to take some young service users, who we will train as ‘co-researchers’, with us when we visit these services. We will ask users of the services we visit to tell us their stories of trying to get help. We will also try to speak to people who couldn’t get help or didn’t want the particular help offered. We will look at relevant documents (eg policies and procedures) and, if possible and with permission from those involved, observe team or referral meetings. We will analyse our data using an approach called ‘framework’ to get some insights into how CYP and their families/carers find and access help and whether they found that help useful or not._x000D_ _x000D_ In Stream 4, the analyses from Streams 1-3 will be explored, compared and contrasted in order to create a model (or models) of effective and acceptable services for CYP with CMHPs that takes into account how these services are accessed, navigated and used._x000D_ _x000D_ Throughout our study, we will talk to young people and their parents/carers and to those who commission and provide services for them to ensure what we are doing remains relevant to them.","The mental health of children and young people (CYP) is a national and international priority, with around 1 in 10 UK CYP having a mental health difficulty. Most of the need lies with CYP experiencing ‘common’ mental health problems (CMHPs). CMHPs are a range of psychological, emotional and behavioural problems that includes anxiety, depression, OCD, self-harm, PTSD, gender identity issues and emerging personality disorders. While health needs for this population group are rising, services across the UK tend to be fragmented, uncoordinated and variable, and most struggle to meet demand._x000D_ _x000D_ This study aims to develop a model of effective service design for CYP with CMHPs by examining the factors that facilitate access to, and navigation of, services for CYP with CMHPs and the effectiveness and acceptability of those services. CYP with CMHPs typically do not require hospitalisation so the services investigated will be out-of-hospital services providing primarily assessment/triage, early intervention and supported self-care. This evidence-based model will help inform the NHS and assist commissioners and providers in the design and transformation of out-of-hospital services for this population group. _x000D_ _x000D_ The study has 4 work streams. In Stream 1, a series of systematic reviews of the international literature will be conducted, specifically: (a) a descriptive review identifying the range of service models; (b) an effectiveness review that identifies and evaluates those service models where comparative effectiveness data are available; (c) an acceptability review that identifies and evaluates those service models where acceptability data are available; and (d) an economic review that considers provider and user costs/benefits associated with specific service models. The reviews will be synthesised using EPPI-Centre meta-synthesis principles. In Stream 2, a survey and the literature from Stream 1 will be used to map services in England & Wales across a range of different service dimensions (theoretical underpinnings, location, staffing, provider, delivery platform, etc). A typology of service provision for CYP with CMHPs will be derived from Streams 1 and 2. In Stream 3 (a collective case study), 8-10 services will be purposively sampled from Stream 2's service map to reflect the various dimensions of the typology. At each site, in line with the principles of case study research, we will: (a) conduct interviews with key stakeholders, ie providers, managers & users (including those who could not or did not access services); (b) obtain relevant documents; and (c) observe, where possible, key interactions. The three case study data sets will be analysed using Framework. We will also collect economic data (time spent delivering services, equipment costs and user out-of-pocket expenses) in Stream 3 for which bottom-up estimates of costs associated with services will be calculated from NHS and PSSRU sources._x000D_ _x000D_ In Stream 4, data from Streams 1-3 will be synthesised to elicit a model (or models) of effective and acceptable service design for CYP experiencing CMHPs that integrates all of the factors associated with accessing, navigating and receiving help from services for this population group._x000D_ _x000D_ Service user & provider perspectives will permeate the entire study via an advisory group (which will include commissioners of services), having an NHS manager & service user group as co-applicants, and via employing young service users as co-researchers.",8.1 ORGANISATION AND DELIVERY OF SERVICES,MENTAL HEALTH HRCS22_06817,Department of Health and Social Care,NIHR,Developing a multi-component intervention for the prevention and management of delirium in hospice in-patient units: a targeted behaviour change approach.,"Background Delirium is a distressing condition which is commonly experienced by patients in hospices. Prevalence in palliative care in-patient settings ranges from 13 to 42% on admission and 58 to 88% in the last weeks of life2. It is characterised by disturbances in attention, awareness and cognition which have a rapid onset and fluctuating course3. Delirium is associated with serious adverse outcomes and for hospice patients it can result in the loss of decision-making capacity and prevent meaningful communication at a critical time4, 5. Multiple risk factors have been identified for delirium in patients admitted to hospitals (as distinct from hospices) including sleep deprivation, dehydration and use of psychoactive drugs6, 7. There is strong evidence that the use of multi-component interventions (MCIs) which address modifiable risk factors in hospitalised patients can significantly reduce new onset delirium 8. Strategies to address risk factors are used both to prevent delirium and to treat established episodes. People who have been admitted to a hospice are at particular risk of delirium because of the advanced nature of their illness, but there is little evidence on effective prevention and management of delirium in this setting. The risk factors for delirium among hospice patients may vary from those in other settings and different approaches to its prevention and management may be appropriate for patients nearing the end of life.5, 9 There is a need for research to develop and test an intervention to prevent and manage delirium which is tailored to the hospice setting. Aim To develop a multi-component intervention for the prevention and management of delirium in hospice in-patient units. Plan of Investigation Workstream 1: To identify risk factors for delirium and strategies for addressing delirium that are relevant to palliative care. A systematic review of risk factors for delirium in palliative care will be conducted. An expert panel of palliative care and delirium academics and clinicians will draw upon evidence and clinical guidelines to agree a list of risk factors for delirium, and a list of staff behaviours to address delirium, that are relevant to hospices. Workstream 2: To explore hospice staff's current practice in addressing delirium and barriers and enablers to improving practice. Qualitative observations and interviews will be conducted in two hospices. The qualitative data collection and analysis will be structured using a behaviour change framework10, and the lists of relevant factors identified by the expert panel. Workstream 3: To design a targeted behaviour change intervention to improve care of delirium by hospice staff. Drawing upon the qualitative findings, the expert panel will agree target behaviours of hospice staff that are priorities for change to improve delirium care. A modified version of nominal group technique will be used to reach consensus. The 'Behaviour Change Wheel'10 framework will be used to support the design of an intervention to prevent and manage delirium in hospices which focuses on these target behaviours. A hospice working group will be engaged in this process. Workstream 4: To implement components of the intervention and evaluate their feasibility and acceptability. Components of the intervention will be implemented and a process evaluation will be carried out with a focus on feasibility and acceptability. The intervention design will be refined on the basis of this. An intervention manual and protocol will be produced for use in a future pilot study and eventual testing of the intervention's effectiveness in a cluster randomised controlled trial. Potential benefits of this research This project will make significant progress towards improving the prevention and management of delirium in hospice patients and reducing associated adverse outcomes, including the distress it causes to patients, their families and staff.","Improving care of delirium in hospices What is the problem to be addressed? Delirium is a condition in which people become confused over a short time due to causes including infection, medication, dehydration and sleep problems. Several of these may occur at the same time. People with delirium may find it hard to think clearly, pay attention and remember things. They may become restless and agitated or withdrawn and sleepy. They may lose the ability to make decisions about their care and to have meaningful communication with family and friends. Delirium is distressing for patients, their families and people caring for them. People who have been admitted to a hospice are at particular risk of delirium because of the advanced nature of their illness, but little is known about how to prevent or manage this frightening condition in hospices. There is strong evidence that delirium can be prevented in hospitals using 'multi-component interventions' aimed at the potential causes of delirium. These include: ensuring patients have enough to drink; changes in routines to encourage good sleep patterns; reviewing medication and investigating infections. This approach may be useful in hospices, but there may also be important differences in how delirium should be cared for. For example, the understanding and knowledge of staff; patient risk factors and approaches to treatment may differ from those in hospitals or other settings. Delirium is very common among people admitted to hospices and its effect on patient's ability to communicate and make decisions may be particularly distressing for patients and their loved ones at this critical time. It is important to develop an approach to preventing and managing delirium that is tailored to hospice care. Aim: To develop an approach to prevent people admitted to hospices from developing delirium and to improve the care of those who experience delirium. What will I do? Review previous research and guidelines to draw up a list of causes of delirium and of staff skills and behaviours that are important for delirium care in hospices. An expert panel of delirium and palliative care researchers and hospice staff will discuss and agree the list. Carry out a study in two hospices to observe the ways that hospice staff work to prevent and manage delirium. I will also interview staff members to explore their understanding of delirium care and what would help or hinder improvements in practice. The expert panel will use this information to prioritise a number of aspects of staff care which, if changed, should improve delirium care in hospices. Design an approach which will focus upon these target aspects of care (known as 'behaviours'), using a tool called 'The Behaviour Change Wheel' to find the best ways to help hospice staff change these behaviours. A hospice working group, including staff, patients and relatives, will work with me to develop the approach. Staff will try out these ways of working to check if they are practical to carry out and acceptable to staff and patients. Produce a manual which will describe this approach to improve delirium care in hospices. In future studies this could be put into practice to see if it makes hospice care better for patients and their families.I will involve patients and carers who have experience of palliative care or delirium throughout this project. They will advise on aims; study design; the research summary and other documents; sensitive approaches to carrying out research in hospices; developing the approach and sharing the results. The research results will be shared with many different people and groups including hospice patients and carers; researchers and health professionals working with delirium or in palliative care; health services and charities. This will involve publishing them in academic journals, newsletters and online and carrying out presentations, talks and workshops. I expect this project to be an important step forward in improving delirium prevention and care in hospices and reducing the difficulties and distress that delirium can cause patients and their families.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;7.2 END OF LIFE CARE;8.1 ORGANISATION AND DELIVERY OF SERVICES,MENTAL HEALTH HRCS22_03005,Medical Research Council,MRC,Developing a new class of antibiotics based on efflux resistant 4-oxoquinolizines for multidrug-resistant ESKAPE pathogens,"Antimicrobial resistance (AMR) is a major concern, with increased levels of multidrug resistance (MDR) in many pathogens, resulting in treatment breakdown in the clinic. The O'Neil report suggested that infections caused by antibiotic resistant bacteria could become the leading cause of mortality worldwide, with up to 10 million deaths per year by 2050. The situation is exacerbated by the very poor pipeline of new antibiotics, especially in the case of high priority pathogens identified as being of critical concern by WHO and others. In many Gram-negative bacteria, efflux pumps play a significant role in resistance to antibiotics and, simultaneously, the ability of bacteria to develop stable high level resistance through target site modifications. Although the development of stand-alone efflux pump inhibitors, which can be used in conjunction with antibiotics to suppress this response, is an attractive idea, it has not been possible to advance candidates to the clinic. We have taken a different approach, by identifying differential binding sites of inhibitors and substrates to efflux pumps, and generating hybrid molecules where efflux-resistance is a feature of the molecule. Such efflux resistance breaker (ERB) modified antibiotics have significant potential for therapeutic development as stand alone therapies and/or as part of a combination therapy. We have good evidence that these compounds are effective against Acinetobacter baumannii, and the medicinal chemistry optimisation and validation of the technology will extend the utility to other WHO priority pathogens, for which new antibiotics are urgently required. Data generated in this project will provide a framework for the development of efflux-resistant antibiotics, which are potentially more robust in clinical use. The project will focus on lung infection as the primary indication, aiming to [provide early data to support development of new treatments for hospital and ventilator-associated pneumonia.",,5.1 PHARMACEUTICALS,INFECTION HRCS22_03782,Medical Research Council,MRC,"Developing a school-based, transdiagnostic, preventative intervention for adolescent mental health","Objective: to capitalise on advances in experimental psychology, social science and clinical research to develop a novel hybrid preventative intervention for adolescent mental health, that embeds specific emotional training techniques into an adapted group-based Interpersonal Therapy (IPT) programme. This is a longitudinal randomised allocation study, with three assessment points at baseline, post-intervention and 1 year follow-up. Participants: 540 high risk (top 25% for general psychopathology) young people aged 13-14 (school years 8 & 9) randomised into intervention (N=270) and non-intervention (N=270) arms of the study. Measures: Mental health, Wellbeing, Emotion processing (experimental tasks and questionnaires assessing negative emotion perception, emotion regulation, and interoception), social relationships (social network measures achieved via peer-nomination, as well as questionnaire measures of family and peer relationships, bullying and loneliness), and key demographics will be measured using standard and well validated instruments. Process evaluation: Mixed-methods approach to study the acceptability, feasibility and barriers to delivery, including thematic analysis of focus-group interviews with recipients of the intervention and key stakeholders. Statistical Analyses: Mixed-linear analyses to address whether the intervention leads to improvements in the mental health and well-being. Structural equation modelling to test if the intervention's impact on mental health and wellbeing is mediated by changes in emotional processing and social relationships. Stable trait autoregressive trait and state analyses to test bi-directional relationships between emotional processes, social relationships and mental health vulnerability over time. Scientific deliverables: Pre-registered scientific protocol, intervention clinical manual, scientific papers, conference presentations, analysis plan & analysis scripts, curated dataset for sharing.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;7.1 INDIVIDUAL CARE NEEDS",MENTAL HEALTH HRCS22_05361,Department of Health and Social Care,NIHR,Developing and Evaluating A Multifactorial Intervention to Improve Cardiovascular Outcomes in Adults with Type 2 Diabetes and Current or Previous Diabetic Foot Ulcers (MiFoot),"Research questions: Is there geographic and demographic variation in outcomes in people with type 2 diabetes (T2D) and diabetic foot ulcer disease (DFUD), such as cardiovascular disease (CVD), mortality, and amputation? Which risk factors explain the excess risk of CVD specific to DFUD? Which elements of previous interventions in people with DFUD are effective? Can a complex intervention aimed at medication optimisation and behaviour change be effective, cost-effective and sustainable in preventing CVD events in people with DFUD? Background: Individuals with T2D and DFUD (~50-60,000 in the UK) have CVD much in excess of those with T2D alone. CVD is the leading cause of death in this group, but interventions to reduce event rates have not been developed or tested. Traditional CVD interventions may not be appropriate for this high-risk population; for example, weight-bearing physical activity and some glucose lowering medications are contraindicated in DFUD. An evidence-based CVD prevention intervention for people with T2D and DFUD is a significant unmet patient need. Aim: Reduce CVD events (including mortality) in adults with T2D and current/previous DFUD. Objectives: Evaluate risk of worsening morbidity or mortality in DFUD Evaluate existing interventions to reduce CVD risk in DFUD Develop a multifactorial complex intervention to prevent CVD events in T2D and DFUD Evaluate the intervention s effectiveness, cost-effectiveness and sustainability Methods: There will be four workstreams (WSs), with PPI/E integrated throughout. WS1: Analyse routinely-collected primary and secondary care data to understand the healthcare needs, disease burden and sociodemographic/geographic factors associated with DFUD, and estimate the incidence of CVD-related events and mortality. WS2: Perform a systematic review, meta-analysis and mixed treatment comparison of existing interventions for people with DFUD. We can then use evidence about what has, and has not, worked well before to design our intervention. WS3: Develop a complex intervention to reduce CVD events in people with T2D and DFUD by combining patient and healthcare professional views (qualitative study), findings from WS1 and WS2, PPI/E input, and our in-depth experience. It will likely use one-to-one, group and online sessions to target medication optimisation and behaviour change, including seated exercise. We will estimate the expected economic benefit of intervention implementation. WS4: Perform a randomised controlled trial, informed by previous WSs, with internal feasibility study and process evaluation to test the intervention effectiveness (an extended Major Adverse Cardiovascular Event [MACE] composite as primary outcome) and cost-effectiveness for preventing CVD events. Participants (n=392) will be randomised 1:1 to intervention or control conditions. Delivery timelines: PPI: Pre-funding to post-funding (Deliverable: Month 63) WS1 and WS2: Months 1-12 WS3: Pre-funding to month 39 WS4: Months 4-63 (including setup) Dissemination: Primarily months 13-24, 40-52 and 60 onwards. Anticipated Impact and Dissemination: The primary impact, if achieved, will be a substantial reduction in CVD outcomes for those with DFUD. Academic and non-academic outputs will be disseminated through well-established methods, including press releases, social networks, open days, and relevant charities. Wider effects include improved disease self-management ability and quality of life. These benefits will likely translate to economic benefits for the NHS.","Problem Type 2 diabetes (T2D) can lead to heart attack, stroke, and early death. The risk of these is increased in people with T2D who have had diabetic foot ulcer disease (DFUD). In the UK, 50,000-60,000 people have DFUD, which are slow healing wounds on the foot that may lead to amputation and disability. Aim Reduce the very high risk of heart disease, stroke and early death in people with T2D and current/previous DFUD, so that the risk is similar to people with T2D who have not had DFUD. Research plan 1: Use digital data that is routinely collected during patient care (including demographics, medical history, medications) from GP and hospital records to understand healthcare needs of people with current/previous DFUD. We will look at how many people with DFUD and T2D have heart disease, stroke and early death, and whether certain groups are at greater risk than others. 2: Conduct a detailed review of existing interventions to find out what has, and has not, worked well before. 3: Combine 1 and 2, with PPI/E input and our own experience to develop a care package (MiFoot) to reduce heart attacks, stroke and early death in people with T2D and current/previous DFUD. MiFoot will likely include one-to-one, group, and online sessions. It will also help people to exercise while sitting, manage their medicines, and support their wellbeing and fitness. 4: Test if MiFoot prevents heart attacks, strokes and early death, and is good value for money, through a randomised controlled trial comparing MiFoot with usual care. How we will involve patients Discussions with people with T2D and their carers formed the basis of the initial MiFoot design, as well as important parts of the study design and this application (such as this summary). The team includes an expert by experience, who reviewed the application. We will recruit a patient/carer panel of 15 people with T2D and current/previous DFUD to meet at least monthly. The meetings will be led by panel members and will support development of a best practice guide for PPI/E with people with T2D and current/previous DFUD. Panel members will be involved in developing MiFoot and making sure that the trial is acceptable for participants. We will work to ensure that panel members are consulted and involved throughout the research and receive adequate training. PPI/E costs have been included. What we will do with the results We will share findings with people living with diabetes, public, health care professionals, and NHS decision-makers. The PPI/E panel and our Centre for Ethnic Health will advise on the best ways to reach patients. This will include engaging with local/national press and charities (including Diabetes UK), social networks, open days, and a website.",6.1 PHARMACEUTICALS;6.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.7 PHYSICAL,CARDIOVASCULAR;METABOLIC AND ENDOCRINE HRCS22_03805,Medical Research Council,MRC,Developing and commercialising a non-invasive test of adrenal insufficiency for children on steroids.,"Nearly half a million (4.5%) of UK children are prescribed inhaled steroids for asthma, many on high doses. All steroid formulations cause adrenal insufficiency (AI). Untreated, AI (cortisol deficiency) leads to circulatory collapse & death through adrenal crisis. Symptoms are non-specific and diagnosis frequently delayed. Concern about AI is rising with the increasing prescription of potent steroids in all medical specialties. In August 2020 the NHS National Patient Safety Agency issued an alert that Steroid Emergency Cards be issued to all patients, including those on inhaled steroids. The practical challenge is identifying and diagnosing patients suffering from AI. Dr Elder has developed a non-invasive test for AI, The Nasacthin Test, a nasal spray with salivary sampling. Nasacthin enables investigation of children at home or the clinic, with no requirement for hospital day-care or blood sampling. It will allow early diagnosis, prevent adrenal crisis and help paediatricians understand the steroid-induced disease burden. The technical challenge is obtaining market authorisation and commercialisation of the Nasacthin test which will require a clinical development plan (CDP), regulatory approval, paediatric normative data, and a cost-effectiveness analysis. Diurnal is ideally placed to help Dr Elder create a CDP and progress her research, boosting her skills in product development, and helping her career development by working with pharmaceutical physicians to understand opportunities in the pharmaceutical industry and potential for collaboration with academia. Diurnal is a leading international endocrinology company focused on AI with experienced clinical, regulatory and commercial teams. This award would facilitate a new product coming to market, benefit the UK economy, and make a major contribution to reducing the disease burden of children using steroids.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,METABOLIC AND ENDOCRINE HRCS22_07288,Department of Health and Social Care,NIHR,Developing and evaluating a tool to protect patients from fabricated data in health systematic reviews,"Background When conducting systematic reviews, researchers identify all randomised controlled trials (RCTs) on a given topic, and combine the results to obtain a summary of the evidence that says whether or not a treatment is safe and effective. The results of systematic reviews are very influential. They are included in clinical guidelines, are used by healthcare payers to determine which treatments should be available, are used by clinicians to make treatment decisions, and are used by funders to set research priorities. However, it is now clear that there are a substantial number of fabricated RCTs in the scientific literature. These appear to describe genuine clinical trials, but in reality they are partially or wholly made up. Because systematic reviews include all relevant RCTs, any fabricated studies are likely to be included. However, there are no established ways for deciding whether any of the included trials are fabricated, and usually no checks are done at all. This means that fabricated trials go undetected. They then contribute to the findings of reviews, meaning that health decision-makers rely on bogus information. This puts patients at risk. Aim To develop and evaluate a tool to detect fabricated RCTs during the production of systematic reviews, so that they can be excluded. Objectives To supplement an existing scoping review and qualitative study with a review of grey literature and survey of experts to produce a comprehensive list of methods for detecting fabricated RCTs. To evaluate the impact and feasibility of identified methods by retrospectively applying them to a large sample of published systematic reviews. To develop a novel tool for identifying fabricated RCTs in systematic reviews, using a Delphi process. To establish the feasibility of implementing the novel tool into the process of conducting systematic reviews, and its impact upon review conclusions, by prospectively testing it in the production of systematic reviews. Methods WP1: We require a comprehensive list of methods for detecting fabricated data for subsequent WP. We will supplement an existing scoping review and qualitative study with a grey literature review and survey of experts. WP2: We will apply the list of methods to 50 systematic reviews, to obtain empirical evidence about their impact on review conclusions. WP3: We will enter the list of methods into a two-round Delphi study of relevant experts, to achieve consensus around the content of a novel tool for detecting fabricated RCTs in health systematic reviews. WP4: In partnership with Cochrane, we will test the tool in the production of new systematic reviews. We will use surveys and a user workshop of authors and editors involved in testing to gather feedback around usability, and will use this to finalise the tool. We will produce training materials for the tool. Impact A validated, feasible tool for detecting fabricated RCTs in health systematic reviews will be produced, and made freely available, along with associated training materials. This will inform Cochrane policy, and will protect against harm caused by fabricated RCTs in many clinical areas.","Clinical trials are performed to test medical treatments. The results are usually published in medical journals. Systematic reviews identify all the clinical trials published on a given topic, and combine the results in a summary of the evidence that says whether or not a treatment works and is safe. The results of systematic reviews can be very influential, and are often included in clinical guidelines, which are then referred to by doctors when deciding which treatments to use. Unfortunately, sometimes people commit fraud, and publish reports of clinical trials that are partially or wholly made up. These reports appear to describe genuine clinical trials, but they do not. There are no established ways for the authors of systematic reviews to decide whether trials appear to be fraudulent, and often no checks are done at all. This means that fraudulent trials contribute to the findings of reviews, and consequently that doctors rely on bogus information when deciding on the best way to treat patients. This could mean prescribing treatments that don t work, or are harmful. This puts patients at risk. We will develop a checklist that researchers can use to detect fraudulent clinical trials, so that they can be excluded when producing systematic reviews. We will do this by getting experts to agree on criteria that can be used to say that a trial is untrustworthy. An example of a possible criterion would be a study claiming to have recruited a suspiciously large number of participants in a short timeframe. We will first identify the possible criteria by reviewing all of the literature on detecting fraud and by sending a survey to journal editors to see how they approach the problem at present. We will test the criteria on lots of systematic reviews, and will use an approach known as a Delphi process to find out which criteria are supported by expert opinion. This will allow us to select which criteria to use. We will combine the selected criteria into a checklist that can be used to identify the fraudulent trials. We will then test this checklist in new systematic reviews, to see if it is easy to implement and what impact it has on the findings. We will ask people to use the checklist when producing systematic reviews and will gather feedback. The feedback will be presented at a final meeting of people involved in this testing, where we will discuss how the checklist could be improved. We will then make these improvements. The checklist can then be used in systematic reviews to make sure fraudulent trials do not influence the results. We will also make training materials so that researchers know how to use the checklist.",8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_23263,The Health Foundation,THF,Developing and implementing machine learning driven analytics for quality improvement in health care,"Translating the increasingly large and detailed amount of health care data into information that can be used to improve care quality is challenging. Artificial intelligence, and in particular approaches based on ‘machine learning’, has developed rapidly over recent years. Machine learning involves the use of algorithms to detect and learn from patterns in data. This project led by King’s College London used machine learning to support better use of data in order to improve the quality and consistency of care for stroke patients. The project team completed training prediction models for 30-day mortality after stroke using machine learning methods, the results of which have been published in BMC Neurology. The training models have been published in a Github repository to make it easy for others to use, build on or implement the work. Training prediction models have also been completed for stroke-associated pneumonia, a common and serious complication of stroke. External validation of an adapted version of the mortality model was carried out with the national stroke quality register in Sweden. This showed that the model had excellent accuracy and could be used to make fair comparisons of stroke quality and outcomes across countries. The model will be used by the SSNAP for benchmarking NHS stroke services from 2023. This will be the first example of machine learning being used at scale by national clinical audits/quality registries to support quality improvement benchmarking, as well as one of the first examples of different health systems aligning to benchmark and compare quality of care across countries.",,8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE;STROKE HRCS22_03848,Medical Research Council,MRC,Developing contextually specific interventions to reduce alcohol consumption amongst increasing and higher risk drinkers within the Drink Less App,"Emerging research increasingly highlights the need to view alcohol consumption as an occasion-level phenomenon, rather than a weekly number of drinks. We will adapt two intervention components of an existing app, Drink Less, so that they incorporate information about the context of an individual's drinking occasions (e.g. location, company etc.) to provide targeted support in cutting down. In Stage 1, two approaches to collecting contextual data in the Drink Less drinking diary will be compared. 50 new app users will use one of two versions of the app. In version 1 separate characteristics of drinking occasions will be recorded (e.g. location, company) whilst in version 2 predominant occasion types in the UK (e.g. 'big night out') will be listed so that people can select the occasion type most similar to theirs. After two weeks of use, participants will evaluate the usability of the app via a survey and interviews with a subset of participants. This, alongside engagement data will be used to determine which method will be taken forwards to intervention development. In Stage 2 we will co-produce with end-users and key stakeholders two adapted intervention components, Self-Monitoring & Feedback and Action Planning. These interventions will be targeted at individual drinking contexts as measured in Stage 1. Contextually specific messaging will be developed with reference to behaviour change theories such as COM-B and Michie et al's. Behaviour Change Technique Taxonomy and through consultation with experts and PPI groups. Focus groups will then be held with potential users who will evaluate the messaging. This will determine the final design of the two contextualised drinking components. In Stage 3 to refine the developed interventions, we will conduct interviews with users, an app developer, and experts in mHealth in order to ensure the developed interventions are technically and theoretically sound, helpful, visually appealing and acceptable to users.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,CANCER AND NEOPLASMS;CARDIOVASCULAR;GENERIC HEALTH RELEVANCE;ORAL AND GASTROINTESTINAL;STROKE HRCS22_05912,Department of Health and Social Care,NIHR,Developing imaging based and patient reported disease metrics to stratify childhood inflammatory eye disease: Childhood Uveitis Signs and Symptoms Study (ChUSS),"Childhood uveitis (intraocular inflammation) comprises a heterogenous group of conditions, the most common being juvenile idiopathic arthritis (JIA). However, 20% - 50% of childhood uveitis occurs as isolated idiopathic ocular disease. One in five children with uveitis reach adulthood having already permanently lost vision in at least one eye. Disease activity can continue through to mid-adulthood. The key to preventing uveitis related blindness is prompt control of disease. Novel immunomodulatory therapies have been shown to be effective in JIA uveitis (JIAu), but up to a quarter of children with JIAu do not respond to these new therapies, and we lack high level comparative therapeutic research for other forms of paediatric uveitis. We also lack disease classification and quantification metrics sufficiently sensitive and robust to allow prognostication research. Uveitis is currently qualified and quantified using slit-lamp biomicroscopic examination, and graded using a subjective, qualitative scale which is open to interobserver variability when used in adults, and not validated for use in children. Optical coherence tomography (OCT), is a non-invasive, high speed, high resolution modality, with a recent adaptation (OCT angiography, OCTA) capable of imaging uveal vasculature. Childhood uveitis is conventionally described as 'asymptomatic', but arguably this reflects the absence of tools to capture the child's experience of disease, which is sometimes subtle but nevertheless tangible. Additionally, for children with uveitis, symptoms may be an informative discriminator of disease subtype. I hypothesise that A) disease symptomatology, and B) imaging (optical coherence tomography / OCT-angiography) can be captured with precision in childhood uveitis, and can: quantify disease activity, acting as diagnostic and monitoring tools, and providing a surrogate endpoint describe clusters of separate disease subgroups provide (as a disease biomarker) a method of predicting disease stratification by response to treatment and / or risk of adverse outcome.I propose to undertake three invstigations Application of emerging technology to develop imaging based prognostic and monitoring biomarkers Methods: Investigation of feasibility, repeatability, reliability and reproducibility of OCT/OCTA imaging in childhood (ages 2-18) across age groups and across sites, and clinical validation of imaging derived disease biomarkers. Development of age-specific subjective disease activity scoresMethods: Information gathering from children / families affected by childhood uveitis, face validity analysis of items through council of clinical expertise, piloting of tool and investigation of construct validity and internal consistency. Multicentre prospective cohort studyMethods: Harmonised collection of clinical and sociodemographic data. Longitudinal follow up of this cohort (providing currently unavailable data on natural history), and logistic and Cox regression modelling of the association between imaging derived and patient reported parameters and outcomes of interest (therapeutic response, adverse ocular structural outcomes) with adjustment for potential confounders. My ambition is to deliver the metrics needed to classify and quantify disease type and severity in childhood uveitis, enabling disease stratification and sensitive, robust, validated measurement of therapeutic response, in order to improve prognostication and disease management precision.","Background:Childhood uveitis is a rare inflammatory eye disease. One in every five affected children loses vision in at least one eye before reaching the age of 16, due to structural damage caused by uncontrolled inflammation. The uveitis can continue to be active into mid-adulthood. Uveitis can affect the front (anterior), middle (intermediate) or back (posterior) section of the eye. In childhood the most common type of disease is a chronic (long-lasting) anterior uveitis. Many different infectious and non-infectious diseases can result in uveitis, but for the majority of children (>80%) the disease is 'idiopathic', that is, no cause has yet been found. Approximately half of all children with uveitis also have a disease causing inflammation of the joints: juvenile idiopathic arthritis (or JIA). Children with JIA must travel to a specialist centre every three months to have eye examinations in an attempt to pick uveitis up early enough to prevent visual loss. This is necessary as not all children with uveitis are aware of the inflammation, and the disease can start at a young age before children are able to describe what's happening to them. Study Aims - filling the evidence gaps identified by patients:A recent national priority setting (James Lind) exercise involving patients and families affected by inflammatory eye disease identified key gaps in our understanding of disease for the majority of affected children: We do not understand the causes of disease We cannot predict response to our existing therapies We cannot predict long term outcomesNewly emerging 'biological' therapies have proven themselves to be effective for certain populations of children with uveitis, but: We do not know if children with milder disease truly benefit from these (and other) powerful systemic medications which require frequent blood monitoring, frequent hospital admissions, and carry significant short and long term risk of adverse events.The current disease scale which we use to monitor response to therapies is based on adult disease (which differs significantly), and is open to variability between specialists. All families who participated in recent patient group events (funded by an NIHR Enabling Involvement award, organised by me) at one of the UK's largest centres for paediatric uveitis supported the development of more objective and sensitive tools. Critically, for a disease which has long been considered as 'silent' or asymptomatic in all but the most advanced stages, almost all families supported the development of patient reported measures of uveitis disease activity. Design and methods: I am going to use new non-contact imaging technologies ('optical coherence tomography' cameras) and assess their ability to reliably and sensitively monitor disease severity identify patterns of disease in different groups of childrenI am also going to develop child and carer reported instruments, guided by affected families, to assess how children are affected by active disease. These new disease measurement tools ('metrics') will be tested within a UK multi-centre study which will recruit children newly diagnosed with uveitis, collect the details of their family, birth and medical history, and watch their disease over time (a 'longitudinal inception cohort study'). This study will allow us to identify the predictors of outcome, including response to therapy. The developed 'metrics' may be able to improve outcomes by personalising our approach to disease counselling and treatment, and go on to help other scientists understand what drives disease at a detailed level. This work will be supported by a patient steering group, and a multi-disciplinary national group of specialists (the Paediatric Ocular Inflammation Group) who will also support the dissemination of study findings, and provide a pathway through which the study findings can improve clinical practice.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,EYE HRCS22_22808,The Academy of Medical Sciences,AMS,Developing light sheet microscopy of murine and human gut to assess (pre)diabetic microvascular disease,"A complex microvascular network pervades the body to regulate physiological parameters, such as metabolite delivery and oxygenation. Endothelial cells line the vasculature and form the barrier that selectively regulates these processes. Pericytes further support microvascular integrity and provide additional functional regulation. Diabetes causes vascular injury that can lead to important complications. Perhaps best studied is diabetic retinopathy, characterised by endothelial dysfunction and pericyte apoptosis that leads to vessel regression, followed by regrowth of poor quality leaky neovessels, causing blindness. It remains unclear whether diabetes and pre-diabetic conditions like obesity cause similar vascular abnormalities throughout the rest of the body. The intestine has a highly specialised microvascular network which has roles in nutrient absorption and immune cell regulation, and which acts as a barrier to microbial entry. Mice and humans with diabetes have a leaky gut wall, but the potential role of endothelial cells and pericytes in this disturbance is unknown. Historically, the intestinal vasculature has proved difficult to assess due to imitations of sample preparation and image resolution. This project will optimise a novel light sheet microscopy technique to allow three-dimensional imaging of the microvascular network of the intestine in health and disease, focussing on the identification and staining of endothelial cells and pericytes within these tissue preparations, along with imaging gut wall permeability. It will then explore altered gene transcription in the gut endothelium. These data will advance our understanding about how diabetes increases gut permeability and will support my future intermediate clinical fellowship proposal.","Networks of small blood vessels transport oxygen and nutrients throughout the body. Scientists currently study these networks by cutting very thin “sections” of tissue to examine on a slide under a microscope, but this means we can only get flat 2-dimensional images. I want to use a new type of ‘light sheet’ microscope that images large tissue samples by moving a laser beam through them to study whole blood vessel networks in 3 dimensions. I will be concentrating on blood vessels in the gut as these are important in how we absorb nutrients and toxins from our diet. I want to know if diseases like diabetes and obesity are linked with abnormal gut blood vessels or with a gut wall that is more “leaky” than in the healthy state. A particular focus will be cells called pericytes which support the structure and function of blood vessels. We know that some people with diabetes have fewer pericytes in the back of the eye and that this damages blood vessels, leading to a disease called retinopathy, which can cause blindness. Little is known about pericytes in gut blood vessel networks and whether they are abnormal in people with diabetes. This is partly because pericytes are difficult to see in 2-dimensional microscope images. I want to use our light sheet microscope to solve this problem and hope this information can tell us if treatments targeting gut blood vessels might help people with diabetes.",1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),METABOLIC AND ENDOCRINE HRCS22_03893,Medical Research Council,MRC,Developing mechanistic understanding to improve the activity of bicyclic peptides as novel antimicrobials,"Antibiotic resistance poses a serious threat to public health and requires novel therapeutic approaches. The most important class of antibiotics, beta-lactams, target penicillin binding proteins (PBPs). These are essential components of bacterial cell wall biosynthesis, inhibition of which leads to cell death. PBPs remain an attractive target but the prevalence of beta-lactamase driven resistance and, rarely, target-based mutations, necessitates new classes of PBP-targeting drugs. BicycleTx have recently developed PBP-inhibiting bicyclic peptides (Bicycles) using their proprietary phage-screening technology. Now, further work is needed to understand the interactions of these compounds to PBPs, whether target mediated resistance impacts upon Bicylcle binding, and how cell-permeating properties can be optimised. The company has recently obtained a high-resolution (~1.5A) PBP3:Bicycle X-Ray co-structure to understand how Bicyles bind and to develop structural-activity relationships (SAR) using analogues and iterative cycles of medicinal chemistry. I will look at developing and characterising Bicycle resistance mutants in target pathogens. Identifying and better understanding any potential mechanisms of resistance to Bicycles will be used to reduce vulnerabilities. The challenge of drug permeation is common to all Gram negative antibiotic discovery work. Usefully, BicycleTx have developed a split luciferase luminescence assay to monitor Bicycle accumulation in the periplasm. This assay will be used to screen for cell permeating peptides which can be integrated into the peptide warhead to give effective and broad-spectrum Gram negative inhibition. The end goal of this work will be a further improved and characterised new class of PBP-targeting compounds, de-risked against resistance and able to permeate important clinical pathogens.",,5.1 PHARMACEUTICALS,INFECTION HRCS22_07449,Department of Health and Social Care,NIHR,Developing palliative and end-of-life care research partnerships and capacity in the North West Coast of England,"Research is an important part of excellent care, with health and social care organisations involved in research activity known to provide better care. However, in the North West Coast area of England we know that research activity in the important area of palliative and end-of-life care is much lower than in other parts of the country. This is despite much higher needs than on average. It is important that we invest in research in North West Coast England to ensure that the particular needs of the populations in this area are properly taken account of, and that care is planned and provided to meet these needs in the best possible way. _x000D_ _x000D_ The purpose of this partnership is to bring together clinicians, health care organisations, researchers and the public to effectively plan important and high-quality research in palliative and end-of-life care that is relevant to North West Coast and more generally across the country. _x000D_ _x000D_ Over 18 months we will do three types of activity:_x000D_ _x000D_ First, we will work with patients and family carers, clinicians, research nurses, and healthcare organisations (including hospitals, primary care, hospices), to understand what the main barriers are to palliative care research locally, and how we can best overcome these to meet the needs of those in the North West Coast area. _x000D_ _x000D_ Second, we will work to develop clinically relevant, high quality research grant applications in areas of identified need. We will support junior researchers and doctors, nurses and other health and social care professionals newer to research to be an important part of developing these applications so that they learn how to develop strong and excellent research applications now and for the future._x000D_ _x000D_ Third, we will put solutions in place identified in the first part of this work to help people to conduct research in this area. This might include training people to discuss palliative care research with possible participants, helping people to develop research policies to streamline the ‘red tape’ associated with research, helping patients and the public to be more involved in developing research, and building a long-standing palliative care research network across North West Coast.","BACKGROUND We want to build a broad palliative care research partnership across the North West Coast region between Universities, providers, patients and the public, and existing infrastructure such as the CRN and ARC. This will enable the delivery of high quality, practice relevant grant applications that focus on needs, especially those of our underserved populations. The North West Coast has high palliative care need (third highest prevalence in England) and historically low recorded NIHR research activity (second lowest research recruitment rate in England). There are known challenges to conducting research in palliative care such as identification and recruitment of populations, but also challenges of poorly established research infrastructure. Having an active, confident, sustainable palliative care research network across North West Coast will spotlight good research practice, build research capacity, and combat barriers to research._x000D_ _x000D_ OBJECTIVES_x000D_ i)To develop a sustainable palliative care partnership infrastructure across NWC, embedded within existing organisations such as the CRN and ARC, involving strong PPI, as a focus for palliative and end-of-life care research in the region. _x000D_ ii)To work with palliative care providers, patients and the public, and research staff to further understand local barriers and facilitators to palliative and end-of-life care research, and develop and implement solutions to these barriers. _x000D_ iii)To build clinical capacity in palliative and end-of-life care research through the mentorship of emerging research leaders and share academic expertise across organisations._x000D_ iv)To facilitate the development of high-quality research grant applications that address important clinical research questions that meet the needs of the NWC population (and beyond) focused on the NIHR palliative and end-of-life care calls (NIHR PHR, EME, HS&DR and HTA) in 2022. _x000D_ _x000D_ PARTNERSHIP PLAN_x000D_ _x000D_ a)DEVELOP AND EMBED AN ACTIVE PALLIATIVE CARE PARTNERSHIP NETWORK ACROSS NORTH WEST COAST (to meet objective i) Activities to embed this will be actioned throughout the phased activities below. _x000D_ b)PHASE ONE (0-6 months): RAPID IDENTIFICATION OF CURRENT LOCAL BARRIERS TO RESEARCH AND THEIR SUSTAINABLE SOLUTIONS (to meet objective ii) This will include an online survey and working groups (with providers, research staff, and the public) using nominal group techniques to facilitate a consensus on barriers and solutions to research across NWC. _x000D_ c)PHASE TWO A (7-12 months). PERSONAL MENTORSHIP AND SUPPORT TO CO-DESIGN AND PREPARE RESEARCH GRANT APPLICATIONS (to meet objective iii and iv). This will include peer support and action learning sets, 1:1 mentorship and the buy out of time for emerging research leaders. _x000D_ d)PHASE TWO B (7-18 months). IMPLEMENT IDENTIFIED SOLUTIONS TO ENABLING BETTER PALLIATIVE AND END-OF-LIFE CARE RESEARCH ACROSS NORTH WEST COAST (to meet objectives ii and iv). This will draw from phase one, but may include recruitment training, work on enabling research governance, and further developing our PPI networks. _x000D_ e)PHASE THREE (7-12 months) DEVELOPING AND SUBMITTING HIGH QUALITY CLINICALLY RELEVANT RESEARCH PROPOSALS (to meet objective iv)_x000D_ _x000D_ The outputs of this work will include; high quality applications to forthcoming palliative care calls; a sustainable infrastructure to facilitate excellent research; greater capacity to engage in palliative and end-of-life care research; and developing communities of practice.",7.2 END OF LIFE CARE,GENERIC HEALTH RELEVANCE HRCS22_12967,Cancer Research UK,CRUK,Developing personalised risk prediction for women at increased risk of Vulval Cancer,"Vulval squamous cell carcinoma is a rare malignancy that affects up to 1300 women in the UK annually. Early detection of disease reduces surgical morbidity and improves survival. While there is no role for generalised screening, there are a number of conditions which increase the risk of vulval cancer. These include autoimmune driven inflammatory dermatoses ( lichen sclerosus, lichen planus), extra-mammary Paget’s disease and HPV-driven vulval intraepithelial neoplasia (VIN). “ What is the risk of developing cancer in lichen sclerosus ( including being able to identify those at greatest risk)” was one of the top five research questions at a recent priority setting partnership. Developing a cancer risk prediction model will help individuals understand risk, help tailor follow-up to reduce intensity of clinician assessments and design population-based interventions. The aims of the study are: 1. To establish the incidence and prevalence of lichen sclerosus (LS) and lichen planus(LP) using a UK population approach 2. To establish the incidence of vulval squamous cell carcinoma in LS, LP and VIN and to compare the risk of vulval cancer in women at increased risk using a case-control approach 3. To identify diagnostic pathways and intervals in the diagnosis of precursor conditions (LS, LP and VIN) and vulval cancer 4. To establish the route of diagnosis of all vulval squamous cell cancers from 1st presentation Data will be obtained from CPRD GOLD and Aurum, with a common protocol applied across the databases for cohort construction and analysis. The study populations will consist of any individual with a diagnosis of LS, LP, VIN, or vulval cancer between 01/01/1998-29/02/2020, with follow-up until 29/02/2020. Hazard ratios for the outcomes of interest among patients with LS/LP/VIN, as compared with controls, will be estimated from Cox regression models. All analyses will be replicated in a cohort of age-matched controls ( women with no diagnosis of vulval conditions) These studies will contribute to the design of a risk prediction model of vulval cancer in women at increased risk ( i.e LS/LP/VIN). In addition, an improved understanding of the diagnostic routes of vulval cancer will assist in designing interventions for early detection.",,2.4 SURVEILLANCE AND DISTRIBUTION;8.1 ORGANISATION AND DELIVERY OF SERVICES,CANCER AND NEOPLASMS HRCS22_06390,Department of Health and Social Care,NIHR,"Developing the evidence and associated service model to support older people living with frailty to manage their pain and to reduce its impact on their lives: a mixed method, co-design study.","Aim_x000D_ To understand how pain management services for older people with frailty should be organised and delivered._x000D_ _x000D_ Background _x000D_ Pain is common in later life and especially common in older people with frailty. Frailty is described as becoming more vulnerable to poorer health in later life. For older people with frailty, pain can be particularly impactful on their lives, on their ability to socialise and participate in activities. Pain can make frailty worse._x000D_ _x000D_ The negative impact of pain on a person’s life should not be an inevitable part of getting older. There are treatment options to enable people to cope better with pain and minimise the impact. Pain Management Programmes (PMPs) and psychological therapies aim to improve strength and movement and enable engagement in enjoyable activities. Whilst the content of PMPs varies, they typically include pain education, exercise, coping strategies, goal setting and peer support. However, PMPs and pain services generally, have not typically been aimed at, or designed for, older people living with frailty. _x000D_ _x000D_ Improving care for older people with frailty is an NHS priority. Our aim is to find out what a good pain service for older people living with frailty should be._x000D_ _x000D_ Methods: _x000D_ The research will be overseen by a patient and public involvement group (Oversight PPI Group) who will provide lay representative guidance and input throughout the project. _x000D_ The research will include:_x000D_ _x000D_ 1) A review of studies which investigated PMPs and psychological therapies for pain, which included older people. This will enable us to identify what might be important and appropriate for older people with frailty._x000D_ _x000D_ 2) Interviews with older people living with frailty and pain to understand how pain impacts on them and how they could be better supported with pain management and access to pain services. For some interviews, we will include their spouse or partner (or another significant person in their life). _x000D_ _x000D_ 3) We will interview Health Care Professionals (HCPs) including nurses, psychologists, physiotherapists and GPs, as well as the commissioners who make decisions on what health services should be funded. We will include HCPs from various pain services in different locations. The interviews will help us understand the challenges of working with older living people with frailty in different services and how they might need to change to better engage with this group._x000D_ _x000D_ 4) With the Oversight PPI Group, we will use the learning from the review and the interviews to create ‘knowledge resources’. We will use these resources in workshops which will include older people, HCPs and commissioners to help co-design a pain service specifically for older people living with frailty. The workshops will ensure that all views are considered. _x000D_ _x000D_ Following the workshops, we will work with the Oversight PPI Group and commissioners to develop guidance and information for the elements of a good pain service for older people with frailty. This will detail who should deliver it, how a service might fit into, or alongside, existing services, and if services need to be tailored or modified for people with different levels of frailty or from different ethno-cultural communities. _x000D_ _x000D_ Dissemination_x000D_ Findings and information will be distributed nationally to achieve widespread impact on services and to help individuals with frailty to improve their quality of life and function.","Research question_x000D_ How should pain management services for older people with frailty be organised and delivered?_x000D_ _x000D_ Background_x000D_ Improving care for older people living with frailty is a core aim of the NHS Long Term Plan (2019). Pain prevalence is particularly high in older people with frailty (median prevalence 44%) and negatively impacts on their mobility, daily life, ability to socialise and sleep. Pain accelerates frailty progression. The impact of pain on daily life is potentially modifiable and therefore presents an attractive target for services to facilitate improvements in the lives of older people living with frailty._x000D_ _x000D_ Although pain disproportionally affects older people living with frailty, there is a notable gap in research and provision of pain management services for this group. The need to develop new models of care for older people living with frailty is highlighted in the NHS Long Term Plan. Research to investigate how pain management services for older people with frailty should be organised and delivered will help inform robust commissioning decisions._x000D_ _x000D_ Aim_x000D_ To develop content, delivery mode, implementation strategies, commissioner and professional guidance for pain management services that enable older people with frailty to manage their pain and reduce its impact on their lives, relationships, function and quality of life._x000D_ _x000D_ Methods_x000D_ This study will have 4 phases and use mixed research methods. An Oversight Patient and Public Involvement Group (Oversight PPI) will contribute to all research components._x000D_ _x000D_ Phase 1. Mapping review of trials of PMPs and psychological therapies will map research evidence to develop hypotheses about processes and change mechanisms to inform strategies that meet the specific needs of older people with pain and frailty._x000D_ Phase 2. Qualitative interviews with 30 older people with pain and frailty, including joint interviews with their significant other, to determine how their pain needs can be met and potential service models that might optimise their access and provide support._x000D_ Phase 3. In three Clinical Commissioning Groups (CCGs) we will identify what pain services have been commissioned (referral source, eligibility, exclusions, delivery mode) and undertake qualitative interviews with healthcare professionals (HCPs) and commissioners to identify opportunities and barriers to engaging older people with pain and frailty._x000D_ Phase 4. With the Oversight PPI Group, we will create knowledge resources from research components 1, 2 & 3. We will use these in sequential co-design workshops (3 sites) with stakeholders (older people, HCPs, commissioners) to produce pain management guidance specific to the needs of older people with frailty for varied service contexts. _x000D_ _x000D_ Timelines for delivery: _x000D_ • Months 1-11 Mapping review _x000D_ • Months 4-17 Interviews with older people; families/carers; qualitative analysis_x000D_ • Months 5-17 Interviews with HCPs & commissioners; qualitative analysis_x000D_ • Months 21-27 Co-design workshops _x000D_ • Months 31-36 Key outputs; Pain and Frailty Service Commissioning Pack; dissemination_x000D_ _x000D_ Dissemination and Impact_x000D_ Main output will be a Pain and Frailty Service Commissioning Pack to support commissioning of services aligned with the needs of older people with frailty and pain. This will be nationally disseminated, building on existing links with NHS England, NHS RightCare, CCGs and pain services, with potential for national impact, together with benefits for individuals.",8.1 ORGANISATION AND DELIVERY OF SERVICES,MUSCULOSKELETAL;NEUROLOGICAL HRCS22_02689,Medical Research Council,MRC,Development and Evaluation of a Training Package to support the Remote Assessment and Management of People with Movement Impairment and Disability,"The problem: Physical disabilities are common throughout life. Usually, hands-on detailed movement assessment results in a targeted rehabilitation plan, with ongoing evaluation required as needs change. During Covid-19, many people, of all ages, have received no rehabilitation, and rehabilitation need is escalating with recovering Covid-19 patients; creating a ""tsunami of rehabilitation need"". In response, clinicians are rapidly adapting and creating telerehabilitation solutions to manage caseloads and prioritise those at risk of deterioration, with little specific guidance, training or support. Professional bodies and clinical networks highlight the marked variations in approaches used, expressing concerns about potential inequity and inefficiency. Our rapid literature review underlines this problem, citing lack of specific guidance/training as barriers to effective telerehabilitation implementation. This has immediate and long-term relevance given the ""new-norm"". Research aim: Develop a Toolkit & Training package for the current/future workforce, wherein telerehabilitation will be integral to rehabilitation assessment and management. Study Design: Knowledge to Action Framework, methodology commonly used in implementation science. Key steps include: (i) literature review to inform guidance/provide examples of best practice; (ii) national online survey to identify clinicians' needs, (iii) production and evaluation of the Toolkit through iterative cycles of data collection, evaluation and refinement (initially in the SouthWest); (iv) national roll-out/evaluation, (v) production of final training package for use within clinical/educational arenas. Study outputs: Practical guidance, process pathways and training to optimise the confidence and competence of clinicians to effectively implement telerehabilitation in people recovering from Covid-19 and those with physical disability from across the lifespan.",,7.3 MANAGEMENT AND DECISION MAKING;7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT),INFECTION HRCS22_06294,Department of Health and Social Care,NIHR,Development and initial evaluation of a school-based intervention for ADHD,"Background: Attention deficit/hyperactivity disorder (ADHD) is a prevalent and impairing neurodevelopmental disorder affecting 2-5% of children. These children are at risk of negative health, social and educational outcomes; ADHD incurs an estimated 670 million annual cost to health, education and social care in the UK. Children with ADHD often experience severe difficulties at school despite drug treatment: effective psychosocial interventions are needed. There is mixed evidence for the effectiveness of existing school-based interventions for ADHD, which are complex and resource-intensive, contradicting the preferences of teachers for short, flexible strategies that suit a range of ADHD-related classroom-based problems. They are also poorly evaluated. Aims: To develop an acceptable and feasible intervention for ADHD in primary schools that is feasible to further evaluate in a methodologically rigorous trial. The intervention will take the form of a 'toolkit' of strategies. The main aims are to: Develop a prototype toolkit Refine the toolkit so that it is feasible and acceptable to implement in the school setting Establish whether a future definitive trial of efficacy is feasibleAdditional aims: Update, identify and synthesise existing evidence to select strategies for inclusion in the toolkit Identify suitable outcome measures to assess core ADHD symptoms, child and teacher wellbeing and identify an appropriate primary outcome for a future definitive trial Develop and test a framework for costing the toolkit, and for assessing cost-effectiveness in a future definitive trial Assess whether observational measures of behaviour, classroom functioning and teacher-reported ADHD symptoms indicate improvement following use of the toolkitMethods. I will apply Intervention Mapping, a framework for developing theory- and evidence-informed behaviour change interventions, combined with extensive co-creation from a stakeholder group comprised of school staff, people with ADHD, parents and specialists in education and ADHD. The intervention will be assessed for feasibility and acceptability and further modified in an iterative optimisation study, with 16-32 children with ADHD and staff participating from eight primary schools. Timeline for delivery. The initial development of the intervention will take place over 18 months, with the iterative optimisation study running for 2 years. Anticipated impact: Following this project, the intervention will be suitable to be evaluated for efficacy and cost-effectiveness in a larger trial. An effective intervention for ADHD that can be delivered by non-specialists in school will improve the functioning of children with ADHD in a setting where they struggle most. Improved function at this crucial stage has the capacity to significantly improve the developmental trajectory of children with ADHD, their current and future health and relationships as well as educational and occupational functioning. The same strategies could be applied while children wait for assessment and might reduce the need for specialist intervention and demands on child mental health services. My intervention will offer initial support to those children who face long delays accessing specialist mental health services. It could be used to identify children who need specialist support, and to support children with milder problems who do not meet clinical thresholds.","Background. Every classroom will have on average at least one child who will struggle to sit still, pay attention and resist impulses to do things like jump out of their seat. When these problems are really severe this can be due to ADHD, or 'attention deficit hyperactivity disorder'. Children with ADHD face major difficulties at home and school. They are less likely to learn well and make good friendships than other children. Children with ADHD are also more likely to have accidents and injuries, and other mental health problems. Teaching a child with ADHD can be difficult, both one-to-one and as part of a whole class, and this can impact on the classroom experience for other children. Medicines that help to reduce symptoms of ADHD do not suit every child. Even when drugs work, children with ADHD need extra help to address struggles at school. Strategies are needed to help teachers support them. Existing advice for teachers is in the form of complicated programmes that try lots of different things at the same time. As a result, teachers struggle to learn and use the programmes, meaning children do not benefit from them. As every child and school are different, teachers tell us that they need a range of simple options that they can choose from to suit each child with ADHD. Aims and methods. I plan to design a 'toolkit' with a collection of strategies teachers can use to help children with ADHD cope better in primary school. I have worked with teachers and parents to develop this project. There are two main parts: Designing the toolkitI will use a method called 'Intervention Mapping'. This sets out a clear framework to design treatments that are acceptable to people who use them and are based on the best available evidence. This will be informed by theories about how children learn new skills and how the symptoms of ADHD come about. I will work closely with school staff, people with ADHD, parents and professionals to design the toolkit. Testing and improving the toolkitTo test whether the toolkit is acceptable and practical for teachers to use, I will conduct an experimental study. Eight primary schools and a total of 16-32 children with ADHD will take part, each using the toolkit for one school term. I will collect feedback about what went well and what did not, and whether I should make any changes before the next school tries the toolkit. I plan to use several different ways to explore whether the toolkit is acceptable and potentially helpful for children with ADHD. Teachers and parents will complete questionnaires, and I will run focus groups with school staff and interview parents and children about their experiences. This will inform whether the toolkit is ready to be tested further in future research. Future benefits. If the testing of the toolkit shows that it may be helpful, I will go on to do a larger scale study to investigate how much children benefit and if it is value for money. If the toolkit does help children with ADHD cope in school, these children will learn better and find school less stressful. This might prevent them from developing other mental health problems and help them avoid getting into accidents, trouble with teachers, and fights. They could go on to have a better chance of getting good qualifications, better jobs and have positive relationships with other people. In other words, it might lead to improved health and better life chances. Teachers might also find it easier to teach the whole classroom and be less stressed.",7.1 INDIVIDUAL CARE NEEDS,MENTAL HEALTH HRCS22_13101,Cancer Research UK,CRUK,Development and testing of a high resolution respirometry protocol to define T cell mitochondrial fitness in health and disease.,"T cell dysfunction is a key driver of disease and also tightly correlated to metabolic alterations. This project aims to develop a practical and feasible measure of metabolism allowing the identification of key bioenergetic profiles in disease. This work will facilitate greater biological insight into the pathogenesis of cancer and autoimmunity but also have wide clinical relevance for diagnosis, as a biomarker for disease severity, reveal new therapeutic targets and by refining existing treatment strategies. Currently available metabolic assays are limited by cost, requirement for large number of cells and few metabolic readouts. We propose developing a novel method for measuring mitochondrial metabolism using the O2K platform which will enable the development of the first multiparameter metabolic functional phenotype, be economical and require fewer cells. AIMS: 1. To develop a robust protocol for high resolution respirometry on a. patient samples b. murine T cells 2. Establish the potential clinical application of this platform in: a. Marrow infiltrating T cells from myeloma patients compared to normal donors a. Comparing two designs of chimeric antigen receptors used in clinical trials (CD19 41BBzeta vs CD19 28zeta CAR T cells) METHOD: Murine samples from wild type mice (PW,CA) will be transferred to the Chakrabarti lab with the aim of optimising cells for transit, establish the number of cells needed for replicable oxygraphy readouts and ascertain the utility of standard protocols used in the lab. Further, using courier networks already used for national clinical trials, approved ethics, LL will provide peripheral blood samples for parallel validation of human cells. This initial work will facilitate the development of a robust T cell respirometry protocol which will then be validated on murine cells from established murine models of cancer and autoimmunity as well as marrow infiltrating cells from patient with multiple myeloma. This platform will then directly compare the bioenergetic profiles of T cells in healthy donors compared to myeloma patients and then compare two CAR designs currently used clinically. These data will form the basis for further applications to analyse other patient groups, refined T cell subsets and evaluation of murine models. The development of a practical, feasible, economical measure of metabolism and the insight this provides to the dysfunctional T cells which drive disease will mark a paradigm shift in the assessment of bioenegetic profiles of health and disease. This technology has wide application to research, has potential to impact patient.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),CANCER AND NEOPLASMS HRCS22_07269,Department of Health and Social Care,NIHR,Development of a clinical decision aid for the differential diagnosis of transient loss of consciousness,"BACKGROUND: Transient loss of consciousness (TLOC) – defined as spontaneous disruption of consciousness not due to head trauma and with complete recovery – has a lifetime prevalence of 50%. It is one of the commonest neurological complaints in primary and emergency care. Over 90% of TLOC is due to either syncope, epilepsy or dissociative seizures (DS, also known as Psychogenic Nonepileptic Seizures ). The rapid and accurate distinction of these diagnoses is vital to allow appropriate further management but at least 20-30% of patients are not managed optimally or misdiagnosed. We have previously demonstrated that, in patients with established diagnoses of epilepsy, syncope, or DS, an automated classifier using only information from 36 questions based on patient experience and lay witness reports (the initial Paroxysmal Event Profile, iPEP) could accurately diagnose 86.0% of patients (with 100% sensitivity and 91.7% specificity for syncope) AIMS: To calibrate the iPEP for discrimination between syncope, epilepsy, and DS in patients newly presenting with TLOC, validate its performance in an independent sample, and to explore acceptability of the use of such a tool to people with TLOC and witnesses. METHODS: Nested qualitative-quantitative prospective single-centre development and validation of the iPEP in patients presenting to Emergency Departments, syncope or epilepsy clinics with first presentations of TLOC, with semi-structured interviews conducted with a purposive sample of participants from the quantitative study. The iPEP will be calibrated using a previously-described procedure for variable selection and training of Random Forest (RF) classifiers, and validated with assessment of overall classification accuracy, alongside sensitivity, specificity, positive and negative predictive values, and area under receiver-operating curve for each of the three target diagnoses. Performance will be evaluated against a benchmark set by results from previous research in patients with established diagnoses of epilepsy, syncope, and DS. OUTPUTS: Results will be submitted for publication in academic and professional literature. If performance from feasibility can be replicated in validation, the iPEP will be suitable to begin process of registration as a medical device for implementation in clinical pathways to minimise inappropriate referrals and treatment, streamline patient pathways, and enable earlier ordering of appropriate investigations to ensure prompt and appropriate diagnosis and management. If pilot performance could be replicated in this population and proportional savings from current estimated costs of misdiagnosis achieved, this could potentially save £63.9 million of annual UK healthcare expenditure.","Background Transient loss of consciousness is a medical term for blackouts . This means sudden loss of awareness or self-control without obvious cause (like head injury). Blackouts are a very common problem in Emergency Departments (EDs). Some causes are not dangerous, others need urgent treatment. There are three main causes. Syncope (fainting): caused by a brief drop in blood supply to the brain. Epileptic seizures (fits): due to too much electrical activity in the brain. Dissociative seizures: automatic (uncontrolled) responses to difficult emotions, thoughts, sensations, or situations. It can be hard to work out which explains a person s blackouts. About 3/10 people with blackouts currently get the wrong tests or diagnosis. This can be dangerous. People who faint may need to see a cardiologist (doctor specialising in the heart). Those who have seizures should see a neurologist (specialist in the brain). Aims We want to help people get the right diagnosis and treatment sooner. We previously made a list of 134 questions for people with blackouts and witnesses to their attacks. These questions helped to tell the difference between the three main causes. We chose the most important questions and used them to create a computer programme to predict the cause of a person s blackouts. The computer programme was almost perfect at deciding who had fainted, and who had a seizure. We now need to find out if the programme can do this when people first seek medical help. Methods We will ask people who go to the ED with a blackout to answer our questions. We will also ask people who have been referred to specialists for faints or seizures. We will use 100 people's answers to train the programme to predict the right diagnosis. We will test its predictions on 150 people. Experts will agree the correct diagnosis for these people. We will compare the experts diagnosis with that predicted by the programme. We also want to know what people who have blackouts think of the programme. We will ask 30 people about their experience and use their answers to improve it. PPI We have designed this research with people who experience blackouts, to ensure it is useful for them. Epilepsy Action, STARS, and FND Action all support people who experience blackouts. They have helped with design and will remain involved through a Research User Group. Dissemination When finished, we will have tested whether our programme predicts the cause of blackouts when people first seek medical help. Before using the programme we would carry out another study in several centres to test if it helps people get the right tests and treatments sooner. We will share our results in academic papers, through patient organisations, and on social media.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,NEUROLOGICAL HRCS22_07378,Department of Health and Social Care,NIHR,Development of a core outcome set for clinical research on interventions for speech impairments in Stroke: COS-Speech,"Research question: What is the core outcome set (COS-Speech) and agreed measures for speech intelligibility after stroke? Background: Dysarthria (reduced speech intelligibility) is a common consequence of stroke leading to social isolation and low self-confidence. This speech difficulty after stroke has been neglected with few research studies. Dysarthria can occur after any type of stroke and varies in severity of impairment. There are different types of dysarthria (e.g. spastic, hypokinetic), which can also co-occur with and without aphasia (language difficulties). Our Cochrane review of dysarthria intervention found a lack of consensus around outcome measures and the need for a core outcome set for speech recovery was highlighted. A core outcome set would be of use in both clinical practice and research studies to compare the findings from different therapy trials of dysarthria. Aims and objectives: The first aim is to agree what aspects of communication we should measure when monitoring speech recovery, i.e. what is the core outcome set for all types of dysarthria caused by any type of stroke (COS-Speech)? The second aim is agreement of 'how' to measure speech recovery, i.e. what tests/assessments/scales/behavioural sampling we should use with COS-Speech? Methods: Using active co-design and patient, public involvement, we will develop a core outcome set with relevant stakeholders to reach an international consensus for COS-Speech following existing guidance using an e-Delphi process. The stakeholder participants will include people with lived experience of dysarthria after stroke, clinicians and researchers. We will use internationally accepted standards for COS development, which provides guidance on COS scope, stakeholder involvement and consensus methods. To reach agreement of how to measure the core outcome set we will systematically evaluate the possible measurement tools, this will be followed by consensus agreement. Our evaluation will use the recommended international guidelines to examine reliability, validity, responsiveness and interpretability. Timelines for delivery: Work package 1: The development of COS-Speech months 1-18. This will include ethics approval (month 1-2), recruitment video (month 1-2), recruitment of stakeholders (months 1-4), long list of possible domains (months 1-4), e-Delphi round 1 and analysis (months 6-9), round 2 and analysis (months 10-14), Consensus meeting (month 15), write up and dissemination with PPI months 16-18. Work package 2: A systematic review of the measurements for COS-Speech months 5-18 (14 months). This will run concurrently with work package 1. In months 5-6 we will identify all existing dysarthria instruments (scales/tests/assessments) and systematically review these (months 5-15). A further Consensus meeting to agree which measures should map onto each domains in COS-Speech (month 16). Write up and dissemination with PPI month 16-18. Anticipated impact and dissemination: A systematic review of the various tests/scales and assessments for dysarthria. A core outcome set for dysarthria (COS-Speech) agreed through consensus. Through consensus, relevant measures (where possible) will be mapped onto the COS-Speech domains. Co-produced blogs and use of social media with the PPI research advisors will be produced to reach a wider audience of patients, public and health professionals to explain COS-Speech and associated measures.","Acknowledgement: We would like to acknowledge the support in writing this section from Annette Dancer our PPI co-applicant. Background to the research: Dysarthria, where speech is less clear, slurred or sounds different after stroke is distressing for those affected. This can have a major effect on a person s confidence to mix and talk to other people. There is not much research in dysarthria and the ones we have all measure different things. To be able to compare research it is important they all measure the same things so we can work out which treatment is best. It is important that research looks at what is meaningful to those affected by dysarthria which is a long term condition. We will include all different types of dysarthria after stroke and those who also have problems with finding the right words or understanding (called aphasia). People with dysarthria after stroke should be involved in planning research and choosing 'what' and 'how' speech recovery is measured. We would also include views from clinicians and researchers working in dysarthria after stroke. This will help clinicians know which speech measures are most important for patients. Researchers will know what speech measures they should always include when doing dysarthria research. The question we have jointly developed with our stroke survivors who have dysarthria is, can we identify how best to measure speech recovery after a stroke? This research aims to: Identify and agree what needs to be measured in speech recovery called 'a core outcome set' (COS-Speech) Agree what tests/scales or assessments should be used to measure these core outcomes How we will do this research? For aim 1 we will: record a short video explaining the project use this video to advertise the research and to get people involved get people involved from three key groups: People who have lived experience of dysarthria after stroke People working clinically in this area such as speech and language therapists People involved in dysarthria research We will ask all of these people to express their views on how to measure speech recovery We will do this by sending round several questionnaires over email so people can decide on the most important and least important A computer programme will help us to monitor all the answers We can then all agree in workshops what aspects of speech recovery should be measured leading to our core outcome set COS-Speech For aim 2 we will: Consider all the tests/scales or assessments that could be used to measure COS-Speech Look at all of these and work out which are the best ones Agree with our three key groups which should be used We will share all our findings in clear and plain language",2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),STROKE HRCS22_02187,Medical Research Council,MRC,Development of a digital intervention to promote healthy growth during the first 2 years of life,"The 2018 SACN report 'Feeding in the First Year of Life' highlighted excess energy intake and weight gain in infants as a concern, as this is an established risk factor for obesity. Modifying energy intake and weight gain is challenging because many infants have inherent tendencies towards higher than optimal appetite and a preference for sweet tasting foods. Furthermore, many parents use feeding to calm their unsettled infant or promote longer sleep duration, and may view rapid weight gain as healthy or advantageous. 3 interventions have succeeded in changing target behaviours among infants during exclusive milk-feeding and/or complementary feeding - BABY MILK (UK), NOURISH (Australia) and INSIGHT (US) - but all were delivered face-to-face. Due to increasing workload pressures on healthcare providers, there is a need for a behavioural intervention that does not require staff time, is cost effective, sustainable, widely accessible and scalable to the population level. We will use a person-based, evidence-based approach to develop a digital intervention to encourage and support parents to feed their infants appropriately to promote healthy growth from birth to 2 years. The intervention will target behaviours associated with infant weight gain (milk-feeding, complementary feeding, sleep, crying and activity), and will adapt BABY MILK, NOURISH and INSIGHT for digital delivery. Feeding is an emotive subject for parents, and variation in infant traits pose unique challenges; hence the intervention will be developed with parents using a person-based approach. This goes beyond assessments of acceptability, usability and satisfaction; the intervention will be modified during the process to make it more persuasive, feasible, and salient in order to enhance initial and sustained engagement by users. It will be designed as new content for a widely-used app (Baby Buddy) and will include information appropriate to the infant's age and developmental stage, and enable interaction.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE HRCS22_06672,Health Education England,HEE,Development of a medication adherence tool for people with bipolar disorder which will both identify non-adherent behaviour and the individual’s barriers to medication adherence,"BackgroundNICE recommends research to develop effective methods for identifying and addressing barriers to medication adherence. Furthermore, a recent systematic review concluded that there is a need for an adherence tool that is easy to administer, correctly identifies non-adherent patients and identifies key barriers to medication adherence.An estimated 40% of patients with bipolar do not adhere to their prescribed directions of medications. Medication non-adherence in bipolar leads to relapse, hospitalisation, functional impairment and suicidality. The probability of hospitalisation is five times or higher in non-adherent patients with bipolar.No gold standard exists for identifying and addressing medication non-adherence in the mental health population. Firstly, research has focused primarily on expert opinion regarding the barriers to adherence resulting in adherence rating scales and interventions derived from experts, instead of patient perspective. Secondly, existing scales focus on the nature of non-adherence e.g. frequency and magnitude rather than the underlying causes. Finally, there is an absence of health psychology theory underpinning the development of most scales despite this being critical for the development of any behaviour change intervention.In contrast to other rating scales, the Identification of Medication Adherence Barriers Questionnaire (IMAB-Q) elicits from patients their likely barriers to adherence, and by mapping to the Theoretical Domains Framework (TDF) it offers evidence-based solutions to address any identified barriers. The IMAB-Q has been validated with over 600 patients prescribed cardiovascular medicines. However, its development and validation excluded the mental health population. There is, therefore, a need to provide mental health patients with the same opportunities as people with physical health problems.AimTo develop and test a tool for patients with bipolar which will both identify whether an individual is non-adherent and if so, their individual barriers to medication adherence [we are referring to this tool as an 'adherence tool']MethodI will identify barriers to medication adherence in bipolar through a systematic review. I will then explore these barriers in greater depth through focus groups and interviews with patients with bipolar and their carers. These data will inform the decision regarding whether to develop a new or adapt the IMAB-Q statements. I will then map these statements to the TDF domains e.g. a statement like 'Taking my medicines is a high priority' will be mapped to the 'Motivation' domain. These statements will be iteratively tested for face validity by healthcare professionals, medication adherence research experts, patients and carers until no further refinement is recommended. The final version of these statements will be our adherence tool.An estimated sample of 600 eligible patients is adequate for recruitment to a validation study to investigate the psychometric properties of the adherence tool under investigation. Objective measures (blood plasma levels of drug and prescribing and dispensing records) will be used to test construct validity. I will use classic test theory and item response theory to test structural validity. I will investigate test-retest reliability at two weeks with a sample of 30 patients.OutputThe expected output is a validated adherence tool for patients with bipolar to identify non-adherent patients and their individual barriers to adherence. There will be multiple routes of dissemination (e.g. publication, conferences, press, meetings) to academics, clinicians, patients and carers, the public, participants in the research and mental health advocacy groups. Patient/NHS benefitThe immediate benefit is an accurate, feasible and acceptable approach to identify non-adherent patients for targeting resource use. The intermediate-term benefit is that identifying an individual's barriers to medication adherence will guide the selection of the best intervention(s) to deploy for improving adherence. This will be explored in further research following this project.","Aim To develop a tool for patients with bipolar to find out if they are taking their medication as prescribed (adherent) and if not, what might be stopping them doing so (barriers). We are calling this an 'adherence tool'.BackgroundBipolar disorder is a long-term mental health condition which causes severe mood swings and makes it difficult for patients to hold on to a job or relationship, reduces their quality of life and increases suicide risk. Medication is the most common treatment but around 40% of patients do not take their medication as prescribed. This is called non-adherence and can cause symptoms of bipolar to return leading to hospitalisation, difficulty in daily functioning and suicides. So, it is important to find out when patients are non-adherent and then work with them, and sometimes their carer, to find the best solutions to manage their condition.We do not have one best way of finding out the reasons for medication non-adherence in a mental health population. There are some questionnaires that ask 'are you taking your medicines as prescribed?' But, we understand that some people are worried about telling healthcare professionals if they are not taking their medication. Also, knowing that someone is non-adherent does not help with finding a solution.There is a tool called the Identification of Medication Adherence Barriers Questionnaire (IMAB-Q) which was developed and tested with patients prescribed medication for heart problems. It does not ask patients whether or not they are taking their medicines. Instead, it gives them a short list of things that might stop them from taking their medicine and asks them if they have any of these problems. When scores from all the answers are added together, it predicts non-adherent patients and the reasons for this. The IMAB-Q links each question to health psychology theory. This means that a patient's answers tell us what things we should do to help them overcome the problems they face.But, when IMAB-Q was developed, it excluded mental health patients. So, it may or may not be right for patients with bipolar since reasons for non-adherence in mental health patients may be different. For example, embarrassment and lack of motivation may be more important reasons for non-adherence in mental health patients due to symptoms of the illness.MethodI will look at existing literature and speak to patients with bipolar and their carers. I will use this information to find out whether to: Develop a new adherence tool or Adapt the IMAB-Q I will then show the new or adapted tool to healthcare professionals, research experts in medicine taking, patients and carers. I will keep making changes to this tool until everyone is happy with it. Then, I will test this tool with around 600 patients with bipolar prescribed a mood stabiliser medicine called lithium. I will ask the participants to complete the adherence tool. Using routine blood tests, I will be able to tell if the patient has been taking the prescribed amount. I will also look at the pharmacy and prescribing records of the participants. I will then compare the participant's scores on the adherence tool with the blood test results and the prescribing and/or dispensing records. These comparisons will tell me whether the adherence tool is finding non-adherent patients. After finishing my doctoral training, I plan to use the adherence tool to test a new way of finding and helping non-adherent patients in my hospital. I plan to link the questions from the adherence tool that I developed to health psychology theory. This means that a patient's answers will tell me what things we should do to solve the problems.Patients and their carers will benefit from my research as it will find non-adherent patients and their individual reasons for the non-adherence. This will help provide the necessary and appropriate support required for that individual. This will improve medication adherence and thus improve patient's outcome.Patients and public involvementPatients and carers have influenced the development and design of this research proposal. In addition to the discussion with many patients and carers (during my clinical practice and other meetings), I have worked closely with a patient and a carer to develop this research application. I will continue to seek their contribution including in recruitment process, developing leaflet, and disseminating findings.DisseminationI will tell patients, public, health care professionals and academics by writing news articles and through patients and carers engagement forums (e.g. Bipolar UK), and conferences.",7.1 INDIVIDUAL CARE NEEDS,MENTAL HEALTH HRCS22_09513,Health and Care Research Wales (Welsh Government),,Development of a novel lung-on-a-chip platform to investigate breast cancer metastasis,"Most cancer patients do not die from the primary tumour but from its metastasis. Understanding and treating cancer metastasis is an ongoing challenge for the field. Current in vitro and in vivo cancer models are incapable of satisfactorily predicting the outcome of various clinical treatments on patients. This is seen as a serious limitation and efforts are underway to develop a new generation of highly predictive cancer models with advanced capabilities. Another major limitation is the accuracy and relevance of biological data that can be gleaned from the current animal and cell-based models. How mouse models are manipulated to develop secondary tumours is not reflective of the human situation and current in vitro cell-based metastasis models do not yet reflect the complex issues of cells under shear forces escaping the vasculature to establish a secondary tumour. Such studies use cross- species comparison (mouse vs human), whereas this proposed study will be a human vs. human comparison, which is more applicable and relevant for patients and can thus be beneficial to the NHS and population in Wales. Improving available models is important as understanding how and why particular primary tumours home to specific secondary sites could open new avenues for treatment. In this regard, organ-on-chip models of cancer metastasis emerge as powerful predictors of disease progression. They offer physiological-like conditions where the (hypothesised) mechanistic determinants of the disease can be assessed with ease. Combined with high-throughput characteristics, the employment of organ-on-chip technology would allow pharmaceutical companies and clinicians to test new therapeutic compounds and adjust patient treatments. Microfluidic -based technologies have gained popularity in the biological field and have advantages over traditional cell culture models due to their time and reagent efficiency, and their suitability for high throughput screening. Importantly, microfluidic systems more faithfully reproduce the in vivo tumour microenvironment in terms of gene expression profiles, cell-cell interactions, and nutrient and oxygen gradients. Furthermore, microfluidic systems could assist in understanding metastasis biology and help predict the impact of potentially harmful drugs on human systems, thereby replacing the need for animal models in the early stages of drug development in a fast and economic manner, to accelerate the diagnosis of cancer and to test personalised treatments using cells from patients. This study will create a novel bioengineered breast cancer metastasis into the lung model, based on an established organ-chip technology (i.e., Human Emulation System), which better simulates microenvironmental complexity such as the inclusion of fluidic shear forces and mechanical stretching which are not available in current in vitro models. By combining a model lung that incorporates an air- liquid interface and mechanical stretching mimicking breathing, with breast cancer cells under shear force as if in blood circulation, our proposed model will help explore the biology of breast cancer metastasis to the lung. This system will reproduce the complexity of each patient to stand for the genetic heterogeneity of tumours and at the same time maintain this complexity low to keep the model clinically relevant. Cells from patients will be used to develop personalised models of cancer metastasis and help progress drug therapies for the NHS.","Breast cancer occurs due to changes in the breast tissue which allow cells to grow out of control. Though breast cancer is one disease, it comes in different types and forms depending on where in the breast it starts and whether it is non-invasive or invasive. Cancer metastasis is the subsequent spread and invasion of the cancerous cells into other parts of the body beyond the breast tissue. The bones, lungs, brain, and liver are the most common places for breast cancer to spread to. Cancer spread is a leading cause of death in breast cancer patients. Although our knowledge and treatment of breast cancer are improving, how breast cancer cells gain the ability to spread around the body is still not fully understood. To understand this better and identify the critical steps associated with breast cancer spread, we plan to develop a new laboratory model of breast cancer spread to the lung which will better imitate what occurs in the body when breast cancer spreads into healthy lung tissue. This will allow us to study the disease in detail and identify what factors help it spread. At present, models that study the spread of breast cancer include animals that don’t faithfully represent the human disease or cells grown in petri-dishes in 2D which doesn’t reflect cells in the body in a 3D environment. As a result, these models are either too complex to unravel the step-bystep changes or limited by their lack of complexity. This project proposes to take advantage of recent advances made by organ-on-chip technology, which are devices that better mimic the working of the body (i.e., any organ in the body, for instance, the lungs including the mechanism of breathing and 3D environmental conditions). We propose using this organ-on-a-chip platform to create a lung-on-a-chip that will help us better understand the cause of breast cancer spread into the lung tissue. Lung-on-a-chips are translucent devices that provide a window into the inner workings (i.e., the lung tissue composition, mechanical stretching imitating breathing, and flow rate imitating blood flow speeds) of the human lung without having to invade a living body. It has the potential to be a valuable tool for testing the effects of environmental toxins, absorption of inhaled therapeutics, and the safety and efficacy of new drugs. Such a tool may help accelerate drug development by reducing the reliance on current models. The ability to recreate realistically both the mechanical and biological sides of the in vivo coin is an exciting innovation. Adopting this platform for modelling cancer metastasis will lead us a step closer to a greater insight into how this disease works. This is important because patients experiencing breast cancer spread have few treatment options. Therefore, by developing a more realistic cancer model we will learn more about why breast cancer spreads to the lung in addition to other sites, and potential new ways to treat it. These models are a promising tool for drug screening in both drug development and personal drug administration for NHS patients.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_13979,Cancer Research UK,CRUK,"Development of a patient-derived, mucosoid-microbiota model to identify novel gastric adenocarcinoma biomarkers triggered by the intestinal metaplasia-associated microbiota","Background In the UK, only 20% of patients will survive for 1 year after a diagnosis of stage 4 gastric cancer (GC). Gastric adenocarcinoma (GAC), caused by Helicobacter pylori infection, follows a linear progression from atrophic gastritis, gastric intestinal metaplasia (GIM) and finally GAC. Biomarkers for the early stages of GAC are currently not recommended for use by the British Society of Gastroenterology. Ideally, non-invasive early detection tests would circumvent the current need for endoscopic surveillance of high-risk patients. Recently, microbiome sequencing studies have established that during GAC, there is a reduction in H. pylori and an enrichment of opportunistic oral bacteria. We, and others, have shown that some of these bacteria inhibit the growth of H. pylori in vitro, suggesting a role for these bacteria in the later stages of GAC. In a complementary study, we have combined RNAScope in situ hybridisation (ISH) technology and immunostaining to localise H. pylori and non-H. pylori bacteria in GIM tissue. This will inform which bacteria are directly interacting with gastric epithelial cells (GECs) and thereby likely to play a role in driving pre-malignant changes in GAC. Aims Thus, we aim to develop a patient-derived mucosoid-microbiota culture (MMC) model to identify indicator bacteria responsible for driving novel biomarkers, which can be used for the early detection of GAC. Methods We will take a different approach by culturing patient-derived organoids and gastric bacteria from matched endoscopic biopsy sites of GIM and non-GIM controls. We will generate mucosoid cultures, as previously described, and infect these with the patients autologous H. pylori strain and up to 3 members of their non-H. pylori microbiota. These MMCs will then be used to GEC responses to chronic (2-week) infections with H. pylori versus H. pylori and the GIM-microbiota, using single cell RNA-sequencing. Custom RNAScope ISH probes will then be designed against the identified bacterial isolates and candidate biomarkers to test their expression ex vivo, using matched FFPE tissue sections. How the results of this research will be used This will form a proof-of-concept study to validate a personalised approach in identifying novel biomarkers. Further, this will pave the way to secure additional funding to translate indicator oral bacteria and host biomarkers into non-invasive oral swabs and blood tests, respectively, for the early detection of GAC. Moreover, this will provide a pipeline, which can be applied to understanding bacterial-host interactions in mucosally-derived cancers, such as colorectal cancers.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_02528,Medical Research Council,MRC,Development of a system to simultaneously detect mutations and epigenetic marks,"Changes to epigenetic marks, in particular cytosine methylation, are an key feature of many diseases. For example, it has been shown that CpG-island hypermethylation is a common occurrence in cancer cells. Despite their well-established importance in many diseases, the number of genome-wide maps of DNA modifications is different healthy and diseased tissue types is small. The reason for this is that bisulfite sequencing, the current state-of-the-art method for reading DNA modifications, is more expensive than standard genome sequencing, and requires more material, due to the DNA-damaging nature of chemicals involved. Furthermore, bisulfite sequencing results in a much higher error rate per base. Most projects therefore choose to not perform genome-wide measurements of cytosine methylation. We recently published a new method for sequencing epigenetic marks, called TAPS, that is both cheaper and results in data of very similar quality as standard DNA sequencing. Here, we propose to develop algorithms to identify both genetic variation and epigenetic marks from the same sequencing data simultaneously. This would make it possible to perform only one experiment, at similar cost to standard sequencing, and produce information regarding the genotype and gene regulatory state of a sample at once. We believe that this would greatly increase the utility of the TAPS method, but more importantly it would lead to a more epigenetic information being generated routinely, leading to a much better understanding of the role of epigenetic marks in different diseases.",,1.4 METHODOLOGIES AND MEASUREMENTS,GENERIC HEALTH RELEVANCE HRCS22_02387,Medical Research Council,MRC,Development of an intervention for improved management of self-reported abnormal vaginal discharge by women in rural north India.,"Self-reported 'abnormal vaginal discharge' (AVD) is a common clinical symptom of sexually transmitted infections (chlamydia, gonorrhoea or trichomoniasis) or endogenous reproductive tract infections (bacterial vaginosis or candidiasis) and its clinical management is done through the syndromic management approach. This approach was advocated by WHO for low resource settings where laboratory diagnostics is unavailable. However, it is now accepted that AVD (or vaginal discharge syndrome) is neither sensitive nor specific for sexually transmitted infections (STIs), leading to considerable over treatment with antibiotics (up to 65% for gonorrhoea and chlamydia). While more cases of AVD may be attributed to RTIs (bacterial vaginosis and candidiasis) than to STIs, there may be other cultural and psychosocial factors leading to the complaint. In South Asia, a large body of literature suggests that self-reported AVD may be associated with mental health risk factors including stress, social conflict, marital discord, gender disadvantage and poverty. Studies in India and Pakistan have found a strong association between AVD and scores on mental health screening instruments, suggesting a link between AVD and common mental disorders (CMDs). This further confounds the management of AVD in S. Asia. Our aim is to develop an intervention to overcome the limitations of syndromic management by (1) introducing rapid diagnostic tests to detect and manage BV, TV and CA (2); introducing gold-standard PCR tests for NG,CT for those with sexual risk assessment scores (as PCR tests are comparatively expensive); and (3) adding CMD screening and management to identify high mental health risk individuals and use additional assessment tools for these. The intervention will be implemented in Tehri Garhwal in India, with 20 selected health workers and 40 women seeking care for AVD; a review of the outcomes and a process evaluation will lead to an intervention pilot in the next stage.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;4.3 INFLUENCES AND IMPACT,INFECTION HRCS22_22141,"National Centre for the Replacement, Refinement and Reduction of Animals in Research",NC3Rs,Development of an invertebrate model of alternating hemiplegia of childhood,"Heterozygous mutations in ATP1A3, encoding the Na+,K+-ATPase (NKA) alpha3 subunit, are identified as the cause of a",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_02615,Medical Research Council,MRC,"Development of inhaled, dual EP2/4 receptor agonists for the treatment of idiopathic pulmonary fibrosis","Idiopathic pulmonary fibrosis (IPF) is a fatal chronic fibrosing interstitial lung disease with median survival of 3 years. IPF is characterised by formation of fibroblast/myofibroblast foci that excrete excessive extracellular matrix resulting in airway stiffening and loss of pulmonary function. Recent work demonstrated a link between a decrease in prostaglandin E2 (PGE2) signalling and fibrotic disease. Restoration of this pathway via activation of EP2 and EP4 receptors can inhibit, and in some cases reverse, remodelling processes associated with fibrosis. Through an MRC DPFS-funded hit to lead campaign we have identified novel, dual EP2/4 receptor agonists that inhibit fibroblast migration, proliferation and differentiation to a variety of IPF-associated growth factors. We now propose a full Lead Optimisation project to further develop these leads, consisting of chemistry to explore core modification, side chain optimisation and improvement of compound physicochemical properties. As EP2 and EP4 receptors are not restricted to lung we will pursue an inhaled delivery approach to facilitate targeting of compounds directly to their site of action, minimising systemic exposure. We will conduct in vitro characterization against human lung fibroblasts to optimise efficacy against a range of phenotypic responses important in IPF. We will perform detailed pharmacokinetic studies to confirm compound suitability for inhaled delivery. Finally, we will perform pharmacokinetic/pharmacodynamic profiling in the murine bleomycin model to determine efficacy against a chronic pulmonary fibrosis and remodelling response. The ultimate goal is selection of a candidate suitable for progression to GLP long-term inhaled non-human toxicology studies.",,5.1 PHARMACEUTICALS,RESPIRATORY HRCS22_19412,Cancer Research UK,CRUK,Development of rejection-resistant allogeneic chimeric antigen receptor T cells,"Chimeric antigen receptor (CAR)-T cells are a breakthrough in cancer treatment, recently approved in advanced B cell malignancies. An important limitation is that CAR-T are currently made as bespoke autologous products, which is expensive, has a 10% failure rate, and a 3-week+ lag-time. In addition, CAR-T quality depends on ‘fitness’ of patient T cells, so is highly variable. A potential solution is batched allogeneic CAR-T (allo-CAR-T) from healthy donors. However, 2 critical obstacles preclude this: graft versus host disease (GvHD) induced by allo-CAR-T, and rejection of allo-CAR-T by the recipient. GvHD is a potentially fatal syndrome, mediated by T-cell receptors (TCR) of allo-CAR-T, which attack 'foreign' host tissues. To prevent GvHD, investigators have used genome-editing to delete the TCR, a complex approach with risks of genotoxicity. I have developed an alternative allo-CAR-T manufacturing platform without genome-editing. Here, a TCR-specific binder is fused to a Golgi-retention signal (KDEL), and co-expressed with the CAR in one viral vector. TCR-KDEL blocks TCR assembly, enabling TCR-negative CAR-T generation in a single step. This strategy will be tested in a first-in-human MRC-funded phase-1 trial in B cell malignancies (KCAT19), commencing 2021. However, KCAT19 does not address host rejection of allo-CAR-T. Rejection reduces efficacy by preventing long-term CAR-T engraftment, and occurs by little-explored mechanisms. In this proposal I will examine how allo-CAR-T are rejected, and develop new methodologies to prevent this. My overall aim is to produce truly ‘off-the-shelf’ CAR-T, which do not cause GvHD and persist long-term in patients. Using samples from patients treated on the KCAT19 trial, I will dissect rejection, investigating the immune cell types and pathways involved in this process, and will correlate clinical results with biological findings. Simultaneously, I will develop multiple protein-based methods to prevent rejection. One likely major mechanism of rejection is recognition of foreign human leukocyte antigen (HLA) molecules on donor cells by host T cells. Thus, I will test Golgi-retention approaches to HLA, as well as a novel fusion-protein I have developed which simultaneously downregulates TCR and HLA class-1. I will combine these strategies with expression of non-classical HLA to prevent natural killer cell-based rejection. I will engineer allo-CAR-T resistance to pharmacological immunosuppression, enabling use of these drugs to prevent rejection without blocking CAR function. I will test my approaches extensively in vitro and in humanised murine models. The proposal is highly translational, with a genuine prospect of rapid progression to clinical testing during the felowship.",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_11767,Economic and Social Research Council,ESRC,Development of the WESTERN plan for supporting active ageing in retirement and care facilities,"The main aim of this programme of work is to develop a prototype active ageing intervention and digital platform that engages older adults and fosters the maintenance of physical, cognitive and emotional health and wellbeing. Specifically, by the end of the 12-month funding period, the key outcomes will be: 1. An optimized, evidence-based, package that meets the user needs and is acceptable and effective in meeting its aim of translating care and retirement settings as ones that endorse rather than disavow active ageing. 2. An implementation plan that maps out the steps necessary to appropriately market the WESTERN plan and realize widespread, long-term adoption.","This research aims to address the problem of maintaining mobility, wellbeing, and quality of life in older adults in sheltered accommodation, assisted living, care homes and people who require outreach care. In other words, this project will aim to provide a personalized programme that transforms these settings into ones that facilitate rather than impeded active ageing. Often when individuals reside in such facilities there is a tendency to succumb to an ageing stereotype characterized by a detachment from the wider social community, a reduction in physical activity, apathy towards cooking and eating healthy, balanced meals, and feelings of helplessness. Consequently, age-associated conditions such as cognitive impairment, loss of physical function, frailty and poor mental health are highly prevalent within this population. Fortunately, many of these issues are preventable (or at the very least, can be decelerated) through simple lifestyle behaviours. Providing a system to motivate, prompt and support older adults to include health-enhancing 'self-care' behaviours into their daily routines can promote active ageing, and curb any preventable mental, physical, and emotional decline. The WESTERN plan (Walking, Exercise Snacking, Tai-chi, Edification, Relationships, Nutrition) aims to provide a simple, personalized programme that is rooted in behavioural science to optimize motivation, engagement, and acceptability. The plan, which will be provided on a target-user informed digital platform for integration of behaviour change techniques, scalability and dissemination, will provide structure for users, care staff and family members and act as a basis for continued growth, value, belongingness and thriving health and wellbeing in residents.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;7.1 INDIVIDUAL CARE NEEDS,GENERIC HEALTH RELEVANCE HRCS22_01084,Medical Research Council,MRC,Developmental Assembly of the Serotonin System,"The serotonin system powerfully modulates physiology and behaviour in health and disease. It is the most widely used pharmacological target for treating depression and anxiety, and depression has become the leading cause of disability worldwide. Despite its functional importance, there are surprisingly few studies that analyse how serotonin neurons are able to reach nearly all neural circuitry with their miniscule cell numbers. Spectacular progress has been made over the past decades in identifying and understanding how molecular guidance cues work to instruct axon projection. But less attention has been paid to the cellular context in which these cues are produced, presented, and interpreted by growing axons. This could be partially caused by the fact that majority of the axon guidance cues were identified and studied in sensory systems. Although sensory systems provide powerful models for studying synaptic transmission which are restricted to confined brain regions, it is unknown how projections utilize volume transmission find their targets and how they stabilize the connection. The serotonin system is an ideal system to answer this question because it utilizes both wiring and volume transmission, and it is the only neural system that projects to the entire brain. My recent work revealed that the dorsal raphe serotonin system contains parallel sub-systems that have largely complementary whole-brain collateralization patterns and distinct functions. Systematic investigation into the development of the serotonin system can be extremely useful for uncovering new molecular mechanisms underlying neuron-specific development. In addition, it may provide entirely novel targets for therapeutic interventions of psychiatric and other disorders. We have been applying cutting-edge single-cell mRNA sequencing technology (scRNA-seq) to reveal the transcriptomic identities of mouse midbrain serotonin neurons in both DR and median raphe (MR). Combining these scRNA-seq profiles with viral-genetic tracing results of the projection defined serotonin neurons will allow me to identify the molecular features of each the projection-defined serotonin sub-systems. We shall then build the developmental trajectory for each of the main sub-systems and identify the molecular cues guiding/maintaining the formation of each serotonin sub-circuits during development. We shall validate the candidate genes’ function in serotonin projection wiring specificity in mouse models. Finally, we shall elucidate the relationship between genetic defects of the serotonin system and psychiatrically relevant behaviours in mouse models.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MENTAL HEALTH;NEUROLOGICAL HRCS22_01322,Medical Research Council,MRC,Developmental origins and niches of the haematopoietic system,"To harness the full therapeutic potential of haematopoietic stem cells (HSCs) and lineage-restricted progenitors to treat blood-related disorders, we aim to better understand their birth in the embryo. Haematopoietic stem and progenitor cells are generated in asynchronous waves from haemogenic endothelium in the yolk sac and the dorsal aorta through a process termed endothelial-to-haematopoietic transition (EHT). EHT is critically dependent on the transcription factor Runx1. In our past work, we have progressed towards fully unravelling the CIS regulatory complexity of Runx1 during EHT and obtained new insights on the timeline and process of early haematopoietic commitment. In our future programme, we will take advantage of new tools we developed and available cutting edge technologies to perform a series of complementary studies that will transform our ability to gain a deep level mechanistic understanding of early blood development. We will combine our unique Runx1 enhancer-reporter transgenic models with chromatin conformation analysis, single cell omics and functional assays to i) discern the principles of Runx1 regulation during the establishment of haematopoiesis, ii) deconstruct the HSC-generative niche with the aim to recreate critical components in vitro, and finally, iii) to elucidate the developmental trajectories of mesoderm contributing to yolk sac and AGM blood cells and their contribution tothe haemato-immune system. Our studies will offer exciting opportunities for translational applications into human models of normal and perturbed developmental haematopoiesis.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,BLOOD;GENERIC HEALTH RELEVANCE HRCS22_17331,Diabetes UK,,"DiRECT extension, for a total of 3-years weight-loss maintenance and follow-up","Information collected from DiRECT study intervention participants at routine diabetes monitoring suggest that almost half have achieved and maintained a weight loss of 15kg at 12 months. Many are no longer diabetic. Under the current DiRECT protocol, support for weight-loss maintenance will cease at 2 years. Evidence from long-term weight management studies show that, without continued support, significant weight regain is very likely. Under the planned extension to DiRECT, at their 2 year review appointment intervention participants will be offered continued attending for weight loss maintenance support, every 3 months, for a further 3 years. Participants will continue to attend their GP surgery for review appointments with the specifically trained Practice Nurse or Dietitian to follow their individually tailored dietary programme for weight-loss maintenance. People who do not wish to continue will return to usual NHS primary care management. Extension of the study will help participants maintain the improvements in weight and diabetes control they have achieved in the initial 2 years of the study, and prolong freedom from diabetes for those that have achieved this for a total of 5 years, more in line with data available after bariatric surgery, which is increasingly required for clinical guidelines.",,6.6 PSYCHOLOGICAL AND BEHAVIOURAL;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,METABOLIC AND ENDOCRINE HRCS22_19463,Wellcome Trust,,Dietary restriction of micronutrients to slow ageing and treat disease,"In biomedical science, there is a growing realisation that the mechanisms of ageing underlie many major debilitating age-related diseases. Interventions in the ageing process therefore have the potential to make an immense impact on our healthspan. The most potent of these interventions is dietary restriction (DR) – decreasing dietary intake but avoiding malnutrition. Translation of DR to humans is impeded by our lack of knowledge on exact mechanisms and the optimal diet. DR is thought to result from a reduced intake of the macronutrient protein. Recent data in from my lab, however, suggests that restriction of micronutrients results in similar benefits to healthspan. I propose that by studying the restriction of micronutrients, translation is facilitated and more specific insight into mechanism is gained, as it provides a more precise intervention. I will elucidate the mechanisms of how dietary micronutrients affect ageing and disease using a systematic and comprehensive research program using the fly. I will screen for micronutrients that improve health and will test specific mechanisms based on my previous work connecting phosphate, copper and mitochondrial oxidative stress. Work in two disease models will complement these approaches, together providing key novel insight into the connections between diet, disease and ageing.","Ageing is a major challenge in our society. Many age-related diseases, such as cancer, cardiovascular disease and dementia are thought to share mechanisms fundamental to the ageing process. Interventions into ageing itself therefore have the potential to transform our well-being. The most potent of these interventions is dietary restriction (DR): reducing food intake but avoiding malnutrition. Previous research has suggested intake of protein is responsible for these effects. In my lab I recently found that restriction of micronutrients can have similar effects. I propose that the restriction of micronutrients is easier to apply in humans and will also provide us more information on the underlying mechanisms that could be used to develop drugs. My fellowship will use a comprehensive study in the fruit fly to test the effects of micronutrients on lifespan and disease. These studies will together provide novel insights on how to reap the health benefits of DR.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_02157,Medical Research Council,MRC,Differential targeting of the HSV1 vhs endoribonuclease - preferential degradation of cellular transcripts on the endoplasmic reticulum?,"Herpes simplex virus type 1 (HSV1) virion host shutoff (vhs) protein is an endoribonuclease that specifically targets mRNAs by binding to the translation initiation machinery at the 5' end of the mRNA, but the subtlety of its specificity remains to be delineated. Using RNAseq of infected human fibroblasts we have recently shown that cellular mRNAs exhibit a wide range of susceptibility to vhs activity during HSV1 infection, ranging from no effect to a 1000-fold reduction after 12 hours. Pathway analysis of transcripts reduced by more than 30-fold has revealed a surprising enrichment in pathways related to the extracellular environment, particularly the remodeling of the extracellular matrix. Furthermore, the most vhs-susceptible transcripts were determined to be enriched in transcripts encoding membrane/secreted proteins in general. This proposal therefore aims to test the novel hypothesis that vhs specifically targets transcripts that are translated on the endoplasmic reticulum (ER), resulting in important alterations to the extracellular environment. The specificity of vhs activity against ER bound transcripts will be delineated using differential expression analysis of total and ER-bound cellular transcriptomes from cells infected with Wt and vhs- viruses. Vhs-induced alterations in the extracellular proteomes will be assessed using tandem mass tagging mass spectrometry of similar infections. Additionally, the vhs interactome will be defined to determine the nature of vhs targeting to specific subsets of mRNAs. Finally, the role of vhs in paving the way for HSV1 glycoprotein translation - the most abundant transcripts present at later times in infection - will be determined. These studies will further our understanding of the molecular consequences of HSV vhs activity within the cell and its impact on the global make-up of the cell, data that will impact on other alphaherpesviruses and viruses in general that encode endoribonucleases.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_06925,Department of Health and Social Care,NIHR,Digital Assessment of Wellbeing in New Parents (DAWN-P): a feasibility study of digital screening for postnatal depression,"Epidemiological studies show that 17% of mothers (and 9% of fathers) suffer an episode of major depression (postnatal depression: PND) in the year following childbirth and that suicide is the leading cause of maternal death in this period. The consequences and costs of PND are particularly high due to its impact on infants as well as parents. If detected, PND usually responds well to psychological treatment and/or medication. Hence, improving access to perinatal mental health care for both parents is a priority in the NHS Long Term Plan. The main barrier to access in NHS practice is inefficient PND screening. Recommended practice is for health visitors to administer a well-validated PND screening scale at postnatal visits, usually the 10-item Edinburgh Postnatal Depression Scale (EPDS). However, our audit of 14,200 mothers found that only 41% were screened, resulting in a whole sample rate of caseness of just 3%, consistent with national reports that >50% of cases go undetected. To improve access, we developed a new smartphone app (ClinTouch DAWN-P) that allows parents to monitor their mood with EPDS on a daily basis from 36 weeks gestation, uploading real-time responses to a secure server. A proof-of-concept study, over 8 weeks perinatally, in 15 mothers and 8 partners showed the app to be easy, acceptable, safe, and valid against the standard EPDS. This solution addresses existing screening barriers: (i) limited staff time for screening, (ii) parental unwillingness to disclose difficulties to a professional, (iii) language barriers and (iv) no partner/father screening. The current proposal addresses specific uncertainties in preparation for a full-scale RCT, which will test whether digital screening: identifies more true positives than usual practice; leads to better mental health 6 months postpartum; is safe, acceptable and cost-effective. The full-scale RCT design will be informed by the current proposal which aims to (i) refine the DAWN-P digital screening, in collaboration with key stakeholders; (ii) evaluate feasibility/acceptability of delivering a full-scale, single-blind RCT within NHS services; (iii) optimise RCT design, parameters and procedures. The design will be a single-blind pilot RCT of digital screening vs. standard practice in a randomised sample of n=80 antenatal mothers, recruited from two maternity services, with a partner/father (n=20) sub-study. Participants randomised to the experimental arm will use DAWN-P app daily from ≥36 weeks pregnancy until 8 weeks postpartum, in addition to usual care. Participants scoring above threshold on screening (digital or conventional) will have diagnosis confirmed at interview. This sample is sufficient to assess feasibility outcomes and estimate key parameters with adequate precision to inform definitive trial sample size. Qualitative interviews will be conducted with n=30 participating mothers and with n=30 health professionals. Using Framework Analysis, relevant overarching themes will be identified to explore any acceptability and implementation issues. We have involved parents, health visitors and Greater Manchester commissioners of mental health and maternity services in the study design and the dissemination plan. We will produce a range of outputs for mixed audiences: peer-reviewed papers, conference/seminar presentations, and participant newsletters/blogs/videos published on our website and social media.","Postnatal depression is hugely disruptive for parents and their children. Around 17 mothers and 9 fathers in every 100 experience depression in the year after their baby s birth. Parental depression can affect parents wellbeing, the parent-infant bond and children s development. It can also affect parents and children s long-term physical and mental health. If postnatal depression remains untreated, it has a heavy economic burden for society – around £74,000 for each case. Medication or talking therapy can be used to successfully treat postnatal depression, but identifying who needs treatment is difficult. Around half of cases of postnatal depression are currently missed. Our study seeks to improve this vital step. Most people of childbearing age (94%) own a smartphone. We have developed a smartphone app that asks questions about parents daily mood to help identify postnatal depression quickly and efficiently. Last year, we ran a small study and found this digital screening accurately identified parents needing postnatal depression treatment. Now we want to gather more information about our digital screening app compared to usual NHS care. For example: How much do parents use the app and what do they think about it? What are the main costs of digital screening compared to usual care? Are parents happy to complete all the assessments we plan to use? This information will help us design and run a much larger study in future. To gather this information, we will invite 80 women in the late stages of pregnancy (after 36 weeks) to participate in the current study. We will divide participants, by chance, into two groups of 40 women. The first group will receive usual NHS care. The second group will receive usual NHS care plus the digital screening app. We will gather information using questionnaires and phone interviews when participants start the study, when their babies are 8 weeks old and again at 6 months old. Assessments will ask about mood, NHS resource use and app acceptability. If a parent from either group has possible postnatal depression, they will receive an extra phone call assessment and signposting. Over the past 18 months, we have discussed this research with Patient and Public Involvement (PPI) contributors many times. Their ideas fed directly into the study design. During the study, two people with experience of postnatal depression will lead a diverse, 8-person PPI group. The PPI group will meet every 2-3 months using a video-conferencing platform (e.g. Zoom). They will provide regular guidance on the research (e.g., recruitment strategies, app design) and will receive support/training as needed throughout. We will communicate research findings to the public via local engagement events, plus blogs/newsletters/videos. We will present findings to health professionals and researchers via research conferences and research journals.",4.4 POPULATION SCREENING,REPRODUCTIVE HEALTH AND CHILDBIRTH;MENTAL HEALTH HRCS22_14892,Versus Arthritis,,Digital support for physical activity in rheumatoid arthritis (DASH-RA),"Physical activity is beneficial for people with rheumatoid arthritis and is a key non-pharmacological management strategy which directly impacts on quality of life. However, people with rheumatoid arthritis report barriers to taking part in physical activity and are often reluctant to participate for fear of symptom exacerbation. Traditionally, support to engage with physical activity has been provided through face-to-face behaviour change interventions but limitations with access have been identified. Interventions using digital technology may address the limitations of face-to-face interventions and provide a more flexible support option. Research is required to establish the most usable, acceptable and effective ways to encourage long-term adherence to physical activity in people with rheumatoid arthritis via digital behaviour change interventions. Therefore, the aim of this studentship is to develop a prototype digital behaviour change intervention for people with rheumatoid arthritis, to facilitate sustained engagement with physical activity. This will be conducted across three work packages (WP): WP1a: Survey to explore existing use of physical activity digital interventions for people with rheumatoid arthritis including content and evidence of engagement. WP1b: Rapid review to identify existing research evidence relating to digital interventions for physical activity in rheumatoid arthritis. WP2: Development of a prototype digital behaviour change intervention informed by behaviour change theory through an intervention mapping process and co-design workshop. WP3: Investigation of the usability and acceptability of the prototype intervention through 12-week pilot and individual semi-structured interviews with 12-15 participants. The outcome of the studentship will be a prototype digital behaviour change intervention for people with rheumatoid arthritis to facilitate and sustain engagement with physical activity. This intervention will be ready for feasibility testing and have preliminary evidence of how the intervention might work for different groups in different circumstances.",,5.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.7 PHYSICAL,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_22180,"National Centre for the Replacement, Refinement and Reduction of Animals in Research",NC3Rs,Direct replacement of secondary antibodies by affimer proteins,"Antibodies are indispensable tools in science, medical research and diagnostics. Sensitive",,5.1 PHARMACEUTICALS,GENERIC HEALTH RELEVANCE HRCS22_23102,The British Academy,,Disability: Experiences and Perspectives from Zimbabwe’s Indigenous Doma people,"Disability literature is largely dominated by scholars and studies from the global North, and these studies are based on global North theories and concepts. This distorts the realities of people with disabilities in the global South as their voices remain on the fringes of disability discourses. The aim of this proposed ethnographic qualitative project is to shed light on disability in the global South by utilising the Indigenous Ubuntu philosophy. This study will be undertaken within the Doma communities in northern Zimbabwe through narrative interviews. Participants will include people with disabilities and their families, traditional leaders and other key stakeholders e.g., Disability organisations’ representatives. The significance of this project is that it seeks to challenge the global hegemonic discourses on disability by transforming the ways in which disability is understood. This project will ultimately contribute to both national and international policy making.",,7.1 INDIVIDUAL CARE NEEDS,GENERIC HEALTH RELEVANCE HRCS22_17189,Wellcome Trust,,Discovering New Pathways of Preleukaemic Dysregulation from Single Cell Transcriptional and Chromatin Landscapes,"Blood stem cells ensure the constant supply of new blood cells throughout a person’s lifetime.  The normal function of blood stem cells critically depends on the fine tuning of which genes should be active at any given time.  Moreover, a large number of leukaemias arise when this fine balance of gene activities is disturbed.  Through my research I want to answer the following questions: • What are the mechanisms which regulate gene activities to ensure normal blood stem cell function?  • Can we identify new strategies to treat leukaemia by reversing the disturbed balance of gene activities? To answer these questions, I plan to use a combination of experimental and computational approaches, in order to discover how individual regulator genes are connected to form complex networks that control normal blood cell differentiation, and also reveal how perturbation of these complex networks can cause leukaemia.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_20014,Cancer Research UK,CRUK,Discovering the structural and mechanistic principles of human helicase-loading control and its misregulation in cancer,"We will investigate human DNA replication control. A key step during DNA replication is the loading of the replicative helicase in late M and early G1 phase of the cell cycle, which is essential for assembly of replication forks in S-phase. Helicase loading has to be exceptionally efficient, otherwise parts of the genome are left unreplicated, which results in chromosomes instability. At the same time, helicase loading has to be completely blocked in S-phase, otherwise parts of the genome become replicated twice, which would result in hyper-recombination and chromosome breaks. For these reasons, the mechanisms that guarantee highly efficient and genome wide helicase loading have major relevance for genome stability and tumorigenesis. Currently, the underlying control principles are not well understood, in part due to the absence of a biochemical system, which is essential to fully uncover the regulatory, mechanistic and structural basis of these reactions. We have recently reconstituted human replicative helicase loading with purified proteins. Now, we will take advantage of this major breakthrough and discover how efficient helicase loading across the entire genome is achieved. We are exceptionally well placed to carry out this work, as our 10+ years’ experience with a yeast system resulted not only in the discovery of fundamental principles and structures of key complexes, but also allowed us to establish a large array of relevant research protocols. Crucially, as yeast helicase loading employs simplified regulation, the mechanisms that guarantee genome stability in healthy human cells and their misregulation in cancer cells remain largely unknown. We will use a combination of biochemical, structural, proteomic, genomic and cell biology approaches to generated a holistic insight into human helicase loading and their misregulation in the context of lung cancer. Our focus is on lung cancer, due to its poor treatment options and its susceptibility to inhibition of helicase loading. This work will be relevant to a vast array of researchers and clinicians interested in DNA replication, genome stability and tumorigenesis. Importantly, the identification of mechanisms that inhibit human helicase loading will underpin the development of novel DNA licensing inhibitors with potential for cancer therapy.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_23086,The British Academy,,Discrimination in healthcare settings and the nocebo effect,"Many medication side-effects are the result of negative patient expectations rather than the pharmacological action of the drugs, thus triggering a “nocebo effect.” Negative expectations can be generated by contextual factors that contribute to the perceived quality of care. Research shows that perceived discrimination in healthcare settings among Black, Asian, and other Minority Ethnic (BAME) groups is associated with lower perceived quality of care. Yet no work has considered whether perceived discrimination contributes to experiences of nocebo effects among BAME groups, leading to potentially poorer medication adherence and health outcomes. Using a population-based sample representing the four largest UK racial/ethnic groups, this study investigates the extent to which perceived discrimination in healthcare settings contributes to nocebo effects through increased side-effect experience. Results will inform large longitudinal studies to confirm the identified causal relationships and explore BAME individuals’ healthcare experiences, and help develop interventions to reduce nocebo effects among BAME groups.",,7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_02177,Medical Research Council,MRC,Dissecting mechanisms of alveolar repair failure and lung destruction in lymphangioleiomyomatosis,"Lymphangioleiomyomatosis (LAM) is a rare lung disease. Loss of TSC2 causes mTOR activation in LAM cells which accumulate in the lungs causing cysts by an unknown mechanism. We hypothesise that cysts form when mTOR activation causes LAM cell senescence in turn inducing senescence in surrounding alveolar type II (ATII) cells reducing alveolar repair. Using single cell sequencing we have shown that ATII cells in LAM express a senescence gene signature and in both human LAM and an animal model, senescence protein markers parallel lung damage. In the proposed work we will systematically examine how senescence leads to lung damage in LAM. We will examine alveolar epithelial cell gene transcription using single cell RNA sequencing of LAM lung cell populations from lung transplants and study early LAM biopsies by laser capture microdissection / RNA sequencing. Using gene expression and upstream regulator analysis tools we will examine cell death and repair pathways in epithelial cells and how they are regulated by LAM nodule derived proteins. Using LAM biopsies with linked clinical data we will confirm how these proteins are related to disease duration and disease activity measured by prospective loss of lung function. We will then study how senescence is regulated in vitro using novel 3D LAM nodule spheroids co-cultured with alveolar epithelial cells with individual mediators inhibited using small molecules, blocking antibodies and CRISPRcas9. We will validate these findings and test pharmacologic strategies on senescence, air space enlargement and nodule size in an immunocompetent murine TSC2 null xenograft model. Drugs affecting mTOR mediated senescence including metformin, resveratrol and mediators identified above amenable to intervention will be compared with rapalogues. These experiments will inform how lung damage occurs in LAM and other lung diseases where mTOR activation occurs, with the aim of improving treatment of LAM and potentially other lung diseases.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,RESPIRATORY HRCS22_15481,Wellcome Trust,,Dissecting molecular mechanisms mediating ERK1/2 regulation of neural differentiation,"During embryogenesis, that is the process of embryonic development after fertilisation, cells divide many times, and at some point, these cells become different from one another. This process requires turning on specific genes that make distinct cell types, such as nerve or muscle cells. My project aims to find out how this happens focusing on a specific cell type called neuromesodermal progenitors (NMP) that can contribute to two different embryonic tissues, depending on exposure to specific signals. One such signal is the Fibroblast growth factor (FGF) which regulates neural induction. It is known that inhibition of ERK1/2 activity, a protein controlled by FGF, is involved in the activation of neural genes in NMP cells. This process requires the removal of a protein complex called Polycomb, that blocks the activation of these genes. However, how the Polycomb protein complex is removed is unknown.  During my PhD project, an analysis of the proteins with changed activity upon ERK1/2 protein inactivation, will begin to dissect the molecular mechanisms regulating neural differentiation. My findings may facilitate improved protocols for directed differentiation of human cells in vitro and have wider implications for how cell state can be manipulated for therapeutic effect.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_15603,Wellcome Trust,,Dissecting structural and functional contributions of promoter interactions in gene regulation,"Understanding how complex multicellular organisms, made up from trillions of cells within multiple tissues, develop from a single fertilised egg requires turning specific genes on and off at the right place and time, in a pre-determined order. The entire process is encoded within the DNA sequence of the genome in each individual cell. In humans, there are about 20,000 genes, which encode functional units such as enzymes or haemoglobin, but these only constitute 1-2% of the DNA sequence in each cell. The DNA also contains surrounding regulatory elements that control the output of genes. There are 3 classes of such elements: promoters, enhancers and boundary elements. It is becoming increasingly clear that the roles of these elements overlap one another.   In this work, I will study the characteristics of promoter interactions and the resulting impact on gene regulation. I will be particularly interested in how promoters control gene expression by changing the three-dimensional architecture of the genome as well as the conditions by which promoters interact with enhancers. Ultimately understanding the process of gene expression will enable us to understand how these genes are normally switched on and off during development and how this goes awry in human disease.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_18737,Wellcome Trust,,Dissecting the crucial role of (p)ppGpp in S. aureus stress survival,"The stringent response is a complex regulatory mechanism utilised by bacteria to survive stress. The response is controlled by the nucleotides (p)ppGpp, which function to shut down growth until conditions become more favourable. Our work has identified four ribosomal-associated GTPases (RA-GTPases) as (p)ppGpp-binding targets in Staphylococcus aureus. We showed that the activity of these RA-GTPases is inhibited upon binding to (p)ppGpp, leading to defects in ribosome assembly, slowed bacterial growth and tolerance to antimicrobials. However, our mechanistic understanding of how this occurs, the function of each RA-GTPase in ribosome maturation, as well as a general role for (p)ppGpp in stress-related processes, is limited. This project will use multidisciplinary approaches to characterise (p)ppGpp-controlled signalling pathways. Specifically, I will address three related but independent aims. I will: 1) use structure-function studies to understand how (p)ppGpp binding and inhibition of ribosome-associated GTPases impacts ribosome assembly; 2) identify additional (p)ppGpp-regulated pathways using capture-compound mass spectrometry and transposon mutagenesis; 3) determine the importance of this signalling system for virulence in immune cells. These objectives will provide important mechanistic data on the crucial role for this signalling system in bacterial survival, and will identify essential cellular targets that may be exploited for therapeutic gain.","Staphylococcus aureus is a human pathogen responsible for a significant amount of disease worldwide. When this bacterium invades a human host it encounters a number of different stresses. The bacteria respond to this by switching on a signalling cascade controlled by two nucleotides termed (p)ppGpp, that function to shut down growth until conditions improve. Little is known about how (p)ppGpp coordinates the shutdown of diverse cellular processes. We recently discovered four GTPase enzymes involved in ribosome maturation as binding targets for (p)ppGpp. I will now investigate the function of these GTPases in the cell and ascertain how (p)ppGpp binding disrupts ribosome assembly. I will also identify additional cellular pathways that are regulated by (p)ppGpp, and uncover the role for (p)ppGpp in chronic infections. By doing so we will better understand how S. aureus can survive in the human host and can begin to design therapies to disrupt this process.",2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_01914,Medical Research Council,MRC,"Dissecting the mechanism of action of CHD1L, a novel regulator of HIV-1 infection","HIV remains an important cause of morbidity and mortality. We have uncovered a novel polymorphism in African populations correlated with HIV viral load set point. We have shown that the gene responsible is CHD1L, is a novel cellular factor negatively regulating HIV-1 infection. To study its mechanism of action, we have knocked out CHD1L in inducible pluripotent stem cell (iPSC)-derived macrophages. We have also created CHD1L knockdown vectors and expression vectors and are validating them in Jurkat and THP-1 cells. We will discern cellular pathways involved in CHD1L's regulation of HIV-1 with these cells, using transcriptomic and TMT-mass spectrometry based proteomic approaches. To identify protein binding partners of CHD1L, we will conduct SILAC-IP using lysates from uninfected and HIV infected cells. We will pinpoint the step(s) of the virus life cycle affected by CHD1L using engineered vectors expressing different fluorophores upon integration and upon activation of the viral promoter. This will be complemented by qPCR based techniques to detect the HIV genome in different stages of its life cycle, direct visualisation of the chromosomal location of viral integration sites with FISH, and assessment of nucleosome remodelling of the viral promoter with chromatin histone immunoprecipitation assays. The results of the above studies will be followed up with specifically designed experiments. Effects on viral integration will be confirmed with in vitro integration assays. Protein interactions will be confirmed with traditional immunoprecipitation/western blot techniques, using relevant mutant viruses and expression vectors. Should CHD1L alter the viral integration landscape, the distribution of the integration site will be determined. We will also create a panel of mutant CHD1L expressors, inactivating different domains/residues of the protein to examine the specific biochemical activities of CHD1L that are crucial for its regulation of HIV.",,5.2 CELLULAR AND GENE THERAPIES,INFECTION HRCS22_03021,Medical Research Council,MRC,Dissecting thermogenesis by brown adipose tissue and skeletal muscle in lean and obese subjects,"The identification of brown adipose tissue (BAT) in adult humans ~15 years ago led to substantial interest in activating BAT to increase energy expenditure as a novel tool to treat obesity and associated metabolic disease. However, our understanding of the pathways regulating BAT activation and even how BAT utilises metabolic substrates during thermogenesis remains limited. Even the fate of glucose uptake by BAT is unclear, although we previously demonstrated high lactate production by human BAT. A major problem is the reliance on PET imaging that cannot detect uptake and release of multiple substrates in real time. While glucose uptake by BAT is reduced in obese subjects (the target patient group), whether this causes defective BAT thermogenesis or compensatory activation in other pathways is unknown. In addition, BAT positive status improves metabolic outcomes, potentially through communication with other metabolic organs but how this occurs is unclear. In this research project we will develop arterio-venous sampling of BAT and skeletal muscle as a novel technique and use this in combination with microdialysis to to quantify substrate utilisation by BAT, skeletal muscle and white adipose tissue (WAT) in lean and obese volunteers during warm and cold exposure in real time. We will also infuse 13C-glucose to determine the fate of glucose in vivo and the fate of multiple substrates in vitro using our primary human brown and white adipocyte and myoblast cell models. We will determine the role of the lactate receptor in BAT using our in vitro models and also in vivo using mice with global disruption of this receptor. Finally, we will perform proteomics/peptidomics analyses on blood and dialysate to identify the in vivo BAT secretome for the first time to identify potential candidates with therapeutic potential. This research will identify key thermogenic pathways and any dysregulation in obesity, this may identify targets for subsequent therapeutic manipulation.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,METABOLIC AND ENDOCRINE HRCS22_05894,Department of Health and Social Care,NIHR,Do Safe and Well Visits delivered by the Fire and Rescue service reduce falls among older people? (FIREFLI),"Aims of the research _x000D_ The Fire and Rescue Services (FRS) routinely carry out approximately 670,000 Safe and Well Visits (SWV) each year in people’s homes. The aim of the SWV is to reduce fire risks, support independent living, improve quality of life and help prevent avoidable hospital admissions and excess winter deaths. A part of the SWV is looking at ways to prevent falls. We want to find out if these SWV are effective at reducing falls, improve quality of life in older people and if the visits are good value for money. _x000D_ _x000D_ Background to the research _x000D_ About a third of people over the age of 65 and half of those over 80 will fall each year. Most of these falls, happen at home. Falling may cause people to lose confidence, feel as if they have lost their independence and become withdrawn. About a fifth of falls require medical attention. There were around 210,000 falls-related emergency hospital admissions in England in 2016. It costs the NHS a lot of money to treat falls; about £2.3 billion a year. The problem is likely to get worse as people are living longer. We know that interventions to improve home safety appear to be effective at reducing falls, especially in people at higher risk of falling and when the visit is carried out by an occupational therapist. What we don’t know is whether SWV undertaken by members of the Fire and Rescue Service will reduce falls._x000D_ _x000D_ Design and methods used_x000D_ To find out if SWV reduce the number of falls people have and improve their quality of life, we will run a randomised controlled trial. We will recruit 1156 people aged 70 years and over from lists of people held on FRS databases. We will allocate half of the people to receive a SWV from the FRS at the start of the study, which will last about an hour. The other half will receive the SWV after 12 months when they have finished the study. Everyone will receive a falls prevention leaflet from Age UK and their usual care from their GP and/or other health care professionals. They will be asked to fill in a monthly falls calendar for 12 months and three postal questionnaires over a 12 month period to collect information about falls, quality of life, how often they’ve used NHS services and if they are doing any activities which makes them more likely to have a fire in their home. A statistician and health economist will analyse the data to find out if the SWVs reduce falls and if they are good value for money. We also want to find out if the SWV are acceptable to older people and the FRS. We will explore this through a series of indepth interviews._x000D_ _x000D_ Patient and public involvement (PPI)_x000D_ We will work with a group of older members of the public and ask for their help with the study. We will seek their advice about the best way to ask people to take part and stay in the study. We will ask them to read and give feedback on the paperwork used in the trial and to ask them the best way to let everyone know about the results of our study. _x000D_ _x000D_ Dissemination_x000D_ Once we have completed the trial, we will work with the PPI group, the FRS taking part in the study and Age UK to make sure our results can be used by as many people as possible. We will send participants a summary of our findings, present the results at conferences and publish the results. We will share these findings with other FRS and other relevant people.","DESIGN: A pragmatic individually randomised controlled trial using equal randomisation, with a qualitative and economic evaluation._x000D_ _x000D_ AIM: To determine whether Safe and Well Visits (SWV) delivered by the Fire and Rescue Service (FRS) will lead to a reduction in falls and an improvement in health-related quality of life among older people living in the community._x000D_ _x000D_ SETTING: Participants’ homes._x000D_ _x000D_ TARGET POPULATION: Men and women aged 70 years and over who live in the community, residing in areas covered by Humberside and Kent FRS. _x000D_ _x000D_ INCLUSION CRITERIA: Men and women aged 70 years and over; community dwelling in areas covered by Humberside and Kent FRS. _x000D_ _x000D_ EXCLUSION CRITERIA: People who live in residential/nursing homes; are bed bound; are unable to give informed consent and do not have a consultee living with them who can provide outcome data; have had an OT visit within the past 12 months; a SWV within the past 3 years or who are passed to the FRS as an urgent referral and therefore require a SWV within 12 months._x000D_ _x000D_ INTERVENTION: SWV delivered by Humberside and Kent FRS, usual care from healthcare professionals and falls prevention leaflet._x000D_ _x000D_ CONTROL:Usual care from healthcare professionals, falls prevention leaflet. _x000D_ _x000D_ PRIMARY OUTCOMES:the number of falls per participant over the 12 months from randomisation and the EQ-5D-5L (EuroQol). _x000D_ _x000D_ SECONDARY OUTCOMES: time to first fall; proportion of participants reporting at least 1 fall and multiple falls (2 or more falls); fear of falling; fall related injuries and costs; loneliness (UCLA 3-item); fire risk taking behaviours; uptake of flu jab, smoking status; attendances to participants’ homes by the FRS. _x000D_ _x000D_ SAMPLE SIZE: We will recruit 1156 participants and randomise them 1:1 (i.e., 578 to control and 578 to intervention). This allows for 10% attrition and provides 90% power (using 2-sided significance at the 2.5% level) to show a difference in the percentage of participants who experience at least one fall in the 12 months following randomisation from 35% in the control group to 25% in the intervention group. Assuming an attrition rate of 20%, 1156 participants would give us 90% power to detect an effect size of 0.23 in the second primary outcome of EQ-5D-5L._x000D_ _x000D_ PROCESS EVALUATION: A mixed methods process evaluation will include: (1). Observations of those delivering the SWV to assess if key falls prevention components are included. (2) Completion of an intervention delivery inventory to record the exact elements of the intervention delivered. (3) Participant questionnaires will record adherence with the intervention. (4) Qualitative interviews with trial participants will explore acceptability and how suggested changes are incorporated into everyday life; interviews with those delivering the intervention will explore their experiences and challenges of delivering SWV; interviews with service leads will explore current provision and incorporating trial findings into service development. _x000D_ _x000D_ PROJECT TIMETABLE AND RECRUITMENT: Project duration 36 months starting 01.02.20. Set up 01.02.20 to 31.07.20 (month 1-6); recruitment and randomisation July 2020 to July 2021 (months 6-18) randomisation will be 22 participants per week; follow up until the end July 2022 (months 19-30); analysis and report writing will be completed by January 2023 (months 31-36)._x000D_ _x000D_ DISSEMINATION: summary results to participants; academic publications; conference presentations; briefing documents",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,INJURIES AND ACCIDENTS HRCS22_18348,Versus Arthritis,,"Do non-steroidal anti-inflammatory drugs (NSAIDs) reduce the appearance of sacroiliac joint bone marrow oedema on MRI, in spondyloarthritis?","Active inflammation in the sacroiliac joints, observed on magnetic resonance imaging (MRI), is used increasingly in the diagnosis of axial spondyloarthritis. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of patients with spondyloarthritis. However, it is not known whether the MRI appearance of active inflammation in the sacroiliac joints is affected by NSAID use. We hypothesise that a significant proportion of patients with axial spondyloarthritis who, in the absence of NSAIDs exhibit evidence of bone marrow oedema consistent with active sacroiliitis would, in the presence of such medication, exhibit no such evidence of active sacroiliitis. We propose a non-randomised cross-over trial. Male HLA-B27+ patients with axial spondyloarthritis, recruited from rheumatology clinics, will be asked to undergo a one-week NSAID-free wash-out period, after which they will receive an MRI scan (baseline) of their sacroiliac joints. Participants will then re-start NSAID therapy, as per their usual care. Six weeks after re-starting therapy, those with a positive scan for sacroiliitis will receive another MRI scan (follow-up). We will determine the proportion of participants with MRI-observable sacroiliitis that resolves with NSAID use. The results of the proposed study will inform recommendations regarding medication use prior to MR imaging in spondyloarthritis.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_15372,Wellcome Trust,,Do psychedelic drugs have long-term implications for structural and behavioural plasticity in a mouse model?,"Plasticity describes changes at various levels of organisation of the nervous system which result from experience. It is hypothesized that psychedelic drugs can induce plasticity at cellular, structural and functional levels, aiding lasting remission from numerous neuropsychiatric disorders. They offer a unique opportunity to study heightened plasticity as a potential neural pre-requisite of behavioural flexibility. Using a mouse model, I aim to determine whether psychedelics induce long-term anatomical and behavioural plasticity changes and to determine if the context of drug administration affects the quality of on- and off-drug experience. Our approach will be a combination of (1) behavioural investigations of the quality of on-drug psychedelic experience under different contexts and of off-drug effects on cognitive flexibility, (2) longitudinal off-drug structural MRI imaging, and (3) in-vivo microelectrode array electrophysiology to understand single network function and information processing. These studies will elucidate whether the psychedelic-induced structural and functional changes persist after the acute intoxication phase and if they can help explain the lasting behavioural changes that have been observed in human studies.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;NEUROLOGICAL HRCS22_06418,Department of Health and Social Care,NIHR,Does a guided relaxation audio track increase yield of expressed milk and breastfeeding rates in mothers of very preterm infants? A small randomised controlled trial and nested exploratory work,"BackgroundComplications arising from premature birth are the leading cause of neonatal death in the UK and infants who survive have increased rates of disability. Very preterm infants can't feed orally and are fed through a tube directly into the stomach. Receiving the maximum amount of mother's own milk improves outcomes, including survival. Despite this, mothers of preterm infants are at risk of poor milk supply. A Cochrane review showed that there are few randomised controlled trials related to human milk expression for premature babies. Research Question 'In mothers of babies born at less than 32 weeks' gestation (Population), does use of a guided relaxation and visualisation audio track (Intervention), compared to standard care (Control), increase expressed milk volume, rate of human milk feeding and measures of maternal mental health (Outcomes)?' AimsThe primary aim is to increase the volume of human milk expressed by mothers of very preterm babies and improve long-term human milk feeding outcomes for these babies. Study OutlineThe study will be a small non-blinded randomised controlled trial. Mothers of one or more infants born at 23-31 weeks' gestation and intending to express breastmilk for at least seven days will be recruited. Participants will be randomised either to routine care or to listen to a 15-minute intervention soundtrack while expressing milk, for 21 days or as long as desired beyond this time. Mothers will fill out questionnaires and weigh all expressed milk in a 24-hour period, at 3-4 time points in the first few weeks of their baby's life, depending on how premature the infant is. There is then a simple two-question outcome measurement at 36 weeks' post-menstrual age (PMA) - this is about a month before the baby's due date and is often near the time of discharge from hospital. Participants recruited in the first 14.5 months will continue longer follow up by completing the same outcome measurement at 9 and 18 weeks after term (approximately 2 and 4 months after the due date, respectively). Primary outcomes are maximum 24-hour weight of expressed milk by day 21 and proportion exclusively human milk feeding at 36 weeks PMA. Secondary outcomes are proportion expressing at least 750ml milk in 24 hours by day 21; maternal anxiety and distress scores; milk weight expressed per minute at day 21; proportion with any human milk feeding at 36 weeks PMA and proportion with exclusive human milk feeding at 18 weeks after term. TimelinesTrial recruitment period is 19 months. The length of an individual participants' involvement will be between 26 and 35 weeks, dependent on prematurity of the infant. Anticipated Impact & DisseminationThis intervention has the potential to benefit hundreds of thousands of preterm babies and their families globally. It is easily distributed by downloading the soundtrack. Findings will be disseminated to academics, neonatal teams and parents via established academic and clinical pathways, social media messaging and existing parent information sources such as charity partners 'Bliss' and 'Best Beginnings'.","Babies who are born early (prematurely) are more likely to have serious health problems, which can affect them for the rest of their lives. Being born early is also the most common cause of death for babies in the UK. Parents are more likely to be anxious and depressed when their baby is born early. We know that giving breastmilk to premature babies is very important for their health, but this isn't always easy for mothers. Being anxious may make it more difficult to express breastmilk. This is a trial for women who gave birth very early - when they were less than 7 months pregnant. It aims to increase the amount of breastmilk mothers can express, which in turn will improve their chances of breastfeeding their babies when they go home. Babies who are born this premature can't breastfeed directly, instead they have milk put into their stomach through a tube. The ideal milk to give to premature babies is breastmilk. Breastmilk prevents serious gut illnesses, infections and eye problems, and builds babies' brains for their long-term development. Mothers are advised to express milk from their breasts, by hand or using a pump, to give to their very premature babies. However, it can be hard for mothers who give birth this early to express enough breastmilk for their baby, which might stop them from exclusively breastfeeding when their baby is strong enough. This trial will randomly allocate half the mothers to listen to a relaxation and visualisation soundtrack while expressing milk and half the mothers to normal care while expressing milk. The soundtrack will talk the mother through tensing and relaxing their muscles to make them feel more relaxed, and also picturing their baby and imagining their milk flowing. We want to see if listening to the soundtrack increases the amount of milk mothers can express in the first three weeks after birth. We want to see if the soundtrack will help more mothers to exclusively breastfeed around the time their baby goes home. We will also look at whether mothers listening to the soundtrack feel less anxious or distressed. If this kind of simple, easily downloadable soundtrack improves mothers' milk supply, makes them more likely to breastfeed their babies and decreases their anxiety, it could help thousands of families in the UK and many more across the world.The trial will be conducted by a team of experts with experience in looking after premature babies and doing this kind of research. More than 650 mothers of premature babies have already helped plan the trial. They told us that their major problem was not being able to express enough milk, which is why this is the central question we will look at. Along with some of these mothers, the national neonatal charity Bliss will be on the team of people running this study. This will make sure that the research is looking at questions that are important to families, that information given to families is easy to understand and that families are at the heart of getting the study results to those who need them. We plan to present the results of the study to health professionals at conferences and in scientific journals. We will work with children's charity Best Beginnings to make new parent-friendly postcards explaining how best to express milk for premature babies and we will make social media-friendly bitesize summaries of the results for families to share online.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_17301,Dunhill Medical Trust,,Does dose-controlled brain stimulation enhance motor rehabilitation in chronic stroke patients?,"Stroke is a leading cause of disability among older people. Around three quarters of stroke survivors are left with difficulties moving a limb, which has a profound effect on independence. The need to find effective treatments to promote recovery and independence after stroke is increasingly important, both because the number of older people in the population is increasing, and because more people are surviving stroke. In small studies, non-invasive brain stimulation, such as transcranial direct current stimulation, can promote rehabilitation after stroke(3,17–21), by enhancing motor learning(6,7,25–30). However the effects are variable and so tDCS has not yet made the transition to use in clinical practice(6,7). Some of this variability is likely due to individual differences in how much current enters the brain and where it goes(9). Recent work on current flow modelling has enabled the question of 'how much' and 'where' to be accurately estimated for the passage of electrical current into an individual's brain(8,31,32). In this project, we will use current flow modelling to create individualised, optimised tDCS interventions with higher reliability and efficacy than traditional approaches. Firstly, we will assess the validity of current flow models in chronic stroke patients using diffusion tensor magnetic resonance electrical impedance tomography (DT-MREIT), an MRI technique that measures the pattern of current flow through the brain(11,33,34). Current flow inside the healthy brain can be predicted with high precision using current flow models(35), however, there is currently no empirical data about how lesioned tissue may influence current flow. This insight into how such lesions might distort or alter current flow would be hugely beneficial for validating current flow models, and allowing the design of optimised, dose-controlled tDCS delivery in stroke patients. The second and third studies will compare the effects of optimised, dose-controlled tDCS with conventional tDCS application in chronic stroke patients. We will quantify how optimisation increases overall beneficial effects, and reduces inter- and intra-individual variability, in physiological (study-2) and motor learning (study-3) measures. In study 2 we will examine the neurophysiological changes induced by tDCS to primary motor (M1) and sensory cortices (S1), thought to be associated with positive rehabilitation outcomes(36). Study 3 will assess the effects of tDCS protocol on upper-limb motor learning, a key process for recovery of motor function. This will provide crucial insight into how the application of tDCS can be made more effective in patient populations such as stroke.","Recent research has shown the benefit of combining physiotherapy with a form of non-invasive brain stimulation known as transcranial direct current stimulation, or tDCS. This technique involves placing two electrodes on the participants’ scalp and passing a small, barely perceptible electric current through the brain. Patients who are given tDCS while undergoing rehabilitation tend to show greater improvements in movement control than those who do not. However the effects of tDCS can be very different across individuals. This is likely due to differences in the shape of individuals' head causing variations in how much current actually enters the brain and where this current actually flows. These differences are even greater in individuals with stroke, as the damaged brain tissue can distort the path of current flow. In other words, there is currently no established and validated way to control the effective dose of the treatment. However, the amount of current, and the path it takes through an individual's brain, can be estimated using a technique known as current flow modelling. In this set of studies we plan to investigate how adjusting tDCS settings on the basis of individual differences in current flow can enhance the beneficial effects of tDCS on upper-limb stroke rehabilitation. We will use a novel MRI technique, called diffusion tensor magnetic resonance electrical impedance tomography (DT-MREIT) that can measure the actual flow of current though the brain of chronic stroke survivors with tDCS. We will use this to assess the accuracy of our current flow models applied to stroke patients with different lesion locations and sizes. This is an essential requirement for delivering precise stimulation to an individual's brain. We will then create optimised tDCS treatments where the amount of current entering the brain, and which parts of the brain it affects, are the same in all patients. In our subsequent studies we will assess whether our optimised tDCS treatments results in less variability, and greater positive effects on motor rehabilitation and measures of brain activity. We predict that tDCS optimised for each individual will enable it to have a positive effect in all stroke patients. This work will provide crucial validation that tDCS can be made more effective in patient populations suffering from age related diseases such as stroke.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,STROKE;NEUROLOGICAL HRCS22_14500,The Scar Free Foundation,,"Does major trauma accelerate the ageing process and can it be alleviated by physical activity?","Major trauma survivors have a 5-year increased risk of death compared to the general population. These patients are also at increased risk of developing other age-related diseases such as dementia earlier than non-injured counterparts, suggesting that they may be ageing faster. Until recently there has been no reliable biomarker for a person’s biological versus their chronological age, but Horvath has reported a DNA methylation profile, termed the epigenetic clock, that showed a very strong association with chronological age, with deviations from this association indicative of the degree of biological ageing. There are also proteomic biomarkers being developed that give an indication of an individuals ageing trajectory and risk of future age-related disease, for example the Somascan proteomic platform. Furthermore, our own studies show that physical activity can help to reduce the ageing trajectory, benefitting several body systems. Aims and Hypothesis: We hypothesise that major trauma victims will show evidence of accelerated age-specific DNA methylation. In addition, that those subjects who have engaged in regular physical activity will show a lower impact of trauma on their biological age. Methods: The ADVANCE cohort of military trauma survivors, plus matched uninjured veterans represent an ideal cohort to test the hypothesis. They are all male and young thus reducing potential variance in data. In addition their thorough check-ups at Stanford Hall provide data for their level of involvement in physical activity/exercise. We will use stored blood samples (whole frozen EDTA blood, or blood spots), to measure DNA methylation using the Illumina Human Methylation EPIC array and calculate the DNA methylation age of injured and uninjured veterans. Serum will also be analysed for protein markers of accelerated ageing, using the Somascan platform. Data on physical fitness (6 min walk test, Chester step count, military multistage fitness test) will be used to divide the cohort in to those in the top quartile and those in the lower quartile in order to assess potential impact of physical activity on DNA methylation age. We aim to gain sufficient pilot data to apply for further funding from funders such as the MRC or Wellcome Trust by analysing 100 military and 50 healthy subject samples.","Until recently there has been no way of measuring how fast someone was ageing but now a test is available that uses blood cells to determine how biologically old a person is. Survivors of a major injury, such as that experienced in conflict by the military or a road traffic accident in civilian life, have shortened lifespans. They also develop age-related diseases such as heart disease, diabetes and dementia earlier than non-injured adults. This suggests that because of their injuries they may be ageing faster. In this study we aim to measure biological age in a large group (150) of military veterans from the Afghanistan conflict, assessing 100 who were injured and 50 who were not.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,GENERIC HEALTH RELEVANCE;INJURIES AND ACCIDENTS HRCS22_03108,Medical Research Council,MRC,Does maternal immunity to SARS-CoV-2 protect against SARS-CoV-2 infection in infants under 12 months old in Scotland?,"We will test the hypothesis that maternal SARS-CoV-2 immunity is associated with protection against SARS-CoV-2 infection in infants under 12 months old. We will undertake two case-control studies. Study 1 will compare infants born in Scotland 1/8/21-31/7/22 with PCR-confirmed SARS-Cov-2 infection in the first year of life to infants without SARS-CoV-2 infection in the first year of life, matched 1:4 by date of birth, to determine: a) the odds of maternal COVID-19 vaccination prior to delivery b) the odds of maternal vaccination prior to pregnancy versus vaccination during pregnancy versus no vaccination c) the odds of maternal SARS-CoV-2 infection prior to delivery d) the odds of maternal SARS-CoV-2 infection prior to pregnancy, versus SARS-CoV-2 infection during pregnancy, versus no infection e) the odds of maternal SARS-CoV-2 infection during the first year after delivery. Study 2 will compare similar cases/controls, but limited to Greater Glasgow & Clyde and matched 1:2 by date of birth, to determine: a) the odds of maternal SARS-CoV-2 IgG seropositivity during pregnancy b) the odds of detectable SARS-CoV-2 neutralising antibodies during pregnancy c) the odds associated with maternal SARS-CoV-2 IgG concentration. Case/controls and linked maternal data will be identified from routinely collected NHS and national records data. Data on confounding factors will include infant sex, gestation, maternal age, ethnicity, and deprivation index. In study 2, excess blood from antenatal screening will be used to undertake SARS-CoV-2 IgG MSD-ECL assay and neutralisation assays. Using conditional logistic regression, a multivariable model will be created to explore the interactions between maternal SARS-CoV-2 infection/immunity/COVID-19 vaccination, and other demographic/socio-economic predictors of infant SARS-CoV-2 infection. Data will be linked and pseudo-anonymised within NHS Safe Haven. Use of unconsented data will be approved by ethics/privacy committees.",,3.4 VACCINES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION,INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_23273,The Health Foundation,THF,Does place matter? An examination of geographical inequalities in COVID-19 in England,"Early in the COVID-19 pandemic, the perception was that ‘we are all in this together’ and that the virus ‘does not discriminate’. However, government data has since highlighted that deaths from COVID-19 are almost double in poorer communities and higher in places with larger black, Asian and minority ethnic populations. This has led to concerns that not everyone is experiencing COVID-19 in the same way. But we do not know enough about why or how this might change over time. In this project, a team from Newcastle University will use several sources of data to understand how the COVID-19 pandemic has developed over time in different types of places and communities. The project team will use information on virus cases and deaths in each area to understand how these are impacted by living and working conditions, housing, employment and access to services and leisure facilities, for example. This work will help to uncover how and why some communities are affected more than others by COVID-19, and to identify which ones are more at risk from future waves and other pandemics. This will also help staff in public health, social care and the NHS provide better support to high-risk communities. The results of this work will be published on a website that will use maps to show differences in the pandemic across the country. The results of the research will help with local NHS and public health planning, as well as in policy development, media and parliamentary debates.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",GENERIC HEALTH RELEVANCE;INFECTION HRCS22_02008,Medical Research Council,MRC,"Does the central noradrenergic system play a role in agitation in Alzheimer's disease?","BACKGROUND: The locus coeruleus (LC), the major source of the brain's noradrenaline (NA), undergoes early neurodegeneration in Alzheimer's disease (AD). The LC upregulates arousal in response to stress via connections with the amygdala and prefrontal cortex to perform emotion regulation and response inhibition. Agitation in dementia (defined as emotional distress associated with motor overactivity, verbal or physical aggression) is distressing, common and difficult to treat. My systematic review on the neurochemistry of agitation in AD found the strongest evidence for compensatory postsynaptic overactivity secondary to LC neuron loss. LC signal intensity, a valid indicator of LC integrity, can be measured using magnetic resonance imaging (MRI) in vivo. KEY GOALS: To investigate whether the central NA system plays a role in agitation in AD, the study will ask: 1) Is lower structural LC integrity in early AD associated with agitation? 2) Is agitation associated with deficits in emotion dysregulation (increased sensitivity and reactivity to threat) and poor response inhibition, and does this explain any association between LC integrity and agitation? 3) Does propranolol (a centrally active beta-blocker) modulate emotion dysregulation and response inhibition in patients with AD and healthy older adults? METHODOLOGY: The study will recruit 50 patients with mild-moderate AD and 50 healthy older controls. The AD group will undergo MRI to assess LC structural integrity and LC-amygdala coupling during perceived threat. The AD and control group will complete behavioural tests and receive a single 40mg dose of propranolol to assess the effect of NA blockade on cognition (sensitivity to perceived threat, inhibitory emotional control and motor response inhibition). OPPORTUNITIES: This study could inform new biomarkers to identify/stratify individuals with AD prone to agitation and lead to new therapies (e.g. beta-blockers) for study in future clinical trials.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_04245,Department of Health and Social Care,NIHR,Donor Health and Behaviour,"Donated blood is a crucial resource for healthcare systems, enabling blood transfusions that save millions of lives every year around the world. But the evidence needed to improve the safety and efficiency of blood donation is weak and underdeveloped, risking harm and waste. The current Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics, led by Professor Emanuele Di Angelantonio, has shown ways to improve blood donor health and ensure a steady supply of blood to the NHS. Professor Di Angelantonio s new BTRU, in Donor Health and Behaviour, will build on this foundation. Working with colleagues at the Universities of Cambridge, Oxford and Nottingham and NHS Blood and Transplant (NHSBT), the proposed BTRU will conduct research to address major challenges identified by NHSBT, such as: Understanding why people do, and don t, donate blood Finding ways to encourage a more ethnically diverse range of people to donate blood Understanding the impact of new approaches, such as asking specific people to donate blood instead of the current system which encourages everyone to donate Using information technology tools to improve communications within NHSBT Promoting safe and effective donation practices Identifying risks of adverse health effects of blood donation (e.g., fainting, iron) and evaluating measures to prevent these Developing new methods for recruiting and retaining donors These objectives will be addressed by: (i) large-scale online surveys, (ii) interviews and focus groups within ethnically diverse communities, (iii) analyses of available large-scale datasets, (iv) designing new and innovative clinical trials and (v) gathering data on donor biological characteristics. We will work with blood service staff, blood donors, patients, members of the public and policy-makers to ensure that the impact of our work is relevant, acceptable, available and understandable to the general public, and that national and international blood services are aware of the research to support policy and practices. The two main achievements of the BTRU are to produce (i) results and scientific resources that inform NHSBT policy and practice and (ii) direct advice to NHSBT and donors.","Donated blood is a crucial resource for healthcare systems, enabling blood transfusions that save millions of lives every year around the world. But the evidence needed to improve the safety and efficiency of blood donation is weak and underdeveloped, risking harm and waste. The current Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics, led by Professor Emanuele Di Angelantonio, has shown ways to improve blood donor health and ensure a steady supply of blood to the NHS. Professor Di Angelantonio s new BTRU, in Donor Health and Behaviour, will build on this foundation. Working with colleagues at the Universities of Cambridge, Oxford and Nottingham and NHS Blood and Transplant (NHSBT), the proposed BTRU will conduct research to address major challenges identified by NHSBT, such as: Understanding why people do, and don t, donate blood Finding ways to encourage a more ethnically diverse range of people to donate blood Understanding the impact of new approaches, such as asking specific people to donate blood instead of the current system which encourages everyone to donate Using information technology tools to improve communications within NHSBT Promoting safe and effective donation practices Identifying risks of adverse health effects of blood donation (e.g., fainting, iron) and evaluating measures to prevent these Developing new methods for recruiting and retaining donors These objectives will be addressed by: (i) large-scale online surveys, (ii) interviews and focus groups within ethnically diverse communities, (iii) analyses of available large-scale datasets, (iv) designing new and innovative clinical trials and (v) gathering data on donor biological characteristics. We will work with blood service staff, blood donors, patients, members of the public and policy-makers to ensure that the impact of our work is relevant, acceptable, available and understandable to the general public, and that national and international blood services are aware of the research to support policy and practices. The two main achievements of the BTRU are to produce (i) results and scientific resources that inform NHSBT policy and practice and (ii) direct advice to NHSBT and donors.",4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT),BLOOD HRCS22_23155,The British Academy,,Double Trouble: The effect of violent conflict on the abuse and misuse of prescription and non-prescription medicine in the MENA region,"Violent conflict has a profound and detrimental effect on public health when civilians are injured, diseases spread and health infrastructures collapse. This project builds upon previous collaboration between the applicants to investigate an often neglected aspect of public health during conflicts: the impact of violent conflict on the abuse and misuse of prescription and non-prescription medicines ('drugs') amongst local populations. It combines Conflict Studies and Medical Sociology to understand the impact of different forms of violent conflict on patterns and levels of drug abuse/misuse in four MENA region countries: Iraq, Libya, the Syrian Arab Republic and Yemen. The study uses a quantitative survey and semi-structured interviews with community pharmacists to gather data about pharmacists' experiences, perceptions and responses to drug abuse/misuse in conflict societies. The results and recommendations for more effective identification and management will be disseminated to non-academic user audiences in the public health infrastructure of the countries involved.",,7.1 INDIVIDUAL CARE NEEDS,MENTAL HEALTH;DISPUTED AETIOLOGY AND OTHER HRCS22_22215,"National Centre for the Replacement, Refinement and Reduction of Animals in Research",NC3Rs,Drosophila based screening to replace mammalian systems to identify the functional role of candidate genes in controlling muscle dyadic architecture,"Scientific and clinical background: Diseases of the heart (cardiomyopathies) remain a leading cause of morbidity and mortality for which additional treatment strategies are needed. An emerging and consistent finding across a range of cardiomyopathies is that there is ultrastructural remodelling in cardiac myocytes consisting of loss and disorganisation of surface membrane structures known as transverse (t-) tubules. This loss of t-tubules is a key causal factor of perturbed cellular calcium homeostasis which contributes to the two leading causes of morbidity and mortality; contractile failure and arrhythmias. Importantly the t-tubule network is highly plastic and it can be restored, albeit in a disordered manner, following some therapeutic interventions and this is associated with improved cardiac function. However, the factors (genes) that control the formation and organisation of the t-tubule network and consequently impact on dyadic architecture and cellular calcium homeostasis are very poorly understood and are not advanced rapidly with traditional animal-based experimental methodologies. Scientific aims: This PhD seeks to use a novel to the field, albeit proven, interdisciplinary approach to identify genes that regulate the t-tubule network. We will achieve this by combining bioinformatic methodology, functional and ultrastructural assessments using the Drosophila somatic muscle paradigm and validation in human induced pluripotent stem cell derived cardiac myocytes (hiPSC-CMs). The Drosophila somatic muscle paradigm is a powerful tool in this context as the somatic muscles of Drosophila share structural and functional homology with mammalian cardiac muscle. Additionally, Drosophila shares considerable genetic homology with humans and what little we understand already about mammalian cardiac t-tubule regulators was founded on work originally performed in Drosophila. These factors, in combination with the available powerful Drosophila genetic tools, enable a rapid screen with functional and structural assessment of putative t-tubule regulatory genes. 3Rs aims: The programme of work principally provides a Replacement strategy whereby the model organism Drosophila melanogaster is used as a rapid and comprehensive screening tool to evaluate a bioinformatically informed panel of candidate genes for their t-tubule regulatory role. Notably, in addition to identifying which genes have t-tubule regulatory roles, the functional and ultrastructural methodology that we will employ will also provide additional information on the role of these genes in controlling dyadic structure and function. Using the proposed strategy, we anticipate that over the course of five-years, our own group will completely replace the need to use ~ 1,000 mice for the generation conditionally targeted allele founders. Additionally, based on conservative criteria and a sample of published work using genetically altered mice to study t-tubules in the heart, our approach has the potential to replace the use of several thousand mice each year worldwide. 3Rs legacy: Two key determinants leading to a long-lasting legacy from our proposed approach are demonstration of feasibility and wider applicability and training in the methodology. That Drosophila is suited to addressing a wider array of clinically or scientifically driven questions is undeniably supported by the high degree of conservation between the human and Drosophila protein coding genomes and that the vast majority of human disease-causing genes have Drosophila homologs. In addition to fully open access sharing of the interdisciplinary methodology that we develop, we have an extensive track record in providing tailored training in Drosophila techniques that we will lever to promote widespread adoption of the use of Drosophila across a broad portfolio of research disciplines locally, nationally and internationally via engagement workshops, conferences and engagement events.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MUSCULOSKELETAL HRCS22_05590,Department of Health and Social Care,NIHR,Drowning Prevention for newly mobile infants under 2 years in Bangladesh,"Research question How can the risk of drowning be reduced in newly mobile children under 2 years in Bangladesh? Background In Bangladesh, drowning is the leading cause of death in children over 1 year, with the highest rates of drowning deaths found in 1-4-year olds. Newly mobile children are at particularly high risk. Unfortunately, existing interventions to prevent drowning have been shown to be unsuitable for children under 2 years. Barriers to prevent children accessing water have design and uptake challenges, and daycare models to provide increased supervision have poor attendance/adherence within this age range. Aims and Objectives Our aim is to develop a sustainable and scalable intervention to reduce the burden of drowning for newly mobile children under 2 years in Bangladesh. To achieve this, the study will generate qualitative and quantitative data to explore, formulate, design and test solutions that remove or mitigate the challenges faced by caregivers to protect and supervise their youngest children from drowning. Methods This multi-phase community-based study will be conducted across two sub-districts of Bangladesh; Kalapara in the south, and Sherpur Sadar in north. The study will follow the six sequential steps to intervention development, outlined by the Quality Intervention Development (6SQuID) framework. We will use Human Centred Design (HCD) processes to engage with key stakeholders, to inform our understanding of the problem and co-design suitable interventions with communities. This four-year study comprises six phases: Planning and capacity building (3 months) - to develop the capacity of study collaborators in HCD processes. Explorative social science and context analysis (12 months) - We will take a mixed methods approach, utilising qualitative data methods including focus group discussion, key informant interviews, risk mapping and observational studies. We will also technically assess existing interventions against ISO standards, and engage with end-users to understand design and implementation challenges. Identifying and prioritising possible solutions (3 months) - Communities will be involved in the development of design concepts which will be prioritised based on expected feasibility, effectiveness, cost and acceptability. Prototype development (9 months) - An iterative approach will be taken to design the final intervention for piloting, by building, testing, and re-designing prototypes based on experiential learning. Piloting and evaluation (15 months) - We will evaluate the acceptability, fidelity and sustainability of the interventions using the RE-AIM framework. Dissemination and ensuring sustainability (6 months) - Findings will be shared with communities, national stakeholders and international communities of practice, and used to inform national drowning prevention policy and programmes. Anticipated Impact We anticipate that interventions developed in this study will reduce drowning risk for children under 2 years in rural Bangladesh. Findings will inform the ongoing development of a national drowning prevention programme coordinated by the Ministry of Women and Children's Affairs (MoWCA), and the national drowning prevention strategy. Findings will also be fed into global and regional best practice, through the World Health Organization drowning prevention guideline development group. Project partners are already actively involved in these fora.","Globally, drowning is a major cause of injury and death and Bangladesh has one of the highest rates of drowning in the world, especially among children. Drowning is the leading cause of child deaths for 1-17 year olds. Over the past 15 years, CIPRB has researched and implemented several effective drowning prevention solutions focussed on children. Daily exposure to water represents a real drowning risk in Bangladesh, especially for rural preschool children. The risk of drowning in rural areas is twice that of cities due to high levels of poverty and easy access to water bodies. Our intervention areas have significant numbers of ponds and ditches - natural drowning hazards for children aged 1-5 years - that drive drowning rates even higher. One project area (Kalapara) has one of the country s highest rates of drowning. Caregivers have the constant challenge of providing supervision to small children whilst also working, preparing food, or undertaking household chores. This means that toddlers are often cared for by other young siblings. CIPRB has developed a successful community daycare model that reduces drowning rates in preschool aged children. However, our analysis shows that families are reluctant to allow children under 2 years (=highest risk group) to attend daycare. We have planned an interdisciplinary project with six key phases to identify and test better ways to prevent newly mobile infants under 2 years old from drowning. We will work with communities in the north and south of Bangladesh to (1) build the skills needed by communities and our research partners to carry southout this research in rural Bangladesh; (2) understand the challenges of keeping under 2s safe from drowning; (3) identify and prioritise possible solutions; (4) prototype solutions with designers and community members; (5) trial the best solutions in communities and evaluate them on use and maintenance, effectiveness, and ability to roll out the interventions across Bangladesh; and (6) share the findings and make sure that the value of the solutions is not lost when the research project ends. By working with communities in two distinct areas of in the north and south of Bangladesh, we will better understand how to roll out successful interventions for different circumstances and environments. Using an inclusive, human-centred design approach, we aim to identify the solutions that are most acceptable to communities, whose input will be central to the whole process. We anticipate the findings from this research will inform a national drowning prevention programme run by Bangladesh s Ministry of Women & Children s Affairs, and other non-governmental policy and programme areas. In addition, findings will be relevant to preventing child drowning in other South-East Asian countries, where over 30% of global drowning deaths occur.",7.1 INDIVIDUAL CARE NEEDS,INJURIES AND ACCIDENTS HRCS22_02404,Medical Research Council,MRC,Dynamic Imaging in Viral Encephalitis Defines Unique Roles for Chemoattractants.,"BACKGROUND Herpes simplex virus (HSV) encephalitis is a devastating disease of brain inflammation characterised by blood-brain barrier (BBB) breakdown and leucocyte migration, particularly early neutrophils, forming perivascular 'cuffs'. No immune therapy is established therefore 10-30% die and most survivors have neurological morbidity. Targeted therapy which mitigates deleterious leucocyte migration and BBB breakdown is desperately required. Leucocytes migration is determined by chemokines, but increasingly atypical chemoattractant proteins/receptors are recognised. However, their role in neutrophil migration and behaviour in the brain, such as the production of neutrophil-extracellular traps (NETs), are not known. Together the Co-PIs have the individual techniques to image this in real time by Multiphoton Intravital Microscopy (MP-IVM). AIM Determine the relative contribution of typical/atypical chemoattractants on neutrophil migration into the brain and the behaviour driving BBB breakdown. SPECIFIC AIMS 1. Establish specific neutrophil migration behaviours which are associated with BBB breakdown in a murine model of HSV encephalitis. 2. Determine the contribution of typical/atypical chemoattractant receptor/ligand interactions driving this behaviour. 3. Interrogate the differential production of NETs and associated processes in BBB breakdown METHODS 1. In an intrathecal murine model of HSV inoculation, neutrophil migration and BBB breakdown will be imaged by MP-IVM in LysM-Green Fluorescent mice. Typical/atypical chemoattractant expression will be determined by RT-Polymerase Chain Reaction and confirmed by Enzyme-Linked Immunosorbant Assay. 2. Candidate chemoattractants in knock-out or antibody-treated mice will be interrogated by MP-IVM in relation to neutrophil migration and BBB breakdown 3. NETs will be imaged by MP-IVM and single-cell RNAseq of transmigrated neutrophils will explore associated processes in the UK Co-PI's BBB model",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_20587,Wellcome Trust,,Dynamic Structural Biology: New Tools and Strategies for General Applications,"X-ray crystallography and cryo-EM are essential tools for structural biologists, but these data are almost always from samples held at 100 K. Life is dynamic and function is not compatible with the cryogenic conditions. X-ray Free Electron Lasers (XFELs) offer new opportunities because their unparalleled intensity reduces the crystal size requirements such that even submicron size crystals yield high quality structures.1-3 The fs pulse provides extraordinary temporal resolution and data without radiation-induced alterations.4-9 XFELs are motivating new serial data collection methods at room temperature.10-13 Synchrotron beamlines like Diamond’s VMXi with high-flux, micro-focus, and fast detector are also pushing serial methods that complement XFELs. What is critically missing are tools to manipulate microcrystal samples and to correlate enzyme kinetics, spectroscopy, and time-resolved structural biology. Therefore, the specific aims of this proposal are to i) extend and generalize experimental methods in enzyme kinetics to microcrystalline samples, and ii) and iii) to develop time-resolved structural biology in general at XFELs (ii) and at synchrotrons (iii). In particular, we will correlate room-temperature, serial crystallographic and spectroscopic data to determine the electronic and atomic structures of metalloenzymes engaged in catalysis. Some of our enzymes create Fe(IV)=O intermediates, whereas beta-lactamases are responsible for antimicrobial resistance.","To capture atomic resolution ""movies"" of macromolecules engaged in function has been a grand challenge in structural biology since Nobel laureate Max Perutz attempted to measure the structural impact of O2 binding to hemoglobin crystals. His large crystals cracked when he tested this function because it triggered significant conformational dynamics. We are currently experiencing a step-change in time-resolved functional studies linked to serial femtosecond crystallography. This room temperature technique exploits micron-size crystals and fs pulses from X-ray Free Electron Lasers (XFELs, new sources that are 9-orders of magnitude brighter than synchrotrons like Diamond Light Source). We will will correlate room-temperature, serial crystallographic and spectroscopic data to determine the time-resolved electronic and atomic structures of metalloenzymes engaged in catalysis. Both types of data come from the same sample and X-ray pulse. Some of our target enzymes use O2 to create reactive Fe(IV)=O intermediates, whereas beta-lactamases are responsible for antimicrobial resistance.",1.3 CHEMICAL AND PHYSICAL SCIENCES;1.4 METHODOLOGIES AND MEASUREMENTS,GENERIC HEALTH RELEVANCE HRCS22_03267,Medical Research Council,MRC,Dynamic integration of ingestive behaviours and homeostasis by hypothalamo-neurohypophysial system glucagon like peptide 1 receptors,"This proposal aims to characterise the exact physiological roles of gut peptide receptor GLP-1R in the hypothalamo-neurohypophysial system (HNS) of female and male rats. We will use adeno-associated viruses (AAVs) delivered by stereotaxic surgery to the rat brain. The AAV retrograde capsid variant, AAV2-retro, enables retrograde access to projection neurones including nucleus tractus solitarius (NTS) to supraoptic nucleus (SON) projections. We will firstly determine the neuropeptide identities of retrograde labelled NTS neurones projecting to the SON by RNAscope. We will inject AAV2-retro-Cre into the SON which will retrogradely trace back to mark NTS connecting neurones. We will deliver a separate Cre-dependent AAV directly to the NTS in the same surgery, for example, AAV FLEx system shRNA targeting the preproglucagon mRNA. In all studies we will investigate, feeding and drinking, hormone release, and cell signalling pathways. We will knockdown SON Glprs using AAV-shRNAs and investigate postprandial responses in a fasting-refed rats as well as schedule-fed rats to identify effects on feeding circuits. We will use state-of-the-art biosensor cells to precisely monitor the real-time release of vasopressin and oxytocin in SON and posterior pituitary explant cultures maintained in a dish. We will investigate the short-term and longer-term consequences of daily liraglutide treatment on the rat SON and pituitary gland by exploring proteome-wide phosphorylation changes by phosphoproteomics. We further plan to recruit healthy human volunteers (male and female) as part of a randomized crossover trial to determine the short-term actions of liraglutide on HNS hormone release. This project will inform about how the HNS integrates responses from food and fluid intake to maintain homeostasis. These data may help with design and development of new drugs for more targeted methods of activating receptors at specific sites, and thus influence therapeutic strategies.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_03824,Medical Research Council,MRC,Dynamic regulation of human immunity by Interferon Regulatory Factor 8 (IRF8),"Human immunity critically depends upon the coordinated production of functionally specialised cells by haematopoiesis, under the control of lineage-specific transcription factors (TFs). Rapid adaptation of haematopoiesis is required to meet the demands of immunity, especially in the production of innate myeloid cells; neutrophils, monocytes and dendritic cells (DCs). Interferon regulatory factor 8 (IRF8) is a pioneer TF for myeloid cells and critical lineage-determining TF for DCs. IRF8 plays a pivotal role in demand adaptation as illustrated by predominant granulopoiesis and monocyte/DC depletion in IRF8 deficiency, the association of IRF8 variants with blood parameters and immune diseases, and suppression of IRF8 in sepsis and cancer. In Aim 1 I will use single cell multiomic genetic and epigenetic approaches to achieve an integrated analysis of the chromatin architecture of the IRF8 locus, genome-wide chromatin occupancy by IRF8 and associated regulatory networks, mapped in developmental time and across myeloid cell lineages. Extending these approaches to Aim 2, I will determine the changes in IRF8 expression, chromatin occupancy and enhancer activation driving abnormal haematopoiesis in patients with sepsis and breast cancer. This will identify regulatory networks and mechanisms that are modified by disease. In Aim 3, I will define the effects of rare, loss-of-function mutations in IRF8 on downstream activities and analyse protein structure-function relationships as potential therapeutic targets. Finally in Aim 4, I will determine the effect of variations in regulatory regions on the lineage-specific and dynamic expression of IRF8 by eQTL analysis to fine-map the architecture of IRF8 regulation. Together these approaches will define the dynamic role and regulatory mechanisms of IRF8 in immune cell haematopoiesis with the ultimate goal of targeting IRF8 to manipulate immune responses for therapeutic gain.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_05706,Department of Health and Social Care,NIHR,E-PLAYS-2 (Enhancing Pragmatic Language skills for Young children with Social communication impairment) trial; evaluation of a computerised intervention to promote communicative development and collaborative skills in children,"Many children experience difficulties with social communication (also known as pragmatic language ability); that is, the use of language for social purposes. These children struggle with conversational tasks such as appropriate use of greetings, conversational turn-taking, understanding of non-literal language such as jokes, irony or sarcasm, social conventions like politeness, taking the perspective of the other person and responding with relevant information. These difficulties have profound effects on children’s social development, mental health, and education and are strongly associated with bullying, isolation and school exclusion. There is a lack of available interventions for such children. _x000D_ We have developed E-PLAYS (‘Enhancing Pragmatic Language skills for Young children with Social communication difficulties’) a fun computer game for children 5-7 years-old with social communication difficulties. It is played by children in pairs. Games designers, teachers, speech and language therapists and children helped us to develop E-PLAYS, and young people with communication difficulties gave feedback._x000D_ _x000D_ Previous studies by our team showed that children receiving E-PLAYS scored better on language tests, used more appropriate verbal communication and showed more enjoyment of social interaction than a similar group of children who didn’t receive E-PLAYS. These studies also showed that enough children agreed to take part, that schools' teaching assistants could deliver the E-PLAYS programme faithfully to the manual and that teaching assistants and children rated the game as fun and enjoyable. _x000D_ _x000D_ Our two previous studies were run with small numbers. We now want to run a large trial with 504 children. We want to follow these children up to find out whether E-PLAYS delivered by teaching assistants in schools is effective and whether it is good value for money. We will ask schools to take part in the study and will measure children's language skills before and after they have used E-PLAYS for 10 weeks with their teaching assistants and a partner child from their class. Their teachers will observe classroom behaviours to see if they notice any differences. We will observe and interview children to see whether they like using E-PLAYS. We will also observe and interview teaching assistants and ask them to complete a survey and take part in a focus group to see how they use E-PLAYS, if it fits well into their school day, if they feel confident with it and if they think the instructions are clear._x000D_ _x000D_ If we show that E-PLAYS is effective for children with social communication difficulties, we will make it available, together with an online manual, to all schools in the UK. Against a backdrop in 2020 where children’s socialisation with peers, communication skills and peer relations have suffered and the most deprived individuals have been hit the hardest, E-PLAYS aims to develop children’s social and collaborative skills by making novel use of technology. It is likely to be welcomed by schools, parents and children.","BACKGROUND_x000D_ A number of children experience difficulties with social communication (also known as pragmatic language ability). These difficulties can include initiating conversation and responding appropriately, problems with varying communication to match the context or listeners' needs, recounting a coherent narrative and understanding non-literal language. Whilst such children may have adequate or even advanced vocabulary and grammar, they can struggle with everyday conversational tasks. There is a lack of evidence-based, cost-effective interventions for children with social communication difficulties; in fact, language therapies as a whole have attracted little research funding. Language disorders remain little known by the public and under-researched by comparison to conditions with similar prevalence and impact, such as ADHD, childhood obesity and dyslexia. Furthermore, the limited take up of technology in this field is widely regarded as a missed opportunity. We therefore plan to conduct a study to evaluate the effectiveness of a digital intervention for children with social communication difficulties. _x000D_ INTERVENTION_x000D_ The E-PLAYS (Enhancing Pragmatic Language skills for Young children with Social communication difficulties) intervention is a novel technology in the form of a fun computer game. E-PLAYS is played by children in pairs and comprises 10 weekly sessions of 30 minutes each, supervised by a teaching assistant. E-PLAYS will be delivered in special and mainstream primary schools in the UK. This study builds on a previous pilot study and feasibility trial (E-PLAYS-1). The pilot study showed some indication of efficacy with regard to language improvement; the feasibility trial showed acceptable recruitment and response rates._x000D_ OBJECTIVES_x000D_ The primary objective is to examine the impact of E-PLAYS on children’s social communication skills within a school setting. Secondary objectives are to investigate the effect of E-PLAYS on classroom behaviour and peer relations. _x000D_ DESIGN_x000D_ A two-arm pragmatic cluster-randomised controlled trial, with allocation at the school level, with an internal trial, comparing care as usual plus E-PLAYS with a control group receiving care as usual, outcomes up to 40 weeks, in primary schools. The trial will include embedded economic and process evaluations._x000D_ PARTICIPANTS_x000D_ We will recruit 84 schools and 504 children aged 5-7 years-old who will be selected by teachers using the Social communication Questionnaire. _x000D_ OUTCOME MEASURES: _x000D_ The primary outcome will be a measure of pragmatic language ability as assessed using the Test of Pragmatic Skill by blinded research assistants. Secondary outcome measures, also administered by blinded research assistants, include measures of narrative production, perspective-taking and recall. Other secondary measures of communication, classroom behaviour and peer relations will be provided by teachers. Parents will provide data on quality of life and resource use to inform the economic evaluation. _x000D_ Interviews, observations and focus groups will establish teaching assistants' views on training and E-PLAYS’ ease of use. _x000D_ IMPACT_x000D_ We will definitively test E-PLAYS and plan for implementation, if effective. One of the strengths of this study is that E-PLAYS could be rolled out nationally immediately and at no charge. Dissemination will take place through practitioner networks, social media and public engagement events as well as academic outputs.",6.7 PHYSICAL,MENTAL HEALTH HRCS22_11679,Economic and Social Research Council,ESRC,ESRC Postdoctoral Fellowship 2020 - Electronic cigarettes: role in smoking cessation and potential risks for children and young people,"My five specific objectives for the fellowship are to: 1. Publish two additional papers containing further findings from my PhD, one based on my survey data from 2,000 smokers and one using my 46 qualitative interviews with smokers and local stop smoking service (SSS) staff. 2. Take forward a practical implication arising from my PhD by working with colleagues from PHE, ASH and NCSCT to target my relevant findings at key SSS and local authority audiences. 3. Undertake focused, structured training in statistics (LSHTM's 'Statistical Methods in Epidemiology' and 'Advanced Statistical Methods in Epidemiology' modules and UCL's 'Meta-analyses with R' short course) to further cement my quantitative capabilities, and in clinical leadership skills (the Kings Fund's 'Emerging Clinical Leaders' course), to help me create my own research team in the coming years. 4. Build a network of international collaborators to increase my impact and independence as a postdoctoral researcher through mentoring by Professor Martin McKee - who is undoubtedly one of the most effective and prolific creators of collaborations in my field - and through attendance at the two foremost international conferences for tobacco research (the World Conference on Tobacco or Health and the Society for Research on Nicotine & Tobacco Annual Meeting). 5. Develop funding applications, building on my PhD research, to expand my future focus to include the potentially 'game-changing' impact of Juul's recent arrival into the UK e-cigarette marketplace, given this company's products have been shown to be the primary cause of the adolescent 'vaping epidemic' experienced in the United States. This future research would explore the ways in which Juul and other key e-cigarette products are influencing adolescent smoking and vaping habits within England, including whether this varies between youngsters from different sociodemographic backgrounds. Specifically, I aim to apply for an ESRC New Investigator Grant and an NIHR Advanced Fellowship.","My PhD investigated why e-cigarettes have proved to hold such a broad appeal across society, and whether this could be at the cost of smokers using more effective ways to try to quit tobacco. E-cigarettes are now by far the most common choice of quit route for smokers who do not wish to simply go 'cold turkey' when trying to end their addiction to conventional tobacco cigarettes. However, in contrast to the huge rise in e-cigarettes' popularity, attendances at local stop smoking services (SSSs, which offer one-to-one support from trained smoking cessation advisors) have declined for seven consecutive years. Given these services have repeatedly been shown to be considerably more effective than any other routes for quitting smoking, my PhD sought to better understand whether the rise of e-cigarettes could be influencing this drop in service attendance, as well as investigating what kinds of issues influenced smokers when they were weighing up which quit route to use. I have already published two papers of PhD findings. My systematic review filled an important research gap by collating the worldwide scientific literature on which demographic groups were most likely to use e-cigarettes. Meanwhile, a qualitative paper with the results of my 46 interviews delineated the complex range of factors that play a role in smokers' decision-making about whether to use quit routes such as e-cigarettes or SSSs. It also highlighted the diverse attitudes towards e-cigarettes shown by different SSSs and how this influenced the kinds of support offered to their clients. This fellowship would allow me the opportunity to publish two further papers of findings, helping to maximise the potential of my PhD research. The first would be a further quantitative paper showing what kinds of knowledge and beliefs amongst the 2000 smokers that I surveyed were related to their use of SSSs and e-cigarettes. This would therefore provide a natural complement to my already-published interview findings, giving my research more reach to those audiences who are most comfortable with quantitative analyses. The second would be a further piece of analysis from my qualitative dataset. In light of my finding that SSSs offer very varying levels of support and advice around e-cigarettes, my second paper would drill down further into my interview data to tease out what the key influences are that determine what policy a service arrives at regarding e-cigarettes. This would thus provide important insights for PHE, ASH, NCSCT and other organisations with an interest in ensuring equal provision of support to smokers in different parts of the country. Finally, the fellowship would also allow me to develop a funding proposal to move my investigations on to crucial, related research questions in the years following. Specifically, this future bid would involve analysing the impact of 'Juul' e-cigarette devices on vaping and smoking habits amongst children and young people, an age group whose attitudes and behaviours fundamentally determine the health harms caused by smoking within society. Most smokers, after all, take up the habit in adolescence, when they have less understanding about the tenacity of nicotine addiction; in previous research, 90% of smokers had started by age 18 and 95% by age 21. The manufacturer Juul have dominated the vaping market for years in the US but have only arrived on UK shores much more recently. These specific devices have been shown to be driving the far higher rates of teenage vaping seen in the US but, as yet, their impact on UK youngsters' vaping and smoking habits are unknown. This line of enquiry has been sparked both by my PhD's systematic review, which showed the highest rates of vaping were amongst older adolescents and younger adults, and by my qualitative fieldwork, where younger interviewees often relayed experiences of feeling targeted by e-cigarette marketing or spoke of the popularity of vaping amongst their peer groups.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,CANCER AND NEOPLASMS;CARDIOVASCULAR;RESPIRATORY;STROKE HRCS22_07300,Department of Health and Social Care,NIHR,Early Psychosis Informatics into Care [EPICare],"Development work questions What are the essential and desirable elements needed for a digital psychosis registry and clinical decision support system (CDSS) developed to improve recovery for people with first episode psychosis (FEP) in Early Intervention Psychosis (EIP) services in England? What informatics challenges need to be addressed? Background EIP services are nationally mandated to provide multidisciplinary care to people experiencing FEP, which disproportionately affects deprived and ethnic minority youth. Despite NHS investment in EIP, people from historically underserved populations have unequal access, and only 30-40% achieve full recovery. Equitable delivery of prompt, personalised targeted treatments, driven by a national digital registry and CDSS would reduce these disparities in care and prognosis. In other disease areas, like stroke, cancer and dementia, informatics innovation has achieved significant advances; given psychosis is the third most burdensome heath condition, it is essential and just that we achieve the same parity of health improvements. In this Programme Development Grant, we will complete the first stage of work to ensure onward success of a digital psychosis register and CDSS for early psychosis care (EPICare). Aims and Objectives Aim: To co-design a framework, protocols and toolkits for onward development, implementation, and evaluation of EPICare. Objectives: Establish a network with strong public involvement and engagement (PPIE) and other essential stakeholders to identify essential and desirable elements of EPICare and minimize unforeseen challenges (Work Package-WP1). Address key questions on informatics architecture, infrastructure, governance, and integration to facilitate onward development and testing of EPICare in diverse NHS Trusts (WP2). Identify implementation factors from the outset, to ensure they are considered in designing, implementing, and sustaining the future deployment of EPICare in a measurable way (WP3) Development Work Plan In WP1, we will use a participatory co-design framework to convene a stakeholder group and establish the parameters and essential features of EPICare. In WP2, we will work closely with NHS Trust IT teams to identify how key data items can be retrieved from Electronic Health Records (EHRs); design the software architecture and data model and create an infrastructure plan in preparation for future implementation of EPICare. In WP3, we will investigate opportunities and challenges of co-designing this novel intervention with PPIE, clinical, technologist and organisational stakeholders, and identify factors likely to influence future implementation into routine practice. Timelines for delivery Month 1-4: Hold first full stakeholder meeting; evaluate national EIP data survey, understand existing EHR data availability, begin consultation meetings with Trust IT teams. Month 4-9: Two further stakeholder meetings: agree EHR data to be collected; develop IT build protocols, data model and infrastructure toolkits; agree pilot and demonstrator sites. Month 9-12: Fourth stakeholder meeting; sign-off of proposed EPICare framework, protocols, and toolkits; implementation evaluation of shared decision-making; draft full Program Grant for Applied Research (PGfAR). Anticipated Impact and Dissemination We will integrate co-designed knowledge from our WPs and draft the framework, protocols, toolkits and PGfAR application for the onward build, pilot, implementation, and evaluation of EPICare. Our stakeholder network will review and sign-off these deliverables.","Background People with psychosis can hear voices, have confused thoughts or poor motivation. They can withdraw from friends and family. There is a national network of Early Intervention in Psychosis (EIP) services to support people with first episode psychosis (FEP) with psychology, vocational support and medication. Psychosis affects over 8000 people for the first time every year in England and people who are poor or from ethnic minorities have a higher chance of developing psychosis. When they do, these groups may find it more difficult to recover, and benefit less from treatments. EIP services already collect data, but it is not currently possible to use this to provide patients or clinical teams with timely information to guide the best treatment or help address disparities in care. We want to develop a secure, computerised national database that tells patients and staff how much progress each person is making, called EPICare. We will combine it with an artificial intelligence tool called a clinical decision support system (CDSS). EPICare will automatically and securely reminders about evidence-based treatment options and progress. The NHS could use the database to discover if any group is missing out treatments unfairly. This type of data innovation has already helped make stroke and cancer care fairer and better. To begin EPICare, we need to set up a group of patients and practitioners to tell us what information they need, how to collect data and help the developers check the system will work well. Aim: To produce guidelines for EPICare to make sure it gives patients, staff and people who plan NHS services the right information at the right time. Methods: We plan three work packages (WP) to work together: First, we will bring together a group of 10 people with experience of psychosis from diverse backgrounds. They will be joined by clinical staff, local and national service managers and researchers. They will meet four times to decide what features EPICare should have. Second, we will work closely with NHS IT teams to identify how to get data safely and accurately from IT systems into EPICare, and to understand how EPICare will work and what it will look like to people using it. Third, we will study the above activities to understand opportunities and challenges of co-designing a novel intervention, and to identify the factors that are likely to influence future implementation into routine practice. Anticipated Impact: At the end of 12 months, we will have co-designed a feasible set of guides to allow us to build and test EPICare in a future larger study. We will also have established a diverse and inclusive stakeholder group who are fully engaged with the future co-development of EPICare.",8.1 ORGANISATION AND DELIVERY OF SERVICES,MENTAL HEALTH HRCS22_06707,Department of Health and Social Care,NIHR,Early Recognition of Raised Intracranial Pressure in Craniosynostosis using Handheld Optical Coherence Tomography,"Research question Can handheld optical coherence tomography (HH-OCT) improve early recognition of raised intracranial pressure (ICP) in craniosynostosis? Background Craniosynostosis is characterised by premature closure of cranial sutures. This may cause raised ICP, which can lead to optic atrophy, developmental delay, blindness and death if left untreated.1 Prevalence is 3.1-7.2 in 10,000 live births and rising.2 Treatment for those believed to be at risk of raised ICP involves surgical expansion of the skull vault, which carries risks including disability and death. Currently, there is no agreed protocol over who to treat and when; a popular option is prophylactic vault expansion for all patients with multisuture and syndromic craniosynostosis1, but this may represent unnecessary surgery for many infants. Aims and objectives To evaluate whether HH-OCT improves sensitivity/specificity for detecting raised ICP in craniosynostosis, compared to the current clinical protocol, involving neurosurgical and ophthalmic examinations and visual evoked potentials. Additionally, to characterise and quantitatively analyse HH-OCT changes and develop a management algorithm for craniosynostosis. Methods A diagnostic accuracy cohort study will be conducted at GOSH. 260 patients with craniosynostosis will be recruited. Clinical examination, visual evoked potentials (VEP) and HH-OCT will be performed. Patients with signs of raised ICP will be referred for surgery, during which intracranial measurement of ICP will be done. Raised ICP will be defined as that over 20mmHg. Sensitivity and specificity of HH-OCT for predicting raised ICP will be analysed. Timelines for delivery This study will take place over three years. Year 1 will include a systematic review of literature, recruitment and data analysis. Year 2 will consist of data collection and analysis, as well as presentation and publication of preliminary data and interesting cases. Year 3 will include finishing data collection and analysis, development of the management algorithm, thesis writing and dissemination of findings. Anticipated impact and dissemination This world-first study could optimise management of infants with craniosynostosis if OCT can recognise raised ICP earlier than existing methods. It could protect infants from unnecessary operations where not required. Finally, it could improve understanding of the pathophysiological mechanism between raised ICP and the eye. Findings will be disseminated via scientific journals, conference presentations, social media and local and national press. If successful, the treatment algorithm could be incorporated into clinical management guidelines.","Craniosynostosis is a condition where a baby's skull does not grow properly. It happens when the joining parts of the baby's skull called 'sutures' close before their head has fully formed. As a result, babies with craniosynostosis usually have an unevenly shaped head. The condition affects about 1 in 2000 babies. It can be very severe and can cause vision loss, learning disabilities, blindness and death, if not treated appropriately. Many babies with craniosynostosis need surgical treatment. This involves making the skull bigger to prevent rising pressure in the skull. It is important that doctors recognise rising pressure in the skull because too much pressure can lead to problems with the brain and vision. However, it is very hard for doctors to measure this so some babies may have risky surgery without the need for it. I want to look at a special technique called optical coherence tomography (OCT) to see if this can identify babies who are at risk of rising pressure in the brain. OCT is a scanning device that looks at the structure of the eye in amazingly minute detail. Up until recently, we could not use this technique on babies because they could not cooperate with the large table-mounted device for adults. However, our team are now using a hand-held OCT device that only takes a few seconds to scan the eye. I want to use the device to look for early changes in parts of the eye (the optic nerve and the retina). These changes could predict if a baby is at risk of rising pressure in the skull. My study will take place at Great Ormond Street Hospital - an international centre of excellence for child healthcare and the largest of only four centres in the UK treating craniosynostosis. My study will involve seeking consent from parents in craniosynostosis clinics. I will then scan the babies' eyes with handheld OCT to see if there are any changes in the eyes to suggest that there might be rising pressure in the skull. Finally, I will compare my results with the actual pressure measure in the operating theatre to see how good OCT is at predicting rising pressure in the skull. I will involve patients, families and members of the public in Expert Advisory Group meetings twice per year where I will provide study updates and seek feedback. I will work with our press teams to share my findings via newspapers, radio and television. I will work with the craniosynostosis charities Face Value and Headlines to publish significant news items via their websites. I will share findings on social media including Facebook and Twitter. Finally, I will present at clinical conferences and publish in scientific journals. My study has the potential to radically improve the care that babies with craniosynostosis receive. I hope to dramatically improve patient outcomes, including quality of vision and quality of life. I aim to improve early referral for those children who need surgery, whilst also protecting other children from unnecessary surgery when it is not required. If successful, the findings could feed into national clinical guidelines for craniosynostosis.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,REPRODUCTIVE HEALTH AND CHILDBIRTH;MUSCULOSKELETAL HRCS22_06892,Department of Health and Social Care,NIHR,Early Vitrectomy and Intravitreal Antibiotics for post-operative exogenous eNdophthalmitis (EVIAN) study: A feasibility multicentre randomised controlled trial,"Research question To explore the feasibility and acceptability of carrying out a randomised clinical trial of early surgical treatment compared to standard treatment for endophthalmitis. Background Primary Objectives: To assess the recruitment and retention rates of participants,willingness of surgeons to refer patients into the study,and willingness of participants to be randomised. Secondary objectives: To report mean (SD) visual acuity gain from randomisation to 6 months after randomisation as measured using an ETDRS chart at a starting distance of 4 metres in patients treated with early vitrectomy and with standard treatment, and to report the mean difference with 95 % confidence intervals. To assess the safety of early vitrectomy plus intravitreal antibiotics versus standard of care. Methods This is a multicentre,national clinical trial with 1:1 randomisation and control group. Follow-up period:6 months. Ophthalmic Entry Criteria: Symptomatic visual loss attributable to newly-diagnosed postoperative,exogenous endophthalmitis. Best corrected vision worse than 35 ETDRS letters in the study eye We will recruit 70 patients: 35 patients allocated to each study arm. We estimate our expected 70% recruitment rate (95%CI:60-80) will be achieved if 105 eligible patients with acute endophthalmitis are approached. Twenty UK sites have confirmed participation,committing total of 250 endophthalmitis participants over 21-month recruitment period. Timelines for delivery (start adjusted/delayed due to Covid-19 pandemic) Start:March 1st 2021 End:March 1st 2024 Months 1-6: Staff recruitment/support,document development,obtaining regulatory approvals (ethics,R&D approvals),setting up trial management,randomisation systems,trial databases,and constituting trial management group (TMG). Months 7-27: Site initiation and training planned for months 4-12. Recruitment of trial participants will run between months 7-27 lasting 21 months,with trial intervention and follow-up assessments completed within timelines. Data entry/data cleaning will be a continuous process. Months 27-30: Final follow-up assessments;final data entry;data cleaning, and database lock. Final trial steering committee/TMG meetings. Months 31-36: Data analysis and report writing;Dissemination of trial report Anticipated Impact and Dissemination Impact The role of early vitrectomy for any type of exogenous endophthalmitis remains unproven.The absence of evidence for patient treatment has led to lack of consensus among clinicians with unacceptably wide variations in clinical practice regarding thresholds of visual acuity to surgically intervene,and timings of vitrectomy operation after initial non-response to antibiotic eye injections. Study outcomes will enable development of a full clinical trial that will aim to improve evidence-based guidelines,and reduce the socioeconomic burden and NHS management costs provided that feasibility is shown and a promising signal of efficacy. Dissemination We aim to publish study results in peer-reviewed journals and present results at national/ international clinical meetings (in particular,Royal College of Ophthalmologists,European Society of Retina Specialists,BEAVRS).One patient co-applicant will co-present study findings alongside principal investigators at a UK meeting. The patient advisory group (PAG) will create a lay Results summary for research participants,and assist with results disseminating to non-professional audiences (Moorfields/BRC websites) and Moorfields Patient Involvement Days.The Royal National Institute of Blind People (RNIB) have agreed to webpost recruitment calls, and disseminate trial results on RNIB website/networks to promote uptake by NHS users.Results disseminated to trial centres for discussion at local and regional clinical governance meetings.","What is this study about? To assess the feasibility of doing a trial of the benefit of prompt surgery for a rare but blinding bacterial infection known as “endophthalmitis,”which can complicate invasive eye procedures. Endophthalmitis causes rapid loss of vision. Antibiotic injections may not be sufficient to control the infection and up to 50% patients need surgery to remove the infected vitreous (vitrectomy). Usual care involves intensive and extended inpatient and outpatient management over a 6-month period. The impact on the well being of patients and their carers, both physically and psychologically, is immense often with severe pain and sight loss, which may or may not recover. It is usually managed in specialist tertiary centres at very considerable cost to the NHS recently estimated by the RNIB as much as £1 million annually. How will this study help patients? Earlier surgery, by removing infected vitreous material at diagnosis rather than after failure to respond to intravitreal antibiotics, may accelerate recovery from the infection. Early vitrectomy may improve vision recovery, patient well-being, reduce NHS and patient costs with less hospital visits, and assist in endeavours to reduce antibiotic usage. What will we do in this Study? In order to measure the possible benefit of earlier surgery, we need to conduct a feasibility study of a multicentre randomised controlled trial. The complication is rare, and patients and their carers are severely shocked and emotionally distressed by its occurrence. So we need to discover if the trial we are planning is possible in the reality of urgent care management of these people in current NHS environments. This includes whether both patients and their surgeons can be recruited. We will keep the study simple but key components include close involvement of patient advisors to ensure participant experience during this traumatic time is handled as sensitively as possible.The Health Economic component is to assess whether the relative cost and benefit of earlier surgery could be assessed in a definitive study. Participants will be randomly allocated to vitrectomy performed at an earlier stage of the condition, or later if needs be in accordance with standard care. Standard follow-up for both arms will continue until stable. What do our patients think about the study? We undertook a focus group and interviews with patients who had vitrectomy for endophthalmitis exploring their views and experiences. The consensus was the study was worthwhile. They advised us to approach study patients in an undisturbed environment with nursing support, giving them at least 48 hours to reflect on trial information. We have modified the study design to implement this. Based on their advice, we plan patient advisory group meetings during the study to guide our research. Two co-applicants are previous endophthalmitis patients.",6.4 SURGERY,EYE HRCS22_18504,Cancer Research UK,CRUK,Early detection of clinically-relevant mutational signatures,"Background: Mutational-signatures are a read-out of the cellular abnormalities that arise in a cell as it turns from being normal to being malignant. Already, my team has shown that mutational signatures can be informative of DNA repair defects that may be targets for therapeutic intervention. Critical to the success of this proposal is our unique position as a pioneering team in comprehensive genomic characterisation and in clinical applications of mutational signatures. The overarching principle in this proposal is to advance ways of using mutational-signatures in order to detect a shift in physiological state. This is irrespective of whether they are known abnormalities (e.g. DNA repair deficiencies) or functional abnormalities that are less well-defined (e.g. replication stress). These physiological shifts could be an indicator of early cancer development, or a harbinger of poor clinical outcome. They may be ideal candidates for early detection, serving as a biomarker for medical intervention. Aims and Methods: There are three inter-related objectives. First, we will apply computational methods on cancer data and experimental data to identify on-going mutational-signatures that may be clinically important. Second, once these have been identified, we will develop the assays to be able to detect these clinically-relevant mutational signatures from samples where there are limiting DNA quantities (e.g. from a blood test). Third, we will test our assays on patient samples to understand whether they truly have clinical utility. How the results of this research will be used: We anticipate being able to delineate clinically-relevant mutational signatures and to find ways of utilising them as biomarkers as early as possible during a patient’s cancer journey, ideally, from something as simple as a blood test.","Background: Mutational-signatures are a read-out of the cellular abnormalities that arise in a cell as it turns from being normal to being malignant. Already, my team has shown that mutational signatures can be informative of DNA repair defects that may be targets for therapeutic intervention. Critical to the success of this proposal is our unique position as a pioneering team in comprehensive genomic characterisation and in clinical applications of mutational signatures. The overarching principle in this proposal is to advance ways of using mutational-signatures in order to detect a shift in physiological state. This is irrespective of whether they are known abnormalities (e.g. DNA repair deficiencies) or functional abnormalities that are less well-defined (e.g. replication stress). These physiological shifts could be an indicator of early cancer development, or a harbinger of poor clinical outcome. They may be ideal candidates for early detection, serving as a biomarker for medical intervention. Aims and Methods: There are three inter-related objectives. First, we will apply computational methods on cancer data and experimental data to identify on-going mutational-signatures that may be clinically important. Second, once these have been identified, we will develop the assays to be able to detect these clinically-relevant mutational signatures from samples where there are limiting DNA quantities (e.g. from a blood test). Third, we will test our assays on patient samples to understand whether they truly have clinical utility. How the results of this research will be used: We anticipate being able to delineate clinically-relevant mutational signatures and to find ways of utilising them as biomarkers as early as possible during a patient’s cancer journey, ideally, from something as simple as a blood test.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_18507,Cancer Research UK,CRUK,Early detection of oesophageal adenocarcinoma (OAC) from Barrett’s oesophagus (BO): defining genetic and microenvironmental drivers of BO-OAC transition,"Background: Oesophageal adenocarcinoma (OAC) is a deadly disease whose incidence has increased substantially in recent years. OAC is preceded by a well-identifiable pre-cancer condition named Barrett’s oesophagus (BO). However, not all BOs will transform into OAC and the transition from BO to OAC remains hard to predict due the scarcity of effective tools for early detection. Currently, BO surveillance is achieved through endoscopic monitoring, which is a costly and invasive procedure that could be reduced with reliable molecular and cellular markers of BO-OAC transition for early patient stratification. Aims: The purpose of this research is to study the transformational events triggering BO-OAC transition at the molecular and cellular level to enhance early detection. Our preliminary data show that patients with BO can be divided into groups based on their genetic and tumour microenvironment drivers. We propose that the early identification of these drivers can be used to inform OAC early diagnosis. Leveraging on the complementary expertise of our team, we propose to: - Integrate the study of genomic and tumour microenvironment data to derive BO-OAC transition groups - Correlate these groups with disease prognosis - Characterise them experimentally - Validate their use as markers of progression in a case-control cohort Methods: We will compare genomic and transcriptomic alterations across hundreds of BO-OAC pairs and divide them into groups according to the drivers of transition from pre-cancer condition to fully transformed cancer. We will then use high-dimensional immune profiling to characterise the microenvironment of these BO-OAC groups and correlate their molecular and cellular features to prognosis. Finally, we will characterise the driver potential of the alterations across groups in co-cultures of patient-derived epithelial and stromal cells and validate their use as early detection markers in a case-control cohort. How the results of this research will be used: This research will be useful to: - Identify the diverse molecular routes leading to OAC - Associate them with the cellular environment that surrounds the tumour - Inform discovery of molecular and cellular biomarkers predictive of BO transformation The knowledge gained from this study will underpin better risk stratification biomarkers to be tested in future clinical trials.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_20204,Cancer Research UK,CRUK,Early diagnosis and Personalised therapy for myelodysplastic syndromes,"Background Recent studies from cohorts of individuals with normal blood counts have shown that acquisition of clonal haematopoiesis is common with aging. Importantly, genetic aberrations found in such individuals mirror those seen in myelodysplastic syndrome (MDS), a haematopoietic cancer affecting 5000 individuals in the UK, characterised by low blood counts and transformation to acute myeloid leukaemia (AML). The presence of subclinical clonal haematopoiesis (“clonal haematopoiesis of indeterminate potential”,CHIP) confers a 10-15-fold increased risk of MDS or other haematopoietic cancer, rising to 50-fold if variant allele frequency exceeds 10%. Notably, treated MDS/AML patients retain such clones with or without additional genetic abnormalities, following conventional treatment. Thus clonal haematopoietic stem and progenitor cells (HSPC) appear to serve as founder clones that can evolve to MDS and these clones are stable and resistant to current treatments. A central question driving this proposal is how and when does CHIP transition to MDS/haematological cancer? If patients most at risk of cancer could be identified, they could be prioritised for early follow-up and therapeutic strategies. In patients diagnosed with MDS, a wide range of clonal heterogeneity exists at presentation and throughout treatment. This co-existent clonal genetic variegation suggests that MDS driver mutations have a range of cellular behaviours that may also depend on epigenetic or micro-environmental factors. Identifying genotypic and phenotypic determinants of clonal dominance will permit prioritisation of pathways for further therapeutic targeting. Objectives/Methods 1. To undertake in vivo drug screens in zebrafish to define small molecules that selectively deplete haematopoietic stem and progenitor cells (HSPC) carrying MDS-associated mutations 2. To understand the clonal heterogeneity of MDS, and the impact of both genotypic and phenotypic variation in mutated haematopoietic cells in driving the evolution to AML 3. Define and quantify the utility of CHIP as a biomarker for the development of MDS (and other haematopoietic malignancies) How the research will be used Objective 1 will identify known drugs that have been validated in murine xenografts that can selectively kill HSPC with MDS/CHIP mutations. These compounds will be used for future mechanistic/drug development opportunities Objective 2 will provide a comprehensive understanding of the cell autonomous clonal dynamics of MDS. Future therapeutic strategies will be defined using genotype combinations, and transcriptional phenotypes that lead to MDS. Objective 3 will define the natural history of evolution of CHIP to haematopoietic malignancy and identify methods to stratify those patients at greatest risk of malignancy using CHIP as a biomarker.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS;BLOOD HRCS22_20820,Wellcome Trust,,East London Genes & Health: human knockouts in a population genomic medicine cohort of British-South Asians,"East London Genes & Health is a long term programme for population genomic medicine research in British-South Asian adults. Unique features include high rates of health deprivation, especially diabetes, cardiovascular disease and mental health; high rates of consanguinity (including human knockouts, rare predicted loss of function variants occurring as homozygotes); local excellence in e-health record access/analysis; and recall for further research by genotype/phenotype. In this proposal we wish to continue and expand successful East London Genes & Health recruitment and commence a new site Bradford Genes & Health - to reach 100,000 volunteers; add value to the Genes & Health resource through SNP array genotyping all samples; and by sequencing and analysing consanguineous individuals. This will then enable us as a collaborative team to ask detailed research questions about adult-human knockouts. Specifically we will perform population based analyses of naturally occurring adult-human knockouts to better understand their population genetics, and (with Deciphering Developmental Disorders) recessive disease; contribute to and establish The Human Knockout Project, a worldwide database of population-based studies of human knockouts; perform blood -omics to study major perturbations of biological systems including downstream networks; and deeply study individuals with knockouts and other variants in reported Mendelian disease genes.","East London Genes & Health is a long term programme of health research in British-South Asian adults. Unique features include high rates of poor health, especially diabetes, cardiovascular disease and mental health; high rates of related parents (leading to naturally occurring ‘human knockouts’, inactivating genes); excellent electronic health record data on volunteers; and recall of volunteers for additional research studies. We wish to expand successful East London Genes & Health recruitment and commence a new site Bradford Genes & Health, to reach 100,000 volunteers. We will analyse the genes of all volunteers to look for known genetic variants, and sequence the genes of those with related parents to find rare coding variations in genes. With this information we can ask research questions about human ‘knockout genes’ including how they affect populations, biological systems and networks, establishing a worldwide database including health data, and a better understanding of recessive human disease.",2.4 SURVEILLANCE AND DISTRIBUTION,MENTAL HEALTH;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;GENERIC HEALTH RELEVANCE HRCS22_05579,Department of Health and Social Care,NIHR,Effectiveness Of Group Arts Therapy Compared To Group Counselling For Diagnostically Heterogeneous Psychiatric Community Patients: Randomised Controlled Trial In Mental Health Services,"Aim: We want to test if arts therapies groups are effective for patients with different types of mental illness._x000D_ _x000D_ Background: Arts therapies use different art forms and creative activities to help people living with mental illness. These include music therapy, dance-movement therapy and art therapy. Each has a different focus: on the ‘ear’ (music), the ‘body’ (dance-movement) and the ‘eye’ (art). They are usually provided in regular group meetings over a few months. Arts therapies may help patients to express emotions and have experiences which might not be possible in talking therapies._x000D_ _x000D_ Different people prefer different art-forms. If patients can choose which art-form they like best, they may be more likely to attend and benefit from this. While arts therapies are popular with many patients, they are not always provided in NHS services. So far, there has been little research to show that they are helpful. Existing research has involved people with only one diagnosis (such as schizophrenia). This is different to how arts therapies groups are provided as they usually include people with different mental illnesses._x000D_ _x000D_ Design and methods used:_x000D_ We will ask patients in community mental health services if they would like to participate in a form of group arts therapies and, if so, which one. They will then be divided in two groups by chance. Half will receive their preferred form of arts therapy group. The other half will be offered group meetings with general talking and support, but no use of arts. Patients can attend for up to 40 sessions over 5 months. We will interview patients at the beginning and end of treatment, 6 and 12 months later. We will then compare the two groups to see if patients receiving arts therapies had a better improvement of symptoms and quality of life._x000D_ _x000D_ PPI:_x000D_ Patients who took part in our previous studies told us that it was important that they could access the art-form they preferred. They also suggested that future research included more than one art form. We will include music, visual art and dance and ask patients which one they prefer. This means that patients have a choice and can access their preferred art form. _x000D_ We discussed our ideas for this study with the Service User and Carer Advisory Group on Research (SUGAR). The group recommended that we:_x000D_ _x000D_ -use video clips to explain what arts therapies are to patients and referring clinicians_x000D_ -ask patients if they enjoyed the sessions and experienced support from other group members_x000D_ -include views from clinicians in charge of the patient’s care._x000D_ _x000D_ We have included all of these suggestions. We will continue to ask SUGAR for advice on how to provide information to patients and how to share our findings. We will attend their meetings regularly to share our progress and challenges. One of the co-applicants is a service user who has attended different arts therapies groups. She will be a full member of the research team and help to coordinate a lived experience advisory panel (LEAP). We will also ask the funder to include a user representative on the Steering Group for the Trial._x000D_ _x000D_ Dissemination:_x000D_ We will share our findings based on advice from our service user co-applicant, SUGAR and the professional organisations of the different arts therapies. We will have a website with information about the arts therapies and the trial. We will present the study idea, protocol and findings at conferences and professional meetings, and publish in open access journals.","Design: Two-arm, single-blinded, multi-site, pragmatic randomised controlled trial, with internal pilot._x000D_ _x000D_ Setting: Secondary mental health out-patient services._x000D_ _x000D_ Target population:Patients with different mental disorders in mental health services._x000D_ _x000D_ Inclusion: Outpatient in secondary mental health care;motivation to attend group arts therapy for 5 months and expression of preference for one of the three forms;18+ years of age;primary diagnosis of ICD-10[1] F2 (schizophrenia and related psychotic disorders), F3 (mood disorders), F4 (anxiety and other non-psychotic disorders);at least moderate symptom level on BSI[2];_x000D_ _x000D_ Exclusion: Primary diagnosis of organic, substance misuse or personality disorder;duration of current mental disorder <6 months (i.e. patients with short-term crises);physical condition that prevents attendance of groups;insufficient command of English for communication._x000D_ _x000D_ Health technologies being assessed: Group arts therapies (art therapy, music therapy, dance-movement therapy), as compared to group counselling as an active control, both provided in 40 sessions over a 5 month period._x000D_ _x000D_ Measurement of costs and outcomes: Costs of group arts therapies and the control condition will be documented by the study team; costs of other care will be calculated based on electronic medical records; Patient self-ratings and observer ratings will be obtained in interviews with blinded research assistants at baseline, end of treatment, 6 and 12 months post-intervention; ratings include symptoms on the Brief Symptom Inventory[2] and quality of life on the Manchester Short Assessment of Quality of Life[3]_x000D_ _x000D_ Sample size: 167 in 20 clusters in each arm, assuming an ICC of 0.01 and a co-efficient for variation of cluster size of 0.5, to detect an effect size of 0.5 on a 5% significance level with 90% power. Allowing for 15% drop out, we will require 2 x 197 patients. Allowing for the additional loss of one cluster (treatment group) in each arm, we will need to recruit 210 patients in each arm, i.e. a total of 420 patients._x000D_ _x000D_ Difference between current and planned care pathways: Group arts therapies are already provided in some services in the NHS. Yet, provision is highly inconsistent, not evidence-based and rarely considers patient preferences._x000D_ _x000D_ Project timetables including recruitment rate:_x000D_ _x000D_ Pre-study: All approvals_x000D_ Month 1-2: Trial set up and preparation_x000D_ Month 3-8: Recruitment of 180 patients for first groups in internal pilot across 3 sites, site recruitment rate 10 per month_x000D_ Month 9-13: Group therapies in internal pilot_x000D_ Month 10: Decision about moving to full trial _x000D_ Month 11-16: Recruitment of 240 patients in full trial across 3 sites, Recruitment rate 10 per month (Avon, Luton); 20 per month (London)_x000D_ Months 17-21: Group therapies in intervention and control arms in full trial_x000D_ Months 13-28: 6 month follow-ups (internal pilot and full trial), qualitative interviews_x000D_ Months 25-34: 12 month follow-ups (internal pilot and full trial)_x000D_ Months 34-39: Analysis, report writing and dissemination _x000D_ Study duration: 39 months_x000D_ _x000D_ Expertise in team: The team includes expertise in developing and evaluating complex interventions (Priebe, Carr), managing large multi-site trials in arts therapies (Priebe, Crawford), music therapy (Carr, Sandford), art therapy (Huet, Havsteen-Franklin), dance-movement therapy (Karkou, Feldtkeller), personal experience of arts therapies (Smith), bio-statistics (Hooper) and health economics (Mihaylova)",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_05885,"Public Health Agency, NI",PHA,Effectiveness and cost-effectiveness of a peer-led walking programme to increase physical activity in inactive older adults: “Walk With Me Study”,"Many older adults would benefit from being more physically active, especially those living in areas of socioeconomic disadvantage. Interventions delivered by peer mentors (trained members of the public) have shown promise at increasing people’s physical activity levels in previous research, but their effectiveness in this population was unknown._x000D_ ‘Walk with Me’ is a 12-week peer-led intervention developed to enable older adults from areas of socioeconomic disadvantage to become more active. The intervention was developed using guidance from previous successful interventions and with input from older adults who lived in these communities. They indicated that despite having ‘busy’ lives, having a peer mentor to walk with would help them become more active._x000D_ In a pilot study, 50 people aged 60–70 years agreed to take part. Participants that were interviewed following the intervention rated it favourably and reported increasing their activity. The study showed that it would be possible to conduct a larger study to test if a walking intervention delivered by peer mentors can increase older adults’ physical activity._x000D_ The aim of the proposed project is to further examine if a peer mentor can help older adults increase their physical activity over 1 year compared to a control group. We hope to find out the costs and benefits to the health service and the experiences of people taking part._x000D_ In this we aim to recruit 348 inactive older adults aged 60 years and over living in socio-economically disadvantaged communities, mainly through General Practices as this approach worked best previously in the pilot study, but also through community groups. Participants will be allocated by chance to one of two groups. One group will be paired with a peer mentor for a 12-week walking programme. The other group will be a 12-month wait list group. The peer mentor will meet with the participant each week with the aim of supporting them to increase their activity and find opportunities in the local community to engage in other programmes so they can maintain their activity._x000D_ We will measure if the programme works using an activity monitor. All participants will be asked to wear this for one week at the start and end of the programme and after 12 months. We will also discuss the impact of the programme with some participants and peer mentors to understand their views of the Walk with Me programme._x000D_ The Community Development and Health Network and the Institute of Public Health in Ireland are partners in the research programme. Along with service users, they have helped us develop the Walk with Me programme and this research project, including outcomes that matter to older adults and the programme materials. Two independent older adults will be on the steering group._x000D_ The key questions that this study will answer are whether the Walk with Me intervention will help inactive older adults become and stay active and what the costs and benefits are for older adults and the NHS. The findings will be shared with the public, older adults groups and public health staff through social media, blogs, reports, presentations and research papers.","Research Question: What is the effectiveness and cost-effectiveness of a peer-led walking programme to increase moderate-to-vigorous physical activity in adults aged 60 years and over living in socio-economically disadvantaged communities?_x000D_ Background: The proportion of the population aged 65 years or older is increasing. Typically, physical activity and health declines with age, which is why action to promote active healthy ageing is a major public health priority, particularly in socio-economically disadvantaged older adults. This trial builds on our Walk with Me NIHR-PHR funded pilot study._x000D_ Aims: The aims of the project are to: (1) conduct a full-scale randomised controlled trial of the Walk with Me peer-led walking intervention to estimate changes in physical activity at 12 months for older adults living in socio-economically disadvantaged communities; (2) assess differences between groups in secondary outcomes; (3) assess the cost-effectiveness of the Walk with Me intervention compared to a minimal intervention control group; and (4) understand older adult’s and per mentor’s experiences of the intervention._x000D_ Methods: Two-arm, assessor blind, randomised controlled trial recruiting 348 older adults using a GP invitation letter (85%) or from community groups (15%). The Walk with Me intervention is a 12-week peer-led walking intervention based on social cognitive theory comprising three stages. Stage 1 (weeks 1–4) involves the participant setting initial pedometer step goals. Stage 2 (weeks 5–8) involves setting short- and long-term physical activity goals. Finally, stage 3 (weeks 9–12) emphasises behaviour rehearsal and practice and signposting participants to other activity programmes in their community. Participants in the control group will receive information on active ageing and healthy nutrition._x000D_ Setting: The study will target community-dwelling older adults, aged 60 years or over living in areas of socio-economic disadvantage, defined as the most disadvantaged quartile of electoral wards in Northern Ireland._x000D_ Delivery: Trained peer mentors (n=35) will deliver the intervention. These are nonprofessional individuals who are similar to the target population, but sufficiently physically active._x000D_ Primary outcome: mean between-group change in accelerometer measured moderate-to-vigorous physical activity at 12 months from baseline, powered to detect 50 mins/week difference in moderate-to-vigorous physical activity._x000D_ Secondary Outcomes: SF-12; EQ5D-5L; Warwick-Edinburgh Mental Well-Being Scale; blood pressure, body mass index and waist circumference; adverse events._x000D_ Qualitative Research: Focus groups with 30 intervention participants and their mentors at 12-weeks (post-intervention) and 6 months about their experiences._x000D_ Health Economic Evaluation: The primary economic outcome will be incremental cost per QALY. We will assess the potential benefits and return on investment via cost-consequence analysis, within-trial cost-utility analysis and a long term model._x000D_ Analysis: Using intention-to-treat approach, we will compare the primary outcome between groups within a generalized linear mixed model including mentor as a random effect._x000D_ Public health impact: Evidence-based, cost-effective interventions to promote physical activity in older adults living in socio-economically disadvantaged communities are needed to address health inequalities. Peer-led interventions have the potential to provide a timely response to this urgent problem.",6.7 PHYSICAL,CANCER AND NEOPLASMS;CARDIOVASCULAR;MUSCULOSKELETAL;ORAL AND GASTROINTESTINAL;STROKE HRCS22_05741,Department of Health and Social Care,NIHR,"Effectiveness, cost effectiveness and safety of gabapentin versus placebo as an adjunct to multimodal pain regimens in surgical patients: A placebo controlled randomised controlled trial with blinding (The GAP study)","Gabapentin is a medicine used to treat epilepsy and pain caused by damaged nerves. Recently, doctors have begun using gabapentin to treat pain after an operation, with the intention of reducing the amount of other drugs needed while maintaining good pain relief. Doctors want to try to reduce the amount of other drugs because they cause side effects, often delaying discharge from hospital and leading to slower recovery. There is uncertainty about whether adding gabapentin to the usual drug regimen will result in good pain relief, fewer side effects overall (including side effects from all of the drugs used to treat pain) and faster recovery after surgery._x000D_ _x000D_ We want to conduct a study known as a randomised controlled trial (RCT), in which patients undergoing different types of surgery (heart, chest/lungs and belly/gut) are allocated by chance to receive gabapentin or an identical looking dummy pill in addition to the usual drug regimen for each type of surgery. We will give patients gabapentin or a dummy pill one hour before surgery and for two days after surgery. Every other aspect of care will stay the same. We will then compare information about participants who received gabapentin with information about participants who received the dummy pills to determine whether gabapentin reduces the amount of time patients stay in hospital after the operation, the amount of other pain medication they take, and to assess how gabapentin influences pain in hospital and four months after surgery. We will also perform a health economic analysis to determine whether using gabapentin provides better health outcomes for patients undergoing surgery and is cost-effective for the NHS relative to current pain management protocols._x000D_ _x000D_ We have chosen to conduct the study in patients undergoing different types of major surgery (heart, chest/lungs and belly/gut), rather than just one. We are using this approach because we want to ensure that the results can be applied to patients undergoing different operations and who receive different types of care. We will conduct the study in two phases. In phase 1, we will determine whether we can recruit patients from the three different types of surgery and whether patients are able to take gabapentin or dummy pills as instructed. We expect Phase 1 to take a year. If successful, we will move on to Phase 2 and continue recruiting. We hope to recruit a total of 1500 patients (up 500 from each type of surgery). Patients will be recruited from two hospitals, Bristol and Southampton. The overall duration of the study will be 4 years. The team includes a patient, surgeons, doctors with expertise in treating pain in the different types of surgery, researchers with expertise in conducting clinical trials and a health economist.","Design: Pragmatic placebo-controlled RCT with blinding of participants, care teams and researchers and an internal pilot phase (Phase 1). Phase 1 will determine the feasibility of recruitment from three surgical populations (cardiac, thoracic, abdominal). Progression to Phase 2 will depend on showing satisfactory recruitment in Phase 1. The full RCT will evaluate the effectiveness and cost effectiveness of gabapentin (as an adjunct to standard analgesia) vs placebo. Participants will be randomised in a 1:1 ratio to the usual multimodal analgesia regimen plus gabapentin or placebo._x000D_ _x000D_ Setting: Two NHS hospitals (Bristol and Southampton) providing all three types of surgery._x000D_ _x000D_ Target population: Adults undergoing non-emergency cardiac, thoracic and abdominal surgery._x000D_ _x000D_ Inclusion criteria: Adults undergoing non-emergency surgery: cardiac surgery (surgery on the heart and great vessels carried out via midline sternotomy); thoracic surgery (surgery on the lungs and surrounding tissues); abdominal surgery (open or laparoscopic surgery within the abdominal cavity)._x000D_ _x000D_ Exclusion criteria: Participants may not enter study if ANY of the following apply: 1) Expected to have a minimum length of hospital stay of less than 2 days; 2) Taking anti-epileptic medication(s); 3) Allergy to gabapentin; 4) Planned epidural analgesia; 5) Planned use of any gabapentanoids in the peri-operative analgesic protocol other than the study medication (this includes but is not restricted to: pregabalin, enacarbil gabapentin, 4-methylpregabalin and phenibut); 6) Known renal impairment (for such patients, estimated glomerular filtration rate (eGFR) <30ml/min/1.732); 7) Weight <50kg; 8) Inability to provide written informed consent to participate in the trial; 9) Unwilling to participate in follow-up; 10) Prisoners; 11) Already taking gabapentin; 12) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption; 13) Currently taking an investigational medicinal product as part of another clinical trial._x000D_ _x000D_ Health technologies being assessed: Usual multimodal analgesia regimen for each surgical group plus 600 mg gabapentin (or placebo) one hour prior to surgery and 600 mg a day gabapentin (or placebo), (300 mg in the morning and 300 mg in the evening) given post-operatively for 2 days._x000D_ _x000D_ Measurement of costs and outcomes: The primary outcome for the full trial will be length of post -operative hospital stay. Secondary outcomes include: 1) Opioid consumption in the period from surgery until hospital discharge; 2) Acute post-operative pain assessed using the visual analogue scale (VAS) completed at 1hr, 4 hr, 12 hr post-surgery and then twice daily to discharge; 3) Adverse health events from randomisation to 4 months including side effects of medication (e.g. nausea; vomiting; pruritus; sedation; confusion) and on-going pain; 4) HRQoL measured using the EQ-5D 5 level questionnaire and Short-form (SF) 12 completed at baseline and at follow-up at approximately 4 weeks and 4 months; 5) Resource use to 4 months (measured during the hospital stay, at 4 weeks and 4 months); 6) Chronic pain measured at baseline and at 4 months using the brief pain inventory (BPI)._x000D_ _x000D_ Sample size: We will aim to recruit 1500 patients in total, with a minimum of 376 per surgical stratum. This will provide at least 90% power at 5% significance (two sided) to detect a difference in the proportion of patients discharged at current median time (5 days for cardiac and abdominal surgery, 3 days for thoracic surgery) of 12.5% in each stratum and 80% power to detect a difference of 10% in any surgical strata recruiting in excess of 430 participants. We expect to recruit about 500 participants in Phase 1 and 1000 more by the end of Phase 2. Criteria for progression from Phase 1 to 2 will be at least 60% of patients referred for surgery eligible to participate in GAP and at least 50% consent to randomisation after 6 months of recruitment._x000D_ _x000D_ Project timetable: 48 months: 8m set-up; 30m recruitment (Phase 1: 12m; Phase 2: 18m); 4m follow up on all participants; 6m analysis and report._x000D_ _x000D_ Expertise in team: The team is multidisciplinary and includes patients, surgeons and anaesthetists from each specialty, a clinician with pain management expertise (director of the Bristol Integrated Pain Management Health Integration Team, HIT), trialists and a health economist.",6.1 PHARMACEUTICALS,GENERIC HEALTH RELEVANCE HRCS22_23082,The British Academy,,Effects of natural and urban environments on human stress and function,"The overwhelming majority of the human evolutionary journey was spent in natural environments. Consequently, nature provided the parameters within which natural selection has acted to shape the physiology of our species. However, the last 200-300 years has seen mass migration to urban centres. The replacement nature’s forests, plains, coastlines and mountains with alien cityscapes has created a mismatch between our nature-adapted physiology and the highly-urbanised world many of us inhabit today. As predicted by evolutionary theory, this mismatch has led to chronic stress. The stress-reducing effects of spending time in natural environments are well documented. Importantly, it remains unknown how our environment impacts key functions essential to survival; namely immune, cognitive and physical function. Using an experimental protocol, we will assess whether stress and functional capabilities differ between natural and urban environments. The results will increase understanding of how natural ancestral environments influence humans navigating today’s urban world.",,3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,GENERIC HEALTH RELEVANCE HRCS22_02850,Medical Research Council,MRC,Efficacy of Mirococept (APT070) for Preventing Ischaemia-Reperfusion Injury associated with Kidney Transplantation-2 (EMPIRIKAL-2),"Delayed graft function (DGF) is a manifestation of ischaemia-reperfusion injury (IRI) and has a deleterious effect on the lifespan of the graft and the patient. We are seeking to define a therapeutic approach for the prevention of IRI to the kidney during the period immediately after transplantation. This damage is linked to activation of the complement system that occurs through recognition of the grafted organ as foreign and/or damaged, as shown in a MRC funded programme of work. We have approached this problem firstly by engineering a recombinant form of a human complement-regulatory molecule known to be present in the normal kidney at low density and secondly by modifying this molecule so that it can be delivered to the graft by perfusion before transplantation and retained within the kidney at increased density during the period that damage is thought to occur. Preclinical and exploratory clinical studies have indicated that this approach is safe and has the potential to reduce the incidence of DGF in renal transplantation. A Phase IIb dosing/efficacy study has completed the first cohort of 80 patients, the results of which indicate the need for dose escalation. We are now seeking to extend the study using a revised design based on the results of a new dose escalation study in isolated pig kidneys. The revised clinical design involves two stages: Stage 1, a Phase II dosing/efficacy study (for which funding is presently sought); and Stage 2, a Phase III confirmatory study (for which no funding is sought at the present time). This design will enable us to reach a satisfactory endpoint with a smaller number of patients than the original trial. The study will show whether treatment of the donor kidney with the engineered construct lowers the incidence of DGF and improves the mid-term function of the graft.",,6.1 PHARMACEUTICALS,RENAL AND UROGENITAL HRCS22_07480,Department of Health and Social Care,NIHR,Eladocagene exuparvovec for treating aromatic L-amino acid decarboxylase deficiency [ID3791],"Aromatic L-amino acid decarboxylase (AADC) deficiency is an extremely rare autosomal recessive neurometabolic ‘Parkinsonism’ disorder. AADC deficiency is caused by mutations in the gene that produces the AADCenzyme which is involved in the synthesis of the neurotransmitters serotonin and dopamine in the brain. Multiple genetic mutations can cause AADC deficiency, each resulting in different severity of symptoms and levels of response to treatment[1] . Symptoms of AADC deficiency often present in the first year of life and include developmental delays, lack of muscle tone, movement disorders, oculogyric crisis, and problems affecting the autonomic nervous system, such as excessive sweating and nasal congestion[2],[3] . Most cases of AADC deficiency present with severe symptoms [3] . It is often difficult to accurately determine prognosis because of variability in the severity of symptoms and the rarity of the condition. Life expectancy for people with AADC deficiency is unknown because of the variability and rarity of the disease but it can result in premature death. While published survival estimates are limited, it is reported that patients with severe AADC deficiency live for less than 10 years from birth[3],[5],[6] . Most people with AADC deficiency in the UK are children and young adults, but some people with AADC deficiency can live to adulthood. _x000D_ _x000D_ The disease is reported to have a worldwide incidence of 1 in 55,000,000 with about 150-200 people diagnosed in 30 countries[4] . However, the incidence rate may be higher because there are likely people who are undiagnosed. No UK incidence rate has been reported but there are believed to be less than 10 people with AADC deficiency in the UK. AADC deficiency is more prevalent in people of East Asian family origin[7] . _x000D_ _x000D_ Treatments for AADC deficiency do not treat the underlying cause of the disease and focus on managing symptoms, usually treating dopamine and serotonin deficiency. Medical treatment options include dopamine agonists, monoamine oxidase inhibitors, pyridoxine, anticholinergic agents, folinic acid, L-Dopa, benzodiazepines, and melatonin[3] . Treatment usually involves a combination of drugs depending on symptoms [3] . Other supportive treatments include physiotherapy, speech therapy, occupational therapy, feeding and nutritional assessment and psychological treatment[3] . Usually, only mild forms of AADC deficiency respond to treatment and not all symptoms can be relieved._x000D_ _x000D_ References_x000D_ 1 Helman G, Pappa M, and Pearl P (2014) Widening Phenotypic Spectrum of AADC Deficiency, a Disorder of Dopamine and Serotonin Synthesis. JIMD Reports 17: 23-27._x000D_ 2 Brun L, Ngu L, Keng W et al. (2010) Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 75(1): 64-71._x000D_ 3 Wassenberg T, Molero-Luis M, Jeltsch K et al. (2017) Consensus guideline for the diagnosis and treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. Orphanet Journal of Rare Diseases 12(1): 12._x000D_ 4 AADC Research Trust website (Accessed 28/04/2021)_x000D_ 5 Hwu W-L, Muramatsu S, Tseng S-H, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med 2012. 4: 134ra61._x000D_ 6 Das S, Huang S & Lo AW. Acceleration of rare disease therapeutic development: a case study of AGIL-AADC. Drug Discov Today 2019. 24: 678–684._x000D_ 7 Hyland K and Reott M (2020) Prevalence of Aromatic L-Amino Acid Decarboxylase Deficiency in At-Risk Populations. Pediatric Neurology 106: 38-42.",To evaluate the benefits and costs of eladocagene exuparvovec within its marketing authorisation for treating aromatic L-amino acid decarboxylase deficiency for national commissioning by NHS England.,6.2 CELLULAR AND GENE THERAPIES,NEUROLOGICAL HRCS22_01093,Medical Research Council,MRC,Electron tomography of prokaryotic cell surfaces,"My laboratory uses electron tomography, combined with several structural and cell biology techniques, to study cell surfaces of prokaryotes at the atomic level. Surface molecules mediate all cellular interactions with the environment and play important roles in important processes including cell adhesion, biofilm formation and antibiotic tolerance in pathogenic bacteria. Our research aims to push the boundaries of cellular structural biology, with technical developments aimed at identifying molecules on cell surfaces, and resolving their high-resolution details on prokaryotic cells. While structural biology of many cell surface molecules reveals fundamental information about bacteria and archaea, or work has clear biomedical relevance, since surface molecules allow pathogenic bacteria such as P. aeruginosa to evade antibiotics and infect humans by forming biofilms.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_22857,The Academy of Medical Sciences,AMS,Elucidating functional and spatial characteristics of CD8+ T cell populations in coeliac disease,"Celiac disease (CD) is common, increasing in prevalence, and leads to significant morbidity and impaired quality of life for patients. Treatment with a gluten-free diet is burdensome, and there is a significant unmet need for improved diagnostics and therapeutics. Whilst the role of the gluten-specific CD4+ T cell in CD immunopathology is well-studied, the cytotoxic CD8+ T cell populations are less well understood. Specifically, the role of TCR-dependent CD8+ T cell processes in CD, and the antigens that drive them, remain unknown. Our recent work has identified a population of intestinal CD8+ T cells, restricted by a particular TRB V gene (TRBV28), which are highly enriched in both active and treated CD. This population displays features of shared antigen-restriction and clonal expansion, with an activated, cytotoxic, high-regulated phenotype. We hypothesize that this novel CD8 population has an unappreciated role in CD pathogenesis, potentially responding to as yet uncharacterised key antigens. This work seeks to explore the functions, cell-cell interactions, and spatial localisation of this CD8+ T cell population. Specifically I will: 1. Define the transcriptional and phenotypic responses of intestinal TRBV28+ CD8+ T cells in CD to cytokine and TCR stimulation using combined single-cell gene expression/protein assays. 2. Examine the localisation and potential cell-cell interactions of intestinal TRBV28+ CD8+ T cells in CD using spatial transcriptomic approaches. 3. Test putative cell-cell interaction pathways in vitro intestinal-derived T cell clones. This work may provide insights into our understanding of CD pathogenesis, with potential translational benefits including novel diagnostic and therapeutic strategies.","In coeliac disease (CD), gluten in the diet triggers the immune system to damage the gut lining, leading to troublesome abdominal symptoms. Treatment with a gluten-free diet is challenging and impairs quality of life. There is a real unmet need for better CD tests and treatments. In CD, one immune cell subtype, CD4+ (helper) T-cells, respond directly to gluten and trigger the inflammation. However, we know less about T-cells in the gut lining (epithelium), the CD8+ (killer) T-cells. These cells directly cause gut damage in CD. We do not fully understand what activates them and how they cause damage. Our previous work found one type of CD8+ T-cell (identified by a surface receptor) is highly enriched in CD. This persists even with treatment. These cells look like they are responding to a specific, unknown signal (antigen), and may be causing inflammation. This project will examine what this interesting cell population does when stimulated, where they are in the gut, and what other cells they interact with. We will study their role using methods which explore the genes activated in individual cells (single-cell RNAseq) and how this changes with stimulation. We will then map the location and gene expression of these cells in the gut. This will help us understand what these cells do in CD, where they are acting, and with which other cells they are interacting. In summary, this project will explore the role of this new cell type in CD, which may lead to improved tests and treatments.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,ORAL AND GASTROINTESTINAL HRCS22_02432,Medical Research Council,MRC,Elucidating molecular determinants of Trypanosoma cruzi persisters.,"Quiescent, less-drug susceptible T. cruzi parasites pose a key challenge for Chagas disease drug discovery. There currently is no understanding of these persister forms at the molecular level. Here, I propose to use single-cell RNA-sequencing (scRNA-seq) to, for the first time, reveal population heterogeneity in the intracellular amastigote population and to characterise the persister parasites through their gene expression profile. For this I will employ drop-seq technology on methanol-fixed parasites, including the complete intracellular parasite population isolated from mammalian host cells and populations enriched for persisters through fluorescence-activated cell sorting. Expression level differences will be validated both at the mRNA and protein level. The transcriptome data will dramatically increase our understanding of persisters and allow identification of persister markers. To demonstrate physiological relevance of the in vitro persisters, I will use the identified marker genes to probe for persisters in tissues from infected mice. Finally, I propose a large high-content screen with 130,000 compounds to identify compounds that can promote either entry or exit from the persister state. The high-throughput screen will be based on previously demonstrated dye-retention as a persister marker, whereas validation will be carried out with the persister markers found through scRNA-seq. Compounds that stimulate persister replication will be tested in combination with compounds known to kill replicative parasites in intracellular viability assays to test this type of combination as an new treatment approach. Overall this work will provide key information regarding T. cruzi population heterogeneity and the nature of T. cruzi persisters and will enable further research into the fundamental biology of persisters as well as support drug discovery efforts allowing creation of better assays, specific detection of persisters and rational identification of drug targets.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_03154,Medical Research Council,MRC,Elucidating the role of sleep in FTD and AD: from neurons to networks in vivo,"Sleep disturbance is common to several progressive dementia-related illnesses. As well as affecting cognition, sleep impairment has also been recently implicated in pathological protein accumulation and neurodegeneration, suggesting that sleep may be a promising treatment target for dementia. Nevertheless, defining and realising the potential of sleep-targeting therapies requires a more complete understanding of the most relevant disease-specific sleep phenotypes. Brain activity during normal sleep is characterised by circuit-specific brain oscillations that play a key role in memory and learning, and a major open question concerns how such brain activity is dysregulated in major dementias such as Alzheimer’s Disease (AD) and frontotemporal dementia (FTD), and the underpinning disease-specific markers of neuronal dysfunction. Here, using an innovative approach involving both rodents and humans, I will examine how FTD and AD affect sleep electrophysiology measures that reflect underlying disease effects on sleep neurobiology. I will assess sleep in a cohort of well-characterised gender and age-matched (behavioural-variant) FTD and amnestic-AD patients (identified through the Queen Square Specialist Cognitive Disorders Clinic), and healthy controls (N = 5/group), using electroencephalography (EEG headbands) in the home environment. I will further perform parallel electrophysiology (multi-channel NeuroPixels) experiments in mouse models of AD and FTD to characterise disease-specific neuronal dysregulation that underlies impaired sleep oscillations. Finally, I will design and test novel auditory stimulation paradigms that are aimed at restoring impaired brain oscillations. These pilot data will form the basis for a larger clinical study assessing the potential of this intervention to enhance sleep oscillations in AD and FTD patients, with the ultimate aim to improve cognitive-behavioural function and delay disease progression.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,NEUROLOGICAL HRCS22_19415,Wellcome Trust,,Enabling advance imaging of synaptic function in living males and females over the course of the life-span with Positron Emission Tomography (PET),"Synapses are damaged in over 130 different brain diseases and yet thus far there are no reliable ways to measure synaptic structure or function in vivo in a preclinical or clinical setting. The recent discovery of promising Positron Emission Tomography (PET) radiotracers for imaging synapses, by targeting the synaptic vesicle glycoprotein 2A (SV2A), has the potential to transform clinical diagnosis, neuropathology, drug development and treatment of multiple brain diseases. Two major bottlenecks to deliver on this promise are: (1) the unavailability of high-yield and high-molar activity [18F]MNI1126, the lead SV2A PET radiotracer; and (2) the lack of a quantitatively accurate and validated SV2A brain PET atlas during normal aging in rodent models. This project will generate synthetic routes and radiochemistry methods for efficient production of [18F]MNI1126, it will develop detailed template resources for quantitative analysis of SV2A PET signal in different brain regions over the course of natural aging in the rat and mouse, and it will validate SV2A PET in vivo outcomes at unprecedented scale and resolution using synaptome mapping technology. The development of SV2A PET technology proposed in this award will catapult the use of quantitative SV2A PET in many brain diseases in humans and model organisms.","Synapses are the connections between the nerve cells in the brain and they are essential for all our thoughts and actions. Synapses are damaged in most brain diseases and until recently there were no tools for monitoring them in the living brain. Researchers discovered a synthetic small molecule that can be used to monitor synapses in humans and animals. When injected, the molecule binds to the synaptic protein SV2A, which can then be detected using a brain imaging approach used in the clinic called Positron Emission Tomography (or PET). This project aims to develop this SV2A PET tool so that it can be used to better understand how the brain works during health and disease, to better diagnose patients and to discover new medicines to treat brain diseases.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,MENTAL HEALTH;NEUROLOGICAL HRCS22_17916,Wellcome Trust,,Enabling imaging of cells and tissues across scales,"We seek funding for an array tomography scanning electron microscope (SEM) with ATLAS 5 software together with components to upgrade an associated light microscope, to enable 3D correlative light and electron microscopy (CLEM) of cells and tissues with nm resolution. Array tomography SEM allows for the detection, mapping and automated imaging of serial sections of resin embedded samples and is non-destructive technology.   This technology is transformative and will enable high resolution 3D correlation of molecular machineries with cellular structure and specific cell and tissue processes. Using this new technology, our initial consortium of PIs will address the following specific objectives:  1.  To elucidate the mechanism of 3D patterning during organogenesis (Pichaud) 2.  To characterise the fundamental principle that regulate intracellular trafficking of cargoes and membrane, storage and lysosomal degradation (Brodsky, Futter and Schiavo) 3.  To determine the molecular basis for the interaction between the HIV virus and its host cells and tissues (Jolly and Marsh) 4.  To elucidate the fundamental mechanisms of nuclear remodelling during passage through mitosis (Baum) 5.  To elucidate the connectivity underlying circuit function (Hausser and Wilson) Altogether, our proposed studies will elucidate fundamental mechanisms of cell and tissue morphogenesis, homeostasis, function repair and infection.","Correct cell function depends on the successful interaction between molecular machineries, which support critical tasks such as the transport of molecules in and out of the cell, the ability for cells to respond to their external environment, and ensure cells maintain the right shape. Yet cells do not usually function alone but exist as part of a collective, making up organs and tissues. Thus, to effectively study cells we must take into account both their molecular machineries and their environment, requiring us to move seamlessly from the microscopic to the macroscopic, examining cells across spatial scales. This is not trivial, as the technologies required to study molecules are different from those used to study whole cells and groups of cells. The new microscope we will acquire with this funding will bridge this gap by allowing us to overlay molecular information onto cellular structures and within cell collectives.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_05841,Department of Health and Social Care,NIHR,"End of Life Care for Infants, Children and Young People: a mixed methods evaluation of current practice in the United Kingdom","Aims of the research_x000D_ This study will increase understanding about the different ways in which end of life care is provided for children and young people, and examine how these different models of providing end of life care impact on children and their families._x000D_ Background to the research_x000D_ Around 4500 babies, children and teenagers in England and Wales will require end of life care each year. Currently, the provision of this care varies across the country and little is known about how this variation impacts on children and their families. There are growing numbers of specialist palliative care services and children’s hospices in the UK, but there is little evidence to tell us how these services should be developed and what their role should be in supporting children and young people at the end of life. We also know very little about the costs of care and how best to use these resources to improve care for these children and their families._x000D_ Design and methods_x000D_ This research has three linked studies._x000D_ Study 1 (a survey) will identify the different models of providing end of life care for babies, children and young people (age 0-25) in the UK. To do this, we will ask all cancer services for children, teenagers and young adults, and other wards that provide specialist care to babies (neonatal units) and children (paediatric intensive care units) to tell us how end of life care is provided in their service, who provides this care and how much it costs._x000D_ Study 2 (a qualitative study) will learn more about these models by interviewing bereaved parents about their experiences of their child’s care at the end of their life, the impacts of this care, and how care could have been improved. We will also run group interviews with healthcare professionals to explore their experiences of meeting children’s end of life needs and their views on the factors that influence this._x000D_ Study 3 (a quantitative study) will investigate the impacts (which we call outcomes) of the different models of end of life care for children and their families. The findings from study 2 will help us to decide which outcomes to measure but these are likely to include quality of care at the end of life, place of death, whether care is planned (advance care planning), and treatments at the end of life. To do this, we will collect information from the medical records of around 4000 children treated in cancer services, neonatal units or paediatric intensive care units. We will also collect information from around 800 bereaved parents of children who received care in neonatal or paediatric intensive care units. We will use all this information to examine whether outcomes for children and families vary according to the different models of end of life care we identify in study 1, and assess the associated costs._x000D_ Patient and public involvement_x000D_ Two groups of parents have identified this as an important topic for research, suggested key outcomes to measure and provided input on how to involve families in the study. One bereaved parent is a member of the research team and a parent panel will input on what information to collect from families, how to do this and help the research team to interpret the results and develop information for parents and professionals at the end of the study._x000D_ Dissemination_x000D_ We will work with parents, professional organisations and charities to disseminate the findings to inform future guidance and service development for end of life care for children.","Research question_x000D_ Do outcomes for infants, children and their families, and resources required, vary depending on the_x000D_ model of End of Life (EoL) care that they receive?_x000D_ Background_x000D_ 4500 children die in England and Wales every year and although there are increasing paediatric palliative care and hospice services, these services vary in their professional configuration, services provided, funding sources and population served. There is little evidence on the models of care, quality of care, resourcing and outcomes of children and their families who use these services. Most of the recommendations in the NICE guidance are based on low quality_x000D_ evidence._x000D_ Aims and objectives_x000D_ Aim: To identify and investigate different models of providing EoL care for infants, children and young_x000D_ people, in terms of outcomes and experiences for children and parents, resource use and costs to families and the NHS._x000D_ Objectives:_x000D_ 1.To identify and describe current models of delivering EoL care to infants, children and young people_x000D_ in the UK._x000D_ 2.Identify barriers and facilitators to implementation of these EoL models_x000D_ 3.To assess inequalities in access/availability of these models of care._x000D_ 4.To explore whether the experiences and outcomes for child or parent vary dependent on the model of EoL care_x000D_ received._x000D_ 5.To compare the resource implications of the different models of EoL care for the NHS and families._x000D_ Methods_x000D_ This mixed methods study of three linked workstreams and cross-cutting health economics theme will_x000D_ examine three exemplar clinical settings which care for >50% of children that die each year:_x000D_ cancer services, paediatric intensive care units (PICU) and neonatal units (NNU)._x000D_ WS1: A questionnaire survey of Service Leads will systematically capture data relevant to current_x000D_ practice to providing EoL care, develop a typology of models of EoL care and associated resource use_x000D_ and costs. These models will inform the sample selection in WS2 & 3 and the analyses in WS3._x000D_ WS2: A qualitative study will explore how these models are implemented and experienced, and identify_x000D_ the important outcomes and resources associated with EoL care. Focus groups with healthcare_x000D_ professionals will explore experiences of meeting EoL care needs and views on the factors affecting_x000D_ access to EoL care including identification of any inequalities and barriers in access. Interviews with_x000D_ bereaved parents will explore experiences of their child’s treatment and care towards the end of their_x000D_ life and associated costs to them._x000D_ WS3: We will use routinely collected data to compare EoL outcomes (e.g. high intensity treatments,_x000D_ place of death) in children with cancer who have died and had different EoL models of care. Then_x000D_ prospective data collection in PICU and NNUs will collect data on 800 dying children including other_x000D_ outcomes (e.g. choices given to parents, symptoms). Data collection from the parents after death will_x000D_ provide additional information. We will assess whether outcomes vary according to the different_x000D_ models of EoL care and assess the associated resource use and costs._x000D_ Timelines for delivery_x000D_ This 4 year study includes ongoing dissemination to key audiences (parents, service providers,_x000D_ commissioners) via knowledge exchange events, web-based platforms, social media and_x000D_ clinical/academic forums._x000D_ Anticipated impact and dissemination_x000D_ The results will inform service delivery in order to utilise finite resources to maximise impact",7.2 END OF LIFE CARE,GENERIC HEALTH RELEVANCE HRCS22_09574,Health and Care Research Wales (Welsh Government),,Engaging care home residents in research: identification of barriers and facilitators and the development of an intervention to support residents in decision-making and advance planning for research (ENGAGE Study),"• Background Although twice as many people live in care homes as there are hospital beds, far less research is conducted in care homes [1]. This exclusion is partly due to practical difficulties and ethical concerns about including this ‘vulnerable’ group in research [2]. This has resulted in a poorer evidence base for the care provided for frail older people who often have complex care needs but are under-represented in health and care research. It is also important that older people living in care homes have opportunities to participate in research as members of society. The impact of COVID-19 on populations such as care home residents has highlighted the stark inequalities in health outcomes experienced by groups who are least likely to be involved in research [3]. Care homes are less research active than NHS settings, have access to less research training and support, and may benefit from interventions to support the development of an environment where opportunities for residents to participate are integrated into care [1]. One of the additional challenges in involving residents in research is the high prevalence of conditions such as dementia which results in around 70% of residents lacking capacity to provide consent to take part in research [4]. In these situations, a family member will be consulted to help make a decision about their participation based on the resident’s wishes and preferences about taking part. Residents without a family member to act as consultee may require an alternative decision-maker – usually a nominated member of the care team – to represent the resident’s wishes and preferences [5]. Knowing the resident’s wishes may help families and staff acting as consultees in the event of a loss of capacity [6]. However, discussions with older people about their preferences about research, including in the event of a loss of capacity, are rare and there are currently no legal mechanisms for prospectively appointing who acts as ‘consultee’ [7]. The Nuffield Council on Bioethics has long recommended the commissioning of research on the feasibility of developing a (non-binding) advance statement on research participation which could influence decisions on research participation after loss of capacity (Recommendation 18) [8]. Advance Care Planning (ACP) is increasing being used with care home residents to ensure that the care and treatment they receive when they are no longer able to make their own decisions is in accordance with their wishes and preferences prior to the loss of capacity [9]. The contents of ACP conversations can be recorded in the form of an advance statement or directive and may include choosing a proxy decision-maker (e.g someone to hold Power of Attorney). Extending these discussions to explore their research preferences may support residents’ autonomy through providing an opportunity to express their wishes about future research participation and who makes decisions about research on their behalf [6]. Discussions about complex issues under conditions of uncertainty, such as future research preferences, may benefit from additional support. Supported decision-making is particularly valuable for people with dynamic cognitive function and fluctuating capacity that place them at the margins of autonomy [10]. The development of tools to facilitate conversations may encourage residents to explore their views about participating in research and support them to make informed decisions about research opportunities. This may take the form of ‘Conversation Cards’ which are cards featuring pictures or statements that can facilitate putting thoughts and feelings into words. They have previously been developed for use in various contexts such as with palliative care patients discussing end-of-life issues and for people living with dementia [11] but have not previously been developed for use in research contexts. The views of older people living in care homes, and those who care for them, about the acceptability and utility of advance planning for research, including the use of supportive interventions such as Conversation Cards, have not previously been explored. • Aims and objectives: Building on existing links with organisations such as Social Care Wales and ENRICH Cymru (Enabling Research in Care Homes), the aim of this PhD Studentship is to identify ways in which to engage and support care home residents to make informed decisions about participation in research and to develop an intervention to support residents’ inclusion in research at a time when they may no longer have capacity to make a decision. This will be achieved through: - identifying resident-level barriers and facilitators to care home residents’ participation in research, including residents who are able to provide their own consent and those whose capacity to consent is impaired. - exploring care home residents’, families’, and staff’s views about encouraging early discussions to elicit residents’ preferences about research participation and facilitate Advance Care Planning for research. - developing a communication intervention to help care home residents discuss their preferences about participation in research. • Design and method: This PhD Studentship project will consist of three stages: Stage 1: Identifying barriers and facilitators to care home residents participating in research 1a. A scoping review of existing literature will be conducted to identify the barriers and facilitators to involving older people living in UK care homes in research. It will be conducted using established scoping review methods [12]. The review will focus primarily on resident-level factors that enable or prevent residents engaging with research, with the aim of identifying potentially modifiable barriers and facilitative interventions that will form the basis for the following work. 1b. Informed by the review findings, a survey will be conducted with residents, families, and care home staff across Wales, including those already part of the ENRICH Cymru network and those who are less/not currently research active. Participants will be recruited through organisations such as ENRICH Cymru, care provider organisations such as Care Forum Wales, and social media and those identified from the Care Inspectorate Wales database of care providers. The survey will be available in both online and paper-based formats to enable participation from a broad range of participants. Care home residents will be supported to participate through the provision of accessible information about the survey and the development of guidance documents for residents and the relatives and staff who will support their inclusion. Questions will be designed to explore participants’ views about current opportunities for residents to participate in research, decisions about participation, and the barriers and facilitators to their involvement. There will be a particular focus on issues related to equality, diversity and inclusion. Participants will also be invited to indicate if they are happy to be contacted to participate in an interview to be conducted in Stage 2. The findings from Stages 1a. and 1b. will inform the further stages of the project and identify areas for the development of future interventions. Stage 2: Exploring views about advance planning for research participation by care home residents Semi-structured interviews will be conducted with approximately 20-25 residents, families, and care home staff across Wales. The total sample size of 20-25 is based on the numbers anticipated to achieve sufficient saturation and information power (as determined by the research team) to address the research question and is informed by similar studies conducted previously. Participants will be recruited through the survey in Stage 1b and other routes such as research networks and social media. Participants will be purposively sampled to ensure maximum variation using a sampling frame developed a priori. Interviews will be conducted either in person or remotely (by telephone or a video conferencing platform such as Zoom) depending on factors such as visiting restrictions in place at the time. A sampling frame will be developed to ensure a broad range of stakeholders are included. The interviews will explore their views about residents participating in research and encouraging early discussions in order to elicit residents wishes and preferences and facilitate advance planning for research. Interviews will be audio-recorded and transcribed verbatim. Thematic analysis [13] will be used to qualitatively explore participants’ views and attitudes towards advance planning for research, including identifying barriers and facilitators and appropriate timing for these discussions. The findings will inform the next stage of the project. Stage 3: Development of a communication support intervention for care home residents Using intervention development methods (e.g MRC guidance on developing complex interventions [14](updated version pending)), a communication and/or decision support intervention will be developed to facilitate discussions with care home residents about research participation which will support informed decision-making and ACP for research. This may take the form of ‘Conversation Cards’ which will be developed to feature pictures or statements about the key concepts that are relevant to decisions about participation in care home research studies. These concepts will be obtained from Stages 1a, 1b and 2 and the wider literature on research participation decisions. The intervention will include mechanisms for recording the outcomes of conversations, with the potential for residents to record these formally as their advance statement of wishes about research in the event that they lose capacity to consent to future research studies. The intervention will be produced in collaboration with care home residents, families, and staff and undergo small scale piloting to explore the initial acceptability of the intervention using established acceptability tools [15]. To support the use of the intervention, an education/training resource will be developed for care home staff that will increase their knowledge and awareness about their role in supporting residents to access research opportunities. • Planning and use of resources: The use of project management support and tools will ensure that the project is conducted using maximal time and resources available. Project planning will include time and resources for skills development and training, the development of research protocols, and obtaining appropriate ethical opinion and other approvals/permissions as required. Sufficient time will be built into the research plan to allow for the recruitment of participants and data collection, which can be a challenge in some settings such as care homes. Costs have been requested to support travel to conduct interviews (where appropriate), a digital audio-recording device, vouchers to be offered to participants as a token of thanks, and costs to support Public Involvement through meeting attendance and travel costs for the Lay Advisory Group. Costs have also been requested for the student’s attendance at specific training courses (with travel) and conference costs to support the dissemination of the findings. Additional costs for this project, such as external transcription costs, graphic design input, and a stakeholder co-design event, are supported through a parallel application to Cardiff University’s School of Medicine PhD Studentship Consumables fund. • Method of analysis: This mixed methods project will combine evidence synthesis, survey, qualitative research, and intervention development methods. The survey data will be reported using descriptive statistics with open response data coded thematically. The qualitative data from interviews will be analysed using Thematic Analysis which, through identifying patterns and themes, enables a rich and detailed account to be provided which captures participants’ views and experiences [13]. The findings from the scoping review, survey and qualitative research will be triangulated to inform the development of the intervention. This will include identifying the intended recipient and implementer of the intervention, its component(s), content and format. Established intervention development theories and frameworks - including the MRC guidance on developing complex interventions – and the development of a logic model will underpin the intervention development process. • Expected outputs and outcomes: Initial prototype intervention The key output from this project is an initial draft of an intervention to support care home residents to have facilitated discussions about their research preferences and enable advance planning for research where appropriate. The form and content of the intervention will be informed by the earlier stages of the project, and following consultation with organisations such as Sight Cymru, but may take the form of ‘Conversation Cards’. The prototype intervention will be developed in preparation for future testing. Costs are included for expert graphic design support to ensure that the intervention is acceptable and accessible for care home residents. An application for further funding to evaluate the feasibility and effectiveness of the intervention will be developed towards the end of the project. Stakeholder summaries ‘One page’ summaries will be created for stakeholders including researchers, care home staff, and social and health care practitioners to share the key messages from the project. In addition, creative methods will be used to design accessible summaries for care home residents and their families using alternative formats such as graphic design or audio-visual media. Educational/training materials An additional output for this project will be the creation of a training and learning resource for care staff to complement the existing training for ‘research ready’ care homes currently under development by ENRICH Cymru Wales. This will be created towards the end of the project and will share the key findings from this project using a pedagogically focused approach to help care home staff understand the practicalities of supporting residents to access research opportunities. To enable access to the resource across Wales, the materials will be hosted on/made accessible through a sustainable online platform. This may be through the ENRICH Cymru website to complement resources around involving residents with limited capacity (invited contribution from Shepherd in 2019, https://www.swansea.ac.uk/enrich-cymru/enrich-cymru-for-care-home-staff/ ) or Social Care Wales’ curated research pages to complement to a curated page on research and capacity to consent (invited contribution from Shepherd in 2020, https://socialcare.wales/curated-research/research-and-capacity-to-consent ). Future research will evaluate and further refine the learning resource in collaboration with ENRICH Cymru and their network of ‘research ready’ care homes. Planned publications: 1 Scoping review findings on the barriers and facilitators to involving older people living in UK care homes in research: Journal of Nursing Home Research 2 Stakeholders’ views about current opportunities for residents to participate in research, decisions about participation, and the barriers and facilitators to their involvement from the survey: Journal of Social Care 3 Views about residents participating in research and facilitating advance planning for research from the qualitative interviews: Health and Social Care in the Community 4 Reporting of the intervention development process: Trials or BMC Research Methodology • Dissemination and impact: Dissemination In liaison with organisations such as Centre for Ageing and Dementia Research (CADR), and in addition to publications in academic journals, the research findings will be disseminated through a series of academic conference presentations. These will include: - International Clinical Trials Methodology Conference - British Society of Gerontology (Care Homes Special Interest Group) Symposium - National Social Care Conference - PRIME Centre Wales conference Research blogs will also be used to disseminate the findings, including through: - Centre for Trials Research - PRIME Centre Wales - NIHR Enabling Research in Care Homes (ENRICH) - NIHR Dementia Researcher - Institute Welsh Affairs (IWA) Impact Implementation planning will be informed by the Knowledge to Action (K2A) Framework [16], with the iterative development of a ‘pathway to impact’ plan during the duration of the project. Short term impacts will include increasing awareness about research with care home residents, families and staff both within the ENRICH Cymru network and care homes yet to join the network. Longer term impacts include supporting care home residents to participate in research and contributing to research capacity building in care homes in Wales and beyond. The ENRICH Cymru network has recently been funded by Health and Care Research Wales for the next three years as part of a planned expansion and development of the network. ENRICH Cymru have formally confirmed their support for the project. Opportunities will also be sought to share and develop this area of research with social care research organisations across the UK such as the NIHR School for Social Care Research.","Older people living in care homes, particularly those with dementia and similar conditions, are less likely to be involved in research than other populations despite often having the highest and most complex care needs. This is primarily due to the complex ethical and practical issues surrounding the inclusion of people unable to provide informed consent, which affects about 70% of care home residents. It is also because care homes are less ‘research active’ than other care settings. The current lack of research involving care home residents results in a poorer evidence-base for their care. The impact of COVID-19 on care home residents has highlighted the stark inequalities experienced by groups who are least likely to be involved in research. Care home residents are increasingly being encouraged to have advance care planning discussions about their care preferences. These could be extended to include discussions about research participation, although these more complex conversations may benefit from interventions to support and facilitate discussion. Effectively engaging care home residents in discussions about their views towards research may enable those who care for them to support their decision-making about involvement. It also provides an opportunity for their families and carers to represent their wishes and preferences in the event that they are unable to make their own decisions about participation in the future. This mixed-methods PhD project aims to explore how care home residents and their carers can be better engaged in research, and the barriers and facilitators to their inclusion. Using established intervention development methods, an intervention will be developed to support conversations about research with care home residents and facilitate advance planning for research participation. The findings will support opportunities for care home residents to participate in research, have their voices heard, and receive quality evidence-based care in the future.","8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_11619,Economic and Social Research Council,ESRC,Enhancement of ECHILD with a mother-child and Unique Property Reference number link,"Aim: To enhance the existing ECHILD database by 1) adding in maternal and sibling information via a pseudonymised mother-child link and 2) scoping the requirements for linking household unit information using Unique Property Reference Number (UPRN). The enhanced resource will facilitate policy-relevant research on the impact of family and household characteristics on child outcomes, including how maternal health, family violence, and children and young people's experiences of maltreatment or adversity influence child health, school outcomes and additional needs such as special educational needs and social care support. Objectives: 1. Link hospital records of births in ECHILD to maternal hospital records (for children born from 1997 onwards). This will enable analysis of the impact of maternal demographic and health characteristics (e.g. age, hospital admissions for chronic conditions or drug, alcohol, violence or self-harm, or prior pregnancies from 1997 onwards) on child outcomes. 2. Extend ECHILD to include hospital and education records for children born from 1984-1995. This will allow us to link children born from 1997 onwards to their mother's education (from 2001/2, mothers aged <=36 in 2021), care experience (from 2005/6, mothers aged <=31), and child in need support records (from 2010, mothers aged <=28 years). 3. Support re-use of ECHILD by producing meta-data and code and reporting linkage quality of the mother-child link. 4. Scope the options and obtain permissions for linking individuals in ECHILD to an encrypted Unique Property Reference Number (UPRN). This would enable linkage of de-identified indicators of environmental exposures and household characteristics. 5. Involve Government, the NSPCC and other third sector collaborators, parents and young people, in developing research priorities for the ECHILD mother-child and UPRN link. 6. Work with NHS Digital, DfE and ONS to support annual refreshes of the data, and to sustain the ECHILD resource for wider re-use.","ECHILD is a research database that joins together existing health, education and social care information for all children in England. We are using this linked data to better understand how education affects children's health, and how health affects children's education. ECHILD allows us to gain a detailed picture of the challenges that many children face as they grow up. Research using ECHILD will help government and the providers of services to better understand children's needs, to join up services, and to see which children might not receive the services they need. ECHILD currently uses data about children from schools, hospitals and children's social care. However, some key bits of information are missing. For example, including information on maternal characteristics (such as age, education, and health needs) could help inform the best ways to support young adults in becoming parents. Information on household and neighbourhood characteristics (e.g. number of siblings, overcrowding or air pollution) could provide evidence for government on the impact of these factors on health and education within and across household members. We are therefore proposing to further develop ECHILD by adding in maternal and household information. This will allow us to answer more research questions and generate evidence about the best ways to support young families. Individuals cannot be identified in the database and it can only be used for research and planning services. We have talked a lot with young people and parents to find out what they think about ECHILD and the kinds of questions they think future research should address. We will continue to involve the public throughout our new study.",2.4 SURVEILLANCE AND DISTRIBUTION,GENERIC HEALTH RELEVANCE HRCS22_06764,Department of Health and Social Care,NIHR,Enhancing CAMHS Referrals (EN-CAMHS),"Background_x000D_ More than 260,000 children in the UK were referred for help to Child and Adolescent Mental Health Services (CAMHS) in 2018/2019; and this number has risen steadily for the last five years. Following the difficulties young people have experienced through the pandemic, this is likely to rise further. About a quarter of children referred to CAMHS by their GPs, schools or parents are rejected for treatment by the service because the service isn’t well suited to the need, but mainly because the correct referral process has not been followed. This is clearly distressing for children and families who may wait a long time for an appointment at CAMHS and are turned away without necessarily being signposted elsewhere. The process is also costly to services because time is wasted reviewing documents about children who should have been referred for alternative help. We know that children are wrongly referred to CAMHS for a variety of reasons including: lack of awareness by referrers GPs/schools about when children should be sent to CAMHS; lack of knowledge by referrers about other support services; referrers not completing the correct documentation, as well as a range of other reasons._x000D_ _x000D_ Aim_x000D_ We aim to understand what the difficulties are in making referrals to CAMHS services. We want to improve the quality of referrals to CAMHS services so that only children and young people who can be helped by CAMHS are referred; and so that others can be guided to receive help they need elsewhere. A key objective is to talk widely with young people and families, with schools and GPs, people working in CAMHS and mental health leads so that we understand fully what the problems are and how we can develop solutions. We also aim to work with GPs, teachers and parents to find ways to develop and share information about alternative local resources for children who cannot be supported by CAMHS._x000D_ _x000D_ Design & Methods_x000D_ We shall work closely with CAMHS staff and agencies/stakeholders who refer children to CAMHS including GP practices, schools and parents. Through 8 focus groups, we shall document the CAMHS referral process and learn about where problems exist and the reasons why referrers do not always make good referrals nationally and locally. Through a further 4 focus groups, we shall discuss together possible ways to solve the problems identified. We shall also examine data from CAMHS sites to help us understand problems in the referral process. We shall explore problems at a local CAMHS site level and also at regional and national levels, supported by our mental health partners on the project. We shall talk extensively with people to try to find ways to solve the current problems._x000D_ _x000D_ PPI_x000D_ PPI is at the heart of this process. Young people and families who have experienced the CAMHS referral process (successfully and unsuccessfully) have worked with us on this grant application and will be involved throughout the project. We shall continue to work with these groups and families throughout the project._x000D_ _x000D_ Dissemination_x000D_ We want to share our lessons learned in this project widely to enable us to improve the quality of referrals to CAMHS across England. We shall publish our consultation work with referrers in academic journals, on our project website and share widely through social media, mental health charities and other organisations. We will use innovative and accessible techniques such as animation to reach children and young people as well as professionals.","More than 260,000 children in the UK were referred for help to Child and Adolescent Mental Health Services (CAMHS) in England in 2018/2019; and this number has risen steadily for the last five years. This number is expected to rise further following the difficulties Children and Young People (CYP) have faced through the pandemic. About one quarter of children referred to CAMHS by their GPs, schools or parents are rejected for treatment by the service because they are not deemed eligible for the service criteria, their service needs cannot be met by a local service but mostly because the correct referral process has not been followed. This is clearly distressing for children and families who may wait a long time for an appointment at CAMHS and are turned away. The process is also costly to services because time is wasted reviewing referral documents and following up with referrers about children who should have been referred for alternative help._x000D_ _x000D_ Aims and Objectives_x000D_ Our overarching aim is to find low-cost and widely reusable mechanisms to reduce inappropriate referrals. Our key objectives are to: 1) engage key stakeholders extensively to clarify the barriers they face in making appropriate referrals 2) analyse CAMHS referrals data to understand and identify problems 3) identify the specific requirements for viable and sustainable solutions 4) explore with key stakeholders how we can improve the referral process and provide signposting to alternative sources of help for CYP 5) identify how best the proposed solutions could be embedded into routine CAMHS referral pathways._x000D_ _x000D_ Methods_x000D_ We shall consult extensively with key stakeholders across 12 focus groups to clarify the criteria for referrals to CAMHS and to understand the barriers to making appropriate referrals including referrals to other services more suited/better aligned to the CYP need. We shall analyse the CAMHS referral data to understand problems in the CAMHS referral pathways. We shall aim to identify with stakeholders potential sustainable solutions to the current problems. We shall also examine the challenges to the adoption and sustainability of proposed solutions. _x000D_ _x000D_ PPI_x000D_ We shall build on our established collaborations with YP and their parents/carers/families. Regular consultations with YP and other CAMHS stakeholders will ensure the study remains relevant and meaningful. Our work will be informed by our advisory groups comprising YP, parents/carers and relevant practitioners/professionals. Our PPI consultations have already indicated the need for improvements to the CAMHS referrals processes._x000D_ _x000D_ Impact and Dissemination_x000D_ We shall identify the problems in CAMHS referrals processes working extensively with key CAMHS stakeholders across England, including young people and their families. Our confirmed collaborators, including our key referrers (GPs, schools), YP partners (CAMHS.Digital; Youth Mental Health Matters), parents/families partners (PLACE, CALM Connections), other third sector collaborators (e.g. MQ Mental Health; Anna Freud Centre; McPinFoundation; 42nd Street), four NHS CAMHS providers, and national and regional strategic leads for CYP mental health will ensure our outputs are shared widely with key beneficiaries. Our extensive dissemination strategy, supported by our long list of mental health and YP collaborators, will ensure maximum impact and enable our outputs to be disseminated to all relevant CAMHS stakeholders.",7.3 MANAGEMENT AND DECISION MAKING,MENTAL HEALTH HRCS22_18938,Wellcome Trust,,"Enriching Engagement Extended Pilot: Oxford's Institutional Research Engagement Fund programme","This proposal is to extend the initial Oxford Enriching Engagement pilot scheme (Institutional Research Enrichment Fund award 217077/Z/19/Z, 2019-2020) for devolved Wellcome Research Enrichment: Public Engagement funding. This extended pilot programme will build on, enhance and enrich the significant work that has already taken place to further increase the effectiveness and dynamism of this scheme to achieve the desired outcomes. Enriching Engagement will continue to support a diverse range of Wellcome-funded researchers to apply for, and if funded deliver, high-quality PER activities that result in tangible positive changes and outcomes, drawing upon the expertise of Oxford's PE staff. This extended pilot will also enable an increase in evidence to be gathered on outcomes, successes, challenges and lessons learnt from this approach across the whole pilot period (which, if this extension is funded, will be April 2019 - December 2021) and gather medium and longer term outcomes from the initial pilot phase. This learning has the potential to shape future engagement funding mechanisms and inform other institutions and networks on running their own devolved funding schemes - the latter has the potential to significantly increase the effectiveness and efficiency of these institutions' plans from the get-go, therefore offering significant added-value.",,2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),GENERIC HEALTH RELEVANCE HRCS22_14934,Marie Curie,,"Ensuring proactive efficient and effective out of hours palliative care provision: examining the role, contribution and impact of the HCA","Background/ Scope of the study: Most people spend their last year of their life at home, with many wishing to die there1-2. Multi-disciplinary teams comprised of GP, District Nurse, Specialist Palliative Care Nurse and Health Care Assistants (HCAs) have a key role to play in enabling this. HCAs are not regulated nor subject to standardised training, yet play a crucial role in the provision end of life care 3-5, often being the first to recognise and alert professionals to patient changes6. A patient priorities exercise demonstrated that out of hours (OOH) palliative care services (i.e. between 18.30 -08.00 hours) are integral to the care of patients at end of life7. Little is known however, about the role, contribution and impact HCAs have on OOH palliative care services. Aim: To examine the HCA role, contribution and impact on service delivery and patient care in out of hour’s community palliative care provided by hospice organisations. Methods: The study will be conducted over four phases. Phase one involves a scoping review of policy and literature, devised according to guidelines 27-28, to examine published evidence and policy that informs HCA practice, and to identify gaps in knowledge. Phase two comprises an online census of all Hospice Directors of Nursing or Community of Nursing Services Managers across the UK (n=260), to examine HCA workforce characteristics, roles, employment contracts, organisational and regulatory guidelines for service provision within community based OOH care. Each hospice will be initially contacted to identify and confirm the contact details of the Director of Nursing or Community of Nursing Services Manager. This will be followed by an email invitation with a hyperlink to the survey using Qualtrics, and two reminder emails. These findings will provide an understanding of the HCA role and OOH community based practices in hospice organisations. The survey data will also be used to inform the sampling matrix for the selection of case studies in phase 3. Data will be analysed using SPSS (v 23) and free text replies subject to content analysis and response rates according to CHERRIES checklist30. Phase three will comprise a series of in-depth organisational case studies31 across six hospices located in the UK. Hospices will be purposively selected as case studies to ensure a variety of organisational and service settings in which HCAs are involved in community based OOH care are included. The aim will be to explore the HCA role, contribution and impact on hospice organisation OOH service models and the extent to which they help patients stay in the home. Each case study will include in-depth interviews and documentary analysis. In-depth interviews will be undertaken with a purposive sample of HCAs (n=5-7), patients and carers (n=2-4), key health professionals (n= 3-5) and managers (n=2-3). Participants’ demographic information will be collected using a brief questionnaire. Documents relating to the HCA role and polices, and structures of community based OOH working will be obtained from each organisation. A framework approach34 will be used to guide data analysis processes. Phase four will comprise of deliberative workshops, consisting of two deliberative panels, with a total of 30 key stakeholders, held in two locations in the UK. The workshops will be held over a period of one day on two separate occasions. Deliberative panels with selected participants from each study site (i.e., HCAs, healthcare professionals and management n=10-12) and a purposive snowball sample of key stakeholders (patient and carer representatives (n=8), service managers (n=5) and policy makers (n=5) will be invited. The findings across the three previous phases will be integrated to provide a synthesis to inform phase 4 discussion. A four-phased deliberative panel approach will be adopted36; enabling facilitated discussion of findings, reflection, identification and development of strategic recommendations relating to HCA role in community based OOH service provision. Panels will be audio recorded and subjected to thematic analysis. Proposed Outcomes: First, it will provide a detailed understanding on the HCA workforce and the role they play in community based OOH palliative care provision. Second the results will raise the profile of HCAs and assist in future national workforce planning in hospice palliative care. Finally, the project will make policy and practice recommendations for enhancing the HCA role in community based OOH hospice care provision.","Most of the last year of a person’s life is spent at home with some care being delivered during out of normal working hour’s periods such as, evenings, night time and weekends. Out of hours palliative care in the home can be delivered by health care professionals including doctors, nurses and healthcare assistants. Healthcare assistants deliver most of the bedside patient care by helping qualified nurses. They are not required to be trained to any national standard and are usually only provided with informal job-related training. Research suggests that healthcare assistants support family members, provide most of the personal care to patients in the home and play a key role in delivering care to the dying. However, their role and influence on the delivery of out of hour’s palliative care is unknown but may help a patient remain at home. The research will be undertaken in four distinct but related phases. 1. We will look at what has already been published to find out what is known about the healthcare assistant’s role in out of hours community palliative care and what gaps in knowledge exist. 2. A survey, based on phase one findings, to identify how healthcare assistants are employed across UK hospices will be undertaken. This will look at out of hour’s community service provision and the assistant role, describing the numbers, types and training nationally as well as describing the organisational guidelines. 3. Case studies across several hospices in the UK, will explore the experiences of the health care assistants and the impact of their role in the out of hours period that help patients stay in their home. This will involve analysis of out of hour hospice service documents and interviews with members of the out of hours care team (such as healthcare assistants, specialist palliative care nurses, district nurses and general practitioners) patients and caregivers and managers of the service. Documents, transcriptions, and notes from the interviews will be analysed to identify themes. 4. Findings from across the three phases will be analysed and two workshops will be held with key stakeholders to consider how the research findings can inform policy recommendations about the role healthcare assistants in the delivery of out of hour’s palliative care.",8.1 ORGANISATION AND DELIVERY OF SERVICES;7.2 END OF LIFE CARE,GENERIC HEALTH RELEVANCE HRCS22_17406,Wellcome Trust,,Epidemics Ethics,"With this proposal we seek to establish a global community of bioethicists (to be known as 'Epidemics Ethics') combined with a range of online resources and activities together capable of providing real-time, contextually appropriate support to assist researchers, policy-makers, communities, and responders in identifying, analysing and addressing ethical issues arising in the context of global health emergencies. Epidemics Ethics will complement the newly established Public Health Emergency Preparedness and Response Ethics Network (PHEPREN) by providing: timely responses to ethical problems, access to networks of experts, an array of online resources including seminars, workshops, blogs, and ethics briefings on issues of current concern. A key aim of Epidemics Ethics will be to support the establishment of fair, collaborative partnerships to enable ethics research to be conducted by ethics scholars in low and middle-income countries in the context of broader supportive international collaborations. With this in mind, capacity building will be a key focus.",,"8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_17718,Wellcome Trust,,Epidemiology and outbreak prediction of yellow fever virus,"Yellow fever virus (YFV) outbreaks are escalating worldwide despite the existence of a vaccine. Global travel raises the chance that YFV will become established in Asia, where populations are not vaccinated and an outbreak would be catastrophic. Our ability to predict and control YFV outbreaks is reduced by our lack of knowledge about (i) transmission of YFV in its sylvatic reservoir (non-human primates) and (ii) how YFV escapes from this reservoir to spread amongst people in urban areas. Severe under-reporting in both humans and non-human primates hampers our ability to directly study YFV transmission behaviour. Recent advances in portable genome sequencing and virus genomic epidemiology (including phylodynamics) offer new opportunities to use virus genomic data to reconstruct unobserved outbreak dynamics, even when sampling is sparse. I will combine these techniques to improve our understanding of YFV epidemiology, by: (i) integrating viral genomic data into newly-refined YFV mathematical models for improved outbreak prediction; (ii) implementing phylodynamic approaches to identify drivers of sylvatic transmission, and; (iii) exploiting new strategies to generate virus sequences from traditionally neglected times and locations. My Fellowship research findings will improve YFV outbreak prediction and contribute to the development of refined vaccination strategies.","Mosquito-borne virus outbreaks are intensifying worldwide. Escalation of yellow fever virus (YFV) is particularly concerning because - despite widespread vaccination - it kills more than other mosquito-borne viruses. Severe under-reporting has prevented deeper understanding of how YFV spreads. We know strikingly little about YFV transmission in its animal reservoir, or how YFV escapes this reservoir to cause large outbreaks of human disease. Recent breakthroughs in virus genome sequencing and analysis offer new opportunities to generate data and reconstruct YFV transmission behaviour from sparsely sampled cases. My goal is to combine and exploit these new approaches to improve our understanding of YFV. I will implement innovative sequencing strategies to more effectively obtain YFV genomes from undersampled populations, and use these data to improve computational models of transmission. My research will identify what drives virus spread and improve our ability to predict and control outbreaks of YFV and other zoonotic diseases.",2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_03190,Medical Research Council,MRC,Epigenetic pathways in healthy aging and neurodegeneration,"Cognitive decline and dementia are among the most frightening and challenging aspects of aging. Age is the number one risk factor for mental decline although the underlying mechanisms remain unclear. Age and environmental risk factors interplay with genetic risks to impact the predisposition to cognitive impairment. Although most research has focused on the accumulation of protein aggregates that characterize diseases like Alzheimer’s, to date, therapeutics directed to the aggregates have been unsuccessful in clinical trials, highlighting the need to identify pathways that are upstream of plaques and tangles formation, or even new independent mechanisms. The chromatin state, composed of genomic DNA and post-translationally modified histones, is the molecular substrate for the integration of environmental stimuli and genetic instructions into the epigenetic landscape. Epigenetic regulation has emerged as a critical player in aging of lower organisms and, because of its role in integrating environmental stressors into the genome, represents a probable—and therapeutically tractable—player in age-related diseases. My studies on epigenetics of aging brain and Alzheimer’s disease (AD) have revealed that epigenetic plasticity is central to AD, and that healthy aging and AD are distinct epigenetic states. Genome-wide epigenetic analyses in human brain have revealed that different histone marks are differently associated with healthy aging and disease, and that they drive different downstream functional pathways, such as pro-disease (through H3K27ac and H3K9ac changes) and disease protective pathways (through H4K16ac changes) (Nativio et al, Nature Neuroscience 2018; Nativio et al, Nature Genetics; 2020). My overarching hypothesis is that among the molecular changes associated with aging, some are adaptive responses that counteract unavoidable stressful factors—in contrast to changes that favour disease onset. The identification of epigenetic protective mechanisms activated upon stress will be valuable to the design of strategies aiming to prevent, and perhaps treat, age-related neurodegeneration. For the future, I plan to mechanistically interrogate the epigenome to discover chromatin pathways that confer resistance to age-related neurodegeneration and that promote healthy aging. Because of the interplay between environment and genetic risk, I will also investigate the functional relevance of genetic risk variants in the context of epigenetic regulation.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_02289,Medical Research Council,MRC,Essential ionic triggers for enveloped virus entry,"To cause disease, viruses must first enter cells and many viruses do this by hijacking the endocytic network by mimicking cellular cargos. Once inside an endosome, a virus is effectively trapped, and must escape to continue its lifecycle. Here, we propose experiments that will provide new understanding of the endosome escape mechanism, based on our exciting new research findings. Viruses escape from endosomes using protein spikes that cover their exterior and mediate the merging of the viral and endosomal membranes (fusion). The spikes respond to chemical signals within endosomes causing structural changes, switching spikes from a pre-fusion to a fusion-active conformation. This allows spikes to interact with the endosomal membrane from the inside, and soon after, fusion occurs allowing the viral genome to enter the cell. How spikes respond to chemical signals is poorly understood, and highlighting this, we recently showed that an important class of viruses known as bunyaviruses require potassium ions (K+) to escape from endosomes. We showed K+ is required to switch spikes from pre-fusion to fusion-active states, which represents a paradigm shift in the understanding of virus entry. In this project, we will examine whether the K+ requirement is a characteristic of the wider bunyavirus group and whether other ions within endosomes mediate similar spike changes. Next, we will use cryo-EM and X-ray crystallography to reveal high-resolution structures of spikes in their pre-fusion and fusion-active conformations. Finally, we will use genetic techniques to identify spike residues that mediate these structural changes. Together these experiments will characterise endosomal fusion triggers and reveal the molecular details of how spikes become fusogenic, which is critical for virus entry. Improved understanding of endosome escape is required to aid the rational design of strategies to block spike fusogenesis; drugs that can do this would prevent infection and disease.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_03325,Medical Research Council,MRC,Establishing a network to catalyse collaboration for reducing immune ageing (CARINA: CAtalyst Reducing ImmuNe Ageing),"The CARINA network will actively engage with researchers from different disciplines, and at different career stages, to facilitate re-focussing of their research towards immune ageing and intervention. An initial meeting of the listed individuals will showcase a short summary of their activities (2 slides, 5 mins each). Breakout sessions of different groups will be set tasks to discuss how to deliver each of our aims, which are: A gap analysis of key research questions Establish new interdisciplinary partnerships Assimilate new technology and experimental systems Explore disciplinary cross-over with immunity Investigate routes for intervention Widen stakeholder engagement Each group will summarize their discussions and we will identify key observations that will be collated and sent to the whole network. This identifies initial key areas of potential for integrated expertise and would potentially deliver research impact. Subsequently there will be a series of online meetings where we will expand our discussions to further pinpoint areas that coalesce research activity towards a new direction for impact on ageing immunity. For these online meetings, we will encourage our early career academics to lead the discussions. A second face to face meeting, within the first 12 months, will use intermixing of discussion groups and structure the discussions around the promising areas for research - gaps that can ideally be met through interdisciplinary studies. Months 12-24 will follow a similar pattern of meetings, the difference being that we will be able to identify areas for interdisciplinary grants by the partners of the network. Subcontracted support from the British Society for Immunology (BSI) is crucial for effective communication and conference delivery and is more cost effective than recruiting a single Project Manager, as many different experienced individuals from the BSI will deliver support for different aspects of the network.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_17155,Wellcome Trust,,Establishing the role of Staphylococcus aureus RNA-binding proteins in regulating host adaptive responses and antibiotic resistance.,"Staphylococcus aureus is a major human pathogen associated with thousands of deaths each year. S. aureus can adapt to survive and thrive inside human immune cells (macrophages) and has developed resistance to multiple antibiotic classes making it a dangerous pathogen.  We hypothesise that S. aureus uses the interactions between proteins and RNA to control the adaptation to surviving inside human macrophages and to avoid being killed by antibiotics.   We will assess how the pathogen changes which proteins are bound to RNA when exposed to environmental challenges including those seen in human infection and antibiotic treatment. We will assess how these changes occur in the whole organism and in specific key proteins. We aim to engineer bacteria which have proteins which can’t properly bind RNA and to see if they are less fit to survive in simulated infection, when infecting human immune cells, in an insect model of infection and when exposed to antibiotic therapy.   The identification of critical pathways involved in the adaptation of S. aureus to the host environment may reveal new therapeutic targets for the control of infection.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_23265,The Health Foundation,THF,Ethnic inequalities in health care utilisation and care quality,"The number of people in the UK who are living with multiple long-term conditions (MLTCs) is rising, and those with MLTCs have reduced quality of life and a higher risk of mortality. There is evidence that people from some minority ethnic groups may be at a greater risk of having MLTCs when compared to people from the white majority population. There is growing evidence of ethnic inequalities in health care, in particular in relation to access to services. However, to date, there has been little evidence uncovered on ethnic inequalities in the prevalence, health care utilisation and care quality for people with MLTCs. About the project The project team will synthesise existing evidence and use nationally representative data to provide an up-to-date description of how MLTCs vary across ethnic groups in the UK. They will describe ethnic differences in health care quality (including continuity of care) and outcomes (including quality of life and survival) for people with MLTCs, and will provide evidence on these inequalities for policy makers, practitioners and academia. A combination of survey data and electronic health record data will be used to understand the level of health care need and the differences in each of these data sources. The project team will describe and appraise the current evidence, make it accessible to interested parties, and identify the gaps.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",GENERIC HEALTH RELEVANCE HRCS22_23264,The Health Foundation,THF,Ethnic inequalities in mortality and service use in people with mental disorders and multi-morbidities during the COVID-19 pandemic,"There are stark inequalities in the UK mental health care system for people from minority ethnic groups, including poorer access to evidence-based treatments and higher rates of detention. Life expectancy in people with mental disorders is 15 to 20 years lower than the general population, mostly due to preventable long-term physical health conditions – and this is also seen in minority ethnic groups. The COVID-19 pandemic has magnified these inequalities, with an alarming trend towards higher COVID-19 infections and mortality in minority ethnic groups. Research by King’s College London indicates higher rates of death during the UK lockdown in people with mental disorders. The pandemic has led to some routine health care being suspended, people being discharged from secondary care and care being delivered remotely. This, alongside people staying away from hospital, may have contributed to higher numbers of deaths in people with mental disorders, possibly with disproportionate impacts on people from minority ethnic groups. This research project will involve analysing more than 50,000 records from primary and secondary mental health care to assess whether changes to services as a result of COVID-19 magnified inequalities in care pathways, and whether it was associated with more deaths in people with mental disorders and long-term conditions. With the support of Black Thrive, a partnership for Black wellbeing, 50 interviews will be held with mental health service users across London, Birmingham and Manchester to understand their perspectives. All recommendations resulting from the research will be co-produced with people with lived experience, informing health care delivery and improving patient safety, as the pandemic continues.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",MENTAL HEALTH HRCS22_19828,Wellcome Trust,,Europe PMC 2021-2026,"In the next five years, the necessity for open science to solve global challenges will become increasingly apparent, and the need for Europe PMC as a critical piece of infrastructure will crystallise in the minds and usage patterns of researchers. The world of scientific publishing will undergo major changes, as routes for rapid and transparent publishing emerge, and efforts such as Plan S push towards universal open access. Europe PMC will support these goals by aggregating millions of articles and making them widely available. With a leading role in preprint aggregation and standards development, Europe PMC will be the go-to resource for searching life sciences literature from publication through review, revision, and citation. Publications at all stages need to be grounded in unambiguous links to supporting data, authors and reviewers, funding, and institutions, to build transparency and trust in the content; building these links will be a major direction for Europe PMC. Finally, transformative change in content search and retrieval will come from the development of AI methods that work on open access full text, encouraged by the Europe PMC platform for text and data mining, as well as the demonstration of machine learning benefits in user interfaces.",,1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),GENERIC HEALTH RELEVANCE HRCS22_19970,Wellcome Trust,,European Variation Archive,"The European Variation Archive (EVA, https://www.ebi.ac.uk/eva/) is a primary open repository for archiving, accessioning and distributing genome variation, including single nucleotide variants, short insertions and deletions (indels), and larger structural variants (SVs) in any species. Services to researchers include long-term archiving of variants; calculation of standard variant annotation; and an intuitive browser to query and view variants from studies or across an entire species. The EVA peers with the NCBI-based dbSNP and dbVar databases to form a worldwide network for exchanging and brokering submissions, and to assign permanent study and locus identifiers. As described in this proposal, the EVA will become solely responsible for variant locus accessioning for all non-human species. We will provide access to all of the controlled access variation data in the European Genome-phenome Archive (EGA) in the EVA browser. The EVA will continue leading community standards bodies, including tasks for the Global Alliance for Genomics and Health (GA4GH), to develop data models for variant representation, data formats and APIs for data integration with other resources. EVA’s comprehensive API is extensively used by translational and species-specific resources.","The European Variation Archive (EVA, https://www.ebi.ac.uk/eva/) is an open and freely accessible repository for single nucleotide and structural genetic variants from any species. It currently provides access to 520M unique variants across 232 studies containing 322,587 samples from 27 species. The EVA facilitates data access through its browser which allows users to query by study, gene, variant identifier or chromosomal location. Both EVA’s technology and data are used by projects such as H3Africa and Open Targets where they are integrated with project-specific data to improve services for the community",2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),GENERIC HEALTH RELEVANCE HRCS22_18453,Wellcome Trust,,Evaluating Health Impacts of Climate Adaptation Strategies,"Focus Area 3: Adaptation to climate change This research will develop a new evaluation tool for sustainable adaptation that will comprehensively incorporate direct and indirect health effects of adaptation interventions. It will explicitly focus on the wider effects of adaptation for the health and socio-economic wellbeing of the most vulnerable populations. The research will integrate insights from climate and hydrological sciences, social sciences, and health and economic sciences of disease burden and well-being.   The evaluation tool will be developed through cross-disciplinary interaction on concepts and methods, and then calibrated through empirical study of existing adaptations, focused on flooding. Flood risk is a prevalent climate impact globally and diverse adaptations currently being implemented globally. New empirical insights into flood adaptation will be generated focussing on three adaptation interventions for: flood infrastructure, planned relocation, and catchment-based planning across Ghana, Ireland, and UK. The project will undertake proof-of-concept evaluations for these interventions to develop the tool, generating specific lessons on flood adaptation and wider lessons on climate change adaptations more broadly. The research will engage with UK stakeholders and other national and international agencies to ensure the tool, evidence and planned user interface will be policy-relevant for adaptation planning at the global scale.","Climate change will have widespread impacts: plans and investments are underway to adapt to those risks. Both climate impacts and adaptive responses have consequences for health and wider well-being. Is adaptation sustainable? Our answer is that adaptation a) needs to include hidden impacts on health and wellbeing of those affected; and b) ensure that those investing in adaptation judge it in terms of effectiveness, fairness and robustness to future change. We will develop a tool to help make decisions that meet these criteria. We will test the tool by evaluating different types of adaptations to flood risk that involve building hard defenses, moving people away, or preparing communities to cope and recover. The project will lead to a) a tool that we will develop alongside agencies that will use it; b) a wider understanding of sustainable adaptation; and c) specific knowledge about the health impacts and sustainability of flood adaptations.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_05847,Department of Health and Social Care,NIHR,Evaluating Patient Outcomes and Therapies for Inherited Optic Neuropathies,"Background Inherited optic neuropathies are a group of disorders characterised by severe bilateral loss of central vision. The two most common forms are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON patients carry one of three mitochondrial DNA (mtDNA) mutations (m.3460G>A, m.11778G>A, and m.14484T>C), whereas most patients with DOA harbour pathogenic mutations in the nuclear gene OPA1 (3q28-q29). Recent studies have shown promising results with gene replacement therapy in LHON patients carrying the m.11778G>A mutation treated within 1 year of disease onset. As part of this major translational drive for inherited optic neuropathies, it is imperative that we clearly define the natural history of the disease in treatment nave patients and establish better outcome measures to evaluate the benefit of potential interventions on quality of life (QoL). Aims and objectives As part of this NIHR Advanced Fellowship, I will: Investigate the natural history of LHON. Evaluate if gene therapy can benefit patients carrying the m.11778G>A mutation who have been affected for longer than 1 year (i.e. chronic LHON). Develop a patient-reported outcome measure (PROM) for patients with LHON and DOA.Design and Methods Prospective Natural History Study of LHONI will recruit 120 patients with LHON carrying one of the three common mtDNA mutations and with disease duration of up to 10 years. Patients will be seen at baseline and on a 6-monthly basis thereafter. A standard assessment protocol will be used to collect data on best-corrected visual acuity (BCVA) and other parameters of optic nerve structure and function. Gene Therapy Trial for Chronic LHONI will recruit 30 patients carrying the m.11778G>A mutation with disease duration of more than 1 year and up to 5 years into a randomised, double-masked, sham-controlled, clinical trial of rAAV2/2-ND4 (GS010). Patients will be randomised in a 1:1 ratio to an intravitreal injection of GS010 or sham treatment in both eyes. The follow-up period will be 24 months. The primary efficacy endpoint will be the change in LogMAR BCVA from the pre-treatment baseline to 24 months post-treatment. A mixed-effects analysis of covariance (ANCOVA) will be used to determine the effect of treatment. Patient-Reported Outcome Measure (PROM) for Inherited Optic NeuropathiesA conceptually grounded and psychometrically robust PROM will be developed that assesses and measures the QoL of individuals with LHON and DOA, across multiple domains. Anticipated Impact and Dissemination This NIHR Advanced Fellowship will provide valuable information on the evolution of visual parameters in LHON, which can be used both in clinical practice to advise patients and to evaluate therapies. The gene therapy trial for chronic LHON will inform us if this approach can be beneficial in later stages of the disease, and if relevant, the data can be used to power and plan for a larger study. A validated PROM to assess QoL in LHON and DOA will be useful, not only for monitoring disease, but also as an important outcome measure of the patient experience in future clinical trials.","Background Inherited optic neuropathies are genetic diseases that damage the optic nerve - the specialised cable that sends visual information from the eye to the brain. They affect at least 1 in 10,000 individuals in the United Kingdom, resulting in severe loss of vision and blindness in the young adult population. Although a large number of genetic defects (mutations) can cause inherited optic neuropathies, the damage caused to the optic nerve is invariably due to impaired function of mitochondria, which are the powerhouses producing all the energy that a cell needs to survive. The two most common inherited optic neuropathies are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 70% of all patients affected with LHON carry a particular mutation in mitochondrial DNA, m.11778G>A, with the number referring to its location in the mitochondrial genetic code. Most patients with DOA carry a mutation in the gene OPA1 which is located on chromosome 3 (3q28-q29). The management of patients with inherited optic neuropathies remains challenging as there are limited treatment options to slow or prevent ongoing loss of vision. This situation is further complicated by important gaps in our understanding of how the disease progresses over time and how best to measure the significant visual impairment that patients face in their day to day lives. Fortunately, important progress is being made. We have successfully used a gene therapy product (GS010) injected in the eye to replace the defective gene that causes LHON in patients carrying the m.11778G>A mutation. Patients who were treated within 1 year of being affected experienced significant improvement in their vision. Aims The aim of this fellowship is to improve the management of patients with LHON and DOA. It will provide us with the tools needed to evaluate the benefits of potential treatments for these blinding diseases. Design and Methods Prospective Natural History Study of LHONI will recruit 120 patients with LHON who have lost vision for up to 10 years. The participants will be assessed every 6 months to measure their vision and determine how well their optic nerves are working. Gene Therapy Trial for Chronic LHONI will recruit 30 patients with LHON carrying the m.11778G>A mutation who have experienced visual loss for more than 1 year and up to 5 years (i.e. chronic disease). The participants will be split equally into two groups. One group of 15 patients will receive the gene therapy injection (GS010) in both eyes. The other group will receive a sham injection in both eyes (i.e. the eye will be pressed with a syringe that has no needle to simulate that an injection has been given). All participants will be followed for a period of 24 months to monitor their vision. This study will tell us if patients with LHON can experience visual improvement when treated later in the course of their disease with gene therapy. Patient-Reported Outcome Measure (PROM) for Inherited Optic NeuropathiesThrough a series of patient interviews, we will develop, refine, and then validate a questionnaire (PROM) that enables patients with LHON and DOA to report their experience of living with their condition and to assess their quality of life, which will be important when evaluating treatments. Patient and Public Involvement (PPI) I have worked closely with several patient advocacy groups to establish the aims of this fellowship proposal. I will discuss the progress made and the results obtained as part of the PPI activities planned during the course of this research programme. I will disseminate our results to the wider research community through publications in peer-reviewed journals and presentations at scientific conferences.",6.2 CELLULAR AND GENE THERAPIES,EYE HRCS22_06015,Health and Care Research Wales (Welsh Government),,"Evaluating effectiveness, safety, patient experience and system implications of different models of using GPs in or alongside Emergency Departments.","Hospital emergency departments (EDs) are under increasing, sometimes extreme, pressure. Patients are experiencing long hours of waiting to be seen. We have seen media reports of emergency services in crisis. This situation has arisen partly because people attend EDs with problems that GPs could deal with. Finding better ways to assess and treat patients coming to EDs could have a major impact on the experience and care of the millions of people attending EDs and on all NHS services by providing evidence of how best to manage resources. _x000D_ Many EDs now work closely with GPs in three main ways: _x000D_ • Assessing patients and sending them back to their GP; _x000D_ • Assessing patients and sending them to a GP clinic next door to the ED; _x000D_ • Placing GPs in the ED as extra staff to provide treatment._x000D_ _x000D_ It is not known how well these arrangements provide care or if they make a difference to how quickly patients receive treatment and referrals for tests and other services. Our study will look at what works, for whom and in what circumstances._x000D_ _x000D_ In this study we will look at:_x000D_ _x000D_ 1. What are the different ways of working, how are they are organised and how common are they? _x000D_ 2. How do they work in practice? Do they do what they were meant to do? _x000D_ 3. Hospital admissions, re-attendance, waiting times, patient safety and staff and patient satisfaction _x000D_ 4. What are the key factors that lead to a better service? _x000D_ _x000D_ We will survey all 200 EDs in England and Wales to find out how they work with GPs. We will call together an expert group of health care professionals, policy makers, patients and public who will examine the findings and _x000D_ 1. Decide how best to group together the different ways of working_x000D_ 2. Choose a number of problems that people often go to GPs and EDs for, such as back pain or fever in children_x000D_ This will help us in the next part of the study when we will choose 12 EDs to look at more closely, three for each of the main ways of working with GPs and three EDs without GPs. We will collect information from patient case notes and hospital clinical records. We will interview patients, doctors and hospital staff. We will look at any differences in how the chosen common problems are managed by GPs and ED doctors, including treatment costs and how patients felt about their experience. _x000D_ _x000D_ Overall, our results will show which are the best ways of working and why. The findings will be presented to a second meeting of health care professionals, policy makers, patients and public members who will help us decide, using the evidence we have gathered, which way of working delivers the best care for patients and makes best use of NHS resources. They will help us create a toolkit to guide emergency services commissioners to plan and put into practice the best arrangements for using GPs in EDs in their particular circumstances. _x000D_ _x000D_ We will report our results to health professionals through publications, presentations, training events and meetings. We will use national, local and social media and patient networks to inform patients and the public._x000D_ _x000D_ Our study team brings together professionals with a wide range experience in primary and emergency care and includes two active members of the public who have experience of using EDs. The public contributors will work with the researchers at all stages to plan and undertake this study and publicise the results. Members of the public will also be supported to play an active part in our expert group meetings.","Background: The emergency care system is in crisis and evidence is needed urgently to understand how to manage workload and demand to safely achieve the highest standards of clinical and operational care,(1) and whether the recommended addition of co-located GPs,(2) adds value. The evidence base to support service models of General Practitioners (GPs) working within EDs is weak,(3-5) with three main GP-ED models in use: GPs working geographically adjacent to EDs; GPs serving in a triage and screening capacity; and GPs fully integrated into ED service provision.(6) The effectiveness of each model on service provision and quality and safety of care delivery is unclear._x000D_ We therefore propose a realist evaluation to understand how the contextual differences between the three main GP-ED models (patient, staff and organisational factors) influence how the services function in different settings (mechanisms) to generate variations in intended and unintended outcomes (effectiveness and safety of care provided; patient and staff experience; resource consequences and economic impact),(7) based on an effective practice framework.(8)_x000D_ Method: Phase 0: Preliminary work involving analysis of National Reporting and Learning System ED patient safety incident reports for the most frequent and harmful incidents related to GPs and ED clinicians.(9)_x000D_ Phase 1: A national Survey will be undertaken to characterise which GP-ED models are in use in England and Wales and the aims of the services they provide. Also, a rapid realist (literature) review of the context and mechanisms by which different models achieve their outcomes, (10) to generate initial working theories and iterate the GP-ED models taxonomy.(6) This will be explored and clarified in a Stakeholder conference and a set of ‘marker conditions’ (presenting conditions thought to be managed differently by GPs and ED clinicians i.e. investigation & admission rates) will be confirmed for subsequent in-depth analysis in Phase 2._x000D_ Phase 2: Using a mixed methods design, 12 study sites will be purposively sampled for quantitative data collection (Interrupted Time Series analysis of NHSE/NWIS (Wales) and Emergency Care Dataset analysis, plus description of case mix and outcomes, and for economic/resource use evaluation). This will be integrated with qualitative data collection (‘marker conditions’, field observations, key informant interviews, incident report analysis) using techniques such as pattern matching for a mixed methods synthesis. Three sites will be selected for each of the three main model types and three that do not use co-located GPs. _x000D_ Phase 3: Segmented regression analysis of quantitative interrupted time series data, economic modelling of resource and outcome data, combined with field observation and interview data will inform the realist evaluation to compare how the different contexts and mechanisms lead to the outcomes across the GP-ED models and identify what works for whom and in what circumstances. Findings will be provided to Survey participants and a second Stakeholder conference for feedback on credibility, transferability and discussion. _x000D_ Outcomes: to produce a transferable evidence base for commissioning and delivery concerning effective use of GP skills in different ED settings in terms of: cost-effectiveness; resource use; safety of care; patient and staff experience; capacity considerations and training; and sustainability and resilience, in the context of local systems.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_13433,Wellcome Trust,,"Evaluating prevalence, incidence rates and mortality attributable to antibiotic-resistant bacterial infections and potential biases caused by underuse of blood culture in Wahidin Hospital, a tertiary-care hospital in South Sulawesi, Indonesia","The burden of antibiotic-resistant bacterial infection (ARBI) in low and middle-income countries (LMICs) is largely unknown. Microbiology data is rarely analyzed and reported. Few publications available did not take account of bias caused by low number of blood culture utilization, categorize ARBI based on infection origin (community-onset or hospital-onset) and evaluate mortality attributable to ARBI. I propose to evaluate the situation of ARBI in a tertiary-care hospital in 2015-2018 in Sulawesi, Indonesia. I will analyze three routinely available data sets; including microbiology, hospital admission and antibiotic prescription data sets. I will use standard methods to estimate prevalence, incidence rates and mortality attributable to ARBI among bacteremia patients. I will categorize infection origin as recommended by WHO GLASS. I will evaluate and describe timing of blood culture collection and antibiotic prescription among patients who had parenteral antibiotic prescribed. I will evaluate whether reported parameters for ARBI were associated with timing of blood culture collection and antibiotic prescription.  The results from this study will improve our standings on ARBI, diagnostic stewardship and antibiotic stewardship in Indonesia, and could be used to inform healthcare workers and policy makers in the country and other LMICs on resource allocation and intervention for actions against ARBI.","Antibiotic-resistant bacterial infection (ARBI) is an infection caused by bacteria that can stop antibiotic from working against it. This causes people to be sick for longer and increases death risk. Researchers regularly analyze data of bacteria growth by blood culture test. However, in developing countries, those data are rarely analyzed and underuse of blood culture tests could bias the results. I will evaluate ARBI situation in a tertiary-care hospital in 2015-2018 in Sulawesi, Indonesia. I will analyze large data sets and report parameters representing ARBI situation. Using antibiotic prescription data, I will also evaluate whether the blood culture test is used as often and within the timing as it is recommended and whether the underuse of blood culture test led to ARBI reports bias. The study results will improve our standings on ARBI and could be used to inform healthcare workers and policymakers for actions against ARBI.",2.4 SURVEILLANCE AND DISTRIBUTION,INFECTION HRCS22_07414,Department of Health and Social Care,NIHR,Evaluating remote delivery of Cognitive Remediation for people severe mental health conditions,"Background: Cognitive impairment is one of the main predictors of poor functioning and recovery in people with severe mental health conditions (SMI). Cognitive remediation (CR), a psychological treatment, addresses these cognitive problems in people with SMI and meta-analytic studies suggest that CR benefits both cognition and functioning. Successful NHS implementation of CR could improve recovery trajectories and reduce the disease burden on service users, services, and society. The ECLIPSE Programme Grant for Applied Research (PGfAR) evaluated NHS implementation in psychosis services and developed capacity for routine therapy delivery across the NHS. One clear result from this and other studies is the importance of a therapist for achieving benefit. Aim: To expand the work of ECLIPSE by increasing access to CR benefit by evaluating therapist-supported remote CR. This involves developing training resources for remote delivery for both service users and therapists to support remote CR delivery and evaluate implementation feasibility and acceptability in NHS services. Objectives: 1) to develop resources for therapy delivery and resources for service users to overcome the digital divide so remote CR can be trained and delivered on digital technology platforms (WP1); 2) to evaluate the feasibility and acceptability of the therapy procedures (WP2); 3) to estimate resource utilisation for this approach (WP3). Work plan: We have already had service user support in developing this proposal but in addition in Step 1 we will recruit a dedicated service user advisory panel to support the adaptation of therapy procedures and development of training resources for digital inclusion. In Step 2 we will conduct an acceptability and feasibility evaluation of the remote CR procedures using a case series design including 25 participants. All participants will be assessed before and after therapy with measures assessing personal goals, functioning and cognition as well as quality of life and service utilisation. Participants will be invited to take part in exit interviews to explore their therapy experience in detail. In Step 3 we will conduct acceptability and feasibility analyses and report on indications of therapy usefulness and cost-benefit. The programme will deliver a therapy manual, video training resources for service users and augment existing CR therapist training procedures with recommendations for technology use and best practice for remote delivery. Timeframe: This programme will be completed in 12 months. Impact: The resources developed and evaluated in this programme will allow NHS services to expand the implementation of CR. This will be particularly beneficial for more rural mental health service providers and for service users for whom travelling to the clinic represents a barrier to accessing care. The cost estimation will provide information on the cost of the remote CR method. Dissemination: The therapy manual, video training resources and recommendations for best practice will be widely available to the NHS and incorporated into the existing training platform. The feasibility and acceptability results will be disseminated via peer review publications and to service user and staff participants.","Background: Many people with a severe mental health condition experience cognitive problems. These include difficulties in paying attention to a conversation, remembering or learning new information, scheduling and organising tasks. Cognitive difficulties have a severe and negative impact on functioning and recovery in this group. Cognitive Remediation (CR) is a therapy targeting cognitive difficulties and supporting functional recovery in people with severe mental health conditions. This approach is increasingly recommended and included in clinical guidelines. Our previous work: We recently completed a NIHR Programme Grant for Applied Research evaluating ways in which CR can be used in NHS early psychosis services. This research also developed capacity for this therapy to be delivered more routinely across the NHS. One aim of this research was to compare distinct CR delivery methods with different levels of therapist input including individual one-to-one CR and CR delivered in a group format. Crucially the study results showed that both group and individual CR can improve service users recovery goals. However, restrictions on face-to-face contact limit their feasibility, and like other psychological therapies, CR will need to be adapted for remote delivery. This requires procedures and training resources to be co-developed with service users and technologies tested. Our aims: There is no evidence suggesting that delivering CR remotely is feasible or even acceptable to people with severe mental health conditions. This proposal will expand on our previous work by evaluating therapist supported remote CR. This will be the same therapy format but delivered entirely using remote digital platforms using video meetings and remote monitoring of a service user s laptop. Work plan: We will develop procedures and training for therapist supported remote CR delivery and test their acceptability, ease of use and feasibility. We will do this with the support of a service users advisory panel to guide our decisions. Our therapy evaluation will include twenty-five individuals with a wide range of severe mental health conditions. We will also include those with long-term conditions identified as needing this intervention the most by clinical guidelines in England and Scotland. Impact: Therapist supported remote delivery of CR will be important during times when social distancing measures are imposed. However, developing a therapeutic approach that is acceptable and feasible will also allow wider therapy dissemination. One finding from our previous research is that the therapist input is crucial to achieve improvements. Offering independent therapy may not be a good alternative option for those who find it difficult to attend appointments or must travel a long way to reach the clinic. For these individuals, therapist supported remote CR may be a more suitable alternative.",5.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_05922,Department of Health and Social Care,NIHR,"Evaluating the Safety, Acceptability and Efficacy of Autonomic neuromodulation using trans-cutaneous vagal stimulation in uncontrolled hypertensive patients (SCRATCH –HTN): a pilot study evaluating a novel noninvasive device-based strategy","Hypertension or high blood pressure (BP) is the leading cause of cardiovascular morbidity and mortality. Despite the widespread availability of antihypertensive drugs, nearly 40% of all treated patients fail to achieve the recommended level of BP. Several factors contribute, including drug-resistance, poor adherence to prescribed medications, and/or drug-intolerance. For the uncontrolled hypertensive patients, the lack of an alternative therapy is an urgent unmet clinical need. One potential strategy is to target the autonomic imbalance that many hypertensive patients exhibit. Exploiting this therapeutic pathway and taking advantage of recent advances in device-based neuromodulation, we developed a novel device-based solution for hypertension treatment. The device works by algorithm-based electrical stimulation of the specific region of the external ear (tragus), innervated by the branches of several cranial (Vth, Xth) and spinal nerves (C2/3). This form of transcutaneous autonomic neuromodulation (tAN) non-invasively redresses the autonomic imbalance leading to a reduction in sympathetic activity. A proof-of-concept study involving drug-resistant/uncontrolled hypertensive patients demonstrated that our proprietary tAN algorithm effectively reduces the systolic BP in the drug-resistant cohort by >10mmHg, with the beneficial effect lasting for >1 month after the discontinuation of therapy. This project aims to develop the tAN into an effective treatment strategy for hypertension by 1) undertaking a randomized, double-blind, sham-controlled study to evaluate the safety, acceptability and efficacy of tAN in hypertension; 2) building a pre-production tAN device compliant with the regulatory medical, safety and electrical standards; 3) undertaking a health economics study to determine the cost implications and adoption challenges of the technology. By the completion of the project, we expect to have the clinical data, ISO13485 quality management system and a medical device regulations-compliant device ready for regulatory approval within 6 months. If efficacious, this device is a potential game-changer which provides a non-invasive, self-administered, low-cost hypertension treatment option.","Raised blood pressure (BP) or hypertension is the single most preventable cause of stroke, heart attack, heart failure, cardiovascular death, and is the leading risk factor for developing dementia, and kidney failure. By lowering BP the combined risk of associated disability and death can be reduced by more than a half. However, despite the widespread availability of antihypertensive medications, ~40% of all treated hypertensive patients fail to achieve the recommended level of BP ( The brain subconsciously controls the heart and blood pressure by sending commands via specialized nerves. In hypertensive individuals, there is an imbalance in the activities of these nerves and currently available medical treatments do not target them effectively. Studies have shown that non-pharmacological approaches can potentially redress this imbalance, and thereby reduce BP in these patients. Several companies are working on solutions using this approach, all involve invasive devices and/or in-hospital procedures that are costly. In contrast, the new solution is non-invasive, does not require hospital procedures/stay, and of low cost. Results of our proof-of-concept study show that using a very specific electrical stimulation algorithm, applied non-invasively to the skin of the outer ear (this approach is called transcutaneous autonomic neuromodulation) BP can be effectively reduced in drug-resistant patients. The aim of this project is to develop this new technology into a clinical treatment of hypertension ready for regulatory approval and clinical adoption. We will: 1) undertake a clinical study designed to determine the treatment efficacy in a large cohort of hypertensive patients; 2) design and build a pre-production prototype device in compliance with the regulatory standards; 3) undertake a health economics study and to develop an effective strategy to facilitate adoption of the technology by the NHS. We have set-up a strong PPI initiative and interviewed patients. All interviewed patients considered this solution to be highly preferable to drugs. If using the new method the BP is reduced by >10 mmHg in just the drug-resistant hypertensive population, it would save the NHS >£500m in annual costs by reducing the incidents of associated strokes, coronary heart disease and kidney failures. It is expected that the treatment of high blood pressure will be regulatory approved and available for clinical use within 6 months and to become a recommended NICE intervention for the treatment of hypertension within 5 years after completion of the project.",6.3 MEDICAL DEVICES,CARDIOVASCULAR HRCS22_01714,Medical Research Council,MRC,Evaluating the impact of the Mais Médicos (More Doctors) programme in Brazil,"The Programa Mais Médicos (more doctors programme) (PMM) is a key strategy to expand Brazil's family health strategy in underserved areas. Little robust evidence exists on the impact of interventions to increase human resources for health (HRH) such as the PMM on access to healthcare, health outcomes, and wider health system impacts. The evidence gap is largest in low- and middle-income countries where distributional inequalities in HRH are greatest. Robust impact evaluations of the PMM as an internationally recognised supply-side intervention is vital to inform HRH policy in Brazil and globally. We plan to evaluate the PMM using quantitative and qualitative methods. We will conduct quantitative analysis of all municipalities for national generalizability. For qualitative analyses, we will select 24 municipalities in the Integrated Development Region of the Federal District (RIDE/DF) and the state of Paraiba that have introduced PMM doctors. We will conduct a quasi-experimental evaluation of routinely available data using difference-in-difference methods to assess the impact of the PMM on mortality and morbidity. We will expand these analyses to examine heterogeneity of impact across programmatic factors (e.g. different municipalities and types of doctors) and population characteristics (including age, sex and racial groups) to draw inference on health inequalities. We also plan to evaluate whether PMM uptake across municipalities was in line with Federally-established criteria of need, and what effect expansion in non-priority municipalities may have had on overall impact. We will conduct qualitative research in the form of clinic observation and semi-structured interviews with national implementers, local health managers and PMM doctors to better understand facilitators and barriers to successful implementation, including broader health system constraints and how these were addressed by managers and clinicians.",,"8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_06031,Department of Health and Social Care,NIHR,Evaluating the integration of the Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) into primary care and its impact on patient treatment and care.,"When a person becomes seriously ill health professionals treating them need to make decisions quickly. They may have limited information about the person’s medical history or about their wishes about treatment. The sick person may not be able to tell them what matters to them. To help health care professionals decide what is the best treatment for that person Emergency Care Treatment Plans can be used. These record what the person would or would not want to happen in certain situations. The plans are usually written by the person’s doctor after discussing it with them. One type of plan, called ReSPECT, is now being used in many NHS hospitals in the UK. However, it might be better to write these plans when the person is living at home rather than after they have been admitted to hospital. ReSPECT forms are now being used by GPs and other primary care staff in the UK. _x000D_ _x000D_ We want to find out:_x000D_ • What patients and their families who have been involved in the ReSPECT process think about it?_x000D_ • What GPs and care home staff think about the ReSPECT process?_x000D_ • What members of the public think about emergency care treatment plans?_x000D_ • What other health professionals such as ambulance staff think about the ReSPECT process._x000D_ • What makes it work well and what stops it working well? _x000D_ • How does the ReSPECT process makes a difference to decisions about medical treatment when a person is seriously ill?_x000D_ _x000D_ To answer these questions we will use different methods to gather information about the ReSPECT process in primary care. _x000D_ 1. We will identify 12 GP practices in three different areas across England. In each practice we will speak to people who have a ReSPECT form. If the individual cannot take part, we will speak to a member of their family. We will ask the person or their family about their experience of having the conversation with their doctor. We will also ask them what they think about the process and the form. We will speak to GPs who complete ReSPECT forms to find out their views and to managers of care homes who have residents with a completed ReSPECT form._x000D_ _x000D_ 2. To get a wider range of views we will:_x000D_ a. speak to groups of other health professionals_x000D_ b. speak to members of patient organisations and faith leaders._x000D_ c. carry out two national surveys, one for GPs and one for the public_x000D_ _x000D_ 3. We will look at the medical records of people who have a ReSPECT form in our 12 GP practices. We will find out if these people have been seriously unwell since the form was completed. If they have, we will check to see if the decisions made when they were ill matched the recommendations on their ReSPECT form._x000D_ _x000D_ 4. We will bring together all the information we get from these different methods and use it to work out how the ReSPECT process can work best to improve patient treatment and care._x000D_ We will present our findings at a stakeholder meeting. We will invite patient representatives and health and social care professionals to this meeting. We will ask their views about our research and how we can use it to improve the ReSPECT process._x000D_ We will develop information materials and videos about the ReSPECT process based on our research for patients, their families, and health care professionals. We will distribute these through local, regional and national organisations to make sure our findings help to improve patient’s treatment in emergency situations._x000D_ _x000D_ Our study lay advisory group will advise us on every stage of the study and help with our analysis.","Research questions: _x000D_ 1. How, when and why is the ReSPECT process used in primary care?_x000D_ 2. What is the impact of the ReSPECT process on patient treatment and care?_x000D_ _x000D_ Background: Emergency Care Treatment Plans (ECTPs) integrate DNACPR recommendations into overall treatment plans for use in acute or emergency situations when recovery is possible or may be unlikely. They are complementary to, and fit within, the broader concept of advance care planning (ACP). There has been little evaluation of the use of ECTPs to date. The Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) is a standardised ECTP developed by a national working group in 2016. It has been adopted in several Clinical Commissioning Groups across England. The recent COVID-19 pandemic has precipitated an increased focus on ECTPs among health care professionals and the public. We propose a mixed-methods evaluation of the ReSPECT process in primary care to determine how, when and why it is used, and what effect it has on patient treatment and care._x000D_ _x000D_ Our overall aim is to evaluate the use of the ReSPECT process in UK Primary Care and its impact on patient care._x000D_ _x000D_ Our objectives are to:_x000D_ 1. understand how ReSPECT is currently used in primary care from the perspective of patients, their families, clinicians and care providers_x000D_ 2. describe the views of patients, the public, and primary and community health care professionals on emergency care treatment plans in general and ReSPECT in particular_x000D_ 3. identify enablers and obstacles to embedding ReSPECT in primary care practice_x000D_ 4. explore the impact of ReSPECT on patient treatment decisions_x000D_ 5. develop a consensus on how ReSPECT should be used in primary care_x000D_ _x000D_ Methods: We propose four work packages_x000D_ WP1: A qualitative study using interviews with GPs, patients and their families/carers, and care home managers of to explore how and why ReSPECT conversations occur and recommendations are made, their ethical basis, and the experiences of patients and their families of the decision-making process. _x000D_ _x000D_ WP2: Focus groups with health care professionals, and members of patient and community groups to explore their views on the principles and practice of ReSPECT and other forms of anticipatory decision-making. Interviews with faith leaders to explore the extent that the values underpinning the ReSPECT process reflect or are dissonant with specific faith traditions. A national survey of public attitudes to ECTPs and ACP, and a national survey of GPs to explore their experience and views of anticipatory decision-making._x000D_ _x000D_ WP3: An analysis of congruence of ReSPECT recommendations and subsequent treatment decisions made using an analysis of ReSPECT forms and corresponding patient records._x000D_ _x000D_ WP4: A synthesis of key findings from the study and a stakeholder meeting drawing on experience based co-design to identify strategies to support integration of the ReSPECT process to primary care practice. _x000D_ _x000D_ Timeline: months 0-3 study set up; WP1 months 3-18 ; WP2 months 3-15; WP3 months 6-18; WP4 months 18-24._x000D_ _x000D_ Dissemination and outputs: We will have a dissemination programme for patients and the public, including lay summaries and video resources. Dissemination to practitioners and policy makers will include suggestions for learning resources and frameworks for integrating ECTPs into routine primary care practice.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_16688,Versus Arthritis,,Evaluation and Implementation of electronic-rehabilitation programmes for chronic knee pain in the UK,"Background Frequent knee pain is estimated to affect one in four adults, limiting physical function and mobility and reducing quality of life.1-5 Osteoarthritis (OA) is the leading cause of chronic knee pain in those aged 45 years or older.6 The economic consequences of arthritis on the lives of individuals, the health service and on employment are high.7 There is evidence to support exercises in reducing pain and improving functioning.8,9 Education and support are also required in managing pain more effectively.10-11 Arthritis Research UK and UK government organisations recommend a public health approach by targeting physical inactivity as well as communicating the benefits of physical activity to individuals with musculoskeletal conditions. Physiotherapists are key in providing exercise therapy and support to individuals to manage their knee OA. However, a challenge for the NHS is that physiotherapy services are overstretched. Challenges for patients have been in accessing physiotherapy for exercise therapy, training and education and also being motivated to continue with their rehabilitation. Therefore, it is important to develop alternative approaches to providing individual and clinic-based physiotherapy services through embracing technology and using the evidence supporting telehealth, such as Internet developed interventions. Objectives The overall aim of the study is to evaluate the feasibility and acceptability of two e-rehabilitation programmes in individuals with knee pain, one is a group Internet-delivered physiotherapist-prescribed home exercise acommpanied by Internet-interactive educational sessions, known as ‘Group E-Rehab’; and the other is a web-based home exercise programme with motivational text support system known as: ‘MyKneeExercise’. Plan of Investigation The study is designed as a feasibility study with nested qualitative study. We will build on and expand for use in the UK, e-rehabilitation programmes (developed in Australia). For the ‘Group E-Rehab’ intervention, we will train physiotherapists to deliver the Internet-delivered physiotherapist-prescribed home exercise. For the ‘MyKneeExercise’ intervention, this is home web-based and requires no physiotherapist input to deliver this e-rehabilitation programme. We will then undertake an exploratory feasibility trial involving both quantitative and qualitative data collection. Patients with knee pain who meet the inclusion criteria will be randomised to receive Group E-Rehab, MyKneeExercise, or usual care. We will test the feasibility and acceptability of these interventions; assess the potential use of the e-rehabilitation programmes by physiotherapists in primary and community care; and refine the trial procedures for a definitive RCT. Exploitation of the Results E-rehabilitation programmes have the potential to improve health services, by providing new models of service delivery enabling more patients to receive support and training to equip them to more effectively manage their chronic knee pain, reducing the burden on our overstretched physiotherapy services. Internet-delivered physiotherapist-prescribed home exercise supplemented with Internet-interactive educational sessions ‘Group E-Rehab’ and a web-based home exercise programme ‘MyKneeExercise’ have the potential for future implementation by the NHS as prescribed UK e-rehabilitation programmes.",,6.7 PHYSICAL,MUSCULOSKELETAL HRCS22_05668,Department of Health and Social Care,NIHR,Evaluation of the health impacts of the UK Treasury Soft Drinks Industry Levy (SDIL),"People who drink a lot of sugary drinks are more likely to develop tooth decay, obesity, diabetes and heart disease. Sugary drinks often contain lots of calories, and people can easily consume many calories from sugary drinks without feeling full. New UK guidance recommends that we consume less sugar than used to be the case._x000D_ In 2015, Public Health England said a tax on sugary drinks would be a way to help us all consume less sugar. In March 2016, the UK Government announced a tax on sugary drinks would start in April 2018. Details of the tax aren’t clear yet, but the tax will be higher for drinks with more sugar and will probably not apply to pure fruit juices. The two year delay is so that companies can reduce the amount of sugar in their drinks and avoid the tax. As no other country has tried this sort of tax, we don’t know what the effects will be._x000D_ We have talked to people working in government, public health, drinks companies and health advocacy groups. They think the tax will have all sorts of effects, and not just on health. Our study will look at the most important of these, tracking how things change over time. Studying a wide range of effects of the tax will help us be more certain that the results we see are true. For example, if purchases of sugary drinks, tooth decay and childhood obesity all go down, and purchases of other drinks go up, this will increase our confidence that the tax has had a positive impact on health._x000D_ Because we want to study how things have been changing since before the tax was announced to after it is implemented, we will mostly rely on information that is regularly collected by other organisations. This means we will be limited in what we can study. We will use data from supermarkets to explore the effects of the tax on the price, sugar content, and range of drinks available. We will use market research data to track changes in purchases of drinks. We will also study purchases of confectionary to see if people switch from sugary drinks to sugary foods. We will use government data to study effects of the tax on: diet, childhood obesity, and hospital admissions for tooth decay._x000D_ Any effects of the tax on what people eat and drink will take time to change their health. We will use advanced statistics (or ‘modelling’) to predict the effect of any changes in sugary drinks and diet on diseases and deaths 5-15 years later. From this, we will be able to predict financial savings for the NHS._x000D_ The tax’s effects might go beyond health. For instance, a healthier population should be more economically productive. Or people drinking less sugary drinks might mean fewer jobs in the food industry. We will use economics to predict the impacts of the tax on the whole UK economy._x000D_ We will also explore how different groups respond to the tax. We will conduct interviews and focus groups, and analyse newspapers and social media to explore how the public, politicians, public health professionals, and the sugary drinks industry feel about the tax. By studying these things over time we will be able to see, for example, whether any early opposition mellows over time._x000D_ In the UK, children drink more sugary drinks than adults. Obesity, heart disease, diabetes and tooth decay are more common in poorer people. Across all our work, we will look for any variations in effects between age groups, men and women, and levels of income._x000D_ Finally, we will engage the public and stakeholders in interpreting and sharing our findings.","We will conduct a natural experimental evaluation of proximal, intermediate & distal outcomes (work package (WP) 1), micro & macro-economic evaluation (WP3), & qualitative process evaluation (WP4) over 3 2-year time periods (2014-20). Simulation modelling of health & economic outcomes will focus on longer time horizons (WP2). In WP5, findings from WP1-4 will be synthesised and interpreted to refine intervention theory, and stakeholders engaged in dissemination._x000D_ WP1 – will use interrupted time series & regression analyses to evaluate impacts of the SDIL on:_x000D_ 1. Soft drink product diversification, formulation & price by brand, category & product size (volume) using data from 6 leading supermarket chains_x000D_ 2. Purchases of SSBs, all other drinks, confectionary & toiletries overall & by age, sex & socio-economic position (SEP), using household purchasing data from Kantar World Panel_x000D_ 3. Consumption of SSBs & confectionary overall & by age, sex & SEP using data from the National Diet & Nutrition Survey_x000D_ 4. Prevalence of childhood obesity using data from the National Child Measurement Programme & hospital admissions for severe dental caries using data from Hospital Episode Statistics (HES) overall & by age, sex & SEP._x000D_ WP2 – will adapt an existing life table model (PRIMEtime) for proportional multistate life table analyses. Data from WP1 will be used to estimate the effect sizes for SSB consumption & free sugars from drinks. We will estimate the impact of these changes on health outcomes over the short (5 years), medium (5-10 years) & long term (>10 years). Disease outcomes of interest will include dental caries, T2DM, cardiovascular & kidney disease, & obesity-related cancers (e.g. colon, kidney, liver, breast & pancreas)._x000D_ WP3 – will involve: (i) a micro-economic evaluation, modelling (using PRIMEtime) the health & social care cost impacts & health outcomes (QALYs gained); & (ii) a macro-economic evaluation, to assess the wider impacts of SDIL on industry, households, Treasury and UK economy._x000D_ In (i) NHS costs will be estimated using programme-budgeting & HES data. Social care & wider societal costs will be assessed overall & by age, sex, utility score & ICD10 codes. Data on dental caries & associated health care costs will be incorporated & we will extend the cost estimates to cover children & adolescents._x000D_ In (ii) we will use a Computable General Equilibrium (CGE) model of the whole economy that includes the cost minimising & profit maximising behaviour of producers, consumption & saving behaviour of households & government, taxation mechanisms & the use of labour, capital & other factors in order to produce goods & services for investment or consumption, & includes trade across international borders._x000D_ WP4 – will use qualitative methods to determine the perceived acceptability & impacts of the SDIL. We will conduct thematic Framework analysis of interviews with professionals & focus groups with the public, thematic content analysis of newspapers articles & social media (twitter) output & analysis of survey questions on consumer attitudes to SSBs collected by Kantar in their household purchasing panel._x000D_ WP5 – will involve synthesis of the findings from WPs1-4 using our systems map & refinement of intervention theory. Triangulation of evidence generated using different methods from WPs1-4 will facilitate corroboration of findings, supported by techniques such as pattern matching. We will engage stakeholders in dissemination.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE HRCS22_05064,Department of Health and Social Care,NIHR,Evidence review facility to support national policy development and evaluation,"Background The decisions of professionals and policymakers should be informed by rigorous, transparent and up-to-date research because their actions can do harm as well as good. Systematic reviews of research are required, because individual studies can be atypical and subject to bias and chance. Robust, timely and relevant evidence syntheses, produced through dialogue with policymakers and in consultation with local users, can inform the development and implementation of national policy. Aims We propose to continue to provide the bespoke reviews service we currently provide for the DHSC. The service will: facilitate the use of research evidence through rigorous reviews translate review findings for use in policy contexts continue to develop the theoretical, methodological and organisational foundations for evidence synthesis for policy and practice. Research plan A collaboration between three leading organisations in evidence synthesis (including systematic reviews, scoping reviews and evidence mapping) is proposed: The EPPI-Centre (UCL), the Centre for Reviews and Dissemination (University of York), Faculty of Public Health & Policy (LSHTM). Led by the EPPI-Centre, the Facility will: Maintain an efficient and responsive review facility that delivers timely, rigorous, relevant and appropriate reviews to policy customers Develop and maintain an inter/transdisciplinary team which utilises and develops appropriate methodologies Engage with stakeholders and other users in order to ensure our reviews reflect a range of perspectives and are cognisant of the context of their intended application. Research team The collaboration is exceptionally strong in terms of its experience in: conducting reviews; developing methods; and engaging with policymakers and other stakeholders and ensuring review findings are useful to decision-makers. The team has worked across health and social care, public health, policy analysis, evaluation, and public involvement and is involved in a range of national and international networks spanning each domain. The PIs will be responsible for the programme of work as a whole, including liaison with the Department of Health and Social Care and policy teams. A management team of named co-investigators will meet regularly to monitor progress. Experienced researchers will lead reviews and user engagement activities, with specialist input from members of other organisations, when required. Information technology support and publications, marketing and communications will be managed through the EPPI-Centre. Finances will be managed by UCL. A programme advisory group and ad hoc advisory groups (to include all relevant stakeholders) for individual reviews will guide the work. Potential impact Research is only one piece of the evidence jigsaw that inform decisions, however we expect that national policy will be informed and impacted by the results of our work. Our key audience will be the policy customers , with whom we engage directly. Successful dissemination of outputs requires focusing the research in terms of setting, audience, and timeliness. Our work in patient and public involvement and setting up ad hoc advisory groups will all be valuable means of communicating research findings. In addition, all three organisations are well known in the Cochrane and Campbell Collaborations and other international networks, offering opportunities for impact in terms of review findings, and methodological development.","What is the Policy Review Facility? The Policy Review Facility is a team of researchers from three universities (University College London, the University of York and the London School of Hygiene and & Tropical Medicine). We are experts in producing evidence reviews that bring together the findings from high- quality research. Our reviews help decision- makers and health and social care professionals make decisions about the services they provide and how best to deliver them. How do we make sure our reviews are reliable? We use a scientific and systematic approach to find research, to assess whether it is trustworthy and to bring the evidence together. This helps to ensure we produce a complete, fair and reliable picture of the evidence. Members of our team have been doing this kind of work for many years and we have a world-wide reputation for producing high- quality evidence reviews. We are also known for developing new methods to ensure evidence reviews meet the needs of decision-makers. How do we make sure our reviews address important issues? We work closely with the people who ask us to undertake reviews to understand their needs. We also aim to make our reviews relevant and useful to professionals who might use a review to help deliver services, as well as to patients and other service- users affected by those decisions. We involve patients and the public in our reviews to understand the issues that are important to them. We work with service providers to understand how services are currently delivered and how an evidence review might support future delivery. How do we involve patients and the public? When starting a new review we invite patients and the public to meet with us and talk about their experiences of a condition and the services they receive. Recently, we met with a group of young people affected by adverse childhood experiences who told us about the kinds of problems they face and the services they would find useful. This helped us to understand how existing research relates to their experiences and what new research may be needed. Patients and the public also help with communicating review findings. How do we make sure people know about and use our findings? We communicate the findings of our evidence reviews in different ways. In a recent review on Lyme disease, patient organisations helped us to understand the language that patients prefer when reading reports and they made our reviews available on their websites. In a review on weight management services, the people responsible for delivering services advised us how best to share our findings. All our reviews are available, free of charge. We offer short, Plain English summaries and in-depth reports.","8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_06922,Department of Health and Social Care,NIHR,ExACT-CF: Exercise as an Airway Clearance Technique in people with Cystic Fibrosis – A randomised pilot trial,"Background: Routine chest physiotherapy, which aims to loosen, mobilise and expectorate airway secretions, is a cornerstone of clinical care for people with cystic fibrosis (CF). Guidelines advise at least one session daily, choosing from various modalities that exist under the umbrella term airway clearance techniques (ACT). However, many people with CF find ACT time-consuming and burdensome. Unsurprisingly, therefore, the question "can exercise replace chest physiotherapy" was assigned a top 10 research priority by people with CF, alongside reducing treatment burden. There is growing evidence that exercise (with coughs and huffs) may be an alternative to chest physiotherapy, however the willingness of people with CF to be randomised into such a trial and their experiences need testing. Aims and Objectives: We will assess the feasibility of recruiting people with CF into a trial where they will be randomised to either continue usual care (chest physiotherapy) or to stop this and replace it with exercise as an ACT (ExACT). This randomised pilot trial will inform the design, management, and delivery of a future larger randomised, controlled, non-inferiority trial. Key objectives include: assessing feasibility and acceptability of methods of participant recruitment and retention; assessing feasibility of quantitative and qualitative (outcome and process) data collection; exploring intervention engagement; and refining methodology for the definitive trial. We will measure short-term (28-days) clinical impact of stopping routine chest physiotherapy. Methods: We will conduct a two-arm randomised pilot trial, with people with CF >12 years (n=50). The trial will include assessments at baseline and following 28-days of usual care or ExACT, with additional home lung function and exacerbation questionnaires at 1, 7, 14 and 21-days, and an embedded qualitative component. Data collection methods will include those proposed for a definitive trial, e.g., research database logging chest physiotherapy, lung function in clinic and at home, wrist worn physical activity monitoring and questionnaires evaluating quality of life, treatment burden, and mood; and qualitative interviews exploring intervention use, acceptability and fidelity. Feasibility measures include reports on recruitment, retention, measurement completion, adverse events, interviews exploring the acceptability of trial procedures to people with CF and their clinical teams, and a trial satisfaction questionnaire. Early signals regarding the clinical impact and safety of stopping chest physiotherapy will be measured using lung clearance index and monitoring processes, as well as preliminary health economics analysis. Timelines for delivery: The proposed work schedule is 18-months. Months 0-5 comprise the study set-up phase, protocol development and acquiring regulatory approvals. Months 6-11 comprise recruitment and the pilot trial. During the final stage (months 15-18) we will use the findings of the pilot trial to develop the main phase ExACT-CF trial protocol, prepare a grant application, and disseminate our study findings; involving our PPI group throughout. Anticipated impact and dissemination: Study findings will be shared with stakeholders; healthcare professionals, people with CF and their families, national (UK CF Trust) and international (CF Warriors) CF charities. Dissemination will occur via social media, peer-reviewed publications, conference presentations and virtual educational events. This project will inform a larger evaluation (definitive trial).","Cystic fibrosis (CF) is the UK s most common inherited genetic condition and affects more than 10,500 people. The disease causes problems with the movement of salt and water in the body, resulting in sticky mucus building up, mostly in the lungs and gut. Thick mucus in the airways leads to repeated infections which, over time, damage the lungs. Chest physiotherapy is prescribed to loosen and clear sticky thick mucus from the airways and so to help to reduce lung infection. Chest physiotherapy is a routine treatment to keep people with CF healthy. However, many say it is time-consuming and a burden. People with CF have asked if doing exercise could have the same effect as chest physiotherapy sessions for helping clear mucus. Exercise could be more enjoyable and less burdensome. Through a recognised priority setting partnership, the CF community recently ranked research to reduce the burden of their care and answer whether exercise can replace chest physiotherapy , as their number 1 and 7 priorities. Surveys show that many people with CF have occasionally chosen to replace chest physiotherapy with exercise for airway clearance, and we recently confirmed this through a UK-wide survey. We now need to know if they would be willing to take part in research that asks some to stop chest physiotherapy and to exercise (with coughs and huffs) instead. New medicine (modulators) have recently become available for many people with CF, bringing dramatic improvements in their health. Some people who have started modulators are considering whether they can reduce or stop treatments – including chest physiotherapy. So, we need to know the effects of stopping chest physiotherapy and determine if exercise can be used instead - our study aims to understand this. Our recent survey in people with CF, their families, physiotherapists and doctors, showed us that many consider hard exercise with coughs and huffs to be able to clear mucus from the airways. We will study 50 people with CF (>12 years old) for 28-days. We will ask half of them to continue their usual care, and half to stop chest physiotherapy and do exercise that gets them breathing deeply (with coughs and huffs) instead. We will see if people are willing to start and continue with such a study and what they think of the study processes. We will also see how stopping chest physiotherapy and replacing it with exercise affects measurements of their lung function. Within the study we will talk with people with CF and members of their CF team to understand their experiences. This information will tell us whether a larger study can answer the question of whether certain forms of exercise can safely be used as an alternative to chest physiotherapy.",6.7 PHYSICAL,CONGENITAL DISORDERS HRCS22_06756,Department of Health and Social Care,NIHR,Examining Impact of Local Area Coordination as a Preventative Intervention in Adult Social Care,"The UK government posits prevention as a potential solution to the ASC crisis and key to transforming ASC systems. The transformative potential of preventive interventions lies in their ability to relieve demands and financial strain on formal services, while simultaneously developing more effective systems of support and empowerment for citizens and communities. Currently we lack a detailed understanding of how, why and under what circumstances prevention can improve the lives of ASC service users and reduce the need for statutory services. This proposal addresses this important evidence gap by examining the impact of one particular model of prevention, Local Area Coordination (LAC).This prospective and retrospective study investigates whether and how LAC impacts upon the lives of people who engage with the service and the communities in which it operates. This project is a unique collaboration between academics, LAC managers, frontline staff, voluntary/community organisations and people who participate in LAC services. The research will: Provide the first comparative analysis of well established LAC programmes. Utilise qualitative data from LAC participants to inform the development of a cost consequence framework addressing a significant knowledge gap on the impacts of prevention. Situate its impact by comparing the experiences of those who engage in LAC with those who have disengaged addressing gaps in knowledge around causality and the counter-factual. Embed service user involvement; both through the service user advisory board and through the participatory action research approach to reflect their voices. This project will examine LAC through the integration of participatory action research and nested economic study approaches. The research combines quantitative and qualitative examination of secondary process and LAC system level data, alongside experiential qualitative data gathering on the LAC network in place and on participants' experiences of LAC and the outcomes they perceive it to produce. These data, alongside the review of secondary data sources, are used to develop the cost consequences analysis framework. It is this distinctive combination of methods which will produce a more extensive examination of the effectiveness of LAC; both in terms of its capacity to deliver benefits to the lives of service users (and the communities they live in) and as a preventive intervention. With increased emphasis on preventative ASC approaches and community based programs in the aftermath of COVID-19, this research will provide timely analytical findings to strengthen and inform policy in this field. Our trusted relationships with the National LAC network and broader relationships with both practitioners and national policy makers through both our Enabling Social Action and COVID-19 projects, provide the foundations for ensuring that the findings can have direct impact on decision-making. The findings will provide a stronger evidence base for understanding how, why and under what circumstances LAC can make a difference to ASC provision and create an analytical framework which can be applied to other preventative interventions.","Demand for Adult Social Care services are increasing, however the funds to support this are limited. National and local governments are looking for ways to tackle this challenge. One key approach is to look at what early support they can give to people to help them avoid needing to use more services later on. These types of services are called preventative interventions . As well as helping to reduce the demand on social care services, it is suggested that these types of support can also be good for communities and give people more of a say over services. The challenge however is that money needs to be found for these new services, but we are not sure how effective they are, why they work, and in what situations. To understand this we need to do new research on these preventative schemes. This research looks at one type of preventative scheme called Local Area Co-ordination. It was introduced in the UK in 2012 and is currently used by 13 local authorities. This system has a basic set of guidelines for local authorities. Doing research on Local Area Coordination gives us a good opportunity to compare how it is used and what effects it has on different people s lives in different locations. We will be working with all the members of the Local Area Coordination Network, but the research will focus in particular on the way the scheme is used in Leicestershire, York, Derby and Thurrock. This research is important as we need to be clear about the benefits that preventative schemes can offer to people who use services and to how local authorities provide these services. The research will ask: How people experience local area coordination What shapes whether or not people have a positive experience Whether Local Area Coordination prevents people from having to use other social care services. By asking these questions the research will understand where Local Area Coordination works well and why, and how it could be improved. It will also help us to understand whether these types of schemes provide an effective way to support social care services. Because it is difficult to be able to prove whether or not providing these types of support actually stops people from needing other services later on, the research is using a range of different tools and expertise. We are talking to people about their experiences of the scheme and how they think it has helped them. We are talking to the teams who provide Local Area Coordination to understand how they make Local Area Coordination work. We also have economics experts to try to understand the costs and the benefits that the scheme creates.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_22899,The Academy of Medical Sciences,AMS,Examining the long-term effects of the combination of metformin and clemastine on remyelination and neuroprotection; a follow-up study of the Cambridge Centre for Myelin Repair trial Two,"Background: My research aim is to promote brain repair in people with multiple sclerosis (MS). Specifically, I work to identify treatments that regenerate myelin, which restores function and protects demyelinated axons. CCMR Two is a randomised, placebo-controlled, phase 2 trial, which is testing the ability of 6-months of treatment with the combination of metformin and clemastine to promote remyelination in people with relapsing-remitting MS. However, the required duration of treatment, and the durability of repair, is unknown. In this proposal I aim to assess the long-term efficacy of a strategy to promote brain repair. Objectives: 1. To examine the durability of visual evoked potential (VEP) latency improvements in response to treatment with metformin and clemastine. 2. To compare the effectiveness of different outcome measures in a follow-up study to a remyelination trial. 3. To gain insights into how a remyelination-promoting drug should be deployed in clinical practice. Methods: In a follow up study of the CCMR Two participants (n=50), I will re-examine full-field VEP, alongside multifocal-VEP (MF-VEP), and repeat assessments of visual acuity, optical coherence tomography and serum neurofilament light. Participants will be invited at 6 and 12-months after their discontinuation of the investigational medicinal product. Treatment effects between follow-up and baseline will be tested using linear mixed models. Impact: We anticipate that this research will support the increasingly clear position that pharmacological promotion of remyelination in people living with MS is achievable. We further anticipate that we will find a sustainability to repair following treatment with a remyelinating drug.","Multiple sclerosis affects over 125,000 people in the United Kingdom and is the leading non-traumatic cause of disability in young adults. The most urgent need for people with MS are treatments which slow, stop or reverse disability progression. Many believe that the most effective way to prevent progression is through remyelination: repairing the primary defect (demyelination) and thus protecting the underlying nerve fibre from degeneration. The Cambridge Centre for Myelin Repair (CCMR) has recently shown that the anti-diabetes drug metformin, especially when given alongside clemastine, promotes remyelination in rats. These drugs are now being tested against matched placebos in a clinical trial of 50 people with relapsing-remitting multiple sclerosis (the CCMR Two trial). However, there is a risk that a positive effect of the drugs might be missed over this short-duration trial, and there is additionally a one-off opportunity to study how durable the repair process can be in people with MS. This project is therefore designed to determine whether myelin repair, measured through visual and blood markers of nerve damage, are maintained over time. This will be achieved by inviting each of the 50 participants from CCMR-Two to return for further assessments at 6 and 12 months after they complete the trial. Our conclusions will have big impact for people with MS. These drugs represent a safe and cost-effective strategy to treat progression and the lessons we learn will allow us to better understand how to deploy these drugs to improve the lives of people with MS.",6.1 PHARMACEUTICALS,NEUROLOGICAL HRCS22_06931,Department of Health and Social Care,NIHR,Exercise as medicine in oncology: a feasibility study investigating a patient-centred approach to exercise for head and neck cancer survivors,"Research question What is the feasibility of implementing personalised, flexible, and collaborative exercise programmes for head and neck cancer (HaNC) survivors? Background Rates of HaNC have almost doubled in the last decade. Treatment is aggressive and often multi-modal, resulting in fundamental changes to physical fitness, musculoskeletal function, breathing, speech, swallowing and appearance. Survival rates have improved, with increasing numbers of survivors, living longer with chronic side-effects. Physical exercise has proven benefits in several cancer groups; reducing fatigue, low mood, treatment toxicities and mortality rates, although few studies include HaNC survivors. This group has multiple challenges, often being less physically active pre-diagnosis with high alcohol and tobacco consumption, many patients have considerable co-morbidities, low socio-economic status and poor health literacy. HaNC services are centralised, with many living long distances from treatment centres. Recent evidence demonstrated that personalised exercise programmes tailored to circumstances and preferences improved outcomes and adherence. Further work is indicated to increase engagement, improve delivery and implementation of physical exercise in HaNC survivors. Aim: To investigate delivery of personalised, flexible, and collaborative exercise programmes in HaNC. Objectives To investigate: HaNC survivors eligibility, recruitment, adherence, and retention rates. Feasibility of delivery, integration into pathways, intervention components, and fidelity. Frequency, intensity, time, and type of exercise prescribed based on needs and preferences. HaNC survivors and professionals views on acceptability, processes and integration to care. Suitable outcome measures and determine sample size for a definitive study Methods This single armed study will assess feasibility of personalised exercise programme for 70 patients diagnosed with HaNC, across two centres. Patients referred for curative treatment can enrol at any time between diagnosis and up to 8-weeks post-treatment. Those intended for palliative care or classified as high-risk on an exercise risk stratification tool will be excluded. Intervention An 8-week exercise programme which has been successfully piloted with seven HaNC survivors. It includes i) needs analysis with personalised goals and exercise preferences ii) programme prescribed, guided and supported by a Cancer Exercise Specialist iii) flexibility to accommodate changes in symptom-burden, preferred exercise type and location iv) content adhering to physical exercise cancer guidelines v) personalised exit plan to promote maintenance. Adherence will be facilitated by bespoke support tools, co-created by our PPI group. Outcomes Primary outcomes are uptake, adherence and compliance. Secondary outcomes are safety, cardiorespiratory fitness, strength, endurance, agility and balance. Patient-reported outcomes include a fatigue scale, activity levels and QoL. Patients and staff interviews will explore the intervention s acceptability and its integration into clinical care. PPI: PPI will be integral throughout the project Impact and dissemination: Findings will be shared on a website and Twitter-feed. Outcomes will be presented in journals and at conferences. Briefings will be sent to patient groups and charities. This study will provide a roadmap for exercise integration into the care pathway. Ultimately it aims to improve the physical and mental health of HaNC survivors, thereby improving survival and reducing NHS costs Timelines 0-4m Ethics, resource development 5-17m Recruitment 7-19m Intervention delivery 20m Data collection complete 20-24m Analysis, dissemination","Background We aim to increase head and neck cancer (HaNC) patients engagement in physical exercise. There are many proven benefits of exercise following cancer treatment, aiding recovery, reducing risk of cancer returning, improving physical and psychological well-being and quality of life (QOL). However, the vast majority of HaNC patients have low levels of physical activity both pre- and post-treatment. There are multiple reasons for this; HaNC treatment is often aggressive with severe side-effects e.g. profoundly dry mouth, breathing through a hole in the neck, shoulder dysfunction, poor swallowing making it difficult to exercise; apprehension about participating in groups due to altered facial appearance; many are from low socio-economic areas, with high risk smoking and alcohol behaviours and other health problems; HaNC services are regional, requiring long journeys to access specialist support. Our survey of 400 HaNC patients found a desire to participate in an exercise programme, if tailored to individual needs and preferences. We will develop a collaborative, flexible, patient-centred personalised programme, with tools to support HaNC-specific barriers to exercise, and test whether this is feasible and acceptable. Design We will recruit 70 HaNC patients, pre-treatment and up to 2 months post-treatment, across two large HaNC units in NW and NE England. In consultation with a HaNC Physiotherapist, patients will work with a local Cancer Exercise Specialist to devise a personalised exercise programme (including options for time, frequency, intensity, type, location, remote delivery), using support tools to overcome HaNC-specific barriers, with weekly virtual support, delivered over 8-weeks. We will assess; rates of uptake, retention and exercise completion; patient reported symptoms and QOL; physical fitness. We will interview patients and healthcare professionals to understand how acceptable they found the programme and explore any issues with integrating it into HaNC care. Our study will determine whether further research into personalised exercise programmes is feasible and worthwhile for HaNC patients. PPI Our PPI group helped identify this as an important research area, recognising the benefits of exercise, but that HaNC patients find it difficult to participate. They have since met regularly to develop the study design, advising on assessments, timing and delivery of the programme. Our experienced patient co-applicant has assisted in project development and will chair regular PPI meetings throughout the study. They will help develop information resources, support tools and top-tips guidance, comment on findings and help disseminate outputs to reach a broad audience. Dissemination We will present results at conferences and in scientific articles. We will: inform publishers of the UK HaNC clinical guidelines of our findings; advise local health service managers; and distribute accessible information to charities and patient groups regularly. The public will be able to access updates and results via our website, Twitter feed and press releases.",5.7 PHYSICAL;6.7 PHYSICAL,CANCER AND NEOPLASMS HRCS22_00011,Medical Research Council,MRC,"Experiencing the micro-world - a cell's perspective","In the body, most cells grow in close contact with other neighbouring cells and with a local matrix of proteins and sugars that combine to provide an instructive microenvironment. Until recently, most research labs (in both academic and industrial settings) have used 2D cultures of cells on plastic to study cell behaviour, a significant departure from what is actually happening in vivo that can limit the applicability of their research. However, there has been a recent and dramatic shift away from traditional 2D culture to the use of complex, 3D cultures, that more effectively mimic the micro-environment experienced by cells in vivo. This development impacts directly on fields such as regenerative medicine, drug discovery and cancer research, with significant opportunities for improved in vitro modelling of cell behaviour. Despite these improvements in culture techniques, the interaction of the cells with their local microenvironment - a key target in therapies for cancer, wound healing, and fibrosis etc. - remains a 'black box' with technologies unable investigate these environments at the cell level. This proposal will 'open that box', developing the technology and methodology urgently required to fully explore 3D cell cultures on length scales comparable, or smaller than, single cells. The currently accepted protocol to characterise natural and synthetic matrices, uses a bulk rheometer to produce a single, averaged value of the viscosity and elasticity of the material, destroying the sample in the process. Information about the matrix local to the cells growing inside the samples is lost. Our vision is to image and characterise 3D cell culture environments in all three spatial dimensions, over an extended time course, and on a single multifunctional instrument so that the information can be integrated and mapped. To achieve this we will develop a minimally-invasive technique to measure the 3D micro-rheology of the extracellular matrix using nano- (smaller than the cells) and micro-sized (can be the same size at the cells) beads as local probes. These probes will be held at a fixed position within the matrix using an optical trap and their Brownian motion in all three spatial dimensions tracked using multiplane imaging. The micro-rheology (viscosity and elasticity) of the extracellular matrix local to the probe is extracted from temporal analysis of the Brownian motion. To achieve deep 4D (x,y,z, time) images of live 3D cell cultures, we will combine light sheet microscopy with adaptive optics (a technique for correcting for sample aberrations that reduce image quality deep into complex samples). The final multifunctional platform will be the exciting culmination of these 4 microscopy techniques - optical trapping, multiplane imaging, light sheet microscopy and adaptive optics - capable of imaging and micro-mechanically sensing the 3D environment close to cells. The output from this work will be the innovation required to allow scientists to study how cells interact with their local microenvironment, combining technologies in a way that's not been possible previously, to observe both the cells, and the forces they exert and are responding to, as they grow and move in 3D space over time. The ability to study cell behaviour in this way is of importance for developing therapies for diseases where cells respond abnormally to signals from their local matrix, such as cancer, providing targets for new drug design. We will include a demonstration of how this can work in our study using both traditional anti-cancer drugs and more innovative therapies such as functionalised nanoparticles. We anticipate that the technology will be useful to both academics and industry (particularly drug discovery in the pharmaceutical industry) and we will work closely with these groups throughout the course of this project to ensure that, once proven, this technology can work for them.",,1.4 METHODOLOGIES AND MEASUREMENTS,GENERIC HEALTH RELEVANCE HRCS22_23510,Breast Cancer Now,,Exploiting mechanisms of centrosome dysfunction in the treatment of 17q23-amplified breast cancer,"Background Relapsed and metastatic breast cancer poses high risk to patient survival as resistance to multiple lines of chemotherapy is often observed. Identifying new druggable targets is an imminent need to treat recurrent breast cancer. My group has discovered an aberrant genetic mechanism causing centrosome dysfunction in breast cancer cells that harbour 17q23-amplification, a well-known, recurrent copy number alteration (CNA) found in around 10% of all primary breast tumours that is associated with medium to poor clinical outcomes. We identified a vulnerability linked to this mechanism: a complete reliance on centrosomes for cell division. The defect is linked to the overexpression of TRIM37, an E3 ubiquitin ligase located at 17q22-23 within the amplicon. Importantly, our work showed this defect can be exploited to eliminate cancer cells with 17q23-amplification: treatment with an inhibitor of Polo-like kinase 4 (PLK4), which blocks centriole duplication and leads to centrosome loss, drives cells into catastrophic mitoses resulting in cancer cell death. Aims We aim to expand our understanding of the mechanisms driving the cytotoxic effect of PLK4 inhibition and the mutations leading to resistance to PLK4 inhibition. We will also identify additional pathways/processes whose targeting synergises with PLK4 inhibition or TRIM37 overexpression to drive cancer cell death. Techniques and Methodology Genes whose mutation leads to resistance to PLK4 inhibition will be identified by a genome-wide CRISPR screen and direct targeting of proteins in TRIM37 complex. Additional CRISPR screens will be performed to discover depleted mutants in response to PLK4 inhibition or TRIM37 overexpression. Subsequent validation and characterization of identified targets will involve targeted gene-knockouts, microscopy, biochemical and cell biological approaches. Impact on breast cancer research This proposal will test and define the therapeutic potential of targeting centrosome dysfunction in 17q23-amplified breast cancer. It will also advance our understanding of this poorly understood breast cancer CNA.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_12470,Marie Curie,,"Exploration of 24/7 lone working practices, support, and education needs of Marie Curie Healthcare Assistants (HCAs) providing palliative care in the community across the UK.","Rapid changes in response to covid-19 has had a profound and ongoing effect. Whilst coronavirus has brought more attention to how patients’ lives are ending, little is known about the experience and support for lone workers who provide the care. Prior to covid-19, the demand for palliative care was projected to rise by 42% by 2040. The pandemic however has led to a surge in demand for palliative care, yet there exists a stark lack of evidence from those who provide the 24/7 frontline care, especially from the unregistered Health Care Assistant (HCA) perspective. HCAs are the largest group of staff in Marie Curie delivering direct care in the community. Recruitment to those roles nationally is ongoing and retention of staff is low – in 2019 only 55% of new HCA recruits were still in post after 12 months. To date, no studies have focused on the HCAs lone working practice across the 24/7 period, resulting in little understanding of their needs to provide such care, or how healthcare providers can support them in their role. To gain greater insight into this subject a qualitative exploratory design will be adopted. A series of one-to-one interviews will be undertaken with HCAs employed in MC community palliative care teams for a maximum of 12 months. Interviews will be guided by a semi-structured interview guide, formulated by a review of the literature and experts in the field of palliative care. The findings will provide an understanding of MC HCA workforce role and experiences in the delivery of lone working to palliative care patients and caregivers in a pandemic and will highlight the educational and support needs of the workforce across the 24/7 period. The project will make policy and practice recommendations for supporting the HCAs in community–based palliative care.","Lone working is defined as ‘those who work by themselves without close or direct supervision’. There can be benefits to lone working, such as the rewards of being able to provide one-to-one, personal care and support for people. However, providing palliative care in the community can be challenging and stressful for lone workers, especially when providing symptom management and emotional support to patients and families without the support of a co-worker. As a result, staff turnover, especially for HCAs can be high which is difficult for the organisation managing care in the community and for patients and families when staff keep changing. The Covid-19 pandemic has had profound effect on patients’ lives, as well as healthcare staff. Prior to the pandemic we knew that demand for palliative care was projected to rise, but the pandemic has led to a rapid increase in demand for palliative care in the community. Little is known, so far, about experiences and the needs of the frontline HCAs who work alone 24/7 delivering palliative care in the community. For that reason, it is important and beneficial to understand the challenges and rewards that newly appointed HCA lone workers experience when caring for patients with palliative and end of life needs in the community. This can then help identify what their support and learning needs are to help them remain in their role and provide the best palliative and end-of-life care to patients and families in the community. To gain this knowledge and understanding the researcher will interview a group of HCAs employed in Marie Curie community palliative care teams. The project will make policy and practice recommendations for supporting HCAs in community–based palliative care",7.2 END OF LIFE CARE;8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_15086,Cancer Research UK,CRUK,"Exploratory development of CB213, a LAG3-PD1 targeting Humabody for a first in human Phase I clinical trial in PD-1 refractory/relapse patients","Combination therapy utilising two or more agents to simultaneously target synergistic pathways is already considered a cornerstone of cancer therapy. The benefits of mAb-based combination therapy is also well known and has been illustrated very clearly by the positive survival impact for advanced melanoma patients who received the combination of ipilimumab plus nivolumab. However, the fact that a substantial proportion of these patients also experienced an increase in treatment-limiting (treatment-related) toxicity proved that simple combinations are not always the answer. It is increasingly clear that in order to lift the tail of the survival curve beyond the effect of mere combinations requires the sort of profound effect that can only be achieved by accessing novel biology through the simultaneous engagement of one or more targets by bi-/multispecific molecules. Crescendo has created a transgenic mouse capable of producing fully human VH domains ('Humabody VH') in response to immunisation. In the absence of any contaminating immunoglobulin light chains, the Humabody VH are imbued with highly robust biophysical characteristics and make excellent building blocks for creating multivalent/multispecific fusion molecules. CB213 is a uniquely formated tetravalent Humabody molecule capable of optimally engaging and antagonising both PD1 and LAG3. CB213 is uniquely designed to drive dual-checkpoint blockade solely in those highly exhausted T cells co-expressing both targets in a way that simply combining monospecific monoclonal antibodies against each individual target (or indeed any 'standard bispecific format) is unable to achieve. CB213 uniquely not only drives enhanced proliferation and activation in the most dysfunctional TILs but also avoids the peripheral sink of PD1-single positive T-cells with the view to delivering an improved safety profile over other competing bispecifics. In combination with its small size (~60kDal) and the use of a serum albumin binding domain for half-life extension, CB213 has optimal PK characteristics for driving deeply into and accumulating in tumours thereby enhancing its ability to access the TME. CB213 is a first in class molecule optimally formatted for delivery of safe, effective therapeutic benefit in a patient population with high unmet need and Crescendo would welcome the opportunity to work with CRUK to explore the development of CB213 in a first-in-human clinical trial of relapse/refractory PD-1 patients.",,6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_17617,Diabetes UK,,Exploring combination therapy to optimise costimulation blockade in autoimmunity,"Costimulation blockade is a widely used strategy to dampen T cell responses in the setting of autoimmunity. It slowed beta-cell destruction when trialled in individuals with new onset type 1 diabetes (T1D), however benefits were deemed insufficient to support routine use of this therapy. One drawback of inhibiting CD28 costimulation is that this same pathway is also needed to support regulatory T cell (Treg) homeostasis. Thus, at the same time as inhibiting pathogenic T cells, the treatment also reduces Treg numbers. This undesirable side-effect impairs natural immunosuppression. We have found that this limitation can be offset by combining costimulation blockade with low dose IL-2 therapy. The resulting combination therapy supports Treg homeostasis while retaining inhibition of pathogenic T cell responses. Preliminary data suggest this combination therapy is highly effective at inhibiting diabetes in a mouse model. We now wish to follow up these exciting findings to understand key mechanistic questions about this therapy and its potential utility. Are the Treg that are rescued in this manner equivalent to normal Treg in their phenotype and suppressive properties? Is the therapy still effective if administered after diabetes has developed? Our findings could lead to a new approach for therapeutic intervention in T1D.",,5.2 CELLULAR AND GENE THERAPIES;5.1 PHARMACEUTICALS,METABOLIC AND ENDOCRINE HRCS22_20372,Wellcome Trust,,Exploring innate-like and adaptive gamma delta T cell paradigms in health and disease,"γδ T-cells have been retained in vertebrates for ~500million years, and are of increasing therapeutic interest, but their mode of ligand recognition and immunological niche has remained largely mysterious. Here we build on the emergence of parallel innate-like and adaptive human γδ T-cell paradigms to address unresolved ‘keystone’ questions in γδ T-cell biology. Firstly, we will exploit multidisciplinary approaches to explore the diversity of innate-like and adaptive γδ biology in different tissues, their coordination with other immune responses, and how these change in disease states such as inflammation and cancer. Secondly, we will identify molecular targets of γδ-TCRs from innate-like subsets and structurally characterise their TCR/ligand interactions and cellular/molecular recognition mechanisms, focussing significantly on the strong emergence of Butyrophilin family molecules as critical TCR-ligands for such populations. Thirdly we will exploit cytomegalovirus infection as a unique human model to identify novel ligands for antigen-experienced adaptive-like γδ T-cell subsets. Finally, we will develop and apply new methodology to image and phenotype distinct human γδ T-cell subsets in solid tissues, using multispectral immunofluorescence and digital spatial profiling. This programme should help revolutionise our understanding of γδ T-cells, and provide a solid foundation for ongoing efforts to therapeutically harness the γδ T-cell compartment.","Background to the research problem Our research is focussed on an unusual type of immune cell called ‘gamma-delta T-cells’. These are evolutionarily ancient and powerful, capable of recognising and killing infected or cancerous cells. However, it has remained unclear how gamma-delta cells recognise signs of abnormality on target cells, and in which immune scenarios this occurs. Our approach Our research plan combines different techniques to explore two key subtypes of gamma-delta T cells, and determine the molecular targets they recognise on infected or cancerous cells. We will also assess how they function in different tissues of the body, and how their function changes during disease states. Expected impact The research should revolutionise our understanding of a very important and poorly understood type of immune cell, and will pave the way for scientists to exploit them in new therapies against infection and cancer.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM;GENERIC HEALTH RELEVANCE;INFECTION HRCS22_11563,Economic and Social Research Council,ESRC,"Exploring minority ethnic doctors' career transitions in medicine: a life course approach","This project will provide an in-depth understanding of how ethnic minority doctors transition through the various stages of a medical career in the UK and how ethnicity, nationality, social class and gender are relevant to their career progression. Although ethnic minority doctors are well-represented in the medical profession, extant research indicates that they still face barriers to their inclusion and their career progression (Booth, 2021; Iacobucci, 2020; Moberly, 2018; Pearce, 2021; Rimmer, 2020; Safro-Anin, 2020) which exacerbates doctor shortages (GMC, 2019). Our research will provide a detailed picture of how ethnic minority doctors navigate each stage of a medical career (from A level student to Consultant), to highlight to aspirants, doctors and their employers how to improve the career support offered to them. Through an innovative mixed method design the project addresses many of the themes of the ESRC call to investigate changes in working lives and power in the workplace, in particular focussing on transition into and through professional careers. Our key objectives are: 1. To use a life-course approach to examine how ethnic minority doctors transition through each stage of a medical career and explore how the climate around race and ethnicity (both in society and within the medical profession) is relevant to the barriers faced and the strategies employed at each stage. By using a life-course approach we can examine how the changing patterns of race and racism in the UK feed into the experience of progressing a medical career. Although, over the years, steps have been taken to address racial discrimination in the medical field, inequalities still remain (Rimmer, 2021; Ross 2020). Our life-course approach will allow us to explore in some depth how the medical profession and the doctors themselves have responded to the challenges faced by ethnic minority doctors and the further actions that can be taken. 2. To increase understanding of how ethnic minority doctors achieve career success, and explore the barriers, enablers, inclusion, voice, exit and career strategies that are used. We have scant knowledge of the success strategies and enablement factors of ethnic minority doctors and such knowledge is crucial to facilitate the career success of future doctors. We require further insight into inclusion, voice and exit as racism remains a problem in many healthcare organisations (Adebowale & Rao, 2020). 3. To understand the diversity of experiences and approaches of ethnic minority doctors and how experiences and strategies might differ for ethnic minority doctors from different ethnic minority groups, different nationalities, different social class backgrounds, and for male and female doctors. Intersectionality in the careers of ethnic minorities is an area which has received little research attention in the UK and is something that we as a team, with much experience in research on ethnicity, gender, social class and nationality, are well-equipped to address. Much of the ethnic diversity in medicine is due to doctors of South Asian heritage and doctors from other ethnic minority groups may differ to the South Asian group in their experiences. Likewise, the experiences of UK trained and IMG ethnic minority doctors may also differ, as may the experiences of ethnic minority doctors from middle and working class backgrounds. Extant research also shows that female ethnic minority doctors face additional barriers (Woodhams et al, 2021). 4. To learn lessons to support the career success of ethnic minority professionals from other fields. By increasing knowledge of how, over time, a group of ethnic minority professionals navigate their careers against a backdrop of changing societal notions of race and diversity, we can provide more insightful advice on career progression provided to ethnic minority professionals from other fields.","Medicine is, within the UK, one of the most ethnically diverse professions but despite this, evidence suggests that ethnic minority doctors still face more challenges to their career progression than their white counterparts. The aim of this project is to increase our understanding of how ethnic minority doctors (and would-be doctors or 'aspirants') manage their transitions through the distinct stages of a medical career (from A level student to Consultant). We are seeking to discover what barriers they face and what strategies contribute to successfully being able to progress from one stage of a medical career to the next. We intend to use this knowledge to improve the career support to ethnic minority doctors and to help to improve doctor retention in the NHS. The NHS has long faced challenges with ensuring it has sufficient numbers of doctors. There are limited numbers of training places and doctors take many years to train and gain necessary experiences but there are issues of burnout and the number of doctors leaving the profession. In addition doctors are retiring earlier with the rate of early retirement of doctors tripling since 2008 (Moberley, 2021). These factors, combined with the impact of the pandemic on our health services, mean that the doctor shortage is likely to be exacerbated with fewer medics on hand to meet increased demand. Issues of retention and support for UK doctors are likely to increase in importance in the post-pandemic years As ethnic minority doctors are a key cohort of this workforce, and a group that has traditionally have faced problems with progression, then it is urgent and appropriate for us to examine in some depth how ethnic minority doctors transition through their careers. We recognise that there is a great deal of diversity within the category of 'ethnic minority' hence project will also help us to better understand the specific role that is played by other demographic features in the career of ethnic minority doctors (or aspirants). We want to examine whether barriers and strategies for success are different for ethnic minority doctors from different minority ethnic groups (e.g. do Black doctors, who are fewer in number, face different barriers or use different strategies to Asian doctors who are better represented?); different nationalities (e.g. what are the specific challenges and strategies for doctors who trained overseas?); and different social class backgrounds (e.g. how does coming from a family with fewer financial resources influence the way you navigate a career in medicine?). We will also look in detail at the extent to which male and female ethnic minority doctors face different barriers and use different strategies to transition through the career stages. We will examine the career transitions of early, mid and late career-stage doctors to deepen our understanding of the challenges faced and the strategies adopted to address those challenges are different career points. In addition, as within medicine, careerists often move through different career stages at similar ages, it will also provide us within insight into how different generations of ethnic minority professionals perceive the relevance of their ethnicity to their career transitions and whether the strategies they adopt differ. We will be able to reflect on whether changing narratives around ethnicity in society and the increasing importance placed on promoting diversity and inclusion has influenced the way in which different generations of medics reflect on career barriers and the strategies for progression.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_02239,Medical Research Council,MRC,Exploring the Links Between Regulatory T cell Populations and Development of HLA Antibodies in Renal Patients Awaiting Transplantation.,"Immunologically sensitised patients account for approximately 50% of the renal transplant waiting list and have circulating antibodies (Ab) against different HLA. Getting a suitable donor kidney for those with a very broad array of HLA Ab can be difficult, because of the risk of immediate Ab-mediated rejection, so they wait a long time, and more of them die whilst waiting. Once transplanted, these patients suffer higher rates of rejection and shortened graft lives, consequent on activation of immune memory responses. Relatively little is understood about why some patients become sensitised whilst others don't, nor why different routes of sensitisation associate with different relative risks. My project is to investigate the hypothesis that sensitisation arises in some patients but not others due to variation in the ability of patients own regulatory T cells (Tregs) to suppress interactions between alloreactive T and B cells. Building on established techniques, I will first document the number and phenotype of Treg subsets in patients with failing transplants or pregnant renal patients, the two main routes of sensitisation. I will then look at the functional differences between patients' Tregs using two suppressor assays, including one to suppress B cell production of Ab. Then, using fluorospot assays to assess anti-HLA interferon gamma and IL-17 production, I will compare the suppressive capacity of Tregs from patients sensitised by pregnancy to those sensitised by a failing transplant. Finally, I will explore the variation in Treg protease activated receptor (PAR) expression and whether manipulating signalling through surface PAR-4 can enhance Treg suppressive ability. I will also test whether cathepsin K is a natural Treg ligand for PAR-4. All this work will inform whether future therapeutic interventions based on boosting patients Treg numbers or suppressive capacity can prevent HLA sensitisation and improve the wellbeing of patients awaiting a kidney transplan",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_13720,Cancer Research UK,CRUK,Exploring the implications of new and novel alternative nicotine products in superdiverse areas for health inequalities,"Background While inequalities in nicotine/tobacco use have largely been explored from the perspective of socio-economic status (SES) or class, there has been little focus to date on the ways in which multiple aspects of population diversity – including SES, age, gender, race/ethnicity, nationality, religion and immigration status – intersect differentially to shape the use of nicotine/tobacco products. The availability and use of increasingly diverse nicotine/tobacco products – such as e-cigarettes and shisha – has also created new questions about the implications for health inequities. Therefore, this project will use a place-based approach to focus on the increasing demographic complexity of populations in urban areas and the ways in which nicotine/tobacco use and provision is becoming more diverse. Moving beyond monolithic approaches to diversity which focus on singular aspects of diversity and assume ‘within group’ homogeneity, this research will instead adopt a ‘superdiversity’ approach. It will consider the multiple and intersecting differences associated with diverse populations within a particular neighbourhood and how these relate to nicotine/tobacco use. Given these newer products are likely to vary significantly in their relative harm, differences in understandings, perceptions and experiences of use in a superdiverse area must be explored to identify the health inequalities likely to emerge, and the implications for the adaptability, acceptability and intensity of smoking cessation interventions. Research Aim This project will explore understandings, perceptions and experiences of use of diverse nicotine/tobacco products among people in a superdiverse area of the UK (Handsworth, Birmingham), to identify potential health inequalities and approaches for facilitating a switch by individuals to less harmful products. Methods A qualitative research design will be co-produced in conjunction with the local community. Ethnographic mapping of the study area will identify the availability and consumption of different nicotine/tobacco products. Semi-structured interviews with adults from the area will explore ‘rules of access’ to these features. A maximum variation sampling strategy will be developed to reflect the diverse make-up of Handsworth residents. Providers of nicotine/tobacco products will also be interviewed to investigate the variable uptake and demand for particular types of nicotine/tobacco products. Results The findings and analysis will be disseminated through the researchers’ existing networks and will include ‘key findings’ papers for policy-makers and also academic papers for high impact, peer-reviewed journals.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,CANCER AND NEOPLASMS HRCS22_19462,Wellcome Trust,,Exploring the role of glypicans in modulating morphogen signalling and stem cell dynamics,"Wnt and Hedgehog signalling regulate intestinal stem cell dynamics to ensure intestinal renewal, function and integrity is maintained. The activation of these two pathways involves crosstalk and communication between the mesenchymal and epithelial layers of the intestine. However, a puzzling conundrum is that both Wnt and Hedgehog carry hydrophobic lipid moieties that are required for receptor binding and signalling but that also hinder their solubility and diffusion and hence ability to move between intestinal cells. In Drosophila, the glypican Dally-like protein (Dlp), which possess a lipid binding pocket, binds and shields the lipid moiety of Wnts to aid transport. Dlp is also essential for initiating Hedgehog signalling but its precise mechanism of action is unknown. I will determine if Dlp also binds the lipid moieties of Hedgehog and what such binding means for Hedgehog solubility, transport and receptor engagement. I will determine if mammalian homologues of Dlp also bind the lipid moieties of Wnt and Hedgehog to regulate their activity and whether they are required in the mouse intestine for Wnt and Hedgehog signalling to orchestrate stem cell dynamics. A deep understanding of how glypicans modulate Wnt and Hedgehog signalling will answer major questions in developmental and stem cell biology.","In order to build and maintain complex tissues cells communicate with each other to coordinate their actions. They do so by sending signalling molecules to each other. A breakdown in communication leads to abnormal development and disease states, including intestinal cancers. Hence it is vital to understand how signals are packaged, transported and recognized by cells. Using molecular biology and Drosophila genetics I will elucidate how glypican proteins facilitate the spread of signalling molecules between cells and their recognition on intended recipient cells. Then by altering glypican expression in the mouse intestine, I will investigate what role glypicans play in sending and receiving signals in vivo in the mammalian intestine and if they are needed for intestinal regeneration and health. A thorough understanding of glypican function in cell-to-cell communication is expected to facilitate the design of therapeutic interventions to treat diseases such as intestinal cancers that arise from aberrant signalling.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS HRCS22_09540,Health and Care Research Wales (Welsh Government),,ExtraPeritoneal End Colostomy Trial (ExPECT): Feasibility phase,"Background Parastomal hernia (PH) is a common complication of stoma formation. 100,000 people in the UK have stomas. Prevalence of stomas is growing as the population ages and cancer survival improves. Stoma appliances cost £230 million/year. PH increases the cost of stoma care due to frequent leaks, skin problems, specialist appliances and nursing care. Parastomal hernias are known to have a significant impact on quality of life. Evaluating a technique to improve symptoms and quality of life is the focus of the proposed research. Surgical repair of PH is challenging, requires the use of mesh and carries a high risk of complications and recurrence. The most serious complications of PH is bowel strangulation and obstruction. The ACPGBI have highlighted PH as an immediate research priority. Several meta-analyses demonstrate a reduction in PH formation with mesh prophylaxis, but are limited by heterogeneity of techniques, mesh and endpoints. The largest RCT available to date does not show any benefit from prophylactic mesh placement. There are continued concerns regarding mesh related complications (infection, erosion, chronic pain), and use of mesh adds significantly to the cost of the index operation. As a result, in the latest guidance, NICE does not recommend mesh prophylaxis. We propose a non-mesh prophylactic surgical technique to prevent parastomal hernia using an extraperitoneal (EP) approach. High quality data on EP colostomy formation are presently lacking but case series suggest equivalent rates of hernia prevention to mesh prophylaxis. In their recent review the ACPGBI Parastomal Hernia Group 2018 concluded that there was insufficient evidence to ascertain whether EP stoma construction reduces PH. As such there is a pressing need for a randomised controlled trial of EP colostomy formation compared with the standard transperitoneal (TP) technique. Aims The proposed study aims to test the feasibility of progression to a multicentre randomised controlled trial to evaluate EP colostomy formation to prevent PH and improve quality of life. Plan The feasibility study will be conducted across three sites. 60 patients will be randomised to either EP route or the standard TP route for end colostomy formation. Participants will be followed up at 6 weeks, 6 months and at 1 year. The proposed primary endpoint is the Colostomy Impact Score. Other patient reported outcome measures known to be associated with parastomal hernia will be collected, as well as global quality of life (EQ-5D) at baseline and at follow up. Data will be entered onto a web-based database at the three centres, and collected and analysed centrally. Progression will be feasible if it is demonstrated that: 1.Patients and surgeons will recruit/participate in a trial 2.Patients are able to complete and return questionnaires 3.Surgeons are trained to perform the standardised EP technique 4.Data are co-ordinated across sites 5.Patients are followed up effectively Summary/benefits At the end of the feasibility study we will have demonstrated proof of principle for the infrastructure of a randomised clinical trial. The study will provide invaluable information on the recruitment rate, reproducibility of the technique and the appropriateness of the endpoint measures. This will allow the methodology to be refined and inform the design of a multicentre randomised controlled trial towards reduction of the global morbidity and cost of PH.","This study will test a surgical method of making a colostomy (or stoma) to reduce the chances of a hernia (or bulge) forming near it. The technique involves bringing the bowel out through a short tunnel underneath the muscles of the abdominal wall before attaching it to the skin as usual. This phase will test the study processes needed for a future larger trial to answer the research question of whether it can prevent hernia formation. 100,000 people in the UK have a bowel stoma. A commonly experienced problem is a hernia (or bulge) around the stoma site (a parastomal hernia). Such hernias can lead to leakage of faecal fluid, skin irritation, cosmetic problems from the bulge and chronic pain. All of these reduce patient’s quality of life. The most serious complications are bowel blockages or loss of blood supply, both requiring emergency surgery. An effective surgical technique is required to prevent parastomal hernia from developing in the first place as repairs once they appear aren't always successful. Early studies suggest that using a technique to tunnel the stoma inside the thin inner layer of the abdomen (peritoneum) reduces the risk of PH. However, those studies are small and may not have followed patients for long enough to see if they had developed PH. Also, none of the studies asked about specific symptoms or did any assessment of the patients' quality of life after surgery. We hope that a large scale clinical trial will tell us how well the tunnelled technique prevents hernias, reduces symptoms and improves quality of life. The aim of the proposed study is to test the running of such a trial. The work will test the willingness of patients to have the procedure and of surgeons to perform it. We will also test the ability of questionnaires to record the symptoms and problems people have with hernias, and test the suitability of questionnaires which assess quality of life. We want to show that the questionnaires chosen are suitable to measure an improvement in quality of life with the alternative technique.",6.4 SURGERY,ORAL AND GASTROINTESTINAL HRCS22_06026,Medical Research Council,MRC,Extracorporeal Photophoresis in the treatment of Chronic Lung Allograft Dysfunction: a randomised controlled trial (E-CLAD UK),"Lung transplantation offers hope to people with life-threatening lung disease. Sadly, many transplanted lungs do not maintain normal function after transplant due to damage inflicted by the recipient’s own immune system. This loss of function is known as chronic lung allograft dysfunction or CLAD for short. CLAD affects half of all recipients within 5 years, meaning average survival after lung transplant is only 6 years. As damage worsens, lung function drops and lungs then fail completely, causing premature death. There is an urgent need for treatments that stop CLAD early to protect lung function, preserve quality of life and prolong survival._x000D_ Extra-corporeal photopheresis (ECP) uses a machine to separate blood outside the body into white (immune) cells and red cells. The white cells are then shut down with light treatment. Both the white and red blood cells are then returned to the patient. The treated white cells reprogram the immune system to stop further damage. ECP is routinely used to treat complications after bone marrow transplant._x000D_ _x000D_ Our aim is to assess if ECP is effective at treating CLAD. We will test if adding ECP treatment to current care is more effective at stabilising transplant lung function than standard care. We aim to understand how ECP works in CLAD, which patients are most likely to benefit, and ultimately help the NHS decide if ECP should be used to treat CLAD. Some studies using ECP to treat CLAD have shown promise at slowing progression. These studies were done in single hospitals in selected patients and without comparison to those not getting ECP, so there is insufficient evidence that ECP is effective in treating CLAD for the NHS to use it routinely._x000D_ _x000D_ Our trial, in all 5 UK adult lung transplant centres, allows eligible patients with CLAD, who consent, to be randomly allocated to receive either ECP and standard care or standard care alone for 6 months. We will recruit 90 patients over 3 years, 45 to each group, allowing reliable comparison between the groups. Breathing tests will be used to monitor progress of CLAD. The number whose breathing tests stabilise over the 6 months will then be compared to see if this happens more frequently in the ECP group. We will measure changes in quality of life, exercise capacity, survival and assess the safety of ECP and interview patients. We will collect blood from patients to understand how ECP is working, to help identify differences between those in whom CLAD stabilises with ECP and those in whom it does not; this may help us predict which patients are most likely to benefit from ECP._x000D_ _x000D_ We have significant public and patient involvement (PPI). Initial ideas were shared with a panel of transplant patients, relatives and the public. Modified plans were then shared at a national PPI event, which recommended we research patient experiences post-transplant, and with a panel of lay members who endorsed the need for this study. A patient with experience of ECP and CLAD, and a member of the public, are co-applicants and involved in writing the lay summary and conducting the research. A larger Patient Advisory Group will collaborate throughout the study._x000D_ _x000D_ Findings will be shared and key messages discussed at meetings, patient groups and with charities before publishing in freely available medical journals and the lay press. Plans have been shared with NHS commissioners, who pay for transplant care, to ensure the relevance of the trial to decisions on funding.","RESEARCH QUESTION: _x000D_ Does Extracorporeal Photopheresis (ECP) therapy for chronic lung allograft dysfunction (CLAD) after lung transplant halt disease progression and if so by what mechanism?_x000D_ _x000D_ BACKGROUND: _x000D_ Lung transplantation is often the only treatment option for life-threatening chronic lung disease. However, many recipients develop CLAD due to immune mediated damage of the transplanted lungs. CLAD affects 10% of recipients each year, giving a 50% prevalence by 5yrs. The impact of CLAD, causing respiratory failure and premature death, means median survival from time of lung transplant is only 6yrs. There are no proven therapies so there is an urgent need to identify ways to halt CLAD progression, preserve quality of life and prolong survival. One potential treatment is ECP in which a recipient’s leucocytes are isolated from whole blood, sensitised, irradiated with UV light and reinfused. These irradiated leucocytes exert immunomodulatory actions slowing immune damage. Uncontrolled retrospective studies of ECP have shown promise at slowing CLAD progression, yet robust evidence is needed to determine definitively if it works, how it works and in which recipients._x000D_ _x000D_ AIMS AND OBJECTIVES: _x000D_ This randomised controlled trial will compare efficacy of ECP plus standard of care (SOC) versus SOC alone in the management of CLAD. Additional objectives are to characterise immune responses occurring in recipients responding to ECP compared to non-responders, and those receiving SOC alone, to identify the mechanism of action; to determine if CLAD phenotype, clinical factors or immunological markers in blood can predict who will benefit from ECP; and, to conduct interviews with patients, to understand experiences of living with CLAD and of receiving ECP therapy._x000D_ _x000D_ METHODS: _x000D_ A phase II, prospective, 2-arm, randomised, open-label, multicentre trial to evaluate the efficacy of ECP in stabilising lung function in lung transplant recipients with progressive CLAD. Eligible recipients (n=90) will be randomised 1:1 to ECP plus SOC (treatment arm) or SOC (control arm) alone for 6 months. Randomisation will be stratified by CLAD phenotype. The primary outcome is a composite responder endpoint defined by (i) lung function stabilisation, as indicated by FEV1 and FVC declining by less than or equal to 10% at 6 months and (ii) no rapid initial decline, as characterised by FEV1 or FVC declining by greater than 20% at 3 months. Safety will be monitored by serious adverse events and all-cause mortality. Regular blood samples will provide mechanistic insights, and 30 recipients will participate in a qualitative interview sub-study._x000D_ _x000D_ TIMELINES: _x000D_ Total study duration is 57 months; months 1-9 full protocol development, governance approvals, contracting, and set up of 5 sites. Months 10-45, 36 months recruitment; data collection will close at end of month 51. Months 52-57 data analysis, final report and dissemination._x000D_ _x000D_ IMPACT AND DISSEMINATION: _x000D_ The study will provide robust evidence on the efficacy of ECP for CLAD informing decisions by clinicians globally and commissioners regarding its place in the management of lung transplant recipients. We have engaged with NHS specialist commissioners who support our proposal and will engage with NICE to conduct a technology appraisal for ECP in CLAD. Study results will be shared widely with patients, charities, and at national and international clinical meetings, and with open access publications in leading medical journals.",5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,RESPIRATORY HRCS22_21432,Innovate UK,IUK,FAB - Targeting cell senescence to treat chronic wounds,"This project aims to develop a novel approach to healing chronic wounds, a major societal health concern in the elderly and in diabetics. For most healthy people, a cut or scrape heals rapidly on its own, but in diabetics and the elderly wounds can fail to heal, remaining open, needing treatment and causing suffering for months. Five Alarm Bio (FAB) is developing drugs that help the body defend against the chemical damage of aging, damage that is one of the reasons that chronic wounds fail to heal. This project will aim to prove the concept that FAB can use those drugs as a treatment for chronic wounds. FAB will test these new drugs for their ability to keep skin cells healthy for longer, and for their ability to help those cells close up artificial 'wounds' in cell culture in the lab. Success in the project will allow FAB to take the best drugs forward, ultimately to testing them on real patients.",,5.1 PHARMACEUTICALS,INJURIES AND ACCIDENTS;METABOLIC AND ENDOCRINE HRCS22_06194,Department of Health and Social Care,NIHR,Facilitating Bystander Cardiopulmonary Resuscitation Training in high-risk areas (FACT),"Cardiac arrest is when someone’s heart stops beating and they stop breathing. People who see cardiac arrests are called bystanders. They can help save the person’s life by doing cardiopulmonary resuscitation (CPR) and using a heart restarter machine before an ambulance arrives. The heart restarter machines are also known as publicly accessible defibrillators (PADs)._x000D_ _x000D_ In some areas people are more likely to have a cardiac arrest. In some of these areas not many bystanders do CPR either. We are calling these high-risk areas. High-risk areas are usually deprived areas with a higher number of people from diverse communities living there. The study from the University of Warwick will work with people from high—risk areas in different parts of England. We want to find out what stops people from helping someone having a cardiac arrest. We want to come up with some activities to help people overcome the things that stop them doing CPR or using a heart restarter. _x000D_ _x000D_ The study is in 3 parts_x000D_ _x000D_ 1. The study team will look at information from other studies that have looked this problem in similar areas. We will discuss the problem with people from high—risk areas at about 4 workshops in the West Midlands. We want to see what they think about the problem. We will see if what the other studies say is similar to or different from their own experiences. We will then discuss ideas about activities that might help make things better._x000D_ 2. The study team will look at all the information from the discussions and work out what sort of activities might work to improve things. They will also work out what it is about the activities that seems to make a difference. At another workshop, the researchers will discuss their ideas with local people and people from organisations interested in improving the numbers of bystanders doing CPR, like the Resuscitation Council UK. The people taking part will decide which activities could work in the local high-risk areas and decide which are the best ones to try out in the next part of the study._x000D_ 3. These activities, will be tried out in two places in the West Midlands to see how they work. Information will be collected from people taking part in the test activities to see what they thought. This information will be used to decide if any changes need to be made to the activities before trying them out in a few other areas in England. People taking part will be asked for their thoughts on the activities to see if the activities work for most people or don’t work for most people in the way they should._x000D_ _x000D_ Members of the public will take part in this study in different ways. Two will be members of the study team and two more will be on the committee that makes sure the project is going as planned on behalf of the funder. We will have a public advisory group that will meet several times a year to hear how things are getting on with the project and to advise the study team. Other people will take part in the workshops in part 1 and part 2 of the study. Others will take part in the events run to test out the chosen activities._x000D_ _x000D_ This study will help organisations trying to improve the numbers of bystanders doing CPR in the areas that need it the most to know what activities could help improve things.","Background_x000D_ Improved survival from out-of-hospital cardiac arrest (OHCA) is associated with early cardiopulmonary resuscitation (CPR) and use of defibrillation, often by members of the public before emergency medical services arrive. Although bystander interventions (CPR and use of publicly accessible defibrillators (PAD)) have been improving over recent years there is variation between areas. High risk areas have been identified in England where there is a higher incidence of cardiac arrest combined with lower than average bystander CPR rates. These areas are characterised by deprivation, higher than average minority group populations and populations in manual occupations. There is little international evidence and only one ongoing study in the UK in Scotland, to inform initiatives to improve the situation. Understanding reasons for lower bystander intervention rates and developing interventions to tackle them is urgently needed to provide stakeholders with evidence and tools to help towards their efforts to meet NHS England Long Term Plan aims to reduce health inequalities and to improve survival from OHCA by 4,000 people a year by 2028._x000D_ _x000D_ Aims_x000D_ To identify reasons for low bystander resuscitation rates in high-risk communities through literature and primary evidence synthesis and to develop, implement and evaluate theoretically informed interventions. _x000D_ _x000D_ Objectives_x000D_ 1. To establish a community based public involvement advisory group to co-produce key aspects of the study. _x000D_ 2. To identify barriers and facilitators to performing CPR or publicly accessible defibrillator use in high-risk areas through realist evidence synthesis and develop theoretically informed interventions._x000D_ 3. Prioritise interventions with community partners and other stakeholders for evaluation._x000D_ 4. Develop a realist informed evaluation framework and associated data collection tools, including assessment of locally made intervention changes. _x000D_ 5. Conduct an implementation evaluation with embedded feasibility study. _x000D_ _x000D_ Design and methods_x000D_ A collaborative realist enquiry, informed by the Theoretical Domains Framework (TDF) and associated Behaviour Change Wheel (BCW), consisting of a realist evidence synthesis, intervention development and implementation evaluation with embedded feasibility in three work packages (WPs)._x000D_ _x000D_ WP 1 is a realist synthesis, informed by the Theoretical Domains Framework, of published and primary evidence on facilitators, barriers and associated interventions relevant to improving bystander CPR. It will use cross-disciplinary literature and data from workshops with people from communities with characteristics of high-risk areas. The synthesis will produce conjectured context, mechanism and outcome theories which will inform intervention design and prioritisation in WP2. In WP3 we will implement interventions and conduct a theoretically informed realist evaluation in up to six English high-risk areas._x000D_ _x000D_ Timelines_x000D_ WP1 and WP 2 will be complete in 18 months and WP3 and dissemination by 36 months._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ The evaluated interventions will be available for use by training providers and promotion by campaigning organisations to help increase participation in CPR and defibrillation training. Planned dissemination to stakeholders will be strengthened through their engagement in intervention development in WP2. Findings will contribute much needed knowledge to the subject.",8.1 ORGANISATION AND DELIVERY OF SERVICES,CARDIOVASCULAR HRCS22_03854,Medical Research Council,MRC,"Factors predicting the transition from acute to persistent pain in people with 'sciatica' - the FORECAST study","Sciatica is a common condition (43% lifetime prevalence) and is associated with higher levels of pain, disability, poorer quality of life, and increased use of health resources compared to low back pain alone. Although many patients recover, a third develop persistent sciatica symptoms. Unfortunately, it remains unclear, why some patients develop persistent sciatica as none of the traditionally considered clinical parameters (e.g., symptom severity, routine magnetic resonance imaging, depression) are consistent prognostic factors. Given the failure of traditional variables as prognostic factors, a novel approach is required to understand who may develop persistent pain. FORECAST includes a prospective prognostic cohort study that aims to: 1. Explore mechanism-based subgroups in patients with sciatica, using deep phenotyping. 2. Investigate whether a mechanism-based approach can identify factors that predict pain persistence in patients with sciatica. We will evaluate prognostic factors for pain persistence in n=180 patients with acute/subacute sciatica. Prognostic variables will be assessed at baseline and outcome at 3 and 12 months. This will include self-reported sensory and psychosocial profiles, quantitative sensory testing, blood inflammatory markers and advanced neuroimaging. We will use principal component analysis followed by clustering methods to identify subgroups. Univariate associations and machine learning methods optimised for high dimensional small datasets will be used to identify the most powerful predictors and model selection/accuracy. This project is based on our strong feasibility data and has been shaped by in-depth patient involvement. The results will provide crucial information about the pathophysiological drivers of sciatica symptoms and identify prognostic factors of pain persistence. This will ultimately facilitate patient stratification and streamline management pathways to increase quality of life for patients with sciatica.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,NEUROLOGICAL HRCS22_06846,Department of Health and Social Care,NIHR,"Feasibility of a RCT to examine the effectiveness of auditory-cognitive training to improve hearing aid users' speech perception outcomes, compared with hearing aids alone","There are 11 million people in the UK (1 in 6 of the population) with a significant hearing loss (HL)4. The most common management strategy for HL is the provision of hearing aids (HAs). Although HAs substantially improve speech understanding through the amplification of quiet sounds, HA users face disproportional difficulties when listening to speech in noise5,6. Listening in noise is a frequent and complex real-world listening challenge that relies on peripheral hearing, central auditory processing and cognition7,8. Auditory training (AT) can be described as training the brain to listen through active engagement with sounds. It is a low-cost intervention that can be tailored and delivered to individuals via computers and the Internet. Our previous systematic review of the published literature assessing this question showed robust evidence for improvements for trained auditory tasks9. However, transfer of learning to untrained outcomes was highly variable and evidence quality was very-low to moderate study quality, highlighting a need for further high-quality research. We have since published the results of a high-quality AT study for adults with mild HL10. Results showed significant post-training improvements for measures of self-reported hearing and cognition that index executive functions (higher-order cognition). A second study of HA users with mild to moderate HL showed a significant post-training improvement in performance for a cognitively demanding real-world listening task (competing speech) and improvements for a dual-task of listening and memory at a challenging signal-to-noise ratio (both executive tasks), following just 3 hours of phoneme discrimination in noise training11. Finally, with the aim of maximising these benefits, we asked whether training cognition directly (Cogmed working memory training)2,12 could offer greater improvements to HA user s real-world speech understanding2,. Although improvements were shown for trained span tasks, this type of learning did not transfer to generalised improvements in speech perception. These results suggest that it may not be possible to train the cognitive components of speech perception in isolation11. As such, any cognitive enhancement to aid HA users real-world speech understanding should be embedded within task-relevant (i.e. speech) training programs, which is the focus of this research. We want to tailor auditory-cognitive training (ACT) programs designed specifically for HA users, with optimal training stimuli based on high-quality research evidence, that will be freely available to NHS patients. This study will examine the feasibility of delivering and evaluating a RCT of auditory-cognitive training (ACT). The RCT is required to provide high-quality evidence that ACT is an acceptable, effective and cost-effective intervention to improve speech perception, communication and quality of life for new HA users. Using a mixed-methods approach, we will examine feasibility of the interventions (ACT delivery) and the research (RCT delivery), from the perspectives of new NHS HA users and audiologists. Rate and parameter estimates will be used alongside qualitative methodology to inform accessibility, acceptability and implementation of ACT and the RCT within the standard NHS audiology pathway. A total of 105 patients recruited across two sites (Nottingham and Kings Mill Hospital) will be randomised to one of three groups (treatment as usual (TAU)/TAU + phoneme discrimination n-back ACT/TAU + competing speech ACT; n=35 patients per group). We will assess the acceptability and completeness of pre- and post-training outcomes measures (speech perception [primary outcome], higher-order cognition, and hearing- and health-related quality of life) and identify any costs associated with ACT delivery to inform future cost-effectiveness analysis. Findings of this study will be used to identify whether the pragmatic trial can be conducted effectively. The RCT is required to provide high-quality evidence that ACT is an acceptable, effective and cost-effective intervention to improve speech perception, communication and quality of life for NHS patients.","The problem There are 11 million people in the UK with long-term hearing loss. Hearing loss isolates people, cutting them off from society. The standard treatment is to amplify quiet sounds using hearing aids, but listening also requires cognition (memory and attention), particularly in noisy and challenging everyday environments. Our novel solution Our research has shown that computer games designed to help people practice listening to speech can improve cognition and listening abilities for people with hearing loss and hearing aid users. These games, termed auditory training , could help patients better understand speech in noise, improving communication, which can improve quality of life. In the future, we need a large research trial to understand all of the benefits of these games to patients. First, we need to find out if the large trial could work, and if so, how best to design it. To do this, we are carrying out a feasibility study. Feasibility study We will: Carry out an 18-month study with 105 first-time hearing aid users recruited from two NHS audiology clinics. Understand how to provide the games to patients and the cost of doing this. Check the games can be delivered via the Internet to patients in their own homes. Work with audiologists at NHS departments to check how many patients can take part in the feasibility study and how many will be needed for the trial. Find out what patients and clinicians think about the games and the research. Measure the time taken to collect and analyse research data. Publicise the results. If feasible, design the large trial. The feasibility study will help ensure the trial provides high-quality evidence and value for money. We will involve patients in designing the feasibility study, which should make it easier for future patients to take part in the trial.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,EAR HRCS22_13968,Cancer Research UK,CRUK,Feasibility study investigating circulating peripheral mitochondrial DNA as a potential non-invasive biomarker for diagnosis and surveillance of high risk cutaneous melanoma,"Background Cutaneous melanoma is the UK’s fifth commonest cancer and is the leading cause of death from skin malignancy. Our recent work highlights the phenomenon of tumour cells obtaining their energy through mitochondrial transfer from its surrounding mesenchymal stem cells, which confers a survival advantage for the emerging cancer. Others have shown that mitochondrial DNA (mtDNA) mutations predominate in the cancer cells. Mitochondrial DNA is an attractive choice for screening and surveillance because it is easily distinguished from nuclear DNA, there is a substantially higher DNA copy number per cell (hundreds versus one) and a significantly lower number of possible mutations in the mtDNA. Such findings suggest the possibility of detecting peripherally circulating mtDNA as a simple and reproducible biomarker for the early detection of recurrence or disease progression. Aims A feasibility study in melanoma patients to test the following: 1.To identify patients presenting with high-risk primary melanoma and isolate mtDNA from primary tumour and blood samples pre and post-operatively. 2. To detect novel and existing mutations associated with high-risk primary melanoma 3. Can we detect mtDNA mutation associated with primary tumours in plasma samples taken pre and post-operatively? Methods We will undertake an exploratory study in patients presenting with high-risk primary melanoma (AJCC II), prior to staging with sentinel node biopsy and in subsequent follow-up. Historical specimens from melanoma patients held in the Norwich Biorepository will also be studied. Preoperative and sequential postoperative blood samples will be collected from 30 high-risk patients over 12 months. Circulating mtDNA will be compared with mtDNA in the primary melanoma and also from normal white cells from the peripheral blood as internal control. PacBio SMRT Technology analysis will also investigate the frequency of specific mtDNA mutations. The ratio of tumour to normal mtDNA will be assessed using real-time PCR to determine if melanoma derived mtDNA could be further developed to investigate the frequency of specific mtDNA mutations against patient outcome with melanoma. Clinical outcomes data (sentinel node status, recurrence-free survival) will be matched against the circulating mtDNA count and mutational burden. How the results of this research will be used Data generated in this exploratory study will be used as a paradigm to undertake larger phase III investigations of the therapeutic utility of mtDNA to determine clinical decision making for melanoma patients in the early detection and early treatment phases and for the surveillance of high-risk patients in follow-up.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_15904,Stroke Association,,Feasibility study of a supported self-management intervention for stroke survivors with aphasia (StarStep study),"Background: Stroke survivors with aphasia (SSWA) have particularly poor long-term outcomes including reduced psychological and social wellbeing. National clinical guidelines recommend ‘self-management’; however, the evidence base for SSWA is weak. During my PhD project, I explored the suitability of self-management as an approach for SSWA and used Medical Research Council guidance to outline the core components of a supported self-management intervention. Further collaboration with key stakeholders (SSWA, family members and SLTs) is needed to develop this approach before feasibility testing. Aim: To refine and feasibility test a supported self-management intervention for SSWA and their family members. Methods: •Stage One: Working together with key stakeholders in a series of workshops, I will refine and optimise the content of the intervention and develop training for SLTs to facilitate the approach. •Stage Two: I will undertake a non-randomised feasibility study with 30 SSWA and their family members. I will evaluate recruitment and retention rates and the feasibility of outcome measures. I will undertake a fidelity assessment and explore the acceptability of the intervention through qualitative interviews with participants. Expected outcomes: A supported self-management intervention which is feasible to deliver and can be tested in a future, large scale effectiveness randomised controlled trial.","Background: Stroke survivors with aphasia (SSWA) have particularly poor long-term outcomes including reduced psychological and social wellbeing. National clinical guidelines recommend ‘self-management’; however, the evidence base for SSWA is weak. During my PhD project, I explored the suitability of self-management as an approach for SSWA and used Medical Research Council guidance to outline the core components of a supported self-management intervention. Further collaboration with key stakeholders (SSWA, family members and SLTs) is needed to develop this approach before feasibility testing. Aim: To refine and feasibility test a supported self-management intervention for SSWA and their family members. Methods: •Stage One: Working together with key stakeholders in a series of workshops, I will refine and optimise the content of the intervention and develop training for SLTs to facilitate the approach. •Stage Two: I will undertake a non-randomised feasibility study with 30 SSWA and their family members. I will evaluate recruitment and retention rates and the feasibility of outcome measures. I will undertake a fidelity assessment and explore the acceptability of the intervention through qualitative interviews with participants. Expected outcomes: A supported self-management intervention which is feasible to deliver and can be tested in a future, large scale effectiveness randomised controlled trial.",7.1 INDIVIDUAL CARE NEEDS,STROKE HRCS22_03019,Medical Research Council,MRC,Fibrin-targeting PLGA microspheres for prevention of post-operative peritoneal adhesions; a pre-clinical proof of concept study,"Post-operative adhesions are a leading cause of surgery-associated complications. Based on our recent novel finding of the 'anti-adhesion macrophage barrier', we propose fibrin-targeting microspheres (fMS; PLGA microsphere conjugated with anti-fibrin antibody) as an innovative strategy to prevent adhesion formation. fMS is designed to accumulate on the fibrin clots exposed on the damaged tissue surface mimicking resident macrophages and reinforce the macrophage barrier to shield fibrin clots. fMS treatment has potential advantages over current barrier products, including greater specificity to the lesion at risk of adhesions, extensive access to difficult-to-access localizations, and little risk of displacement and misplacement. Our pilot study showed promising results. Thus, this project primarily aims to establish robust pre-clinical proof of concept for fMS treatment. We will first optimise the size and anti-fibrin antibody conjugation of fMS, and then establish a dose-effect relationship and long-term effect and safety of the optimised fMS. The obtained data will be further strengthened by assessing in a different model of post-operative adhesion. Also, we will collect biological information that is related to the safety and efficacy of fMS treatment, including biodistribution of fMS, the cover ratio of fibrin clots by fMS and/or macrophages, impacts of fMS on the mesothelial and peritoneal cells. Reconstitution of peritoneal resident macrophages following the surgery-induced 'macrophage disappearance reaction' and impacts of fMS on this process will be characterised. fMS treatment has potential to improve surgical outcome and enhance post-operative quality of life of a huge number of patients with reducing the healthcare cost. Obtained results will justify the progression of fMS treatment to the next stage of development toward clinical application. Previously unknown scientific data will also be obtained, paving the way to novel research projects.",,5.1 PHARMACEUTICALS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_11609,Economic and Social Research Council,ESRC,Financial lives and wellbeing in low-income groups post Covid-19 (FinWell-Covid),"This study builds on two pre-existing samples of low-income individuals in Glasgow (n=69) and Lambeth & Southwark in London (n=29) in whom we explored the relationship between their financial lives and their health and wellbeing. Methods used were: (1) an intensive financial diary, documenting all incomings and outgoings over a six-month period; (2) combined with monthly interviews, to collect quantitative and qualitative data, including health and wellbeing; and (3) two Q methodology studies (n=93) which explored the wider issues of perceptions, not only of the sample but also professional stakeholders, on causes of and solutions to health inequalities in such communities. The similar mixed method study we now propose presents a unique opportunity to identify, in depth, changes in the wider social determinants of health induced by COVID-19 itself as well as its associated interventions (e.g. social distancing and isolating) in some of the most economically-vulnerable members of society. This would be done by continuing to work with our previous samples, some new additions and with the various responsible finance and civil society organisations through which participants were recruited. Data would be collected via a new financial diaries app and continuing with interviews via remote technology. An online Q study would also be conducted, but, this time, with a focus on perceptions of COVID-19 and societal responses to it. These data will be useful in enhancing the acceptability of, adherence to and effective delivery of evidence-based strategies for future prevention and containment.","Amongst those hit hardest by COVID-19, and the associated social and economic measures put in place to combat it, will be people in low-income settings, and, within that group, those in hard-to-reach groups continually threatened by financial exclusion. People in such situations already live in precarious financial situations which could be amongst the most vulnerable to measures such as social distancing and self-isolation. Having recently worked with groups in Glasgow and London to explore the relationship between their financial lives and their health and wellbeing, we have an opportunity to follow up with these same groups in order to assess the impact of COVID-19 and measures such as social distancing on their financial portfolios, their short-term health and wellbeing and wider social determinants of health. We propose to do this via a unique combination of financial diary keeping and regular interviews which we have developed for working with such groups, and which can be adapted for remote working. In addition, we will seek the views of such groups as to perceptions of causes and solutions to COVID-19 which can be reconciled with more evidence-based data from other research projects.","1.3 CHEMICAL AND PHYSICAL SCIENCES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",GENERIC HEALTH RELEVANCE;INFECTION HRCS22_06889,Health Education England,HEE,First-phase ejection fraction guided management of aortic stenosis,"Background Aortic stenosis (AS) is the most common form of primary heart valve disease in moreeconomically developed countries, with a prevalence of moderate or severe disease of approximately 3% in those aged 75 years.It is often asymptomatic but when symptoms develop and/or there is a reduction in left ventricular (LV) ejection fraction (EF), survival without intervention is poor. Symptoms or reduced EF are thus Class I indications for aortic valve replacement (AVR) in severe AS. However, the management of asymptomatic severe AS with preserved EF is challenging and a measure that would accurately predict survival in asymptomatic AS would be invaluable with regard to decisions on expectant management or elective AVR. We have developed a novel measure of early systolic function: first phase ejection fraction (EF1) that shows promise in robustly predicting outcomes in patients with asymptomatic AS.Aims and objectives To examine whether patients with lower EF1 are more likely to develop symptoms and need more intensive clinical monitoring or early surgical intervention than those with preserved EF1. In addition, in an exploratory study in patients proceeding to AVR, we will assess whether EF1 is predictive of outcomes after AVR since this is another potential use of EF1. Methods Patients with asymptomatic severe AS (n=300) will be recruited from Guy's and St Thomas' NHS Foundation Trust and King's College London NHS Foundation Trust. Patients will have clinical examination, medical history review, echocardiography, central blood pressure measurements, blood test for biochemical biomarkers, a 6 minute walk test and, if clinically indicated to clarify symptom status, an exercise tolerance test. EF1 will be measured by an automated method developed in collaboration with Tomtec. Patients will be followed-up at 6 monthly intervals according to standard care for a minimum of 12 months or until AVR or death by a clinician blinded to the value of EF1. The primary outcome will be a composite event of: indication for AVR (based on a reduction in EF Timeline for delivery Milestone 1: setup imaging analysis workstations with Tomtec on both sites (Months 1-2) Milestone 2: patient recruitment (Months 3-21) Milestone 3: patient monitoring and follow up (Months 3-33) Milestone 4: Data analysis, conference presentation and publication (Months 30-36) Anticipated impact and dissemination The findings of this fellowship will benefit patients and service delivery in the NHS by establishing EF1 guided management of patients with AS. This will determine which patients need close monitoring or immediate valve replacement and which patients can be reassured and monitored less frequently.","A new test (called EF1) may tell us which patients with a narrowed heart valve need an operation. Aim: I think a new way of measuring how well the heart pumps (called EF1) will help to provide the best care for patients with a narrowed heart valve. I will see if the test can tell which patients need an operation to replace the narrowed valve. I will improve the test so that it can be made automatically during a standard heart scan. Background: Sometimes a valve at the top of the heart becomes narrower with age. It stops pumping properly and prevents the blood being pumped out of the heart from returning into the heart. This is known as 'aortic stenosis'. The narrowed valve makes the heart work harder to pump blood and puts a strain on the heart. Some people with this condition don't notice anything wrong until it is too late. In these people, the heart suddenly gives up from the strain and they may die. I have developed a new test called EF1 that measures how well the heart is pumping under the strain of the narrowed valve. I think this will tell which patients should have an operation to keep them feeling well. I will see if the test can tell which patients need an operation to replace the narrowed valve and which patients can be safely seen by doctors once or twice a year. Design and methods: Patients with a narrowed valve who have not developed symptoms, such as feeling short of breath, will be asked to volunteer to have the new test. About 300 patients will have the new test so that I have enough people to make a decision whether this test works or not. The test will be done during the ultrasound heart scan that is done in all patients with suspected heart problems. As part of the project I will test an automatic computer system for measuring EF1. If this works well, then all doctors and clinical care workers will be able to use the test easily and reliably. After patients have the test, I will see them regularly to find how well the test can predict which patients develop symptoms. Potential benefits to patients and the NHS: I hope the results of this research will help patients and improve clinical services in the NHS by helping us give the right treatment at the right time. Patient and public involvement: The patient and public review panel from our Cardiovascular Imaging group helped me to write this summary. This group will be helping me to explain to patients what will happen if they volunteer for this research and explain the results at the end of the project.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CARDIOVASCULAR HRCS22_11550,Economic and Social Research Council,ESRC,"Forging new families in contemporary contexts: Exploring interpersonal relationships, power and abuses of power within online sperm donation","Sperm donation plays a critical role in starting and building a family. It is the only way that many people can conceive, including single women, women in same-sex relationships, and because of male infertility in mixed-sex relationships. Thus, sperm donation has a crucial function in an equitable society. Increasingly, potential recipients and donors are connecting via websites and social networking sites, in what has become a large, global, but wholly unregulated, market. This phenomenon has been largely hidden from societal and academic view, despite reports of donors abusing recipients. For the first time, we will provide a holistic and in-depth understanding of online sperm donation, exploring the interpersonal relationships, power relations and abuses of power that are occurring across the five levels of its social ecology: individual, relationship, community, societal and temporal. Relationships are central to online sperm donation - whether between donors and recipients, between donors/recipients and their life partners, or between the people who use and own the online platforms. Yet virtually nothing is known about these relationships: how are they initiated, negotiated, sustained or ended? Given that donors are in a position of power - holding the sperm that recipients require - and there is emerging research and increasing media reports of donors abusing recipients via these online platforms, we urgently need academic insight into the power relations and abuses of power in this context: how is power operating across the social ecology of online sperm donation and how is it being reinforced, abused or resisted? Building on the team's existing and ongoing work in this area, we will address these knowledge gaps. Thus, our first aim is to understand the interpersonal relationships, power relations and potential abuses of power across the social ecology of online sperm donation. Reflecting the five levels of the social ecology (see Annex A), we will meet this aim via five objectives, which will: 1. evidence recipient and donor experiences of interpersonal relationships, power and abuses of power; 2. demonstrate how their partner and the person they conceive with narrate their experiences of these; 3. evidence how site users forge interpersonal relationships and subcultural norms within the online sperm donation platforms, and the role of online platform owners in creating and governing these; 4. demonstrate the broader social narratives participants draw on to understand and explain these experiences; 5. track how these experiences unfold over time. Meeting these objectives will provide unique and holistic evidence on online sperm donation, bringing this into public knowledge at a time of rapid expansion within the online sperm donation market, and increasing questions about unregulated assisted conception practices (Cheshire, 2019), online harms (HM Government, 2019) and violence against women (British Council, 2016). Based on the above findings, our second aim is to explore the imagined ideal futures of those involved in online sperm donation and work with them to facilitate personal, professional and social change in online sperm donation. We will meet this aim via two objectives, which will: 6. produce a set of comics and visual social-ecological power drawings that distil the findings from Objectives 1-5; 7. undertake workshops with those involved in online sperm donation, reflecting on the comics and power drawings to imagine ideal futures for online sperm donation and to co-design and co-implement actions to achieve change. Meeting these objectives will harness the knowledge generated from the research by collaboratively working with those involved in online sperm donation to raise public awareness and inform policy, legislative, social, and service-delivery responses.","The Universal Declaration of Human Rights describes the family as the ""fundamental unit of society"", and in 1969, the United Nations recommended that ""governments should, as a matter of urgency, make universally available information, education and the means to assist couples and individuals to achieve their desired number of children"". However, many people need help from a sperm donor to start or build their family, and even now, there are lots of barriers to them receiving this help at an NHS or private clinic. So, instead, many people are looking for a sperm donor online. Unfortunately, there is very little information available to them about what online sperm donation involves and how it might change their lives for the better - or, possibly, for the worse. In the media, for example, there have been stories of men registering with online sperm donation sites and then being abusive to women who are looking for sperm. Relationships are at the heart of online sperm donation so our project starts there. There are the relationships between the person looking for sperm and the person who donates the sperm, and between these people and their life partner (if they have one). There are also the relationships between the many people who take part in the online sperm donation websites, and between these people and the person who owns the website. Sometimes, these relationships go well; sometimes, they do not. The first aim of this project is to look at how people experience these relationships, who is being positioned as powerful, and any abuse that is happening. In the first part of the project, the main way that we will look at these relationships is by talking with people who want sperm and people who are looking to donate sperm. We will talk with them three times over two years, starting with their online search to find sperm or donate sperm. Over the two years, we will also talk to these people's life partner, and the person they find who gives them the sperm or who they donate their sperm to. In the second part of the project, we will look at the relationships between the many people who take part in online sperm donation websites, and between these people and the person who owns the website. The main ways we will look at this is by joining the online websites as a researcher and following how people interact with and treat each other over one year, and by talking with the people who own the websites. The research will increase everyone's understanding of three important topics in our society: violence, health, and the internet. For violence, it will make people more aware of how women looking for sperm online (and possibly other people, too) are being abused, what support they need, and how we can stop this abuse from happening. For health, it will help decide whether NHS clinics should have more funding for sperm donation and who can access it, and whether the government should regulate online sperm donation. For the internet, it will help people discuss how the internet affects our lives and what safety and support we need online. It will be essential to ask the people involved in online sperm donation what they think needs to change in online sperm donation (e.g., public awareness, policies, laws, support services). So, the second aim of the project is to find out what people involved in online sperm donation think is the 'ideal future' for online sperm donation and work with them to make these changes. In the third part of the project, we will run workshops to share the research findings using comics and drawings, and together, work out what needs to change in online sperm donation, plan and do activities that will lead to this change, and log what changes happen. During the whole project, we will also share our findings with people involved in online sperm donation, researchers, professionals working in abuse, health, and internet safety, people who make policies and laws, and the public, to help effect change.","8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_18280,"Alzheimer's Research UK",,Frontotemporal dementia-causing mutations in C9orf72: investigation of the toxic mechanism,"A mistake in the C9orf72 gene is the most common cause of frontotemporal dementia and of motor neuron disease. Therefore, identifying how this gene causes neuronal death should reveal important new insights into the causes of dementia and other neurodegenerative diseases. We recently used fruit flies to show that two specific proteins called poly-(GR) and poly-(PR) instigate the neuronal death caused by the C9orf72 mistake. We will now build on these exciting findings by combining analysis of fruit flies with investigation of the brains of people with the C9orf72 mistake and by converting patient skin cells into neurons that we can grow and study in the laboratory. Recent evidence suggests that the levels and transport of RNAs and proteins are affected by the C9orf72 mistake. We will use state-of-the–art microscopy techniques in conjunction with innovative methods to measure the levels of all RNAs and the generation of all proteins within neurons. This powerful approach will enable us to pinpoint the specific RNAs and proteins affected by poly-(GR) and poly-(PR). This will identify the most important factors leading to neuronal death and give insight into developing specific therapies.","A mistake in the C9orf72 gene is the most common cause of frontotemporal dementia and of motor neuron disease. Therefore, identifying how this gene causes neuronal death should reveal important new insights into the causes of dementia and other neurodegenerative diseases. We recently used fruit flies to show that two specific proteins called poly-(GR) and poly-(PR) instigate the neuronal death caused by the C9orf72 mistake. We will now build on these exciting findings by combining analysis of fruit flies with investigation of the brains of people with the C9orf72 mistake and by converting patient skin cells into neurons that we can grow and study in the laboratory. Recent evidence suggests that the levels and transport of RNAs and proteins are affected by the C9orf72 mistake. We will use state-of-the–art microscopy techniques in conjunction with innovative methods to measure the levels of all RNAs and the generation of all proteins within neurons. This powerful approach will enable us to pinpoint the specific RNAs and proteins affected by poly-(GR) and poly-(PR). This will identify the most important factors leading to neuronal death and give insight into developing specific therapies.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_17396,Cancer Research UK,CRUK,"Full Duration Studentship - Accelerator Award A26825 ""ACRCelerate: Colorectal Cancer Stratified Medicine Network""","Studentship asssociated with programme: Colorectal cancer (CRC) remains the second most common cause of cancer death, and patients with stage 3/4 cancers at diagnosis only have a 10% survival rate at 5 years. Chemotherapy relies on the use of combination cytotoxics against the proliferating tumour epithelium, with novel targeted therapies having disappointing trial results to date. CRC presents an opportunity for precision medicine as it is common, has known and established driver molecular pathways and pre-treatment molecular stratification is achievable. Recent advances in sequencing technology and biological models have resulted in paradigm shifts in our understanding of CRC biology, but have failed to significantly impact upon patient care. Indeed, stratified medicine clinical trials such as FOCUS4 have been hampered by the lack of robust preclinical prediction, which have left many therapeutic arms of the trial unfilled. This Accelerator application brings together a European-wide consortium at the forefront of CRC research to align and interrogate a suite of state-of-the art preclinical models (GEMMs, organoids and PDXs). Our platform will accelerate therapeutic target identification and preclinical validation of new and repurposed drugs, to accomplish rapid clinical translation. Our focus will be to generate and share models of CRC that correlate with human CRC molecular subtypes, to enhance testing of CRC therapeutics in functionally relevant microenvironments. By placing molecular phenotyping and stratification at the heart of this programme we will target biologically plausible pathways known to be dysregulated in CRC, and design molecularly stratified clinical trials to test them, to ensure that no therapeutic opportunities are overlooked. The overarching aim of this proposal is to generate robust and reproducible preclinical data to de-risk future clinical trials based on patient stratification. We will employ and develop preclinical models that recapitulate the molecular subtypes of CRC, characterise their signalling pathways, use DNA and RNA sequencing to subtype the models, identify and test new therapeutics and integrate the data in a bioinformatic analysis pipeline. The data will be shared amongst the consortium for cross-validation, reducing the number of mice used in cancer research and to inform future stratified clinical trials for CRC.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_05238,Department of Health and Social Care,NIHR,Function REplacement in repeated Self-Harm: Standardising Therapeutic Assessment and the Related Therapy: FReSH START,"Aims and Objectives, To develop and evaluate the cost-effectiveness of a new approach to psychological therapy for people who repeatedly self-harm and who are being treated in mainstream NHS practice. Background and rationale A recent Cochrane review indicates how little evidence there is on the management of repeated self-harm in adults. Seven published RCT come from specialist services and include only people with a diagnosis of personality disorder. Therapies are intensive, of long duration and require specialist therapists; there is no published evidence of cost-effectiveness. What is needed is evaluation of a therapy that can be delivered to a wider population. Our approach involves modifying three existing therapies (behavioural activation, acceptance and commitment therapy, psychodynamic interpersonal therapy), training therapists in their use and conducting a definitive Phase 3 RCT with an internal pilot, cost-effectiveness analysis and process evaluation. Research plan, Work Package 1: Develop initial training package Work Package 2: Testing implementation of the training package Work Package 3: Non-randomised feasibility study Work package 4: Definitive RCT with internal pilot and process evaluation WP1a A Q methodology study with adult participants with personal experience of repetitive self-harm. Participants will complete a Q sort of reasons for self-harm online. Interview with a sub-sample of respondents online or by telephone about their choices. WP1b: Systematic review of self-reported accounts of means of recovery from repeated self-harm - will support development of a portfolio of alternative activities to be discussed in therapy. WP1c: Facilitated consensus groups will develop supporting materials for the therapeutic assessment and subsequent therapy, formulate how best to integrate the self-harm assessment into each of the three different therapies and explore the challenges of incorporating into NHS care pathways. Groups will develop a brief three-day training programme for each therapy. WP2a: A National survey of provision of candidate therapies will identify provision of the three therapies of interest, seek expressions of interest from therapists and identify NHS sites for participation in the RCT. WP2b: Semi-structured interviews will explore therapists experience of the training once delivered. Interviews with service leads will explore the challenges of incorporating our approach into existing care pathways. WP3a: A non- randomised single arm feasibility study in 30 participants across three sites will test delivery and development of the intervention, whilst refining processes for the subsequent definitive trial. We will assess recruitment, follow-up, intervention delivery & acceptability rates, with clear progression criteria based on a traffic light system. WP3b: An interview and observational study (with the consent of participants, each therapy session will be audio-recorded) will explore with therapists and participants receiving the intervention their experience of assessment and therapy. WP4a: Definitive RCT with internal pilot – an individually 1:1 randomised controlled trial N= 630 of referral to experimental therapy vs NICE compliant Treatment as Usual, with internal pilot. Randomisation will use minimisation, stratified for site, sex, referral source, time since first episode, and possibly CORE-OM score (dependent on ranges seen in the feasibility study). Primary outcome will be 12 month Quality of life using Clinical Outcomes in Routine Evaluation - Outcome Measure (CORE-OM). Secondary outcomes will include measures of reliable and clinically significant improvement on the CORE-OM; repetition of self-harm; hopelessness; depression; social connectedness; Quality-adjusted life years (QALYs), using utility as measured by the preference based measure CORE 6D generated from CORE-OM; ; Self-reported resource use– primary and community care and medications and private financial burden due to self-harm. Analysis will be by intention-to-treat, with no planned interim analysis. We will undertake a within-trial cost-effectiveness analysis using QALY as the outcome measure. WP4b: A process evaluation will explore the process of implementation of the therapeutic approach across sites and therapists. Projected outputs & dissemination plans A novel clinical assessment for people who repeatedly self-harm . A training programme to broaden the range of therapies, and therapists, available to people who self-harm and do not need to have either a diagnosis of personality disorder or treatment in a specialist clinic. RCT evaluation of a widely applicable therapeutic approach. Dissemination will be via academic publications and presentations. We will facilitate knowledge transfer through sustained contact with clinical services and clinical commissioning groups nationally throughout the programme of work. The PI is an Expert Adviser for the NICE Centre for Guidelines and will ensure the findings are included in future revisions. Via our PPI we will ensure the results are available to service user groups. If the therapy is effective we will produce plans for distribution of training and materials in the NHS. Benefits to patients and the NHS PPI, embedded throughout the programme through involvement of our two co-applicants and an advisory group, will ensure the training programme and therapy-delivery is tailored to the needs of service users. The benefit to the NHS will be the first ever cost-effectiveness analysis of therapy for repeated self-harm.","Multiple repetition of self-harm is common and is associated with poor quality of life and with an increased risk of suicide even when the immediate reported reason for an act is not attempted suicide. There is currently no treatment, deliverable in mainstream mental health services, that works well for individuals with a history of multiple repetition. The aim of this programme of research is to develop and evaluate a new approach for helping individuals who repeatedly self-harm - based upon changing existing therapies so they are more useful in helping people who repeatedly self-harm. Current treatment tends to focus on the act of self-harm as a symptom of underlying distress. However, personal accounts of reasons for repetition also identify positive motivations such as feeling a stronger person or feeling more in control of one s life. We wish to develop a new approach that can accommodate all potential motivations and allow therapists and service users to identify, and work with, these positive functions. A goal of therapy is then to explore what these functions of self-harm say about an individual s values and help consider new ways to achieve change that reflects those values. There are a number of current therapies that work with service users on personal goals and values; Behavioural Activation (BA), Acceptance and Commitment Therapy (ACT) and Psychodynamic Interpersonal Therapy (PIT). We want to adapt these therapies so they are more appropriate for individuals who repeatedly self-harm. We will first develop an acceptable assessment that can be used to help individuals think about what benefits they gain from self-harm. It is widely known that service users find it difficult to say why they self-harm. Q methodology is a way to make this easier, and we will use it to ask people how their own experience relates to reasons for self-harm reported by others - we have identified many such reasons from a recently completed review of first person accounts of reasons for self-harm, and an analysis of social media postings. The output from this initial work will be a new way of describing reasons for self-harm, from the service user s perspective. We will review published self-reported accounts of recovery both in the published literature and on social media. We will then work with experienced therapists and service users to establish how to incorporate the new assessment and what we know about self-reported reasons for change, into therapy. We will then develop a training programme for therapists who already have some training or experience in the approaches to support them in using the materials with individuals who repeatedly self-harm. After identifying and training suitable therapists we will evaluate the effectiveness of this approach in a Randomised Controlled Trial.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_18560,Cancer Research UK,CRUK,Function of novel epigentic modification pathways and their role in cancer,"Function of novel epigenetic modification pathways and their role in cancer BACKGROUND Epigenetic modifications on DNA, RNA and histones regulate many important biological processes. Enzymes that mediate these modifications are often found mutated in cancer and consequently such enzymes represent targets for drug discovery. Our lab has a track record in the discovery and mechanistic characterisation of enzymes that modify histones and RNA, and the evaluation of small molecule inhibitors targeting such enzymes. Given these connections to cancer, we expect that the characterisation of novel pathways leading to histone and RNA modifications will lead to the discovery of new validated targets for drug discovery. AIMS The aims in this proposal are threefold: Work Package 1 involves the molecular dissection of two new chromatin modification pathways (H4T80 phosphorylation and H3K37 methylation) both of which we identified in the previous quinquennium. Work Package 2 involves the molecular characterisation of three different classes of RNA modification: pseudouridylation, methylation, and uridylation. We will investigate the biological roles of the enzymes that mediate them, giving attention to their chromatin-based functions following recruitment to promoters. Work Package 3 will concentrate on evaluating the importance of RNA modifying enzymes in cancer using small molecule inhibitors and CRISPR knock-out technology. METHODS Work Package 1: We will address the molecular and biological processes regulated by new histone modification pathways in both yeast and mammalian cells using unique antibody reagents we have developed and standard chromatin-appropriate techniques. Work Package 2: We have developed several biological and chemical tools, as well as new mass spectrometry methods of detection, which will be used to characterise the function of RNA modifications. All modifications will be dissected in appropriate cancer cell systems. Work Package 3: We are in close collaboration with STORM Therapeutics, a drug discovery biotech, that is developing small molecule inhibitors against enzymes we have shown to be involved in cancer. These molecules will be provided to us to evaluate them in cell-based viability assays and in synthetic lethality screens. HOW THE RESULTS OF THIS RESEARCH WILL BE USED We expect the results of this proposal will be used to (a) define new targets for drug discovery, (b) provide mechanistic understanding for already established cancer targets and (c) define the selectivity and specificity of small molecule inhibitors against specific epigenetic targets.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_18237,Cancer Research UK,CRUK,Functional genomics of breast cancer,"We have redefined breast cancer as a constellation of 10 genomic driver-based subtypes. This new molecular taxonomy of breast cancer will now be translated into the clinic in stratification, tumour monitoring and therapy studies. In parallel we will continue to develop models to characterize the biology of these subtypes.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT),CANCER AND NEOPLASMS HRCS22_13794,North West Cancer Research,,Funding for extraction of DNA for WGS from samples,Extraction of DNA for whole genome sequencing from the samples currently held by the University,,1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),CANCER AND NEOPLASMS HRCS22_16012,Dunhill Medical Trust,,Further EvAluation of SCD-WELL: mindfulness THERapy for older adults (FEATHER),"Background It is increasingly recognized that most neuropathological processes start years before the onset of dementia. It is important to target intervention in the earliest stages when neurodegeneration is limited. There is evidence that subjective cognitive decline (SCD) is associated with increased risk for future cognitive decline. (1) Persons with SCD also experience increased depressive symptoms, which have been shown to increase dementia risk in the general population. (2) Objectives Our main objective is to evaluate the effects of an 8-week Caring Mindfulness-Based Approach for Seniors (CMBAS) compared to a health education programme (HEP) on depressive symptoms in older adults with SCD. Our secondary objective will be to improve our understanding of the relationship between SCD and depressive symptoms. We would first seek to replicate the previous finding of an association between SCD and depressive symptoms, and then seek to explain this association via statistical mediation. Further objectives will be to investigate whether CMBAS improves cognition in areas most sensitive to dementia. Methods We will utilize data collected during the SCD-WELL trial, a pan-European randomized study of CMBAS versus HEP in 160 older adults with SCD. Data are being collected at baseline (pre-intervention), week-8 (post-intervention) and week-24 (follow-up). Standardized measures are collected by blinded raters, and include Geriatric Depression Scale (GDS) (3); Cognitive Difficulties Scale (measures subjective cognitive complaints) (4); World Health Organisation Quality of Life (5); Physical Activity Scale (6); Big-Five Inventory (Personality) (7); Loneliness Scale (8); Pittsburgh Sleep Quality Index (9); Psychological Well-being (10); and an extensive range of cognitive measures. These include the Mattis Dementia Rating Scale-2 (11); Rey Verbal Auditory Learning Test (12); Trail Making Tests (13); verbal fluency (14); Stroop (15); and WAIS Coding/Matrix Reasoning/Vocabulary (16). Statistical analysis The CMBAS and HEP groups will be compared on baseline demographic, cognitive and medical variables in order to describe the sample and identify covariates needing to be adjusted for. The analysis will follow Intention-to-Treat. The change on the primary outcome, Geriatric Depression Scale, will be compared between CMBAS and HEP at weeks 8 and 24 using ANCOVA. Characteristics of responders and non-responders will be evaluated using baseline variables. Impact An intervention that reduces the incidence of dementia and depressive symptoms would have enormous societal, personal and economic value. CMBAS, if successful, could be promoted as a non-pharmacological therapy that could have a major positive effect on the mental health and quality of life of older patients.","Background Results from clinical trials for dementia have been disappointing. One explanation is that most treatments have been tested in patients with a diagnosis of dementia when the brain is already damaged. People experiencing mild memory problems who still perform well on memory tests are more likely to develop dementia. This condition is called subjective cognitive decline (SCD). People with SCD frequently experience depression, and depression is also a risk factor for dementia. Objectives Our main objective is to evaluate if people with SCD who take part in an 8-week mindfulness therapy have a greater reduction in their symptoms of depression compared to those taking a health education course. Our secondary objective will be to improve our understanding of the relationship between SCD and symptoms of depression by looking at factors linking the two. Further objectives will be to investigate whether mindfulness therapy improves memory and thinking skills affected by dementia. Methods We will use data collected for a European clinical trial called 'SCD-WELL' taking place in France, Germany, Spain and the UK. SCD-WELL is comparing the beneficial effects of a mindfulness therapy to those of a health education course in 160 adults with SCD. The main study (ongoing, already funded) is looking at the effect of the groups on participants' anxiety, but this Fellowship proposal will explore many other outcomes which are also relevant to people with SCD. Participants are asked to fill in a number of questionnaires and are given tests that measure thinking and memory before the start of the groups, at 8-weeks (when the groups have concluded) and 4 months later. The questionnaires and memory tests will collect information about depressive symptoms, subjective cognitive complaints, quality of life, physical activity, personality traits, loneliness, quality of sleep, and wellbeing. Statistical analysis We will compare the two groups to see whether symptoms of depression change more in the group receiving mindfulness therapy relative to those receiving the health education course. We will compare the two groups to see whether mindfulness therapy has a relatively greater effect on memory and thinking skills. Impact An intervention that reduces the occurrence of dementia and symptoms of depression would have enormous societal, personal and economic value. Mindfulness-based therapy, if successful, could be a promising therapy to reduce the risk of dementia and also to have a major positive effect on the mental health and quality of life of older adults.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,NEUROLOGICAL;MENTAL HEALTH HRCS22_03237,Medical Research Council,MRC,GCRF Action against Stunting Hub,"Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,ORAL AND GASTROINTESTINAL;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_01675,Medical Research Council,MRC,Gastroenteritis: rehydration for children with severe acute malnutrition (GASTRO-SAM),"Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea (3 watery stools/day) which is accompanied by poor outcomes (case fatality 21%). Rehydration guidelines for SAM are exceptionally conservative and controversial, as they rely upon expert opinion, recommending restriction of intravenous (iv) to cases with advanced shock and exclusive use of low sodium oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. We aim to evaluate standard (non-SAM) liberal strategies for both iv and oral rehydration in SAM children with diarrhoea. The Phase II trial will generate feasibility, safety and preliminary data on survival to 7 days and 28 days of rehydration strategies incorporating two strata for management of (A) severe dehydration comparing both rates of rehydration and volume of iv replacement and (B) the composition of ORS for children with some dehydration (and post iv-rehydration) designed as a factorial trial. The two major questions to be addressed are (1) In Stratum A involving SAM children with clinical signs of severe dehydration (~10% loss) whether 'liberal' rehydration strategy using 100mls/kg of isotonic Ringers Lactate with either (i) standard WHO Plan C for rapid rehydration over 3-5 hours (incorporating boluses for shock) versus (ii) slower fixed rate of intravenous rehydration over 8 hours (and no boluses) are safer and result in better outcomes versus (iii) current WHO SAM guidelines recommending oral rehydration with low-sodium ReSoMal and restricting iv to those with advanced shock only (15 ml/kg bolus (plus one repeat). (2) In Stratum B in children with diarrhoea with clinical signs of 'some dehydration' and follow on treatment post-intravenous rehydration whether oral rehydration with (i)WHO standard oral rehydration solution (ORS) for non-SAM results in less hyponatraemia and less adverse outcomes than (ii) current recommendation advocating low sodium (ReSoMal) ORS.",,6.1 PHARMACEUTICALS,METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL HRCS22_02017,Medical Research Council,MRC,Gene Editing in X-Linked Agammaglobulinaemia,"X-linked agammaglobulinemia (XLA) is caused by a mutation in Bruton's Tyrosine Kinase (Btk) which is encoded at the Xq22.1 locus. When developing lymphocytes reach the pre B-Cell phase they express a pre B Cell receptor and after cell surface expression it dimerises sending survival signals via Btk. Mutations of this molecule lead to the cessation of B-cell development. Patients therefore have absent B Cells and no detectable Immunoglobulins. This project will assess the CRISPR-Cas system of gene editing to correct this mutation. This involves nucleofection of cells with the Cas 9 protein complexed with a guide RNA complementary to our chosen target. This leads to a double stranded DNA break (DSB) at the Btk gene locus. Subsequently a Adeno Associated Virus 6 vector will be used to introduce a normal Btk minigene gene into the locus. Following optimisation of the technique in a Btk knockout DG75 cell line, we will trial it in CD34+ cell from healthy donors and then XLA patients. CD34+ cells will be separated from blood using Magnetic-Activated Cell Sorting. Editing efficiency will be determined by Digital Droplet PCR. Subsequently, we will perform in vitro comparisons will assess the function of gene edited patient cells. To assess for off target effects we will use GUIDE-sec (Genome-wide, unbiased identification of DSBs enabled by sequencing). This method involves tagging any DSBs in the genome with a blunt double-stranded oligodeoxynucleotide (dsODN). Integration points are then identified using PCR amplification and sequencing of products. We finally aim to test gene edited cells in a NSG mice model. Primary and secondary transplantation will be performed and each experiment will consist of 3 groups (negative control, gene edited group and positive control). To assess restoration of the humoral immune system we will perform flow cytometry to determine B Cell numbers, test vaccination, Immunoglobulin quantification and cell proliferation assays.",,5.2 CELLULAR AND GENE THERAPIES,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_23308,LifeArc,,Gene therapy for Non-Ketotic Hyperglycinemia,"Non-Ketotic Hyperglycinemia (NKH) is a life-limiting inherited metabolic disease that affects the chemical changes in cells of the brain and liver. It is marked by a build-up of glycine (an amino acid) in the body because of a mutation in genes that encode parts of the glycine cleavage system (GCS). Most patients carry mutations in glycine decarboxylase, an enzyme that is part of the GCS. NKH becomes apparent in babies soon after birth with lethargy, breathing difficulties and neurological problems, including epilepsy and developmental delay. Current treatments for NKH have limited effect and there is no cure. The project aims to develop gene therapy for NKH using a virus-based vector, to restore the activity of GLDC in the brain. This strategy has the potential to treat any patient with a loss-of-function mutation in GLDC and could be used for the other main NKH-causing gene, AMT. In this project, the team will test novel gene therapy vectors in a GLDC-deficient mouse model that displays key features of NKH. It will evaluate whether treatment restores GCS activity and whether this can reduce metabolic defects in the brain, normalise gene expression and improve neurological features. As a step towards clinical implementation, the team will also test whether the impact lasts over time and is safe. This will support development towards the final stages of pre-clinical testing – including the start of GMP manufacture and pre-clinical studies to support application for a clinical trial.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES,METABOLIC AND ENDOCRINE HRCS22_01718,Medical Research Council,MRC,Genetic and environmental determinants of age-acquired skewed X-inactivation and escape from X-inactivation,"The fundamental aim of this project is to understand the role of genetics and the environment in age-acquired skewed X-inactivation and in regulating the expression of genes on Chromosome X in females. This project will assay skewed X-inactivation in 4000 ageing female twins from the deeply-phenotyped TwinsUK cohort. We will investigate the relationship between skewing and environmental factors, and determine if skewing can act as a biomarker for healthy ageing or disease prediction. Age-acquired skewing is heritable - we will utilize three strategies to explore its genetic basis. Classical twin modeling will be used to identify Gene x Environment interactions on the heritability of skewing. We will perform a GWAS in 4000 twins to identify individual loci associated with skewing. Genome-wide genetic correlation methods will be used to identify shared genetic architecture underlying skewing and autoimmune diseases or cancer. This project will comprehensively investigate escape from X-inactivation by deeply sequencing chromosome X transcripts in autoimmune relevant cell-types obtained from 50 female twins and by re-purposing existing large multi-tissue and longitudinal 'omic datasets from up to 850 deeply phenotyped female twins. This will allow investigation of which genes escape X-inactivation, and importantly how escape varies across individuals, across twin pairs, across tissues and over time. Identification of regulatory variants (eQTLs and splice eQTLs) have been critical to interpretation, and eventual translation, of GWAS signals. Most eQTL studies do not include Chromosome X, and those that do have not taken the skewed status of the individuals into account, which may bias eQTL tests. This project will identify eQTLs on Chromosome X in a large multi-tissue dataset after accounting for skewed X-inactivation, and use these eQTLs to interpret GWAS loci.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_15158,Versus Arthritis,,Genetic and molecular bases of defective tolerance induction in autoreactive B lymphocytes in systemic sclerosis,"The presence of circulating antibodies is a hallmark of immune dysregulation in systemic sclerosis (SSc). These autoantibodies are detectable prior to disease onset, define disease subsets, predict distinctive pattern of organ involvement, response to treatment and prognoses. However, it is unclear how autoreactive B cells are generated, escape tolerance and promote SSc disease. Our recent studies have revealed evidence for defects in B cell tolerance induction in immature transitional SSc B cells. Using purpose-designed protocols, we have discovered that transitional B cells can be divided into 4 distinct phenotypic and functional subsets, T1, T2, T3 and CD27+B cells. The T1 and T2 subsets are distinguishable by their differential capacity to undergo tolerance by apoptosis or by anergy following the engagement of their BCR. The T3 subset displays anergic functional status. CD27+transitional B cells, in contrast, respond rapidly to T cell-independent stimuli by producing IL-10. These studies established a novel paradigm for the developmental pathway of human transitional B cell maturation and tolerance. Using the paradigm, we uncovered defective tolerance induction in T1 B cells in SSc patients that lead to the expansion of circulating autoreactive IL-6-producing B cells. In addition, transitional as well as mature SSc B cells showed a defect in differentiating to IL-10 producing B cells. This PhD proposal will explore the genetic and molecular bases of defective tolerance induction, IL-6 production and defect in IL-10 production by B cells in SSc. By carrying out single cell genetic profiling and analysing major signalling pathways, the study can provide fundamental information on the cause(s) of defects in tolerance induction, preferential differentiation to IL-6 production and diminished IL-10 production by B cells in SSc patients. The study can also revealmolecular signatures that distinguish transitional B cells destined to become pathogenic rather than regulatory B cells.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_01781,Medical Research Council,MRC,Genome engineering as an approach to identify crucial miRNA targets in cancer,"MicroRNAs (miRNAs) have a crucial role in cancer development and progression. During a particular cellular process, they act by base-pairing with the 3'UTR of hundred of mRNA targets to repress their protein translation. Notably, it has been elegantly demonstrated that in Caenorhabditis elegans, the let-7 miRNA does not function to reduce gene expression noise broadly but to directs vulva development through regulation of a single target. Whether this mode of miRNA regulation also occurs in other systems, such as human, remains largely unclear. Prediction of miRNA targets, experimental validation and rescue experiments have suggested that this could be the case, but this has never been addressed systematically. Considering that a single miRNA can regulate thousands of transcripts, using this method to precisely address this question, for any single putative target, would be very time consuming. Herein, we aim to develop CRISPR-CAS9 pooled screening technologies that specifically and rapidly address this important biological question. The discovery of key targets of important miRNAs in cancer or other diseases can reveal new therapeutic targets/biomarkers. This proposed work follows from our recent study pending revision, in Nature Communication, where we discovered that two miRNAs, miR-100 and miR-125b, are induced by TGFb in advanced PDAC and are important effectors of the tumourigenic TGFb response. We developed a novel method to identify all the targets of these miRNAs, that we called RIP-USE, which indicated that these two miRNAs co-regulate hundreds of transcripts after TGFb induction, but could not identify the key targets of such miRNAs. Therefore, we now want to develop a series of CRISPR/CAS9 screening methods that would permit to identify the crucial miRNA targets. We will focus on the oncogenic miR-100 and miR125b as well the tumour suppressor miR-205 and miR-203 to develop methods that can be used to discover key miRNA targets for any miRNA of choice.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_05722,Medical Research Council,MRC,Genotype of Urothelial cancer: Stratified Treatment and Oncological outcomes (GUSTO): Phase II study,"We want to improve the outcomes from Bladder Cancer. We think this can be achieved by using the genetic information within each cancer to tailor treatments to individual patients. However, before testing our approach, we have to understand if this is possible within the NHS and if our choices appear to work._x000D_ _x000D_ Bladder cancer is a common disease and one of the most expensive cancers for the NHS. The treatments for aggressive bladder cancer include surgery to remove the bladder, radiotherapy to the pelvis, chemotherapy and immunotherapy. These treatments combine local approaches to the bladder with whole body treatments to stop the cancer spreading. _x000D_ _x000D_ Combined treatments have the best cure rates, but have most complications, are expensive and affect a person’s well-being for many months. Regardless, our current approach is to treat all individual patients as though they have the same type of bladder cancer, with everyone receiving the same treatment schedules._x000D_ _x000D_ However, treating all bladder cancers in the same way may not be best for individual patients. For example, some cancers respond exceptionally well to chemotherapy and so may not need surgery. Other cancers may respond better to immunotherapy and so need this treatment alone or as a boost to chemotherapy. Finally, some cancers do not respond to either chemotherapy or immunotherapy and so need immediate surgery. Recent advances have suggested the genetic information within a bladder cancer may identify which treatment is best for an individual patient. This approach has not yet been tested in a clinical trial. We think it is time to test the ability of genetic profiling to direct a patient care. We want to understand if tailored treatments are better than the current standard of care. These tailored treatments include surgery, immunotherapy or chemotherapy alone and in combination._x000D_ _x000D_ We will recruit patients from our clinics and test whether we can profile their cancers quickly (so that their treatment is not delayed) and whether their cancers appear to respond to a tailored approach. We will randomise patients to our new pathway or standard care. We will look to see how many respond to chemotherapy and/or immunotherapy, and whether immediate surgery is better than standard care._x000D_ _x000D_ In this study we will assess the practicalities of our proposed pathway, our underlying assumptions and prepare for a large trial that fully tests our choices. The larger trial needs key information to help its planning and proof that our hypotheses appear to work. If successful, our approach would improve survival rates for bladder cancer, reduce the cost of treating these patients and reduce the number of potentially toxic treatments individuals would need.","Research Question: Does the use of genomic stratified care indicate sufficiently improved treatment activity to warrant a phase III trial in invasive bladder cancer? _x000D_ _x000D_ Background: Bladder cancer is one of the commonest and most expensive human malignancies. Survival rates are not improving. Standard of care for muscle invasive bladder cancer (MIBC) is radical pelvic treatment (either cystectomy or radiotherapy) following neoadjuvant cisplatin based chemotherapy (NAC). NAC improves survival, but individual outcomes are mixed: 20-30% of cancers Completely Respond (pCR, defined as pT0) to NAC, whilst 40% are locally advanced at cystectomy. NAC may be harmful in chemoresistant tumours by delaying radical treatment. Multiple unselected immunotherapy trials are in progress and threaten to slow radical treatment further and escalate treatment. We propose a study to develop a gene expression subtype-selected approach to individualised care._x000D_ _x000D_ Aim: Obtain information to guide the design of a phase III trial with respect to the feasibility of gene expression subtyping, the distribution of gene expression subtypes in the NHS population, the heterogeneity of intermediate endpoints (pCR) by subtype following standard of care treatment, and assess the activity of gene expression subtype-guided experimental treatments._x000D_ _x000D_ Objectives:_x000D_ Stage 1: Assess the feasibility of gene expression subtype stratification in terms of the recruitment of patients and gene expression subtype assessment (time to allocation and success rate). _x000D_ Stage 2: Confirm feasibility of recruitment of patients, assess assumptions concerning the proportion of each gene expression subtype in recruited patients, assess the assumptions regarding the respective pCR rates in the MIBC control population and conduct a sample size re-estimation for stage 3._x000D_ Stage 3: Assess the pCR rate in each gene expression subtype to explore treatment activity, evaluate acceptability of the trial design to patients, investigate toxicity and tolerability and explore survival outcomes to determine if a confirmatory phase III randomised controlled trial (RCT) is warranted. _x000D_ _x000D_ Methods: Multi-centre, prospective, open-label, multi-stage, individually randomised phase II trial. Eligible patients will be registered into the study and their TURBT samples will be assigned a gene expression subtype using the GUSTO classifier (consisting of the Decipher platform and the TCGA 2 classification system). Eligible patients will be randomised (1:1) to Standard Care (NAC and Radical Cystectomy) or Radical Cystectomy with Gene expression subtype-guided Care (Basal and Neuronal tumours receive NAC, Durvalumab and Tremelimumab; Luminal Infiltrated tumours receive Durvalumab and Tremelimumab; Luminal/Luminal Papillary tumours proceed directly to radical cystectomy. Patients will be followed up for a minimum of 12 months post-cystectomy._x000D_ _x000D_ Timelines for Delivery: Following set up (12 months), we will recruit to Stage 1 over 6 months (aiming for 30 patients). If pre-defined progression criteria are met (recruitment rate, time to gene expression subtype allocation and gene expression subtyping success), we will progress to Stage 2 and continue to recruit for a further 18 months (aiming for 176 patients). If progression criteria are met (recruitment rate, gene expression subtyping distribution, pCR rates and confirmation of sample size assumptions) we will progress to stage 3 and continue to recruit for a further 12 months overall recruitment target 320 patients). We will have 6 months analyses and dissemination._x000D_ _x000D_ Anticipated impact of dissemination: Initial impact will be to determine the feasibility of gene expression subtype-guided care and inform the design of a phase III RCT to evaluate effectiveness. We will also establish gene expression subtyping and test viability of personalised approaches for BC. Dissemination of this phase II trial will be through medical conferences, journals and social media. Dissemination to patients will be through advocacy networks, embedding Patient and Public Involvement (PPI) and printed/social media. If gene expression subtype-guided care is shown to be effective in a future phase III RCT it will improve survival rates, reduce the medical/financial burden of managing BC, could lead to chemotherapy and immunotherapy sparing approaches and earlier radical treatment in appropriate cancers.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;5.4 SURGERY;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,CANCER AND NEOPLASMS HRCS22_23306,The Health Foundation,THF,Geographies of exclusion and inclusion: A comparative investigation of families,"Although there is a clear link between young people’s mental health and the emotional support they receive from their families, there are currently gaps in the evidence on how this support can lead to positive or negative mental health outcomes, and the impact of wider social and economic factors. This project run by the University of York aims to unpack how social and economic factors shape a family’s capacity to mobilise, consolidate and redistribute the necessary resources (financial, emotional and caring) to protect its younger members. The project will focus on the perspectives and experiences of people aged 16–25 years in two communities in North Yorkshire: a rural coastal area experiencing social and economic deprivation (Scarborough) and a more affluent urban community (City of York). The research design will ensure that differences in socio-economic status, as well as gender and ethnicity, are equally represented across both localities. It will compare how economic, social, cultural and environmental factors intersect with differing spatial contexts, and how these contexts shape families’ abilities to provide emotional support to young people. The project will use qualitative and participatory arts-based methods, including interviews with young people, focus groups with agencies that support young people and arts-based participatory workshops. The project will also recruit young people from youth-led organisations as co-researchers, giving ‘voice’ to young people who are often marginalised from the mechanisms that shape policy and practice. Integrating analysis of place-based inequalities with a more holistic perspective of the family will contribute to addressing research gaps and help with the development of local policies, especially those aimed widening health inequalities in North Yorkshire.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",GENERIC HEALTH RELEVANCE HRCS22_02861,Medical Research Council,MRC,Geostatistical design and analysis of randomised evaluations with a geographic basis,"This project will develop methods for the design and analysis of randomised trials with a geographical basis - studies that include individuals on the basis of their location and where an intervention has a specific location. Cluster randomised trials are the most common method of evaluations for these studies. Spatial effects are typically ignored in these designs: neither spatial correlation nor spatially varying intervention effects are considered. This can lead to inefficient cluster design, treatment effects that vary arbitrarily with cluster design, and the inefficient sampling of participants, among other problems. We will develop and evaluate methods for the design and analysis of cluster trials that explicitly account for spatial effects and develop and assess a novel study design in which intervention locations are randomised across a continuous area. WP1 will adapt geostatistical models to the cluster randomised trial and develop methods for treatment effect estimation, power and sample size analysis, cluster design, and approaches to contamination. We will evaluate the methods using simulated data. WP2 will extend the methods of WP1 to develop the ""spatial trial"" design in which interventions are randomly located or randomised to fixed locations or to a specific sequence of locations over time. We will document the different variations of spatial trial design and examine power and sample size, treatment effect estimators, restricted randomisation schemes, and efficient sampling methods. We will evaluate the methods using simulated data. WP3 will develop a software package implementing the methods with accompanying documentation for public release. WP4 will re-analyse a cluster trial of a sanitation intervention in urban and rural areas. We will also work with academic and implementation partners to provide training in these methods and develop proposals for trials using these methods.",,6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_14235,Marie Curie,,"Getting prescription medications right at home, in hospital & hospice: An Activity Theory analysis to improve patient safety and confidence in palliative care","Background Approximately 20% of NHS serious incident reports involving palliative patients relate to prescription medications. Underlying causes and contributing factors are poorly understood. Historically established divisions of labour and normative rules (practice etiquette) shape prescribing and medication use. Process disturbances mean experienced outcomes do not always match the intended outcomes in healthcare practice, for example, due to boundaries and misunderstandings between different groups and roles. Patient behaviour adds additional complexity, for instance, if they accept or reject medications, and patients are commonly the only constant across home, hospital and hospice contexts. Thus, prescribing and medication use is a multi-step process requiring coordination of many organisational systems, enacted through professionals, patients and carers. This study is the first use of patients’ activity systems as the unit of analysis, within and across the contexts of home, hospital and hospice, to investigate and model practices of prescribing and medication use for symptom control (incorporating everything necessary to get the right medication at the right time). Aim To compare intended/‘what happens on paper’ processes with experienced/‘what happens in the real world’ practices identifying when, how and why process disturbances in prescribing and medication use impact on quality and safety. Research questions What are the experiences of patients, carers and professionals of prescribing and medication use in palliative care in and during movement across home, hospital and hospice? How does the division of labour and practice etiquette between professionals, carers and patients reinforce or destabilise prescribing and medication use practices and what impact does this have? Objectives To develop a practice-based model for the multi-step process of prescribing and medication use in palliative care With this model, to identify and develop an extended understanding of disturbances and safety concerns for patients within or when moving across hospice, hospital, and home To develop a multi-perspective understanding of 'hot' (attracting attention, viewed as problematic by participants) and 'cold' (not attracting attention from participants, observed by research team) spots in processes and practices of prescribing and medication use for palliative care To use understanding of practice disturbances to create a learning, analysis and recommendation toolkit identifying targets for innovation and improvement. Methodology The study uses the conceptual tools of Activity Theory to study effort (work/activity) for prescribing and medication use. This will entail analysing real-life practices during palliative care and how these compare to intended processes described in care guidelines and service models. Activity Theory identifies and analyses contextualised historically established divisions of labour and disturbances in working practices with a shared object (goal), in this case achieving symptom control through accurate and effective prescribing and medication use. Understanding disturbances is key to improving outcomes. Phase 1: Scoping review to develop a visual model illustrating intended process in typical prescribing/medication use episodes within and across three contexts: home, hospital and hospice. Phase 2: Direct observation of everyday practice (3x1 week), conducting informal conversations around the acts of prescribing and medication use in each context prior to purposive sampling of patients and informal carers (n=30(15x2)) and healthcare professionals (n=40) for qualitative semi-structured interviews. Data collection methods include field notes, audio-recording, and pictorial representations of processes. Identified disturbances and risks will be explored and categorised (objective 2). Analysis of multiple perspectives will create understanding of actual prescribing and medication use processes (objective 3). This will be mapped to the initial model expanding it into an authentic practice-based model for the whole multi-step process (objective 1) which can be used to identify targets for improvement interventions (objective 4). Ethical approval will be sought. A patient and public involvement (PPI) co-applicant is involved in designing and delivering the study. A steering group will oversee the study and a PPI engagement group will work with the research team. Outputs and impact A theoretically-informed, empirically-evidenced model to identify targets for innovation and improvement in prescribing and medication across palliative care contexts will be produced. Impact will be achieved via: Publications in high impact peer-reviewed journals A dissemination event to share and refine findings and develop outputs including toolkits to help patients, carers and professionals with prescribing and medication use A plain English report freely circulated to policymakers, commissioners, clinicians, researchers and the public Using findings to design an interventional feasibility study targeting improvement priorities.","Background People with palliative care needs use prescription medications to achieve symptom control. 'Daily hassles' with medications are commonly reported. What happens in 'real life' and the effort required to achieve effective medication management in palliative care is poorly understood. Aims The study will collect information from patients, carers and professionals to: 1. Model 'real life' processes underlying medication management including: Decision-making Prescribing Monitoring and supply Use (Administration) Stopping/disposal of medications Moving across healthcare contexts. 2. Understand challenges patients and carers face and what they do/do not do to achieve effective medicines management. 3. Understand impact of professional practices on medicines management. Design and Methods Three types of context will be identified in order to recruit from home, hospital and hospice. We will develop a visual process model of how using prescription medications should work. We will then observe and explore what really happens and collect information about peoples' experiences of medicines management to develop a 'real life' model. Activity theory, which can be used to good effect in analysing healthcare processes, is being used to understand what happens, who does what, and what occurs when a patient moves across contexts. Patient and Public Involvement (PPI) Consultation with patients, families, friends, carers and healthcare professionals helped develop this proposal. A PPI co-applicant is part of the team, they will: Provide an ‘expert-by-experience’ perspective Assist the research team to engage a wider PPI population Co-produce study dissemination products and activities. All participants will be invited to a dissemination event and receive the study report. Benefits and Impact Understanding processes will help develop effective use of prescription medications. Recommendations for professionals can improve current practice. Tools will be created to help patients and carers with medication management. Further research will test ideas from this study to reduce palliative care medication risks.",8.1 ORGANISATION AND DELIVERY OF SERVICES;7.2 END OF LIFE CARE,GENERIC HEALTH RELEVANCE;MENTAL HEALTH HRCS22_23234,Royal Academy of Engineering,,Global Sanitation Technology,"Using robust approaches to designing, testing, and implementing novel onsite sanitation technologies and processes, this research aims to address engineering challenges associated with achieving the UN Sustainable Development Goal of universal access to safely managed sanitation. Examples will include more affordable, easier-to-assemble septic tank designs and modular methods to treat faecal sludge in rapidly urbanising cities and emergency settings. His approach combines laboratory experiments, fieldwork, mathematical modelling, and collaboration with in-country practitioners and end users to co-develop engineering solutions that will improve the lives of the poorest members of society in developing countries.",,3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.3 NUTRITION AND CHEMOPREVENTION,GENERIC HEALTH RELEVANCE;ORAL AND GASTROINTESTINAL;INFECTION HRCS22_01248,Medical Research Council,MRC,Global Study of Thalassaemia,"The inherited disorders of haemoglobin are by far the commonest monogenic diseases. Over 300,000 babies are born each year with either sickle cell anaemia or a form of thalassaemia; 80% of these births occur in low or middle-income countries. The commonest forms of severe thalassaemia are the  thalassaemias, which are divided into  thalassaemia major and the co-inheritance of  thalassaemia and haemoglobin (Hb) E, HbE  thalassaemia. Globally, HbE  thalassaemia comprises about 50% of severe cases of  thalassaemia and occurs at its highest incidence in parts of India, Bangladesh and throughout Southeast Asia. The management of HbE  thalassaemia is in many ways more difficult than that of other severe forms of  thalassaemia because it has such an extraordinarily diverse clinical phenotype, ranging from a transfusion-dependent disorder similar to  thalassaemia major to a condition which is compatible with survival into adult life with little or no transfusion. As well as this phenotypic diversity the management of HbE  thalassaemia is further complicated by the instability of its clinical manifestations over the first few years of life. Another difficult aspect of the phenotype associated with its clinical management is the fact that the steady-state haemoglobin levels in the mild and severe phenotypes often only vary between 1-2 g/dl. Surprisingly however, there are very few data on the natural history of this disease and its overall mortality, either in the developed or developing countries. Over the last 15 years we have developed partnerships with a variety of countries in Asia, notably Sri Lanka, to study HbE  thalassaemia. This work has two major objectives. First, to try to understand some of the reasons for the remarkable phenotypic variability of the disease. Second, to describe its natural history and, in particular, to follow the course of older patients with this condition who have not received regular transfusion to determine whether a lifelong course of a low haemoglobin level is associated with complications as these patients age. By raising money from several different sources it has been possible to build a new treatment centre for these patients in Kurunegala, Sri Lanka, which now cares for over 600 patients with  thalassaemia, 200 of which have HbE  thalassaemia. We have also raised money for the building of a major diagnostic centre at the University of Kelaniya in Colombo, to which is attached an adult thalassaemia centre and full facilities for diagnosis at the protein and DNA level. The third aspect of this programme is directed at micromapping the frequency of the thalassaemias in Asian countries. Little work has been done on the population frequency of these diseases since the 1980s and there are very limited data, a major deficiency in trying to determine their true public health problems. Most of the published data is based on one or two centres and it is already clear that the distribution of the thalassaemias is extremely heterogeneous within different countries. Therefore extensive mapping of their frequency is required from numerous different regions in high-frequency populations. Towards this end we have carried out several micromapping studies and are also trying to develop an Asian Network between countries which have already developed this type of technology and those where facilities for the diagnosis and management of the thalassaemias are non-existent.",,2.4 SURVEILLANCE AND DISTRIBUTION,BLOOD HRCS22_07022,Department of Health and Social Care,NIHR,Glycaemic control in labour with Diabetes (GILD),"Women with diabetes in pregnancy have their blood sugar levels closely monitored during labour in order to minimise the effects of high sugar on their baby after birth. High blood sugar in the mother can cause low blood sugar in the baby. However, this monitoring is intrusive and expensive. New evidence suggests that it may not be as important for preventing problems in the baby as previously thought._x000D_ A research study is planned but, before this, we want to find out from doctors and midwives:_x000D_ • Exactly how they care for pregnant women with diabetes in labour_x000D_ • Exactly how common it is to find low blood sugar levels in babies_x000D_ • What complications it causes for babies and mothers in practice_x000D_ • What types of sugar monitoring in labour should be tested in future research_x000D_ • How acceptable such research would be to staff and pregnant women._x000D_ This is an important issue as diabetes in pregnancy is increasing in the UK. It currently affects 5% of all pregnant women. Most have gestational diabetes, which develops during pregnancy and goes away after birth, with the rest having diabetes before they get pregnant._x000D_ _x000D_ The risk we are focusing upon is mother’s high blood sugar leading to low blood sugars in their babies. This happens when the baby in the womb produces more insulin to help process the high levels of sugar transferred across the placenta from their mother. At birth, the umbilical cord is cut and this high sugar supply stops suddenly. The baby struggles to cope with this change in their sugar levels especially as their high insulin levels take time to drop to normal. This can potentially be avoided by regular feeding but blood sugar can fall despite feeding and babies may suffer brain damage. The baby’s blood sugar has to be carefully tested to prevent this. Additionally, by trying hard to ensure mothers’ sugars do not become elevated there is a risk of low blood sugar that can cause harm to the mother if this is not recognised and treated._x000D_ _x000D_ Our research plan is to:_x000D_ • Ask hospitals throughout the UK about their local guidelines on monitoring blood glucose levels in labour and the newborn baby_x000D_ • Survey hospital staff to find out what blood sugar monitoring systems (e.g. finger prick test or electronic sensor devices) they use and what training is needed to improve care_x000D_ • Survey women with recent experience of diabetes in pregnancy to hear their views on monitoring in labour and the birth outcomes which are important to them_x000D_ • Conduct an audit in UK hospitals to determine how often they see low blood sugar in both mothers with diabetes in labour and in their newborn babies and what problems are associated with this._x000D_ Our goal is to design a research study comparing blood sugar monitoring strategies in labour for women with diabetes. We will then ask women, experienced doctors and midwives during telephone interviews whether theoretically they would be willing to be involved in such a study, and what they feel the barriers would be._x000D_ _x000D_ We will also recruit women who have experienced diabetes in labour to be members of an advisory group to the project. We want this research to be directly relevant to improving women’s experience of maternity care, and be acceptable to families we are recruiting to answer questionnaires and take part in interviews. We will consult our advisory group on the wording of study information, questionnaires, analysing the data we collect, writing up the results and sharing them with different groups.","RESEARCH QUESTION_x000D_ Is it feasible to run a trial to assess the clinical and cost-effectiveness of permissive versus intensive intrapartum glycaemic control in women with pregnancies complicated by diabetes?_x000D_ _x000D_ BACKGROUND_x000D_ Diabetes in pregnancy affects at least 5% of pregnant women. For most women this is gestational diabetes (GDM) (87.5%), but 12.5% women have pre-existing diabetes. There is evidence that ‘tight’ glycaemic control in pregnancy reduces the risk of adverse outcomes for the mother and the baby._x000D_ Traditionally ‘tight’ glucose control (target 4-7 mmol/L) is recommended in labour. Treatment with intravenous insulin may be needed during labour to maintain ‘tight’ control, however, this increases the risk of maternal hypoglycaemia in labour, which carries a risk to the mother. Hourly intrapartum testing is also intrusive for women and time consuming for health care practitioners. Conversely, accepting more permissive glucose levels in the mother may be detrimental to the baby. Maternal hyperglycaemia results in increased fetal insulin production because of excess placental transfer of glucose and can lead to neonatal hypoglycaemia._x000D_ _x000D_ AIMS AND OBJECTIVES_x000D_ To determine current practices in intrapartum glucose control and decide on how best to conduct a future trial in all forms of diabetes._x000D_ _x000D_ METHODS_x000D_ Work package 1_x000D_ - Conduct three national cross-sectional surveys of:_x000D_ a) Current UK clinical guidelines on intrapartum care in pregnant women with diabetes and neonatal hypoglycaemia in the babies_x000D_ b) Current practice, training and experience of midwifery staff and other health care professionals in intrapartum glycaemic control in the UK _x000D_ c) Women who have/had diabetes in pregnancy to hear their views on glucose monitoring in labour and the birth outcomes which are important to them_x000D_ - Conduct a national audit of intrapartum care in pregnant women with diabetes exploring current practice and adherence to clinical guidelines on maternal glycaemic control._x000D_ Work package 2_x000D_ To reach consensus by a Delphi survey on the most important clinical components of a future trial of permissive versus intensive intrapartum glycaemic control (types of diabetes to be included, glucose levels, frequency of monitoring, outcomes) in pregnancies with diabetes._x000D_ Work package 3_x000D_ Design a clinical trial comparing blood sugar monitoring strategies in labour for women with diabetes. _x000D_ Work package 4_x000D_ Understand facilitators or barriers to conducting a trial comparing permissive to intensive glycaemic control for women with diabetes._x000D_ _x000D_ TIMELINES FOR DELIVERY_x000D_ We will deliver this scoping study in 24 months._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION_x000D_ The results of this study will be essential for the planning of any future randomised trial in this area. It will increase our understanding of the current practice of intrapartum care for women with diabetes, the prevalence of maternal and neonatal hypoglycaemia and the frequency of complications arising from it. It will increase awareness of the problem amongst health care professionals and parents. It will highlight training deficiencies in this area. The research findings will be disseminated via a published HTA monograph, research papers published in high-impact peer review journals and presentation at medical and midwifery conferences locally, nationally and internationally. They will also be made available via Diabetes UK and Gestational Diabetes, alongside plain English summaries.",7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES,METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_01704,Medical Research Council,MRC,Good School Toolkit-Secondary Schools Pilot Trial,"The Good School Toolkit-Secondary School is a whole-school intervention to prevent physical, sexual and emotional violence against students, from school staff, peers, and within student intimate partnerships. We will conduct a phase 2 cluster randomised controlled trial with 2 arms and parallel assignment. 8 schools will be selected from a list of eligible schools in Kampala, stratified by faith/non-faith status and level of financial resources. Schools will be pair-matched and randomly allocated to receive the Toolkit plus usual care versus usual care and wait-listed to receive the Toolkit. The Toolkit will be implemented over 18 months. We will conduct a survey with all staff (about 200) and 960 randomly selected students in all 8 schools before randomisation, and again after the 18 month implementation. Observations, qualitative focus groups discussions and individual interviews will be conducted with students, staff, administration, caregivers and key stakeholders throughout the 18 month implementation. The main outcome of this phase 2 trial is whether criteria for progression to a phase 3 trial are met, defined as: >80% of staff and students reporting acceptability and >80% reporting understanding in endline survey; >3 of 4 intervention schools implementing with fidelity at endline; >6 of 8 schools agree to participate in the baseline survey; >6 of 8 schools participating in the baseline survey agree to be randomised, >6 of 8 of schools randomised agree to endline data collection; >70% of eligible students respond to surveys. Findings from the research will be fed back to Raising Voices iteratively during the implementation period so that the intervention can be refined and optimised. If a phase 3 trial is warranted, it would represent the first test of a whole school approach to prevent these multiple forms of violence in sub-Saharan Africa.",,6.6 PSYCHOLOGICAL AND BEHAVIOURAL,INJURIES AND ACCIDENTS HRCS22_11748,Economic and Social Research Council,ESRC,Green Walks: Healthy Ageing,"The core aims of the project is to offer new functionality to navigation packages used world-wide, and to bring a new app to market, which focuses on prolonging good health as users age. In order to achieve these aims, Green Views is divided into two connected packages which: a) guide users to green spaces within walking distance of their front door; and b) encouraging older users to continue venture outside despite the challenges older age presents. More specifically, the project will pursue the following objectives: A1: Generate a green-view database of an urban centre by extracting images from existing mapping platforms to calculate the amount of visible green space along roads A2: Develop a mapping system to generate circular walks of 10, 20, and 30 minutes from any starting point within the database. These walks will be optimized to take in the largest amount of green space possible B1: Develop a web site collecting observations from walks in Norfolk. These raw observations will be refined into a creative-commons collection of things to look, listen, and smell for at particular times of the year. B2: Develop an iOS app which loads circular walks from Obj A2 and recommends observations from Obj B1 to seek out during the walk.","During and post Covid-19 lockdowns, the importance of access to green spaces for mental health has been highlighted. However, in the UK, we have deeply entrenched disparities in access to green spaces. A majority of care users over 64 and/or from non-white backgrounds do not believe they have local greenspaces within easy walking distance. Green Walks will aid the UK population in finding greenspaces within easy walking distance of their homes, signposting environmental changes (such as flowers coming into bloom or local events) as incentive to get out of the house, and accompany care-users on their walks The project will generate a green view database, using AI tools to extract images from existing mapping platforms to calculate the amount of visible green space along roads The team will co-design a web-based AI search interface and mobile app together with social prescribing link workers and end users to generate personalised walks to and from home, through areas with the highest green views The app will use spatialised audio to guide the user along the walk, as well as providing social accompaniment, and quick access to help and/or companionship. It will monitor the user's progress through GPS, motion data, and quick self-reported mental health cues. The project contains a citizen-science element allowing stakeholders to add areas of interest, areas to be avoided, community information, and incentives for care users to get out of the house and into green environments and will interpret data about use of the green spaces by other users.",1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,GENERIC HEALTH RELEVANCE HRCS22_18713,Wellcome Trust,,"Growing Old in the Soviet Union, 1945-1991","Research produced by the project will provide historians and gerontologists with access to a rich body of work that sheds light on hitherto unknown experiences of ageing in the Soviet Union - the world's first socialist state. This will be achieved by conducting extensive research over a 4-year period on: 1) state policies and attitudes to providing healthcare for older adults; 2) individual and collective experiences of ageing; and 3) the influence of gerontology on domestic and international politics. The project will change how historians consider the role of older adults in the Soviet Union after World War Two. Although scholars have probed issues of identity, trauma, and the meaning of life under late socialism, the role of elderly people has been largely overlooked, in spite of the ageing revolutionary vanguard. A focus on the period 1945-1991 will establish older adults and ageing as an integral part of the post-war narrative of Soviet history, and will make a distinctive contribution to current debates about ageing societies. Knowing what it was like to grow old in the Soviet Union will help historians relate debates about ageing and gerontology to political developments in international relations, healthcare, science, and welfare.","This project is the first to comprehensively examine ageing in the Soviet Union, 1945-1991. In the 1960s and 1970s the Soviet government was confronted with the problem of an ageing population and as a result state interest in the field of gerontology (the study of ageing) expanded immensely. The project first examines state approaches to ageing that include scientific research, healthcare policy, medical services, and psychiatry. Second, it explores more subjective aspects of ageing by finding out what it was like growing old in the world's first socialist society. The final aspect of the project focuses on the influence of gerontology in the Soviet Union and abroad through a study of the Institute of Gerontology in Kiev. This holistic approach to examining ageing will provide scholars with an important blueprint for the study of ageing societies in history and contribute to how people and societies understand the ageing experience.",1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,GENERIC HEALTH RELEVANCE HRCS22_02522,Medical Research Council,MRC,"HCD: Synthesis of networks of evidence on test accuracy, with and without a 'gold standard'","Overall objective: We will develop general methodology to synthesise networks of evidence on the sensitivity and specificity of tests for any given disease. The approach will be applicable across clinical areas and will simultaneously produce pooled estimates of singular, joint and comparative accuracy, allowing for imperfections in 'reference standard' tests where appropriate. The framework will accommodate data of varied types, e.g. studies reporting results on (i) Test A vs a Gold Standard (GS) test; (ii) A vs B vs GS; (iii) A vs B without a GS; (iv) A vs GS and B vs GS reported separately; (v) B vs C vs GS etc. We will demonstrate how the assumption that any one of the tests in the network is a GS can be relaxed. Why are these estimates needed? Estimates of sensitivity and specificity, informed by systematic reviews and meta-analyses, are crucial for decision-making about which test and/or combination of tests to use for any given disease. For example, these are key parameters in decision models used by NICE to compare the effectiveness and cost-effectiveness of testing strategies. Why are new methods needed? Standard methods (i) cannot produce estimates of the accuracy of tests used in combination, accounting for likely dependencies between them; (ii) produce unnecessarily imprecise estimates of comparative accuracy, (iii) are critically reliant on the assumption that a GS test exists and has been applied in all studies. Proposed advanced methods are not yet fit for general use: for example, involving estimation of infeasible numbers of parameters. Methods: We will work within a Bayesian multi-parameter evidence synthesis framework, allowing data of varied types to be synthesised together through specification of the relationships between parameters. We will draw on - and extend - existing methods for meta-analysis of comparative test accuracy, and latent class models that have been proposed for estimation of accuracy in the absence of a GS.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,GENERIC HEALTH RELEVANCE HRCS22_02376,Medical Research Council,MRC,HCD: TEST - Test Evaluation Using Structured Tools,"New test technologies improve patient health by changing how, when, where and in who tests are used. Current approaches to test evaluation are dominated by test accuracy studies and often ignore impacts created in other ways. We will develop tools to assist researchers and reviewers identify how a test will impact on patients, the study designs and outcomes to measure, and methods for sample size calculation. WP1 will establish a cohort of test evaluations from reports published by HTA organisations (including NICE and WHO) and summarise the evaluation approaches used. WP2 will assess the ways new tests improve or are detrimental to patient health in a sample of test evaluations from this cohort, considering: patterns in test impact related to technology and condition; how evidence reviews consider the ways tests create impact; and where available, the magnitude of effects observed. We will select a sample representative of test technologies and health conditions, sampling 50 to 100 test evaluations until saturation of types of impact. Each test technology will be researched in depth to understand its potential to impact on patients. WP3 will use a subset of test evaluations from WP2, chosen to cover the ways tests impact on patient health. For each route we will consider alternative study designs and outcomes that measure impact, and consider trade-offs between feasibility, validity and efficiency. WP4 will identify and develop sample size calculations for each study design and outcome considered in WP3 and validate their performance in simulation studies. We will investigate and develop approaches for time-to-event outcomes (such as time to diagnosis/treatment) and for outcomes that only apply in subgroups conditioned on disease state and test result. Project outputs will include guidance, checklists and software tools to improve the process of evidence review and generation, allowing the most clinically effective and cost effective tests to be identified.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,GENERIC HEALTH RELEVANCE HRCS22_01954,Medical Research Council,MRC,"HCS: Case study, Context and Complex interventions (TRIPLE C) - development of guidance and publication standards to support case study-based research","There is increasing recognition that the conventional scientific quest for certainty, predictability and linear causality (often via RCTs) needs to be augmented by the study of how we can best deal with uncertainty, unpredictability and emergent causality. Case study research offers a vital resource for such research, and for those keen to develop methods that support meaningful evaluation of complex interventions in health care. The literature on case study methodology is diverse, drawing on varied disciplines and epistemologies. It has yet to be formally evaluated in ways that allow researchers, funders and decision makers to better understand the interaction between context and the implementation of complex system-level interventions over time. This study asks: What are the key steps in producing case study research into the influences of context on complex system-level interventions that advances knowledge and informs policy and practice? How might 'high' and 'low' quality in such case studies be defined and assessed? And, how can such case study research best be reported in order to maximise value? It uses meta-narrative review to collate and summarise diverse literature on case study methods, including the range of theoretical and methodological approaches to studying contextual influences; combined with an online Delphi survey with an international and interdisciplinary panel of up to 30 case study experts from academia, policy and practice. The output will be draft methodological guidance and publication standards for case study in health system and public health research. This will be piloted with 3-5 research teams that have published exemplar (i.e. highly-cited) case studies, and with a panel of 10 external experts, to consider the extent to which the range of case study methods have been adhered to by real-world case studies and refine guidance. Final guidance/standards will be disseminated via social media, journals and a knowledge sharing event.",,8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_02095,Medical Research Council,MRC,HDHL: A precision nutri-epigenetic approach to tackle the mother-to-child transmission of impaired glucose metabolism,"PREcisE will operate the overarching hypothesis that the transgenerational association between maternal gestational diabetes and risk of T2D and glycaemic adversity in the next generation(s) can be partially explained by a causal association mediated by durable epigenetic modification of 'maternal glucose responsive (MGR)' loci. The hypothesis is that: - The risk is causal, dose dependent and interplay with maternal psycho-social factors; - The risk is mediated and/or modulated by the glycaemic load and/or the inflammatory score of the diet; - The risk is causally associated with the regulation of genes in the major metabolic tissues (i.e. liver, skeletal muscles, adipose tissues); - There are causal pathways linking the alteration of MGR loci and glycaemic health in the offspring, part of which is mediated through early growth. PREcisE project harnesses very large data prospectively collected from Spain, Germany, Finland, France and The Netherlands, including randomised control trial and combines with long lasting collaboration with the pregnancy and childhood (PACE), the early growth (EGG) and recent Global MethQTL consortia, to establish the mother-to-offspring transmission of glycaemic health through robust epigenetic factors. The consortium will reach sufficient power to perform its research through the use of data and biological atlas collected prospectively by its PIs.",,"2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",METABOLIC AND ENDOCRINE HRCS22_02372,Medical Research Council,MRC,HOD2: Toward Holistic Approaches to Clinical Prediction of Multi-Morbidity: A Dynamic Synergy of Inter-Connected Risk Models,"Clinical prediction models (CPMs) are models that are used to predict the risk of clinically relevant outcomes in individuals with a particular disease or health condition. They are increasingly used to support clinical decisions, yet they seldom reflect the interplay between developing multiple comorbidities. Specifically, CPMs operate in silos of disease risk, where different (and independent) models are derived to predict the risk of a single adverse clinical outcome. Current approaches to predicting multi-morbidity through CPMs incorrectly assume that the probability of patients developing multi-morbidity is the product of the risks from individual models. Our proposed solution is to advance multi-state modelling, to develop a ""CPM-Network"" that can appropriately predict the risk of different (but related) clinical outcomes, with the associated benefits to patient care, healthcare planning and service utilisation. Multi-state survival models present a way of predicting risk of a patient moving between different 'states'. While such multi-state CPMs are appealing since they account for competing risks and can predict risks of different clinical events within a given disease area, they do not scale to model the risks of different clinical events across disease areas, in a cumulative sense. As we move from a single event (i.e. two-state) CPM, to a multi-disease (i.e. multi-state) CPM, we find combinatorial complexities that cannot be overcome in the existing multi-state modelling framework. As such, this proposal will extend competing risk and multi-state techniques, to allow development of CPMs that reflect a realistic and holistic view of a patient's health and care. Our research question is: what is the feasibility and potential benefits (compared with existing approaches to predict multi-morbidity) of developing a CPM-Network? We will address methodological challenges in this space such as computational complexity, model overfitting and model validation.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,GENERIC HEALTH RELEVANCE HRCS22_06674,Department of Health and Social Care,NIHR,HPV testing in cervical cancer screening: using behavioural science to understand attendance and anxiety,"Background: The NHS Cervical Screening Programme (NHSCSP) is rolling out human papillomavirus (HPV) testing as the primary test across England, meaning that all women attending screening will soon find out their HPV results. With changes to the protocol for screening, it is extremely important that psychology and behavioural science informs NHSCSP information materials and wording in test results letters. This is to ensure that women understand their results, are not unnecessarily anxious and re-attend their next screening appointment. This is particularly relevant for women who test positive for HPV with normal cytology, as it is anticipated that this will be a complex result to understand and that some women in this group may display heightened anxiety. Women in this group will be recalled to screening at 12 months rather than 3 years, and it is critical that these women re-attend in order for the NHSCSP to achieve sensitivity gains of switching to HPV primary testing.Aims: This DRF will be carried out in the context of HPV primary testing in the NHSCSCP. It aims to identify demographic and psychological predictors of anxiety and of screening re-attendance among women testing positive for HPV with normal cytology.Methods: Four research projects are proposed which will directly inform a fifth applied outputs project. Project 1 will be a systematic review to consider how women react to testing positive for HPV in the context of cervical screening. Project 2 will involve analysis of existing data from a cross-sectional survey (~N= 673) considering differences in anxiety, distress and intention to re-attend between women with different test results in NHSCSP HPV primary screening. Project 3 will be a cross-sectional survey of women testing HPV positive with normal cytology results to consider theoretically driven predictors of anxiety and attendance at screening. Project 4 will be a qualitative study to gain in-depth insights into how women with HPV positive/normal cytology view their results and to understand their information needs. Project 5 will inform and develop NHSCSP information materials and test result letters, guided by results from projects 1-4, PPI and collaborator input.Dissemination and Impact: This DRF will be extremely timely in providing the NHSCSP with evidence which can be used to improve patient outcomes, as HPV primary testing roll-out will start across England in 2019. On completion of this DRF, the NHSCSP will be able to improve existing test result letters and HPV information materials, and incorporate a new leaflet into the programme specifically for women who test HPV positive with normal cytology. All materials resulting from this DRF will help ensure information clarity, reduce unnecessary patient anxiety and maximise patient re-attendance at screening.","BackgroundHuman papillomavirus (HPV) is a common sexually transmitted infection. HPV causes nearly all cervical cancers. There are around 3,000 new cases of cervical cancer every year in the UK.The NHS Cervical Screening Programme (NHSCSP) aims to prevent cervical cancer by looking for abnormal cells in the cervix and removing them before they turn into cancer. The NHSCSP will soon test all cervical screening samples for HPV before deciding whether to look for abnormal cell changes. This is called HPV primary testing and will soon be rolled out across England. This means that all women attending cervical screening will learn their HPV test results through letters delivered to their home. The results letters will tell women whether they are HPV positive or HPV negative, as well as whether they have any abnormal cell changes.It is very important that psychological research helps decide what NHSCSP results letters and information leaflets say. We know that knowledge about HPV and its connection to cervical cancer is poor amongst women in the UK. We also know that some women can get upset, confused and/or experience stigma after testing positive for HPV, partly because of it being sexually transmitted. Therefore, the wording and information in NHSCSP letters needs to make sense and be clear so that women correctly understand their risk of getting cervical cancer. It is also very important that women are not worried about their results if they do not need to be.In HPV primary testing, one group of women who might especially struggle to understand their screening results is those who test positive for HPV but have no abnormal cell changes. This is because they will find out they have HPV, but they will not get invited to screening again for another 12 months and will not get any treatment. This is because although HPV puts them at higher risk of getting cervical cancer, without any abnormal cell changes it is very unlikely that they will get cervical cancer within 12 months. It is likely that their immune system will get rid of HPV in this time. However, this can be complicated for women to understand and difficult for the NHSCSP to know how to communicate in letters. We think that some women in this group may not understand these test results. It is important that these women are not too worried or upset about their test results, and they come back to cervical screening again in 12 months.Doctoral Research Fellowship:I aim to do research which will explore how women understand and react to being told they are HPV positive with no abnormal cell changes. I want to understand what things are most important in making sure that these women are not very upset (anxious) and that they attend their next screening appointment in 12 months. The main focus of this work is to help decide what information should go into NHSCSP test results letters, and to make a new information leaflet for women in this group which can be posted along with their letters. To do this, I will do five projects: Review previous research to understand how women react to testing positive for HPV in the context of cervical screening. Look at questionnaire answers from an existing survey of women who have taken part in HPV primary testing to see if those with HPV/no abnormal cells are more upset (anxious and distressed) compared to women with other test results. Invite women with HPV/no abnormal cells to complete a survey which asks them questions about how they understand their results and what they think of cervical screening. I will then use statistics to work out which things make them more/less anxious and more likely/less likely to attend screening again (e.g. certain beliefs about HPV might make them more anxious). Do interviews with women with HPV/no abnormal cells to find out in-depth information about how they understand their results and what would be helpful to include in the NHSCSP letters and leaflets. Use all the information from projects 1-4 to make a new information leaflet to be included alongside results letters for women with HPV positive/no abnormal cells. Also, where necessary, help change the wording of existing NHSCSP general HPV information leaflets and letters.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS;INFECTION HRCS22_20062,Wellcome Trust,,Haematopoietic stem cell fate and bone marrow microenvironment changes in severe infection: cellular and molecular mechanisms,"This work has two main goals: to identify the mechanisms leading to the degeneration of haematopoietic stem cell (HSC) niches during severe infections, and to measure and improve stem cell recovery post-infection. I will use a murine model of severe malaria, infection by Plasmodium berghei, which I know leads to loss of HSC function and dramatic changes to the bone marrow microenvironment. I will take advantage of my well-established multidisciplinary research approach, combining advanced microscopy, quantitative analyses, molecular manipulations and validation through human samples, to investigate the cellular and molecular mechanisms leading to HSC niche damage, the extent of regeneration following treatment and the consequences of repeated infection/treatment cycles. Finally, I will test molecular interventions that may preserve the HSC niche and HSC function, uncoupling HSC damage from a still active immune response.","The spread of antimicrobial resistance is leading us towards a future where severe infections will not all be easily treatable with traditional medicines, therefore the human population will experience more and more severe infections overall. It is important that we develop new therapies, maximising our immune response but curbing deleterious effects on the rest of the body. Until now, cells of the immune system have been the most studied because they are the front-line soldiers dealing with pathogens directly. However, we now know that our entire blood production system switches gear in response to infection, and the stem cells that maintain it are put under great strain. Here we will use advanced microscopy and other technologies to look inside the bone of mice affected by malaria to understand how blood stem cells are affected by the disease and how we can protect them.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,BLOOD;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_03105,Medical Research Council,MRC,Haemostasis in critically ill patients with advanced chronic liver disease,"Better tests to evaluate haemostasis in patients with chronic liver disease (CLD) are required to reassure clinicians when blood component support is not required and to guide transfusion in the event of bleeding. I am acutely aware of this both as a clinician specialising in thrombosis and haemostasis at one of the largest regional liver centres in Europe, and also as a working group member for the ISTH on 'Haemostasis in patients with liver disease'. Aim: to identify novel methods to assess haemostasis in critically ill patients with CLD, and determine their association with bleeding and thrombosis. Objective 1:To evaluate the clinical utility of thrombin generation (TG) and thromboelastography (TEG) in critically ill patients with CLD in reducing blood component use Objective 2: To identify clinical and laboratory risk factors (including TG, TEG, clot lysis time [CLT] and neutrophil extracellular traps [NETs]) for bleeding and thrombosis I will set up a prospective observational multicentre cohort study to recruit 250 patients with CLD admitted to critical care, and 30 healthy controls. Blood samples and clinical data will be collected on admission, day 1 and day 5 with clinical outcomes recorded up to day 28 (or liver transplant, discharge or death, whichever is sooner). Major bleeding will be defined by the HEME tool and thrombosis will require confirmation with objective imaging. Thrombin generation will be measured in both plasma and whole blood, along with TEG, CLT and NETs. We will establish the proportion of patients with normal haemostatic profiles on admission, the stability of profile over the initial 5 days of admission and the effect of blood components transfused on haemostatic profile. Associations between clinical risk factors, admission TG and TEG parameters with later bleeding/thrombosis will be evaluated, as will the relationship between markers of NETs and aetiology of CLD, presence of sepsis on admission and later thrombosis.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,ORAL AND GASTROINTESTINAL;BLOOD;CARDIOVASCULAR HRCS22_13077,Cancer Research UK,CRUK,Hamlet.rt: multi-centre expansion,"Background Heuristics, Algorithms and Machine Learning: Evaluation & Testing in Radiation Therapy (Hamlet.rt) is a technology-enabled prospective clinical study aiming to build predictive radiomic models for individualisation of radiotherapy in Head & Neck, Prostate, Brain and Lung cancers. It was established as a single centre study in Cambridge in October 2019. The study concept arose from a patient focus group, and aims to answer a key question: ""Can machine learning models that incorporate large, longitudinal imaging, clinical and patient-reported data, predict radiotherapy toxicity much better than current simple clinical review of individual patient’s radiotherapy plans?"" This application relates to a multi-centre expansion of the original prospective clinical study. Aims This application aims to extend the original study to 10 additional radiotherapy centres, in order to increase the amount of available patient data to over 2,000 patients, enhance the diversity of patients included in the study, and to establish a robust method for cross-validation of predictive models. In addition, the expansion of the study supports the development of complementary translational sub-studies to evaluate tumour response to radiotherapy. Methods The study will utilise image analysis, feature extraction and machine-learning based radiomic analysis of radiotherapy image datasets to establish image features that correlate with treatment outcome. Outcome data is captured through the use of serial electronic patient reported outcome measures completed by patients during radiotherapy and every 3 months for up to 2 years post completion of radiotherapy. For brain tumour patients, diffusion tensor magnetic resonance imaging (DT-MRI) will also be captured in order to build image based models of white matter connectivity, in order perform spatial correlation of radiation effects with assessment of neurocognitive function. How the results of this research will be used The results of the project will be used in two ways. The first is to deploy machine learning models that can assist clinicians in identifying patients at increased risk of treatment toxicity from radiation therapy into the clinic, assisting clinicians to individualise treatment for patients, or engage in early interventions to monitor and treat treatment toxicity. The second is to provide biosamples and high quality clinical outcome data for a series of subsequent translational research studies, that will correlate tumour biology with therapy response.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_17920,Diabetes UK,,Harnessing genetic information in the SDRNT1BIO to understand Type 1 diabetes and its complications,"This proposal is for costs to support an analysis of genome wide single nucleotide polymorphism (SNP) data in a large cohort of people with Type 1 Diabetes (T1DM), and controls so as to: To discover new genetic loci associated with type 1 diabetes including adult onset T1DM To discover new genetic loci associated with diabetes complications and other relevant phenotypes in T1DM To investigate mechanisms through which genotypic hits for T1DM or complications influence disease risk With DUK support we recently enrolled 6152 people with type 1 diabetes, stored biosamples, and linked their study data to their electronic health care records (The Scottish Diabetes Research Network Type 1 Bioresource-SDRNT1BIO). The JDRF recently supported the large scale genotyping of this cohort using spare lab and consumables capacity in an initiative on genetics of nephropathy. Only genotyping costs were covered. This application is a request for support for two post-doctoral scientists to now utilise these genetic data.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,METABOLIC AND ENDOCRINE HRCS22_05106,Department of Health and Social Care,NIHR,"Health Financing Fragmentation and Universal Health Coverage in Brazil, Colombia, Mexico and India","The way health systems are structured and financed has major implications for the quality and comprehensiveness of the services they deliver, whether patients use those services, how much they cost and who pays, and whether they deliver improvements in health outcomes. In many low- and middle-income countries (LMICs) health financing is highly fragmented. This can produce different health sub-systems within a country, each with different organizations, eligibility criteria to access services, benefit packages and premiums, payment systems and mechanisms to manage financial risk across patient populations. This fragmentation can negatively impact health system goals including ensuring access to high quality care to all patients, irrespective of their ability to pay. Patients served by fragmented health systems may encounter significant financial and practical barriers that prevent them from receiving the high quality, co-ordinated, and continuous care they need, with the poor and disadvantaged affected most. Despite high levels of health financing fragmentation in LMICs, there is little evidence on its nature, drivers, consequences, and potential solutions. Our research programme seeks to fill these evidence gaps through a range of research activities across four countries which have high levels of poverty and inequality: Brazil, Colombia, Mexico and India. Health systems in these countries are fragmented, but the nature and consequences of this varies in important ways. We have worked closely with key stakeholders from government, academia and local community organisations in each country to identify key research priorities that we will address and key questions that we will answer through a program of locally-driven collaborative research. Stakeholders will continue to be involved throughout the research programme to maximize the relevance of the research and ensure that new knowledge generated translates into improvements that benefit both health systems and individual patients. The research is divided into five work packages that aim to: quantify the nature and variation of financing fragmentation in our four focus countries; investigate how financing fragmentation affects health system goals, including improved access and quality of health services at lower cost to patients; to evaluate the impact of key health system reforms on fragmentation and health system goals; to understand the political factors which drive financing fragmentation and how these can be addressed; increase the use of research evidence in health policy and practice. Our research programme is especially focused on understanding the implications of financing fragmentation for vulnerable groups and how health policy can be better designed to improve their health and well-being. A key benefit of our research will be to strengthen research capacity in partner countries, by supporting the development of a future cadre of research leaders and strengthen institutional and societal capabilities to demand, generate, and utilise high-quality policy-relevant research. In the long term, this work aims to support health system strengthening efforts not just in the four countries, but in other countries where health systems are fragmented, by building a body of translatable research practices and outputs with important insights to address fragmentation, reduce inequity in access to high-quality healthcare, and improve the health of vulnerable populations globally.","Health financing fragmentation is a major challenge to advancing UHC and achieving health equity in LMICs. Financing fragmentation can compromise healthcare coverage and system efficiency, increase costs through service duplication, and result in diverse benefit packages to different population segments. From the patient’s perspective, navigating multiple providers across different healthcare delivery systems can affect access, co-ordination, and continuity of care and can compromise safety, quality, and efficiency. People experiencing poverty and disadvantage are affected most. Despite high levels of health financing fragmentation in LMICs, there is little evidence on its nature, drivers, consequences, and potential solutions. Our four-year research programme will be rooted in Brazil, Colombia, Mexico and India, which are global exemplars for studying how financing fragmentation impacts health system goals, including UHC. We will undertake a multi-disciplinary programme of policy analysis and evaluation research, drawing on methodologies from health economics, health services research, political economy, and population health sciences. Our overall aim is to improve understanding of the nature and impacts of health financing fragmentation in LMICs to inform future health system strengthening efforts and drive progress towards UHC. Five connected work packages (WP) that use a range of epidemiological, statistical, econometric, and policy analysis methods to analyse locally collected and collated data will examine health financing fragmentation from different perspectives: WP1 will quantify fragmentation across countries nationally and sub-nationally using novel metrics; WP2 will investigate the impact of fragmentation on health system goals (including UHC) during ‘normal times’ and during COVID-19; WP3 will evaluate multiple health policy innovations affecting health financing fragmentation–both retrospectively and prospectively; WP4 will examine the political determinants of health financing fragmentation; WP5 centres on stakeholder engagement to build capacity to close the evidence-to-policy gap. A key cross-cutting focus is on the implications of financing fragmentation for marginalised groups and identifying lessons to improve health equity. Each LMIC partner led the development of their own research plans through extensive CEI activities. We have planned for a series of CEI activities throughout inception, implementation, evaluation, and dissemination to ensure regular community engagement in the research process for each WP and country. We believe this to be essential to strengthening final research outputs and health and policy outcomes by ensuring that all research is locally driven and owned, and transparently and inclusively produced. Capacity strengthening at individual, organisational and network levels is a priority in our research programme and is a dedicated focus in our Theory of Change model. Capacity strengthening needs have been locally identified and are integral to research planning. Our research programme will deliver robust policy-relevant research on health financing fragmentation that is locally-demanded and contextually relevant to community stakeholders. Our knowledge mobilisation and capacity building activities will ensure that these outputs translate into sustained impacts on research environments and policy making, strengthened health systems and improved health and well-being of vulnerable populations.","8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_11723,Economic and Social Research Council,ESRC,Health Security as Practice,"As described in the Summary below, the fellowship has three strands of proposed work. In this section I set out the precise objectives to be achieved under each of those strands. 1. Publications a) Completion of a monograph manuscript based on the PhD thesis that I successfully defended in December 2020. This is targeted at either Johns Hopkins University Press of MIT Press, both of which have extensive track-records of publishing the leading monographs in this field. It is intended that a monograph proposal will be submitted to these publishers prior to the beginning of the fellowship, with the manuscript being submitted by the end of the fellowship period. b) Completion of a research article (co-authored with Dr. Jonna Nyman) provisionally entitled 'Photography as Method: An Invitation to the Field'. Targeted at International Political Sociology. This will be submitted by the end of the fellowship period. c) Completion of a research article (co-authored with Dr. Lisa Stampnitzky) 'Rethinking Practice, or the Strange Case of International Relations' Fixation with Bourdieu', for submission to Journal of International Political Theory. d) Completion of a single-authored research article, 'Food for Thought, or International Relations' Neglect of Food as a Security Problem', to International Studies Quarterly. e) Conference presentations at the International Studies Association and European International Studies Association conferences, which are the pre-eminent global conferences for work in the field of health security. 2. Funding bid Submission of a proposal to either the ESRC New Investigator Scheme on biosecurity practices in UK agriculture, building on the methods utilised in the PhD but expanding into another important area of health security practice. Further details are provided under 'Summary', below. 3. Workshop and Network on Health Security and Borders a) Workshop to a hosted at the University of Sheffield bringing together approx. 25 practitioners and academics in the area of health security and borders (See Summary below) b) Using the above workshop to inaugurate a Network on Health Security Borders as a vehicle for continued collaboration between academics and practitioners. The Network's purpose will be identifying and creating new opportunities both for knowledge exchange and for research. It will be maintained through an email list, a website and (if funding can be secured) an annual one-day workshop.","As described in the 'objectives' section, the proposed activities under the fellowship are threefold. The first strand is oriented around publication. I am currently preparing a book proposal, targeted at Johns Hopkins University Press and MIT Press. As such, the principal activity under the fellowship would be working on, and ultimately completing, this research monograph, taking my thesis research as a starting point, expanding upon the analysis, and rewriting and restructuring it for a wider audience. In addition, I am currently co-authoring two articles with members of the Department of Politics and International Relations at Sheffield. Both are targeted at high-impact journals. The fellowship would also allow me to work on, and complete, these collaborative articles. Second, the fellowship would enable me to develop funding proposals for future research. This next project on health security and agriculture seeks to build on and extend my doctoral research. The SARS-CoV-2 pandemic has shown the centrality of ecology to understanding and mitigating global health risks. Along with deforestation, intensive animal agriculture is the prime cause of zoonotic risk (i.e. from diseases that cross the species barrier from animal to human). Whilst the political ecology literature has considered the linkages between ecology, capitalism, and intensive animal agriculture, there has been little rigorous assessment of the links between the proliferation of zoonotic disease and socio-ecological relations. Meanwhile, within IR, health (in)security has invariably been equated with exogenous threats: the control and containment of the cross-border spread of pathogens (usually originating in the Global South). Though not necessarily 'wrong', this does not account for the fact that zoonotic threats can emerge from industrial agriculture practices in the Global North - not only from what is often portrayed as a 'dangerous' and 'disease-ridden' Global South. This proposed project acts as a corrective to these gaps. In the project to be proposed to funders, I would build on the praxiographic research methods used during my PhD to undertake extensive non-participant observation of health security practices in UK agriculture, from farm to fork, in order to analyse the ways in which zoonotic risks are both understood and routinely responded to. Once this research proposal is consolidated, the fellowship will enable me to identify and pursue any additional training I may need (particularly methods training). The third proposed activity is a stakeholder workshop on 'Health Security and Borders'. COVID-19 has further highlighted the importance and urgency of furthering our knowledge and understanding of the linkages between health, security, and borders, highlighting the importance of understanding how health security actually works - routinely - in practice. My PhD thesis has gone considerable way to advancing our knowledge on such questions - particularly in the case of the UK Border. As such, it is proposed that a workshop will bring together key stakeholders with an interest in health security at the UK Border (e.g. PHOs, Public Health England (PHE), Department for Transport (DfT), the Association of Port Health Authorities and others), as well as academics with relevant research interests, to discuss the findings and implications of cutting-edge research (by myself and other academics from a variety of disciplines) on health security practices at borders. Importantly, the proposed workshop is intended to be the first step in creating a new Network on Health Security and Borders comprised of academic researchers and health security practitioners, to create new opportunities both for knowledge exchange and for research. In terms of my own career ambitions, the creation of the network during this fellowship would enable me to extend my existing networks, and to position myself as one of the leading researchers in leading researchers in this subfield.",3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,INFECTION HRCS22_11749,Economic and Social Research Council,ESRC,Healthy cognitive ageing: Empowering older adults through self-testing,"Older adults experience cognitive deterioration from 50 years on, affecting work, daily activity, and quality of life. With 12.3 million (19%) in the UK aged 65+, rising to 25% by 2050, we need sustainable, effective ways to identify cognitive changes and keep older adults active, social, and productive. This is impeded by inadequate NHS resources and flawed methods. We will solve this by developing an online cognitive test for older adults to use at home with a standard computer / laptop and webcam, providing instant results and guidance to manage cognitive changes. By 12 months, we will develop a functioning prototype. We know which tests pick up cognitive changes in older adults in lab conditions. Here, we will be using this knowledge to develop an accessible online test for older adults. This will empower them to self-monitor their cognition and take steps to maintain quality of life and independence, much as self-testing blood sugar levels empowers people with diabetes. Accordingly, we have three key aims: 1) Iteratively develop a combination of tasks for the test which minimises burden and duration for the end-user, while maximising effectiveness and accuracy of outcomes. 2) In parallel, collaborate with the steering committee to maximise test accessibility, acceptability, desirability, and useability. 3) Work with the steering committee to develop guidance and reports for test users, to ensuring these are meaningful for older adult users and services they use for support. Completing these aims will enable us to produce a functioning online cognitive test prototype. For a sustainable product, during the Award we will explore routes to market using expertise from Zinc, input from our Innovation / Commercial teams, and exploring connections with industry specialists. This may also involve founding a spin-out company and seeking third-sector adoption, possibly by selling test licences to appropriate third-sector bodies for clients / members. A second option is self-pay, which enables further user testing. A third, longer-term possible goal is exploring NHS partnership via organisations like NHS Providers and Public Digital. Due to the nature of the Healthy Ageing Catalyst award, these later objectives are not yet concretely defined and will be clarified as the project progresses with the help of the Zinc support programme.","From around age 50, people experience increasing problems with thinking (""cognition""), and 1 in 5 go on to develop diagnosed cognitive impairment. In our ageing population, rising numbers of older people are experiencing worsening problems with memory, concentration, and multitasking. Without support, this increasingly affects day-to-day life. As average retirement age rises, it also prevents older adults from maintaining skilled work. This affects individuals' activity and wellbeing, and employers lose critical skills and experience from their workforce. Accordingly, identifying these cognitive problems in older adults is crucial to helping them access support, continue working, and fully enjoy life. However, NHS resources cannot assess all older adults for potential cognitive changes. Here, we outline a new approach to identifying cognitive problems, while minimising reliance on stretched healthcare resources. We will develop an online-access cognitive test for older adults, which can be self-administered at home to test and track cognitive changes. The test will use simple computer-based tasks which are already individually proven to detect changes in memory, concentration, and multi-tasking. This will allow older adults to independently self-test their cognition, as people with diabetes check their blood sugar, without attending specialist clinics. The test will produce results meaningful to the older person, healthcare professionals, and workplace support systems like occupational health. It will provide results-based recommendations, such as signposting to support services, or using practical, brain-training and social strategies to help manage cognitive changes. We aim to empower older adults to monitor their own cognitive wellbeing, and to identify those needing support to reduce avoidable impact on their wellbeing and work.",7.1 INDIVIDUAL CARE NEEDS,MENTAL HEALTH HRCS22_18414,Cancer Research UK,CRUK,"High content FLIM, FRET, and localisation imaging to characterise inter-cellular heterogeneity in PI3K signalling to glycolysis in breast cancer and improve treatment strategies","Background Breast cancer is diagnosed in over 50,000 women in the UK every year and almost a quarter will die from the disease. Improved treatments are needed, but the development of curative therapies remains challenging. Heterogeneity between cells in levels of target inhibition, subsequent modulation of downstream target function, and variation in the dependence of key cell functions on the target all contribute to incomplete tumour cell elimination and therapy failure. Phosphoinositide-3 kinase (PI3K) signalling is activated in breast cancer due to mutations in either PIK3CA or PTEN; furthermore, several phase II & III clinical trials are ongoing with PI3K inhibitors in breast cancer. Live cell imaging with single cell resolution combined with the implementation of fluorescent ‘biosensors’ enables the direct observation of intercellular heterogeneity and its linkage to cell fate. These data will inform the development of more effective strategies to target PI3K signalling in cancer patients. Aims 1. Development of an automated multiplexed FLIM and homoFRET platform linked to complex analytic methods for long term time-lapse studies of heterogeneity in PI3K signalling and cell fate 2. Understanding of how intercellular heterogeneity in response is linked to the emergence of resistance and improving strategies to reduce variance in therapeutic responses to PI3K targeting in breast cancer Methods Heterogeneity in connectivity strengths between different nodes of cell signalling/regulation can undermine therapy efficacy. We will establish and use multiplexed high-throughput biosensor imaging to characterise intercellular variation at regulatory nodes of PI3K activity, Akt, glucose metabolism, and energy stress in breast cancer cell lines and organoids in response to PI3K&AKT inhibitors. Long term imaging using a unique high-content analysis (HCA) platform providing fluorescence lifetime imaging (FLIM) of heteroFRET, fluorescence anisotropy imaging of homoFRET, and intensity-base localisation analysis will enable heterogeneity in the activity of key molecules or pathways and the strength of their connectivity to be linked to cell fate in response to therapy. Finally, we will test strategies to limit intercellular variability and thereby improve the uniformity of therapeutic responses. The first strategy involves targeting PI3K-glycolysis signalling at multiple points to limit relief of negative feedback mechanisms. The second strategy involves limiting the activity of epigenetic regulators to reduce variability in cell state. How the results of this research will be used The multiplexed, single cell time-course analysis will enable an improved understanding of therapy response in heterogeneous cancer cell populations, and thereby the development of more effective combination therapies.","Background Breast cancer is diagnosed in over 50,000 women in the UK every year and almost a quarter will die from the disease. Improved treatments are needed, but the development of curative therapies remains challenging. Heterogeneity between cells in levels of target inhibition, subsequent modulation of downstream target function, and variation in the dependence of key cell functions on the target all contribute to incomplete tumour cell elimination and therapy failure. Phosphoinositide-3 kinase (PI3K) signalling is activated in breast cancer due to mutations in either PIK3CA or PTEN; furthermore, several phase II & III clinical trials are ongoing with PI3K inhibitors in breast cancer. Live cell imaging with single cell resolution combined with the implementation of fluorescent ‘biosensors’ enables the direct observation of intercellular heterogeneity and its linkage to cell fate. These data will inform the development of more effective strategies to target PI3K signalling in cancer patients. Aims 1. Development of an automated multiplexed FLIM and homoFRET platform linked to complex analytic methods for long term time-lapse studies of heterogeneity in PI3K signalling and cell fate 2. Understanding of how intercellular heterogeneity in response is linked to the emergence of resistance and improving strategies to reduce variance in therapeutic responses to PI3K targeting in breast cancer Methods Heterogeneity in connectivity strengths between different nodes of cell signalling/regulation can undermine therapy efficacy. We will establish and use multiplexed high-throughput biosensor imaging to characterise intercellular variation at regulatory nodes of PI3K activity, Akt, glucose metabolism, and energy stress in breast cancer cell lines and organoids in response to PI3K&AKT inhibitors. Long term imaging using a unique high-content analysis (HCA) platform providing fluorescence lifetime imaging (FLIM) of heteroFRET, fluorescence anisotropy imaging of homoFRET, and intensity-base localisation analysis will enable heterogeneity in the activity of key molecules or pathways and the strength of their connectivity to be linked to cell fate in response to therapy. Finally, we will test strategies to limit intercellular variability and thereby improve the uniformity of therapeutic responses. The first strategy involves targeting PI3K-glycolysis signalling at multiple points to limit relief of negative feedback mechanisms. The second strategy involves limiting the activity of epigenetic regulators to reduce variability in cell state. How the results of this research will be used The multiplexed, single cell time-course analysis will enable an improved understanding of therapy response in heterogeneous cancer cell populations, and thereby the development of more effective combination therapies.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_21742,Innovate UK,IUK,High sensitivity multiplex testing with a novel cardiac biomarker for rapid triage of acute chest pain patients enabling healthcare efficiencies and improved patient outcomes,"Acute myocardial infarctions (AMI/heart attacks) are one of the most common causes of death throughout the developed world. Each year ~720,000 UK citizens attend an emergency department (ED) with acute chest pain (ACP), representing ~6% of ED visits. Whilst the majority will not be suffering an AMI, due to the life-threatening nature of these symptoms, all patients must be monitored until successfully triaged. This places a huge strain on the NHS. The Gold Standard for ACP triage relies on assessment of clinical symptoms, electrocardiogram, and elevation/changes in troponin (cTn) biomarker levels (a marker of myocardial cell-death). Since most AMI patients display negative ECG symptoms, biomarkers play a crucial role ACP triage. However, cTn takes time to reach reliable measurable levels. This limits its usefulness for those presenting with early symptoms onset and requires cTn-levels to be monitored over time (a diagnostic pathway). Furthermore, cTn requires high-sensitivity testing (hs-cTn) undertaken in the hospital laboratory. These tests are slow restricting use to long (3-hr) diagnostic pathways. This results in an extended length-of-patient-stay, impacting on patient outcomes/experience and ED efficiency/productivity. Whilst point-of-care diagnostic devices are available, none can deliver reliable high-sensitivity testing. 'Cardiac-Myosin-binding-protein-C' (cMyC) is an emerging myocardial necrosis biomarker. Unlike cTn, cMyC reaches elevated levels in the blood soon after AMI onset, improving diagnostic accuracy and enabling use with early presenters. However, cMyC levels fall equally as fast with time raising reliability concerns for late presenters. There are also barriers to clinical take-up, requiring clinicians to move from the trusted Gold Standard of cTn, or pay for additional testing. Osler seek to overcome these challenges through the application of a novel point-of-care diagnostic platform for the cost-efficient and reliable, simultaneously multiplexed, high-sensitivity testing of both cMyC and hs-cTn biomarkers.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CARDIOVASCULAR HRCS22_22905,The Academy of Medical Sciences,AMS,High-grade glioma treatment design through mapping spatial differences in the DNA damage response of cancer stem cells,"These studies aim to develop surgically-relevant preclinical models of glioblastoma which reflect the spatial intratumoural heterogeneity of parental tumours to help understand why certain tumour regions may be more resistant to current treatment, and design new targeted combination therapies to overcome this resistance. Objectives: 1) Generate and characterise spatially-defined preclinical models of glioblastoma using MRI-guided intra-operative neuronavigation. 2) Validate the extent to which cultured glioblastoma stem cell (GSC) models reflect GSCs within their native microenvironmental niches using single-cell RNA sequencing (scRNAseq). 3) Confirm spatially-defined GSC models can be used to characterise subclonal differences in the DDR of cells from the same tumour and design targeted treatment combinations with pan-tumour efficacy. Glioblastoma is the most common brain cancer and contributes to ~190,000 brain tumour related deaths/year globally. These tumours demonstrate extraordinary intratumoural heterogeneity, however increasing understanding of genetic diversity within tumours has not yet led to improvements in patient survival. Despite surgical resection followed by DNA damaging radiotherapy and temozolomide chemotherapy, average survival remains close to one year. Critically, tumours harbour difficult-to-treat subpopulations of GSCs, which possess unlimited regenerative potential and enhanced DNA repair capabilities. However, our early data suggests GSCs from spatially-distinct tumour regions exhibit divergent responses to DNA damage. Consequently, we anticipate the spatially-defined models proposed here will be transformational in understanding how spatial variation impacts resistance to current DNA damaging treatments functionally, and this will allow us to rationally design new targeted treatment combinations with pan-tumour efficacy.","Patients with a glioblastoma normally have surgery followed by radiotherapy and chemotherapy to tackle cancer cells left behind. Unfortunately, despite these treatments, average survival remains close to 1 year. Chemo- and radiotherapy work by damaging the DNA of cancerous cells. But within every tumour there are various groups of difficult-to-treat cells which have different treatment resistance properties based on their location. During operations to remove a brain tumour, surgeons typically use neuronavigation to cross-reference their exact location with a patients MRI scan. In the proposed studies we will use this ‘GPS-for-brain-surgery’ to sample different geographical locations of a tumour. In the laboratory these samples can be processed to grow the cells from each of these areas within a single patient’s tumour and compare their properties. Our aim is to understand how separate groups of difficult-to-treat cells find different ways to survive current treatments. By comparing how these groups of cells respond to DNA damage using detailed molecular and genetic testing, our studies will provide new insight into how they survive treatment. We will search for a common weakness or Achilles’ heel in DNA repair processes shared by cells from all regions of a tumour, then through testing treatments that target these particular weaknesses, we will identify new ways to tackle the treatment resistance often observed in glioblastoma. The studies should provide ways to kill different groups of difficult-to-treat cells in all parts of a tumour simultaneously leading to better patient survival rates in the future.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_20135,Wellcome Trust,,Host determinants of disease outcomes in arboviral infections,"Infections of animals or humans by viruses can result in many different clinical outcomes. Studying natural models of infection and disease can help us gain a full understanding of the mechanisms of viral pathogenesis, in the knowledge that this is influenced by virus-host co-evolution. In this proposal, we will study bluetongue, a vector-borne disease caused by bluetongue virus (BTV). Bluetongue is one of the major viral diseases of livestock. Essentially all domestic and wild ruminant are susceptible to BTV infection but the resulting clinical symptoms vary considerably (from mild fever to lethal haemorrhagic fever). In this proposal, we will address how a pathogenic virus renders some infected hosts seriously ill, whilst causing only mild/no disease in others, despite abundant viral replication in both. We will use in vitro and in vivo experiments to address our overarching hypothesis that the clinical fate of BTV infection is determined by the complex balance between virus replication in the face of the host’s innate and adaptive immune responses. The outcomes of this proposal will inform appropriate control strategies for this veterinary disease and generate an intellectual framework of value in understanding disease susceptibility in many other arboviral diseases of humans and animals.","In this proposal, we will study “bluetongue”, one of the most important diseases of livestock, in order to address a fundamental question in infectious diseases: how can a pathogenic virus render some infected hosts seriously ill, whilst causing only mild disease in others, despite abundant viral replication in both? Bluetongue disease is caused by bluetongue virus (BTV), a virus transmitted to animals by biting midges. BTV can infect essentially all domestic and wild ruminant species, but infection results in variable levels of disease. Sheep are more susceptible to bluetongue disease. On the other hand, goats and cows are more “resilient”, they develop high levels of virus in their blood but rarely show signs of sickness. We believe that these differences in clinical outcome are caused by events during the early stages of infection when the virus is attempting to replicate within a cell that is urgently mounting an antiviral immune response against the virus. In this project, we will experimentally test this idea. The results will advance our understanding of individual susceptibility to bluetongue disease, inform the design of appropriate control measures and serve as a model to study disease susceptibility in many other viral diseases of humans and animals.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_02875,Medical Research Council,MRC,Household clustering of multimorbidity and associations with health and social care need,"Aim Examine spatial clustering of multimorbidity in individuals, households, and neighbourhoods, and explore how this is associated with health and social care use and mortality. Objectives 1. Complete a systematic review of research examining clustering of multimorbidity and healthcare need within households. 2. Examine spatial clustering of multimorbidity within individuals, households, and neighbourhoods. 3. Examine how household multimorbidity composition and neighbourhood characteristics are associated with health and social care outcomes. 4. Examine the generalisability of findings in a second, large population dataset, exploring how observed associations vary in a different context. Methods 1. Systematic review of literature examining clustering of multimorbidity in households and associations with health and social care utilisation and adverse health outcomes. 2. Cross-sectional observational study using a large population dataset (Lothian DataLoch) to examine spatial distribution of multimorbidity/complex multimorbidity (MM/CMM) in individuals, households and neighbourhoods. 3. Multi-level modelling to examine associations between individual, household and neighbourhood characteristics and health and social care use and mortality. 4. Replication of objective 2 and 3 analysis (Welsh SAIL Databank) to examine generalisability of findings and further explore spatial patterns of multimorbidity in a different social, organisational and geographical context. Scientific and medical outcomes Enhance understanding of how MM/CMM clusters in households and neighbourhoods, and associations with health and social care use and mortality. Application of tools capable of examining multiple levels of complexity will provide a new way of understanding the mechanisms driving multimorbidity and health inequalities, supporting development of strategies to better organise health and social care for people with multimorbidity.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",GENERIC HEALTH RELEVANCE HRCS22_06570,Department of Health and Social Care,NIHR,Housing and health: improving understanding of how energy-inefficient housing affects health through novel data linkages with large UK health datasets and economic modelling,"Background Cold homes are a major public health problem, contributing to a high proportion of the health and mortality impacts of cold weather. People who are vulnerable (e.g. due to age or disability) also tend to spend more time at home. Cold and hard-to-heat homes are an important driver of socioeconomic health inequalities, but their full impact on the development of chronic conditions over many years remains poorly understood and potentially underestimated. Approach My proposed programme of research aims to directly address these gaps, using a range of methods, in order to inform better decision-making and improve public health. This will involve the following work programmes: WP1. A review of the evidence for associations between long-term exposure to energy inefficient or uninsulated homes and/or cold indoor temperatures and chronic health problems, focusing on key health risk factors and new onset or diagnosis of common chronic diseases (cardio and cerebro-vascular disease, asthma and COPD, obesity, diabetes, anxiety, depression, dementia). This review will include epidemiological studies with 1 year follow-up, from countries with temperate or continental climates. WP2. A: Anonymised data linkage of the UK Biobank and SAIL Databank to household-level Energy Performance Certificate (EPC) energy efficiency data, which exist for over half of UK homes. These novel linkages will in turn enable detailed investigation of the associations between housing energy inefficiency (a key predictor of both cold indoor temperatures and fuel poverty) and health, as well as enhancing both resources for future research. B: Using linked UK Biobank data, I plan to analyse associations of home energy efficiency with risk factors such as blood pressure, cholesterol levels and BMI. I will then investigate longitudinal associations between exposure to energy inefficient housing and new diagnoses of a range of chronic health conditions. C: Using linked SAIL data, I plan to investigate longitudinal associations between housing energy efficiency and severe health outcomes such as heart attacks, strokes, COPD and asthma exacerbations, and on mortality, using causal inference approaches. WP3. Updating the Health module of the HIDEEM (Health Impact of Domestic Energy Efficiency Measures) model, using WP1 and WP2 findings, which informs national policy and spending decisions. Patient and Public Involvement An NIHR Patient Involvement Fund supported me to involve 12 people with lived experience of difficult-to-heat homes in developing this proposal, and they have shaped it in several ways, including the range of outcomes and use of a new health dataset. My fellowship plans have PPI woven throughout, including through PPI panels who will meet every 3-4 months, and regular involvement of two lay advisors. This will shape each project's methods, and how findings are interpreted and communicated. Dissemination, engagement and impact I have planned a series of dissemination and engagement activities involving policy-makers, charities, advocacy groups and members of the public, and will develop summaries tailored policy briefs, blogs and infographics. This will facilitate translation of the findings into public health benefits, by influencing housing policy and expenditure decisions, minimum housing quality standards, and informing local health-focused warmer housing schemes.","The problemOver 3.5 million people in the UK struggle to keep their home warm, and the impacts on health can be severe. Spending time in a cold home, often caused by an inability to pay for heating and/or living in poor-quality 'energy inefficient' housing - affects both mental and physical health. It can even result in severe illness or death. Much is known about these kinds of short-term health effects, but cold, difficult-to-heat housing may also be harming long-term health, with the impacts unfairly spread across society. Hard-to-heat housing also harms the environment and our economy. It costs the NHS alone approximately 1.3 billion/year, but even this may be underestimated. What research is needed and why? We do not yet fully understand exactly how cold homes affect longer-term health and people's chances of developing chronic illnesses, or what this costs the NHS. This is partly because it has been hard to study this issue in the past because housing and health data are often not linked together, and/or because previous studies have only included small numbers of people (so they can only look at very common health problems), or don't cover a long time. In turn, this makes it harder to be confident about how to tackle the problem most effectively. This research project will help to improve understanding of the longer-term health impacts, and what they cost. Research proposal In my PhD research, I plan to provide evidence to help inform action to reduce the health impacts of cold or difficult-to-heat housing. I will do this through three projects:· A study bringing together all available evidence about longer-term impacts of energy-inefficient or cold housing on the risk of developing a range of health problems over a year or more.· Two studies of how living in cold and difficult-to-heat homes affects chronic illness risks, over several years, using data from two very large-scale datasets linked to information about housing energy efficiency: The UK Biobank study (using a major existing research study of >500,000 people aged approximately 40-80) will look at the impact of living in an energy-inefficient home on important risk factors like blood pressure and cholesterol, and on the chance of people developing chronic health problems. A study using housing data linked to SAIL (Secure Anonymised Information Linkage) Databank will look at the impact of living in an energy-inefficient home on the risk of severe problems such as heart attacks, strokes and asthma attacks, and on the risk of dying.· Updating an existing model that estimates the costs and benefits of making housing more energy-efficient, helping to influence Government spending decisions. Patient and public involvement and sharing findingsPPI activities so far have confirmed the importance of this research. They have also informed this application, including shifting the focus to a wider range of health outcomes (including mental health); prompting my decision to use the SAIL databank, with a more diverse group of people; and taking a closer look at the underlying causes.I am committed to involving people with lived experience of cold/difficult-to-heat homes and chronic health problems closely, including through a PPI panel for each project, who will meet every 3-4 months, and monthly calls with two lay advisors with lived experience, who will join the advisory panel. This will shape the questions and approach for each project, and how the findings are interpreted and communicated. I will use a plain English summary for each project (developed with PPI involvement), blogs and infographics, media articles and interviews, and a series of public events to share the research findings.",2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,GENERIC HEALTH RELEVANCE HRCS22_09553,Health and Care Research Wales (Welsh Government),,How can immersive virtual reality be used to facilitate recovery and rehabilitation of patients following a stay in intensive care?,"Post intensive care syndrome (PICS) is a very common occurrence in people who have experienced a stay in an Intensive Care Unit (ICU) and can be significantly debilitating. A mix of cognitive, psychological and physical impairments leads to a profound impact on the lives of patients and their families. Whilst standardised developments in treatment strategies during a stay in ICU have positively impacted survival, there are few, if any recognised standardised programs for supporting recovery and rehabilitation post-ICU. Additionally, the recent Sars-CoV2 pandemic has seen a significant increase on the number of ICU admissions, inflating the already large number of 130,000 discharged alive form ICU across the UK each year. This has created a “tsunami of need” for effective post-ICU rehabilitation, with recent UK critical care guidelines recommending a holistic and accessible approach to recovery. This pressing issue is further compounded by the documented lack of available staff and resource to support holistic recovery post-ICU. A potential avenue for developing accessible interventions at relatively low cost for people recovering from ICU lies within immersive virtual reality (VR). VR has been utilised in a variety of healthcare settings and has demonstrated promise in a range of clinical areas. For instance, VR has shown equal effectiveness to conventional therapies in rehabilitation after stroke, but with the added benefits of independent home-based use, more accurate feedback and the ability to stimulate users more than traditional methods. Building on our previous feasibility work with VR in ICU settings, this study aims to create a VR mediated, home-based intervention to support post-ICU rehabilitation and evaluate how readily this may be adopted by patients and healthcare providers. To achieve this aim we plan to research the patient experience of recovery from critical illness to identify intervention priorities and outcome measures considered important and acceptable to ICU survivors, their loved ones and relevant critical care and rehabilitation staff. Using this information, we will adapt a VR kit already in use within the NHS to co-produce (with service users and key stakeholders) a VR-mediated intervention to aid recovery and rehabilitation after critical illness. This intervention will then be tested in a small group of patients discharged from ICU to examine the feasibility and acceptability of the intervention and delivery in an at-home setting. The intervention will be evaluated via a series of qualitative interviews with study participants and healthcare professionals involved in intervention delivery to provide in-depth and contextual analysis of the intervention’s feasibility and acceptability, plus detailed insights into the applicability of outcome measures for critical care research, including economic evaluation. The information generated by the feasibility study will provide important insights into a potential new therapeutic and resource light intervention for supporting and improving recovery and rehabilitation in people experiencing PICS. Not only will this benefit ICU survivors directly, but in learning about the components of recovery and how to adapt DR.VR for self-directed use at home, we will have developed a framework that can be simply altered to generate accessible, low cost interventions for a plethora of patient groups.","People admitted to intensive care (ICU) often experience ongoing health problems once they leave and have returned home. This is described as Post Intensive Care Syndrome (PICS) and can include problems with memory and thinking, physical impairments and reduced psychological wellbeing. This can result in a reduced quality of life, which also affects family members and friends. Although improvements have been made in caring for people within ICU, there is no standard approach to care after leaving ICU to support patients' recovery. A lack of staff and resources have also been a barrier to standard post -ICU care. With the recent increase in admissions to ICU, there is an urgent need to find ways of supporting the recovery of people with PICS that is readily available to patients. A recent review of how to combat PICS suggested that home-based and virtual care plans would be one way of making sure that as many people as possible could take advantage of rehabilitation support. Immersive virtual reality (VR) can be accessed simply at home with an easy -to-use headset. VR has already been shown to be useful in helping relaxation and in combatting pain and anxiety. We think that VR might help support people recovering from PICS at home and this study is aimed at developing a VR program (intervention) that can be used at home. In order to do this, we are proposing a three stage program of research. First, we need to understand what the recovery journey looks like. We will conduct a series of focus groups with ICU survivors, their family members and healthcare professionals involved in the care and rehabilitation of ICU patients. In these sessions, we will explore what the patient recovery journey looks like what the critical parts of recovery are. We will also work with these groups to determine, in terms of recovery, what is important to measure (known as outcomes) to find out whether or not a homebased care intervention works or not. The second stage will use data from the focus groups which will then be used to alter an existing VR set-up (DR.VR) to specifically support the recovery of ICU patients, working with previous ICU patients and their family members to inform the design. We will also ask this group what features need to be included when testing the intervention at home and use this input to design the next stage of the project. In the third part of the study, we will test the adapted VR intervention in a small group of patients admitted to ICU. The aim of this study will be to see if using a home-based VR intervention is possible and if people are happy and willing to use it. We will also explore how acceptable participants find the outcomes selected from the earlier focus groups. We will do this by interviewing participants about their experience. We will also interview the healthcare professionals involved in the care and rehabilitation of these participants to gather their views on the VR intervention. The interview data will be analysed qualitatively to provide an in-depth understanding of the intervention and outcomes. This data can then be used to inform the design of larger studies in the future to test how effective the VR intervention is at supporting the recovery of ICU patients. At the end of the study, we will share the results with all of the study participants and more widely through appropriate web pages, social media and organisations concerned with the care of ICU patients.",5.3 MEDICAL DEVICES,GENERIC HEALTH RELEVANCE HRCS22_02873,Medical Research Council,MRC,How do senescent stromal cells subvert the treatment response in acute lymphoblastic leukaemia?,"Our overarching purpose is to understand better how stromal cells influence and are influenced by cancer cells. We recently identified the development of cancer-associated fibroblasts (CAF) from bone marrow mesenchymal stromal cells (MSC) in acute lymphoblastic leukaemia (ALL). We modelled the de novo development of CAF in vitro from either normal, healthy human MSC or the stromal cell line HS27a upon exposure to ROS-inducing chemotherapy. We could also model their development in vivo, where CAFs formed a nestin-positive niche at which the ALL target cells were 'rescued' from chemotherapy agents upon transfer of mitochondria from the CAF. The CAFs we have identified clearly demonstrate features of senescence which is a tumour suppressor mechanism which is cell-intrinsically activated in the context of cellular stress. We have found that the development of senescence relates not only to chemotherapy exposure but to exposure to certain genetic subtypes of ALL. We hypothesise that senescence of stromal cells plays a role in modulating the differential outcome of treatment in different genetic subtypes of ALL. We aim (1) To characterise senescence development in CAF derived from subtypes representing childhood and adult ALL (2) To characterise the interaction of senescent stromal cells with the different genetic ALL models in murine bone marrow microenvironment. Within the aims, we will probe the system using relevant chemotherapy drugs and commonly-used agents with senolytic capacity,",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_02815,Medical Research Council,MRC,How does SARS CoV-2 infect blood vessels?,"Vascular symptoms including hypercoagulation are a key feature of severe COVID-19. They have been assumed to arise via infection of endothelial cells, however recent RNAseq analyses revealed that instead it is pericytes - vascular mural cells with intimate connections with endothelial cells and several vital roles in vascular function - which express the receptor, ACE2, which allows SARS CoV-2 to enter cells. Determining which cells mediate vascular and therefore extrapulmonary organ infection is vital for selecting optimal therapeutic interventions. Through our groups' expertise in vascular biology, virology and clinical haematology, we will identify whether pericytes or endothelial cells are the primary vascular target of SARS CoV-2. We will utilise a pseudotyped SARS CoV-2 virus (PV), which undergoes a single round of infection and expresses a reporter protein in target cells. We will first compare the efficiency of infection in cultured human pericytes and endothelial cells, before injecting PV into mice and tracking reporter expression across pericytes and endothelial cells of different organs. As SARS CoV-2 does not bind murine ACE2, parallel experiments will test a PV mutated to bind murine ACE2 as well as mice expressing human ACE2. Because increased inflammation and APOE4 genotype both alter vascular permeability and are associated with severe COVID19, we will repeat these experiments in animals with LPS-induced inflammation or that express human ApoE3 or 4. By identifying the cells that first become infected with SARS CoV-2 and the conditions that increase infection, this project will enable proper targeting of therapies to the relevant cells.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_19448,Wellcome Trust,,How expectation shapes perception: from cortical layers to brain-wide networks,"The way we perceive the world is strongly influenced by our expectations about what we are likely to see at any given moment. However, the neural mechanisms by which the brain integrates sensory inputs and expectations, and thereby generates the contents of perception, have yet to be established. I propose that, upon presentation of a predictive cue (e.g., a siren), memory systems pre-activate templates of expected stimuli (an ambulance) in the deep layers of visual cortex, leading to biased processing of sensory inputs from the very moment they arrive. Such biased processing then leads naturally to biases in perception, in extreme cases even hallucinations. I will test this proposal by addressing three complimentary questions: 1) How do the neural computations underlying perception unfold over time? 2) What is the fundamental computational architecture of visual cortex? 3) What is the neural source of expectations? I will combine psychophysical tasks probing participants’ perception with neuroimaging tools with exquisite temporal (MEG) and spatial (high-field fMRI) resolution to address these questions. The overarching aim of my research is to provide a mechanistic account of subjective perception. Ultimately, these insights may improve our understanding of clinical disorders characterised by aberrations in perception, such as psychosis.","The way we perceive the world is strongly influenced by our expectations about what we are likely to see at any given moment. For instance, when driving in a rainstorm, our prior knowledge about streets leads us to perceive horizontal, fast-moving blurs as cars, and vertical, slow-moving shapes as pedestrians, even if the blurry shapes themselves are ambiguous. Despite all of us experiencing this remarkable phenomenology, the brain mechanisms underlying it are largely unknown. I will conduct brain-imaging experiments aimed at addressing this question. I will give people tasks that reveal influences of prior expectations on perception, while using brain-imaging technologies to pinpoint the ongoing neural computations in memory and visual systems. The ultimate goal of my research is to understand the mechanisms by which the brain generates perception. These insights may improve our understanding of clinical disorders like psychosis, which are characterised by aberrations in perception, such as hallucinations.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;NEUROLOGICAL HRCS22_02030,Medical Research Council,MRC,Human rhinovirus VP4: membrane pore-forming capsid protein and conserved target for broadly neutralising antibodies,"The picornavirus capsid comprises sixty copies of each of VP1, VP2, VP3 (which form the icosahedral non-enveloped particle) and VP4 which is a small, myristoylated internal protein which stabilises the capsid structure. During cell entry, VP4 is irreversibly externalised and interacts with membranes to form a multimeric pore thought to be involved in delivery of the RNA genome into the cell. In this project we will use virus particles, VP4 peptides, liposome model membranes and biochemical and structural approaches to gain fundamental understanding of how VP4 multimerises and inserts in the membrane and how VP4 emerges from the HRV capsid. The capsid is dynamic and undergoes a process of 'breathing' whereby internal components such as the N-terminus of VP4 are transiently exposed at the capsid surface. Antibodies raised against N-terminal VP4 peptides can recognise VP4 and neutralise the virus. The N-terminus of VP4 is highly conserved and existing evidence from studies with HRV and related picornaviruses strongly suggests that antibodies against VP4 are highly likely to be broadly neutralising. We will define protective epitopes in VP4 and present them in an immunogenic form to induce antibodies that react with the emerging N-terminus of VP4, neutralise the virus and protect against infection in an established murine model for HRV infection.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_17539,Duchenne UK,DUK,Hydrotherapy,"The quality of life in young males with DMD is negatively impacted by daily pain, changes in body composition and a lack of support to undertake physical activity. Hydrotherapy represents a potential means of involving boys and adolescents with DMD in activity that could benefit the negative factors influencing their quality of life. This project has 2 goals: 1)to allocate a clinical physiotherapist to a project implementing hydrotherapy in young males with DMD to establish whether there are meaningful benefits to their daily life. 2)to conduct patient and parent interviews to understand the barriers to completing a hydrotherapy intervention and ensure our future research addresses meaningful outcomes for those with DMD.",,6.7 PHYSICAL,MUSCULOSKELETAL;CONGENITAL DISORDERS HRCS22_20460,Cancer Research UK,CRUK,Hyperpolarised carbon-13 MRI for metabolic imaging of renal cell carcinoma,"Background Hyperpolarised carbon-13 Magnetic Resonance Imaging (13C-MRI) is a new method for probing tissue metabolism non-invasively and has recently been translated into humans. The technique can measure the exchange of intravenously injected hyperpolarised 13C-pyruvate to 13C-lactate in real-time, catalysed by the enzyme lactate dehydrogenase. Our preliminary results with the method have demonstrated the formation of 13C-lactate in both normal human kidneys and in clear cell renal cell carcinoma (ccRCC): within the tumour, significant metabolic heterogeneity was demonstrated. This project will evaluate and develop the method as a clinical imaging tool in oncology. It will investigate metabolic imaging habitats as a measure of tumour heterogeneity and determine whether the technique can provide an early biomarker of successful response to neo-adjuvant therapy. Aims 1. Develop models of hyperpolarised 13C-MRI in ccRCC tumours 2. Biological and technical validation of hyperpolarised 13C-MRI 3. Data modelling and imaging segmentation approaches for hyperpolarised 13C-MRI 4. Correlation with conventional imaging, textural features, tumour habitats and circulating tumour DNA Methods Patients with ccRCC will be studied with multiparametric MRI and hyperpolarised 13C-MRI as a model of metabolic reprogramming. Patients will be imaged prior to surgery, as well as before and after neo-adjuvant therapy. • Pre-operative imaging will be compared to tissue specimens to validate metabolic imaging with histology, immunohistochemistry, metabolomics and RNA-seq. • Imaging-derived tumour habitats will be correlated with histology to evaluate the relationship between conventional/metabolic imaging and tumour heterogeneity. • Temporal changes in the metabolism of hyperpolarised 13C-pyruvate before and after neo-adjuvant therapy will be monitored as part of the WIRE study, to assess if hyperpolarised 13C-MRI can be used as an early imaging biomarker of treatment response. • Hyperpolarised 13C-MRI will be compared to conventional MRI, textural features of tumour heterogeneity and circulating tumour DNA to establish the temporal relationship between these biomarkers and their relative sensitivities for detecting response to therapy. • Novel pathways of pyruvate metabolism will be explored in tumours with loss-of-function mutations in the enzyme succinate dehydrogenase. • Methods to model and analyse hyperpolarised 13C-MRI data will be developed. How the results of this research will be used: This programme will develop hyperpolarised 13C-MRI as a clinical research tool and will explore whether it could be used more routinely in ccRCC. The technique has the potential to provide novel imaging biomarkers for assessing early response to treatment and may be used to non-invasively assess tumour metabolic phenotype and heterogeneity.","Background Hyperpolarised carbon-13 Magnetic Resonance Imaging (13C-MRI) is a new method for probing tissue metabolism non-invasively and has recently been translated into humans. The technique can measure the exchange of intravenously injected hyperpolarised 13C-pyruvate to 13C-lactate in real-time, catalysed by the enzyme lactate dehydrogenase. Our preliminary results with the method have demonstrated the formation of 13C-lactate in both normal human kidneys and in clear cell renal cell carcinoma (ccRCC): within the tumour, significant metabolic heterogeneity was demonstrated. This project will evaluate and develop the method as a clinical imaging tool in oncology. It will investigate metabolic imaging habitats as a measure of tumour heterogeneity and determine whether the technique can provide an early biomarker of successful response to neo-adjuvant therapy. Aims 1. Develop models of hyperpolarised 13C-MRI in ccRCC tumours 2. Biological and technical validation of hyperpolarised 13C-MRI 3. Data modelling and imaging segmentation approaches for hyperpolarised 13C-MRI 4. Correlation with conventional imaging, textural features, tumour habitats and circulating tumour DNA Methods Patients with ccRCC will be studied with multiparametric MRI and hyperpolarised 13C-MRI as a model of metabolic reprogramming. Patients will be imaged prior to surgery, as well as before and after neo-adjuvant therapy. • Pre-operative imaging will be compared to tissue specimens to validate metabolic imaging with histology, immunohistochemistry, metabolomics and RNA-seq. • Imaging-derived tumour habitats will be correlated with histology to evaluate the relationship between conventional/metabolic imaging and tumour heterogeneity. • Temporal changes in the metabolism of hyperpolarised 13C-pyruvate before and after neo-adjuvant therapy will be monitored as part of the WIRE study, to assess if hyperpolarised 13C-MRI can be used as an early imaging biomarker of treatment response. • Hyperpolarised 13C-MRI will be compared to conventional MRI, textural features of tumour heterogeneity and circulating tumour DNA to establish the temporal relationship between these biomarkers and their relative sensitivities for detecting response to therapy. • Novel pathways of pyruvate metabolism will be explored in tumours with loss-of-function mutations in the enzyme succinate dehydrogenase. • Methods to model and analyse hyperpolarised 13C-MRI data will be developed. How the results of this research will be used: This programme will develop hyperpolarised 13C-MRI as a clinical research tool and will explore whether it could be used more routinely in ccRCC. The technique has the potential to provide novel imaging biomarkers for assessing early response to treatment and may be used to non-invasively assess tumour metabolic phenotype and heterogeneity.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_18195,Cancer Research UK,CRUK,ICR Stratified Medicine Technology Hub: SMP2 - Costed Extension,"The CRUK-SMP2 is undertaking the large volume national molecular pre-screening which integrates with the National Lung Matrix Trial. There is a testing platform using Illumina's technology to query 28 different genes for mutations, copy number alterations and translocations. The pre-clinical justification for each biomarker–drug combination has been rigorously assessed creating molecular exclusion rules and a trumping strategy in patients harbouring concomitant actionable genetic abnormalities. Patients carrying specific DNA alterations are recruited to one of the 18 different cohorts.",,6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),CANCER AND NEOPLASMS HRCS22_20847,Wellcome Trust,,"IDDO: FAIR, equitable and sustainable data platform for infectious diseases","The COVID-19 pandemic has once again exposed the lack of coordination and cooperation across the research and development efforts of the infectious disease community. A key indicator of this failing is the lack of international, interoperable data platforms to provide rapid insight into disease pathogenesis and treatment. Access to data is an important tool for accelerating evidence, product development, and scientific innovation. Enhanced technology, infrastructure and systems for data platforms will increase Findability, Accessibility, Interoperability, and Reuse (FAIR), so that science can advance in a rapid, robust and innovative way, saving lives in the affected communities. Recognising the importance and complexity of the task at hand, this project brings together the vast experience of IDDO, Vivli, and other key stakeholders to deliver a broad, effective, and sustainable data platform(s) for infectious diseases. In this project, IDDO will: • Enhance its platform for improved findability, discovery, and persistence which ensures that data are available in the long-term; • Optimise and accelerate its data curation capacity; • Streamline and accelerate its data access workflow; • Develop a business plan to secure the sustainability and success of the platform",,2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),INFECTION HRCS22_23333,LifeArc,,IL13RA2-targeted T-cell therapy for paediatric high-grade gliomas,"High-grade gliomas (HGG), referred to as Diffuse Midline Gliomas (DMG), are childhood central nervous system tumours that are very difficult to treat. DMG is the second most common type of primary, high grade brain tumour in children and, sadly, fewer than 10% of children live more than two years after diagnosis. With this project, Dr Karin Straathof’s team is developing a type of immunotherapy for DMG using immune cells called T cells. T-cells play a vital role in our immune system, recognising and eliminating cells infected with, for example, a virus. However, unlike infected cells, cancer cells often go unnoticed by T cells as they appear similar to the healthy cells from which the cancer has developed. To get around this, and use the power of T cells as cancer therapy, T cells can be engineered to recognise cancer cells using an artificial receptor called a chimeric antigen receptor, or CAR for short. Early results with CAR T-cell therapy for adults with high-grade gliomas show that these engineered T-cells can attack the tumour. However, the responses are variable and relatively short-lived. This is probably because tumours such as DMG create an environment in which the CAR-T cells can only work for a short period of time. Therefore, in this project, patient T cells will not only be engineered with a CAR which enables the T cells to recognise the tumour, but also with other modules which provide the T cells with extra ‘powers’ to continue to work despite barriers put up by the tumour to avoid CAR-T cell attack. The team aims to develop a CAR T-cell that responds specifically to a membrane protein, IL-13RA2, which most paediatric HGGs express. In addition, the team aims to: engineer the CAR T-cells with functional modules to overcome challenges at the tumour site test different modules using relevant pre-clinical models select the most promising approach to translate into a clinical study.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES,NEUROLOGICAL;CANCER AND NEOPLASMS HRCS22_05105,Department of Health and Social Care,NIHR,IMPACT: Innovations using Mhealth for People with dementiA and Co-morbidiTies,"Health systems in low- and middle-income countries are ill-equipped to cope with rapidly aging populations and associated chronic disease. Dementia is a particular problem in Peru and challenges the health system on many fronts. People with dementia often have other health problems as well (co-morbidities) which go untreated, cause suffering and cost money. There is almost no social care infrastructure and care is provided almost entirely by over-stretched family members. The COVID-19 pandemic has particularly affected the elderly and cognitively impaired in Peru, which has the highest death rate per capita from COVID in the world. Our goal is to strengthen the health system in Peru to meet the challenges highlighted by dementia by using technology and trained community health workers to bring expert diagnosis, treatment and support right to where it is needed – to the homes of patients and carers. To achieve this, we will run four linked lines of work to: i) assess whether the healthcare system can care for more people with dementia ii) improve the diagnosis of dementia and comorbidities iii) improve the care of people with dementia and their carers iv) evaluate the costs of dementia to society as a whole Can the Peruvian health system care for more people with dementia? We will interview people with dementia, carers, support organisations, health professionals and government officials. We will find out about current dementia care in Peru and what is needed to improve it Diagnosis: Dementia and its comorbidities are hard to diagnose in people who live far from health centres or have had little formal education. We will make an ‘app’ to help community health workers diagnose people with dementia and record their comorbidities. We will test how well this app diagnoses 1600 people across four distinct regions of this diverse country. Care: People with dementia can be difficult to look after, partly because of their comorbidities. Caregivers can also become stressed or unwell. This means families need easy access to help and advice. Moreover, although there is no cure for dementia, group-based activities, physical exercise and proper treatment of comorbidities all help people to live well with dementia. But this type of care is not readily available in Peru. A project in the United States has developed a way of providing this care with smartphones. Because most Peruvians have smartphones, we can use them to develop a similar service, testing whether providing this care with smartphones is feasible in Peru. Costs: We will measure the cost of dementia and comorbidities in Peru. The health system needs to know how much dementia care will cost, so that it can introduce cost-effective plans for better care. We will work with dementia charities in Peru and around the world to keep our research focused on patients. We will collaborate with the Peruvian Ministry of Health to develop a National Plan for Dementia, and integrate the findings of our research into the existing health system for the benefit of the most disadvantaged and marginalised in society. We focus on Peru in order to understand the context in depth, but are confident that our findings will be applicable much more widely in South and Central America. In the second half of the project, we will share our methods with the Latin America and Caribbean Consortium on Dementia (LAC-CD) in order to analyse health systems readiness across three other countries in the region.","Background: Health systems in LMICs are poorly equipped to care for chronic mental and physical disease, which are rapidly increasing with aging populations. Cognitive impairment challenges health systems on multiple fronts, incurring huge human and financial costs. Latin America has the highest projected increase in dementia incidence globally, and in Peru there are ~300,000 people with dementia (PWD). Many are undiagnosed and lack basic support. Care is often provided exclusively by family members. PWD have twice as many co-morbidities as those without dementia which, despite being treatable, are often missed, poorly managed and reduce quality of life for PWD and their carers. Aims and objectives: Project IMPACT will use dementia as a tracer condition to strengthen health systems in Latin America through sustainable, integrated, person-centred, community-delivered, technology-enabled innovation. Our specific objectives are to i) evaluate health systems readiness to provide support for PWD; ii) develop and implement an mHealth application for diagnosis of dementia by community health workers (CHWs) in Peru; iii) determine the feasibility of an mHealth-delivered, CHW-supported intervention to improve health-related quality of life for PWD and their carers; iv) assess the socioeconomic burden of dementia in Peru. Through these objectives, and in combination with our Outreach, Capacity Building and Engagement activities, we will identify barriers to and facilitators for high-quality health systems. Methods: Our strongly interdisciplinary team includes researchers, policymakers and community representatives working together across 5 interrelated work packages (WPs). WP1 (Health System Readiness) will assess the needs of PWD and their carers and the readiness of the Peruvian health system to meet those needs. The tools developed will also be applied in 3 other Latin American countries. WP2 (Diagnosis) will co-produce an mHealth app for CHWs to find cases of dementia and record co-morbidities. We will evaluate the acceptability and accuracy of this app in 1600 PWD and controls from four distinct regions of Peru: the capital city (Lima), a coastal semi-urban region, the Andes mountains and the Amazon jungle. We will test integration of the app into primary health care. WP3 (Intervention) will adapt an existing mHealth intervention, developed in the US, to the Peruvian context. The intervention will include co-morbidity management help, motivation for physical exercise and group-based activities and carer support. Its implementation will be assessed in a feasibility study. WP4 (Health Economics) will estimate the economic burden and impact on quality of life of dementia and co-morbidities using questionnaires administered to the PWD and controls identified in WP2. WP5 will oversee all project management activities and engage stakeholders and the wider community to increase awareness and tackle sigma. Anticipated impact and dissemination: We will work with patients, carers, health care workers, not-for-profit organisations, academics and policy makers to co-design our research and ensure maximum impact for PWD in Peru and beyond. We envisage: i) the diagnostic app being implemented nationwide within the health service; ii) preparing for a full trial of the complex intervention; iii) informing the design of a National Dementia Plan in Peru; iv) adaptation and application of health system readiness tools in other Latin American countries.",7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS,NEUROLOGICAL HRCS22_12740,Leeds Hospitals Charity,,IMPRESSeD: IMproving facial PRosthesis construction with contactlESs Scanning and Digital workflow.,The funding is supporting a 3 year fellowship project that aims to improve the way we make facial prostheses for patients with facial defects by using digital technology.,"The funding is supporting a 3 year fellowship project that aims to improve the way we make facial prostheses for patients with facial defects by using digital technology. The are four key stages to the fellowship: • Stage 1 has been completed and has reviewed past research to find out how other researchers have measured the success, costs and benefits of making facial prostheses. • Stage 2 is nearing completion and has been testing different workflows for making facial prostheses to see how accurately we can design and make facial prostheses using computers. • Stage 3 is a small trial that will provide evidence to support a larger trial that will compare patient preference, costs and benefits of making prostheses by hand or using digital technology. This initial trial has recently started at Leeds Teaching Hospitals NHS Trust and will be starting at Guy’s and St Thomas’ NHS Foundation Trust in the coming weeks. • Stage 4 is being undertaken alongside the other stages of project and will consider whether there is enough evidence to use the digital technology in the NHS or whether larger studies are required.",5.3 MEDICAL DEVICES,ORAL AND GASTROINTESTINAL;MUSCULOSKELETAL HRCS22_21731,Innovate UK,IUK,IMmunity Profiling of pAtients with Covid-19 for Therapy and Triage (IMPACTT),"The IMPACTT project will study the immune profiles of 3,000 patients infected with SARS-CoV-2 in order to understand our immune responses to the virus. This project will generate five outputs: 1\. Generation of a panel of immune related biomarkers that are predictive of response to treatment, including adverse events 2\. Understanding why some patients have very mild symptoms, yet others have severe reactions that result in ventilation and even loss of life; 3\. Identification of novel therapeutic targets; 4\. Publicly available database of the immune profiles of 3,000 patients; 5\. Creation of a biorepository of 3,000 patient samples to support further research into the SARS-CoV-2 virus.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_19395,Cancer Research UK,CRUK,INCAR: Innovative CAR Therapy Platforms,"Background The Innovative CAR Therapy Platform (INCAR) initiative aims to launch a consortium of European centres to support in-depth research into Chimeric Antigen Receptor (CAR) engineered cellular therapies. INCAR brings together world-class centres (University of Milan-Bicocca, Ospedale Pediatrico Bambino Gesù, ASST Papa Giovanni XXIII, Cancer Research Center FICUS, and University College London) with established programmes in CAR therapies for a range of malignancies, and with a number of phase I/II studies either open or in implementation. The goal of the consortium is to improve patient outcomes and broaden applicability of T-cell therapies by dissecting biological factors influencing CAR T-cell mechanisms of action. Aims Uniquely possible within a collaborative academic network, the consortium will take advantage of differences in cellular platforms, CAR design, manufacturing and gene transfer methods to dissect key biological factors which influence the mechanism of action of CAR-engineered cellular therapies. We anticipate this approach will rapidly enhance our understanding of mechanisms responsible for efficacy and toxicity as well as catalyse further research in the field. Method The proposed goal will be achieved through the complementary approaches of the participating teams in terms of clinical and academic expertise, skills and techniques, as well as of the core facilities underpinning the host institutions. The project will capitalize on development of novel automated manufacturing platforms and preclinical systems to investigate potency and toxicity. Furthermore, CAR T-cell interactions with their microenvironment and the biological determinants of T-cell potency will be unraveled through transcriptional analysis and Next-generation flow-based immune monitoring. Emphasis will be placed on a collaborative scientific approach, establishing standardized protocols, constructive data-sharing and rigorous output assessment, to ensure progress is rapidly achieved. A project management team will schedule collaborative meetings to maximize outputs and a patient’s association will play an integral part in the Consortium’s steering committee. How the results of this research will be used Identification of factors contributing to T-cell fitness, genotoxicity mediated through CAR T-cell manufacture and dissection of the role of the microenvironment in CAR T-cell responses will be disseminated through the consortium to stimulate further academic investigation as well as development of novel optimised manufacturing methods, standardised release criteria, immune monitoring tools and recommendations to accelerate progress in CAR T-cell immunotherapy. We believe this is a unique opportunity to exploit differences in delivery of CAR T-cell therapies to better understand these highly innovative therapies and catalyze further breakthroughs in the treatment of cancer.",,5.2 CELLULAR AND GENE THERAPIES;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_03211,Medical Research Council,MRC,INSULIN SENSING IN THE BRAIN AND THE EFFECTS OF INSULIN RESISTANCE ON METABOLIC BEHAVIOUR,"The brain Dorsal Vagal Complex (DVC) senses insulin to regulate glucose metabolism and feeding behavior in rodents. Obesity causes insulin resistance and completely disrupts the regulative functions of the CNS. Three days of high-fat diet feeding is sufficient to cause insulin resistance in the DVC by increasing mitochondria fission and ER stress. This leads to rising blood glucose levels and food intake. I aim to understand the molecular events that trigger insulin resistance in the DVC. To achieve this, I will use a combination of molecular and chemical tools coupled with mass spectrometry analyses to identify new target molecules involved in developing brain insulin resistance in animals. I will also use in vivo readouts, including glucose clamp and feeding studies, to understand the effects that insulin resistance has on whole-body glucose metabolism and feeding behavior. The neuronal population(s) involved in these processes are unknown. I will identify the neuronal networks that sense insulin in the DVC and regulate metabolic functions in rats by using a combination of genetic models with immunohistochemistry and electrophysiology techniques.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MENTAL HEALTH;METABOLIC AND ENDOCRINE;NEUROLOGICAL HRCS22_15181,Stroke Association,,Iatrogenic cerebral amyloid angiopathy and intracerebral haemorrhage,"Iatrogenic amyloid-beta cerebral amyloid angiopathy (iCAA) is associated with intracerebral haemorrhage in young patients with a history of procedures involving the head and neck in childhood. We hypothesise that these patients acquired amyloid-beta protein during these procedures, as has been demonstrated in animal models. This is a new and emerging disease with significant potential public health implications. The aim of this programme of research is to further characterise the clinical features and risk factors associated with iCAA, via three feasibility studies: 1. Clinical surveillance in a population at risk of iCAA: We will perform detailed clinical and radiological assessments (including blood tests, neuropsychological testing, electroencephalography, MRI, lumbar puncture) of 10 individuals who received cadaveric human growth hormone prepared using the Hartree-modified Wilhelmi procedure, as preparation for a larger surveillance study. 2. Body fluid biomarkers for iCAA: We will analyse blood and cerebrospinal fluid from 10 patients with known iCAA in order to identify diagnostic and prognostic biomarkers of interest. 3. CAA in animal models of amyloid-beta transmission: We will use inoculation experiments to test our hypothesis that there are different strains of amyloid-beta, and that these strains result in different clinical phenotypes and patterns of disease.","Iatrogenic amyloid-beta cerebral amyloid angiopathy (iCAA) is associated with intracerebral haemorrhage in young patients with a history of procedures involving the head and neck in childhood. We hypothesise that these patients acquired amyloid-beta protein during these procedures, as has been demonstrated in animal models. This is a new and emerging disease with significant potential public health implications. The aim of this programme of research is to further characterise the clinical features and risk factors associated with iCAA, via three feasibility studies: 1. Clinical surveillance in a population at risk of iCAA: We will perform detailed clinical and radiological assessments (including blood tests, neuropsychological testing, electroencephalography, MRI, lumbar puncture) of 10 individuals who received cadaveric human growth hormone prepared using the Hartree-modified Wilhelmi procedure, as preparation for a larger surveillance study. 2. Body fluid biomarkers for iCAA: We will analyse blood and cerebrospinal fluid from 10 patients with known iCAA in order to identify diagnostic and prognostic biomarkers of interest. 3. CAA in animal models of amyloid-beta transmission: We will use inoculation experiments to test our hypothesis that there are different strains of amyloid-beta, and that these strains result in different clinical phenotypes and patterns of disease.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,STROKE HRCS22_15344,Wellcome Trust,,Identification and characterisation of host proteins important for human cytomegalovirus,"During viral infection, the host cell produces proteins that inhibit viral replication, known as antiviral restriction factors (ARFs). The virus can overcome this inhibition by degrading these proteins. Human cytomegalovirus (HCMV) is a herpesvirus that successfully evades the hosts antiviral response and establishes life-long latent infection. I aim to investigate the interaction between host and viral proteins in order to identify factors important for host defense against HCMV infection. I will use proteomics to map the network of virus-host interactions in cells artificially expressing viral proteins. I will perform these experiments in the presence of reagents that inhibit protein degradation to allow detection of proteins that would have been degraded. I will use a flow-cytometry based assay to determine whether any candidate proteins are HCMV restriction factors. novel ARFs identified from this experiment will be characterised by further functional studies. I will also investigate the mechanisms in which HCMV degrades certain host proteins and will explore specifically why these proteins are targeted. These studies will be useful to further our understanding of virus-host interactions during HCMV infection as well as expand our knowledge of viral protein function.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_02269,Medical Research Council,MRC,Identification and characterisation of the molecular components associated with the human erythroid island niche in normal and abnormal erythropoiesis,"The transcription factor KLF1 is essential for the development and maturation of red blood cells (RBCs). A significant number of RBC disorders, including severe cases of anaemia, have been associated with KLF1 mutations. Research to date has focused on the intrinsic role of KFL1 in RBCs but KLF1 is also expressed and plays an extrinsic role in macrophages associated with the erythroid island (EI) niche. We developed a novel in vitro model of the human EI niche using induced pluripotent stem cell derived macrophages and have generated a database of EI-associated KLF1 target genes that encode factors that can promote RBC maturation. We now plan to test secreted and membrane-associated EI factors for their ability to enhance the maturation of RBCs using recombinant proteins and synthetic biotinylated peptides captured in on streptavidin-coated plates. Patients heterozygous for the dominant negative KLF1-E325K mutation present with circulating nucleated cells and a profound anaemia. To determine how KLF1 deficiency in the EI niche contributes to their pathology we will differentiate macrophages from iPSCs carrying a tamoxifen inducible iE325K-ERT2 and iPSCs derived from CDA patients. We will test their ability to support the proliferation and maturation of RBCs and identify factors that are aberrantly expressed within the genetically defective niche using RNA sequencing, comparative proteomics and chromatin immunoprecipitation. Chimeric co-cultures will be used to define the intrinsic and extrinsic effects of the E325K mutation and we will define the erythroid- and macrophage-specific targets of KLF1-E325K. Knock-in and knock-out iPSCs will be generated using CRISPR/CAS9 technology to validate the function of these targets. The characterisation of factors associated with the EI niche will impact on the treatment of anaemia, by identifying novel drug targets and designing optimised protocols for the production of therapeutic RBCs from limitless sources such as iPSCs.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,BLOOD HRCS22_23662,Cancer Research UK,CRUK,Identification and nucleotide resolution mapping of alkyl adducts in human DNA,"Background Carcinogen induced DNA damage is increasingly implicated as a significant contributor to mutational landscape of human tumours and thereby affects cancer risk. We hypothesise that exposure to endogenous alkylating agents (AAs) arising in situ from N-nitrosatable substrates contributes to this landscape by inducing a spectrum of pro-mutagenic alkyl adducts in DNA. However, the alkyl adductome cannot currently be established due to a lack of appropriate analytical methodology. As AAs are known carcinogens, alkyl adductome characterisation will enable their role in human cancer to finally be defined. Aims Our overall aim is to characterise the human alkyl adductome at the genomic and nucleotide level. Specifically, we will develop and apply: 1. ion-mobility (IM) coupled to liquid chromatography-mass spectrometry (LC-MS) to characterise O6-alkylguanines (O6-alkGs) and phosphate triesters (PTEs) in human DNA at the genome level. 2. ChIP-exo-based methods to determine the sequence context of O6-alkG distribution. Methods Oligodeoxyribonucleotides (ODNs) containing O6-alkGs and PTEs with alkyl groups reported to be present in human DNA will be synthesised. These will be incubated with the E. coli ada dual O6-alkG-PTE alkyltransferase (Ada) and transfer of the alkyl groups to the two Ada active sites will be detected and quantified, following protease digestion, by IM-LC-MS. Alkylated active site peptides (ASPs) will be obtained through chemical synthesis and a data repository developed. Human DNA will then be incubated with Ada and the alkylated ASPs analysed enabling the alkyl DNA adductome to be extensively defined at the whole genome level. O6-alkG binding at the nucleotide level will employ ChIP-exonuclease-based methods. Temozolomide-treated DNA will be digested with SauIIIa1 and incubated with Atl1 to isolate O6-alkG containing fragments. These will be further digested with a) lambda exonuclease and processed for next generation sequencing and b) lambda exonuclease and exonuclease I to generate Atl1 footprints for pentanucleotide library hybridation sequencing analyses. To validate these methods, MGMT-expressing T98G glioma cells will be incubated with temozolomide with or without the MGMT inhibitor, lomeguatrib, and the nucleotide distribution of O6-alkGs determined at the gene and nucleotide levels. How the results of this research will be used This work will help to provide a more comprehensive picture of the alkyl adductome and will address a fundamental deficit in our understanding of how AA exposure increases mutational and cancer risk. Development of these high throughput biomarker methods will inform cancer risk and prevention strategies at the individual and population levels","Background Carcinogen induced DNA damage is increasingly implicated as a significant contributor to mutational landscape of human tumours and thereby affects cancer risk. We hypothesise that exposure to endogenous alkylating agents (AAs) arising in situ from N-nitrosatable substrates contributes to this landscape by inducing a spectrum of pro-mutagenic alkyl adducts in DNA. However, the alkyl adductome cannot currently be established due to a lack of appropriate analytical methodology. As AAs are known carcinogens, alkyl adductome characterisation will enable their role in human cancer to finally be defined. Aims Our overall aim is to characterise the human alkyl adductome at the genomic and nucleotide level. Specifically, we will develop and apply: 1. ion-mobility (IM) coupled to liquid chromatography-mass spectrometry (LC-MS) to characterise O6-alkylguanines (O6-alkGs) and phosphate triesters (PTEs) in human DNA at the genome level. 2. ChIP-exo-based methods to determine the sequence context of O6-alkG distribution. Methods Oligodeoxyribonucleotides (ODNs) containing O6-alkGs and PTEs with alkyl groups reported to be present in human DNA will be synthesised. These will be incubated with the E. coli ada dual O6-alkG-PTE alkyltransferase (Ada) and transfer of the alkyl groups to the two Ada active sites will be detected and quantified, following protease digestion, by IM-LC-MS. Alkylated active site peptides (ASPs) will be obtained through chemical synthesis and a data repository developed. Human DNA will then be incubated with Ada and the alkylated ASPs analysed enabling the alkyl DNA adductome to be extensively defined at the whole genome level. O6-alkG binding at the nucleotide level will employ ChIP-exonuclease-based methods. Temozolomide-treated DNA will be digested with SauIIIa1 and incubated with Atl1 to isolate O6-alkG containing fragments. These will be further digested with a) lambda exonuclease and processed for next generation sequencing and b) lambda exonuclease and exonuclease I to generate Atl1 footprints for pentanucleotide library hybridation sequencing analyses. To validate these methods, MGMT-expressing T98G glioma cells will be incubated with temozolomide with or without the MGMT inhibitor, lomeguatrib, and the nucleotide distribution of O6-alkGs determined at the gene and nucleotide levels. How the results of this research will be used This work will help to provide a more comprehensive picture of the alkyl adductome and will address a fundamental deficit in our understanding of how AA exposure increases mutational and cancer risk. Development of these high throughput biomarker methods will inform cancer risk and prevention strategies at the individual and population levels",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,CANCER AND NEOPLASMS HRCS22_22898,The Academy of Medical Sciences,AMS,Identification of novel druggable targets in canine insulinoma through single-cell transcriptomic analysis,"Aims and objectives: The key aim of this project is to identify novel therapeutic targets in canine insulinoma (INS). I hypothesise that single-cell transcriptomic analysis (scRNA-Seq) will reveal novel druggable targets with the potential to inhibit growth or function of INS, ultimately enabling improvement of treatment modalities for both canine and human INS patients. To achieve this aim, I will pursue the following objectives: 1)Undertake scRNA-Seq on fresh and frozen surgically-excised canine INS, to understand their transcriptomic landscape and to determine whether cryo-archiving of surgical samples is feasible in future studies without data loss. 2)Compare scRNA-Seq of the canine INS cell line canINS to that of surgically-excised canine INS and human INS cell line CM, to understand whether this is an appropriate model. 3)To utilise these data to identify potential novel druggable targets in canine INS. INS is the most common pancreatic neuroendocrine tumour in dogs. Despite current multimodal treatment protocols, the prognosis for INS is poor in 95% of the cases, because primary INS is frequently inoperable and/or micrometastases are present during surgery. This funding will allow me to optimise the scRNA-Seq protocol and workflow to process canine INS patient samples. Optimising cryopreservation holds strong appeal as it will allow me to archive samples more effectively in future, for batch processing. To identify candidate druggable targets, I will select differentially expressed genes with a plausible effect on INS proliferation and progression, for in vitro functional validation experiments and immunohistochemistry on a canine INS tissue microarray.","Dogs and humans can develop a tumour of the pancreas that produces too much insulin, called an ‘insulinoma’. These tumours cause signs such as collapse at exercise and very low blood sugar. Insulinomas are difficult to cure by surgery because they spread to other tissues very commonly, and current drug treatments do not work very effectively. New treatments are needed to improve patient survival. This project will study canine insulinomas using a new technology that allows each cell to be examined individually, to see which genes are turned on and which are turned off. This will allow us to identify which genes are crucially important for survival of insulinoma cells, and then to design new treatments targeted at these genes specifically. We will use tumour tissue which is surplus to diagnostic requirements, taken from pet dogs undergoing surgical removal of insulinomas at the Royal Veterinary College. An important part of this project will also be to understand whether it will be possible in the future to study tumours that have been frozen after surgery. If this is the case, it will greatly improve our ability to collect samples, because they can be frozen on the day of surgery and then studied in batches. We will also be using a technique called tissue culture to grow insulinoma cells in the laboratory, and studying these to see how closely they resemble insulinoma cells in actual tumours. We hope that this work will improve treatment options for both dogs and humans with insulinoma.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_02268,Medical Research Council,MRC,Identification of novel mechanisms of fetal-haemoglobin induction by common genetic variation in patients with sickle cell disease,"Our project aims to dissect quantitative trait loci (QTL) for the variable persistence of fetal haemoglobin (HbF) in patients with sickle cell disease (SCD). The HbF trait is clinically important: its variable expression contributes significantly to differences in disease severity. Our research strategy is three-pronged: starting with genetic fine-mapping in four ethnically-diverse patient populations and a total of >3,000 patients, we will move on to functional studies in primary erythroid cells derived from individuals carrying specific variant haplotypes and will finally focus our observations by investigating human erythroid cells lines where individual genetic variants have been introduced through genome editing. Our main goals are (1) to identify novel molecular mechanisms by which common genetic variants at the HbF QTLs BCL11A and HBS1L-MYB affect pathways for the regulation of HbF; (2) to identify at least two novel causal SNPs driving the set of subloci occupying these QTLs and to weave those and robust sentinel SNPs into a universally-applicable polygenic score for the prediction of fetal haemoglobin and, ultimately, disease severity. (3) Our final goal is to help build research capacity in Africa: our collaborators in Tanzania and Nigeria will not only provide patients cohorts, but will also send trainees (one of them a post doc) to take charge of the genome-wide SNP data created for their patients, building a sustainable resource for future research. The post doc will investigate functional effects of key variants at 2 subloci by testing for changes in transcription factor binding (EMSA, ChIP), chromosome conformation (4C-seq) and gene expression, including HbF production. Novel pathways identified by our work are intended to ultimately lead to the development of affordable treatments of this devastating condition that each year causes thousands of childhood deaths in Sub-Saharan Africa.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,BLOOD HRCS22_15527,Wellcome Trust,,"Identification, characterisation and therapeutic targeting of gene regulatory complexes and networks in leukaemic stem cells.","Transcription factor (TF) networks are cardinally dysregulated in Acute Myeloid Leukaemia (AML), with many of these dysregulated TFs known to have developmental and homeostatic roles in normal haematopoiesis. I will focus on the E-twenty six (ETS) TF Pu.1 that is known to play an important role in myeloid and lymphoid development. Conventionally, Pu.1 is better known as a tumour suppressor during AML development but, more recent studies within the Huntly Lab have suggested an alternative role for Pu.1 in the maintenance of AML. I will be using an Npm1c/Flt3-ITD double-mutant mouse model, which recapitulates AML, to study Pu.1 in relevant leukaemic cell populations. I propose to study Pu.1 using chromatin-related genomic and proteomic techniques and will integrate these with gene expression analyses across normal-, early AML- and late AML-derived cell types. I will then aim to corroborating my findings from murine systems in AML patient samples. An understanding of changes in gene expression and the 3D chromatin structure caused by the binding of PU.1 and/or its interactors will unveil novel mechanisms of transcriptional regulation in the AML setting. Looking into the future, the combination of these experimental approaches may enable the development of therapeutics to specifically target PU.1-associated pathways AML.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_18226,"Alzheimer's Research UK",,Identify and rescue dysfunctional memory processes in mouse models of Alzheimer’s disease,"Cognitive dysfunction comprises a key symptom in AD in humans, it is important to develop a sensitive behavioural paradigm in mice that mimics our everyday experiences and allows characterisation of normal and abnormal memory processes in detail. This will strength the use of genetic mouse models as a vital platform for understanding and developing treatment for Alzheimer’s disease. Our rodent appetitive delayed-matching-to-place task simulates our daily experience of spatial memory updating, provides measurements to dissociate different components of memory processing, and sensitively shows memory decline at an early stage of normal ageing. This project aims to use this task to identify memory dysfunction in a newly developed APP knock-in mice model that overcomes shortcomings in the previous transgenic AD models. It will examine if memory retrieval is impaired in these knock-in mice; it will verify if the impaired function can be rescued by optogenetically reactivating the memory cells or by upregulating neurotransmission through receptors involved in memory retrieval; it will depict the relationship between memory cells and synaptic changes in the AD mice. Together, this project will advance our understanding of what memory processes are critically affected in AD mice and provide new targets for treating the memory impairment.","Cognitive dysfunction comprises a key symptom in AD in humans, it is important to develop a sensitive behavioural paradigm in mice that mimics our everyday experiences and allows characterisation of normal and abnormal memory processes in detail. This will strength the use of genetic mouse models as a vital platform for understanding and developing treatment for Alzheimer’s disease. Our rodent appetitive delayed-matching-to-place task simulates our daily experience of spatial memory updating, provides measurements to dissociate different components of memory processing, and sensitively shows memory decline at an early stage of normal ageing. This project aims to use this task to identify memory dysfunction in a newly developed APP knock-in mice model that overcomes shortcomings in the previous transgenic AD models. It will examine if memory retrieval is impaired in these knock-in mice; it will verify if the impaired function can be rescued by optogenetically reactivating the memory cells or by upregulating neurotransmission through receptors involved in memory retrieval; it will depict the relationship between memory cells and synaptic changes in the AD mice. Together, this project will advance our understanding of what memory processes are critically affected in AD mice and provide new targets for treating the memory impairment.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_06296,Department of Health and Social Care,NIHR,Identifying Cancer Recurrence within Patient Care Pathways across Linked National Clinical Datasets,"For patients having curative surgery or radiotherapy for their cancer, the aim of their treatment is to get rid of the cancer without it coming back several years later. For these patients, cancer recurrence is the single most important outcome of care. Cancer recurrence is a key outcome in research of primary cancer treatments. Also, cancer recurrence is a starting point of research that will help to improve the care and outcomes of patients whose cancer recurs. Treatment options for cancer are increasingly complex and there are growing gaps in evidence on the best treatment combinations. Data on cancer recurrence is needed to address these gaps and to ensure all patients receive the best care._x000D_ _x000D_ Routinely collected digital healthcare data can be used to identify cancer patients but cannot currently be used to detect cancer recurrence. Studies using these types of data, including national clinical audits and studies comparing different treatment options, are therefore unable to use cancer recurrence as an outcome or to study the care and outcomes of patients whose cancer recurs. National clinical data on cancer recurrence is needed to be able to compare treatment options in all patients, not just the selected groups who are included in randomised clinical trials. It would also allow comparisons of treatments that are unlikely to be assessed in randomised clinical trials._x000D_ _x000D_ With more information collected in national clinical datasets, we can build a detailed picture of patient care from diagnosis and treatment, through monitoring, to later investigations and treatments. Patients who are treated with an aim to cure them of their cancer tend to have predictable patterns of care, first with a treatment phase followed by a longer period of regular but less frequent hospital visits for monitoring. If their cancer returns, this will appear in the data as a change in frequency and type of hospital visits, tests and treatments. A group of clinical experts will use evidence from research, clinical guidelines and clinical audit to help to develop clinical rules which will identify cancer recurrence in the data. Sophisticated computer science methods, known as ‘machine learning’, offer alternative ways to detect patterns of care that tell us it is very likely the cancer has recurred. _x000D_ _x000D_ The research will develop methods to identify cancer recurrence for bowel cancer in national clinical datasets, and find out how well the methods work for identifying breast and prostate cancer recurrence. To do this, we will:_x000D_ - Identify the care and outcomes pathways of cancer patients across national clinical datasets with information on: diagnosis, pathology; imaging; chemotherapy; radiotherapy; surgery; hospital attendances; and dates and causes of death._x000D_ - Split this data into a development dataset to be used to develop cancer recurrence indicators and a validation dataset to check how well these indicators work._x000D_ - Develop methods to identify if and when bowel cancer has recurred in the development dataset using clinical rule-based approaches and machine learning methods. _x000D_ - Test the validity of the different indicators in the validation dataset using clinical expert adjudication for a sub-set of patients. Use this to recommend the best indicator._x000D_ - Demonstrate the use of the indicator for bowel cancer recurrence._x000D_ - Test how well the indicator works for identifying breast and prostate cancer recurrence.","Background:_x000D_ Information on cancer recurrence is not available in routine national clinical data, preventing important cancer research from being carried out in population-based studies. Providing this outcome would allow researchers and analysts to estimate the risk of recurrence for different groups of patients, to provide much needed evidence on the best combinations of treatments, and to evaluate the care and outcomes of patients whose cancer has recurred._x000D_ _x000D_ Aims and objectives:_x000D_ The aim is to develop and validate methods to phenotype cancer recurrence after curative treatment for bowel cancer in linked national clinical datasets. And to assess how well the methods extend to breast and prostate cancer. Specifically:_x000D_ 1. Construct care and outcomes pathways of cancer patients across datasets, from diagnosis and treatment to subsequent investigations and treatments for recurrence_x000D_ 2. Develop four indicators of the presence and timing of bowel cancer recurrence, one using clinical rule-based methods, one using statistical modelling and two using machine learning (ML) methods _x000D_ 3. Validate the four indicators, including using clinical adjudication for a subset of patients_x000D_ 4. Demonstrate the clinical use of the optimal indicator for bowel cancer_x000D_ 5. Assess how well the optimal indicator extends to breast and prostate cancer_x000D_ _x000D_ Methods and timeline:_x000D_ WP1 (pre-start to month 3) Construct the diagnostic, care and outcomes pathways of cancer patients across national Cancer Registration data, Cancer Waiting Times, administrative, imaging, chemotherapy, radiotherapy and mortality data._x000D_ WP2 (months 2-10): Develop a clinical rule-based indicator for bowel cancer recurrence: starting with a forward searching step using pre-defined sets of codes; enhanced by a backward-searching step to identify additional common coding patterns missed by the forward searching step; and applying a final iteration of the clinical expert review to these additional codes._x000D_ WP3 (months 6-14): Use unsupervised ML methods to identify clusters of bowel cancer patients with distinct patterns of types and timings of healthcare activity and classify each cluster as indicating recurrence or not. Use statistical modelling and supervised ML methods to identify patterns of diagnoses and healthcare activity that accurately predict that the cancer has recurred, using any signal from the data across the entire care pathway._x000D_ WP4 (months 12-18): Validate the indicators, including using clinical adjudication for a subset of patients. Recommend the optimal indicator._x000D_ WP5 (months 19-27): Demonstrate the clinical use of the optimal indicator for bowel cancer._x000D_ WP6 (months 28-34): Assess how well the optimal indicator extends to breast and prostate cancer._x000D_ Dissemination (months 32-36). _x000D_ _x000D_ Dissemination and impact:_x000D_ Algorithms and methods will be published in full in peer reviewed articles and in online data science repositories, and publicised through stakeholders on the steering committee. The research will accelerate improvements in cancer services by enabling (amongst others): _x000D_ 1. Prediction of prognosis to better inform patients_x000D_ 2. Evidence on the optimum modalities of cancer care_x000D_ 3. Conduct of clinical trials (by identifying patients with recurrence for inclusion in trials and providing recurrence as an outcome measure)_x000D_ 4. Service evaluation and feedback to care providers for quality improvement_x000D_ 5. Discovery of aetiological factors and novel cancer treatment targets",8.1 ORGANISATION AND DELIVERY OF SERVICES,CANCER AND NEOPLASMS HRCS22_06995,Health Education England,HEE,Identifying and understanding risk factors for instability and adverse events associated with chest physiotherapy in ventilated children: A mixed methods study.,"Background Paediatric intensive care units (PICU) support the complex medical needs of children with life threatening conditions. There are 20000 admissions annually within the United Kingdom (UK). Chest physiotherapy (CPT) is considered an integral part of care for these patients and national standards report that PICUs require 24 hour access to physiotherapy. Despite the role of CPT being widely acknowledged the overall clinical impact is unknown. CPT has been associated with instability and adverse events. Significant fluctuations in stability can contribute to organ failure or lung damage, with the potential to lead to a prolonged PICU admission or even death. At present the risks and benefits of CPT in ventilated children are unknown. It is therefore important to identify which patients are likely to benefit most and in which situations CPT may present a significant risk. Aim To identify and understand the risk factors for physiological instability and adverse events associated with chest physiotherapy in ventilated children. Objectives To describe current chest physiotherapy practice in UK paediatric intensive care units. To gain an in-depth understanding of the decision making processes used by physiotherapists and perceived risk factors for instability and adverse events. To quantitatively assess the physiological instability and adverse events associated with CPT and identify risk factors that predict instability. To evaluate if physiological instability associated with CPT is related to poorer long-term PICU outcomes.Methods This is a convergent parallel mixed methods study, comprising of two work packages which will run concurrently. Work Package 1 This consists of two phases: phase 1 will inform phase 2.Phase 1 - An electronic survey will be sent to physiotherapists working in the 22 UK PICUs. Key survey content will include CPT techniques used, referral criteria, and perceived risk factors. Descriptive analyses will be undertaken for the objective data and thematic analysis used for the open questions. Phase 2 - Semi-structured interviews, with 16-24 physiotherapists, will be used to gain an in-depth understanding of the decision making processes and perceived risk factors for physiological instability and adverse events. Thematic analysis will be used to identify and explore themes. Work Package 2 An observational cohort study will be completed to assess the prevalence of physiological instability and adverse events associated with CPT and identify risk factors that predict instability. Routinely collected physiological outcomes and adverse events will be collected prior to, during and after CPT intervention, using high resolution monitor data and electronic patient records managed in a digital research environment. Data will be collected over one year, providing an approximate sample of 1144. Multilevel analysis will be used to investigate change in the physiological variables and allow risk modelling. Dissemination and anticipated Impact The dissemination strategy includes publications, presentations, and a dissemination event. The study findings have the potential to minimise instability and adverse events associated with CPT, and improve outcomes for the individual patient. Impact will also be through improved consistency of CPT across the NHS. This project will create a new network of PICU physiotherapists, increasing collaboration.","Background Paediatric intensive care units support the complex medical needs of children with life threatening conditions. There are 20000 admissions to paediatric intensive care units each year in the United Kingdom (UK) and 65% require life support through the use of a breathing machine. Chest physiotherapy is considered part of routine care for these patients. The goals of chest physiotherapy are to re-expand the lungs and clear lung secretions, which prevents complications and helps children breathe on their own. National and international standards report that patients on paediatric intensive care units require access to a physiotherapist 24 hours a day.There is a small amount of evidence providing support for the effectiveness of physiotherapy on paediatric intensive care. However in some circumstances chest physiotherapy has been linked with children becoming more unstable, including problems with oxygen levels, heart function and pain. How physiotherapists make decisions and manage the risks of instability and harmful events in children on intensive care has not been studied. Hence there are no guidelines to support these complicated decisions. At present it is not clear which patients are likely to benefit most from chest physiotherapy and in which situations it may present a risk. Aim To identify and understand the risk factors for instability and harmful events which may occur due to chest physiotherapy in children on intensive care. This will inform the development of recommendations for clinical practice. Design and Methods This study will have two work packages, which will run at the same time.Work Package 1 Phase 1 - An electronic survey will be sent to all physiotherapists who work in paediatric intensive care in the UK. Questions will include what chest physiotherapy techniques are used, how patients are referred, and the risk factors assessed and monitored by the physiotherapists.Phase 2 -h; Interviews with 16-24 physiotherapists will take place. We will use the findings from phase 1 to guide the questions. This phase will provide a more in-depth understanding about how physiotherapists make decisions on paediatric intensive care, what they consider as risks, and how these risks are managed. Work Package 2 This part of the study will use health related measures (e.g. oxygen levels, heart rate and blood pressure) to examine the effects of chest physiotherapy and potential risk factors for instability. Routinely collected data from three intensive care units at a specialist children's hospital will be used. No contact with patients or their families will be required, and no change to care will occur. Data from approximately 1000 patients will be collected over one year.Values and measurements will be taken from patient monitors and electronic patient records. These will be recorded before, during and after chest physiotherapy treatment.Patient and Public Involvement In the design phase of this study the parents/carers of children on intensive care were asked where they felt more research was needed. Investigation into everyday procedures was highlighted as being important, with one parent suggesting a focus on 'the effect of treatments; to determine the best results and outcome for the child'.A steering group will be set up at the start of the project and will include parents/carers and relevant medical and nursing staff. They will provide guidance and support for study management and dissemination. Dissemination The results from the study will be shared with families, professionals and other researchers through publications, presentations, a dissemination event, and the use of social media. It is expected that the study findings will provide evidence for clinical decision making and improve the quality of care for children on intensive care.",6.7 PHYSICAL,RESPIRATORY HRCS22_09200,"Chief Scientist Office, Scotland",CSO,Identifying and validating predictive Biomarkers in advanced oEsophageal adenocarcinoma – a springboard to REAListic medicine (BE-REAL).,"Oesophageal adenocarcinoma (OAC) commonly presents at an advanced and thus incurable stage. Within the UK, Scotland has the highest incidence (972 cases/100,000 people in 2017). Chemotherapy is the main treatment, with side effects a significant feature. Side effects reduce quality of life and mean not all patients can receive chemotherapy. There is no accurate way to predict who will get side effects. Despite treatment, most patients will die within 12 months of diagnosis. There are a small group of patients (~10%) with long-term control and therefore improved survival and quality of life. The reason for this is unknown. If a reason for this sensitivity to chemotherapy can be found, it may allow a reduction in chemotherapy dose with subsequent reduction in side effects, improvement in quality of life and treatment of more patients. Previous research suggests the reason may lie in how the cancer repairs itself. I want to investigate this on a bigger scale, using existing samples from a trial in older, frailer patients with OAC. I want to develop a way to predict side effects and identify a test, after diagnosis, to enable a more individual treatment decision that will improve patient quality of life and reduce toxicity",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_17332,Cancer Research UK,CRUK,Identifying autoimmune signatures in patients receiving checkpoint immunotherapy,"Background: Fighting cancer with immunotherapy represents a fundamentally different strategy to other treatment modalities. Its power lies in the ability to tap into the immune system's diverse antigen recognition potential and relax regulatory checkpoints that normally control immune activation. This results in the immune system attacking the tumour. The principle checkpoints that are targeted in cancer immunotherapy (CTLA-4, PD-1) are the very same that we have studied in the context of preventing autoimmunity. It is therefore unsurprising that a significant side-effect of cancer immunotherapy is the emergence of autoimmune adverse events. While some of these are easily treated using anti-inflammatory drugs, with the advent of combination therapy more severe side effects are evident, including the development of chronic conditions with significant patient impact such as autoimmune diabetes. There are presently no reliable ways to tell whether a patient receiving immunotherapy will develop autoimmune side-effects, and up to 40% of patients on combination therapy are forced to discontinue treatment due to adverse reactions. Aim: The aim of our project is to take knowledge of T cell phenotypes obtained from patients with autoimmunity, including patients with CTLA-4 deficiency, and test whether this can be used to predict the development of autoimmune side-effects in cancer patients receiving immunotherapy. A major focus for the work is analysis of follicular helper T cells (Tfh) since we have extensive data suggesting that these T cells are modulated by immune checkpoints, particularly CTLA-4. Methods: Fresh blood samples from 30 patients with advanced melanoma will be analysed at baseline then 3wk, 6wk and 12wk and after combined CTLA-4/PD-1 immunotherapy. Optimised flow cytometry panels will be used to provide detailed immunophenotyping information on peripheral blood cells, serum will be frozen for autoantibody and cytokine analysis and clinical data will be recorded. We will test defined hypotheses based on our expertise in CTLA-4/PD-1 biology and use in vivo models to help us dissect the therapy-induced changes we see. How the results of the research will be used: A major challenge in the field of cancer immunotherapy is distinguishing desirable clinical responses from adverse events at an early stage. Predicting individuals who will benefit and those who may experience life-threatening side-effects is critical. The results will be used to help clinicians to make informed choices about which patients will benefit from continued immunotherapy and which show the hallmarks of burgeoning autoimmunity and might best be served by discontinuing or changing therapy.","Background: Fighting cancer with immunotherapy represents a fundamentally different strategy to other treatment modalities. Its power lies in the ability to tap into the immune system's diverse antigen recognition potential and relax regulatory checkpoints that normally control immune activation. This results in the immune system attacking the tumour. The principle checkpoints that are targeted in cancer immunotherapy (CTLA-4, PD-1) are the very same that we have studied in the context of preventing autoimmunity. It is therefore unsurprising that a significant side-effect of cancer immunotherapy is the emergence of autoimmune adverse events. While some of these are easily treated using anti-inflammatory drugs, with the advent of combination therapy more severe side effects are evident, including the development of chronic conditions with significant patient impact such as autoimmune diabetes. There are presently no reliable ways to tell whether a patient receiving immunotherapy will develop autoimmune side-effects, and up to 40% of patients on combination therapy are forced to discontinue treatment due to adverse reactions. Aim: The aim of our project is to take knowledge of T cell phenotypes obtained from patients with autoimmunity, including patients with CTLA-4 deficiency, and test whether this can be used to predict the development of autoimmune side-effects in cancer patients receiving immunotherapy. A major focus for the work is analysis of follicular helper T cells (Tfh) since we have extensive data suggesting that these T cells are modulated by immune checkpoints, particularly CTLA-4. Methods: Fresh blood samples from 30 patients with advanced melanoma will be analysed at baseline then 3wk, 6wk and 12wk and after combined CTLA-4/PD-1 immunotherapy. Optimised flow cytometry panels will be used to provide detailed immunophenotyping information on peripheral blood cells, serum will be frozen for autoantibody and cytokine analysis and clinical data will be recorded. We will test defined hypotheses based on our expertise in CTLA-4/PD-1 biology and use in vivo models to help us dissect the therapy-induced changes we see. How the results of the research will be used: A major challenge in the field of cancer immunotherapy is distinguishing desirable clinical responses from adverse events at an early stage. Predicting individuals who will benefit and those who may experience life-threatening side-effects is critical. The results will be used to help clinicians to make informed choices about which patients will benefit from continued immunotherapy and which show the hallmarks of burgeoning autoimmunity and might best be served by discontinuing or changing therapy.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);7.1 INDIVIDUAL CARE NEEDS,CANCER AND NEOPLASMS HRCS22_01809,Medical Research Council,MRC,Identifying disease promoting macrophages and tissue-identity in endometriosis,"Endometriosis is a chronic inflammatory condition associated with debilitating pelvic pain and/or infertility that affects 176 million women worldwide. It is defined by the presence of endometrial-like tissue ('lesions') outside the uterus, commonly in the pelvic cavity. Treatments for endometriosis are limited and recurrence rates are high. There is an unmet need for new therapies. Macrophages are present at high densities in lesions and play a vital role in the pathophysiology of endometriosis by regulating lesion growth, vascularisation, neurogenesis and pain generation. In cancers, macrophages with different origins exist side-by-side. 'Tissue-resident' macrophages become educated by the tumour and promote disease whilst infiltrating 'monocyte-derived' macrophages act as innocent bystanders. We do not know if different subsets of macrophages exist in endometriosis, or if a subset promotes disease. Our preliminary data indicates that lesion-resident macrophages have multiple origins e.g. endometrium, peritoneum and circulating monocytes. We also have evidence that significant phenotype heterogeneity exists amongst lesion-resident macrophages. We aim to identify which macrophages drive endometriosis and how the lesion educates 'pro-disease' macrophages using our in-house endometriosis mouse model with validation in patient biopsies. The identification of 'pro-disease' macrophages in endometriosis could inform the design of a therapy targeting pathogenic macrophages whilst leaving those critical for normal tissue function intact. Our objectives are to: 1. Determine phenotype diversity amongst endometriosis macrophages using scRNA-Seq 2. Use lineage tracing to determine ontogeny and fate of lesion-resident macrophages 3. Use targeted depletion strategies combined with imaging of lesions to determine which population drives disease 4. Identify lesion 'tissue-identity' signals required for macrophage recruitment/ differentiation using antibody arrays",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_06788,Department of Health and Social Care,NIHR,"Identifying multi-agency, trauma-informed and integrated solutions for unmet need of individuals experiencing homelessness in Northumberland and North Tyneside","People experiencing homelessness are disproportionately affected by social vulnerabilities, substance use, mental ill-health, and trauma – Northumberland and North Tyneside have identified them as an exceptionally vulnerable population. These individuals frequently present at hospital Emergency Departments (ED), often not requiring acute hospitalisation, which reflects their underlying complex social issues. They often receive fragmented support across health, social care, housing, and criminal justice systems, adding to difficulty accessing support when needed. Our study aims to identify multi-agency trauma-informed solutions to support the social and health vulnerabilities and mental health needs of homeless people in Northumberland and North Tyneside. This will enable these individuals to have timely and holistic cross-sectoral support, ultimately improving their mental well-being. Objectives are to: 1. develop a profile of underlying needs for individuals experiencing homelessness presenting at the ED in Northumberland and North Tyneside 2. develop a robust system-wide multi-agency pathway, which recognises trauma and complex needs for this population and provides holistic wraparound support from social and health care, voluntary and statutory partners 3. explore the feasibility, acceptability, and requirements for adopting trauma-informed approaches within the multi-agency pathway We will undertake case study analysis, service mapping, and interviews/ focus groups with people affected by homelessness and service providers across different sectors, followed by co-developing a multi-agency pathway (work-packages 1-3). Feasibility of adopting trauma-informed approaches, including trauma-informed training across the pathway, will be examined in work-packages 4-5. Solutions and pathways from this project will then be applied and evaluated in larger studies with other rural and coastal regions. Our team comprises social and health care, mental health, Local Authority, Citizens Advice, police, voluntary sector and people with experience of homelessness. This partnership will ensure real-world and meaningful outputs for all partners, including populations affected. This co-produced working enhances the potential for implementation and reduces time to impact .","Individuals affected by homelessness have very poor mental health. Rural and coastal areas like Northumberland and North Tyneside have increasing numbers of people facing homelessness. These individuals often attend hospital emergency, and have complex problems, such as poverty, unemployment, housing problems, and domestic violence. A major problem is that support for these problems is not always joined-up making it harder to get mental health and social support needed. Our aim is to find ways to provide joined-up support for people experiencing homelessness in Northumberland and North Tyneside. This support will mean that these individuals receive the right support at the right time from relevant services, and ultimately have better mental well-being. Partners on this project from social care, health, mental health, Citizens Advice, housing, police, and people experiencing homelessness have expressed that this support is much-need in Northumberland and North Tyneside. We have, therefore, come together to carry out this research. We will speak to people affected by homelessness, different health and social care professionals and charities. This will help understand the best way of providing joined-up support. We will also find out how an understanding of traumatic experiences can be included in the support that is provided to people affected by homelessness. People experiencing homelessness will be involved in all aspects of this research. Their contributions will ensure that the research is meaningful and that the voice of neglected groups is heard. The findings will be promoted widely through those in health and social care and the wider public. Our research will contribute to wider plans for improving mental health in North East England. The joined-up support model we develop together in this research can be applied and tested further in larger studies including other rural and coastal areas in the country, which are affected by similar issues.",7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_03161,Medical Research Council,MRC,Identifying neuroprotective mechanisms against DNA damage accrual in aging and neurodegeneration,"The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Genomic instability (GIN) is an important feature of neurodegeneration and a hallmark of neuronal ageing (1), that if averted could lead to prevention, delay or reversal of GIN-related neurodegenerative disease, thus representing an important therapeutic avenue. Most mature neurons are non-replicative cells that need to live for 80+ years and all this time require the ability to deal with exogenous (e.g. chronic ionizing radiations(2, 3)) and endogenous (e.g. metabolic by-products; reactive oxygen species: ROS(4, 5)) factors that create DNA-damage (6). These injuries can range from simple nicks or R-loops following defective transcription to highly toxic double-strand DNA breaks (DSBs) caused by factors such as ROS and other metabolic by-products (7) that can cause breakage of the DNA. In mature neurons these lesions are counteracted by the DNA-damage response (DDR) via yet not very well-defined mechanisms (6, 8). It is proposed that failure to impede GIN formation and/or execute DNA repair will cause cell cycle re-entry, chronic inflammation, premature senescence, aggregation of proteins or cell death, processes that would lead to initiation of diverse neuropathology including loss/degeneration of motor or cognitive functions (1, 9-12). Hence, accumulation of GIN throughout healthy life represents one of the hallmarks of neurodegeneration (13) and numerous neurodegenerative diseases including Huntington’s Disease (HD), Parkinson Disease (PD)(5,14) and Alzheimer’s Disease (AD)(15), bear hallmarks of GIN build-up. Although GIN is probably a central player in neurodegeneration either in specific pathologies or aging, to date there is no comprehensive understanding of the cause-effect relationship nor there is any approved therapy to combat neurodegeneration via maintenance of genomic stability (6). On the other hand it needs to be noted that because at molecular/GIN level there is a strong negative correlation between cancer and neurodegeneration (16), finding the specific feed-back loops that are common can allow the repurposing of cancer drugs for neuropathology (8). The overall AIM of the Balmus Laboratory at UK-DRI will be to identify the genetic factors and the specific endogenous lesions involved in GIN-related neurodegeneration in mature neurons and how these molecular processes contribute to neurodegenerative disease (i.e. death via cell cycle re-entry) such as PD or AD as well as aging. Moreover, by finding genetic factors that can modify the accumulation of GIN and thus control neuronal homeostasis we aim to find the intervention points (biomarkers and druggable targets) that can protect human mature neurons from GIN built-up and thus achieve protection, delay or reversal of neurodegeneration.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_01867,Medical Research Council,MRC,Identifying novel neuro-computational treatment targets for mood instability,"Our mood could be the single most important determinant of life satisfaction, affecting all areas of our functioning and the actions we take in daily life. Clinically, mood instability is a highly debilitating feature of many psychiatric disorders, especially bipolar disorder, and is linked to risky and often harmful behaviours. This year, a commission for improving psychological treatments urged a return to basic mechanistic processes, which historically yielded many significant advances in evidence-based treatment but have unfortunately been largely ignored in recent research and treatment. The computational psychiatry approach is a promising and rigorous means of recapitulating symptoms into cognitive, behavioural and neurobiological processes. I will use this interdisciplinary approach to characterise the two-way relationship between mood instability and decision-making in bipolar disorder. Specifically, I will test a recent neuro-computational model in which elevated mood leads potential rewards to be perceived as bigger than they are, potentially leading to risk-taking behavior and further escalation in mood. I will use experimental tasks that manipulate mood states and model the resulting impact of mood on behaviour. By remotely deploying these tasks through a smartphone app, I will test whether model parameters from these tasks can track the trajectory of patients' mood instability in daily life. I will combine lab- and smartphone-based measures of mood instability with functional MRI to characterise the neural circuits that mediate the mood bias on reward perception. Finally, testing the translational potential of this approach, I will evaluate whether this mood-on-reward-perception bias and fluctuations in the underlying neural signals can be reduced by mood regulation strategies. Taken together, this work will deliver a refined mechanistic understanding of mood instability that will provide a direct pathway for novel psychological intervention",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",MENTAL HEALTH HRCS22_02393,Medical Research Council,MRC,Identifying the genetic architecture of brain health and disease in the presence of heterogeneity and multi-morbidity,"Alzheimer's disease and other forms of dementia are known to be highly complex conditions; phenotypes vary substantially across individuals, the majority of individuals have multiple chronic health conditions, and a wide range of genetic and lifestyle factors have been implicated in disease risk. However, the contribution and interaction of different mechanisms to produce distinct forms of Alzheimer's disease is not well understood. A complete understanding of how genetics, multi-morbidity and lifestyle factors give rise to heterogeneity in disease phenotype is crucial for developing targeted multi-faceted treatments and lifestyle interventions, as well as for identifying who they will benefit. In this fellowship I propose to develop new statistical approaches that can identify clusters of individuals with common disease trajectories and characterise how genetic factors and co-morbidities alter disease progression patterns. I propose to develop methods that can provide improved statistical power for detecting associations by (i) using machine-learning to bring together subjects at different disease stages to characterise heterogeneous trajectories across the full disease time course, enabling early stage subjects to be assigned to a subgroup trajectory; (ii) developing techniques that can cluster imaging, genetic and multi-morbidity information, particularly by jointly leveraging the structure of genetic and phenotypic information in combination. I will apply these techniques to provide new insights into variability in trajectories of the two most common forms of dementia, Alzheimer's disease and Parkinson's disease, and aging, which is the biggest risk factor for dementia and a key confound to distinguishing dementia at early disease stages. I will then test whether these imaging genetics profiles of health and disease can be used to screen for Alzheimer's disease and Parkinson's disease in population studies.",,2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),NEUROLOGICAL HRCS22_19000,Wellcome Trust,,Imaging and activation of glymphatic clearance: a novel strategy for Alzheimer’s Disease,"There is a critical need for early and accurate biomarkers of the pre-symptomatic phase of Alzheimer's disease (AD), to maximise the efficacy of emerging therapies. Recent evidence implicates cerebral glymphatic exchange as a key mechanism in early AD pathogenesis [Figure 1] [1-4]. I will develop the first non-invasive method for the quantitative assessment of glymphatic clearance, using MRI. These novel methods will be carefully validated by comparison with the invasive measures [5], that I have previously established, in normal, aged and AQP4 null mice. I will apply these novel techniques longitudinally to mouse models of ageing and AD (amyloid and tau) to investigate impairment of glymphatic clearance relative to more established markers of AD pathogenesis such as structural imaging, perfusion and histological assessment of plaque/tangle burden. As such, these data will be the first to elucidate the chronology of abnormal glymphatic clearance in AD pathogenesis. Finally, I will combine these methods with targeted optogenetics to assess the interaction of vessel tone and vasomotion to rates of glymphatic clearance in order to characterise the underlying mechanisms that drive CSF-ISF exchange.","Alzheimer’s disease is a devastating illness that causes severe memory loss. Despite the huge social, economic and emotional burden of the condition, there is currently no cure. The development of effective treatments is hindered by the difficulty of accurately identifying the early phase of the disease, years before symptoms become apparent. Recent evidence has come to light, from experiments performed in the rodent brain, of a previously unrecognised “waste removal” system that clears excess fluid and toxins from the brain. It is thought that impairment of this pathway, known as the “glymphatic” system, may be a critical causal factor in the development of Alzheimer’s disease. However, currently this pathway cannot be measured in humans. I will develop the first non-invasive method to image the glymphatic system using MRI, enabling assessment in the human brain for the first time. This method will be used to better understand how impairment of the glymphatic system contributes to Alzheimer’s disease and how this may be affected by the changes in properties of the brain blood vessels. Taken together, this proposal may lead to a new method for early detection of Alzheimer’s disease and identify a new target for effective drug treatment .",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,NEUROLOGICAL HRCS22_15320,Wellcome Trust,,Immune Sexual Dimorphism in HIV-1 Infection,"A HIV positive mother is almost two-fold more likely to transmit her infection to a female foetus than a male in-utero. Females have two X-chromosomes which encode several immunological factors. Usually the second is silenced but some genes escape this and are more highly expressed in females. One example is TLR7, a sensor for interferon (IFN), our strongest innate antiviral response. Preliminary data supports the hypothesis that the female immune system, through greater IFN production, selects for IFN-resistant HIV viruses that replicate with lower capacity than IFN-sensitive viruses, which we propose are transmitted to males. Placental macrophages, Hofbauer cells (HC) express all required receptors for HIV infection and sit at the interface of maternal and foetal blood. We propose they are involved in in-utero HIV transmission and differ between female and male foetuses to explain sex discordance in in-utero HIV susceptibility.  We plan to investigate IFN-resistance and viral replicative capacity of HIV transmitted heterosexually between adults, then ascertain whether HC’s differ in HIV-susceptibility between female and male placentae. By attributing IFN and/or HC a role in the reduced male in-utero HIV susceptibility relative to females, we will explain how HIV crosses the placenta and can start working to prevent it.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_01211,Medical Research Council,MRC,Immunology of Digestive Disease,"Goals To define mechanisms of innate immune sensing, how defects in these processes lead to inflammation and how pathogens usurp detection by innate sensors. The HIV-1 accessory gene nef is a key HIV-1 pathogenicity factor. Our previous work showed that Nef increases the replicative capacity of HIV-1 in CD4+ T cells by triggering a signalling pathway mimicing CD4+ T cell activation with anti-CD3, and inducing key host cell factors required for viral replication (1). Proteomic analysis of CD4+ T cell signalling compartments showed that Nef positively regulates signalling by interfering with ubiquination and destruction of key CD4+ T cell signalling molecules and inhibiting Cbl activity (2). Mucosal DCs are the first cells encountered by HIV-1. They continuously sample environmental material and generate signals that determine either maintenance of immunological tolerance or activation of an adaptive immune response. Internalization of HIV-1 into DCs is mediated by dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), important in dissemination of HIV-1 infection. To investigate the suggestion that pathogens can subvert DC-SIGN functions to avoid immune recognition we studied the signalling pathway activated by DC-SIGN triggering and showed that the signalling cascade involves activation of Rho via the guanine nucleotide exchange factor (GEF) leukaemia associated Rho GEF (LARG), important for enhancing infectious synapse formation (3). LARG has since been shown to be an essential factor for HIV-1 replication. The chronic gastrointestinal illness Crohn’s disease (CD) is thought to be due to a breakdown in immune tolerance to commensal bacteria in patients with a certain genetic background. The strongest associated CD susceptibility gene is NOD2, a cytosolic recognition receptor controlling immunity against intracellular bacteria and the inflammatory response, expressed exclusively in the monocyte lineage cells, intestinal epithelial cells and Paneth cells. We have shown that NOD2 senses intracellular bacteria and links with the antigen presentation machinery in DCs, can induce autophagy in these cells in concert with another CD susceptibility gene, ATG161L1, and is necessary for bacterial handling of MHC class II antigen presentation by human DCs. DC in CD patients are autophagy induction defective and have defects in MHC class II antigen presentation and bacterial destruction. These defects could result in abnormal clearance of bacterial components and trigger mucosal inflammation. For the first time we linked two of the strongest CD susceptibility genes within a single functional pathway (4). Most recently we have found that DCs in CD patients fail to induce miR-29 in response to NOD2 stimulation, and so do not downregulate IL-23 adequately at the end of an immune response (5). Future research plans Future work will concentrate on characterizing: (a) the function of NOD2 in relation to other PRRs and its role in intestinal epithelial cells and Paneth cells; (b) the mechanism of NOD2 mediated autophagy; (c) how post-translational modifications in microbes alter PRR sensing; (d) mechanisms of nucleic acid sensing in DCs and their implication for DC function; and on (e) genomic and chemical library screening of pathways, such as xenophagy, that are dysregulated in CD to define druggable targets. References: (1) Simmons et al. 2001 Immunity 14:763 (2) Simmons et al. 2005 Immunity 23:621 (3) Hodges et al. 2007 Nature Immunol 8: 569 (4) Cooney et al. 2010 Nature Med 16: 90 (5) Brain et al. 2010 Autophagy 3: 412.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_18748,Wellcome Trust,,Immunometabolic cross-talk in the inflamed diabetic heart,"Diabetic cardiomyopathy (dbCM) is a complication of type II diabetes (T2D), characterised by systemic inflammation, impaired cardiac function and disrupted metabolism. However, the impact of systemic inflammation on the development of the myocardial inflammation and cardiac metabolic derangement that lead to dbCM remain unknown. This study will address how chronic adaptive inflammation driven by systemic metabolic stress in T2D causes cardiac dysfunction. Specifically, I hypothesise that it is caused by inflammation due to T-cell infiltration and not by direct metabolic perturbations that can lead to impaired energetics (reduced PCr/ATP ratio). Specifically, the aim is to use integrated experimental approach combining metabolic analysis with T-cell phenotypic profiling in murine and human T2D to address three research challenges: A. Does infiltration of cardiotropic T-cells impair cardiac substrate plasticity and energetics in dbCM? B. Do myocardial succinate efflux and signalling via SUCNR1 promote cardiac Teff and/or Treg activation by modifying T-cell metabolism and do they enhance pro-inflammatory T-cell differentiation? C. Does stimulation of GCK-mediated glycolysis increase regulatory T-cell migration to the heart causing a switch in the nature of immune response from pro-inflammatory to immunosuppressive? Does the resultant reduction in myocardial exposure to pro-inflammatory cytokines improve cardiac function and mitochondrial performance?","While the exact causes of diabetes are still not fully understood, the link between obesity and type-2-diabetes (T2D) is firmly established.Progression of T2D disrupts the supply of energy to the heart causing it to fail. Obesity triggers changes to the body’s metabolism including fat tissue releasing fat molecules into the blood and activating type of immune cells called T-cells.T-cells migrate causing inflammation in many parts of the body.Within heart cells, the energy from food is released by cell components called mitochondria.Problems with mitochondria contribute to  T2D but what initiates them is unknown.I will examine whether T cells cause heart inflammation in T2D and whether this leads to faulty mitochondria and shortage of energy supply.Currently, there is no treatment to improve heart energy supply in T2D.I propose to develop a new metabolic therapy to prevent destruction of energy supply to the heart by reducing the recruitment of  inflammation-causing T-cells in T2D.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE;CARDIOVASCULAR HRCS22_01863,Medical Research Council,MRC,Immunotherapy and clear cell ovarian cancer,"Clear cell ovarian cancer (CCOC) displays a chemo-resistant phenotype and patients with advanced disease have a poor overall survival. Four of five patients with advanced, heavily pre-treated CCOC had a complete or partial response following treatment with drugs inhibiting the PD-1 checkpoint however the mechanism behind the anti-tumour response is unknown. In several other cancer types the frequency and location of immune cells in the tumour microenvironment, as well as the levels of overexpression of PD-1/PD-L1 either on the cancer cell or tumour, influence response to checkpoint blockade. Immune related gene expression signatures (irGES) can also predict response to treatment in certain tumour types. This proposal has three aims. First we will undertake a comprehensive analysis of the immune landscape of advanced CCOC biopsies using immunohistochemistry with Definiens digital analysis as well as mass cytometry to profile the quantity of the major populations of immune cells alongside their spatial arrangement. We will also detail their irGES at baseline via nanoString. Second, we will use this information to validate the immune landscape of a mouse model of CCOC using the same techniques above and performing a cross species analysis of the results. Third, we will assess how anti-PD1 therapy changes the immune ecosystem using the techniques described above in samples taken from the mouse model following treatment with anti-PD-1 therapy and in samples from a clinical trial that will provide baseline and on-treat biopsies from patients. These aims will enable us to achieve our overall objective of understanding the mechanism behind response and resistance to anti-PD1 in CCOC in order to devise treatment plans that will improve response rates and duration of response in patients.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_15666,Wellcome Trust,,"Impact of a pea-rich diet on the human gut microbiome, metabolomic profile and gut barrier function","The gut microbiota has a profound impact on host physiology affecting overall health through the fermentation of carbohydrates such as plant polysaccharides (Thursby and Juge, 2017 474:1823). However, little is known about the impact of pulses on the gut microbial metabolism. Previous work at JIC showed that pea mutations in the gene encoding for galactinol—sucrose galactosyltransferase resulted in changes in myoinositol, galactinol and raffinose metabolites in the seeds. This may influence gut microbiota structure and function, where major gut symbionts such as Ruminococcus gnavus can metabolize raffinose family oligosaccharides (RFO) as shown at QIB (Cervera-Tison et al, 2012 78:7720, Lafond et al. 2020 11:579521).Nonetheless, RFO have been associated with discomfort when intestinal fermentation occurs. We want to understand whether the changes  in RFO content in the seeds of pea mutants beneficially affect human gut barrier function and immunity. For this, pea mutants will be characterised and metabolic effects of these mutants will be determined on the faecal microbiota. Finally, functional assays using human-based organoids will be used to assess gut barrier function and immune response.The expected impact of this multidisciplinary work is to select a pea candidate mutant line that could be used for future human intervention studies.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,ORAL AND GASTROINTESTINAL HRCS22_19055,Cancer Research UK,CRUK,Impact of chemotherapy on anti-cancer immunity in molecularly-stratified subgroups of colorectal cancer- Supported by the Bobby Moore Fund,"Background Adjuvant chemotherapy improves overall survival (OS) in only 3-4% of stage II and 15-20% of stage III colorectal cancer (CRC). Thus, biomarkers are urgently needed to select patients who should be given adjuvant chemotherapy; this has become even more relevant given our recent data which suggest that a subgroup of stage II/III patients defined by microsatellite instability (MSI) status and high expression of the immune checkpoint regulator PD-L1 derive no benefit and may even be harmed by 5FU-based chemotherapy. The median OS for advanced disease (stage IV) patients is currently less than 30 months, and 5-year OS rates are 6%. The recent success of cancer immunotherapy in a number of cancer has demonstrated the clinical effectiveness of reactivating anti-tumour immune responses, but so far, immunotherapies have only demonstrated activity in the small subset (~4%) of stage IV CRC patients with MSI disease. Aims and Methods Combining chemotherapy with immunomodulatory drugs is widely recognised as having great therapeutic potential in a range of cancers, and many clinical trials are underway. The challenge of realising the potential of such approaches in CRC is to understand the immunomodulatory effects of chemotherapy in specific molecular subgroups so that rational combinations with immune-oncology (IO) agents can be implemented in selected patient populations. In this programme, we will use clinically relevant disease models and integrative multi-omics analyses of colorectal tumours to explore the following main aims: 1. Validate that the PD-L1(high) subgroup of early stage CRC represents a distinct clinical subgroup that fails to benefit from 5FU-based chemotherapy that may instead benefit from anti-PD-L1 immunotherapy. 2. Investigate the impact of 5FU-based chemotherapy on tumour-intrinsic immunomodulatory signalling in specific molecular and genetic subgroups of CRC. 3. Assess the impact of epigenetic modifying agents (EMAs) such as HDAC inhibitors on tumour cell death and anti-tumour immunity when used alone and in combination with chemotherapy in molecularly-defined CRC. 4. Determine the efficacy of using IO agents such as PD-L1 in a targeted manner to exploit the immunomodulatory effects induced by chemotherapy and EMAs in molecularly-defined subsets of CRC. How the results of this research will be used The overall goals of this programme are to identify immunomodulatory signals/biomarkers in CRC that are constitutively expressed and/or induced in clinically important genetic contexts by chemotherapeutic agents and explore the potential of using epigenetic and immunomodulatory therapies in combination with standard chemotherapy in these specific molecular subgroups.",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_02244,Medical Research Council,MRC,Impact of socioeconomic circumstances on risks and life-course consequences of preterm birth: studies into differential exposure and susceptibility,"Aims To identify the causal pathways from maternal socioeconomic status to preterm birth. To explain and quantify the interaction between preterm birth and socioeconomic conditions on later life health and educational inequalities. To evaluate the potential effectiveness of policy or intervention on reducing inequalities in preterm birth prevalence and health and educational outcomes in later life. Three research questions have been identified: 1- How do key exposures, such as maternal health and behaviours, mediate the pathway from maternal socioeconomic status to preterm birth? 2- How does preterm birth influence the relationship between maternal socioeconomic status and adolescent outcomes for health and education? 3- What is the effect of interventions to improve birth outcomes, and outcomes for children born preterm, on later life inequalities associated with socioeconomic circumstances? Methods Secondary analysis of data sources: Millennium Cohort Study (MCS) and the Welsh SAIL databank. The MCS is a birth cohort of almost 19,000 children born in the UK in 2000/01. The SAIL databank is a collection of anonymously linked data across Wales, including birth extracts, health data from primary and secondary care, and educational data. Analysis will be through causal mediation analysis, fourfold decomposition analysis to separate mediated and interactive effects, and simulation of intervention effects. Outcomes will be measured using mortality and morbidity measures (e.g. ICD10 diagnosis), healthcare usage and exam results at Key Stage 3, GCSE and A-Level. Scientific and Medical Opportunities Results will be used to inform policymakers, and Obstetric and Paediatric clinicians of potential intervention points to reduce preterm birth burden, and identify a particularly at risk cohort of children who are currently not supported by policy or intervention in the UK. The results will demonstrate the potential benefits of intervention on later life outcomes.",,2.4 SURVEILLANCE AND DISTRIBUTION,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_02103,Medical Research Council,MRC,Improved diagnostics in food allergy (ID-in-FA) Study,"AIM To determine the diagnostic accuracy of two complementary, novel approaches to diagnose food allergy, in a representative clinical cohort. BACKGROUND Food allergy is an increasing public health issue affecting up to 6% of UK children, and can cause life-threatening anaphylaxis. Conventional tests assess the presence of allergen-specific IgE (""sensitisation"") rather than true clinical reactivity, and are associated with a false positive rate of over 50%. This results in over-diagnosis, causing unnecessary dietary/social restrictions and anxiety. Improved diagnostics which can be performed in the outpatient setting are thus an important goal. METHODS We will recruit children with indeterminate allergic status despite conventional testing, recruited from our specialist clinic and undergoing open, oral food challenge (FC) to clarify a diagnosis of food allergy to peanut, egg or cow's milk. Skin prick testing, blood tests (incl. components) will be performed immediately prior to oral FC, together with: 1. Intranasal food challenge - a straightforward procedure in which low doses of food protein are administered into the nasal mucosa, causing a mild hay fever-like response in allergic but not non-allergic individuals. 2. Mast cell activation test (MAT) - in which patient sera are incubated with primary human mast cells and subsequently stimulated by allergen in vitro: pilot data indicates this is a robust test, with excellent diagnostic performance. The results of these tests will be compared to conventional tests, using Receiver Operating Characteristic curve analysis (with oral FC as the gold standard). TRANSLATIONAL CAPABILITY Pilot data indicates both techniques confer significant diagnostic accuracy over existing conventional testing. This study will provide the necessary validation to secure follow-on translational funding and commercial investment, to accelerate product development through to regulatory approvals and ultimately clinical use.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_01702,Medical Research Council,MRC,Improving Mental Health Literacy Among Young People aged 12-15 years in Indonesia: IMPeTUs,"Depression is the leading cause of disease burden in low-to-middle income countries. The World Health Organisation has engaged in a programme of scaling-up mental health services, but significant challenges remain. Improving mental health literacy in children and young people, a core part of recent, global health strategies has the potential to address some of these challenges. The aim of this study is to co-develop and feasibility test, a culturally-appropriate toolkit to promote depression-focused mental health literacy and self-management skills in Indonesia, for children aged 12-15 years. This mixed methods study will comprise four phases. Phase 1 (a systematic review of peer reviewed studies and grey literature) will identify the range of approaches to mental health literacy and depression self-management and critically review current evidence regarding intervention effect. Phase 2 will comprise semi-structured interviews with key stakeholders including policy makers, clinicians, teachers, adolescent service users, carers and young people aged 12-15 years to explore their views on depression and identify priorities for the intervention. Photo elicitation methods will be incorporated into interviews with children and young people. Phase 3 will comprise iterative workshops with local stakeholders to present our findings and co-produce a testable, culturally appropriate toolkit to promote mental health literacy and depression focused self-management in 12-15 year olds in Java, Indonesia. In phase 4, we will undertake nine in-depth case studies to compare three different implementation pathways (ie. schools, CAMHS services and primary care centres) in three geographically different areas in terms of levels of culture, urbanisation and health service development (Jakarta, Bogor and Magelang). We will examine the impact, acceptability and feasibility of our prototype intervention and produce evidence-based guidelines for wider implementation.",,5.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_18484,Wellcome Trust,,Improving Teacher Retention,"To fund a partnership with EEF to deliver a funding scheme with supporting activities that is intended to support the development and testing of interventions aimed at improving the retention of science teachers in secondary schools. The aims of the Programme are to: a) build an evidence base on the most effective ways of improving science teacher retention, ensuring any findings are shared across the country, and particularly in areas of disadvantage; and b) ensure the results of this work are accessible to policymakers and practitioners.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,GENERIC HEALTH RELEVANCE HRCS22_18668,Cancer Research UK,CRUK,"Improving cancer prevention, risk-stratification, and detection using large-scale prospective studies in diverse populations - Studentships","Background We have established, in China and the UK, some of the world’s largest prospective cohort studies. Their size, maturity, differing exposure patterns and ranges, and availability of genetic and biomarker data, provide an unprecedented opportunity to further advance our knowledge about causes of cancer in diverse populations, leading to improved strategies for prevention, early-detection and management. Aims Building on previously funded work, we aim to bring together the Million Women Study (MWS) and China Kadoorie Biobank (CKB), along with UK Biobank (UKB), to: (i) investigate the causal relevance of major modifiable risk factors (e.g. infections, adiposity, physical activity and diet) for cancers and important subtypes, and explore potential mechanisms and gene-environment interactions; (ii) assess the role of pre-existing morbidity in cancer incidence and detection; (iii) quantify breast cancer risks associated with clinical factors and develop risk stratification tools for breast and other cancers; (iv) assess the feasibility of large-scale recruitment and blood collection into a new MWS sub-cohort for validation of novel methods for early detection of cancer. Methods The MWS and CKB include more than 1.3 and 0.5 million participants, and, by 2023, will have ~200,000 and ~40,000 incident cancers. Integrated analyses in both cohorts, and in UKB, will utilise the vast array of exposures, many similarly recorded across studies, and well-phenotyped outcomes with unprecedented power to analyse cancers of unmet need (totalling e.g. 8000 oesophageal, 9000 pancreatic, and 7000 liver cancers). Evidence for mechanisms and causality will be assessed using available multi-omic biomarker and genetic data. In CKB, associations with 16 infectious pathogens will be examined in a case-cohort study of ~30,000 cancers and ~10,000 controls. In the MWS, the predictive value of breast density and other features will be investigated using ~500,000 mammographic images. Modelling of the joint effects of risk factors will provide estimates of absolute risk for specific subtypes of breast (ER-positive, triple-negative), and other cancers. Pilot studies of blood collection methods, and estimation of response rates, will inform protocol development and a future funding application for the proposed MWS sub-cohort of ~200,000 women. How the results of this research will be used Our findings will inform global cancer prevention strategies, elucidate mechanisms, and enable identification of individuals who may benefit from targeted screening and preventive interventions. The new data collections will represent valuable resources for data sharing and future studies of machine-learning based predictors, omics-based biomarkers, and validation of early diagnostic tests.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),CANCER AND NEOPLASMS HRCS22_06169,Department of Health and Social Care,NIHR,Improving diagnosis and rehabilitation of visual perception problems after stroke,"BACKGROUND Of the 100,000 people a year in the UK who suffer a stroke, up to 76% are left with visual perception problems. These problems are distinct from sensory vision like reduced visual fields or reduced visual acuity and, instead are related to difficulties in interpreting the images from the eye such as needed for object recognition, reading, or eye-hand coordination. Due to a lack of systematic screening with time-consuming standardised tests, an estimated 75% of patients with these visual perception problems are not diagnosed and guidelines on rehabilitation are limited. Patients therefore do not receive the rehabilitation they need. I have developed a practical screening tool for visual perception problems that can be used to systematically screen all stroke survivors. AIM I aim to transform my prototype screening tool into a functional, comprehensive tool and identify the most appropriate rehabilitation methods. In this way, I hope to create a practical, operational package for everyday use in the NHS. OBJECTIVES, METHODS, DELIVERABLES AND TIMELINE Objective 1 is to update images of three tasks of my prototype (months 1-9). I will establish the normal range of scores on tasks with the new images in an online observational study with 80 healthy volunteers. This work package will deliver 12 updated pictures for the screening tool. Objective 2 is to evaluate reliability and diagnostic accuracy of my screening tool (months 6-39). To achieve this, 109 stroke survivors will complete the new screening tool (twice), a gold standard visual perception test and tests for cognition (e.g. language, memory) and sensory vision. This work package will deliver measures of test-retest reliability, sensitivity and specificity, convergent and discriminant validity. Objective 3 is to develop rehabilitation recommendations as a follow-up pathway for my screening tool. I will update an ongoing evidence synthesis of interventions (months 12-18) and involve six nominated international experts to develop recommendations (months 18-30). Next, I will discuss feasibility/acceptability with stakeholders (clinicians, patients, behaviour change scientists) (months 21-30). This work package will deliver rehabilitation recommendations for each visual perceptual problem that my screening tool screens for. ANTICIPATED IMPACTMy research will increase awareness amongst researchers and clinicians about the assessment and rehabilitation options for visual perceptual problems after stroke. Furthermore, my tool can become the new gold standard for assessment of visual perception problems after stroke. With my screening tool, non-specialist clinicians would be able to screen stroke survivors for visual perception problems in 15 minutes. The rehabilitation recommendations would make it truly unique and desirable for clinicians. It would give them a tool set to deliver best-practice rehabilitation. These measures can have life-changing impact for patients. They would increase a patient's independence and self-esteem. Even without treatment, a clear diagnosis can offer reassurance and reduce anxiety. DISSEMINATION TO STAKEHOLDERS Clinicians: professional development opportunities, updated leaflets with professional bodies, presentation at regional and national meetings, UK Stroke Forum and social media engagement. Patients: lay summaries on my website and engagement with patients' groups (e.g. Stroke Association, Clinical Research Network Stroke Patient and Carer Panel).","BACKGROUND Stroke is a common and life-threatening condition. Almost 8 in 10 stroke survivors have visual perception problems such as difficulties with recognising objects or faces. These problems hinder stroke survivors in doing everyday tasks like driving, sending a text message or meeting friends. The available screening tools for visual perception problems are time-consuming. Therefore, clinicians most often have to rely on what patients report and on their own observations. Unfortunately, many problems are missed that way. Diagnosis and rehabilitation of visual perception problems are in the top 5 research priorities set by patients and clinicians. Rehabilitation can include training (e.g. online reading training), adaptations to the environment (e.g. remove distractions), or coping strategies (e.g. use memory or other senses). Different vision problems need different rehabilitation approaches and it is important to ensure that the most appropriate rehabilitation is offered to patients for their condition. The newest rehabilitation approaches are not yet known to all clinicians and are therefore not offered to all patients. A screening tool for visual perception problems is the first critical step to resolve the problem. Next, up-to-date recommendations for rehabilitation are essential. I have already developed a novel screening tool for visual perception problems. It has tasks such as naming pictures, recognising faces, and reading text. To my knowledge, my screening tool is the only one that is quick to administer, making it suitable for use in busy clinical settings and that is based on recent scientific insights on how the brain works. AIM I will now test if my screening tool gives similar results to the current best practice test (that is accurate but time-consuming). I will also develop recommendations for rehabilitation. In the long term, this will allow clinicians to quickly screen for visual perception problems after stroke and provide each patient with the best possible rehabilitation. These measures should have life-changing impact and enable stroke survivors to live independently for longer. DESIGN AND METHODS Screening tool I will investigate how well my screening tool can identify stroke survivors with visual perceptual difficulties compared to the current best practice visual perception test. I will also research if we get similar test results when administering the test to the same patients on two occasions. Rehabilitation recommendations I will review the literature on rehabilitation and consult clinical experts (e.g. occupational therapists, psychologists) and stroke survivors through structured brainstorming sessions. I will use this information to inform development of recommendations for rehabilitation that are effective and acceptable. PATIENT, CARER, AND PUBLIC INVOLVEMENT Ten stroke survivors, carers and members of the public have been involved in designing this research proposal. They gave feedback on which research questions to prioritise, how to make sure that the research procedures were acceptable to participants and how patients could be involved in the future. During the fellowship, I will meet with the Stroke Patient and Carer Panel North East and North Cumbria to ask their advice on patient information sheets, recruitment, the acceptability of research procedures, and sharing research findings. I also plan to involve two stroke survivors as a members of my steering committee, which will oversee the project, and as members of the panel that decides on which rehabilitation to recommend. DISSEMINATION I will share my results with clinicians at professional development opportunities organised by professional bodies for occupational therapists, psychologists, and the UK Stroke Forum. I will share my results with stroke survivors and their carers through my contacts with the Stroke Association, radio stations for visually impaired, Stroke Patient and Carer Panels, Stroke4Carers.org, lay summaries on my website, and through social media.",7.1 INDIVIDUAL CARE NEEDS,STROKE;EYE HRCS22_02614,Medical Research Council,MRC,Improving early detection and diagnosis of breast cancer among multi-ethnic rural communities in Malaysia - implementation of the CENP,"Phase 1 will involve conducting an evidence synthesis of studies about community navigation programmes. The views of community advocates and stakeholder groups will be elicited via focus groups with women from different socioeconomic backgrounds and ethnic groups in rural areas of Segamat and individual interviews with key informants. Phase 2 will involve co-designing a culturally sensitive CENP, the selection of navigators and the development of training modules and health education materials. Phase 3 will test the appropriateness and acceptability of the new programme via FGs. Phase 4 will conduct a comparative evaluation in Segamat district which has 11 sub-districts, 5 of which provide data for the SEACO platform. The 5 sub-districts are approximately similar in terms of socio-demographic profile and health service profile. One intervention sub-district and two comparator sub-districts will be chosen randomly from the 5 rural sub-districts. SEACO completes an annual enumeration and multiple population-wide health surveys in these sub-districts. A sample of 466 at the 'intervention sub-district' and 466 at each 'comparator sub-district' will be drawn randomly from SEACO data to participate in the evaluation. A sample size of 1400 will allow 80% power to detect, as statistically significant at the 5% level, an increase of 8% or more in the proportion aware of a breast cancer symptom in the CENP site compared with comparator sites after the intervention (based upon baseline awareness of a breast lump as a cancer symptom of 65% from our previous Newton-funded study). The sample size of 1400 will also allow 80% power to detect an absolute increase in the proportion of women who visit a doctor in the 6 months following CENP of 8% in the CENP site compared with comparator sites. Phase 5 activities will involve dissemination and writing joined-up policy and practice briefs for the Ministry of Rural Development and the Ministry of Health.",,8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),CANCER AND NEOPLASMS HRCS22_02228,Medical Research Council,MRC,Improving empiric antibiotic prescribing by applying a Bayesian decision theory approach to phenotypic and genomic resistance data.,"The aim of this project is to provide a Baysian predictive tool that can be used by clinicians to decide on the best empiric choice of antimicrobial (AM) in a variety of clinical scenarios. The basis of this model will be phenotypic antimicrobial resistance (AMR), patient outcome, and whole genome sequence data for bloodstream infections. Severn pathology lab and Winpath LIMS serves 3 NHS trusts generating about 2000 Gram-negative isolates per year from blood cultures with associated AMR and outcome data. We will collect up to 1000 of these isolates. Using the data extracted from LIMS, clinical, biochemical and microbiological data can be associated with each sample's unique identifier. These isolates will be sent in batches for WGS to the MicrobesNG facility in University of Birmingham. We will receive monthly data report on blood cultures sent from hospitals sharing Winpath LIMS. We will use the data within the R statistics environment to apply a Bayesian predictive modelling approach with Bayesian network decision theory to our local phenotypic AMR data. We will derive predictive probabilities for resistance and outcomes by assessing the extent of correlations at multiple levels: a) to derive estimates of co-resistance between AMs; b) to model correlations with metadata; c) to understand temporal effects on the model. Following collection of the WGS data and completion of the initial model we will compare our predictive model to our genomic data and integrate these results into our final model. This will be piloted at University Hospitals Bristol NHS Foundation Trust to assess and improve usability in a real-world context..",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,INFECTION HRCS22_05072,Department of Health and Social Care,NIHR,Improving experiences of severe stigmatising skin diseases in Ghana and Ethiopia,"Research question What community and health facility strategies will improve experiences of severe stigmatising skin diseases (SSSDs) in Ethiopia and Ghana? Background SSSDs are a significant cause of disabling physical and psychological morbidity, disproportionately affecting impoverished and marginalised communities in low and middle-income countries. Most are communicable but despite established, effective antimicrobial therapies remain intractable public health problems. Early diagnosis and treatment reduce disability, but many individuals are diagnosed late. Explanations include low awareness in at-risk populations (including health systems), and inaccessibility and prohibitive costs of healthcare. Individuals often seek treatment from traditional practitioners. When diagnosed, prolonged (and sometimes painful) treatment and management makes adherence challenging. These problems are compounded by stigma and discrimination. In our work, we will focus on leprosy, yaws, Buruli ulcer (BU) and cutaneous leishmaniasis (CL), all have been identified as priority diseases in our study countries, Ghana and Ethiopia. To align with WHO strategy we take an integrated approach to SSSDs. Aims and Objectives We aim to improve outcomes for people with SSSDs by strengthening the care cascade through scalable strategies for earlier detection, improving management to reduce disability and counteracting stigma. This will be achieved through a series of linked studies in Ghana and Ethiopia addressing the following objectives: (1) to evaluate integrated community-based strategies for early diagnosis, adherence support and stigma reduction; (2) to undertake facility-based trials of dressings for BU; (3) to develop clinical and patient reported outcome measures for CL; (4) to promote collaboration and build research capacity in Ghana and Ethiopia. Methods In both Ghana and Ethiopia, we will develop and evaluate complex interventions for early case detection, diagnosis, improving treatment adherence and addressing stigma using the MRC framework of: (i) comprehensive formative research to develop a community of practice, (ii) intervention development using co-creative approaches, (iii) piloting, followed by (iv) impact evaluation, including health economic and detailed process evaluation. Combined, this process will take 42 months. In Ghana, we will address the specific challenge of delayed wound healing in BU by conducting a multicentre randomised controlled trial to compare Dialkylcarbamoyl chloride-coated dressings with Vaseline-gauze dressings. We will determine rates of healing at 16 weeks, and secondary infection. Improved dressings for BU may allow wound care to be undertaken in a community setting minimising impact on the individual and their family. In Ethiopia we will assess the utility of suggested clinical and patient centred outcomes for individuals with CL. We will develop a clinical severity measure to assess disease activity and determine the frequency and severity of adverse effects in a prospective cohort of patients with parasitological confirmed CL. Anticipated Impact and Dissemination Our interconnected studies will strengthen the care cascade and contribute to better health outcomes for patients and communities, and we anticipate rapid meaningful impact. Our interventions will further benefit other SSSDs and skin health generally, and results will translate to other endemic regions. We will involve affected individuals, community organisations, programme partners and health care agencies in the development of the work and share all outputs openly.","Aims We aim to improve outcomes for individuals with leprosy, yaws, Buruli ulcer and cutaneous leishmaniasis which are very severe, infectious skin diseases that stigmatise, disfigure and cause major physical disability, psychological distress and social isolation. Using a group of connected studies in Ethiopia and Ghana we will address major clinical, social and public health challenges associated with these diseases and skin health generally. Background These skin diseases are more common in low and middle-income countries. There are major problems with late diagnosis of these diseases, which is exacerbated by a lack of dermatologists and stigma. Adverse outcomes also occur because obtaining and completing effective treatment may be challenging. We need more evidence to help decide which combination of complex treatments work best and which strategies best combat the stigma experienced by affected individuals and their families. Design and methods We will assess approaches- called integrated case finding - to find people with these skin diseases in Ghana and Ethiopia. We will engage with and train a range of people in communities including volunteers, health workers and traditional healers. We will teach community members about the diseases and establish a peer support and stigma reduction programme, having assessed which approach will work best, to improve outcomes for those affected by these conditions. We will conduct studies to optimise the supply chain of drugs and assess whether our group of interventions increases the number of people diagnosed, increases the number completing treatment, improves outcomes and is cost-effective. We will test which wound dressing works best to heal Buruli ulcer in Ghana. We will compare a novel anti-bacterial dressing to the routinely used Vaseline dressing in a multicentre randomised controlled trial. We will determine whether the newer dressing is associated with faster wound healing and a better experience for children and adults. We will examine the economic impact and costs of treatment. We will undertake a study following children and adults with cutaneous leishmaniasis during treatment and for one year afterwards in Ethiopia. This will help us understand how cutaneous leishmaniasis affects patients and the economic impact of the disease. The initial steps will involve focus groups of patient to characterise their experiences, followed by the evaluation of tools to assess treatment outcomes. Community and public involvement This proposal has been developed by building on existing partnerships between researchers and other stakeholders including Ministries of Health, patients and community representatives to ensure relevance and impact. We will continue to involve these groups throughout the programme and dissemination activities. Dissemination We will share findings widely through public engagement activities, academic publications and presentations, policy papers, presenting to World Health Organization and ministries of health and extensive social media campaigns.",6.3 MEDICAL DEVICES;8.1 ORGANISATION AND DELIVERY OF SERVICES;7.1 INDIVIDUAL CARE NEEDS,INFECTION;SKIN HRCS22_02600,Medical Research Council,MRC,Improving haematopoietic reconstitution in blood stem cell transplantation procedures through the regulation of stem cells and their niches,"Haematopoietic stem cell (HSC) transplantation (HSCT) is routinely performed in patients with haematological, genetic or metabolic disorders. Regenerating haematopoiesis after HSCT requires: 1) harvesting sufficient donor HSCs, 2) optimal HSC homing to the bone marrow and 3) expansion and differentiation of donor HSCs in the recipient. However, HSC engraftment efficacy significantly decreases during ageing and in certain haematological diseases, hampering the use of HSCT as a therapeutic option. Among different HSC sources for transplantation, umbilical cord blood (CB) is an ideal source that can be non-invasively harvested, cryopreserved and is associated with reduced risk of disease transmission or acute graft-versus-host disease. However, several CB units are necessary for transplantation and engraftment is delayed. This proposal aims at understanding and modelling the regeneration process following HSCT. The main goal is to identify cell-intrinsic and -extrinsic mechanisms that regulate HSC proliferation and lineage commitment during bone marrow regeneration. Our translational aim is instructing HSC to more efficiently/rapidly/long-lastingly regenerate the haematopoietic and immune systems. We will use xenografts and ectopic bone ossicles to model human HSCT in a humanised niche environment. Human cells will be analysed by 10x scRNA-seq and scATAC-seq to generate a cell-cell communication network between human HSCs and niche cells. Metabolic profiling (glycolysis, OXPHOS, mitochondrial activity, ROS) will be complemented with and Mass Cytometry and imaging studies. Finally, the role and potential of novel regulators of HSC quiescence and emergency haematopoiesis will be tested. The complementary expertise of the four teams in the cellular and molecular heterogeneity of human HSCs, their regulation through inflammatory factors, cellular metabolism and microenvironmental cues could facilitate overcoming current limitations in HSCT.",,5.2 CELLULAR AND GENE THERAPIES,BLOOD HRCS22_05972,Department of Health and Social Care,NIHR,Improving health care burden amongst sepsis survivors by reducing infection-related rehospitalisation,"Background Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host responses to infection. The incidence of critical care (ICU) treated sepsis is increasing while improvements in management have reduced mortality. Every year generates an estimated 60/100,000 population new sepsis survivors in England, who are at risk for impaired health status, hospital readmission, and increased risk of dying in the year following sepsis.Approximately 30% of sepsis survivors have unplanned rehospitalisation within 30 days that increases to 65% by one-year, with two-thirds being infection-related. My PhD studies revealed acute loss of memory lymphocytes in septic patients alongside other features of immunosuppression. Concept These studies explore impaired immune competence as a biological mechanism underpinning infection-related rehospitalisation in sepsis survivors. To the best of my knowledge, this will be the first pilot randomised controlled trial (RCT) that focuses on how the immune system recovers following hospital discharge and uses vaccination as a controlled antigen challenge to augment immune system recovery in sepsis survivors. Aims Aim 1: Investigate the epidemiology of infection-related rehospitalisation to identify predictors, risk factors, pathogens and timing in sepsis survivors A pilot RCT of pneumococcal vaccine in sepsis survivors addresses the aims 2, 3 and 4. Aim 2: ascertains how the innate and adaptive immune systems recover over time in sepsis survivors Aim 3: tests the biological effect of pneumococcal vaccine in sepsis survivors Aim 4: Identify factors that could guide the design of an effective vaccination strategy and inform key outcomes to a necessary degree of precision for designing future definitive RCT in sepsis survivors (feasibility). Plan of investigation Aim 1 will be addressed by retrospective cohort studies using data from the Intensive Care National Audit & Research Centre Case Mix Programme Database linked to the Health & Social Care Information Centre Database. After identifying septic patients who survive their hospitalization and patients who have a subsequent infection related rehospitalisation, I will describe the incidence and timing of infection related re-hospitalization and insure that these are distinguishable from other causes of rehospitalisation. Using sensitivity analyses and matched control populations, I will explore the causal role of sepsis in infection related rehospitalisation. The NIHR Health Informatics Collaborative Critical Care (NHIC) Theme databases will be used to describe pathogens in infection-related rehospitalisation in sepsis survivors. At the completion of aim 1, I will understand the factors that identify sepsis survivors who are at high risk of developing infection and likely to survive one-year, which will form the target population for testing vaccination effects. Aims 2, 3 and 4 are addressed using the double blind and placebo-controlled pilot RCT of pneumococcal vaccine. The sample size to help refine the end points to necessary degree of precision for informing definitive efficacy trial will be used. Both groups will undergo regular blood sampling during one-year follow-up period to assess how vaccination alters leukocyte subsets and their function. Detailed immunological profiling of the placebo group will address Aim 2. Comparisons of immune characteristics between the vaccinated and placebo group answers whether vaccination improves the immune recovery seen in sepsis survivors, which addresses Aim 3. As pilot RCT, implementation issues, potential barriers, event rates, and population averaged treatment effects will be explored, which addresses Aim 4. Potential Patient and NHS benefits If vaccine related memory loss is persistent in sepsis survivors, this will require devising vaccination schedules in these patients. If vaccination reduces infection-related rehospitalisation in sepsis survivors, this could translate into reduced antibiotic use, and better life expectancy. Vaccination is a low-risk and low-cost intervention.","Background Sepsis is a life-threatening dysfunction of the body organs triggered by an infection. This common condition accounts for ~25% of adult intensive care unit (ICU) admissions, with mortality rates of 30-40%. In 2012 sepsis affected approximately 85 cases per 100,000 population in the UK, and this incidence is increasing. Many sepsis survivors have an impaired quality of life and 1-in-6 do not survive one year after their hospital discharge. Sepsis survivors are at much higher risk of infection-related rehospitalisation. Exact reasons are unclear. I recently found that loss of specialized white blood cells responsible for immune memory against common bacteria is commonplace during sepsis. This defect is likely to weaken the body's defences and thus predispose the individual to repeated bouts of infection. Long-term persistence of this defect, persistence of acutely impairment seen in the immune system during sepsis alongside changes in bacterial flora following hospitalisation are potential reasons underlying infection-related rehospitalisation in sepsis survivors. Infection-related rehospitalisations in sepsis survivors create a vicious cycle of deteriorating health and increased health care costs. This project will test a safe, low-cost, and feasible intervention to break this cycle by augmenting recovery of the damaged immune system in sepsis survivors to prevent infection-related rehospitalisations. These studies are designed to understand the salient features of infection-related rehospitalisations and immune system recovery in the year following hospital discharge in sepsis survivors. My project tests two hypotheses. First, that a subgroup of sepsis survivors at particularly high risk for Infection-related rehospitalisations can be identified using routinely collected clinical variables. Second, that vaccination augments recovery of the damaged immune system in sepsis survivors. Aims Aim 1: Investigate the epidemiology of infection-related rehospitalisation to identify predictors, risk factors, pathogens and timing The aims 2, 3 and 4 are addressed by pilot randomised controlled trial (RCT) of pneumococcal vaccine in sepsis survivors. Aim 2: Ascertain how the innate and adaptive immune systems in sepsis survivors recover over time using placebo group samples Aim 3: Test the biological effect of pneumococcal vaccine in sepsis survivors using vaccine group samples Aim 4: Identify factors that could guide the design of an effective vaccination strategy and inform key outcomes to a necessary degree of precision for designing future definitive RCT in sepsis survivors. Design and methods used First aim is addressed by linking the Health and Social Care Information Centre (HSCIC) database to two data sources using admissions between 2009 and 2016: Records from the Intensive Care National Audit and Research Centre database and the NIHR Health Informatics Collaborative Critical Care Theme database. The epidemiology of rehospitalisation episodes including its incidence, timing, and risk factors amongst sepsis survivors will be studied. Common bacteria responsible for infection-related rehospitalisation will also be identified. Comparing characteristics of sepsis survivors to non-sepsis survivors would identify true magnitude of risk for infection-related rehospitalisation due to sepsis. The target population for the pilot RCT will be informed by this study. To the best of my knowledge, this will be the first pilot RCT that focuses on understanding how the immune system recovers in sepsis survivors and whether vaccination helps with recovery. This will inform whether vaccination could be used to reduce infection-related rehospitalisation in a future definitive trial. The intervention arm of the RCT will receive pneumococcal vaccine and there will be a blinded placebo arm. Both groups will undergo regular blood sampling and detailed assessment of immune system changes during one-year follow-up period. Immune changes in the placebo arm will address Aim 2. Comparing immune changes between the vaccinated and placebo arm will inform whether vaccination improves immune function in sepsis survivors (Aim 3). Feasibility and other outcome data will inform future study design (Aim 4). Patient and Public involvement Sepsis survivors have already been involved in discussions in preparation for this grant. I plan to include patients and their carers as members of the project advisory group to inform the trial protocol, help with preparation of patient information leaflets, and consent forms. Dissemination The findings will be disseminated to the public, health care professionals and scientists by publishing in peer-reviewed journals and professional organisation websites (such as ICNARC and the Intensive Care Society), and by discussion with patient support groups (e.g. at UK Sepsis Trust meetings).",2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_06346,Health Education England,HEE,Improving iDEntification of inflammatory ArthritiS (IDEAS) in Primary Care: a multi-disciplinary team approach,"This research aims to address the clinical research question: Can we identify people in the pre-clinical phase of inflammatory arthritis (IA) earlier in primary care? A phase of imminent IA has been demonstrated to precede rheumatoid arthritis (RA) onset. Secondary care models have evolved to predict the early development of RA, even before synovitis is clinically apparent, through anti-CCP antibody testing. Most musculoskeletal complaints first present in primary care. It has been estimated that people who are subsequently diagnosed with RA visit their GPs four times with musculoskeletal complaints, during a nine month period, before being referred to a specialist for their diagnosis and treatment. As a podiatrist I have a specific interest in early identification because 31% of cases of IA are known to have had their first symptoms in their feet. My fellowship will complement existing programmes of research by aiming to improve the early identification of people in the pre-clinical phase of IA through the use of more targeted anti-CCP testing in primary care. Objectives: To develop and preliminary test a model for the early identification of people in the pre-clinical phase of IA in primary care through targeted anti-CCP testing and by a better understanding of presenting musculoskeletal complaints, such as those in the feet To evaluate the cost-effectiveness of improving early identification of people in the pre-clinical phase of IA in primary care To develop, refine and test the feasibility of the 'IDEAS in Primary Care' (IDEAS-PC) modelUsing existing primary care data from the Leeds 'Co-ordinated Programme to Prevent Arthritis' (n4250) multiple binary logistic regression will be used to identify specific joints or joint groups that are associated with increased probability of anti-CCP positivity. To provide temporal validation for the model two sources of external data will be used to investigate presenting symptoms. A care pathway analysis undertaken with clinicians and patients, literature review and data analysis will inform the structure of the cost-effectiveness decision analytical model to estimate the expected costs and QALYs for the current pathway and implementation of the IDEAS-PC model. Relevant theory, evidence synthesis and co-design with clinicians and patients will be used to develop the IDEAS-PC model with training and education materials to support delivery. Feasibility testing of the IDEAS-PC model will be conducted to explore intervention fidelity and acceptability prior to undertaking a pilot study transitioning into a full clinical trial, following on from my SCL. My training programme will act as a vehicle towards my establishment as a clinical academic leader in musculoskeletal healthcare. This fellowship will maximise the use of existing world-class data and infrastructure, as well as develop new collaborations to support the proposed programme of research and the dissemination and implementation of findings. Research aimed at improving identification of people in the pre-clinical phase of IA will lead to better targeted anti-CCP testing and improve early referral to secondary care. The findings from this programme of research will underpin formal testing in a clinical trial beyond the scope of this SCL.","Can we identify people who have rheumatoid arthritis before they get inflammation that damages their joints? Rheumatoid arthritis (RA) is caused by inflammation (swelling) in the joints, generally affecting multiple joints, whereas osteoarthritis normally affects individual joints when overused. People who have RA typically visit their GP four times with musculoskeletal (bone, joint, tendon or muscle) problems before they are referred to a hospital specialist (rheumatologist). As a podiatrist, who looks after foot problems, I know that almost a third of people with RA start with pain in their feet and would like to find out which foot problems occur first. We know that early treatment leads to much better results for patients who have RA. There is an opportunity to identify people who are likely to develop RA before they get swelling in their joints by having a specific blood test (for anti-CCP antibodies) when they complain of new musculoskeletal problems. Unfortunately not everyone can be referred for this test as it is considered too expensive and often GPs don't know when they should be sending patients to be tested. The purpose of this research is to work out whether we can identify people in the very early stages of developing RA when they see their GP. I will look at whether the extra costs of identifying people early saves money for the NHS in the long-term. If it is more expensive, I will work out if people have less problems because they have been referred to see a hospital specialist early. In this study I will: 1) Use research data already collected in Leeds from approximately 4250 people nationwide who saw their GP with a new musculoskeletal problem and had an anti-CCP test. I will work out which musculoskeletal problems occur in the people who are anti-CCP positive and therefore more likely to develop RA. In the people who are anti-CCP positive I will find out specifically what foot problems they had initially. This will help podiatrists recognise those people who should have an anti-CCP test. 2) Work with patients and health professionals to compare what currently happens when a patient sees their GP with a new musculoskeletal problem until they are diagnosed with RA. I will compare this with having the anti-CCP blood test to identify people earlier to see if it saves money and/or means that patients have fewer problems in the long-term. 3) Use research data and the expertise of patients and health professionals to develop a new approach to care and a training package to help health professionals use it in their clinics. It will be tested in 24 GP practices to see if they are able to use it in their normal clinics. Patients will be asked about their experiences of the care they received. People with RA have been actively involved in developing this research. They expressed concern about delay in diagnosis, which was highlighted by one member's comments 'now that I know what the journey was like I would like to have been referred to the consultant sooner'. This research will be developed with patients and health professionals to provide insights into what works. The research team in Leeds are already working with GP practices nationwide, and this will help us share what we find. It will ensure it has the best chance of being used by GPs and other health professionals to identify people in the very early stages of developing RA. The results will also be presented to health professionals at conferences and shared with national charities and patient groups, including Versus Arthritis and the National Rheumatoid Arthritis Society.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_09391,"Public Health Agency, NI",PHA,Improving mental health among at-risk young people in a challenging border region.,"""Northern Ireland has one of the highest rates of mental health problems in Europe with almost 25% of people having reported a mental health disorder in their lifetime. In the North-Western border region (Derry/Donegal), the rates of suicide and depression are particularly high, coincident with socioeconomic deprivation and extremely high unemployment rates among young adults. Many mental health problems emerge before age 18 with the period from 18-25 being a particularly susceptible developmental time in a person’s life and there is growing concern about the high numbers of college students with mental disorders. Colleges are an excellent environment for detecting young people at high risk of mental disorders and applying evidence-based treatment approaches to prevent and treat common mental disorders at an early stage. We currently form an interdisciplinary team (Psychology, Psychiatry, Stratified Medicine, Genetics, Mental Health Charity) conducting the Ulster University Student Wellbeing study and associated analyses. This study commenced in September 2015, as part of the WHO World Mental Health Surveys International College Student Project and has recruited 1600 participants to date. Consistent with other recent studies prevalence rates of lifetime and 12-month mental health and substance disorders, ADHD and suicidality in students were high, with more 50% of new undergraduate students reporting any lifetime disorder (McLafferty et al PLoS ONE, under revision). While 10% of new entry students received treatment for emotional problems in the previous year, 22.3% of students with problems said they would not seek help, indicating a large unmet need. We have also profiled biological markers in saliva samples from students and excitingly, preliminary analyses indicate DNA methylation changes as a potential biomarker for depression (Lapsley et al, in prep). We wish to extend this screening trial to a partner Institution (Letterkenny Institute of Technology) in Donegal to establish rates of depression, other mental illnesses, and biomarker status in the matched population. We also wish to undertake an RCT to provide a treatment which is effective, increases therapy accessibility and availability and overcomes stigmatization worries by maintaining student’s anonymity. The HIT will incorporate a randomised control trial. Participants will be randomized to either a novel cognitive-behavioural and problem-solving therapy developed by our collaborators in The Netherlands (world-leaders in this area), or receive usual care. Impact of the intervention will be assessed by longitudinal follow-up throughout the course of study. The primary psychosocial outcome measure will be presence of depression/anxiety symptoms following the intervention and secondary outcomes will include academic performance, participation/engagement, dropout and presence of mental and physical health disorders. In addition, biological outcomes such as changes in the novel DNA methylation markers we have identified will be assessed. Overall the study aims to extend our screening trial based on our current successful model for recruitment and identification of likely beneficiaries based on psychometric and biological markers, as well as trialling a novel intervention based on the latest developments in cognitive-behavioural approaches, comparing this to a standard treatment model as part of this personalised medicine driven trial.""",,4.4 POPULATION SCREENING;6.4 SURGERY,MENTAL HEALTH HRCS22_13620,Wellcome Trust,,"Improving mental health for marginalised groups at Oxford's Wellcome Centres","This proposal will address the intersection of mental health and Equality, Diversity & Inclusion (EDI) within Oxford’s three Wellcome Centres. Mental health concerns permeate a broad range of challenges relevant to EDI, including social exclusion, chronic illness and disability, and minoritised populations (detailed below) that are disproportionately affected by mental ill-health. By identifying specific mental health challenges that different groups face, we can improve equality. Through normalisation of discussions around mental health in the workplace, and building an appreciation for how these issues affect people differently, we foster inclusion. If we can recruit and retain a broader range of researchers further into their careers, we improve diversity, and therefore our science. An increasingly inclusive, fair and kind research culture will lower the risk of mental ill-health for all our team and staff members within the high-impact but high-pressure academic environment. Our specific objectives are to: (i)  Conduct an in-depth, expert review of mental health as it relates to EDI within our Centre work environments. (ii)  Implement recommendations arising from this review relating to policies, communication and practices. (iii)  Build a broad, cross-Centre programme promoting positive research change around mental health and EDI.",,"8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE;MENTAL HEALTH HRCS22_13500,Cancer Research UK,CRUK,"Improving our understanding of e-cigarette and refill packaging in the UK (E-PACKS): How is it used for product promotion, how is it perceived by consumers, and could it be changed to discourage youth while encouraging adult smokers to quit?","Background: There is limited research on e-cigarette packaging and labelling, particularly in comparison to cigarettes. Few studies have explored how e-cigarette packaging is being used by manufacturers to promote these products, whether the product information on packs complies with current regulations, and consumer perceptions of the warnings and messaging on e-cigarette packs. Aims: The project aim is to determine whether further regulations on e-cigarette packaging are needed in the UK and, if this appears to be the case, provide recommendations to help the UK Government in developing guidelines that help make e-cigarette packaging more appealing to smokers and less appealing to young people and non-smokers. Methods: Two studies will be conducted. The first will be a systematic analysis of e-cigarette packs currently on sale in the UK to document the types of pack design and promotional features used and to assess whether the packaging of e-cigarettes and refills in the UK complies with current regulations. The second study will involve sixteen focus groups in England and Scotland to explore how young people (11-17 year olds) and adults (non-smokers, smokers who do not use e-cigarettes, and smokers who do use e-cigarettes) view e-cigarette packaging, including flavour descriptors and health messaging, and their views on alternative health messages and possible further regulations on e-cigarette packaging. What value will the programme of work deliver? The work will help improve our knowledge of e-cigarette and refill packaging in the UK, including how is it used for product promotion and perceived by consumers. It will also allow an understanding of whether the pack could be used to promote healthier choices among smokers while protecting non-smokers.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,CANCER AND NEOPLASMS HRCS22_03204,Medical Research Council,MRC,Improving sleep and circadian disruption in Dementia,"The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added from 2020. A common symptom for people living with dementia is disturbed sleep. However, there is still little known about whether sleep is just a consequence of dementia, and therefore could be utilised as an indicator of early disease, or a driver in pathogenesis of the disease. Both these explanations may be true but either way, there is a wealth of knowledge still to uncover in this field. This UK DRI programme will validate and develop technology to quantify vigilance states, sleep symptoms and physiology across the 24-hour day (i.e. circadian rhythm). The team will validate the new technologies developed under rigorous sleep lab conditions prior to testing in the home environment. Main objectives and research goals: 1. To validate and implement technology to characterise circadian and sleep disturbances in the home that can be scaled to be used in dementia and its preclinical phase. 2. To develop and validate approaches to integrating sleep and circadian disturbances with other sensor information to predict variation in behavioural and cognitive symptoms, and clinical events such as falls and disease progression. Four parallel research strands will be pursued: 1. Circadian Assessment: The team will validate accelerometers as a low-cost approach to assessing circadian sleep rhythms in order to facilitate their use in the monitoring of large populations and the evaluation of interventions. 2. Home EEG monitoring: The team will evaluate devices capable of prolonged (ideally 24 hours) home EEG recording. Requirements to be met are the accurate assessment of sleep stages (REM and NREM), sleep continuity and EEG features during sleep and wakefulness. 3. Contactless sleep and circadian assessment: In addition to the focus on wearable technology, they will develop passive monitoring for sleep and circadian rhythm that can be scaled independently of patient compliance. They will evaluate passive approaches to sleep assessment using movement sensors attached to beds and sheets, automated video analysis and integration of multi-modal data produced by a ‘Healthy Home system’ including home radar. 4. Technology evaluation: New technology will be evaluated in the Living Home, part of the Clinical Research Building at the University of Surrey.",,"5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES",NEUROLOGICAL HRCS22_06969,Department of Health and Social Care,NIHR,Improving the diagnosis of oesophageal and gastric cancers by system-wide identification and analysis of missed diagnoses of oesophageal and gastric cancers during endoscopy,"Research question Why does endoscopy fail to diagnose upper gastrointestinal cancer and how can we make this a less common occurrence in future? Background Missing oesophageal and gastric cancers at endoscopy and consequent diagnostic delays reduce the chance of cure and survival. Having an endoscopy that does not diagnose cancer but later being found to have oesophageal or gastric cancer is termed post endoscopy upper GI cancer (PEUGIC). This occurs in approximately 8% of people with oesophageal or gastric cancer. Suboptimal endoscopy quality will be one of the main reasons and there is known to be unwarranted variation in endoscopy performance between hospitals. Understanding the reasons for PEUGIC through detailed review of all aspects of the endoscopy and associated clinical care at the hospital where it was undertaken and identifying correctable factors are vital to saving lives from oesophageal and gastric cancer. Aims and objectives Phase 1. Identify all PEUGIC prospectively in the English NHS Phase 2. Develop a secure web-based PEUGIC root cause analysis tool Phase 3. Quantify the reasons why PEUGIC occur at a national level Phase 4. Develop local and national interventions to reduce the occurrence of PEUGIC Methods Linkage of almost real-time Hospital Episode Statistics and National Cancer Registration and Analysis Service databases every quarter to enable identification of people with oesophageal and stomach cancer who had an endoscopy in the previous 6-36 months, where their cancer was not detected (PEUGIC). Based on the current national root cause analysis tool for post colonoscopy colorectal cancer, a proforma will be developed that captures the data items required to undertake a comprehensive root cause analysis of PEUGIC. The system will enable every endoscopy provider to be informed of each PEUGIC soon after the patient is diagnosed with cancer and the need for a root cause analysis, but also facilitate this by providing a structured method to report the results of the root cause analysis. The results will be captured centrally to enable collation and analysis of the reasons for PEUGIC at a national level. This will enable the identification of for example high-risk patient groups or endoscopy practices for PEUGIC.The intelligence generated will then be used to suggest interventions to reduce the incidence of PEUGIC through local and national quality improvement efforts. Timelines for delivery We plan to begin in July 2022 with phases 1 and 2 delivered within a year and phases 3 and 4 in the second year of the project. Anticipated impact and dissemination The project will improve the process of diagnosis of people with oesophageal and gastric cancer and reduce the number of missed diagnostic opportunities. National organisations responsible for endoscopy standards will share the learning from PEUGIC cases with hospitals throughout the UK, in coordination with the research team and press releases. Our PPI partners will contribute to dissemination of the learning through social media and their websites. A summary of the detailed analysis of missed cancer cases will be presented at conferences and published in medical journals to further share learning internationally.","Aims We want to find out why cancer may not be found during endoscopy (flexible telescope examination of the oesophagus (gullet) and stomach), to reduce the risk in future. Background 15,800 people in the UK are diagnosed with oesophageal or stomach cancer annually. Around 8% (approximately 1200 per year) had an endoscopy that did not find their cancer in the three years before diagnosis. This is known as post-endoscopy upper gastrointestinal cancer or missed cancer. Missing cancers is bad, as the earlier they are identified, the more treatable they are and the better the outcome. This research is needed to find out why cancer is missed at endoscopy, tackle differences between hospitals and reduce missed cancers. The second highest endoscopy research priority for the British Society of Gastroenterology is "How can we improve the quality of upper gastrointestinal endoscopy?”. The rate of missed cancer endoscopy is the most important endoscopy quality measure. Design and methods used Developed with the assistance of the Research Design Service. We have experience of using routine NHS data to identify missed cancers that occurred in the past. However, to make a difference to endoscopy now, we need to identify and investigate missed cancers as soon as possible after they occur. This project will: 1. Adapt methods we have used successfully to identify and investigate missed bowel cancers. When a new potentially missed oesophageal or stomach cancer is found, we will tell the hospital who did the endoscopy and ask them to review the records in detail to understand why it was missed (root cause analysis). 2. Pool the results of these detailed analyses of missed cancers nationally to understand the common reasons for cancers being missed. Use these results to get the NHS to take steps to limit missing cancers in future. Patient and public involvement Mimi McCord, chair of Heartburn Cancer UK (co-applicant and co-author of this summary) commented “It is imperative that an accurate diagnosis is achieved at the first endoscopy. Early diagnosis is vital to achieve a good outcome and possible cure with a cancer that has an appalling prognosis.” Heartburn Cancer UK, Action Against Heartburn and the Oxfordshire Oesophageal and Stomach Organisation fully support this project and have contributed to the study design, particularly around, as far as possible, having a “no blame” approach, and being open with patients when cancer is found to be missed. Dissemination National organisations responsible for endoscopy standards will encourage participation through the external approval of endoscopy units and share the learning from missed cancer cases with hospitals throughout the UK. A summary of the detailed analysis of missed cancer cases will be presented at conferences and published in medical journals to further share learning internationally.",7.3 MANAGEMENT AND DECISION MAKING,CANCER AND NEOPLASMS HRCS22_02259,Medical Research Council,MRC,Improving the diet of pregnant women: a mixed methods study,"There are two UK dietary guidelines for pregnant women that aim to minimise ingestion of toxic metals, which flow freely through the placenta to the fetus with adverse effects on neurodevelopment. The guidance is not informed by up-to-date data on dietary intakes and exposure levels, nor has there been any evaluation of the effectiveness of current guidance. A mixed methods observational cohort study of 400 healthy primigravid women will: (1) evaluate understanding of the UK guidance on fish and game/gamebird consumption in pregnant women and midwives; (2) compare dietary intakes with the guidance; (3) measure blood lead and mercury and urine arsenic concentrations; (4) estimate the contribution of diet to the biomarker concentrations. This will be achieved by quantitative assessment of dietary intakes with food-frequency questionnaires at 10- and 28-weeks' gestation and opportunistic blood and urine sampling at the same times through community antenatal clinics. Qualitative interview group studies with pregnant women will enable evaluation of knowledge and impact of the guidance. A questionnaire will be used to establish knowledge of the guidance by midwives, and how and when they disseminate information, with further in-depth data collection through qualitative interview groups. The research will provide an evidence-base for clarification and effective dissemination of dietary guidance related to toxic metals to enable women to make informed choices about their diet with optimisation of the health and development of the baby.",,3.3 NUTRITION AND CHEMOPREVENTION,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_14018,Wellcome Trust,,Improving the outcome of children with congenital athymia.,"Congenital athymia causes life-threatening T-cell immunodeficiency. The only definitive treatment is thymus transplantation (TT). Despite lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus, repopulated by recipient bone marrow-derived lymphoid progenitors, supports functional T-cell development restricted to host MHC alleles. Though lifesaving, TT results in subnormal circulating T-cell numbers and frequent autoimmune complications. I aim to dissect the cellular and molecular mechanisms of lympho-stromal crosstalk and thymopoiesis in the context of MHC-mismatched TT by using single-cell and spatial genomics on pre-transplantation cultured thymic tissue and post-transplantation graft biopsies. Donor thymocytes, possibly including long-lasting lymphoid progenitors, remaining at the time of transplantation despite lympho-depleting preparatory culture, may contribute to this crosstalk and assist thymic epithelial cell (TEC) homeostasis. Other recipient-derived haematopoietic cells may migrate into the graft to replace direct interactions between developing host thymocytes and TECs. Alternatively host TECs may develop in the transplanted thymus. I hypothesise that partial MHC-matching improves crosstalk signalling, achieving better immunoreconstitution and less autoimmunity. Optimising in vitro differentiation and maturation of TECs derived from pluripotent stem cells will make the in-depth investigation of MHC-TCR interactions and downstream signalling possible. New insights into TEC biology will advance alternative approaches to thymus replacement therapy.","The thymus gland produces white blood cells, called T-cells, an essential part of the immune system. Infants born without a thymus (athymia) lack T-cells, are extremely vulnerable to infections and may die. Thymus tissue necessarily removed from otherwise healthy infants during surgery for heart defects can be grown in the laboratory and transplanted into athymic infants. Although the tissue type of these infants is not matched with the thymus they receive, transplanted patients can fight infections and survive. However, T-cell numbers rarely reach normal levels and sometimes these cells mistakenly attack the patient’s own body causing autoimmune complications. This may be due to lack of tissue-type matching. Using new research techniques to investigate how non-matched thymuses can support T-cell development and the mechanisms underlying complications, I aim to gain fundamental insights into thymus functioning, paving the way for the development of alternative treatment approaches to improve patient outcomes.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_05941,Department of Health and Social Care,NIHR,Improving the post-stroke cognitive care pathway,"BACKGROUNDThere is a clear need to improve continuity of care post-stroke, particularly for psychological consequences. Post Stroke Cognitive Impairment (PSCI) is highly prevalent and complex. The prognosis of cognitive recovery or decline remains unclear. Managing cognitive changes post stroke is the most frequently reported unmet need with no support pathway in place. Better diagnosis and monitoring is key to targeting interventions and undertaking high quality research of interventions to improve outcomes for stroke survivors. AIMS & OBJECTIVESThe aims of the fellowship are to predict the likelihood of PSCI at 6-months and long-term post stroke from acute Oxford Cognitive Screen (OCS) to describe the experience and unmet needs of living with cognitive changes post stroke, to use this information to co-design a cognitive care pathway for stroke including clinician training, a cognitive trajectory guide based on acute OCS, enhanced discharge summaries and 3 points of follow up once home. to test the feasibility of the cognitive care pathway intervention.METHODSFirst, a risk prediction model using acute OCS scores will be evaluated. The key initial outcome will be presence of PSCI at 6-months. The model will be developed in OX-CHROINIC cohort data and validated in independent harmonized Individual Patient Data from 3 longitudinal studies from across the UK.Second, qualitative interviews will provide in-depth insight into the patient and carer perspective. This, together with the prediction model will inform the cognitive pathway development. A group of 6 (patients, carers, clinicians, service stakeholders) will follow an iterative, implementation-based co-design approach to develop the pathway and constituting pragmatic elements: (i) training for clinicians, (ii) a cognition trajectory guide, (iii) enhanced transfer of information to primary care and (iv) the cognition reviews once home (1-,3-,6-month) as the core intervention. Finally, two different stroke services will implement the proposed care pathway to determine feasibility and acceptability. Both service-level and patient-level outcome data will be collected pre and post intervention to inform a potential stepped wedge trial design. TIMELINES Year1: Risk prediction model1 + harmonising data + semi structured interviews on PSCI experiences and needsYear2: Continued Interviews + validation of risk prediction in independent harmonised cohortYear3: Working groups iterative co-design of care pathway elementsYear4+5: Feasibility study in 2 different stroke services Anticipated impact and disseminationThe immediate impact for clinical practice lies in delivering an improved post-stroke cognitive pathway including an OCS-based cognitive trajectory guide for discussion. The implementation-based co-design approach will include early conversations with the Integrated Stroke Delivery Networks to ensure it is aligned to the ongoing developments in stroke services. A definitive trial will determine the benefits of the cognitive pathway with additional check-in support for those discharged home with cognitive problems. This would ultimately result in a changed national approach to cognitive care post stroke. There will be multiple routes to dissemination of the research (e.g. publication, conferences, press, training, videos) to academics, clinicians, patients and carers, the stroke community and wider public.","AIMS:1. Improved understanding of changes in peoples' thinking abilities after stroke.2. Improved understanding of peoples' needs and wishes for dealing with their changes in thinking after stroke.3. Design a roadmap which outlines support for people whose thinking is affected by stroke.4. Prepare for a large study to test whether the new roadmap is helpful and practical.BACKGROUNDFor a long time, research and therapy for people affected by stroke have focussed on obvious changes like arm or leg strength and speech. However, more subtle changes of stroke can have a major impact. Commonly after a stroke, people have changes in specific thinking abilities (cognition) related to damage in the brain. These may include difficulties with understanding, reading, writing, remembering, spatial awareness and planning activities. Stroke care aims to repair damaged areas of the brain as soon as possible. However, hospitals focus on urgent medical treatment and must follow this with relatively short amounts of therapy before sending people home. As a result, many stroke patients feel abandoned after hospital because stroke is actually a long-term condition. Instead of being the same as before a stroke, people must adjust to a new life with variable types of brain damage.Sometimes peoples' thinking abilities recover well but for others, changes remain or become worse.The Oxford Cognitive Screen (OCS) was made to quickly test for changes in different aspects of thinking commonly affected by stroke. What is less clear is how this information can help stroke patients understand their condition and clinical teams make decisions about the kind of support people require, both whilst in hospital, and long-term for life after stroke.METHODS (*visual summary in Figure 1) I will combine studies that have assessed (over longer periods) thinking abilities of large groups of people who have had strokes. I will use this to establish whether OCS cognitive profiles can help to give stroke survivors some idea of their futures. I will interview stroke survivors and their families or friends about: What it means to live with post-stroke cognitive changes? Whether and how they want to know about future predictions? What their wants and needs are for long-term support? With a group of stroke survivors, carers and clinicians, we will develop simple tools to discuss changes in thinking, what extra follow up reviews should be like and how information is passed on to GPs. I will test the new pathway in 2 different places in the UK to find out if this approach could work and if there any downsides. I also want to know what the most important things are to measure for a larger studyPEOPLE WITH LIVED EXPERIENCEThis research proposal has been developed with people from the Stroke Voices in Research panel from the Stroke Association. Stroke survivors and their close family have suggested key aspects and reviewed materials. More stroke survivors will be involved in the research itself, in the pathway development, in reviewing study materials, in management of the research and in making the results known.MAKING THE FINDINGS KNOWNTo make findings from this research known, I will: Write academic papers as well as plain language news articles. Support the people who were involved to talk about their experience and the findings of this research. Present our findings to people who have had strokes, the wider public, clinicians and academics. Work closely with the Stroke Association news teams.This plain language summary has been produced in partnership with Bloo Anderson (stroke survivor)",7.1 INDIVIDUAL CARE NEEDS,STROKE HRCS22_06634,Department of Health and Social Care,NIHR,Improving understanding of indications for and timing of surgery in infants with Necrotising Enterocolitis,"What influences surgical decision-making in Necrotising Enterocolitis (NEC) and can routinely available data be used to accurately identify surgical NEC? Background Necrotising enterocolitis (NEC) causes severe bowel inflammation and critical illness in predominantly preterm infants with 1000 cases yearly in the UK.2 Despite intensive care treatment, 25% fail to improve requiring surgery to remove ischaemic bowel. Early identification of infants that would benefit from surgery is challenging but important since delay in surgery may contribute to poor outcomes. About 20% of NEC infants die before surgery.3 Mortality rate following surgery is 35% and, in survivors, 9% remain on parenteral nutrition at 1 year with 59% experiencing neurodevelopmental problems.4 Work I have undertaken demonstrates that a delay to undertaking surgery in NEC is associated with poor outcome.1 I hypothesise that early, accurate identification of neonates with surgical NEC will allow earlier surgical intervention and ultimately improve outcomes. Objectives WS1-Identify previously developed methods for the identification of surgical NEC WS2-Evaluate accuracy of previously reported methods for identification of surgical NEC in a multi-centre dataset WS3-Understand current surgical decision-making in NEC Methods WS1) Systematic review +/- meta-analyses -Months 1-9 Systematic review of methods that identify surgical NEC (preliminary search: 3019 results [PubMed-28/7/21]). Primary outcome will be effectiveness of a method to correctly identify surgical NEC in derivation / validation cohorts. Meta-analysis of effectiveness estimates will be undertaken if appropriate. Results will be incorporated into WS2. WS2) Diagnostic test accuracy study of methods which identify surgical NEC -Months 7-18 Methods identified in WS1 will be evaluated on our existing dataset of routinely collected data extracted from 4 neonatal units (680 infants) (including clinical, laboratory [WCC, CRP, platelets, blood gases] and vital signs [HR, BP]). Reference test is diagnosis of surgical NEC, or death before surgery with confirmed NEC. WS3) Mixed methods study of current practice -h;Months 19-33 i)Survey of all (~250) UK consultant paediatric surgeons with focussed interviews of 25 surgeons to understand current practice around surgical decision-making-h; purposive sampling of survey responses will identify a maximum diversity sub-set of surgeons for interview. Thematic analysis of transcripts will identify relevant themes related to rationale for surgical practice. ii)Prospective observational study of relationship between surgical decision-making and outcomes - to record actual practice a 9-month cohort study (50-75 infants with confirmed NEC in 10 high-volume units) will be undertaken. Semi-structured interviews will be conducted with surgeons about surgical decision-making soon after decisions were made, including babies who did and didn't have surgery. Clinical and outcome data will be obtained with linkage to the National Neonatal Research Database allowing exploration of variations in surgical decision-making and outcomes. Impact and dissemination This research will identify an optimal method to identify surgical NEC, describe current surgical decision-making and enhance our understanding of its association with outcome. Existing data suggest that accurate identification and earlier surgery has genuine potential to improve important life-long outcomes. Results will be co-produced with PPI partners and disseminated across traditional scientific and new media channels aimed at key stakeholders.","Aims of the research Necrotising enterocolitis (NEC) is a devastating disease of the bowel that causes babies to require intensive care treatment with some needing major surgery. Babies who survive NEC have a high incidence of significant long term health problems. I want to understand how surgeons currently decide which babies get surgery and to investigate whether better methods than are currently used can help surgeons identify which babies need surgery and when. Ultimately I aim to use this information to improve outcomes for these babies. Background Necrotising enterocolitis causes severe bowel inflammation resulting in babies becoming critically unwell. It mainly affects premature babies (who can be born as early as 22 weeks) in the first few weeks of life. Around 1000 babies per year in the UK develop NEC. A quarter of babies don't respond to intensive care treatment and require surgery to remove bowel which has died to prevent them from getting sicker. Sadly, about a third of the most unwell babies don't survive. Those that do are often left with significant long-term health problems. These include neurological disability and being left with inadequate bowel to feed normally meaning they require long-term feeding into the vein. NEC is a significant burden to families as well as health resources. Deciding which babies will benefit from surgery is challenging. Surgeons must weigh up the risks and benefits of performing major surgery on a tiny baby in the knowledge that surgery itself may cause harm. This uncertainty causes delays in performing surgery which may contribute to poor outcomes. Work I have undertaken demonstrates a link between later surgery and worse outcomes prompting my aim to explore whether performing surgery earlier may improve outcomes. To do this I need to be able to identify babies who need surgery accurately and earlier than we do at present and understand more about how surgeons determine timing of surgery currently. Design and method To investigate the best way to identify babies who need surgery for NEC and relate those to outcome I will: Identify previously reported methods of identifying babies who need surgery for NEC. This will be done through a detailed review of the existing research in this field. I will then use an existing large database of babies with NEC from 4 neonatal units (680 babies) to test the how good these methods are.I will also undertake work with surgeons to understand how they currently make decisions about surgery in babies with NEC and explore the impact of how decisions were made on clinical outcomes. Understanding how surgeons make decisions and the impact on outcomes is important for implementation of the findings of my research. Patient and public involvementNECUK (the UK family support charity for NEC), along with a parent group, have been fully involved in the conception, development and design of my proposal and strongly agree on its importance. I will meet with them regularly throughout the study to ensure that my work is acceptable and relevant to parents and patients. Representatives from BLISS, the preterm baby charity, will also attend these meetings. Dissemination Results will be disseminated at multidisciplinary meetings, peer-reviewed publication and via charity partners including on the NECUK and BLISS websites. I will give presentations at charity partner meetings alongside traditional scientific presentation and peer-reviewed journal publication, specifically targeting surgeons and neonatologists. Ultimately my findings are likely to inform future research exploring the role of better surgical decision-making in improving outcomes.",6.4 SURGERY;7.3 MANAGEMENT AND DECISION MAKING,ORAL AND GASTROINTESTINAL;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_06443,Department of Health and Social Care,NIHR,Improving violence risk assessment and intervention in first episode psychosis,"Research questionHow can violence risk best be routinely assessed in Early Intervention in Psychosis (EIP) services, and what interventions should be provided for those at higher risk?BackgroundWhilst the majority of patients with severe mental illnesses are never violent, a range of psychiatric diagnoses confer a modestly but significantly increased risk. For psychotic illnesses such as schizophrenia, absolute risks are clinically relevant. Assessing and managing this is a core feature of psychiatric practice. Whilst forensic psychiatry services specialise in this, thresholds for their involvement are extremely high. The majority of frontline risk assessment is undertaken by general services.This is particularly relevant to EIP services. These community teams promote recovery in patients experiencing a first episode of psychosis- a high risk phase of illness for violence. Predicting who is at higher risk of future violence is challenging. Furthermore, whilst there are some promising approaches to violence reduction, evidence in psychiatric populations is limited. Better assessment of violence risk to guide allocation of individualised, evidence-based non-harmful interventions at this unique time-point is essential to reduce violent outcomes.A number of tools exist to structure risk assessment; however none are practically amenable to settings such as EIP services. Clinicians instead rely on unstructured clinical judgement. A simple, free tool (OxMIV) has been developed that offers both practicality of use and favourable performance. This could be an invaluable adjunct to clinical judgement in EIP services. The prediction model has been validated in Swedish patient registries, but more work is needed to understand its performance in UK populations and role in clinical practice. By analysing changes in practice brought about when patients are identified as high risk with OxMIV, clearer interventions for violence reduction can be developed and tested.Aims and objectivesThis project aims to (1) externally validate OxMIV's performance in patients presenting to EIP services, (2) qualitatively evaluate and refine its clinical use, and (3) model its impact including beginning to develop interventions to link it to.MethodsOffline evaluation using clinical documentation will test predictive accuracy compared to assessment as usual without impacting clinician behaviour, allowing for re-calibration. Qualitative methodology will establish consensus on the role of OxMIV in the clinical pathway. Experiences of first use by patients and clinicians will be explored including acceptability and feasibility. Informed by these stages, the tool will be used prospectively in clinical practice. As well as violent outcome data, changes in practice will be modelled in detail.Anticipated impact and disseminationBy evaluating OxMIV in this staged manner, this project will both potentially provide a clinically validated tool whose role in clinical work is well understood, and provide an evaluation framework applicable to other areas of psychiatry. It will also start to develop a complex intervention for violence risk reduction that can be tested on a larger scale. Improving the approach to violence risk in EIP services will benefit patients, services and wider society. Results will be disseminated through engaging patient groups and online, and be published in high-impact peer-reviewed medical journals.","BackgroundSchizophrenia and other 'psychoses' are severe mental illnesses which can profoundly affect how you feel, think and act. Receiving early specialist treatment can help increase the chances of making a full recovery and leading a fulfilling life. Community mental health teams called 'Early Intervention in Psychosis' (EIP) services help people with the first signs of psychotic illness recover.The majority of people that suffer with this type of illness never act violently, and only a small fraction of all violent crime is committed by people with severe mental illness. However, developing a psychotic illness does increase your chances of behaving violently for complex reasons. There are certain 'risk factors' that might increase the chances of this happening, such as if you have behaved violently previously or also have difficulties with drug use.One thing EIP services have to assess therefore is whether a patient might, due to having some of these risk factors, be at risk of behaving violently. Importantly this can guide what help someone might need to reduce the risk. Prediction can be difficult though. There are some tools to structure risk assessment, but these need lots of resource so are unhelpful for EIP services.Researchers have now developed a simpler tool,'OxMIV'. It uses information that is routinely asked about to estimate violence risk. One potential role for this is to support clinicians in EIP services. It has so far been tested using data about patients in Sweden. More work is needed to see if it is helpful in the UK and in clinical practice.As well as being difficult to assess, it is often unclear what should be done to reduce risks. Some approaches are probably helpful, like treating symptoms and reducing substance use, but evidence is limited. One way to improve this is to look in detail at what happens when clinicians use a tool such as OxMIV. By understanding what changes are made when someone is assessed as higher risk, we can develop clearer treatment options and test what helps. Aims of project- Test the accuracy of the 'OxMIV' tool in patients under EIP services. - Understand the challenges of using the tool in practice, and develop the best way to do so. - Observe the impact when the tool is brought into practice.Design and methodsThe tool must first be tested for accuracy in this new group of patients without changing clinician behaviour. Clinical documentation will be used to make a prediction with the tool and check for violent incidents. OxMIV will be compared to the judgement the clinician made at the time to see whether the tool would have helped, or if it needs adjusting.'Qualitative' methods will be employed to plan how the tool might best be used and to trial this with a sample of patients and clinicians, exploring experiences and problems through group discussions, interviews and surveys.The tool will then be introduced into an EIP service. Accuracy will be tested and changes in treatment modelled.Patient and public involvementPatient and family experience and views on the tool are integral to the project. Patients will be directly involved in the qualitative aspects of the study. One key aspect of the work is the acceptability of the tool for patients, and their experience of how clinicians share and discuss violence risk. DisseminationThe results of the study will be published in medical journals. They will be fed back to patient groups locally and nationally through the Royal College of Psychiatrists and charities. They will also be shared with the public in a variety of online formats.",2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),MENTAL HEALTH HRCS22_13964,Versus Arthritis,,In vivo assessment of PEP-GAG hydrogels for spinal disc repair,"We propose to examine the in vivo safety and efficacy of a novel hybrid hydrogel as a treatment for low back pain (Figure 1). There are over 10 million people in the UK who have persistent back pain. Low back pain is strongly associated with degeneration of the intervertebral discs, the soft tissues between the vertebrae that enable articulation. During the degeneration process, there is a loss of glycosaminoglycans (GAGs) from the proteoglycan-rich gel in the nucleus of the disc, which reduces its swelling pressure and adversely alters biomechanical performance [1]. Current surgical treatments for disc degeneration are highly invasive and have low long-term success rates. One promising alternative is ‘nucleus augmentation’, that is, the injection of a biomaterial into the nucleus to restore its height and function. Although some materials have been proposed for this purpose, there has not yet been widespread clinical uptake of this technology, partly due to reported complications such as implant extrusion [2], as well as the documented risk that large-bore needle puncture causes further damage and reduction in biomechanical performance of the disc [3]. A new versatile family of self-assembling peptides has been de novo designed at the University of Leeds to self-assemble into nanostructured networks in consistent and reproducible manners [4]. Previous work in our group has found that a peptide-glycosaminoglycan (PEP-GAG) hybrid hydrogel could have potential as a nucleus augmentation material, with the ability to form a gel in situ, allowing injection as a liquid through very fine gauge needles [5]. Formulations of the PEP-GAG hydrogel have been tested and optimised using novel in vitro methods developed by our group [6]. The outcomes of these studies have demonstrated that the PEP-GAG hydrogels can mimic the behaviour of the heathy nucleus pulposus, both in terms of its mechanical properties and its ability to draw in water, which is essential to restore healthy disc biomechanics [7]. Through work with an external consultant and a roadmapping exercise, a clear market for the technology has been identified, however it was concluded that further evidence from in vivo studies was necessary before any commercial parties would consider a licence deal. We propose to use this funding to conduct an in vivo study to demonstrate safety and efficacy of the hydrogels. We will use an aging sheep model that naturally exhibits disc degeneration [8,9] and utilise the novel activity monitoring facilities available at the University of Cambridge [10] to provide functional outcome measures alongside post-mortem measures of biological and biomechanical performance. In parallel, we also propose work to increase the translation potential through further engagement with commercial partners, clinical key opinion leaders and patients. If successful, this study will progress the technology to a readiness level for commercial investment and provide support for the use of the hydrogel in clinical trials.",,5.3 MEDICAL DEVICES,MUSCULOSKELETAL HRCS22_05691,Department of Health and Social Care,NIHR,"In younger adults with unstable ankle fractures treated with close contact casting, is ankle function not worse than those treated with surgical intervention? The FAME Trial","Every day in the UK around 170 people break an ankle. They tell us that they have pain and physical limitations for several weeks, or sometimes months, after the injury. It can also mean that they have to take a long time off work. We know some people can have pain in their ankle as well as some functional limitations for as long as three years or even longer._x000D_ _x000D_ In most hospitals, simple ankle breaks are treated with a plaster cast or a walking boot. If the break is more complicated with the broken bones out of place, or if they wouldn’t stay in line when walking in a boot or plaster, an operation is performed to fix the bones in place with screws and a plate._x000D_ _x000D_ A recent study looked at treatments for these complicated breaks in people over 60 years old. It compared the results of the standard treatment, involving an operation, with using a closely moulded plaster cast, avoiding the operation. By the end of the study there was no real difference in the ankle function and quality-of-life experienced by the two groups. This suggests that using the special plaster was just as good as having surgery for treating this sort of ankle break in older people._x000D_ _x000D_ Now we want to know if this is the same for younger people._x000D_ _x000D_ Involving patients at 25-30 hospitals across the UK we want to see how using the special plaster cast instead of the operation affects the outcome of an ankle break in people aged 18-60. We would only include people who would normally have had an operation to treat the ankle break. We want to look at functional outcomes - how well people are and what they can do after a certain recovery time. We will also work out the costs of the different treatments - to the NHS, to the individual, and to wider social care services._x000D_ _x000D_ We will start with a pilot study at a smaller group of hospitals looking closely at the processes we are using. We do this to find out if we can find enough people who want to take part before we go ahead with the big study. It also allows us to make any changes to make the main study better before we get started. All the information from this pilot study will be included in the main study too._x000D_ _x000D_ We think we will need 890 people to take part to compare the two treatments properly. If people agree to take part, they will be put into one of the two groups by a computer program to make sure that the groups are similar and the comparison is fair. After the operation or the plaster cast treatment, all the patients in the study will have the usual additional treatment and follow up that is currently standard practice at the hospitals. _x000D_ _x000D_ The researchers will ask patients about their health and abilities and return to work and usual activities, as well as any complications and specific costs. The answers will be collected at the outset, and at 6 weeks, 4 months and 1 year after the injury, and the results from the two groups compared. A few questions will be asked each year for five years to find out about any longer term effects. _x000D_ _x000D_ This project was developed by a team of patient representatives, clinical experts in orthopaedics, study management specialists, experienced statisticians and health economists. The Oxford Clinical Trials Research Unit, based within the University, will assure the quality of the study. Monitoring committees of patient representatives and independent experts will oversee the progress and conduct of the study.","BACKGROUND_x000D_ Ankle fracture is one of the most common musculoskeletal injuries sustained in the UK. Many of these patients experience ongoing pain and physical impairment with the consequences of the fracture and its management lasting for several months or even years. The broad aim of ankle fracture treatment is to maintain the alignment of the joint whilst the fracture heals. More severe injuries to the ankle, those which require realignment or are expected to be unstable, are routinely treated surgically. However, even with advances in surgery, there remains a risk of complications; for patients experiencing these the associated loss of function and quality-of-life is considerable. Non-surgical treatment is an alternative to surgery and involves applying a cast carefully shaped to the patient’s ankle to correct and maintain alignment of the joint; the key benefit being a reduction in the frequency of common complications of surgery. The potential risk of non-surgical treatment is a loss of that alignment with a consequent reduction in ankle function._x000D_ _x000D_ AIM_x000D_ This study aims to determine whether functional outcomes four months after treatment in patients with unstable ankle fractures treated with close contact casting are not worse than those treated with surgical intervention, which is the current standard-of-care._x000D_ _x000D_ DESIGN_x000D_ This trial is a pragmatic, multicentre, randomised non-inferiority clinical trial and embedded pilot; with twelve months clinical follow-up and parallel economic analysis. A surveillance study using routinely collected data will be performed at five years._x000D_ _x000D_ METHODS_x000D_ All adult patients with unstable ankle fractures are potentially eligible to take part in this study. Eligible patients will be identified in daily trauma meetings and fracture clinics and approached for recruitment prior to their treatment. Treatments will be performed in trauma units across the UK by a wide range of surgeons to ensure generalisability. Surgical treatment, including position, implant choice and rehabilitation will be at the discretion of the treating surgeon. Non-surgical treatment will be close-contact casting, a technique which has gained in popularity since the publication of the AIM trial. Eight hundred and ninety participants (445 per group) will be randomly allocated to operative or non-operative treatment. The trial will employ 1:1 random allocation by a remote computer system, stratified by centre and by fracture severity. Data regarding ankle function, quality of life, complications and costs will be collected at six weeks, four and twelve months and then annually for five years following treatment. The primary outcome measure is ankle function measured using the Olerud and Molander ankle score at four months from treatment, with a parallel economic analysis._x000D_ _x000D_ TIMELINES FOR DELIVERY_x000D_ Funding commences in May 2019 and the trial is expected to take 46 months, with reporting soon afterwards. The five-year follow-up of long-term outcomes will run to month 92, and the report will be produced shortly after completion._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION_x000D_ The 12 months results will be presented and published internationally. Patient representatives will help disseminate the results through patient advocacy groups and beyond routine scientific media. This is anticipated to be the only pragmatic trial reporting outcomes after non-surgical treatment in unstable ankle fractures in younger adults and as such will inform the NICE ‘non-complex fracture’ recommendations at their scheduled update in 2024.",6.4 SURGERY,INJURIES AND ACCIDENTS HRCS22_06983,Department of Health and Social Care,NIHR,Increasing Physical Activity in a Medium Secure Service: The Development and Feasibility of a Physical ACTivity Intervention (IMPACT),"In the UK there are 3500 individuals detained in medium secure units. Service users in such settings have complex and serious mental illness (SMI), often with co-morbid physical health problems and a life expectancy of at least 10 years shorter than the general population. They often have low levels of physical activity. There is little evidence about physical activity interventions for medium secure service users in the United Kingdom. Aims: We aim to co-produce, with medium secure service users, the content and delivery of an intervention to increase physical activity. We shall assess feasibility, acceptability and pilot data collection methods for outcomes relevant for a future randomised controlled trial. Research questions Can an evidence-based intervention aimed at increasing physical activity in medium secure services be co-produced? Can this co-produced evidence-based intervention be implemented in medium secure services? What are medium secure service users and staffs perceptions and experience of the physical activity intervention? Is the intervention sufficiently developed to be evaluated in a future pilot Randomised Control Trial? Plan of investigation: This is a 24-month mixed-methods study in four phases using the Medical Research Council Complex Interventions Framework. Phase 1: To identify the barriers and facilitators in medium secure care to increased physical activity; we will co-produce a questionnaire for all service users to complete in two NHS medium secure units (N=90; N=102) and conduct staff focus groups in each unit (6-10 in each group, 12-20 in total). Phase 2: To identify views on designing, delivering, establishing engagement and maintaining commitment to attend physical activity interventions, we will conduct a focus group with service users and key stakeholders with expertise in promoting physical activity and behavioural change within medium secure environments (6-10 participants). Phase 3: To co-produce a physical activity intervention, we will conduct an intervention development group with service users, our patient and public representatives, staff from Phase 1 and service users and key stakeholders from Phase 2 (6-10 participants). We will produce guidelines for training to facilitate consistent intervention delivery and replication. Phase 4: 15-20 medium secure service users from each medium secure unit will participate in this phase. Using a quasi-experimental one arm, pre-test post-test design we will assess their physical activity levels pre and post-intervention. Pre-test, basic demographic data, information on current medication, body weight, physical activity, mood functioning; mental well-being and motivation will be collected. We will repeat measures after 3 months and then at follow up at 1 month and 3 months post-intervention. Qualitative data will be collected on acceptability, and pilot recruitment, participation, retention and causes of drop-out, data collection, and outcome measure to inform a future pilot randomised control trial. Benefits: We anticipate that incorporating a co-produced physical health intervention into medium secure services could improve a service user s physical status and lower the risk of physical disorders such as cardiovascular disease and diabetes. Furthermore, it could reduce psychiatric symptoms, improve well-being and self-esteem in service users making it an interesting and promising treatment option in secure care.","Many people become overweight due to the effects of poor diet, and less active lifestyles. Being obese can affect people s heath and lead to type 2 diabetes and heart problems, People with severe mental health problems find it more difficult to live healthy lifestyles. They have a shorter life span by about 10-20 years and obesity rates up to four times higher than the general population. Maintaining a healthy lifestyle is more difficult for people in medium secure mental health units. This type of service provides care and treatment to adults with severe mental health problems, who present a serious risk of harm to others and to themselves, and who are prevented leaving hospital. Service users in such units have often experienced chaotic lifestyles; problematic relationships, employment and substance use issues. Limited physical activity and weight gain is recognised as a major health problem for people in secure units A recent audit of 83 service users in such a unit found only 18 had lost or maintained their admission weight whilst the remaining 65 had increased their weight since admission. This study will work with service users and professionals in two NHS medium secure units to design and evaluate a way of improving the levels of physical activity for service users. What we will do: Design a questionnaire for service users to understand what helps or hinders their participation in physical activities. Explore with staff and service users in a discussion group what strategies may improve engagement, maintain commitment, avoid drop-out and overcome barriers to being physically active. Hold a service user and staff discussion group to develop a physical activity intervention based on evidence from parts 1 and 2. Evaluate the intervention for 3 months by collecting information about service-users participation, body weight, physical activity, mood, mental well-being and motivation. We will also interview all service users and some staff. How we plan to involve people: The study involves genuine involvement and partnership working with service users. We have a service user on the team, and Creative Minds, a charity that develops creative activities to improve wellbeing in service users in such units. We will continue to work together with service user groups at both study sites so we co-produce a physical activity intervention that is relevant to the needs of people in such services. We will establish whether this is practical, acceptable and useful for the people it is aimed at (feasibility study). This type of study examines the practical issues in establishing such a study and therefore can iron out any of these problems before further funding is granted to do a much larger study.",7.1 INDIVIDUAL CARE NEEDS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,GENERIC HEALTH RELEVANCE;MENTAL HEALTH HRCS22_06625,Department of Health and Social Care,NIHR,"Increasing access to CBT for psychosis patients: a randomised controlled trial evaluating brief, targeted CBT for distressing voices delivered by Assistant Psychologists (GiVE3)","Background Psychosis is a severe mental health problem that is typified by the symptoms of delusional beliefs and auditory hallucinations ( voices ). These symptoms cause significant distress and disability to patients. Cognitive Behaviour Therapy for psychosis (CBTp) has strong evidence for its clinical and cost effectiveness and is recommended for all psychosis patients by the National Institute for Health & Care Excellence (NICE). Despite this recommendation, CBTp is rarely made available to psychosis patients within NHS Mental Health Services - partly due to a lack of resources. NICE have requested that research be conducted to explore ways of delivering CBTp in less resource-intensive forms. A recent innovation that may be useful in this respect is the development and evaluation of single-symptom forms of CBTp. Aims The long-term aim of this research is to increase the number of psychosis patients who are able to access CBTp. Specifically, the proposed study seeks to evaluate a less resource-intensive CBT-informed intervention specifically targeted at the psychosis symptom of distressing voices. Our Guided, self-help CBT intervention for voices (the GiVE intervention) is less resource-intensive in two ways: firstly, the number of sessions (10 sessions as opposed to the recommended minimum of 16 sessions); and secondly, the structure and targeted nature of the intervention which creates potential for it to be delivered by briefly trained therapists (Assistant Psychologists; APs), as opposed to highly trained therapists. Research question In comparison to usual care, is the GiVE intervention effective at treating distressing voices when delivered to psychosis patients by briefly trained APs? Plan of Investigation The proposed study will be a pragmatic, two-arm RCT comparing a Guided, self-help CBT intervention for voices (the GiVE intervention – delivered by APs) and treatment as usual to treatment as usual alone, recruiting across three sites, using 1:1 allocation and blind post-treatment and follow-up assessments. Potential benefits to patients and the NHS If the GiVE intervention is found to be effective when delivered by APs, this intervention could significantly increase access to CBT-informed interventions for psychosis patients distressed by hearing voices. Implementation across secondary care services could pave the way for other symptom-specific and less resource-intensive CBT-informed interventions for psychosis patients to be developed and evaluated. Increased access to CBT-informed interventions as part of a pathway of evidence-based interventions will generate benefits for: 1) individual patients (reduced distress and enhanced recovery); 2) service-level patient benefit (increased access to evidence-based psychological therapies); and 3) economic benefits to the NHS (in terms of the reduced use of high cost mental health services).","Aims Our research aims to give more people with a diagnosis of psychosis the chance to receive a helpful talking therapy. Background Psychosis is a severe form of mental health condition. People with a diagnosis of psychosis may experience distressing delusional beliefs and hearing voices. The National Institute for Health & Care Excellence recommend Cognitive Behaviour Therapy for psychosis (CBTp) as one of the best treatments for people with a diagnosis of psychosis. But only 26% of people with a diagnosis of psychosis have the chance to receive this talking therapy. CBTp is scarce because it can take a long time to deliver and needs to be delivered by highly trained therapists. We have adapted CBTp in several ways to reduce its length and make it less resource-intensive. Firstly, we have targeted CBTp at only one of the problems commonly associated with psychosis – hearing voices. Secondly, this targeted approach has enabled us to reduce the number of sessions over which the therapy is conducted (from the recommended minimum of 16 sessions, down to 10 sessions). Finally, we have structured the therapy in the form of a workbook to enable briefly trained therapists to guide people through the therapy. Our therapy is called Guided self-help CBT intervention for distressing voices (also known as the GiVE intervention). Our briefly trained therapists are called Assistant Psychologists. They have a degree in psychology and usually work in NHS Mental Health Services under the supervision of highly trained therapists. We want to see if our GiVE intervention is helpful for people with a diagnosis of psychosis who hear voices, when delivered by Assistant Psychologists. Design and methods used We have successfully completed a smaller version of this study. The lessons that we learnt from the smaller version have helped us to design this larger study. We will include 130 people with a diagnosis of psychosis in our study: 65 people will be offered the GiVE intervention over 10 sessions, delivered by an Assistant Psychologist 65 people will continue to receive the usual support and treatments offered by their mental health team Our findings will tell us if the GiVE intervention is helpful to people with a diagnosis of psychosis who hear voices, when delivered by Assistant Psychologists. Patient and Public involvement PPI is an integral part of the study management team and our study approach. The Lived Experience Advisory Panel (LEAP) has contributed by: Helping to design the GiVE intervention Deciding the type of therapists who will deliver the GiVE intervention Advising on the duration of the GiVE intervention and how to deliver it In the future, the LEAP will contribute by: Reviewing the study documents Helping study recruitment Understanding and sharing our findings.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_02821,Medical Research Council,MRC,Indigenous peoples responding to Covid-19 in Brazil: social arrangements in a Global Health emergency,"This proposal is focused on indigenous peoples' response to the COVID-19 pandemic in Brazil, a country which now has the second highest number of infected people in the world (2,962,442 cases by 7th August). In the absence of clear national public-health leadership, most of the 300 different indigenous peoples are taking responsibility to contain the spread of the new coronavirus among their communities into their own hands. They are at high risk as result of recent sociopolitical developments such as mining development and migration into remote areas. In addition, it is likely that many indigenous infections and deaths remain undocumented. Using anthropological knowledge and methodology, such as rapid appraisal and participatory ethnographies which includes online interviews, documentary, bibliographic and visual data, we will identify indigenous responses and mobilisation of strategies to mitigate risk and bear witness to undocumented impact on indigenous lives. We will work closely with the Secretaria Especial de Saúde Indigena (SESAI, attached to the Brazilian Ministry of Health) seeking to cooperate with global and public health agencies and policies, as well as engage decisionmakers to shape better responses to face this outbreak. In accordance with indigenous peoples' modes of existence, we propose three programme axes to frame the research and actions: 1. Health, Care and Death; 2. Mobility and Circulation; and 3. Gender. A digital platform 'Amerindian Response COVID-19 - Anthropology Platform' will also be developed and used as a tool to publish brief reports in real time, using different media, in addition to academic papers. Monthly reports will be addressed to SESAI and eight case studies will be conducted across Brazil's regions. key lessons will be drawn to reduce transmission and impact of this and future pandemics, in this and comparable countries.",,2.4 SURVEILLANCE AND DISTRIBUTION,INFECTION HRCS22_18930,Versus Arthritis,,Inflammatory arthritis - time to reveal the bigger picture,"Rheumatoid arthritis (RA) is a debilitating autoimmune disease affecting 1% of the UK population. One of the defining features is daily rhythmicity in inflammation. RA patient commonly experience early morning pain and stiffness (even in the advent of biologic treatments) severely impacting quality of life. Our studies in pre-clinical models recognise that the inflammatory environment within the joint exhibits 24h (circadian) variation, but mechanisms driving this remain to be elucidated. Additionally, there is an increasing appreciation that RA is associated with changes in the composition of the gut microbiome, although the full impact of this is not yet understood. This microbial community is a critical regulator of immunity which exhibits circadian oscillations in abundance and function. To date, the vast majority of studies aimed at understanding mechanisms driving inflammatory arthritis do not consider time-of-day, providing only a snapshot. To see the bigger picture, we must take time-of-day into consideration. This proposal defines an integrated programme of research spanning human RA studies and pre-clinical models aimed at establishing mechanistic links between the clock, immunity and microbiome. The overarching aim is to understand the temporal dependence of mechanisms driving the development, progression and treatment of inflammatory arthritis, with the ultimate goal of identifying novel therapeutic targets. Clinical studies include analysing the cellular composition and activity of joints at the peak and trough of inflammation. Furthermore, patient fecal samples and blood samples will be utilised to provide a temporal profile of the gut microbiota and its metabolic outputs in health and disease. This work package will be supported by pre-clinical models using transgenic mouse lines and microbial manipulations to explore mechanisms driving temporal variation in disease and the microbiome and their consequences.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_20064,Wellcome Trust,,Information-seeking in health and disease,"People spend a substantial amount of time seeking out information (e.g., reading, asking questions, internet browsing). It is theorized that common psychiatric conditions, including depression and anxiety, are characterized by abnormal information-seeking patterns. These patterns could potentially be measured and used to facilitate diagnosis and treatment selection. However, the precise links between information-seeking and psychopathology are unknown. In fact, we know little about how to quantify information-seeking or the mechanisms that control it. My aim is to understand (i) how people decide to seek or avoid information and (ii) how those decisions relate to mental health. I have developed tasks to quantify key drivers of information-seeking (including valence of information, uncertainty, instrumental utility). I will test participants to assess whether psychopathology symptoms are linked to abnormal influence of these drivers on information-seeking. I will also combine pharmacological manipulation with neuroimaging to examine whether the influence of these drivers is dependent on dopamine – a neuromodulator that malfunctions in several conditions in which information-seeking is theorized to be altered- and identify the neural computations involved. I will assess whether these drivers are over/under expressed in individuals diagnosed with affective disorders, and conduct experiments to determine how these alterations impact well-being.","The human pursuit of knowledge drives intellectual development and social engagement. It is theorized that the tendency to seek out information is altered in common psychiatric conditions including depression and anxiety. Because people regularly engage in information-seeking online, there is a constant stream of data that could theoretically be used to facilitate diagnosis and treatment selection. However, the precise links between information-seeking and mental health have not been established. Moreover, we know little about how to quantify information-seeking or the neural mechanisms supporting it. I aim to fill these gaps. I have developed tasks to quantify distinct drivers of information-seeking across domains of knowledge. I will test participants to assess links between abnormal influence of these drivers and psychopathology symptoms. Further, I will examine whether certain psychotropic drugs alter information-seeking behavior and characterize the underlying neural mechanisms. Additional studies will examine how patterns of information-seeking impact mental health.",1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,MENTAL HEALTH HRCS22_20825,Wellcome Trust,,Innate immunity and inflammation in tuberculosis: insights from the zebrafish and therapeutic opportunities,"Despite > 60 years of antitubercular chemotherapies, tuberculosis (TB) has been the leading infectious cause of death.  My laboratory pioneered the zebrafish - Mycobacterium marinum tuberculosis model to better understand TB pathogenesis. It enabled surprising discoveries about tuberculosis with immediate implications for new therapeutic modalities. Here, we will use the zebrafish to discover genetic alterations that impact upon immunity and inflammation in early TB. This will uncover human genetic susceptibilities to tuberculosis and druggable pathways underlying them. Our key goals are to: - Map and characterize hypersusceptible zebrafish mutants identified in a forward genetic screen. We will identify their causative lesions and characterize which infection step is altered in them and how, so as to understand how these genes modulate infection. - Identify gene-regulatory networks involved in early granuloma formation. RNA-seq analyses will provide a blueprint of gene expression changes associated with tuberculous granuloma formation, which we will link dynamically and functionally to the individual processes involved to determine their consequences. - Determine mechanisms of human primary immunodeficiencies to mycobacterial infections using the zebrafish. We will model in the zebrafish known human genetic mutations that increase human susceptibility to mycobacterioses to determine their susceptibility mechanisms, particularly in early infection.","Tuberculosis remains a major problem in much of the world, sickening ~ 10 million people and killing ~1.4 million per year. This is because the only vaccine is not that effective and six months of multidrug treatment are required for cure, making treatment adherence difficult, especially in poor parts of the world which suffer the most from TB. We think that improved therapies and effective preventions require better understanding of how the TB bacteria cause disease and which host responses to infection are beneficial versus harmful. We have developed the zebrafish as a model for TB, exploiting its optical transparency that allows us to visualize how TB bacteria and host cells interact at each step to cause disease. The zebrafish is amenable to genetic mutation, so we can observe the impact of mutations and determine how they alter infection outcome. Our work is leading to completely new TB treatments.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_14395,Stroke Association,,Innovating remote self-delivered sentence therapy for post-stroke aphasia to enhance everyday conversations,"Innovating remote self-delivered sentence therapy for post-stroke aphasia to enhance everyday conversations People with aphasia and their communication partners experience difficulty in everyday conversations, which negatively impacts social relationships and wellbeing. There has been significant progress regarding wordlevel therapies, but less progress in establishing effective therapies for sentence processing. Usage-based Construction Grammar, a new theory of sentence processing, suggests a greater role for stored syntactic frames. It emphasises factors such as frequency and integrates sentence structure with meaning and use, making it valuable in designing therapies. My PhD joins the UTILISE project, currently funded by a Stroke Association project grant. UTILISE therapy applies Construction Grammar principles by stimulating high frequency sentence frames, then introducing new lexical content to allow greater creativity. The existing project examined lab-based intervention which represents relatively low-dose treatment. I plan to evaluate a new version of the intervention which facilitates higher therapy dose by remote, self-delivery of UTILISE software. In the novel following phases, I will examine the impact of therapy order by comparing outcomes of UTILISE therapy followed by word naming therapy with the reverse order. I will gain the views of participants and family members regarding remote therapy and factors influencing self-delivered treatment dose. Finally, I will analyse whether outcomes generalise to participants’ everyday conversations.","Innovating remote self-delivered sentence therapy for post-stroke aphasia to enhance everyday conversations People with aphasia and their communication partners experience difficulty in everyday conversations, which negatively impacts social relationships and wellbeing. There has been significant progress regarding wordlevel therapies, but less progress in establishing effective therapies for sentence processing. Usage-based Construction Grammar, a new theory of sentence processing, suggests a greater role for stored syntactic frames. It emphasises factors such as frequency and integrates sentence structure with meaning and use, making it valuable in designing therapies. My PhD joins the UTILISE project, currently funded by a Stroke Association project grant. UTILISE therapy applies Construction Grammar principles by stimulating high frequency sentence frames, then introducing new lexical content to allow greater creativity. The existing project examined lab-based intervention which represents relatively low-dose treatment. I plan to evaluate a new version of the intervention which facilitates higher therapy dose by remote, self-delivery of UTILISE software. In the novel following phases, I will examine the impact of therapy order by comparing outcomes of UTILISE therapy followed by word naming therapy with the reverse order. I will gain the views of participants and family members regarding remote therapy and factors influencing self-delivered treatment dose. Finally, I will analyse whether outcomes generalise to participants’ everyday conversations.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,STROKE HRCS22_06375,Department of Health and Social Care,NIHR,Innovation in the Allied Health Professions: Evaluation of supplementary prescribing by dieticians and independent prescribing by therapeutic radiographers,". Background Evidence suggests non-medical prescribing (NMP), initially performed by nurses and pharmacists, offers improved service efficiency, access to medicines, cost savings, quality of care and better use of knowledge and skills. NMP was extended to advanced practice allied health professionals, e.g. podiatrists, dietitians (D) and therapeutic radiographers (TR). However, there is little evidence regarding D-TR prescribing effects or its implementation. Dietitian supplementary-prescribing (D-SP) and therapeutic radiographer independent-prescribing (TR-IP) are widely supported with improvements to service delivery and standards of care keenly anticipated. Aim: to identify effective prescribing practice and innovative service models through evaluation of D-SP and TR-IP implementation. Objectives: The objectives are to: Review evidence to inform D-TR prescribing Describe and classify D-SP and TR-IP services and identify innovative service models across England Examine D-SP and TR-IP prescribing activity and trends and factors that support or inhibit uptake or implementation Explore patient/carer views and experiences of D-SP and TR-IP Identify impact of D-SP and TR-IP on patient choice, experience, access to medicines and outcomes Assess quality, safety and clinical appropriateness of D-SP and TR-IP practice Explore cost-consequences of D-SP and TR-IP service models Evaluate quality, effectiveness and cost of D-TR prescribing educational programmes Develop non-medical prescribing (NMP) implementation toolkit for D-TRs Plan of investigation A four-phase study informed by principles of case-study design, using mixed methods Phase 1 (months 1-6) involves a rapid review. Phase 2 (months 1-30): surveys of a) NHS trusts across England to assess current situation of D-TR practice and identify innovative models and b) D-SP-TR-IPs to explore prescribing activity and trends, Phase 3 (months 10-36): embedded case-study using mixed methods to compare cost-consequences and outcomes of D-SP-TR-IP. A three stage longitudinal in-depth analysis of six diverse D-TRs in their practice settings pre-post prescribing training over 27 months. Stage 1: Pre-NMP training (months 10-12): will explore current organisational management, delivery and experience of care, identifying contextual information and factors facilitating success. Data collected as follows at each site: i) Interviews: D-TRs, manager, colleagues, patients/carers (n-5) ii) Documentary evidence iii) Observation of D-TRs over one working week (maximum 5 days), using electronic diaries and to collect information on medicines management, work activity and related costs (n-40-60 consultations) iv) Patient questionnaires (n-24-42) v) Case-record review (n-10) Stage 2: During NMP training (months 13-24): D-TR two-monthly interviews to monitor NHS and private resources involved in delivery of training. Stage 3: Post NMP training (months 25-36): all stage 1 procedures repeated at least 3 months post-qualification to allow embedding in practice. Analysis (months 10-38) will comprise interim analysis of phase 2 and 3 data, followed by consideration of complete data sets, including convergent evidence across case-sites. Economic analysis will compare pre-post findings within case-sties and consider NHS and private costs in a costs-consequences framework, and assess value of the training programme. Phase 4 (months 12-42) will synthesise phase 1-3 in a participatory co-design to discuss emerging findings (months 16 & 37), develop a D-TR NMP model of implementation and an online tool-kit (months 16-37). Months 37-42: write up and dissemination Research Team: combines expert knowledge of NMP, workforce development, dietetics and therapeutic radiography professional expertise, pharmacy/medicines optimisation, statistics, and health economics. Our long-time patient advisor and patient involvement group will guide the study throughout. Impact: comprehensive D-SP-TR-IP evaluation will evidence cost, effectiveness and patient benefits to inform policy developers, service commissioners; guide professional bodies, and managers and support wider implementation. It will allow informed decision-making about extension of prescribing rights to other healthcare professionals and inform NMP development in other countries who look to follow our experience.","A recent change in the law allows Dietitians (Ds) and Therapeutic Radiographers (TRs), working at an advanced level, to prescribe medicine for patients that they treat. Dietitians, who manage diet and feeding for many health problems, can prescribe medicines from a treatment plan agreed with a doctor. This is known as supplementary prescribing . Therapeutic Radiographers, who deliver radiotherapy and manage the side effects of this for people with cancer, can assess patients and prescribe medicine without the need of a doctor. This is known as known as independent prescribing . Research on prescribing by other professionals, such as nurses and pharmacists, shows benefits to patients and to the NHS. From talking to patients, we know that faster access to medicines is important and this change may be welcomed if patient safety is assured. We aim to study the effect of Ds & TRs prescribing on patients, staff and services. We will study how prescribing is used and identify where it works well, in order to help managers to plan services. The study will be conducted by an experienced research team, including a patient advisor, and will be guided by clinicians, managers and a patient group to advise when best to approach patients and help design tools and written information. After reviewing literature on Ds & TRs roles, we will carry out surveys to explore where Ds & TRs are employed and how they are practicing. Repeat surveys will identify changes over time. We will also select 6 sites where Ds & TRs are about to take the prescribing qualification and compare practice, costs and patient experience before and after. We will do this by observing practice, timing consultations, assessing prescriptions, asking patients to complete a questionnaire, and studying routine data including safety reports. Patients/carers, Ds & TRs and their managers/teams will be interviewed to explore views and experiences. A toolkit will be developed to guide health service managers. The study lasts 3.5 years. A patient newsletter will report on study progress and final summary provided to participants. Findings will be presented at conferences, in scientific journals and feedback events.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_01334,Medical Research Council,MRC,Integrating cognition and systems neuroscience to understand child development,"Trajectories of cognitive and brain development are established early in life. Across the lifespan, early developmental differences are associated with a host of long-term social, educational, economic and health outcomes. This research programme is dedicated to understanding those trajectories, their consequences, their underpinning neurobiology, and the factors that guide their origins during childhood. The purpose of the programme reflects MRC strategic priorities: We apply a systems neuroscience methodology to the early detection of vulnerabilities, with the precision characterisation of children’s phenotypes. Our goal is to understand the complex and co-occurring cognitive, behavioural and mental health difficulties that are impactful for young people, regardless of whether they conform to a standard clinical presentation. This systems perspective focuses on developmental trajectories rather than on outcomes alone, seeking to identify multiple overlapping causal factors, and establish biological, social and environmental risk factors. Finally, we aim to build capacity in this area through the training of early career scientists and development of specialist longitudinal cohorts of young people, with multi-level phenotyping. Despite disruption caused by the pandemic, we have been highly productive. Since 2016, team members have published over 80 scientific articles. Additionally, we delivered a wide-ranging translational outreach and participatory engagement programme, in partnership with national charities and education groups. This was recognized by the Vice-Chancellor’s Award for Impact and Engagement (2020). In the same period our work informed Government policy surrounding child mental health and education, within the context of the pandemic. The scope and scale of our programme were made possible by expanding core MRC funding, with four project grants and numerous scholarships bringing more than £1.8m of external funding. The result is a large and vibrant team of talented early-career scientists, arriving from diverse scientific backgrounds, including industry, clinical practice and multiple academic routes. This team takes full advantage of the special environment at the MRC CBU, undertaking ambitious interdisciplinary science that would be difficult elsewhere. Central to this unique environment are the synergies created by common priorities and complementary expertise. Shared cohorts, collective methodological skills, theoretical integration and the dovetailing of clinical and basic science create a research culture that drives innovation and collaboration. In the next QQ we feed into and benefit from new cross-cutting CBU priorities: transdiagnostic approaches to disorders, understanding responses to adversity and building models that bridge brain and mind. We plan new collaborations to build computational theory that integrates neurobiology, cognition and behaviour as they unfold over development.",,"1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",NEUROLOGICAL;GENERIC HEALTH RELEVANCE;MENTAL HEALTH HRCS22_15450,Wellcome Trust,,Integration of context and task rules by the nucleus reuniens.,"Deciding the best way to behave is often dependent on where you are. For example, cheering loudly when someone scores a goal is a good way to behave if you are watching a football match in the pub, but not if you are watching it on your phone in the library.The ability to tell where you are is governed by a part of the brain called the hippocampus, while deciding the most appropriate behaviour is governed by the prefrontal cortex. By communicating intricately with each other, it is proposed that these regions allow you to modify behaviour based on your location. However, the hippocampus and prefrontal cortex are not connected to each other, and therefore we do not understand how they communicate so effectively.In this proposal we will investigate that idea that this communication occurs through a region called the nucleus reuniens. We will investigate how this region connects with both prefrontal cortex and hippocampus; we will carry out computational modelling to investigate how this communication might occur; and then carry out behavioural experiments that will allow us to directly test how neurons in the nucleus reuniens allow the modification of behaviour based on where we are.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,NEUROLOGICAL;MENTAL HEALTH HRCS22_01362,Medical Research Council,MRC,Integrative computational and systems biology approaches for deciphering cellular regulomes that promote carcinogenesis,"Numerous genetic aberrations affecting a large number of gene products contribute to tumour development and the accepted hallmarks of cancer, often making therapies based on single targets ineffective. These aberrations and their consequences are propagated via transcriptional, translational and post-translational networks. The resultant information circuits can extend across cell and tissue types and also modulate the microenvironment. How to integrate and model this percolation of information and properties across different biological scales, in both time and space is accepted as a major challenge to fully understanding the aetiology, progression and dynamics of tumorigenesis. Novel computational methods, tools and resources are essential to address this challenge. Transcriptomic and copy number assessment studies suggest that specific sets of key pathways that regulate cellular phenotypes are pathologically altered in cancer. However, pathway centric approaches are not completely effective because pathways don’t operate in isolation; instead, multiple interacting pathways form a complex web of networks. Methods to decipher cellular information flows (whether they are signalling, metabolic or regulatory) can shed light on the underlying cellular complexity and identify systems level properties. The objective of this research programme is therefore to develop a network perspective of tumorigenesis using a mixture of both integrative data driven as well as computational modelling approaches. The programme harnesses data science approaches coupled with computational and systems biology methodologies to develop novel methods, tools and resources for systems level biomedical data-integration. It addresses these objectives by 1) modelling multi-scale cellular regulomes involved in tumorigenesis, 2) developing these model into knowledge discovery systems to assist in understanding of cancer datasets, and 3) Using these resources to elucidate phenotypic impact and identify therapeutic intervention points of these regulomes for further experimental evaluation.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_20816,Wellcome Trust,,Integrative imaging of brain structure and function in populations and individuals,"Neuroimaging enables the mapping of many aspects of the brain’s anatomy, connections, and function. New landmark studies including UK Biobank and the Human Connectome Projects are taking neuroimaging to the scale of populations. Such studies deploy multiple imaging modalities with the aim of learning more about the brain, and identifying imaging markers relevant to neurological disease. However, we cannot currently take full advantage of the richness of these new resources, including:  major advances in the quality of data;  complementarity of multi-modal imaging;  large subject numbers;  and linked information about health outcomes, genetics and risk factors. Our vision is to extend the reach of imaging neuroscience. This requires new research across multiple domains: from integrated cross-modal analysis, to more detailed and biologically-interpretable markers, to machine learning. We aim to enable neuroimaging to achieve its full potential, from the modelling of variation in populations to the characterisation of individual subjects. We will deliver powerful modelling approaches and research platforms, continuing our long track record of disseminating software for use by basic and clinical neuroscientists. Further, we will leverage our leadership in big data projects to demonstrate how these approaches and computational tools can advance our understanding of the brain and its diseases.","Neuroscientists and doctors use neuroimaging to study the brain without cutting into it. We can see different brain tissues, map brain connections, and even watch brain activity in real time. To discover more about how the brain works, and how diseases occur in the brain, Big Data imaging studies of thousands of volunteers are now underway. However, imaging neuroscientists are not yet able to take full advantage of such huge, high-resolution, and complex datasets - for example to detect disease early enough to treat successfully. Using new imaging neuroscience and Artificial Intelligence (AI) research, we aim to learn much more about how the brain varies across different people, and changes with disease. We aim to bring our research together with the new big datasets so that we can even learn how to predict disease in new patients in the future.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_21271,Innovate UK,IUK,Intercellular transfer of therapeutic DNA for gene and cancer therapies,"Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.",,5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES,GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS HRCS22_00815,Medical Research Council,MRC,Interim grant funding agreement - Accelerating detection of disease (ADD) Challenge,"https://ourfuturehealth.org.uk/ Our Future Health will be the UK’s largest ever health research programme, bringing people together to develop new ways to prevent, detect and treat diseases. To deliver the outcomes and benefits of the ADD Challenge, the Challenge will build a cohort of 5 million individuals donating biological and digital data to support research on early detection and improved risk stratification of diseases and create a testbed for healthcare innovation. Early identification of disease will enable earlier intervention and thus more treatment options including the implementation of the prevention measures to improve outcomes and public health. The Challenge will position the UK as a world leader for early detection and prevention research and provide an urgently needed platform for the development and validation of new diagnostic tests and technologies. An additional phase of the project increased the level of support to develop the OFH Database.",,4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),GENERIC HEALTH RELEVANCE HRCS22_09296,"Chief Scientist Office, Scotland",CSO,Interleukin-1β Protects Against Multi-Organ Endothelial Injury.,"Multi-organ endothelial dysfunction, often presenting as thrombotic microangiopathy, is typical of numerous potentially fatal conditions including accelerated hypertension, pre-eclampsia, vasculitis and antibody-mediated transplant rejection, as well as being a complication of treatment with vascular-endothelial growth factor (VEGF) inhibitors. Severe injury may occur in the brain, eye, heart and kidney through shared mechanisms that remain poorly defined. The inflammasome is a component of the innate immune system present in myeloid cells, and its activation results in the production of the pro-inflammatory cytokine interleukin-1β (IL-1β). IL-1β antagonism is used to treat a range of auto-inflammatory diseases and has recently been suggested as a therapeutic strategy in atherosclerosis. My preliminary data suggest a novel protective role for IL-1β from multi_x0002_organ endothelial dysfunction. These effects appear to be mediated through the VEGF system. This fellowship will explore these findings more deeply and help to gain better mechanistic insights into the results of previous clinical trials. It will also start to define the potential for IL-1β to act as a clinical disease biomarker and for the pathways involved in its generation as targets for novel therapeutic interventions.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CARDIOVASCULAR HRCS22_22706,The Academy of Medical Sciences,AMS,Intermittent fasting mediated metabolic reprogramming reshapes the T cell immunity and preserves white matter integrity after stroke,"Ischemic stroke is the world's leading cause of disability and is particularly prevalent in the huge population of hypertensive patients. Hypertension also has an unfavourable effect on neurological outcome of stroke patients, thus posing an enormous burden to the patients' families and the society both in China and the UK. So far, there are only few effective ways to improve the neurological recovery after stroke, and those are restricted to selected patients and ultra-short time windows, exluding most patients from treatment. The impact of T cells on the ischemic brain injury lasts long into the late phase of stroke. We found that intermittent fasting, as a caloric restricted dietary management strategy, had profound impact on the fate of T cells that could be favourable for stroke patients. Therefore, we propose that by adjusting the hypertensive patients' diet, we may change the stroke patients' T cell fates into a less damaging but more healing type thus improving neurological outcomes after stroke by altering gene transcripts from the T cells’metabolic molecules. Dietary intake is the everyday essential for all patients and intermittent fasting is a cheap yet effective dietary management that is attracting increasing attention in treating various diseases. The findings of this project can give insights into the protection mechanism of intermittent fasting for ischemic stroke and may potentially benefit the huge population around the world with stroke or at high risks of stroke, which in turn would reduce the global economic and social burden of chronic disability attributable to stroke.","Ischemic stroke leads to severe and long lasting neurological deficts. White matter injury attributable to hypertension-related cerebral small vessel disease and ischemic stroke itself is gaining increased attention due to its additional devastating effects on the brain. Demyelination is a critical feature of white matter injury and it can elicit profound activation of antigen-specific adaptive T cells. Importantly, glycolysis and fatty acid synthesis are two critical metabolic checkpoints in determining the fate of T cell differentiation, with pro-inflammatory Th17 cells highly relying on the energy supply for proliferation. In contrast, anti-inflammatory regulatory T cells (Tregs) are less dependent on glycolysis and fatty acid synthesis. Therefore, metabolic modulation of T cells is emerging as a promising strategy for the treatment of neuroinflammatory disorders. We previously found that cerebral ischemic stroke induces significantly increased glycolysis and fatty acid synthesis in the peripheral T cells, which in turn polarizes T cells into Th17 cells instead of Tregs, both of which play important but distinct roles in the cerebral ischemic brain injury. In a preliminary study, we found that intermittent fasting, a potent calorie-restrictive diet, can significantly inhibit the expression of Foxk1, a forkhead transcription factor regulating glycolysis in CD4+ T cells, thus putting forward the hypothesis: intermittent fasting can reshape the differentiation of CD4+ T cells into more regulatory T cells but less Th17 cells after stroke. Foxk1 may serve as a critical regulator of the metabolic reprogramming of T cells after intermittent fasting which contributes to the attenuation of T cell-mediated white matter injury after ischemic stroke with or without hypertension. This collaborative project between China and the UK soughts to address the above hypothesis by 1) establishing a more clinically relevant hypertensive stroke mice model and generating the T cell-specific Foxk1 conditional knockout mice; 2) performing RNA sequencing, targeted lipodomics and seahorse glycolytic stress tests in flow cytometry sorted CD4+ T cells from intermittent fasting-treated hypertensive mice. This project may lead to a translation-friendly complementary stroke therapy in the context of hypertension and white matter injury that can improve long term neurological functions. Meanwhile, digging into the underlying mechanisms of intermittent fasting-mediated immunomodulation for secondary brain protection may also advance the current understanding of the metabolic reprogramming of post-stroke T cell responses and pave the way for the discovery of novel metabolic immune modulatory targets for stroke.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CARDIOVASCULAR;STROKE HRCS22_01495,Medical Research Council,MRC,Internet-delivered Cognitive Therapy (iCT) for young people with Post Traumatic Stress Disorder (PTSD),"Need. Post-Traumatic Stress Disorder (PTSD) in youth is a common problem in the UK and globally. Most young people are exposed to traumatic events before they are 18 years old; about 15% will develop PTSD which may persist for years if untreated. PTSD is associated with impaired social and academic functioning, poor quality of life, increased suicidal behaviour, and significant comorbidity. Highly effective psychological treatments exist but are not commonly available in the NHS. There is an urgent need to disseminate these effective treatments for PTSD in youth. Solution. We will build software for an Internet-delivered version of our effective face-to-face Cognitive Therapy for PTSD, which will be accessible online via computers, tablets, and smart-phones. Internet delivered Cognitive Therapy (iCT) for PTSD offers huge potential for very wide, cost-effective dissemination of a highly effective treatment. Rationale. We have developed a specialist treatment, Cognitive Therapy for PTSD, and shown in 2 RCTs that it is highly effective in treating PTSD when delivered face-to-face to adolescents. We have also developed Computerised CBT (C-CBT) for depression, and shown that it is enthusiastically embraced by adolescents, and clinically effective. Work with adults shows that PTSD is a condition which can be successfully treated with internet-delivered CT. The gap in provision is for internet-delivered CT for PTSD in youth. Plan. The project has 2 phases. In the first phase, we will build software for internet-delivered Cognitive Therapy (iCT) for PTSD. In the second phase, we will evaluate iCT in an RCT (vs Face-to-Face Cognitive Therapy and a Wait List (delayed treatment) condition) to provide feasibility data on acceptability, compliance, retention, and delivery of the intervention, and to provide point estimates of the effect sizes (and confidence intervals) of iCT on PTSD and co-morbid problems.",,5.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_11520,Economic and Social Research Council,ESRC,Intersectional Perspectives for Community Inclusion: Understanding the Past and Shaping the Future with Older Marginalised IDD and LGBT+ People,"AIMS The research aims are to: (1) develop understandings of how to co-create inclusive physical, social, cultural, and virtual community spaces and places, services, and resources for and with mid-older aged IDD (including those with profound and multiple disabilities wherever possible) and LGBT+ people (aged 45 years and older) to enhance community participation and (2) translate our findings into inclusive policy and practice. Although we have specified an age band for the current research, we will be focusing on the notion of generation within our sampling and analytical frame to, as Pritchard and Whiting (2014) suggest, organise our understandings of age-related issues 29. This is necessary to fully understand the life course perspective and how that translates into community inclusion since the norms of a generation provide strong social locations for the thoughts, attitudes and actions of people born into a particular era 30. Here, we will include people of the 'lost generation', 'baby boomers' and 'generation X' whose lives were differently affected by economic hardship, uncertainty, confidence, resourcefulness, technology and education. OBJECTIVES The project aims will be achieved through the following objectives: i) Build collaborative, transdisciplinary partnerships to generate and analyse qualitative and quantitative data through the ARCGIS storytelling tool to establish how mid-older people with IDD and those who identify as LGBT+ attribute meaning to inclusion, exclusion in online and local community participation (WP1 and WP2). ii) Generate and analyse data through qualitative social network analysis using egocentric sociograms (relational, online and community based) to identify online and local experiences of community inclusion and participation over the lifespan amongst 1) mid-older people with IDD and 2) those who identify as LGBT+, and 3) identify points of intersection across groups. (WP2). iii) Conduct interviews and deliberative dialogue workshops with professional and practitioner stakeholders to understand how spaces and places can be made accessible to provide supportive, inclusive communities for mid-older people with IDD and those who identify as LGBT+ (WP2). iv) Use data and analyses from WP2 and 3 to generate potential solutions for the development of local / online community spaces and places which facilitate inclusion, minimise exclusion and encourage social and community participation in mid-older IDD and LGBT+, reducing layers of inequality (WP3 and WP4). v) Translate and mobilise knowledge from research findings to provide strategies and recommendations to influence policy and practice to improve inclusion and reduce experiences of exclusion for mid-older people with IDD and those who identify as LGBT+ in everyday local and online community life? (WP4 and WP5). RESEARCH QUESTIONS The objectives translate into the following research questions: i) How do mid-older people with IDD and those who identify as LGBT+ attribute meaning to inclusion, exclusion in online and local community participation? ii) How do mid-older people with IDD and those who identify as LGBT+ experience societal inequalities, patterns of inclusion and exclusion over the lifespan, and at points of intersection across groups? iii) How might spaces and places be made accessible to provide supportive, inclusive communities for mid-older people with IDD and those who identify as LGBT+? iv) How might local / online community spaces and places be co-created to facilitate inclusion, minimise exclusion and encourage social and community resilience in mid-older IDD and LGBT+ people as to reduce layers of inequality? v) How might policy and practice shape and improve inclusion and reduce experiences of exclusion for mid-older people with IDD and those who identify as LGBT+ in everyday local and online community life?","Many older people experience exclusion from the communities they live in. The World Health Organisation has recognised this through their Age Friendly Cities and Communities programme, which encourages the development of different spaces and places to improve older peoples' inclusion in their communities and cities. Historically and politically people with intellectual and developmental disabilities (IDD) and people who identify as lesbian, gay, bi, trans + (LGBT+) have been socially excluded from their communities throughout their lives; when people with IDD were housed in institutions and homosexuality was seen as an illness or criminalised. These life experiences put older people from these two groups at greater risk of inequality, discrimination and exclusion in community contexts. Using online technology has also been difficult for older people, particularly for people who already experience exclusion such as those with IDD and those identifying as LGBT+. So far, very little research has been done with these two groups to hear their experiences of local and online community inclusion and exclusion and to better understand how community inclusion can be strengthened in England and Scotland. This study aims to develop knowledge of the community spaces and places (local and virtual) that people with IDD and LGBT+ use in their everyday lives. The main research questions examine how older people with IDD and LGBT+ describe and experience inclusion and exclusion and what these mean to them. We will explore how local and online community places can be improved to reduce social inequalities. Finally, the research will look at how these new ideas might be used to shape government policy and organisational practices. The research is organised in five related work packages. Which are jointly led by university researchers and practitioners in third sector organisations. All stages of the research will be guided by people with lived experience in IDD and LGBT+ in advisory groups. People with IDD and LGBT+ lived experience will work as trained co-researchers on the project. We will use a variety of verbal, visual and geographical methods to access marginalised voices in appropriate ways and enable diverse people's views to emerge. In work package (WP) 1 we will build strong relationships within the study communities, set up advisory groups of older people with IDD and LGBT+, train co-researchers and create an international reference group of 'critical friends' for the project. In WP2 we will recruit participants and access their stories of spaces and places in their communities over time. This will involve generating and co-analysing interactive mapping software data, photography and social network interviews to gain a rich and authentic understanding of inclusion and exclusion. Third sector representatives will also be interviewed for their views. In WP3, we will bring the different data sets together, jointly reflect on and synthesis findings, analysing patterns of inclusion and exclusion across both IDD and LGBT+ groups and understanding what they mean in real world contexts. Four events will be held in WP4 with participants, family members, carers and service providers to evaluate potential new policy and practice solutions for local and online community inclusion. WP5 will translate and share co-produced project knowledge (via knowledge mobilisation champions) across communities, private, public and third sector organisations. This will lead to practical, accessible ideas and a road map for change in community inclusion for people with IDD and people who identify as LGBT+. Findings will also be shared in local, national and international conferences/seminars, publications, third sector and two showcase events and across social media. An impact tracking and evaluation plan has been devised to make sure that findings from this project have impact at individual, community, and policy levels.",1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,GENERIC HEALTH RELEVANCE HRCS22_17971,Cancer Research UK,CRUK,Investigating Biomarkers for the Early Detection of Pancreatic Cancer in Genetically Engineered Mouse Models of New Onset Diabetes-Associated Ductal Adenocarcinoma,"Background: Pancreatic cancer is the most deadly of cancers, and urgent improvements are needed in the management of this disease. There are two reasons for these appalling statistics – a lack of effective treatments, and also a lack of symptoms or markers associated with early disease. Because of the low incidence of pancreatic cancer, screening in the general population is problematic, however, screening in high risk populations is feasible. Patients who present with adult new onset diabetes over the age of 50 have ~1% chance of being diagnosed with pancreatic cancer in the following 3 years, making these patients an attractive population for screening. We hypothesise that there are proteins present in the blood of these patients that could be used for early detection. We have developed a mouse model that phenocopies this phenomenon and thus presents a significant opportunity to discover biomarkers for early detection of pancreatic cancer. Aims: • To discover early markers of pancreatic cancer in a mouse model of pre-neoplastic lesion-associated diabetes. • To investigate putative biomarkers of early disease across GEMMs models of pancreatic cancer of different genetic backgrounds. • To validate pancreatic cancer biomarkers in human pancreatic cancer patient samples. Methods: We will use plasma proteomics to investigate biomarkers in the blood of our mouse model of new onset diabetes associated with PDAC, at different stages throughout disease progression. We will also investigate biomarkers in other autochthonous mouse models of pancreatic cancer of different genetic backgrounds, focussing on the small subset of those that present with diabetes. We will interrogate biomarker candidates ex vivo, to determine their source and also if they play any role in pancreatic cancer. Finally, we will validate the most promising biomarkers in human pancreatic cancer patient samples. How the results of this research will be used: In pancreatic cancer early detection could have massive impact. If detected at an early stage, when surgical resection of the tumour is possible, the 5-year survival rate is 39%, compared to only 3% in patients with metastasis at diagnosis. Ultimately we propose that a test for the most specific and sensitive biomarker identified by our research could be made available for screening in high risk individuals, particularly cases of new onset diabetes.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_22878,The Academy of Medical Sciences,AMS,Investigating MRI markers of placental function derived from a multiparametric computational model of placental perfusion in a cohort of early onset Fetal Growth Restricted pregnancies,"Placental insufficiency occurs when the placenta cannot supply a fetuses oxygen and nutritional demands, resulting in fetal growth restriction (FGR). This is responsible for over a third of stillbirths. There is no diagnostic test. I have developed a multi-compartment MRI model of placental function that separates signals relating to fetal and maternal perfusion, and estimates feto-placental blood oxygen saturation (fbO2). Previous research found fbO2 was significantly lower in FGR compared to controls (56±6.2%vs75±9.6%, FGR vs control, P = 0.02). The reduction correlated to disease severity. Aims 1. Better understand the MRI features of pregnancies diagnosed with early onset FGR through performing multiparametric placental and fetal MRI with multi-modal placental phenotyping using ultrasound, circulatory proteins and targeted histological analysis. 2. Investigate the utility of previously derived novel MRI marker of placental function in diagnosing placental insufficiency, and their correlation with disease severity. Objectives •Recruit 39 women diagnosed with FGR •Phenotype the placenta with blood biomarkers and ultrasound imaging •Perform multiparametric MRI of the placenta and fetus •Collect clinical outcome data •Perform targeted histology of placental lesions to enhance standard histology •Analyse MRI data, investigating difference in MRI signals within and between placentas, and how these correlate to clinical outcome and histology Developing imaging that relates to placental function and fetal oxygenation and organ perfusion will improve our understanding of placental insufficiency and fetal adaptive strategies. Novel markers have the potential to transform clinical care by better informing management decisions, and so impact on long-term outcome.","Placental insufficiency, where the placenta cannot meet the oxygen and nutritional demands of a growing baby, is responsible for over a third of UK stillbirths. Currently there are no diagnostic tests to determine placental function. There is no safe way of assessing the baby’s oxygen levels in the womb. Doctors rely on ultrasound markers of the disease to make difficult management decisions, including the best time to deliver a baby. They must weigh up the risk of complications from a preterm birth against the risk of injury or death of the baby from remaining in the womb with low oxygen levels. Optimising the information used to make these decisions is vital to the health of the baby and mother. This study aims to discover whether a safe medical imaging technology (Magnetic Resonance Imaging (MRI)) can be developed to assess how well the placenta is working during pregnancy. We have developed an MRI model of placental function that estimates the baby’s blood oxygen level. We want to apply this to investigate: • How MRI markers of placental function relate to pregnancy outcome and postnatal microscopic placental examination in a group of pregnant women with very small babies • How babies adapt to low oxygen levels by imaging other organs Our long-term aim is to establish an effective MRI test of placental function. This will transform clinical care of pregnancies with small babies, by informing doctors on how the placenta is functioning and how this is impacting the baby's health.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_02705,Medical Research Council,MRC,Investigating SARS-CoV-2 Transmission in UK Jewish Communities,"This study, in a UK Jewish community, will investigate the role of children, cross-protection from non-SARS-CoV2 coronaviruses, asymptomatic transmission, household structure, and pre-existing conditions on transmission and burden of disease. This will generate strong evidence for major unknowns in infection natural history, and by using transmission models we can translate findings to improve UK projections of subsequent waves. Uniquely this community has maintained community level records on treatment both within and outside the home for all members providing an unparalleled record of the impact of COVID-19 and combined with their highly-connected population structures and large inter-generational household structures make them an ideal case-study in understanding drivers of transmission in high-risk communities and in particular the role and/or risks associated with children. We will undertake a cross-sectional survey enrolling 500 households. We will collect information on household structure, social mixing, evidence of COVID-19 and collect samples for serological testing for SARS-CoV-2 and HCOV infection. We will collect detailed data on community understanding and perceptions of risk and acceptability and feasibility of future control strategies such as vaccination. We will use these data to fit a mathematical transmission model of SARS-CoV-2 and estimate risk of each transmission in different settings, such as households, schools, synagogues and yeshiva, which is critical as the community (and the country) exit lockdown. By analysing households, we will quantify transmission from children, by comparing the force of infection by household size and composition. This information is critical for re-opening of schools in the Autumn.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION",INFECTION HRCS22_01603,Medical Research Council,MRC,Investigating antibody affinity maturation during B cell exhaustion in viral infection,"The humoural immune system continuously attempts to clear chronic infections where antigen persists. An example of this is HIV infection where anti-viral antibodies continue to be produced until the immune system eventually collapses. Longitudinal sampling shows that the virus mutates to become resistant to antibody neutralisation over time. However, antibodies then develop to neutralise the mutated virus pressuring the virus to mutate again. Recent studies of the co-evolution of antibodies and virus highlight the great selection pressure the antibodies exert on the virus. Thus, it would be advantageous for the virus to employ additional mechanisms to evade humoural responses. I hypothesise that one mechanism is to drive antigen-specific B cells to an exhausted phenotype. This undermines the effectiveness of the immune response by side-tracking HIV-specific B cells away from differentiation into antibody secreting long-lived plasma cells. Chronic infections, including HIV, result in increased frequencies of exhausted B cells (CD21low/CD27low cells). In this study, HIV-specific B cells will be separated by FACS using autologous envelope protein probes. Exhaustion markers will be quantified allowing correlation of antibody affinity for HIV with B cell exhaustion at a single cell level. In addition, transcriptional profiling of each B cell will allow greater definition of their exhaustion phenotype. This will allow evaluation of whether the exhausted subset acts as an alternative cell fate for the B cells that are most highly affinity-matured. To establish whether B cell exhaustion aids virus escape from neutralising antibodies, I will use flow cytometric analysis of longitudinal samples to link the frequency of exhausted B cells with the ability of virus to escape contemporaneous serum neutralisation. From this work I will define whether virus-induced B cell exhaustion limits the appearance of neutralising anti-HIV antibodies and thus contributes to immune evasion.",,1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_15437,Wellcome Trust,,Investigating compounds to increase the efficacy of antimicrobials used for targeting Helicobacter pylori,"The bacteria Helicobacter pylori (H. pylori) is a pathogen that infects the stomach of ~50% of the population, and can led to the development of peptic ulcers and gastric cancer. Although the treatment currently consists of a triple therapy of antibiotics and proton pump inhibitors, many strains have developed a resistance to antibiotics, and the disease can recur within a patient. H. pylori also colonises the stomach within a thick mucus layer, which can prevent drugs from reaching the site of infection. Two compounds have been found to increase the effectiveness of antibiotic therapy against resistant strains within patients; bismuth salts and the long term use of aspirin. I will conduct further research on ways to use these therapies in combination with antibiotics in order to provide a more effective treatment. I will also explore the possibility of encapsulating bismuth salts in a protective protein shell (apoferritin) to aid drug delivery across the stomach mucous. Using additional treatments alongside the antibiotics in treating H. pylori infection may increase their efficacy, and prevent the disease recurring. Elimination of the disease in a patient would also reduce the need for repeated antibiotic treatment, which can lead to incidences of antimicrobial resistance.",,5.1 PHARMACEUTICALS,INFECTION HRCS22_01623,Medical Research Council,MRC,Investigating genetic and environmental risk for psychosis mediated through L-Type voltage gated calcium channels,"Both genetic and environmental factors are known to be important in determining risk for the major psychotic disorders such as schizophrenia and bipolar disorder. Genomic studies have identified genetic variants in L-Type Voltage Gated Calcium Channels (L-Type VGCCs), particularly in the CACNA1C gene, as strongly associated with risk for both schizophrenia and bipolar disorder. Exome sequencing studies of schizophrenia have further confirmed an excess of mutations in L-Type VGCCs in patients compared to controls. This highlights the importance of understanding the molecular and behavioural consequences of mutations in L-Type VGCCs in relation to psychiatric disorders. Calcium entry through L-Type VGCCs plays a critical role in controlling neuronal gene expression and neuronal plasticity. To characterise the specific effects of mutations in CACNA1C associated with psychosis we will investigate the effects of reduced CACNA1C gene dosage on behaviour and the control of gene expression. We will use a novel hemizygotic deletion rat model (Cacna1c +/-) that recapitulates the predicted effects of deleterious point mutations in CACNA1C associated with increased risk for schizophrenia. We will investigate the effects of reduced dosage of Cacna1c on behaviour, focussing on changes in associative learning, and on molecular pathways involved in the regulation of plasticity. We will also investigate the effects of early life stress on the molecular pathways regulated by Cacna1c, building on our recent finding that pre-pubertal stress results in sustained reductions in Cacna1c expression. Finally we will determine whether juvenile stress exacerbates psychosis-related behavioural phenotypes and changes in gene expression in Cacna1c hemizygous deletion animals. This work will be an important step in advancing understanding of the mechanisms through which a major genetic risk locus for psychosis impacts on brain function and how genetic risk interacts with environmental risk.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH HRCS22_03760,Medical Research Council,MRC,Investigating lung regeneration and repair pathways in Cystic Fibrosis,"Cystic Fibrosis (CF) is a lethal genetic condition affecting over 10,000 people in the UK. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator(CFTR) gene leading to decreased function of the CFTR chloride channel. CF patients develop a destructive lung disease as a consequence of this, associated with significant morbidity and mortality. Despite advances in care, the median age of death is 32, and the only cure for advanced lung disease is transplantation. Novel CFTR modulators partially correct the abnormal chloride transport in CF and have significant effects on mucus clearance and lung function, but leave patients with residual lung damage. Basal cells are present throughout the human airways and migrate and proliferate in response to injury, acting as stem cells. They produce different progeny cells in steady state and repair, so may be an excellent target to develop strategies that augment lung repair. Aims: 1. To phenotype basal cells from people with CF compared to healthy controls in terms of gene expression, proliferation and migration. 2. To assess proliferation and differentiation of CF 3D organoid culture compared to healthy controls and assess regenerative capacity after injury 3. To test whether CFTR modulators affect basal cells and can promote repair in 3D organoid culture. 4. To compare clinical outcomes following CFTR modulator therapy in people with CF with novel outcomes of repair and established measurements of inflammation. Methods: I will undertake basal cell culture and 3D organoid culture of patients with CF and healthy controls. These will then be characterised with RNAseq, qPCR, and immunohistochemistry. Migration and proliferation assays will be performed. Basal cells and organoids will be co-cultured with CFTR modulators to compare with clinical outcomes in vivo. The potential of lung tissue to regenerate and repair is accepted but has not been extensively studied, particularly in CF.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES,CONGENITAL DISORDERS HRCS22_06835,Department of Health and Social Care,NIHR,Investigating methods of incorporating Real-World Data in Health Technology Assessment (HTA) Decision-Making: application in Rheumatoid Arthritis,"Research question This project will determine how statistical methods can be developed to incorporate evidence from non-randomised studies into a health technology assessment (HTA). In particular, how to combine data from randomised controlled trials (RCT) with real-world data (RWD) to improve the appropriateness of clinical effectiveness estimates. The evaluation of biologic treatments for patients with rheumatoid arthritis (RA) will be used as a case-study. Background A HTA seeks to evaluate a medical intervention by synthesising evidence regarding its safety, clinical effectiveness, and cost effectiveness. The clinical effectiveness evidence is largely based on RCT data. This evidence is reliable because RCTs have high internal validity. However, findings from RCTs are not always generalizable to the patient population. RWD refers to data collected from sources other than RCTs (e.g. patient-registries or single-arm trials). RWD are more reflective of observations seen in everyday clinical practice, but are susceptible to bias. HTA agencies have acknowledged potential advantages in combining RCT data with RWD, and recommend further research into methodological development for this purpose. Aims To identify and develop meta-analytic methods which can be used to synthesise clinical effectiveness data obtained from RCTs and RWD, whilst accounting for bias inherent in RWD. To evaluate the methods under different conditions, with a focus on individual participant data (IPD) availability, and the number of RCTs in the synthesis. To investigate how the methods can be developed to adjust for bias in clinical effectiveness estimates recorded over time. To investigate how the methods impact on decision model estimates and conclusions in HTAs.Methods I will update a systematic literature review to identify existing meta-analytic methods combining RCT data with RWD. I will then develop and apply the methods to combine IPD from RCTs and single-arm studies in RA. I will also apply the methods to data from the Clinical Practice Research Datalink. I will perform a simulation study to evaluate methods by applying them to datasets generated under conditions where the number of studies with available IPD is varied, the number of RCTs is varied. I will develop and apply bias-adjustment methods (e.g. multivariable regression) to update Health Assessment Questionnaire estimates recorded over time, using data from the British School of Rheumatology - Biologics Register. I will update a published HTA by implementing the methods to obtain an adjusted pooled clinical effectiveness estimate, and re-run the decision model to calculate an updated incremental cost effectiveness ratio estimate.Anticipated impact and dissemination The research undertaken in this project will be detailed in articles submitted for publication to relevant academic journals. I will communicate my research findings via a public and patient advisory group. I will present my work at international conferences attended by expert researchers. The work will impact other researchers who are interested in methodological development and evidence synthesis, and aid analysts, performing future HTAs, in a more robust synthesis of diverse sources of evidence. Ultimately, it will enable HTA agencies to make better decisions regarding treatments, improving the healthcare-quality experienced by patients in the National Health Service.","Background to the research In research, the best way to test whether a treatment works is to do a clinical trial. This usually involves randomly giving a patient one treatment and comparing it with another treatment. This is called a 'randomised controlled trial'. However, at least half of patients are not allowed to be in clinical trials. This is because researchers want participants to be very similar to one another so that they can test the treatment properly. Patients might be excluded if they cannot consent for themselves (e.g. due to disability). They might also be excluded because they have other diseases or are very sick. These people still need to be treated when they are seen by a doctor. It can be difficult for doctors to know what to prescribe for them because they don't know what works. As a solution, researchers will often look at information from everyday practice to look at people who cannot be in clinical trials. This might include information from GP surgeries, walk-in clinics or hospital appointments. We call this 'real-world data'. It includes seeing whether patients get better when they are prescribed a treatment by looking at their measurements. However, real-world evidence has weaknesses over clinical trials because patients are not selected randomly so there might be other reasons that they are getting better or worse. For some treatments, there may be a lot of evidence from clinical trials and real-world data. This evidence is usually summarised in a document called a 'Health Technology Assessment' (HTA). The Government's National Institute for Health and Care Excellence (NICE) relies on these HTAs to work out if a treatment is of good value. They then make recommendations to the National Health Service on what treatments to buy. They have said that researchers should look at methods of combining information from clinical trials and real-world data so that they get the best picture about what works. Aims The aims of my study are: To build-on current methods for combining information from clinical trials and real-world data. To test these methods in the real-world setting. To adapt the methods to assess information from real-world data To look into how the different methods affect conclusions in HTAs.Methods To achieve the aims: I will look at previous research on methods of combining information from clinical trials and real-world data. I will then apply the methods to see what treatments work for patients with rheumatoid arthritis. I will use a computer program to create artificial (made-up) measurements to see how the methods perform in different situations. In particular, when there are not many clinical trials about the treatment. I will add to the methods and apply them to information recorded over time using the Health Assessment Questionnaire from a patient registry. I will see whether using the new methods improves the estimates of the treatment's value. I will update a previous HTA that assesses treatments for rheumatoid arthritis and see if the conclusions change.Patient involvement A group of patients with rheumatoid arthritis will help me with this project. I will ask them to tell me about outcomes that are important to them. I will also talk about the work I have done and how it will impact them as service users. Dissemination I will write up my work in research articles so that other researchers have a chance to look at my work. I will tell people about my study using social media. I will also go to conferences around the world to tell people about my findings.",8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),INFLAMMATORY AND IMMUNE SYSTEM HRCS22_15620,Wellcome Trust,,Investigating protein synthesis during dormancy in Pseudomonas aeruginosa,"Much of our understanding of bacteria, and the biological processes which sustain them, comes from the study of rapidly growing populations in nutrient-rich conditions. However, in natural environments and during infections, bacteria are often stressed and starved of key nutrients. Upon starvation, many bacteria dramatically reduce biological processes and effectively enter a hibernating state where they become highly tolerant of antibiotics. I’m interested in how bacteria regulate this state of dormancy, both at the single-cell level and across populations of cells. Specifically, since data suggest that rates may fluctuate between cells, I’m interested in how protein synthesis is coordinated in time and space during starvation and how these dynamics relate to antibiotic susceptibility. Using the opportunistic pathogen Pseudomonas aeruginosa, I will label and analyse protein synthesised during starvation via fluorescence microscopy and FACS. By employing a FACS-based Tn-Seq screen and mass-spectrometry to find proteomic changes, I will identify, validate and characterise regulators of protein synthesis during starvation. This study will provide both a descriptive and a mechanistic understanding of protein synthesis during bacterial starvation, giving insights into how this activity coordinates with cellular physiology and contributes to antibiotic tolerance.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_15313,Wellcome Trust,,Investigating the behavioural and neurobiological effects of SSRI discontinuation in mice,"Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression in the UK. However, they have long been known to cause adverse symptoms upon abrupt discontinuation, including heightened anxiety, sleep disturbances, nausea and dizziness. Despite evidence that over half of patients will experience SSRI discontinuation symptoms, there is very little research on the condition or its causes. This project aims to study the effects of discontinuation of long-term treatment with the SSRI paroxetine, in adult mice. First, we will optimise a protocol of long-term paroxetine treatment and discontinuation. Behavioural measurements of key SSRI discontinuation symptoms, including anxiety, will then be measured during the discontinuation period. Discontinuation symptoms may be caused by the rapid depletion of the neurotransmitter 5-hydroxytryptamine (5-HT), hence a combination of modern neuroscience techniques including large-scale monitoring of 5-HT neuron firing and high-speed measurement of 5-HT release dynamics will be used to explore this possibility. Finally, we will use a chemogenetic approach to precisely manipulate 5-HT neurons to investigate their causal role in SSRI discontinuation symptoms. We hope this research will elucidate the underlying mechanisms of SSRI discontinuation symptoms and will place us in a good position to deliver clinical advances vitally needed in this area.",,6.1 PHARMACEUTICALS,MENTAL HEALTH;NEUROLOGICAL HRCS22_15509,Wellcome Trust,,"Investigating the biological function of the E3 ligase, HOIL-1","Ubiquitin is a small protein that is attached to different targets affecting their subsequent behaviour. This addition can ‘tag’ the target for destruction by the cell, affect its localisation or promote various interactions with other proteins. E3 ligases are a group of enzymes responsible for the addition of ubiquitin onto a target, and I am interested in an E3 ligase termed HOIL-1. People who lack HOIL-1 accumulate abnormal glucose deposits called polyglucosan in their cardiac tissue, leading to heart failure. These observations suggest that HOIL-1 has a critical role in preventing the accumulation of such deposits and the overall goal of my project is to discover how this is achieved. In my initial experiments, I found that HOIL-1 is able to attach ubiquitin to glucose and thus, I hypothesise that by tagging with ubiquitin, HOIL-1 marks this molecule for destruction. People lacking HOIL-1 cannot initiate destruction and therefore accumulate the abnormal polyglucosan deposits. My aim for this project is to gain insight into how ubiquitin is added by HOIL-1. Furthermore, I aim to identify additional targets associated with HOIL-1. By discovering its targets, we can further understand its role within the human body and consequently, its potential role in disease.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_17867,Versus Arthritis,,"Investigating the clinical utility of the type-I interferon signature as a predictive biomarker for response to rituximab, and understanding how it drives B cell dysfunction in SLE","B cells are central to the pathogenesis of systemic lupus erythematosus (SLE), thus providing the rationale for the use of rituximab (B cell depletion) therapy. However, not all SLE-patients respond to rituximab, and upon B cell repopulation some patients relapse. In addition to B cell abnormalities, an upregulation of interferon (IFN)-I-induced genes in the blood (IFN-I signature) has been identified in 60-80% of SLE-patients. We have recently demonstrated that the concentration of IFNα is critical in determining the fate of immature-naive B cell maturation. At lower concentrations of IFNα, B cells differentiate into both plasmablasts and immunosuppressive regulatory B cells (Bregs), whereas at higher concentrations the B cell response is channelled towards plasma cell maturation. Furthermore, SLE-patients with an elevated IFN-I signature show a skewed response towards autoantibody-producing plasma cells and reduced Breg frequency. We hypothesize that an elevated IFN-I signature in SLE-patients predetermines clinical response to rituximab-therapy. We propose that the lack of response is due to high levels of IFNα inhibiting the differentiation of newly repopulated immature B cells into Bregs whilst promoting autoantibody production. To test this, we propose to screen SLE-patients prior to and after rituximab for IFNα-signature, autoantibodies to IFNα, Breg frequency/function, and autoantibody-producing plasma cells. We will evaluate how signals downstream of the IFNα receptor on B cells change in response to increasing concentrations of IFNα, and whether inhibiting certain signals restores Breg function in SLE-patients. Furthermore, we will assess how IFNα alters chromatin accessibility and transcriptional output of the IL-10 locus on immature B cells in rituximab-treated SLE-patients that relapse after B cell repopulation. Our work will provide a novel tool to predetermine response to rituximab. Identification of the biological pathways by which high-levels of IFNα inhibit Breg differentiation could lead to new therapies, and also benefit patients with other IFNα-driven autoimmune diseases.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_15483,Wellcome Trust,,Investigating the cytoprotective role of NRF proteins against drug-induced cardiovascular toxicity,"Many drugs used to treat cancers and HIV cause life-threatening heart problems which limits their use. Research into how to reduce this risk has previously been difficult due to a lack of experimental methods which accurately mimic the human cardiac system. However, new 3D human-cell models have been developed which reproduce the adverse drug reactions seen in patients. These new models have been used to show that increased expression of an important protective protein NFE2L (NRF2), provides protection from the toxic effects caused by a commonly used breast cancer drug. We believe that by increasing the activity of human NFE2L proteins (NFE2L1-3), we may protect cardiac cells from other adverse drug effects. Here, we will combine 3D human cardiac models with gene editing methods and advanced cell imaging techniques to manipulate expression of all NRF family proteins and monitor the protective effects under normal and high-glucose conditions, which are known to reduce the protective effects of NRF2. The results from this study will aid the development of new therapeutic strategies to prevent or reverse heart toxicity from commonly used cancer and HIV drugs.",,5.1 PHARMACEUTICALS,CARDIOVASCULAR HRCS22_09307,"Chief Scientist Office, Scotland",CSO,Investigating the epidemiology of endemic Giardia in Scotland using a whole genome sequencing approach,"The Scottish Parasite Diagnostic and Reference Laboratory and Health Protection Scotland have established that the majority of Scottish cases of the gastrointestinal parasite Giardia duodenalis are acquired locally rather than being travel-related; the source of infection in most cases is unknown. We will investigate molecular diversity and epidemiology of Giardia in Scotland using whole genome sequencing (WGS). We will develop a novel WGS-based parasite genotyping system, applying it to a large collection of human isolates collected in Scotland, to determine molecular types and to identify genetically-linked clusters of cases. Information will be integrated with metadata from Health Protection Scotland to improve understanding of Giardia epidemiology. We intend to improve healthcare in Scotland through (a) increasing capacity to characterise parasites at a molecular level, (b) determining the presence and distribution of zoonotic strains and (c) developing molecular/bioinformatic tools to underpin disease surveillance and control, allowing evidence led changes to laboratory testing policies. The tools developed in this project will permit the identification of genetically-linked clusters of cases, allowing for the detection and management of outbreaks. These tools can also be used to trace transmission routes in order to provide evidence for risk assessment.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_19327,Wellcome Trust,,Investigating the functional basis of shared genetic etiology across autoimmune diseases,"Autoimmune diseases are a diverse set of conditions afflicting ~10% of the population worldwide, they pose a substantial personal and socioeconomic burden, and they have no cure. Currently prescribed treatments have variable efficacies and can be associated with severe side effects such as malignancies and even fatal opportunistic infections. Designing improved therapeutic strategies requires a better understanding of the pathways that drive these conditions to achieve an optimal modulation of the immune system. Investigating the biological consequences of disease-associated genetic variants provides an avenue for delineating critical pathophysiological mechanisms. However, for each of these conditions, tens to >100 different loci have been found to influence disease risk. Therefore, prioritization is required, and the approach taken in this proposal is to focus on genetic variation shared across multiple autoimmune diseases, including a polymorphism in the tyrosine kinase 2 (TYK2) gene that protects against no fewer than 11 such conditions. The key goals of this research are to (i) investigate the molecular basis of shared genetic risk across autoimmune diseases; (ii) elucidate the downstream signatures and impact of shared genetic risk to help define key disease pathways; and (iii) investigate how key disease pathways can be fine-tuned for maximal benefit.","Autoimmune diseases are thought to arise when cells of the immune system - which normally fight off infections - become inappropriately activated and instead mount a response against the body leading to pervasive tissue damage. These diseases, which include conditions such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and inflammatory bowel disease, are estimated to afflict ~10% of the population worldwide. They pose a substantial personal and socioeconomic burden and they have no cure. There is a fundamental need to develop improved therapeutic strategies to treat these diseases through an optimal modulation of the immune system - that allows substantial symptom alleviation - but without leading to the severe or even fatal side effects that can occur with currently available treatments. Interrogating the biological consequences of genetic factors that contribute to the development of multiple autoimmune conditions provides an approach for elucidating key mechanisms underpinning these diseases. The proposed research aims to (i) investigate the basis of shared genetic risk across different autoimmune conditions at the molecular level; (ii) elucidate the downstream cellular changes arising due to the genetically determined molecular differences to help define key disease pathways; and (iii) investigate how key disease pathways can be optimally regulated.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_22794,The Academy of Medical Sciences,AMS,Investigating the impact of adiposity-redox defence interaction on redox homeostasis and inflammatory and cancer-related pathways in human colonocytes,"Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and numbers continue to rise. CRC is a complex, multifactorial and multistage disease. Notably, abdominal/visceral fat is a major risk factor for obesity-related diseases and, in particular, cancer. Adipose tissue excess promotes changes in redox homeostasis and inflammation, modifying adipokines and reactive oxygen species (ROS) production/secretion. As such, low-grade inflammation promotes adverse metabolism, affecting homeostasis of redox systems and promoting modification in cell metabolism and signalling cascades at the level of colonocytes. Systematic oxidative stress and inflammation are, therefore, closely interlinked in obesity, but the effect of oxidative stress on colonocytes and its contribution to CRC pathogenesis is not fully understood. Although the body has mechanisms to prevent initial changes related to inflammation and oxidative stress, this redox homeostasis is compromised in excessive weight, and antioxidant defences reduced. Moreover, consumption of essential micronutrients is reduced in obese individuals, leading to malnutrition. Low selenium (Se) intake has been associated with increased body fat and modulation of redox status and inflammation in adiposity and with increased CRC susceptibility. Considering the interplay between adiposity, inflammation, oxidative stress and cell signalling, and in view of relatively low Se status in obese individuals, this project aims to i) assess the impact of adiposity on coloncytes’ metabolic and cell signalling pathways, inflammation and oxidative stress; ii) characterise the effect of modulating antioxidant defences, via Se supplementation, on the interplay between adipocytes and colon cells. A novel approach to co-culture adipocytes (from lean or obese individuals) with colon cells will be used to explore how soluble factors present in adipocytes’ microenvironment affect colonocytes homeostasis and this cross-talk influences oxidative stress, inflammatory and cancer-related pathways. This system will allow to i) understand how oxidative stress and inflammation in adipocytes from obese, compared to adipocytes from lean individuals, may affect inflammation, oxidative stress, antioxidant defences’ markers and cellular bioenergetics in colonocytes and induce activation of cancer-related pathways; ii) identify how Se supplementation may regulate such biomarkers in colonocytes. This proof-of-principle work will provide evidence, in an in-vitro system, of the molecular mechanisms by which oxidative stress/inflammation levels within adipocytes may be regulated by Se and colon epithelial cells’ homeostasis maintained. By providing a strong mechanistic understanding of the molecular links, it will offer unrivalled opportunities to identify potential new therapeutic targets and inform multinational intervention studies, which will define nutritional recommendations for optimal health and lead to future preventive","Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related death in people. Increased body fat (obesity and overweight) have been reported as one of the main factors responsible for the rise in CRC cases. For this reason, a major focus for research, as well as public health policy, is to understand the mechanisms by which obesity impacts on cancer development and how these mechanisms can be altered to prevent or treat this condition. Excessive body weight promotes changes in the body that make it more susceptible to signals (e.g. inflammation and oxidative stress) that impair the antioxidant defences of the cells, especially in the colon. In addition, obese individuals usually have reduced fruit and vegetable intake consumption and consequently low intake of micronutrients important for optimal health and regulation of antioxidant defences, such as the micronutrient Selenium (Se). This project aims, therefore, to investigate the impact of adiposity on cell metabolism, inflammation and oxidative stress in the colon. An in-vitro system comprising of cells from fat and colon tissue cultured together will be used to identify the mechanisms involved and to define the role of Se in modulating such pathways. By providing a strong understanding of the molecular links between oxidative stress, inflammation in colon epithelial cells associated with obesity and carcinogenesis, and by identifying key biomarkers related to antioxidant defences, this study will offer a great opportunity to define potential new targets and develop, in the future, preventive and therapeutic strategies.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_19605,Cancer Research UK,CRUK,Investigating the metastatic microenvironment in pancreatic cancer,"Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. We recently found that PDAC liver metastasis critically depends on the early recruitment of metastasis associated macrophages (MAMs) to the liver, resulting in the transactivation of resident hepatic stellate cells into myofibroblasts (mFbs) and the formation of a growth promoting metastatic niche. Our recent findings suggest that MAMs and mFbs also suppress cytotoxic T cell functions at the metastatic site, thereby allowing disseminated cancer cells to escape immune surveillance. Our data suggest that MAMs and mFbs play a key role in PDAC metastasis and may serve as potential therapeutic targets for PDAC liver metastasis. However, the molecular mechanisms needed to form a hospitable metastatic niche remain poorly understood. Aims: Our overall objective is to gain a better understanding of how MAMs and mFbs affect anti-tumour immunity at the metastatic site of PDAC, in order to develop more effective therapeutic approaches for metastatic pancreatic cancer patients. The specific objectives are: 1. To understand the role of macrophage-derived granulin in T cell infiltration at the metastatic site. 2. To identify MAM and mFb immunosuppressive factors that inhibit cytotoxic T cell functions in metastatic PDAC. 3. To test, in pre-clinical PDAC metastasis mouse models, whether genetic and pharmacological blockade of granulin, and the newly identified immunosuppressive regulators, restores anti-tumour immunity. Methods: - Molecular tools and genetic mouse models to study the role of macrophage-derived granulin in T cell exclusion in metastatic PDAC. - Flow and mass cytometry analysis to understand the effect of granulin on immune cell infiltrates at the metastatic site. - RNA-Seq and bioinformatic analysis to identify characteristic immunosuppressive transcriptional profiles of MAMs and mFbs derived from mouse and human PDAC liver metastases. - In vitro primary cell co-culture models to assess the molecular mechanisms by which MAMs and mFbs suppress T cell functions. - Pre-clinical imaging to understand the effect of MAMs and mFbs immunosuppressive functions in metastatic PDAC mouse models. - Fresh and archived liver biopsies from metastatic PDAC patients to validate our findings obtained from pre-clinical animal models. How the result of the research will be used: In this proposal we aim to understand the mechanisms by which MAMs and mFbs impair anti-tumour immunity in order to develop more effective combination therapies for metastatic pancreatic cancer, a disease with unmet clinical needs.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_17694,Wellcome Trust,,Investigating the molecular mechanisms of intracellular bidirectional cargo transport,"Intracellular trafficking pathways depend on the opposing microtubule-based motors kinesin and dynein. Both types of motor can simultaneously bind the same cargo for bidirectional transport on microtubules. Kinesin and dynein bind to many of the same cargo adaptors (e.g. BICD-family). However, it is unclear how opposite-polarity motors are linked to the same vesicle and how adaptors regulate directional switches in the cell. My research goal is to use post-Golgi Rab6-vesicles to investigate how bidirectional transport is coordinated. Mechanistic insight into this process is necessary to understand how cells correctly distribute cargo to maintain their function. I will first structurally characterise how purified Rab6 recruits motors and adaptors. I will subsequently reconstitute bidirectional motility of Rab6-liposomes in vitro with purified proteins. With this tool, I will explore how combining different motors and BICD adaptors alters motile behaviour using single-molecule total internal reflection microscopy. To address how motors are organised during bidirectional transport, I will determine the architecture of a multi-motor Rab6-liposome complex on microtubules using cryo-electron microscopy and tomography. Structural observations will be validated using site-directed mutagenesis and imaging of Rab6-vesicles in cells using lattice light-sheet microscopy. Together, this will provide extensive structural and functional information about dynamic bidirectional transport mechanisms.","Cells require accurate transport of organelles and vesicles to maintain their proper function. Transport of cellular cargo is mainly carried out by molecular motors kinesin and dynein. These motors walk on microtubules, which act as polarised tracks to allow trafficking in the cell. Kinesin and dynein move in opposite directions on microtubules yet can bind to the same cargo. This leads to back-and-forth movement of cargo (bidirectional transport) but the regulation of directional switches is unclear. My goal is to understand how kinesin and dynein activities are coordinated on bidirectional vesicles. To this end, I will primarily use protein biochemistry, electron microscopy and fluorescence-based microscopy techniques to investigate the structure and dynamics of bidirectional vesicles. Together, this will provide a mechanistic insight into what happens to the kinesins when dynein is active (or vice versa) and how distribution of cargo is regulated to ensure a cell's function is maintained.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_19965,Wellcome Trust,,Investigating the physiological DNA replication initiation reaction,"In all cells chromosome replication requires key initiator proteins to unwind the DNA at specific sites termed origins. Despite the fundamental importance of DNA replication initiation, crucial aspects of the process remain poorly understood. My vision is to identify all essential features of both the bacterial replication origin and DNA replication initiation proteins in vivo. This comprehensive reverse genetic analysis will guide biochemical investigations into the activities associated with deleterious mutations, thereby revealing the interactions and steps necessary for the physiological initiation reaction. Towards this goal I have created a bespoke tool: an inducible heterologous replication initiation system that allows construction and characterization of mutations within endogenous replication initiation factors. This methodology, combined with assays we developed to analyze DNA replication initiation in vitro, led us to identify a new essential bacterial replication origin element (Richardson et al. Nature 2016). We will build upon this successful approach and go on to develop more sophisticated heterologous replication systems, opening the door to studying all aspects of chromosome replication. Importantly, the bacterial DNA replication machinery is an underexploited drug target. Knowledge of bacterial DNA replication resulting from this work will provide a guide for disrupting this process in pathogenic species.","In all organisms genome duplication is required for cell proliferation. This essential process involves the concerted activity of several multiprotein complexes to replicate an exact copy of the DNA. The bacterial DNA replication machinery is significantly simpler than the related eukaryotic system, making it well-suited for detailed analysis. Additionally, the bacterial DNA replication machinery is an attractive drug target, and new antibiotics are urgently needed to combat drug-resistant strains. In all cells chromosome replication requires key initiator proteins to unwind the DNA at specific sites termed origins. Despite the fundamental importance of DNA replication initiation, crucial aspects of the process remain poorly understood. This knowledge-gap is a result of DNA replication being an essential activity required for cell viability. To circumvent this challenge I have developed new tools that allow the normally essential DNA replication initiation factors to be either removed or mutated. This opens the possibility of determining all of the sites within both the chromosome origin and the initiation proteins required for DNA replication initiation. My long-term goal is to expand this toolkit and investigate the entire DNA replication machinery.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_22979,The Academy of Medical Sciences,AMS,Investigating the pleiotropic effects of aneuploidy in antifungal resistance.,"Antifungal resistance is a rapidly emerging global problem, and the fact that fungal pathogens can leverage genome instability (e.g., aneuploidy) to evolve resistance is a major impediment to developing effective antifungal drugs. My research proposal aims to address the multi-scale effects of aneuploidy in antifungal resistance. The goal is to define predictable, targetable changes in fungal cells and at the host-fungal interface during the evolution of antifungal resistance. Aneuploidy, a genome with gain or loss of chromosomes, is detrimental for cellular fitness; however, it is also associated with hyperproliferative diseases, including cancer. In clinical fungal isolates, aneuploidy is frequently observed to confer phenotypic variation and drives resistance by overcoming antiproliferative stress. Despite its clinical importance, no direct strategies are available against aneuploid diseases. My recent work, for the first time, identified a hypo-osmotic signature commonly associated with the aneuploid state, independent of its random karyotypes, and this biophysical property may underlie the high adaptability of aneuploidy to antifungals. Here, I propose to investigate how aneuploid fungi leverage their unique biophysical changes to provide a permissive extracellular (Aim 1) and intracellular (Aim 2) environment for tolerating the host and antifungal stress. Furthermore, evolutionary genomics approaches will be used to elucidate the genetic basis of acquired antifungal resistance (Aim 3). My discoveries in this research program will not only improve our understanding of diseases associated with large-scale genome instability but also provide a paradigm shift for antifungal designs based on distinctive host-fungal interactions and physical-chemical properties triggered by aneuploidy.","Fungal infections affect billions of people worldwide and cause >1.5 million deaths each year. Despite the high mortality, over the past 30 years, only three classes of antifungal drugs are available to treat patients, and the unmet clinical needs of new antifungals remains unsolved. Consequently, life-threatening multidrug-resistant fungal pathogens (“superbugs”) have emerged rapidly in the past decade. The CDC has listed two common human fungal pathogens, both Candida species, as major antibiotic-resistance threats. A common challenge to thwart antifungal resistance is that fungi survive antifungal therapies by frequently altering their genome contents, such as aneuploidization (gaining or losing chromosomes), through erroneous cell divisions. This is commonly observed in clinical fungal isolates as fungi can immediately become aneuploid after entering the host due to the host stress. To stop this process, my work aims to identify key mechanisms underlying the development of antifungal resistance in aneuploid fungi. I recently discovered a general stress state caused by excessive water inflow in aneuploid cells, and this observation establishes a causal link between biophysical changes and cellular adaptability, enabling antifungal resistance. Here, I will first identify protein factors from aneuploid fungi that protect fungal populations from the host and antifungal stress. Then, I will investigate how aneuploid fungi “buffer” stress to survive antifungal therapies. Lastly, I will evolve fungal pathogens under antifungal stress to track genomic changes and further predict the onset of antifungal resistance. Together, the research outputs from this project will significantly improve our understanding of aneuploid diseases to combat antifungal resistance.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_20225,Wellcome Trust,,Investigating the role of lung Tissue resident memory T-cell in the immunopathology of human TB,"This proposal will examine the involvement of lung Tissue resident memory (Trm) T-cells in the human immune response to TB. Using unique access to fresh human lung tissue, we find evidence of non-recirculating T-cells, consistent with a Trm subset. The importance of Trm to pathogen immunity is becoming increasingly apparent and limited data from mice indicates they are highly active against TB. However, nothing is known about their role in humans and this is important because, as Trm do not recirculate, they are missing from TB immunology data generated to date, which comes from blood. Even bronchioalveolar lavage does not accurately describe the Trm response. We know T-cells are crucial for immunity to TB, and our failure to establish T-cell correlates of protection may come from not taking Trm into account. We will use novel tools, including single cell sequencing, Mass Cytometry and multiparimeter fluorescence microscopy to investigate the role of Trm in the TB response in human lung. Then, using a novel 3D-granuloma model we will test this observational data to determine the functional details of protective or harmful T-cell responses. This will establish the T-cell correlates of protection in humans and provide a basis for rational vaccine design.","TB remains the leading cause of death from infectious disease globally, and an improved vaccine is desperately needed. Unfortunately, the most recent attempt to do so failed. The truth behind this failure is that, as a field, we still do not understand the immune correlates of protection and therefore, vaccine development remains a shot in the dark. TB is primarily a disease of the lung, and yet immune correlates of protection in humans have been exclusively studied the blood. There is a growing understanding that blood and tissue are not the same; and that many immune cells, once in tissue, do not in fact recirculate. This proposal seeks to address this problem by studying TB immunity in human lung tissue. This will revolutionise our understanding of human TB immunology and represents the best chance of discovering the immune correlates of protection, from which an improved TB vaccine can be developed.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM;INFECTION HRCS22_13945,Action Medical Research,,Investigating the role of transcription factor GATA1 in Diamond-Blackfan anaemia pathogenesis and diagnosis,"Background _x000D_ Diamond-Blackfan anaemia (DBA) is a very rare inherited condition, usually diagnosed within the first year of life and characterised by severe anaemia. Anaemia is a condition where there are too few red blood cells in the blood and therefore not enough oxygen can be carried around the body. This results in persistent tiredness and other symptoms such as breathlessness, headache, rapid heartbeat and difficulty in concentrating. Around half of children with DBA also have physical changes - they are often short for their age and may have delayed puberty. There is presently no cure for DBA and long-term treatment involving regular blood transfusions or steroid drugs can cause complications. Around 70 per cent of children with DBA have been found to have faulty genes affecting the ribosomes, tiny structures found in all cells which make new proteins. These gene changes (or mutations) cause impaired synthesis of a protein, GATA1, which is essential for the production of new red blood cells. Inadequate levels of this protein result in anaemia. However, this explanation does not account for the 30 per cent of children with DBA who do not have ribosomal gene mutations. In addition, rare mutations in the GATA1 gene itself have been also been identified in DBA patients, further highlighting the critical involvement of this protein in DBA. _x000D_ _x000D_ The research project_x000D_ These researchers have provided evidence suggesting that, as part of its role in red blood cell production, the GATA1 protein may also control genes that are responsible for the production of ribosomes themselves. They now plan to investigate directly the possibility that GATA1 controls ribosome production in red blood cells and to test their prediction that rare mutations in the GATA1 gene could impact on ribosome production and lead to DBA. The team will also explore the development of a new diagnostic test to identify mutations in GATA1-controlled ribosomal genes that may account for some of the undiagnosed DBA cases. This work will improve our understanding of the causes of anaemia in DBA and could ultimately lead to new treatments and improved diagnosis for children who do not currently have a confirmed genetic explanation. _x000D_","Background _x000D_ Diamond-Blackfan anaemia (DBA) is a very rare inherited condition, usually diagnosed within the first year of life and characterised by severe anaemia. Anaemia is a condition where there are too few red blood cells in the blood and therefore not enough oxygen can be carried around the body. This results in persistent tiredness and other symptoms such as breathlessness, headache, rapid heartbeat and difficulty in concentrating. Around half of children with DBA also have physical changes - they are often short for their age and may have delayed puberty. There is presently no cure for DBA and long-term treatment involving regular blood transfusions or steroid drugs can cause complications. Around 70 per cent of children with DBA have been found to have faulty genes affecting the ribosomes, tiny structures found in all cells which make new proteins. These gene changes (or mutations) cause impaired synthesis of a protein, GATA1, which is essential for the production of new red blood cells. Inadequate levels of this protein result in anaemia. However, this explanation does not account for the 30 per cent of children with DBA who do not have ribosomal gene mutations. In addition, rare mutations in the GATA1 gene itself have been also been identified in DBA patients, further highlighting the critical involvement of this protein in DBA. _x000D_ _x000D_ The research project_x000D_ These researchers have provided evidence suggesting that, as part of its role in red blood cell production, the GATA1 protein may also control genes that are responsible for the production of ribosomes themselves. They now plan to investigate directly the possibility that GATA1 controls ribosome production in red blood cells and to test their prediction that rare mutations in the GATA1 gene could impact on ribosome production and lead to DBA. The team will also explore the development of a new diagnostic test to identify mutations in GATA1-controlled ribosomal genes that may account for some of the undiagnosed DBA cases. This work will improve our understanding of the causes of anaemia in DBA and could ultimately lead to new treatments and improved diagnosis for children who do not currently have a confirmed genetic explanation. _x000D_",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,BLOOD HRCS22_15309,Wellcome Trust,,Investigating the roles of transcription factor eomesodermin in the establishment and maintenance of the trophoblast lineage in the early mouse embryo,"The placenta is an organ crucial in supporting the development of mammalian embryos. The cells that ultimately produce the placenta (“trophectoderm” or “trophoblast” cells) produce important signals to pattern the developing embryo, and the placenta itself is instrumental in transporting nutrients to, and waste products away from, the embryo. Eomesodermin (eomes) is a protein essential in the specification and maintainance of trophoblast cells, and the trophoblast stem cells that can be derived from the embryo. However, its mechanism of action hasn't been investigated in depth. Therefore, in this project, we will ""tag"" the eomes protein, allowing us to isolate it from the cell, and observe what regions of the DNA it binds to, what genes it thus activates, and which proteins it interacts with. Once we identify potential “target” genes of eomes, we will delete them from trophoblast stem cells, as well as from embryos themselves, to see what the effects are on the development and maintenance of trophoblast cells and the placenta. This will help dissect the function of eomes and its target genes in the placenta and embryonic development. This, in turn, can also give us insight into placental defect-associated diseases in human embryonic development.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_15324,Wellcome Trust,,Investigating whether Human Embryonic stem cell derived Neuromesodermal progenitors require positional identity to produce spatially restricted progeny.,"The neuromesodermal progenitors (NMPs) are a group of cells found in the developing embryo, which form the spinal cord and surrounding muscle.  NMPs are present at the tail end of the embryo, first producing the head, then trunk and finally the tail end, changing the genes they express as they do this. A subset of these time-regulated genes includes the HOX genes, named HOX1-HOX13. At early stages, NMPs poised to make the neck express HOX1, while successively later NMPs that make the trunk and tail progressively express more of the genes until HOX13 is expressed in tail tip.  Studies removing these genes showed that each one is necessary to make vertebrae of a particular identity.  It is unknown whether the expression of HOX genes in NMPs at different times during development is important to set identity. It is currently only possible to make NMPs in culture with neck and upper trunk identity.  Therefore, I hope to develop a method to make human NMPs which express all the Hox codes.  Once we have done this, we will research what is controlling how the cells gain Hox identity.  Finally, I will research if HOX code controls NMP differentiation when placed into embryos.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_15663,Wellcome Trust,,Investigation of base and prime editing to correct COL7A1 mutations and development of organoid model for RDEB,"Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a severe skin disease with no cure. Normally, two layer of the skin are held together by rope like structures called anchoring fibrils, which are made of Type VII Collagen (C7). However, in patients with RDEB the anchoring fibrils don’t work and the layers of the skin are fragile, resulting in blistering, chronic wounds, and cancer. RDEB is caused by mutations in the gene COL7A1, which makes C7. I aim to correct those COL7A1 mutations with new gene editing tools called base editor and prime editor, to fix the anchoring fibrils in patient cells. After editing COL7A1, I will use molecular techniques including Sanger sequencing, qPCR, western blot and immunofluorescent microscopy to confirm if the edit worked and if it fixed C7 function. It’s also important to know whether the gene editors have affected areas of the DNA which I don't want to edit, so I will do “off-target analysis” to test the safety of these tools. Additionally, I aim to make 3D models of ""RDEB skin in a dish"" to aid future research. By the end of my PhD I aim to have aided the development of potential cures for RDEB.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,SKIN;GENERIC HEALTH RELEVANCE HRCS22_22730,The Academy of Medical Sciences,AMS,Investigation of the correlation between bone-defect healing and the mechanical loads occurring in biomimetic 3D-printed bone scaffolds – towards better design of implants to repair large bone defects,"Background: Bone defects are caused by trauma or bone-tumour removal. When the defect is large or occurring in a weight-bearing bone, incomplete healing after surgical reconstruction is likely. Artificial 3D-printed porous scaffolds can be osteoconductive, osteoinductive and large enough to bridge critical-size defects, and allow patient- and defect-specific customisation. Their manufacturing techniques permit the control of their mechanical properties so that they resemble the host bone, which is crucial for avoiding shielding leading to bone loss. Porous scaffolds have hence shown a promising capability to facilitate rapid healing of large bone defects. Jeffers and colleagues (Addit Manuf J 22; Biomaterials 194; Appl Mater Today 15) have recently 3D-printed non-degradable biomimetic bone scaffolds from titanium and polyamide (stiffness larger than or similar to that of trabecular bone, respectively), and implanted them into cylindrical defects in sheep femura in vivo. Micro-CT and histological slices acquired six weeks post-surgery revealed directional bone growth into the entire length of the scaffold. The researchers concluded that scaffold stiffness compliance with the host bone is vital for bone regeneration, and that implant permanence is essential for its structural role of bearing loads through bone healing. Objectives: We hypothesise that osteogenesis on the scaffold struts correlates with the mechanical loads acting in the struts. Accordingly, the aim of the proposed project is to employ in-silico modelling to calculate the mechanical loads (strains and stresses) occurring within 3D-printed bone scaffolds bridging critical-size defects in sheep femura, while exploiting the imaging data already acquired (i.e., without actual use of animals). The analysis outputs will be used to study potential correlation between osteogenesis and loads in the scaffold struts. These data will identify the ranges of scaffold and bone-tissue loads promoting osteogenesis, which will be utilised in the design of scaffolds allowing transfer of loads encouraging ‘optimal’ bone formation and regeneration. Methods: The in-vivo experiments previously conducted in the visit institution will be recreated in silico. The available pre-operative CT scans of each sheep femur will be segmented to create a 3D geometrical model. A detailed model of each scaffold will be generated from the drawings used to manufacture it. A large defect will be virtually created in the mid diaphysis of the femur, and the scaffold will be implanted into the defect to mimic the in-vivo surgical procedure. Inhomogeneous mechanical properties will be assigned to the bone based on the density of each bone voxel as depicted in the CT scans. Physiological loading conditions will be derived from the literature. A commercial finite-element solver will be used to calculate the loads occurring within the scaffold and host bone. All computational simulations will be juxtaposed with the equivalent micro-CT images obtained post-operatively. Correlations between the scaffold loads and the rate and spatial pattern of osteogenesis on the scaffold struts will be examined. An iterative optimisation procedure of adjusting the architectural features of the scaffold, and employing the computational simulations to explore the effects of these adjustments on the scaffold loads to be transferred to the forming bone, will be followed.",,5.3 MEDICAL DEVICES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MUSCULOSKELETAL HRCS22_11586,Economic and Social Research Council,ESRC,"JPI MYBL EWG Care, Inequality and Wellbeing in Transnational Families in Europe: a comparative, intergenerational study in Spain, France, Sweden & UK","This innovative comparative research project will investigate the relationships between care, inequalities & wellbeing among different generations of transnational families in the UK, Spain, France & Sweden. The COVID-19 crisis has brought into stark relief the care deficits many European countries are confronting as ageing societies, with low-paid women migrants often filling gaps in formal care provision, while their own caring responsibilities for kin are often overlooked. Demographic shifts due to population ageing & increased international migration are leading to major changes in the provision of care, social protection & intergenerational responsibilities. These transformations may exacerbate existing inequalities facing migrant families with care needs. The project will compare migrant carers' and transnational families' experiences within four partner countries with contrasting welfare models, migration regimes & post-colonial legacies. Using a multi-sited family-focused ethnographic & participatory action research methodology, we will work with partner organisations to train migrant peer researchers & support them to undertake research with families, building trust & capacity within communities. We will select a diverse sample of 100 transnational families with care needs (25 in each country) of different ethnicities & varying legal status from two contrasting regions in each country to compare experiences at different urban and rural scales, as well as between countries. We will engage with 3 or 4 different generations, including family members living in countries of origin/other settlement countries. We will select 20-30 case study families for in-depth ethnographic research. We aim to match the sample with family members living in more than one partner country to explore onward migration & resource flows & compare differing entitlements to social protection. The study will provide unique insights into how family care practices are negotiated between & within different generations of transnational families in Europe, while also considering their family ties in countries of origin. This timely project will capture the health, economic, social & emotional impacts of the COVID-19 pandemic on transnational families as the crisis unfolds, including changing intergenerational caring responsibilities & mobility strategies. It will explore the impacts of care on younger, middle & older generations' wellbeing & opportunities & how social reproductive & productive work are shaped by intersecting inequalities of gender, age & generation, disability, race, ethnicity/cultural background & socio-economic & legal status. It will include a specific focus on young caregiving & how this affects children's wellbeing, education & opportunities. This interdisciplinary project will also explore how language barriers may perpetuate inequalities facing transnational carers & how younger generations may provide 'language-brokering' & help older family members to navigate bureaucratic legal & administrative systems to claim their rights. The project will achieve significant societal impacts by providing a valuable evidence-base to inform policy in improving the wellbeing & equality of transnational families in Europe. It will embed the learning in practice through the co-production of culturally appropriate tools & training materials that support young & adult carers & transnational families. The findings & outputs will be disseminated through community screenings, regional stakeholder workshops, key academic & practitioner conferences & an international interdisciplinary Symposium. The project will produce 14 high impact journal articles in the fields of migration studies, social & emotional geographies, childhood & youth studies, family sociology, sociolinguistics & migrant language education & a co-edited volume. The dataset will be archived for future researchers' use.","This innovative comparative research project will investigate the relationships between care, inequalities & wellbeing among different generations of transnational families in the UK, Spain, France & Sweden. The COVID-19 crisis has brought into stark relief the care deficits many European countries are confronting as ageing societies, with low-paid women migrants often filling gaps in formal care provision, while their own caring responsibilities for kin are often overlooked. Demographic shifts due to population ageing & increased international migration are leading to major changes in the provision of care, social protection & intergenerational responsibilities. These transformations may exacerbate existing inequalities facing migrant families with care needs. The project will compare migrant carers' and transnational families' experiences within four partner countries with contrasting welfare models, migration regimes & post-colonial legacies. Using a multi-sited family-focused ethnographic & participatory action research methodology, we will work with partner organisations to train migrant peer researchers & support them to undertake research with families, building trust & capacity within communities. We will select a diverse sample of 100 transnational families with care needs (25 in each country) of different ethnicities & varying legal status from two contrasting regions in each country to compare experiences at different urban and rural scales, as well as between countries. We will engage with 3 or 4 different generations, including family members living in countries of origin/other settlement countries. We will select 20-30 case study families for in-depth ethnographic research. We aim to match the sample with family members living in more than one partner country to explore onward migration & resource flows & compare differing entitlements to social protection. The study will provide unique insights into how family care practices are negotiated between & within different generations of transnational families in Europe, while also considering their family ties in countries of origin. This timely project will capture the health, economic, social & emotional impacts of the COVID-19 pandemic on transnational families as the crisis unfolds, including changing intergenerational caring responsibilities & mobility strategies. It will explore the impacts of care on younger, middle & older generations' wellbeing & opportunities & how social reproductive & productive work are shaped by intersecting inequalities of gender, age & generation, disability, race, ethnicity/cultural background & socio-economic & legal status. It will include a specific focus on young caregiving & how this affects children's wellbeing, education & opportunities. This interdisciplinary project will also explore how language barriers may perpetuate inequalities facing transnational carers & how younger generations may provide 'language-brokering' & help older family members to navigate bureaucratic legal & administrative systems to claim their rights. The project will achieve significant societal impacts by providing a valuable evidence-base to inform policy in improving the wellbeing & equality of transnational families in Europe. It will embed the learning in practice through the co-production of culturally appropriate tools & training materials that support young & adult carers & transnational families. The findings & outputs will be disseminated through community screenings, regional stakeholder workshops, key academic & practitioner conferences & an international interdisciplinary Symposium. The project will produce 14 high impact journal articles in the fields of migration studies, social & emotional geographies, childhood & youth studies, family sociology, sociolinguistics & migrant language education & a co-edited volume. The dataset will be archived for future researchers' use.",1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;7.1 INDIVIDUAL CARE NEEDS,GENERIC HEALTH RELEVANCE HRCS22_19525,Cancer Research UK,CRUK,Kinase-phosphatase coupling at the kinetochore and the maintenance of chromosomal stability,"Background We have recently identified a feedback network that integrates the activities of the two main kinases (Aurora-B/MPS1) with the two main phosphatases (PP1/PP2A-B56) that act at the kinetochore. These are the principle regulators of the spindle assembly checkpoint (SAC) and kinetochore-microtubule attachments, and therefore they are the cells primary defence against cell division errors and aneuploidy. The vast majority of cancers fail to segregate their genome correctly, leading to chromosomal instability (CIN) and accelerated tumour evolution, and I predict that defects in this feedback network could be responsible. The principle is that the network itself, rather than the individual components, imparts key properties such as robustness and reliability to the chromosome segregation process. These properties are likely to be weakened in cells with CIN, to allow the type of subtle errors needed for tumours to propagate viable levels of aneuploidy. It is therefore critical that we understand how the whole network functions together within the context of cancer. I will tackle this problem using an interdisciplinary mix of quantitative cell biology, computational modelling and molecular biology to characterise the network in a range of cells with and without CIN. In parallel, I will draw on the power of synthetic biology and gene-editing to; 1) determine the full mechanistic details of the network, 2) uncouple it to determine how it best safeguards cell division, and 3) manipulate it to examine the effect on CIN. Aims (1) To determine the mechanistic details of the feedback network (2) To understand how the network regulates the SAC (3) To understand how the network regulates kinetochore-microtubule attachments. (4) To investigate if perturbations to the feedback network cause CIN. Methods The proposal relies on the fact that all aspects of the feedback network can be quantified accurately, and manipulated efficiently, in human cells. I have established a number of different methods to achieve this, including a novel chemical-genetic system to inducibly relocalise endogenous phosphatases with small molecule drugs. This is the first time phosphatases have been manipulated in this way and I will exploit this technology throughout this proposal. How the results of this research will be used These studies will reveal how kinases and phosphatases work together to safeguard cell division and how this could be perturbed to cause CIN. Collectively, this may provide new opportunities for cancer treatment by identifying network weaknesses that could be exploited therapeutically to target cancer cells with CIN.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_13401,Wellcome Trust,,LMICSS - AAP Malawi,LSTM is submitting an application for salary supplements in connection with two roles at MLW: • Director of MLW • Deputy Director Total Number of Current Applications in progress for LMICSS from LSTM for all programmes:   1 Total Number of Current Applications in process for LMICSS to be held at MLW:  1 (comprising 2 nominees),,8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),INFECTION HRCS22_06387,Medical Research Council,MRC,LOOC - Lymphatic mapping Of Oropharyngeal Cancer,"Cancer at the back of the mouth and throat is usually discovered after it has spread to lymph glands in the neck. Treatment therefore involves dealing with both the original tumour (in the mouth/throat) and the spread cancer in the lymph glands._x000D_ This type of cancer sometimes spreads to both sides of the neck, not just the side on which the original tumour was located. The decision as to whether to treat the other side of the neck as well depends on various factors including the aggressiveness of the tumour, whether the patient smokes and whether or not the HPV virus is present in the tumour. This is inevitably inexact, and assessing the likelihood of the cancer spreading to the other side of the neck always involves an element of estimation. Some patients end up being treated unnecessarily on both sides (often with severe and lasting effects on swallowing, meaning they have to use a feeding tube), while others receive treatment on one side only but the cancer comes back on the other side._x000D_ This study will provide more accurate information on which to base the decision as to whether to treat_x000D_ the other side of the neck. The study will use a procedure known as sentinel node biopsy (SNB) to establish (with a high degree of accuracy) whether or not the cancer has spread to the other side of the neck. The study will be in_x000D_ two stages. The first stage is the imaging stage. A radioactive substance called Lymphoseek will be injected into_x000D_ the tumour. Lymphoseek moves quickly into the lymph nodes and can then be detected using a handheld gamma camera. The first nodes the Lymphoseek moves into are the “sentinel” nodes. Patients already undergo an examination under anaesthetic (EUA) and the patients in the study will have the Lymphoseek injected and the sentinel nodes detected during this EUA. The use of the handheld camera is relatively new so all of the patients in the study will also have a CT scan the next day to double check whether the handheld camera identified the sentinel nodes correctly._x000D_ The second stage of the study, the surgery stage, will involve a new group of patients having the imaging procedure. Those who do have sentinel nodes in the other side of the neck will have them removed during the EUA. Those nodes will then be examined thoroughly for signs of cancer. A separate limb of stage one of the study will involve some patients whose main tumours are easily accessible also having their tumour injected with Lymphoseek under local anaesthetic in an outpatient clinic. In the study this will take place several days after the initial injection with Lymphoseek. If this procedure is found to be acceptable to patients, it would mean that patients could have the Lymphoseek injected before the EUA, thereby allowing time for the sentinel nodes to be identified by CT scan so that they can be removed during the EUA. This will provide a way to ensure that, even if the handheld camera cannot be used, the sentinel nodes can still be removed while the patient is under anaesthetic for the EUA._x000D_ If the study is successful, the patient will be able to have much more accurate information about whether their cancer has, or might, spread to the other side of the neck, without having to undergo an additional general anaesthetic.","BACKGROUND:_x000D_ _x000D_ Oropharyngeal cancers (OPC) affects tonsil, tongue base, soft palate, and pharynx. OPC is predicted to become the most common form of head and neck cancer worldwide with epidemic proportions in the next decade. Patients usually respond well to treatment despite most presenting with involved (metastatic) lymph nodes at diagnosis. Patients with metastatic disease are offered treatment to both sides of the neck without evidence of metastasis on the contralateral side, due to risk of occult (non-radiographically apparent) metastasis. Treatment related morbidity affects survivor’s quality of life but can be significantly improved when only one side of the neck is treated. Lymphatic mapping and sentinel node biopsy (SNB) could be used to diagnose occult metastasis in the contralateral neck and thus guide treatment to those that would benefit from it._x000D_ _x000D_ SNB and lymphatic tumour mapping:_x000D_ _x000D_ SNB is a surgical staging procedure in which sentinel lymph nodes (SLN) are identified by lymphatic mapping of an injected radiotracer detected on Single Photon Emission Computed Tomography (SPECT). SNB is recognised in OPC but due to combination of difficult access to the tumour and the outpatient gantry-based SPECT imaging equipment, traditional lymphatic mapping requires transfer between departments under general anaesthetic preventing use in routine practice. New technology may allow one-stop injection and imaging in OPC._x000D_ _x000D_ _x000D_ STUDY AIMS:_x000D_ _x000D_ •Validate lymphatic mapping protocol in OPC using new technology (Lymphoseek, freehand SPECT (fhSPECT))_x000D_ and_x000D_ •Establish lymphatic drainage pattern and occult metastatic rate in the contralateral neck in OPC_x000D_ _x000D_ _x000D_ DESIGN:_x000D_ _x000D_ Multicentre phase II surgical imaging study_x000D_ _x000D_ 1.IMAGING PHASE (n=75): Develops an imaging protocol to establish lymphatic drainage pattern in a population of patients with proven unilateral neck metastasis from OPC during routine examination under anaesthetic (EUA). Four peritumoural injections of Lymphoseek are given followed by freehand SPECT (fhSPECT)scan under GA. SPECT/CT scan (gold standard for lymphatic mapping) will be carried out the next day._x000D_ Outcome – rate of contralateral drainage. Accuracy of fhSPECT Vs. SPECT/CT. Number of contralateral nodes on SPECT/CT will be used as the denominator in calculating the sensitivity of fhSPECT in independently verified images. fhSPECT should achieve sensitivity >94% Minimum of 20/75 patients demonstrate contralateral drainage to proceed to surgical stage._x000D_ Imaging substudy: Develops a secondary imaging protocol in case of <94% sensitivity of intraoperative fhSPECT Twenty patients from imaging phase with easily accessible tumours will be invited to undergo a second imaging intervention. A single injection of Lymphoseek is given in clinic followed by fhSPECT and SPECT/CT._x000D_ Comparator – SPECT/CT performed in initial phase_x000D_ Outcome – Sensitivity of outpatient imaging (single injection, fhSPECT and SPECT/CT) compared to gold standard (SPECT/CT from initial phase). Acceptability of outpatient injection compared to under GA._x000D_ _x000D_ 2. SURGICAL PHASE (n=75): Investigates feasibility of surgically staging the contralateral neck. A new study group of patients will be invited to participate. During EUA excision of contralateral nodes identified on imaging* is undertaken (sentinel node biopsy). Serial sectioning of excised (sentinel) nodes to identify micrometastasis. Outcome is occult metastatic rate of contralateral nodes (positive sentinel node biopsy). Contralateral drainage rate will be identified in the imaging phase, expected SNB positive rate of excised nodes 25-40%. Outcome of this study will prove feasibility of future research in which management of the contralateral neck is based on surgical staging_x000D_ *protocol based on result of imaging phase",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_03766,Medical Research Council,MRC,Learn to Discover (L2D): A Training Platform in Data Sciences and Machine Learning for Biomedicine and Health Researchers.,"In bio and health sciences data complexity and volume is now outstripping the compute-intensive physical sciences. Challenges of massive datasets, needs for real-time predictive modelling and computer execution of human intelligence-level tasks are growing rapidly. To address this, research and education leaders in the applications of data science and quantitative approaches to bio-, biomedical and health research will build on an outstanding track record to create a data science, ML and AI e-learning and training platform called Learn 2 Discover (L2D) to meet the needs of their wider peer community. L2D will develop specific, highly relevant skills for participant's immediate needs. Insights into the data challenge of other fields will narrow persistent knowledge gaps - for example, through L2D, drug developers might encounter more data aware clinicians and conversely laboratory scientists might appreciate the priorities of health practitioners and what data is gatherable. L2D will deliver: a) Core skills in data handling, supervised and unsupervised ML, working with complex, high dimensional data. (""live"" within 4 months of start-up) b) A portfolio of ""use case"" scenarios e.g. image analysis, digital pathology, neuroscience, drug development, molecular structure-function, genotype-phenotype relationships, synbio, cancer diagnostics and functional genomics using validated real-world data c) Insight into advances in AI and Deep Learning e.g. various neural networks, reinforcement learning, autoencoders and natural language processing and more d) Good practice in computing and data handling to address the reproducibility crisis e) Web publishing for sharing predictors and code f) Accessing cloud computing to spin-up flexible resource for large compute problems g) Collaborative coding and project workshops with skilled tutors h) Support materials and coaching for ""local"" trainers in universities and businesses to facilitate the uptake and adoption.",,2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_19083,Wellcome Trust,,Learning as Bayesian inference.,"For biological organisms, learning involves changing synaptic weights -- that is, changing the connection strengths among neurons -- with the goal of setting the weights to values that ensure the animal functions as effectively as possible. This, however, is hard: information is noisy and often ambiguous, and must be used to set over 100 trillion weights. To understand how animals do this, we treat learning as a probabilistic inference problem: given sensory information, the goal is to compute a probability distribution over weights, not just point estimates, as is commonly believed. This leads to learning rules that contain a feature not found in any other proposed learning rules: the more uncertain a neuron is about the weight of a synapse, the more plastic that synapse is. This makes intuitive sense: if the uncertainty about a weight is large, new information should strongly influence its value, while if the uncertainty is small, little learning is needed. It also allows synapses to efficiently use incoming information, greatly improving learning. Finally, it allows organisms to match learning rates to incoming information -- speeding up learning when the rate of new information is high, and slowing it down when the rate is low.",,1.4 METHODOLOGIES AND MEASUREMENTS,GENERIC HEALTH RELEVANCE HRCS22_07183,Department of Health and Social Care,NIHR,Learning from proactive deprescribing experiences within the Care Homes Independent Pharmacist Prescribing Study to develop national policy regarding deprescribing in care homes for older people,"Research question What are the individual and system level behaviour change components required to enable the creation of policy to inform and drive effective implementation of proactive deprescribing within the care homes setting? Background Approximately half of older care home residents are prescribed at least one inappropriate medicine which can predispose them to adverse outcomes such as falls, morbidity and hospitalisation. It is therefore important that inappropriate medicines are discontinued in a timely manner i.e. interventions implemented which effectively facilitate proactive deprescribing. The NIHR funded Care Homes Independent Pharmacist Prescribing Study (CHIPPS) was designed to estimate the effectiveness and cost-effectiveness of pharmacist independent prescribers (PIPs) assuming responsibility for medicines optimisation in care homes. The process evaluation found that proactive deprescribing varied within the 25 pharmacist prescribers from 3 medicines per 20 residents to 28 medicines. We will use this experience to elucidate the barriers and enablers associated with deprescribing in the care home environment and develop appropriate policy. Aim To develop policy to support effective implementation of proactive deprescribing within care homes. Objectives Describe the types of medicines commonly proactively deprescribed in CHIPPS and characterise variation in this behaviour within CHIPPS intervention care homes. Identify enablers and barriers to proactive deprescribing within CHIPPS intervention care homes. Identify the mechanisms of action leading to proactive deprescribing and their linked Behaviour Change Techniques (BCTs). Develop policy to support creation of the appropriate environment, training and inter-professional and patient relationships to implement proactive deprescribing in care homes. Methods Phase 1: Secondary analysis of the existing CHIPPS proactive deprescribing data to identify trends and variation in practice. Phase 2: Identify a purposive sample (according to Phase 1 trends) of CHIPPS practitioners and conduct semi structured interviews, informed by the Theoretical Domains Framework (TDF), to identify and prioritise the barriers, enablers and therefore relevant TDF domains pertinent to proactive care home deprescribing. Phase 3: Based on Phase 2 data, for each identified TDF domain, identify all possible BCTs, to address the barriers and enablers. Convene a modified Nominal Group Technique workshop to facilitate target audience selection and characterisation of BCTs to support implementation of proactive care home deprescribing. Phase 4: Convene a policy development and dissemination working group of national opinion leaders to develop the policy to include guidance for addressing broader structural and system level considerations. Disseminate policy at national, regional and local levels. Timelines for delivery Months 0-3: Phase 1 Ethical approval obtained Phase 2 Expressions of interest for Phase 2 participants Months 3 to 8: Phase 2 Ethical approval obtained for Phase 3 Participants for Phase 3 identified and recruited Data analysis iterative as data collated Phase 4 meeting organised Month 9 -10: Phase 3 Months 11-12: Phase 4 Policy dissemination to target audiences Dissemination and Impact Dissemination through relevant policy leads such as NHS England and Improvement, Department of Health and Social Care and deprescribing networks. Impact will be better design of interventions to facilitate proactive deprescribing and ultimately more timely discontinuation of medicines whereby risks outweigh the benefits.","Aim The aim of this project is to use what we have learned from placing 25 pharmacist prescribers in care homes across England, Scotland and Northern Ireland, to develop policy about how to support healthcare professionals to stop medicines that are no longer benefiting older people in care homes. Background We know that residents in care homes for older people regularly receive large numbers of medicines and are exposed to large numbers of medication errors. One approach is to stop medicines which are either no longer necessary or could possibly cause harm in the future. Within a large scale research project which we undertook across the UK, we found that some pharmacists were more likely to stop medicines than others. If we understand why this is more common in some care homes than others, then we can develop policy to support all care homes to stop medicines that are not beneficial or possibly harmful. Methods Firstly, we will look at why and how prescribing changed within our large study to help us understand what medicines people were more or less willing to stop and who was more or less likely to stop them. This will help us to identify who we want to talk to in order to find out why this does and doesn t occur and what things need to change to make this more likely. We will interview general practitioners, pharmacists and care home managers from the research study to help us understand what happened and why. From these interviews we will look for common descriptions of what prevents medicines from being stopped and what helps. We will use the information we get from these interviews tells us what things we could possibly do to make things better. We expect that this will give us a long list of options and therefore we will work with a group of experts who work in and with care homes to agree which options are best. Finally, using standard methods, we will develop a draft policy document and approach to getting our plan into practice. This will be presented to people responsible for implementing policy to obtain their feedback on how best to do this. Patient and public involvement The two patient and public involvement members who supported our previous large project will continue with us on this project management committee. They have inputted into our project proposal, and will be actively involved in all stages. Dissemination We will design our policy to increase its chances of being put into practice and present it to the national lead pharmacist and individuals responsible for improving medicines use and care for residents within care homes.",7.3 MANAGEMENT AND DECISION MAKING,GENERIC HEALTH RELEVANCE HRCS22_11599,Economic and Social Research Council,ESRC,"Learning from the trajectories of mental health challenges for children, young people and parents over the course of the Covid-19 pandemic","Our two studies conducted throughout the pandemic in the UK and Japan have shown that the pandemic has continued to affect the mental health of children and young people and parents, that there are unmet needs, and that the pandemic-related effects and needs differ by individuals' background characteristics, as well as by country. Consequently, the main objective of the research is to use the existing structure of the Co-SPACE and C-C nation-wide cohort studies in the two countries, to improve our understanding how to best support families coming out of the COVID-19 pandemic and, in particular, how that may vary across countries and pandemic-contexts. Specifically, we will examine: (i) How mental health consequences for children, young people, and parents vary according to key characteristics during the pandemic, and how this relates to the different experiences families have had within and across countries; (ii) Who is and is not 'bouncing back' over longer term and while coming out of the pandemic; (iii) What would help the immediate and long-term recovery of families in both Japan and UK. A further objective is to support and improve use of patient and public involvement (PPI in research in Japan to achieve direct societal impact. While PPI is common in health and social care research in the UK, the concept is still relatively new in Japan and rarely included in studies other than clinical trials. The Co-SPACE group has rich experience of including PPI in their previous work and have involved groups of teachers, parents, and young people throughout the research process since the start of the project. Inspired by the collaboration with the Co-SPACE team, the C-C group launched the C-C conference in 2020 to involve adolescents in the selection of survey items, a novel approach in Japan where PPI is not as commonly conducted or required in health and social care research. Hence, we will continue working in partnership with young people, parents, and members of the public to plan, manage, design, and carry out the currently proposed research. We will work with young people via Leaders Unlocked to co-develop guidance for policy makers and practitioners in Japan and the UK, this way improving policy, communication, and service design post COVID-19 pandemic.","COVID-19 and the related public health measures have led to major disruptions to families' lives, with different pressures arising for children, young people, and their families over time. The Co-SPACE project in the UK and CORONA-CODOMO (C-C) project in Japan are two nation-wide online survey-based studies tracking how children, young people, and parents have been affected since the start of the pandemic. Both studies, separately, have found that lockdowns and school closures were associated with deteriorating mental health and increased stress in young people and parents. Certain groups (e.g., families with financial difficulties, and with children with special education needs) appear to have been particularly vulnerable to elevated stress and mental health symptoms throughout the pandemic. However, at this point, we still know little about how to best support families coming out of the COVID-19 pandemic and, in particular, how needs may vary across countries and pandemic-contexts. The proposed project builds on a successful existing collaboration that will further utilize available expertise in international data analysis, text-mining approaches, patient and public involvement, and translating research into practice. In turn, it will promote knowledge exchange and involvement of early career researchers. The aim of this proposal is to: (i) capitalise on what can be learned from these parallel international surveys about the impact of COVID-19 and how it has been managed across countries; (ii) develop a further understanding of medium and long-term impacts of the pandemic on the mental health symptoms of young people and parents, as well as their pathways to recovery; and (iii) together with young people and families, co-design guidelines for policy makers and health authorities, which will help to mitigate identified medium to long-term mental health consequences of the pandemic and current policies and to tailor future pandemic management strategies to minimise mental health impacts on young people and families. The above aims will be achieved through three workstreams, while actively engaging young people and parents from both countries in decision making throughout the research lifecycle: (1) The already collected online survey (including cross-sectional) data will be merged and analysed using a multi-level modelling approach to examine how immediate mental health consequences for children, young people, and parents across Japan and the UK have varied over the COVID-19 pandemic according to policies and restrictions, as well as child, family, and other key characteristics; (2) Three 6-monthly follow-up surveys with comparable measures will be conducted and analysed using time series and text-mining approaches across both countries to examine who is and is not 'bouncing back' and what are the medium and long-term consequences of the pandemic; (3) Through a series of online events, we will co-design guidance for policy makers and practitioners with young people from both countries in collaboration with the Leaders Unlocked, an organisation which enables young people and underrepresented groups to have a voice on issues that matter.","2.4 SURVEILLANCE AND DISTRIBUTION;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",MENTAL HEALTH;INFECTION HRCS22_23190,The British Academy,,Learning to care in unprecedented times: the impact of COVID-19 on nursing education,"Even before the COVID-19 outbreak, there was a crisis in the healthcare workforce, with 40,000 unfilled nursing vacancies. This case study of a group of final year pre-registration nursing students aims to assess the impact of the COVID-19 pandemic on this group in the midst of the emergency and the immediate aftermath, and the wider repercussions for nursing education. It will explore the students’ experiences of the pandemic and inform any immediate support they may require. The project will document the short-term graduate outcomes for this cohort and their ‘imagined futures’, exploring the role of class, gender and ‘race’ in shaping their educational trajectories. In doing so it will offer vital sociological insights into the impact of the pandemic on nursing education, the support that this cohort and future nursing students may require, and the implications for addressing the workforce shortage.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_06126,Department of Health and Social Care,NIHR,Listen2Baby - Improving monitoring of the baby during uncomplicated labour: a study using experience-based co-design,"Background UK guidance recommends that women without medical or obstetric risk factors, up to 45% of women, are looked after by midwives during labour and birth, and fetal wellbeing is assessed using regular ‘intermittent auscultation’ (IA) of the baby’s heart rate. There is clear national guidance about the timing and frequency of IA during labour, but successive national enquiries have identified that IA is often not carried out as recommended and that this contributes to death or severe health problems in babies. There is little or no evidence about the best IA device, timing, frequency or counting techniques; midwives’ practical experience of IA; women’s or partners’ experience; or IA training. In the absence of evidence, the barriers to conducting IA in line with national guidance are poorly understood. Aims and objectives The aim of this study is to improve the quality and safety of fetal monitoring in uncomplicated labours through (a) improved understanding of the organisational context and practice of IA, and (b) development and evaluation of a range of solutions, a 'toolkit' to improve IA practice; and to produce evidence to inform practice change and service development in midwifery and maternity care more broadly. Objectives: i. Describe the range of IA devices, counting methods, and training used ii. Describe the practice of IA and identify the facilitators of and challenges to midwives following national guidance iii. Explore and describe women’s and partners’ experience of IA iv. Develop a toolkit to improve IA practice based on findings of i-iii v. Test the feasibility and acceptability of the toolkit, develop a systematic, theory-driven plan for implementation, and evaluate effectiveness. Methods We will use experience-based co-design (EBCD) to develop a practical toolkit to improve IA practice and an implementation plan which we will evaluate for feasibility, acceptability and effectiveness. I. We will carry out a survey of practice in all 220 UK midwifery units, and in the 35 UK obstetric units without a linked midwifery unit, to describe the range of IA devices, methods, IA training and details of IA audits. II. We will use observational fieldwork, structured conversation and semi-structured interviews in a purposive sample of at least eight NHS settings to capture aspects of tacit IA practice, and explore and understand midwives’ perspectives on IA practice. III. We will convene, and carry out focus groups with, a lived-experience user group to explore and describe women’s and partners’ experiences of IA. IV. Using the research evidence generated in components I-III, we will work with midwives, service users, and key policy and practice stakeholders to co-design a toolkit to improve the practice of IA. V. We will used mixed methods including qualitative interviews and field notes, and an uncontrolled before and after study to test feasibility and acceptability and evaluate effectiveness in our research sites. Outputs, dissemination and impact In addition to academic publications and presentations, the primary output will be an evidence-based co-designed toolkit for IA, including practical guidance for implementation, which can be embedded in and disseminated through national maternity safety initiatives. We anticipate benefit in terms of midwives’ increased confidence in IA skills and knowledge, improved quality of IA, translating into improved safety for babies, within 4-6 years of the start of the project.","What we know For women experiencing an uncomplicated labour, UK guidance recommends that midwives monitor the baby’s heart rate using a hand-held fetal stethoscope or ultrasound device. This is known as ‘intermittent auscultation’ (IA), which means ‘listening at regular intervals’, and is used in the labours of up to 300,000 women every year in the UK. National guidance says that midwives should listen to the baby’s heart rate straight after a contraction for at least one minute, and that they should do this and record the baby’s heart rate every fifteen minutes during the first stage of labour, and every five minutes in the second (pushing) stage. Several national investigations have found issues with the way IA is carried out in practice that have contributed to death or severe injury in babies. Problems include IA not being carried out at the right time or often enough; the baby’s heart rate not being recorded properly; and midwives not recognising or acting on concerns about the baby’s heart rate. What we want to find out There is no research evidence about the best way to do IA in practice, including what is the best device or counting method to use, and we don’t know why IA is not always carried out in line with national guidance. Most research so far has focused on continuous electronic monitoring (where the woman has a belt around her tummy, producing an electronic or paper trace of the baby’s heart rate), which is used for women with pregnancy complications. Our research will find out how midwives do IA in practice, what devices and counting methods they prefer to use and why, and what problems they have in following national guidance about IA. We will also find out what IA is like for women and their partners. We will work with midwives, women and their partners, and other national experts, to use this information to design and test a practical ‘toolkit’ to help midwives do IA in the best way to ensure safety for babies. How we will do this research We will carry out a survey of all UK NHS organisations to find out what IA devices, counting methods and training packages midwives use. We will watch midwives using IA in different units across the UK and talk to them about what doing IA is like from their point of view. We will also speak to women with different experiences of having their baby’s heart rate monitored using IA. We will collect the key points from all this information. Together with midwives, women and other experts we will then use ‘experience-based co-design’ (EBCD) to design a practical ‘toolkit’ to improve the practice of IA. This means holding meetings to feed back the research results to midwives, women and partners, and others with an interest or expertise in IA. We will discuss the results together, agree what to work on and form small co-design groups to design solutions. Together these solutions will form our toolkit, which we will then test in a small number of units to see whether and how it works. Finally, we will get everyone involved together to share the final toolkit. We don’t know what the toolkit will look like yet because it will come out of the EBCD process, but it could include a website, videos, posters or prompt cards. Throughout the project, we will work closely with women, midwives, and senior NHS and government policy colleagues to make sure that the results of this research, and the toolkit we produce, will lead to changes in practice to improve the way that IA is carried out.",8.1 ORGANISATION AND DELIVERY OF SERVICES,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_13084,Wellcome Trust,,Liver Fluke (Opisthorchis viverrini) in Southeast Asia: Can Transmission be Halted Through Mass Drug Administration?,"Transmission of the human-infective and carcinogenic trematode Opisthorchis viverrini is ongoing in Southeast Asia. Despite decades of control, an estimated 10 million people are currently infected in Thailand and Laos. Determining which interventions will be most effective requires an understanding of fundamental epidemiological processes, many of which are poorly understood. Using longitudinal egg-count data and parasite population genomics, I propose to estimate anthelmintic efficacy, rates of reinfection, parasite migration within and between countries, and the role of zoonotic hosts (cats and dogs) on O. viverrini transmission. I will incorporate these processes into a predictive agent-based model which will allow the impact of interventions to be simulated. The model output will be informative to policy makers, and the results communicated to at-risk communities. In particular, I will investigate the impact of repeated mass treatment with praziquantel on parasite transmission, an approach that is currently being used on a large scale globally to control macroparasites. Whole-genome sequencing will be key to investigating O. viverrini population structure, migration rates and parasite relatedness between humans and other zoonotic hosts. Therefore, an improved O. viverrini reference genome will be produced with long-read sequencing, and methods to sequence parasites from non-invasive samples will be developed.","The parasitic worm Opisthorchi viverrini is largely unknown outside of endemic communities, however it causes a liver cancer which is among the leading causes of death in Northeastern Thailand and Laos. Ongoing efforts to control O. viverrini, which is contracted from eating raw fish, have involved health education and case treatment, though it is uncertain if these efforts are sufficient to eliminate the parasite. I propose to improve our understanding by applying modern statistical methods to diagnostic data collected on the parasite in Thailand and Laos. In addition, I will sequence DNA from worms in different locations to learn about how O. viverrini migrates between regions, and whether cats and dogs harbour the same parasites as humans. I will incorporate the findings into a model which can be used by policy makers to test the impact of different disease control measures, including large scale treatment with a deworming drug.",2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_23089,The British Academy,,Living through the pandemic in post-Brexit Britain: emotional damage and forms of resilience among middle-aged European citizens,This study examines the effects of the Coronavirus epidemic and Brexit on the emotional wellbeing of middle aged European citizens who have transnational caring responsibilities in the UK and in Europe. This qualitative research aims to produce an in-depth understanding of the participants’ emotional landscape and to explore how their sense of belonging in the UK has been eroded by this combination of factors. The disconnect engendered by Brexit and the forced estrangement from family in Europe have prompted many EU nationals to return home causing a loss of workforce for the UK economy at this crucial time of recovery. This research will explore their experience to identify their needs and to highlight the resources they are using to adapt to the changes. The results will inform government at national and devolved levels to devise a strategy to retain their contribution by rebuilding a sense of home in Britain.,,7.1 INDIVIDUAL CARE NEEDS,INFECTION;MENTAL HEALTH HRCS22_12167,"Children's Cancer and Leukaemia Group",,Living-REFoRMS - A living systematic review of early phase studies for children and young people with relapse and refractory rhabdomyosarcoma,"New treatments are continuously being developed for rhabdomyosarcoma which has not responded to initial therapy (refractory) or has come back after treatment (relapsed). Keeping track of new developments so that the most accurate information is used to help families and clinicians make treatment choices is a particular challenge in current medical practice. A recent CCLG-funded study called REFoRMS included a systematic review of treatments for children and young people with relapsed and refractory rhabdomyosarcoma (REFoRMS-SR). Systematic reviews are a form of research where all previous studies in an area are found and their quality is assessed before the results are combined to summarise the best evidence available at that time. This new project plans to do two things: 1. Develop a living systematic review of studies into new treatments (early phase studies) in relapsed and refractory rhabdomyosarcoma called Living-REFoRMS. Living systematic reviews are a relatively new method where, instead of only having one search of the literature, the evidence is regularly searched, assessed, and summarised so that the information is the most up-to-date that it can be. This living systematic review will look for completed research and currently open trials in this area, from all around the world. 2. Develop a high-quality, regularly updated, online resource to share the findings from Living-REFoRMS that will be accessible to families and clinicians, and will help and support decision making in relapsed and refractory rhabdomyosarcoma. The online resource will be developed with and hosted by the CCLG, and we will use their experience in communicating complex childhood cancer information to ensure it best serves the community. The project will include a project steering group of families with experience of relapsed and refractory rhabdomyosarcoma, and professionals with expertise in this area, who will meet regularly to advise the researchers on this project.","New treatments are continuously being developed for rhabdomyosarcoma which has not responded to initial therapy (refractory) or has come back after treatment (relapsed). Keeping track of new developments so that the most accurate information is used to help families and clinicians make treatment choices is a particular challenge in current medical practice. A recent CCLG-funded study called REFoRMS included a systematic review of treatments for children and young people with relapsed and refractory rhabdomyosarcoma (REFoRMS-SR). Systematic reviews are a form of research where all previous studies in an area are found and their quality is assessed before the results are combined to summarise the best evidence available at that time. This new project plans to do two things: 1. Develop a living systematic review of studies into new treatments (early phase studies) in relapsed and refractory rhabdomyosarcoma called Living-REFoRMS. Living systematic reviews are a relatively new method where, instead of only having one search of the literature, the evidence is regularly searched, assessed, and summarised so that the information is the most up-to-date that it can be. This living systematic review will look for completed research and currently open trials in this area, from all around the world. 2. Develop a high-quality, regularly updated, online resource to share the findings from Living-REFoRMS that will be accessible to families and clinicians, and will help and support decision making in relapsed and refractory rhabdomyosarcoma. The online resource will be developed with and hosted by the CCLG, and we will use their experience in communicating complex childhood cancer information to ensure it best serves the community. The project will include a project steering group of families with experience of relapsed and refractory rhabdomyosarcoma, and professionals with expertise in this area, who will meet regularly to advise the researchers on this project.",6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT),CANCER AND NEOPLASMS HRCS22_06358,"Chief Scientist Office, Scotland",CSO,Long-Term Outcomes Of Synthetic Mid-Urethral Slings (Mesh Tapes) In Surgical Treatment Of Stress Urinary Incontinence In Women – A Long-term Follow-Up Of The SIMS RCT,"Urinary incontinence in women is a major issue for the NHS and for society, with the number affected and cost of treatment posing a significant burden on healthcare. _x000D_ _x000D_ Stress Urinary Incontinence (SUI) is the involuntary loss of urine through exercise, laughing, etc. It is the most common form of incontinence in premenopausal women and can have a significant negative effect on women’s quality of life. Non-surgical treatments seek to increase the support of the urethra with pelvic floor exercises but if these fail then surgery is the only alternative._x000D_ _x000D_ In the most common surgical procedure, standard mid urethral slings (SMUS or mesh tape), a long strip of polypropylene mesh/ tape is placed under the urethra to provide support. An alternative procedure, single-incision mini-sling (SIMS) is almost 50% less mesh volume and designed to have advantages over SMUS. A pilot study has shown SIMS to have fewer operative complications; less pain during and after the procedure; can be done under local anaesthesia; with earlier recovery of participants; shorter hospital stay; earlier return to normal activities and/or work. Economic analysis has also shown potential economic benefit to the NHS resources and wider society._x000D_ _x000D_ In the HTA-funded SIMS study 600 women, aged over 18 years, from 21 hospitals in the UK randomly received either a SIMS or SMUS procedure. The progress of these women has been followed up over 3 years, post operatively, measuring potential benefits, risks and costs associated with each procedure and will be reported fully in early 2021. It will help inform decision making for patients with SUI, their surgeons and the relevant policy makers with regards the most clinically and cost-effective procedure for women with SUI._x000D_ _x000D_ We now propose to further follow-up these women (SIMS cohort) up-to 10 years following their operation. The aim of the SIMS long-term follow-up (up to 10 years) is three-fold. Firstly, to provide women, clinicians and policy makers with further clinical and economic information to aid decision making. The embedded qualitative study will explore women’s voices about the decision-making process to undergo SUI surgery. Secondly, to provide detailed long-term safety information on mesh based SUI surgical procedures. Thirdly, the duration of this long-term follow-up (10 years) will provide new information on the landscape of any late-onset adverse events and associated surgical procedures._x000D_ _x000D_ We have consulted with women and the public to decide the optimum length of the long-term follow-up. Our team is the same expert team that delivered the initial SIMS study and further enhanced with two expert clinicians and two patients/ public representatives. We will send yearly questionnaires to the SIMS participants. We will ask about their urinary symptoms and how they affect their quality of life and any treatments they have received since the SIMS study operation. We will use the same follow-up tools and process that we used in the initial SIMS study and have proven successful in keeping the study participants well engaged with the study (87% and 81% response rates at 1 & 3 years respectively). We will collect information on further treatments for continence or adverse events from medical records and routine data sources. We will ask participants to take part in an interview about their experiences of treatment, the impact on their life, and what they think with hind sight about the treatment decisions they made.","Research Question: What is the long-term safety, effectiveness and cost effectiveness of synthetic mid-urethral slings (MUS - mesh tapes) in surgical treatment of stress urinary incontinence (SUI)?_x000D_ _x000D_ Background: Urinary incontinence is a common and disabling condition affecting women of all ages but primarily over 40s. SUI is the most common type of UI and often requires surgery. MUS (mesh-based procedure) have been the mainstay of surgical treatment for SUI for the last 2 decades. In the last 5years, there has been a growing public concern on the lack of robust, industry independent evidence on MUS long-term effectiveness and safety. The urgent need for this evidence has been highlighted by the recent NICE guideline (NG123), Cochrane review and the 2020 public inquiry report “First Do No Harm”. _x000D_ _x000D_ Aim: To determine the long-term safety, effectiveness and cost effectiveness of MUS (mesh) in surgical treatment of SUI in women while comparing single incision mini-slings (SIMS) versus standard mid-urethral slings (SMUS). _x000D_ _x000D_ Methods: Long-term follow-up of the SIMS trial participants using annual questionnaires up to 10 years follow-up. Primary outcome is patient overall assessment of the outcome of the procedure using PGI-I validated questionnaire (success defined as Very much/Much Improved). The primary economic outcome will be incremental cost per quality adjusted life years (QALY) gained at 10 years. Secondary outcomes include composite outcome of success on PGI-I and no further continence surgery; late onset (>3 years) adverse events (AEs); reoperation rates for SUI and/ or treatment of AEs; impact of the procedure on women’s QoL and sexual function. We will use patients’ medical records to ascertain type of further surgery received / admission for AEs. We will use routinely collected dataset on hospital admissions and procedures (NHS Digital and eDRIS) to enhance the quality of our data including non-responders to follow-up questionnaires. We have also included an embedded qualitative study using semi-structured interviews that will explore: patient experiences/ satisfaction with treatment and impact on QoL and; patient perceptions of decision process and decision outcomes (e.g. decisional regret and decisional conflict). Analysis will use intention to treat but we will also use a secondary per protocol analysis. _x000D_ _x000D_ Study Timeline: Start June 2021. Months 1-4 study initiation, Months 1-78 complete annual follow-up up-to 10 years; Months 43-50 the 7-year analysis, write-up and publication, including qualitative component; Months: 75 and 82: routinely collected dataset reports; Months: 79-82: final analysis including health economic analysis, and write-up._x000D_ _x000D_ Impact and Dissemination: The SIMS long-term results are expected to have a significant impact due to the ongoing highly publicised public debate on the use of mesh in women with SUI worldwide. It will allow us to provide robust long-term data on the use of mesh to treat SUI in women which are currently not available. It will also provide crucial evidence whether the technology of using significantly less mesh volume in SIMS (50% less than SMUS) has comparable longevity and safety compared to standard length MUS. If proven this could change clinical practice towards safer use of mesh procedures. The results of the study will be included in updates of NICE and EAU guidelines, which directly influence practice in the UK and worldwide respectively.",6.3 MEDICAL DEVICES,RENAL AND UROGENITAL HRCS22_06661,Department of Health and Social Care,NIHR,Long-term Outcomes in Long Standing Persistent Atrial Fibrillation Comparing Catheter Ablation and Thoracoscopic Surgical Ablation,"Background Atrial fibrillation (AF) is the most common arrhythmia worldwide and causes detrimental effects on quality of life, morbidity (stroke and heart failure) and mortality. The most challenging type of AF to treat is long-standing persistent AF (LSPAF), which is in part due to atrial substrate undergoing extensive electro-anatomical remodelling. Anti-arrhythmic drugs have proven to be less effective to restore sinus rhythm in symptomatic patients when compared to catheter ablation. At present, catheter ablation is the main interventional treatment for symptomatic LSPAF patients. The alternative option to catheter ablation is thoracoscopic surgical ablation, currently being investigated by our group in a randomised control trial (CASA-AF RCT, NIHR EME 12/127/127) with a follow-up period of 12 months. The longer terms effects of thoracoscopic surgical ablation in this cohort is not known. Research question Is thoracoscopic surgical ablation superior to catheter ablation at maintaining arrhythmia-free survival in the long-term (36-months) after a single procedure using implantable loop recorder monitoring? Aims and objectives This study aims to explore the long-term effectiveness of thoracoscopic surgical ablation when compared to catheter ablation at 36-month follow-up using implantable loop recorder, which monitors the heart rhythm. Additionally, further objectives include the comparison of arrhythmia burden reduction between the two groups, cost-effectiveness, biomarkers to predict outcomes and quality of life for patient-centric outcomes. Methods As part of the CASA-AF study, patients have been recruited and randomised to have either thoracoscopic surgical ablation or catheter ablation. During the procedure, the patients have had an implantable loop recorder inserted, which monitors their rhythm. The patients in the study have consented to keep their implantable loop recorders at the end of the CASA-AF trial. All the patients in the trial will be contacted, and if they agree to participate in the new study, we will obtain written consent to continue to monitor their implantable loop recorder and analyse the data. These implantable loop recorders have an expected battery life for at least 3 years. The study will begin at 12 months after their index procedure date until the end of the battery life. The loop recorded data will be reviewed monthly, in addition patients will attend clinical follow-up at 24 months and 36 months. This clinical review will consist of clinical examination, questionnaires, collecting blood and ECG. Timelines for delivery The trial will begin on 1st January 2020 and will require 20 months to complete patient follow-up. We will need another 4 months to complete data analysis and to publish the results to a peer-reviewed journal. Anticipated impact and dissemination Long term efficacy results of catheter ablation and thoracoscopic surgical ablation will potentially allow clinicians to offer an alternative procedure to patients with symptomatic LSPAF. These results will provide invaluable evidence to inform guidelines, which as it stands is devoid of robust randomised controlled trial data in this arena. This data will be highly relevant to inform the best patient care.","Background Atrial fibrillation (AF) is a heart rhythm problem, which causes an irregular heartbeat. It is the most common rhythm disturbance worldwide. AF can lead to significant symptoms and distressing health problems (stroke and heart failure). As people live longer, more people will need services for AF, putting financial pressure on the NHS. The longer a person has AF, the more difficult it is to go back into a normal heart rhythm. Those who have continuous AF for longer than a year are described as having longstanding persistent AF (LSPAF). This is the most challenging type of AF to treat and makes up a large proportion of all AF patients. The drugs that are used to treat AF do not work well in LSPAF. Currently, patients with LSPAF may be offered a procedure to help improve their symptoms. It involves putting a flexible thin tube (catheter) into a blood vessel in the groin and up into the heart. This procedure has modest success rates in improving symptoms in the long term. Recently, keyhole surgery has been used for these patients and evidence shows that it is better than the catheter procedure. However, we do not know how well people are doing beyond one year. Feedback from a patient focus group reported that they would like to understand the long-term results of the procedures to make an informed decision. Purpose To investigate this further, we plan to monitor patients from a previous research study who have already had both procedures. They have a small device implanted under the skin to monitor their heartbeat. This heartbeat monitor has a battery life of around 3 years, and the previous research study followed up patients for only 1 year. We will ask this group of patients if they would like to participate in this new study and obtain written consent. We will aim to make use of the remaining 2 years of monitoring on the device to identify whether they have had a recurrence of the abnormal rhythm. This project will have two stages. The first stage will involve downloading information from the implanted device that monitors their heartbeat on a monthly basis. The second stage of the study will include two clinic visits to collect blood and answer questionnaires; one at 2-years and another at 3-years from the procedure. We will assess the costs incurred over the 3 years for both procedures. Furthermore, in combination with quality of life scores from questionnaires, we will analyse the cost-benefit for patients and the NHS. The results may help to inform clinical guidelines (UK and international) on whether surgery has better outcomes for patients in the long term compared to the catheter procedure.",6.4 SURGERY,CARDIOVASCULAR HRCS22_07720,Department of Health and Social Care,NIHR,Lorlatinib for untreated ALK-positive advanced non-small-cell lung cancer [ID3896] - Part 2,"Lung cancer falls into two main groups: around 80 to 85% are non-small-cell lung cancers (NSCLC) and the remainder are small cell lung cancers. [1] NSCLC can be further classified into squamous cell carcinoma and non-squamous cell carcinoma. Approximately 70% of NSCLC are of non-squamous histology and can be either large-cell undifferentiated carcinoma or adenocarcinoma. [2] Most lung cancers are diagnosed at an advanced stage, when the cancer has spread to lymph nodes and other organs in the chest (locally advanced disease; stage III) or to other parts of the body (metastatic disease; stage IV). In 2018, 39,754 people were diagnosed with NSCLC in England & Wales. Of these people, 49% had stage IV disease and 12% had stage IIIB/C. [3]_x000D_ _x000D_ Lung cancer caused over 35,000 deaths in the UK between 2016-2018. [4] Forty-five percent of people with lung cancer survive for more than 1 year after diagnosis. [5]_x000D_ _x000D_ Anaplastic lymphoma kinase (ALK) fusion genes are chromosomal alterations that occur between the tyrosine kinase portion of the ALK gene and other genes. They are believed to be involved in the growth of tumours. ALK translocation can occur in NSCLC of any histology, although it is thought to be most common (almost exclusively) in tumours with adenocarcinoma histology. Approximately 3–7% of all lung tumours contain ALK mutations[6]._x000D_ _x000D_ For the majority of people with NSCLC, the aims of treatment are to prolong survival and improve quality of life. Treatment choices are influenced by the presence of biological markers (such as mutations in EGFR-TK, ALK, ROS-1 or BRAF, or levels of PD-L1 expression), histology (squamous or non-squamous) and previous treatment experience. People with confirmed ALK-positive NSCLC are likely to be offered initial treatment with ALK-targeted treatment. NICE recommends crizotinib (TA406), ceritinib (TA500), alectinib (TA536) and brigatinib (TA670) as treatment options for adults with untreated ALK-positive advanced NSCLC. People with NSCLC of an unknown ALK status may be offered initial treatment with platinum-doublet chemotherapy._x000D_ _x000D_ References_x000D_ 1 Types of lung cancer. Cancer Research UK. Accessed February 2021._x000D_ 2 Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. [Available from: https://seer.cancer.gov/csr/1975_2016/ ]. Accessed February 2021._x000D_ 3 National Lung Cancer Audit annual report (for the audit period 2018) (2020). Royal College of Physicians. Accessed February 2021._x000D_ 4 Lung cancer mortality statistics (2018). Cancer Research UK. Accessed February 2021._x000D_ 5 Lung cancer survival statistics (2013 - 2017). Cancer Research UK. Accessed February 2021._x000D_ 6 Zappa C, Mousa S (2016). Non-small cell lung cancer: current treatment and future advances. Translational Lung Cancer Research. Accessed February 2021.",To appraise the clinical and cost effectiveness of lorlatinib within its marketing authorisation for untreated ALK-positive advanced non-small cell lung cancer.,6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_00019,Medical Research Council,MRC,"MARCH: Social, Cultural and Community Assets for Mental Health","The 'MARCH' Network proposes that Assets for Resilient Communities lie at the heart of Mental Health (M-ARC-H) and is dedicated to advancing research into the impact of these assets in enhancing public mental health and wellbeing, preventing mental illness and supporting those living with mental health conditions. Specifically, it will advance our understanding of the impact of social, cultural and community assets including the arts, culture, heritage, libraries, parks, community gardens, allotments, leisure centres, volunteer associations, social clubs and community groups, of which there are an anticipated 1 million in the UK. The network will bring together a Disciplinary Expert Group of researchers with a Policy Group of major national policy bodies, a Patient Public Involvement Group of national mental health charities, and a Community Engagement Group of national organisations. Across three years, our network will unite research with policy and practice to tackle critical questions of research priorities, methods, and implementation in this field; understand and resolve barriers to mobilising community assets; and provide training and support to the next generation of researchers. Specifically, our network will address questions organised in two core work streams (WS): WS1. Cross-disciplinary research and challenges: (a) What evidence is there, from a cross-disciplinary perspective, for how and why community assets impact on public health and wellbeing and the lives of those living with mental health problems, and where are the gaps for future research? (b) How can we use a cross-disciplinary approach to provide meaningful data to different stakeholders and users? WS2. Equity of engagement and access innovation: (a) Who amongst the UK population, demographically and geographically, currently engages with these programmes and how does participation vary dependent on mental health? (b) What are the current barriers and enablers to engagement at an individual, organisational and policy level and how can we develop innovative approaches to enhance engagement, especially amongst the vulnerable? This research work will be complemented by a rich portfolio of impact, engagement and training activities (see 'Impact Summary'). This network aligns with strategic priorities of the AHRC and ESRC as well as having a secondary relevance to the priorities of the MRC (through its consideration of the role of community assets and social prescribing to support medical approaches to mental health), NERC (through its exploration of the impact of green spaces) and EPSRC (through its focus on the opportunities provided by technology for driving research forwards). It has also been designed in response to the Network Plus Research Agenda. In addition to the objectives already discussed in the prior Je-S section, it is responsive to many of the mental health challenges cited in the agenda. For example, the call specification noted that only 25% of people with mental health problems receive ongoing treatment. Whilst there are recognised economic and resource constraints with delivering sufficient mental health services, this Network proposes to focus on the role that existing community assets could play in providing support to a much wider range of people in the UK including those on waiting lists. As another example, the call specification raised that 70% of children and adolescents with mental health problems have not had appropriate interventions at an earlier age. This Network will involve working with policy makers and community organisations to see how research could help overcome barriers to access with the aim of engaging more young people and those who are hard to reach. Overall, the network will seek to understand and support future research into how community assets could be mobilised to encourage more resilient individuals and comm",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)",MENTAL HEALTH HRCS22_06081,Medical Research Council,MRC,MEErKAT MEsenteric Excision and Kono-s Anastomosis Trial,"Crohn’s is a disease that makes the bowel red, swollen and painful. It is a chronic disease. This means that it is ongoing and lasts a life time, although people may have times when they are well and times when symptoms are more active. Some people get few flare-ups. Other people may have really bad and long lasting symptoms. At present there is no cure for Crohn’s, but drugs can treat the symptoms. In some people the drugs do not work or stop working and these people may need surgery. Whilst surgery can also stop symptoms for a long time, the disease can return. Further drugs and even further surgery may be needed. _x000D_ _x000D_ Many surgeons feel that the way the bowel and the tissue containing the blood and other vessels supplying the bowel (the mesentery) is removed and the way the healthy bowel ends are re-joined can affect the chances of getting further disease. Two changes to the way surgeons operate have been proposed. One involves taking out more of the mesentery and the other involves doing another type of bowel join. This is known as the Kono-S join. There are many fans of these recent surgical changes and we know that they are safe. But we need to test that they are better than the usual method in stopping further disease. _x000D_ _x000D_ So that we can test this we want to ask people who need surgery for their Crohn’s disease if they would let us carry out one or both of these methods. We will then see if they have made the chances of further disease less one year later. The type of surgery a person has will be decided by chance. People would be checked as is usual by speaking to a doctor and having a telescopic camera test or colonoscopy through the back passage to look at the bowel join. _x000D_ We also need to see why these new methods may work. Some clues may be found by looking at those who get further disease after surgery and seeing what part of the join the disease has come back to. This can be done with the telescopic camera so long as the bowel is marked with a small tattoo at the time of the surgery. We use these tattoos all the time when doing telescopic camera tests so we know they are safe. The tattoo will only be seen if you look into the bowel. To try and understand what causes the different outcomes between methods, we will also do blood tests and take samples from different bowel areas before and after surgery to see how the immune system - which drives disease in Crohn's - is altered after the different operations._x000D_ _x000D_ We have asked a patient panel to see if they think this is a good way to see if the new methods work. They have helped us to put this test together and are happy that it is safe and the right thing to do. They will also help us to make sure we let other doctors and surgeons know the results of the study.","DESIGN_x000D_ Multicentre, superiority, 2×2 factorial, randomized, open-label trial with a minimum one-year follow-up. _x000D_ _x000D_ SETTING_x000D_ 12 UK NHS hospitals._x000D_ _x000D_ POPULATION_x000D_ People undergoing ileocaecal resection for primary/recurrent Crohn’s disease where an anastomosis is carried out. Post operative medical treatment will be in line with the recommendations from the BSG guidelines._x000D_ _x000D_ INTERVENTIONS_x000D_ Participants will be randomised (1:1:1:1) to one of four groups: (1) Kono-S + radical mesenteric resection; (2) Kono-S + close mesenteric resection; (3) Standard anastomosis + radical mesenteric resection; (4) Standard anastomosis + close mesenteric resection. A mechanistic component will determine in those that develop endoscopic recurrence, the locality and mechanism of that recurrence. _x000D_ _x000D_ OUTCOMES._x000D_ Primary outcome_x000D_ Time to endoscopic recurrence (after a minimum of 12 months and maximum of 3 years follow-up) using Rutgeert’s score (>/=i2)._x000D_ Secondary outcomes_x000D_ 1. Incidence of severe endoscopic recurrence (Rutgeert’s score >/=i3); _x000D_ 2. Symptomatic recurrence at 12 months and at the end of the trial; _x000D_ 3. Time to recurrence for all groups; _x000D_ 4. Surgical recurrence at a minimum of 12 months and a maximum of three years; _x000D_ 5. Radiological and surgical anastomotic leak as defined by the latest consensus; _x000D_ 6. Other complications for each intervention; _x000D_ 7. Mesenteric disease activity index. _x000D_ Mechanistic outcomes_x000D_ 1. Locality of recurrence_x000D_ 2. Degree and anastomotic locality of peripheral blood mucosal and/or mesenteric fibrocytes and immune factors especially T cell clonality._x000D_ _x000D_ SAMPLE SIZE_x000D_ We require 308 patients (77 per group; 154 per group for the factorial design) for 90% power; 5% (two-sided) significance, reduction in 1-year endoscopic recurrence from 50% to 30% (hazard ratio 0.515), 104 recurrences, surgeon effects (12 sites, 2 surgeons, ICC 0.01) and 5% attrition._x000D_ _x000D_ PROJECT TIMETABLE _x000D_ M1-8 set-up; M9-20 internal RCT pilot, M21 stop/go assessment, M21-38 RCT main trial recruitment, M39-50 follow-up only; M51-56: closedown and analysis. _x000D_ _x000D_ ELIGIBILITY CRITERIA_x000D_ People aged 18-75 years with Crohn’s Disease who have been clinically assessed as appropriate for ileocaecal resection and anastomosis. Exclusion criteria include those with markedly extensive inflammation affecting the vascular root of the mesentery seen on imaging or at operation; undergoing stoma formation; contraindication to subsequent colonoscopy; inability to consent, pregnancy._x000D_ _x000D_ MECHANISTIC SUBSTUDY_x000D_ The locality of recurrence will be investigated using endoscopic assessment of mucosa relative to mucosal tattoos placed at the time of operation. The degree and anastomotic locality of different fibrocytes and immune cells, focussing on mucosal T cell clonality and exhaustion, especially T cells with CD8 gene expression, will be compared before and after each intervention utilising flow cytometry, multiplex PCR and sequencing and qPCR. _x000D_ _x000D_ COMPLEMENTARY SKILLS_x000D_ Clinical, methodological, statistical, immunological skills + patient experience.",6.4 SURGERY,ORAL AND GASTROINTESTINAL HRCS22_01635,Medical Research Council,MRC,MICA: Childhood arthritis and its associated uveitis: stratification through endotypes and mechanism to deliver benefit; the CLUSTER Consortium.,"Juvenile idiopathic arthritis (JIA) and its associated eye inflammation, JIA-uveitis, can cause long-term disability and poor quality of life for children and well into adult life. Currently there are no validated tools with which to predict disease course or outcome, select treatment or predict response. Our proposal brings together internationally recognised leaders in childhood arthritis, JIA-uveitis, and bioinformatics, with industry, patient and clinical partners, as the CLUSTER consortium. Our goal is to define distinct 'endotypes' or 'strata' of childhood arthritis and JIA-uveitis, reflecting treatment response and disease course; integrate these with prognostic biomarkers; generate stratification algorithms, facilitate targeted treatment choices and propose new therapies. The specific scientific aims of CLUSTER are to: 1. Discover, replicate and validate biomarkers for prediction of treatment response to drive stratified medicine approaches in JIA and JIA-uveitis; 2. Identify mechanisms and pathways in JIA and JIA-uveitis to define novel therapeutic targets and facilitate stratification; 3. Identify disease and treatment-response strata with markers for stratification; 4. Work with industry partners to deliver new stratified clinical trials in JIA and/or JIA- uveitis. CLUSTER will build on success of the MRC-funded consortium CHART comprising 5000 JIA cases with biosamples and data (clinical, genetic, omics), and include new cases and cohorts. Initial analyses will inform power calculations for proteome, transcriptome and immunome data generation. Integrated iterative analysis will define strata, biomarkers of response, and enable design of new clinical trials partnering with patients, clinicians and industry. Validated strata with robust predictive biomarkers for JIA and JIA-uveitis will lead to earlier control of inflammation, improved outcomes, reduced disability and exposure to side effects and generate long-term health care savings.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,EYE;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_01597,Medical Research Council,MRC,MICA: Control of tumour cell apoptosis by nuclear F-actin bundling,"Fascin is an actin binding and bundling protein that is significantly up upregulated in most human cancers and contributes to metastasis. As fascin is not expressed in normal epithelial cells, it is a very attractive target for therapeutic intervention to halt tumour cell invasion. However, despite being discovered nearly 20 years ago and levels analysed in hundreds of cancers, we still know relatively little about the factors that control fascin function and this is a significant barrier to strategic development of therapies. Our recent published and unpublished data has revealed that fascin can associate with a number of previously undescribed binding partners and localizes to the cell periphery, nuclear envelope and inside the nucleus. Our exciting preliminary data has shown that nuclear localised fascin can regulate F-actin bundling within the nucleus, and when this phenotype is artificially enhanced, this results in commitment of tumour cells to apoptosis. The goal of the current study is to use a range of biochemical methods coupled with advanced cell-based imaging approaches to determine the molecular mechanisms that regulate nuclear fascin localisation under homeostatic conditions. In partnership with the major pharmaceutical company AstraZeneca, we will then employ a series of high-content, high resolution imaging screens to identify potential upstream regulators that can promote nuclear fascin and F-actin bundling leading to tumour cell death. These approaches combined will provide significant insight into novel mediators of fascin function and localisation, as well providing new tools and targets for modulators of nuclear F-actin. In the longer-term our goal is to use this information to develop new therapeutic strategies to target tumour cells and initiate cancer-specific cell death.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_02529,Medical Research Council,MRC,MICA: Early Phase Dose-finding Trials: Development of reporting guidance to improve knowledge transfer,"Results from early phase dose-finding trials (Phase I or Phase I/II) directly influence decisions on further drug development and ultimately whether the selected dose(s) can be confirmed as safe and efficacious. Poorly reported dose-finding trials with inadequate rigour may lead to bias in reporting and lack of reproducibility. This wastes time and resources, but more importantly, may unethically expose participants to ineffective or even harmful interventions. The main CONSORT Statement provides recommendations for reporting parallel group randomised trials, where participants are randomly assigned to different interventions. They do not address many methodological features such as interim dose-decisions (escalate, de-escalate, stay or stop) that arise in the design, conduct, analysis and interpretation of early phase dose-finding trials. The quality of reporting of such published trials is often inadequate. To address this unmet need and reduce research waste, we will 1. Extend the CONSORT reporting guidance for dose-finding trials to improve reporting, using gold-standard methods for developing consensus-based guidelines recommended by the CONSORT Group (Moher et al 2010) 2. Actively involve, engage and disseminate outputs to stakeholders, including trialists (clinicians, statisticians, trial managers), funders, regulators, patients and public, journal editors and peer reviewers. Besides scientific publications, we will also produce lay summary papers for the public and patient community. Motivated by the desire to capture diverse views of experts across sectors with multidisciplinary roles, we have strategically brought together a team of national and international statistical methodologists and trialists (clinicians with drug discovery expertise and statisticians) in early phase trials in both academia and pharmaceutical industry, a CONSORT Group representative, a patient and public representative (PPI), with oversight from an Independent Expert Panel.",,6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),GENERIC HEALTH RELEVANCE HRCS22_02277,Medical Research Council,MRC,MICA: Exploiting in silico modelling to address the translational bottleneck in regenerative medicine safety,"Successful clinical translation of regenerative medicine therapies requires robust preclinical tools for safety, immunogenicity and efficacy purposes. We will develop a translational preclinical toolkit for the clinical translation of regenerative medicine therapies by combining in silico, in vitro and in vivo approaches. The current clinical translational bottleneck in liver cell therapy development concerns safe delivery of the cell therapy to the site of liver disease; protection of the delivered cells from the host immune systems; as well as ensuring successful cell engraftment and subsequent function at the injury site. We will address this translational bottleneck by encapsulating cells in a biocompatible and biodegradable micromatrix. Mathematical modelling in combination with state-of-the art experimental approaches will provide mechanistic understanding into the role of cell encapsulation in ensuring the safety, immune system evasion and efficacy of these next-generation liver cell therapies. We will develop predictive mathematical models that integrate data obtained from complementary in vitro and in vivo approaches thus providing a bridge from understanding gained through reductionist in vitro assays to in vivo animal models. The quantitative and predictive approach will enable identification and optimisation of cell therapeutic approaches in terms of encapsulation protocols ensuring desired mechanical, anti-inflammatory, engraftment and functional properties and dosing regimens, thereby providing quantitative preclinical evidence for or against the use of encapsulation technologies. This preclinical toolkit will therefore facilitate successful clinical translation of next-generation cell therapies for liver disease. The in silico approach will have wider impact across the UKRMP Hub disease exemplars, such as lung and joint, and beyond into wider disease conditions, e.g. cardiovascular, by enabling translational bottlenecks to be overcome.",,1.3 CHEMICAL AND PHYSICAL SCIENCES,GENERIC HEALTH RELEVANCE HRCS22_17835,Versus Arthritis,,MICA: Exploiting specialised pro-resolution molecule mediated analgesia to identify novel targets for the treatment of chronic pain,"Osteoarthritis (OA) is the leading cause of chronic pain. Specialised resolution molecules (SPMs) have robust analgesic effects in models of chronic pain, acting via microRNAs (miRNAs) to shut-down multiple pro-inflammatory signalling pathways to restore tissue homeostasis. Levels of the SPM precursor 17-HDHA are significantly associated with pain thresholds in healthy volunteers and levels of OA pain. Aim: to identify the miRNAs critical to the analgesic effects of the SPMs to provide new strategies for OA pain treatment. A clinical study will identify miRNAs associated with 17-HDHA levels and OA pain, with validation in people with diabetic neuropathy +/- pain. Bioinformatic analysis will categorise dataset commonality for the two conditions. Using a publicly available synovial fluid dataset we will focus on miRNAs both implicated in the effects of 17-HDHA and locally at the painful joint. The top 30 clinically relevant miRNAs will be mechanistically probed. Levels of 17- HDHA will be augmented in mice in the presence (and absence) of a clinically relevant model of OA pain behaviour, and blood levels of the top 30 clinically relevant miRNAs will be quantified to confirm which miRNAs are modified by 17-HDHA. Using microfluidic chambers for the culture of mouse sensory nerve axons we will quantify the effects of 17-HDHA on calcium (Ca2+) transients in cell bodies after axon terminals are stimulated with PGE2 plus capsaicin (to mimic hyperalgesia). The effects of manipulating (with inhibitors or mimics) 10-15 of the 17-HDHA modifiable miRNAs on evoked Ca2+responses (in the presence and absence of 17-HDHA) will confirm which miRNAs are essential for the inhibitory effects of 17- HDHA on sensory excitability. The identification of the clinically and functionally relevant miRNAs that underpin SPM_x0002_mediated natural analgesia will provide crucial mechanistic understanding which will underpin the development of novel approaches for treating chronic OA pain.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MUSCULOSKELETAL HRCS22_02881,Medical Research Council,MRC,MICA: Investigating the role of the adenosinergic pathway in anti-tumour immune dysfunction in cutaneous squamous cell carcinoma (cSCC),"Background Cutaneous squamous cell carcinoma (cSCC) is one of the commonest cancers worldwide, yet treatments for advanced cSCC are limited, with anti-PD-1 therapy giving complete responses in only 15% of patients. Recent evidence indicates the adenosine pathway contributes to immune dysfunction and poor clinical outcome in cSCC. Investigation of adenosine pathway inhibition in cSCC may lead to improved treatment for aggressive cSCC. Aims To delineate the role of the adenosine pathway in dysfunctional cSCC immunity using adenosine pathway blockade, alone and with anti-PD-1, to enhance anti-tumour immunity. Objectives 1. Establish whether the effects of adenosinergic pathway inhibition in cSCC differ according to the target of blockade (i.e. CD39, CD73, A2AR). 2. Determine whether a combination of adenosinergic pathway antagonists is more effective than single agents at promoting anti-tumour immunity in this cancer. 3. Examine whether boosting anti-tumour immunity via the adenosinergic pathway is augmented by anti-PD1. Methods 1. Tissue slice culture (TSC) of ex vivo human cSCC will be performed separately with a CD39 inhibitor, anti-CD73 antibody, and an A2AR inhibitor. 10x single-cell RNA sequencing of lymphocytes and macrophages will delineate changes in individual cell types; immune cell functional state will be quantified using flow cytometry (FC), immunofluorescence (IF), supernatant cytokine analysis (SCA), and tumour cell killing (TCK) assays. 2. Tissue slice of cSCC cultured with simultaneous blockade of CD39, CD73 and A2AR, will be compared with single agent blockade and immune responses analysed with qPCR, FC, IF, SCA, and TCK assays. 3. Combined adenosine and PD-1 blockade of cultured cSCC slices will be analysed with qPCR, FC, IF, SCA, and TCK assays. Implications The results from this cSCC TSC project to investigate the adenosine pathway in cSCC immune dysfunction will help inform future clinical trials on cSCC immunotherapy.",,2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),CANCER AND NEOPLASMS HRCS22_02855,Medical Research Council,MRC,MICA: Large-Scale Vaccine Fill and Phase I Clinical Trial of the RH5.1/Matrix-M Vaccine against Blood-Stage Plasmodium falciparum Malaria,"The Need: Delivery approaches and platforms that can impart sustained and durable immunity are essential to the success of vaccines against a wide variety of difficult human diseases. Examples include seasonal respiratory viruses (such as influenza, RSV), emerging/pandemic pathogens (such as SARS-CoV-2) as well as parasites (such as Plasmodium - the causative agent of malaria). Rationale: We previously developed the first vaccine to show in vivo impact in humans against the disease-causing blood-stage form of the P. falciparum human malaria parasite. The vaccine (called RH5.1) targets the conserved and essential RH5 antigen used by the parasite to invade erythrocytes. With previous MRC DPFS funding support we successfully produced this novel recombinant protein to high yield using new platform biomanufacturing technologies, and with USAID funding, we tested RH5.1 formulated in AS01 adjuvant from GSK in a large Phase I/IIa trial in healthy UK adults. We identified a ""delayed-fractional booster"" immunisation regimen that dramatically improved the maintenance of the human antibody response over 2.5 years' follow-up, as compared to routine vaccine boosting at monthly intervals. Solution & Development Plan: We now propose to fill our remaining RH5.1 vaccine material (~250mg) to give a second vaccine batch. We will test this vaccine batch in a Phase Ia clinical trial in healthy UK adults in order to i) refine the vaccine delivery regimen, testing a delayed versus delayed-fractional booster regimen; and ii) to bridge to the new Matrix-M adjuvant, with our partner Novavax. RH5.1/Matrix-M offers the possibility of an efficacious blood-stage malaria vaccine that can proceed to future field efficacy testing, as well as a route to identification of a delayed-booster immunisation regimen that affords long-lasting human immunity. Importantly, this work will also exemplify robust vaccine platform delivery technologies that have broad applicability to a range of human diseases.",,3.4 VACCINES,INFECTION HRCS22_02851,Medical Research Council,MRC,MICA: Point-of-care assessment of drug-induced liver injury (POC-DILI),"There is a significant unmet need for a rapid, quantitative, point-of-care (POC) biomarker assay to diagnose drug-induced liver injury (DILI) early after paracetamol overdose (POD) (primary context-of-use). Antidote treatment for POD is time-critical, being optimally effective if started within 8h of overdose and near ineffective if delayed >20h. Cytokeratin-18 (K18) is an accurate, early DILI biomarker. In contrast to the current standard, alanine aminotransferase (ALT), K18 can sensitively discriminate between patients with and without DILI within 8h of overdose. This enables prompt, targeted, treatment of patients in need. To detect K18, and therefore DILI, a POC lateral flow assay (LFA), which detects biomolecules in a sandwich immunoassay format in <20mins, will be used. LFA uses a line of immobilised capture antibodies (CAb) and gold nanoparticles (AuNP) coated with a detection antibody (DAb). Capillary blood will be applied to the device and a sandwich complex formed between the two Ab and K18. This immobilises the AuNP on the LFA strip resulting in a red line. The assay must be quantitative to allow patients with DILI to be identified with fit-for-purpose sensitivity and specificity. This will be achieved by using optically bright AuNPs coated with a Raman reporter and analysed using Surface Enhanced Raman Scattering (SERS). By illuminating the AuNP line with a handheld Raman reader, a SERS spectrum of the Raman reporter can be obtained. An algorithm developed by our industrial partner will produce a read-out that is easy to interpret at the time of measurement. In its primary context-of-use (supported by the National Poisons Information Service) this innovation will be used by a nurse or other healthcare professional to risk assess a POD patient at first presentation. Those with an increased risk of DILI could then receive immediate treatment. We envisage our assay being further refined for use in drug development and resource-limited settings.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,INJURIES AND ACCIDENTS HRCS22_01371,Medical Research Council,MRC,MICA: Targeting the RA synovial fibroblast via cyclin dependent kinase inhibition - a phase IIa study,"This project aims to repurpose a small molecule anti-cancer drug as an anti-fibroblast drug for RA. The past 20 years have seen major advances in RA therapy; more aggressive use of conventional drugs, and biological targeted therapies have each made a significant impact. However, disease remission remains uncommon and around 20% of patients remain refractory to all therapies. This represents a significant unmet need and suggests key aspects of RA pathogenesis remain untargetted. In health, a delicate nutritive synovial membrane (SM) lines joint cavities. This comprises a few macrophages and fibroblasts in a loose connective tissue stroma. In RA the SM is the focus of autoimmune attack but, in addition to inflammatory cell infiltration, resident synovial fibroblasts (SF) become hyperplastic, forming a vascularised, inflammatory, quasi-malignant pannus which invades articular cartilage and bone. The resultant joint damage underlies the disability and reduced quality of life that characterise RA. Cell proliferation relies on the coordinated activation of specific regulatory proteins: orderly progression through the cell cycle is tightly controlled by the formation and activation of complexes comprising cyclin proteins and cyclin-dependent kinases (CDK). These complexes are in turn regulated by endogenous CDK inhibitors (CDKI). The concept of inhibiting CDKs to correct uncontrolled cell proliferation has led to the evaluation of small molecule CDKI in cancer. RA SF have reduced endogenous CDKI levels, and correction of the deficit normalises their dysregulated phenotype. Indeed, small molecule CDKI ameliorate synovitis in pre-clinical arthritis models. In partnership with the SME Cyclacel, we propose a phase IIa repurposing study of a CDKI in patients with refractory RA. Stage 1 will focus on safety and tolerability, to determine an appropriate dose to progress to stage 2, where we will seek evidence of potential therapeutic activity alongside PK and PD biomarkers.",,6.1 PHARMACEUTICALS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_03855,Medical Research Council,MRC,MICA: Towards targeted treatment for complex regional pain syndrome through determination of the underlying molecular mechanisms,"In order to understand the genetic basis for complex regional pain syndrome (CRPS), we recruited two patient cohorts and discovered that four SNPs, each in a different gene, were enriched in CRPS cohorts compared to healthy controls. All four genes are linked to the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. We therefore hypothesise that the SNPs identified cause aberrant activation of NLRP3 to promote the development of the chronic inflammatory pain seen in CRPS. In order to study CRPS, we will initially generate a cellular model by the introduction of each SNP allele into a monocyte cell line THP-1 using CRISPR/Cas9 gene editing (already achieved for one SNP). Macrophages are highly plastic cells and exist in at least three different states based on environmental cues: naïve M0, pro-inflammatory M1 and anti-inflammatory M2. The transition between M1 and M2 cells is important in wound resolution and healing. We will identify whether the CRPS mutations alter inflammasome activity in macrophages in different activity states by differentiating THP-1 cells harbouring the CRPS SNPs into M0, M1, M2 and M1>M2 states. Inflammasome activity will be determined by measuring pro-inflammatory cytokine secretion (interleukin IL-1B, IL-18) and gasdermin D-driven cell death following activation of NLRP3. These results will be validated in primary macrophages taken from healthy controls with the CRPS-associated SNPs. We will investigate whether the CRPS mutations alter the cross talk between pain and inflammation by measuring the effect of inflammatory mediators released by macrophages on nociceptor sensitisation. We will develop a co-culture system with macrophages and nociceptors differentiated from embryonic stem cells. Nociceptor activity will be measured using electrophysiology. Lastly, we will investigate the effect of inflammasome modulators, provided by NodThera, on the pain and inflammatory responses in the co-culture model.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL HRCS22_21574,Innovate UK,IUK,MISFIT – Maximising Inclusiveness in Sports through Female-centric Innovation and Technology,"The needs of older women are largely ignored in many areas of life,?and this is particularly true when it comes to sport and exercise. Yet sustaining fitness and activity levels for women as they age has life-changing and lasting benefits in relation to?physical health,?happiness?and?mental wellbeing. In the?older female population, a particular barrier to remaining physically active is lower limb pain and injury risks.?Women aged 50+ face particular barriers to getting and/or staying physically active. As well as an increased incidence of pain, discomfort and injury, this group are not well-supported in terms of assistive and appropriate sports technologies, sportswear and footwear -- which tend to be developed for, and marketed to,?young people.? In fact, the majority of exercise and sport-related injury prevention research is conducted on young, often male, adults, largely in the context of elite sports. The effects of gender and ageing on bodily biomechanics and physiology remain poorly understood, making it challenging to remove or even address these barriers and changes to injury risks. Furthermore, conventional biomechanics studies are limited to laboratory-based research with small participant numbers, preventing large-scale data insights of normal people,?doing normal?sports,?in normal settings. There is an urgent need to progress our understanding of female sports biomechanics through life, and develop relevant technologies and products to support inclusive sports participation by women of all ages.? Project MISFIT aims to address this gap in the Healthy Ageing space by developing a new movement analytics service that is designed specifically for older women. This will provide?evidence-based?information?regarding?bespoke?exercise regimes?and?injury prevention?to?support continued?safe participation in?physical activity. MISFIT will build on KYMIRA's?award-winning sports apparel solutions, which will be adapted for older females. The project?uses?smart garments?equipped with sensors and pressure measuring insoles, to capture and integrate kinematic (movement), kinetic (force) and?physiological data during everyday sports.?MISFIT will enable large-scale data-gathering to provide population-level insights into injury mechanisms and optimum exercise regimes as women get older. MISFIT will translate the data and learnings to provide a sports advisory service to users. In a further innovation, award-winning sports footwear developer Ida Sports will use the service to inform the user-centric design of a new range of sports footwear?to support?women?to continue in sport participation?as they age.",,7.1 INDIVIDUAL CARE NEEDS,CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE HRCS22_07095,Medical Research Council,MRC,MR-PRo-adrenomedullin (MR-proADM) and ImmunoXpert Evaluation of procalcitonin-guided antibiotic duration in Children with Infection for Stratification of Effectiveness (PRECISE),"WHAT IS THE PROBLEM?_x000D_ The Department of Health recommends that antibiotics should be given for as short a course as is safe, to prevent antimicrobial resistance. Most hospitals in the NHS use a blood test called C-Reactive Protein (CRP) to monitor the body’s response to infection, but it is not specific for bacterial infection and shows a delayed response to infection. An alternative would be a Procalcitonin (PCT) test which is specific for bacterial infection and responds more quickly than CRP, but is not routinely used in the NHS. We are currently running a randomised, controlled trial (the BATCH trial) to see whether PCT testing to guide how long to give intravenous antibiotics (into a vein) for infection in children, is beneficial. New markers of infection, which measure the body’s response to infection, have been studied, and it is suggested they could provide additional information to help identify which children will benefit from PCT testing to guide antibiotic use._x000D_ AIM OF THE RESEARCH_x000D_ We will embed a smaller study on the newer markers of the body’s response to infection, into the current randomised controlled trial of PCT testing to guide antibiotic use. This will help us to identify groups of children in whom PCT testing to guide antibiotic use might be beneficial, harmful or ineffective. This can make it safer for some patients, and in others reduce unnecessary PCT testing, thus saving money, as the PCT test will not be offered to those in whom it will be of no benefit._x000D_ WHAT WILL BE DONE, AND WHO WILL BE INVOLVED?_x000D_ In the current trial, children admitted to hospital with bacterial infection and receiving intravenous antibiotics for more than 48 hours are randomly assigned to one of the two treatment arms; PCT-guided or usual care. Doctors and patients know which treatment arm they are in. Four hospitals enrolling children in the current trial will take part in the new study. Parents will be given information about the study and invited to take part. Additional blood samples will be taken on all children in the study (not just those in the PCT arm) to measure the new markers of the body’s response to infection, so groups with low and high levels of these markers can be determined._x000D_ PATIENT AND PUBLIC INVOLVEMENT_x000D_ A parent member of the BATCH trial team, Mrs Sarah Jones has provided advice on the study. In addition, the Liverpool GenerationR Young Person’s Advisory Group are actively involved in the BATCH trial. The group consists of young people aged between twelve to seventeen year olds, who helped design the consent forms and patient information leaflets for the BATCH trial. Sarah Jones and the public involvement lead for the Liverpool group attend monthly BATCH team meetings and provided advice on the acceptability of additional testing and use of salvaged clinical samples for testing in the BATCH trial._x000D_ HOW WILL THE RESEARCH BENEFIT PATIENTS?_x000D_ If the study shows that PCT-guided management is better than current practice, in certain groups of children with infection treated with intravenous antibiotics but not others, then the test will only be offered to those children who are likely to benefit from it. This will lead to improved safety and quality of patient care and reductions in the spread of antimicrobial resistance. It will also reduce time in hospital, and save costs.","BACKGROUND: The host-response to bacterial infection is highly heterogeneous, there is therefore a need for stratified treatment strategies instead of the traditional “one-size-fits-all” approach. A precision medicine approach can improve patient outcomes by identifying endotypes in whom the intervention is likely to be harmful or ineffective. In the PRECISE sub-study, we aim to use an embedded mechanistic study to determine endotypes of endothelial dysfunction (mid-range proadrenomedullin (MR-proADM)) and host immune response (ImmunoXpert score: TRAIL, IP-10 and CRP) in whom a Procalcitonin (PCT)-guided antibiotic algorithm might be a) particularly beneficial, b) ineffective, or c) harmful._x000D_ RESEARCH QUESTION: In children hospitalised with suspected or confirmed bacterial infection, do endothelial dysfunction and a likely viral host immune response profile (as indicated by biomarkers) diminish the effectiveness of a PCT-guided antibiotic algorithm in reducing intravenous (IV) antibiotic duration, compared to usual care? _x000D_ HYPOTHESIS: In children treated with IV antibiotics for suspected or confirmed bacterial infection; a) persistent endothelial dysfunction will be associated with increased duration of IV antibiotics and a PCT-guided antibiotic algorithm may be harmful, and b) a likely viral or other host immune response will be associated with reduced duration of IV antibiotics and a PCT-guided antibiotic algorithm may be ineffective. (Figure 1)_x000D_ AIM: The aim of the PRECISE sub-study (embedded within the BATCH trial), is to determine if there are specific sub-groups of patients, for whom a PCT-guided antibiotic algorithm may be beneficial, harmful or ineffective._x000D_ STUDY DESIGN: Embedded mechanism of action study within a multi-centre, prospective, individually randomised, un-blinded two-arm RCT comparing PCT-guided antibiotic algorithm versus usual care. Recruitment to the host trial commenced in June 2018._x000D_ PARTICIPANTS: Children aged 72 hours up to <18 years hospitalised with suspected or confirmed bacterial infection._x000D_ PRIMARY OUTCOMES: Time until IV antibiotic therapy is stopped will be the primary (time-to-event) endpoint, same as BATCH trial. Baseline MR-proADM and ImmunoXpert scores will define subgroups for the primary comparison, and serial measurements for additional analyses._x000D_ SECONDARY OUTCOMES: Total duration of antibiotics (oral and IV), time to switch from broad spectrum to narrow spectrum antibiotics, time to discharge from hospital, suspected adverse drug reactions, hospital acquired infection up to Day 28._x000D_ PROJECT TEAM: Carrol (CI), Thomas-Jones (Co-CI), Waldron (BATCH trial manager), Pallman (BATCH statistician), Jones (PPI), and Faust, Patel, Paulus, Bernatoniene, Nabwera (all BATCH co-applicants)._x000D_ TIMETABLE: MONTH 1-12: Sample collection and archiving MONTH 12-15: Measurement of MR-ProADM and ImmunoXpert in plasma samples blinded as to randomisation arm. MONTH 15-18: Data cleaning, statistical analysis, prepare for EME report, dissemination._x000D_ IMPACT AND DISSEMINATION: Our research will lead to earlier and more accurate identification of patients who will benefit from a PCT-guided antibiotic algorithm and those in whom it might cause harm, which means that complications and deaths can be averted. This means shorter stays in hospital, less antibiotic exposure and fewer deaths. The results of the PRECISE sub-study will be disseminated locally, nationally and internationally amongst clinical and lay groups.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,INFECTION HRCS22_01376,Medical Research Council,MRC,MRC Brain Banks: Joint Application to Underpin Neuroscience Research,"This joint application from the MRC Brain Banks in Edinburgh, London, Newcastle and Oxford is submitted in accordance with the wishes of the MRC Neuroscience and Mental Health Board (NMHB). After the last funding round for the MRC Brain Banks in 2011, NMHB indicated that a future joint application would be preferred and that the applicants should demonstrate progress in efficiency and improving standards of work in accordance with an agreed set of metrics. This application fulfils this request, and aims to underpin neuroscience research in the UK by providing high-quality human brain tissue samples and data in the formats required by researchers in both academic and industrial settings. The four banks in this application together cover the collection of human tissue samples from a range of major neurological diseases, and normal tissue samples to act as controls. This provides an invaluable resource to underpin neuroscience research in UK, particularly in recently identified priority areas such as dementia. The banks have demonstrated in this application that they can work to the standards set in the metrics agreed with the NMHB, and have improved their efficiency of operations. The banks already support a number of major researchers in academia and industry in UK and overseas, including several who are currently funded by MRC. The provision of high quality tissue samples and accompanying data is essential for the success of these projects; the MRC brain banks constitute a critical infrastructure for this research. In order to develop this important work further, funding for a 5 year period is requested; earlier funding awards for periods of 2 years has not been conducive to long term planning and strategy. The costs of brain banking in the UK compare very favourably with those in Europe and in the USA; over the next 5 years the banks will continue to work to improve efficiency of operation and to operate a cost recovery programme.",,1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),NEUROLOGICAL HRCS22_22894,The Academy of Medical Sciences,AMS,Machine learning to identify predictors of outcome and survival in the treatment of mUM (metastatic uveal melanoma) with M-PHP (melphalan percutaneous hepatic perfusion).,"Ocular melanoma, the most common primary ocular malignancy in adults, carries a poor prognosis: 50% of patients develop metastatic disease with a 10-25% 1-year survival and no established standard of care treatment. The liver is often the only site of metastatic disease [1] and current systemic treatments have poor response rates (<​20%), especially in those with progressive hepatic disease [2]. More recently, melphalan percutaneous hepatic perfusion (M-PHP); a novel treatment delivered by Interventional Radiologists via a minimally invasive approach has shown improved hepatic and overall progression-free survival versus best alternative care whilst exhibiting a reasonable side-effect profile. However, there remains a disparity in survival within this heterogeneous group of patients, with as many as 40% not responding to therapy (progressive disease/stable disease). Currently, we cannot predict who they will be and there is an unmet clinical need to identify which patients are more likely to respond. We aim to use Machine learning and Artificial Intelligence with the combination of pre-procedural imaging and routinely collected clinicopathologic datasets to accurately predict patient outcomes including survival and response to M-PHP therapy. We will develop and validate this ML model to provide a non-invasive decision support tool and thus aid the doctor-patient shared decision-making process to improve patient outcomes, cost-utility and spare patients the risk of ineffective and potentially toxic treatment.","Uveal melanoma, the most common primary eye tumour in adults, has a terrible prognosis with half of patients suffering from metastatic or distant disease. Only one out of every ten patients are alive after one year. Immunotherapy (medication), surgery, or, more recently, chemotherapy directly focused at the liver known as melphalan percutaneous hepatic perfusion(M-PHP) are all options for patients but deciding which treatment is best is not clear. The latter has shown promise and has the added benefit of being delivered through a small hole via the groin and neck. However, there is still a large discrepancy in survival, with four out of every ten patients failing to respond to therapy. At the moment, we cannot foresee who they will be, and being able to find which patients are likely to respond and which treatments are likely to be useful will improve decision making and save patients from ineffective treatment and side effects. Machine learning is a type of artificial intelligence that is used to find complicated patterns in big datasets, such as treatment response or survival outcomes. A computerised tomography (CT) scan creates detailed images of the inside of the body using X-rays and a computer. We know that these scans contain information that is currently hidden, and our goal is to employ artificial intelligence to extract and uncover this information to help predict treatment responses. Finally, we plan to develop a tool to aid in shared decision-making for metastatic uveal melanoma patients to improve current treatment paths.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_22997,The Academy of Medical Sciences,AMS,Macrophage driven therapy resistance in AML: from macrophage subset characterisation to the potential for therapeutic intervention,"Acute Myeloid Leukaemia (AML) is a common haematological malignancy in adults, with survival rates less than 20% for the majority of AML patients. Therapy resistance is a major reason for poor survival in adult AML, and is strongly influenced by cells residing within the bone marrow (BM). AML cells interact with immune cells (e.g. monocytes – macrophage precursors) in the BM. Therapy resistance can occur via interactions between leukaemic cells and immune cells present within the BM. CD163+CD206+ macrophages are present in high numbers in the BM of blood cancer patients, including AML and Multiple Myeloma (MM). It is well-established that CD163+CD206+ macrophages promote therapy resistance in MM. However, the contribution of macrophages, towards therapy resistance in AML is poorly understood. This study aims to characterise macrophage subsets from AML patients, and to better understand how distinct macrophage subtypes impact upon therapy response in AML. Recently, I have shown that leukaemic cell-to-macrophage contact, and secreted factors from CD163+CD206+ macrophages, protect AML cells from therapy-induced apoptosis. Utilising cell and molecular based approaches, the objectives of this research are to: (i) characterise macrophage subsets from AML patients at the molecular and functional level; and (ii) determine the capacity of these macrophages to limit therapeutic efficacy in AML cells. By comprehensively characterising macrophage subsets from AML patients, and ascertaining their impact on therapeutic response, this research will advance our understanding of how macrophages drive AML pathogenesis, instructing future studies aimed at targeting specific Mφs, as a strategy to circumvent therapy resistance in AML.","Resistance to cancer therapy is a major reason for treatment failure, disease recurrence and poor survival in acute myeloid leukaemia (AML); a common blood cancer in adults, currently only 1 in 5 patients survive for 5 years or more after diagnosis. AML originates within the bone marrow and communication between cancer cells, and other cells residing within the bone marrow, significantly contributes towards therapy resistance. Immune cells called “macrophages”, are present in high numbers in the bone marrow of blood cancer patients with AML and multiple myeloma; another cancer of the blood. These macrophages are known to contribute towards cancer therapy resistance, through direct physical contact with cancer cells and/or releasing factors that aid in cancer cell survival. It is important that we identify which type of macrophages are capable of driving this therapy resistance in blood cancers, as very little is known about how this occurs. This work will answer a number of questions on how this happens and the research is important in order to explore the potential of new drug treatments for blood cancers.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_03064,Medical Research Council,MRC,Magnetic resonance Imaging abnormality Deep learning Identification (MIDI),"A clinically validated decision-making tool to identify abnormalities on brain MRI scans does not exist. This project meets this clinical need by developing such an abnormality detection tool using deep learning, enabling immediate automated triage of abnormalities with target product profile diagnostic performance matching that of a consultant neuroradiologist. This is important as 330,000 patients wait >30 days for their MRI reports in the UK. The number is forecast to increase, due to more demand for MRI than the availability of radiologists to report these scans. UK-specific workforce shortages in radiology are negatively impacting patient care by delaying diagnosis; a similar picture is seen globally. Immediate triage of a brain MRI into normal/abnormal allows early intervention to improve short- & long-term clinical outcomes. Furthermore, detecting illnesses early would result in lower costs for the healthcare system given less specialised medicine & fewer hours of treatment are needed for patient recovery. The proposal is enabled by another deep learning labelling tool, allowing MRI scans to be labelled at scale. Our publications confirm that the core approach is not only feasible & effective but also allows subcategorization into relevant groups as secondary objectives. However, there is a technology gap that must be filled to provide a capability ready for a clinical trial. A key objective is to complete analytical validation by 30 months in multiple prospective external test sets. Preparation for Class 2a Medical Device regulatory approval of software & phase III trial design, including a health economic evaluation, will be achieved within 36 months. A trial, beyond the current Award, will complete clinical validation. The commercial exploitation pathway will be developed during the Award prior to the trial where a 3rd party (i.e. commercial partner) will be responsible. IP relates to the software we will generate for the triage tool in the proposal.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,NEUROLOGICAL HRCS22_01199,Medical Research Council,MRC,Maintaining Genetic and Chromosomal Stability in the Mammalian Germline,"Genetic mutations and chromosomal aneuploidies that arise during germ cell development and meiosis can cause embryonic lethality, miscarriage and genetic disease in the next generation. Aneuploidies such as trisomy 21, which causes Down syndrome, are relatively common in human conceptions, and typically originate during the meiotic divisions of female oocytes. A number of risk factors, including meiotic recombination frequency, distribution of meiotic recombination sites, and maternal age have been identified for oocyte aneuploidy. Furthermore, data from mouse models suggests that age-dependent loss of chromosome cohesion is associated with age-dependent increases in meiotic segregation errors in post-natal oocytes. However, the fundamental mechanisms underlying these processes in mammalian meiosis are not completely understood. This research programme will investigate mechanisms regulating meiotic recombination in mammals, and mechanisms impacting on the maintenance of chromosome cohesion in post-natal mammalian oocytes. We have previously identified components of the ubiquitin-proteasome system as regulators of meiotic recombination frequency in mice. Genetically modified mice carrying mutations in these components of the ubiquitin-proteasome system have reduced meiotic recombination frequencies and defects in pairing homologous chromosomes during meiosis that can cause chromosome segregation errors. However, we do not know how the ubiquitin-proteasome system regulates the early stages of recombination that are defective in these mutants. We will therefore use genetically modified mouse models to investigate how these enzymes influence the machinery that initiates meiotic recombination, and whether recombination in particular regions of the genome are more sensitive to these ubiquitin-proteasome system components. We will also investigate how meiotic chromosomes are organised in mouse spermatocytes and oocytes, and study how meiotic chromosome organisation impacts on the frequency and distribution of meiotic recombination in mice. The second part of this research programme will investigate a novel pathway that we have identified operating in mouse oocytes which helps prevent loss of chromosome cohesion, meiotic chromosome mis-segregation and aneuploidy in post-natal mouse oocytes. This pathway also involves components of the ubiquitin-proteasome system, and regulates the abundance of cohesin proteins associated with meiotic chromosomes. As this pathway also appears to operate in embryonic stem cells, which are derived from early mouse embryos, we will use embryonic stem cell models to investigate how chromosome cohesion is regulated by the ubiquitin-proteasome system. We will use the mechanistic insights that we gain from embryonic stem cells to generate genetically modified mouse models to test whether manipulation of this pathway can slow the age-dependent loss of chromosome cohesion that occurs in post-natal mouse oocytes.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_05670,Department of Health and Social Care,NIHR,"Management of diarrhoea in patients with stable ulcerative colitis: multi-arm multi-stage trial of low FODMAP diet, amitriptyline, ondansetron, or loperamide (MODULATE)","Aims of the research:_x000D_ We want to find out whether treatments used for diarrhoea in people with irritable bowel syndrome (IBS) can help people with stable ulcerative colitis (UC) and diarrhoea, with no sign of active bowel inflammation._x000D_ _x000D_ Background to the research:_x000D_ About 1 in 5 people with UC report ongoing diarrhoea, even when there is no sign of bowel inflammation. These symptoms can be difficult to treat because, when there is no inflammation, simply using more powerful drugs does not seem to improve them. They also cause discomfort and distress, reducing peoples’ quality of life, and impacting on their psychological health and mood._x000D_ _x000D_ This is a similar situation to people living with IBS, who often experience troublesome diarrhoea that reduces quality of life. In IBS, a low FODMAP diet improves diarrhoea, because some poorly absorbed sugars (FODMAPs) increase small intestinal water content. Drugs like ondansetron (an anti-sickness drug), amitriptyline (an old-fashioned anti-depressant drug), or loperamide (an anti-diarrhoeal drug) can also be effective in IBS with diarrhoea. This is because they change bowel activity, and can relieve tummy pain. These treatments may therefore help people with UC with diarrhoea who have no active bowel inflammation, but we are unsure as there are no large studies._x000D_ _x000D_ Design and methods used:_x000D_ Doctors will invite people with UC who have diarrhoea, and who do not currently have active bowel inflammation, to take part. We will check people are suitable with a questionnaire, a camera test of the lower bowel, and blood and stool tests at their local hospital._x000D_ _x000D_ All participants will be provided with standard first-line dietary advice. People will also be given one of the following: a low FODMAP diet; ondansetron; amitriptyline; loperamide; or no additional treatment. A computer will randomly decide who gets which one. People will be asked to follow the diet or take the tablets for 6 months, in addition to their doctor’s usual treatment for UC. People will be aware which treatment they get._x000D_ _x000D_ We will follow people up at 8 wks and 6 mths. We will ask people to fill out questionnaires about symptoms, quality of life, and mood, and provide blood and stool again at 6 mths. We will record side effects during treatment, and adherence to each treatment. We will look at how many flare-ups people experience, whether usual treatment for UC has been changed, and whether surgery has been required. As we need almost 500 people, the study will take place in 26 UK hospitals._x000D_ _x000D_ Patient and public involvement:_x000D_ We have involved patients in the development of this application. Specifically, we have a co-applicant with experience of UC, and support from Crohn’s and Colitis UK. We will continue to collaborate closely with patients and families if the study is funded._x000D_ _x000D_ The team:_x000D_ We are a team of doctors, researchers, and patients. Together we have a special interest in UC, long-term conditions, medically unexplained symptoms, and carrying out similar research studies. The research will be run by a clinical trials research unit with experience in carrying out large scale studies._x000D_ _x000D_ Dissemination:_x000D_ We will publish the results in academic journals and present them at conferences. We will feed back to all doctors and dietitians involved in the study. We will hold a public involvement workshop towards the end of the study to discuss how to share findings with our study participants and the public in an accessible way.","Design: Pragmatic, seamless, phase 2/3, open, parallel group, MAMS RCT, with internal pilot._x000D_ _x000D_ Setting: 26 secondary care centres._x000D_ _x000D_ Target population: Adults with stable UC and at least moderate discomfort from diarrhoea on GSRS, despite optimal medical therapy._x000D_ _x000D_ Inclusion criteria: >/=18 years; stable UC (Mayo score 1, CRP >/=5mg/L, or FC >/=250mcg/g); steroids within the last 2 mths; coeliac disease; previous colorectal cancer or dysplasia; allergy/contraindication to, or previous failed trial of, study interventions; pregnancy/breastfeeding._x000D_ _x000D_ Health technology being assessed: Phase 2: Control (standard first-line dietary advice); low FODMAP diet; ondansetron; amitriptyline; loperamide (all drugs titrated)._x000D_ Phase 3: Control; up to 2 interventions with greatest evidence of efficacy in phase 2._x000D_ _x000D_ Patients allocated 1:1:1:1:2 in phase 2, (larger group = control) (4). In phase 3, this is reversed to 2:1 or 2:2:1, with final ratio 5:8 or 5:5:7. Allocation via minimisation with random element, minimised on centre, degree of discomfort from diarrhoea, and extent of UC._x000D_ _x000D_ Measurement of outcomes: Via self-completed questionnaires._x000D_ _x000D_ Phase 2 primary (8 wks): Improvement in diarrhoea, via GSRS (minor discomfort or less);_x000D_ Phase 3 primary (6 mths): Disease-specific quality of life via IBD-Q._x000D_ _x000D_ Secondary (8 wks and 6 mths)_x000D_ Adverse events and safety;_x000D_ Symptoms: Improvement in discomfort from loose stools, diarrhoea, urgency, abdominal pain;_x000D_ Disease activity: Escalation of medical therapy, need for surgery, FC, CRP;_x000D_ Mood: HADS;_x000D_ Adherence._x000D_ _x000D_ Sample size: Phase 2: 66 patients per intervention arm and 132 control give 90% power to detect an absolute difference of 17% (50% intervention, 33% control) in proportion achieving improvement in diarrhoea, with a 1-sided 20% significance level, assuming 10% lost to follow-up._x000D_ Phase 3: with 2 (1) interventions carried forward: additional 38 (20) per intervention arm; 19 (10) control, give 90% power to detect a 16-point difference in IBD-Q, with 2-sided 2.5% (5%) significance, assuming an extra 10% lost to follow-up, and SD of 32 (5, 6). Total patients: 491 (426)._x000D_ _x000D_ Analysis: ITT, as per CONSORT._x000D_ Phase 2: Multivariable logistic regression fitted to achieving improvement in diarrhoea at 8 wks, with adjustment for stratification factors. Progression to phase 3 based on achieving reduction in diarrhoea, as well as safety and adherence. At most, 2 interventions progress._x000D_ Phase 3: The primary analysis compares mean IBD-Q scores between groups using a linear regression model adjusting for stratification variables and baseline IBD-Q. Multiple imputation for missing data._x000D_ _x000D_ Internal pilot: Progression criteria assessed at 4-6 mths (recruitment) and after a further 6 mths (adherence and follow-up). Patient outcomes included in the final analysis._x000D_ _x000D_ Difference between current and planned care pathways: Low FODMAP diet or pharmacological therapy added to current optimal UC treatment. All patients receive standard dietary advice sheet._x000D_ _x000D_ Project timetable:_x000D_ 45 mths:_x000D_ 9-mth set-up;_x000D_ 25-mth recruitment;_x000D_ 6-mth follow-up;_x000D_ 5-mth analysis, write up, dissemination._x000D_ Recruitment rate: 14 pts/mth during pilot, then 20-30 pts/mth, from 26 centres._x000D_ _x000D_ Expertise in team: Gastroenterology, dietetics, psychiatry, statistics, trial design/delivery, PPI.",6.1 PHARMACEUTICALS;6.7 PHYSICAL,ORAL AND GASTROINTESTINAL HRCS22_01859,Medical Research Council,MRC,Manipulating the peripheral nerves of the niche to improve epithelial regeneration of the salivary gland,"Against a backdrop of an ageing population in the developed world, the impetus to find ways of increasing not only length of life but quality of life is strengthening. In the field of regenerative medicine, significant progress has been made in cell-based therapies, while the manipulation of the stem cell niche to promote tissue regeneration has received less attention. A major component of the niche is peripheral nerves, and there is evidence that peripheral nerves are essential for the development, function and replacement of cells in numerous tissues and furthermore that neuronal signals (such as acetylcholine) are themselves vital within all three of these areas. I previously demonstrated that replacement of saliva-producing acinar cells by SOX2+ stem cells in the salivary gland is governed by parasympathetic nerves and acetylcholine signalling during homeostasis and following irradiation injury. My hypothesis is that peripheral nerves and/or acetylcholine signalling of the niche can be manipulated to promote epithelial tissue regeneration. To address this question, I will use as a model the salivary gland (SG), which relies on peripheral nerve input and contains defined progenitor cell populations. In addition, quantitative measures of function for the salivary gland are easily obtained (e.g. saliva production), fresh tissue is readily available, and clinically, there exists a significant unmet need to regenerate SGs following diseases such as Sjögren's Syndrome or therapeutic radiation for head and neck cancer. This project will test the role of the nerves in stem cell transplant in mouse SG and will develop and test locally acting acetylcholine receptor agonists to reactivate resident stem cells. Ultimately, the project will test a novel targeted therapeutic intervention based on manipulating niche signals to promote organ regeneration.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES,NEUROLOGICAL HRCS22_17214,Versus Arthritis,,Manipulation of monocytes/macrophages for the control of arthritis pain using pro-resolving lipid mediators and blockade of CX3CR1 receptor,"Workstream 3: Development of stratified care for shoulder pain Objective: Integrate results from Workstreams 1&2 to develop a screening and decision tool supporting optimal targeting of shoulder pain treatments. Methods: (a) Semi-structured interviews with approximately 15 patient-clinician dyads to investigate their perceptions of cause and prognosis of shoulder pain, uncertainty and communication around treatment and referral, and opinions regarding the potential of stratified care. Grounded theory and constant comparative method will be used to identify themes, investigating overlaps and contrasts between individuals in the dyad. (b) Nominal Group meetings, involving patients, GPs, physiotherapists, and secondary care specialists. Informed by interview results and evidence from Workstreams 1&2, they will agree: design and format of the tool; matched treatments for defined subgroups; type of training and information materials for clinicians and patients. Key outputs: Evidence-based screening & decision tool with matched treatments for subgroups (stratified care), and supporting materials for clinicians and patients.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_22621,Welsh Government Office for Science,WGOS,Mapping subicular mnemonic circuitry,"Memory loss represents a key symptom of dementia and is associated with significant impact on quality of life for its sufferers and, consequently, on society as a whole. With more than 200,000 new cases of dementia expected each year, understanding the neural mechanisms underlying memory processing remains a central, and increasingly urgent, goal of neuroscience. My project seeks to understand how circuits in the brain encode, store and recall memories for places and events experienced in our everyday lives. A brain region called the ‘hippocampus’ represents a key brain circuit responsible for memory processing and my work is aimed at understanding how it interacts with other brain areas during learning. In particular, I aim to decode the signals the hippocampus sends out to the wider brain (what is saying), identify the target brain regions for those specific signals (to whom), each during different stages learning (when). To do this I will study the functional connectivity between the principal output region of the hippocampus (the subiculum) with brain regions known to be important in learning and memory.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,MENTAL HEALTH;NEUROLOGICAL HRCS22_02746,Medical Research Council,MRC,Mapping the growing global burden of dengue to help countries plan for the next decade of dengue control,"Dengue is one of the fastest growing uncontained emerging infectious diseases. Computational models play an important role in estimating disease burden because of the limitations of epidemiological data. This year, new goals for reducing the global burden of dengue between 2021-2030 will be set, but current models are insufficient for tracking progress. In this fellowship I will develop the next generation of global dengue models that take into account the spatio-temporal variation in multiple types of epidemiological data to predict the past, present and future global burden of dengue. A systematic search will assemble incidence and prevalence data at a sub-national level with geospatial models used to make predictions for data deficient areas. A Bayesian multi-serotype dengue transmission model fit to dengue incidence and prevalence data will then give consensus estimates of how dengue burden has changed 2000-2020. These predictions will give insights into how dengue was able to spread so rapidly and help design strategies to contain future arboviral pandemics. With data on >4 million individual-level dengue patient records I will characterise spatio-temporal trends and causal determinants of delayed treatment seeking and misdiagnosis. Using multivariate regression approaches I will then assess the contribution of each of these to the risk of severe disease and death after accounting for relevant confounders. This will give new insights into how to prevent dengue deaths through non-therapeutic approaches. Projecting these models using future climate, urbanisation and immunity scenarios will allow new predictions of future changes in dengue burden. A national feasibility assessment will then rank countries in their ability to meet 2021-2030 goals based on epidemiological, operational and financial barriers. This work can be used to define target product profiles of novel interventions and identify under or over-achieving control programmes.",,2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);1.4 METHODOLOGIES AND MEASUREMENTS,INFECTION HRCS22_01519,Medical Research Council,MRC,"Maternal and Perinatal Health Research collaboration, India (MaatHRI): improving outcomes in pregnant women with iron deficiency anaemia","India contributes to a sixth of annual maternal deaths globally and over 5 million Indian pregnant women suffer a life-threatening complication. This project aims to establish a UK-India collaborative platform for maternal and perinatal health research (MaatHRI), and use it in the first instance to improve the clinical management and outcomes of pregnant women with iron deficiency anaemia which is a major contributor to maternal deaths in India. Objective-1 is to establish MaatHRI in 18 hospitals in two states covering ~100,000 deliveries yearly to continue the survey of 6 severe pregnancy complications initiated during the pilot work. Objective-2 is to investigate the risk factors, clinical characteristics, management and outcomes of anaemic heart failure through an unmatched case-control study using MaatHRI (cases 900 pregnant women with anaemic heart failure; controls 3600 women with anaemia but no heart failure). In-depth review of hospital notes of cases and deaths due to anaemic heart failure will be conducted in each hospital by an expert panel. Lessons identified will be combined with evidence from the case-control study to develop pregnancy care guidance. Objective-3 is to examine the safety of induction and augmentation of labour in pregnant women with anaemia through a cohort study of 10,800 pregnant women with haemoglobin level <10 g/dl using MaatHRI. Results will lead to guidance and interventions to reduce any risk associated with induction and augmentation of labour. Objective-4 is to explore the feasibility of establishing MaatHRI in other states by disseminating the study outputs and mapping potential hospitals through workshops. Objective-5 is to develop studies on the other surveyed complications and follow-up projects from the outputs. Survey of infectious diseases in India that are emerging risk factors for pregnancy complications will be initiated in year-4 to estimate their prevalence and case fatality, and to develop further studies.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_17156,Wellcome Trust,,Maximising T cell cytotoxicity and persistence for long term anti-cancer protection in adoptive cell therapy (ACT).,"One of the functions of the immune system is to recognise and kill cancerous cells.  This is done by specialised immune cells called cytotoxic T cells.  However, there are many ways in which this process can go wrong, and this leads to the development of cancer.  Many recently developed treatments for cancer are designed to improve the ability of the T cells to recognise and kill the tumour cells, but this is still imperfect and there is lots of room for improvement.  I aim to make alterations to the signals that occur inside T cells after they “see” an abnormal tumour cell, in order to make them more effective at killing cancer cells and to stay around and do this job for longer.  I will test modifications by making relevant alterations to T cells in the lab, and then assessing their ability to kill cancer cells in a petri dish and to destroy tumours in mice with cancer.  Different modifications will enable me to understand how T cells function, and where modifications can be made to improve their tumour killing function.  This could be used in future to modify patients’ own T cells to treat their cancer.",,5.2 CELLULAR AND GENE THERAPIES,CANCER AND NEOPLASMS HRCS22_05362,Department of Health and Social Care,NIHR,Maximising the health benefits gained from bariatric surgery,"Background Bariatric surgery is the only effective treatment for patients with severe obesity, producing sustained weight-loss, amelioration of obesity-associated co-morbidities, reduced mortality and economic savings. In the UK ~1.5 million people fulfill the National Institute for Health and Care Excellence bariatric surgery eligibility criteria. However, in 2013Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), the most common bariatric procedures undertaken, produce comparable weight-loss and resolution of co-morbidities, with ~60% of T2D patients being in 'remission' 2 years post-surgery. However, at an individual level, post-surgery health benefits, in terms of weight-loss and improvement in obesity-associated co-morbidities, are highly variable. Up to 20% of patients derive little post-operative clinical benefit in the long-term. RYGB and SG are different anatomically and differentially alter circulating gut hormones, key regulators of energy homeostasis. However, there are no criteria to determine whether a patient would derive most benefit from RYGB or SG. Given the severely limited access to bariatric surgery the key question that needs to be addressed is 'How do we maximize the health benefits obtained from bariatric surgery?' I am ideally placed to address this question. My research is at the forefront of international research efforts focused on understanding how bariatric surgery mediates its beneficial effects. Using experimental medicine approaches, my work has identified gut hormones as key regulators of energy homeostasis. I lead the University College London Hospitals (UCLH) Bariatric Centre for Weight Management and Metabolic Surgery, one of the largest UK bariatric centres with an embedded translational research programme. My new data suggest that post-operative health outcomes can be improved by utilizing genetics to optimize bariatric procedure selection and by implementation of post-operative strategies. Aims My overall aim is to maximize the health benefits obtained from bariatric surgery by utilizing the following inter-related strategies: Genotype-based bariatric procedure selection.Implementation of an early post-operative exercise-behavioural programme.Post-operative pharmacological interventions tailored to the patients' post-operative biology. Establishment of a bariatric biobank to facilitate reverse translational studies to gain further mechanistic insights into the variability in response to surgery. Plan of investigation in order to achieve my aims 1) Establish a multi-disciplinary obesity clinical trials team, within a research framework that integrates patient/public involvement, to allow effective translation of my research findings into clinical practice.2) Undertake a randomized-controlled trial to evaluate whether an early post-operative exercise-behavioural intervention improves post-operative weight-loss, metabolic outcomes and functional activity. 3) Establish a bariatric biobank (serum, DNA and tissues obtained at the time of surgery, including gut, liver, subcutaneous and visceral fat and muscle) to facilitate reverse translation. 4) Determine whether allocation of surgical procedure (RYGB or SG) based upon the FTO-linked SNP rs9939609 improves post-surgical weight loss and metabolic outcomes by undertaking a randomized trial. 5) Investigate whether 'poor' post-operative weight-loss response can be improved using personalized pharmaceutical interventions tailored to the patients' post-surgery biology. 6) Collaborate with and attract other investigators to translational obesity research to complement existing research in this focus area and establish inter-institutional translational research networks. BenefitsThis project will bring immediate benefits to patients and the NHS by identifying strategies that maximize the health benefits obtained from bariatric surgery. By establishing a multi-disciplinary obesity translational research team, together with mechanisms for training these individuals in a range of obesity research methods, I will increase capacity for the delivery of broad ranging obesity research within the UK. This will benefit patients and the NHS by allowing the effective translation of research findings into clinical practice, bringing health benefits to patients and reducing the health burden of obesity.","Aim of this research To improve the treatment of obesity by Ensuring that obesity surgery is delivered in the best way possible to improve the health of obese patients Gaining new knowledge about obesity by studying people having obesity surgery. BackgroundOne quarter of UK adults are obese having an unhealthy amount of body fat. Obese people die at a younger age and are more likely to have type 2 diabetes (high blood sugar levels), high blood pressure, heart attacks, strokes and cancer. The National Health Service (NHS) costs of treating obese people are about 17 billion a year. The causes of obesity are complex but we know that genetic make-up plays a role. Losing weight by dieting and exercise improves health but staying at a lower weight is difficult because the body's weight-control systems try to return weight back to the higher level. There are no drugs available in the UK to help people lose weight in the long-term. Obesity surgery is the only treatment that causes long-term weight-loss. This surgery reduces the risk of obese people dying making them healthier by improving and preventing many of the illnesses linked to obesity. For patients with type 2 diabetes, 6 out of every 10 can stop all of their diabetes drugs after surgery. The National Institute of Health and Care Excellence (NICE) decides which treatments the NHS will offer based on health benefits and cost. Using their rules around 1.5 million UK people could have obesity surgery. However, only 6,000 operations were carried out in 2013 due to limited access. Obesity surgery alters the path that food takes through the gut. We do not know exactly how the surgery works but we know that it 'resets' how bodyweight is controlled. I have shown that hormones from the gut control eating and blood sugar. Obesity surgery alters the levels of these hormones and this contributes to the beneficial effects of obesity surgery. Unfortunately, around 1 in 5 people do not respond well to obesity surgery in terms of improved health. Given that access to obesity surgery is limited and that surgery itself carries a risk, although very small, of dying we need to maximise the health benefits obtained from this limited resource. The main ways of achieving this are to target obesity surgery to patients who will benefit most, ensure that after surgery patients receive support to maximise the effects of surgery and collect samples and information from patients undergoing surgery to increase knowledge about obesity. My new research suggests that we can increase the health benefits obtained from surgery by Using a person's genetic make-up to select which type of surgery they should have.Helping patients increase their exercise levels after surgeryUsing new drugs in patients with a poor weight loss after surgery to correct their gut hormone levels. We now plan to test if these approaches improve weight loss and health outcomes by carrying out studies (clinical trials) in patients. Design and methods An expert team of health care professionals and scientists will carry out the following studies in obese patients. 1) Patients will be invited to take part in a clinical trial where we will study two types of obesity surgery and determine if the patients' genetic make-up influences the effects of surgery by comparing health outcomes after two years. 2) After surgery patients will be randomly assigned to either standard care, (being told to exercise more) or to participate in a supervised 12-week exercise programme. We will compare health comes in these two groups at 1 year after surgery. 3) In patients with poor weight-loss following surgery we will test if giving drugs to correct their hormone levels reduces their appetite and helps them lose weight. 4) Blood and tissue samples will be collected in patients having obesity surgery and used to learn more about obesity. The results of these studies will lead to changes in how obese patients having obesity surgery are cared for and will improve the health of people with obesity. Patient and public involvement Obese patients and patients who had undergone obesity surgery have been involved in designing these studies. Patients/public members will be part of our research team and will contribute to the final design, write patient information sheets and summaries of our findings. DisseminationWe will publicise our findings using presentations at local groups, national and international meetings, via the web and social media, in the press and on radio and television.",6.1 PHARMACEUTICALS;6.4 SURGERY,CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE HRCS22_06585,Department of Health and Social Care,NIHR,"Measurement of the Aerosol Generating Potential of Intubation, Extubation and associated airway procedures – MAGPIE study","Research Question What are the relative risks of aerosol production from airway management techniques used during surgery or intensive care, and what strategies can be employed to reduce aerosol generation? BackgroundThe COVID-19 pandemic has had an unprecedented impact on global health and the world economy. The SARS-CoV-2 virus is highly contagious and the potential of airborne viral transmission from aerosols is a concern. Certain medical interventions, including those for anaesthesia and intensive care, are designated 'aerosol generating procedures' (AGPs) and deemed to carry increased risk of viral transmission. There is currently little to no quantitative evidence on the aerosolisation risk for many AGPs. Current national and international AGP guidelines are based on weak epidemiological evidence. Stringent measures introduced to minimise the potential risk of aerosolised SARS-CoV-2 transmission to staff and patients have reduced the ability of the NHS to restart important services including elective and cancer surgery. These methods have prolonged operations and reduced healthcare efficiency to 60% of capacity. 15bn has been allocated for PPE acquisition which is more than 10% of the annual NHS budget. Surgical waiting lists are expected to double by the end of 2020 from 4million to 10million patients The use of enhanced PPE: Is hugely costly for the NHS Impairs communication between teams Increases the risk of medical errors Reduces staff and patient interactions Increases stress and anxiety for healthcare workers and patients Produces vast quantities of non-recyclable wasteThis study aims to quantify the aerosol generated by currently identified AGPs. Methods WS1 - MAGPIE studyWorking with the Bristol Aerosol Research Centre, I will use highly sensitive, accurate optical particle sizers to analyse the airborne particles generated by common AGPs used in anaesthesia and intensive care. This will quantitate aerosol concentration, size distribution and persistence of particles generated during these AGPs WS2 -h; AGPercept surveyA national survey of medical professionals involved in performing AGPs will determine attitudes towards the risk of viral transmission and impacts of precautions against bioaerosols. This will be undertaken both before and after dissemination of the WS1 results to identify barriers to practice change. WS3 -h; ROADMAP studyThis aims to identify and develop strategies to reduce aerosol production during airway management procedures to allow essential NHS services to get back on track Benefits to patients and the NHS within 24 months This research aims to quantify aerosols generated from current AGPs. If any investigated AGPs generate less aerosol than a standard cough, their relative risk of aerosolisation is low and may be declassified as an AGP. This would enable more appropriate risk assessment and mitigation, potentially yield huge-cost savings for the NHS and improve theatre efficiency enabling resumption of surgical services. Strategies will be explored to reduce the risk from AGPs identified as generating substantial aerosols to effectively prevent viral transmission. Dissemination will be undertaken to inform national AGP policies. Future Benefits Understanding the potential for aerosol generation will be useful in assessing the risk of transmission of other respiratory pathogens, including novel emergent viruses.","Aims of the Research Measure the amount of particles (aerosol) released into the air during medical procedures Measure how long particles (aerosol) remain in the air following medical procedures Develop ways to reduce the amount of particles (aerosol) released into the air during medical proceduresBackground The COVID-19 pandemic has had a huge effect on global health and the world economy. Coronavirus spread during hospital procedures is a big concern. Safe delivery of essential NHS services is affected by the need to reduce coronavirus spread to staff and patients. Aerosols can be created during medical procedures and occur when tiny particles are suspended in the air. Aerosols can carry viruses, like the coronavirus. These aerosols may cause infection by allowing hospital staff or patients to breathe coronavirus into their lungs. Many operations need a general anaesthetic, where a patient is not awake for surgery. A breathing tube is placed to allow surgery to be performed. Insertion and removal of the breathing tube may produce an aerosol which risks spreading coronavirus to staff in the operating theatre. This risk means all staff present must wear enhanced personal protective equipment (PPE) such as 'respirator-type' face masks. It is unknown how much aerosol is produced for many procedures and how long aerosols remain in the air. The use of enhanced PPE: Is expensive for the NHS Increases the risk of medical mistakes Reduces staff and patient contact Makes talking and hearing more difficult for healthcare workers and patients Increases stress and anxiety for healthcare workers and patients Is uncomfortable Makes teamworking more difficult Produces lots of non-recyclable wasteThe amount of PPE is limited. PPE needs to be used where it is most needed. At the moment, staff wear enhanced PPE for every patient having an operation to reduce coronavirus spread. Staff and patients are not allowed to move in or out of a room for 10 minutes at the start and end of surgery because of the risk from aerosols. This increases the time taken for every operation and has almost halved the number of patients having an operation each day. This includes operations for life-threatening conditions like cancer. Design and Methods This research will be performed with an experienced team of aerosol specialists and airway doctors. Workstream 1: Using highly accurate scientific equipment I will measure the amount of aerosol produced during medical procedures to help patients breathe. These procedures include insertion and removal of breathing tubes for patients having a surgical operation, and facemasks used on intensive care. Workstream 2: I will perform a national survey of medical staff at risk of viral infections from aerosols. The aim is to find out barriers that may prevent new guidelines being used. Workstream 3: I will produce methods to reduce aerosols when a breathing tube is inserted or removed Patient and Public Involvement I undertook a survey of local anaesthetists. The survey showed aerosols were their biggest concern for catching coronavirus. It also showed enhanced PPE increased stress and anxiety, increased the risk of mistakes and caused operations to take longer. Input from a patient representative in a local hospital was supportive:'Having read your proposal the benefits that would be created are clear. The loss or reduction of staff/patient contact is key in my view, certainly in terms of reassurance and also clear understanding of procedures taking place.' Dissemination The results will be shared with: Participants Government policy makers The Royal College of Anaesthetists and Intensive Care Society Journals/conferences TwitterThe results will help produce regulations for safe NHS working, improve NHS efficiency, reduce non-recyclable waste and save the NHS money.",3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,INFECTION HRCS22_15953,Dunhill Medical Trust,,Measuring and enhancing resilience to chronic pain in elderly patients with arthritis using neurofeedback,"This research proposes to test and develop an alternate therapeutic strategy for elderly patients with chronic arthritic pain, whose pain is not adequately controlled by analgesics or who prefer not to take analgesics. We have shown that the expectation of pain relief is associated with increased alpha waves in the frontal cortex. These alpha waves are thought to mediate top-down control in the brain. Initial studies from our group have demonstrated substantial changes in the power of alpha waves in the frontal cortex in healthy volunteers subjected to moderately severe shoulder pain over several minutes. We think that this may be a neural signature of pain resilience. We would like to develop these studies further to confirm our initial findings, establish a signature for pain resilience and to use this to develop robust methods of neurofeedback that will provide useful and safe therapy for elderly patients with chronic arthritic pain.","Chronic pain in older people with arthritis is a major cause of disability and consulting in primary care. Available therapies are limited, including pain killers which may cause side-effects. We have identified potential brain mechanisms for vulnerability and resilience to chronic pain. The brain in patients with chronic pain is always expecting bad things to happen and tends to focus on the negative aspects of pain experience. These effects can be reversed by cognitive (talking) therapy. This increases control by forebrain structures of other areas of the brain responsible for pain perception. We think we can measure brain waves relating to increased control of pain. This project will identify a detailed brain signature of resilience to pain using recordings from the brain surface. We will use this signature to train elderly patients to increase their resilience to pain by giving them immediate feedback on how their brains are responding.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MUSCULOSKELETAL;NEUROLOGICAL HRCS22_15343,Wellcome Trust,,Mechanism of HSV-1 pUL51/pUL7 focal adhesion stabilization,"Herpesviruses cause a significant degree of global morbidity but also provide powerful tools with which to probe intricate cellular processes. Herpes simplex virus pUL51 and pUL7 are conserved across herpesviruses and form a complex in infected cells. This complex promotes wrapping of nascent virions and recent work in our lab has shown it also localises to and stabilizes focal adhesions, reducing the ability of infected cells to detach from the substrate and potentially enhancing cell-to-cell spread. We will use live-cell fluorescence microscopy to investigate how the pUL51/pUL7 complex modifies focal adhesion dynamics during infection. Additionally, we will use quantitative mass spectrometry to identify binding partners of the pUL51/pUL7 complex at focal adhesions. The interactions of the complex with these cellular partners will be structurally and biophysically characterised, allowing us to design specific mutations that disrupt focal adhesion association but maintain envelopment functionality. We can then specifically probe the effect of focal adhesion modulation upon replication and cell-cell spread of the virus. Understanding how herpesviruses modify focal adhesions to enhance spread may open up new avenues for therapeutic and vaccine development as well as providing insights into focal adhesion biology.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_22705,The Academy of Medical Sciences,AMS,Mechanism of Tar-Induced Pyroptosis of Human Coronary Endothelial Cell in Myocardial Infarction Caused by Plaque Erosion,"Acute myocardial infarction (AMI) is one of the major diseases which endanger human health. The main causes of AMI currently include three pathological mechanisms: plaque rupture(PR) , plaque erosion(PE) and calcified nodules. For a long time, we have been working on the prevention and treatment of PR, ignoring that about one-third of AMI is caused by plaque erosion. Furthermore, due to the unclear understanding of the mechanism of PE and the lack of effective in-vivo diagnostic methods, the treatment of PE has become an international problem that needs to be solved urgently. Our previous study found that the occurrence of PE is closely related to smoking, but absent of other cardiovascular risks, such as diabetes mellitus, hypertension and hyperlipemia.. Therefore, our project is to study the relationship between smoking and PE. The results of the study will provide an important theoretical basis for the precision management of AMI and a potential new target for intervention.","Plaque erosion (PE) is one of most important pathological mechanisms of acute myocardial infarction (AMI). Our group reported for the first time in the world that optical coherence tomography (OCT) could identify PE in vivo and developed a new algorithm for characterising PE by OCT. Importantly, we found that the occurrence of PE is closely related to smoking. Autopsy study showed that extensive endothelial cells death and detachment was observed at the site of plaque erosion, resulting in thrombosis ultimately. But the exact mechanism led to endothelial cells death is not clear. Our in vitro study showed that tar, the main component of tobacco, can induce a special type of death in endothelial cells, called pyroptosis, by activating NLRP3 inflammatory body. Therefore, we speculate that tar-induced endothelial cell pyroptosis may play a central role in thrombosis caused by PE. The present project, as an extension of our previous study, will focus on mechanism of endothelial cells death and thrombosis in PE. Our goal is to elucidate the molecular mechanism of tar-activated NLRP3 inflammatory bodies inducing endothelial pyroptosis. In addition, we will innovatively apply autopsy to confirm the important role of endothelial pyroptosis in PE .The results of the study will provide an important theoretical basis for the precision management of AMI and a potential new target for intervention.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CARDIOVASCULAR HRCS22_15561,Wellcome Trust,,Mechanisms and regulation of PEPITEM secretion,"The migration of immune cells such as T-lymphocytes to areas of inflammation plays an important role in the inflammatory response. T-lymphocyte migration follows a circadian (daily) rhythm, with more T-lymphocytes migrating into tissues in the morning than the evening. If this process is not carefully regulated, this can lead to an exaggerated inflammatory response which contributes to diseases. PEPITEM is a small peptide hormone which inhibits T-lymphocyte migration and is made by another type of immune cells, B-lymphocytes. Patients with inflammatory diseases cannot make PEPITEM in sufficient quantities to control T-lymphocyte migration. Our preliminary studies indicate that a protein able to cleave other proteins (protease) is responsible for PEPITEM release from B-lymphocytes and that this might be under circadian control. In my project, I aim to identify the protease that leads to PEPITEM release, and investigate how the PEPITEM pathway follows circadian oscillations. I will look at the expression of genes and proteins involved in the PEPITEM pathway at different time of the day to see how this pathway is regulated by circadian rhythms. This project will help to understand the dysregulation of inflammation that occurs in many chronic inflammatory diseases.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_01231,Medical Research Council,MRC,Mechanisms in Disorders of Energy Balance,"Obesity and its metabolic consequences are major threats to public health with an unmet need for improved therapy and prevention. Understanding the mechanisms involved in the control of human energy balance is essential to develop new treatments. By focusing upon a cohort of patients with severe early onset obesity, we have previously uncovered novel, highly penetrant alleles causing childhood obesity and gone on to establish the mechanisms of molecular dysfunction in many of these conditions. Over this quinquennium our work on the biology of energy balance and its disorders will have three broad aims: i) To continue to explore how human genetic variation that strongly predisposes to disorders of energy balance such as obesity exerts its effects at the molecular, cellular, organismal and human level and, where possible, to translate that knowledge into improved diagnosis or treatment ii) To further understand how disruption of particular imprinted genes can lead to obesity phenotypes. This will include further exploration of the bi-stable, potentially stochastic pattern of obesity seen with loss of Nnat and the development of a murine model of PWS that exhibits hyperphagia and obesity iii) To explore aspects of the basic biology underlying variation in leptin production and secretion, and to establish the extent to which a potentially clinically relevant phenotype of partial leptin deficiency might exist within the broader population of people with obesity",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,METABOLIC AND ENDOCRINE HRCS22_01331,Medical Research Council,MRC,Mechanisms of Differential Vulnerability to Social Media and Digital Technologies in Adolescence,"Adolescent mental health has declined substantially in the last decade (Sadler et. al, 2018), stretching health services and making the area a medical research priority (MRC, 2019). Concurrently, widespread digital innovation has radically altered child and adolescent behaviour (91% of 12-15 year-olds now own a smartphone; Ofcom, 2021). This has spurred pervasive concern that digitalisation and social media use might be decreasing adolescent mental health and well-being (Chief Medical Officer, 2019). This research programme provides a step-change to this societally-important topic, by pioneering a three work packages rooted in the MRC CBU’s research tradition of taking an applied problem, distilling theories and measures, defining neurocognitive mechanisms, and translating findings back to applied contexts. WP1: The central focus of this work package is to pioneer the study of neurocognitive mechanisms that link social media use to decreases in mental health and well-being using secondary datasets and targeted data collection. The programme will investigate whether stages of pubertal development predict heightened sensitivity to social media. Further it will explore whether neurocognitive changes occurring throughout adolescence (e.g., heightened social influence and reward sensitivity, along with development of relevant brain networks) are predictive of more negative relations between social media use and mental health. WP2: This work package will investigate maladaptive social media use in clinical populations, an area of substantial concern where pre-existing theoretical approaches can substantially inform discovery science and translation (RCPsych, 2019). While big data studies allow for rigorous statistical modelling, their variables can be superficial; in contrast, qualitative research collects rich data but often lacks generalisable hypothesis testing. To build a solid foundation for this innovative line of research, this package will bring together the strengths of both approaches. A qualitative study will examine how adolescents with lived experience and clinicians perceive social media to impact their mental health or the mental health of their patients respectively. A quantitative study of the MHYPE dataset will complement this by testing whether specific patterns of social media use are indicative of an adolescent having any, or a specific, clinically-diagnosable mental health disorder. This will allow this research programme to understand which concerns about social media use negatively impacting mental health are transdiagnostic (e.g. the ‘always on’ nature of social media) and which are disorder-specific (e.g. eating disorder content). Subsequently, this work package will progress to more detailed investigations using theoretical and cognitive approaches to understand the mechanisms behind how social media exacerbates disordered mental health. WP3: For investigations in WP1 and WP2 to be successful, this research programme needs to focus on concrete and measurable components of social media use. This programme will therefore go beyond the commonly-used, abstract and unreliable self-report measures of time spent on social media, to directly measure activities in and features of digital spaces. WP3 will develop two supporting methodologies: smartphone-based data collection and digital data donation.",,"1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",MENTAL HEALTH HRCS22_01300,Medical Research Council,MRC,Mechanisms of Fibre Toxicity (cross-Unit project),"It is well established that exposure to naturally occurring mineral fibres, such as asbestos, is associated with development of disease, including incurable mesotheliomas. However, the potential of newer manufactured nanofibres e.g. carbon nanotubes (CNTs) to trigger similar disease-associated molecular changes is under-explored. Extensive studies on the toxicity associated with exposure to fibres has led to the fibre pathogenicity paradigm (FPP); the degree of toxicity is related to the diameter, length and biopersistence of the fibre. The data suggest that nanoparticles with a high aspect-ratio (HAR) - long thin rigid fibres - are potentially toxic. By exploiting the combined expertise of two laboratories, the aims of this cross-Unit programme are built around the hypothesis that exposure to biopersistent nanofibres with a HAR initiates a series of events that leads to the development of mesothelioma. Detailed mechanistic information is therefore essential to: 1) construct a “nanofibre-toxicity pathway” 2) identify the key molecular changes that drive the very prolonged process (~40 years) of tumour development. 3) identify novel biomarkers of exposure prior to disease progression. By employing longitudinal studies in animal models, and comparing this with changes in patients with mesothelioma, we will able to identify at which point these alterations occurred during disease development and thus establish their position in the toxicity pathway. Through the exposure of animals to distinct types of fibres (long CNTs and different classes of engineered nanomaterials, using long asbestos fibres as a reference), we aim to determine the differences and commonalities between these agents at a molecular level and use this information to understand the potential hazards associated with human exposure to CNTs. This research is essential since there is a lack of information about the consequences of pleural exposure of mammals to long CNTs, and the mechanisms underlying carcinogenesis induced by these materials, have not been elucidated. The data generated through these integrated projects will increase our understanding of the processes of disease development associated with pathogenic fibre-induced toxicity, provide new biomarkers to assess the exposure of the population to potential hazards and inform the future ‘safe by design’ of these new classes of nanomaterials.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_20320,Wellcome Trust,,Mechanisms of lineage restriction in development and reprogramming.,"Mechanisms that lead to the establishment and maintenance of cell identity are paramount for organismal health. They also underpin successful cellular reprogramming for disease modelling and cell replacement therapies. We will investigate the roles played by the epigenome and co-factors in regulating lineage transcription factor-mediated establishment and stabilisation of cell fate in vivo and in vitro. Firstly, controlled activation and degradation of engineered transcription factors (TFs) will be used to challenge cell identity in developing frog embryos. We will compare transcriptional profiles and chromatin landscape in “permissive” tissues that respond to TF over-expression by undergoing full lineage reprogramming, and “non-permissive” tissues that resist reprogramming, as well as probing heterogeneity of transcriptional response in individual cells. Secondly, mechanisms responsible for differential response to TF will be identified through interference with the epigenome as well as via alteration of the co-factors repertoire present in embryonic tissue. Finally, we will explore mechanisms underlying lineage fidelity in mammalian ES cells that have been engineered to co-express TFs specifying conflicting lineages. Overall, this work will reveal how the response to lineage determining TFs is controlled by integration of epigenetic features and co-factor availability in both the developing embryo and in reprogrammed mammalian cells.","Cells in the developing embryo need to know how to become one cell type or another and how to keep that identity throughout life, something that is controlled by the activity of specific parts of the DNA and stabilised by the binding of control proteins. In our project, we will investigate why some cells in the developing frog tadpole are more resistant to changing their identity that others when we experimentally manipulate the proteins that direct cell fate. We will also see what happens when we try and make one cell adopt two identities at the same time. Increased understanding of the changes in DNA and proteins that cause adoption of stable cellular identity will help us explain how normal development is regulated. It will also aid us in making new cells to repair and replace those damaged in many sorts of diseases such as diabetes and Parkinson’s disease.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,NEUROLOGICAL;GENERIC HEALTH RELEVANCE HRCS22_02431,Medical Research Council,MRC,Mechanisms underlying neuronal-microglia interactions during development in health and disease,"The formation of the brain involves diverse populations of cell types undergoing a precise sequence of developmental processes, that vary in space and time. However, to create functional circuits, these diverse cell types need to come together at appropriate times and numbers for cortical wiring to begin. This involves some coordination between cell types to ensure appropriate types and numbers are present at the right time and place. The lack of or dysregulation of this coordination during development can lead to cellular imbalance that ultimately impacts normal cortical circuit function and leads to dysfunctions as seen in neurodevelopmental disorders. Here, I propose to understand how this coordination occurs between two different cell lineages, namely pyramidal cells and microglia, during development. Specifically, I will study the molecular mechanisms as to how microglia sense and react to changes in pyramidal cells and tune their development accordingly. By using different types of transgenic mice and genetic manipulations, I aim to determine how pyramidal cells can affect the development, maturation, survival and function of microglia, by addressing the following goals: (1) Characterise the development of microglia in the developing mouse neocortex and establish the impact of alteration of pyramidal cell activity on microglia development. (2) Elucidate the molecular mechanisms involved in the establishment of neuronal-microglia proportions, by analysing the differentially expressed genes to identify specific ligand and receptor pairs. (3) Determine the impact of genetic mutations that has been linked to neurodevelopmental disorders, specifically in pyramidal cells, on microglia development and function, by analysing microglial cell biological behaviour, transcriptional changes and impact on rodent cognitive and behaviour tasks.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL;MENTAL HEALTH HRCS22_20424,Wellcome Trust,,Mechanistic investigation of the cross-talk between spliceosomal complexes and polyadenylation factors,"Splicing and polyadenylation are two essential steps of gene expression that account, to a great extent, for the complexity of eukaryotes. The two processes are catalysed by the spliceosome and the polyadenylation apparatus – two macromolecular machines of megadalton-size which contain more than 70 and 20 proteins, respectively. The two machines associate physically to form composite assemblies, where cross-talk events support emerging layers of regulation of splicing and polyadenylation. These assemblies are primarily unexplored from a mechanistic perspective, due to their excessive size, complexity and dynamics. By employing state of the art technologies and our long-standing expertise in the structural biology of splicing, the time is now ripe for a thoroughgoing investigation of these assemblies. Thus, we aim to stall and isolate composite assemblies relevant for: (i) the coupling between splicing and polyadenylation, (ii) the definition of exons during constitutive and alternative splicing and (iii) protection of genes from premature polyadenylation. Afterwards, we will characterise their 3D structures and functions by electron cryo-microscopy and complementary biochemical methods. The proposed research is expected to be eye-opening and bring a substantive contribution to our understanding of how fundamental processes of gene expression integrate mechanistically.","Building an organism requires accurate reading and processing of instructions encoded in the DNA. This task is accomplished by nano-molecular machines able to process the encoded information in a combinatorial fashion, producing a high complexity of the organisms out of a limited set of instructions. Inaccurate processing can cause various diseases. Two information-processing nano-machines bind one another to act in a coordinated manner, as composite assemblies. The working of these supra-molecular entities is unclear, as we don’t know how all of their working parts look like and how they are organized in space and coordinated in time. Our goal is to characterize the 3D structure of the composite nano-machines in different snapshots. The vivid picture that would result should enable our understanding of how the information stored initially in DNA is processed at a superior level.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_21070,Arts and Humanities Research Council,AHRC,Media and Epidemics: Technologies of Science Communication and Public Health,"As the ongoing Covid-19 pandemic has made increasingly clear, outbreaks of infectious diseases represent a veritable 'stress test' for a country's underlying socio-economic and political structures. This includes its ability to harness technologies and infrastructures of communication to overcome such public health crises, for example by implementing population surveillance measures, communicating with broader publics, coordinating epidemic responses or devising strategies of preparedness against future outbreaks (Budd et al. 2020). As medical and social phenomena, epidemics tend to be highly mediatized events, although the limits and local inflections of that mediatization are yet to be subjected to sustained critical attention in both historical and contemporary settings. Furthermore, they provide significant opportunities to reflect on the ways in which technology and society co-constitute each other. By becoming testing grounds for various technologies of epidemic management, epidemics accelerate innovation, adaptation and change, but also bring to the fore inequalities of access, legal, ethical and privacy dilemmas, questions of public trust, effective communication of science and (mis)information overload. The recent resurgence of the term 'infodemic' is a stark reminder that epidemics are not only corporeal experiences, but also events of intense meaning making (Bashford and Hooker 2001), in the course of which social actors scramble to cope with myriad anxieties and uncertainties. Our concern in this project is to historicize contemporary digital transformations in the field of public health, but also to advance academic and public conversations about the actual meaning of the 'Digital Age,' both as a heuristic device and lived reality. By probing the interconnected development of medicine, media and technology, we hope to draw attention to a neglected field of historical and cultural inquiry and answer a question of significant contemporary relevance: How digital is the Digital Age? A long-term, trans-regional and trans-disciplinary perspective on the technological aspects of epidemic management can help us to understand how media and technology shape the making and communication of knowledge about public health, but also to probe the extent to which electronic dematerialization has been relevant to managing such outbreaks in the first place. Bridging the past and present of digital technologies, the project's thematic scope overlaps with both strands of the CHANSE call, 'Cultural transformations in the digital age?' and 'Digitalisation and social transformation'. In particular, we aim to understand contemporary digital transformations in the field of public health by locating them within a longer, culturally specific history of innovation and social change. We pay attention to the social inequalities, exclusions and ethical dilemmas that have framed technology use in public health since the mid-20th century as well as the intersections between political power, the mediatization of epidemics and the public communication of science. The project aims to intervene in current debates about the Digital Age by conceptualizing media and technologies of communication both as objects of historical and cultural inquiry and instruments of learning about past epidemics. Drawing on the repertoire of the humanities and the performing arts, it makes use of neglected historical archives and technologies old and new to develop educational tools that bring historical awareness to contemporary challenges around technology, media and public health, and promote media literacy more generally.",,"1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;7.3 MANAGEMENT AND DECISION MAKING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE;INFECTION HRCS22_14713,Wellcome Trust,,"Medical Pluralism at the Periphery: Health, Modernity and Ethnicity in Guangxi, China, 1920s-1950s","In many ethnic-minority regions of China, multiple forms of medical practice and knowledge play a role in healthcare. As most of the major hospitals mainly serve cities, many people in rural areas can only access the health services provided by village practitioners who have studied one-year courses in medical institutions. Some people in ethnic minority communities also turn to religious forms of treatment, such as enchantment and rituals, which have often been the traditional means of healthcare. This means that multiple forms of healthcare coexist, but there is a lack of extensive, historically-grounded research on what this means in practice. My project will explore how this situation can be traced back to the early and mid-twentieth century by studying medical plurality in Guangxi, a peripheral, multi-ethnic province in Southwestern China. I will consider how medical practices and knowledge in different communities – Western missionaries, Western-trained doctors, Han Chinese and ethnic minorities – interacted with each other. A historical analysis of these relationships will allow us to understand the tensions that exist between different forms of healthcare today, and suggest pathways toward more cooperative forms of engagement among different medical communities.","In many ethnic-minority regions of China, multiple communities of medical practice and knowledge coexist uneasily. As most hospitals mainly serve cities, many people in rural areas can only access the health services provided by village practitioners who have studied a one-year course in medical institutions. Some in ethnic minority communities also turn to religious forms of treatment, such as enchantment and rituals, which have often been the traditional means of healthcare. My project will provide a historical analysis of how different communities of medical practice and knowledge interacted with each other in Guangxi, a multi-ethnic, peripheral province in Southwestern China, throughout the first half of the twentieth century. A historical analysis of these relationships will allow us to understand the tensions that exist between different forms of healthcare today, and suggest pathways toward more cooperative forms of engagement among different medical communities.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_01190,Medical Research Council,MRC,Medical and Regulatory Genomics,"We use computational approaches to reveal the interdependencies between transcription, chromatin and the underlying genomic sequence - and to investigate transcriptional control mechanisms and their disruption in disease. We have an established track record in studying the roles of chromatin structure in mutational spectra, and in how tumour genomes evolve during cancer progression. We aim to test hypotheses addressing three broad aims. Our first aim is to reveal new functional interactions between chromatin structure and transcriptional activity. We still lack a convincing and quantitative account of the relationships between nuclear organisation, chromatin structure and expression dynamics over time. Developing such models will have important consequences for our understanding of noncoding variation in disease. Our second aim is to understand the roles of chromatin structure and mutational bias in the evolution of regulatory sites, within the catastrophe strewn genomes of tumours, and during the evolution of isolated human populations. Using a novel approach we have demonstrated unexpectedly high mutational loads at active regulatory sites in most cancers, relative to matched control sites. We are extending this approach to allow us to test the hypothesis that certain site classes accumulate lower levels of mutation than expected, suggesting purifying selection in tumours. Classes showing unexpected increases or decreases of mutational load, suggesting selection in specific tumour types, may suggest new candidate targets for therapeutics. In parallel we will extend our regulatory mutational load metrics to comparisons between isolated human populations (eg from the Shetland archipelago) and cosmopolitan populations, to detect regulatory site classes with unexpected loads, correlated to phenotypic traits. We aim to gain novel insights into the impact of rare regulatory variants on quantitative traits relevant to disease predisposition, ultimately aiding the development of ‘personalised’ medicine based upon genome sequencing. Finally, we aim to explore the frequencies and roles of regulatory domain lesions in developmental disorders and cancers. Structural variants (SVs) are known to play critical roles in tumourigenesis, but there are currently no methods to reliably disentangle mutational bias from selection operating on SVs in cancers. Such methods are essential to establish which SVs host potential new therapeutic targets, and which are simply well tolerated by tumours. We are developing new models based upon experimental measurements of the mutational spectra in relevant cell types, to estimate the expected spectra in tumours, and rigorously infer candidate breakpoints that may be under selection.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_07012,Health Education England,HEE,Medicines Optimisation in Paediatric Patients (MOPPet): A qualitative human factors study on the causes of Drug Related Problems in hospitalised children.,"Medication safety in children is of great concern with the incidence of paediatric medication error rates estimated at approximately 20%. However, medication errors and adverse drug events (ADEs) are only part of the problem. Drug Related Problems (DRPs) include errors and harms, but also include include sub-optimal use of medicines and those issues with medication that are related to patient acceptability.It is estimated that the incidence of DRPs in children is 40%.This research seeks to understand how DRPs arise in paediatric in-patients. Following the MRC framework for the development of complex interventions, I will use sociotechnical theory and human factors engineering methods to describe medication processes in children's wards, and to use this theoretical understanding to develop recommendations for intervention development. There will be three work packages:WP1 - The current evidence base will be identified. A systematic review of the literature relating to interventions to reduce the incidence of medication error in paediatrics will be undertaken and will also include drug related problems as an outcome. The Cochrane EPOC group's systematic review methodology will be adopted. Appropriate databases will be searched, as will public policy databases and the grey literature. WP2 - a qualitative exploratory study is proposed to develop theoretical understanding of current practice, and to model the systems around medication use in children in hospital. I will use work domain analysis (WDA) to map the medication process in six different hospitals in the north of England. WDA is a cognitive engineering technique that identifies how people, purposes, the environment and tools and technology interact in a task or process. This will also capture how processes are adapted to ensure the task goals are achieved. Multiple data sources will be used to build the WDA: Procedures, policies and guidelines will be used to construct how the process is supposed to function Participant observation will be used to describe and identify how processes are delivered in practice, and also to describe the contextual information surrounding the way people interact with each other, their environment and the tools they are provided with to complete the tasks. In-depth interviews with patients, carers and staff will be used to understand the experience of medication use and the processes and the environment in which they work. Documents, field notes and interview transcripts will be analysed inductively and brought together to form the WDA. The WDA will be validated with a number of focus groups consisting of staff and experts, and a validation focus group specifically for children and young people.WP3 - Recommendations for interventions will be developed in partnership between patients, the public and professionals using the principles of experience-based co-design (EBCD). Experienced facilitators from partner institutions and members of the research team will undertake two consensus workshops. Health professionals, patients and carers will be presented with the findings from WP2 and asked to work together to propose interventions that can then be tested in later studies.This study involves the public in the design of safety interventions, which is novel. By using cognitive engineering theories, interventions that are developed in this study are likely to be more effective than those used previously. The recommendations will then go forward to develop a strategy for medication safety research in paediatric care supported by patient safety collaboratives.","Children and young people are at greater risk of drug related problems.Currently everything that the NHS tries to do to improve medication use in children is related to reducing how often errors happen. However, very little research has focussed on how to maximise the benefit of medicines for children, which may lead to better health outcomes for them. There are many other things about medicines that might cause harm to children that are not necessarily related to errors - these are called Drug Related Problems and can include side effects or issues that stop patients taking their medicine. This study aims to understand what nurses, doctors, pharmacists and patients do in the real world that may lead to drug related problems happening.I will observe healthcare professionals in hospital wards and departments, in particular to find out how they work with patients and carers, with each other and how they use tools, technology and information that is available to them. I will interview these people about their experiences and will build a model to explain how medication tasks run in real life.Using the results of this research, I will then work with health professionals and patients to develop recommendations for different ways of working that we can then test in later studies.Patients and the public will be involved throughout this research. I intend to have two parent representatives on the group that oversees the research project to provide me with advice and guidance on how the study should be run from the public perspective. Because I am studying medicines use with children and young people, I will also set up a children and young persons advisory board. The SMG and YPAB will provide input into the design and delivery of all aspects of the research. The YPAB will also help me design information about the research for children and young people and will also help me to understand the data that I collect during the project.As the research progresses, I will present the findings at scientific conferences and will also write papers for scientific journals. In addition I will also work with the YPAB to explore how we present the findings to children and young people, to help them understand what medication processes are like in hospital and to show service users how we will attempt to make them safer.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_01118,Medical Research Council,MRC,Membrane protein biosynthesis and quality control,"Our Programme conducts research into the general areas of protein folding, maturation, and quality control. We are addressing at the molecular and mechanistic level three inter-related questions. How are proteins properly matured to their final functional form? How does the cell recognise and degrade the products of mistakes in the maturation process? How do failures in protein maturation and quality control contribute to disease? The first two questions are being addressed using biochemical reconstitution to identify the key machinery that aids in the maturation and degradation of membrane proteins. Once identified, the individual pathways are studied in isolation using biophysical and structural methods to understand how they operate. The third question is addressed by determining how perturbation of maturation or quality control pathways affects the physiology of intact cells and whole organisms. We investigate different types of proteins, but are particularly interested in integral membrane proteins that are assembled at the endoplasmic reticulum. We anticipate this research to have long-term impact on human health for two reasons. First, membrane proteins, an area of particular interest to our Programme, play crucial roles in nearly all areas of human physiology and are major targets for most currently available drugs. Thus, understanding their biosynthesis may lead to new ways of regulating their functional expression to alter physiologic pathways for health benefit. Second, defective protein processing and degradation play central roles in several diseases including Cystic Fibrosis, Alzheimer’s disease, and Prion diseases. Understanding cellular quality control of the proteins in these diseases could therefore open potential avenues for future therapeutic strategies.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE HRCS22_01330,Medical Research Council,MRC,Mental Health Neuroscience Programme,"The goal of the Mental Health Neuroscience Programme at the MRC CBU is to exploit the potential of cognitive neuroscience to improve mental health treatment. To survive, organisms maintain homeostasis by predicting, detecting, and regulating their internal state. Many neuropsychiatric disorders show profound disruptions in homeostatic processes, including motivational drive, appetite, and interoception. The scientific aim of the Mental Health Neuroscience Programme over the next quinquennium is to elucidate the role of homeostatic mechanisms in mental health disorders, and their clinical potential as treatment targets. The programme has three interlinked objectives: (1) discover homeostatic mechanisms driving mental health disorders; (2) disrupt putative sources of these processes in experimental medicine studies; and (3) determine the treatment potential of homeostatic interventions. Dr Nord’s group employs methods from experimental psychology, cognitive neuroscience, computational psychiatry, and physiology, with a particular focus on causal approaches (psychopharmacology, non-invasive brain stimulation, and psychological interventions). Over the next quinquennium, Dr Nord’s team will develop novel experimental assays to probe body-brain learning in a number of domains: motivational drive (led by research assistant Quentin Dercon), circadian rhythm (led by PhD student Sara Mehrhof), inflammation (led by PhD student Alicia Smith), and appetite (led by investigator scientist Hugo Fleming). Together, these studies will build a new theoretical model of homeostatic learning in mental health disorders. These assays will also be tested as predictors of individual vulnerability to symptoms of mental ill-health. Over the next ten years, the most promising assays will be tested as putative biomarkers of treatment response in early-stage clinical trials. To advance the second objective of the programme, Dr Nord’s team will also employ causal methods to disrupt homeostatic mechanisms. The central methodological component of this stream will be neurostimulation, in particular, the development of offline transcranial ultrasound stimulation (tUS) protocols in humans (led by research assistant Alec Sargood, in collaboration with Rik Henson, Ajay Halai, and Matt Lambon Ralph) The third stream of the programme focuses on biological routes to improve psychological therapy. New models or treatments for disorders are only truly translational if clinicians and patients use them, so clinical collaboration and patient experience is at the crux of this work. This includes reverse translation studies revealing the neurocomputational basis of psychological therapy, as well as collaborative work on novel therapeutic augmentations (in collaboration with Tim Dalgleish). The underlying framework of Dr Nord’s programme is translation from discovery science through experimental medicine studies and into early-stage clinical testing. This contributes to the long-term strategy of Dr Nord’s programme: providing a theoretical and methodological framework that links psychological and biological models of mental health disorders, to eventually improve the precision and effectiveness of mental health treatment.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MENTAL HEALTH;NEUROLOGICAL HRCS22_16967,Wellcome Trust,,"Metabolic Characterization of Natural Killer T Cell responses to sterile, hypoxic injury","It has been described that ischemia-reperfusion injury (IRI), such as during organ transplantation, evokes damaging sterile inflammation and secondary tissue injury that is dependent on iNKT cell activation, but the underlying mechanisms remain elusive. Similarly, in sickle cell disease (SCD) mice, RBC sickling and widely disseminated microvascular ischemia can be triggered by hypoxia/reperfusion (H/R), presenting a global and scalable model of sterile, NKT-mediated inflammation. We propose here to use state-of-the-art metabolic methodologies to investigate the response to hypoxia and reperfusion (H/R), which ultimately causes NKT cell activation and tissue damage in SCD. Mice carrying the human sickle cell alleles are available and were crossed with NKT-deficient Ja18 mice, thus generating our novel Sickle-Ja18 mouse model which exhibits reduced tissue damage in response to H/R. Together with in-vitro co-culture experiments, we will explore (1) the intrinsic and (2) APC-mediated mechanisms of sterile inflammation caused by hypoxia and reperfusion in the context of sickle cell disease with the ultimate goal to identify metabolic mechanisms downstream of ischemia to interfere with disease pathogenesis. We anticipate that this research will increase our understanding not only of SCD, but also the pathology of IRI, organ transplantation and sterile inflammation.","Ischemia-reperfusion-injury (IRI), the tissue damage caused after a period of lack of oxygen, evokes damaging inflammation and is a major concern for example in liver transplantation. IRI leads to sterile inflammation, but the underlying mechanisms remain elusive. Recent advances found a key role for iNKT cell activation, a type of innate T-lymphocytes. Mice with sickle cell disease, in which damaged red blood cells cause widely disseminated IRI, can be used as a scalable model of sterile, NKT-mediated inflammation. We will investigate how the response to hypoxia and reperfusion causes NKT cell activation and tissue damage in sickle cell disease. Two hypotheses will be explored: the change in oxygen levels has an effect on (1) antigen presentation to NKT cells, and (2) on the differentiation into different NKT cell types. We will explore these hypotheses with the ultimate goal to identify metabolic mechanisms downstream of ischemia to interfere with disease pathogenesis.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_22883,The Academy of Medical Sciences,AMS,Metabolics and clinical based predictive models for acute kidney injury after coronary artery bypass grafting,"Aims We aim to develop a machine learning-based model based on clinical and metabolomics data to accurately predict postoperative acute kidney injury (AKI) after coronary artery bypass grafting. Background Acute kidney injury after cardiac surgery is associated with significant mortality, morbidity, and excess healthcare costs. Using a machine learning approach, we have developed a novel prediction model that integrates metabolomic preoperative urine profiling of samples from a study biobank and clinical data from a national audit dataset. In 130 patients undergoing various heart surgery procedures, we have shown that the predictive performance of combined metabolomics and clinical model (c-statistic of 0.87) exceeded that of either the clinical model (c-statistic of 0.86) or metabolomics model alone (c-statistic of 0.82).To take this work further, we now want to focus on (1) isolated coronary artery bypass graft (CABG) cohort with balanced outcomes and control patients, (2) assess prediction by AKI stage (1, 2, 3) and add postoperative metabolomic data to the model. Hypothesis A combined metabolomics-clinical prediction model outperforms models based on either metabolomics or clinical features alone. Methods Using the clinical and metabolomics prediction models developed in our pilot study, we aim to assess model performance for AKI prediction based on 200 urine samples taken from 100 isolated CABG patients pre-operatively and post-operatively (half with AKI outcome and half without). The modelling process will take into account urine metabolomics and clinical predictors. Outcomes and impact To develop a prediction tool to enable clinicians to identify and prevent acute kidney in the NHS.","After heart surgery, the kidneys can suffer damage and can stop functioning. This complication is called a renal failure or acute kidney injury. This is a serious complication because it increases the risk of dying after heart surgery and the risk of other major complications. As a result, patients that develop renal failure usually stay longer in hospital. This results in a significant financial burden for the NHS and the use of resources that impact other patients that await treatment. If we could identify which patients are at risk of developing this serious complication early on, it could give us time to prevent it. The current tools for prediction are not good enough. Our preliminary data shows that we could develop an accurate tool to anticipate this complication based on a urine sample analysis and routine clinical patient information we collect before the operation. As a cardiac surgery trainee, this subject area is important to me because I could make a difference in the postoperative management of my patients. I also find exciting the project because I can get involved in two rapidly developing areas of medical research. One area is metabolomics - the large scientific study of chemical processes involving metabolites. This enables us a unique understanding of an individual's biological processes that are altered during disease. The second area is machine learning, a branch of artificial intelligence that enables the use of computer algorithms that can automatically predict a complication through experience and the use of big data.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,RENAL AND UROGENITAL;CARDIOVASCULAR HRCS22_23049,The British Academy,,Metaphors we listen with: the neural correlates of timbral brightness investigated by pitch-timbre interference and fMRI,"Brightness is among the most studied aspects of music perception, and arguably among the most important musical cues actively shaped by performers, composers, and audio engineers. Psychoacoustically, sounds described as bright exhibit a high-frequency emphasis in the spectrum and sounds with more high-frequency energy are described as bright. However, relatively little is known about the neural mechanisms that facilitate those metaphorical descriptions. Do sounds seem bright because our auditory and visual systems communicate directly, or because they each link to a supramodal area where a higher level, more abstract representation of what brightness entails is coded? Interactions between numerical value and brightness level of digits have been shown to modulate activity in the parietal lobe, an area previously implicated in magnitude processing. Implementing an analogous auditory paradigm of pitch-brightness interactions, this study will investigate by fMRI whether they implicate the parietal lobe or, alternatively, visual areas.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,EAR;NEUROLOGICAL HRCS22_05913,Medical Research Council,MRC,Metformin in Li Fraumeni (MILI) trial: A Phase II randomised open-label cancer prevention study of metformin in adults with Li Fraumeni Syndrome,"This clinical study is investigating the use of a drug called metformin as a way of reducing the cancer risk in people with Li Fraumeni Syndrome (LFS)._x000D_ _x000D_ What is Li Fraumeni Syndrome or LFS? _x000D_ LFS is a rare genetic condition that predisposes people to develop one or more cancers. It is caused by a mutation in a gene called TP53, either inherited from a parent or occurring as a new mutation at conception.TP53 is the most important anticancer gene in the body – its job is to stop cells becoming cancerous after they become damaged or stressed. For most people with cancer the gene is only mutated in their cancer cells but, for people with LFS, it is mutated in all the cells in the body. This means there is a very high risk of developing cancer for people with LFS – a lifetime risk of 90% for women, and about 70% for men. Many people with LFS develop multiple cancers over their lifetimes. Cancers associated with LFS include rare bone and soft tissue sarcomas, childhood brain tumours and leukaemias, but also more common cancers such as breast cancer._x000D_ _x000D_ How can people with LFS protect themselves from cancer? _x000D_ Currently there are no treatments to reduce this high risk of cancer. For LFS women there is risk-reducing mastectomy to guard against breast cancer. Other than that, people with LFS have regular health checks and imaging – like whole-body MRI scans and check-ups with specialists – to catch any new cancers early. Research shows that, for people with LFS, spotting cancer early improves survival. Currently there is an agreed protocol for such check-ups in the UK and other countries, but many people are still not getting the care and scans they need._x000D_ _x000D_ Why is the MILI study testing metformin? _x000D_ Metformin is a well-known and safe drug used to treat diabetes. Laboratory experiments have shown that, in mice with LFS, metformin can reduce the risk of them developing cancer. This is because metformin alters the metabolism of cells with mutated TP53 and makes them act more like normal cells. A small study was carried out in people with LFS which showed that metformin treatment caused the same kind of cellular changes that had been seen in the treated mice. However, this is not enough to conclude that metformin will reduce the risks of cancer in people with LFS. For that, a larger clinical trial is needed – involving more patients and a much longer duration of treatment._x000D_ _x000D_ How many people will take part in the MILI study? _x000D_ The MILI study aims to enrol 224 patients with LFS in the UK, a large fraction of the approximate 600 people with it in the country. In order to get the numbers of patients needed to address more detailed questions, such as whether metformin is better at preventing certain types of cancer than others, the study will be run in US, Canada, as well as the UK and the results will be pooled together. Altogether it is expected that around 600 LFS patients from around the world will be included. Half the people on the trials will take metformin every day for up to 5 years and the other half will not – all participants will have regular check-ups for cancer, including whole-body MRI. Five years has been estimated as long enough to give an early indication of whether differences in cancer incidence are due to treatment rather than being random (i.e., chance events) although longer follow-up may be implemented in the future._x000D_ _x000D_ How will the study answer whether metformin works? _x000D_ The data from each of the trials will be put together to create one large meta-analysis to tell us definitively whether metformin reduces the risk of cancer by comparing the number of people who developed cancer in the metformin vs non-metformin participants. In addition to answering the question about reducing cancer risk, the trial will also include regular quality of life questionnaires and biological studies to better understand what it is in the cells of people with LFS that is most associated with cancer development. If the study is successful, and shows that metformin is effective, it can be licensed as a standard cancer prevention treatment for people with LFS. This trial will provide important information about LFS and give hope to families across the world who currently face the devastating impact of cancer on themselves and their children._x000D_ _x000D_ How have people with LFS been involved in designing MILI? _x000D_ The idea of using metformin for cancer risk reduction was first proposed in the LFS community in 2013 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637189/) and the LFS community has been involved in the creation, development and management of this trial. In addition, money raised by the UK LFS charity, the George Pantziarka TP53 Trust, will help pay for the travel costs for participants attending clinics and taking part in the trial. All results, including interim results, will be shared with the LFS community at meetings and online.","Research Question: The purpose of the MILI study is to evaluate whether metformin can prevent or delay the emergence of cancer in people with LFS. _x000D_ Background: Li Fraumeni Syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline or de novo pathogenic variants in TP53. Males and females with LFS have a 70% and 100% lifetime risk of cancer respectively, with around 50% having their first cancer diagnosis before the age of 46 and 31 years respectively. Typical LFS “core” malignancies include bone and soft-tissue sarcomas, breast, brain and adrenocortical cancers but less commonly lung, colon, haematological, skin, stomach and ovarian cancers. Recent evidence from LFS mouse models reveals that abnormal mitochondrial metabolism acts as a driver of cancer formation (tumorigenesis) in LFS and is reversed with the widely-used anti-diabetic drug metformin. _x000D_ Aims and Objectives: _x000D_ The primary aim is to determine the impact of metformin on the time to diagnosis of cancer in LFS, corresponding with a primary objective of comparing cancer-free survival at 5 years from randomisation between study (metformin) and control (no metformin) arms. Secondary aims are to determine the impact of metformin on: i) time to diagnosis of non-invasive/pre-cancerous lesions, ii) overall survival, iii) clinical characteristics of emerging cancers, iv) safety, tolerability and acceptability, vi) effect on quality of life and vii) lifestyle factors. Research Questions: to compare site and type of TP53 mutation with outcome, measure impact of metformin on metabolism, and investigate serum biomarkers which may correlate with tumorigenesis. Parallel studies in Canada, Germany and USA will be recruiting to a similar protocol and, upon study completion, data will be pooled in a definitive individual patient meta-analysis. This will be the world’s largest study in LFS and its first cancer prevention study. The purpose of this EME proposal is to request support for the UK MILI trial._x000D_ Methods: _x000D_ Randomised open-label Phase II trial, n=224 adults with LFS, 1:1 randomisation to metformin (intervention) versus no metformin (control). _x000D_ Timelines for Delivery: _x000D_ 10/2022: Ethics/MHRA submission_x000D_ 12/2022: First Trial site opens to recruitment_x000D_ 01/2023: First Participant recruited_x000D_ 12/2024: Recruitment completed_x000D_ 12/2029: Study assessments completed_x000D_ 09/2030: Data analysis completed _x000D_ 12/2030: Study closed _x000D_ Impact/Dissemination:_x000D_ Trial data will support MHRA/NICE application for metformin as cancer preventative in LFS. Publications will advance understanding of tumorigenesis in LFS and somatic TP53 mutation-associated cancers.",6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_15362,Wellcome Trust,,MicroRNAs in Branchial Arch Development,"Embryonic development of the face and neck is a complex process. In vertebrates it begins with the formation of temporary segments called branchial arches. Within these segments, cells must express the correct genes to properly form various structures and tissues, such as the jawbone. Furthermore, these genes need to be expressed at the correct time and in the correct segment. This requires precise regulation, and one mechanism by which cells can accomplish this tight control is using microRNAs. MicroRNAs are known to be involved in important developmental processes, but no studies have profiled the full collection of microRNAs expressed in developing branchial arches. In this project we aim to identify key microRNAs that function during mouse branchial arch development. We will achieve this using a technology called small RNA-sequencing, which will allow us to determine the abundance of all microRNAs expressed in each stage and time. Following this, we will use computational programs to predict the genes they may regulate and later validate these predictions in the lab. This project will identify new contexts for which microRNAs function in and increase our understanding of the precise regulation in place during facial development.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_03174,Medical Research Council,MRC,Microglial spatiotemporal diversity and role in susceptibility and resilience to neurodegenerative disease,"The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Microglia have important developmental, homeostatic and neuroimmune functions and growing evidence supports that aberrations in each of these broad functional roles can contribute to neurological dysfunction across the lifespan, including dementia-causing neurodegenerative disease1. The discovery of neurodegenerative disorders where the primary disease-causing mechanism appears to be a fault in microglial function (“microgliopathies” e.g. Nasu-Hakola disease (NHD) caused by TREM2/TYROBP mutations2 and HDLS/POLD caused by CSF1R mutations3) supports causative roles and the broader concept that neuronal degeneration can be driven in a non-cell autonomous manner. Mutations in TREM2 and other microglial-enriched genes also increase risk of AD and amyotrophic lateral sclerosis (ALS)4, and recently we and others at UoE (Prof Seth Grant) showed the predominance of microglial and neuroimmune changes within the global tissue-level transcriptomic response in AD and other proteinopathies5,6. Studies using experimental neurodegeneration models showing altered disease trajectory in mice deficient in TREM27,8, inflammasome components9, or with pharmacological modulation of microglial proliferation10-12 further support disease-modifying roles of microglia / neuroinflammation. Microglia and related CNS myeloid cell types also sense and transduce body-to-CNS signals triggered by systemic inflammatory processes (e.g. infection, chronic vascular/metabolic disease), some of which themselves are risk factors for and modifiers of neurodegeneration. Recent studies have also described aberrant synaptic pruning in AD-like pathology13.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_23136,The British Academy,,Mind Wandering and Metacognition in Children,"Mind wandering poses a serious threat to children’s learning. Failing to attend to instruction because of task-unrelated thoughts may impede children's chances of acquiring crucial skills or knowledge. The link between mind wandering and learning has been studied extensively in adult student populations. Yet, despite its clear educational significance, there is a striking evidence gap on the impact of mind wandering on learning in children. The proposed research will address this important research gap by conducting an examination of 5-8 year-olds’ meta-awareness of mind wandering and their understanding of how mind wandering can impact on learning. Outcomes of this work will provide a springboard for the development of new interventions geared toward detecting and refocusing lapses of attention in educational settings.",,1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,MENTAL HEALTH HRCS22_19947,Wellcome Trust,,Miniature microscopes for ultra-high frame rate imaging in freely moving animals,"We propose to develop the first miniaturised microscopes for high-speed (kHz) voltage imaging in freely moving animals. Voltage changes that mediate neuronal computations, and electrical signalling in non-neuronal tissues, are too fast to observe with miniature microscopes currently used for imaging in freely moving animals. To address this, we will build miniature microscopes that use Single Photon Avalanche Diode (SPAD) sensor technology to obtain frame rates > 10 fold higher than existing systems. Our proof-of-principle ex-vivo data shows that SPAD sensors can image sub-threshold and spiking activity of neurons reported with genetically encoded voltage indicators (GEVIs). As the sensors used for these experiments have a similar footprint to the standard CMOS sensors in current miniature microscopes, it will be feasible to use SPADs to image fast electrical signalling even in freely behaving animals. Our goals are: 1. To develop miniature microscopes that incorporate our established SPAD technology, along with custom made drivers and control software, to image 10s of neurons in freely moving animals. 2. To develop a second system using state-of-the-art SPAD sensors to image 100s of neurons in freely moving animals. 3. To validate the systems by recording from genetically identified neurons during spatial exploration and action selection.","Precise electrical signalling at a millisecond time scale is critical for healthy functioning of the brain and organs such as the heart. Future advances in understanding functions and disorders of the brain, and electrical activity in other organs, will require new tools to resolve fast electrical signals in identified cells in freely moving animal models.  Recently developed fluorescent indicators enable electrical signals to be observed with microscopes. However, because current microscopes able to do this are bulky they can only be used with animals that are restrained, which severely limits their usefulness. To address this, we propose to develop miniature microscopes that by incorporating novel imaging sensors will be capable of extremely high frame rate imaging of the electrical activity of populations of neurons, or other cells, in freely moving animals. By facilitating widespread adoption of these systems we expect to transform investigation of electrical signaling during complex behaviours.",1.3 CHEMICAL AND PHYSICAL SCIENCES,GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_17889,Wellcome Trust,,Mining the Past,"This is a project to conserve, catalogue and exploit the archives of the National Union of Mineworkers (NUM). It presents the opportunity to develop a nationally significant archive for occupational and industrial health at the MRC and a Midlands network for coal related archive collections. The NUM records are currently held in poor conditions at the union’s headquarters in Barnsley. The project involves the removal of the archives to professional conservation facilities for drying and cleaning prior to storage at the MRC. It includes the sorting and cataloguing of the collection for research use as well as a public engagement programme. The project will: • Remove the collection to Harwells for conservation treatment • Re-box, sort and summarise the collection for immediate access and use in promotional activities • File/item list the collection for full online catalogue access • Select and digitise items for research, teaching and exhibitions. • Develop a project website • Co-host seminars with the Centre for the History of Medicine (Warwick) on coal, industry and health • Develop a Midlands network of coal related archive collections for future collaboration, education and outreach activities • Use the NUM archive as a focus for the development of a national industrial health and welfare archive",,1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),GENERIC HEALTH RELEVANCE HRCS22_06710,Department of Health and Social Care,NIHR,Missing data in paediatric clinical trials; why does it happen and what can we do about it?,"Research questionThis research will address two problems in paediatric randomised controlled trials (RCTs): Lack of understanding as to why missing data occurs, and how it can be reduced. Limited guidance on appropriate statistical methods, and how these are implemented, when missing data are suspected to be Missing Not At Random (MNAR).Background There are not enough well-designed, high-quality paediatric trials leading to treatments being used which have only been tested in adults or not tested at all. Preliminary results from a literature review has shown that retention rates may be lower in paediatric trials compared to adult trials. If paediatric trials were of higher-quality with fewer missing data, more evidence would be available on appropriate treatments. If data are missing, failure to appropriately account for these in analyses can lead to bias and loss of precision, such that misleading conclusions may be drawn from the results. An estimated 65% of studies do not report how missing data were dealt with, and that even if reported, the methods used were inadequate. Analyses of data from paediatric RCTs are often carried out under the Missing At Random (MAR) assumption but sensitivity analysis methods that allow missing data to be Missing Not At Random (MNAR) are rarely carried out, despite RCT analysis guidance. Aims and objectives The overall aim is to improve the estimates of effectiveness and cost-effectiveness of paediatric trials through: Reducing missing data Improving the analyses of incompletely observed data suspected to be MNARMethods There are four projects in this research: Literature review of retention rates in paediatric trials Qualitative study using interviews with children/young people and their parent/carer(s) who have taken part in paediatric RCTs: exploring their understanding of retention; identifying reasons for missing data and investigating the acceptability of alternative data-capture methods and data-linkage. Literature review of statistical methods for analyses where missing data are suspected to be MNAR. Quantitative analyses involving a simulation study to compare statistical methods for analyses where missing data are suspected to be MNAR, and an illustration of these methods using real trial data.Anticipated impact and dissemination In the short-term, my research will inform those currently conducting paediatric RCTs in how to reduce missing data at follow-up, improving retention. For future RCTs, this research is likely to change the data collected (for example, from schools/parents) which can be used in analysis methods when missing data is suspected to be MNAR. In the medium to long term, this will improve estimates of effectiveness and cost-effectiveness of treatments from paediatric trials and increase the subsequent evidence base for paediatric treatment. I will disseminate the results of this research to patients through working with charities, patient and public involvement groups, the Science Media Centre and University Press Office. I also additionally raise awareness of my research with trialists, clinicians and statisticians through publishing articles and practical guidance in how to implement methods found in Projects 2 and 4.","Aim of the research To improve trials testing treatments in children/teenagers by reducing the amount of missing data and using better methods to deal with it if it happens. Background In a trial for children/teenagers, we collect data to see which treatments work best. Trials for children/teenagers are more complicated than in adults because data can be collected from children and their parents/carers. Missing data can mean researchers make the wrong decision about whether a treatment works. Missing data may occur because patients do not like how questions are asked, feel too ill, stop taking part in the trial or for other reasons that we do not know about. Little is known about how to reduce the amount of data that is missing and the best way to summarise results of trials with missing data in children/teenagers. Design and methods Aim 1: Understand how to support/encourage children/teenagers, and parents/carers, to provide data in trials.In Project 1, I will look at reports of trials of treatments for children/teenagers to understand why children/teenagers and their parents might not provide data. In Project 2, I will interview children/teenagers and their parents/carers who are taking part in trials to understand their opinions and experiences about: reasons for missing data (for example, the child/teenager felt ill) how they can be helped to complete questionnaires (such as, completing on an app) whether they would allow other information to be collected (such as, school records) also collecting the same data about the child/teenager's illness from parents/carersAim 2: Improve the understanding and use of methods for dealing with missing data. If data is missing, we might be able to estimate it using other data that is available. There are several methods to do this, but they depend all on why the data is missing. I will focus on methods that can be used when we think the reason for missing data is related to the missing data itself. For example, when a child/teenager is too ill to complete a questionnaire on health and therefore it is missing. This type of missing data is 'Missing Not At Random' (MNAR) and is rarely used in trials at the moment. Trials in children/teenagers are suited to using these MNAR methods because there are often data available from parents/carers or school records (which are almost always available). In Project 3, I will review the literature on methods used to summarise results of trials when the missing data are MNAR. In Project 4, I will test these methods. I will create different copies of the trial results based on data from real trials (data simulation). I will then use these copies of the data to compare the methods found in Project 3 and report which of these methods works the best. I will also repeat the calculations of the results of completed trials in children/teenagers using the methods found to see what happens to the results, and if it affects the decisions about treatments that were made from these results. Impact Improving trials in children/teenagers will make the results more trustworthy, which will help doctors to make better decisions about the best treatment for children/teenagers who are ill. Patient and public involvement I will work with an existing group for children/teenagers with different experiences of research in health and other groups of children/teenagers who have different health problems and their parents/carers. Dissemination I will disseminate the results of my research by: publishing articles, attending conferences, working with the press office and writing summaries for children's medical charities and teams that carry out trials.",8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_00909,Medical Research Council,MRC,MitoCluster: an integrated phenotyping and mouse model generation platform for mitochondrial disease and dysfunction,"Primary mitochondrial diseases (PMDs) caused by mutations in nuclear (nDNA) or mitochondrial DNA (mtDNA) that impair energy production, affect 1/4,300 in the UK. Despite causing severe disability and shortened lifespan, management is primarily symptomatic. This reflects incomplete understanding of underlying pathogenesis and few reliable, non-invasive biomarkers to diagnose and monitor disease progression. The UK is at the forefront of PMD clinical and scientific research. MitoCluster is well-positioned to connect this world-leading expertise with mtDNA genome editing (mtGE) and deep phenotyping skills, to create a multi-site UK-wide platform for much-needed PMD mouse model generation, breeding and phenotyping. Aim 1 (WP1) will generate a refined phenotyping platform, including measures of muscle fatigue and weakness, the leading targets of drug development given impacts on quality of life. We will combine in-cage assessments at Mary Lyon Centre with biochemical, imaging, metabolomics and single-cell sequencing at partner sites. Aim 2 (WP2 and 3) will generate 6-9 novel mtGE mouse models using two approaches: (1) phenotype-first, in which breeding of heterozygous mitochondrial mutator (PolgA+/D257A) mice results in random heritable heteroplasmic mtDNA mutations - lines are selected via measurable phenotypes; (2) targeted, based on programmable nuclease (mtZFN) or cytosine base editing (DdCBE) methods to obtain predefined deleterious mtDNA mutations. These will be subject to deep phenotyping through our refined platform (WP1) and undergo combined single-cell mtDNA/RNA-Seq in different tissues over time, to generate a publicly available atlas of somatic heteroplasmy dynamics. We will harness our strong Pharma partnerships to evaluate the impact of existing and novel compounds in a whole organism context (Aim 3) and develop and deliver courses in mtGE model generation and maintenance (Aim 4), to grow the UK skills base across academia and industry.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,METABOLIC AND ENDOCRINE HRCS22_01312,Medical Research Council,MRC,Mitochondrial dysfunction: Understanding how dysfunctional mitochondrial redox metabolism underpins pathology,"Reactive oxygen species (ROS) produced by mitochondria cause oxidative damage that impairs the ability of mitochondria to make ATP and to carry out their metabolic functions. They may participate also in cellular redox signalling pathways. One important aspect of our work is to investigate how oxidative damage to mitochondria contributes to human pathologies. We have worked out a way of targeting small bioactive molecules, such as antioxidants, to mitochondria in order to counter the effects of ROS and to examine the effects of doing so at cellular and whole animal levels. The bioactive molecule is attached chemically to a lipophilic cation such triphenylphosphonium. These cations accumulate selectively, first in the cytosol, driven by the plasma membrane potential, and then several-hundred fold in the matrix of mitochondria, driven by the membrane potential across the inner membrane. A second important aspect is to determine whether and how mitochondrial ROS alters the activities of proteins in putative signalling and protective pathways by reversibly modifying the redox state of critical protein thiols in mitochondria. We use a range of free radical and proteomic approaches to identify the proteins involved, and to identify the cysteine residues and any redox modifications. Finally, we take this information and use it to rationally design potential therapies for diseases that arise from mitochondria dysfunction. Currently our main focus for therapy is the ischaemia/reperfusion injury that arises from stroke and heart attack.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE HRCS22_22926,The Academy of Medical Sciences,AMS,Mitochondrial function in doxorubicin-induced cardiotoxicity,"Doxorubicin (DOX) is a chemotherapeutic drug that can cause serious cardiotoxic side effects leading to heart failure. Different mechanisms have been proposed for this toxicity, though there is no specific cardioprotective drug available to prevent functional decline. I previously established a clinically-relevant rat model of DOX-induced heart failure and characterised metabolic changes with non-invasive in vivo hyperpolarized magnetic resonance spectroscopy (MRS). These data show that cardiac oxidative metabolism is impaired before functional decline. I have furthermore shown that activation of the adenosine monophosphate-activated kinase (AMPK) with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) prevents functional decline, but the mechanism for this remains elusive. AICAR is known to increase fatty acid uptake and oxidation, thereby improving mitochondrial function. This could make mitochondrial energy generation more efficient, leading to adequate energy provision to maintain cardiac function. Improved mitochondrial function could also prevent reactive oxygen species (ROS) production and mitochondrial permeability transition pore (mPTP) opening, indicative of the early stages of cell death. I therefore propose to purchase a state-of-the-art mitochondrial bioanalyzer, the Oroboros O2k FluoRespirometer, which allows simultaneous measurements of mitochondrial substrate oxidation, ATP generation, ROS production and mPTP opening. I will assess mitochondrial function in isolated cardiac mitochondria of saline control, DOX and DOX+AICAR rats at three time points in the chemotherapy regimen. Before mitochondrial isolation I will measure cardiac function with CINE MRI and cardiac metabolic fluxes with hyperpolarized MRS to establish a clear picture of functional, metabolic and mitochondrial changes in the heart during DOX-chemotherapy and to elucidate the cardioprotective mechanism of AICAR.","Chemotherapy has greatly improved cancer survival rates, especially in breast cancer patients. However, some chemotherapeutic drugs such as doxorubicin have side effects on the heart and cancer survivors can end up developing heart failure as a consequence of their cancer treatment. Unfortunately, it is still poorly understood what exactly happens in the heart that causes this toxicity and decline in function. It is also impossible to predict which patients will suffer long-term heart problems due to their cancer therapy. An imaging tool to screen patients regularly to check for early signs of toxicity on the heart would therefore be desirable to detect any changes early and intervene with appropriate treatment. I have previously established in rats that a non-invasive and non-radioactive imaging technique called hyperpolarized magnetic resonance can detect early changes in how the heart generates energy after chemotherapy. This could potentially be translated as a screening tool into cancer patients. In order to fully understand what underlies the early changes in energy generation that hyperpolarized magnetic resonance can detect I now want to perform a study using an Oroboros O2k FluoRespirometer. This device can accurately assess in the cellular powerhouses, the mitochondria, how energy is made and whether there are any signs of toxic radicals forming that may impact their function. Assessing mitochondrial function with this device will be vital to fully understand the underlying pathology of doxorubicin cardiotoxicity and may lead to a cardioprotective drug that can boost mitochondrial energy generation and protection from heart failure.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CARDIOVASCULAR HRCS22_01240,Medical Research Council,MRC,Mitochondrial oxidative damage and human diseases,"Mitochondria are central to the function of human cells because they make energy available to the cell in a usable form and because they are central to a number of pathways of cell death. Consequently it is unsurprising that defects in mitochondrial function contribute to a number of human diseases, including neurodegenerative diseases such as Parkinson's disease and Friedreich's ataxia. Damage to mitochondria also contributes to the pathophysiology of heart attack, stroke and diabetes. In this project my group are developing new tools to target molecules to mitochondria in order to understand the processes by which mitochondrial damage occurs and to develop ways in which this damage can be prevented or repaired in human diseases. In carrying out this work we seek to understand how mitochondrial damage occurs in yeast, cultured mammalian cells and in rodent models of mitochondrial damage. One of the most important causes of mitochondrial damage is thought to be the formation of free radicals by mitochondria as a byproduct of their normal function. These short lived but reactive species cause damage to mitochondria DNA, proteins and lipids thereby disrupting normal mitochondrial function. A consequence of this damage is that it causes cells to undergo cell death by both apoptotic and necrotic pathways. We are particularly interested in understanding the links between mitochondrial damage and increased cell death. To unravel the role of mitochondrial free radicals in cell death requires a range of techniques from molecular biology, cell biology and biochemistry. In addition to these standard approaches, we are also developing a strategy that is proving to be particularly useful. This is the selective targeting of molecules to mitochondria within cells. To do this we use the large membrane potential across the mitochondrial inner member to drive the uptake of lipophilic cations to which we have attached biologically active molecules. These active molecules include antioxidants and reporter molecules designed to respond to free radicals. By using these molecules we are able to both estimate and block mitochondrial oxidative damage, and thereby infer its role in cell death. In related work we are also developing strategies to direct large molecules such as proteins and nucleic acids to mitochondria in order to repair the damage caused to mitochondria by free radicals. The approaches we are developing may allow us to measure or manipulate mitochondria processes independently of the rest of the cell. This has scientific potential in helping us understand the roles of mitochondria within the cell. As some of the molecules being developed may prevent or repair mitochondrial damage they may lead to improved therapies for human diseases involving mitochondrial dysfunction. These include degenerative diseases such as Parkinson's disease and diabetes and the general pathological changes associated with ageing.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE HRCS22_01265,Medical Research Council,MRC,Mitophagy Signalling in Health and Disease,"A major focus of this research is to decipher the signals that regulate autophagy under physiological conditions and we are particularly interested in the autophagy of mitochondria, a process termed mitophagy. Mitochondria, the key energy-generating organelles of the cell, have the potential to cause great cellular harm and death when they become damaged, in part due to uncontrolled release of cytochrome c and production of reactive oxygen species. Because of this, a failure in mitochondrial quality control has strong links to diseases such as cancer and neurodegeneration. One critical quality control pathway that is emerging is mitophagy, the clearance of mitochondria by autophagy. Autophagy is a catabolic process whereby a membrane compartment, termed an autophagosome, engulfs excess, impaired and/or toxic components and delivers them to the lysosome for degradation. It is now evident from cell-based work that mitochondria can be specifically incorporated into autophagosomes, but how and where this occurs physiologically is still poorly defined. Addressing these issues is vital, not only for understanding the aetiology of diseases such as Parkinson’s, but also because mitophagy has great potential as a therapeutic tool. Our work has revealed for the first time that mitophagy occurs at a high rate in specific cells and tissues in vivo under normal conditions, including those of clinical relevance such as dopaminergic neurons in relation to Parkinson’s. However, we do not know the signalling pathways controlling these instances of mitophagy. Our objective is to resolve the mechanisms that regulate physiological mitophagy, delineate the relevant signalling pathways and to determine how these mechanisms relate to development of disease. Using a combination of biochemistry and cell biological techniques, we will molecularly define how the autophagy initiating ULK1 kinase complex becomes activated to drive mitophagy and in turn determine when and where this becomes important in vivo.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE HRCS22_14648,Brain Research UK,,Modulating speech recovery after stroke,"Speech and language impairment (aphasia) is a severely disabling disorder. Patients with impoverished speech are more likely to withdraw socially and suffer from depression, and when a person has anomia (word finding difficulties) after stroke, everyday communication becomes a source of profound frustration both for the person with anomia and their families. Unfortunately, provision of speech therapy within the NHS is far below that needed to provide optimal rehabilitation. While some patients recover, many do not. This project aims to use a novel brain stimulation paradigm I recently developed (tACS) to help these patients recover. The aim is for tACS to interact with brainwaves at a particular type of frequency that has been shown to be valuable for speech. tACS is a non-invasive, safe and painless method of brain stimulation. In a previous study I showed that, when paired with behavioural training, this tACS brain stimulation method can boost learning. Here, I propose pairing my brain stimulation paradigm with anomia training to boost speech recovery in patients suffering from chronic aphasia following stroke. To ensure maximal effectiveness of the brain stimulation I will use a novel tool to personalise the dose to each patients’ own brain scans. It is hoped that this type of brain stimulation will provide a low-cost, portable neurorehabilitation tool that can be used alongside training to reliably boost patients’ recovery after stroke. Boosting speech function recovery would have a great impact on patient wellbeing, increasing independence, ability to return to work and overall quality of life.","Speech and language impairment (aphasia) is a severely disabling disorder. Patients with impoverished speech are more likely to withdraw socially and suffer from depression, and when a person has anomia (word finding difficulties) after stroke, everyday communication becomes a source of profound frustration both for the person with anomia and their families. Unfortunately, provision of speech therapy within the NHS is far below that needed to provide optimal rehabilitation. While some patients recover, many do not. This project aims to use a novel brain stimulation paradigm I recently developed (tACS) to help these patients recover. The aim is for tACS to interact with brainwaves at a particular type of frequency that has been shown to be valuable for speech. tACS is a non-invasive, safe and painless method of brain stimulation. In a previous study I showed that, when paired with behavioural training, this tACS brain stimulation method can boost learning. Here, I propose pairing my brain stimulation paradigm with anomia training to boost speech recovery in patients suffering from chronic aphasia following stroke. To ensure maximal effectiveness of the brain stimulation I will use a novel tool to personalise the dose to each patients’ own brain scans. It is hoped that this type of brain stimulation will provide a low-cost, portable neurorehabilitation tool that can be used alongside training to reliably boost patients’ recovery after stroke. Boosting speech function recovery would have a great impact on patient wellbeing, increasing independence, ability to return to work and overall quality of life.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,STROKE HRCS22_00108,The Francis Crick Institute,Crick,Molecular Mechanism of Autophagy – Resolving Autophagosome Formation in Time and Space,"How does the cell form a customized waste basket when bacteria suddenly invade the cytoplasm, when mitochondria stop functioning threatening the cell by releasing reactive oxygen species or when nutrients become so scarce that the cell needs to reclaim and recycle a diverse range of cellular building blocks? Autophagy holds the answer to all those seemingly unrelated challenges a cell may face throughout its life. Autophagy initiates a fascinating cellular response by converting small vesicles into sheet-like structures which upon closure give rise to double membrane vesicles allowing fusion with the lysosome/vacuole. There the cargo is degraded allowing for the recycling and repurposing of all contained cellular building blocks equipping the cell with a powerful mechanism to adapt to its ever-changing environment by maintaining cellular homeostasis. Additionally, autophagy also equips the cell with the ability to neutralize potentially cytotoxic threads such as invading pathogens, damaged or non-functional organelles or protein aggregates explaining the many beneficial properties attributed to autophagy for human health. Consequently, deregulation of autophagy is associated with many human diseases such as cancer, neurodegeneration and infection. Autophagy is a captivating but also very complex process which requires multiple cellular factors and layers of regulation. The individual steps involved are difficult to study solely in the crowded environment of the cell. Hence, the lab has developed a cell-free system to re-build the process of autophagosome formation in the test tube to understand when, where and how each of the components contributes to autophagosome formation. This system can be manipulated at will, allowing us to dissect and visualize the different steps in order to gain unprecedented insights into the mechanism. In order to understand autophagosome formation at the molecular level we will take advantage of our cell-free system to understand the structural and mechanistic basis of vesicle tethering and fusion – the very first steps during autophagosome formation. We will employ biophysical approaches including single-moleculefluorescence resonance energy transfer (FRET)-based vesicle fusion assays to identify the machinery required for vesicle tethering and fusion. In parallel, we will employ biochemical and cell biology approaches to understand how posttranslational modifications (e.g. phosphorylation) regulate membrane formation. Functional membrane tethering and fusion intermediates will be analysed by cryo-electron microscopy and single particle analysis or by tomography-based approaches. High resolution structures of vesicle tethering and fusion intermediates will significantly advance our knowledge of autophagy guiding future efforts to identify novel strategies for therapeutical intervention.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_01299,Medical Research Council,MRC,Molecular Mechanisms of Cell Death,"Cell death is a fundamental cellular response that plays a crucial role both during development and in the removal of unwanted or damaged cells following stress, injury or infection. Inappropriate cell death regulation contributes to many human diseases, including cancer and autoimmune and neurodegenerative disorders. Proteins/pathways that control cell death have also been identified as defined nodes that form key decision points to regulate the response to toxic insult. This Programme aims at understanding the fundamental mechanisms of cell death that regulate life/death decisions at the cellular level. By understanding the underlying molecular and cell biology of these processes, we aim to deliver field-changing mechanistic insights into toxicology and disease. Our research Objectives are to develop a number of strategies including develop a number of strategies including novel ‘in vitro’ reconstituted models which, combined with an integrated molecular, cell biological and proteomics-based approach, place us in a prime position to examine the molecular determinants of cell death. In particular, we will employ cutting-edge technologies to: 1. obtain novel insights on the regulation and molecular architecture of multiprotein signalling complexes that direct cell fate 2. define signalling networks conferring drug-induced mitochondrial toxicity or cell survival in translational models of hepatotoxicity 3. selectively target nodes of resistance to cell death in patient-relevant 3D tumour models. The data generated through these integrated approaches will provide novel insights into the fundamental mechanisms of cell death that underlie the response to toxic injury, thus informing strategies to mitigate toxicity of existing therapies as well as newer agents under development.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE HRCS22_19751,Cancer Research UK,CRUK,Molecular Oncology Group,"Background: Over the last 10 years, our Group has made important contributions to our understanding of the fundamental processes underlying melanoma development and progression. Our studies have had significant impact on melanoma patient care. We have developed tractable models of melanoma that have allowed us to study gene-gene and gene-environment interactions. With our move to Manchester, we have established excellent connections to clinical colleagues at the Christie NHS Foundation Trust, and developed a translational programme that aims to inform patient stratification and the clinical management of melanoma and other cancers. Aims: Our aims are: • To investigate how ultraviolet light drives melanoma development. • To develop new treatments for uveal melanoma. • To develop new drugs for melanoma and other cancers. • To develop new treatments for prostate cancer. • To develop a precision medicine platform for melanoma and other cancers. Methods: Underpinning all of our studies are the models of disease we have developed and refined over the past ten years, including genetically engineered mouse models (GEMM) and patient-derived models (cell lines, PDX, CDX) models. We have extensive expertise in next generation sequencing (NGS) approaches and functional analysis of cancer biology. We will use our GEMMs to dissect the gene-gene and gene-environment interactions on melanoma development and progression, and to study responses to immunotherapies to guide optimisation of these drugs in the clinic. We will develop and study GEMMs of uveal melanoma and prostate cancer, which, coupled with analysis of patient samples, will allow us to identify novel targets and develop or optimise much-needed new therapeutic approaches for these cancers. Using patient-derived models, we will identify new therapeutic targets for melanoma and other cancers, and investigate mechanisms of resistance, allowing us to develop precision medicine approaches for melanoma and other cancers, and to develop new anti-cancer drugs. Impact: Our philosophy is that patient care should be based on improved knowledge of cancer biology. Our overarching aim is to understand the processes of cancer to develop better approaches to prevention, to develop new drugs, and to improve the clinical management of cancer patients.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_20036,Wellcome Trust,,Molecular basis for motor-cargo cooperation in mitosis,"Defects in chromosome segregation give rise to aneuploidy and chromosome instability, important hallmarks of cancer. Equal partitioning of sister chromatids to daughter cells requires microtubules to assemble into a mitotic spindle and to power chromosome segregation. Microtubules depend on multiple microtubule motor proteins to assemble into a spindle and segregate chromosomes. However, how motors cooperate with each other and with their cargos to drive mitosis is still virtually unknown. I will use a holistic mechanistic approach to understand how motor cooperation ensures faithful mitosis. We will focus on two key mitotic motor families, the non-motile Kinesin-13 microtubule depolymerases and CENP-E, critical for chromosome alignment, as paradigms for understanding motor cooperation during cell division. Combining structural and cell biology with single molecule reconstitution, we will define how Kinesin-13 motors cooperate with Kinesin-8 translocating motors for microtubule end targeting and depolymerization, and how CENP-E cooperates with the outer kinetochore of unaligned chromosomes, to achieve chromosome biorientation and segregation. These studies will provide a mechanistic understanding of the emerging role of kinesin-cargo cooperation in ensuring faithful cell division. Understanding these interactions will create new opportunities for the rational design of kinesin inhibitors in the treatment of cancer.","It is essential to all living organisms to transmit their genetic information, packed into chromosomes, accurately from one generation to the next. When a cell divides, it distributes the previously duplicated chromosomes to each daughter cell so that they inherit the same genetic message. Defects that result from unequal chromosome segregation can lead to dramatic consequences for an organism. Aneuploidy is frequently observed in cancer and results in genetic diseases such as trisomies including Down’s syndrome. To segregate its chromosomes equally, the cell uses microtubules: these are long dynamic filaments, which store energy to move the chromosomes apart. Multiple nanoscale molecular motors organize the microtubules so that they can assemble to form the chromosome segregation machinery called the spindle. This proposal seeks to understand how these motors coordinate their activities to shape microtubules into a spindle, and attach and move chromosomes along it. We will define how motors achieve movement and transport at the molecular level, and how failure in the process can lead to cancer or cell death. This research is key to understanding the molecular processes of cell division in the eukaryotic kingdom and will create opportunities for the discovery of anti-cancer drugs targeting these motors.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS HRCS22_20365,Wellcome Trust,,Molecular basis of chromosome synapsis and genetic exchange in mammalian meiosis,"Meiotic cell division is defined by a unique and highly dynamic programme of events that results in homologous chromosome segregation following crossover formation. In mammals, the telomeric ends of chromosomes become tethered to the nuclear envelope by the meiotic telomere complex (MTC), where they undergo rapid movements, driven by microtubule forces transmitted by the LINC complex, that facilitate the identification and alignment of homologous chromosome pairs through recombination. Once established, homologue chromosome pairs become synapsed along their length by the zipper-like assembly of the synaptonemal complex (SC), which provides the unique three-dimensional architecture necessary for recombination intermediate resolution and crossover formation. We will uncover the structure, assembly mechanism and recombination function of the SC, the mechanistic basis of nuclear envelope tethering by the MTC and the mechanism of force transduction by the LINC complex. This will be achieved through a structural biology approach of biophysics, crystallography and cryo-EM, coupled with collaborative structure-directed mutation in mouse meiosis. Our work will result in unprecedented molecular understanding of how the mammalian SC, MTC and LINC complex operate together as an integrated molecular machine to achieve their essential functions of mammalian meiosis, and crucially how their dysfunction leads to human infertility, miscarriage and aneuploidy.","Sperm and egg cells each contain 23 chromosomes, which combine upon fertilisation to achieve the full complement of 46 chromosomes that defines human life. These reproductive cells are produced by meiosis, in which the chromosome number is halved and genetic material is shuffled to enhance diversity. We aim to uncover how the elaborate chromosome choreography of meiosis is achieved by a series of integrated protein machines, including ropes and pulleys that drag chromosomes around the cell and a zipper that binds chromosomes together to enable genetic exchange. We will utilise biochemistry and structural biology to reveal the how the ‘cogs’ of these machines work together at the most fundamental molecular level to ultimately achieve their remarkable cellular functions. Through this work, we will uncover how meiosis normally produces healthy sperm and eggs, and how it goes wrong in infertility and recurrent miscarriage, which affect 15% and 5% of couples, respectively.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_15375,Wellcome Trust,,Molecular characterisation of post-translational regulation in offensive Type VI secretion systems,"The Type VI secretion system (T6SS) is a nanoweapon used by many Gram-negative bacteria to deliver toxic ‘effector’ proteins into neighbouring cells. The targeted cells are most often rival bacteria, but can also include the host or microbial fungi. Understanding what triggers the T6SS weapon to assemble and fire will improve our knowledge of how microbes compete for resources, and how diverse communities of microbes develop. Two T6SS firing ‘strategies’ have been identified: offensive T6SSs assemble and fire pre-emptively, whereas defensive systems only fire in retaliation upon sensing incoming attacks from neighbours. A signalling system of proteins which mediate both strategies has been identified. However, key molecular details of how this is used to orchestrate ‘offensive’ T6SS firing are lacking. In this study, we will elucidate the molecular mechanism of these offensive T6SS protein-protein interactions, using the model T6SS of the opportunistic pathogen, Serratia marcescens. Using a combination of genetic, biochemical and cell biology approaches, we will determine the trigger that activates the pathway, how this signal is transduced to activate the T6SS, and the conservation of this regulation in clinical isolates. Long-term, understanding how bacteria interact in diverse communities will contribute to novel strategies to tackle bacterial infections.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_02067,Medical Research Council,MRC,Molecular characterization in human neurons of genes associated with severe obesity identified from consanguineous pedigrees.,"Up to 10% of severe early onset obesity has an identified monogenic cause. We showed that studying the disease in consanguineous Pakistani pedigrees enriches for homozygous variations, increasing the likelihood of finding causative mutations. Using this approach, we have identified that homozygous and compound heterozygous loss of function mutations in ADCY3, which encodes for adenylate cyclase 3, and homozygous mutations in the gene ROCK1, which encodes for Rho-kinase 1, are linked to severe obesity. In this proposal, we will study both these genes in detail, as well continue our search for other new obesity candidates. Given the role of the brain in the regulation of body-weight and food intake, we will molecularly characterize these genes in human neurons. Using single nucleus RNAseq, we will identify human neurons expressing ADCY3 and ROCK1. We will characterize the heterogeneity of the neurons and define markers for different populations. We will use RNAscope single molecule FISH to map where both of these genes are expressed within the human hypothalamus. Using CRISPR/Cas9 gene editing, we will 'knock-in' the ADCY3 and ROCK1 mutations that are associated with obesity into human pluripotent stem cells and then differentiate them into hypothalamic neurons. In the cells with ADCY3 mutations, we will study the effect on the primary cilia and leptin responsiveness. In the cells with ROCK1 mutations, we will measure leptin and insulin responsiveness. Using single cell RNAseq, we will examine the transcriptomic consequences of the mutations on the neurons. Using CoDE-seq, an augmented whole-exome sequencing approach that additionally enables the accurate detection of CNVs, we will continue to further identify candidate genes associated with severe obesity. Where the weight of evidence dictates, these will be molecularly characterized as above. Our aim is to uncover novel appetitive control pathways and reveal new potential therapeutic targets to tackle obesity.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,METABOLIC AND ENDOCRINE HRCS22_02012,Medical Research Council,MRC,Molecular mechanism of viral transgene silencing by KAP1 (TRIM28),"Transcription of transposable elements is tightly regulated to prevent damage to the genome. A key source of regulation of transposable elements is the family of KRAB domain-containing zinc finger proteins (KRAB-ZFPs) and KRAB-associated protein 1 (KAP1). KRAB-ZFPs recognize specific transposable elements and recruit KAP1, which controls the assembly of an epigenetic silencing complex including histone H3K9 methyltransferase SETDB1. The chromatin remodeling activities of this complex repress transcription of the targeted transposable element and any adjacent genes. We have performed a detailed and quantitative set of biochemical and structural analyses on the tripartite motif (TRIM) of KAP1. Our preliminary data show that KAP1 forms homodimers through a coiled coil domain. Moreover, KAP1 dimers assemble into higher-order oligomers via B-box domains, and KAP1 forms a tight 1:1 complex with the KRAB domain. However, the structure and composition of the KAP1 repressor complex, and how its assembly impacts the structure and physicochemical properties of its chromatin binding site, remain unknown. Here, we propose to identify the molecular mechanisms through which KAP1 recruits and activates chromatin-modifying enzymes at target transposable elements. We will determine three-dimensional structures at near-atomic resolution of a KAP1/KRAB-ZFP retrotransposon recognition complex, and a repressor complex containing a KRAB-ZFP, KAP1 and SETDB1, by X-ray crystallography and cryo-electron microscopy. We will design structure-based mutations to identify functionally important structural features and protein interaction interfaces with biochemical and cell-based functional assays. Our work will provide a detailed mechanistic understanding of how KAP1 represses transcription of transposable elements. Reactivation of transposable elements can cause serious human disease. This work will inform the design of compounds that inhibit pathogenic activation of transposable elements.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_02439,Medical Research Council,MRC,Molecular mechanisms enabling cDC2s to control Th2 cell priming,"The molecular control of cDC2 functions is not sufficiently understood. Progress has been hampered by the heterogeneous nature of cDC2s in vivo; the few activated cDC2 needed to prime naïve T cells are outnumbered by non-activated cDCs that also migrate. We have recently shown that, after stimulation with Schistosome Egg Antigen (SEA), cDC2 become able to prime naïve T cells to become Th2 in vivo. But at a molecular level our understanding of cDC2 functions, particularly Th2-priming cDC2s, is still insufficient. The intestine is a productive tissue for the study of cDC2 functions; it contains more cDCs and T cells than any other organ system. We have established techniques for purification and functional analysis of bona fide migrating intestinal cDC2. We have performed microarray analyses of both types of cDC2s (CD11b+ single-positive cDC2 and CD11b+CD103+ double-positive cDC2). Both cDC2 populations prime Th2 responses in vivo after stimulation with SEA. We found only three genes that significantly change their expression in both SEA-stimulated cDC2 populations. Our RNA sequencing data confirm that these genes are expressed by cDC2s in the small intestine, lymph, and intestinal lamina propria. Two of the three genes (Rasgrp3 and Il1f9) are known to control cytokine production by myeloid cells, but neither has yet been ascribed a function in cDCs. Here we have two aims. First, we will investigate the functions of Rasgrp3 and Il1f9, to understand how they contribute to cDC2s ability to prime Th2 responses, both in vitro and in vivo. Second, we will deliver labelled antigens in vivo and generate single-cell sequencing data to identify clusters of genes expressed by the few activated antigen-carrying Th2-competent migratory lymph cDC2s, among the heterogeneous migratory cDC2. Thus, we aim to uncover novel molecular functions in cDC2, that will enable improved manipulation of the adaptive immune response, both in the intestine and in other tissues.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_19733,Wellcome Trust,,Molecular origin of non-disjunction in human meiotic and early mitotic divisions,"In humans, pregnancy with the wrong number of chromosomes (aneuploidy) is common and the risk increases with maternal age, rising from ~2% for women under the age of 25, to around 35% for women over 40. Aneuploidy is a leading cause of early miscarriage, whilst affected full term births exhibit severe medical problems. Most aneuploidies arise from chromosome segregation errors that occur during the meiotic divisions of the oocyte or early mitotic divisions of the embryo. The next challenges are to determine the mechanisms of chromosome segregation in oocytes, to understand how high fidelity is ensured and to identify the origin of aneuploidies found in early human embryos. Work on model systems has identified adaptations to the kinetochore which direct and monitor specialized pathways of chromosome segregation during meiosis. However, the extent to which similar mechanisms function in human oocytes is unknown. Indeed, our recent work revealed unexpected properties of kinetochores in human oocytes, potentially contributing to the high error rate. We will perform a detailed examination of kinetochore behaviour in human oocytes and early embryos to gain the first insights into chromosome segregation at the start of life and uncover potential sources of error.","A specialized cell division called meiosis produces eggs and sperm. A high proportion of human eggs are faulty because they have the wrong number of chromosomes, particularly in older mothers. Fusion of such defective eggs with a sperm results in infertility, miscarriage, or diseases such as Down Syndrome. We aim to understand the mechanisms by which chromosomes are distributed into human eggs and to determine if their function is altered in reproductively challenged patients. Our team of clinical reproductive scientists and cell biologists will use advanced microscopy to examine fluorescently-labelled factors in human immature eggs as they undergo meiosis and in the first cell divisions after fusion of the egg and sperm. We anticipate that our work will provide a better understanding of the pathways that sort chromosomes into human eggs and inform future work to identify the causes of infertility.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_02839,Medical Research Council,MRC,Multi-modal assessment of liver grafts undergoing normothermic machine perfusion to stratify quality and deliver therapy,"The perfusion programme has three key linked aims and is a preclinical, experimental study whereby human organs will be normothermically perfused. Up to 40 livers will undergo normothermic perfusion during the three year period of the study. Access to human organs discarded from transplantation is already in place through national approval from NHSBT and ethical committees. In addition access to the national organ donation biobank (QUOD) will provide control tissue samples from organs that are transplanted and linked clinical data to establish correlation of the biomarkers with clinical outcomes. We will analyse whole organs and cell subsets looking for injury, senescence and cell death using an array of cutting edge technologies (e.g. proteinomics, cell free DNA, Raman spectroscopy, multiplex multi-sensing fiber optics) together with point of care biochemical analysis. Perfusate, tissue, bile and urine samples will be taken for analysis across the course of the perfusion up to 48-72 hours (or longer if perfusion technology allows it). Using MR spectroscopy and Raman spectroscopy we will assess changes in the liver structure during machine perfusion. The biliary cellular compartment will be assessed in real time continuously using in vivo multicore fibre based multiparametric multiplexed sensing which will be confirmed with traditional biochemical parameters to determine accuracy. We will use machine learning and informatics to analyse data generated and if organs are used clinically, we will link the experimental data with the clinical outcomes using the QUOD and NHSBT If organs are not used clinically, cell populations will be rested in vivo/vitro and additional data generated as feedback on the predictive ability of the assays used. These cell populations will then be infused in the liver during normothermic machine perfusion and effects assessed using the above assays.",,5.2 CELLULAR AND GENE THERAPIES;5.4 SURGERY,ORAL AND GASTROINTESTINAL HRCS22_22904,The Academy of Medical Sciences,AMS,Multidimensional transcriptomic analysis of tuberculosis granulomas to define pathophysiological mechanisms,"Tuberculosis (TB) has a huge global burden, killing 1.4 million people in 2019, and is caused by infection with Mycobacterium tuberculosis (Mtb). Despite the long course of standard anti-tuberculous therapy, treatment is not always successful, often leading to drug-resistant TB. The host response to Mtb plays a key role in TB immunopathology, where a balance exists between protective and pathological processes. The granuloma is the key determinant of outcome in TB, where each granuloma consists of a macrophage-rich core and peripheral T cell / fibroblast layer. Great heterogeneity exists simultaneously between granulomas of each individual. The spatial organisation of these cell types with each other and surrounding extracellular matrix are emerging as critical determinants of granuloma formation and disease progression. My microenvironment spatial transcriptomic analysis of TB lymph node samples by laser capture microdissection has already demonstrated key pathways that differentiate TB from another granulomatous disease, sarcoidosis, and identified potential new therapeutic host targets in tuberculosis. However, greater resolution is needed to achieve cell-level expression data. These samples had been carefully selected, with all samples taken from patients who were naïve to antituberculous or immunosuppressing therapy. Complete spatial profiling of the same samples would allow full transcriptomic characterisation of the different cell types in the granuloma. Furthermore, integration of the spatial data with the cellular depth of single cell RNAseq data from human TB granulomas will provide unprecedented insights into events within TB granulomas.","Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) infection, killing millions of people each year. Prior to the COVID-19 pandemic, TB was the leading cause of death worldwide due to a single infection and deaths are increasing. Standard TB therapy consists of multiple antibiotics taken for at least six months, and is often poorly tolerated due to antibiotic side effects. Despite completing the full course of antibiotics, the treatment is not always successful. Our immune response to Mtb plays an important role in disease outcome, where either insufficient or excessive response causes harm, yet this process is incompletely understood. Therefore, finding medicines which alter specific immune responses are likely to benefit TB treatment. New technologies allow us to study disease at a cellular level and we have shown how genes influence our response at the microscopic level. The 3-dimensional surroundings play an important role here, affecting the resulting severity of TB disease in each person. We have carefully selected TB samples from untreated patients and have studied this genetic information to identify potential new drug targets for TB treatment. More detailed analysis of these samples, taking into account the 3-dimensional cellular organisation, is likely to generate better understanding and more specific TB treatments. The same approach could be used to understand and better treat other difficult human conditions such as inflammatory diseases and cancer. Ultimately, promoting a balanced immune response in TB, together with antibiotic therapy, is likely to reduce treatment duration, reduce disease severity, and improve survival.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_02457,Medical Research Council,MRC,Multimodal profiling of inflammatory and immune cells to determine stage and treatment response in non-alcoholic steatohepatitis and type II diabetes,"Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, affecting 2/3 of people living with type 2 diabetes in Europe. For most patients, NAFLD is a benign condition, but a minority of patients develop non-alcoholic steatohepatitis (NASH) and liver fibrosis which can progress to cirrhosis, liver failure and liver cancer. Currently the only means of distinguishing patients with NASH and fibrosis from those who have uncomplicated steatosis is to perform a liver biopsy. It is neither convenient nor desirable to use this invasive and costly procedure to risk-stratify patients. Non-invasive markers can help detect established advanced disease, but are not reliable at detecting patients with NASH and fibrosis at risk of progression. One reason for the absence of a reliable biomarker is our incomplete understanding of NASH pathogenesis, which we will address in the current proposal. Our preliminary data using cytometry by time of flight to study peripheral blood mononuclear cells has shown an increase in cytotoxic CD8+ T cells and Th1 cells in patients with NASH and significant fibrosis compared to patients with simple steatosis or healthy controls. We hypothesise that adaptive immune cells, specifically pro-inflammatory T cells, play a pathogenic role in NASH. Single cell transcriptomics and downstream mechanistic studies will give us unique insights into the pathogenesis of NASH and inform biomarker selection and lead to novel treatment targets. We will: 1. Use cutting-edge CITE-Seq single cell RNA sequencing to determine type, activation status and clonality of T cells (and other immune cells), in liver, blood and adipose tissue sampled at the time of bariatric surgery from patients with type 2 diabetes, obesity and fatty liver. 2. Determine function of T cell subsets identified in Objective 1 in in vitro models of lipotoxicity and fibrosis. 3. Determine effect of treatment-induced NASH resolution on T and other immune cells.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM;ORAL AND GASTROINTESTINAL HRCS22_05078,Department of Health and Social Care,NIHR,Multimorbidity in children with HIV and severe acute malnutrition in sub-Saharan Africa,"Background One-third of children hospitalised with severe acute malnutrition (SAM) in sub-Saharan Africa have HIV infection (HIV-SAM). Children with HIV-SAM have 3-fold higher mortality, slower nutritional recovery and a higher risk of relapse compared to children with SAM alone, despite current interventions. Mortality following hospital discharge is predominantly driven by infections, compounded by poor nutritional convalescence. Moreover, children are discharged to homes characterised by poverty and multiple caregiver vulnerabilities. Addressing this complex multimorbidity requires a deeper understanding of the underlying biological and social pathways to inform new intervention approaches. Aims and Objectives Our aim is to define causal pathways underlying multimorbidity in HIV-SAM, and to develop and test multimodal interventions addressing the biological and social factors preventing convalescence. Our objectives are: Characterise the multimorbidity of HIV-SAM to identify tractable pathways for intervention. Develop multimodal packages of interventions for children with HIV-SAM. Test the effects of single and combined biomedical and psychosocial interventions on morbidity and mortality, and determine the cost-effectiveness and mechanism of action of the intervention packages. Methods Our interdisciplinary programme unites two networks of researchers in southern and east Africa and will be conducted in three stages. In Stage 1, we will leverage existing samples and data from each network to characterise HIV-SAM multimorbidity. We will use targeted and exploratory omics-based techniques to undertake molecular characterisation of HIV-SAM to identify tractable biological pathways for intervention. We will define the social and environmental determinants of HIV-SAM through in-depth qualitative research to understand the contexts in which child convalescence occurs. In Stage 2, we will develop and optimise intervention packages aimed at (i) preventing infections; (ii) improving nutrient bioavailability; and (iii) enhancing psychosocial support for caregiver-child pairs. In Stage 3, interventions will be tested in an adaptive clinical trial in Kenya, Zimbabwe and Zambia. We will recruit 732 children with HIV-SAM at the time of hospital discharge and randomise them to: (i) a double-sized control arm, (ii) anti-infection arm, (iii) nutrition arm, (iv) psychosocial arm, and (v) a combination of all intervention packages for 12 weeks. The primary composite outcome will be morality or hospitalisation by 24 weeks, with secondary outcomes of morbidity, growth, neurodevelopment, HIV viral load, CD4 count, and adverse events. Mechanistic sub-studies will define mechanisms of action for each intervention. Process evaluation and health economics evaluations will inform feasibility and cost-effectiveness of interventions. Timelines for delivery Stage 1 and Stage 2 will last 18 months. In Stage 3, trial enrolment will take 2 years, with 6 months of follow-up. Anticipated Impact and Dissemination Malnutrition and HIV impair child survival and human capital in high-burden countries. An effective package of care for children with HIV-SAM would reduce mortality, decrease hospital re-admissions and promote healthy growth and neurodevelopment. We will disseminate findings to participants through community advisory boards and caregiver meetings; to researchers through academic papers, policy briefs and media channels; and to policymakers through our partnerships with Ministries of Health and UNICEF, which will help to sustainably scale-up effective approaches.","Malnutrition in its most life-threatening form, severe acute malnutrition (SAM), can require hospital admission in children under 5 years of age to treat medical complications and regain weight. Up to one-in-five children die in hospital, despite the best available treatment, and one-in-ten die in the year after discharge. If children have both SAM and HIV infection (HIV-SAM), the risk of dying is three times higher, and there are long-term effects on learning, growth and risk of heart disease as adults. SAM and HIV affect multiple body systems, including metabolism, immune defence, hormone pathways, and gut function. Children leave hospital before all these systems are fully restored, meaning there is an ongoing risk of dying after discharge. Children also return to the same home environment, which is often complicated by poverty, caregiver depression, and poor engagement with medical care. We believe there is an urgent need to improve recovery in children with HIV-SAM after they leave hospital, by tackling underlying medical and social causes of ill-health. In this project, we bring together two networks of researchers from southern and east Africa with experience in HIV and SAM, to better understand how these two conditions interact in children. We will use stored blood and urine samples from children with HIV-SAM to pinpoint underlying problems in the body s immune and metabolic functions, to help us find “targets” for new medical treatments. We will also interview caregivers of children with HIV-SAM to understand the challenges they face once children leave hospital, including their own mental health, social support and ability to access care. We will then develop several new treatments for HIV-SAM. First, we will redesign the therapeutic food that children receive so that it is more easily digested; second, we will select antibiotics to give to children as they leave hospital to prevent infections, which are the leading cause of death; and third, we will provide social and mental health support for caregivers of children with HIV-SAM. Finally, we will do a clinical trial, which compares the new treatments (either alone or combined together) against the best current treatment, which is therapeutic food, anti-HIV drugs and an antibiotic called cotrimoxazole. We will compare how many childen die or get readmitted to hospital, and how children grow and develop, between the treatment groups. We will explore how well the interventions are taken up, and how cost-effective they are. At the end of this project, we hope to better understand how HIV and SAM interact to prevent children from thriving, and to have several promising new treatments for HIV-SAM. We will tell the communities involved in the research about our findings, as well as policymakers who make decisions about new treatments for HIV and SAM.",2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.1 PHARMACEUTICALS;7.1 INDIVIDUAL CARE NEEDS;6.1 PHARMACEUTICALS,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_23053,The British Academy,,Multiplication and sleep- does learning before sleep improve recall?,"Educators are becoming increasingly aware of the potential impact of sleep on learning. Studies show that learning new vocabulary before sleep, rather than in the morning, leads to better memory in children and adults. However, no research has investigated whether the same improvement generalises to learning numerical facts. Being able to fluently recall multiplication tables is a key skill associated with success in mathematics, but many children and adults struggle with this [1]. Timing learning prior to sleep could be a simple intervention to help. Firstly, we will investigate whether timing the learning of complex multiplication facts prior to sleep improves undergraduate students' recall. This study will serve as a proof of principle for future studies with simple multiplication facts with children. Secondly, a focus group with parents of primary school-aged children will explore parents' acceptability of learning of multiplication facts around bedtime.",,5.6 PSYCHOLOGICAL AND BEHAVIOURAL,NEUROLOGICAL HRCS22_02847,Medical Research Council,MRC,Multiresolution predictive dynamics of COVID-19 risk and intervention effects,"SARS-CoV2 is a novel virus, and even as new data improves scientific insight, many uncertainties remain about key aspects of transmission. Throughout the pandemic, mathematical and statistical models of COVID-19 have had an important role in the analysis of epidemiological data, in forecasting incidence trends and in assessing the potential impact of different intervention strategies. Models developed by the Imperial College COVID-19 response team have been particularly influential, but the absence of detailed data on transmission patterns have necessitated important assumptions that limit their predictive performance. This project will (a) extend predictive models of transmission trends to include complex spatiotemporal correlation to better capture new seeding events and improve early identification of hotspots of transmission, (b) understand the causal effect of interventions on transmission and the limits to which this inference is possible, (c) systematically collate and analyse data on transmission in specific contexts (households, schools, workplaces and care homes) to derive specific transmission parameter estimates for those settings to be used to improve the ability of models to predict the impact of targeted non pharmaceutical interventions, (d) Understand how important epidemiological parameters are changing with time and what is driving these changes. This work will directly support the Imperial team's input into the UK COVID-19 response via the SPI-M, NERVTAG and SAGE committees and our partnerships with PHE and the Joint Biosecurity Centre (JBC).",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_03114,Medical Research Council,MRC,"Multiscale modelling of progression in Parkinson's disease","Disease progression is a key feature of PD, defined in terms of pathology within a brain region (c.f., symptom severity) and the spread of pathology between regions (c.f., new symptoms). Progression is highly variable, and potential mechanisms span many biological scales: with differences in where the disease begins, pattern of damage across circuits, co-existing pathologies, abnormal neural dynamics, cellular vulnerability and organelle dysfunction all thought to contribute. This project aims to map the mechanisms of disease progression in Parkinson's disease (PD) across multiple biological scales, from cells to circuits, in the same individuals. Framing PD progression as differences in the cortical burden of disease (cortical dominant = fast; brainstem dominant = slow), we will identify individuals with extreme phenotypes of progression from an existing cohort to: (i) Define longitudinal changes in brain microstructure in vivo. (ii) Map the molecular and cellular dynamics using in vitro human models from the same individuals. (iii) We will integrate data (i) and (ii) to inform a deep generative model, where mechanisms at one scale-quantified via model parameters derived from experimental measures-provide information used by the next. This will characterise how these pathophysiological mechanisms at different scales interact to result in the clinical syndrome observed. This program will deliver an open framework of integrated resources that can then be used in a translational setting.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_02923,Medical Research Council,MRC,Musculoskeletal functional ability in three diverse Sub-Saharan Africa Populations; assessing muscle strength & function to understand healthy ageing,"In sub-Saharan Africa (SSA) shifting demographics, rapid urbanization and associated lifestyle changes are generating an exponential rise in non-communicable diseases of ageing, of which musculoskeletal diseases are a significant proportion. There is an urgent need to reduce the time people spend living with locomotor disabilities and dependence, and to maximize functional ability amongst the growing ageing populations in resource poor countries in SSA. This proposal focuses on three countries, The Gambia, South Africa and Zimbabwe. Hypothesis: In the diverse ageing populations, high levels of adiposity and chronic infection with low levels of dietary diversity and physical activity are, in differing combinations, responsible for growing levels of sarcopenia and poor functional ability. WP1: What is the epidemiology of muscle strength, mass and function in each country? We collaborate with a team currently planning extensive community-based population prevalence surveys in The Gambia, Zimbabwe and South Africa. We have a unique and time-limited opportunity to add to these surveys. We will collect data from questionnaires, DXA scans, muscle strength and function, physical performance and blood tests. We will quantify musculoskeletal multimorbidities including sarcopenia and determine associations with disability and HRQoL. WP2: What are the clinical, nutritional and metabolic risk factors for low muscle strength, mass and function? Identifying risk factors for muscle impairment will aid understanding of mechanisms underlying muscle dysfunction. We will examine clinical, nutritional and metabolomic markers, and determine predictors of sarcopenia. Findings fed-back to local communities, national health leads and policy makers. This project grant offers a highly-cost effective opportunity, taking advantage of a funded research platform. This MRC investment would permit detailed and novel study of muscle in some of the most rapidly ageing populations in the world.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION,MUSCULOSKELETAL HRCS22_21044,Arts and Humanities Research Council,AHRC,"Museums, Crisis and Covid-19: Vitality and Vulnerabilities","The Covid-19 crisis is having a significant impact on the museum sector, nationally and globally. It is exposing the vulnerability of museums, their staff, projects and collections. Elsewhere, innovative programming is demonstrating the vitality and versatility of an engaged, responsive and participatory museum service, proving that museums are places of relevance even in a crisis. This research project focuses on how museums can continue to contribute to community resilience and wellbeing in a time of crisis. It addresses sector adaptability as it adjusts audience engagement and collaboration (such as new collecting practices, programming and exhibitions) in response to Covid-19. The differing responses during the Covid-19 crisis - in some museums staff were furloughed yet elsewhere they have been involved in responsive projects - uncovers deeper attitudes to the essential (or otherwise) nature of museum services. Going forward, this project will lead and inform the sector as it adapts to effective community-digital possibilities that still embraces new thinking in participation and engagement. Alongside this, the project evaluates how we adapt our practices to be mindful of audience diversity, digital poverty, and the isolation challenges for vulnerable audiences arising from Covid-19. Rising to that challenge this project: 1. identifies how museum pedagogy and practices must adapt to new audience needs; 2. explores possibilities for co-produced community-digital innovation; and, 3. investigates the offer museums can make to support community resilience during and in the aftermath of the Covid-19 crisis. The importance of this project lies in the following areas. Firstly, new knowledge about the understanding of the impact of Covid-19 on the museum sector in NI that will both inform the Department for Communities (DfC) and have national relevance. Secondly, by generating new thinking around the community-digital dynamic and leading innovation as museums adapt. Thirdly, understanding the new needs around community resilience and wellbeing, arising from Covid-19. The Museums Association's response to the Covid-19 enquiry described museums as vital in supporting communities, promoting community cohesion, enabling wellbeing, and reflection on significant public issues. Many of our museums work with vulnerable groups, who will remain cautious/shielding post lockdown e.g. the Dementia Friendly Programme (NI Museums Council). This project will investigate the impact of putting such programmes on hold, how they can be effectively adapted/reinstated, and make recommendations for immediate application/future planning.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,INFECTION;GENERIC HEALTH RELEVANCE HRCS22_06052,Department of Health and Social Care,NIHR,N-Tidal B personal respiratory monitor: an MHRA-notified non-interventional clinical and health economic study with asthma patients to generate the evidence for award of a Class IIB license.,"This registrational clinical study is an observational, longitudinal study which does not impact on patients' standard care pathways. A total of 140 patients with poorly-controlled moderate-to-severe asthma will be enrolled at two sites from out-patient asthma clinics, emergency admissions and primary care. The six-month study duration has been determined to ensure that sufficient asthma exacerbations are captured. The sample size has been determined to provide an accurate estimate of the sensitivity of the device in predicting exacerbations. It is estimated that up to 60% of exacerbations may be predicted by a warning signal from the device based on Tidal Breathing CO2 (TBCO2) change. Assuming a 95% confidence level, it is calculated that 93 exacerbations would be required to obtain an estimate to within ±10% of the true value, which is regarded as an acceptable level for the grant of a Class IIB medical device license. Previously collected data has suggested a mean of 0.79 exacerbations per patient in a six-month period. Thus, to ensure at least 93 exacerbations, a minimum of 117 patients are required. The total of 140 patients is based on 85% of the patients completing the study. Patient inclusion criteria are: (i) aged 7 years and over; (ii) a primary diagnosis of asthma; (iii) poorly-controlled asthma, at BTS Treatment Steps 3-5; (iv) patient or parent/legal guardian providing written informed consent. Patients who are unlikely to be able to comply with the requirements of the study or with other respiratory disorders will be excluded. The study will collect the following from each participant: Twice-daily short respiratory records of their TBCO2 waveform data for six months Records of asthma condition and exacerbations according to standard criteria via a phone-based thrice-weekly asthma symptom diary Clinical reviews and quality-of-life at two-month intervals On enrolment, patients will undertake a clinical assessment, lung function tests and pulse oximetry for correlation with their initial TBCO2 waveforms. They will also complete quality-of-life questionnaires. Participants will be provided with an N-Tidal B monitor to capture TBCO2 respiratory records twice-daily at home (morning and evening). Participants will breath normally into the device for a period of 75 seconds. The twice-daily records will identify both within-day and day-to-day variation in TBCO2 waveforms. Each patient will also visit the study sites at months 2, 4 and 6 (at study end), for clinical assessments, ease-of-use of the device, quality-of-life questionnaires and healthcare resource use. They will also be assessed by phone when the symptom diary and PEF is suggestive of an asthma exacerbation[References 21], or assessed in hospital if they require oral steroids/hospital admission. A sample of patients/carers will also be interviewed at the end of the study to discuss barriers/enablers to using the device. The outcomes of this programme will be: Refined asthma alert algorithm to be incorporated into the N-Tidal B. Efficacy, safety and technical evidence required for the grant of a Class IIB medical device license. Clinical papers for publication in respected peer-reviewed medical journals This study will take 30 months to complete, starting on 1-Nov-2018.","Asthma is the most common lung condition, affecting 5.4 million people in the UK. Many people with asthma suffer from breathlessness, chest infections and frequent hospital admissions. Currently, there is no way that people with asthma are able to monitor their condition easily and detect flare-ups early enough to take treatment and avoid going to hospital. As it is hard for people with asthma to know when their lungs are becoming more inflamed and not working as well, it is difficult for them to use their medicines at the right time to manage their asthma well. As a result, asthma leads to 60,000 emergency hospital admissions each year and results in over 1,400 deaths, the majority of which are avoidable. We have found that people with asthma breathe out a gas, carbon dioxide (CO2), in a different way to healthy people. The pattern of breathing out CO2 changes further when patients are having a flare-up of their disease. If patients could monitor their CO2, they may recognise when their asthma is getting worse, and take earlier action to avoid flare-ups getting out of hand and going to hospital. Cambridge Respiratory Innovations Limited is developing a low-cost hand-held device, N-Tidal B, for patients to monitor their asthma at home. This device measures the CO2 pattern when a patient is breathing in and out normally. In this research, we will provide 140 patients with asthma with a N-Tidal B device. We will ask them to breathe in and out of the device for 75 seconds in the morning and evening for six months, as well as keeping a diary of asthma symptoms, flare-ups and GP or hospital visits. This information will tell us which CO2 patterns best match up with their condition becoming worse, for example having more symptoms of asthma, needing to take stronger asthma medicines or going to hospital. The patients will not be able to see the CO2 pattern, but this information will help us decide which CO2 patterns should provide alerts to patients in the future, so that they can take earlier treatment and possibly avoid emergency visits to hospital. The study has been designed together with a group of patients, who will also design participant information and monitoring study progress. The results of this study will enable us to obtain approvals for the device to display alerts and to be available to NHS patients. With alerts, the device could help people with asthma detect and predict when they are becoming unwell, enabling earlier treatment, reducing the severity and length of flare-ups, prevent hospitalisation and improve quality-of-life. A device like this which reduces avoidable hospital admissions could save the NHS up to £21 million per year.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,RESPIRATORY HRCS22_05712,Department of Health and Social Care,NIHR,NHS productivity national assessment,"This work will be measuring the growth in the productivity of the English National Health Service (NHS) across financial years. Productivity is defined as the ratio of the total amount of outputs produced by the NHS to the total amount of inputs used. The higher the amount of outputs produced for a given amount of inputs, the higher the productivity. The NHS produces an array of diverse outputs in a number of different healthcare settings, e.g hospitals, which are included in our comprehensive measure, as well as adjusting, where possible, outputs for the quality of care and measures of success of treatments. NHS inputs include labour, materials and buildings/other assets. Assessing the productivity of the NHS is important in the current economic environment, as resource (financial) constraints are putting ever more pressure on the NHS to realise significant efficiency improvements. Producing annual estimates of productivity growth for the NHS will provide policymakers with a thorough assessment of the achievement of the NHS.","This work will be measuring the growth in the productivity of the English National Health Service (NHS) across financial years. Productivity is defined as the ratio of the total amount of outputs produced by the NHS to the total amount of inputs used. The higher the amount of outputs produced for a given amount of inputs, the higher the productivity. The NHS produces an array of diverse outputs in a number of different healthcare settings, e.g hospitals, which are included in our comprehensive measure, as well as adjusting, where possible, outputs for the quality of care and measures of success of treatments. NHS inputs include labour, materials and buildings/other assets. Assessing the productivity of the NHS is important in the current economic environment, as resource (financial) constraints are putting ever more pressure on the NHS to realise significant efficiency improvements. Producing annual estimates of productivity growth for the NHS will provide policymakers with a thorough assessment of the achievement of the NHS.",8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_04450,Department of Health and Social Care,NIHR,NIHR Applied Research Collaboration - North East and North Cumbria (ARC NENC),"Over the last nine months, we have embarked on an extensive and transparent process of stakeholder engagement, Care System mapping and research prioritisation work. This was informed by our pre-existing detailed regional knowledge of unmet health and care needs and related national policy. Over 300 individuals contributed views including CEOs, practitioners delivering health and social care, commissioners, academics, and adult and youth members of the wider public. Notes were collated and analysed via Word-cloud software and thematic mapping, to identify eight research priorities. These priorities were fed back to a large meeting of over 100 stakeholders (13/06/18). We also ran three Public Engagement events to discuss our process and findings – these were with two adult panels (in Newcastle and Teesside) linked to Voice, our PPI/PPE network, and a Young People s Advisory Group workshop (YPAG). At all events, we sought views on our vision, aims and objectives, priorities and planned mode of working. Finally, our priorities were discussed with the CEO of our emerging Integrated Care System (ICS) and the Medical Director of NHS England (NHSE) (Cumbria and North East) which confirmed that they aligned with regional priorities. Thus, we are confident that our strategy is based upon the needs of our population and Care System, and aligned with the region-wide whole system research strategy recently launched by AHSN NENC (http://www.ahsn-nenc.org.uk/wp-content/uploads/2018/08/RESEARCH-STRATEGY-FOR-NENC.pdf). Our vision is to achieve: Better, fairer health and care at all ages and in all places . We aim to develop and sustain a regionally engaged and responsive network of clinicians, public health and social care practitioners, policy makers, commissioners, VCS providers, lay members and researchers who are all focused on applied research and innovation to prevent illness, improve care and sustainability, promote population health and reduce health inequalities. Our objectives are to: Develop region-wide principles of research, co-production and evidence sharing Promote intersectoral work across all our research infrastructures Build capacity in evidence generation and knowledge mobilisation Enhance capability via skill-building and access to experts in evaluation methods Enable public and patient partners to shape evidence generation and translation Conduct high quality applied research and implementation for priority health and social care issues Mobilise evidence to shape innovation with embedded process and outcome evaluation All research, knowledge exchange and implementation will be focused on our priority Research and Cross-cutting themes. Whilst these were developed through extensive consultation, they are not set in stone. Thus we will review priorities as work progresses and also as our Care System and local populations evolve. We have worked with partners in the Combined Sustainability and Transformation Partnership (STP) for the North East and North Cumbria under the leadership of CEO Alan Foster, which is an aspiring Integrated Care System (ICS), awaiting approval to proceed as an ICS in shadow form (estimated) springtime 2019. Our Research themes are: Multimorbidity, Ageing and Frailty (Multimorbidity) Supporting Children and Families (Families) Prevention, Early Intervention and Behaviour Change (Prevention) Integrating Physical, Mental Health and Social Care (Integration) Our Cross-cutting themes are: Inequalities and Marginalised Communities (Inequalities) Assistive Technologies/Data Linkage (Technology) Evaluating Change with Pace and Scale (Evaluation) Knowledge Mobilisation/Implementation Science (Mobilisation) We also have three enabling structures: a Public and Patient (PPI) strategy group; Implementation Advisory Group (IAG); and Training Network. Research Strategy Short (1-2 years) Recruit key administrative posts to successfully manage and deliver ARC NENC Finalise PPI strategy for the ARC in collaboration with the PPI strategy group Recruit 11 ARC fellows (one per theme; one each in partner university not leading themes) Recruit 22 PhD students linked to the Research Themes/Cross-cutting Themes Conduct work implementing 4 care pathways (Frailty, Back pain, Deteriorating Patient, Child Allergy) Run the first open funding call for research across the ARC Appoint 4 Knowledge Mobilisation Fellows through open competition across the care system Appoint an embedded Knowledge Mobilisation Fellow to specifically support national lead topic work Appoint 1 ARC/CRN posts to lead applied research delivery across NENC Plan a multi-modal communications strategy within and across the ARC Work with other ARCs on areas of mutual interest and/or complementary skills. Medium (3-4 years) Deliver early research projects to time and within allocated resource Refine knowledge brokerage activity and knowledge exchange resources Disseminate early findings through a range of media, including specific social media channels Run stakeholder workshops to re-assess research priorities Hold two more open funding calls for research across the ARC Develop further care pathways in conjunction with AHSN for roll out/implementation Review theme network membership against regional priorities and ongoing Care sector co-funding Implement the ARC PPI strategy and promote co-creation within themes Host a national conference on our proposed lead topic(s) Long term (5+ years) Review success to date with the emerging ICS, AHSN and ARC Stakeholder Boards Establish ongoing implementation plans to maintain sustainability of research implementation Produce a best-practice model of how to mobilise and implement evidence in local practice and policy Prepare for successor funding (and/or develop an ARC Sustainability plan) Continue disseminating emerging early findings through a range of media, including social media Lead an international conference/workshop on key areas of cross-ARC research and implementation Share via relevant networks new learning on applied research methodologies, data capture and implementation Partner with AHSN NENC in leading a whole-system review of our integrated regional research strategy Sustain capacity built in the care system (ARC Fellows, PhDs and internships/ training) through securing external research funding and permanent contracts within partner organisations. Measuring success During the first three months, Theme leads and the Executive Board will confirm measures of success and risk against their PPI-supported objectives and NIHR requirements: a framework of Care Outcomes including economic indicators; Care Delivery Indicators including economic indicators; Research Excellence including external grants; Public Involvement; Sustainability including capacity building; and Value including co-funding. This will be reviewed at all Executive and Stakeholder meetings. Progress across the ARC will also be reported on: Communication / Dissemination, Cross-ARC Collaboration and progress on care sector plans for Implementation. Metrics for a national role will be determined in conjunction with other ARCs and relevant national bodies.","The North East and North Cumbria covers a large geographical area but has a small population of under 3 million people. This region also has the highest rates of poverty (22%), unemployment (12%), poor health and early death in England. For example, premature cancer death rates are 25% higher in the North East than the South East, with particular hotspots in Middlesbrough and South Tyneside. Over 70% of our adults are obese or overweight, particularly in North and South Tyneside. For very young children, the highest rates of obesity are found in rural places like Cumbria. A third of people in the North East do no exercise, compared to a quarter in South East England and we have the highest levels of heavy alcohol use in the country. It is clear that we have much to do to improve the health of our population and provide care that helps people in this region have the same health outcomes as people in other parts of England. Despite this challenge, the North East and North Cumbria is one of just two areas in England without the earlier version of an Applied Research Collaboration (which have had £5-10 million over the last decade). We prepared for our new ARC by meeting with over 300 people in large workshops, smaller groups and individually. These conversations have taken place since November 2017, and have included a wide range of clinicians and other practitioners leading or delivering health and social care, as well as prevention experts, researchers, commissioners, volunteers, patients, carers and young people s groups. Key short and medium term priorities stood out during these discussions and have been included as themes in our proposal: care for vulnerable people, especially older individuals with more than one health condition (Multimorbidity); supporting children in early life (Families); keeping people well, rather than waiting to treat complicated health problems (Prevention); and tackling linked mental, physical and social problems together across organisations and near to where people live (Integration). There was particular concern for people living in deprived communities, including those living a long way from hospitals and health centres (Inequality). Many felt that new tools could be developed to help deliver better health and social care, including electronic or digital devices that produce information about people s state of health or their recovery (Technology). Lastly, many people felt that new treatments or ways to support people to remain healthy take too long to become available; they were keen for research to speed up (Evaluation) and for evidence to be used by those delivering care (Mobilisation). These eight research priorities form the basis of our plans going forward. We have assembled teams of researchers and practitioners who wish to work together with lay people to design, deliver and implement research that supports a long term aim of better, fairer health and care at all ages and in all places so as to minimise illness and reduce avoidable costs of care in our region.",8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_04433,Department of Health and Social Care,NIHR,NIHR Applied Research Collaboration Greater Manchester,"In April 2016, Greater Manchester (GM) took control of the £6 billion health and social care budget for its 2.8 million inhabitants. This new system, led by the GM Health and Social Care Partnership (GMHSCP), brings together the NHS, local authorities, charities, voluntary and community groups to transform the way public health and care services are designed, commissioned and delivered. These partners are our partners for NIHR ARC-GM. Health and care services are being redesigned around local communities, with greater emphasis on prevention, on closer integration, and on public health through greater alignment with other public sector services such as transport, housing, community development, and education. The population of GM has substantially worse health than most areas of England; for example the highest avoidable mortality rate, poorer healthy life expectancy, lower employment, and higher rates of smoking, long-term conditions and mental health conditions. GM also has a rapidly changing health and care landscape in which the devolved health and social care budget presents many opportunities for research. The health and care system faces significant financial challenges and research is needed to inform resourcing strategies and decisions. We have built our NIHR ARC-GM around these themes. Our strategy reflects this GM context and the priorities identified by GMHSCP from extensive engagement with the health and care system and with our diverse communities (via the GM Engagement Framework). The NIHR ARC-GM will be part of the GM health and care ecosystem, ensuring that its work is directly informed by the needs of both the local population and the health and care system. We will be hosted by Health Innovation Manchester (HInM), whose Board represents the GMHSCP, the GM Provider Federation, the GM Joint Commissioning Board, Local Authorities, universities and industry. These stakeholders also co-fund HInM and HInM works with them to create one integrated system which both supplies and demands innovation. The role of HInM is to accelerate innovations through evaluation and support the rapid implementation of those that are cost-effective and likely to contribute to wider economic gain (Figure 1). Our over-arching goal is to improve the health of the GM population and the quality and sustainability of the health and social care they receive. We will achieve this by co-producing excellent research in areas prioritised by the system and by enhancing its impact through supported implementation into policy and practice. Our broad research themes reflect the specific priorities of GM and resonate nationally; they will have enduring relevance and they reflect where GM has research expertise committed to making a difference in GM. Our research themes of Organising Care, Economic Sustainability, Mental Health, Healthy Ageing and Digital Health are complemented by cross-cutting themes of evaluation methodology and implementation science. We will ensure cross-fertilisation and synergy by ensuring each project connects a minimum of one research theme and one cross-cutting theme. In moving from CLAHRC to ARC we have moved from doing implementation towards supporting and researching implementation in order to enhance the embeddedness and sustainability of evidence-informed change within the local health and care system. Co-production is at the heart of our approach; that is researchers, practitioners and the public working together throughout the entire research process, because we know that this makes the uptake and impact of research more likely. We will work with our partners to translate their strategic priorities into answerable research questions, ensuring that co-produced research is relevant, useful and applicable to local service needs and achieves impact on policy and practice within GM and beyond. Within 6 months we will: Embed within HInM; establish our core infrastructure, monitoring procedures and governance structures; inform HInM s implementation strategy. Develop ways of working with partners, the public and communities across GM; establish ARC-GM s position within GMHSCP and HInM consultation and prioritisation processes. Deliverables: joined-up systems; co-development of a theoretically- informed, evidence-based implementation strategy for HInM. Short-term objectives (0-2 years): Establish our public and community involvement, engagement and participation (PCIE) panel and co-produce terms of reference and a full PCIE strategy; ensure research themes have meaningful and appropriate plans for PCIE. Deliverables: an effective PCIE strategy with PCIE embedded in each theme; Establish our five research themes with engagement of local organisations and communities; co-produce excellent, relevant research. Deliverables: research and outputs progressing against milestones; demonstrable involvement and engagement in shaping the research; undertaking planned dissemination; Establish research capacity building. Deliverables: Five PhD students competitively recruited and integrated into research themes; a comprehensive GM NIHR Academy Members' and Associates' Network of pre-doctoral, doctoral and post-doctoral students and early career researchers; Begin collaborative research with other NIHR ARCs in areas of ageing and frailty, mental and physical multimorbidity, health economics and knowledge mobilisation. Deliverables: Joint projects underway; an area of national ARC leadership established; Work with the GMHSCP to develop the evidence to support the case for further devolution from 2021. Deliverable: research evidence integral to the case and wider learning for ICSs with embedded innovation systems. Medium-term objectives (3-4 years): ARC-GM will be a high-performing research and implementation partner in GM, with a reputation for providing relevant, actionable research in high priority areas; Co-produced research will have produced knowledge being actively implemented; Our implementation science expertise will have influenced the roll out of innovation in GM; Ensure added-value by each research theme securing external funding for at least two new research projects; The work of NIHR ARCs nationally will be visible and influencing policy. Long-term objectives (5 years+): GM will be known internationally for integration of excellent research into the health and care ecosystem, and for the difference the research has made to NHS and social care planning, delivery and health outcomes; NIHR ARC-GM will have an effective implementation strategy adopted in GM and beyond; Sustainable funding of NIHR ARC-GM by GM partners, NIHR and other research funders; Research capacity increased including a minimum of five doctoral graduates with supported transition to postdoctoral status; Career advancement opportunities for NIHR ARC-GM early career researchers. Greater capacity in the health and care ecosystem to evaluate and implement sustainable innovations.","Although Greater Manchester has many strengths, people here have poorer health and die earlier. These are particular problems for disadvantaged groups. The organisations in Manchester have come together in the Greater Manchester Health and Social Care Partnership to tackle these challenges. In 2016, we became the first area to take charge of its £6bn annual budget for health and social care, taking control to better support local people. To make the right decisions, the Partnership needs accurate information at the right time and research can provide this information. Even more importantly, we must ensure this research is used. Our Applied Research Collaboration (ARC) will bring together researchers and health and care providers to do great research which can be used to improve health. The Partnership has created a new organisation called Health Innovation Manchester (HInM) which joins together researchers, the health and care system and other partners, such as industry. HInM discovers new ways of delivering care and getting them into practice. The Greater Manchester ARC will be part of HInM, to help meet this goal. What will our new ARC do? First, everything we do will involve working closely with patients, the public, professionals, charities and industry, to ask the right questions and give useful answers. Second, we will draw on the wide range of expertise available locally to understand and address health problems and needs. Third, we will focus on doing high quality research around the needs of local people, and helping services make changes to care. We will focus on five themes, which we know are important in Greater Manchester: 1. How can we help older people stay healthy and happy for longer? 2. How can we organise services to better meet people s needs? 3. How can we prevent mental health problems and help people get and stay well? 4. How can we ensure that local services remain affordable in the long-term? 5. How can we use the latest technology to help achieve all this? All these questions are also relevant nationally. We will work with other ARCs on research and on spreading good ideas widely. We also have two themes to support all our work, exploring new ways to do high quality research, and developing new methods to help people put ideas into practice. What do we aim to achieve? In the first 1-2 years, we will work with all our partners, and with the public, patients and carers, to start the right research to solve local and national problems. Within 3-4 years, we will make a big difference to helping HInM achieve its goals, by doing high quality research and making sure the results are used, as well as supporting others to do the same. Within 5 years, we will be known as a leader in research that makes a difference to people s lives locally and more widely. Devolution means Greater Manchester is in a unique position to make a difference locally and nationally. Our ARC will be a major contribution to making that happen.",7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),MENTAL HEALTH HRCS22_04291,Department of Health and Social Care,NIHR,NIHR Applied Research Collaboration North West Coast,"Building on CLAHRC-NWC s legacy, ARC-NWC focuses on addressing the considerable health inequalities across our region. This requires inter-disciplinarity with wide engagement of residents working alongside the professionals planning and providing health and social care, and academics. Therefore we have further expanded our consortium of Universities, Health and Social Care providers, Public/Community Advisers, Charities, and Commissioners, enhancing responsiveness to diverse needs, to achieve step-changes in delivering evidence-based improvements in health and social care that address regional and national priorities and effectively reduce health inequalities. Initially we shall always systematically interrogate existing evidence, identifying areas of uncertainty or conflict, before undertaking new applied research or proactively implementing relevant research. ARC-NWC s infrastructure embeds co-production with Partners and full public participation within communities of learning and practice, supported by our academic resources. ARC-NWC will deliver high-quality applied research and implementation projects, strategically aligned through our Research Development, Delivery and Implementation Pipelines (diagrams 2&3), encompassing robust systems for co-conception/production/delivery and Partner prioritisation, mainstreaming health inequalities. This ensures our programmes are attuned to Partners priorities and the needs of the varied communities they serve, adapting to the challenges posed by structural change within the 10-year plan including Integrated Care Systems, Universal Personalised Care, the new GP contract and associated reorganisation. To ensure sustainable excellent innovation, we will concentrate on supporting small to medium-sized self-contained studies, cross-ARC programmes and pump-priming competitive collaborative applications for external funding. Our research themes have been co-produced with Partner and Public/Community Adviser involvement, and are supported by clear simple structures co-designed to facilitate involvement. Our themes address key challenges for health and care: personalised care complexity, population health, and place-based health systems. Cross-cutting themes have been chosen to apply academic excellence to support programme-wide activity. Our Implementation and Capacity-building team will ensure research findings inform changes to practice and policy to maximise health and care outcomes. Supported by the Innovation Agency, we will work with industry to drive regional economic growth. Objectives: Short-term We have widened our collaboration to include primary, social care and third sector providers, STP/ICSs and charities. This is occurring incrementally as new NHS and LA structures emerge and we target specific areas for increasing engagement, particularly in social care; it ensures we work with areas of greatest need, and builds on the expanding CLAHRC-NWC collaborations. We shall use the number of new collaborators (e.g. project participation and leadership, committee participation) and the development of a community of implementation champions across NHS and Local Authority Partners as measures of success. Refreshed governance arrangements and policies will be implemented from the outset. Theme Management Groups will be established, co-developing theme programmes prioritised according to standard criteria agreed across wider collaborations through the Public and Partner Fora. We will co-develop outlines for new partner-initiated projects through 2019 ready for ARC-NWC, as well as identifying CLAHRC-NWC work to continue, using our cross-cutting theme resources (see Themes Organogram). Integration of Public/Community Advisers from the outset, working with relevant ARC-NWC Partner staff and supported by core ARC-NWC academics, will ensure co-production. Prioritised outlines will be co-developed into full proposals, then reassessed including external peer-review (see Pipelines, diagrams 2&3). We will facilitate integration of equity across all of our work through the universal application of our co-developed health-inequalities toolkit (www.hiat.org.uk). Theme Management Groups will collate data on progress, successes, outcomes and impacts in their areas, and monitor co-production, Public and Community Involvement (P&CIEP). We will refresh Theme objectives annually. Building research skills within Partners, Public and Community Advisers is a key aspect of ARC-NWC s strategy. We will offer 25+ PhD and Masters Studentships, to be recruited from year 1; as will recruitment for our rolling programme of knowledge mobilisation internships (over 70 completed in CLAHRC-NWC). Progress measures will include the numbers and diversity of backgrounds of recruits, completion rates, policy/service impacts, publications where applicable, professional destinations, and in the case of the research interns, projects they then conduct within their employing organisations or communities. Prioritised implementation projects (see Implementation Pipeline diagram) will be supported through our evidence-based IMPACT programme, aligned to Innovation Agency and other health and care quality improvement structures. More detail is provided in our Implementation Strategy outlined below. We will collaborate with other ARCs from the outset to maximise synergies. We shall measure progress in joint working with other ARCs by the number of joint projects, grant proposals, associated activity, grant income and co-authored publications, BITEs and other outputs. Medium-term By year three we anticipate consistent Pipelines of co-produced research and implementation initiatives across all Themes. We will evaluate our processes and outcomes using our CLAHRC-NWC evaluation systems adapted in consultation with Partners and Public/Community Advisers. With the large variety of Partners and activities, ARC-NWC cannot be evaluated using traditional academic metrics alone. Some aspects of success can be captured by publications metrics arising from the collaboration, but that would fail to capture much of what ARC-NWC is trying to achieve– empowering our Partners and Communities to co-produce research and implementations far beyond academia. Therefore, in addition the Themes will also be evaluated by, for example, grant applications, BITEs, the flow-through to implementation and impacts, integration of co-production, P&CIEP, and Health Inequalities embedding. We plan a steady flow of external grant applications, awards and outputs arising from theme programmes Longer-term For sustainability we intend that ARC-NWC is engaged in a robust programme of increasingly externally-funded research with established Pipelines to widespread implementation. We will ensure Partner links with NIHR and regional infrastructures to support applied health research are sustainable through collaborative networking developed through ARC-NWC. Our aim is that rolling Research, Evaluation and Implementation cycles will be embedded within our Partners core expectations to ensure collaborative applied research and implementation is sustainable. The legacy of ARC-NWC will be not just the completed projects, associated outcome benefits and publications, but a co-ordinated, well-connected network of empowered organisations and communities, sustaining Organisational Excellence, with the skills and confidence to continue to co-produce externally-funded work relevant to local needs, targeting health and care inequalities delivering real, lasting change through applied research and implementation.","The North West Coast region faces stark health inequalities. Average life expectancy can vary across Local Authority areas/wards by up to 12 years; for average healthy life expectancy this can be up to 27 years. Simultaneously, there are significant barriers to translating discoveries in academic health research into practice which improves lives (Cooksey, 2006). The Applied Research Collaboration North West Coast (ARC NWC) brings together health and social care providers, NHS commissioners, local authorities, universities, public advisers, the Innovation Agency (Academic Health Science Network) and more to address these problems. It will support the development, delivery and implementation of research into practice, enabling real and positive change for patients and the public, with an overarching focus on reducing health inequalities. We build on the CLAHRCNWC legacy, a successful collaborative programme of applied health research and implementation which has run from 2014. CLAHRCNWC has established infrastructure, connections and novel methodologies to address major challenges in this area. ARC will be an evolution of CLAHRCNWC, strengthened by some of CLAHRCNWC s key outputs, and with a broadened consortium including Primary and Social Care, and the third sector. Co-production is key to ARC NWC; projects will involve and in some cases be driven by partners and the public throughout the research life-cycle. This ensures research is relevant to local communities needs, practical, and shortens the delay between generating research findings and putting them into practice. Our established Neighbourhoods for Learning, a novel approach established by CLAHRCNWC for deep involvement of communities – will ensure co-production. Health Inequalities will remain a core focus of our work, aided by the CLAHRC-developed Health Inequalities Assessment Tool (HIAT) which integrates public involvement and assesses whether activities could potentially deliver a reduction in health inequalities. The partnership has jointly chosen three research themes reflecting local needs. These are: Person Centred Complex Care , Improving Population Health and Equitable Place-based Health and Care . ARC NWC s cross-cutting themes will provide expertise and guidance to support research theme activity: Care and Health Informatics , Methodological Innovation Development Adaptation and Support and Health and Care across the Life-course . NIHR s investment, combined with significant matched resources pledged by partners, will grow infrastructure to support a varied portfolio of projects across each theme to support our aims. ARC NWC s aims are: Engage and involve organisations which have a role in, or connection to, health and care service delivery, across social, primary, secondary care, public health and third sectors. Embed public involvement and health inequalities in all our work, from idea generation to implementing findings. Further develop partners and local communities research and implementation capacities and skills. Develop a portfolio of high quality applied research which responds to health inequalities. Support and evaluate implementation of research findings that address health priorities, to increase the sustainability and resilience of health and social care systems, locally and nationally. Shorten delays between research needs being identified, studied, and findings implemented. Ensure broader economic gains through increased research investment regionally. Collaborate with other ARCs and NIHR infrastructure to address national priorities.",7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_04385,Department of Health and Social Care,NIHR,NIHR Applied Research Collaboration Wessex,"Mission: To improve health and well-being of people of Wessex across the life course targeting quality, safety, effectiveness and efficiency of health and care services by undertaking and supporting implementation of leading-edge applied health research for patient, community and population benefit. Focus: The NIHR Applied Research Collaboration (ARC) Wessex will bring together public and community, expert researchers from a wide range of disciplines, clinical leaders of health and care systems and other stakeholders. It will work across the Wessex health and care system to ensure local reach and national impact. It will provide fresh thinking, evidence and methods to enable health and care systems to become more effective at promoting health, improving quality of life and enhancing efficiency. Our work will stimulate and impact on system improvements and health and care reforms. ARC Wessex strategy: We will build on our strengths in applied health and implementation research and patient engagement, and focus on strategic priorities of the Sustainability and Transformation Plans (STPs) for Wessex providing a detailed case for change (Figure1). Our 3 themes together with a cross cutting theme (entitled health systems & workforce), (Figure 2), concentrate on components of care management and public health and address critical gaps in: health and well-being; care and quality; and finance and efficiency. Our research will meet the demands of, and reflect the diversity of, our local communities. Ageing & dementia: supporting independent living for people with complex health needs will test strategies to identify those with high treatment burden and promote self-management through technology and increased service users choice and control. It will introduce and evaluate organisational and workforce interventions to increase the capacity of teams to deliver safe and effective care and improve management of multi-morbidity. Healthy communities: improving public health across the lifecourse will implement and evaluate strategies to address childhood obesity, improve early detection and modification of diseases amenable to prevention, and identify people facing fuel poverty or alcohol misuse. Long-term conditions: integrating person-centred approaches to optimise healthy living will identify, implement and evaluate strategies and technology for self-directed support to support active living by establishing and embedding interventions that mobilise patient capacity and engage patients and communities to minimise crises. Health systems & workforce: supporting health and social care by improving service delivery will model, implement and evaluate methods to achieve pro-active management of demand for health and social care, reducing service fragmentation, and develop a framework for organisations to evaluate workforce implications of introducing healthcare innovations. Alignment of ARC aims with Academic Health Science Network (AHSN): Our strategy and objectives are closely aligned with the Wessex AHSN, seeking to speed innovation adoption across the region s health system to create a healthier population and a thriving economy. Our research themes connect with the AHSN priority areas of dementia, nutrition, medicines optimisation, reducing harm from alcohol, workforce and healthy ageing. Strategy for translating applied health research for patient benefit: The ARC's implementation strategy (Figure 3) involves building knowledge, skills and capabilities to ensure adoption-ready organisations. We aim to enhance capacity of workforce and health and care organisations to apply and embed evidence. This will be achieved by projects developing resources to support implementation and plans to enact these. Each theme will have clinical academics, public contributors and programme leads drawn from relevant STPs and CCGs. ARC Wessex has ambitious objectives to: Create a distributed model for conduct and translation of applied health research that links knowledge generators with knowledge adopters across Wessex and nationally. Generate, synthesise and implement evidence on care, organisational and technology innovations to enable efficient and sustainable services. Develop and evaluate behavioural, social and technological means to aid people to stay healthier for longer and take control of their own health and care. Develop meaningful, timely solutions to improvement challenges through application of operational research. Build local NHS, public health, local authority and related inter-sectoral capacity to implement evidence into practice and capacity to evaluate service change. We will deliver: Short-term (1-2 years) One Wessex ARC community, linked nationally: vibrant and connected interdisciplinary, multi-professional applied health research community responsive to patient and public voice. Early evidence: on workability and outcomes of introducing novel approaches to achieve health promotion, reduce service fragmentation and promote effective supported self-management. Medium term (3-4 years) Evidence of real world effectiveness: of tools to support pro-active demand management, digital applications to sustain healthy living and community engagement and interventions to promote voice, choice and control. Building workforce capacity: amongst the formal and informal health and care workforce and applied health research community to deliver sustainable person-centred care pathways and address complexities of healthcare delivery and diversity of patient experiences. Long-term (5+ years) A learning and collaborative system: where research outputs reach the right places, are used and make an impact on health and wealth agenda. Embedded person-centred approaches to health and care delivery: that reduce service fragmentation and treatment burden and build engagement with people with complex needs through better service (re)design and workforce management. How success of proposed ARC will be evaluated Alongside theme-specific metrics performance indicators will be developed, facilitating tracking of ARC progress against objectives including measures of: growth in capacity to conduct research that addresses local priorities, with national reach; production of practice changing research leading to better outcomes for patients and public and improved ways of working for local health and care organisations and workforce; growth in infrastructure to facilitate an “adoption” ready health system; evidence of adoption of ARC innovations to achieve health care improvement; community and public involvement and impact on research – from prioritisation, through conception, conduct, dissemination and implementation. Wessex ARC values In order to deliver our ambitious programme, our ARC will apply a set of values that resonate with our collaborating organisations: forward thinking health and social care for patient and public benefit, clinical academic excellence, respect for colleagues across the health and care system, openness and flexibility, and working collaboratively with a clear commitment to delivery.","Home to successful research organisations, Wessex is one of the busiest health research areas in England. ARC Wessex will work closely with these teams and build on success of CLAHRC Wessex. We will provide fresh-thinking, new knowledge and methods. This will promote health, raise quality of life and improve our ability to deliver health and social care services. We have three research themes: 1) Healthy Communities; 2) Ageing and Dementia; and 3) Long-term Conditions. Our research focuses on: Identifying groups of people at risk of preventable illness and those whose treatment plans take a lot of time and energy. Helping people stay healthy, stay well and remain independent by creating and sharing plans to support healthy living and self-management of conditions. Improving patient voice, choice and control over own health. Reducing the effort or burden of treatment faced by people living with complex health needs or long-term conditions. A Health Systems and Workforce theme runs across the three themes and focuses on: Providing methods to manage demand on health and social care and make services more joined-up. Making best use of NHS and social care staff to improve quality and effectiveness of services. Our goals are to: Work across research teams and service providers in Wessex and England to build research skills, produce new knowledge and use this to improve practice. Champion new approaches to person-centred care based on evidence. These will result in better health and care services which minimise patient effort, reduce waste and expense and can last. Support people to stay healthier for longer and take control of their own health and care. Develop meaningful answers to health and care challenges by using scientific methods to study difficult organisational problems. Strengthen Wessex s ability and skills to apply knowledge into practice in order to get benefit of our work. We will deliver: In 1-2 years: A united health research community which listens and responds to local public and community voice. Early signs of usefulness and results of introducing our approaches. In 3-4 years: Proof of how our approaches will work in the real world. A bigger community of staff better able to carry out and make use of research so we can improve healthcare. In 5+ years: New knowledge used to improve health of local population. Improved design of services and better use of staff to provide person-centred care. Our work will result in people who: Stay healthier for longer. Get better sooner. Have confidence to manage their long-term illnesses. Are treated as a person, not a collection of illnesses all treated individually. Receive regular, safe care delivered by staff with the right attitude and skills. Find their treatment requires less effort and can access joined-up services. We will work closely with everyone affected by our research, including patient and public communities. Our markers of success will be: More people doing research, with better skills. Better health results. Better ways of working. Seeing our findings used in real-life. Better public and community involvement with greater effect.",5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT),GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_04467,Department of Health and Social Care,NIHR,NIHR Applied Research Collaboration West,"The overall aim of NIHR ARC West is to engage its partners, and public contributors, in the conduct of collaborative applied health and care research to facilitate the implementation of research evidence and thus improve health and care outcomes. Its ethos is to focus on research and implementation that is equitable (fair), appropriate (providing optimal care at the right time and place for prevention or care), and sustainable (taking account of resource-use and future continuation). This will be delivered in ARC West by focussing on four key research themes identified as of crucial importance for the population in the West and nationally, and reflecting local health and care system priorities and substantive research strengths: Public health and prevention, Mental health, Integrated and optimal care, and Healthier childhoods. Each theme is led by a practising clinician or public health practitioner with strong research interests and clear understanding of the pressures of working in front-line clinical, public health and social care practice. Research and implementation projects in the four research themes will be delivered by ARC research staff, working closely with health and care practitioners and supported by academics with strong methodological expertise and experience of implementation and multidisciplinary applied health and care research in four cross-cutting methodological themes: Behavioural and qualitative science, Applied data science, Health economics, and Evidence. The cross-cutting themes will ensure the conduct of high quality research and employment of robust methods for implementation and evaluation. The identification of appropriate topics and delivery of outputs and impacts are enabled by the inclusion of Health Integration Teams (HITs) – a model unique to the West, developed by Bristol Health Partners and CLAHRC West to promote integrated care by bringing together all relevant stakeholders (see attached summary). HITs have worked across system boundaries to develop new patient pathways, introduce and evaluate service changes (e.g. increasing liaison psychiatry hours, teleclinics for kidney transplant follow-up), coordinate services in particular areas (e.g. dementia, sexual health), improve aspects of public health (e.g. increasing activity in older people, preventing child injury, improving neighbourhood environments), and support vulnerable groups (e.g. problem drug users, children with multiple adverse experiences). ARC West will employ this strategy to address the following objectives: Short-term objectives (1-2 years) are to: Work with our partners in the local health and care system, particularly STPs, ICS and WEAHSN, to implement evidence-based interventions, innovations and service changes in collaboration with HITs, and evaluate promising developments of local relevance scalable for national impact Participate in nationally-relevant evaluations of interventions with the AHSN national network to improve outcomes for patients and the public Increase public involvement in research and implementation, and collaborate with communities to better reflect the diversity of our population and its needs in our work Encourage the inclusion of quantitative, qualitative and economic evaluation whenever interventions are introduced in local health and social care settings Identify shared interests with other ARCs to plan collaborative research Ensure that existing evidence is reviewed and considered before ARC projects are initiated or implementation occurs Increase the understanding and use of research evidence in health and care practice, with additional support for allied health professionals Medium-term objectives (3-4 years) are to: Develop methods to integrate health and social care data to facilitate embedded evaluation of service changes and evidence implementation Develop methodological innovations to evaluate promising interventions for effectiveness and efficiency, and optimise health outcomes Develop understandings of the process of implementation and insights into how to make interventions more efficient through application of innovative methods Develop mixed methods evaluations for local or national implementation of digital platforms across our research themes in collaboration with the WEAHSN, other ARCs and HITs. Develop and evaluate effective and acceptable methods for de-implementation Long-term objectives (5+ years) are to: Develop the potential of integrated data from health and social care through linkage and triangulation resulting in more rigorous evaluation approaches, routine policy monitoring and improved patient outcomes. Participate in nationally-relevant evaluations of interventions and service changes with improved outcomes for patients and the public Ensure sustained implementation of effective and efficient interventions and services by working in partnership with local and national commissioners and service-providers The ARC research themes were chosen to reflect the needs of the population and health and care system priorities: Public health and prevention: to respond to the prevention agenda in STPs and to focus on areas of importance to public health practitioners Mental health: to address local concerns about high rates of suicide/self-harm and common mental disorders Integrated and optimal care: to reflect the requirements of the STPs/ICS in our area for service/pathway integration, increased efficiency and sustainability, better inclusion of social care, and to develop person-centre care for those with multi-morbidity Healthier childhoods theme: to prevent and reduce the impact of adverse childhood experience and to reduce the burden of and inequalities in common childhood illness We will monitor progress and measure success in relation to outputs, outcomes and impacts. Outputs will include publications, successful funding applications, wider adoption and roll-out, delivery and uptake of training, and number of co-funded collaborations. Outcomes will include number of successfully implemented interventions and/or evaluations, and value of co-funding for ARC research projects. We will measure impact as evidence of adoption of effective interventions (or de-implementation for ineffective interventions), inclusion in national guidance and attributable health improvement in patients and the population. The translation of research findings into improved health and care practice will be facilitated by the presence of practising practitioners as director, implementation lead, and research theme leads and the involvement of HITs that are fully embedded in the local health and care system. The successful implementation of effective and cost-effective prevention and care, more effective implementation of evidence-based guidelines, and the development of interventions to accelerate the uptake of robust evidence are ARC West s proposed methods for improving the sustainability of the health and care system and patient and the public outcomes.","ARC West is a partnership between the organisations and individuals that provide, plan and support health and social care in the West of England alongside the public that use these services and four local Universities, each with a world leading reputation in research to support better health and social care services and improvements in patient and public health. The “ARC” West Applied Research Collaboration has evolved from the “CLAHRC” West Collaboration for Leadership in Applied Health Research and Care. ARC West aims to ensure that the health of our citizens is as good as the best anywhere, and that the care they need is provided fairly and at the right time and place. We will support services that give value for money, are affordable in the local economy and effective in improving health and reducing health inequalities. These aims are focused on four broad themes, chosen because they are particularly important for people in the West and we have an international reputation for carrying out research in these areas. We aim to improve sexual health, reduce problems related to addiction to tobacco, alcohol and illegal drugs, and promote healthier lifestyles through the Public health and prevention of ill health theme. An Integrated and optimal care theme aims to enable joined up and improved person-centered care for people with multiple health problems and to ensure frail and older people are better supported in the community, reducing their need for hospital care. We have a Mental health theme to improve services for people with common mental illness such as depression and anxiety and reduce levels of self-harm and suicide, particularly in people facing economic hardship. Crucially, we have a Healthier childhoods theme, to focus on improving care for the most troubled and vulnerable children and families and providing better care for the prevention and treatment of common childhood illness. ARC West will achieve these aims by conducting the most relevant health-related research and by making the best use of information collected by public services. We will work with local Health Integration Teams (HITs). HITs include public health and NHS practitioners, scientists, and public contributors who decide which parts of health and healthcare systems need to be improved, and then carry out research to discover the changes that could make most difference to people s health and well-being. We will include public contributors in all our work and seek to attract new people to represent our local communities. There will be courses and other training provided to help health and care staff put research evidence into practice. At ARC West we have formed strong partnerships with health and social care leaders and decision-makers committed to using evidence effectively. Together with patients and the public, we will improve and re-organise services locally providing a blueprint for national service improvement. High quality research provides the clearest opportunity to improve health and care. We have developed the ARC West proposal to make best use of all our resources to improve health and well-being locally and nationally.",5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE;INFECTION HRCS22_04236,Department of Health and Social Care,NIHR,NIHR Bristol BRC,"The NIHR Biomedical Research Centre (BRC) Bristol is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. We will conduct innovative medical science research to improve health and healthcare, and encourage closer working with industry. We have world-leading scientists working on many aspects of health, from the role played by individual genes and proteins to analysing large collections of information on hundreds of thousands of people. We have extensive experience in taking science from the laboratory bench or computer and developing it into new drugs, treatments or health advice. This will make a real difference to patients, and attract new investment from research funders, charities and industry. What sets BRC Bristol apart is the strand of exciting and ground-breaking population health research that runs through it. This is about examing patterns of health and illness in large groups of people and we have particular expertise in interpreting this information to learn about causes of disease. Uniquely, we can combine this work with our laboratory-based science and the knowledge of the doctors working directly with patients to identify possible treatments and find out how effective they are. To make the most of this expertise throughout our BRC, we will have three cross-cutting themes. In Translational Population Science we will use sophisticated techniques to analyse not only the genetics of many thousands of participants in our studies, but also the microorganisms they live with, the proteins their body makes and changes to their DNA molecules that may be important in predicting disease. We will use this information to work out what factors might help prevent illness, predict how a disease might affect an individual and which treatments are most effective. Alongside this, the Biostatistics, Evidence Synthesis and Informatics theme will help our researchers use cutting edge approaches to organise and analyse different information types. Our Research Themes cover a wide range of clinical areas: Cardiovascular Disease: reducing complications and increasing the chance of survival for patients undergoing cardiac surgery. Infection and Antimicrobial Resistance (AMR): reducing antibiotic use, preventing the spread of infections and making vaccines more effective. Mental Health: predicting who is most at risk of mental illness and developing novel approaches to prevention and treatment. Musculoskeletal Disease: investigating how different treatments and lifestyle choices can improve arthritis and joint disease. Nutrition, Diet and Lifestyle: improving health by changing diet and exercise patterns. Perinatal and Reproductive Health: making IVF more successful, predicting and preventing birth complications, and understanding how the menopause affects health. Surgical Innovation: developing better ways to evaluate novel surgical techniques. Our Training, PPI and PPE Theme will ensure we ask patients and the public to advise us on what research we should do, how we should do it and what we should do with the findings. We want to develop future generations of researchers so we will have an extensive training programme, aimed at equipping the very best scientists, doctors and allied health professionals to carry out cutting-edge medical research.","The NIHR Biomedical Research Centre (BRC) Bristol is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. We will conduct innovative medical science research to improve health and healthcare, and encourage closer working with industry. We have world-leading scientists working on many aspects of health, from the role played by individual genes and proteins to analysing large collections of information on hundreds of thousands of people. We have extensive experience in taking science from the laboratory bench or computer and developing it into new drugs, treatments or health advice. This will make a real difference to patients, and attract new investment from research funders, charities and industry. What sets BRC Bristol apart is the strand of exciting and ground-breaking population health research that runs through it. This is about examing patterns of health and illness in large groups of people and we have particular expertise in interpreting this information to learn about causes of disease. Uniquely, we can combine this work with our laboratory-based science and the knowledge of the doctors working directly with patients to identify possible treatments and find out how effective they are. To make the most of this expertise throughout our BRC, we will have three cross-cutting themes. In Translational Population Science we will use sophisticated techniques to analyse not only the genetics of many thousands of participants in our studies, but also the microorganisms they live with, the proteins their body makes and changes to their DNA molecules that may be important in predicting disease. We will use this information to work out what factors might help prevent illness, predict how a disease might affect an individual and which treatments are most effective. Alongside this, the Biostatistics, Evidence Synthesis and Informatics theme will help our researchers use cutting edge approaches to organise and analyse different information types. Our Research Themes cover a wide range of clinical areas: Cardiovascular Disease: reducing complications and increasing the chance of survival for patients undergoing cardiac surgery. Infection and Antimicrobial Resistance (AMR): reducing antibiotic use, preventing the spread of infections and making vaccines more effective. Mental Health: predicting who is most at risk of mental illness and developing novel approaches to prevention and treatment. Musculoskeletal Disease: investigating how different treatments and lifestyle choices can improve arthritis and joint disease. Nutrition, Diet and Lifestyle: improving health by changing diet and exercise patterns. Perinatal and Reproductive Health: making IVF more successful, predicting and preventing birth complications, and understanding how the menopause affects health. Surgical Innovation: developing better ways to evaluate novel surgical techniques. Our Training, PPI and PPE Theme will ensure we ask patients and the public to advise us on what research we should do, how we should do it and what we should do with the findings. We want to develop future generations of researchers so we will have an extensive training programme, aimed at equipping the very best scientists, doctors and allied health professionals to carry out cutting-edge medical research.",4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),CARDIOVASCULAR HRCS22_05423,Department of Health and Social Care,NIHR,NIHR Global Health Research Group on Addressing Smokeless Tobacco and building Research capacity in south Asia (ASTRA) at the University of York,"Smokeless tobacco (ST) refers to tobacco products that are consumed without being burnt. Smokeless tobacco has historically been assumed to be less harmful than cigarettes; however, most ST products are highly addictive and are known to cause cancers of the mouth, pharynx and oesophagus, as well as leading to cardiovascular deaths and pregnancy problems._x000D_ The types of ST used worldwide vary greatly and products used in South Asia usually contain higher levels of cancer-producing chemicals than those used in Europe and the US. There are 300 million ST users in the world, with the vast majority (85%) living in South Asia. Despite almost 350,000 people dying every year due to ST-related cancers and other diseases, ST remains largely neglected by policy makers and researchers. Policies to reduce tobacco use are mainly based on research carried out on cigarettes and/or in high-income countries. Furthermore, most South Asian institutions do not have enough researchers or funds to carry out high quality research in this area. Based on the principles of equality and respect, we have set up ASTRA; a collaboration begun in 2018 between six leading UK universities, a WHO Global Knowledge Hub on ST and six institutions in Bangladesh, India and Pakistan. ASTRA is conducting world-class research to prevent ST-related deaths in South Asia. Our research is providing information on how to prevent young people from starting to use ST and how to help adults to stop using it. ASTRA is also helping to train and support new and existing researchers in South Asia, now and in the future. ASTRA’s research activities are guided by talking to stakeholders (people who will be affected by our research, including ST users, health workers, and policymakers). _x000D_ We have organised our activities into five work-streams, as follows: 1. ASTRA-Youth; assessing the impact of tobacco control policies on uptake of ST in adolescents: 2. ASTRA-Sellers; examining the implementation of tobacco control policies in the ST supply chain: 3. ASTRA-Cessation; evaluating interventions to help adults to quit ST: 4. ASTRA-Policy; measuring gaps in ST control policies, to inform policy makers; and 5. ASTRA- Economics; estimating the economic impact of ST use. Scientific evidence from the above studies will provide a sound basis for policy recommendations to improve ST control. Another key feature of ASTRA is to enhance capacity in applied health research in South Asia, and use this capacity to support wider tobacco control efforts in this region._x000D_ Since ASTRA began, we have set ourselves up as a strong international team, able to deliver world-class research on ST. Despite the global pandemic, our research studies are progressing well and we have been granted a one-year extension to enable us to complete them fully, and to maximise the impacts of our research. We have already published 14 articles and a factsheet, and launched a video to raise awareness of ST. We have also put ourselves in a good position to be able to apply successfully for Unit status and new funding for further large-scale studies.","The University of York (henceforth York) has an excellent research reputation and a vision to become a global leader in research - its key strategic objective. In its strategic plan (2014-2020), York is committed to expand its research activity and continue to build its international alliances and collaborations. The strategy states Research excellence defines York and further strengthening and improving our research, to be dynamic, inspirational and life-changing in its impact, is an absolute priority. Ranked 28th for International Outlook in the latest THE World University Rankings, York is ideally placed to respond to the global challenges of our time. York's seven research themes (https://www.york.ac.uk/research/themes/), including health and well-being, align its academic strengths with both the United Nation's sustainability goals and the four strategic objectives of the UK Aid Strategy (gov.uk). York's response to the Global Challenges Research Fund (GCRF) is ambitious. Supported by several recent grants (e.g. GCRF, European Union [EU], Research Councils UK [RCUK], Wellcome Trust) and strategic investments (posts, research office support, pump-prime funding), York's research in international development is thriving. Recently, York was successful in securing several GCRF grants in the fields of global health histories, tobacco control, environment, agriculture, human rights and biology. Consequently, York's researchers are already in partnership with communities across the global South and are addressing some of the world's most pressing health, environmental and social challenges. York has created a vibrant and multidisciplinary International Development Network (https://www.york.ac.uk/idn/). York has recently made a strategic investment by creating a Centre for Global Development, which will bring academics from different disciplines together to create innovative solutions to address key global challenges. York is now a growing hub for excellent global health research. Its research centres such as: Centre for Immunology & Infection (CII), Centre for Novel Agricultural Products (CNAP), York Environmental Sustainability Institute (YESI), Centre for Health Economics, Centre for Global Health Histories and Department of Health Sciences are bringing excellent researchers from diverse disciplines together to create innovative solutions to tackle global health challenges. Through its efforts, York is determined to leave a legacy for research in the UK and for its partners in the global South. York's excellence in research was recognised in the Research Excellence Framework (REF 2014), where York was joint first for its research environment. The impact of its research was ranked as predominately world leading (i.e. 80% 4*, 20% 3*). York was also rated 7th nationally in public health, health services and primary care. The University is also committed to Athena SWAN (current status bronze) and the Concordat to support the career development of researchers. The Department of Health Sciences host for ASTRA - has over 130 active multi-disciplinary research staff, including clinical academics in public health, primary care, health policy and mental health, which together position York as a premier provider of applied health research. Its six core research groups (https://www.york.ac.uk/healthsciences/research/research-in-healthsciences/) are poised to build on its established world-leading research excellence. The Department's annual research income exceeds £7m per year with a diverse portfolio of funders. York has been increasingly recognised as a global leader for its tobacco control research in South Asia. Over recent years, York has established extensive research collaborations within South Asia. These have led to the foundation of two research organisations in the region, the securing of competitive research grants of more than £10 million, the publication of more than 60 scientific papers and a significant research impact within tobacco control. In Pakistan and Bangladesh, York's commitment to build applied health research capacity has culminated in establishing The Initiative (http://theinitiative.org.pk/) and The ARK Foundation (http://arkfoundationbd.org/) research organisations with capacity to conduct large multicentre trials and a national reputation in tobacco control research. In response, the University of York has invested in two new posts; a Professor and a Lecturer in Global Health. ASTRA is harnessing institutional support from both within and outside its host Department. Within the Department, ASTRA is drawing upon the expertise of its six research groups; Cancer Epidemiology, Cardiovascular Health, Health Services and Policy, Mental Health and Addictions, Public Health and Society and York Trials Unit and Statistics. York's recent and significant investment in Mental Health and Addictions is helping to widen ASTRA's expertise in health psychology, addiction science, psychometrics (new appointments), and in understanding industries' interference in public health policy (Wellcome Trust's Senior Investigator Award). ASTRA's research is embedded within York's Trial's Unit (a NIHR recognised Clinical Trials Unit) - internationally recognised for conducting large and efficient trials in health and social care. ASTRA is supported by York's Centre for Health Economics (CHE), which has recently secured £8 million in grants from RCUK and NIHR to improve health systems and evaluate health policies in low- and middle-income countries (LMICs). We benefit from the infrastructure provided by York's Research Centre for the Social Sciences (ReCSS) for research and dissemination activities. To build and sustain its research activities, the group has taken advantage of several internal funding initiatives. For example: ReCSS network grants enable early career researchers (ECRs) to develop innovative and interdisciplinary ideas. The Centre for Future Health - a multimillion-pound investment by the University of York and Wellcome Trust - offers a variety of funding schemes to prime new ideas to address global health challenges. These include pump-priming, collaboration, career establishment and impact grants. York's ESRC Impact Acceleration Account offers support for knowledge transfer and fostering new and existing collaborations. We are also able to draw upon York's national and international links e.g. membership of the White Rose University Consortium, Russell Group and Worldwide Universities Network, which allow us to use a wider pool of experts, funds, and collaborations. We are driven by the NIHR/GCRF principles for global research partnerships to ensure equity and equality in priority setting. ASTRA is a result of York's efforts, spanning over several years, to bring together a group of scientists, policy makers and advocates from South Asia and the UK together to address priority research topics in tobacco control. At a two-day summit in York in 2013, our South Asian partners proposed the establishment of a consortium to advance research for strong and evidence-based policies to reduce use of ST(2) and agreed on key knowledge gaps.(3) These needs were reiterated in September 2017 in New Delhi at another meeting organised by the WHO Framework for Convention for Tobacco Control (FCTC) Secretariat and WHO Global Knowledge Hub on ST. Our research plan reflects priorities identified by our South Asian partners and stakeholders, and we retained scope to amend this following ASTRA's inception meeting and through planned stakeholder workshops in each country at the start. Through these workshops, and pre- and post-workshop surveys, we are sharing our research plans with stakeholders and co-create/refine our research questions and approaches.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),CANCER AND NEOPLASMS;CARDIOVASCULAR;MENTAL HEALTH;STROKE;GENERIC HEALTH RELEVANCE HRCS22_05147,Department of Health and Social Care,NIHR,NIHR Global Health Research Group on Adolescent Health and Wellbeing,"The UN Global Strategy for Women’s, Children’s and Adolescents’ Health (2015 – 2030) outlines how countries need to realise rights to physical and mental health and wellbeing in combination with social and economic opportunities to shape prosperous and sustainable societies. Embedded within the UN Sustainable Development Goals, and recognising national disparities, this strategy is especially pertinent to the adolescent population, as it is set against a backdrop of unparalleled global change, shaping the health and wellbeing of the largest population of adolescents in human history. Adolescence is recognised as a critical phase in life for achieving human potential, influenced by interaction with the social environment, shaping and supporting the acquisition of physical, cognitive, emotional, social, and economic resources which form the foundation for later life health and wellbeing, and influence future generations. Despite their key role in society, adolescents and young adults have until recently been overlooked in global health and social policy. This may be a key reason why fewer concrete health gains from economic development can be identified for them relative to other age groups. The literature points to a need for contextualised research that can inform intervention strategies to mitigate adverse conditions and nurture elements that can provide material and social protection and resilience for adolescents, enabling them to maximise their life chances. In Malawi, the setting for this research, despite some efforts there has been limited progress towards meeting the needs of adolescents (26.1% of the population). For example, programming intended to extend health services to adolescents remains problematic, with essentially no universal health coverage for the youngest age groups, adverse social norms that preclude the use of contraception before the first birth, and many service-side barriers in achieving ‘Youth Friendly’ health services. The current COVID-19 pandemic is also magnifying these challenges, and the impacted service provision in health and education sectors has had disastrous impacts on adolescents through school closures and exacerbation of poverty owing to economic shutdown._x000D_ With this backdrop in mind, our interdisciplinary group will use a socio-ecological model to focus on the health and wellbeing of adolescents in Malawi. We will take a multifaceted transdisciplinary approach to understanding the context of both urban and rural settings through a formative research phase, generating new knowledge on the best preventive and nurturing strategies for adolescent health and wellbeing. This formative work will support the co-creation, testing and evaluation of pilot interventions and prototypes in collaboration with adolescents, influencers, parents, and other sector stakeholders, building on established linkages and with full participation of youth through our engagement programme. Interventions will focus on (1) water, sanitation and hygiene, (2) gender, sexual and reproductive health rights, and (3) inspiring social and emotional wellbeing including mental health. These areas will be supported by an examination of policy and economic frameworks needed to support long term synergy of investments and real change. A key outcome will be to ensure more effective peer, parental and multisectoral support, and novel approaches to contextualise and trial multi-sectoral intervention strategies which can be taken to scale","The United Nations estimate that there are more young people (10-24 year olds) alive today than at any other time in human history, the majority of which live in low and middle income countries. Within these settings, adolescence is affected by the multiple health and wellbeing burdens that are exacerbated by poverty including HIV and other infectious diseases, undernutrition, and gender norms that underpin poor sexual and reproductive health, injury and violence, and non- communicable diseases. Despite this, adolescents are often the most neglected group in health care service provision, particularly those in early adolescence (10–14 years), a time considered critical in shaping their future lives. _x000D_ In Malawi, the setting for this research, despite social mobilization to prohibit child marriage, engagement of traditional leaders in moving away from unhealthy cultural traditions, and expansion of youth-friendly health services, there has been limited progress towards meeting the needs of adolescents. For example, national rates for completion of the full eight years of primary school remain low (44% male; 37% female). Adverse gender norms weigh heavily on girls and young women such that age-specific fertility for adolescents remains high, and there is an unmet need for family planning services. Programming intended to extend health services to adolescents remains highly problematic, with essentially no universal health coverage for the youngest age groups, highly adverse social norms that preclude the use of contraception before the first birth and many service-side barriers. Additionally, the current COVID-19 pandemic is magnifying the challenges for communities and for service provision in health and education sectors and has impoverished a whole generation of adolescents and limited their life chances. _x000D_ With this backdrop in mind, this interdisciplinary group will focus on the health and wellbeing of adolescents in Malawi. We will take an all round approach to understanding young people’s lives in both urban and rural settings through an extensive formative phase. We will undertake ‘co-creation’, testing and evaluation of promising approaches to some of the identified challenges in collaboration with adolescents, influencers, parents, and others active in development work. With a focus on (1) gender, sexual and reproductive health rights, (2) aspirations and wellbeing including mental health, and (3) water, sanitation and hygiene, work in these areas will be supported by an examination of policy and economic frameworks that are needed to support long term change._x000D_ We anticipate that our holistic approach to examining the lives of adolescents can bring immediate benefits, as well as benefits throughout their future adult lives and for the next generation of children. In order to achieve these aims we need to gain a clear understanding of the opportunities and barriers to adolescent health and wellbeing in low income settings such as Malawi, while recognising and examining important gendered, regional and rural-urban differences. A key outcome will be to ensure more effective peer, parental and multisectoral support, and availability of new approaches to bring forward and test new ways to mitigate adverse conditions and foster elements that can provide material and social protection, and resilience for adolescents, enabling young people to maximise their life chances.","5.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL;8.2 HEALTH AND WELFARE ECONOMICS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_05265,Department of Health and Social Care,NIHR,NIHR Global Health Research Group on Clean Energy Access for the prevention of Non-communicable disease in Africa through clean Air: CLEAN-AIR(Africa) at the University of Liverpool,"More than 3 billion people worldwide still rely on traditional solid fuel and kerosene, burned in_x000D_ inefficient stoves, to meet their everyday household energy needs. The resulting household air_x000D_ pollution (HAP) is the single largest environmental cause of global disease burden, responsible for 4.3_x000D_ million premature deaths annually, of which 3.8 million are caused by non-communicable disease_x000D_ (NCD). HAP also results in over 100 million lost healthy life years (DALYs) in lower-and-middle_x000D_ income countries (LMICs) from respiratory, cardiovascular diseases and cancer, as well as serious_x000D_ injuries from scalds, burns and (kerosene) poisoning. Burning of solid fuels also contributes to climate_x000D_ change, deforestation and the poverty cycle disproportionately affecting women and children._x000D_ Our previous research has been instrumental in highlighting the global importance of moving from_x000D_ solid fuel cooking technologies to clean fuels such as liquefied petroleum gas (LPG) to impact on the_x000D_ Global Burden of Disease (GBD) from HAP (including developing WHO Guideline Recommendations_x000D_ for indoor air). Research is needed to identify and overcome the challenges of achieving large-scale,_x000D_ equitable and sustained transition to clean fuels and to demonstrate the achievable impacts on health,_x000D_ household finances and the environment, to inform national policies._x000D_ The CLEAN-AIR(Africa) Research Group will address this research gap by working directly with_x000D_ Cameroon, Ghana and Kenya government ministries who have recently made ambitious_x000D_ commitments to scale-up household access to LPG by a significant proportion of the population. The_x000D_ Group will benefit from enhanced UK expertise and will engage with the health sector, research and_x000D_ academic partners in each focus country._x000D_ The Group has four primary goals:_x000D_ Goal 1: to inform strategies to support more equitable uptake of clean fuel across the population by_x000D_ evaluating enabling/ inhibiting factors and testing interventions to address identified barriers and_x000D_ facilitate equitable adoption/ use of LPG (including consumer finance solutions)._x000D_ Goal 2: to estimate the impacts of scaled LPG adoption, in line with governmental targets, on health_x000D_ and climate by using advanced statistical techniques, thereby providing evidence for_x000D_ national/international policymakers to advocate for widespread transition to clean fuel._x000D_ Goal 3: to develop capacity through health systems strengthening in the partner countries, equipping_x000D_ health practitioners to intervene early to ‘prescribe’ clean household energy solutions to their patients._x000D_ With support from WHO and our focus country health sector and academic partners, we will develop_x000D_ curriculum materials for upskilling the health sector about the health impacts of HAP and prevention_x000D_ through clean household energy adoption. Training will be delivered through routine continuing_x000D_ professional development and national training programs for health professionals (e.g. community_x000D_ health workers, nurses and clincians) and bespoke in-country workshops._x000D_ Goal 4: to facilitate engagement between the general public and policymakers as research is_x000D_ undertaken alongside national policy implementation. Informed by experience in Cameroon, the_x000D_ Group will host public engagement events in all three countries, bringing communities, ministry_x000D_ representatives, private sector and civic society stakeholders together to exchange knowledge on_x000D_ how best to achieve rapid transition to clean household energy to benefit population health and_x000D_ environments.","a) Building on strategic objectives of University of Liverpool (UoL): The CLEAN-AIR(Africa) Research_x000D_ Group builds on the UoL’s 10-year ‘Strategy 2026’, placing global activities at its core, with the_x000D_ strategic aim of being ‘a global university at the forefront of knowledge leadership’. This builds on a_x000D_ history of global concerns, dating back to the founding of the Medical School in 1835, tropical_x000D_ medicine and global public health being a particular focus, given the importance of Liverpool as a_x000D_ world trading port. Today, UoL has an international reputation in public health and health equity._x000D_ Expanding our global health research addressing non-communicable diseases (NCDs), maternal_x000D_ health and child mortality is a priority._x000D_ b) Why the institution is well placed: The Institute of Psychology, Health and Society (IPHS), headed_x000D_ by Prof Tom Walley, is ideally placed to support the Group and its aspirations. Its applied research_x000D_ was ranked third in the UK for impact judged as outstanding in Unit of Assessment 2 (UoA 2) in_x000D_ Research Excellence Framework (REF) 2014. It hosts a number of NIHR investments, including_x000D_ membership of the NIHR School of Public Health Research, with funding for applied health research,_x000D_ totalling £44m._x000D_ Since 2005, the Department of Public Health and Policy within IPHS has been designated a WHO_x000D_ Collaborating Centre for Policy Research on the Determinants of Health Equity (WHO CC), codirected_x000D_ by Prof Dame Margaret Whitehead and Prof Nigel Bruce. The WHO CC has built up a critical_x000D_ mass of researchers from a range of disciplines, addressing questions around the causes and_x000D_ solutions to health inequalities, and with a record of successful research training. The Group will draw_x000D_ on the skills of the WHO CC to enhance the world-leading theme on household air pollution, energy_x000D_ and health, led by Pope. These skills include social anthropology (led by Kierans); policy impact_x000D_ simulation modelling of preventive measures for NCDs (O’Flaherty); and the evaluation of health_x000D_ inequalities impact of natural policy experiments (Barr). IPHS will contribute 1 fully-supported PhD_x000D_ studentship._x000D_ c) Institutional partnerships and investments: We will work closely with our network of UK and_x000D_ International partners, built up over two decades, to produce policy-relevant research directly_x000D_ informing Government decision-making and build training and research capacity in the UK and in our_x000D_ LMIC focus countries. Existing partnerships include leading international research groups in_x000D_ household air pollution (HAP) and health, WHO (Environmental and Social Determinants of Health),_x000D_ experts in modelling climate impacts and global networks for the clean energy and health agenda_x000D_ (see Partnerships for details). Working directly with the health sectors of Cameroon, Ghana and_x000D_ Kenya (through partnerships with leading Universities and their Schools/ Departments of Public_x000D_ Health, WHO country offices and with support form WHO head office) we will develop sustainable_x000D_ health systems capacity through health professional education in household air pollution, NCDs and_x000D_ equitable approaches to prevention._x000D_ d) Involvement of partners in the research: Our LMIC partners comprise leading research institutions -_x000D_ Douala General Hospital (DGH - Cameroon), Kintampo Health Research Centre (KHRC - Ghana) and_x000D_ Stockholm Environment Institute-Africa (SEI-Africa - Kenya). Their established research_x000D_ infrastructures and networks are essential in supporting the Group’s research program and they will_x000D_ be involved in all aspects of the research program (e.g. through our steering committee meetings,_x000D_ team briefings and the public-stakeholder engagement events). Our collaborating partners from each_x000D_ institituion all have (i) extensive relevant research experience in household air pollution, noncommunicable_x000D_ diseases and prevention strategies and (ii) established health research networks and_x000D_ have the experience and expertise necessary to inform the strategic direction of the Group to achieve_x000D_ its goals. Our research programme compliments activities that our LMIC partners have been_x000D_ undertaking through their own institutions. In Cameroon our partner from DGH has led the Cameroon_x000D_ Burden of Obstructive Lung Disease (BOLD) Study (Wellcome Trust funding) and has coordinated_x000D_ both of the LPG Adoption in Cameroon Evaluation (LACE) 1 and 2 Studies (US CDC and NIH_x000D_ funding). In Ghana our partner from KHRC co-led the Ghana Randomised Air Pollution and Health_x000D_ Study (GRAPHS – NIH funding) and has since coordinated the Ghana Rural LPG Programme_x000D_ (USAID funding). In Kenya our partner leads a substantive research portfolio in sustainable_x000D_ development including a specific action agenda of “bringing clean, safe, affordable cooking energy to_x000D_ households across Africa”._x000D_ In addition to our research partners, we have engaged with leading academic insitutions in each of_x000D_ our focus countries who have (i) connections with our lead research institutions and (ii) strong public_x000D_ health departments and expertise. These include the University of Douala (Cameroon), the University_x000D_ of Ghana and Moi University (Kenya). Our academic partners are all highly experienced in the field of_x000D_ Public Health and in training medical students and health practitioners. Assisted by WHO country_x000D_ officers, they will lead in the development of training modules of HAP, health and prevention_x000D_ strategies within the health sector._x000D_ e) Involvement of the public in the research: Local users of our research include community members,_x000D_ leaders and in-country stakeholders and policymakers (e.g. ministry of health, energy and_x000D_ development) who will be involved through community-participtatory approaches (e.g. Photovoice),_x000D_ consultations, workshops, and our 2-way public engagement and stakeholder events that will be held_x000D_ in each country towards the end of the third year of funding.",8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),RESPIRATORY;GENERIC HEALTH RELEVANCE HRCS22_05145,Department of Health and Social Care,NIHR,NIHR Global Health Research Group on Digital Diagnostics for African Health Systems,"Research questions: _x000D_ 1. How does a lab-on-chip digital diagnostic perform under different use-cases in African healthcare settings and how can it be optimised for use? _x000D_ 2. How can digital diagnostics like this best be integrated into healthcare practice and policy in Africa?_x000D_ _x000D_ Background:_x000D_ Most of the population of Africa do not have access to diagnostic tests on the WHO essential list. Digital diagnostics have potential to transform this situation, enabling highly accurate diagnostics to be brought to where they are most needed. Digital diagnostics use lab-on-chip technology to detect analytes, generating, processing, storing, and transmitting digital data, with real-time connectivity, providing actionable results to the user and data for disease surveillance. We have developed a modular digital molecular diagnostic platform called Lacewing, which features the sensitivity of PCR in a handheld, easy-to-use, robust, rapid, and cheap, sample-to-answer format, suitable for point-of-need diagnosis in African healthcare settings. We have developed a series of tests for different diagnostic situations including detection of malaria parasites and other pathogens, and distinguishing causes of childhood febrile illness. Data from each diagnostic test is transmitted to a smart phone which provides the user interface and secure onwards transmission of data. _x000D_ _x000D_ Aims and objectives:_x000D_ To develop an evidence-base to support the development, implementation, and impact of digital diagnostic technology in African health systems, whilst training a cohort of African Digital Diagnostic Fellows who will be the future proponents of this technology. We will evaluate this in the context of the following use-case scenarios i) Malaria: community screening and clinical management; ii) Management of childhood febrile illness; iii) Environmental pathogen detect._x000D_ _x000D_ Methods:_x000D_ Formative research will involve situation analyses, user stories, focus group discussions (FGDs) and key-informant interviews (KIIs), which will be analysed using principles of human-centred design, the social-ecological model of behaviour and diffusion of innovation theory. Participatory co-design will be used for definition, ideation, prototyping, and testing, of Lacewing in different use-case scenarios. Diagnostic placement in health systems and potential impacts of digital diagnostics will be analysed and theory of change models developed. Diagnostic accuracy will be assessed against relevant gold-standard and commonly used comparator tests. Applications of data from digital diagnostics will be assessed using simulations and modelling based on data generated in prototyping and diagnostic accuracy studies and publicly available data._x000D_ _x000D_ Timelines for delivery: _x000D_ The project will run over 48 months_x000D_ _x000D_ Anticipated impact and dissemination:_x000D_ Through this pathfinder project based around a state-of-the-art, point-of-care digital molecular diagnostic device, we expect to generate multiple types of evidence to determine whether digital diagnostics would be feasible, viable, usable and sustainable solutions for high priority diagnostic gaps in Africa. Throughout the project we will involve users, stakeholders and policy makers, to ensure that the benefits of digital diagnostics have the best possible chance of being realized. By training a cohort of Digital Diagnostic PhD Fellows, we will establish increased capacity for digital diagnostic development, and adoption across Africa.","Aims of the research: _x000D_ We want to investigate whether a new type of diagnostic test, called a digital diagnostic, will be better than currently available diagnostic tests in African health care settings. We want to look at this in scenarios where there are important gaps in the availability, accuracy, or data collection from current diagnostic tests. These scenarios are: 1. detection of malaria parasites; 2. Cause of fever in young children; 3. detecting bacterial contamination of water and food. _x000D_ _x000D_ Background to the research: _x000D_ Making the correct diagnosis when someone is ill ensures they receive the right treatment and have the best chance of getting better. In rich countries it is taken for granted that when someone is ill, all of the tests that are needed can be performed to reach a diagnosis. In much of Africa, most people do not have access to essential diagnostic tests, either because they live too far away from the relatively few laboratories that can offer these tests or because they cannot afford them. As a result most treatment is based on informed guesswork of the most likely cause. This results in overuse of antibiotics and antimalarial drugs, which in turn favours the development of resistance. _x000D_ _x000D_ We have developed a digital diagnostic device, called Lacewing, which makes diagnoses by detecting tiny molecules from a drop of blood or saliva on the surface of a microchip and generates electronic signals. These signals are transmitted to a smartphone and give the user a diagnosis. Because the “lab-on-chip” does all of the work, the technology is very easy to use and enables very accurate diagnosis to be made by rapidly by a cheap, robust and fully portable handheld device. This means that the capability of an advanced diagnostic lab can now be taken to the patient. _x000D_ _x000D_ _x000D_ Design and methods used: _x000D_ We want to understand whether the Lacewing diagnostic will work properly, whether it will provide accurate diagnoses, and whether we can optimise it to give the maximum chance that it is adopted into practice in African healthcare systems. To do this, we need to fully understand the context in which it will be used, and understand the perspectives of all of those who might be impacted, from the patients and healthcare workers right up to ministries of health and international policy makers. We do this through different types of interviews and focus groups. We optimise the design of Lacewing in partnership with the intended users – so called “co-design”. We assess the potential impact on health systems to understand how other aspects of diagnosis and care might be affected. We compare accuracy of diagnoses using Lacewing against those of the best possible ""gold standard"" diagnostic tests, and also against any tests in common use in Africa. _x000D_ _x000D_ _x000D_ Community Engagement and Involvement: _x000D_ The involvement of community members, as potential end-users of the diagnostics, is central to the co-design process. Wider community engagement will be undertaken for the diagnostic accuracy studies to ensure that the research is appropriate and approved by the local communities. _x000D_ _x000D_ _x000D_ Dissemination:_x000D_ Dissemination is an essential component of our work. We want to share our results widely with communities in Africa, with policy makers, and with the commercial sector. We will do this using creative tools, videos and demonstrations, to raise awareness of the potential of digital diagnostics to transform health care in Africa.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING,INFECTION HRCS22_05161,Department of Health and Social Care,NIHR,NIHR Global Health Research Group on HIV-associated Fungal Infections,"Invasive fungal infections are a growing global threat to human health, affecting >150 million people and accounting for up to 1.5 million deaths per year. However, this burden is under-appreciated and medical mycology is chronically underfunded. Research into improvements in diagnosis and treatment and implementation of this research are essential to reduce death and disability. Four HIV-associated fungal infections - cryptococcal meningitis, talaromycosis, Pneumocystis jirovecii pneumonia (PCP), and histoplasmosis - are responsible for 250,000 deaths per year, and up to 20% of all HIV-associated mortality. The WHO has recognized that HIV deaths cannot be further reduced until these major complications of advanced HIV disease are effectively addressed. _x000D_ This proposal brings together a team of leading researchers, clinians, NGO partners (MSF and DNDi), and community and patient representatives, to improve the diagnosis and treatment of these HIV-associated fungal infections and ensure that these improvements are made widely available to the underserved populations most commonly affected in Africa (DRC, Mozambique, Guinea, Malawi, Botswana, South Africa), and SE Asia (Vietnam). Specifically, our partnership will:_x000D_ 1) Implement improved treatment for cryptococcal meningitis, building on the results of 2 landmark trials, ACTA and AMBITION-cm, completed by partners in this consortium, demonstrating improved survival with regimens that are practical and affordable in resource-limited settings. _x000D_ 2) Optimize the screen-and-treat strategy, to identify and treat early cryptococcal disease, before it becomes clinically apparent, in Africa. Semi-quantitative tests will be evaluated for cryptococcal antigen screening, and the PK of pre-emptive treatment with modified-release flucytosine determined. Screening will be evaluated to prevent talaromycosis, cryptococcosis, and histoplasmosis in SE Asia, and histoplasmosis and emergomycosis in Africa. The cost-effectiveness of pre-emptive therapies for cryptococcosis, and of combined screening for the 3 major fungal infections prevalent in SE Asia will be modelled. _x000D_ 3) Initiate a programme of earlier-stage, laboratory-based work on PCP, and develop a clinical cohort and sample bio-bank as a resource to develop and test novel diagnostic tests for PCP, which constitutes the major barrier to reducing PCP deaths. _x000D_ 4) Support a comprehensive training and capacity strengthening programme in clinical (epidemiology, health economics and/or public health), and laboratory research, and including 3 laboratory, MSc, 2 taught MSc and 3 PhD places. Training will be enabled by a recent strategic UK-African partnership based at the University of Cape Town (UCT) between the MRC Centre for Medical Mycology and UCT, and will build on our extensive experience of training and capacity strengthening within existing multinational projects. Our goal is to train and mentor clinicians and researchers who will help drive and develop this partnership beyond the initial 4-year period._x000D_ Our partnership will be equitable, with leadership shared across the work packages, insights from qualitative research, guidance from a community advisory board, and priorities set at initial meetings led by LMIC partners. In addition to the direct impact of the work, we will liaise with national, regional, and international bodies (MoHs, MSF and other major NGOs, UNITAID, WHO) in order to effectively scale the results and impact of our work.","Invasive fungal infections are a major threat to human health, but their importance is under-recognized. Research into improved diagnosis and treatment and their implementation are essential to reduce death and disability but have been chronically underfunded. Four fungal infections most frequently seen in people living with HIV - cryptococcal meningitis, talaromycosis, Pneumocystis jiroveci pneumonia (PCP), and histoplasmosis - are responsible for approximately 250,000 deaths per year, accounting for up to 20% of all HIV-associated mortality. The WHO has recognized that HIV deaths cannot be significantly reduced until these major complications of advanced HIV disease are addressed. _x000D_ _x000D_ This proposal brings together a team of leading researchers, clinical leaders, and NGO partners (Medecin-Sans-Frontiers and DNDi), as well as civil society and patient representatives, to improve the diagnosis and treatment of these HIV-associated fungal infections and ensure that these improvements are made widely available to the underserved populations commonly affected in LMICs in Africa (DRC, Mozambique, Guinea, Malawi, Botswana, South Africa), and SE Asia (Vietnam). We will implement early diagnosis and improved treatment for cryptococcal meningitis, building on the results of 2 landmark trials conducted by members of the consortium, demonstrating improved survival with regimens that are practical and affordable in resource-limited settings. Novel diagnostic and treatment strategies proven in cryptococcal disease will be evaluated in talaromycosis, a leading cause of HIV-associated fungal infection in SE Asia. Studies will test ways to optimize screening programmes for early manifestations of cryptococcosis, talaromycosis, and histoplasmosis, in order to identify and treat these infections before they become life-threatening. We will also initiate laboratory work and develop a clinical cohort in order to develop novel diagnostic tests for PJP, which constitutes the major roadblock to reducing PJP deaths. Promising diagnostic and therapeutic interventions will be subjected to health economic analysis and used to leverage future funding for definitive trials._x000D_ _x000D_ Priorities and detailed work packages will be defined in liaison with policy makers, clinicians, and patient and civil society representatives. In addition to the impact of the work in the countries where the studies will take place, our track records of partnerships with global and regional bodies (Ministries of Health, WHO, the Global Fund, PEPFAR, UNITAID, Southern African HIV Clinicians Society, MSF, other major NGOs, and civil society organisations) will enable the results of our work to be scaled for impact on a regional and global scale._x000D_ _x000D_ A pivotal component of the proposal is a comprehensive training and capacity strengthening programme in clinical research (with courses in epidemiology, health economics and public health), and in mycology, enabled by a recent strategic UK-African partnership between the MRC Centre for Medical Mycology and University of Cape Town (UCT). The training will build on our extensive experience of training and capacity strengthening within existing multinational projects, providing unique opportunities for young African and Asian clinicians and scientists to build careers in medical mycology. Our goal is to build an international coalition of clinicians and researchers who will continue to drive and develop this programme beyond the initial 4-year period.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.1 PHARMACEUTICALS,INFECTION HRCS22_05430,Department of Health and Social Care,NIHR,NIHR Global Health Research Group on genomic surveillance of malaria in West Africa at the Wellcome Trust Sanger Institute.,"DRUG AND INSECTICIDE RESISTANCE ARE ROADBLOCKS TO SUSTAINABLE MALARIA_x000D_ CONTROL IN AFRICA_x000D_ Malaria is a major cause of childhood mortality and socioeconomic disruption in Africa. Malaria_x000D_ control efforts have been ramped up over the past 15 years and this has made a significant impact,_x000D_ e.g. it has halved the number of deaths due to malaria. However there is a serious risk that these_x000D_ gains could be reversed in the foreseeable future, because Plasmodium parasites (that cause_x000D_ malaria) and Anopheles mosquitoes (that transmit the parasites from one person to another) are_x000D_ becoming increasingly resistant to malaria control interventions. In West Africa, the most immediate_x000D_ concern is the rise in Anopheles resistance to the insecticides that are used to treat bednets and to_x000D_ spray the insides of houses, which are absolutely crucial for sustainable malaria control in this region._x000D_ There is also worldwide concern about a new form of Plasmodium resistance to the first line_x000D_ antimalarial drug (artemisinin combination therapy or ACT) that is rapidly speading across Southeast_x000D_ Asia, and while there is no evidence that this has yet spread to West Africa, it is an incipient threat_x000D_ particularly in northern parts of the region where the ecological conditions are ripe for resistance to_x000D_ take root._x000D_ WHY WE NEED TO START PUTTING IN PLACE MODERN GENOMIC SURVEILLANCE SYSTEMS_x000D_ It is essential that national malaria control programmes (NMCPs) have effective tools to monitor_x000D_ resistance, both to know what are the best drugs and insecticides to use, and also to provide early_x000D_ warning that their interventions are causing resistance to rise to dangerous levels, indicating the need_x000D_ for a change in strategy. However current methods of monitoring drug and insecticide resistance are_x000D_ cumbersome, time consuming and not always accurate. Over the past few years there have been_x000D_ major technical advances in genome sequencing as a surveillance tool for antimicrobial resistance in_x000D_ other infectious diseases, and this is rapidly becoming the standard method used in UK public health_x000D_ labs. There are many technical challenges in getting this to work for malaria parasites and_x000D_ mosquitoes, but we now have proof of concept in our UK research lab and it is time to start putting_x000D_ these systems in place in Africa._x000D_ WHAT WE AIM TO ACHIEVE WITH THIS FUNDING_x000D_ We will establish laboratory and computational systems for genomic surveillance of malaria at the_x000D_ University of Ghana in Accra and the MRC Unit in The Gambia. These two sites have been selected_x000D_ because of their excellent laboratory infrastructure, their critical mass of scientific expertise, their_x000D_ strong links with NMCPs, and the many different challenges for malaria control in the two locations._x000D_ Once the technical systems are in place, we will work with local partners to optimise the pipeline for_x000D_ reliability, scalability and cost-effectiveness, and to learn how to integrate it most effectively into_x000D_ NMCP operations. We aim to learn how to translate genomic data into actionable knowledge, e.g. by_x000D_ providing early warning of newly emerging resistance, and by showing how specific interventions are_x000D_ causing levels of resistance to rise or fall. By the end of this project, we aim to have sufficient proof of_x000D_ concept to start integrating these systems into the routine working practices of NMCPs in Ghana and_x000D_ The Gambia, and to provide a working example of how such systems could be deployed at other_x000D_ locations in Africa.","BACKGROUND OF STRATEGIC INVESTMENT_x000D_ The Sanger Institute has played a pioneering role in genome research on infectious pathogens. One_x000D_ of the first genomes to be sequenced at Sanger was the malaria parasite Plasmodium falciparum, and_x000D_ in 2006 the Institute committed to a major programme of basic research on malaria, with the long term_x000D_ goal of translating this into new tools to control and eliminate the disease. Our 2016-21 quinquennial_x000D_ plan comprises five major scientific programmes in Cancer, Malaria, Infection Genomics, Human_x000D_ Genetics and Cellular Genetics. Sanger researchers have made seminal discoveries about how_x000D_ parasites invade human red blood cells, genetic resistance to malaria in African children, Plasmodium_x000D_ drug resistance, Anopheles insecticide resistance and other fundamental parasite biology. Sanger_x000D_ has also made an impact on malaria research worldwide through the large data resources and novel_x000D_ technologies that it has developed and made openly available to the research community._x000D_ From its inception, the Sanger Malaria Programme has worked in close collaboration with research_x000D_ groups in developing countries. Together with the MRC Centre for Genomics and Global Health at_x000D_ Oxford University, it serves as the resource centre for MalariaGEN, a data-sharing network of malaria_x000D_ researchers in more than 35 malaria-endemic countries (www.malariagen.net). Over the past 12_x000D_ years, MalariaGEN has established an international reputation for generating large open access_x000D_ datasets, which have become the benchmark for Plasmodium and Anopheles population genomics;_x000D_ for promoting equitable data sharing between researchers in rich and poor countries; and for research_x000D_ capacity building in malaria endemic countries._x000D_ STRATEGIC CASE FOR DECENTRALISATION_x000D_ This proposal represents a major shift in the way that we work with our collaborators in malaria_x000D_ endemic countries. When we started out on genome sequencing of Plasmodium parasites and_x000D_ Anopheles mosquitoes from field samples, there were massive technical and computational_x000D_ challenges to overcome, and both we and our collaborators saw it primarily as basic rather than_x000D_ applied research. It also required expensive capital equipment and infrastructure, and it made_x000D_ practical sense for the genome sequencing to be done at Sanger. There has been remarkable_x000D_ progress in all of these areas over the past few years, and it now makes both the economic and the_x000D_ technical for the genome sequencing done to be locally._x000D_ The case for decentralisation is in large measure a successful consequence of our past strategic_x000D_ investment. Having put in place the scientific foundations and developed much of the underlying_x000D_ technology required for genomic surveillance of malaria, we are now in a good position to translate_x000D_ this into practical tools and procedures that will help national malaria control programmes (NMCPs) to_x000D_ achieve their objectives. Making the transition from centralised to local genome sequencing is not just_x000D_ a matter of installing the equipment and training local staff, because genomic surveillance is one of_x000D_ the most rapidly growing areas of 'Big Data', i.e. the data generated by a local sequencing machine is_x000D_ greatly amplified in information content and practical value if it is part of a global data sharing network._x000D_ For example, if a new form of parasite drug resistance or mosquito insecticide resistance emerges_x000D_ elsewhere in the world, it will greatly help an NMCP to monitor and manage the problem if the_x000D_ genomic analysis software is continually updated to incorporate the most useful genetic markers,_x000D_ which are likely to have been discovered elsewhere. Therefore, as well as installing the equipment_x000D_ and providing training, it is crucial to build local leadership in the new science of genomic_x000D_ epidemiology, combined with mechanisms of sharing data across different sequencing labs. It_x000D_ requires the development of informatic systems to share data, and also the development policies and_x000D_ guidelines for international data-sharing that are acceptable to all stakeholders._x000D_ Through our work in coordinating MalariaGEN, we have considerable experience and track record in_x000D_ working with a wide range of local partners, but the transition from centralised to local genome_x000D_ sequencing is a game-changer. It will involve a learning process on both sides, i.e. we need to get a_x000D_ deeper and more detailed understanding of the practical problems confronting NMCPs, and NMCPs_x000D_ need to know about what new genetic approaches can potentially offer, so that we can work together_x000D_ to develop surveillance tools that will be useful and effective in the real world._x000D_ CHOICE OF LOCATIONS TO DO THIS PILOT WORK_x000D_ One of the strategic questions that we considered in formulating this proposal was how many partner_x000D_ labs to involve and where they should be located. Since we are actively collaborating with labs in_x000D_ many different countries on the ODA list there were multiple options. In view of the budget we decided_x000D_ to restrict it to two labs, as we think that a budget of ~£700k over 3 years is the minimum that will be_x000D_ required to get things up and running effectively and sustainably at a single location. Thus 70% of the_x000D_ £2m budget request will go to two labs in different malaria endemic countries. It should be noted that_x000D_ the ~£500k requested for work at Sanger will be used primarily for project management, training,_x000D_ informatic support and operational support; this will be underpinned by a substantial amount of R&D_x000D_ work to be undertaken by Sanger using its core funding from the Wellcome Trust._x000D_ The selection of Ghana and The Gambia as the two pilot sites was based on the following_x000D_ considerations._x000D_ 1. Developing two labs in different parts of the same region will help to build critical mass and regional_x000D_ cooperation._x000D_ 2. It will allow us to optimise surveillance tools for different malaria control use cases in a range of_x000D_ epidemiological settings, from holoendemic to near-elimination. Many parts of West Africa have_x000D_ extremely high malaria transmission, e.g. at our Navrongo partner site in northern Ghana, but there_x000D_ are also parts that now have very low transmission, e.g. in the coastal regions of The Gambia and_x000D_ northern Senegal._x000D_ 3. West Africa has rising levels of insecticide resistance, which have the potential to disrupt vector_x000D_ control. Resistance to artemisinin and partner drugs is currently not a problem but there is a real risk_x000D_ that it could emerge due to high levels of selective pressure at the fringes of transmission in north of_x000D_ the region._x000D_ 4. The University of Ghana and MRC Gambia both have excellent laboratory infrastructure, with_x000D_ suitable genome sequencing equipment (Illumina MiSeq) already in place. This will enable us both to_x000D_ benefit from and contribute to local know-how, and to get up and running as quickly as possible._x000D_ 5. The project will have outstanding local leadership and institutional support at both locations. At the_x000D_ Institutional level, Profs. Awandare and d'Alessandro are both renowned malaria experts. The two_x000D_ local project leads, Drs. Amambua Ngwa and Amenga-Etego, are among the most technically_x000D_ accomplished African researchers working in the field of malaria population genetics, with significant_x000D_ experience in epidemiological, laboratory and analytical aspects of proposed work._x000D_ 6. Once we have established proof of concept for genomic surveillance at these two locations, there is_x000D_ great potential to disseminate expertise and know-how to other labs through regional and Africa-wide_x000D_ capacity building networks: WACCBIP led by Prof. Awandare; PAMGEN led by Drs. Amambua Ngwa_x000D_ and Amenga-Etego; and DELGEME led by our close colleague Prof. Abdoulaye Djimde in Mali._x000D_ 7. The strong engagement of NMCPs is critical for the success of this project, and both in Ghana and_x000D_ The Gambia this project will build on strong foundation of NMCP partnership, and a great deal of local_x000D_ enthusiasm for the work proposed.",2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.1 PHARMACEUTICALS,INFECTION HRCS22_05436,Department of Health and Social Care,NIHR,"NIHR Global Health Research Group on stroke at King's College, London","Stroke is now the leading cause of death and disability from non-communicable disease in Africa._x000D_ Stroke is experienced earlier in life than in developed countries, affecting working parents with_x000D_ devastating financial consequences for families. In the UK, coordinated multidisciplinary care with_x000D_ national quality improvement initiatives, supported by the applicants, have significantly reduced the_x000D_ number of strokes and their impact. Sierra Leone is classified as a ‘Least Developed Country’ by the_x000D_ Organisation for Economic Cooperation and Development and as a ‘Heavily Indebted Poor Country’_x000D_ by the International Monetary Fund. There is no dedicated stroke unit and physiotherapists are not_x000D_ trained in Sierra Leone. The programme will improve the outcomes for patients and families in Sierra_x000D_ Leone following stroke within 5 years. It will bring together UK world leading stroke research and care_x000D_ expertise with an existing award-winning research and clinical partnership within Sierra Leone. The_x000D_ huge advantage of having an established partnership ‘King’s Sierra Leone Partnership’ (KSLP), is that_x000D_ administrative, governance and ethical review structures exist to manage the programme. Poor_x000D_ information is a barrier to good research and clinical practice. Stroke registers have demonstrated_x000D_ their value as a research and quality improvement tool in developed countries. The programme will_x000D_ collect the high quality data on stroke illness, care provision, needs and outcomes required to improve_x000D_ health care systems. There are an estimated 1,000 acute stroke admissions per year in Connaught_x000D_ and 34 Military hospitals. Research questions, particularly those around disability, quality of life and_x000D_ feasibility will be co-produced with service users and families. The applicants are very experienced in_x000D_ patient, carer and public involvement (PCPI). A service user led reference group works with the_x000D_ research team in South London and inputs at every level. The investigators will work together with_x000D_ stroke survivors and families to improve research and care processes. Wider stakeholder_x000D_ engagement will be built in and mirror existing successful quality improvement models in Sierra_x000D_ Leone. Plans to set up a stroke care pathway and stroke unit are underway already. Research training will be delivered at all levels_x000D_ including Good Clinical Practice (the international ethical, scientific and practical standard to which all_x000D_ clinical research is conducted). The model will build on partnerships within the UK and Sub Saharan_x000D_ Africa, namely stroke unit development support from Ghana. Community engagement with stroke survivors and their families will be a core part of the activity. _x000D_ The applicants are experienced in training and have many awards and positions of authority_x000D_ recognising their skill. Dame Caroline Leigh Watkins is a nurse and has used many innovative ways_x000D_ to train allied health professional research and stroke care skills. Professor Rudd as National Clinical_x000D_ Director for Stroke and previous President of the British Association of Stroke Physicians has_x000D_ developed stroke as a specialty and leads the national multidisciplinary guideline group and nation_x000D_ quality improvement audit for stroke. The project proposal is to build on an existing partnership and_x000D_ create a platform for further research. Strengthening the health system will aim to improve patient and_x000D_ family health within 5 years. The approach will be to work together in equal partnerships with PCPI_x000D_ input and respect for diversity and inclusion principles.","KCL GLOBAL HEALTH STRATEGY_x000D_ King’s is a global top 20 university and the ‘King’s Strategic Vision 2029’ is ‘to make the world a_x000D_ better place’. KCL has strengths in biomedical and allied health profession education and research,_x000D_ KCL recognised a need to cohere its global health (GH) activities, with a solid base and plan for_x000D_ investment and growth. The new King’s GH Institute (KGHI) is a focal point for King’s GH_x000D_ researchers, a mark of the institutional commitment, and provides expertise in research and education_x000D_ for the wider university. The inclusion of Kings Centre for Global Health within the School of_x000D_ Population Health and Environmental Sciences supports the strategy by bringing expertise together._x000D_ The strategy is “to focus on high value partnerships, where there is good research infrastructure and_x000D_ established collaborations with KCL that can be broadened and deepened; but also committing to_x000D_ long-term research capacity building with less developed partners with important need and potential”._x000D_ Our iBSc in GH, Public Health and MScs in GH, Global Mental Health, and GH and Social Justice_x000D_ attract 160 students annually. KCL plays a leading role in the South London CLAHRC (King’s Centre_x000D_ for Implementation Science coordinates implementation and QI research across health themes), and_x000D_ in two NIHR BRCs (GSTT/ KCL and Maudsley; clinical informatics and translational medicine). The_x000D_ School of Public and Environmental Health hosts the NIHR Statistics lead, the London Research_x000D_ Design Service, the CTU and the CRN. KCL hosts world leading research and clinical expertise that_x000D_ addresses all of the United Nation Sustainable Goal 3 targets, including non-communicable disease._x000D_ In line with the UK aid and international development strategy, the plan is to deliver outstanding_x000D_ applied global health research for the direct and primary benefit of patients, families and the public._x000D_ The focus of the work is the improvement of the management of non-communicable disease using_x000D_ stroke care in Sierra Leone as a model._x000D_ PARTNERSHIPS, STAFFING, FACILITIES, NETWORKS AND SUPPORT._x000D_ This application will build on an award winning partnership with Sierra Leone, King’s Sierra Leone_x000D_ Partnership (KSLP). King’s College, London (KCL) have invested in KSPL with in country academic_x000D_ and support staff. The Freetown team of 15 includes Dr Daniel Youkee (Country Director) , an_x000D_ education manager as well as five clinical academics, 2 research coordinators , 2 nurses and_x000D_ research support staff (operations manager, IT, finance, communications). In London, Dr Andrew_x000D_ Leather directs the partnership with help from skilled operations, partnership, financial and logistics_x000D_ support staff. KSLP actively support education through the College of Medical and Allied Health_x000D_ Science (COMAHS) and has strong government links._x000D_ The 2014-2015 Ebola epidemic has driven a renewed national and international commitment to_x000D_ strengthen weak health systems and led to ongoing redesign of the national strategic health plan,_x000D_ offering a vital opportunity to develop evidence based stroke clinical and preventative care in Sierra_x000D_ Leone and across the sub-region. We aim to develop centralised stroke services in Freetown and_x000D_ establish a stroke unit at Connaught Government Hospital and a stroke team at 34 Military Hospital._x000D_ The recent establishment of a national emergency services telephone hotline, a new ambulance fleet_x000D_ and the training of a new paramedic cadre provide a key opportunity to implement centralised stroke_x000D_ services in Freetown._x000D_ The work will widen the partnership to include world leading stroke researchers and clinicians (Wolfe,_x000D_ Rudd, Langhorne, Sackley, McKevitt, Watkins, Legg), scientists (Peacock, Fox Rushby) and other_x000D_ networks (World Congress of Physical Therapy, Lancet Neurology Commission for stroke in LMIC,_x000D_ Global Burden of Disease Collaboration (cardiovascular), the INDEPTH network, the European Stroke_x000D_ Organisation). The ‘vision’ is to establish a co-produced novel interdisciplinary research program,_x000D_ build research capacity and strengthen stroke care services._x000D_ KCL is supporting this application with a £100,000 towards PHD (or equivalent research training) and_x000D_ reducing overheads by £300,000, thus contributing £400,000 to the award._x000D_ CAPACITY AND CAPABILITY STRENGTHENING AND SUSTAINABILITY._x000D_ The programme will build on existing infrastructure and partnerships and will develop a platform to_x000D_ support further research and clinical quality improvement. It will incorporate methods that have_x000D_ produced step change in the care of stroke in the UK and learn from health systems change research_x000D_ experts based in Sierra Leone and in the NIHR KCL ASSET Global Health Unit. The programme will_x000D_ provide high quality epidemiological and health economic data, evidence based adapted guidelines,_x000D_ and staff training._x000D_ The programme will facilitate on-going projects such as the creation of a Stroke Unit in Connaught_x000D_ hospital with advice from Akpalu (Accra, Ghana). Once the Stroke Unit is established the project will_x000D_ develop a stroke team at 34 Military Hospital, to underpin the creation of a second Stroke Unit_x000D_ (beyond the lifetime of the study). The clinical pathways will strengthen the health system and we will_x000D_ provide stroke care training to the staff. The team has established expertise and resources plus_x000D_ knowledge of access to other opportunities, such as the stroke physician training programme run by_x000D_ the European Stroke Organisation (bursaries to LICs). In parallel, Sackley (Head of Academic_x000D_ Physiotherapy at KCL) will work with the College of Medicine and Allied Health Sciences (Freetown),_x000D_ Quartey (Ghana) and the World Congress of Physical Therapy to finalise the development of a BSc_x000D_ Physiotherapy._x000D_ The project will establish ‘research ready’ governance and ethical processes to support a research_x000D_ able work force The research infrastructure in KSLP will be strengthened through the appointment of_x000D_ research ‘network’ staff and the delivery of basic training such as GCP, consent and data_x000D_ management skills. A cadre of clinical (medical) academics will be developed through mentoring and_x000D_ access to Masters modules in research methodology, enabling at least one person to register for a_x000D_ PhD. More innovative approaches will be used for AHP clinical academics such as, funded_x000D_ secondments, online Masters of Public Health modules, internships, small bite research training and_x000D_ clinical networks with support from UK, Ghana and Rwanda AHP academics._x000D_ The programme will deliver sustainable change through research and clinical capacity and capability_x000D_ improvement. Patient, family and public engagement will lead into quality improvement in stroke_x000D_ services will be underpinned by changes in structure, management and monitoring of stroke disease._x000D_ Stroke guidelines and audit (mirroring the successful RCP Stroke Guidelines and UK Sentinel Stroke_x000D_ National Audit Programme) will be introduced towards the end of the programme. Evaluation of these_x000D_ interventions will take place in the next phase (i.e. beyond the lifetime of this award).",7.3 MANAGEMENT AND DECISION MAKING;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),STROKE HRCS22_05164,Department of Health and Social Care,NIHR,NIHR Global Health Research Group: Implementation of simple solutions to reduce maternal and neonatal mortality and build research capacity in Sierra Leone,"We propose to create an NIHR Global Health Research Group, focussed on reducing maternal and neonatal mortality in Sierra Leone._x000D_ Background to the planned research:_x000D_ In Sierra Leone (SL) 1 in every 17 women will die during pregnancy or childbirth; it is one of the most dangerous places to give birth in the world, with 40% of all maternal deaths occurring amongst teenagers related to poor access to care. It is widely recognised that many women die in pregnancy because the problem is recognised too late, related to late care-seeking behaviour, and treatment delay once admitted. In all of these instances, triage following simply monitoring could be lifesaving. Early recognition is required to allow timely management and treatment to be instigated before serious, irreversible complications or death. Unfortunately in SL, access and availability of monitoring equipment is challenging; Our aims are to:_x000D_ • To evaluate the impact of the CRADLE VSA, a novel monitor that detects blood pressure and pulse and calculates shock, with a traffic light alert, in a rural setting and to validate the use of other point of care (POC) technologies in the management of haemorrhage and sepsis; specifically the Shock Index (SI) readily available on the CRADLE VSA, and a POC creatinine device to detect acute kidney injury._x000D_ • Evaluate the impact of the 2 young lives intervention of mentorship scheme to teenagers, and the contribution hypertensive disorders make on teenage maternal and neonatal mortality._x000D_ • Determine the health economic benefit of implementation of the CRADLE VSA intervention through evaluating the costs of context specific process and impact on clinical outcome measures and define the necessary policy framework for the ultimate roll out of the optimal interventions determined in our current research. _x000D_ • Build junior research capacity through 3 local PhD students (in implementation science, health policy and economics), and incorporate research training into the National School of Midwifery’s curricula and mentoring a cadre of medical/midwifery academics through KCL Master’s modules in Public Health and Research Methodology. This will include working with the MoHS’ Quality Management Directorate to build the country's first PPI programme. UK Academics will mentor senior clinicians and build fellowship opportunities for health professionals, including through the NIHR Leadership Programme._x000D_ Methods_x000D_ 1) An evaluation of the CRADLE VSA in 8 districts (50% of the country) i.e. a rural setting, using pragmatic, stepped-wedge, type 2 hybrid implementation-effectiveness trial, implementing the adapted CRADLE intervention into the remaining 8 districts in Sierra Leone._x000D_ • A feasibility cluster randomised trial to evaluate the mentorship intervention on teenage mortality and other morbidities._x000D_ • Validation of the shock index and Cr POC technologies in high risk pregnancies to predict adverse outcomes. _x000D_ • A cost benefit analysis and subsequent adoption and policy pathway of all these interventions_x000D_ _x000D_ The trials will recruit, and complete data collection and report within the 36 month programme. The observational data in all validation studies will complete within these trials. The outputs will be published in high impact journals, and shared with relevant policy and other stakeholders nationally. We will disseminate at international conferences.","In Sierra Leone 1 in 17 women die in pregnancy. It is one of the most dangerous places in the world to give birth, with nearly half of the deaths occurring in adolescents, due to poor access to care. When a mother dies, her child is 10 times more likely to die within the first two years. We have shown that three quarters of women die from bleeding, infection or blood pressure problems, all of which can be identified by measuring blood pressure and heart rate, and are preventable with simple, cheap interventions. But Sierra Leone lacks monitoring equipment and training which means that women lack timely, lifesaving care._x000D_ _x000D_ In the UK, research underpins health policy and improves care, but in Sierra Leone there are no formal training opportunities to develop research leaders. Over 5 years, King’s College London, Ministry of Health & Sanitation and Welbodi Partnership have carried out discovery science in Sierra Leone. The CRADLE 3 study for example, showed that providing a portable blood pressure and heart rate monitor (CRADLE VSA), with early warning traffic lights, and training resulted in improved care and 60% less women dying around the main City, Freetown. The CRADLE device has been identified as a key strategy to reduce maternal and neonatal deaths but its implementation needs to be optimised, along with evaluation of other related novel interventions including:_x000D_ _x000D_ 1) Evaluation of the CRADLE VSA throughout the country, (where outcomes are worse and treatment most challenging), leading to earlier detection of women who are deteriorating secondary to common pregnancy related problems (Shock Index – also measured by the CRADLE VSA, and a test to identify kidney failure);_x000D_ 2) Introduction and evaluation of a mentorship intervention targeted to pregnant teenagers, to improve access to care and education, and to better understand how blood pressure problems affect the health of this group of pregnant women;_x000D_ 3) An evaluation of how cost effective it would be to introduce the CRADLE VSA and related interventions at scale in Sierra Leone, and the pathways to dissemination by government_x000D_ 4) Development of research capacity through supervision of 3 PhD students (in the area of implementation science, health policy and health economics), inclusion of research training into National School of Midwifery Curriculum and mentoring for medic/midwife academics, and creation of Sierra Leone’s first Patient and Public Involvement Initiative to give women and community members in Sierra Leone a new voice._x000D_ The primary aim of this NIHR Global Health Research Group is to reduce deaths of mothers and their babies in Sierra Leone. To do this we have created a programme of work in collaboration with our research colleagues and implementing partners in Sierra Leone in order to build new research capacity, which is currently underdeveloped, and to develop existing research projects related to the evaluation and implementation of novel life-saving interventions. We will publish in open access, high impact journals, and present our work at international conferences to disseminate our findings widely. Through equitable partnerships, with ongoing stakeholder engagement we hope to drive delivery of sustainable, evidence-based, effective maternity and newborn care.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.3 MEDICAL DEVICES;6.8 COMPLEMENTARY;8.2 HEALTH AND WELFARE ECONOMICS,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_05062,Department of Health and Social Care,NIHR,"NIHR Global Health Research Unit Action on Salt China (ASC), Queen Mary University of London","Salt reduction lowers blood pressure and reduces cardiovascular disease including strokes, heart attacks and heart failure. China is the largest developing country in the world. Salt intake in China is very high with an average daily intake of 12-14 g/d. Over 244 million Chinese adults had hypertension in 2012 and raised blood pressure attributed to 2.33 million cardiovascular deaths. _x000D_ _x000D_ To support China to reduce its population salt intake, the UK–China Collaboration Unit – Action on Salt China (ASC) has been set up, built upon an established collaboration between QMUL (Queen Mary University of London) and TGI (The George Institute for Global Health) China. The aim of ASC is to develop and implement a comprehensive, effective and sustainable salt reduction program in China. The goal is to achieve a 15% reduction in salt intake by 2021, and contribute to China’s commitment of achieving WHO’s target of 30% reduction of population salt intake by 2025. _x000D_ _x000D_ ASC has developed a strategic plan with a series of coherent programs including (1) health education to increase salt awareness; (2) community, school and family-based education programs to encourage individuals to reduce salt used at home; (3) reducing salt in restaurant meals; and (4) reformulation by setting salt targets for processed food, improving nutritional labelling and providing tools to help consumers to choose foods with less salt. Four cluster randomized control trials will be carried out in 6 provinces in 2018-2019, to test a series of salt reduction intervention packages targeting different settings and populations, and scale-up activities will be conducted in 2020-2021. Baseline, mid-term and final assessment of salt intake will be carried out through the gold standard method of 24h urine collection, to assess effects of the interventions. _x000D_ _x000D_ ASC will also launch public health campaign, to engage food industry, catering sector, media and the general public to reduce salt. The progress and outcomes of ASC activities will be delivered through ASC communication tools, including quarterly newsletter, website, press release, and through other communication approaches such as WHO bulletin and WASH (World Action on Salt and Health) website and social media. Research outputs generated from the project will be translated into population wide policies to ensure sustainability beyond the project duration. _x000D_ _x000D_ ASC is led by QMUL in UK and TGI (China), in partnership with several Chinese governmental organizations including three institutions from Chinese Centre for Disease Control and Prevention (China CDC) - Division of Health and NCD Control and Community Health (NCD Division), National Centre for Chronic and Non-communicable Diseases Control and Prevention (NCD Centre), and National Institute for Nutrition and Health (NINH); Chinese Centre for Health Education (CCHE) and China National Centre for Food Safety Risk Assessment (CFSA). _x000D_ _x000D_ A reduction in salt intake will benefit the whole population in China. ASC will deliver measurable health gains to many people. It will also make academic advances and deliver new scientific knowledge, which will benefit many Chinese researchers. The project commenced on June 1, 2017 and will be completed on March 31, 2021. The total amount awarded is GBP 6,607,474.","Global Health is a key area of focus at QMUL, supported by our internationally recognised medical research (we are ranked among the top 5 Medical Schools in the UK for Clinical Medicine and Population Health, 2014 REF); strong clinical expertise through our partnership with Barts Health NHS Trust; strong interdisciplinary teams across QMUL in Life Sciences (QMUL is ranked 9th among UK multi-disciplinary universities and a track record of productive international collaborations). Global Health is a key strand of QMUL’s Life Sciences Initiative (LSI), a multidisciplinary endeavour involving all three of our Faculties. QMUL is a leading health research school with extensive global health experience. _x000D_ _x000D_ Excessive salt intake is linked to over 1.6 million deaths globally each year, about 80% of which occur in developing countries[1]. WHO requires member states to reduce salt by 30% by 2025[2]. Average salt intake in China is high at 12-14 g/d[3]. Salt reduction will have enormous health benefits. _x000D_ _x000D_ The success of the UK’s salt reduction programme[4] was largely attributable to the work of CASH[5]. Following the success of CASH, WASH (World Action on Salt and Health)[6] was set up in 2005 with a mission of reducing salt globally. WASH has helped many countries develop a salt reduction strategy. _x000D_ _x000D_ CASH and WASH brought together broad expertise in nutrition and health (23 experts in UK and over 540 members from 100 countries) which will provide strong support to ASC. QMUL will provide scientific, infrastructure, personnel, financial and administrative support with an in-kind of £227,437. _x000D_ _x000D_ CASH and The George Institute for Global Health China (TGI China) have had many years’ collaboration in NCDs prevention. TGI China is a leading health research institute benefiting from strong links with health authorities in China, especially those related to salt reduction. This application will strengthen our collaboration with TGI China and further expand our partnership in China to health authorities including Chinese Center for Health Education (CCHE), China National Centre for Food Safety Risk Assessment (CFSA) and three departments/institutes from Chinese Centre for Disease Control and Prevention (China CDC) including Division of Health and NCD Control and Community Health (NCD Division), National Centre for Chronic and Non-communicable Disease Control and Prevention (NCD centre) and National Institute for Nutrition and Health (NINH), which have all agreed to be involved. _x000D_ _x000D_ Lifestyle intervention is a priority of the Chinese government, however, there is lack of a comprehensive salt reduction programme. Almost half of the Chinese live in rural areas where many are poor with very high salt intake and limited access to health information. By 2015, there were 592 poverty-stricken counties with more than 55 million living on less than US$1/day. This application is highly relevant to China’s agenda on health and development. Exporting our experience and expertise will help China strengthen their current effort and capacity in salt reduction. Building relationships with key stakeholders in China to produce champions for the cause of salt reduction will assist in sustainability. _x000D_ _x000D_ To benefit the poorer people and maximise the value for money, we will target 5 provinces (Xinjiang, Gansu, Shaanxi, Jilin, Heilongjiang) with high salt intake, large population (>20 million each) and lower GDP. A multidisciplinary team will be formed with engagement from health authorities, research institutes, universities, NGOs, food industry and other social sectors from both UK and China to develop specific research programmes to target the main contributors of salt (food prepared at home, pre-packaged and restaurant food)[7, 8]. Each programme will be led by a delegated participating team who have the expertise and authority in the specific area. Local and central governments will be involved to ensure swift translation of practice to policies. _x000D_ _x000D_ Programme 1: Health education and promotion _x000D_ _x000D_ This will be a nation-wide salt reduction education with various formats depending on the settings to increase salt awareness and master salt reduction skills. Health education and promotion will be a key programme and the basis of all other programmes._x000D_ _x000D_ _x000D_ Programme 2: Reducing salt in home cooking _x000D_ _x000D_ About 80% salt is added by the consumer[7, 8] and a priority is to educate the person who does the cooking at home to use less salt. Tailored health education will be delivered by community health workers, women’s federation, family planning workers and the “new family planning – family capacity building” scheme which aims to increase health literacy of family members. Moreover, we will educate primary schoolchildren to instruct their families to reduce salt. Our previous study, i.e. School-based Education Programme to reduce salt (School-EduSalt) demonstrates that this approach is effective in lowering salt intake by about 25% in both children and adults in northern China[9]. To facilitate the implementation of the School-EduSalt programme, we will develop a smartphone app (AppSalt) to combine School-EduSalt with our previous work on KnowSalt app[10] (an app to estimate salt intake and identify major sources of salt) to allow family members to acquire salt reduction knowledge, set salt target, assess salt intake and monitor progress. _x000D_ _x000D_ _x000D_ Programme 3: Reducing salt from pre-packaged food _x000D_ _x000D_ _x000D_ China became the world’s biggest consumer of pre-packaged food[11]. Most of them are extremely high in salt[12, 13]. The UK is a great example to work with food industry to set incremental lower salt targets to reduce salt in over 80 categories of food. We will deploy similar strategies in China to reduce the salt level in pre-packaged food. Additionally we will work with relevant authorities to amend nutrition labelling regulations on pre-packaged food and urge the adoption of a front-of-pack (FoP) labelling (e.g. traffic light system) to allow consumers to choose healthier food. Furthermore, we will promote the tool, Foodwitch China (a smartphone application have been developed by TGI)[14] to help consumers choose healthy food._x000D_ _x000D_ _x000D_ Programme 4: Reducing salt from food eating out of home_x000D_ _x000D_ More and more people eat out of home nowadays. We will work with restaurants and other food outlets to create healthy eating environment. We will launch various campaigns to target restaurants and canteens in schools, universities, work places and hospitals and train chefs to develop lower salt menu. We aim to set standards on salt in restaurant food and adopt menu labelling. _x000D_ _x000D_ Short term objectives (1-2 years):_x000D_ _x000D_ • Set up governance structure and strategies, and outline scope of work_x000D_ _x000D_ • Finalise protocols _x000D_ _x000D_ • Develop and pilot education materials and tools _x000D_ _x000D_ • Set up mechanisms for restaurants and food manufacturers to reduce salt_x000D_ _x000D_ • Launch all programmes_x000D_ _x000D_ • Complete baseline survey_x000D_ _x000D_ _x000D_ Medium term objectives (2-3 years):_x000D_ _x000D_ • One-third of the target population are aware of the key messages and skills on salt reduction _x000D_ _x000D_ • One-fifth of the target population know the amount and source of salt _x000D_ _x000D_ • One-third restaurants will remind the consumers to select lower salt food _x000D_ _x000D_ • Key food manufacturers commit to reduce salt _x000D_ _x000D_ • Facilitate the amendment of nutrition labelling regulations including adoption of FoP_x000D_ _x000D_ • Conduct mid-term progress assessment _x000D_ _x000D_ _x000D_ Long term objectives (3-4 years): _x000D_ _x000D_ • Two-third of the target population are aware of the key messages and skills on salt reduction _x000D_ _x000D_ • Three-fifth of the target population know the amount and source of salt_x000D_ _x000D_ • Two-third restaurants will remind the consumers to select lower salt food _x000D_ _x000D_ • Preliminary salt targets achieved by the key food manufacturers _x000D_ _x000D_ • Facilitate the finalisation of new nutrition labelling regulation/standards_x000D_ _x000D_ • Conduct final progress assessment and salt intake survey_x000D_ _x000D_ • Develop sustainability strategies _x000D_ _x000D_ • Disseminate the result through various approaches _x000D_ _x000D_ _x000D_ _x000D_ In the 1st two years all of the programmes will be initiated. The focus will be on the design, setting up mechanisms to engage stakeholders and launching all programmes. _x000D_ _x000D_ Each of the Chinese partners involved have unique platforms for promoting healthy lifestyle and salt reduction (see additional information). We have obtained their written support to prioritise salt reduction work. In addition, we have planned various communication and dissemination programmes including conferences, trainings, publications, website etc. to enable us to engage more stakeholders (e.g. food industry, local health authorities) throughout the award period which will be valuable for translating knowledge into practice and policies as well as spreading the messages widely. _x000D_ _x000D_ To ensure sustainability beyond the duration of this award, we will seek to translate research outputs into population wide policies. Due to the huge cost savings that would occur, particularly the prevention of strokes which are very common in China, we have a high likelihood of success in persuading the central and provincial government to adopt the programmes and make them a national policy in China as we have done in several other countries. Furthermore, many of our Chinese partners have the capacity to set or influence policies._x000D_ _x000D_ Acknowledging the importance of capacity building, we plan to retain £200,000 to allow outstanding young researchers in China to apply for this funding to conduct pilot projects that are of global relevance and importance. _x000D_ _x000D_ Our team have expertise in a wide area of health research, especially NCD and lifestyle. We will have regular review on emerging global health issues or research requirements by regular communication, exchanging ideas, collaboration and engagement with stakeholders, so as to retain a responsive capacity to respond to emerging health challenges.",3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT),CARDIOVASCULAR;STROKE;GENERIC HEALTH RELEVANCE HRCS22_05049,Department of Health and Social Care,NIHR,NIHR Global Health Research Unit on Neglected Tropical Diseases at Brighton and Sussex Medical School (Phase 2),"Since 2017, our Phase 1 Global Health Research Unit (GHRU) on Neglected Tropical Diseases (NTDs) has successfully conducted and published research, strengthened individual and institutional research capacity, and delivered impact for patients and policy makers in Ethiopia and Sudan. The GHRU has focused on three of the most overlooked NTDs: podoconiosis, mycetoma and scabies, and has conducted research spanning geospatial analysis, medical anthropology, genetic mapping, drug identification and implementation science. _x000D_ _x000D_ The overarching aim of this programme is to improve the health and wellbeing of people affected by these three NTDs in Ethiopia, Sudan, and Rwanda. In Phase 2, we plan to expand our partnership to include the University of Rwanda and the Rwanda Biomedical Centre (the research arm of the Rwanda Ministry of Health). _x000D_ _x000D_ In Phase 2 of our GHRU, we plan an entirely new 5-year programme comprising 12 research projects. The research questions have been co-created through a process of i) consulting with stakeholders including patients, communities, implementers and policy makers; ii) identifying the areas in which our Phase 1 GHRU has had the most impact; and iii) participating in WHO and disease-group identification of research gaps. The projects will run in parallel and are grouped into four interrelated themes: 1. Mechanisms of disease, 2. Geospatial mapping, 3. Diagnostics and drug development, and 4. Implementation research. _x000D_ _x000D_ Our detailed delivery timeline and milestones are laid out in the attached Gantt chart. During the first year we will concentrate on setting up the programme: signing the head contract, developing and agreeing our collaboration agreements, recruiting research and support staff, recruiting and registering PhD students, finalising our data management plan and starting to develop plans for regional capacity strengthening fora. We will refine our Theory of Change with partners and begin to develop an impact, communications and engagement (ICE) strategy as well as a monitoring and evaluation framework for the programme. We will engage our Strategic Advisory Board and aim to hold our first cross-GHRU meeting. _x000D_ _x000D_ Our ICE strategy will identify important global, regional and national routes through which our research findings may be disseminated. These will include ‘pandemic-proofed’ national and international meetings and conferences and attending and presenting symposia and papers at existing academic and policy fora. We will publish our findings as peer-reviewed articles and will look for opportunities to maximise the impact of these through, for example, Journal ‘Special Issues’. We will develop policy briefs from the studies with policy-relevant outcomes.","Our aim is to improve the health and wellbeing of people affected by three highly neglected conditions, podoconiosis, mycetoma and scabies, in Ethiopia, Sudan and Rwanda. We will conduct research co-created with stakeholders and designed to improve the experience of affected individuals, increase societal awareness, reduce stigmatisation, and expand the evidence base for national and international policy._x000D_ Since 2017, the NIHR Global Health Research Unit (GHRU) on Neglected Tropical Diseases (NTDs) at Brighton & Sussex Medical School has carried out a highly successful needs-driven research programme in partnership with Addis Ababa University and the Armauer Hansen Research Institute in Ethiopia, and the Mycetoma Research Centre, University of Khartoum, Sudan. Our GHRU has focused on three conditions considered severely neglected in terms of research, public attention and political will: podoconiosis (a progressive, disabling form of leg swelling seen in barefoot farmers); mycetoma (a destructive infection of the skin and underlying tissues) and scabies (a profoundly irritating skin condition caused by burrowing mites)._x000D_ Our studies have spanned wide-ranging disciplines to address questions directly relevant to national and global NTD elimination agendas. This research has been conducted within a strong framework of capacity strengthening which has developed infrastructure and financial management at partner institutions and trained 11 PhD students and 5 post-doctoral researchers. All early career researchers have benefitted from training opportunities within and beyond their countries, and from the NIHR Global Health Academy. We will build on these strong foundations in the next 5 years and expand the partnership to include the University of Rwanda._x000D_ We will use a range of methods to investigate new research questions clustered into four interrelated themes: mechanisms of disease, geospatial mapping, diagnostics and drug development, and implementation research. The questions have been prioritised through a process of i) identifying the areas in which our GHRU has had the most impact; ii) participating in WHO and disease-group identification of research gaps in these areas; and iii) consulting with stakeholders including patients, communities, implementers and policy makers. Our research will contribute evidence important to disease treatment and prevention strategies and continue to enhance research capacity to ensure sustainability._x000D_ We will continue to engage with and involve our stakeholder communities through existing fora for podoconiosis and mycetoma patients, by supporting the development of patient groups for scabies, and by hosting consultations with implementers and policy makers throughout the course of the GHRU. We will develop our Impact, Communications and Engagement (ICE) strategy to prioritise activities and channels of engagement for each country setting, including the UK._x000D_ Our ICE strategy will identify important global, regional and national routes through which our research findings may be disseminated. These will include hosting ‘pandemic-proofed’ national and international meetings and conferences, and attending and presenting symposia and papers at existing academic and policy fora. We will publish our results as peer-reviewed articles and look for opportunities to maximise their impact through, for example, Special Journal Issues. We will develop policy briefs from the studies with policy-relevant outcomes.",2.4 SURVEILLANCE AND DISTRIBUTION;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;8.1 ORGANISATION AND DELIVERY OF SERVICES,INFECTION HRCS22_05054,Department of Health and Social Care,NIHR,NIHR Global Health Research Unit on “Health financing for UHC in challenging times: leaving no-one behind”,"RESEARCH QUESTION: How can countries’ health financing and resource allocation strategies be strengthened to accelerate the achievement of Universal Health Coverage (UHC) objectives, with particular attention to left-behind groups?_x000D_ _x000D_ BACKGROUND: The COVID-19 pandemic has highlighted the socioeconomic importance of a resilient health sector. This presents a critical opportunity for change to strengthen progress towards UHC for low- and middle-income countries (LMIC), and to develop a coherent and resilient strategy for health financing and resource allocation. Central to the Unit are the specific needs and circumstances of the marginalised and poor; the Unit’s focus countries - Brazil, India, Indonesia and South Africa - comprise 45% of the world’s population living in absolute poverty, with large left-behind populations (geographically-isolated groups; slum dwellers; socially marginalised castes; ethnic or religious minorities; low-income districts/municipalities). Understanding how to advance UHC in these contexts provides significant opportunities for shared learning and knowledge spill-over benefits for other LMICs. _x000D_ _x000D_ AIMS & OBJECTIVES: The Unit’s aim is to strengthen partner countries’ capacity to adapt health financing policies/ programmes for resilient, equitable and sustained progress towards UHC. This encompasses four objectives: (1) produce policy-relevant research and innovative health economics methods to address major health financing challenges that impede UHC progress; (2) strengthen capability in using health economics/ financing for decision-making among academic researchers and policy-makers; (3) strengthen and develop stakeholder coalitions with policy-makers, civil society partners and the public to improve the relevance and quality of policy-making; and (4) engage with international organisations and decision-makers to share findings, foster global uptake and influence global UHC policies._x000D_ _x000D_ METHODS: Research is grouped into four main policy themes, complemented by four core methods areas. Each theme centres around country-specific and global research questions, with the aim of promoting cross-country collaboration and mutual learning within and beyond the four countries. This will be facilitated by the exploitation, preparation and collection of a wealth of data sources, combined with state-of-the-art methods of policy impact and economic evaluation, equity and political economy analysis. _x000D_ _x000D_ TIMELINE: The five year timeframe will be divided into three phases: (1) inception phase (Feb-Oct 22), during which research plans are formalised in collaboration with stakeholders, and Unit management processes are set-up; (2) primary research phase (Nov22-Jul26), where data collection, analysis, stakeholder engagement, and training is delivered; and (3) final dissemination phase (Aug26-Jan27), in which we will gather and reflect on all Unit outputs, and share with beneficiaries. _x000D_ _x000D_ IMPACT & DISSEMINATION: The Unit will strive for three broad outcomes: (1) inform health system financing reforms with its research outputs; (2) advance the global academic conversation on UHC attainment; and (3) strengthen health economics capability/ financing among early-career researchers and decision-makers in partner countries. This will be achieved by establishing national policy and advisory forums, delivering formal training and mentoring to academic researchers, and sharing research findings broadly via digital platforms and events.","Universal health coverage (UHC) is where all people have access to the health services they need, when and where they need them, and without financial hardship. UHC is an objective shared by countries worldwide. Many low- and middle-income countries (LMICs) have made progress towards UHC, but large challenges remain (due to COVID-19 and other crises). At the same time, the pandemic has highlighted the social and economic importance of health and UHC. There is, therefore, a critical opportunity for change that we embrace in this Unit; to strengthen progress to UHC in such challenging times, using the tools and perspectives of health financing and economics._x000D_ _x000D_ Health financing is a key means to achieving UHC, and it is more than just raising money for health services. It involves deciding how to spend money in the health system, setting the right financial incentives for healthcare providers, and ensuring access to healthcare for all. While crucial to achieving UHC, health financing is often insufficient in LMICs owing to low prioritisation of economic resources and limited expertise. _x000D_ _x000D_ This Unit will use the tools and perspectives of health economics and related disciplines to produce evidence and training to support governments in Brazil, India, Indonesia and South Africa to develop and implement health financing reforms, and accelerate progress towards UHC. These countries host almost half of the world’s poor and are all characterised by large gaps in health outcomes between rich and poor, underlining the global importance of achieving UHC in these locations._x000D_ _x000D_ The Unit will deliver a programme of novel research involving the analysis of existing data, modelling, primary data collection and policy evaluation. This will be shared across four policy themes (PT) and four methodological areas (MA). The PTs involve analysis of national challenges identified through extensive stakeholder consultations: (1) raising money for health; (2) allocating money for health; (3) ensuring healthcare access for left-behind groups; and (4) the role of governance and the interaction between the health system and other sectors. The MAs will feed into the PTs by ensuring the application and development of rigorous, innovative methods to address the challenges identified._x000D_ _x000D_ The main beneficiaries of the work will be state- and district-level policy-makers, managers and clinicians with key responsibilities for health financing policies, as well as civil society organisations supporting healthcare delivery to vulnerable communities. The Unit will engage and involve these stakeholders throughout its duration to co-design research plans, interpret and contextualise emerging findings and refine and disseminate key messages from our research. This will be achieved via regular forum meetings, part-time secondment of policy-makers to the research teams, and training. Strengthening research capability is a top priority of the Unit and we will deliver multiple training and development opportunities to researchers, especially early career researchers, policy-makers and other stakeholders. In summary, the work of our Unit will make a vital contribution to accelerating progress towards UHC in our four partner countries, especially among vulnerable populations, and will inform inclusive, national strategies to achieve this in many other countries.","8.2 HEALTH AND WELFARE ECONOMICS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_04254,Department of Health and Social Care,NIHR,NIHR Royal Marsden BRC,"At the Royal Marsden NHS Foundation Trust (RM) and The Institute of Cancer Research (ICR) Biomedical Research Centre, patients and their families are at the heart of what we do. RM is a specialist cancer hospital with a world-wide reputation. ICR has an outstanding academic reputation and continues to come top in the UK for Biological Sciences and Clinical Medicine. Together, our partnership is able to rapidly transfer scientific breakthroughs into the clinic to transform the lives of cancer patients. Cancer is the UK s biggest killer. Despite significant progress against the disease in the last 20 years, it continues to claim around 160,000 lives every year. Survival rates have improved enormously in some types of cancer but not others. Once the disease has spread round the body it is still usually incurable. The major challenges that our BRC seeks to overcome include: Preventing cancers from developing by identifying people most at risk of the disease. Detecting cancer earlier and more accurately to make cure more possible. Tackling the enormous complexity and unpredictable nature of cancer. Firstly, there are more than 200 types of cancer. Secondly, the same type of cancer can differ between patients as individual cancers can carry their own molecular footprint. Dealing with the ability of cancers to adapt and evolve within the patient and in response to treatment. Patients often respond initially to treatment only for the cancer to sidestep the effects of treatment in a similar way to infections that become resistant to antibiotics. We will: Apply our research into the fundamental processes at work as cancers develop, grow and evolve for cancer prevention, early diagnosis and targeted treatments. We will develop liquid biopsies (blood tests) to diagnose and monitor cancers. Harness our research in cancer biology, cancer imaging, the microbiome (bacteria) and metabolome (breakdown products) to select the right patients for the right treatments. This will improve survival, reduce the use of ineffective treatments and save patients from unnecessary side effects. Build on our international track record for discovering new cancer treatments by developing innovative cancer drugs and precision image-guided radiotherapy. We will expand our surgical research. We will research drugs that activate the patient s immune system to fight cancer and which can control and even cure some advanced cancers. Tackle cancer drug resistance with combinations of treatments. We will develop tests to direct when and how to adapt therapy to prevent drug resistance and to prevent over-treatment of patients. Our responsibility to cancer patients and their families does not end with the delivery of excellent research, or even with the development of new treatments. We will ensure effective new treatments, technologies and strategies for prevention are adopted into routine healthcare by building an evidence base to support this. Long-term, we aim to increase cure rates and to improve survival with smarter, kinder treatments which significantly reduce immediate and long-term side effects and allow patients to live well with and beyond cancer.","At the Royal Marsden NHS Foundation Trust (RM) and The Institute of Cancer Research (ICR) Biomedical Research Centre, patients and their families are at the heart of what we do. RM is a specialist cancer hospital with a world-wide reputation. ICR has an outstanding academic reputation and continues to come top in the UK for Biological Sciences and Clinical Medicine. Together, our partnership is able to rapidly transfer scientific breakthroughs into the clinic to transform the lives of cancer patients. Cancer is the UK s biggest killer. Despite significant progress against the disease in the last 20 years, it continues to claim around 160,000 lives every year. Survival rates have improved enormously in some types of cancer but not others. Once the disease has spread round the body it is still usually incurable. The major challenges that our BRC seeks to overcome include: Preventing cancers from developing by identifying people most at risk of the disease. Detecting cancer earlier and more accurately to make cure more possible. Tackling the enormous complexity and unpredictable nature of cancer. Firstly, there are more than 200 types of cancer. Secondly, the same type of cancer can differ between patients as individual cancers can carry their own molecular footprint. Dealing with the ability of cancers to adapt and evolve within the patient and in response to treatment. Patients often respond initially to treatment only for the cancer to sidestep the effects of treatment in a similar way to infections that become resistant to antibiotics. We will: Apply our research into the fundamental processes at work as cancers develop, grow and evolve for cancer prevention, early diagnosis and targeted treatments. We will develop liquid biopsies (blood tests) to diagnose and monitor cancers. Harness our research in cancer biology, cancer imaging, the microbiome (bacteria) and metabolome (breakdown products) to select the right patients for the right treatments. This will improve survival, reduce the use of ineffective treatments and save patients from unnecessary side effects. Build on our international track record for discovering new cancer treatments by developing innovative cancer drugs and precision image-guided radiotherapy. We will expand our surgical research. We will research drugs that activate the patient s immune system to fight cancer and which can control and even cure some advanced cancers. Tackle cancer drug resistance with combinations of treatments. We will develop tests to direct when and how to adapt therapy to prevent drug resistance and to prevent over-treatment of patients. Our responsibility to cancer patients and their families does not end with the delivery of excellent research, or even with the development of new treatments. We will ensure effective new treatments, technologies and strategies for prevention are adopted into routine healthcare by building an evidence base to support this. Long-term, we aim to increase cure rates and to improve survival with smarter, kinder treatments which significantly reduce immediate and long-term side effects and allow patients to live well with and beyond cancer.",4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),CANCER AND NEOPLASMS HRCS22_04964,Department of Health and Social Care,NIHR,NIHR Trauma Management MedTech Co-operative (short name: NIHR Trauma MedTech Co-operative),"Trauma remains the leading cause of death in the Western World, and it is predicted by the World Health Organisation that death due to injury is set to rise globally from 1.3 million in 2004 to 2.4 million in 2030. Around 90% of trauma related deaths occur before the patient reaches hospital, yet this is the toughest area to make technological advances in. Trauma is the leading cause of death and disability in children of <1 year of age, with this significant incidence sustained as children grow. In the UK alone, 80% of children s injuries are caused by blunt trauma, a physical injury to part of the body. Head injury is present in the majority of cases and accounts for 75% of deaths. The remit of the proposed NIHR Medtech and In vitro diagnostic Co-operative in Trauma Management (MIC) is to support the research of new medical devices and healthcare technologies in order to enable improved management of the trauma care pathway from the point of injury through to stabilisation and recovery. The MIC will have a national remit and will be hosted by University Hospitals Birmingham NHS Foundation Trust which is a UK Major Trauma Centre, home to the Royal Centre for Defence Medicine, and a Regional Burns Centre. New technology will be key to improved survival and reducing long-term disability. The MIC will address this in its three clinical themes; 1) Immediate response to injury at the scene and hospital stabilisation; 2) tissue repair and surgical reconstruction and; 3) re-enablement and rehabilitation. The anticipated benefits of the proposed MIC include early detection of deterioration, reduced mortality and morbidity following trauma, reduced pain and suffering, reduced length of hospital stay, reduced time to maximum recovery, reduced long term dependency and enhanced patient experience. The MIC will use lessons learnt from the military and civilian populations and will work in collaboration with clinical and other health care professionals, patients and patient groups, charities, industry and academic researchers to deliver its aims. The short-term aims will be to identity the unmet needs in Trauma through supporting local and national projects in close working with clinicians and patient groups. In the medium-term we will build a national network to prioritise the clinical needs and look for matching potential solutions from industry and academic researchers to address the need. We will fund some initial pilot projects to produce the preliminary findings for larger scale research studies. Subject to satisfactory outcomes and health economic evaluation, we will facilitate new technology into usable clinical products. Long-term, we will develop a programme of activity with a measurable impact on patient care and clinical outcomes. The main success criteria will be the numbers of newly adopted medical technologies that benefit trauma patients within the NHS. Patient and Public Involvement, Engagement and Participation, and Patient Reported Outcomes activities will play a central role, in collaboration with industry, in identifying what matters to patients, and other end-users of technology, and where industry may wish to focus research development efforts.","Trauma remains the leading cause of death in the Western World, and it is predicted by the World Health Organisation that death due to injury is set to rise globally from 1.3 million in 2004 to 2.4 million in 2030. Around 90% of trauma related deaths occur before the patient reaches hospital, yet this is the toughest area to make technological advances in. Trauma is the leading cause of death and disability in children of <1 year of age, with this significant incidence sustained as children grow. In the UK alone, 80% of children s injuries are caused by blunt trauma, a physical injury to part of the body. Head injury is present in the majority of cases and accounts for 75% of deaths. The remit of the proposed NIHR Medtech and In vitro diagnostic Co-operative in Trauma Management (MIC) is to support the research of new medical devices and healthcare technologies in order to enable improved management of the trauma care pathway from the point of injury through to stabilisation and recovery. The MIC will have a national remit and will be hosted by University Hospitals Birmingham NHS Foundation Trust which is a UK Major Trauma Centre, home to the Royal Centre for Defence Medicine, and a Regional Burns Centre. New technology will be key to improved survival and reducing long-term disability. The MIC will address this in its three clinical themes; 1) Immediate response to injury at the scene and hospital stabilisation; 2) tissue repair and surgical reconstruction and; 3) re-enablement and rehabilitation. The anticipated benefits of the proposed MIC include early detection of deterioration, reduced mortality and morbidity following trauma, reduced pain and suffering, reduced length of hospital stay, reduced time to maximum recovery, reduced long term dependency and enhanced patient experience. The MIC will use lessons learnt from the military and civilian populations and will work in collaboration with clinical and other health care professionals, patients and patient groups, charities, industry and academic researchers to deliver its aims. The short-term aims will be to identity the unmet needs in Trauma through supporting local and national projects in close working with clinicians and patient groups. In the medium-term we will build a national network to prioritise the clinical needs and look for matching potential solutions from industry and academic researchers to address the need. We will fund some initial pilot projects to produce the preliminary findings for larger scale research studies. Subject to satisfactory outcomes and health economic evaluation, we will facilitate new technology into usable clinical products. Long-term, we will develop a programme of activity with a measurable impact on patient care and clinical outcomes. The main success criteria will be the numbers of newly adopted medical technologies that benefit trauma patients within the NHS. Patient and Public Involvement, Engagement and Participation, and Patient Reported Outcomes activities will play a central role, in collaboration with industry, in identifying what matters to patients, and other end-users of technology, and where industry may wish to focus research development efforts.",5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),RESPIRATORY;INJURIES AND ACCIDENTS HRCS22_04076,Department of Health and Social Care,NIHR,NIHR UCLH BRC,"Our BRC is a partnership between one of the UK s leading hospitals (University College London Hospitals - UCLH) and one of the leading Universities in the world (University College London - UCL). We want to ensure that advances in medical science led by UCL scientists are used to develop new and more effective treatments for patients. We will be trying to develop better ways to spot diseases earlier so there is a better chance of curing them. We will do this by using recent advances in understanding how our genes influence our risk of developing different diseases and which type of treatments are best suited to treat a particular disease. We are developing new and very sensitive ways of measuring different proteins in the blood to help show how and whether a treatment is working, not working, or causing problems. This is particularly important when we test new treatments so we can tell which ones are going to work and should be developed as new drugs. We are also developing new types of scans to look at the brain, heart, lungs and other internal organs in the kind of detail that has never before been possible. To make all of this work successfully we will establish effective ways to easily link all of this new information to the patients medical records. This will help us better understand how disease develops and evolves and how treatments work in individual patients and the wider population. Our BRC is very large and our aims are bold. We will tackle some of the most challenging and difficult diseases, where we believe we can make a big difference to patient outcomes over the next 5 years. These include cancer, dementia, heart disease and strokes, brain and nervous system diseases such as multiple sclerosis, motor neuron disease, muscular dystrophy and epilepsy. We will also develop better treatments for mental health problems, chronic lung diseases, and obesity, hearing and dental problems. We will open world-leading research centres at UCLH to allow us to deliver the newest treatments to NHS patients and conduct research studies alongside. One example is proton beam therapy. This is a new, more precise and powerful way of treating cancer with radiation. We will also open a new “cancer immunotherapy centre” that uses gene therapy to make a patient s own immune cells fight cancer cells just like they usually fight infections. We will have a special focus developing more rapid ways of diagnosing and treating life threatening infections and reducing antibiotic resistance. We will develop all of these new techniques and treatments over the next 3-4 years, many of which are ready to be tested in patients at UCLH. Beyond that time scale, we want our BRC to be recognised throughout the world as a leading centre for developing and delivering new treatments, so we can improve the outcomes for patients with the most difficult to treat diseases.","Our BRC is a partnership between one of the UK s leading hospitals (University College London Hospitals - UCLH) and one of the leading Universities in the world (University College London - UCL). We want to ensure that advances in medical science led by UCL scientists are used to develop new and more effective treatments for patients. We will be trying to develop better ways to spot diseases earlier so there is a better chance of curing them. We will do this by using recent advances in understanding how our genes influence our risk of developing different diseases and which type of treatments are best suited to treat a particular disease. We are developing new and very sensitive ways of measuring different proteins in the blood to help show how and whether a treatment is working, not working, or causing problems. This is particularly important when we test new treatments so we can tell which ones are going to work and should be developed as new drugs. We are also developing new types of scans to look at the brain, heart, lungs and other internal organs in the kind of detail that has never before been possible. To make all of this work successfully we will establish effective ways to easily link all of this new information to the patients medical records. This will help us better understand how disease develops and evolves and how treatments work in individual patients and the wider population. Our BRC is very large and our aims are bold. We will tackle some of the most challenging and difficult diseases, where we believe we can make a big difference to patient outcomes over the next 5 years. These include cancer, dementia, heart disease and strokes, brain and nervous system diseases such as multiple sclerosis, motor neuron disease, muscular dystrophy and epilepsy. We will also develop better treatments for mental health problems, chronic lung diseases, and obesity, hearing and dental problems. We will open world-leading research centres at UCLH to allow us to deliver the newest treatments to NHS patients and conduct research studies alongside. One example is proton beam therapy. This is a new, more precise and powerful way of treating cancer with radiation. We will also open a new “cancer immunotherapy centre” that uses gene therapy to make a patient s own immune cells fight cancer cells just like they usually fight infections. We will have a special focus developing more rapid ways of diagnosing and treating life threatening infections and reducing antibiotic resistance. We will develop all of these new techniques and treatments over the next 3-4 years, many of which are ready to be tested in patients at UCLH. Beyond that time scale, we want our BRC to be recognised throughout the world as a leading centre for developing and delivering new treatments, so we can improve the outcomes for patients with the most difficult to treat diseases.",4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),NEUROLOGICAL HRCS22_09302,"Chief Scientist Office, Scotland",CSO,Nasal cathelicidin expression in protection against respiratory syncytial virus,"Respiratory Syncytial Virus (RSV) is the biggest cause of lower airway infections in the world, killing ~100,000 children <5 years old every year, and affecting the elderly as severely as influenza. There are no effective treatments, and we don’t understand why these age-groups get lethal infections when healthy adults have only mild cold symptoms. We discovered that an antimicrobial substance (cathelicidin), naturally-produced in our bodies, can protect against RSV. In humans and mice, cathelicidin stops RSV infection getting started, and, if infection does occur, it is less severe when more cathelicidin is made by the body. The amount of cathelicidin varies in different people’s noses, where RSV virus enters. We propose that infants and the elderly are lacking effective “cathelicidin-shields” in their noses. This missing anti-viral barrier, and its effect on the bacteria that live in the nose, may increase the risk of serious RSV infection. This research will examine those ideas, and test whether ways of boosting cathelicidin production can help to protect against RSV. This research may help us understand who is at risk of severe RSV disease and develop ways to use cathelicidins and/or boost the body’s production of cathelicidin, to prevent and/or treat this life-threatening infection.",,5.1 PHARMACEUTICALS,INFECTION HRCS22_05584,Department of Health and Social Care,NIHR,NeWTS: Neonatal Wireless Transmission System for Monitoring in Intensive Care,"Aim To transform a proof-of-concept wireless vital sign monitoring system designed for use with infants in intensive care into a commercial product. Background Neonatal intensive care (NICU) combines monitoring of vital signs with addressing the developmental and psychological needs of babies and their parents. This is challenging for preterm infants who are extremely small and vulnerable, with fragile skin and who may be in hospital for many months. Parents and staff frequently report that wired sensors create both physical and psychological barriers to care, and limit physical contact. Increasing physical contact has been shown to increase breastfeeding rates, reduce length of stay, and improve neurodevelopmental outcomes. Therefore, the introduction of wireless monitoring could result in savings for the NHS, with a reduction in the one million annual days of NICU, which cost the NHS approximately £800 million in 2018/19. No currently available devices address the unique requirements of babies in NICU. We have designed NeWTS, a novel and bespoke wireless bridge between vital sign sensors and the patient monitor. Our prototype system includes three separate sensor modules (temperature, 3-lead electrocardiogram, and pulse oximetry). This has been successfully tested with 30 babies in NICU Objectives 1. Design review and redevelopment within a quality management system suitable for regulatory approval, with a view to manufacture at volume. 2. Validate the new system by bench testing and a clinical study within the NICU, with data collection relating to reliability, safety, and utility of the system. 3. Develop a health economic model and establish the framework for data collection to inform a future trial of effectiveness and cost-effectiveness. 4. Develop a commercial pathway for regulatory approval and adoption into the NHS. Methods We are working with Team Consulting who are a specialist medical devices consultancy and will undertake the system development which will require four design phases: Requirements and concept Preliminary design Detailed design and batch production Design verification The production prototype will undergo bench testing as well as a single-centre feasibility study (months 16-30). This small study (n=30) will evaluate the reliability, utility, and safety in clinical practice. Infants will have wired monitoring replaced by wireless monitoring from recruitment until discharge, with a primary outcome of frequency of skin-to-skin contact. A decision model of the costs, effects, and utility of the wireless system will be developed to give estimates of cost-effectiveness, influence study design of future clinical trials, and provide evidence for NICE. With support from our wide ranging network, we will develop a sustainable business strategy and establish the optimal route to market. Anticipated Impact At a patient level, NeWTS improves quality of care, reducing barriers between babies and their parents. This will reduce parental anxiety and improve infant's physiological stability, and has the potential to increase breastfeeding rates and reduce length of stay. Impacts for staff include time saved in providing clinical care. Wireless monitoring could therefore be cost saving for the NHS as well as improving quality of care and addressing the drive to improve family-centred care","The need for a wireless monitoring system was highlighted by the frustrations of a father, whose daughter spent her first three months in a Neonatal Intensive Care Unit (NICU). He found all the wires made it difficult to interact, and care for his child. When babies are in intensive care, they need to be continuously monitored, including measurement of their heart rate and oxygen levels. This requires multiple sensors with separate wires. These wires can become tangled and create both a physical and emotional barrier to care. They make nursing staff less keen to take babies out of the incubators for parents to hold. The holding of babies has been shown to reduce parental anxiety and stress, and to improve brain development for babies. The multiple wires can be overwhelming to parents and make them frightened of holding their small babies. Removing the wires from the monitoring equipment could: reduce practical barriers for parents providing care, and save nursing time. increase the opportunities for parents to hold their baby, increase breastfeeding rates and reduce length-of-stay. save the NHS money by improving short- and long-term outcomes. Working with parents and staff at Cambridge University Hospitals NHS Trust (CUH), we have designed, developed, and tested a prototype for a wireless system that connects the sensors to the bedside monitor. This prototype includes wireless monitoring of all three key elements of intensive care monitoring: skin temperature, heart activity (electrocardiogram, ECG), oxygen levels in the blood (pulse oximetry). This funding would allow development of the prototype into a system to meet manufacturing and regulatory standards so that it can obtain the approval required for clinical use. This work will require four workstreams: Design the final system taking into account the technical challenges, user needs (including staff and parents), commercial viability, and commercial manufacturing standards. Create a business that can ensure the new system reaches patients in the NHS. Test the new system with babies in intensive care to make sure it is user-friendly, reliable, and safe. Develop a model to examine the cost and effects of the wireless monitoring compared to current care. The project is being led by a paediatrician, two academic engineers, two health economists, and a parent representative. The project also needs input from experts in design for manufacturing. We are working with Team Consulting who have significant expertise and experience in developing medical devices, and will ensure the final system is competitive for business. A Project Advisory Board made up of parents, clinical staff, and hospital management will advise on developments to ensure the project meets the needs of all involved.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,GENERIC HEALTH RELEVANCE HRCS22_15662,Wellcome Trust,,Network analysis of multimodal COVID-19 patient datasets,"Over recent years there has been an enormous number of developments in the ways we obtain molecular information from patients with disease. This has resulted in the ability to generate multiple measurements per patient for large cohorts, including levels of various proteins in their blood stream, gene activity across multiple different cell types at the resolution of single cell as well as precise methods of counting the numbers of different cells present in the system of interest. At the same time, there is an acute need to integrate this information and enable using all the data at once and not one at a time. Multilayer networks which at each layer summarize information available from a single experiment and then connect these layers allow us to integrate molecular information across various molecular measurements. We aim to develop statistically robust network methods and apply them to a dataset of more than 100 hospitalized COVID-19 patients of different severities. We also aim to compare them with sepsis, hospitalized flu patients and COVID-19 non-hospitalized patients and healthy volunteers to discover better ways to stratify patients and understand the underlying biological mechanisms driving their disease.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_20035,Wellcome Trust,,Neural mechanisms of endogenous pain control,"Pain plays a vital role in self-protection and injury avoidance, and my research to date has outlined a core learning and decision-making framework, based on reinforcement learning theory, that shows how this is achieved in the brain. Recently, I have shown that this controls not only actions, but also the intensity of perceived pain itself (endogenous pain control) - an effect related to predicted uncertainty. This leads to the underlying hypothesis that pain is actively tuned by the value of its information - a precise metric that derives from an estimate of the extra benefit to survival achieved through learning. This leads to a series of testable questions: i) how and where is this information computed, ii) is it opioid-dependent, iii) how is it maintained over time, iv) how and at what level does it control pain representations, v) and can it be targeted to reduce pain. The proposed research describes the series of behavioural and neuroimaging experiments that will answer these questions, aiming to provide a comprehensive circuit level account of the major endogenous pain control process in the brain. Ultimately, the results aim to provide a basis for developing precision interventions for chronic pain.","The magnitude of chronic pain as a global clinical problem is illustrated by the opioid crisis. Opioids work by activating the brain’s powerful endogenous pain-killing system, but cause problems due to co-activation of reward and addiction networks. My research aims to understand why we have such a powerful pain-killing system in the first place, and how it actually works to control pain. Recently, I have identified a specific brain signal in human frontal cortex that may act as a central decision-maker in turning down the level of experienced pain. My proposal involves a set of human experiments built around a core hypothesis about how this signal works: what are the inputs, how does it compute the decision, and where in the brain does it exert its effect on pain? The ultimate goal is to design precision, non-drug (e.g. biomedical engineering) approaches that selectively harness the system to provide pain relief.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;NEUROLOGICAL HRCS22_20608,Wellcome Trust,,"Neural mechanisms of learning, planning, and decision-making","This proposal examines the neural mechanisms supporting decision-making and prospective planning. We will examine how prefrontal cortex (PFC), hippocampus, and entorhinal cortex (EC) interact to support these processes. We will examine how non-human primates (NHPs) make choices in large decision spaces, particularly when novel choice-values have to be inferred ‘online’. We will test different models of value-coding, particularly whether PFC uses a ‘place-like’ and ‘grid-like’ code to construct cognitive maps of values spaces. We will examine how NHPs make ‘online’ choices when sequentially navigating between stimuli/states as rewards move or paths blocked. We will test whether ‘replay’ provides a neural mechanism supporting model-based planning. We will use Transcranial Ultrasound Stimulation to selectively disrupt regions of PFC/hippocampus/EC to examine its effect on neural selectivity and behaviour. These tasks are high-dimensional, yet amenable to mathematical description, and will be combined with high-density recordings to map these computations. Exp.3 will integrate our home-cage training system with wireless data-logging to record neural data continuously, across tasks and sleep, to examine how neural signatures change across days with learning, and acquisition of ‘learning set’. This provides the technology to continuously map the NHP brain during performance of diverse and naturalistic tasks, radically transforming primate neuroscience.","Learning a model of an environment (‘cognitive map’) is critical for decision-making. For example, learning about the London Underground not only facilitates daily transport, but knowing its model features (i.e., use of ticket machines, station maps, transfer stations) provides generalizable knowledge for novel environments (e.g., using the Paris Metro). The ability to use cognitive maps depends on the prefrontal cortex, hippocampus, and entorhinal cortex; dysfunction here impairs learning, memory and decision-making. Developing causal mechanisms of why brain dysfunction disrupts these cognitive processes requires invasively mapping the functional circuitry at the single-neuron level; doing them in a non-human primate is crucial, given their brain is most similar to human. My research examines how neural computations in these areas supports decision-making and construction of cognitive maps, and how disrupting these circuits impairs behaviour. These findings will provide mechanistic accounts of decision-making circuitry, to inform approaches for treatment in psychiatric studies.",1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,MENTAL HEALTH;NEUROLOGICAL HRCS22_01061,Medical Research Council,MRC,Neurobehavioural genetics. Isolation and characterisation of behavioural mutations in mice,"Genetic approaches provide a powerful means by which to examine the biological basis of nervous system diseases such as dementias, neurodegenerative disorders and affective disorders as well as the physiological processes that are affected by them. Almost all mental illnesses are accompanied by abnormal physiological and neurological characteristics that can be readily observed in mice. Phenotype-based approaches have been used successfully in organisms such as Drosophila melanogaster in establishing a genetic basis for many behavioural processes. Use of the chemical mutagen ENU along with hierarchical screening protocols has indicated that phenotype-based approaches in the mouse will be useful in gaining a molecular insight into complex mammalian behaviours.||One of the goals of this group is to identify and characterise ENU-induced mutations that affect specific behavioural processes. The first class of mutations being screened for are those which affect the mammalian circadian clock. The circadian system can be divided into three basic components - the input or entrainment pathway, the central pacemaker and the output pathway. Disruption of any of these components could be responsible for rhythm and sleep anomalies associated with complex psychiatric disorders. Pacemaker function is generally assessed by measuring an identifiable component of the output pathway such as locomotor (wheel-running) activity. The second class of mutations being screened for are those that affect learning and memory. Using these screens, we can identify not only molecular components specifically associated with memory formation but also components associated with neural mechanisms such as migration, plasticity and degeneration.||Paradigms such as Spontaneous Alternation, Novel Object Recognition, Holeboard exploration and Attention testing screens are being used to identify potential mutants. Positional cloning of several mutations identified in these screens is currently underway. This approach is complemented by carrying out molecular analysis of novel mutations. Primarily this involves histological analysis and in situ hybridization of brain regions suspected to be associated with particular behaviours. For example, circadian rhythms are associated with a brain region called the suprachiasmatic nucleus, located in the hypothalamus and consisting of approximately 10,000 cells. Histological analysis tells us whether there is a gross dysmorphology associated with the mutation, indicating that underlying neurodevelopmental processes might be affected.||In addition, by using specific molecular markers known to be associated with a particular behaviour, we can determine the molecular consequences of each mutation. Systematic approaches to characterising molecular pathways associated with behavioural traits are being established.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;NEUROLOGICAL HRCS22_22992,The Academy of Medical Sciences,AMS,Next-generation tumour-homing IL-12 expressing CAR-T platform technology to achieve safe and efficacious therapy for solid cancers,"Chimeric antigen receptor-(CAR)-expressing (CAR-T) cells are artificially engineered cells that can recognise cancer antigen and kill cancer cells. CAR-T cells demonstrate remarkable therapeutic efficacy in haematopoietic malignancies in the clinic as an approved therapy. However, conventional CAR-T cells are inefficacious for solid tumours due to the immune-suppressive tumour microenvironment (TME) and low number of tumour-infiltrating CAR-T cells. State-of-the-art CAR-T cells that express wild-type (wt) interleukin(IL)-12 are still not satisfactory to overcome this issue, due to limited efficacy and unacceptable side-effects. Here, the objective is to overcome this critical CAR-T challenge using a tumour-targeting technology that I recently developed. I aim to develop a new platform technology that CAR-T cells express extracellular matrix (ECM)-binding IL-12 within the TME and test them in cancer-bearing mice. I previously discovered that the specific collagen-binding domain (CBD) protein accumulates within the tumour following intravenous injection. Intravenous injection of CBD linked anti-tumour cytokine IL-12 protein displayed superior anti-tumour effects and less side-effects compared to wt IL-12 in multiple tumour models through localisation. CBD-IL-12 recruited anti-tumour immune cells into multiple difficult-to-treat tumours. Therefore, I will make CAR-T cells express CBD-IL-12 upon CAR-T's tumour antigen-recognition locally within the TME. I hypothesise that CBD-IL-12-expressing CAR-T cells are efficacious for solid cancers with minimal side-effects, solving the marginal response and unacceptable toxicity issues of state-of-the-art CAR-T cells. My central idea is to reconsider CAR-T cells as next-generation drug delivery platforms through localised protein production. This timely research has significant clinical translation potential and may transform the landscape of cancer treatment.","According to the World Health Organization, cancer is responsible for an estimated 9.6 million deaths accounting for 1 in 6 deaths. Recently, immunotherapy has presented revolutionary solutions for the treatment of cancer by engineering immune cells to attack cancer. There is a new approach to cancer immunotherapy, called CAR-T cells. CAR-T cells are designed to find and kill cancer cells. CAR-T cells are extremely effective for blood cancer patients. For example, 70-95% of patients showed cure in certain types of blood cancer. However, CAR-T cells are not very effective for other types of cancers so far, which means >90% of cancer patients have not benefited from CAR-T therapy. This is because of the hostile solid cancer character, where CAR-T cells are inactivated and/or excluded. I previously developed a new technology that can make protein drugs stay in the tumour by collagen binding, which makes cancer therapy more effective and safe. Combining this technology, here, I will develop and test new CAR-T cells that are effective for solid cancer with minimal side-effects. In the new design, CAR-T cells produce tumour-homing collagen-binding protein drugs. The CAR-T-derived drug stays in the tumour, and then CAR-T cells will be activated more to attack solid cancer cells. I will analyse the anti-tumour efficacy, side-effects, and immunological mechanism of action to evaluate this new generation CAR-T cells. The new CAR-T technology holds high translational potential. I propose an idea of localised CAR-T therapy to directly address the issues of CAR-T cells in the clinic.",5.2 CELLULAR AND GENE THERAPIES,CANCER AND NEOPLASMS HRCS22_18915,Cancer Research UK,CRUK,Non-Clinical Training Award Cycle 4 2018,"Non-clinical training at a CRUK centre: At the Institute of Cancer Research researchers are refining radiotherapy for many types of cancer. They are focusing on cancers including sarcomas (cancer of bone, fat, muscle or cartilage), head and neck cancers and children?s cancers._x000D_ _x000D_ The Cancer Research UK Centre at The Institute of Cancer Research and The Royal Marsden is part of a national network of centres funded by Cancer Research UK with the aim of delivering world-leading translational research and improved patient care. Funding to the Cancer Research UK Centre was renewed in April 2014 and supports innovative translational research activities at the ICR and The Royal Marsden aimed at delivering precision cancer treatment. Research infrastructure funding to our joint Drug Development Unit forms a large part of the centre funding and will help expand the number of investigator-initiated trials we undertake and the sequencing analysis of patient samples from these trials. Radiotherapy physics research within the centre is focused on the development of integrated treatment and imaging technologies, preclinical studies of radiation-induced biological effects on tumours and healthy tissues, and the translation of technologies into clinical practice. The aim of this research is to develop the most efficient and accurate radiation treatments. An Informatics Facility has been established to capture, analyse, model and integrate data from across the centre. This is comprised of interdisciplinary staff and includes statisticians, bioinformaticians, computer scientists, data modellers and web developers. Training of the next generation of cancer researchers is also a vital component of the Cancer Research UK Centre with funding provided for clinical and non-clinical PhD training programmes. _x000D_ _x000D_ The centre recognises the importance of engagement activities to encourage the talent of the future and help make young people aware of opportunities for careers in cancer research. We are developing activities designed to engage with school-age students and support their national curriculum learning activities._x000D_ _x000D_ http://www.icr.ac.uk/our-research/our-research-centres/cancer-research-uk-centre",,5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),CANCER AND NEOPLASMS HRCS22_14831,Cancer Research UK,CRUK,Non-Clinical Training Award – Cycle 3 – 2017,"Newcastle Cancer Centre at the Northern Institute for Cancer Research: Non-clinical training_x000D_ _x000D_ Newcastle has now joined the charity's unique network of 'virtual' centres delivering world-class science and improved patient care. The new Centre puts Newcastle at the forefront of cancer research and will bring benefits to patients in the North East._x000D_ The Centre is not a new building, but instead is a collaboration between Cancer Research UK, the Leukaemia Research Fund and the North of England Children's Cancer Research Fund. This will make it easier for scientists to work together with doctors and nurses, so patients can benefit from research breakthroughs more quickly._x000D_ Research at the Centre will concentrate on understanding the basic biology of how and why cancers develop, with a particular focus on blood cancers, such as leukaemia, and childhood cancers._x000D_ Scientists in Newcastle have an impressive track record in the discovery and development of new anti-cancer drugs. Researchers at the new Centre will focus on developing treatments that can be tailored to the genetic 'signature' of an individual cancer patient, instead of a one-size-fits-all approach. This will help to avoid unnecessary side effects and improve survival rates._x000D_ Clinical trials are an important aspect of the Newcastle Centre for Cancer Research. Through this initiative, we aim for more cancer patients in the North East to be given the opportunity to take part in trials of the latest treatments.",,5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),CANCER AND NEOPLASMS HRCS22_05980,Department of Health and Social Care,NIHR,Novel Applications and Implementation of Artificial Intelligence in Paediatric Radiology,"RESEARCH QUESTIONCan an artificial intelligence (AI) algorithm improve decision making in children's fracture detection?BACKGROUNDLimb fractures are the most common traumatic injuries in children. Their detection can be missed leading to pain, discomfort, poor healing and missed treatment opportunities. In some cases, they may be the first marker of child abuse, and missed opportunities for safe-guarding can be fatal. Immediate paediatric radiological opinions are difficult to access nationwide, however an AI algorithm trained on thousands of children's radiographs could offer an immediate and potentially more accurate method of detection, helping to improve patient outcomes through efficiency and reduced errors. AIMSTo develop an AI algorithm capable of detecting paediatric limb fractures, test the diagnostic accuracy of this tool compared to healthcare professionals, and determine whether this could be implemented in clinical care to reduce errors and improve emergency physician confidence in fracture detection.HYPOTHESISAn AI algorithm can be developed for accurate paediatric fracture detection, with performance equivalent to human paediatric radiologist standard for use in an emergency care triage setting. METHODS & TIMELINEThis study will be conducted in several phases over 5 years.WP1 (0-12 months): Stakeholder engagementA survey of parent and paediatric patients attending the radiology department will be conducted, asking how they feel AI should be used in clinical practice, and how they wish to be informed of doctors using these tools. WP2 & 3 (6 - 48 months): Algorithm development and validationCuration and annotation of a large, multi-centre, retrospective dataset of 4 types of paediatric limb radiographs will be undertaken, using double read expert consensus reports by paediatric radiologists as a reference standard. An AI algorithm will be developed and validated on this dataset, before being tested on an independent prospective external dataset. The AI diagnostic accuracy from this external test set will be compared against those of paediatric radiologists. WP4 (48 -h; 60 months): Simulated implementation The algorithm will be tested to see how it might perform in clinical practice through a simulated study. An online multi-reader study of stakeholders (emergency care physicians and consultant nurses) will review radiographs with and without using the AI algorithm to evaluate whether the use of AI leads to changes in diagnosis, reduced errors, different management plans or an increased confidence in diagnosis.IMPACT & DISSEMINATION The immediate scientific and clinical impact of this research would be better fracture care in children. This AI development pipeline (surveying parents and children, developing and validating the AI algorithm, with simulated clinical implementation) will become the standard blueprint method for pre-implementation AI development in the NHS. Guided by PPI, this research will feed into the next phase of regulatory approvals for nationwide implementation and evaluation, where those children most at need will get rapid access to this technology.","WHAT IS THE PROBLEM?Half of all the 12 million children ( There are three problems with identifying children's fractures: Growing bones can look like fractures. Children have different types of fractures than adults (e.g. buckle fractures) Fractures in children are not always obviousWithout an expert opinion from a radiologist (a specialist who looks at medical images), mistakes are made in diagnosing 10% of children's fractures by emergency doctors. Unfortunately, we don't have enough specialist children's radiologists in the NHS to check all X-rays immediately, meaning a delay in recognising mistakes. If fractures are missed, children will be left in pain and won't get the right treatment, leading to long term problems with discomfort and disability. In some cases, a fracture can be a sign of abuse, and crucial opportunities to arrange for the child's safety are missed.WHAT CAN BE DONE?Artificial intelligence (AI) has the potential to be used to find fractures on children's X-rays as accurately as a radiologist. AI is a computer programme trained to carry out actions usually done by humans - in this case to find fractures on X-rays. This could reduce the number of missed fractures, ensure children get the right treatment quickly, reduce inefficiencies for parents and children, and save money for the NHS.HOW AND WHEN CAN THIS BE DONE?Step 1 (Year 1): A large survey of children and parents attending hospital will be carried out, asking their views about using AI for diagnosis and how best to introduce this in the NHS, helping us make our programme as acceptable to patients as possible.Step 2 (Year 2-3): A computer programme (using AI) will be developed to 'learn' which X-rays are normal and abnormal, using thousands of examples of X-rays from children who visited hospitals in the UK over the last 5 years. Step 3 (Year 4): The programme will be tested on new X-rays to see how many mistakes it makes, compared to radiologists. Step 4 (Year 5): The programme will be tested again to see if it would work in real life: how it would change the way emergency department doctors would care for a child and if it reduces mistakes, improves doctors' confidence in decision making, and is easy to understand. At this point, the programme could start to be made freely available across the NHS. HOW ARE PATIENTS INVOLVED?The Great Ormond Street Hospital (GOSH) Young Persons Advisory Group (YPAG) -h; a group of young people interested in medicine and research - and their parents have helped design this study. Four members have volunteered to join a Steering Group for this specific study. They will co-design patient surveys, make sure information about AI can be explained to patients in a user-friendly way and help share our results on websites and social media. HOW WILL THIS HELP PATIENTS?If this programme works well, it could be easily installed in every hospital throughout the NHS, helping doctors make the right decisions. More children's fractures will be correctly managed, quicker and more efficiently, ensuring all children get the right treatment, saving money for the NHS.This series of steps (asking patients and parents, developing a programme, testing it to see if it works, then checking that it works in practice) could become the standard way to develop AI programmes in the NHS, and used as an example for others to follow.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,MUSCULOSKELETAL;INJURIES AND ACCIDENTS HRCS22_20157,Cancer Research UK,CRUK,Novel Genome Integrity Pathways that regulate DNA Replication Termination in Metazoa,"Background: The mechanisms of chromosome replication preserve genome integrity and are fundamental to our understanding of cancer development. Moreover, DNA replication regulation provides multiple opportunities for new cancer treatments. The key step during initiation of chromosome replication is the assembly at replication origins of the DNA helicase known as CMG (CDC45-MCM-GINS), around which the replisome is assembled. Subsequently, CMG is stably associated with replication forks throughout elongation, but then is disassembled in the final step of DNA replication termination, leading to dissolution of the replisome. Recent work indicates that DNA replication termination is regulated by ubiquitylation of the CMG helicase, leading to replisome disassembly in a process requiring the CDC48/p97 ATPase. The E3 ubiquitin ligase and other factors that regulate replisome disassembly in higher eukaryotes have not been reported previously. Aims: This proposal explores the hypothesis that metazoa contain multiple genome integrity pathways that regulate DNA replication termination. The first pathway acts during S-phase, whereas the other mechanisms provide important backup during mitosis, ensuring that the DNA replication machinery is completely disassembled, before chromosome segregation and cell division. Methods: We will use the early embryo of the nematode C. elegans to identify and analyse the ubiquitin ligase that regulates replisome disassembly during DNA replication termination in metazoa. We will explore how the ligase is targeted to the replisome, and investigate the functional implications of replisome disassembly for genome integrity. Similarly, we will screen for factors that mediate backup pathways for replisome disassembly during mitosis, and then investigate how these factors are regulated, in order to preserve genome integrity. Finally, and guided by our study of replisome disassembly in the worm, we will investigate the E3 ligase and other factors that control DNA replication termination in mammalian cells. How the results of this research will be used: If successful, the delineation of multiple pathways for replisome disassembly in metazoa (worm/mouse/human), and the identification and functional analysis of various key players, will identify new candidates for potential future therapies.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_20028,Cancer Research UK,CRUK,Novel approaches to targeting pathogenic megakaryocytes and fibrosis in myelofibrosis,"Background Myeloproliferative neoplasms (MPNs) are bone marrow (BM) malignancies affecting 5-6 per 100,000 individuals/year. Myelofibrosis, the most severe MPN, causes destructive BM fibrosis, severe symptoms, and impaired survival, typically less than 5-10 years following diagnosis. Currently available drug therapies have little impact on fibrosis or survival, and new treatment strategies are urgently required. The key cellular drivers of fibrosis are the megakaryocytes, platelet-producing BM cells that are dramatically increased and over-produce fibrosis-stimulating factors in myelofibrosis. I recently performed the first comprehensive analysis of haematopoietic stem/progenitor cells (hSPCs) and megakaryocytes from myelofibrosis patients and controls, identifying key cell surface targets and transcriptional regulators for possible therapeutic development. Using a combination of single-cell approaches including simultaneous single-cell mutational analysis/RNA-sequencing, I identified that co-expression of megakaryocyte and stem/progenitor surface antigens selectively identifies malignant-clone derived hSPCs, indicating that bispecific antibody therapies may be an exciting new approach for targeting the malignant clone in MPNs. Aims I will focus on cell-surface, cell-intrinsic and cell-extrinsic features of the myelofibrotic BM to identify candidate targets for pre-clinical validation in the following aims: (1) Identification of candidate HSPC/megakaryocyte cell surface antigens for antibody-based therapeutic targeting; (2) Determine the molecular drivers of abnormal megakaryocyte development and function in myelofibrosis; (3) Determine the spatial relationship between megakaryocytes and stromal cells in myelofibrotic bone marrow and the cellular sources of abnormal matrix proteins. (4) Functionally validate priority targets in vitro and in vivo in patient-derived murine xenografts. Methods State-of-the-art, ‘multi-omic’ single-cell approaches and novel imaging platforms will be used including: combined protein/transcriptome profiling using DNA-barcoded antibodies (CITE-Seq/10X Genomics); validating potential molecular drivers of abnormal megakaryopoiesis using forward programming of human pluripotent stem cells for large-scale megakaryocyte generation; imaging mass cytometry to examine cell-matrix interactions, and the MISTRG humanised mouse model to establish patient-derived xenografts. How the results will be used My goal is to develop new therapeutic pathways for MPNs focused on the two major unmet treatment needs: specific targeting of the malignant clone and amelioration of BM fibrosis. These strategies would significantly reduce disease progression and improve outcomes for patients with these malignancies. Collaborating with industry partners in drug discovery and development (Evotec) and immunotherapy (Elstar Therapeutics) will help accelerate translation of research findings to novel therapeutics. Moreover, using single-cell transcriptome and proteome profiling to discover cancer cell-specific drug targets and to gain insight into tumour cell-niche interactions is highly relevant to other blood cancers as well as solid tumours.","Background Myeloproliferative neoplasms (MPNs) are bone marrow (BM) malignancies affecting 5-6 per 100,000 individuals/year. Myelofibrosis, the most severe MPN, causes destructive BM fibrosis, severe symptoms, and impaired survival, typically less than 5-10 years following diagnosis. Currently available drug therapies have little impact on fibrosis or survival, and new treatment strategies are urgently required. The key cellular drivers of fibrosis are the megakaryocytes, platelet-producing BM cells that are dramatically increased and over-produce fibrosis-stimulating factors in myelofibrosis. I recently performed the first comprehensive analysis of haematopoietic stem/progenitor cells (hSPCs) and megakaryocytes from myelofibrosis patients and controls, identifying key cell surface targets and transcriptional regulators for possible therapeutic development. Using a combination of single-cell approaches including simultaneous single-cell mutational analysis/RNA-sequencing, I identified that co-expression of megakaryocyte and stem/progenitor surface antigens selectively identifies malignant-clone derived hSPCs, indicating that bispecific antibody therapies may be an exciting new approach for targeting the malignant clone in MPNs. Aims I will focus on cell-surface, cell-intrinsic and cell-extrinsic features of the myelofibrotic BM to identify candidate targets for pre-clinical validation in the following aims: (1) Identification of candidate HSPC/megakaryocyte cell surface antigens for antibody-based therapeutic targeting; (2) Determine the molecular drivers of abnormal megakaryocyte development and function in myelofibrosis; (3) Determine the spatial relationship between megakaryocytes and stromal cells in myelofibrotic bone marrow and the cellular sources of abnormal matrix proteins. (4) Functionally validate priority targets in vitro and in vivo in patient-derived murine xenografts. Methods State-of-the-art, ‘multi-omic’ single-cell approaches and novel imaging platforms will be used including: combined protein/transcriptome profiling using DNA-barcoded antibodies (CITE-Seq/10X Genomics); validating potential molecular drivers of abnormal megakaryopoiesis using forward programming of human pluripotent stem cells for large-scale megakaryocyte generation; imaging mass cytometry to examine cell-matrix interactions, and the MISTRG humanised mouse model to establish patient-derived xenografts. How the results will be used My goal is to develop new therapeutic pathways for MPNs focused on the two major unmet treatment needs: specific targeting of the malignant clone and amelioration of BM fibrosis. These strategies would significantly reduce disease progression and improve outcomes for patients with these malignancies. Collaborating with industry partners in drug discovery and development (Evotec) and immunotherapy (Elstar Therapeutics) will help accelerate translation of research findings to novel therapeutics. Moreover, using single-cell transcriptome and proteome profiling to discover cancer cell-specific drug targets and to gain insight into tumour cell-niche interactions is highly relevant to other blood cancers as well as solid tumours.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_02856,Medical Research Council,MRC,Novel perimetry for identifying changes in visual field sensitivity in glaucoma,"Glaucoma is a chronic, progressive, degeneration of retinal ganglion cells, characterised by slow, irreversible loss of the peripheral visual field. Prognosis for vision is highest the earlier it is identified and treated. Perimetry, the clinical method for identifying visual field loss involves presenting stimuli (spots of light) to the retina to determine the dimmest that can be detected at multiple locations in the field. However, this technique has major limitations: a) low sensitivity to early damage, and b) high variability in moderate damage, making it difficult to identify further deterioration in those already diagnosed. The conventional test was developed >40 years ago, before the pathophysiology of glaucoma was understood, and has remained relatively unchanged since. With a design that is effectively arbitrary, it is unsurprising that glaucomatous changes are difficult to detect with the current standard clinical test. We recently discovered two functional biomarkers for glaucoma (changes in spatial and temporal summation) which will allow a redesign of perimetry for more accurate and precise measurements of changes in the visual field. In this multi-disciplinary, UK-wide, multi-site, project, we will initiate the path for translation of a novel, more evidence-based form of perimetry from laboratory to the clinical setting. This initial phase of the work will involve optimising clinical test parameters to maximise accuracy, test precision and efficiency in the novel test.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,EYE HRCS22_02683,Medical Research Council,MRC,Novel statistical methods for transcriptomic imputation to enhance understanding of causal mechanisms underlying human diseases,"Integrated analysis of genetic variation and transcriptomic data resources from large-scale tissue-based molecular profiling initiatives has improved understanding of the biological mechanisms controlling the regulation of gene expression across diverse tissues through the identification of expression quantitative trait loci (eQTL). Methods have been developed to detect association of complex traits with gene expression by: (i) building tissue-specific multi-eQTL models in these molecular profiling resources; and (ii) using these models to ""impute"" the transcriptome into genome-wide association studies (GWAS). However, existing transcriptome imputation methods typically: (i) do not take advantage of the observed correlations in expression between cell types driven by cross-tissue eQTLs; and/or (ii) do not account for eQTL model uncertainty, resulting in potential for over-fitting and increased false positive error rates. The overall aim of this proposal is to develop novel statistical methodologies for transcriptomic imputation into GWAS to address these limitations by harnessing multi-tissue expression to detect causal genes for complex human traits in a Bayesian Markov chain Monte Carlo framework to allow for model uncertainty. The methodology will be implemented in user-friendly and computationally efficient software, which will be applicable to individual-level genotype data or association summary statistics. The methodology will be applied to create a repository of imputed cross-tissue transcriptomic profiles across genes for all participants in the UK Biobank, which will be tested for association with rheumatoid arthritis and other musculoskeletal diseases, cardiovascular disease, cancer and diabetes. The repository will also be returned to UK Biobank for archiving and distribution to approved researchers to identify causal genes for any trait of interest available in the resource.",,1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),GENERIC HEALTH RELEVANCE HRCS22_01130,Medical Research Council,MRC,Novel strategies to improve the effectiveness of radiation and targeted therapies in lung cancer,"Lung cancer is a devastating disease and the leading cause of cancer death worldwide. The most common form of lung cancer is non-small cell lung cancer (NSCLC) and patients with early stage disease can be treated with surgery or radiotherapy. However, most NSCLC patients present with locally advanced or metastatic disease. In these cases, chemotherapy, with or without radiotherapy, forms the cornerstone of treatment. Unfortunately, the prognosis remains poor for these patients, despite the development of novel therapies targeted to specific oncogenic drivers (e.g. EGFR, ALK, ROS, RET). Therefore, this programme aims to identify and evaluate novel therapies and targets for their potential to improve outcomes in lung cancer. The areas of focus for this programme are (i) improving the therapeutic margin of radiation by combining with drugs that either modulate the radiation-induced DNA damage response (DDR) or reduce radiation-induced lung toxicity (RILT), (ii) understanding the biological responses of normal cells in the lung when exposed to radiation alone or in combination with DDR inhibitors, (iii) identifying new targets to improve the effectiveness of radiation therapy, and (iv) identifying approaches for combining DDR inhibitors with targeted therapies (without radiation) for potential use in metastatic disease where chemotherapy (with or without combination with targeted therapies) forms the backbone of treatment. The development of DDR inhibitors has progressed rapidly since the demonstration that PARP inhibitors show clinical benefit in patients with BRCA1/2 mutated tumours. This has stimulated the development of inhibitors targeting other components of the DDR, including Ataxia Telangiectasia mutated (ATM) and Ataxia Telangiectasia and RAD3 related (ATR). DDR inhibition is an attractive strategy to improve the effectiveness of radiation, but there remains uncertainty about increased normal tissue toxicity and how to select which DDR approach to use in a particular setting. This program aims to clarify how different classes of DDR inhibitor affect tumour and normal lung tissue, and to identify the DDR approaches that have the potential for the greatest therapeutic margin in lung cancer. Impact: This project will identify and characterise novel combination approaches for the use of DDR inhibitors in NSCLC patients with systemic/metastatic disease. This work will broaden the utility of DDR modulators from combinations with radiation and cytotoxic chemotherapy, to include combinations with cell signalling inhibitors which have greater potential for selective biological effects in tumour cells compared with normal tissues.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_23276,The Health Foundation,THF,Nudge based intervention supported by real time data analytics to improve mechanical ventilator wean – guiding clinical behaviour (ATTITUDE study),"Patients in intensive care units (ICU) are the most vulnerable of hospital patients and need close monitoring and delicate administration of complex therapy. Critical care therapies such as mechanical ventilation can save lives, but inappropriate use is associated with patient harm. Ventilator-induced injury, excessive fluid administration, uncontrolled oxygen therapy and inappropriate sedation can all worsen outcomes. This project aims to use behavioural insights methods to find out whether real-time data analytics and use of a clinical decision support tool can improve the quality of key critical care practices in an adult ICU. It will begin with a review of the existing evidence on the perceptions of clinical decision support aids in health care. The team will then survey doctors and nurses at Royal Victoria Hospital to find out what barriers there are for weaning, oxygen administration, sedation and fluid balance. They will also observe current practice. A behavioural intervention in the form of a clinical decision support tool, driven by real-time data analytics, will then be developed to ‘nudge’ practice, based on identified barriers. There will be other supportive interventions such as educational support if knowledge gap is identified as a barrier. The overall aim is to achieve a significant reduction in the duration of weaning. Improvement in care for patients on mechanical ventilators would lead to improved patient outcomes, including mortality, and reduced health care costs by a reduction in intensive care unit and hospital stay.",,8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_03843,Medical Research Council,MRC,Nutrient competition and metabolite production by the gut microbiota to reduce carbapenem-resistant Enterobacteriaceae growth in the human intestine,"Antimicrobial resistance is a serious threat to human health, resulting in treatment failures, infection relapses, longer hospitalisations, and poor clinical outcomes. The intestine is the primary colonisation site for carbapenem-resistant Enterobacteriaceae (CRE) and serves as a reservoir for CRE responsible for invasive infections (e.g. bloodstream infections). Antibiotics promote CRE intestinal colonisation and faecal microbiota transplantation (FMT) decolonise CRE from the gut. However, there are drawbacks to administering FMT to CRE colonised patients, and FMT needs to be replaced with new therapies that are more effective, safe, rationally designed, and doseable. I hypothesise that antibiotics kill gut microbiota members that compete with CRE for nutrients and/or produce inhibitory metabolites, creating a niche in which CRE can grow. I will develop new microbiome therapeutics consisting of a synthetic microbial consortium and inhibitory metabolites. Inhibitory metabolites will cause an initial reduction in CRE growth. The synthetic microbial consortium will colonise the intestine, outcompete CRE for nutrients, and inhibit CRE growth by producing inhibitory metabolites, resulting in a long-term reduction in CRE growth. An artificial gut model of CRE intestinal colonisation will be used to determine the effects of antibiotics and FMT on nutrient competition, metabolite production, microbial composition, and CRE growth in a faecal microbiota. Synthetic microbial consortia will be designed consisting of gut microbiota members that outcompete CRE for nutrients and produce metabolites that inhibit CRE growth. These new therapeutics will be tested in the artificial gut model to demonstrate their efficacy to inhibit CRE growth in faecal microbiota. This study has the potential to significantly impact clinical practice by developing a new treatment that could be used to prevent or treat CRE intestinal colonisation, and therefore prevent invasive infections.",,5.1 PHARMACEUTICALS,INFECTION;ORAL AND GASTROINTESTINAL HRCS22_23707,Cancer Research UK,CRUK,OPTIMISTICC: OPportunity To Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer,"Background Our Grand Challenge team investigators have discovered that bowel cancers and pre-cancerous states of the bowel are associated with distinct microbiota, including enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, and Fusobacterium nucleatum. Furthermore, we have pre-clinical evidence that treating bowel pre-cancers and cancers with anti-microbial agents can limit tumour growth. Aims Our research programme aims to understand how the microbiome contributes to the development and progression of bowel cancers, and to use this understanding to improve diagnosis and treatment. Our objectives are to: 1) Map the colorectal cancer microbiome. 2) Develop, test, and implement microbiome-targeted therapeutic approaches for colorectal cancer. 3) Share our data, methods, and concepts with the broader scientific, medical, and patient communities. Methods 1) Map the colorectal cancer microbiome. a. Bowel cancer risk: We will perform microbiome sequence analysis of stool samples and bowel tissues from 2000 individuals at risk for hereditary bowel cancer and 15,000 individuals at risk for sporadic bowel cancer, and will look for an association between the microbiome and cancer development. b. Epidemiology of bowel cancer: We will investigate a cohort of 10,000 colorectal cancers for microbiome characteristics and their relationship to geography, lifestyle, and tumour location. c. Bacterial localisation within tumours: We will use single-cell RNA sequencing and microscopic analyses to determine the composition, localisation and cellular associations of the microbiota within tumour tissue. 2) Develop, test, and implement microbiome-targeted therapeutic approaches for colorectal cancer. a. Modelling the impact of microbiota on cancer models: We will reconstitute the microbiota and immune cell components in organoid and mouse models of bowel cancer and measure their impact on tumour growth and behaviour. b. Patient response to treatment: We will investigate the association of the microbiota with patient response to therapies. c. A clinical trial of a novel therapeutic: We will perform the first clinical trial of a microbial community replacement agent in colorectal cancer. d. Development of novel therapeutics: We will investigate the pre-clinical development of anti-microbial approaches including vaccination, targeted antibiotics, and predatory bacteria. 3) Share our data, methods, and concepts with the broader scientific, medical, & patient communities. How the results of this research will be used Our research will test the hypothesis that the bowel cancer microbiota is tumour-promoting and assess methods to treat bowel cancer by microbiome modulation. We expect that this work will be used to improve and develop methods for bowel cancer treatment and control.","Background Our Grand Challenge team investigators have discovered that bowel cancers and pre-cancerous states of the bowel are associated with distinct microbiota, including enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, and Fusobacterium nucleatum. Furthermore, we have pre-clinical evidence that treating bowel pre-cancers and cancers with anti-microbial agents can limit tumour growth. Aims Our research programme aims to understand how the microbiome contributes to the development and progression of bowel cancers, and to use this understanding to improve diagnosis and treatment. Our objectives are to: 1) Map the colorectal cancer microbiome. 2) Develop, test, and implement microbiome-targeted therapeutic approaches for colorectal cancer. 3) Share our data, methods, and concepts with the broader scientific, medical, and patient communities. Methods 1) Map the colorectal cancer microbiome. a. Bowel cancer risk: We will perform microbiome sequence analysis of stool samples and bowel tissues from 2000 individuals at risk for hereditary bowel cancer and 15,000 individuals at risk for sporadic bowel cancer, and will look for an association between the microbiome and cancer development. b. Epidemiology of bowel cancer: We will investigate a cohort of 10,000 colorectal cancers for microbiome characteristics and their relationship to geography, lifestyle, and tumour location. c. Bacterial localisation within tumours: We will use single-cell RNA sequencing and microscopic analyses to determine the composition, localisation and cellular associations of the microbiota within tumour tissue. 2) Develop, test, and implement microbiome-targeted therapeutic approaches for colorectal cancer. a. Modelling the impact of microbiota on cancer models: We will reconstitute the microbiota and immune cell components in organoid and mouse models of bowel cancer and measure their impact on tumour growth and behaviour. b. Patient response to treatment: We will investigate the association of the microbiota with patient response to therapies. c. A clinical trial of a novel therapeutic: We will perform the first clinical trial of a microbial community replacement agent in colorectal cancer. d. Development of novel therapeutics: We will investigate the pre-clinical development of anti-microbial approaches including vaccination, targeted antibiotics, and predatory bacteria. 3) Share our data, methods, and concepts with the broader scientific, medical, & patient communities. How the results of this research will be used Our research will test the hypothesis that the bowel cancer microbiota is tumour-promoting and assess methods to treat bowel cancer by microbiome modulation. We expect that this work will be used to improve and develop methods for bowel cancer treatment and control.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_06759,Department of Health and Social Care,NIHR,OPTimisE - Optimising Physiotherapy for Tennis Elbow,"Background Tennis Elbow (TE) is a painful condition affecting an individual's ability to work. Physiotherapy is recommended but current NHS physiotherapy treatment varies widely and is sub-optimal. Agreeing and testing an optimal physiotherapy treatment could improve patients' outcomes, reduce the number of TE patients developing persistent symptoms and yield cost-savings to the NHS by reducing the need for more costly and invasive treatments, such as surgery. Objectives Develop an optimised TE physiotherapy intervention for use in the NHS Determine feasibility of recruiting and retaining patients with TE Determine treatment fidelity of, and adherence to, the optimised physiotherapy intervention Estimate the number of patients and hospital sites required for a future main trial.Method Phase 1:A consensus exercise involving 10-15 specialist physiotherapists, patients and physiotherapy managers to agree an optimised physiotherapy intervention for TE based on best evidence for use in the NHS. This will use Nominal Group Technique - a method involving ranking of component parts, group discussion and re-ranking to form consensus. A package of care and physiotherapist education package will then be developed. Phase 2a: A multi-centre pilot and feasibility randomised controlled trial (RCT) to determine whether an optimised physiotherapy treatment programme can be delivered, whether patients engage with it and whether a future main RCT evaluating it is feasible. Participants: Adults with TE identified from primary care and physiotherapy clinics. Intervention/control: Participants randomly allocated on a 1:1 basis stratified by site and duration of symptoms to a) the optimised physiotherapy intervention or b) usual physiotherapy treatment. Feasibility outcomes: 1) Rate of recruitment; 2) Attendance; 3) Adherence to treatment; 4) Intervention fidelity; 5) Intervention contamination; 6) Rate of retention, including outcome measure completion. Clinical outcomes: Elbow pain and function (Patient Reported TE Evaluation, Oxford Elbow Score, Quick-DASH) and quality of life (EQ-5D-5L) measured at baseline, 6 weeks, 3 and 6 months. Sample size: 60 participants. Analysis: Descriptive analysis focusing on feasibility outcomes. Phase 2b:Qualitative research with patients and physiotherapists involved in the pilot and feasibility RCT.Participants: Up to 20 patients (purposively sampled for variation in site, age, gender, TE pain and function, treatment adherence) and 10 physiotherapists from different trial sites. Methods:Face-to-face interviews focussing on acceptability of the optimised physiotherapy treatment programme from both the perspectives of patients and physiotherapists that may lead to further refinement of the intervention for a future main trial. Analysis: Thematic analysis.Anticipated impact and dissemination Outputs from the project will be disseminated in open-access peer-reviewed journals, conference presentations, the lay press and social media. These include: Pilot and feasibility RCT protocol Outcomes to assess whether delivery of the newly devised physiotherapy treatment programme is feasible, treatment fidelity acceptable and whether a future main RCT is feasible Evidence of acceptability of the intervention from the integrated qualitative element.Develop myself as a future NIHR research leader with skills and experience in leading a multi-centre RCT, qualitative research and consensus methods alongside leadership in research.","Background to the research: Tennis Elbow is a painful condition that makes it difficult to do work, hobbies and sports. Physiotherapy is recommended but at the moment physiotherapists use lots of different treatments. Research tells us that some treatments might work better than others but not all patients are getting the best treatment. If more patients got better physiotherapy treatment then outcomes could be improved and fewer patients would need injections or surgery. The NHS could also save money. Aim of the research: In this project we will decide what the best physiotherapy treatment package is for Tennis Elbow. We will then test whether it is fit to use it in the NHS. Design and methods used: Phase 1:We will use the best research evidence that mostly comes from Australia and adapt it for use in the NHS. We will ask specialist UK physiotherapists to help design this along with patients and NHS managers.Phase 2a: We will do a 'feasibility trial' to test this optimised treatment to see if physiotherapists working in the NHS can be taught to do it, that patients are willing to receive it and that the ways of measuring if it works are suitable. We will recruit 60 patients at physiotherapy clinics in three different cities. They will then be randomly given either the new optimised physiotherapy or the usual physiotherapy treatment that would have normally been given. Patients will then be asked to complete questionnaires before treatment, after 6 weeks, 3 months and 6 months to measure if their elbow pain is getting better. They will be given the option of doing this online using their smartphone/computer or on paper.Phase 2b:We will interview 20 patients and 10 physiotherapists involved in the feasibility trial to ask their opinions of how it went and how it could be improved. Analysis: We will decide whether it is possible to go ahead with a full research trial based upon: 1) The number of patients willing to participate 2) Whether patients actually attended their appointments 3) Whether patients did the exercises they were asked to do 4) Whether the physiotherapists gave the treatments that they were supposed to 5) Whether the optimised treatment was sufficiently different from usual treatment 6) Whether patients completed their questionnaires and whether they preferred the paper or online method 7) Whether the interviews suggested that the physiotherapists and patients were happy with what they were asked to do during the trial. Patient and public involvement: We already have a group of patients who have all had Tennis Elbow that have helped us design the project. These patients have expressed an interest in remaining involved and will help with design of all of the information given to patients to make sure that it makes sense and is easy to understand. They will also contribute to management of the study, help interpret the findings and report the results. Sharing the findings: At the end of the project we will share the results with participants, in medical magazines and in medical conferences. We hope that we will then be able to set up a full research trial to see if the optimised treatment is more effective than the current usual treatment.",6.7 PHYSICAL,MUSCULOSKELETAL HRCS22_01363,Medical Research Council,MRC,Oesophago-gastric adenocarcinoma: understanding disease pathogenesis and applications to earlier diagnosis,"Understand the underlying clinical, genetic and cell environmental factors that lead to the conversion of a low-risk pre-malignant state into invasive cancer. Find new diagnostic tools that will identify those patients who are at an increased risk of developing cancer. Improve the molecular characterisation of oesophageal adenocarcinoma and identify novel approaches for tumour classification, monitoring and therapy.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL HRCS22_19679,Cancer Research UK,CRUK,Oncogenic control of cell division,"Background: During cancer progression, cells encounter a range of physical environments that differ from those experienced by normal cells in a healthy tissue. These include increased interstitial pressure and over-crowding during phases of uncontrolled tissue growth. In addition, during the process of invasion and metastasis, cancer are likely to lose contact with their native ECM and their normal neighbours, and may even experience shear flow. Because of this, the ability of cancer cells to go on to form metastases depends on their being robust to changes in their extracellular environment. The potential of physical forces in the environment to perturb cell behaviour is especially high during division. To counter this, both normal and cancer cells tend to round up before they divide. In doing so, they assemble a mechanical rigid actomyosin cortex that provides mitotic cells with the space necessary to assemble a spindle. This is likely to be especially important in cancer cells, both because of the unpredictability of the tumor environment, and because cancer cells frequently need the space to assemble a spindle using multiple centrosomes that is large enough to align extra chromosomes. Aims: Here, to elucidate the mechanisms by which oncogenes make cancer cell divisions robust and independent of the environment - a likely pre-requisite for metastasis - we aim to determine: 1: How oncogenic signalling influences mitotic rounding, mechanics, and division. 2: How this contributes to the environmental sensitivity of cancer cells divisions. 3. How physical factors and oncogenes influence cell division in tumour spheres and patient-derived tumours. Methods: MCF10A::RasV12-ER cells will be used as a model system in which to determine the impact of oncogenic Ras-ERK signalling on division. Microfabrication will be used to build devices to modify the local environment in precisely defined ways to explore the environmental-sensitivity of these divisions (+/-RasV12). Tumour spheres will be used as in vitro models of metastatic tissue. Finally, with colleagues at UCL, we will explore and model the 3D environment experienced by mitotic cells in tumours isolated from patients. How the results of this research will be used: By shedding light on the role of oncogenes in enabling cancer cells to divide in hostile environments that would kill normal cells, we aim to identify weak points that make cancer cells susceptible to perturbations that do not harm normal cells. In doing so, we aim to open a door to future anti-cancer therapies.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_01841,Medical Research Council,MRC,One Health Drivers of Antibacterial Resistance in Thailand,"Our strategy for investigating drivers of antibacterial drug resistance in Thailand will be first to rank the influence of different material substances and actions that drive the increased prevalence of 3rd Generation Cephalosporin resistant Escherichia coli and Klebsiella pneumoniae, and Carbapenem Resistant Enterobacteriaceae in Thailand. We will do this by quantifying these bacteria and also chemicals (including antibacteirals) in humans, animals, and the environment, and ranking how strongly these chemicals can select for antibacterial drug resistance, and how well the various identified bacteria compete with and/or pass their resistance to other bacteria. We will then ascertain the importance of different actions in determining the abundance of the chemicals and bacteria under study. We will do this by ranking the contribution of different possible sources of resistant bacteria, by measuring the scale of antibacterial use in different human and animal populations and by using risk factor analysis to consider the relative importance of different actions as drivers of enteric colonisation of 3rd Generation Cephalosporin resistant Escherichia coli and Klebsiella pneumoniae, and Carbapenem Resistant Enterobacteriaceae. We will then conduct focused social science research to investigate the social, cultural, and economic drivers associated with antibacterial use and with heightened risks of human exposure to resistant bacteria. These diverse types of data will be used to construct a dynamic multilevel model of resistance transmission and containment. This phased approach will enable us to integrate our workstreams and identify antibacterial drug resistance-reducing interventions with the best likelihood of success. At all stages we will engage with Thai stakeholders and policy makers identified during the development phase, increasing impact",,2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),GENERIC HEALTH RELEVANCE HRCS22_17388,Wellcome Trust,,"One Health: human responsibility for animal health and welfare in Scotland, 1840-present","This is a collaborative, multidisciplinary project between Edinburgh University Library (EUL) and the Royal Zoological Society of Scotland (RZSS) to catalogue, preserve, selectively digitise and make available for innovative research three significant collections.These collections were identified because of intersections between research, evidence, and debate from different perspectives, human and animal health and well being. The archive collections are from animal protection charity OneKind, Royal (Dick) Veterinary College and Royal Zoological Society of Scotland (RZSS). The objectives are to: • create interoperable standards-compliant digitally-online catalogues • ensure long-term preservation by rehousing collections in archival-quality enclosures; • carry out interventive conservation work on at-risk items; • digitise key illustrative material and make available through interactive technology for public and research access; • design and create a dynamic website for catalogues, providing contextual information for public engagement and research; • undertake interdisciplinary research using collections, including analysis of datasets; • engage research communities and wider public through social media, articles, talks, conferences, interventions and engagement events; • lay the foundations for further projects, funding for research and public engagement, scoping further related collections and forging partnerships with other institutions with related material. • Create a better understanding of the relationships between human and animal health and changing historical trends and ethical positions.",,1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),GENERIC HEALTH RELEVANCE HRCS22_17981,Wellcome Trust,,One cell at a time: building the Human Cell Atlas,"The Human Cell Atlas aims to understand cells at a fundamental level and what this means for health and disease. Our ambitious public engagement programme will explore fundamental questions embedded within the HCA research such as “What does it mean to be normal?” and “What influences peoples’ value and trust in research involving tissue donation and open access data?” We have identified audiences with whom engagement with HCA science has particular relevance. These are: 1) patient groups affected by conditions investigated as part of the HCA, 2) existing and potential organ donors, 3) communities not often represented in conversations around healthcare research and organ donation, and 4) education cohorts whose learning experience could be influenced by the research. Our vision through the engagement with our target communities is to improve outcomes related to the value and trust people place in research with consequent impact on willingness to donate tissue for research, share their data and help to identify areas of unmet need that the HCA could tackle.  Our impact also extends to the global HCA consortium, where the methods and resources created and tested through our work will be made available to the wider community.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,GENERIC HEALTH RELEVANCE HRCS22_09404,"Public Health Agency, NI",PHA,Opportunity-Led - Developing system-oriented interventions to reduce car dependence for improved population health in Belfast,"Reducing car dependency has the potential to contribute to several of the Sustainable Development Goals. None of these can be achieved through single component interventions and thus our theoretical framework for developing and testing our proposed intervention(s) will be informed by complex systems science. Our focus will be on communities where car use is high and our assumptions are that dependency is shaped at multiple levels: at the level of the individual and by the social (e.g. norms), urban and political environments. Thus it is necessary to understand influences at the macro (e.g. urban and political environments), meso (e.g. social context) and micro (e.g. individual) levels to devise and sustain effective interventions to reduce car dependency. Further, their integration within community and urban ecosystems must be tied intrinsically and dynamically to social and ecological relations that bear upon transport management policy and governance. The overarching aim of this project is to co-develop sustainable and scalable systems-level interventions at the intersection of (environmental) infrastructure and (individual) agency to reduce car dependency for improved population health.",,3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,GENERIC HEALTH RELEVANCE HRCS22_23316,LifeArc,,Optimisation of a gene therapy for Oculopharyngeal muscular dystrophy,"Around 1 in 100,000 people globally are diagnosed with the genetic condition Oculopharyngeal muscular dystrophy (OPMD) – although rates are higher in some populations. The condition is caused by defects in a gene that makes PABPN1, a protein that plays a part in several important biological processes. The genetic defects cause the protein to form clumps in cells in the muscles important for lifting the eyelids and for swallowing. It can also affect some arm muscles. The team has collaboratively been optimising a gene therapy approach based on injecting modified viruses that can act as very efficient carriers (vectors) of DNA into skeletal muscle. The vectors carry information that inhibits the production of all PABPN1 made in the cell and makes new protein without the mutation. Currently a number of gene therapies are being tested clinically for the systemic whole-body treatment of rare genetic muscle diseases. While the vector the team has collaboratively developed for OPMD works well when injected directly into the muscle, for long term benefit clinicians would need to treat many muscles in each patient. The team is therefore looking to design a new vector to allow whole-body bloodstream delivery to treat multiple skeletal muscles in the body. The project is using a different vector type with several modifications to the DNA it contains so that it is suitable for skeletal muscle, with the ultimate aim of treating patients with a single injection. This would improve patients’ treatment options, clinical outlook and quality of life. The team will optimise the DNA that encodes the normal protein that is missing in affected cells and screen cells to find the best performing sequence to include in the final gene therapy product. They will also screen other regulatory DNA sequences to minimise the expression of the vector in tissues other than skeletal muscle. These new features will be enclosed in a single vector that will be tested by bloodstream delivery in a mouse model of OPMD, allowing researchers to examine improvement in the function of affected muscles.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES,MUSCULOSKELETAL HRCS22_15021,Cancer Research UK,CRUK,Optimising Immuno-oncology Approaches in Oncology,"Background: The MRC Clinical Trials Unit is the largest of its kind in Europe, running practice changing trials in cancer, infections and neurodegenerative disease. A key programme of activity within the MRC CTU is 'affordable and effective cancer care'. Immune checkpoint inhibitors (ICI) are an approach that has revolutionized cancer treatment, stimulating the body's own immune system to control or eradicate cancers, yet as intravenous (antibody) drugs are burdensome to patients and prohibitively expensive for many health economies. Aims: I aim to undertake a piece of original work within this programme at the MRC CTU, contributing to efforts to optimize ICI treatment across the common cancers. Methods: I will have the opportunity to progress a piece of translational work allied to the REFINE trial (REduced Frequency ImmuNe ChEckpoint inhibition) that is currently in set up and due to open to recruitment by the end of 2021. This will allow us to better understand the pharmacokinetic aspects of extending the interval between ICI treatment in responding patients. REFINE is one of a number of trials testing reduced treatment in cancer, a concept that is naturally challenging to the public and participants within clinical trials. A second strand of my research will work with the PPI groups on these studies, developing common themes and approaches for trials that will ensure optimized questions and recruitment alike. Finally there are a number of academic and commercial studies testing adding ICI to radical treamtent (including the IMPART project at MRC CTU). Through a basket approach I will collaborate with the methodology and meta-analysis groups at MRC CTU to identify the shortest duration of ICI likely to generate the maximal benefit in this situation. How the results of this research will be used: The outcome from these three strands of work, in the context of internationally relevant studies will contribute meaningfully to global cancer care. Furthermore in being exposed to three different areas of work allied to clinical trials I will learn a huge amount in an exceptional environment and fulfill the requirements for a rewarding and high quality PhD",,6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),CANCER AND NEOPLASMS HRCS22_07217,Department of Health and Social Care,NIHR,"Optimising key components of the community mental health policy through implementation of the PARTNERS intervention: learning about personalisation, integration and team-based supervision.","Research questions 1. How can team-based supervision, alongside personalisation and coaching approaches be integrated into practice in the context of a community mental health transformation programme? 2. What enables implementation of the PARTNERS2 service and what are the lessons for policy? Background The NIHR funded PARTNERS2 research programme and NHS England s new policy framework for community mental health both seek to address the enduring problems of community mental health practice: Poor integration between secondary care services, primary care, and the voluntary and community sector; A gap in provision for those discharged from secondary care but not suitable for Improving Access to Psychological Therapy services; and Poor integration between mental and physical health. PARTNERS2 involves a cluster randomised trial and parallel process evaluation of a complex intervention which utilises a person-centred goal setting and coaching approach to address individuals biopsychosocial needs. Co-designed with PPI stakeholders the intervention comprises initial and top-up training for Care Partners, a manual, one-to-one supervision and meta-supervision for supervisors. Concluding the trial and evaluation, we are specifying the mechanisms of supervision and the practices of personalised care, and of working with other services. Our evidence based learning about personalisation, integration and team-based supervision has the potential to optimise the key components of community mental health policy. Aims and Objectives Aim: To enhance the pilot phase of the NHSE community mental health transformation programme, by applying knowledge gained from PARTNERS2: providing evidence regarding the core components required to enhance policy specification and the successful delivery of place based mental health services. Objectives: 1. To apply learning from core components of the PARTNERS intervention - supervision, coaching approaches and integration of care - within two of the policy programme pilot sites. 2. To evaluate and refine theory for how practice and supervision support personalisation and integration of care. 3. To develop policy and practice guidance for supervision, personalisation and integration of care for individuals with significant mental health problems. Research Methods Knowledge generated by PARTNERS2 will be applied directly within two new pilot sites from the community mental health transformation programme. We will co-design working arrangements with each site and tailor our approach to local context. An implementation-oriented realist evaluation (comprising stakeholder workshops, interviews, tape assisted recall, and rapid feedback to sites) will be guided by the Consolidated Framework for Implementation Research, focusing on areas which challenge and enable implementation, and to provide lessons for current policy. Timelines Co-design with PPI, clinical and policymaking stakeholders, implementation, rapid on-line evaluation, real-time feedback, and dissemination will be undertaken within 12 months. Anticipated Impact and Dissemination We will demonstrate how supervision can support personalised responses to individuals with a range of complex mental health problems, enabling policy makers to operationalise the vision of integrative and personalised health care goals. Building on our established involvement in the NHSE transformation programme, engagement and dissemination will be extended from co-design with the two pilot sites, to sharing findings and learning with all twelve NHSE transformation pilot sites, and wider clinical, academic and service user networks.","Background We have been working for the past few years on a research programme called PARTNERS2. Developing a new model of care for people with mental health problems so they can receive better support in primary care. The idea is based upon improving three things: • Helping services to join up so that people s care is more coordinated. • Ensuring that the care people receive meets their specific needs, what we call person-centred care. • Creating a strong supervision structure, so that those providing support are well supported themselves. We believe that the findings from our PARTNERS2 research will be useful for new policies that are currently being tested in twelve community pilot sites by NHS England. Three members of our team are involved with these community pilots and NHS England have agreed that learning from PARTNERS2 would be useful. Therefore, we are proposing a 12-month project to share our learning, directly to sites that might benefit, and gather more feedback so we can better support implementation of this community mental health policy. What will we do? We will support two community pilot sites to use learning from PARTNERS2. We will provide them written manuals, training and supervision for practitioners. We will collect more information to explore what works well and less well as they adopt and adapt PARTNERS2 to their locality. Specifically, we aim to: • Learn about how two parts of the PARTNERS intervention work: a) our coaching approaches b) the ways of joining up care for people across primary and secondary care and the voluntary and community sector. • Develop better understanding about how supervision supports person-centred and joined up approaches to care. • Produce more guidance to support implementation This will be possible through the following research activities: • Workshops in each site with key stakeholders to understand their local mental health care systems, their community pilot site plans and how PARTNERS2 findings could be used and what may enable or challenge implementation; • Work with practitioners and supervisors, training and supporting up to twelve staff members in coaching approaches. Follow progress through research interviews and digital recordings of practice sessions. • Looking at data collected locally. The information will be used to produce a series of case studies, to tell the story of how this work was undertaken and any successes or difficulties encountered. PARTNERS2 has an active service user advisory group and members will be involved in advising us and assisting with dissemination including blog writing, planning and hosting events, and developing a policy paper. Final outputs will include a peer review publication, infographic, a tweet chat, and zoom workshops to engage all twelve community pilot sites in this final phase.",8.1 ORGANISATION AND DELIVERY OF SERVICES,MENTAL HEALTH HRCS22_06165,Department of Health and Social Care,NIHR,Optimising patient risk management in urgent primary care services,"Research questions 1. What structural/organisational resources are available in urgent care services to keep patients safe? 2. What patient risk management work is performed by staff, and how? 3. To what extent is safety-netting/follow-up advice recalled and understood by patients/carers? 4. How can patient risk management in urgent care services be optimised? Background The accurate assessment and management of clinical risk is challenging in urgent care settings (NHS 111, GP Out-of-hours and Urgent Care/Treatment Centres). Safety-netting (informing patients/carers when to reconsult and how) and follow-up advice (planned future review) are key strategies for managing risk. Inadequate safety-netting and follow-up can lead to avoidable patient harm, reputational damage to staff and providers, and incur high NHS medico-legal costs. Urgent care is provided by a variety of organisations, and no evidence currently exists as to best practice. I will address this gap, with key stakeholder involvement, in order to optimise patient risk management during episodes of care. Research objectives i. To map the resources for patient risk management available across urgent care services; ii. To analyse staff safety-netting and follow-up practices; iii. To identify organisational and staff barriers to patient risk management; iv. To assess patient/carer recall and understanding of safety-netting and follow-up advice; v. To identify patient/carer information needs and barriers to implementing advice; vi. To translate the findings into actionable insights to optimise patient risk management. Methods Following the Donabedian model, I have designed four work packages (WP) to collect data on structure, processes of care and outcomes. In WP1, I will design and administer a national survey of urgent care providers to document the range of structural and organisational resources being used to support the management of patient risk. Data analyses will document barriers, map variation and identify 'typical' and 'atypical' services. In WP2, I will recruit six 'typical' services (two NHS 111, two GP Out-of-hours and two Urgent Care/Treatment Centres) for an in-depth comparative case study on processes of care. I will employ ethnographic and conversation analytic methods to characterize how everyday risk work is performed by staff, and how safety-netting and follow-up advice are communicated. In WP3 I will design and administer patient/carer questionnaires, and conduct interviews, to assess the extent to which they recalled and understood any advice given; whether it met information needs; and determine outcomes. Data analyses will identify key components that comprise more and less 'successful' advice, and barriers to implementation. In WP4 I will integrate the findings from WP1-3 and recruit clinical leads and staff from NHS111, GP Out-of-hours, Urgent Care/Treatment Centres and General Practice, to focused group discussions in order to identify and prioritise actionable improvement targets. Timelines for delivery Key deliverables are planned for each WP over a four-year period. Anticipated impact and dissemination Evidence-based quality/safety improvement resources will be made available via the FutureNHS platform that will have immediate impact for services and patients/carers and longer term efficiency savings for the NHS. A knowledge mobilisation plan for engagement and dissemination will be developed with, and for, end users.","Aims of the research Urgent care services (NHS 111, GP Out-of-hours, and Urgent Care/Treatment Centres) play a vital role in assessing patients when GP surgeries are closed. These services typically deal with non-life-threatening conditions, but also conditions that are potentially life-threatening. We know very little about the risk management work being done by urgent care services; by their staff; and by patients/carers themselves. The proposed project aims to fill this knowledge gap and to inform quality and safety improvements. Background to the research Patient risk management is very important in the urgent care context because initial assessments are often done by telephone which can make it difficult to rule out serious illness. Even when patients are seen, staff are unlikely to know them, or necessarily have direct access to their records. In a national analysis of patient safety incidents, urgent care services were responsible for the highest incident rates; with communication failures, with and about patients, most common in these settings including failing to tell patients what to do if their condition worsens (inadequate safety-netting) or not making appropriate onward referrals (follow-up). Design and methods used I will address the following questions: 1. What structural and organisational resources are available in urgent care services to keep patients safe? I will recruit leaders of 40 organisations providing urgent care services across England for a focused telephone survey in order to document and map the range of resources (tools/technologies) in place to keep patients safe. 2. What patient risk management work is performed by staff, and how? I will recruit six services as case studies and spend a four-week period in each, making observations, interviewing 30 staff, recording 180 staff/patient/carer encounters, and reviewing patient record entries. This will allow me to explore the nature and context of risk management work such as delivering safety-netting advice to patients/carers. 3. To what extent is safety-netting and follow-up advice recalled and understood by patients/carers? I will ask 125 patients/carers whose encounters I recorded, whether they recalled and understood any safety-netting/follow-up advice given, and what happened next, in a telephone questionnaire 10-14 days later. The advice recalled will be compared with the advice given. I will then interview 30 patients/carers to understand more about their experiences of using that particular service, including their motivation, and any information sought beforehand. I will explore advice 'successes', as well as potential 'failures', and ideas for improvement. 4. How can patient risk management in urgent care services be optimised? I will recruit 54 staff from NHS 111, GP Out-of-hours, Urgent Care/Treatment Centres, and GP surgeries to participate in eight focused group discussions. I will share the project findings and ask them how they think quality and safety might be improved. Patient/service user and public involvement My project plan has been influenced by conversations with service users, staff, and service leaders, over the last two years. All agree that patient risk management is a crucial area for improvement and that my aims are achievable. A diverse Service User Group will be involved from start to finish, and two members will help steer the research in my Project Advisory Group. Experts from National Voices, the leading coalition of health and social care charities in England, will also provide strategic advice and input throughout. Dissemination During the research I will provide accessible updates on a project webpage, publish in academic journals and present at conferences. I will work with arts practitioners to help engage the public. I will share quality and safety improvement resources with services, meet with key national decision-makers, and hold a meeting to share the overall findings with relevant stakeholders.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_06908,Health Education England,HEE,Optimising psychological treatment for Anxiety DisordErs in Pregnancy: a feasibility study for a Trial of time-intensive CBT versus weekly CBT (ADEPT),"Background: There is increasing recognition that antenatal anxiety disorders are common, affecting 11-16% of women. They are by definition functionally impairing, can persist into the postpartum and can affect parenting. Antenatal anxiety has also been associated with elevated risks of behavioural problems in children. Children of parents with anxiety disorders are at increased risk of developing an anxiety disorder themselves. Therefore there is a clear need for effective treatment during pregnancy. Cognitive-behaviour therapy (CBT) is a well-evidenced treatment for anxiety disorders. Recently, time-intensive versions of CBT have been developed in non-perinatal populations, with comparable treatment effects achieved in a much shorter time for Obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), panic disorder and social anxiety. Most women are in contact with services when pregnant and it is therefore a good time to intervene. Time-intensive CBT for antenatal anxiety disorders has the potential to alleviate maternal symptoms quickly and to prevent negative outcomes for parenting and children. The study will investigate whether (1) antenatal time-intensive CBT (IN-CBT) is acceptable to women with anxiety disorders and; (2) if it is feasible to test the effectiveness of IN-CBT compared with standard CBT in a full-scale trial. Plan of Investigation: The primary objective of the research is to test the feasibility of a definitive trial of antenatal IN-CBT against standard weekly antenatal CBT for anxiety disorders. This will be achieved by two sequential phases of the study: the first stage is the development and piloting of intensively delivered antenatal CBT for anxiety disorders in a case series so that it is tailored and relevant to the specific context in which it is delivered. The second stage is a feasibility study to see if it is possible to test the designed intervention in a full-scale trial with 30 women recruited into each of IN-CBT and standard weekly CBT. This will establish: (i) the best means of recruiting women (physical or mental health settings) (ii) if participants will be randomised (iii) if the intervention is delivered as intended (iv) the acceptability of the interventions (v) the properties of the primary outcome measure and (vi) follow up rates for participation in a full trial. Qualitative interviews will determine the perceived value, benefits, harms or unintended consequences of the intervention that should be measured in a full trial, the value that service providers and users place on the intervention and the outcomes it plans to deliver.This information will establish whether a full trial is appropriate and feasible. Potential benefits to patients and the NHS: In a fullscale trial, if this mode of delivery was found to be superior in terms of benefits for both mother and child, this would change practice regarding treatment of antenatal anxiety disorders. Given the recent expansions of primary care and perinatal services, there are increasing numbers of well-trained CBT therapists who could deliver IN-CBT. Evidence from this research therefore has the potential to shape their practice, focus resources and be of direct benefit to patients within a short time frame. Importantly, effective antenatal treatment could also benefit children and the wider family in terms of reduced exposure to maternal anxiety and less impact on parenting and relationships. Ultimately this could improve the burden on NHS services for adults and children.","Aims of the research: The aim of this research is to investigate if a shorter format of a well-established psychological therapy for anxiety disorders can be used with pregnant women. It will establish if pregnant women find this format acceptable and useful, and if this way of delivering the treatment can later be tested in a large trial. Background to the research: Anxiety disorders include a range of problems including panic disorder, post- traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) and social anxiety disorder. They affect approximately 11% of pregnant women, impact on women's day to day functioning and often last into the postnatal period if untreated. In mothers, parenting, breastfeeding and mood can be affected and children are at an increased risk of developing behavioural and emotional difficulties. Anxiety during pregnancy has been linked to these effects on children and it is therefore an important time to treat maternal anxiety disorders.Cognitive behaviour therapy (CBT) is known to be an effective treatment for anxiety disorders. Many women prefer psychological treatments to medication during pregnancy and so this is often a good fit for women with these disorders. CBT is usually delivered over a period of three months. Recently, good results have been demonstrated with CBT delivered in fewer but longer sessions over two to three weeks for OCD, PTSD, panic disorder and social anxiety. However this format has not yet been tested with pregnant women. Fast, effective treatment delivered in pregnancy may be appealing to women with anxiety disorders and may be more effective than standard CBT in reducing negative effects on parenting and children. Design and methods used: This research will first develop a protocol for the delivery of time-intensive CBT (IN-CBT) for OCD, PTSD, panic disorder and social anxiety disorder. This will be tested with a small number of pregnant women with anxiety disorders and feedback will be sought from participants on outcome questionnaires and assessments for the study. The next part of the research will be a small trial (known as a feasibility study). Women taking part will receive either IN-CBT or standard CBT for their anxiety disorder. This will establish if IN-CBT is acceptable for women, the best way to reach potential participants and if enough women will take part in a trial and will complete postnatal outcome measures. Detailed interviews with women undertaking the treatments will investigate views of both versions of CBT and if the study assessments are acceptable and useful. This information will determine if a larger trial testing IN-CBT against standard weekly CBT will later be possible. If found feasible in this study, a larger trial would then examine whether IN-CBT for antenatal anxiety disorders is more effective in reducing negative outcomes for mother and child than standard weekly CBT. Ultimately, if the intensive format of delivery was found to be better in terms of benefits for both mother and child, this research would influence practice regarding treatment of antenatal anxiety disorders across the UK. Due to recent expansions of primary care and perinatal mental health services, there are increasing numbers of well-trained CBT therapists who could deliver this treatment. Evidence from this research therefore has the potential to shape practice, focus resources and be of direct benefit to patients within a short time frame. By reducing maternal anxiety it could also benefit children and partners of patients. Patient and public involvement: Service user groups have advised on the design of the study. An advisory group of service users will be set up for the study to provide input into the structure of participant interviews and interpretation of the results of the feasibility study. Service users will also be involved in publicising the results of the study. Dissemination: Results from the study will be publicised in presentations, workshops, journal articles, websites and social media. This will reach a range of audiences and national stakeholders including service users, maternity voices partnerships, clinicians and strategic clinical networks, managers, clinical directors, NHS sustainability and transformation partnerships, commissioners and researchers.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_05826,Department of Health and Social Care,NIHR,Optimising the efficiency and value of burn care research; prioritising evidence uncertainties and embedding agreed core outcomes to enable focussed registry-based RCTs.,"Background: World-wide burns affect 11 million people annually of whom 140,000 are in England. Most burns result in scarring which has life-long functional, psychological, and cosmetic consequences for patients. Management strategies and outcomes after burns varies between services. A contributing factor is a lack of quality evidence. Most burn randomised controlled trials (RCTs) are small, single-site and report different outcomes, limiting evidence synthesis. RCTs do not often reflect patient need and evidence gaps. Observational studies lack the strengths gained from randomisation. Although more and better RCTs are needed, they are expensive and challenging to conduct. Innovative registry-based randomised trials (R-RCTs) collecting the Core Outcome Set (COS) items are proposed as a solution. Before these are undertaken, feasibility work is required to optimise main trial design and conduct. Aim: To improve the burn care evidence base by identifying and prioritising evidence uncertainties and optimising the design and conduct of registry-based RCTs to assess core outcomes of relevance to patients, clinicians, and NHS. Objectives: Establish the evidence uncertainties and agree priorities for future burn research. Develop the final measures of the burn COS, and novel methods for embedding data collection within existing registries. Evaluate the feasibility of conducting an R-RCT in a pilot case-study of a prioritised evidence uncertainty.Methods: Three phases will be undertaken in partnership with patients. Phase 1: identify a long-list of evidence uncertainties through an umbrella review, patient and staff interviews and on-line survey. Prioritisation will be through collaboration with the James Lind Alliance (JLA) to achieve a 'top-ten'. One research question will be developed into a pilot RCT. Phase 2: develop and finalise core measures for the agreed burn COS using Core Outcome Set Measurement Instrument (COSMIN) methodology and embed data collection within existing UK and Australian registries. Phase 3: conduct a pilot R-RCT within the registries to establish if a main trial is feasible. Throughout will be the development of an international burn registry research group. Timelines for delivery: Phases 1 and 2 will be completed in two years. The remainder of the time will be spent undertaking the pilot. A dissemination plan, co-developed with patients, will engage clinicians, researchers, funders, and editors through professional organisations, conferences, delivery networks, COS organisations, registry reports and international webinars. Papers reporting literature reviews, interview and survey data, top-ten clinical uncertainties, core measures and R-RCT pilot will be published. Patient involvement will be through steering group membership, project co-delivery and dissemination through support groups, charities, and social media. Impact: The pilot work will demonstrate how to conduct an efficient R-RCT trial which will impact evidence-based NHS care. Methods will be relevant to other clinical specialties. Measures of the agreed COS will lead to improved evidence synthesis. The JLA work will identify important patient-centred research questions for others to use. Efficient evidence development will ultimately impact international guidelines and training, enabling standardised care and improved patient outcomes and NHS productivity. Global burn registry audit and research will increase equity of care. Public understanding of efficient quality research will be important.","Background: Burns affect 11 million people world-wide and 140,000 patients in England each year. Many burn patients have difficulties affecting daily life, such as walking, dressing, poor mental health and living with scars. Burn care is expensive due to operations, long hospital stays, and scar treatment. Despite the importance of these issues, there is limited research available to inform hospital staff how to make treatment decisions. Without strong evidence, staff will use their own preferences and do what they have always done. This limits progress, results in care that varies between hospitals, and means patients may not get the best results. The best evidence for doctors to use to make decisions, is from more than one trial. Evidence put together from several trials is much stronger. To do this, we need all trials to use the same measures of recovery (also called outcomes). Our earlier research with 700 patients and international staff, agreed upon seven important burn outcomes. These are: survival, wound infection, daily living activities, wound healing, long-term pain and itch, psychological problems, and time to return to school or work. We also need our trials to answer questions that are important. We need to do research to understand which clinical questions, patients and hospital staff think are the most important to answer and will most improve recovery. Trials also need to be designed and conducted efficiently. One way is to use routinely-collected data. In burn care, every hospital enters patient details into a database known as a registry. We intend to use this registry data to make trials easier and cheaper. Aims: 1.Agree with patients and hospital staff the top-ten burn care clinical questions lacking evidence. 2.Ensure the agreed outcomes can be routinely collected through burn registries. 3.Test the possibility of doing a large trial using data from UK and Australian registries. Methods: We will work with patients and staff through interviews, and using published research, to agree a list of clinical questions that have not been answered with previous trials. These questions will be ranked through a survey. The top 30 questions will be taken to a meeting with patients, and staff, to agree the top-ten. We will then make sure that we can routinely collect the chosen outcomes from two registries. Finally, we will run a small trial over five UK and Australian hospitals to see if we can test one research question using registry data. The results will show us if patients, doctors, and nurses are happy to take part, if we can collect outcome data from registries and if a larger trial is possible and worthwhile. Patient involvement: Patients will work in a partnership with researchers. Patients have helped to write this application and fully support this research. They will be involved through interviews, surveys, consensus meetings and communication of the results. Patients will benefit the research by drawing on their rich experiences and ensuring the work remains patient-focused. A patient group will advise on project design, progress and the feasibility of a large registry trial. An expert in patient involvement will provide support. Dissemination: The project results will be shared through published papers, conference presentations, newsletters, patient support groups, charities, and social media. Impact: This research will make sure that we use research funding and staff time to answer the most important questions in burn care, that we use the same agreed outcomes to assess patient recovery and that we do trials in the cheapest way. This will ensure evidence is produced more quickly and decision-making about treatment is based on evidence to benefit patients, not on localised historical practice.",8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);7.3 MANAGEMENT AND DECISION MAKING,INJURIES AND ACCIDENTS HRCS22_19786,Wellcome Trust,,Organisation and activation mechanism of AMPA glutamate receptor complexes,"AMPA receptor (AMPAR) operation underlies learning, while receptor malfunction is associated with various diseases. Their uniquely versatile signalling arises from numerous auxiliary subunits that assemble into functionally diverse receptor super-complexes. The combination and stoichiometry of these components, and how they shape neuronal response properties, remains a central open question.We will elucidate the pathways leading to activation of a predominant AMPAR, building on our cryo-EM structures of this receptor, associated with two structurally diverse auxiliary subunits. Using cryo-EM, MD simulations and single-channel recordings, we will assess the differential contribution of core- and auxiliary subunits to the receptor’s characteristic activation time course.We will also investigate the mechanism of leading neurotherapeutics on gating, capitalising on our AMPAR structures associated with these ligands, and study the role of the receptor’s lipid environment through reconstitution into liposomes. We will complement these studies with time-resolved cryo-EM of gating intermediates, and structures of native AMPAR complexes, isolated from mammalian synapses.These experiments will uncover the principles underlying AMPAR organisation and activation. We will derive a comprehensive kinetic model, delineating how activation is modulated by auxiliary subunits, lipids and neurotherapeutics. Elucidating the conformational states selectively targeted by these ligands will facilitate targeted structure-based drug design.","AMPA receptor signaling underlies information processing, while receptor malfunction leads to various brain disorders, rendering them strategic drug targets. The activation of an individual receptor - the process leading to opening of the channel’s pore in response to agonist binding - involves multiple conformational transitions. Their rates and energies determine how the receptor processes information. Activation is modulated by auxiliary proteins that are expressed in region-specific patterns, and by drugs selectively targeting AMPAR subtypes. We will use cryo-EM and high-resolution single channel recordings to study activation of a predominant forebrain AMPAR complex. We will elucidate the modulatory mechanism of two major auxiliary subunits, and of leading AMPAR therapeutics in this process. We will generate cryo-EM structures of activation intermediates and of native AMPAR complexes derived from neuronal synapses. Together, we will lay the framework to understanding the fundamentals underlying synaptic communication and the action of selective neurotherapeutics in this process.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_05614,Department of Health and Social Care,NIHR,Orthotics for Treatment of Symptomatic Flat Feet in Children (OSTRICH),"As a child grows the shape of their foot changes, and most develop an arch in their foot. This doesn’t always happen though, and sometimes the arch does not form, or it might be flat against the ground. When this happens, it is known as having flat feet. Unfortunately, some of these children get pain in their feet, legs, or back because of their ‘flat feet'. At the moment we are not sure which is the best treatment for them, so we are going to conduct a trial to compare three of the most common treatments that are used today. Two of the treatments we are going to test are different types of insoles, which are put inside the child’s shoe. The third treatment is some exercises which we will give children along with some advice about which types of shoes help._x000D_ _x000D_ If a child and their parent or person who looks after them decide that they would like to take part in the trial, they will receive their treatment as part of their normal NHS care. We would like 1085 children aged between six and 16 years old to take part in the study. 423 children will receive usual care and insoles that are individually customised for them; 423 will receive insoles that are of the right size but not customised (off the shelf) and 239 will receive usual care (advice on foot and ankle exercise and routing monitoring). We will ask for their help for 12 months. During this time, we will track their progress by sending them three questionnaires in the post to fill in and we will send them some text messages, to find out how painful their feet are during the first few months. We also want to learn more about the problems that flat feet have caused, and children’s experiences of the treatments delivered as part of the clinical trial. We will explore this through in-depth conversations with children and their parents or the person who looks after them. Once we have finished the trial, we will work with the people who took part in the trial, and clinicians, to make sure that our results can be used by as many people as possible.","Design: A multi-centre, three-armed, pragmatic individually randomised controlled trial._x000D_ _x000D_ Setting: Any primary or secondary care outpatient clinic providing care for children with symptomatic flat feet (pes planus)._x000D_ _x000D_ Target population: Children aged between six and 16 who have symptomatic pes planus. _x000D_ _x000D_ Inclusion criteria: Children aged between six and 16; Child and/or parents able to speak and understand English; Have one or both symptomatic flat feet; parent/legal guardian are able to give informed consent._x000D_ _x000D_ Exclusion criteria: History of major trauma to lower limb; Flat feet secondary to any systematic condition/syndrome/malignancy; History of foot and ankle surgery; Children requiring ankle-foot orthoses or other lower limb device._x000D_ _x000D_ Health technologies being assessed: (i) Pre-fabricated off-the-shelf orthoses plus usual supportive care; (ii) customised foot orthoses plus usual supportive care; (iii) usual supportive care, which will include a standardised exercise programme and footwear advice. _x000D_ _x000D_ Primary outcome: Physical domain subscale of the Oxford Ankle Foot Questionnaire for children (OxAFQ-C). _x000D_ _x000D_ Secondary outcomes: School and Play, Emotional and Footwear subscales of the OxAFQ-C; EQ5D-Y, text message pain scores sent to child’s parents; Child Health Utility (CHU9D). _x000D_ _x000D_ Measurement of costs and outcomes: Costs and outcomes will be measured at baseline, three, six and 12 months. These will be collected using a combination of postal questionnaires and medical records. _x000D_ _x000D_ Sample size: 1085 in a ratio of 2:2:1 (423:423:239)._x000D_ _x000D_ Qualitative evaluation: An embedded qualitative study will explore parental and child experiences of symptomatic flat feet, approaches to its management pre trial, and the impact of the symptoms on wider health, participation and family issues. Interviews at the start and end points of the study will provide rich narratives on parent and child experiences. Post trial interviews will also cover the experience and impact of the interventions used. _x000D_ _x000D_ Internal pilot/feasibility study: In the six months after set-up we will establish the feasibility of main trial in a pilot phase, which will include monitoring recruitment, adherence and completion of three month outcome measures. _x000D_ _x000D_ SWAT: We will undertake at least one recruitment and three retention SWATs._x000D_ _x000D_ The proposed start date of the trial is the 01.06.2019, and it will be 42 months in duration. _x000D_ Months 1-6 Preparation and submission of documentation for ethics and R&D approval etc._x000D_ Months 1-3 consensus development phase _x000D_ Months 3-12 Recruitment to internal pilot. To set up four to five sites, recruiting two or more participants a month _x000D_ Continuation to be agreed with funders_x000D_ Month 13- 24 Recruitment to the main trial (based on 30 sites recruiting 3 participants per month each)_x000D_ Month 25-36 follow up_x000D_ Month 37-42 statistical analysis and report writing_x000D_ _x000D_ 05.02.2019 update: We will undertake some additional process evaluation work. This includes: exploring barriers and facilitators to trial recruitment and experiences of being in the trial; interviewing clinicians about their experiences of trial recruitment and undertaking 30 observations of clinicians delivering the intervention.",6.3 MEDICAL DEVICES,MUSCULOSKELETAL HRCS22_18764,Wellcome Trust,,"Our Health, Our Voices. Engaging underserved audiences in health research.","“A diverse and inclusive public involvement community is essential if research is relevant to population needs and provides better health outcomes for all” (NIHR). Situated in the heart of a vibrant NHS and University research environment, a diverse patient population and communities with some of the poorest health outcomes in England, our team will deliver a 5 year programme of exceptional engagement, within the context of Greater Manchester’s devolved healthcare system. Based on our track record, knowledge and strengths, we will boldly experiment, learn from and reflect on, methods of working with people that address issues of social justice in health research. Our locally embedded long-term programme of activities will combine • Research-driven, arts-led approaches focusing on particular groups and scaled up to national audiences • Listening, responsive and relationship projects • Support for researchers and development of young and diverse engagement talent • Celebrating our communities who drive research • Sharing our learning far and wide, including through income generation methods Thus generating more informed and inclusive health research, and people supported to learn, question, and enabled to actively contribute to such research. Underpinned by significant organisational changes, including the launch of new business model maintaining our not-for-profit status, a communications overhaul, income generation and more efficient processes, we will enhance our reputation as pioneers in our sector, influencing positive change in people, research and practice. Ultimately, we aim to be recognised as an innovative centre for excellence in engaged health research, and a leading practitioner in the UK working with underserved audiences.",No Data Entered,8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_19470,Cancer Research UK,CRUK,Overcoming immunomodulatory drug resistance in myeloma,"Background: The plasma cell malignancy multiple myeloma remains incurable despite advances in therapy. Immunomodulatory drugs (IMiDs) are the backbone of standard and experimental combination therapies at all stages of disease. IMiDs bind to the CUL4 E3-ubiquitin ligase, cereblon, leading to the degradation of neosubstrates including Ikaros and Aiolos, mediating their downstream effects which include decreased expression of the B-cell transcription factor IRF4. Acquired resistance following exposure to IMiDs has been associated with decreased protein and mRNA expression of cereblon. No significant recurrent mutations have been identified in cereblon suggesting a transcriptional, e.g. epigenetic, mechanism may underlie acquired resistance. Mechanisms underlying intrinsic resistance are poorly understood but are not related to differences in Ikaros and Aiolos degradation or cereblon expression. Aims: I aim to identify and target the mechanism by which expression of cereblon is decreased in acquired IMiD resistance and which maintains cell proliferation, despite Ikaros and Aiolos degradation, in intrinsic IMiD resistance. I then aim to investigate the association of IRF4 mutations with outcomes in IMiD treated myeloma patients in order to uncover new insights into the biology of IMiD response. Finally, I aim to identify novel cereblon-binding compounds able to overcome intrinsic and acquired resistance and use these as tools to further explore mechanisms underlying IMiD resistance. Methods: Cell lines with acquired resistance to IMiD compounds have been generated and the DNA and histone methylation profile at the cereblon promoter will be studied to identify differences that may account for altered cereblon expression. Intrinsic resistance will be studied by analysing patient samples incubated ex-vivo with IMiDs prior to analysis. I will use proteomics to identify differences in neosubstrate degradation and RNA-seq to identify gene expression changes between sensitive and resistant patients. The downstream effects of IRF4 will be studied including the impact of the recurrent p.K123R IRF4 mutation. Isogenic cell lines with this mutation will be generated using PITCh-guided CRISPR and the effect on cell proliferation, gene expression and IMiD response examined. Finally, novel cereblon binding compounds will be screened to identify those able to overcome intrinsic and/or acquired resistance. Analysis of the differences in neosubstrate degradation that can overcome resistance will further inform our understanding of the mechanisms of IMiD resistance. Impact: The results of this research will further our understanding of IMiD resistant and refractory states, imperative to help identify pathways to target with novel therapeutics or combinations in order to improve patient outcomes.",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_07228,Department of Health and Social Care,NIHR,PANTHEON 2: towards an HIV self-testing implementation action framework and toolkit,"Background The NIHR PANTHEON PG generated a substantial body of evidence on HIV Self Testing (HIVST), including social science evidence concerning development, implementation and evaluation of HIVST among men who have sex with men (MSM) and trans people in England and Wales. The SELPHI RCT, conducted as part of the PG, demonstrated that HIVST delivery is feasible, acceptable and increases testing uptake. Questions remain as to how HIVST meets the needs of a diverse MSM population and how it is best situated alongside multiple testing opportunities prior to national implementation. Although there have been recent successes in increasing testing and reducing HIV incidence among MSM, these are not shared equitably. MSM are highly heterogenous with interconnected experiences of marginalisation related to ethnicity, migration status, educational attainment, social connectedness, gender and sexual identity. More nuanced understandings of need are required to support HIVST implementation in a way that responds to existing inequities while improving health. Aims and objectives Our aim is to contribute to improving the health equity in MSM in England and Wales by guiding and promoting the commissioning of HIVST. Objectives: Developing a nuanced understanding of the role of social networks, community norms and isolation in relation to HIV testing, and describe how this can be harnessed to optimise HIVST implementation and HIV prevention more broadly. Exploring the role of HIVST in relation to the broader landscape of clinical services, in particular how marginalised MSM perceive HIVST in the context of other testing options. Coalesce all the outputs from the PANTHEON PG with the new in-depth analysis conducted here into an implementation action framework and toolkit to facilitate HIVST rollout across England and Wales. Development work plan Substantial qualitative data collected during PANTHEON will be re-analysed supporting development and implementation of an HIVST rollout plan. Existing data includes 6 focus groups with 47 MSM, 95 in-depth interviews with SELPHI participants and 18 key informant interviews. Work Package 1 will analyse accounts of social networks, community participation and isolation to explore how social ties and connections shape decisions, beliefs and behaviours regarding HIV testing generally, and HIVST in particular. Work Package 2 will develop a better understanding of the utility of HIVST for MSM facing marginalisation based on ethnicity, migration status, educational attainment, social connectedness, gender and sexual identity by analysing accounts of HIV testing decision-making, including concerns about anticipated results and beliefs around test accuracy. Work Package 3 will synthesise all previous outputs from the PANTHEON PG, published literature and outputs from work packages 1 & 2 into an implementation action framework and toolkit to support HIVST rollout across England and Wales. We will use the Consolidated Framework for Implementation Research to propose intervention adaptations to increase the reach of HIVST taking account of issues of marginalisation to meet the needs of those least likely to be engaged by testing services. Anticipated impact and dissemination This grant will support the rollout of HIVST to contribute to the elimination of HIV and the well-being of MSM in England and Wales.","Through our previous work we provided evidence about a new way of testing for HIV, where a person tests themselves for HIV and finds out their result on their own without a healthcare worker present. This is called HIV self-testing (HIVST). We focussed on gay men and trans people because they are at most at risk of HIV in the UK. They can also experience barriers to accessing health care (including HIV testing) due to stigma related to gender and sexual identity, as well as migration status, ethnicity, and social circumstances. Gay men and trans people need to be supported to test for HIV regularly to diagnose infections early as this enables access to HIV treatment for individual health benefit and to prevent onward transmission to others. Our previous research found that gay men and trans people agreed that HIVST should be available as a testing option for them and that they found the test easy to do on their own. Our research also found through a large trial that giving gay men and trans people HIVST kits increased how often they tested for HIV over a 2-year period compared to not being given the HIVST kits. However, despite the evidence we provided there are no current plans to roll-out free HIVST to at-risk groups across England and Wales. This new grant will look at how best to roll out national access to HIVST as an alternative to testing for HIV in health care settings. To do this, we will re-examine extensive data collected through our previous trial and our interviews with gay men and trans people. This will help us to understand better how gay men and trans people view HIV testing in general, and self-testing in particular, and how HIVST can bridge any gaps in testing access and encourage those at risk of HIV to test more regularly. At the end of this study, we will develop a strategy framework to guide policy makers and organisations who plan and fund services on how best to provide national HIV self-testing to reduce health inequalities for gay men and trans people. We will also produce 6 short videos for social media exploring the experiences of individuals who have HIV self-tested and services that provide HIV self-testing. We will have an advisory group to guide the research which will include people living with HIV as well as policy makers. We expect our research to benefit gay men and trans people in England and Wales by providing information about how best to provide new HIV testing options to meet HIV testing needs. Increased use of HIVST will also free up resources and capacity in health care settings that provide face-to-face HIV testing.",4.3 INFLUENCES AND IMPACT,INFECTION HRCS22_02116,Medical Research Council,MRC,PHASE: The Population Health Agent based Simulation nEtwork,"Major population health challenges including non-communicable diseases are not a product of simple, linear causal relationships, but of numerous interdependent and interacting processes, operating at multiple levels. In this context, population health research is increasingly adopting the complex systems perspective - a whole-system view centered on modelling the interactions between individuals and their social and physical environments. Agent-based modelling (ABM) is a complex systems simulation methodology that models individuals embedded in a physical and social environment, with their actions determined by simple decision rules. ABMs can model both individual health behaviours and their upstream determinants, enabling us to better understand the tangled web of processes that drive health and generate inequalities at the population level. PHASE will facilitate the application of ABMs in population health through education, training and collaboration. Network activities will address issues of critical importance to enabling population health researchers and decision makers to apply ABMs: appropriate problem domains; best practices for model development; technical training; and ABM reporting guidelines. Working groups will develop documentation protocols, best-practice guidelines, and computational training. Our initial membership includes population health scientists, ABM specialists, health policy and practitioner groups and industrial collaborators, all of whom will be invited to contribute to our events and working groups. PHASE will also create an ABM study registry that will allow stakeholders to seek help with problems that may benefit from an ABM approach. PHASE will particularly seek to engage with evidence users and researchers from multiple disciplines to generate new transdisciplinary teams that will apply ABMs to important challenges in the prevention of non-communicable disease. This grant is funded by the UK Prevention Research Partnership (UKPRP) which is administered by the Medical Research Council on behalf of the UKPRP's 12 funding partners: British Heart Foundation; Cancer Research UK; Chief Scientist Office of the Scottish Government Health and Social Care Directorates; Engineering and Physical Sciences Research Council; Economic and Social Research Council; Health and Social Care Research and Development Division, Welsh Government; Health and Social Care Public Health Agency, Northern Ireland; Medical Research Council; Natural Environment Research Council; National Institute for Health Research; The Health Foundation; The Wellcome Trust.",,2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION),GENERIC HEALTH RELEVANCE HRCS22_06865,Department of Health and Social Care,NIHR,PHOENIX-Feasibility: Picking up Hidden Osteoporosis Effectively during Normal CT Imaging without additional X-rays (Short Title: PHOENIX-F),"Following NHS screening committee advice, Shepstone and colleagues recently completed the SCOOP study, a five-year pragmatic trial of primary osteoporosis screening which reported that women ≥75 years who underwent screening had 28% fewer hip fractures than those receiving usual care3. We now wish to screen people attending radiology departments for diagnostic computed tomography (CT) scans, because >30% have undiagnosed vertebral fractures or osteoporosis. To identify osteoporosis opportunistically, we developed PHOENIX as an innovative one-stop screening pathway. PHOENIX uses the same fracture risk assessment questionnaire (FRAX) as Shepstone, but here it is given to patients in the CT waiting room. We then retrieve CT images digitally, measure bone density, assess for vertebral fractures and provide a tailored bone health advice summary. PHOENIX software works on the CT scan images already performed for other reasons. Aims PHOENIX-F is a randomised, pragmatic feasibility study to inform a future multi-centre randomised controlled trial (RCT) investigating whether detecting osteoporosis and vertebral fractures in patients undergoing routine CT scans will improve health by reducing the burden of fractures. The primary objective is to test the feasibility of recruitment and retention of patients across five linked hospitals. We are also testing the digital links between our Addenbrooke s hub and four nearby spoke hospitals. By testing the PHOENIX pathway versus usual care, we will also derive sample size estimates to inform the definitive trial by examining the proportion of patients treated for poor bone health at twelve months in the two study arms. Scaling up to multiple UK PHOENIX hubs, the definitive trial will focus on the fracture rate and health-related costs of the PHOENIX pathway. PHOENIX pathway With usual care, the completed FRAX questionnaire is sent to the GP only. With PHOENIX, an Addenbrooke's analyst calculates the ten-year fracture risk (FRAX), retrieves CT scans by NHS Image-Exchange-Portal (IEP), identifies vertebral fractures, measures spine/hip density and creates a bone health report using a NICE-compliant pre-specified algorithm that matches our standard bone density reports. The report is sent to the patients GP, who initiates therapy and/or gives lifestyle advice. Plan of Investigation The study population will consist of women and men aged ≥50 attending for CT, for any reason, where the spine and/or hips are visible. Block randomisation to PHOENIX-F versus usual care will be 1:1 by age and gender within centre. We will determine the number of eligible patients and the number actually recruited within a ten-month recruitment window. After twelve months of follow-up, we will calculate the proportion of PHOENIX pathway patients who are treated for poor bone health in each arm (in single blinded fashion), and determine participant retention. Finally, we will examine recruitment differences according to patient characteristics (e.g. age, gender and indication for scan) to plan the appropriate randomisation schedule in any future trial. Assuming 250 responders from 1250 invites (20%) the true response rate can be estimated with 2.2% precision, and we will have 80% power to detect differences of ≥7% in twelve-month overall retention rates. Recruitment rates of ≥13% and retention rates of ≥73% are stop/go criteria for a definitive trial. PHOENIX costs will be estimated from the viewpoint of the NHS and personal social services. Resources associated with PHOENIX and those that might change as a result of it will be monitored, and we will determine the completion rates of the EQ-5D-5L questionnaire at baseline, six and twelve months. Summary of potential benefits to patients and the NHS The UK s coordinated medical digital imaging network seems ideally suited to this opportunistic screening technology. Targeted screening may improve clinical and economic value through early diagnosis, identifying incident fractures and future fracture prevention.","Osteoporosis makes bones become porous so they break more easily. It particularly affects the spine and hips. While treatment of osteoporosis is now quite straightforward, detection is difficult. In the UK, osteoporosis causes 200,000 vertebral fractures yearly in women and men. Since vertebral fracture pain can feel like ordinary backache, patients are often left undiagnosed, so multiple fractures are common. A computerised tomography (CT) scan uses x-rays and a computer to create images of the inside of the body; two million are performed each year in the UK, often for abdominal or pelvic problems. Nearly a third of those scanned have osteoporosis or vertebral fractures without knowing it. The PHOENIX pathway uses CT images to identify osteoporosis enabling early treatment and potentially preventing future fractures. The new technology makes it simple to measure bone density quickly and identify vertebral fractures from CT images of a patient's torso or pelvis. Measurements of the spine and hips are performed on images acquired from any CT scanner. Patients who are already attending hospital for a CT scan will be invited to participate in this trial, regardless of the reason for their scan. One group of volunteers will be allocated to the PHOENIX pathway to diagnose osteoporosis and vertebral fractures from their CT images with an appropriate therapy recommendation. The other group will follow usual care where they are asked to complete an osteoporosis risk questionnaire that is then sent to their general practitioner. The study aims to discover whether the PHOENIX pathway will lead to better osteoporosis treatment rates and fewer painful fractures. This feasibility study will allow us to evidence patients' willingness to volunteer and consent to a year's follow-up. It will also test Addenbrooke s Hospitals' capability to connect to surrounding hospitals in a hub and spoke model to provide the service.",4.4 POPULATION SCREENING,MUSCULOSKELETAL HRCS22_06198,"Chief Scientist Office, Scotland",CSO,"PHaCT Trial: Preventing Homelessness, improving health for people leaving prison: a pilot randomised controlled trial of a Critical Time intervention","Background_x000D_ People leaving prison who are released back into the community are at a high risk of homelessness. Nearly 1 in 2 who are released do not have a settled home and 1 in 3 are homeless or are in unsettled housing one year later. The life expectancy of people without a stable home is much lower and they have a worse quality of life. There are also wider society impacts of homelessness such as lower community wellbeing, more crime and higher healthcare and justice costs. It has been estimated that on average the yearly cost of one case of rough sleeping could cost £20,128. Although there are good interventions to stop homelessness, they are mostly from the US and we do not know how these work for people with previous prison experience. Critical Time Intervention (CTI) is the name of a type of intervention which aims to support those most in need in society during times of important life changes. They help people at risk of homelessness stabilise their housing situation, particularly those people who are leaving institutions (like prisons). Homelessness services think that this type of intervention works best when it is ‘housing-led’. This is where people are given housing quickly without conditions. There have been no studies which have looked at how good housing-led CTIs are at stopping homelessness and improving the health of UK people who have left prison and if they are good value for money._x000D_ _x000D_ Aims_x000D_ To carry out a pilot 'Randomised Controlled Trial (RCT)’ (where people are randomly allocated to receive either CTI or usual care) in prisons in England and Wales to find out if a full-scale RCT looking at ‘effectiveness’ (if it works) and ‘cost-effectiveness’ (if it is value for money) of a housing-led CTI should be done and to improve the study design._x000D_ _x000D_ Method_x000D_ In the long term we plan to test if a housing-led CTI betters peoples health, quality of life and housing, but first we need to find out if the intervention and study design (research methods) are possible and acceptable. Our pilot RCT will include a ‘process and economic evaluation’ (a method to evaluate if/how the CTI has been implemented as intended and if it provides value for money) with people leaving prison recruited from 4 prisons. Half the participants will be randomly allocated to get the housing-led CTI and the other half will continue with the usual support provided by prisons, probation services and local authorities. We will follow up with all participants 3, 6, 9 and 12 months later. This study will tell us whether the CTI and study design is acceptable and if we should go ahead with a full trial looking at ‘effectiveness’ and ‘cost-effectiveness’ of the intervention. _x000D_ _x000D_ PPI_x000D_ We will organise an Advisory Panel involving people who have experience of homelessness (from the Crisis Member Involvement Team) and professionals (government and the third sector) working across the UK in health, homelessness, and criminal justice sectors. Key organisations have already agreed to be part of this group (MCHLG). _x000D_ _x000D_ Dissemination_x000D_ We will distribute our findings through academic journals and conferences; work with our advisory panel to develop blogs, infographics and press-releases; share findings directly with policy communities; use the social media outlets of the Centre for Trials Research, Social and Public Science Research Unit (SPHSU) and the Centre for Development, Evaluation, Complexity and Implementation in Public Health Improvement (DECIPHer).","Background: For people leaving prison, re-integrating into the community can be a difficult process. Substance use, poor mental health, personal and situational factors such as low levels of literacy and absence of a stable support network, reinforced by a lack of affordable housing and employment opportunities, make them particularly at risk of homelessness. The absence of stable accommodation has a devastating impact on health - people experiencing homelessness are more exposed than the general population to infectious and noncommunicable diseases, mental health problems (including alcohol and substance use), have higher rates of emergency hospital admissions and report lower levels of wellbeing and health-related quality of life._x000D_ _x000D_ Aim: To conduct a pilot randomised controlled trial (RCT) in four male prisons to determine whether a future full-scale RCT assessing effectiveness and cost-effectiveness of a housing-led Critical Time Intervention (CTI) is warranted._x000D_ _x000D_ Objectives: 1) To set-up the project. 2) Deliver trial delivery training and recruit participants. 3) Conduct a pilot RCT in four prisons (collect baseline data; randomise participants; follow-up data collection). 4) Conduct trial analysis (process evaluation; statistical analysis of outcomes; scoping and testing data linkages; economic evaluation). 5) Write-up and disseminate findings._x000D_ _x000D_ Methods and timelines:_x000D_ Project set-up (Months 1-4): Finalise study protocol, trial steering committee and expert advisory group membership. Obtain ethics and governance approvals. Refine logic model and develop intervention and participant information materials._x000D_ _x000D_ Training and recruitment (Months 5-9): Crisis, a national charity for people experiencing homelessness, will train their caseworkers to deliver CTI. Potential participants will be referred to Crisis from probation services and decisions on eligibility will be made at weekly allocation meetings._x000D_ _x000D_ Trial delivery (Months 6-21): Following baseline data collection, individuals will be randomly allocated to CTI or treatment as usual. Follow-up data collection will take place after the individuals have been released from prison at 3, 6, 9 and 12 months._x000D_ _x000D_ Trial analysis (Months 6-22): Qualitative data analysis will inform a process evaluation that explores key components (including intervention reach, recruitment and retention, acceptability and compliance). Statistical analysis will determine whether level of recruitment and retention meet the prespecified progression criteria. A scoping exercise will explore feasibility of linkage of trial data to administrative data sources and test linkages will be undertaken. Pilot economic evaluation analyses combined with a review of existing evidence will lead to the development of an economic conceptual model for the full-scale trial stage._x000D_ _x000D_ Write-up and dissemination (Months 22-24): Report writing (dissemination plan below)._x000D_ _x000D_ Anticipated impact and dissemination: We will report via the NIHR PHR monograph and two open access papers to high impact journals. We will disseminate findings to stakeholders in policy, public health, academia, and the public through seminars, conferences and public events. The key impact from our study will be knowledge on whether conducting a full-scale RCT of housing-led CTI is warranted. Looking longer term, if a future full-scale RCT finds housing-led CTI is effective and cost-effective we would aim for roll-out to prisons across the UK.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,GENERIC HEALTH RELEVANCE HRCS22_14521,Diabetes UK,,POSE-D – Providing Online Self help for Eating disorders in Diabetes,"Background: Binge eating disorder (BED) has been identified as a significant problem in people with Type 2 diabetes. There are currently no psychological interventions for BED tailored to the needs of this group that can be delivered within diabetes services. Aim: To develop an acceptable and effective treatment for BED in people with Type 2 diabetes Methods: An 18 month project with two Work streams. In Work stream 1 - we will adapt an existing, online brief psychological intervention for BED called Guided self-help, for adults with Type 2 diabetes. The intervention has been developed by the research team and is evidence-based. We will conduct four co-design workshops with patients and healthcare professionals separately. In Work stream 2 we will test the feasibility of recruitment, research processes and delivery of the intervention in a case series with 10 participants. We will conduct qualitative interviews with participants to access acceptability. Impact: A brief tailored psychological intervention to help people with Type 2 diabetes to reduce binge eating and the parameters necessary to conduct a full trial. PPI: We will involve our Service User Involvement Facilitator and PPI Advisory Group throughout the research to inform the grant, patient materials and dissemination.",,7.1 INDIVIDUAL CARE NEEDS;6.6 PSYCHOLOGICAL AND BEHAVIOURAL,METABOLIC AND ENDOCRINE;MENTAL HEALTH HRCS22_05173,Department of Health and Social Care,NIHR,POSNOC - POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy: A randomised controlled trial of axillary treatment in women with early stage breast cancer who have metastases in one or two sentinel nodes,"Women with early breast cancer usually have this removed either by breast conserving surgery (lumpectomy) or removal of the whole breast (mastectomy). During the operation, one or two lymph nodes (glands) are removed from the armpit (axilla) to check if the cancer has spread to them, a procedure called sentinel node biopsy. A quarter of women, have cancer in these nodes. Current practice is to offer these women chemotherapy and/or hormone therapy, plus axillary treatment. Axillary treatment is either further surgery to remove all the remaining nodes from the armpit (axillary node clearance) or axillary radiotherapy. Of patients who have axillary node clearance, less than half have cancer in the remaining glands. Both axillary node clearance and axillary radiotherapy can lead to troublesome long term problems: the most common being arm swelling (lymphoedema), restricted shoulder movement, and sensory changes in the arm and hand. As well as being difficult for the patients, these complications are costly for the NHS. As breast cancer is now detected earlier, and we now have much better and more effective chemotherapy and hormone therapy than in the past, axillary treatment may no longer be necessary. _x000D_ _x000D_ A recent randomised trial suggested that routine axillary treatment may not be worthwhile. However, this study was not of high enough quality or large enough to provide reliable evidence about the short term and the long term effects (recurrence of cancer). This proposal aims to provide such evidence. _x000D_ _x000D_ Our study will recruit 1900 women diagnosed with early breast cancer and cancer in their sentinel node biopsy. Patients will be randomised either to adjuvant therapy alone, or to adjuvant therapy plus axillary treatment (axillary lymph node clearance or axillary radiotherapy). Adjuvant therapy is systemic chemotherapy and/or hormone therapy, with radiotherapy to the breast or chest wall if indicated. The main outcome in this trial is recurrence of the cancer within 5 years; other outcomes are complications from the treatment, quality of life, anxiety, spread of cancer to other areas of the body and death. Information about the participants will be collected at clinic visits or over the telephone, and they will also be asked to complete postal questionnaires for the first 3 years.","Design: Pragmatic randomised, multicentre, non-inferiority trial._x000D_ _x000D_ Setting: Hospital breast units, outpatient and inpatient._x000D_ _x000D_ Target population: Women with operable, core biopsy proven, early stage invasive breast cancer, who have had either breast conserving surgery or mastectomy, and are sentinel node positive(i.e. they have metastasis in the sentinel node). In hospitals where sentinel node histology is checked intra-operatively, at the same time as the breast surgery, women will consent pre-operatively and then randomised intra-operatively if their sentinel nodes are found to be positive._x000D_ _x000D_ Inclusion criteria_x000D_ Women will be eligible for inclusion only if ALL of the following criteria apply:_x000D_ • 18 years or older_x000D_ • Unifocal or multi-focal invasive tumour with lesion not greater than 5 cm in its largest dimension, measured pathologically or for women who are randomised intra-operatively largest tumour diameter on mammogram or ultrasound_x000D_ • No axillary nodal metastasis on clinical and ultrasound examination_x000D_ • At sentinel node biopsy have 1 or 2 sentinel nodes with macrometastases (tumour deposit >2.0 mm in largest dimension or defined as macrometastasis on molecular assay) _x000D_ • Fit for axillary treatment and adjuvant therapy _x000D_ • Have given written informed consent _x000D_ _x000D_ Exclusion criteria_x000D_ Women will be excluded if they have :_x000D_ • bilateral breast cancer_x000D_ • more than 2 sentinel node macrometastases or extranodal invasion_x000D_ • neoadjuvant therapy for breast cancer_x000D_ • previous axillary surgery on the same body side as the scheduled sentinel node biopsy_x000D_ • not fit or eligible to receive adjuvant systemic therapy _x000D_ • previous or concomitant malignancy except_x000D_ o adequately treated basal or squamous cell carcinoma of the skin or_x000D_ o adequately treated in situ carcinoma of the cervix or_x000D_ o adequately treated in situ melanoma _x000D_ o contra- or ipsilateral in situ breast cancer_x000D_ _x000D_ Health technologies being assessed: This trial compares adjuvant therapy alone with adjuvant therapy plus axillary treatment(axillary lymph node clearance or axillary radiotherapy). Adjuvant therapy will be based on current guidelines, and will include chemotherapy and/or hormone therapy for all women, and radiotherapy to breast or chest wall if indicated. Human epidermal growth factor receptor 2 (HER2) targeted treatment may be administered when indicated. Axillary and supraclavicular fossa radiotherapy is not allowed when randomised to adjuvant therapy alone. _x000D_ _x000D_ Study assessments: Baseline data will be collected from the participant's medical notes and questionnaires._x000D_ _x000D_ Follow-up Assessments_x000D_ Follow-up will be at 6, 12, 24, 36, 48 and 60 months post-randomisation. The 36 and 60 months follow-up will be a clinic visit (doctor or nurse led), however follow-up at other time points may be conducted by a research nurse over the telephone, according to local practice. _x000D_ _x000D_ Assessments: _x000D_ 1. Follow-up eCRFs will be completed in the clinic or over the telephone to record information on primary and secondary outcomes at 6, 12, 24, 36, 48 and 60 months,_x000D_ 2. Lymphoedema and Breast Cancer Questionnaire (two questions) and QuickDASH questionnaire will be completed in the clinic or over the telephone at 6, 12, 24 and 36 months, _x000D_ 3. Postal questionnaires with up to two reminders, FACT B+4, Spielberger State/Trait Anxiety Inventory and EQ-5D at 3, 6, 12, 24 and 36 months. _x000D_ _x000D_ Primary Outcome_x000D_ The primary outcome is axillary recurrence at 5 years._x000D_ _x000D_ Secondary Outcomes_x000D_ Secondary outcomes assessed at 3, 6, 12, 24 and 36 months are:_x000D_ • Arm morbidity_x000D_ • Quality of life _x000D_ • Anxiety _x000D_ • Economic outcomes_x000D_ _x000D_ Secondary outcomes assessed at 6, 12, 24, 36, 48 and 60 months are:_x000D_ • Local (breast or chest wall) recurrence_x000D_ • Regional (nodal) recurrence _x000D_ • Distant metastasis _x000D_ • Time to axillary recurrence _x000D_ • Axillary recurrence free survival_x000D_ • Disease free survival_x000D_ • Overall survival_x000D_ • Contralateral breast cancer_x000D_ • Non-breast malignancy_x000D_ _x000D_ Sample size: It is estimated that the axillary recurrence rate in the adjuvant therapy plus axillary treatment group at 5 years is 2%. With an absolute non-inferiority margin of 2%, to show that the axillary recurrence rate in the adjuvant therapy alone group at 5 years is not more than 4%, with a one-tailed test for non-inferiority, 1800 patients need to be randomised(with 80% power). Allowing for 5% lost to follow up over the 5 years, gives a sample size of 1900 women. _x000D_ _x000D_ Project timetables including recruitment rate: Total project duration is 10 years_x000D_ Set up (6 months): site training and initiation, awareness raising, developing Case Report Forms and database._x000D_ Feasibility of recruitment (12 months): feasibility assessed based on total recruitment, number of active sites, compliance with the allocated treatment and losses to follow up_x000D_ Recruitment(33 months): 50 sites recruiting, target recruitment 58 to 63 per month_x000D_ Follow up(60 months): clinic visits or nurse led follow up and postal questionnaires_x000D_ Analysis, writing up and dissemination(9 months)._x000D_ _x000D_ Radiotherapy quality assurance: The sites will be required to adhere to the specific radiotherapy planning and delivery guidelines when treating participants in the study. The NCRI Radiotherapy Trials QA (RTTQA) group will be responsible for implementing and coordinating the Radiotherapy Quality Assurance programme.",6.1 PHARMACEUTICALS;6.4 SURGERY,CANCER AND NEOPLASMS HRCS22_13950,Cancer Research UK,CRUK,PRECISION VISION - Using AI for Early Detection and Diagnosis of Head and Neck Pre-cancer and Cancer,"BACKGROUND Head and neck cancers (HNC) are amongst the top ten most common cancers in the world with increasing frequency, poor prognosis and no improvement in survival due to late detection. Patients require extensive surgery and/or chemo/radiotherapy with significant morbidity, poor quality of life and no improvement in survival. Hence, there is a dire need for early identification and referral of these lesions to specialist centres for early intervention. The majority of HNC are preceded by a pre-cancerous stage but a biopsy is required for diagnosis. Photographs of such head and neck (H&N) lesions are taken in tertiary care as a standard-of-care. Some clinical features such as shape and colour etc. can be suggestive of pre-malignancy/malignancy, however, analysis is subjective with inter-observer variability and these features may not be evident sometimes, leading to missed or late diagnoses. There have been significant developments in Artificial Intelligence (AI) for diagnosis and treatment in the last few years. However, its use in clinical diagnosis of H&N cancers has not been reported to date. AIMS To use AI for analysis of clinical images of H&N lesions for early and objective detection of cancer or dysplasia. METHODS Digital images of lesions will be used to optimise/develop and test AI algorithms. Retrospective lesion images with a confirmed histopathological diagnosis will be used for annotations during training and validation. Subsequently the algorithm will be tested on an unseen cohort to determine accuracy, sensitivity and specificity. Correlation with demographics, smoking/alcohol history and prognosis will also be performed. HOW THE RESULTS OF THIS RESEARCH WILL BE USED The main intended outcome is to aid patient triaging and early referral, diagnosis and treatment even before the biopsy stage. It will facilitate establishment of the proposed collaboration, a relevant dataset and pave the way for future grant applications. Data will be presented at conferences to engage patients, clinical/academic colleagues and published in high quality journals and the dataset shaed with other investigators.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_06349,Department of Health and Social Care,NIHR,PREVENTion and treatment of Incontinence-Associated Dermatitis (IAD) through optimising care: development and feasibility of the IAD Manual (PREVENT-IAD),"Incontinence-associated dermatitis (IAD) is skin damage caused by repeated contact with urine, faeces or both. It causes pain, discomfort, infections and pressure sores. 14 million UK people have urinary incontinence and 6.5 million have bowel problems, but the number with IAD in the UK has not been reliably established. It may affect as many as 51% of people with incontinence living at home and up to 30% in nursing and residential care. Prevention and treatment involves skin cleansing & use of products to protect the skin, alongside continence promotion & correct use of incontinence pads, but there are no specific guidelines for IAD management. Many people provide this care (e.g. family carers, unregistered care workers, nurses). The risk of developing IAD could be halved using preventative measures. We want to create genuine changes in the way IAD is prevented and treated and will do this by developing and testing a manual (book), that will include a lay version, with training materials._x000D_ _x000D_ Aims. _x000D_ We want to find out if:_x000D_ 1. We can develop a manual with people with IAD, their carers & health professionals, with a related training package, to guide the prevention & treatment of IAD in care homes & people’s own homes_x000D_ 2. We can work together to design a future research study to establish whether the manual works to prevent and treat IAD and could be tested on a larger group of people_x000D_ _x000D_ Research Question: Is it feasible to develop, manualise and test a package of care for the prevention and treatment of IAD that can be delivered by a range of NHS and other relevant caregivers?_x000D_ _x000D_ Design: _x000D_ The study has 3 parts._x000D_ _x000D_ Part 1. We will search the literature & work with 10-15 people with IAD/their carers and 10-15 health professionals over 4 meetings to (i) find out how they deal with IAD, (ii) what they need to improve this care, (iii) develop a manual to guide prevention & treatment of IAD, (iv) work out what might help or stop people using the manual, (v) develop a plan to introduce the manual (with a training plan & resources) into care homes & the community._x000D_ _x000D_ Part 2. We will work with the same people to design a future study to test if the manual works and can be successfully introduced into a real-word setting._x000D_ _x000D_ Part 3. We will carry out a study to see if the trial we have designed can be done. To do this, we will recruit four large care homes & two home care agencies and randomly allocate these using a computer so three sites receive training in using the manual, while the other three will continue to provide usual care. Over 6 months we will (i) record how many sites/people are recruited to/stay in the study (ii) measure rates of IAD & outcomes important to patients, e.g. pain/satisfaction, (iii) find out whether the manual is used as planned by observing its use in practice & interviewing users (iv) ask people about their experience of being in the study, how the manual worked in practice & what helped/stopped them using the manual._x000D_ _x000D_ Public & patient involvement was key from the start & we worked with patient groups (Bladder Health UK), people with IAD & their carers to develop our plans, so that any changes in care will be of real benefit to patients, carers and health professionals. _x000D_ _x000D_ When we finish the project we will publicise our findings through professional publications, social media & patient newsletters, patient website (www.continenceproductadvisor.org) & at relevant conferences & events.","Background and Rationale_x000D_ Incontinence-associated dermatitis (IAD) is skin damage caused by repeated contact with urine &/or faeces. 14 million adults in the UK have urinary incontinence and 6.5 million have bowel problems, but the incidence of IAD in the UK has not been established. Prevalence of IAD may be up to 51% of people with incontinence living at home and 30% in nursing and residential care. Prevention and treatment involves skin cleansing & application of skin protectants with continence promotion & correct use of incontinence pads, but there are no specific guidelines for IAD management. Odds of developing IAD may be halved using preventative measures. We want to create genuine changes in the way IAD is prevented & treated in care homes and community settings by developing & testing the feasibility of a protocolised manual (including a lay version) with training materials._x000D_ Research Question _x000D_ Is it feasible to develop, manualise & test a package of care for the prevention & treatment of IAD that can be delivered by a range of NHS & other relevant caregivers? _x000D_ Aims _x000D_ 1. Develop & manualise an optimal care package for the prevention & treatment of IAD (IAD Manual) within care homes & by home care agencies, including a training, implementation & dissemination plan_x000D_ 2. Design a future trial of the clinical & cost-effectiveness of the IAD Manual_x000D_ 3. Conduct a feasibility cluster randomised controlled trial (RCT) of the IAD Manual._x000D_ Methods_x000D_ This two-year, mixed methods study comprises 3 phases, culminating in a new intervention & design for a definitive cluster randomised controlled trial (RCT) of the IAD Manual._x000D_ Phase 1:Evidence synthesis and development of the IAD-Manual, training and implementation plan(0-12m)_x000D_ We will update our Cochrane review(1) & purposively sample 10-15 health professionals and 10-15 patients/family carers as stakeholders in a series of 4 interactive 1-day workshops to co-design the IAD Manual, training & implementation plan. We will develop & test a logic model of the active components within the intervention and causal assumptions. Qualitative data will be analysed using framework analysis. _x000D_ Phase 2: Design future cluster RCT of the IAD Manual(9-12m)_x000D_ We will work with the same stakeholders from phase 1 to co-design a future definitive cluster RCT to test the clinical & cost-effectiveness of the IAD manual._x000D_ Phase 3: Feasibility cluster RCT of the IAD Manual & nested process evaluation(12-24m)_x000D_ 4 large care homes & 2 care agencies will be recruited & randomised: 3 to implement the IAD manual, 3 usual care (control). Participants with incontinence will be recruited (48 per site)._x000D_ Data collection – Feasibility outcomes (recruitment rates/attrition) & core outcomes for IAD will be recorded using validated outcome measures (GLOBIAD, IADIT, Wong-Baker Faces Scale, SAPS) at baseline, 3m & 6m. Intervention fidelity will be observed at 3m & 6m by non-participant observation. Up to 20 patients/family members/care staff will be interviewed about acceptability of the IAD Manual & study design _x000D_ Data analysis- a process evaluation, based on the logic model from Phase 1, will be conducted. Qualitative data will be analysed thematically & prevalence, incidence & standard deviations of quantitative outcome measures of IAD will inform sample size calculations for the definitive RCT_x000D_ _x000D_ Dissemination will be through 5 professional publications, social media, a website & patient newsletters & at relevant conferences.",7.3 MANAGEMENT AND DECISION MAKING,RENAL AND UROGENITAL;SKIN HRCS22_01696,Medical Research Council,MRC,PROTEOME-WIDE IDENTIFICATION OF RNA-BINDING PROTEINS PLAYING CRITICAL ROLES IN VIRUS INFECTION,"RNA viruses rely extensively on host RNA-binding proteins (RBPs) to accomplish their biological cycle, offering new possibilities of antiviral intervention. However, the repertoire of RBPs involved in virus infection has remained largely uncharacterised. To uncover the scope of RBPs that interact with viral RNAs in infected cells, we will develop a new method, referred to here as viral (v) RNP capture, using Sindbis virus (SINV) as discovery model. In brief, viral RNAs will be labelled with the nucleotide analogue 4-thiouridine (4SU) in presence of actinomycin D, which inhibits host RNA polymerases, directing 4SU incorporation exclusively to viral RNAs. After labelling, crosslinking between RBPs and viral RNAs will be achieved by irradiation with 365nm ultraviolet light. Proteins covalently linked to viral RNAs will be purified following stringent purification via oligo (dT) and identified quantitative proteomics. Resulting datasets will be used to select candidates for functional assays. Applying an in-house developed mid-throughput approach, we plan to study the effects of RBP overexpression, knock out and inhibition not only in cells infected with SINV but also with closely related and unrelated human pathogens. Finally, the role of RBPs exhibiting strong phenotypes in infection will be studied from a mechanistic perspective combining state-of-the-art methods in virology, RNA biology, super-resolution microscopy and proteomics. We expect to identify fundamental RBPs with regulatory roles in infection that can become antiviral targets for host-based therapies.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_20666,Versus Arthritis,,Pain Centre Versus Arthritis,"The integration of preclinical and clinical expertise within the Arthritis Research UK Pain Centre, coupled with external collaborations, has led to fundamental advances in our understanding of OA pain mechanisms. Key achievements during our first 5 years include identifying discrete pain mechanisms that map to OA pain phenotype both in patients and in animal models, and the integration of preclinical and clinical studies to demonstrate the mechanisms by which NGF, osteoclasts, TRPV1, and CGRP in the joint, spinal sensitization, psychological distress and augmented central pain processing each contribute to OA pain. This new knowledge has informed a multimodal model of knee OA pain, which integrates joint pathology, alterations in peripheral and central pain processing, changing brain morphology and function and psychological factors. During the next 5 years, we will capitalise on these achievements to test mechanistically targeted and novel treatment strategies which reduce the burden of pain in people living with arthritis identify mechanisms of pain progression which can be targeted to substantially reduce the future burden of arthritis. An integrated, multidisciplinary approach combining preclinical and clinical research, in collaboration with academic, industrial, health care and public/patient partners, will underpin our future success.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL HRCS22_23028,The British Academy,,Pain and motivation: the impact of tonic experimental pain on reward- and effort-based decisions,"Pain is important for guiding our behaviour. A child who touches a hot stove, for example, will quickly learn not to repeat that action. Acute pain is thus linked to goal-directed action, but little is known about how pain lasting minutes or hours may influence motivational processes. When pain persists, it might increase comfort or pleasure seeking, inhibit exploratory behaviour, and reduce physical effort. To investigate effects of tonic pain on reward- and effort-based decisions, I will use validated procedures to deliver a safe, extended pain stimulus to healthy human volunteers. Before, during, and after the pain, participants will complete a reward-based reversal learning task to assess reward sensitivity and cognitive flexibility (Experiment 1), or a reward/effort trade-off task to measure physical effort to obtain rewards (Experiment 2). These experiments will provide the first test of whether long-lasting pain has persistent effects on learning and motivation in healthy humans.",,1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,NEUROLOGICAL HRCS22_05473,Department of Health and Social Care,NIHR,Palliative Long-term Abdominal Drains Versus Repeated Drainage in Untreatable Ascites Due to Advanced Cirrhosis: A Randomised Controlled Trial (REDUCe 2 Study),"Our aim is to see if long-term abdominal drains (LTADs) result in better quality of life in patients with fluid in the belly (abdomen) due to liver scarring, compared with current standard of care. _x000D_ _x000D_ The liver can be damaged (scarred), by excessive alcohol and viral infections. If liver damage continues, this scarring leads to permanent damage (cirrhosis). As cirrhosis progresses, it causes a painful buildup of fluid (ascites) in the abdomen. Initially, drugs can treat ascites, but these may stop working, leading to untreatable ascites. A liver transplant is then the best option. Most people, however, do not receive a transplant due to concerns about their alcohol use or lack of donors._x000D_ _x000D_ People with cirrhosis and untreatable ascites who do not receive a liver transplant live on average for about six months. Medical care then focuses on controlling symptoms and having the best possible quality of life. This is known as palliative care. Current standard palliative care for untreatable ascites involves coming into hospital for 1-2 days, putting a thin tube into the abdomen for a few hours and draining 5-15 litres of fluid. This reduces the pain from ascites. However, as the ascites builds up quickly, hospital visits are needed every 10-14 days. Our patients describe repeated hospital drainage as ”devastating” and “unbearably painful”. _x000D_ _x000D_ For people with untreatable ascites due to cancer (rather than cirrhosis), palliative care involves placing another tube, an LTAD, into their abdomen. This tube is fitted in hospital but stays in place for months. Nurses/carers then drain smaller amounts of fluid (1-2 litres) up to three times a week in the community. LTADs avoid frequent hospital visits and can improve quality of life._x000D_ _x000D_ LTADs are not routinely offered to people with cirrhosis as they can have complicated social issues like addiction, making community care difficult. Secondly, people with cirrhosis are at increased risk of ascitic fluid infection. The concern is that LTADs might further increase this risk. It remains uncertain, therefore, if LTADs could improve quality of life for people with cirrhosis._x000D_ _x000D_ We ran a small study (2015-18) with 36 patients with cirrhosis and untreatable ascites. Half received LTADs and half continued with standard hospital drainage. LTAD insertion went well with no major complications. Almost all with LTAD were managed in the community with lower overall costs compared with hospital drainage. Participants were willing to fill in study questionnaires and take part in interviews. Patients and clinical staff told us that LTADs were acceptable to them. _x000D_ _x000D_ We now need a larger study to understand the risks/benefits of palliative LTADs in people with cirrhosis. In this study, people who agree to take part will have ascites drained through either LTAD or repeated hospital visits. Community nurses will visit LTAD patients at home up to three times a week for ascites drainage. Researchers will visit ALL participants at home every 2 weeks for 3 months for safety monitoring and also record quality of life, symptoms, carer workload and use of NHS services (using questionnaires). We will record all infections that occur. We will talk with patients/carers/clinical staff to ask their views about the research. The most important measure chosen to see if LTAD is a good option for people with cirrhosis is quality of life. The study has been designed with help of the patients/caregivers who are part of the research team.","RESEARCH QUESTION: Do palliative long-term abdominal drains (LTADs) result in better health related quality of life (HRQoL) in patients with refractory ascites due to end-stage liver disease (ESLD) compared with standard of care (large volume paracentesis, LVP)? _x000D_ _x000D_ BACKGROUND: Refractory ascites confers a median transplant-free survival of six mths and needs repeated hospitalisation for drainage (LVP). LTADs allow home drainage but are not routinely used in ESLD. Our REDUCe study (LVP vs. LTADs in ESLD) demonstrated feasibility to proceed with a definitive trial. _x000D_ _x000D_ AIM: To assess whether LTADs result in better HRQoL vs. LVP in patients with refractory ascites due to ESLD. _x000D_ _x000D_ METHODS: We will recruit patients with ESLD and refractory ascites, randomised 1:1 to either LTADs or LVP. Community nurses will visit LTAD patients at home, 2-3 times a week to perform drainage (1-2 L per visit). LVP patients will attend hospital every 10-14 days with 5-15 L of ascites drainage. Research staff will visit ALL participants at home fortnightly for 3-mths for safety monitoring and questionnaire-based assessments (Ascites Q, SFLDQoL, EQ-5D-5L, CRRS). The primary outcome will be HRQoL assessed by the SFLDQoL questionnaire. An embedded qualitative study will explore perspectives on LTADs and LVP by patients (n=30), caregivers (n=20) and health care professionals (n=20). The minimal clinically important difference (MCID) is the mean change in HRQoL score for patients reporting a minimal yet perceptible change in HRQoL between baseline and follow-up assessments. We have selected an MCID of 8 points. REDUCe study data showed the pooled baseline mean across SFLDQoL domains (excluding sexual function) was 56.4 (SD=26.1). With 93 participants in each group, we will have 90% power for 5% significance to detect a difference in adjusted mean SFLDQoL scores of 8 points between the LTAD and LVP groups at the end of 3-mths (effect size 0.31). We will assume a correlation between baseline and follow-up measurements of 0.48 (lower bound of 95% CI, REDUCe study data). With an expected 40% attrition, we will recruit 310 patients in total for the trial. Statistical analysis will follow intention-to-treat principles, performing for the primary outcome, a longitudinal analysis of covariance by fitting a mixed effects linear regression model. Qualitative data will be analysed using thematic analysis and triangulation. A probabilistic cost effectiveness analysis will be conducted, service use being assessed by the AHCR and an in house designed hospital use questionnaire. _x000D_ _x000D_ DELIVERY TIMELINES: Study duration 57-mths: 6-mths set up; 18-mths internal pilot with STOP/GO criteria; 29-mths main trial and 4-mths data analysis/dissemination. The pilot will recruit 84 patients from 24 sites. Assuming a successful pilot, 11 more sites will be opened over 5-mths, recruiting the remaining 226 patients from 35 sites. _x000D_ _x000D_ IMPACT: This large UK trial will improve end of life care for an underserved group.",6.3 MEDICAL DEVICES,ORAL AND GASTROINTESTINAL HRCS22_23105,The British Academy,,"Parental Alienation, Domestic Abuse and the Family Courts – a collaborative action research project","Parental Alienation (PA) is an emerging area of scholarship and a highly contested concept. The Children and Family Court Advisory and Support Service describe it as a child’s unjustified resistance towards a parent caused by psychological manipulation by the other parent. In recent years perpetrators of domestic abuse (DA) are increasingly using allegations of PA against their victims with the aim of negating DA. This research aims to explore how PA is used in, and impacts on, child arrangements cases where DA is an issue, how family courts respond to accusations of PA, and how barriers to safeguarding victims of DA and children can be overcome. This study will adopt a collaborative action research framework involving interviews with victims of DA accused of PA in family court cases. The findings will develop national policy for improving family court responses to DA to achieve safer outcomes for victims and children.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;7.1 INDIVIDUAL CARE NEEDS",DISPUTED AETIOLOGY AND OTHER HRCS22_05131,Department of Health and Social Care,NIHR,Partnership for REsponsive Policy Analysis and REsearch (PREPARE): a fast response research and analytical facility to support policy development and evaluation.,"Background Evidence-informed policy presents challenges to policy makers and researchers, in a context that is often highly political and rapidly changing. Researchers are trained to use the most robust empirical methods, but this can mean that studies and reporting do not match the needs or timetable of policy decisions. There is a balance between research that is well-conducted but sufficiently focused and timely to be useful. This facility will provide expert advice and analysis using rigorous but appropriate methods to inform and evaluate policy. Aims Our overall aim is to continue to deliver a high quality, responsive service to inform all stages of national policy development, implementation and evaluation. Specific aims will vary depending on individual requests and projects. Research plan and methods Our approach is multidisciplinary and inter-professional, bringing together an experienced and established team providing expertise in a wide range of methods applied in varied settings. We will employ appropriate methods and perspectives to develop and refine the evidence base for policy, developing specific research plans and methods in response to each project brief. Balancing timeliness with scientific rigour, we will inform policy with relevant, practical analysis. Methods will include scoping research, literature reviews, secondary analysis, economic and statistical modelling, surveys of organisations, staff, patients and the public, and qualitative interviews and focus group discussions. Whenever possible we will use existing administrative and other data sources, including published hospital and NHS performance data, primary care and prescribing data, cohort studies (e.g. the Millennium Cohort Study), and surveys (e.g. Understanding Society, Health Survey for England). Research team A multi-skilled team of researchers from the King s Fund and the University of York will work in partnership, combining expertise in analysis and policy making to deliver rigorous and responsive research. The two organisations have excellent and longstanding reputations for multidisciplinary, innovative, rigorous and influential policy research, and working together we maximise the range of knowledge, skills and experience available. We have a successful history of joint working to deliver the existing PREPARE programme. Timelines for delivery Timescales will vary depending on the individual research project, but in all cases, we aim to respond within two working days to initial requests, confirming feasibility and remit. Research questions will be agreed in a rapid iterative process, after which projects will begin in earnest. For substantive projects, following regular meetings and interim presentations, main findings will be provided to policy colleagues within three months, followed by a process of agreed revisions, internal and external peer review, and production and dissemination of a final report as appropriate. Anticipated impact and dissemination Influencing policy development and improving the evidence base for policy making are the prime drivers of this programme. All projects will aim to inform and impact on health policy and its implementation. Reports will be prepared for the Department of Health and Social Care, and where appropriate we will share findings more widely by developing outputs for publication and wider dissemination to a variety of audiences including NHS managers, practitioners and the public.","What are our aims? We aim to provide information, evidence and analysis to inform health policy decisions in England. Why do we need this research? Policy-making is the process by which governments and others translate their political vision into reality. Health professionals are expected to base clinical decisions on good evidence of what works, but policy makers often lack clear links to an evidence base. This is partly because researchers have not always produced and shared research in a way which meets policy makers needs at the right time. Since 2015 we have successfully provided a fast-response research facility for the Department of Health and Social Care. We respond rapidly to the requests for information and analysis from people who are responsible for policy decisions. We are very keen to continue this and to build on our strong and effective partnership. How will we approach the research? There is sometimes a trade-off between producing either high-quality evidence (which can be time-consuming), and providing information that is less rigorous scientifically but is timely and useful to policy makers who are working to tight deadlines. We will take a balanced approach to this, responding to urgent evidence needs by drawing on a large team with a range of skills and experience of working with policy makers. Although generating new data can be time-consuming and expensive, we aim to provide reports to the Department of Health and Social Care within three months. To achieve this, we will use advanced techniques to analyse existing information so that we inform policy-making usefully and efficiently with good research and analysis. We will also advise on how to evaluate the longer-term impact of new initiatives. How will we involve patients and the public? We will involve patients and members of the public who may be affected by the areas of policy being considered. We will create a standing panel of patient and public involvement champions to contribute to the programme. They will help us to refine research questions and the approach we take, to communicate findings clearly and to all audiences, and ensure that a public voice is heard in policy research. How will we share our findings? We have a website (york.ac.uk/prepare) where our main reports are available to everyone, along with short, accessible summaries. In future we plan to involve our PPI champions in writing summaries, and we plan to experiment with other forms of communication such as infographics, animations, video abstracts and podcasts. We work closely with colleagues in the Department of Health and Social Care to make sure that the findings reach decision-makers, to develop and improve evidence-informed policy making in all areas of health and care.","8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;8.1 ORGANISATION AND DELIVERY OF SERVICES",GENERIC HEALTH RELEVANCE HRCS22_20349,Wellcome Trust,,"Pass the Wnt, from secretion to signalling","A relatively small number of proteins have been suggested to act as morphogens, molecules that spread within tissues to organize cell fate decisions and tissue repair. Among them are Wnt proteins, which, surprisingly for signalling molecules, are relatively insoluble because of a palmitoleate moiety that is essential for signalling activity. A number of proteins are dedicated to Wnt secretion and transport in the extracellular space. In particular, Wntless escorts Wnt from the ER to the cell surface, and Dlp-class glypicans shield the Wnt lipid in the extracellular space before it engages with signalling receptors of the Frizzled family. We will combine structural, biophysical, and genetic approaches to characterise the key interactions that Wnt proteins and their lipid engage with during this journey. Thus, we will determine how Wnts are released from Wntless in secreting cells and allowed to form a complex with Dlp-class glypicans. We will determine the glycosaminoglycans that support the formation of the Wnt-glypican complex before elucidating the complex’s structure and identifying the key determinants of affinity. These measurements will lead to a mechanistic understanding of Wnts’ extracellular transport and subsequent hand-over to Frizzleds and form the foundation of a realistic mathematical model of Wnt gradient formation.","Much like humans in societies, cells in tissues and organs must communicate so that they can coordinate their activities. One common form of cell communication involves secreted proteins that are produced by a subset of cells and spread to surrounding cells, where they bind to surface receptors and trigger changes in gene activity. For cells to work seamlessly together during development and homeostasis, it is crucial that signals spread over the right distance. We are proposing to study this question for a class of signalling proteins called Wnts, which control stem cell behaviour and have been shown to trigger cancer when overactivated. We will map all the interactions that Wnts make in the extracellular space and determine how they ensure that Wnts reach the appropriate cells. With this knowledge, it will become possible to tune the range of Wnt action in the context of regenerative medicine or anti-cancer treatments.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_20285,Wellcome Trust,,Pathophysiological factors in the diagnosis and treatment of the Guillain-Barre syndromes,"100 years after its first description in 1916, we still know very little about the cause of Guillain-Barre syndrome (GBS) that is characterised by severe paralysis due to inflammation in peripheral nerves. We know the disease is precipitated by a wide range of infections that induce antibodies as part of the normal protective immune response; however in GBS cases, rogue antibodies are made by the immune system that inadvertently attack the nerves due to a mistake in immune programming. Understanding how they do this in the different GBS disease variants, and how to use this information to diagnose and treat GBS is the aim of this proposal. We have developed experimental methods for large scale screening of human GBS blood for abnormal antibodies. We have also developed mouse models based on these screening data that can examine disease pathways in nerve tissues, and test new treatments. Through this translational research, our overall goal is to change the GBS landscape for future patients, health care providers and researchers.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_05517,Health and Care Research Wales (Welsh Government),,Pathway Of Low Anterior Resection syndrome relief after Surgery (POLARiS) trial,"Plain English Summary max 3500 (remaining 189 characters) _x000D_ 14,000 cases of rectal cancer are diagnosed in the UK per year. The treatment for advanced rectal cancer is often radiotherapy+/-chemotherapy treatment followed by surgery. This provides good outcomes, with the cancer returning in less than 10% of people. However, the surgery can cause significant long-lasting problems, including problems with bowel, sexual and urinary function. Low anterior resection syndrome (LARS) is a collection of symptoms that people who have undergone a partial or total removal of the rectum may experience, including bowel incontinence or leakage, frequency or urgency of stools, loose stools and incomplete bowel emptying. These symptoms can have a considerable negative impact on patient quality of life and daily functioning. As a result, there is a need to focus efforts on survivorship._x000D_ LARS symptoms are present in 75% of the patients up to 12 months after surgery and remain in up to 50% of patients for more than 10 years with a major impact on quality of life. There is little evidence to support treatment options for patients with LARS. Despite more acceptance of LARS amongst clinicians, with increased subspecialisation of surgeons and poor reporting of LARS, many centres do not have a clear management pathway and/or are unaware of the treatments available. _x000D_ Transanal irrigation (TAI) is a method of managing conditions such as bowel incontinence or constipation. It involves introducing water through the anus to flush faeces (poo) from the bowel. Sacral Neuromodulation (SNM) involves a small battery powered unit being implanted into the lower back. This is connected to electrodes which rest on the nerves in the lower spine. The device continuously sends electrical impulses to the nerves and muscles that control the lower bowel (rectum and anus)._x000D_ These two treatment options may improve quality of life for patients with LARS, however supportive evidence is currently lacking. The POLARiS trial will investigate the clinical and cost benefit of two treatments for patients with major LARS who have previously undergone standard non-surgical treatment without improvement. Patients who are not randomised to SNM or TAI will be offered optimised medical management. _x000D_ The study will monitor the bowel function and quality of life in patients who have undergone rectal cancer surgery in the hospitals involved within the last 10 years of the trial commencing. Those patients found to have poor bowel function (major LARS) will be randomised to one of the treatment options and followed up for 2 years after randomisation. _x000D_ The results of the study will be presented at conferences raising awareness of effective treatment options to clinicians, as well as through publication in peer reviewed journals. Patient material will be developed as part of the output of POLARiS which will offer self-management strategies and explanation of treatment options for patients with LARS. The findings of the study will be highlighted through social media to patient groups and relevant charities. This will inform patients and the public that LARS is treatable and which treatment options are potentially available. Patients who have participated in the study will receive a patient report at the end, with clear outlines of the findings.","Background: 14,000 UK patients are diagnosed with rectal cancer/annum. 52% will undergo major resectional surgery. LARS is a constellation of bowel symptoms described after rectal cancer surgery and includes urgency, faecal incontinence, stool clustering and incomplete evacuation leading to a significant adverse impact on quality of life (QoL). LARS symptoms are present in up to 75% of the patients 12 months after surgery and may persist in 25%. There is little evidence to inform choice of management and this was highlighted as a priority research question by NICE in 2020. Without greater evidence on cost effective treatments for LARS, patients will have a wide variation in care, both through differences in awareness and in access to treatment. _x000D_ Aims and objectives _x000D_ Aim: to answer the following research question: “What is the clinical and cost-effectiveness of Transanal irrigation (TAI) or Sacral neuromodulation (SNM) versus optimised conservative management (OCM) for people with major LARS (low anterior resection syndrome)?” _x000D_ Primary Objective: To conduct an international superiority randomised controlled trial (RCT) within a longitudinal cohort study (TWiCs design) to compare patient reported symptoms and quality of life in patients after rectal surgery. _x000D_ Secondary Objectives: to compare safety, complications, clinical efficacy and cost-effectiveness of the randomised treatments; describe the natural trajectory of patient reported LARS systems and predictors of major LARS; describe patient and staff views on the study and its interventions (including acceptability, impact and implementation)._x000D_ Design: A prospective, international, open-label, multi-arm, phase 3, randomised superiority trial, embedded within a cohort (TWiCs), with internal pilot phase, qualitative sub-study and economic evaluation. _x000D_ Participants: 600 UK patients with major LARS from a cohort of patients undergoing an anterior resection for cancer. Additional international patients to increase power and worldwide impact will be recruited subject to funding. _x000D_ Interventions: Sacral neuromodulation or Transanal irrigation. _x000D_ Comparator: Optimised Conservative Management _x000D_ Outcomes: Primary; LARS score over 24-months; Secondary – quality of life, safety, cost-effectiveness, compliance, acceptability, fidelity. _x000D_ The RCT within the cohort has three 1:1 randomisation options dependent on patient and site eligibility: _x000D_ 1) SNM vs OCM, for patients who would not be eligible to receive TAI _x000D_ 2) TAI vs OCM, for patients who would not be eligible to receive SNM _x000D_ 3) SNM vs TAI vs OCM for patients who are eligible to receive either SNM or TAI. _x000D_ Setting: 20 UK, European and Australian secondary care sites utilising existing networks from the IntAct trial and Australian ALaCaRT._x000D_ Timelines for delivery: 66 months:0-9month set-up;10-36months recruitment (incl. 12month pilot phase),37-60months follow-up;61-66months analysis and dissemination. _x000D_ Anticipated impact and dissemination: POLARiS will, for the first time, accurately describe the natural history of LARS over time, determine the best treatment options for patients with major LARS and standardise practice worldwide. Results will be disseminated through presentation, publication as well as social media. Patient educational material, including a short animation video, will be produced, along with infographics to showcase findings.",6.3 MEDICAL DEVICES,CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL HRCS22_01210,Medical Research Council,MRC,Pathways Involved in Immune Regulation and B Cell Selection,"Goals To understand how the immune system regulates the response to antigens - in particular how B cells are selected and how dysregulation leads to autoimmune disease. Our focus is on how cells involved in long-term immunity are generated and sustained as part of immunological memory. We have developed functional approaches to track cells and characterize pathways involved both in the immune response and in self tolerance. Using these methods we have investigated self-tolerance to intracellular antigens such as those targeted in the autoimmune disease systemic lupus erythematosus (SLE). We have shown that when mHEL, highly tolerogenic on the cell surface, is tethered in the ER by an ER retention moiety it becomes immunogeneic and positively selects self-renewing B1 B cells and high titres of high affinity IgM autoantibody (1). We have used genetic strategies to identify new pathways regulating the immune response to antigens. Genome-wide ENU mutagenesis has been used to screen for defects in the immune response to self and foreign antigens, and we have refined strategies for dissecting immunological defects and for linking biochemical pathways between genes and phenotypes. By using ENU we identified the autoimmune regulator Roquin and determined its role in the negative regulation of follicular helper T (TFH) cells from a screen for autoimmune mice (2). Roquin mediates the destruction of mRNA encoding the T cell costimulatory molecule ICOS, important as TFH cells and ICOS dependent signals are required for germinal centre formation and high affinity antibodies. As TFH cells are activated in rheumatoid arthritis and increased in frequency in SLR, we have developed a potential therapeutic blocking antibody against the human ICOS ligand, as well as PD-1 superagonists, to target TFH cells. With our collaborators at the MRC Genome Stability Unit (University of Sussex) we have contributed to the field of stem cell biology by showing how DNA repair of double strand breaks by DNA ligase IV is essential for the maintenance of stem cells during aging (3). The identification and characterization of Themis, a novel protein required for survival and positive selection of T cells (4) illustrates how rare variants can open up new lines of research. Our recent development of a screening method for defects in immunization led us to identify two ENU mutant strains of mice, both deficient in the guanine nucleotide exchange factor (GEF) DOCK8. Both of these strains failed to sustain an antibody response to T-dependent antigen. Future research plans Our future work will focus on: (a) study of the role of DOCK family proteins in immune function, B cell selection and memory; (b) creation of a consortium to study the genetics of immune disease in humans; (c) development of new therapeutic strategies targeting autoimmiune pathways in humans. References: (1) Ferry et al 2003 J Exp Med 198: 1415 (2) Vinuesa et al 2005 Nature 435:452 (3) Nijnik et al 2007 Nature 447: 686 (4) Johnson et al. 2009 Nature Immunology 10: 831 (5) Randall et al. 2009 Nature Immunology 10:1283 546/3444",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_03340,Medical Research Council,MRC,Peptide-mimetic hydrogels as a long-acting multipurpose drug delivery platform for combined contraception and HIV prevention,"HIV/AIDS is the leading cause of death in women of reproductive age worldwide. HIV and unintended pregnancies are prevalent in developing nations due to the lack of effective female contraceptive choice. HIV/AIDs remains one of the key challenges facing the UK (428 deaths from AIDS-related illnesses in 2017) and our rate of unintended pregnancies are the highest in Western Europe (one in six pregnancies). One of the key issues is that patients struggle to adhere to the complex regimens of HIV and contraceptive therapies, which often require multiple dosing at very specific times each day. Recent strategies have focused on solving patient adherence issues by using long-acting injectable technologies. However, such products have several significant issues that limit their wider use as combined HIV and contraceptive therapies, such as: -the use of water-insoluble drugs that limit the type of drugs that can be incorporated into the product meaning a dual HIV-contraceptive technology is difficult to achieve -fast drug release after insertion leading to potential toxicity issues/concerns over dose received -a need for surgery for implant insertion and removal -a requirement for large needles -stability issues upon storage/transport to the developing world which can result in clogging of syringes and incomplete dosing of drugs. Our project aims to overcome these issues by creating a soluble injection of enhanced stability, for improved ease of administration under the skin. This will form a hydrogel implant in response to enzymes present within the skin to release drugs long-term, removing the need for daily dosing. Our injectable implant is composed of peptide-like molecules which are capable of forming tissue-like hydrogels that can be tailored to gradually release drugs for at least 28 days. This will remove the need for patients to comply with complex drug dosing regimens on a daily basis and improve their adherence to medication. Natural peptides form the building blocks of proteins and tissues. Their use as a drug releasing hydrogel implant for administration under the skin is promising due to their high biocompatibility, but limited by their rapid degradation within hours by enzymes present in the human body. This project overcomes stability issues by studying peptide-mimetics, which retain the positive properties of peptides (e.g. biocompatibility, easy drug attachment) with the ability to form hydrogels that will be stable for the duration of therapy. Peptide-mimetics can be tailored to degrade within the body over months into non-toxic components that are eliminated from the patient, meaning surgical removal is not necessary. Our peptide-mimetics possess high chemical versatility (i.e. wide choice of chemical functional groups). Therefore multiple drugs can be attached directly to the peptide-mimetic hydrogel enabling large quantities of drug to be incorporated to meet in vivo therapeutic need for at least 28 days. Drug detachment proceeds in physiological conditions after the hydrogel forms reducing potential for rapid burst release of drug upon injection. Drug release studies will assess the potential for sustained drug administration in a bid to minimise pharmacokinetic peaks and troughs in drug concentrations. The peptide-mimetics studied in this project are purposefully small molecules that are cheap to manufacture, improving their potential to be clinically translated as a pharmaceutical product and effectively utilised within healthcare budgets for patient and societal benefit. The data obtained will allow the practical utility of this peptide-mimetic hydrogel approach to long-acting injectable administration of drugs to be assessed. This platform has high potential to be adopted as a novel implant for the sustained delivery of drugs for conditions where patients have difficulty adhering to their medicines (e.g.",,1.3 CHEMICAL AND PHYSICAL SCIENCES;5.1 PHARMACEUTICALS,GENERIC HEALTH RELEVANCE HRCS22_17295,Dunhill Medical Trust,,Periodontitis and future cognitive decline,"Periodontitis is widely known as gum disease; it is a progressive destructive inflammatory condition caused by dental plaque. Severe periodontitis (SP) is the sixth most prevalent condition in the world. The global age standardized prevalence of SP in 2010 was 11.2% rising steeply in those aged >65 years. Cross sectional studies suggest an association with dementia but prospective data are lacking. Between 2001& 2003 men enrolled in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) in Northern Ireland completed a Mini Mental State Examination (MMSE). 1400 men with teeth had a periodontal examination. Samples of dental plaque were collected from 727 men and quantitative PCR for common dental pathogens carried out. We aim to fully cognitively assess the surviving men and assess if prior periodontitis, genetic risk, presence of antibodies to common oral pathogens and raised serum levels of proinflammatory cytokines in stored and fresh blood contribute towards dementia risk.","Periodontitis is widely known as gum disease; it is an inflammatory condition caused by bacteria which build up on the surface of the teeth known as dental plaque. Periodontitis affects large numbers of people; almost two-thirds of those aged 65 or older have either moderate or severe periodontitis. Studies have suggested it could increase risk of later dementia. We aim to revisit 1400 men who took part in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) in Northern Ireland from 2001-2003. All men with teeth had a periodontal examination, a genetic test and blood stored; samples of dental plaque were collected from 727 men at this time and we identified what bacteria were present. We aim to carry out a comprehensive cognitive assessment in all surviving PRIME men, analyse fresh and stored blood and perform a genetic analysis to ascertain if prior periodontitis increases the risk of dementia.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,ORAL AND GASTROINTESTINAL;NEUROLOGICAL HRCS22_01356,Medical Research Council,MRC,Persistent Infections,"Understanding the role that viral variation plays in human cytomegalovirus (HCMV) disease has been limited by the large size of the genome and the challenges of getting whole-genome data from patient samples. My group has created a high-throughput pipeline for sequencing complete HCMV genomes directly from clinical material. We plan to capitalise on this by relating the diversity, evolution and strain dynamics of HCMV to clinical outcome in various groups, particularly transplant recipients. This will involve analysing viral genome sequence data from at least 1200 patient samples. We have also used modern genomics and transcriptomics technologies to help establish a particular HCMV isolate (Merlin) as a well characterized research strain for use in laboratory studies. Using Merlin, we plan to determine the functions of HCMV long noncoding RNAs (lncRNAs), in order to assess whether they provide points at which HCMV infections might be suppressed. This will involve detailed functional characterization of viral mutants with completely characterised genomes. Finally, we plan to provide added value to the congenital, genital and transplant-acquired infections programme by developing a pipeline for sequencing human herpesvirus 6 (HHV6) genomes. This will contribute to understanding the evolution and function of inherited chromosomal integration by this virus in human populations, on which evidence for clinical relevance is starting to accumulate from population studies.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_20603,Wellcome Trust,,Personalised adjunctive anti-inflammatory therapy to reduce deaths from tuberculosis.,"Tuberculosis kills more people worldwide than any other single bacterial infection but its clinical consequences and response to treatment are highly variable. Why people respond differently to tuberculosis treatment is unknown, but the identification of markers that predict response could lead to personalised and more effective treatment. Tuberculous meningitis kills around 30% of sufferers. Previously, we showed tuberculous meningitis deaths were reduced by anti-inflammatory steroid treatmen t, but not everyone benefited. Whether steroids reduce deaths in HIV-infected patients was unclear; and we discovered a gene (called LTA4H) which controls tuberculosis inflammation and appeared to predict steroid benefit. Patients over-expressing the gene suffered high inflammation and benefited greatly from steroids; patient under-expressing the gene had low inflammation and did not benefit from steroids. We will perform trials in Vietnam and Indonesia to determine whether steroid-induced surv ival from tuberculous meningitis can be predicted by the LTA4H gene and HIV infection. We will look for other survival predictors and we will investigate whether any of them influence severity and response to treatment in patients with lung tuberculosis, the commonest form of tuberculosis. Our aim is to show tuberculosis deaths can be reduced, especially from the most severe forms, by personalising therapy.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_05871,Department of Health and Social Care,NIHR,Personalised perioperative medicine to enhance recovery after major surgery.,"Background: My proposal propels perioperative medicine into an era of precision medicine for the prevention and treatment of postoperative complications. Multimorbidity after surgery is an escalating, unmet healthcare need affecting millions of individuals worldwide each year. Transient organ injury/dysfunction after surgery impairs functional recovery, delays or prevents further cancer therapy and increases mortality. An early feature of perioperative organ dysfunction is myocardial injury, which reflects cell dysfunction across multiple organs, rather than cardiac ischaemia alone. My over-arching hypothesis is that perioperative multi-organ dysfunction is driven by marked reductions in cardiac vagal (parasympathetic) function, which is frequently impaired in around 35% of higher-risk surgical patients. Loss of cardiac vagal activity is an independent, predictor of morbidity/mortality, reflecting its' essential role for optimal exercise capacity. Surgical patients who sustain complications have profound parasympathetic dysfunction, as evidenced by multiple autonomic measures. This parasympathetic dysfunction is manifest by higher heart rate, which alone is strongly independently associated with perioperative myocardial injury and subsequent (non-cardiac) organ dysfunction. Organ protection through controlled lowering heart rate may therefore reduce multimorbidity after surgery. Plan: Patient-public representation and consultation will underpin the design, implementation and dissemination throughout two core projects. First, I will build on my previous clinical research by developing a low-cost, highly reproducible test that can be used to quantify cardiac vagal activity in the preoperative assessment clinic. This will introduce a personalised/stratified approach that will help us identify which patients may benefit most from lowering heart rate during the perioperative period. Second, in a randomised, double-blind, placebo-controlled trial, I will set out to test the hypothesis that patients undergoing noncardiac surgery with the highest perioperative risk should benefit from ivabradine by slowing heart rate to reduce myocardial injury and postoperative morbidity. I will randomise surgical patients on the basis of whether they have cardiac vagal impairment predictive of acquiring myocardial injury and other organ dysfunction, Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, this trial will definitively answer whether elevated heart rate is a marker of risk or a modifiable determinant of perioperative outcomes. Re-positioning this readily available, cheap drug for perioperative use is rapidly deliverable and highly cost-effective if complications and need for hospital bed use can be reduced. At each stage, the clinical research will evolve with full public-patient involvement, which will enhance the design, implementation and reporting of this body of work. Impact: Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, this trial will definitively answer whether elevated heart rate is a marker of risk, OR a modifiable determinant of perioperative outcomes. Additional elements of my fellowship proposal will equip me with a skillset that enhances both the delivery and implementation of precision medicine in healthcare services. Transitioning from translational basic/clinical studies by acquiring an in-depth understanding of clinical trial methodology, accompanied by further training in delivering precision medicine through robustly designed studies, will support my future leadership role in targeting the right treatments to the right patients at the right time.","Background: Increasingly complex surgical treatments are offered to more patients than ever before. In particular, older patients with serious medical problems are far more likely to undergo surgery today than even 20 years ago. Patients frequently develop medical complications in the days following surgery, including pneumonia and damage to the heart (which is usually undetected by doctors and nurses). Even temporary harm to other parts of the body after surgery prevents individuals from recovering to their normal levels of function. For many patients, this delays further necessary treatments, especially cancer therapies, and increases the risk of dying even after leaving hospital.The impact of these complications can last months and years, contributing to the increasing number of patients struggling to cope with multiple medical problems (called multi-morbidity). Multi-morbidity after surgery is an increasing and unmet healthcare need affecting millions of individuals worldwide each year. An early feature after surgery in many patients is damage to the heart, which reflects cell damage that is happening at the same time to many other parts of the body. Problems with a specialised nerve called the vagus nerve, that helps control the speed at which the heart beats, is often linked to heart damage and other complications after surgery. Poor vagus nerve activity causes higher heart rate, which is strongly linked to heart damage and coincides with other organs of the body not working normally. In this project, my aim is to protect both the heart and other body organs by lowering heart rate after surgery, to ensure that patients gain the best possible result from surgery with rapid recovery and as few complications as possible. Plan: I will develop a simple test using changes in patients' heart rate when they stand up to identify those at risk of complications after surgery because of poor vagus nerve function. I will use this test to select patients who may benefit from a drug which slows heart rate but does not affect other heart functions. The drug called Ivabradine, is already available on the NHS at minimal cost. This treatment may reduce heart damage and other complications after surgery. To make sure the trial is scientifically robust, patients will be randomly allocated to ivabradine or an identical placebo tablet to test which has most effects on heart damage and complications after surgery. Because the main effect of ivabradine is to reduce heart rate, this trial will clearly answer whether high heart rate is either a direct cause of harm to the heart or an effect of ongoing harm from another mechanism. Public & patient involvement: Patient representatives have advised and supported me throughout this proposal. They will lead focus groups and be included on the trial steering committee to represent the patient perspective in all aspects of design, implementation and reporting of this proposal. Expected outcomes:1. Demonstrate that a highly cost-effective drug can improve outcomes after major surgery in hundreds of thousands of patients most vulnerable to complications, for less than 5 per operation. This would reduce NHS expenditure through avoiding the prolonged need for hospital care and treatment of complications after surgery. 2. Establish whether high heart rate indicates more risk, or is a key clinical target to improve outcomes in many other acute clinical settings. 3. Introduce a vital step-change by demonstrating the need for, and benefit of, personalised perioperative medicine. 4. Through a structured training and personal development plan involving extensive patient-public consultation, this proposal will deliver a sustained pipeline of personalised perioperative medicine of the highest quality that can rapidly make surgery a safer treatment option for millions of patients worldwide.",6.1 PHARMACEUTICALS,GENERIC HEALTH RELEVANCE HRCS22_06048,Medical Research Council,MRC,"Phase II multi-centre, double-blind, randomised trial of Ustekinumab in adolescents with new-onset Type 1 Diabetes (USTEKID)","Type 1 diabetes (T1D) is an “autoimmune condition” in which the body’s immune system selectively destroys the insulin making “beta cells” of the pancreas. Unlike the more common type 2 diabetes, it is not related to obesity or lifestyle. Affected individuals are permanently dependent on insulin injections. The condition can be diagnosed at any time from 6 months of age. Around half of all cases are first diagnosed in childhood, and the commonest time to be diagnosed is age 12. Controlling blood sugar levels accurately with insulin injections when there is no insulin produced by the body is very difficult, requiring daily dose adjustments and blood fingerprick testing many times a day. As a result, despite the development of new ways of giving insulin, less than 20% of people with T1D achieve levels of blood sugar control sufficient to prevent the long-term complications of diabetes: blindness, kidney failure, foot problems and heart disease. Blood sugar control is worst during the teenage years, when adolescents find it hard to focus on healthy behaviours and taking medication reliably. At the time of diagnosis, most people have around 10-20% of their body’s insulin making capacity remaining, but this “last bit” of insulin disappears within 1 - 5 years due to continued attack by the immune system. In this initial period, sometimes referred to as a “honeymoon”, the remaining insulin, although limited, makes blood sugar control much easier. Recent evidence suggests that treatments that could slow the loss of insulin by half, would allow 50% rather than < 20% of people to achieve ideal levels of blood sugar control and reduce long-term complications by half. _x000D_ Immunotherapy aims to stop the destruction of the beta-cells, preserving the individual’s ability to make their own insulin. Such treatment would need to be used immediately after diagnosis before the insulin is lost. Since blood sugar control is worst in teenage, and early teenage is the most common age to be newly-diagnosed, developing an immunotherapy for use in adolescents with new-onset T1D is a very high priority and likely to have the greatest long-term benefit. _x000D_ Ustekinumab is an immunotherapy treatment that has been licensed for use in psoriasis, a non-fatal skin condition where it has proved safe as well as very effective, including in adolescents aged 12-18. It works by blocking the development of certain forms of white blood cells, referred to as CD4 T helper cells (Th). Since these same T cells have been implicated in causing type 1 diabetes, we believe it may be beneficial in preserving insulin in T1D. Ustekinumab is very easy to take – it is an injection under the skin (like insulin) that can be given by patients themselves at home. It is given at the start, after 4 weeks and then every 8 to 12 weeks. We recently conducted a small scale study in adults with newly-diagnosed T1D and found that ustekinumab at higher doses (used in psoriasis) has few side effects, reduces the level of Th cells and appears to preserve insulin production. _x000D_ Here we propose a study of ustekinumab in adolescents age 12- 18 with newly diagnosed T1D in 13 paediatric specialist centres across the UK, coordinated by the newly-formed T1D UK immunotherapy consortium. If ustekinumab proves effective, this will pave the way for the introduction of this therapy into clinical practice improving outcomes and quality of life and making blood sugar control easier for adolescents with newly-diagnosed T1D.","Type 1 diabetes (T1D) can be diagnosed at any age from 6 months, most commonly around age 12. T1D is associated with severe long-term complications including blindness, renal failure, peripheral neuropathy with foot ulceration or amputation and reduced QoL. Although good blood glucose control can reduce these risks, less than 20% of patients with T1D in the UK achieve target levels, control being worst in adolescents. By contrast, in the first 1-2 years after diagnosis, over 50% of individuals including adolescents achieve optimal levels of glycaemic control due to residual endogenous insulin secretion. _x000D_ Interventions to slow the autoimmune process (immunotherapy) and preserve endogenous insulin therefore have immense potential to improve outcomes, particularly in adolescents, but none are currently licensed. We and others have shown that CD4 T cells that secrete IFNgamma (Th1) and IL-17 (Th17) are likely to be important to T1D pathogenesis. Ustekinumab is a monoclonal antibody that blocks two key cytokines involved in the generation of Th1 and Th17 cells. It can be self-administered, with low infection risk and is already licensed for psoriasis in children > 12 years of age. In a recent pilot study in adults with recent-onset T1D we have shown that usketinumab has a good safety profile, with reduction in a measureable biomarker of Th1/Th17 cells and evidence of beta cell preservation at higher doses._x000D_ HYPOTHESIS: Blockade of the IL17/IFNgamma axes with ustekinumab in adolescents recently-diagnosed with T1D will result in significant preservation of endogenous insulin (c-peptide) production. _x000D_ AIM: To provide evidence to address our hypothesis in an appropriately powered, adequately dosed randomised controlled trial with relevant mechanistic assessment and evaluation of clinical relevant outcomes. _x000D_ DESIGN: Stage 1 – setup; Stage 2 – All sites open and feasibility review; Stage 3 randomised, multicentre masked placebo controlled study – 2:1 drug:placebo. _x000D_ POPULATION: Adolescents aged 12-18 diagnosed with T1D in the previous 100 days._x000D_ INTERVENTION: Treatment with ustekinumab (anti-IL12/23) at “high” or “low” dose (as determined from dose finding study) or placebo injections, subcutaneously at weeks 0, 4 and then every 8 or 12 weeks to week 52._x000D_ OUTCOMES/ASSESSMENTS: PRIMARY change in 2-hour area under the curve (AUC) insulin c-peptide (endogenous) levels following standard mixed meal tolerance test (MMTT) stimulation at week 52. EXPLORATORY– changes in AUC c-peptide at week 28; insulin dose/kg; insulin dose adjusted HbA1c; hypoglycaemia rates, PROMs, adverse events, infections; Th1 and Th17 cell numbers; multicolour T,B, NK subset profile; antigen specific T cell responses; drug levels. _x000D_ SAMPLE SIZE: A sample size of 72 in a 2:1 ratio has >85% power to detect a 0.2nml/L/min difference between AUC values of the intervention and control arms at twelve months allowing for 10% loss to follow-up. _x000D_ STATISTICAL ANALYSIS (primary outcome): Analysis of covariance that accounts for the baseline value of the AUC mean values. _x000D_ ECONOMIC BENEFIT: Preservation of c-peptide is expected to result in a 50% or greater reduction in severe hypoglycaemia and a similar reduction in long-term complications including the very costly complications of renal replacement therapy, blindness and amputation as well as increased QoL. For teenagers these occur during working age (age 30-50). Health economic benefits will not be assessed in the current study.",6.1 PHARMACEUTICALS,METABOLIC AND ENDOCRINE HRCS22_19369,Wellcome Trust,,Phase coding in the visual system: neuronal processing coordinated by brain oscillations,"The visual system receives a wealth of information of which only little is processed. My aim is to uncover the mechanisms involved in prioritizing information processing of visual scenes. To this end, I will test a novel hypothesis that explicitly predicts how brain oscillations serve to prioritize the flow of sensory information. The core idea is that neuronal oscillations serve to coordinate computations by organizing a temporal code. The theoretical framework predicts that alpha (8–13 Hz) oscillations support a ‘phase coding scheme’ in which a set of neuronal representations will activate sequentially within an alpha cycle. This mechanism serves to convert a complex visual scene into a temporal code: a ‘to-do list’ that can be processed sequentially by downstream regions. Spatial attention and saliency will determine the order in the list by differentially biasing the excitability of the individual representations. I will test this framework using intracranial recordings and magnetoencephalography (MEG) in combination with a new approach: ‘rapid frequency tagging’. Using a novel approach for visual entrainment of the alpha rhythm, I will test the model causally. The mechanism may generalize to brain networks beyond the visual system, thereby providing a general principle for neuronal coding and inter-regional communication.","When driving down a busy street, we receive a wealth of visual input. Our brains are unable to process all this input but have a remarkable ability to decide what to process and what to ignore. My previous research work suggests that ‘brain oscillations’ are essential for controlling the visual flow. Brain oscillations are generated by coordinated activity of thousands of neurons. The strongest oscillation measured in awake humans is the ‘alpha rhythm’ which is produced by neural activity pulsing ~10 times per second. I propose a novel neuronal mechanism according to which different objects in a visual scene are represented sequentially along an alpha cycle. According to this framework information between brain regions is exchanged when the regions oscillate together. This ground-breaking theory provides a mechanistic explanation for how brain oscillations coordinate neuronal activity in order to prioritize the information flow which is presently lacking. We will test the theory by measuring brain oscillations from many brain regions simultaneously using MEG as well as intracranial recordings. The research program will eventually also help us to understand what goes wrong in individuals who have problems focussing in busy settings such as ADHD patients.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;NEUROLOGICAL HRCS22_02644,Medical Research Council,MRC,Placental chemokine compartmentalisation by atypical chemokine receptors.,"We have recently described a novel mechanism of mammalian molecular control whereby the atypical chemokine receptor ACKR2, which scavenges inflammatory chemokines, operates within trophoblasts to block maternal inflammatory chemokine entry to the embryonic circulation. When this control process is disrupted in Ackr2-/- embryos, aspects of intra-embryonic macrophage migration are disrupted. In addition in some mouse backgrounds, and particularly following induction of maternal inflammation, impaired chemokine compartmentalisation is associated with reduced embryonic survival. Importantly ACKR2 is not the only atypical chemokine receptor expressed on trophoblasts. Two other members of this receptor subfamily, ACKR3 and ACKR4, are also expressed on trophoblasts. These two receptors scavenge chemokines of known developmental importance. This Programme Grant application describes studies aimed at gaining an in-depth understanding of the process of chemokine compartmentalisation at a molecular and cellular level. Much of the grant will focus on ACKR2 but, to determine whether this is a broader mammalian phenomenon, we will also study chemokine compartmentalisation in mice in which Ackr3 has been selectively depleted from trophoblasts. Defective chemokine compartmentalisation in the context of ACKR2 has implications for embryonic development, miscarriage and adult immune/inflammatory development. With ACKR3, the major ligand for which is the chemokine CXCL12, we hypothesise that impaired chemokine compartmentalisation will be reflected in defective haematopoietic and vascular development in the embryo and infertility and cognitive impairment in surviving offspring.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_02613,Medical Research Council,MRC,"Plasma-cell depletion therapy for severe Graves' disease","Patients with severe Graves' disease, defined by severe hyperthyroidism, large goitre and inflammatory eye disease, have unmet clinical need and a poor response to conventional treatments. Many patients are ultimately managed by surgical thyroidectomy, with bilateral orbital decompression surgery followed by strabismus and eyelid surgeries. This aggressive autoimmune disease is caused by high concentrations of directly pathogenic TSH-receptor stimulating antibodies (TRAb), which are secreted from terminally differentiated B lymphocytes known as plasma cells. Daratumumab is a recently licenced anti-CD38 monoclonal antibody that selectively depletes plasma cells and thus has the potential to directly target the pathogenic TRAb-secreting cell type in Graves' disease. This adaptive trial will investigate proof of the concept that daratumumab has disease-modifying activity in Graves' disease. We will recruit 30 adult patients with severe Graves' disease defined by TRAb antibody concentrations above 10U/L (normal <1.0), with either severe hyperthyroidism (FT4 >50pmol/L), inflammatory thyroid eye disease (clinical activity score >3), large goitre or thyroid dermopathy. Initially, four different doses of daratumumab and placebo will be given in a randomised dose-response study (5 x n=3 groups). Following an interim analysis, the most promising dose(s) and placebo will be trialled in a further 15 patients. The primary analysis will be a comparison of the percentage reduction in serum TRAb concentration between baseline and 12 weeks in each active IMP group and the placebo group. Secondary outcomes will include changes in serum thyroid hormones (FT3, FT4); subjective and objective measures of thyroid eye disease; thyroid volume measured by ultrasound; participant safety and subjective tolerability. Our adaptive design study will determine whether daratumumab has the potential to change the natural history of this common and morbid condition.",,6.1 PHARMACEUTICALS,METABOLIC AND ENDOCRINE HRCS22_18630,Versus Arthritis,,"Platelets, fibroblasts and macrophages: A pathogenic or protective triad in Rheumatoid Arthritis ?","2.   In the future, the potential to provide coordination and guidance to increase harmonisation of standards at specific points across the entire biosample lifecycle;",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_05038,Department of Health and Social Care,NIHR,Platform Adaptive trial of NOvel antiviRals for eArly treatMent of COVID-19 In the Community (PANORAMIC),"Although vaccination has dramatically reduced the chances of getting COVID and becoming very unwell with it, many people still get so ill that they do need hospital treatment. Vaccines may not protect us fully against new variants of the virus that might develop. So far, a lot of the research has been to see if medicines used to treat other conditions might also work against COVID. Now, new ‘antiviral’ drugs have been developed which act directly against the virus that causes COVID, which could help people with COVID in the community avoid severe disease and hospitalisation. _x000D_ _x000D_ Our PANORAMIC study plans to enrol people either aged 50 or over or aged 18 or over with a medical condition which makes them at higher risk of severe COVID, who have recently developed COVID symptoms, and have had a positive PCR or lateral flow test. They will be randomly assigned by a computer program to receive either standard NHS care for COVID, or one of the new antiviral drugs in addition to the usual care provided by the NHS. People across the whole of the UK will be able to join the study. _x000D_ _x000D_ Our main question will be whether these new antiviral treatments safely help people with COVID-19 avoid the need for hospital admission. We will also test whether these drugs: _x000D_ Shorten the length of time that people have symptoms of COVID _x000D_ Reduce the chance that people living with someone who has COVID also catches it _x000D_ Lessen the amount of the virus we shed when we are infected, _x000D_ Are affected by new variants or changes in the virus once we start using them _x000D_ Offer value for money to the NHS _x000D_ _x000D_ Our team has learned a lot from running the PRINCIPLE study; the world’s largest and most successful community-based trial looking at which existing drugs improve COVID symptoms and reduce the need for hospital admission. So far we have tested five different drugs in PRINCIPLE and nearly 6000 people with COVID have taken part. In this new PANORAMIC trial, we will build on our experience in PRINCIPLE by including more expertise from around the UK to make our study design more suited to testing new drugs, analysing viral samples, assessing value for money, and including patient representatives from diverse and disadvantaged backgrounds to deliver a world-leading study of novel treatments for COVID in the community. Findings will improve evidence supporting treatment for COVID world-wide.","Research question _x000D_ Does antiviral treatment in the community safely reduce hospitalisations/deaths in symptomatic patients with confirmed COVID-19? _x000D_ _x000D_ Background _x000D_ Many people with COVID continue to suffer serious acute illness, with hospitalisations remaining a significant burden on the NHS. _x000D_ _x000D_ Aims and Objectives _x000D_ PANORAMIC’s primary objective is to assess effectiveness of novel antiviral treatment(s) in safely reducing all cause hospitalisation and/or death within 28 days from randomisation, in high-risk patients with a confirmed PCR positive SARS-CoV-2 test result in the community. The main secondary outcomes will be return to full-function, prevention of severe disease, reduction in symptoms, speed of recovery, including among clinically vulnerable groups. _x000D_ _x000D_ A Viral Load Sub-Study will investigate the impact of antivirals on viral load, time to virus clearance and an assessment of potential for development of resistance under drug selective pressure _x000D_ _x000D_ A Post-exposure Prophylaxis Sub-Study will determine how effective the antiviral is in preventing the transmission of SARS-CoV-2 when given to household contacts of index cases who have given consent. _x000D_ _x000D_ Methods _x000D_ PANORAMIC will have UK-wide reach. A master protocol will govern the platform trial with a Bayesian analytic approach. All enrolment (screening, informed consent, eligibility review and baseline data) and follow-up procedures (daily diary, data capture of hospitalisations and deaths) can be performed and captured online on the trial website or by telephone with a member of the trial team. _x000D_ _x000D_ Adults aged 18 or above who are clinically vulnerable and clinically extremely vulnerable, or aged 50 and above, with a positive SARS-COV-2 PCR test or positive lateral flow test and symptoms of COVID-19 illness starting within the previous 5 days will be eligible. They will complete screening and informed consent online or by phone with a member of the trial team and be randomised to receive usual NHS care or an antiviral plus usual NHS care. Antivirals will be delivered directly to the participant using urgent courier. Participants will be asked daily whether they feel recovered by text, phone or email, for 28 days, and follow-up at 3 and 6 months for assessment of longer-term effects. _x000D_ _x000D_ Hospitalisation and deaths will be captured either patient report or by NHS Digital data extracts. Recovery will be patient reported. Safety will be closely monitored appropriate to the stage of development of each agent and availability existing data, with capacity for an intensive monitoring and sampling phase followed by potential graduation to a remote monitoring phase. _x000D_ _x000D_ Timelines for Delivery _x000D_ The University of Oxford University has demonstrated capacity for efficiently and effectively sponsoring national platform trials. Using our established broad approach, we plan to start on September 1st, 2021 with the first patient randomised within one or two months, with first findings out in 18 months. _x000D_ _x000D_ Impact and dissemination _x000D_ PANORAMIC will uniquely expand the evidence about the effectiveness of novel antivirals to benefit COVID patients in the NHS and worldwide. Results will be rapidly disseminated through pre-prints, publications and notification on the trial website, as well as direct to the MHRA, Antiviral Task Force, NICE, the WHO, and guideline developers world-wide.",6.1 PHARMACEUTICALS,INFECTION HRCS22_04017,Department of Health and Social Care,NIHR,Policy Research Unit Behavioural Science,"We propose a PRU incorporating world-class expertise from Newcastle, UCL, Warwick, LSHTM and Cambridge. Our interdisciplinary team has years of experience of working with policy-makers and with each other. We are committed to achieving a step-change in how behavioural science is generated and utilised to optimise the development, implementation, and evaluation of health and care policy and so support achieving DHSC objectives. Our aim will be achieved by adopting the following principles: World class interdisciplinary expertise We are a team with unrivalled expertise in behavioural science and cutting edge methodology supported by a network of collaborators with expertise in key clinical, policy and public health areas. We bring together internationally leading behavioural/social scientists with expertise in and beyond psychology, sociology and behavioural economics (Sniehotta/Michie/Bonell/Kaner/Kelly/Vlaev), world-class methodologists (Burton/Craig/Morris/Vale) and leading expertise in inequalities (Bambra/Kelly) to deliver high quality research and advice meeting DHSC requirements. The team covers a range of disciplines and key methodologies (data science, RCTs, agile trial designs, stepped wedged designs, evidence synthesis, health economics, policy translation, cross-sector work, qualitative and quantitative methods), see research team section. Kelly was Director of the Centre of Public Health Excellence at NICE and led the methods stream of the WHO Commission on the Social Determinants of Health, Michie was DH consultant and founding member of NICE PH Interventions Advisory Committee, Morris was vice-Chair of a NICE PH Advisory Committee. Based on our experience of operating responsive mode facilities such as AskFuse (Bambra/Kaner/Sniehotta/Vale), the NIHR Innovation Observatory (Craig/Kaner) and our involvement in the Obesity (Michie) and Children s (Morris) PRUs we have an excellent understanding of what is required to engage with policy-makers and to provide a facility for effective rapid responses. Our host universities have world-class reputations and strengths across most areas of sciences and humanities. This breadth of knowledge and experience uniquely positions our PRU to rapidly mobilise expertise to answer requests around behaviour patterns and practices of health and social care professionals, managers, commissioners, decision-makers etc. in various settings (e.g., primary, secondary care, local authorities, educational/justice settings, communities) and to rely on the experience of conducting transparent science meeting the highest ethical and governance standards. Working with policy-makers We will work with the DHSC in a collaborative, flexible and responsive manner to co-create a research agenda. This involves creating opportunities to discuss policy priorities to identify opportunities for behavioural science solutions, being available to respond to research and evidence needs from the DHSC and to proactively bring forward evidence and novel research ideas suited to address current and future policies. We have significant experiences of undertaking research in inter-sectorial collaborative research and team members have been involved in advising DHSC and other government units and collaborating with policy-makers across a range of applications (see: research team). Our dedicated work stream Engagement with policy-makers will ensure that the engagement with the Department is efficient. It will allow us to identify key policy areas for our work and design research suited to optimise policy and policy evaluation. Working with and for patients and the public and addressing inequalities Each project undertaken by our unit will have meaningful PPI input and will explicitly address inequalities Patients and the public are key stakeholders, and that they reflect significant diversity in terms of socio-economic position, protected characteristics, culture, language, geographies and access to services. Our research will serve the interests of all stakeholders. Our PPI work will be jointly led by Green, a lay person with considerable PPI experience and Corner, Newcastle s Director of Engagement and build on existing infrastructure in the NIHR Research Design Service (Vale/Sniehotta) and NIHR Innovation Observatory (Craig/Kaner). Bambra/Kelly will co-lead our inequalities theme, ensuring that all our research is sensitive to key social stratifications and aware of the wider social determinants of health behaviours. Utilise cutting edge, rigorous science We will use the best science to address the policy related need for evidence. We have a very clear scientific vision. Behaviour refers to complex patterns of action and practices influenced by complex systems of interacting environmental, cultural, economic, social and individual factors[1,2]. Our work will be guided by well-established theoretical and methodological tools, developed collaboratively across disciplines and successfully applied to policy-related behavioural research across the world. The Behaviour Change Wheel/COM-B (Capability-Opportunity-Motivation-Behaviour model[3]) links policy categories to intervention functions (further defined in the V1 Taxonomy of Behaviour Change Techniques[4]) (Michie/Sniehotta/Vlaev) and mechanisms of change. This allows a systematic and transparent linkage of behavioural science to policy questions which adds to other behavioural science approaches, e.g., dual-process models[5], MINDSPACE[6] and EAST[7] (Vlaev/Kelly/Sniehotta). In addition, we have developed and applied a theory of maintenance[8] (Sniehotta) and experience with Normalisation Process Theory[9] (Kaner) to be able to achieve sustainability of behaviour change. Further, we have led the development of realist approaches to understand how intervention mechanisms interact with context to generate outcomes[10] (Bonell). When analysing policies/interventions we will apply the APEASE Criteria (Affordability, Practicability, Effectiveness/cost-effectiveness, Acceptability, Side-effects/safety and Equity) which integrate issues around PPI and equality/inequality[11]. These tools have been successfully used with DHSC and other policy-makers. We will appoint an independent scientific advisory board to provide outside scrutiny of our work within the PRU. Achieving sustainability and building capacity This PRU will lay the foundations for successful behavioural policy research in the future. Our work will be governed by promoting sustainability for the health and social care systems. We are promoting a legacy of increased capacity in behavioural science, achieving this through co-design, briefing papers, workshop with stakeholders. We will seek to use the experience and opportunities offered by the PRU to continue developing behavioural science tools and theories to facilitate future policy related behavioural research. Finally, we have an excellent track record in capacity development and will actively involve early career researchers and PhD students into the work of the PRU to provide opportunities to contribute to cutting edge translational research (see Research Team Expertise). The UCL Centre for Behaviour Change regularly runs capacity-building workshops, summer schools, conferences, hosts internships and provides consultancy on a co-design basis.","We propose a PRU incorporating world-class expertise from Newcastle, UCL, Warwick, LSHTM and Cambridge. Our interdisciplinary team has years of experience of working with policy-makers and with each other. We are committed to achieving a step-change in how behavioural science is generated and utilised to optimise the development, implementation, and evaluation of health and care policy and so support achieving DHSC objectives. Our aim will be achieved by adopting the following principles: World class interdisciplinary expertise We are a team with unrivalled expertise in behavioural science and cutting edge methodology supported by a network of collaborators with expertise in key clinical, policy and public health areas. We bring together internationally leading behavioural/social scientists with expertise in and beyond psychology, sociology and behavioural economics (Sniehotta/Michie/Bonell/Kaner/Kelly/Vlaev), world-class methodologists (Burton/Craig/Morris/Vale) and leading expertise in inequalities (Bambra/Kelly) to deliver high quality research and advice meeting DHSC requirements. The team covers a range of disciplines and key methodologies (data science, RCTs, agile trial designs, stepped wedged designs, evidence synthesis, health economics, policy translation, cross-sector work, qualitative and quantitative methods), see research team section. Kelly was Director of the Centre of Public Health Excellence at NICE and led the methods stream of the WHO Commission on the Social Determinants of Health, Michie was DH consultant and founding member of NICE PH Interventions Advisory Committee, Morris was vice-Chair of a NICE PH Advisory Committee. Based on our experience of operating responsive mode facilities such as AskFuse (Bambra/Kaner/Sniehotta/Vale), the NIHR Innovation Observatory (Craig/Kaner) and our involvement in the Obesity (Michie) and Children s (Morris) PRUs we have an excellent understanding of what is required to engage with policy-makers and to provide a facility for effective rapid responses. Our host universities have world-class reputations and strengths across most areas of sciences and humanities. This breadth of knowledge and experience uniquely positions our PRU to rapidly mobilise expertise to answer requests around behaviour patterns and practices of health and social care professionals, managers, commissioners, decision-makers etc. in various settings (e.g., primary, secondary care, local authorities, educational/justice settings, communities) and to rely on the experience of conducting transparent science meeting the highest ethical and governance standards. Working with policy-makers We will work with the DHSC in a collaborative, flexible and responsive manner to co-create a research agenda. This involves creating opportunities to discuss policy priorities to identify opportunities for behavioural science solutions, being available to respond to research and evidence needs from the DHSC and to proactively bring forward evidence and novel research ideas suited to address current and future policies. We have significant experiences of undertaking research in inter-sectorial collaborative research and team members have been involved in advising DHSC and other government units and collaborating with policy-makers across a range of applications (see: research team). Our dedicated work stream Engagement with policy-makers will ensure that the engagement with the Department is efficient. It will allow us to identify key policy areas for our work and design research suited to optimise policy and policy evaluation. Working with and for patients and the public and addressing inequalities Each project undertaken by our unit will have meaningful PPI input and will explicitly address inequalities Patients and the public are key stakeholders, and that they reflect significant diversity in terms of socio-economic position, protected characteristics, culture, language, geographies and access to services. Our research will serve the interests of all stakeholders. Our PPI work will be jointly led by Green, a lay person with considerable PPI experience and Corner, Newcastle s Director of Engagement and build on existing infrastructure in the NIHR Research Design Service (Vale/Sniehotta) and NIHR Innovation Observatory (Craig/Kaner). Bambra/Kelly will co-lead our inequalities theme, ensuring that all our research is sensitive to key social stratifications and aware of the wider social determinants of health behaviours. Utilise cutting edge, rigorous science We will use the best science to address the policy related need for evidence. We have a very clear scientific vision. Behaviour refers to complex patterns of action and practices influenced by complex systems of interacting environmental, cultural, economic, social and individual factors[1,2]. Our work will be guided by well-established theoretical and methodological tools, developed collaboratively across disciplines and successfully applied to policy-related behavioural research across the world. The Behaviour Change Wheel/COM-B (Capability-Opportunity-Motivation-Behaviour model[3]) links policy categories to intervention functions (further defined in the V1 Taxonomy of Behaviour Change Techniques[4]) (Michie/Sniehotta/Vlaev) and mechanisms of change. This allows a systematic and transparent linkage of behavioural science to policy questions which adds to other behavioural science approaches, e.g., dual-process models[5], MINDSPACE[6] and EAST[7] (Vlaev/Kelly/Sniehotta). In addition, we have developed and applied a theory of maintenance[8] (Sniehotta) and experience with Normalisation Process Theory[9] (Kaner) to be able to achieve sustainability of behaviour change. Further, we have led the development of realist approaches to understand how intervention mechanisms interact with context to generate outcomes[10] (Bonell). When analysing policies/interventions we will apply the APEASE Criteria (Affordability, Practicability, Effectiveness/cost-effectiveness, Acceptability, Side-effects/safety and Equity) which integrate issues around PPI and equality/inequality[11]. These tools have been successfully used with DHSC and other policy-makers. We will appoint an independent scientific advisory board to provide outside scrutiny of our work within the PRU. Achieving sustainability and building capacity This PRU will lay the foundations for successful behavioural policy research in the future. Our work will be governed by promoting sustainability for the health and social care systems. We are promoting a legacy of increased capacity in behavioural science, achieving this through co-design, briefing papers, workshop with stakeholders. We will seek to use the experience and opportunities offered by the PRU to continue developing behavioural science tools and theories to facilitate future policy related behavioural research. Finally, we have an excellent track record in capacity development and will actively involve early career researchers and PhD students into the work of the PRU to provide opportunities to contribute to cutting edge translational research (see Research Team Expertise). The UCL Centre for Behaviour Change regularly runs capacity-building workshops, summer schools, conferences, hosts internships and provides consultancy on a co-design basis.",3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE;INFECTION HRCS22_19582,Wellcome Trust,,PomBase: A FAIR community resource advancing research from fission yeast to humans,"Because basic molecular mechanisms are shared universally, model organism databases are pivotal resources and drivers of research across species. We will enhance PomBase, the fission yeast model organism database, to place investigations using fission yeast in contexts that illuminate equivalent processes in other species, particularly human. Through data stewardship, literature curation, and data integration, we will create emergent knowledge of eukaryotic cell biology, encompassing how proteins are connected into pathways, how pathways are connected to each other, what genes and pathways relate to human diseases, and what proteins remain unstudied across species. We will develop generic open-source, modular, customisable tools to integrate diverse data types, thereby providing clear, user-responsive presentations of increasing volumes of complex data. We will continue to make substantial contributions to the development of shared infrastructures for semantic standardization of biology, supporting increased data propagation and re-use. We will engage closely with the research community through outreach activities. Our proposal addresses four interconnected key objectives: A1 Enabling fresh biological insights across organisms from quality-assured, standardised curation. A2 Improving core infrastructure and providing innovative tools. A3 Enhancing data acquisition, interoperability, and dissemination. A4 Increasing outreach, community curation and promoting the fission yeast model system.","Because basic molecular mechanisms are shared universally, research using model organisms fuels biological insight across species. Databases dedicated to model species provide critical support for scientists to generate, share, and use results.PomBase, the fission yeast model organism database, works to ensure that researchers can easily find, retrieve, and combine information from diverse sources. We place fission yeast biology in contexts that illuminate equivalent processes in other species, particularly human, yielding emergent knowledge of eukaryotic cell biology. We focus on how proteins are connected into pathways, how pathways are interconnected, what genes and pathways relate to human diseases, and what proteins remain unstudied across species.To present increasingly complex data intuitively, we develop shareable tools to handle multiple data types as well as data quality assurance procedures. Our work helps build a shared infrastructure to standardise biological language, and supports further data propagation and re-use throughout the research community.",1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),GENERIC HEALTH RELEVANCE;INFECTION HRCS22_14210,Versus Arthritis,,Pre-clinical Investigations of Innovative Medical Devices based on Peptide-Enhanced Calcium Phosphates for Enhanced Bone Tissue Regeneration,"Synthetic calcium phosphate (CaP) bone graft substitutes are widely used in surgery, including orthopedic and spinal surgeries. However, tissue healing is frequently unpredictable, especially in ageing or compromised patients (e.g. those with diabetes and/or osteoarthritis). Attempts to overcome these limitations by mixing the CaP bone substitute with growth factors (e.g. BMPs) have met with limited success, but these combinations have also introduced new hazards including adverse reactions that have curtailed their clinical use. More recently, attention has instead been focussed on adding small osteogenic peptides, however these are yet to fully impact the market due to their cost, likely due to scale up issues, medical grade manufacture and the complex changing regulatory pathway. The only commercially available peptide-containing bone graft substitute available is based on processed bovine bone rather than a truly synthetic CaP, which introduces additional risks and ethical issues. The purpose of this project is overcome the established limitations of mixtures of bone graft substitutes with growth factors or peptides by developing an innovative, peptide-enhanced synthetic CaP material that is regulated as a medical device yet elicits consistent and predictable bone tissue healing, even in ageing or compromised patients. The osteogenic peptide will be bound to the synthetic CaP surface using a proven technology that has been demonstrated by our previous research. In reaching technology readiness level (TRL) 4, we have developed a method for anchoring osteogenic peptides to the CaP surface, identified the most promising peptide, established the optimal range of concentrations using in vitro testing, and demonstrated the safety of the device through a small animal (rabbit) in vivo study. We have also performed a market evaluation, defined the regulatory pathway, and engaged extensively with patient groups in order to align our technology with their priorities and the market. These previous studies further suggest that the resulting synthetic peptide-enhanced bone graft substitute will present a far lower risk of side effects, as well as being considerably cheaper to manufacture to a medical grade standard. The work described in this proposal will move this highly promising new technology from TRL 4 to 5 by demonstrating enhanced in vivo bone tissue regeneration, performing ageing and shelf life studies, evaluating the market, and engaging with key stakeholders, including patients, surgeons and regulators. On completion of the project, the efficacy of this innovative enhanced bone graft substitute will therefore have been demonstrated, and the final stages of the pathway to market will be defined. This aligns closely with the ambitions of Versus Arthritis, moving an innovative technology towards the clinic where it will have a transformative impact on musculoskeletal surgery and therefore the lives of patients.",,5.3 MEDICAL DEVICES,MUSCULOSKELETAL HRCS22_06905,Health Education England,HEE,Pre-habilitation of swallowing difficulties in people with head and neck cancer: A pilot cluster randomized trial.,"Research Question for future main trial (PICOT):Do people with head and neck cancer who participate in a complex pre-habilitation behaviour change intervention tailored to educate, counsel and facilitate swallowing exercises over and above routine usual care achieve better dysphagia related quality of life at six months, compared with usual care? Background and main aims for the current pilot study:Difficulty in swallowing or dysphagia is the major issue affecting the long-term health and health related quality of life in people treated for head and neck cancer. A systematic and theoretically-derived pre-habilitation swallowing intervention package comprising psychological support, education and targeted exercises provided before cancer treatment was developed for people with head and neck cancer. The primary aims of this external pilot study are to test the feasibility of a cluster-randomized design and to explore the research processes via a small-scale version of the intended future main trial. Methods and analysis:This two-arm cluster randomized pilot trial will aim to recruit six hospital sites providing multidisciplinary head and neck cancer care. Hospitals will be randomized in a 1:1 ratio and allocated to 'usual care' and 'usual care plus intervention' groups. Usual care consists of the patient meeting a speech and language therapist prior to treatment for general information on side-effects and impact of treatment on swallowing. An exercise leaflet will also be offered. The pre-habilitation intervention comprises: an x-ray swallow assessment, tailored information, personalized exercises and specific strategies to enhance patient activation and engagement. People invited to participate in both groups will be: newly diagnosed with head and neck cancer (Stage II-IV), planned for treatment via one of the conventional modalities of surgery, radiotherapy (+/- chemotherapy), at least 18 years of age, and able to consent to participation. The target recruitment is approximately 12 patients from each hospital over a 6-month period (total n=72). Follow-up will be 6-months after completion of the final oncological treatment. A range of clinical, patient reported and instrumental measures of swallowing will be collected, and the primary outcome will be confirmed. Both quantitative and qualitative methods will be used for the analysis. Important parameters such as recruitment, retention, missing data will be estimated using proportions and 95% confidence intervals. Calculation of sample size will be made incorporating cluster variability (ICC) and clinically meaningful differences in the primary outcome. Process evaluation studies have been built into this pilot work at pre-trial, during trial and post-trial phases. These studies will use qualitative methods to explore: Barriers and facilitators around context and implementation within each site that may impact the main trial. The level of intervention fidelity (delivery by clinicians) achieved during the pilot study, and the feasibility and acceptability of the methods used to determine intervention fidelity. Acceptability to clinicians and patients around participation in the trial, and the intervention itself.Main research output:At the end of this pilot study, the plan for a finalized design and optimized research process will be available to apply for funding of the main trial investigating clinical and cost-effectiveness.","Aim of the research:Most people with cancer in the mouth or throat (head and neck cancer) will have some difficulty in swallowing food and drink at some stage before, during and/or after cancer treatment. Dysphagia (difficulty in swallowing) may persist for months or years after treatment due to side-effects of surgery and chemo/radiotherapy.The aim of this research is to determine whether a pre-treatment swallowing intervention package improves patients' ability to eat and drink thus increasing their quality of life. The intervention comprises multiple components collectively called 'pre-habilitation.' This includes: tailored information, educational counseling, personalized exercises, and specific strategies to help engage with advice and exercises. Background:Head and neck cancer is a growing problem with a 59% increase seen in England between 1995 and 2011. In 2025, almost 12,000 new cases will be diagnosed making it the 6th most common cancer in England. This rise is due to the increase in head and neck cancers related to the human papillomavirus (HPV). Most individuals with HPV-related cancers are otherwise healthy, usually still actively employed, often with young families and generally have a good prognosis. However, difficulty in eating and drinking remains an important concern as it impacts individuals' health and wellbeing, family life, work and personal finances. A dysphagia diagnosis canadd up to 40% to healthcare costs for an inpatient hospital stay, and further costs are associated with long-term management such as tube-feeding. Early intervention might lead to better outcomes than dealing with problems after people have completed all their cancer treatment. This research is a proposal for testing the pre-habilitation intervention described above. Design and method:This research is a pilot study in which a small-scale version of the anticipated large clinical trial will be tested at six NHS hospitals that provide multidisciplinary cancer care. These hospitals will be randomly placed into two groups. Patients newly diagnosed with head and neck cancer who are being treated at the participating hospitals will be approached to take part in this study. Participation will be optional and will not affect cancer treatment. One group will receive the routine 'usual care' which involves meeting with the speech and language therapist (SLT) for general advice and provision of a generic swallowing exercises leaflet. The intervention group will receive the new pre-habilitation package incorporating the components mentioned above. It is not yet known whether this new intervention will make a meaningful difference and therefore it needs to be carefully studied for effectiveness within the NHS context. The SLTs at the intervention hospitals will all receive training in the pre-habilitation package. This pilot study will provide important information about whether hospitals can recruit a sufficient number of patients to the trial, and about whether patients remain in the study long enough to collect all necessary outcome measures. Other factors that may affect results in a large trial will also be explored. This includes whether SLTs deliver the intervention as planned and what patients feel about the intervention and their engagement with it. The information obtained from this pilot study will give funders greater confidence in making future investment to support a large-scale clinical trial of this research. Patient involvement:Patients and the public (PPI) contributed to the initial development of the pre-habilitation intervention, and will continue active participation during this phase. A patient representative will be on the trial steering group to ensure patient interest and safety are paramount and to have input on all patient information produced. The PPI group will also be involved in disseminating findings via social media and at patient conferences. Plain English summaries will be published alongside academic papers.",7.1 INDIVIDUAL CARE NEEDS,CANCER AND NEOPLASMS HRCS22_09393,"Public Health Agency, NI",PHA,Precision Medicine Centre of Excellence,"Precision medicine (also referred to as personalised or stratified medicine) aims to provide early and accurate diagnosis and select the right drug, at the right dose at the right time for patients. It aims to take into account individual differences in people’s genes, environments, and lifestyles when prescribing medication to treat disease. One of the cornerstones of achieving success in precision medicine is to identify biomarkers which are measurable and characteristic to the patient and can be used to predict response to treatments. This will allow potentially costly drugs to be used more effectively by being prescribed only to those that can benefit from them. There is intense interest in the precision medicine approach to treating cancer, partly because current treatments such as chemotherapy affect normal as well as cancer cells leading to unacceptable side-effects, but also because knowledge of the genetic make-up of cancers is developing so rapidly. Precision medicine can also help avoid side-effects by restricting interventions to specific molecular targets in cancer cells, so minimizing ‘collateral damage’ to healthy cells. Innovate UK has made a significant investment in the Catapult Programme - Catapults are intended to help businesses to adopt, develop and exploit innovative products and technologies - the next stepping-stone on the journey to commercialisation. Catapult Centres offer concentrated expertise in areas vital for that journey - such as manufacturing processes, test facilities, type approval and accreditation or supply chain development. Many provide access to cutting-edge equipment and specialist facilities to develop and test ideas in reality. The Catapult vision is to bridge the gap between these ambitious businesses and the expertise of the UK’s world-class research communities. Catapults exist to: • reduce the risk of innovation • accelerate the pace of business development • create sustainable jobs and growth • develop the UK’s skills and knowledge base and its global competitiveness. Precision Medicine was the focus of the 11th proposed Catapult, and in January 2015, Northern Ireland was invited, alongside other regions in the UK, to submit a bid to host the Precision Medicine Catapult (PMC). A robust bid was submitted with strong support across government, academic and industry partners. On consideration of the bids, Innovate UK initially decided that no single centre would be capable of hosting all aspects of the PMC requirement and established a multi-centre Catapult with a central hub in Cambridge and six Centres of Excellence, of which one would be located in Belfast, with a focus on Northern Ireland’s strength in diagnostics development. The Centre of Excellence would be located in the NI Molecular Pathology Laboratory (NIMPL), a hybrid laboratory operated by the Belfast Trust and the Centre for Cancer Research and Cell Biology (CCRCB) at Queen’s University.",,4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),CANCER AND NEOPLASMS HRCS22_18357,Cancer Research UK,CRUK,Precision-Panc: a dynamic therapeutic development platform for pancreatic cancer,"Our increasing understanding of the molecular diversity of cancer is creating opportunities and challenges for therapeutic development. An approach that aligns discovery, pre-clinical and clinical development is required in order to optimise therapeutic development strategies. Pancreatic cancer in particular does not have significantly effective therapies, and does not have a dominant actionable subtype that can be targeted. We have established a stratified therapeutic development platform for pancreatic cancer called PRECISION-Panc. The UK- wide network aligns through development strategies underpinned by innovative science that uncovers key vulnerabilities, and through forward and backward translation aims to define optimal therapeutic strategies for specific molecular segments. In this proposal we focus on opportunities that arise through defects in DNA maintenance, through targeting DNA damage response defective tumours and through immune therapies, aimed at the immunogenic subtype we recently described. We propose 3 initial clinical trials that utilise tissue biopsy to define predictive biomarkers of therapeutic response. In addition, we propose a study with pre- and post-treatment biopsies and liquid biopsies to define clonal evolution arising from treatment selection based on recent data that implicate the rapid emergence of resistance in pancreatic cancer. Central to this is significant pre-clinical activity aimed at further refining these therapeutic strategies and defining novel approaches through laboratory experimentation to inform the development path, and trial data that inform laboratory investigation in an iterative process.",,5.1 PHARMACEUTICALS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_19039,Cancer Research UK,CRUK,Preclinical Precision Pancreas,"Every year around 340,000 people die of pancreatic cancer worldwide, and by 2030 pancreatic cancer is predicted to be the second commonest cause of cancer death in the western world. Most patients present too late for surgery, with aggressive invasive or metastatic disease. Furthermore, current chemotherapies offer little benefit, so we urgently need to better understand the disease and identify better options for clinicians and patients. To do this, we model different genetic subsets of the disease in genetically engineered models. These models mimic human tumours in terms of the genes altered, and also because they develop a dense desmoplastic stroma of fibroblasts, stellate cells, immune cells, and extracellular matrix proteins such as collagen. By studying our models, we can determine the importance of specific genetic and transcriptomic changes identified in human tumours, identify novel targets for therapy, both in tumour cells and in the microenvironment, and test new therapies pre-clinically.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_21819,Innovate UK,IUK,Preclinical development of an innovative electric field therapy device for the treatment of Glioblastoma,"Glioblastoma is the most common and aggressive primary adult brain cancer. Global incidence is 3-5/100,000 persons and rising, with c.3000 UK diagnoses/year. There is no cure and the 5-year survival rate is ~3.4%. Electrotherapy is a new form of cancer treatment applied after tumour resection that directly interferes with cell division, slowing tumour recurrence and prolonging life. However, the only available electrotherapy device for glioblastoma is not recommended for use on the NHS by NICE due to poor patient quality-of-life and low cost-effectiveness. QV Bioelectronics (QVB) is developing a novel approach to deliver electrotherapy in a focal and continuous manner that will potentially double glioblastoma patient life expectancy, leading to up to 10-times higher 5-year survival rates whilst overcoming quality-of-life issues associated with the existing electrotherapy treatment. QVB has developed a working prototype and will perform pre-clinical safety testing as part of this Innovate UK funded project as well as working on other development aspects of their technology. QVB's device is still undergoing pre-clinical development and will not be ready to be prescribed to patients for several years. QVB's technology will be expanded to other types of brain tumours in future, with our research and innovation hub creating a significant number of jobs in the UK, creating a combined global market opportunity worth over £3Bn/year. This will cement the UK's position as global leaders in the growing field of bioelectronics.",,5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,CANCER AND NEOPLASMS HRCS22_19597,Wellcome Trust,,Predicting Antibiotic Resistance Evolution through Mechanistic Understanding of Genotype-to-Phenotype Mapping,"Antibiotic resistance is one of the biggest public health challenges, causing over a million deaths annually. In order to slow down the emergence of resistance, there is a critical need for predictive approaches grounded in experiment. Knowing the effects of mutations and interactions between them (epistasis) is critical for predicting outcomes of selection. Unlike most studies, which are limited to describing these phenomena, my research aims to provide a causal understanding of how existing molecular mechanisms define the effects of mutations and epistasis. Without such causal understanding, predicting evolution is limited to those systems that have been fully experimentally characterized. My goal is to provide the first mechanistic genotype-phenotype map for two regulatory systems consisting of a protein and its DNA-binding site. Doing so would dramatically improve our ability to predict evolutionary outcomes for one of the major forms of resistance (multi-drug resistance through changes in transcriptional regulation of AcrAB-TolC efflux pump) by allowing predictions of DMEs and epistasis without the need to fully experimentally characterize them first. Being able to predict multiple antibiotic resistance evolution from first principles, before any patients take the drug, would improve treatment strategies, while also enabling better evaluations of novel drugs during their development.","Imagine an architect, tasked with converting an old football stadium into a building with a different function, without completely demolishing it. While she might contemplate turning the stadium into a housing project, a shopping mall, or an office space, she will not consider turning it into an airport. This is because the existing architecture of a stadium imposes certain constraints: namely, the walls that surround it prevent airplanes from landing. Evolution operates in much the same way as the architect: the existing molecular structures impose constraints that make it more difficult to evolve certain forms compared to others. I study precisely this – how the existing molecular structures shape the likelihood of evolving antibiotic resistance. By identifying those structures that are less likely to evolve resistance, we can better select potential new targets for drugs, so that the time it takes for bacteria to evolve resistance would be prolonged.",5.1 PHARMACEUTICALS,GENERIC HEALTH RELEVANCE HRCS22_17974,Wellcome Trust,,Predicting CBT response from fear conditioning,"Responses to psychological interventions for anxiety vary greatly. Clients and clinicians want better ways to predict outcomes. One contender is fear extinction, the process through which exposure, the “behavioural” part of Cognitive Behavioural Therapy (CBT) is thought to work. Whilst there are robust differences in fear extinction between individuals with anxiety disorders versus controls, evidence that extinction predicts CBT response is modest.   We first became interested in fear extinction as a mechanistic tool to help understand how CBT works. In order to build algorithms from numerous potential predictors, including fear extinction, we needed to undertake fear conditioning at a scale. We developed a smartphone App FLARe, that remotely delivers a fear conditioning paradigm. Our validation studies showed that fear extinction data from our App mirror that from gold-standard in-lab delivery.  We now want to test the extent to which App-delivered fear extinction data predicts CBT response. We will assess young adults with high anxiety using our App before enrolling them in CBT. We will test the strength of correlation between fear extinction and treatment outcome. We will also explore the extent to which this association is stronger in specific sub-groups (e.g. those who completed more exposure homework during treatment).",,6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_01869,Medical Research Council,MRC,Predicting HLA-specific humoral alloimmunity to improve histocompatibility and immunological risk assessment in transplantation.,"An important strategy to offset the risk of alloimmunity and maximise transplant outcomes is to minimise the number of HLA mismatches between donor and recipient. However, current assessment of HLA incompatibility is inadequate, limited by the assumption that all mismatches within an HLA locus are equally significant. The principal aim of the proposed research is to explore the full potential of applying advanced bioinformatics modelling techniques, incorporating different mechanistic aspects of the immune system and capitalising on analysis of large clinical datasets, to develop new and improved methods for predicting HLA immunogenicity, determining HLA compatibility and defining HLA related immunological risk. Building on previous work, we will develop a computational algorithm to analyse the structure and physicochemical properties of HLA molecules and identify immunodominant B-cell epitopes on donor HLA based on their unique surface electrostatic properties compared to recipient HLA. Similarly, immunodominant CD4+ T-cell epitopes on donor HLA will be detected by investigating the potential of recipient HLA class II molecules to present donor HLA-derived peptides, thus accounting for the indirect pathway of alloreactivity. This immunoinformatics approach to determining donor HLA immunogenicity will be tested and refined by analysis of HLA-specific alloantibody responses and by detection of CD4+ allospecific T-cells in HLA-sensitised patients. The combined HLA immunogenicity algorithm, accounting for both B-cell and T-cell aspects of humoral alloreactivity, will then be validated in large, national, clinical datasets by examining its capacity to assess the risk of alloantibody development after kidney transplantation and whether it leads to improved assessment of HLA incompatibility, compared to conventional HLA mismatching, by enabling selection of HLA incompatible donor-recipient combinations that are favourable in terms of long-term kidney graft survival.",,6.4 SURGERY,RENAL AND UROGENITAL HRCS22_05639,Department of Health and Social Care,NIHR,Prediction and prevention of Asthma attacks in Children,"Background Asthma attacks are costing lives and draining healthcare budgets. Attacks are preventable, but continue to occur with failures to identify early warning signs. Patients, carers and clinicians require reliable data to guide proactive care. However, existing solutions (peak-flows, symptom-diaries) provide incomplete assessments and limited by technique, subjectivity and adherence. Our monitoring device and predictive analytics addresses these needs, providing comprehensive assessments of asthma risk. It continuously, objectively and passively monitors known markers of asthma risk (respiratory rate, nocturnal cough, wheeze) and key environmental triggers. Aims The current solution is developed for adults and CE-marked for research-use. Thus, key aims are to: a) gather clinical data to develop the solution for specific needs of children and parents. b) develop technical back-end infrastructure for interoperability and scalability within existing NHS infrastructure. c) regulatory validation study to collect evidence on clinical efficacy, safety and usability d) enable clinical adoption (incl. CE-marking as medical device, health-economic analysis, commercial, IP, and adoption strategy). Project plan comprises work-packages across clinical, technical, commercial, IP and regulatory aspects. Two clinical studies are planned, first an observational data gathering study to enable development of paediatric-specific solution; second, regulatory validation via Clinical Investigation of Medical Device study. These are accompanied by technical development work-packages on the device, analytics and data system. Finally, we will plan and implement requirements through clinical-adoption and commercial work-packages. Timelines for delivery Project is 36months in total (increased accounting for anticipated COVID-19 impact). Preparations for Study1 (3months) Study1 (15m) Study1 analysis and Preparations for Study 2 (3m) Study2 (12m) Study2 analysis and final preparations for regulatory submission (3m) Anticipated impact and dissemination An automated monitoring and predictive solution has potential to prevent personally devastating and systemically costly asthma attacks. The clinical findings will be disseminated through peer-reviewed publications, whilst clinical adoption will occur via AHSNs.","Asthma is the commonest chronic childhood condition, affecting 1in11 children, characterised by difficulty in breathing and wheezing. Acute asthma attacks remain a leading cause of unplanned hospital admissions, emergency visits and missed school-days. This causes significant disruption in their lives, severe anxiety to parents and a mounting economic burden to the NHS. Moreover, asthma attacks can be fatal: the UK has one of the highest asthma-related death rates in the developed world (1400 annually). Early recognition and management of deteriorations in asthma control can prevent attacks and emergencies. While in most cases symptoms appear before an attack, current tools (e.g. peak-flows and symptom-diaries) are unsuitable for long-term use by children as they (a) require daily active adherence (b) are subjective and dependent on child s technique and (c) do not provide detailed information on various factors associated with attacks. By the time children or parents perceive the decline, it is often too late, requiring them to rush to hospital. The challenge underpinning this unmet need is the inability to detect the signs of deterioration objectively and early at home. BreatheOx, through two InnovateUK awards and other funding, have invented a small non-contact table-top device and associated AI algorithms that automatically monitor a range of physiological and environmental metrics without requiring patients to do or wear anything. Using motion sensors (similar to automated lights), the device captures small movements in the body when someone breathes and the algorithms estimate breathing rates. Acoustic sensors capture other clinical symptoms (e.g. coughing and wheezing), and environmental sensors monitor living conditions (e.g. temperature, humidity and volatile organic compounds) and other environmental triggers (e.g. pollen, air quality, weather). This way, the device collects objective, continuous and long-term data on a range of physiological symptoms, living conditions and outer environment. This has been tested in a clinical study involving adults and CE-marked for research. In this project, we propose implementing this innovative monitoring and prediction technology for children. The aim is to further develop algorithms and clinical decision-support tools for early detection of asthma attacks in children by capturing early warning signs before patients perceive them through continuous long-term monitoring, enabling early treatment to stop attacks at home. Our objectives include demonstrating value in NHS care pathways by deploying the system within existing NHS infrastructure and generating real-world evidence of clinical and economic value. To ensure efficient planning, management and delivery, project team includes BreatheOx (Oxford University med-tech spinout company, for technical, regulatory and commercial input), Birmingham Women s and Children s Hospital NHS Trust (one of the busiest UK paediatric asthma centres), Imperial College London (largest UK paediatric severe asthma translational research programme), AsthmaUK (leading Asthma charity, representing patient and public opinion) and OxfordAHSN (experts in market-access and NHS-adoption).",7.3 MANAGEMENT AND DECISION MAKING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,RESPIRATORY HRCS22_06741,Health Education England,HEE,Predictors of Outcome in Sciatica patients following an Epidural steroid injection: the POiSE study.,"Research Question In adults with disc-related sciatica, what patient, clinical and imaging characteristics are associated with pain and function outcomes following epidural steroid injection (ESI)? Background Sciatica is a shooting leg pain, with or without symptoms of numbness or muscle weakness. In most cases (90%) sciatica is due to a lumbar disc herniation compressing the lumbar spinal nerve root(s), with associated inflammation. Up to 30% of sciatica patients do not improve and are referred to specialist spinal services for tests and further treatments, such as injections and/or surgery. The NICE guideline recommends ESIs for treating severe disc-related sciatica pain. In England the annual cost of ESIs for sciatica is approximately 30 million. Currently, there is no clear evidence on which patients are more likely to do well with ESI. The overall aim of this proposal is to offer patients with disc-related sciatica better individualised information about their likelihood of improvement in leg pain following ESI. The overall objective is to develop and validate a prognostic model to support patient and clinical decision-making regarding this intervention. Specific Objectives and Methods Work-package 1 Objective:Identify key candidate factors potentially associated with outcome following ESI. Methods: Systematic review and meta-analysis of factors predictive of outcome following ESI. Multidisciplinary expert clinical consensus workshop followed by electronic survey with two Delphi rounds to agree the factors potentially associated with outcome following ESI. Work-package 2 Objectives: (i) describe prognosis in patients with severe sciatica, (ii) determine prognostic factors that predict patients' outcomes following ESI, (iii) develop and internally validate a prognostic model for outcome following ESI, (iv) consider differences in outcomes and prognostic factors in those who do, and do not, have ESI treatment. Methods/Analysis: Multi-centre, observational, prospective cohort study nested in routine clinical care recruiting patients with disc-related sciatica, considered suitable for an ESI as part of their normal care. Prognosis for the cohort will be described. For the prognostic model, 439 patients who receive an ESI will be recruited. The primary outcome is leg pain intensity (0-10) at 6 weeks following ESI collected via weekly text messages from the day of consent until 12 weeks following ESI, and at 6 months. Secondary outcome measures will be collected via questionnaires at baseline, 3 and 6 months. Prognostic factors will be tested in those who do not have an ESI (a 'control' group). Statistical analyses will include multivariable linear and logistic regression with mixed effects model, prognostic modelling, classification and regression tree analysis and longitudinal latent class analysis. Work-package 3 Objectives: Externally validate the prognostic model and explore its usefulness with patients and clinicians. Methods: External validation of the prognostic model in separate trial and routine clinical practice data. Workshop with clinicians and patients to inform post-fellowship work to develop a clinically useful tool to support decision-making when considering ESI. Anticipated impact and dissemination This research will directly inform decision-making by patients and clinicians, who will have better information on their likelihood of benefit following ESI. Results will inform UK guidelines and dissemination strategies for sciatica management.","Sciatica can be very painful and in most cases is due to a disc herniation ('bulging' or 'slipped' disc) pressing on a spinal nerve. Sciatica symptoms include severe leg pain, usually below the knee, often accompanied by pins and needles, numbness or muscle weakness in the leg. Pain improves for most people with time, but for some, the pain persists and they are referred to specialist NHS spinal services for an opinion on further management. One management option, if the magnetic resonance imaging (MRI) scan confirms a disc herniation, is a spinal epidural steroid injection (ESI) of anti-inflammatory medicine. The aim of an ESI is to relieve leg pain, improve function and reduce the need for spinal surgery. We know from previous studies that ESIs, on average, provide some relief of leg symptoms in the short-term. For some patients they work well, but not for others. Currently we do not know which patients benefit and which do not. This is the gap in knowledge that this study will address. The aims of the study are to identify and test factors, including patient characteristics, clinical examination and imaging findings that help us to predict who does well and who doesn't after an ESI and explore how this information can be used in clinical practice. Design and methods There are three work-packages in the study. In work-package one (WP1), I will compile a list of factors that could be associated with outcome following ESI. First I will summarise evidence from previous research about the potential factors (e.g. age, pain severity, MRI findings). Then I will ask expert clinicians, who manage patients with severe sciatica (e.g. orthopaedic surgeons, specialist physiotherapists), to agree on a list of factors. At the end of WP1, there will be agreement on which factors to include in the clinical study in work-package two. Work-package two (WP2) is a large clinical study which will recruit 439 patients suffering from sciatica resulting from a herniated disc in the lower back, considered by the clinician as suitable for an ESI to manage their leg pain. I will include patients who have an ESI as well as patients who are suitable and referred for an ESI but do not go on to have this treatment (for example their symptoms recover while waiting for the ESI). Patients who agree to participate will receive a weekly text message for 12 weeks and again at 6 months, asking to rate their leg pain severity in the last week. Participants will also complete postal questionnaires at baseline, 3 and 6 months. Using this information, I can determine what combination of factors predict who does well and who doesn't after an ESI and compare them in the group who did not have an ESI. In work-package three (WP3) I will test if the combination of factors identified in WP2, predict which patients do well with an ESI but in a new group of sciatica patients, using data from clinical trials and routinely collected data of patients who had an ESI.I will explore with patients and clinicians how to use the findings from WP2 in the clinical setting to help clinicians and sciatica patients make better decisions about ESI treatment.Patient and Public involvement Patients with sciatica have shaped this application and will be involved throughout this study advising on issues including recruitment, wording of text messages, questionnaire design and how the findings can be used in clinical practice. Conclusion This research will mean clinicians can offer sciatica patients better information about their likelihood of improvement following ESI, and support patient and clinical decision-making about this treatment.",6.1 PHARMACEUTICALS,NEUROLOGICAL;MUSCULOSKELETAL HRCS22_11675,Economic and Social Research Council,ESRC,Predictors of mental ill-health in mothers caring for a son or daughter with intellectual disabilities,"The main objective of this pioneering research is to take advantage of Scotland's rich informatics environment, linking large datasets to determine the prevalence and determinants of mental ill-health of mothers caring for a son or daughter with intellectual disabilities and mothers post caregiving, across social classes. The proposed research will provide unique insights into the multiple social determinants of health that impact on health outcomes of maternal carers and contribute to building the empirical evidence on intersectionality. With this information, important and overdue questions on mental ill-health, and the complex dynamics of inequality, can be addressed which will subsequently identify gaps in current services and provide evidence to support the design of professional support for mothers at pivotal points in the caregiving trajectory including post caregiving. Secondary objectives: To enrich our understanding of the complex interrelationship between socio-economic factors and caregiving by drawing on big data. To demonstrate the opportunity that this linked data affords for addressing the significant gaps in research about the health and health care of people with intellectual disabilities and their family members. To demonstrate the fundamental value of having a question on 'intellectual disabilities' within Scotland's Census with the hope that other countries within the UK and internationally will include a similar question in future Censuses. Doing so will provide valuable opportunities to access a wealth of data on the health and wellbeing of people with intellectual disabilities and their family members.","An increasing number of parents in Scotland are continuing to care for their son or daughter with intellectual disabilities (an individual with an intellectual impairment and impaired social functioning which started before adulthood, with a lasting development) over a prolonged period of time. This is due to improvements in medical technology, health care, nutrition and the movement away from institutional to community care. While caregiving can be an extremely positive and rewarding experience, it can also have a negative impact on the mental health of parent carers at various points in the caregiving trajectory (i.e. across the life cycle - caring for a child (0-15 yrs), adult (16 - 54yrs), older adult (55+ yrs*) including after the death of a son or daughter with intellectual disabilities (described hereafter as 'post caregiving'). Small scale research suggests that mothers caring for a son or daughter with intellectual disabilities, as opposed to fathers and other carer groups, report poorer mental health potentially making them more susceptible to depression and anxiety. However, there is a dearth of robust research in this area. Scotland's Census 2011**, provides a unique opportunity to identify the mental health of mothers' caring for a son or daughter with intellectual disabilities. This is the only known whole population census in the world whereby mothers with a caring role can be identified, as can households with a child or adult with intellectual disabilities, enabling the individual characteristics of both mother and child to be linked. Scotland's Census 2011 will also be linked to information from different sources (routinely collected health records) to better understand the mental health of mothers at different stages of caregiving, including post caregiving. Aims: To investigate the prevalence and determinants of mental ill-health in mothers caring for a son or daughter with intellectual disabilities, both overall and at different stages of the caregiving trajectory, including post caregiving. Methods: The proposed study aims to take advantage of Scotland's rich informatics environment and datasets to benefit mothers caring for a son or daughter with intellectual disabilities and mothers post caregiving, through data linkage and secondary analysis of routinely collected health data. We will link datasets that tell us about: mothers self-reported mental ill-health (Scotland's Census 2011); use of medications for depression and anxiety (Prescribing Information System) and; hospital admissions for mental ill-health (Scottish Morbidity Records). It is also important to identify possible reasons for mental ill-health (e.g. socio-economic factors such as household structure, employment status, number of children in household), so these can be addressed. Linking these datasets will allow us to investigate how common mental ill-health is in mothers caring for a child, adult or older adult with intellectual disabilities or post caregiving, and additionally, compare this with matched women who do not have this caring role. The proposed study provides a highly cost effective method to address important and overdue questions on mental ill-health and will subsequently provide evidence to inform professionals to support mothers at pivotal points in the caregiving trajectory including post caregiving. It will also provide valuable insight on the impact of the broader social context on mental ill-health. * 'Older adults' are categorised as individuals 55+ years of age as it is generally accepted that individuals with intellectual disabilities, not just people with Down syndrome, show signs of premature ageing. ** Scotland's Census 2011: the only comprehensive consistent source of national and local data about people, their key characteristics, and household composition.",2.4 SURVEILLANCE AND DISTRIBUTION,MENTAL HEALTH HRCS22_02562,Medical Research Council,MRC,Preemptive discovery of insecticide cross-resistance mechanisms for next generation malaria control products,"Malaria control is being impacted by insecticide resistance but newly-available and oncoming insecticides offer the opportunity to effectively manage resistance, provided mechanistic knowledge and monitoring tools become available to inform rational deployment. Genomic and transcriptomic comparisons of resistant and susceptible mosquitoes, which we and others are applying as part of ongoing and recent programmes are powerful for identification of resistance candidates, but lack capacity to pre-emptively identify mechanisms of resistance and cross-resistance for new insecticides. Novel complementary approaches are required to meet this challenge and we propose to combine transcriptomic and functional genomic approaches with a novel chemico-proteomic approach, Activity Based Protein Profiling (ABPP ). We will apply dual pipelines: the first integrates comparative transcriptomic and ABPP analyses to identify differentially expressed genes and correspondent differentially binding enzymes between Anopheles strains with contrasting resistance to the key current IRS insecticide pirimiphos methyl (PM). The second pipeline will apply competitive inhibition of ABPs with insecticide or their reactive metabolites to identify modes of toxicity for each and generate an insecticide-enzyme interaction matrix for identification of cross-resistance candidates. The most promising candidates from each pipeline will be tested using a third functional validation pipeline involving heterologous expression and metabolism, transgenic expression in Drosophila and Anopheles and RNAi to investigate resultant gains and loss of resistance. Our results will provide new knowledge and pre-emptive diagnostic tools for resistance management programmes, and pipelines readily adaptable to future insecticides",,3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,INFECTION HRCS22_23100,The British Academy,,Preferences for facial sexual dimorphism across culture and the sexual orientation spectrum,"Judgments of attractiveness have many important social outcomes, highlighting the need to understand how people form these judgments. One aspect of appearance that impacts perceptions of attractiveness is facial sexual dimorphism (femininity/masculinity). However, extant research has focused primarily on White, Western, heterosexual participants’ preferences for sexual dimorphism, limiting generalisability. Indeed, recent research indicates that these preferences vary by culture, and other work finds differences between gay/lesbian and heterosexual individuals. However, aspects of identity such as culture and sexual orientation do not exist in isolation from one another, but rather intersect, leaving a critical gap in understanding. Our research therefore aims to bridge across these hitherto separate areas of inquiry to provide a comprehensive and generalisable understanding of sexual dimorphism preferences. We will test how individuals’ culture, sexual orientation (including, crucially, bisexual individuals), and gender predict their sexual dimorphism preferences for White and East Asian faces.",,1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,GENERIC HEALTH RELEVANCE HRCS22_05419,Department of Health and Social Care,NIHR,Pregnancy AntihyperteNsive Drugs: which Agent is best? (giant PANDA study),"What is the aim of the study?_x000D_ The aim of this study is to find out which blood pressure medication is best for pregnant women with high blood pressure._x000D_ _x000D_ Why is this important?_x000D_ Around 10% of pregnant women in the UK are diagnosed with high blood pressure before or during pregnancy. Without treatment, high blood pressure can cause damage to the heart and kidneys, and rarely, complications such as a stroke. Sometimes we need to admit women to hospital with very high blood pressure. If we cannot bring the blood pressure down with medication, we may need to deliver the baby, even if premature, to avoid complications for mum and her baby. In pregnancy, we take particular care to treat high blood pressure to try and avoid all complications. A recent report summarised all the studies that have compared blood pressure medication in pregnancy. It found that there haven’t been enough large studies to say which is the best blood pressure medication to use and that researchers need to do more work to find this out._x000D_ _x000D_ We want to find out which of two different treatments currently used in the NHS work best at controlling blood pressure in pregnant women without having troublesome side-effects for the woman or baby. The medications we will compare are called labetalol and nifedipine. Both have been widely used by pregnant women in the UK for many years and are considered safe to use in pregnancy but prescribing varies widely around the country because we do not know which one works best._x000D_ _x000D_ What does the study involve?_x000D_ We will approach around 2300 women in 40-50 maternity units in the UK who have high blood pressure in pregnancy and need treatment. We will offer these women information about the study and give them time to decide if they would like to take part. Women will be asked for their consent and we will then randomly allocate them to one of the two blood pressure medications using a computer. This means that their treatment will be chosen by chance, a bit like tossing a coin, and is the fairest way to test treatments. The women and their doctors will know which medication they are getting to ensure they are taking the correct dose._x000D_ _x000D_ All women will continue to have their usual antenatal care (including their blood pressure measurements) and their doctors will be able to change blood pressure medications as needed, for example to change the dose. Two weeks after joining the study we will contact the women and ask them to complete a short study survey about how they find the blood pressure medication. The women and their babies will be followed up through the pregnancy until they leave hospital after delivery._x000D_ _x000D_ What do other women think of the study?_x000D_ We have asked women who have/had high blood pressure in pregnancy what they thought of this study. They were very supportive of the need for this study and told us what endpoints they thought were important to pregnant women and their families. We have used this information to help design this study and will continue to involve women who have experienced high blood pressure in our work to ensure women’s viewpoints are at the heart of our research._x000D_ _x000D_ The results of this study will help to understand which drug gives the best blood pressure control for the woman and is safe for the baby. The results will be published in widely respected journals and will help doctors and pregnant women with high blood pressure decide which medication is best for each woman.","Research question: In women with pregnancy hypertension (P), what is the effect of a treatment initiation strategy with nifedipine (I) versus labetalol (C) on severe maternal hypertension (O) and a composite of perinatal loss or neonatal unit admissions (O)?_x000D_ _x000D_ Design: Prospective, late phase, pragmatic, parallel group, open-label, multicentre, two-arm randomised controlled trial of treatment initiation with nifedipine or labetalol in women with pregnancy hypertension._x000D_ _x000D_ Setting: 40-50 UK consultant-led maternity units._x000D_ _x000D_ Population: Pregnant women with hypertension._x000D_ _x000D_ Inclusion criteria: Pregnancy (=34+0 weeks’ gestation); pregnancy hypertension (chronic or gestational hypertension or pre-eclampsia); decision made to initiate or continue use of antihypertensive; aged =18 years; written informed consent._x000D_ Exclusion criterion: Contraindication to either agent; already taking both agents and not able (or willing) to be switched onto single agent._x000D_ _x000D_ Health technologies: Treatment initiation with any preparation of modified release nifedipine, a calcium channel blocker, (intervention arm) vs. labetalol, a mixed alpha/ beta blocker, (active control arm) by random allocation (1:1). All other aspects of antenatal and delivery care will follow the usual care pathways underpinned by NICE 2019 guidelines for pregnancy hypertension. _x000D_ _x000D_ Co-primary outcomes: _x000D_ Maternal: Severe hypertension (proportion of healthcare professional measured systolic blood pressure readings (=160mmHg) up to delivery). _x000D_ Perinatal: Perinatal death (stillbirth after 20 weeks’ gestation or neonatal death up to 7 days) or neonatal unit admission up to hospital discharge. Secondary maternal and perinatal outcomes include clinical and patient-reported outcomes in addition to health care resource use._x000D_ _x000D_ Sample size: 2,300 pregnant women with hypertension. Assuming 90% power, 2.5% one-sided significance for non-inferiority, a control group event rate for the co-primary outcome of neonatal unit admission of 25%, 5% loss to follow up, a total of approximately 2,300 women would be required to detect a clinically meaningful non-inferiority margin of 6%. For the maternal co-primary outcome, a sample size of 2,190 will allow the detection of a 2.3% superiority difference between the mean proportions of clinic and hospital systolic blood measurements =160mmHg. This is equivalent to an effect size of 0.14 of a standard deviation, based on a two-sample t-test (5% two-sided alpha, 90% power) e.g. from around a mean of 9.6% to 11.9%. _x000D_ _x000D_ Economic evaluation: A cost-effectiveness analysis using a decision analytical model with a lifetime horizon and an NHS perspective, and a cost-consequence analysis up to hospital discharge._x000D_ _x000D_ Difference between pathways: Standard care pathways advise antihypertensive treatment; both nifedipine and labetalol are currently used in practice. In the trial, choice of antihypertensive treatment will be randomly allocated, but other care will follow usual antenatal care pathways._x000D_ _x000D_ Timetable: Months 1-8: set-up; Months 9-17: internal pilot; Months 18-33: recruitment; Months 34-41: follow-up; Months 42-48: analysis and write-up._x000D_ Expertise in team: The multidisciplinary team draws on UK-wide clinical academic expertise across the health professional spectrum with extensive trials experience in pregnancy hypertension, a PPI co-applicant (experience of pregnancy hypertension) and an experienced Clinical Trials Unit._x000D_ _x000D_ Dissemination and impact: Academic outputs (presentations, papers) and active engagement with public and patient dissemination routes. For impact, the trial is intended to provide definitive evidence to inform guidelines and linked shared decision-making tools for early uptake into clinical practice.",6.1 PHARMACEUTICALS,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_22866,The Academy of Medical Sciences,AMS,Prevalence of cytomeglaovirus and Epstein Barr virus and associated immune-activation and inflammation in adolescents with perinatally-acquired HIV.,"In HIV-infected adults there is evidence of association between cytomegalovirus (CMV) or Epstein-Barr virus (EBV) co-infection with increased inflammation and reduced correlates of immunological health. In turn these co-infections have also been associated with non-AIDS events such as malignancies, cardiovascular or neurocognitive disease. It is known that HIV-infected adolescents have an increased risk of co-morbidities including malignancy compared to their HIV-uninfected peers, however the potential relationship between chronic co-infection with CMV or EBV and associated increased risk of these co-morbidities is not well-described. This study aims to quantify the presence of CMV and EBV in adolescents with perinatally-acquired HIV, and assess for correlates of immune-activation, dysregulation and inflammation that may be associated with non-AIDS diseases including malignancy. Blood samples will be taken from 130 adolescents from the largest tertiary centre, perinatally-acquired HIV clinic in the UK. These adolescents are under lifelong follow-up with more than 81% on suppressive antiretroviral therapy and are very well-characterised as the majority of attendees have been patients since infancy. Routine blood tests will assess HIV control and we will measure CMV and EBV alongside markers of inflammation. Flow-cytometry assays will quantify immune-activation, naïve and memory subsets, proliferation, degranulation and immune-regulation; and Luminex will measure a bespoke immune-oncology panel of proinflammatory cytokines and biomarkers associated with cancer, neurodegenerative or cardiovascular disease. Should the association between HIV co-infection with CMV or EBV be demonstrated to increase the risk for malignancy and other co-morbidities, a therapeutic trial examining treatment of co-infections or anti-inflammatory therapy would be warranted.","Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are common viral infections that tend to causes relatively mild illness in healthy children and adults. However CMV can cause devastating disease in babies who are infected while they are developing during pregnancy and children who have problems with their immune systems, and EBV is known to increase the risk for some types of cancer. These viruses can cause long-term, chronic infection in children with an underlying condition that compromises the ability to fight infection such as Human Immunodeficiency Virus (HIV). It is known that young people with HIV have a 15-fold increased risk of cancer and other diseases affected the heart or brain compared to their HIV-uninfected peers, and so in this study we aim to explore whether having CMV or EBV might increase the chances of these young people developing cancer or other diseases. This study will determine how common CMV and EBV infections are in a group of 130 individuals aged 15-33 years from the largest clinic for young people with HIV in the UK. Using blood tests we will then examine how the body responds to these chronic infections by measuring markers of inflammation and activation, and further explore whether these markers are associated with developing cancer or other diseases. This information will help inform doctors whether new treatment approaches are needed to treat chronic infection with CMV or EBV in these young people.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_06241,Department of Health and Social Care,NIHR,Preventable infant deaths: Improving uptake of safe sleep messages in high-risk families,"5.1 Research questionHow will an intervention targeted to families most at risk, improve safety for babies during sleep, and reduce Sudden and Unexpected Deaths in Infancy (SUDI)? 5.2 BackgroundAdvice for parents on safe sleep has reduced the incidence of SUDI in the general population over the last 3 decades, but less so for more deprived families. SUDI deaths have always been more common in these groups but now about two-thirds (approximately 200/300) occur in this group. An era of global case control studies has identified risk and protective factors for the infant sleep environment, which if adhered to, could reduce deaths further. Using what I have learned about the factors that influence decision making in high-risk families, I can now start to put this evidence into action in the form of a targeted intervention to reduce risk. 5.3 Aim and objectivesThe aim is to develop and evaluate a targeted intervention for improving uptake of safer sleep practices in families at higher risk for SUDI. In order to meet this aim, five work packages with the following objectives are proposed: Examine the prevalence and population demographics of known risk factors of SUDI deaths in England since 2018 using data from the National Child Mortality Database (NCMD). Investigate the factors influencing decision-making for infant care in high-risk families (including fathers/partners and grandparents). Co-produce the support package with families, health professionals, academics, and health services commissioners. Conduct a Realist Evaluation study of the intervention. Write a protocol and funding application for a feasibility study to test intervention methods for assessing effectiveness and investigate scope for widening the intervention to include other child health related topics. 5.4 MethodsI will conduct comparative analyses of NCMD data to describe the prevalence of known risk factors present in recent unexpected infant deaths and compare those at high risk or normal risk of unexpected infant deaths. I will use qualitative thematic analysis of interviews with families. I will use co-production to develop the intervention, bringing together an intervention development team to work together to produce the content. Realist Evaluation methods will then allow me to explore the context, mechanisms and outcomes associated with the intervention. This will include observations, surveys, interviews and focus groups. Finally, I will investigate the most appropriate methodology for a future study and write a protocol and funding application. 5.5 Timelines for deliveryA paper describing the NCMD data will be published at the end of the first year. A paper with the findings from the mixed methods study on high-risk families and wider caregivers will be published at the end of the second year. Two other papers (one on co-production study and one on evaluation study) will be delivered in the fifth year. 5.6 Anticipated impactThe intervention will have the potential to improve sleep safety for infants in high-risk families and reduce infant deaths. Learning from this work will contribute to understanding the mechanisms of complex interventions for high-risk groups across a range of infant care practices.","4.1 AimMy main aim is to develop an intervention to provide education for vulnerable families about infant sleep safety that will reduce the risks their babies are exposed to and ultimately reduce sudden and unexpected infant deaths. 4.2 BackgroundAnnually in the UK, approximately 300 babies under a year die suddenly and unexpectedly (Sudden Unexpected Death in Infancy or SUDI). While public health messages for safe sleep have worked well in the general population, the deaths that now happen are mostly in the most vulnerable families. Many of the deaths in these families could be prevented as the circumstances described almost always have known, avoidable risks present. Specific risks within the infant sleeping environment have been identified by many international studies although how common these are within a population of families in England with babies at high-risk of SUDI is less well known. Bristol University now runs the National Child Mortality Database (NCMD), which may provide some answers to these questions. My research suggests that a wider approach to sleep, combining safety, quality and coping skills for disrupted routines would be most acceptable to high-risk families and the people who support them. Most families I have spoken with have described scenarios that could increase the risk for babies as a result of carers trying to get enough sleep. My programme of research will build on the findings from my previous work into why some families don't follow the recommended advice. This will then shape the design and evaluation of a package of supportive education. 4.3 Design and methods usedThis fellowship has 5 work packages. First, I will work with the NCMD to describe how commonly known risk factors were present in recent English SUDI deaths. Second, I will conduct a survey and talk in depth with families of infants at higher risk of SUDI (especially partners and grandparents) to find out more about their understanding of safe sleep advice and infant care practices. The data from the NCMD work will provide risk information that I will use to guide the questions in the family interviews. Third, I will bring together a team of people including those who will use, deliver and commission the intervention to produce educational resources and information for high-risk families. Integrating different perspectives and expertise in this way will give us the best chance of creating an intervention that will work. Fourth, I will evaluate the new intervention to see how it works in real life, looking for how it works, for whom, in what context. Finally, I will look at whether this approach can resolve other problems within these vulnerable families and write an application for a study to look at whether the intervention is acceptable to families and how best to conduct a future study to test whether the intervention works.4.4 Patient/Public involvementI have directly spoken with over 100 parents and carers about this proposed research, through attending children's centre groups, public engagement activities, and via family support charities. The insights that they have shared with me have directly influenced how I will go about developing and testing the intervention, for example including partners and grandparents and considering sleep deprivation. The effects of poverty on this group can make life unpredictable and communication more difficult so I use both face to face and electronic methods to keep in touch. 4.5 DisseminationThis will include publishing findings and recommendations in peer reviewed journals, speaking at national and international conferences and appealing to a wider audience through public engagement activities.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;7.1 INDIVIDUAL CARE NEEDS,GENERIC HEALTH RELEVANCE HRCS22_07162,Department of Health and Social Care,NIHR,Preventing Sudden Unexpected Deaths in Infancy: an assessment and planning tool for families at increased risk,"Research question How does a risk scoring and planning tool support safer infant sleep during disrupted routines for infants at increased risk of SUDI? Background Advice for parents on safe sleep has reduced the incidence of Sudden Unexpected Death in Infancy (SUDI) in the general population over the last 3 decades, but less so for families living in deprivation. About two-thirds of the deaths (~200/300) occur in this group. Disrupted routines influence decision-making in families at risk, and impact on sleep safety. Incorporating planning for disruption with practical strategies to maintain safety for infants, could save lives. Aims and Objectives The aim of the study is to refine and evaluate a risk scoring and planning tool for improving uptake of safer sleep practices in families at increased risk for SUDI, by: Developing a risk scoring system to quantify the potential risk in different infant sleeping environments. Developing an interface that the target group can use. Conducting a process evaluation study to understand how the tool works in real world conditions. Conducting a scoping exercise to assess the potential for widening this type of tool to other infant safety topics. Writing a protocol for a feasibility study to develop the methodology needed to test the effectiveness of the intervention. Methods We will develop a risk scoring algorithm on distal factors (background characteristics and factors related to birth) and proximal factors (those surrounding the sleeping environment) using existing UK observational data. Distal factors are largely unmodifiable, however the proximal ones are not and can quantify the potential risk in different environments. External validation will be sought using the National Child Mortality Database (NCMD) and from a team collecting similar information in New Zealand. The scoring system and planning tool interface will be embedded in a website being developed and used during a personalised planning activity to maintain safety in different sleeping environments, when routines are disrupted. An infographic of each plan will be sent to recipient s mobile device for sharing with others. A process evaluation involving interviews with families and three health visitor/nursing teams working in deprived areas of Bristol, UK, will investigate the implementation, mechanisms of impact and behavioural outcomes associated with the intervention. We will explore how this approach might be used for other risk-based advice. Finally, we will write a protocol for a feasibility study to develop the methodology needed to test the effectiveness of the tool. Timelines for delivery Months 0-6: develop the algorithm (objective 1), prepare our evaluation protocol, secure ethics, establish research advisory groups. Months 4-7: Develop the user interface for the tool, and guidance about how to use it (objective 2). Months 7-12: Collect and analyse process evaluation data, refine the tool (objective 3). Conduct a scoping exercise for further uses of this type of tool (objective 4). Months 13-15: write the feasibility study protocol (objective 5) and findings for publication. Anticipated Impact and Dissemination This intervention will have the potential to improve uptake of life-saving advice in families with infants most at risk.","Aim To develop a 'risk scoring and planning tool' for families to encourage safer sleep for babies at increased risk of Sudden and Unexpected Death in Infancy (SUDI). Background Every year in the UK, about 3-400 babies die suddenly and unexpectedly. Many of these deaths could be avoided by following safer sleep advice, widely promoted but difficult to follow for some families. Most of the babies who now die, are born to mothers under 25 in the most socially deprived groups. Bereaved families tell us the risks were often a result of a change in their normal routine when caring for the baby, for example when people visit, having a party, or when staying away from home. Our research suggests that understanding their baby s own level of risk and planning for safety during changes to the routine could save lives. The risk scoring and planning tool we propose here includes providing information on a website and to their phones about their baby s risk in certain situations and planning for safety during busy times. Design and methods We will develop a tool from information we already know has saved many babies lives and check this works using information on current deaths of babies in England and from similar work being conducted in New Zealand. Health visitors, family nurses and especially parents will be invited to workshops where they will help us design the tool. It will show parents/carers how the risks to their baby change across different situations. They will be able to plan ahead for changes in routine to keep the baby safe. A picture of the plan will be sent to the parent/carer s mobile phone, that they can share with others, for example their partner. We will test this tool out with health visitors, and family nurses to find out how it works in detail. We will give the tool to three teams of health visitors and family nurses who work with families in deprived areas of Bristol, UK. Interviews with them and family members will find out what they think of it and how they use it. Finally, we will write an application for a study to see how we can test the tool with more people. Patient/Public involvement We have spoken with over 100 parents about this project, at children s centres, public events, and via family support charities. They suggested we include other family members with planning and make the tool available in a website. They suggested “Baby Sleep Heroes” as the name for this website. Dissemination The results of the research will be fed back to all parents and professionals involved and then be published in scientific journals, discussed at conferences, and at public engagement events.",7.1 INDIVIDUAL CARE NEEDS,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_22560,"Department for Environment, Food and Rural Affairs",DEFRA,Preventing and Tackling Mental Ill Health through Green Social Prescribing Project Evaluation,"The aim of this project is to evaluate the Green Social Prescribing Project, in order to iteratively feed into project design and implementation throughout the funded period, and to inform wider rollout of green social prescribing following the initiative. The evaluation will assess processes, outcomes, and value-for-money, and improve understanding of what works, for whom, in what circumstances and why.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;5.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_11630,Economic and Social Research Council,ESRC,Pride and Prejudice: The experiences of young donor-conceived adults in the UK,"This multidisciplinary, multi-method, multi-phase study will answer four key research questions: RQ1: How do young donor-conceived adults construct their social identities, and what are their lived experiences? RQ2: How does the experience of being donor-conceived manifest differently at the intersection of different social identities? RQ3: What are the factors that contribute to well-being among young donor-conceived adults? RQ4: Are the pathways to well-being distinct for young adults who are donor-conceived compared to those who are conceived in more traditional circumstances? Its key scientific objectives will be to: 1. Explore how young adults conceived through sperm donation construct their social identities in relation to their conception, to gain an insight into their lived experiences, and to understand how these experiences relate to other social status differences (i.e. socioeconomic status, gender, race/ethnicity) amongst donor-conceived young adults raised in different family types, through in-depth interviews, focus groups and secondary analysis of conference panel discussions; 2. Understand the similarities and differences between young donor-conceived adults and young adults conceived in more traditional circumstances on a range of previously unexplored positive psychological and social dimensions, testing a theoretically and empirically informed model comprised of robust questionnaire measures; 3. Generate a series of academic outputs that break new empirical and theoretical ground in the social scientific scholarship on donor conception, including at least four articles to be published in high-quality, internationally reputable academic journals in the social sciences, and two presentations at the most relevant and reputable national and international conferences for the proposed project. The non-scientific objectives of the project relate primarily to its pathways to impact, which have been planned to reflect the needs of young donor-conceived adults, for whom empirically informed resources are currently non-existent. As such, the primary non-scientific objectives of this research will be to: 4.(a) Engage with community stakeholders (Donor Conception Network, DCN) to produce three non-academic outputs relating to young donor-conceived adults' perspectives. These are: (i) A research page on the DCN website, to include a short film about the project findings; (ii) A resource for prospective and current parents of donor-conceived children, to ensure that the beneficiaries of the project are not only those who engage with DCN; (iii) A resource for secondary school teachers, to influence educational activities relating to donor conception. 4.(b) Begin to develop a partnership between academic and non-academic stakeholders that will inform future research, achieved through: (i) Consultation and capacity-building with DCN; (ii) Creating opportunities for dialogue and knowledge exchange between key stakeholders through an end-of-project conference. Finally, it is anticipated that this research will significantly positively impact upon my future academic trajectory. Its fifth objective is thus to: 5. Provide opportunities for training in research methods and advanced analytical techniques, and opportunities for the development of management skills; the time to research, to publish in high-impact academic journals, and to share findings with other academics at national and international conferences; and the space to work with and learn from an Advisory Group and a community group, and to develop new networks in both academic and non-academic domains.","The number of children conceived using donated gametes in the UK is consistently increasing each year. As diverse paths to parenthood become increasingly well-trodden, gaining greater scientific understanding of the experiences and outcomes of those who are donor-conceived is vital. Building upon my previous research on the perspectives of donor-conceived children and adolescents, the proposed research will investigate the experiences and outcomes of donor-conceived young adults, a group that has yet to be the focus of systematic study. Understanding the experiences and outcomes of those who are donor-conceived as they move into adulthood is important, not least because it is now generally established that it is during the ages of 18-25 that people develop a real sense of who they are and where they belong. The proposed project will therefore investigate the importance and impact of donor conception on the identities, experiences and well-being of young adults. It will seek to understand how those who are donor-conceived navigate the social world at this particular stage in their development: from attending freshers' week events at university, to attending regular check-ups at the doctors. The proposed research aims to address these issues by using a range of social scientific theories and methods that will put the perspectives of donor-conceived young adults at the forefront of the research agenda. Collecting data from 240 participants in total, including donor-conceived young adults and a control group of those conceived in more traditional circumstances, the research will employ both qualitative and quantitative methods that together allow for both the in-depth investigation of individual experiences, and group comparisons on a range of as yet unstudied psychological and social dimensions. The project has been designed to address the concerns raised about the representative nature of previous research on donor-conceived adults, which has either collected data from individuals who found out about their conception in challenging circumstances and feel negatively about this, or administered questionnaires to individuals registered on online platforms for identifying genetic relatives. The proposed research will also significantly extend the knowledge gained from previous studies of the psychological well-being of donor-conceived children and adolescents, which do not provide information on later development. Finally, the proposed research will move beyond previous scholarship that has primarily focussed on within-family factors. This is important, because little is yet known about the relationship between the social experiences of donor-conceived people and their well-being, although studies of the social climate indicate that donor conception remains socially stigmatised, and research on other topics has highlighted the negative consequences of such stigma for psychological health. This research has been designed in consultation with the Donor Conception Network, the first and largest community-based network in the UK for donor conception families. Beyond being of significant scientific merit, the proposed research therefore responds to the needs of the donor conception community in general, and to the needs of donor-conceived young adults in particular. In 2023, the first cohort of young donor-conceived adults will reach the age at which they can legally identify the donors involved in their conception. Developing appropriate mechanisms to support these young adults through donor identifiability clearly requires an initial understanding of what it is like to be a young donor-conceived adult in Britain today. The proposed research will thus generate novel, and timely, insights that will not only lead to scientific discoveries that are of clear general interest, but will also inform the development of important resources that will benefit people conceived using donated gametes, both now, and in the future.",1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,GENERIC HEALTH RELEVANCE HRCS22_23270,The Health Foundation,THF,Prioritising patients for emergency surgery or not: the impact of COVID-19 (ESORT-C19),"Many patients with common acute conditions, such as appendicitis, are admitted to hospital in an emergency. Some patents have emergency surgery, but others receive ‘conservative management’, which includes the possibility of later surgery. For many patients, it is unclear whether the benefits of emergency surgery are greater than the risks. Following the COVID-19 outbreak, planned surgery in the NHS was cancelled. As a result, NHS waiting lists are now approaching 10 million patients. The NHS urgently needs evidence to inform which patients should be prioritised for emergency surgery. Information for patients on the risks and outcomes of emergency surgery must recognise the impact of COVID-19. This research study will assess the effect of COVID-19 on access to emergency surgery for different patient groups, and will report on the effectiveness and cost-effectiveness of emergency surgery versus conservative management following the COVID-19 outbreak. Evidence-based recommendations, which can be quickly incorporated into NHS guidelines, will be developed on which patients should be prioritised for emergency surgery in the COVID-19 recovery phase. The project team will use Hospital Episode Statistics (HES) data on emergency admissions to NHS hospitals for acute conditions during the COVID-19 pandemic, and discussions with clinicians and patients will provide insights about the impact of the pandemic on decisions made about emergency surgery versus conservative management. The analysis will look at emergency hospital admissions for five acute conditions where there is clinical uncertainty about which patients should have emergency surgery: acute appendicitis, cholelithiasis, diverticulitis, acute (groin) hernia and intestinal bowel obstruction.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_15628,Wellcome Trust,,Probabilistic machine learning for high-dimensional applications in health,"Deep learning is a way to train computers to do complex tasks by learning from large amounts of data. Developing rapidly over the last decade, it has been particularly successful in the understanding of images and natural language. However, deep learning has not had a large impact in important tasks of medical science and healthcare. Traditional statistical techniques are favoured due to their advantages in terms of interpreting their results and understanding the decision-making process. However, such techniques are often difficult to scale up to larger patient populations or to the large amounts of data produced by new technologies like smartphones and fitness trackers. This PhD project aims at combining statistical concepts with recent deep learning technology. In particular, I am interested in developing these methods for estimating the effect of a treatment on a patient’s outcome. I intend to extend existing technology to provide a tool to assess when such an estimation is feasible. Further, I am interested in the stability of such methods when data is corrupted by some controlled mechanism trying to trick the algorithm. I aim at enabling novel data science methods that help health data scientists, health practitioners and ultimately patients to make better decisions.",,8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_05630,Department of Health and Social Care,NIHR,Problem Adaptation Therapy For Individuals with Mild to Moderate Dementia and Depression. The PATHFINDER Trial,"Depression is very common in people with Alzheimer’s disease and other dementias, causing them distress as well as reducing their quality of life and that of their carers. Unfortunately, antidepressant drugs do not have clear effectiveness in these patients and it appears that the most commonly available psychological therapies such as cognitive behavioural therapy or CBT are also not useful. Psychological therapy based upon the principle of problem-solving therapy, in which patients and their carers are helped to find ways to compensate for memory difficulties and to change their environment, relationships and engagement in activity in order to support a positive mood state has been reported to be helpful in the very early stages of dementia. But this has only been shown so far in an American university-based healthcare setting, with people who were mildly affected by dementia and with the use of experienced and expensive therapists. We want to investigate whether this approach can be successfully applied in an NHS setting and with patients who are representative of those seen with dementia and depression in the NHS._x000D_ _x000D_ Working with the Alzheimer’s Society and NHS staff from the memory services and community mental health teams who already work with people who are mildly and moderately affected by dementia, we will adapt an existing form of problem-solving therapy called Problem Adaptation Therapy (PATH). The two most important adaptations that we will make are to develop a form of PATH that can be delivered by existing NHS staff rather than specialist psychological therapists and to make the therapy available in a form that is helpful for people who are mildly and moderately affected by dementia because this is the group who have the greatest need for an effective depression treatment in the NHS._x000D_ _x000D_ In the first phase of the project we will develop a manual that can be used by carers, under the supervision and guidance of NHS staff, to apply the principles of PATH to the person with dementia that they live with or care for. We will test the acceptability of this and the willingness of patients and their carers to be involved in a subsequent trial._x000D_ _x000D_ In the second phase we will carry out a randomised clinical trial, comparing 12 weeks of the modified PATH treatment with current treatment offered as usual within the NHS. We will measure outcomes at 0, 3, 6 and 12 months. The most important outcome of the trial will be improvement in symptoms of depression at 6 months in participants with dementia, but we will also measure quality of life, activities of daily living, cognitive function, anxiety symptoms, satisfaction with therapy and cost-effectiveness of the intervention. In addition, we will examine mental health and perceptions of burden in carers. Our PPI co-applicants suggested that the primary outcome should be at 6 months rather than 3 months (immediately after the intervention ends) as benefits would need to be seen at this later time point in order to justify the investment of time and energy required from participating carers in PATH. We will continue to follow participants for a year to look for evidence of sustained benefits of the therapy._x000D_ _x000D_ If the intervention is successful at reducing depression in people with mild and moderate dementia, this would be the first evidence-based effective treatment available for this important problem, which could quickly be rolled out within NHS services and made available to patients.","PHASE 1 (months 1-12): Adapt intervention based on PATH for delivery in the NHS through interviews with 15-20 patient-carer dyads and 4 professionals' workshops. Assess acceptability to patients, carers and therapists, and likely uptake and adherence. Proceed to Phase 2 if credibility and expectancy scores are >70%, >70% participants complete 2 sessions, ratings are satisfactory on Client Satisfaction Questionnaire (CSQ [35]) and >5 modifiable problems are identified per person._x000D_ PHASE 2 (months 13-54): Assess clinical and cost effectiveness of adapted PATH for depression in dementia in a 6-centre single-blind parallel 2-arm RCT with an internal pilot in the first 12 months to assess feasibility of recruitment and acceptability of randomisation. Continue to full RCT if recruit 125 patients (75% of target)._x000D_ SETTING: Community._x000D_ PARTICIPANTS: 333 people with mild to moderate dementia recruited from Memory Services and CMHTs._x000D_ INCLUSIONS: Mild to moderate Alzheimer's disease (AD) or mixed AD/vascular dementia (SMMSE 10+) with clinically significant depression (score of 8+ on Cornell Scale for Depression in Dementia [CSDD (4)]); sufficiently fluent in English to engage with PATH; identified carer who spends 1hr+ per day on at least 3 days/week with the participant. Psychotropics allowed if dose has not changed in previous 4 weeks and no plan to change during next 12 weeks of PATH._x000D_ INTERVENTION: PATH adapted for people with dementia plus TAU. Psychiatric nurses, occupational therapists, assistant psychologists and psychological wellbeing practitioners from Memory Services, CMHTs and IAPTs will be trained to deliver 10 manualised sessions over 12 weeks under regular supervision from clinical psychologists. Random sessions will be assessed for treatment fidelity._x000D_ COMPARATOR: TAU within which participants will have access to psychotropics, supportive and other therapies at discretion of responsible clinicians._x000D_ RANDOMISATION: 1:1 stratified randomisation via CTU online system._x000D_ PRIMARY OUTCOME: Change in CSDD score from baseline to 6 months._x000D_ SECONDARY OUTCOMES: Patients: CSDD at 3 and 12 months; change in disease-specific health-related quality of life with DEMQOL and DEMQOL-proxy (27), generic quality of life with EQ-5D (28); function with Bristol Activities of Daily Living Scale (29); cognitive function with SMMSE (20); anxiety with Rating Anxiety in Dementia scale (30); cost-effectiveness with Client Service Receipt Inventory (31); satisfaction with CSQ. Carers: Burden with Zarit Burden Inventory (32); mental health with General Health Questionnaire-12 (33)._x000D_ TIMING OF OMs: Assessment at 0, 3, 6 (primary endpoint) and 12 months post-randomisation by blind outcome assessors._x000D_ SAMPLE SIZE: 333 participants will allow detection of a minimum clinically important difference of 2.0 points on the CSDD (an effect size of 0.4 SD) with a 2-sided alpha of 5% and 90% power, assuming 20% loss to follow-up at 6 months._x000D_ TIMETABLE: 1-9 months: Ethical/research approval, adapt intervention, train clinicians. 7-12 months: Assess acceptability, RCT set-up. 13-36 months: RCT recruitment with internal pilot in months 13-24. 37-48 months: Follow-up. 49-54 months: Database lock, analyses, dissemination._x000D_ OUR TEAM: Has experience of successfully delivering multi-site trials, with expertise in dementia (RHo/GL/RD/PB/SB/CF/PW/AT/VO/RG), developing psychotherapy manuals (GL/VO/KL/PW/RG), qualitative research (VL/VO/GL), statistics (NF) and health economics (RHu).",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH;NEUROLOGICAL HRCS22_02937,Medical Research Council,MRC,Prosensory signals: from discovery to application using inner ear organoids,"In the UK alone, one in six people has a hearing disability, rising to one in two for over 70 year-old. The main cause of sensorineural hearing loss is the loss of auditory hair cells residing in the inner ear. A potential therapy for hearing loss could be to induce in the damaged auditory organ the regeneration of new hair cells - a process that is occurring spontaneously in non-mammalian vertebrates. However, the current strategies relying on the manipulation of the molecular signals controlling hair cell differentiation alone are relatively inefficient. An alternative approach could be to re-activate the developmental signals that drive the formation of the 'prosensory' cells, which are the progenitors for both hair cells and their associated supporting cells. However, this requires a better understanding of the molecular mechanisms of prosensory specification. In our previous MRC-funded project, we have uncovered a new role for the Wnt signalling pathway as a dose-dependent regulator of prosensory specification. We also started RNA-Seq and functional screenings aimed at identifying new genes participating to this process. Here, we will pursue this research with new methods to maximize our chances of identifying key regulators of prosensory specification. We will use Crispr/Cas9 mediated gene-knockdown for testing the function of candidate factors, such as the Tcf/Lef effectors of the Wnt pathway, in the embryonic chicken inner ear. We will use single-cell RNA-Seq to characterize mouse prosensory cells and bioinformatics methods to pinpoint the key genes associated to prosensory specification. Finally, we will translate our findings to 3D inner ear organoids, using a mouse stem cell line carrying a fluorescent reporter of Sox2, a prosensory marker. The outcomes of this research could be exploited in the future to induce hair cell regeneration by means of gene therapies or to improve existing protocols for the generation of hair cells in 3D organoids.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.2 CELLULAR AND GENE THERAPIES,EAR HRCS22_20262,Cancer Research UK,CRUK,"Protein lipidation in cancer: discovery, mechanisms and target validation","*Background: Protein lipidation is a diverse class of post-translational modification (PTM), regulated by over 40 enzymes targeting >1000 protein substrates at >3000 sites. The importance of protein lipidation in cancer is well-recognised, with >150 oncogenes and drug targets known to be lipidated and two classes of protein lipid transferase inhibitors progressed into clinical trials. However, the full spectrum of protein lipidation and its dysregulation in cancer remains unexplored, in contrast to widely studied similarly common PTMs (phosphorylation, ubiquitination…). Through CRUK-funded research we have developed expertise at the forefront of this field through invention and application of novel chemical biology tools to probe lipidation, delivery of novel lipidation inhibitors into preclinical development for cancer, and new company formation, supported by a network of outstanding academic and industry collaborations. *Aims: We will determine actionable liabilities and modes of action for two key classes of protein lipidation in specific cancer contexts. A toolbox of highly novel chemical biology approaches will enable us to explore deregulation of co-translational N-terminal lipidation, and identify novel targets in the S-acylation network, the most diverse and dynamic class of protein lipidation regulating up to 25% of all known oncogenes. These ground-breaking studies will be empowered by an integrated technology development platform, and cross-cutting studies to understand co-regulation and crosstalk between the major classes of protein lipidation in cancer. *Methods: The Programme will be delivered in three work packages: (1) Deliver the next step change in chemical biology tools to enable and support the Programme. (2) Determine the roles of key substrates in mode of action of lipidation inhibitors currently in clinical and preclinical development. (3) Identify liabilities and dysregulated oncogenes in the substrate networks of the key zDHHC S-acyltransferases implicated in cancer. *Impact: We will identify and validate novel and actionable liabilities in the protein lipidation machinery in cancer, including identification of novel drug combinations and markers for sensitive cancers which can directly impact patients in ongoing clinical trials, and enable design of future trials to expand the applications of drugs targeting protein lipidation. We will also identify targets for future drug discovery, including emerging target classes. Furthermore, dissemination of our results and novel technologies will empower labs worldwide to study protein lipidation in cancer and cell biology.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_01071,Medical Research Council,MRC,Protein transport and quality control in the secretory pathway,"A key component of cellular physiology is the accurate deployment of every gene product to the correct cellular compartment. Fully one third of the proteins encoded in eukaryotic genomes navigate the secretory pathway, entering this system via the endoplasmic reticulum (ER). Research in the Miller lab is broadly aimed at understanding basic mechanisms of secretory protein biogenesis, focusing on aspects of protein quality control within the ER. We use the budding yeast, Saccharomyces cerevisiae, as a model system, which affords facile biochemical, genetic, genomic and proteomic tools that can be brought to bear on this fundamental biological problem. By using such a tractable model system, we can rapidly discover new pathways and dissect mechanisms that may be directly relevant to a number of human diseases, most notably cystic fibrosis and similar diseases of protein misfolding. The molecular basis for vesicle formation from the ER is relatively well understood and relies on cytoplasmic coat proteins known as the COPII coat. Yet, despite a relatively deep understanding of the mechanisms that drive COPII vesicle formation and cargo capture, we know very little about how this process is regulated to prevent improper traffic of misfolded proteins. We study this problem from two angles: a “cargo-centric” approach examining the folding and trafficking of an individual protein, and a systems-level approach to characterize quality control more broadly. We use high throughput yeast genetics to identify new components that act in various aspects of protein quality control, and biochemical approaches to dissect mechanism. One long-term goal is to understand how vesicle abundance and architecture can adapt to changing physiological needs with respect to cargo load.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_15717,Cancer Research UK,CRUK,Providing detailed insight into the impact of a cancer diagnosis across a full pathway for cancer patients: development and application of novel methodology,"Background: It is well known that a diagnosis of cancer will increase the chance of mortality over the coming years following diagnosis compared to a similar individual (in terms of sex and age) in the general population. However, what is also true is that due to the impact of treatment and the cancer generally, quality of life will also be impacted and this is typically not incorporated when measuring the impact of cancer using standard survival statistics. Aims: The main aim of the project is to provide detailed insights into the impact of a cancer diagnosis across a full patient pathway, determining both the impact on survival (and the cause of death), and the quality of life following cancer. A secondary aim is to understand the differences in impact across population groups; highlighting inequalities and evaluating the potential benefit of removing them. The focus of the project will be driving the methodological developments to appropriately explore the available data in order to achieve the aims set out above. Methods: The research proposal is separated into 3 main components, each with individual objectives that contribute to the overall aims of the project. In the first part of the proposal, we will further develop methodology to calculate the impact of cancer on quality of life across an entire lifespan; using patient reported outcome data. In the second part of the proposal, we will further develop methods to understand competing causes of mortality for cancer patients, and also relate mortality from other causes to those associated with comorbidity associations and those related to long-term treatment effects. The final part of the proposal will concentrate on methods to estimate longer-term stage-specific survival; dealing with issues caused by historically lower levels of data completeness. How the results of this research will be used: The results of this research will be used to better understand the impact of cancer across entire patient pathways, but also to ascertain differences across cancer patient groups that may be preventable. The research will also highlight patient groups that may need further support and screening due to increased mortality risks or high impact on quality of life.","Background: It is well known that a diagnosis of cancer will increase the chance of mortality over the coming years following diagnosis compared to a similar individual (in terms of sex and age) in the general population. However, what is also true is that due to the impact of treatment and the cancer generally, quality of life will also be impacted and this is typically not incorporated when measuring the impact of cancer using standard survival statistics. Aims: The main aim of the project is to provide detailed insights into the impact of a cancer diagnosis across a full patient pathway, determining both the impact on survival (and the cause of death), and the quality of life following cancer. A secondary aim is to understand the differences in impact across population groups; highlighting inequalities and evaluating the potential benefit of removing them. The focus of the project will be driving the methodological developments to appropriately explore the available data in order to achieve the aims set out above. Methods: The research proposal is separated into 3 main components, each with individual objectives that contribute to the overall aims of the project. In the first part of the proposal, we will further develop methodology to calculate the impact of cancer on quality of life across an entire lifespan; using patient reported outcome data. In the second part of the proposal, we will further develop methods to understand competing causes of mortality for cancer patients, and also relate mortality from other causes to those associated with comorbidity associations and those related to long-term treatment effects. The final part of the proposal will concentrate on methods to estimate longer-term stage-specific survival; dealing with issues caused by historically lower levels of data completeness. How the results of this research will be used: The results of this research will be used to better understand the impact of cancer across entire patient pathways, but also to ascertain differences across cancer patient groups that may be preventable. The research will also highlight patient groups that may need further support and screening due to increased mortality risks or high impact on quality of life.",2.4 SURVEILLANCE AND DISTRIBUTION;7.1 INDIVIDUAL CARE NEEDS,CANCER AND NEOPLASMS HRCS22_23219,The British Academy,,Psychological Influences on Citizen COVID-19 Preventive Behaviours and Vaccine Engagement in the UK and US with particular regard to the importance of ethnicity,"This research will review systematically empirical psychological research on citizen reactions during the COVID-19 pandemic in order to establish what robust conclusions can be drawn and to identify limitations. One objective is to examine whether the international research effort might have been better co-ordinated and communicated to support the pandemic response and subsequent readiness. Secondary analyses of largescale datasets collected through the pandemic will be used to assess contextual, localised and sub-group differences in COVID-19 responses. New data, from ethnically diverse samples in the UK and US, will be used in conjunction with our earlier series of surveys to establish changes in COVID-19 vaccine hesitancy and its predictors over time. Predictors considered will include identity resilience, power differentials, mistrust, perceived risk and fear. To inform policy development, forms and effects of uncertainty regarding vaccines and variants are also explored. Analyses will encompass both quantitative and qualitative approaches.",,3.4 VACCINES,INFECTION HRCS22_13642,Wellcome Trust,,Pushing for Patient-Driven Tinnitus Research,"This project aims to promote patient-driven tinnitus research. The project will combine direct patient-researcher interaction with the creative use of online tools to bring insights from patients around the world. We will have tinnitus patients discuss and vote online on the most promising recent publications in the field of tinnitus. We will deliver those insights to researchers. Over time, a core panel of patients will develop sufficient expertise to formulate recommendations for how tinnitus research can become more patient-centred. Finally, we’d like to see at least one study being funded that explicitly follows these recommendations. This project will build on: • Tinnitus Hub’s experience with facilitating patient peer-to-peer interaction and patient-researcher interaction; • Our online engagement tools, including our support forum; • Our connections with tinnitus researchers and our own research experience (including several academic publications). Ultimately, we hope to see tinnitus researchers develop an enhanced understanding of the needs of tinnitus patients, and for these needs to inform and shape their research questions and methods. And we would like tinnitus patients to have the knowledge and means to steer research in a direction that is beneficial for them.",,7.1 INDIVIDUAL CARE NEEDS,GENERIC HEALTH RELEVANCE HRCS22_02176,Medical Research Council,MRC,Quantification of head and trunk control for children with neuromotor and neuromuscular disorders,"This imaging analysis tool will be trained to provide detailed, objective information of the segmental trunk control status of children with cerebral palsy (CP), and spinal muscular atrophy (SMA). Two core processes in the identification of trunk control will be automated: i) measurement of alignment of head and trunk segments to the vertical and ii) identification of when the hands and arms are free from contact with the body and any external surface. A cross sectional dataset (400 CP, 20 SMA1, 40 TD) and small exploratory dataset (40 NMD) will be acquired with each child tested using the Segmental Assessment of Trunk Control (SATCo). This subjective test will be recorded using two ""RGB-D"" cameras each giving 3D information as raw video and depth images. The CP sample (Manchester, Liverpool and Cheshire community services) and SMA sample (Oswestry Hospital and linked centres) would include the range of trunk control problems and body morphology of these populations. Two experienced SATCo clinicians, verified by a third, will label the video identifying i) segmental alignment i.e. when the child loses postural alignment; ii) upper limb support i.e. when the upper limbs contact the trunk or bench; and iii) trunk control status. Using contemporary machine learning methods, the raw RGB-D images and associated labels will train and test our networks through a cross validation process. (For motor function c.f. Case for Support). Exploitation of results includes: a) publication of a substantial public database of (400+20) cases representing trunk control impairment in children with CP and SMA1. This disseminates a public reference and training resource with data, software and instructions enabling inexperienced clinicians to reach the highest standard of clinical assessment of trunk control; b) acquisition of a 6-12-month longitudinal dataset of (20 CP, 5 SMA) children within our clinical network to provide power calculations necessary to plan clinical trials.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,MUSCULOSKELETAL HRCS22_23281,The Health Foundation,THF,"Quantifying health workers’ retention in primary care, its variability and association with outcomes","There is an ongoing crisis in the recruitment of GPs, and similar workforce concerns have been raised around general practice nurses. Recent promises of more GPs and medical graduates will not be enough to cover the emerging shortfall. In light of recruitment problems, it is becoming increasingly important to retain existing practitioners. However, reports have raised concerns about retention trends, and Brexit may also have an impact, with primary care in England relying heavily on overseas-qualified GPs and nurses. Improving retention rates will improve quality of care for patients and continuity of care, which is associated with better health outcomes and higher levels of patient satisfaction. However, very little is currently known about how retention rates have changed over time and how rates vary across the country. This project aims to close the retention research gap using databases of routinely collected administrative data. It will examine retention for two key primary care professions: GPs and nurses. Through this research, the project team aims to provide a blueprint of the use of existing databases in investigating retention and examine the quality of existing data. Metrics of retention will be defined and predictors of retention identified, including quantifying the role of external factors. Retention levels and trends will be quantified, nationally and regionally, and the team will examine the association between retention and future patient outcomes. Regions and practices with characteristics that make them particularly vulnerable to retention problems will also be identified. All of this information will help policy-makers and primary care managers begin to address retention problems.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_13852,Cancer Research UK,CRUK,Quantifying inequalities in cancer care and cancer outcomes in the UK,"Background: There is growing concern that there is significant variation in the quality of cancer care and outcomes across the UK. Although the NHS seeks to ensure that everyone receives the best treatment available and attains the best outcomes possible, significant variation between patient groups persists. The first steps to tackling such inequities are quantifying their size, investigating why they arise and understanding what impact they have on patient outcomes. Data are key to enabling this but, at present, there is a lack of clarity on what information is available and/or required. This application brings together an experienced team from across the UK to respond to the call to address this challenge. Aim: To map, and help improve, the data landscape relating to cancer inequalities. Methods: A wide ranging and representative team of academics, data custodians, patient and public representatives and other stakeholders will collaborate to deliver this aim through four parallel work streams (WS). WS1 will deliver a rapid scoping review of the existing evidence base on cancer inequalities in the UK across the whole care pathway from social determinants to survivorship. WS2 will map the current landscape relating to policy and data initiatives in this area. WS3 will record and describe all the existing data assets that could be deployed to quantify cancer inequalities as well as identify any important gaps. If opportunities exist to rapidly fill gaps using existing data then this WS will produce new metrics initially using prostate, breast and bowel cancer as exemplars (but including additional cancers of unmet need if time and resource allows). WS4 will combine the resulting evidence into a report of findings and then, through discussion with key stakeholders, generate a set of recommendations that will help deliver the evidence required to eliminate cancer inequalities and drive improvements in outcomes across the NHS. What value will the programme of work deliver: The programme of work will provide a more robust quantification of cancer inequalities within the NHS and an evidence-based series of recommendations that will help address cancer inequalities across the UK.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,CANCER AND NEOPLASMS HRCS22_15599,Wellcome Trust,,Quantitative investigation of the control of mRNA degradation in Drosophila early embryogenesis and the impact of stability on developmental processes,"Gene expression allows organisms to convert the genetic code in their DNA into proteins which carry out specialised functions in cells. In early embryonic development, cells tailor their gene expression programme to make specific sets of proteins which allow them to transform into a particular type of cell, for example, a skin cell or a neuron. Gene expression has multiple stages including how the process begins, the tuning and travel of RNA molecules along their journey, their conversion into protein as well as the mechanisms by which the cell disposes of them. My work focuses on these degradation mechanisms. We will use large datasets and computational methods including machine learning to estimate degradation rates across different genes throughout embryonic development in the fruitfly model organism and understand the mechanisms controlling these. Our findings will be validated using cutting-edge methods for imaging mRNAs. We will then use other experimental biology techniques including CRISPR-Cas9 genome engineering to change degradation rates of individual mRNAs and examine the effects on cell fates and developmental processes. This will provide us with a greater understanding of how gene expression is controlled, which has implications for many human diseases including cancer, and applications to regenerative medicine.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_19855,Wellcome Trust,,R-loop coupled chromatin regulation,"Non-canonical chromatin structures are emerging as important components of gene regulation. One example, RNA-DNA hybrid structures known as R-loops, occur frequently in many genomes. Initially studied with respect to genome instability, they have now been linked to transcriptional regulation, heterochromatin formation and recombination. But exactly what regulates R-loop dynamics, and how R-loops influence local chromatin states to affect a wide range of chromatin processes is still poorly understood. Deriving mechanistic understanding of R-loops from genome wide analyses is difficult. We will therefore focus on one functionally important R-loop and exploit a genetically tractable system and a wealth of information to develop deep mechanistic understanding into the regulation and role of an R-loop. We will identify novel factors that stabilize and resolve the R-loop, and establish how their functions are integrated. We will investigate whether the R-loop sets up a transcription-replication conflict that propagates heterochromatinization of the locus, thus setting the expression state. We will also dissect if R-loop dynamics and a gene loop influence promoter dominance to co-ordinate sense and antisense transcription. Active collaborations will enable a broad set of approaches to be used and concepts to be compared between organisms.","DNA predominantly exists as a double helix, but increasingly, alternative structures are being found in our genomes. One of these is called an R-loop, and is formed when the messenger molecule made from DNA – a molecule called RNA – loops back and invades the DNA double helix. The pairing between DNA and RNA is very strong, so R-loops can be stable and form ‘hairballs’ in the genome. This prevent normal processes occurring - the DNA cannot be copied and more RNA cannot be made. Until recently, these R-loops were viewed as ‘problems’, but now have also been found to help specific genomic processes. To improve our understanding of these structures we will focus on a particular R-loop that is easy to study, and identify what it does and how it is regulated. This will provide important information on the broader role of these structures in genome regulation generally.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_06586,Medical Research Council,MRC,RAPTOR: Randomised Controlled Trial of PENTOCLO in Mandibular Osteoradionecrosis,"Most treatments for head and neck cancer include radiotherapy, and despite advances in planning and doses, this leaves survivors at risk of significant late effects. One of the most severe complications is osteo-radio-necrosis ‘bone death caused by irradiation’. This can affect any bone or cartilage in the head and neck but is commonest in the lower jaw. ORN is characterized by exposure and crumbling of the jaw, severe pain, repeated infections, weight loss, restricted mouth opening, difficulty in chewing, and disfigurement._x000D_ Existing treatments include:_x000D_ i. supportive & conservative methods: long-term antibiotics, antiseptic mouthwash and painkillers_x000D_ ii. surgery, which may be curative but is risky, complex and has unpredictable outcomes._x000D_ _x000D_ Some studies of osteoradionecrosis suggest that a combination of three medications (pentoxyphylline, tocopherol, and clodronate: PENTOCLO) may be capable of complete resolution without surgery. Healing in this way is through lifting off of the dead bone fragments leaving intact skin underneath. Some research suggests that just over half of patients get benefit, but this has yet to been proved, particularly in comparison with other treatments_x000D_ _x000D_ This trial proposes to compare PENTOCLO medications against standard supportive medications such as antibiotics, mouthwash and painkillers. Patients will be selected at random for either of the two treatments for at least a year. The trial will also carefully measure pain, side-effects, the need for antibiotics and the instances where deterioration forces the need to resort to surgery instead._x000D_ _x000D_ Discussion with patients during trial design has resulted in an increased emphasis within the protocol for collection of information on patients’ pain and other symptoms, and particularly in providing a ‘safety-net’ for those patients who are deteriorating. As a result, at 3-monthly clinic visits, patients will report their symptoms (pain, eating, mouth-opening, swelling) every 15 days via their smart device using an App.","Research question_x000D_ RAPTOR aims to establish the value of the repurposed drug combination Pentoxifylline, Tocopherol & Clodronate (termed PENTOCLO) in treating osteoradionecrosis (ORN) of the mandible._x000D_ _x000D_ Background_x000D_ Osteoradionecrosis is a well-recognized and feared complication following curative treatment of head and neck cancer with radiotherapy. There are no medical treatments with high level evidence to support their use and many patients deteriorate to the point where they need multiple hospital admissions, destructive removal of all necrotic bone and complex jaw and facial reconstruction. A combination of three repurposed drugs: pentoxifylline, tocopherol and clodronate has been suggested as being able to heal ORN in the majority of cases but requires at least 12 months treatment. In successful cases it has stopped disease progression, improved symptoms and facilitated the exfoliation of necrotic bone. There have, to date, been no randomized trials, or trials making a comparison of PENTOCLO against control treatments, but single arm studies have been encouraging._x000D_ _x000D_ Aims and objectives_x000D_ The aim of RAPTOR is to compare standard supportive care (SSC) against SSC plus PENTOCLO, measuring time-to-healing as primary endpoint. The secondary endpoints are to measure patient symptoms, quality of life, SOMA, extent of necrotic bone, mandibular preservation rate._x000D_ _x000D_ Methods_x000D_ RAPTOR is an unblinded randomised controlled trial where patients in the control arm receive standard supportive care dependent on symptoms including antibiotics, analgesia and antiseptic mouthwash. In the treatment arm, patients additionally receive PENTOCLO and both arms are assessed at clinic visits every 3 months. Blinded remote assessment of primary and secondary endpoints are supported by clinical photographs. Rich data on patients’ symptom burden are collected remotely using a dedicated App every 15 days throughout the trial._x000D_ _x000D_ Timelines for delivery_x000D_ Following 6-months set up time, the trial will be opened with the aid of the national maxillofacial trainee collaborative (MTREC) which we believe may greatly facilitate recruitment. 15 sites will be selected, and recruitment is expected to take 24 months for a total study length of 48 months._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ For the first time, the activity of PENTOCLO will be robustly compared with a control group and these results will form the basis of future treatment decisions and / or to inform the necessity for a larger phase III trial in jaw osteoradionecrosis. The trial will also explore the use of an App to collect ePROM data which will inform its suitability for other trial applications.",6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS;MUSCULOSKELETAL HRCS22_05635,Department of Health and Social Care,NIHR,REACH-ASD Trial: A Randomised Controlled Trial of Psychoeducation and Acceptance & Commitment Therapy for Parents of Children recently diagnosed with ASD,"Background: There are high levels of mental health difficulties in parents of children with Autism Spectrum Disorder (ASD). The period following their child’s diagnosis can be particularly challenging. Groups that educate parents about ASD are often used in the NHS but have not been evaluated and we do not know if they help parents’ mental health. An intervention called Acceptance and Commitment Therapy (ACT) has been used with parents of children with disabilities with some evidence of success. It uses problem solving, mindfulness, and practical exercises to help people reflect on their current situation and manage any distressing experiences and thoughts. Our programme (EMPOWER-ASD) combines education about autism with ACT and we consider this the best approach to help parents’ mental health and to support them in adapting to parenting their child with ASD._x000D_ _x000D_ Aims: To find out if EMPOWER-ASD benefits parents and their families when delivered as part of NHS care, using a randomised controlled trial. We want to know (1) whether it improves parent mental health, wellbeing, confidence and knowledge about ASD, (2) if it improves the wellbeing of the wider family and the child with ASD and (3) if it provides value for money._x000D_ _x000D_ Methods: An initial 10-month period will be used to run 3 intervention groups, seek parent and practitioner feedback, and make any necessary adjustments. The next 4 months will be a pilot of the trial to make sure that we can easily recruit parents to take part. The main trial will last 28 months. Participants will be 380 parents/primary carers with a child aged 2-15 years diagnosed with ASD within the previous year. They will be referred from NHS ASD assessment centres. They will be allocated at random to the intervention group or to the “usual care” group. The intervention group will be offered 5 group-based sessions delivered by a mental health practitioner along with ASD experts. These sessions focus on education about ASD, strategies to help communication and behaviour, navigating the education system and accessing support. They also introduce and practise ACT strategies. The intervention group will have access to supporting online resources._x000D_ _x000D_ We will measure parents’ mental health, wellbeing, knowledge and self-confidence using questionnaires and interviews at the beginning of the trial and over the course of a year. We will also measure aspects of wellbeing for the whole family and for the child with ASD. We will compare the two trial groups on differences in these areas. We will collect details of all other support used by parents to compare the costs of services for each group and to assess whether any improvements are value for money._x000D_ _x000D_ Involvement of parents: The research team includes two parents of children with ASD who will give the parent perspective on all aspects of the project. A advisory group of parents, including an autistic parent, will advise on whether trial information and interview questions are tailored to parents’ needs. We have already sought parents’ views on the intervention and will continue to do so throughout the trial._x000D_ _x000D_ Sharing trial results: The progress of the trial and its findings will be shared with parents, the ASD community and NHS professionals through workshops, social media and websites, and parent and professional networks. The results will be published in scientific journals and presented at conferences. If this intervention works it will be shared with NHS teams, filling an important gap within NHS care.","Background: There are high levels of mental health difficulties in parents of children with Autism Spectrum Disorder (ASD), particularly in the post-diagnostic period. ASD psychoeducation is common NHS practice, but provision is patchy and it does not have a robust evidence base, nor does it directly target parental mental health. Acceptance and Commitment Therapy (ACT) has an emergent evidence base for improving the mental health of parents of a child with disability, but is currently rarely used in UK practice. _x000D_ _x000D_ Aims and Objectives: To evaluate the EMPOWER-ASD intervention, a parental group-based manualised post-diagnostic programme that combines ASD psychoeducation and ACT psychological support: (1) To complete testing of acceptability, qualitative analysis and finalisation of the programme (feasibility phase); (2) To complete an implementation process evaluation; (3) To test intervention effectiveness over treatment as usual (TAU) on: (a) parental mental health, wellbeing, knowledge, adjustment, stress and self-efficacy; (b) family wellbeing, (c) child wellbeing, behaviour and adaptive functioning; (4) To assess its cost-effectiveness._x000D_ _x000D_ Methods: A multi-centre two parallel group single (researcher)-blinded randomised controlled trial of the EMPOWER-ASD programme plus TAU versus TAU alone. Individual randomisation by child, with one “index” parent per child, and stratification by centre, using 2:1 randomisation ratio to assist recruitment and deliver timely treatment. Initial feasibility phase and internal pilot to test recruitment, both with pre-specified progression criteria. Population: parents/primary carers of children 2-15 years with recent ASD diagnosis. Primary outcome: parental mental health (General Health Questionnaire-30) at 52-week follow-up. Secondary outcomes: key parent measures at 12-, 26- and 52-week follow-up and family and child outcomes at 52-week endpoint. Sample: N=380 (256 intervention/124 TAU). Primary analysis will follow intention-to-treat principles. Treatment effects will be analysed using linear mixed models with random intercepts for group membership. Cost-effectiveness acceptability analyses over 52 weeks, with decision modelling to extrapolate to longer time periods._x000D_ _x000D_ Timeline: 49-month project: 3-month start-up; 10-month feasibility phase; 4-month internal pilot (n=60; 4 centres; 4 intervention groups); 28-month main trial (n=320); 4 months for data analysis and dissemination._x000D_ _x000D_ Impact: This study will give the first systematic evidence for a comprehensive post-diagnostic parent-focussed programme for ASD. The intervention is scalable within the NHS and will meet an identified evidence gap in the Improving Access to Psychological Therapy curriculum for ASD and in future modification of NICE guidelines. If effective, the intervention will deliver direct benefits to parents, children with ASD, and whole family systems. It will reduce parental service use and promote efficient take-up of further parent-mediated ASD interventions. _x000D_ _x000D_ Dissemination: A series of high impact publications and presentations at national and international meetings. Trial protocol will be lodged with scientific journal. Intervention manual to be published and disseminated through professional training. Trial progress and findings shared with parents, the scientific community, and all stakeholders through events, web and social media, newsletters, and parent and researcher networks.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_06476,Department of Health and Social Care,NIHR,REalist Synthesis Of non-pharmacologicaL interVEntions for antipsychotic-induced weight gain (RESOLVE) in people living with Severe Mental Illness (SMI),"Background_x000D_ _x000D_ People living with severe mental illnesses (such as schizophrenia) die up to 20 years earlier than everyone else mainly due to preventable physical illnesses such as heart disease and diabetes. One of the main treatments for illnesses like schizophrenia are medicines called ‘antipsychotics’. Unfortunately, most antipsychotics cause a lot of weight gain, causing illnesses such as diabetes._x000D_ _x000D_ There are many different ways to manage and limit the weight gain caused by antipsychotics, including exercise and advice on diet. However, we don’t have a good understanding of what is likely to work for different people, and there is no clear advice for services and service users. _x000D_ _x000D_ This project aims to understand which ways of helping service users to manage weight gain are most likely to work in various circumstances. From this, we will fulfil our aim of producing guidance and advice on how to manage the weight gain associated with antipsychotics._x000D_ _x000D_ Planned Methods_x000D_ _x000D_ We will learn lessons from what has already been written and interview people (service users/patients, family carers, and doctors, nurses, support workers and pharmacists [called clinicians]) with experience and knowledge._x000D_ _x000D_ 1. Literature Review _x000D_ We will use a particular method of literature review (“realist review”) that is ideally suited to making sense of complex situations. To help us to learn lessons from what has already been written, we will search widely for documents that contain information on possible ways to support people on antipsychotics to manage their weight. From the information in the documents, we will work out ‘what works for whom, when, how and why?’ This will enable us to understand why different ways of managing the weight gain are more or less likely to work. _x000D_ _x000D_ 2. Interviews_x000D_ These will build on and expand the findings from the literature. If the interviews identify new areas to explore, we will go back to find and review the literature in that area. We plan to interview up to 30 people with severe mental illness on antipsychotic medication, (including some from minority ethnic communities), and also their family carers. Additionally, we will interview up to 20 clinicians. The interviews will focus on what has helped individual service users to manage their weight and any barriers identified. We will also ask them for their feedback about what we found from the literature._x000D_ _x000D_ 3. Analysis_x000D_ We will analyse the data that we have found in the literature and from the interviews to build an in-depth understanding of what is likely to ‘work’ to help people with severe mental illnesses to manage the weight gain caused by medication. _x000D_ _x000D_ From our fresh understanding, advice and guidance for both service users and clinicians will be produced, to help them understand how they can best manage their own weight, or support others to do so._x000D_ _x000D_ 4. Service User Involvement_x000D_ This research will be carried out with active involvement and input from people with severe mental illness supported by the McPin Foundation (charity supporting experts by experience in research). _x000D_ _x000D_ 5. Dissemination (sharing what we find)_x000D_ We will share our findings with service users, clinicians and policy-makers using conferences, academic papers, newsletters and social media. Two key “end products” will provide guidance for (i) service users, and (ii) clinicians/service providers.","Research question _x000D_ How can non-pharmacological interventions manage and limit antipsychotic-induced weight gain in people living with severe mental illness (SMI)?_x000D_ _x000D_ Background_x000D_ People with severe mental illnesses such as schizophrenia die on average 15 to 20 years earlier than everyone else. Two-thirds of these deaths are from preventable physical illnesses such as hypertension, cardiovascular disease and diabetes, which are worsened by weight gain. Antipsychotics, one of the main treatments, are associated with significant weight gain._x000D_ _x000D_ Aim_x000D_ To use realist synthesis to develop a framework and guidance on non-pharmacological interventions to manage antipsychotic-induced weight gain in people living with SMI. _x000D_ _x000D_ Methods with timelines_x000D_ Realist synthesis will be used to understand and explain how, why, for whom, and in what contexts non-pharmacological interventions help service users to manage antipsychotic-induced weight gain. Context, mechanism and outcome configurations (CMOCs) will explain how the context (situations around a person) affect mechanisms that cause outcomes. Guidance and intervention strategies will be developed as follows:_x000D_ _x000D_ 1. Developing initial programme theory (month 1-2)_x000D_ An initial programme theory, which sets out how and why outcomes occur within an intervention, will be developed._x000D_ _x000D_ 2. Developing search strategy (month 2-7) _x000D_ The initial theory will be refined using academic and grey literature. A Lived Experience Group containing service users and a Stakeholder Group containing clinicians will provide feedback and advice. The proposed initial sampling frame will be:_x000D_ _x000D_ Context: people living with SMI, taking antipsychotics._x000D_ Intervention: non-pharmacological interventions. _x000D_ Mechanisms: triggered by the intervention._x000D_ Outcomes e.g. weight, quality of life, adherence, burden, economic. _x000D_ _x000D_ Searching for relevant documents will continue until sufficient data is found to conclude that the refined programme theory is coherent and plausible. _x000D_ _x000D_ 3. Selection, appraisal, data extraction (month 3-12) _x000D_ _x000D_ The RA, with support from the Project Team, will screen documents against inclusion and exclusion criteria. Text extracted from these documents will be coded as contexts, mechanisms and their relationships to outcomes in NVivo. _x000D_ _x000D_ 4. Primary Data Collection (month 8-16) _x000D_ Realist interviews with up to 30 service users and informal (family) carers, and 20 clinicians will gather data to support, refute or refine the programme theory. Interviews will stop when theoretical saturation is reached. _x000D_ _x000D_ 5. Analysis/Synthesis (month 13-24)._x000D_ Data analysis will use a realist logic to develop the programme theory. The analysis will identify practical intervention strategies to change contexts so that key mechanisms are triggered to produce desired outcomes. Guidance will be produced based on these strategies. The Lived Experience and Stakeholder Groups will provide feedback on the veracity of the findings and the feasibility of the strategies. _x000D_ _x000D_ Anticipated impact and dissemination_x000D_ Producing intervention strategies and guidance for people with SMI will have direct benefit by improving physical health and quality of life. User-friendly information will be produced with the McPin Foundation for service users on strategies to manage and limit antipsychotic weight gain._x000D_ _x000D_ Dissemination will be integral throughout using formats including academic papers, conferences, social media, newsletters and press releases to reach a diverse audience._x000D_ _x000D_ For more information on our planned methods check our PROSPERO protocol: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=268697",7.3 MANAGEMENT AND DECISION MAKING,MENTAL HEALTH;METABOLIC AND ENDOCRINE HRCS22_19234,Cancer Research UK,CRUK,RElapse-specific therapeutic Vulnerability Evaluation in childhood & young adult ALL (REVEALL) (co-funded by Children with Cancer UK),"Background Although knowledge of the driver mutations underlying relapsed and refractory paediatric and young adult acute lymphoblastic leukaemia (ALL) has vastly increased in recent years, outcome remains poor. Potential agents targeting many key oncogenic pathways already exist but the relative rarity of relapsed ALL, combined with the wide genetic diversity, makes the testing of targeted therapy using conventional clinical trial design challenging. Children with incurable disease are therefore potentially missing out on effective treatments due to a lack of information to guide therapy. Aims To address this, we propose the establishment of a nationwide prospective precision oncology study performing real-time comprehensive analysis of primary leukaemia samples combing genetic characterisation with drug sensitivity profiling. Results will guide delivery of targeted agents directly to the patient and drive a deeper understanding of the cellular underpinnings of relapsed ALL. Methods Genomic characterisation will combine whole genome, RNA and ATAC sequencing to identify oncogenic coding variants and aberrant pathways enriched in relapsed and refractory cases. Application of novel in-house bioinformatic pipelines, that integrate sequencing modalities, will allow identification of drivers outside the coding genome, enhancing knowledge of non-coding variants and offering additional potential therapeutic targets, a strategy hitherto unemployed in precision medicine studies. To extend the availability of novel therapies to patients without a genomic target, drug response profiling utilising an in vitro mesenchymal stem cell-based assay to assess sensitivity in primary leukaemic blasts to a panel of targeted agents. A complementary strategy will employ a novel phosphoproteomic characterisation to identify aberrant pathway activation not apparent on genetic testing. Screening results will be combined with genetic characterisation to provide a powerful resource to identify subtype-specific vulnerabilities that can provide predictive biomarkers for treatment allocation. Finally, we will develop a library of patient-derived xenograft (PDX) models to facilitate in vivo validation of our results and provide a vital resource for further study of underlying resistance mechanisms. How the results of this research will be used We believe our approach will provide direct benefit to children with otherwise untreatable ALL. In addition, the wealth of data will provide a key resource for interrogation of relapsed and refractory ALL, deciphering key mechanisms driving resistance, identifying predictive biomarkers for treatment selection and uncovering new targets for drug development.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_21346,Innovate UK,IUK,"RFID to enable ATMP Manufacturing, Cryogenic Supply Chain Scale-Up and Productivity Gains","""Manufacture of cell and gene therapies (also known as Advanced Therapy Medicinal Products or ATMPs) is highly labour intensive and technically complex requiring a three-phase process: Primary Manufacturing (production), Secondary Manufacturing (storage, packing and distribution) and Final Preparation (delivery and patient administration), which due to the specialist requirements are currently undertaken by different organisations, using different processes, in separate and often geographically remote locations. The manual processes and multiple handling required to produce ATMPs results in low throughput and high costs. RFID technology is a well-established technology platform in high-volume sectors, such as the automotive industry and Fast Moving Consumer Goods, and is used to facilitate tracking and traceability of individual components, sub-systems and final product within and between sites. However, these systems cannot be simply transferred across to the ATMP industry due to the unique challenges associated with ATMP manufacture, including aspects of product viability, shelf life, batch sizes, cryogenic temperatures required for product storage and complex regulations to ensure patient safety. This project will develop and demonstrate a full-scale, regulatory compliant, cryogenic RFID system which works across the three stages of ATMP manufacture. The final system will de-risk and overcome a number of critical barriers to enable full and seamless adoption into the ATMP industry.""",,5.2 CELLULAR AND GENE THERAPIES,GENERIC HEALTH RELEVANCE HRCS22_19757,Cancer Research UK,CRUK,RNaseH2 inactivation in cancer cells: a pathogenic mechanism and therapeutic target,"Background Cancer cells with defective DNA damage response (DDR) rely on compensatory pathways for their survival. Pharmacological inhibition of these can induce tumour-specific cytotoxicity. We have recently discovered that the DDR gene, RNASEH2B, encoding a subunit of the heterotrimeric enzymatic complex RNaseH2, is frequently deleted in chronic lymphocytic leukaemia (CLL), multiple myeloma (MM) and metastatic prostate cancer. A principal function of RNaseH2 is to enable ribonucleotide excision repair, a DDR pathway that removes ribonucleotides incorporated into DNA by error-prone DNA polymerases. In the absence of RNaseH2 activity, tumour cells rely on PARP and become sensitive to PARP-trapping inhibitors. The full spectrum of phenotypic consequences of RNaseH2 inactivation in tumour cells is unclear, including which pathways become essential for their survival. Aims Here we begin to unravel the RNaseH2-associated cancer phenotype and identify cellular vulnerabilities of deficient tumours that can be utilised for therapeutic targeting. Specifically, we aim to: 1. Use primary CLL as a model to determine the phenotypic consequences of RNaseH2 defects. 2. Identify other cancers in which RNAseH2 defects can be targeted. 3. Elucidate key redundancy pathways in RNAseH2-deficient cancer cells by candidate and non-biased approaches. Methods We will use an integrated multi-disciplinary approach involving fundamental studies in engineered cell lines, primary tumour cells with defined RNAseH2 status and translational models of CLL and other RNAseH2-deficient cancers. Initially, we will address how RNaseH2-deficiency effects the genomic landscape, tumour burden and inflammation-associated immune evasion by combining our in vitro and in vivo CLL models with cutting-edge genomic analyses and our large patient cohort. Subsequently, we will investigate whether this phenotype exists in other frequent RNAseH2-deficient tumours, such as MM and prostate cancer. Finally, we will use both candidate and non-biased, genome wide approaches to identify the key therapeutic targets in RNaseH2-deficient tumour cells alongside state-of-the-art tumour models to validate their therapeutic utility. How the results of this research will be used Our findings have the potential to provide significant benefit for CLL and MM which, with 3000 deaths every year in the UK, clearly represents an unmet need in haemato-oncology, whilst age and patients’ fragility makes a strong case for the use of novel treatments that can replace chemotherapy. Beyond haematological malignancies, the benefits of our studies will be seen in the wider community of Oncology, with respect to prostate cancer, the most common male cancer and the third most common cause of cancer death in the UK.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_16159,Cancer Research UK,CRUK,RadPath: a pathology network to investigate the immune effects of radiotherapy,"Background: Immuno-oncology (IO) agents are revolutionizing the treatment of cancer, but the underlying mechanisms that are responsible for success or failure, including when combining immune checkpoint blockade with radiotherapy (RT), remain poorly understood. Hence, whilst some clinical success has been seen with RT/IO combinations, the biology of the immune response to RT in patients, in standard of care RT treatments as well as in the context of RT/IO trial combinations, needs in depth investigation to inform future clinical direction and trial strategy. An under-investigated area of immune analysis of patient samples is pathology, despite the potential of new developments in digitalisation, AI and multicolour immunofluorescence (mIF) to quantify different immune cell subsets. Pathological readouts of the tumour immune microenvironment (TIME), how it changes with RT, and how it links to other analyses (eg genomic), as well as clinical outcome, can improve both our basic scientific understanding of the immunology of RT, and hence the design of trials to improve patient outcomes. This proposal has developed from the RadNet Immunology Working Group and focuses on providing immune pathology support across the RadNet network. Aims: We will establish a co-ordinated immune pathology network (RadPath) across RadNet, led by the Institute of Cancer Research, Manchester and Leeds, with the active participation and support from all other centres. This infrastructure will allow samples collected from patients taking part in academic or industry-sponsored trials including RT as a treatment modality, to be analysed for their TIME and, where available, normal tissue. The focus will be on fixed tissue to maximise deliverability, efficiency and affordability. Methods: RadPath will first establish shared standard operating procedures, material transfer agreements and data sharing platforms, building on published collaborative work between RadNet centres. Prioritising initially available samples and those expected within 2 years from ongoing studies, going forward RadPath will also regularly invite potential project proposals. By requiring further academic and/or industrial funding beyond initial set-up, RadPath will develop longer-term sustainability. How the results of this research will be used: The results generated by RadPath will be shared across the network. This will build a network of translational immune pathology science to inform better understanding of the interactions between RT and the immune system, and hence better design of treatment strategies including RT, to improve patient outcome.",,5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT),CANCER AND NEOPLASMS HRCS22_06566,Department of Health and Social Care,NIHR,Randomised Thoracoscopic Talc Poudrage + Indwelling Pleural Catheters versus Thoracoscopic Talc Poudrage only in Malignant Pleural Effusion (R-TACTIC),"Research Question Does the novel combination of Thoracoscopic Talc Pleurodesis (TTP) + Indwelling Pleural Catheter (IPC) result in reduced total time in hospital and reduced breathlessness over 1 month post randomisation compared with standard care (TTP alone) in Malignant Pleural Effusion (MPE)? Background MPE, where large volumes of fluid gather in the lining of the lung due to metastases to the pleura, is common and increasing (50,000 new cases / year) in the UK(1-4). MPE causes disabling breathlessness and distress. Standard Treatment involves drainage of the fluid through tubes inserted between the ribs to relieve symptoms, but fluid recurs in >90% without further treatment(5). Definitive treatment to prevent recurrence is achieved via a camera inserted in the pleural space under sedation (thoracoscopy)(6, 7), when biopsies can be taken to establish diagnosis, and a chemical (talc) is inserted to fuse the lung to the chest wall (thoracoscopic talc pleurodesis, TTP) (8). This requires admission for 3-5 days and prevents fluid long-term in only 60%(5). IPCs are used later in treatment when TTP fails(5). These are tubes inserted as day cases(9) and allow patients to drain at home using vacuum bottles. They provide symptom control(10-12), improve quality of life (13-15), allow long-term drainage and have no “failure” rate. Novel Treatment: Combining TTP + IPC early in care as the first definitive procedure would allow patients to be diagnosed, treated and sent home in one day after a single procedure, drain fluid at home and achieve pleurodesis without any hospital stay. In observational studies, 80% of TTP+IPC treated patients have IPCs removed at 2 weeks (16). Aims / Objectives To assess the effect of combined TTP + IPC early in care through a randomised comparison with the standard pathway. To use qualitative methods to understand the impact of the two treatments on patients and carers. Methods 1. A Definitive Randomised Controlled Trial conducted in 142 MPE patients in centres with a track record of delivery to MPE studies (n>1000). Patients randomised to: Standard care (TTP) Intervention (TTP+IPC in a combined procedure) Co-Primary outcomes: Time in hospital over 1 month post randomisation. Mean breathlessness over 1 month post randomisation using 100mm VASd score which is validated in MPE(17), MCID is established and is reliably measured (18, 19). 2. Qualitative Study Semi-structured interviews with up to 24 patient/care diads (patient and carer interviewed together) (10-12 diads per treatment arm), to understand impact of treatment at 3 months. Timelines for delivery Ethics, regulatory approval, database, CRF (3 months) Centre setup (3 months) Recruitment (142 patients, 24 months recruitment). Follow up (3 months). Database lock, analysis, publication (3 months). Total 36 months. Anticipated Impact / Dissemination If TTP+IPC is effective, the results will change UK practice for thousands of patients, reduce hospital stay and healthcare costs, improve quality of life and prevent further pleural procedures. We will disseminate results widely through patient and specialist meetings and publications, so that results impact care immediately.","The purpose of this study is to improve treatment of patients with malignant pleural effusions (MPE). MPE occurs when cancer spreads to the space around the lung (the pleural space) where fluid accumulates. Any cancer (lung, breast, ovarian, bowel) can cause this, and fluid causes breathlessness with a major impact on quality of life, causing distress for patients and families. To help patients, we drain fluid to relieve breathlessness. The fluid usually comes back and so a further "sticking" procedure is needed. This involves draining fluid and inserting a chemical to fuse the cavity, done using a keyhole procedure under sedation (thoracoscopic talc pleurodesis, TTP) when biopsies can also be taken. This requires admission to hospital for 3-7 days, and fails (the fluid comes back) in 40% of cases. When pleurodesis fails, we insert a small tube in the chest which the patient is sent home with, called an indwelling pleural catheter (IPC). Patients drain fluid themselves at home. Previous studies show IPCs are well tolerated and improve symptoms, and fluid can be drained long-term. However, patients experience pain, there is a risk of infection, and drainage at home is inconvenient. Combining treatments at the start (TTP + IPC) might achieve the “best of both worlds”. This would provide diagnosis and treatment for MPE in a single procedure, avoid admission completely and prevent “failure”, leading to better symptom control and quality of life. Patients with MPE have told us that avoiding time in hospital and improving breathlessness are their top priorities. We will assess this through a randomised trial in five centres, comparing TTP + IPC with standard care (TTP). We will measure time spent in hospital, symptoms including breathlessness, costs and impact on carers and patients to establish which treatment is best. We will conduct this study in 5 expert centres which have previously conducted many randomised trials in MPE patients, and have shown they can perform such studies effectively and safely. A survey of patients with MPE identified being at home as a priority, and the primary focus of this study is time in hospital. We will disseminate results widely including through patient and specialist meetings and publications, so that results impact care immediately.",6.3 MEDICAL DEVICES,CANCER AND NEOPLASMS HRCS22_05196,Department of Health and Social Care,NIHR,Randomised controlled trial evaluating effectiveness of neoadjuvant endocrine treatment in post-menopausal women (EndoNET),"There are 45,000 people who develop breast cancer each year in the UK, mostly in women after their menopause and mainly of a type known as oestrogen-receptor positive, human epidermal receptor-2 negative. The current standard of care is surgery within a month, followed by radiotherapy where required, and anti-hormone therapy (known as endocrine treatment) for 5-10 years. Most people will not require chemotherapy. Almost one half will however be treated by surgical removal of the breast (mastectomy.) For others, lumpectomy (breast conservation surgery), will ensure that a limited amount of breast tissue is removed at surgery._x000D_ _x000D_ Endocrine treatment after surgery is very effective in the long-term treatment of breast cancer; it is however currently unknown whether it is also beneficial to start this same endocrine treatment before surgery. This study is to determine whether doing this – known as neo-adjuvant endocrine therapy - will shrink the tumour prior to operating. This could increase the rates of breast preservation by reducing the number of mastectomies for some women and the extent of surgery for others (removing less tissue leaves less defect). _x000D_ _x000D_ After mastectomy many patients do not want or are unsuitable for breast reconstruction. Even if received, this may not always fully compensate for breast removal. Reducing breast surgery and increasing rates of preserving breasts by treatment with neo-adjuvant endocrine therapy is therefore anticipated to improve cosmetic outcomes, leading to better quality of life. _x000D_ _x000D_ Patients with breast cancer are part of the study leadership team and others have been extensively consulted in the design. They indicated that overall quality of life and preserving the breast were the most important outcomes by which to measure study success. _x000D_ _x000D_ Patients in this controlled trial are allocated by chance to one of two groups, which determines their treatment. All patients will start hormone treatment on joining the trial: group 1 will have surgery within 31 days; group 2 will receive surgery after 6 months of neo-adjuvant endocrine therapy. People in group 2 will be closely monitored with an ultrasound scan at 3 months and 5 months to ensure continued response to this therapy prior to surgery. _x000D_ _x000D_ The trial aims to recruit 1440 post-menopausal women with oestrogen-receptor positive, human epidermal receptor-2 negative breast cancer, from at least 30 NHS hospitals across the UK. There are no age limits. We will invite participants who have chosen not to have or will not require or benefit from chemotherapy. These patients will therefore not be using chemotherapy to reduce their tumour size. However, this study will show if tumour size can be successfully reduced with neo-adjuvant endocrine therapy. Where the NHS provides tests to analyse tumour cancer gene profiles, these can also help decide if chemotherapy is of benefit, in which case it will be offered. _x000D_ _x000D_ Patients in both groups will be asked to fill in quality of life questionnaires at intervals during their 15-month participation in the study. We will publish the results in medical journals and present them at international conferences. People taking part will receive the study findings in writing if they wish and via dissemination on the Oxford Surgical Interventional Trials Unit website.","HYPOTHESIS: Neoadjuvant endocrine therapy (NET) reduces breast cancer (BrCa) size prior to surgery, reducing surgical burden leading to better health-related quality of life (HRQoL) and higher rates of breast conservation surgery (BCS)._x000D_ RESEARCH QUESTION: In post-menopausal women who will not require chemotherapy for >T1, ER+, HER2- invasive BrCa, does NET improve global HRQoL over 15 months and increase breast BCS rates?_x000D_ BACKGROUND: BCS leads to better HRQoL compared to mastectomy. Neoadjuvant treatments have potential to down-size BrCa and reduce extent of surgery (reduce excised volume, reduce re-excision rate and convert mastectomy to BCS) reducing surgical burden and improving HRQoL. NICE guidance recommends NET be considered in post-menopausal women “as an option to reduce tumour size if there is no definite indication for chemotherapy”. In these patients approximately 87% of BrCa is ER+, and virtually all will receive endocrine treatment (ET) after surgery to reduce risk of BrCa recurrence. In the majority (>70%) chemotherapy is not required and so is not available as an alternative neoadjuvant option. Although widely used as an emergency measure during the COVID pandemic, NET is infrequently used in normal routine care and practice greatly varies across the NHS and worldwide. Many women could potentially benefit from having ET in the NET setting potentially increasing BCS rates and improving HRQoL. _x000D_ AIMS/OBJECTIVES: The primary aim is to determine whether global HRQoL is better over 15 months and BCS rates are higher in women who receive NET followed by surgery and adjuvant ET compared to surgery followed by adjuvant ET. Secondary outcomes include HRQoL related to body image and surgery (Breast Q, Hopwood Body Image Scale) and surgical outcomes (excision volumes following BCS, re-excision and repeat surgery rates)._x000D_ METHODS: A prospective, phase III, multicentre randomised controlled trial (RCT). We will recruit 1440 post-menopausal women with ER+, HER- invasive BrCa who are unlikely to require chemotherapy. They will be randomised 1:1 to undergo 6 (+/- 1) months of NET followed by surgery and adjuvant ET versus surgery within 31 days followed by adjuvant ET. Both arms receive the same treatments (surgery, ET, and radiotherapy where indicated), but the sequencing of surgery will differ with both arms starting ET at randomisation with 6 months of the course of ET delivered prior to surgery in the NET arm. The co-primary outcome measures are global HRQoL over 15 months measured by FACT-B and the BCS rate. _x000D_ TIMELINES FOR DELIVERY: The study duration is 69 months including 6 months set-up, 42 months recruitment, 15 months follow-up and 6 months data analysis and final reporting of results. Formal stop/go review will be at month 18 (after 12 months recruitment) to ensure 10 sites have opened and 150 patients are randomised. If met, the trial will recruit for a further 30 months. Data from the internal pilot will be included in the final analysis. Full-scale recruitment has not been factored into the trial until month 27 to allow staggered opening of centres._x000D_ ANTICIPATED IMPACT AND DISSEMINATION: Results will be disseminated at national and international conferences and to patients via the CTU and charities. Demonstration that a NET strategy is effective is likely to be incorporated into national and international guidelines enabling uptake across large numbers of patients reducing breast surgical burden and improving HR",6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_05533,Health and Care Research Wales (Welsh Government),,Randomised trial of clinical and cost effectiveness of Administration of Prehospital fascia Iliaca compartment block for emergency Pre-Hospital hip fracture care Delivery (RAPID 2),"Background_x000D_ Hip fractures are a very common injury for elderly people. About one in three patients who break their hip die within one year and many patients lose mobility and independence. Pain relief before the patient reaches hospital is often inadequate and causes side effects which may slow down recovery. We have recently completed a small study testing whether a local anaesthetic injection into the hip area called Fascia Iliaca Compartment Block (FICB) given by paramedics at the scene of injury is safe and acceptable. We met all the criteria that we set at the beginning of the study, and concluded that it is feasible to undertake a full trial._x000D_ _x000D_ Aim_x000D_ We aim to find out whether the local anaesthetic injection reduces pain, is safe, and improves patient health outcomes, as well as how much it costs the National Health Service (NHS). _x000D_ _x000D_ Design_x000D_ We will carry out a trial where paramedics give patients either the new treatment - local anaesthetic injection or usual care (often morphine). Patients will be allocated to one or other treatment by a random process (similar to tossing a coin) to ensure a fair comparison between treatments._x000D_ _x000D_ Methods_x000D_ We will provide training for the paramedics who take part in the trial, so that they can perform the local anaesthetic injection safely. When a trained paramedic attends a patient he or she assesses as having a hip fracture, (s)he will use a scratchcard to decide which treatment to give the patient. We will compare patients’ pain levels, other outcomes and costs between those allocated to the new local anaesthetic injection and those allocated to receive usual care. The other outcomes we will compare between the two groups during their initial care and up to four months following injury are: length of stay in hospital, deaths, quality of life, ability to walk, and satisfaction with care. We will also monitor safety by identifying any concerning health-related events in each group. We will work out the costs of NHS care in each group. _x000D_ _x000D_ We will carry out the trial in areas within five ambulance services in England and Wales, where a local Emergency Department (ED) has agreed to participate in the research. We will recruit and train 44 paramedics in each ambulance service. We aim to recruit 1400 patients to the study, so that we can detect a difference in improvement in levels of pain of about 10%, which the public and clinical members of our research team agreed would be important to patients._x000D_ _x000D_ We will train and support paramedics and triage nurses in ED to record patient reported pain levels throughout the trial._x000D_ _x000D_ Patient and public involvement_x000D_ Two members of the public have helped us to plan this bid and two patient groups (approximately 40 individuals) reviewed our ideas. Members of the public will continue to be involved throughout this research. During the research, members of the public will attend meetings, help to write information sheets for patients, and help to write up the findings from this research. Members of the public will also sit on our oversight committee to ensure the research is carried out properly, and be part of local implementation teams at sites to ensure the patient voice is heard throughout our research. _x000D_ _x000D_ Sharing our results_x000D_ We will publicise the results of the research using scientific journals, social and professional media and conferences, in the UK and worldwide. Our findings will be incorporated into ambulance service guidelines in the future.","Research question_x000D_ Is Fascia Iliaca Compartment Block (FICB) administered by paramedics in the prehospital setting as pain relief for patients with hip fracture safe, effective and cost-effective?_x000D_ _x000D_ Background_x000D_ Approximately 75,000 people fracture a hip each year in the UK. This excruciatingly painful injury can be devastating – with a high associated mortality rate - and those who survive likely to be more dependent and less mobile than before their injury. Patients with hip fracture occupy 2.5% of all hospital beds at any time and cost the NHS £2 billion each year. Pain relief at the scene of injury is known to be inadequate. Intravenous morphine is usually given to patients by paramedics but opioids are less effective for dynamic pain and can cause serious side effects, including nausea, constipation, delirium and respiratory depression. These may delay surgery, require further treatment and worsen patient outcomes._x000D_ _x000D_ We have recently completed a feasibility study testing whether paramedic provided FICB is safe and acceptable; whether our trial design worked in the prehospital setting, and whether we could collect data needed in a full trial. This initial study - the RAPID trial (now published) - showed that a full trial is feasible, as assessed against pre-specified progression criteria._x000D_ _x000D_ Aim_x000D_ To test safety, clinical and cost-effectiveness of paramedic provided FICB as pain relief to patients with suspected hip fracture in the prehospital environment._x000D_ _x000D_ Methods_x000D_ We will conduct a multi-centre individually randomised parallel-group trial, with a 1:1 allocation ratio between usual care and FICB. Hospital clinicians in five sites (paired ambulance services and receiving hospitals) will train 220 paramedics to administer FICB. We will use individually issued, sequentially numbered scratchcards to conceal randomisation allocation. The primary outcome for this trial is change in pain score from pre-randomisation to arrival at the Emergency Department (ED). We will use the SAIL (Secure Anonymised Information Linkage) databank (in Wales) and NHS Digital (in England) to follow up processes and outcomes using routine anonymised linked data in an efficient study design; and questionnaires to capture patient reported outcomes at 1 and 4 months. 1400 patients are required to find a clinically important difference in primary outcome (standardised statistical effect ~ 0.2; 90% power, 5% significance). Secondary outcomes include mortality; length of stay in hospital; prehospital medications including morphine; presence of hip fracture; satisfaction; mobility; and costs to the NHS. We will assess safety through capture of Serious Adverse Events in each trial arm._x000D_ _x000D_ Timelines_x000D_ This research will take 5 years and 2 months to prepare, conduct, analyse and report. This includes time to complete ethics and governance processes; train paramedics; recruit patients over 24 months and follow up outcomes. We have included a six month period without cost to allow for the time lag in retrieving routine anonymised outcomes. _x000D_ _x000D_ Public and/or patient members have been involved throughout trial development and we will supplement existing PPI membership across trial management and oversight groups._x000D_ _x000D_ Impact and dissemination_x000D_ We will disseminate our results widely, using high impact peer-reviewed journals and conferences, in the UK and worldwide. We expect trial findings to be incorporated into relevant national and international practice guidelines.",6.1 PHARMACEUTICALS,INJURIES AND ACCIDENTS HRCS22_12753,Cancer Research UK,CRUK,Re-awakening radiation sensitivity - Understanding the role of Schlafen11 in mediating radioresistance.,"Background: Radiotherapy is used in the management of almost 50% of all cancer patients. Therefore, understanding why resistance to radiotherapy occurs is essential for radiotherapy to be used most effectively. Whilst detailed mechanisms of radioresistance remain largely unknown, previous analyses have identified DNA damage response (DDR) pathway alterations correlating with radioresistant phenotypes. Schlafen11 is an emerging DDR protein whose expression is lost in almost 50% of cancers and cancer cell lines, primarily through promoter methylation. Mechanistic studies have identified Schlafen11 as a key regulator of response to multiple widely used DNA damaging agents (DDA), including potent radiosensitisers, with loss of Schlafen11 expression resulting in broad resistance to these DDA. Additionally, a number of retrospective studies have demonstrated that Schlafen11 expression loss is a prognostic and predictive biomarker to response to DDA, including chemoradiotherapy combinations. Despite these promising results in multiple cancer types, little is known about the role of Schlafen11 as a mediator of radioresistance. Aims: Our aim is to understand the role of Schlafen11 in modulating radioresistance, as well as develop strategies to reverse this resistance. Methods: Schlafen11, p53 and dual Schlafen11/p53 isogenic cell lines have previously been generated in our lab through CRISPR-CAS9 knock out in eHAP parental cells. Response to radiation will be compared in these isogenic pairs to identify differential sensitivity related to Schlafen11 and p53 expression. Comprehensive analysis of DNA repair, cell cycle and cell death will be performed to gain a detailed mechanistic understanding of these interactions. Additionally, ATR, WEE1 and CHK1 inhibitors will be tested in combination with radiation in these cell lines to investigate if these agents can reverse the Schlafen11 resistance as previously demonstrated in the literature. Further, a whole genome CRISPR knock out screen will be performed in parallel to provide identification of mechanisms of resistance, as well as providing suggestions to how this resistance can be overcome. How the results of this research will be used: The information generated, and skills developed, through this proposal will provide preliminary data for a PhD fellowship proposal aiming to optimise the use of radiotherapy by understanding and modulating the DDR. Additionally, these experiments will expand our understanding of Schlafen11 biology to include its role in predicting sensitivity to radiotherapy.",,5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES,CANCER AND NEOPLASMS HRCS22_06593,Department of Health and Social Care,NIHR,ReDMit Study: Co-designing and feasibility testing a behavioural intervention to encourage appropriate symptom REporting and treatment Decision making and MITigate effects of chemotherapy-induced peripheral neuropathy,"BACKGROUNDChemotherapy-induced peripheral neuropathy (CIPN) refers to peripheral nerve damage caused by neurotoxic chemotherapy agents. CIPN symptomssuch as numbness, tingling, pain, and muscle weaknessare felt mainly on hands and feet. Research show that individuals who reported having CIPN symptoms are three times more likely to have falls or near falls than those who have no CIPN. Patients experience decreased quality of life (QOL) due to lifestyle changes, reduced participation in social activities, and difficulty performing work duties leading to financial losses. There is no effective treatment and prevention for CIPN; to avoid or lessen the seriousness, chemotherapy doses may need to be delayed, reduced or discontinued. It is estimated that of 100 people treated with nerve-damaging cancer drugs, 30 will continue to have symptoms six months or longer after treatment. Because more and more people survive cancer, the number of people living with CIPN will increase year-on-year. The cost burden of CIPN to the NHS will be considerably higher, as will patient and carer economic losses. RESEARCH QUESTIONIs a co-designed behavioural intervention that aims to encourage appropriate symptom reporting and treatment decision making and mitigates effects of chemotherapy-induced peripheral neuropathy acceptable to patients, and would a definitive trial of its effectiveness be feasible to conduct? PLAN OF INVESTIGATION The study is informed by the Medical Research Council Framework on developing and evaluating complex interventions and is divided into three phases.Phase 1 will involve systematic review of studies which explored available interventions for managing the consequences of peripheral neuropathy in cancer and other conditions. Additionally, an empirical analysis of a CIPN dataset from the European FP7 funded eSMART study (n=1100) will be carried out to better understand the natural history of CIPN.The study design draws upon the Common Sense Model of Self-regulation of Health and Illness which will underpin the development of the intervention and identify the essential elements of its components. Phase 2 will involve non-participant observation of chemotherapy consultations before, halfway and at the end of chemotherapy treatment (n=12), semi-structured interviews with patients (n=12) and healthcare professionals (n=12). The theory and empirical evidence gathered during chemotherapy consultation observations and interviews will inform the intervention co-design process using an established approach (Experience-Based Co-Design). Findings will be used to initiate and inform discussion about the intervention.It is likely the intervention will consist of:One-to-one factual information provision about CIPN pre-chemotherapyCIPN screening tool for HCPsAdapted decision making tool Phase 3 comprises a feasibility randomised controlled trial with an embedded qualitative process evaluation. A feasibility RCT design has been chosen to estimate important parameters necessary to design the main efficacy study, usually a costly and time-intensive large scale RCT. DISSEMINATION Patients, clinicians, and other members of the public will be made aware of the results through papers published in journals, presentations at conferences, public engagement, educational and charity events; distribution will be made using social media.","AIMS This study aims to develop and test an intervention that will encourage patients to report symptoms early and make treatment decisions to minimise the effects of chemotherapy-induced peripheral neuropathy (CIPN).BACKGROUND Some cancer drugs cause damage to nerves, a condition called CIPN. The most common symptoms, felt mainly in the hands and feet, are numbness, tingling, pain, muscle weakness, and/or sensitivity to cold. People with CIPN can have functional difficulties in carrying out tasks involving their hands and feet. Studies show that individuals who reported having CIPN symptoms are three times more likely to have falls or near-falls than those who did not. Symptoms result in decreased quality of life due to lifestyle changes, reduced participation in social activities, and difficulty carrying out work duties, leading to financial loss. It is estimated that, of 100 people treated with nerve-damaging cancer drugs, 30 will continue to have symptoms six months or longer after treatment. There is no effective treatment or prevention for CIPN; to avoid or lessen the seriousness, chemotherapy doses may need to be delayed, reduced or discontinued.It is important to prepare patients about the possibility of developing CIPN, to help them recognise and report symptoms early. It is also vital that patients are involved in making decisions when chemotherapy doses are modified to allow symptoms to settle, and help patients to adopt management strategies to mitigate the effects of CIPN on their daily activities.WHAT WILL THE STUDY INVOLVE? Phase 1 Preliminary studies will be conducted to explore available interventions for managing the consequences of nerve damage. Analysis of data from a European study, where 1100 patients reported CIPN symptoms daily, will be carried out to help increase our understanding of CIPN occurrence, severity and recovery.Phase 2a Using an approach called Experience-Based Co-Design (EBCD), patients and healthcare professionals (HCPs) will come together to develop the intervention. This will involve: Observations of patient/HCP consultations: before, halfway through, and at the end of chemotherapy treatment will be conducted to find out more about how CIPN information is currently discussed.Interviews: all patients and HCPs observed will be invited for interviews to learn more about their experiences. The patient interviews will be filmed (with consent).Phase 2b Co-design meetings: all participants in the observations and interviews above will be invited to facilitated meetings. Data from Phase 1 and 2a will be used in co-designing the intervention. Findings will be presented through an edited version of the patient film. Participants will then share and discuss views on the intervention. After the meetings, smaller group work will further refine the intervention.Phase 3 The intervention will be then tested on 40 patients who are at risk of developing CIPN. Using a process called randomisation, a computer will allocate 20 patients to receive the intervention, while 20 patients will receive standard care for CIPN. By doing this, we will find out if the intervention is acceptable to patients, and if a larger study is needed to test its efficacy.It is likely the intervention will consist of:One-to-one factual information provision pre-chemotherapyA CIPN screening tool for HCPsAn adapted decision-making tool PATIENT AND PUBLIC INVOLVEMENT Patients and cancer survivors have been involved in discussions about the study's relevance and usefulness, its design, and this grant application. A study-specific patient advisory group has been formed and will be involved in study management, patient materials' development, data analysis and dissemination. DISSEMINATION Patients, clinicians, and other members of the public will be made aware of the results through journal publication,conference presentations, public engagement activities, educational and charity events; and via social media.",7.1 INDIVIDUAL CARE NEEDS,CANCER AND NEOPLASMS HRCS22_05461,Department of Health and Social Care,NIHR,Real-world testing of software for measuring bone disease on whole-body MRI in patients with prostate cancer and myeloma,"Research question Can using WBMRI and our novel software result in faster, more accurate and/or more confident disease assessment compared with conventional pathways in patients with bone disease from advanced prostate cancer and myeloma? Background WBMRI is useful for assessing bone disease extent and response to treatment by measuring the total disease volume (tDV) and apparent diffusion coefficient (ADC), but requires software to quantify these for clinical application. We have developed a CE-labelled software which can automatically measure the tDV and ADC from WBMRI to assess bone disease. Aims and objectives The aim is to test the real-world performance of our CE-labelled computer software with WBMRI to measure bone disease, by assessing its clinical performance, identify barriers to adoption, and roadmap its wider adoption. The objectives are to: (1) map the interactions of our software with stakeholders; (2) validate use of training for doctors to promote technology uptake; (3) test the performance of WBMRI and software for assessing bone disease response to treatment in prostate cancer and for diagnosing myeloma; (4) determine costs and cost-effectiveness; and (5) evaluate commercial models for NHS deployment. Methods We will (1) evaluate relevant human factors and software usability to refine product; (2) develop and validate training to utilise WBMRI and software; (3) undertake two clinical trials in advanced prostate cancer and myeloma to determine clinical effectiveness; (4) perform health-economic analysis; and (5) explore commercial models for dissemination. Timelines for delivery WP1 [month 3-39]; WP2 [month 1 to 24]; WP3 [month 7 to 48]; WP4 [month 1-6 and 36-48]; WP5 [1-48]. Anticipated impact and dissemination Improved disease management and outcomes for patients; new diagnostic skills and/or faster reporting for radiologists; increased clinician confidence in decision making; standardised cost-effective WBMRI service for the NHS; investment in the UK contributing to economic growth.","The spread of cancer to bones is common. In advanced prostate cancer, bone disease can occur in 90% of patients. In myeloma, a cancer of the bone marrow, 70% of patients have bone damage at diagnosis. Currently, computed tomography (CT) and bone scan imaging (BS) are used to detect cancer spread to bones. However, neither reliably identifies the extent of the disease (myeloma), nor whether treatment is working (prostate). Whole body MRI (WBMRI) is more sensitive for bone cancer and better for assessing whether cancer treatments are working. Despite this, CT and BS are still widely used across the NHS, with patients missing out on WBMRI. As a result, some patients may not get the right treatment and are kept on ineffective treatments for longer, leading to poorer disease outcomes. As WBMRI is relatively new, doctors may need training to be confident about using it. However, standard WBMRI reports by doctors can lack precision. For example, one doctor s idea of “a small amount ” of disease may be different from another. Hence, accurate measurements from WBMRI are necessary to allow the effects of cancer treatments to be objectively monitored. Through an NIHR Invention for Innovation funded project, we have developed a CE-labelled (meeting a safety conformity standard) software which can automatically identify and measure bone disease on WBMRI. The software quickly extracts the total amount of bone disease and its cellular property. The software has been shown to be reliable and accurate for bone disease assessment in prostate cancer. We will test the real-world performance of our software in patients with bone disease from prostate cancer and myeloma. We will study how our software interacts with the users and identify any barriers for use. We will also conduct clinical trials to show its performance. We will undertake our research in five work packages: (1) we will study user interactions with our software and perform a usability analysis to help refine the software; (2) we will create and apply a training module for doctors and scan technicians to encourage WBMRI and software adoption; (3) we will undertake two clinical trials to show the performance of our software and WBMRI compared with standard pathways; (4) we will determine whether using WBMRI and our software is cost-effective; and (5) we will study the commercial approaches to get our software adopted by the NHS. Identified by our patient and public involvement representatives as a priority, this study will generate meaningful impact by showing that using WBMRI and our software can provide faster, more accurate and/or higher diagnostic confidence for assessing bone disease. This can lead to greater confidence that the right treatment is given at the right time, thereby improving longer term patient outcomes.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_02305,Medical Research Council,MRC,Real-world treatment effectiveness in people with type 2 diabetes: Maximising the applicability of clinical trials,"Randomised controlled trials are the gold standard for obtaining unbiased estimates of treatment effects. However, older patients and those with co-morbidity are frequently underrepresented. Consequently, for many ""real-world"" settings, the applicability of trial findings is uncertain. We propose to address this uncertainty using calibration. Following calibration trial participants who are overrepresented (with respect to the 'target' population) contribute less to the overall result, while participants who are underrepresented contribute more. Calibration improves representativeness, while preserving randomisation and hence validity. Hitherto, calibration required individual-level participant data (IPD) for all relevant trials, making it unfeasible in most settings. However, in an MRC-funded methodology grant we developed and validated a novel method of calibration, which can be used even where access to IPD is restricted to a subset of the relevant trials. Together with our recent experience in accessing and analysing IPD for industry-funded trials, this makes calibration a feasible tool for improving trial applicability. NICE guidance on novel drugs for type 2 diabetes (DPP-4 and SGLT2-inhibitors and GLP-1 agonists) noted that the underpinning trial evidence was unrepresentative. Therefore, using IPD, sub-group results, and overall results with baseline characteristics, we will conduct a calibrated network meta-analysis of relevant trials to compare the efficacy of these drug classes, subsequently applying these estimates to an existing health economic model. We will calibrate to the Scotland-wide Diabetes Register, and to two cohorts of people with diabetes based in China. We will produce estimates for people with type 2 diabetes that are both valid and applicable. We will also demonstrate, for the first time, that calibration can be used to improve the relevance of trial results in realistic settings, where IPD is only available for some trials.",,5.2 CELLULAR AND GENE THERAPIES,METABOLIC AND ENDOCRINE HRCS22_06394,Health Education England,HEE,Realist evaluation to DEtermine Mechanisms to increase one-Year colorectal cancer (CRC) Survival in place-based health systems in England (DEMYStify),"Research question 'How can place-based health systems in England increase one-year colorectal cancer (CRC) survival and tackle variations in their area?' BackgroundCRCs account for 42,000 (11%) of all new cases of cancer diagnosed annually in the UK19. Evidence shows that survival is improved if the disease is spotted early20. However less than half of cases are picked up at this stage21. Recent data for the UK shows cancer to be the leading cause of deaths that could be averted or delayed through timely, effective health care and public health interventions22. The trend in one-year CRC survival varies across local health systems with a 16% difference23 between the best and worst performing areas. There are also unexpected ('unwarranted') and unfair differences ('inequalities') in the demographics of those who survive19,20,24.Aim To understand and explain the mechanisms that contribute to increases in one-year CRC survival in specific areas in England. Objectives Identify four case-study sites that have seen increasing or static survival trends including any demographic variation, Explain through targeted interviews, focus groups and analysis why these changes have occurred, Determine how place-based systems could act to increase one-year survival for CRC. Design, methods and timelines for delivery 'DEMYStify' is sequential explanatory research which adopts a realist perspective25. Realist methodology is theory-driven and predicated on the idea that there 'is a [social] reality that cannot be measured directly (because it is processed through our brains, language, culture etc.), but can be known indirectly'26. It focuses on unpacking and explaining the interaction between context, mechanism and outcome25 to explain the 'how' and 'why'. The study is constructed of three work packages [WP]. The first will involve developing the candidate programme theory (CPT)27 providing broad explanations about how population-level changes in one-year CRC survival happen (Yr1). WP2(Yr1) will involve quantitative analysis of trends in one-year CRC survival estimates by Upper Tier Local Authority areas. Four places demonstrating consistently static or increasing one-year CRC survival will be identified. These places will be invited to be case-study sites (Yr2+3) where document review, interviews and focus groups will be used to understand what has contributed to the trend observed. Analysis, using realist evaluation principles, will enable refinement of the CPT (Yr3). Patient, public and stakeholder involvement A PPI panel, formed at the start of this fellowship, will hold this programme of research to account. Members will be invited to collaboratively design core components including scope of focus, health system and stakeholder mapping and dissemination approaches. Views of patients will be heard by including members of well-established support groups as collaborators, lay-chair of the 'context expert group', and interviewees in case-study sites. Anticipated impact and dissemination Findings will directly benefit patients, especially 'at-risk' population groups, by informing the actions of health policy makers, healthcare leaders and third sector organisations. A range of dissemination mediums including academic papers, grey reports alongside workshops and presentations will ensure reach and impact. DEMYStify will inform future work to assess if theory developed is transferrable to other groups of cancer.","Background People with bowel cancer have different experiences and outcomes depending on where they live in England. There is a 16% gap between people surviving bowel cancer to one-year after diagnosis in the best local place compared to the worst. It is well known that early identification of bowel cancer and targeting high-risk populations will improve life expectancy. However, is not well understood why and how some local areas in England manage to deliver improvements and others do not. A National Cancer Research Institute patient member reported that there are 'so many variations in health services across the country anything to make it more consistent should be supported'. Aims My research, DEMYStify, aims to understand how different ways of working within local health services in England affect one-year bowel cancer survival. I plan to investigate what the difference is between areas that have increasing survival figures and those where the figures flatline. The purpose is to develop an understanding about how the services within local areas work together to improve bowel cancer survival and identify actions that can increase local bowel cancer survival and make outcomes more consistent across the country. Design and methods The work will begin by drafting initial ideas before looking back at earlier evidence and reports. Findings will be discussed with patient groups, clinicians and public health experts to inform the focus of the investigation. Past data about changes in survival of people with bowel cancer in England one-year after diagnosis will be analysed. From this, four local areas will be chosen as potential case-study sites. The health systems that serves those communities will be defined and will be invited to get involved. Interviews and focus groups will be conducted with key stakeholders including patient members. Information about any changes that have occurred will be gathered. There will be a strong emphasis on exploring how areas have addressed unfair differences (health inequalities) locally and the contribution this may made to changes in bowel cancer survival at one-year after diagnosis. This type of research is sometimes called mixed methods; discussions are used to try and explain trends in data. A theory development approach will be used to produce robust ideas about how and why increases in one-year bowel cancer survival are achieved. Expected outcomes and how they will be sharedIt is expected that there will be new understanding about how areas in England can work to make progress in increasing one-year bowel cancer survival. Patient groups, academics, policy and health system leaders will be able to gain insights about approaches that should be prioritised and what might be limiting progress. The research will pave the way for future work to understand if this learning is relevant to different types of cancer. As well as sharing findings in academic papers and at conferences, there will be regular and close collaboration with third sector organisations that represent patients with bowel cancer as well as lay representatives. Presentations with community groups as well as blogs, press releases and an informative report will be used to make sure the learning is shared widely and has a marked impact.",8.1 ORGANISATION AND DELIVERY OF SERVICES,CANCER AND NEOPLASMS HRCS22_20016,Cancer Research UK,CRUK,Recurrent somatic mutations in the cancerisation field effect of chronic liver disease,"Background Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. 90% of HCC develops in patients with chronic liver disease (CLD); the causes of CLD are changing, with rapidly rising obesity and type 2 diabetes driving non-alcoholic fatty liver disease (NAFLD). Patients with CLD form a clear at-risk population for HCC development, amenable to early detection. The liver in CLD is marked by a cancerisation field effect; the mechanistic basis of this is unknown. We hypothesised that it could be encoded at HCC-associated genomic loci. We used whole genome sequencing of non-malignant human CLD tissue, but did not find HCC-associated driver mutations. We identified recurrent somatic mutations in several disease-relevant genes, including FOXO1 (insulin and AMPK signalling) and ACVR2A (activin signalling), with evidence of convergent evolution in the same liver. Mutations in FOXO1 are at a single AMPK phospho-site and we have found that these mutations are functional. Aims We aim to understand the role of these recurrent somatic mutations in the cancerisation field effect of CLD, to understand HCC development. We hypothesise they will be: 1) Functional in diseased hepatocytes, leading to mechanistic insights into HCC pathogenesis; 2) Functional in mouse models of CLD, modulating development of HCC; 3) Identifiable in CLD patients, with potential as diagnostic and prognostic biomarkers. Methods In Work Package (WP) 1 we will develop novel in vitro models of these recurrent somatic mutations to understand the functional consequences of these mutations and why they provide a positive selective advantage to diseased hepatocytes. We will validate these findings in liver tissues from patients with CLD. In WP2 we will develop novel mouse models with mosaic hepatocyte-specific Foxo1[mut] knock-ins and Acvr2a-knock-outs to understand their effect upon normal liver biology, their role in the development of CLD and HCC tumorigenesis. We will study the effect of mutant hepatocytes upon surrounding hepatocytes, non-parenchymal cells and systemic metabolism. In WP3 we will develop novel assays identifying liver-derived recurrent somatic mutations in circulating cell-free DNA. We will use these assays in larger patient cohorts to understand their prognostic implications upon CLD and HCC development. How the results of this research will be used If successful, we will deliver: 1) A mechanistic understanding of recurrent somatic mutations in hepatocytes; 2) An understanding of the role of recurrent somatic mutations in mouse models of HCC development; 3) Novel assays to predict risk of HCC development in human CLD.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_22116,"National Centre for the Replacement, Refinement and Reduction of Animals in Research",NC3Rs,"Refining, reducing and replacing non-model amphibian experiments on amphibian infectious diseases","With the urgent conservation issue posed by infectious diseases, licensed experimental",,2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_02019,Medical Research Council,MRC,Regular as clockwork: the role of circadian rhythms in gut inflammation,"Inflammatory bowel disease (IBD) carries significant morbidity for 1% of the adult population. There is increasing evidence that circadian rhythms control chronic inflammation, although this has yet to be explicitly elucidated in gut inflammation. Aim 1: Assess the impact of colitis on the circadian clock The circadian clock temporally gates immune responses in the lung and joints. To determine the circadian clock's role in gut inflammation, samples will be collected from our mouse model of colitis at six time points across the circadian (24h) day and compared to healthy controls. I will characterise the extent of circadian dysfunction in colitis through analysis of clock function and gut inflammation at an RNA, protein and cellular level in addition to in vivo bioluminescent clock reporter technology. Aim 2: Determine the impact of targeted clock disruption on the host with colitis I predict that disruption of core clock genes will worsen the colitis phenotype. Bmal1 is a core clock gene that can be disrupted systemically or locally in cells of interest such as intestinal epithelial cells. The impact of clock gene disruption on the oscillating transcriptome in health and colitis will provide valuable information on the specific pathways and cell types involved in clock-driven inflammation in the gut. Aim 3: Determine whether time of day influences host response to IBD therapy Circadian expression of multiple drug targets has been shown in non-colon tissue. I will perform transcriptome analysis on healthy and inflamed colonic tissue to identify oscillations in drug targets. The group has previously shown colonic oscillations in gene expression of ppar-gamma, a drug target for the IBD therapy mesalazine. I will use mesalazine to treat the model of colitis at different time points, to coincide with peaks and troughs in PPAR-gamma expression and inflammation. In gastroenterology, this potential chronotherapeutic approach is entirely novel.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,ORAL AND GASTROINTESTINAL HRCS22_16986,Diabetes UK,,Relative contributions of fructose bisphosphatase-1 (FBP1) and other possible mediators to the antihyperglycaemic action of salicylate,"Repurposing’ studies utilising salicylate (SA) analogues with improved side effect profiles, such as salsalate, are on the cusp of achieving clinical use in type 2 diabetes (T2D) SA is one of few drugs believed to ameliorate insulin resistance, consequently SA has the potential by itself, or in support of people making lifestyle changes, to reverse/delay progression of T2D, associated complications, stress and anxiety. Clinical adoption of SA and selection of individuals for trial is hampered by incomplete understanding of drug mechanism. Recently, another T2D drug metformin, has been found to act through AMP-dependent regulation of fructose bisphosphatase-1 (FBP1) and it is possible that SA, through actions on the mitochondria, shares this action. To support properly targeted repurposing of SA, we will study the role of FBP1 in the SA mechanism, following the template established earlier for our award-winning studies on repurposing of metformin. The outcome will be to define FBP1-dependent and independent actions of SA on glucose uptake, glucose production, anti-inflammatory effects on tissues, including protective effects of SA on kidneys, which could support use of SA in T2D with kidney disease, where metformin is contraindicated. In future this information will enable selection of the individuals best suited to SA",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.1 PHARMACEUTICALS,METABOLIC AND ENDOCRINE HRCS22_03791,Medical Research Council,MRC,Reliable and Efficient Estimation of the Economic Value of medical Research (REEEVR),"Value of Information (VoI) analysis is not regularly used by healthcare research funders or the National Institute for Health and Care Excellence (NICE) due to high skill requirements and computational demands. Regression/approximation to estimate Expected Value of Partial Perfect Information (EVPPI) have reduced skill requirements but are only reliable for simple cost-effectiveness models (CEMs). We developed multilevel Monte Carlo (MLMC) to reliably estimate EVPPI, but must be implemented in programming languages such as R or C++, making it inaccessible to Microsoft Excel users. We will develop an online tool for reliable and efficient EVPPI estimation in four workstreams. Workstream 1 will assess the limits of approximation/regression for EVPPI by comparing with gold standard Monte Carlo estimation. We will explore decision tree and Markov CEMs with increasing structural complexity, parameter dimension/correlation, and number of decision options. Workstream 2 will develop software to convert Excel CEMs to R/C++, which works by 'crawling' over the eXtended Markup Language (XML) and Visual Basic scrips underlying Excel CEMs to re-express the net benefit function in R/C++. Example CEMs will come be provided by our partners at NICE and Source Health Economics. We will encourage community extension by making all code publicly available and providing thorough documentation. Workstream 3 will develop R/C++ code for running MLMC on generic R/C++ CEMs. Workstream 4 will package the conversion and MLMC software as an easy-to-use online tool. Based on user-supplied information on the CEM and the findings of workstream 1 our tool will recommend if MLMC is required or if regression/approximation are sufficient. These workstreams will be supplemented by a workstream collaborating with NICE and Source Health Economics to increase the use of our online EVPPI estimation tool, and a final workstream involving outreach to research funders to use VoI for research prioritisation.",,8.2 HEALTH AND WELFARE ECONOMICS,GENERIC HEALTH RELEVANCE HRCS22_05785,Department of Health and Social Care,NIHR,Remote Extra-clinic Monitoring of ADHD In the NHS (REMAIN) Study,"Research questions: Will an integrated multi-modal digital health monitoring system (DHMS), linked with electronic health records(EHR), improve the monitoring of treatment effectiveness and adverse effects in children with Attention Deficit Hyperactivity Disorder (ADHD)? Will it enhance long-term outcome evaluation for ADHD services? Background: Since the 1990's, use of UK ADHD stimulant medication has increased 34-fold, and is currently being prescribed to 1-in-200 children. Current management of ADHD is challenging: Overstretched NHS ADHD clinics cannot meet National guidance on clinical monitoring schedules. Data collection methods for monitoring treatment effectiveness and adverse effects rely on postal returns from teachers/parents, which are inefficient, provide low returns and hinder informed decision making. ADHD rating scales which assess intervention effectiveness are very subjective. Low inter-rater agreement is common, and susceptible to nocebo and placebo effects, which hinders safe and effective practice.Systematic reviews show that monitoring symptoms and adverse effects can be improved by online web-applications, and we have developed an online system called Me_health_e. ADHD rating subjectivity could be addressed using wearables to provide objective measures of activity and sleep, combined with online neuropsychological tests of attention and impulsivity. No NHS mental health services have integrated these approaches within a user-designed DHMS; the added benefits for these DHMS in assessing treatment effectiveness and safety above current approaches need clarifying. Objectives & timelines The main aim: To investigate if a user-designed DHMS can improve the quality of information available for monitoring treatment effectiveness and safety in childhood ADHD treatment? Objective - this will be addressed using five evolving workstreams (WS 1-5), incorporating research synthesis (WS1) qualitative (WS2,5), epidemiological (WS3-4) and computational techniques (WS3-4) WS1: Systematic review to understand the theoretical models and evaluate the most effective approaches to monitor symptom tracking and adverse outcomes in ADHD and other long-term paediatic conditions using DHMS. (months 1-6); WS2: Qualitative study to optimise the usability of ADHD symptom tracking and adverse effects monitoring. Bringing together multiple stakeholders (parents, children, academics, clinicians, engineers, NHS system engineers) to co-design, plan and implement changes to the objective measurement devices, Me_Health_e system and, and improve the feasibility of WS3 protocol (months 6-18) WS3: A prospective cohort study to examine the feasibility and drug target validity of symptom tracking and adverse effects monitoring in ADHD via adapted Me_Health_e and objective measurement systems (wearables and online neuropsychological performance tests) in non-clinic settings at home and school. (months 18-38). WS4: A data-linkage study to nest the WS3 cohort into EHR and linked school data to evaluate representativeness of WS3 cohort and their long-term outcomes (months 38-60).Impacts: Creation of the first validated DHMS for both subjective and objective data collection in home/school settings; ready for trial evaluation in the NHS to its test impact on ADHD treatment effectiveness, adherence and reduction of adverse effects. Cost-savings beyond improving ADHD outcomes, include reduce caregiver, teacher and clinician burden. Provides proof of principle of this DHMS as a secure NHS pipeline to enhance patient reported outcomes which can be readily extended to monitoring other long-term health conditions","One in twenty-five children have Attention Deficit Hyperactivity Disorder (ADHD). To receive a diagnosis, children need to have severe and chronic problems with inattention, impulsivity and hyperactivity, both at school and home. These problems are debilitating, and studies have shown they can dramatically affect people throughout their life: preventing them doing well at school, holding down friendships, and later on, jobs, relationships, and maintaining their health. Medication can help. Nearly half of children diagnosed with ADHD in NHS child and adolescent mental health services (CAMHS) are offered medication at primary school age. They work by reducing the main symptoms of ADHD. However, when children start medications, specialist CAMHS doctors need to monitor carefully how well a child responds. Each child is different. If doctors prescribe too much ADHD medication or increase doses too quickly, side-effects like poor sleep, poor appetite, headaches, and mood changes can make things worse. Give too little, or too slow, a child's ADHD symptoms and their difficulties remain. There are several major problems with how ADHD is managed. Current ways of checking for side-effects or whether the medication works are too awkward to use efficiently. The NHS aims to be paperless, but parents and teachers are often asked to fill out paper-based questionnaires via the post. These rarely get back to the doctor and enter a child's health record. This creates difficulties, as doctors need this information to check medications are working. National guidance recommends regular questionnaire checks, and appointments when starting ADHD medications. Doctors say everyone is too overstretched to meet these recommendations. Another problem is that teachers and parents assess the same children differently, and disagree about what behaviours are due to a child's ADHD symptoms. For doctors, these disagreements make prescribing the right dose difficult, as they cannot determine who may be more accurate. Finally, clinicians and family want to know that ADHD treatments help their child later on. Information is not collected once children leave NHS care, so clinical services cannot show parents that their treatment can make long-term differences at school or home. I am proposing a research project which tackles these issues using digital technologies. The REMAIN study will build and test an innovative digital system which aims to make completing questionnaires on ADHD symptoms and medication side-effects much easier. It also tests whether wrist-based activity trackers(wearables) and online attention tests, provide a better way of checking medication effects. To ensure the digital systems I develop, are engaging and user-friendly, this study will put specialist healthcare designers alongside children with ADHD, caregivers, clinicians, teachers, data-scientists to try and create the most user-friendly health monitoring system in the NHS. We will all work together to select the best features home/school based online ADHD system; finding the ideal way to integrate online-questionnaires, wearable and online psychological tests. After this, I will build the system using commercial partners, who specialise in tech development within these areas. I will then test whether the system works in NHS practice. I will recruit families with children with ADHD before they start medications, and see whether families and doctors like using the new system. I will test the activity and attention data to see whether it changes as we would expect during medication increases. I will then link this information electronic health records, hospital and education record to see whether it can help us understand the effect of ADHD treatments over the long-term.If by the end of this fellowship, I aim to be ready to test the digital system in randomised trial, and eventually offer it across the NHS.",6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),MENTAL HEALTH HRCS22_03123,Medical Research Council,MRC,Removing the marketing power of cigarettes: A multi-method study aimed at protecting the health of adolescents in Latin America,"Flavoured cigarettes may encourage young people to try smoking, start to smoke or continue to smoke. Growing market share for flavoured cigarettes in many Latin American countries is due to 'capsule cigarettes', which have frangible capsules in the filter that can be burst to change the flavour. There is limited research on capsule cigarettes, even though they appeal to youth and are a potential route into starting or continuing to smoke. In response to the growing importance of the cigarette stick as a promotional tool for tobacco companies, researchers have begun to explore ways of making the cigarette stick 'dissuasive', for instance by including health messaging and/or making it an unappealing colour. Our objectives are to understand: 1) how tobacco companies' market flavoured cigarettes in Latin America and the impact these have on the adolescent smoking attitudes, intentions, and behaviours, and 2) whether dissuasive cigarettes may deter adolescents from smoking. Three interlinked studies will be conducted in four Latin American countries where flavoured cigarettes have high market share (Argentina, Guatemala, Mexico and Peru). Each study will be conducted in the same four urban and rural locations in each country. In Study 1, we will use a codebook to record how flavoured cigarettes are promoted in retail outlets and via the cigarette pack and stick, and whether single cigarettes are sold. Study 2 will involve focus groups with adolescent smokers and non-smokers to explore their thoughts on flavoured and dissuasive cigarettes. Study 3 will use school surveys with an embedded discrete choice experimental design to assess whether cigarette stick design can influence the desirability of, and interest in, smoking. We will engage with our project partners, which include regional networks and the Ministries of Health in each country, and other key stakeholders, to help us interpret the results, refine a communication plan, and ensure the results are widely shared.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,CANCER AND NEOPLASMS;CARDIOVASCULAR;RESPIRATORY;STROKE HRCS22_02542,Medical Research Council,MRC,Replication-dependent histone pre-mRNA misprocessing and innate immune sensing,"Most antiviral responses are initiated by innate immune receptors that detect viral nucleic acid. Since the basic molecular structure of DNA and RNA is conserved across species, the existence of such receptors implies the necessity for mechanisms to avoid the sensing of self nucleic acids as non-self. The monogenic type I interferonopathies, disorders associated with enhanced type I interferon signalling where such signalling is considered central to pathogenesis, emphasize the fundamental importance of nucleic acid signalling in the induction of type I interferon, and highlight the risks to human health of nucleic acid sensing as an antiviral strategy. One way to avoid a situation of type I interferon-mediated autoinflammation is to physically separate self nucleic acids from viral nucleic acid sensors. Thus, it was previously considered that the double stranded (ds) DNA sensor cyclic GMP-AMP synthase, cGAS, was exclusively confined to the cytosol. However, in a surprising recent finding, it has been shown that cGAS can be found within the nucleus, begging the question as to how genomic DNA does not trigger a potent type I interferon response. The present study builds on an observation that we have made, suggesting that chronic type I interferon activation can occur due to a disturbance of histone protein stoichiometry, and consequent abnormalities in chromatin state. As a corollary of this, we suggest that histones play an essential role in rendering nuclear DNA non-immunogenic. The overall goal of our proposal is to understand how a disturbance of chromatin histone composition leads to engagement of the type I interferon signalling machinery. To do this, we will take advantage of a unique patient resource, acquired over almost two decades. Additionally, we will derive a series of cellular tools that we can use to interrogate this question.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_01222,Medical Research Council,MRC,Reproductive and cardio-metabolic health,"Our aim is to provide the evidence base that will improve treatment success with IVF and enable stratified and effective antenatal care in IVF and spontaneous conceptions (SC). This is important because up to 40% or pregnancies are affected by one or more of miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, preterm birth or delivery or a small or large for gestational aged infant, but we do not know the best way of preventing these. IVF is now the commonest treatment for infertility with >250K IVF cycles completed per year in the UK and on average 1 in 30 primary school children were born as a result of in vitro fertilisation (IVF). Success rates vary by couple and treatment characteristics but are between 20-30%. There are suggestions that IVF per se, and pregnancy complications in IVF and SC have important adverse effects on future offspring cardio-metabolic health, but whether these associations are causal and if so their magnitude is unclear. Our objectives are to accurately predict and identify causal paths for: (i) response to IVF; (ii) healthy pregnancy and perinatal outcomes in IVF and SC; and (iii) offspring cardio-metabolic health. Methods Our focus will primarily be on maternal smoking, physical activity, sleep patterns, adiposity, pregnancy metabolic profiles and fetal (cord-blood) DNA methylation as potential predictors or risk factors. We will use data from detailed clinical and general pregnancy/birth cohorts. We will work with relevant consortia, including the EuroCHILD pan-European birth cohort that we are involved in establishing from 26 existing cohorts, early growth genetics (EGG) consortia, in which we co-lead maternal-offspring genetic analyses, the Genetics of Diabetes In Pregnancy (GENdip) consortia that we have recently developed, and the pregnancy/birth cohorts working group aligned to the Consortia Of METabolomics Studies (COMETS), which we lead, as well as the Pregnancy And Child Epigenetics (PACE) consortia, which we work closely with alongside Relton’s MRC Integrative Epidemiology Unit programme. We will triangulate results across the following analytical methods applied to these data sources: multivariable regression (MV), Mendelian randomization (MR), non-genetic instrumental variable (IV) analyses, within sibship and negative control studies. Translation Building on our successful impact on clinical guidelines in the first five-years of this programme, we will continue to work with relevant clinicians, patient groups and NICE guideline developers. For new methodological developments we will provide and share datasets and code and widely disseminate these.",,"2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION",REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_03017,Medical Research Council,MRC,Reproductive function in teenage and young adult cancer patients in the UK,"The care of cancer patients increasingly recognises the multimorbidity that may result from treatment. Loss of fertility is a prominent concern among patients, and while most do not lose their fertility, prediction at an individual level is difficult except at extremes of risk, and information on new treatments is very scarce. We will undertake a prospective analysis in teenage and young adult (TYA) male and female patients using the National Cancer Research Institute (NCRI)-linked network of treatment centres to address our hypothesis that cancer treatment and age affect fertility-related biomarkers and long-term reproductive health. This will generate an assessment of post-recovery reproductive function following contemporaneous and emerging treatment regimens, and prediction of that risk in individuals and patient groups. The primary endpoint is the prevalence of gonadal failure or dysfunction by diagnosis and treatment regimen at 2 years after diagnosis, with secondary longer-term outcomes. To determine this, we will recruit patients before starting treatment, and collect blood samples for endocrine analysis of gonadal function at that time, with detailed treatment data. Additional samples will be collected at 1, 2 and 3 years after diagnosis. We will recruit patients at presentation with a new cancer diagnosis, and also recruit patients previously treated who now present with a relapse. This will increase the proportion of likely high-risk therapies and treatments with novel targeted therapies, on which there are currently minimal data relating to reproductive effects. The prospective design of the study allows for detection and adjustment for previous gonadal toxicity.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_18888,Versus Arthritis,,Reprogramming resolution in the arthritic joint,"‘…maximise the value of human tissue samples and resources while minimising duplication of effort. This requires better characterisation of tissue samples…and increased linkage to accurate clinical data. Sample collections must then be made more easily discoverable and accessible for use in high quality, ethical research’. To achieve this vision the Funders have highlighted the need for systems to make collections discoverable (Action 9). It also recognised the need for increased harmonisation of collection and storage of samples and the importance of public engagement around tissue donation for research.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_03063,Medical Research Council,MRC,Repurposing approved drugs as potent antiviral combinations to treat COVID-19 disease,"We hypothesise that antiviral drug combinations against SARS-CoV-2, suitable for oral or intranasal administration, will provide therapeutic opportunities for ambulatory COVID-19 patients that are more efficacious and with less propensity for the development of drug-resistant mutants. We will address this hypothesis by exploiting a comprehensive robust multi-step pre-clinical in vitro and in vivo testing platform for novel drug combinations that ranges from HTS screening of unbiased combinations of drugs with known antiviral activities against SARS-CoV-2 and pharmacometrics to ensure potential for human use, to therapeutic efficacy models in SARS-CoV-2-infected well-differentiated primary human airway epithelial cell cultures (WD-PAECs) and animals (Syrian golden hamsters and hACE2 mice) with the most promising combination drug hits. Promising hits will be subjected to antiviral screening against a panel of variants of concern (VOCs) and endogenously circulating coronaviruses to ensure broad activity against SARS-CoV-2 VOCs and the potential for pan-CoV antiviral activities. We will extend this testing platform to non-biased screening of extensive approved drug libraries that have not previously been mined for drug combinations to treat COVID-19 with a view to ensuring a pipeline of future therapies against SARS-CoV-2. It should also be noted that we will make our pipeline available to the UK-CTAP to make recommendations for candidate evaluation. For this, a candidate/combination could enter evaluation at any WP that is appropriate given data that are available at the time. This project will provide comprehensive data to enable robust decision making regarding the entry of combination antiviral drugs hits into the UK COVID-19 clinical trial platforms or the de-prioritisation of drugs from further development.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS,INFECTION HRCS22_03900,Medical Research Council,MRC,Research and Training to create assets in the form of new companies to develop a new model to generate innovative therapies,"Cancer is an evolution machine. Decades before diagnosis, a multitude of different clones, carrying differential sets of mutations are setting the scene that makes almost any targeted therapy obsolete. The new era of personalised medicine and of immense knowledge of the genetics, epigenetics, gene expression, metabolomics, and clonal evolution of tumours, converges with the completion of flagship synthetic lethality studies, interrogating pan-cancer functional genomics. However, target discovery still focuses on finding targeted therapies against well-established cancer drivers from which cancer has already evolved out of, even years before diagnosis. This results in limited response rates in the clinic and quick evolution of resistance for targets against such drivers for example BRCA targeted PARP inhibitors. Our Approach: We are stopping the chase for moving targets by building a highly advanced drug discovery machine, that leverages the wealth of data of this new era to identify vulnerable mechanisms that cancer cannot evolve out of and the specific context in which they are effective. To achieve that, we identify cancer systems biology and specific mechanisms of irreversible cancer dependencies through advanced computational methods. Our current approach sets the bar very high, to produce complete and sustained therapeutic responses. We have invented methods that have already produced potential candidates with strong independent validation.My role will be to start as a Founder Analyst within DeepScienceVentures under their unique framework for venture creation. It's a part-time role. As a secondee, my goal is to join the host institution to create a company that will bring novel curative therapies to cancer patients. In order to make this successful, I will apply my skills sets of machine learning/artificial intelligence, understanding heterogeneity, developing patient based biomarkers and hands-on experience in preclinical trials.",,5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),GENERIC HEALTH RELEVANCE HRCS22_05253,Department of Health and Social Care,NIHR,Research to Improve the Detection and Treatment of Latent Tuberculosis Infection (RID-TB),"Aims and objectives: We will identify the factors influencing uptake of latent TB infection (LTBI) testing and completion of treatment among migrants entering the UK, develop materials to communicate and support LTBI testing and treatment interventions, evaluate the effectiveness and cost-effectiveness of a new Mycobacterium tuberculosis RD1-specific C-Tb skin test compared to interferon-gamma release-assay (IGRA) and assess the effectiveness and cost-effectiveness of a 12-dose rifapentine-based regimen with and without adherence support compared to current standard of care. Background: Following declines in the incidence of tuberculosis (TB) during the 20th century, there was a resurgence of the disease in England from the late 1980s to 2005. Consequently, NHS England and Public Health England (PHE) launched a strategy in 2015 to bring about a sustained decline with screening for latent TB infection (LTBI) as a funded element of the plan. LTBI testing and treatment reduces tuberculosis incidence by preventing reactivation, and is expected to create a cost saving to the NHS after about five years (NHS England). However, high rates of testing, treatment uptake and treatment completion are essential prerequisites to accrue these benefits. Research plan: In this 5-year programme of research, we have designed studies to improve access to diagnosis and enhance treatment uptake and completion in individuals with or at risk of LTBI. Through four interrelated workpackages conducted in parallel, we will combine a behavioural science theory-based approach together with clinical trials, health economics and modelling to assess interventions designed to support uptake of testing and treatment, and treatment completion. Studies will be conducted in high-volume primary and secondary care settings that are part of the LTBI screening programme in London. Workpackage 1 focuses on diagnostics. Study 1 will assess the diagnostic performance (concordance, sensitivity, specificity and predictive values) of the C-Tb test against the IGRA (the current standard of care). A minimum of 692 IGRA-tested individuals are required to provide 90% power to demonstrate C-Tb sensitivity and specificity against IGRA to within 5% of 94% accuracy. Study 2 will be a pragmatic randomised controlled trial (RCT) to assess C-Tb use within the NHS. Impact will be measured by comparing the proportion of patients who begin LTBI treatment after a positive C-Tb result to the proportion starting treatment after a positive IGRA. 400 individuals per arm are required in Study 2 to demonstrate non-inferiority of tests with 90% power, at 10% delta, assuming 60% attendance for treatment per arm and 5% one-sided alpha. Workpackage 2 will focus on behavioural science using mixed-methods. This will include qualitative work exploring people s experiences of LTBI testing (workpackage 1) and treatment (workpackage 3), including reasons for declining either or both of these, and quantitative assessments using validated measures of beliefs around illness and treatment. Through a process of co-creation, we will iteratively develop educational materials aimed at identified perceptual barriers to uptake and completion of testing and treatment. Workpackage 3 will address adherence and treatment completion. In a pragmatic, four-arm RCT, we will trial two interventions, alone and in combination, in comparison to standard care: a novel 12-dose weekly rifapentine/isoniazid LTBI treatment regimen vs. the standard daily rifampicin/isoniazid for 12 weeks, both with and without a novel adherence support intervention. 600 individuals will enable detection of an increase of at least 20% in any of the intervention arms (pairwise comparisons) with 90% power, assuming 5% significance 2-sided. Adherence support will comprise an electronic medication monitor reminder box (which also measures adherence) and educational materials developed in Workpackage 2 (see above). Workpackage 4 will employ economic analysis to calculate if changes to diagnosis and/or treatment are cost-effective. An integrated transmission-dynamic health-economic model will synthesise data obtained within the RID-TB programme and evidence from sources including the scientific literature, census data and life-tables from national statistics, the LTBI/TB screening and TB surveillance data. The model will consider different age-groups, and different social/ethnic groups, subdivided into UK-born and foreign-born individuals, which can differ in their size, age-structure, rates of migration, rates of occurrence of latent and active TB, and in the patterns of social mixing within and between different groups that affect TB transmission rates. This will allow estimation of the long-term, national-level benefits of the studied interventions. Projected outputs: Our patient and public involvement network will facilitate dissemination of findings and educational materials to groups most affected by LTBI. Co-applicants include senior staff at PHE, who are well-placed to ensure that study results are considered in national policy. We will present to clinicians and researchers at national and international conferences, and publish in open-access peer-reviewed journals. Benefits to patients and the NHS: If successful, these novel interventions will improve uptake and completion of LTBI treatment; if cost-effective, they will save the NHS money. Benefits would arise from reduced risk of developing active TB for individuals, and reduced risk of onward transmission in the population.","Background: The number of tuberculosis (TB) cases in the UK has increased over the past three decades, and remains high despite a recent decline. There were over 6,000 cases in 2016. The UK has the second highest rate of TB in Western Europe and four times that of the US. NHS England and Public Health England (PHE) have published a national TB strategy, which recommends testing new migrants entering the UK from countries where TB disease and latent TB infection (LTBI) are common. Someone has LTBI if they are infected with Mycobacterium tuberculosis but do not have signs of active disease. Around a third of immigrants to the UK from countries where TB is common may have LTBI. This is important because LTBI can later progress to active disease, making the person ill and putting them at risk of passing the infection to other people. This can be avoided by treating people who have LTBI, but it can be difficult to ensure they are diagnosed and supported to take treatment. We will investigate approaches to improve how these measures are delivered. Testing: In 2011 national guidelines stated that a blood test for LTBI provided good value for money. However, more recent analysis suggests that a skin test (tuberculin skin test, TST) may be better value. Currently the LTBI screening programme uses blood tests, called interferon-gamma release assays (IGRA). The TST may not always correctly identify who has LTBI as reliably as IGRA. This can lead to unnecessary treatment if results are falsely positive. There is now a new skin test available, called C-Tb, which research suggests is as good as IGRA in correctly identifying LTBI. We propose to compare the C-Tb test to IGRA to see whether it is more accurate, easier to obtain a diagnosis, and offers better value for money for the NHS as part of the national migrant-screening programme. We will also do research to understand what people think of C-Tb, and their experience of testing for LTBI. Treatment: Only between one-third-to-two-thirds of people offered LTBI treatment take it. We will do research to understand why people agree to be tested and treated, and what factors stop them. This will allow us to develop support materials that help people complete treatment. We will also assess whether people are more likely to complete treatment if it consists of weekly tablets rather than the current approach of using daily tablets. We will do this comparison with and without the support materials, so that we can tell how well they also work. We will assess the value for money of each intervention. Our team has the skills needed to undertake this research including patients, scientists, NHS managers and policy experts.",7.1 INDIVIDUAL CARE NEEDS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,INFECTION HRCS22_06565,Department of Health and Social Care,NIHR,Responding to people in danger. A development and feasibility study to co-develop a community pharmacy response service for domestic abuse and suicidal ideation.,"Aim - This project aims to develop and test the feasibility of a service for people in danger from either domestic abuse or suicide, to access help through community pharmacies. _x000D_ _x000D_ Background - The current COVID-19 situation has increased the number of people feeling suicidal, and has increased domestic abuse. Both of these situations are distressing and can be fatal. However, these deaths are preventable, and harm can be minimised, if people are able to access timely and appropriate help. _x000D_ _x000D_ Community pharmacies are known to be highly accessible, with long opening hours and no requirement for an appointment. Due to the distressing nature of these issues, we aim to make the service as discreet as possible. Discussions with members of the public has indicated that a name with an analogy may help to make it discreet. There has been a positive response to an initial suggestion of using the analogy of a lifeguard and life-ring. The details of how the service would work, the training and service resources and a promotional strategy will be co-developed in the first stage of the project. _x000D_ _x000D_ Design and methods used - In phase one, we will hold 8 interviews with local experts, 2 lay focus groups and 3 development workshops with members of the public and pharmacy staff. Through these activities we will develop the name, concept, design and resources for the new service. Resources will include developing a clinical assessment and referral tool, and a training package for the pharmacy staff that will deliver the service. _x000D_ _x000D_ In phase two, we will launch the service to 8 pharmacies across Lincolnshire. The service will be promoted in local community venues. We will train 3 members of staff from each of the 8 pharmacies in the scheme. We will collect data on the usage of the service and on the number of referrals made. We will also collect data from 4 pharmacies who will not be using the service, as a control. _x000D_ _x000D_ We will need to know if the proposed service is successful and if there is a favourable opinion of the service from members of the public, the pharmacy staff, and the organsiations that accept referrals. We will assess this by holding interviews with 3 customers and the staff in each of the pharmacies that took part. We will conduct an e-survey in local communities. We will finish with a summary workshop with the pharmacy staff and members of our public and patient panel. By working together, we aim to develop a user-friendly service to offer safety and support to people in danger. _x000D_ _x000D_ Public and patient involvement - It is important to us that the views of the public and patients are taken into account in the design of this service. Our proposal is based on consultation with members of the public and relevant organisations. A diverse panel of members of the public has been set up to work with the researchers throughout the project to give their views. _x000D_ _x000D_ Dissemination – If the study finds that the proposed service is successful, it may lead to a larger research trial for further testing. This has the potential to become a widespread service through community pharmacies. The concept of the service, and the results from the study will be actively promoted to relevant organisations and the public, plus publications.","Research question_x000D_ How feasible and acceptable is a co-produced community pharmacy response intervention for identifying and referring people in danger from suicidal ideation or domestic abuse? _x000D_ _x000D_ Background_x000D_ The effects of the COVID-19 pandemic have worsened the incidences of suicidal ideation (SI) and domestic abuse (DA). Barriers to care for people experiencing DA and SI include: capacity, psychological burden, timing and level of severity. This intervention addresses these barriers by developing a discreet response service for people in danger through community pharmacy. Pharmacies offer long opening hours and access without an appointment. This will allow more people in need to access appropriate and timely care. _x000D_ _x000D_ Aim: To co-develop and evaluate the feasibility of a community pharmacy response intervention for people in danger from DA or SI._x000D_ _x000D_ Objectives: _x000D_ 1.To develop a point of contact and triage referral resource in partnership with relevant experts and local referral organisations, for both DA and SI._x000D_ _x000D_ 2.To co-develop with patients / public and professionals the scope and features of a discreet response intervention in community pharmacy, to include the name, logo, promotional strategy and protocol for delivery in a pharmacy._x000D_ _x000D_ 3.To co-develop with patients / public and professionals a training package and mentoring support service for pharmacy staff delivering the intervention._x000D_ _x000D_ 4.To deliver the intervention in a purposive sample of community pharmacies and collect feasibility data on intervention usage and consequent referrals._x000D_ _x000D_ 5.To ascertain and evaluate client, public and professional views on accessibility, acceptability, implementation, feasibility and intervention fidelity in practice._x000D_ _x000D_ 6.To evaluate the potential for the intervention to be scaled up for a future trial, including economic and statistical considerations._x000D_ _x000D_ 7.To engage with the public and professionals to disseminate findings and reporting of the intervention as an output. _x000D_ _x000D_ Methods_x000D_ This study will co-develop and evaluate the feasibility of an intervention in community pharmacies to respond to people in danger from either SI or DA, with parallel engagement of a steering group and PPI panel. _x000D_ _x000D_ Development - Qualitative interviews will be held with 8 representatives from referral organisations, followed by 2 lay focus groups and 3 co-production workshops with 8 lay people and 4 pharmacy staff in each workshop. _x000D_ _x000D_ Feasibility - Purposive sampling will be used to recruit 8 intervention and 4 control pharmacies, based on rural or urban location, sole pharmacy or co-located. The pharmacies will then be randomised to give 8 intervention and 4 control pharmacies. 3 members of staff from each intervention pharmacy will be trained, followed by implementation of the intervention. Service use and referral data will be collected from the intervention pharmacies, and data on requests for assistance from control pharmacies over 6 months. Public acceptability will be measured using an e-survey and interviews with 3 customers per intervention pharmacy. A feasibility workshop will be held with the 24 intervention participants, steering and PPI group. _x000D_ _x000D_ Timelines for delivery: 6 months development, 9 months implementation, 9 months evaluation. _x000D_ _x000D_ Anticipated impact and dissemination_x000D_ The findings will be actively disseminated to the public, stakeholders and research community. This study will inform a future cluster randomised trial",8.1 ORGANISATION AND DELIVERY OF SERVICES,MENTAL HEALTH;DISPUTED AETIOLOGY AND OTHER HRCS22_19058,Cancer Research UK,CRUK,Restoring response to immunotherapy by targeting the extracellular matrix,"Background Patients with cancer that respond to immunotherapy benefit from prolonged progression free survival. Response rates vary across cancer types, with solid carcinomas generally being the poorest at between 10-20 %. Understanding the differences between responders (the 10-20%) and non-responders (the 80-90%) could identify ways to improve response rates. Targeting tumour extracellular matrix (ECM) can restore immune cell infiltration into tumour and response to immunotherapy in preclinical models. However, tumour ECM is also a protective barrier to disease progression. Therefore, targeting specific ECM components may restore immune cell infiltration without removing the barrier. We conducted a multi-level characterisation of a tumour microenvironment and identified a ECM signature, the matrix index (MI), that is prognostic in thirteen different human cancers and associates with immunosuppressive phenotypes. Moreover, my preliminary data suggest that MI molecules have altered structure in disease. I hypothesise that these disease forms of MI molecules block immune cell infiltration and therefore targeting them may improve cancer immunity. Aims The central aim is to improve cancer immunity by targeting MI molecules. The project focuses on triple negative breast cancer, where the MI is an especially strong feature. We will: • Determine which cells contribute MI molecules in the tumour microenvironment, and characterize disease forms of MI molecules, to identify targetable structural motifs. • Identify tissue areas where one or more MI molecule correlates with T-cell exclusion from tumour parenchyma. • Determine which MI molecule(s) and structural motifs are most important in immune cell migration. • Test inhibiting MI molecules as a way to improve immunotherapy responsiveness. Methods MI molecules from patient tissues and cells will be characterized using a combination of transcriptomics and our unique tissue proteomic and glycomic pipelines. Imaging mass cytometry will be used to construct a matrix-immunity map. Engineered 3D tissue models will be used to investigate immune cell trafficking within altered tumour ECMs. Murine models which recapitulate low immune infiltrate will be used to test targeting MI molecules to restore responsiveness to immunotherapy. How the results will be used These results will help explain why many patients do not respond to immunotherapy. This may help clinical selection of patients most likely to respond to immunotherapy, and be used to inform the development of ECM targeted therapies. ECM characterization and target data acquired though our analysis pipeline will be made publicly available through our dedicated tumour microenvironment website (www.canbuild.org.uk).","Background Patients with cancer that respond to immunotherapy benefit from prolonged progression free survival. Response rates vary across cancer types, with solid carcinomas generally being the poorest at between 10-20 %. Understanding the differences between responders (the 10-20%) and non-responders (the 80-90%) could identify ways to improve response rates. Targeting tumour extracellular matrix (ECM) can restore immune cell infiltration into tumour and response to immunotherapy in preclinical models. However, tumour ECM is also a protective barrier to disease progression. Therefore, targeting specific ECM components may restore immune cell infiltration without removing the barrier. We conducted a multi-level characterisation of a tumour microenvironment and identified a ECM signature, the matrix index (MI), that is prognostic in thirteen different human cancers and associates with immunosuppressive phenotypes. Moreover, my preliminary data suggest that MI molecules have altered structure in disease. I hypothesise that these disease forms of MI molecules block immune cell infiltration and therefore targeting them may improve cancer immunity. Aims The central aim is to improve cancer immunity by targeting MI molecules. The project focuses on triple negative breast cancer, where the MI is an especially strong feature. We will: • Determine which cells contribute MI molecules in the tumour microenvironment, and characterize disease forms of MI molecules, to identify targetable structural motifs. • Identify tissue areas where one or more MI molecule correlates with T-cell exclusion from tumour parenchyma. • Determine which MI molecule(s) and structural motifs are most important in immune cell migration. • Test inhibiting MI molecules as a way to improve immunotherapy responsiveness. Methods MI molecules from patient tissues and cells will be characterized using a combination of transcriptomics and our unique tissue proteomic and glycomic pipelines. Imaging mass cytometry will be used to construct a matrix-immunity map. Engineered 3D tissue models will be used to investigate immune cell trafficking within altered tumour ECMs. Murine models which recapitulate low immune infiltrate will be used to test targeting MI molecules to restore responsiveness to immunotherapy. How the results will be used These results will help explain why many patients do not respond to immunotherapy. This may help clinical selection of patients most likely to respond to immunotherapy, and be used to inform the development of ECM targeted therapies. ECM characterization and target data acquired though our analysis pipeline will be made publicly available through our dedicated tumour microenvironment website (www.canbuild.org.uk).",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_23180,The British Academy,,Rethinking Wellbeing: Evaluating the Neoliberalisation of Wellbeing in the Workplace Using Artworks as a Critical Lens,"Workplace wellbeing programmes have increasingly become a central part of work and organisational life within a neoliberal economy, offering solutions to stressful working environments and the challenge of maintaining good physical and mental health. Yet how is wellbeing to be appraised when organisational austerity measures and modern efficient management approaches lead to a lack of wellbeing? This confuses the centrality of the idea of wellbeing as something critical to life with ‘wellbeing’ as an imposed free-market enterprise motivated by profit and productivity. By examining how contemporary artists critique the obsession with performance and quantification within neoliberal organisations, this interdisciplinary project will assess this confusion in a new way. It will evaluate how different aspects of neoliberalism have appropriated wellbeing, by demonstrating how art adds a much needed complexity to the debate around Positive Psychology and self-optimisation in the workplace.",,1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),GENERIC HEALTH RELEVANCE;MENTAL HEALTH HRCS22_02085,Medical Research Council,MRC,Retinoic acid metabolism blocking agents (RAMBAs) to treat hand osteoarthritis,"Pathogenesis of osteoarthritis (OA) remains poorly understood, but there is a general consensus that mechanical load and inflammatory signalling drives tissue catabolism. Hand OA has strong genetic heritability. A recent GWAS identified common polymorphic variants in ALDH1A2 in individuals with severe hand OA. ALDH1A2 codes for the enzyme that is responsible for synthesising retinoic acid. We have shown experimentally that retinoic acid levels drop dramatically in response to mechanical injury of cartilage and maintaining levels of retinoic acid in the chondrocyte at the time of injury with talarozole, a retinoic acid metabolism blocking agent (RAMBA), prevents the up-regulation of injury-driven inflammatory response genes. We have also confirmed this reciprocal relationship in patient tissues by showing that the articular cartilage (removed at time of hand surgery) of individuals homozygous for the high-risk variants had significantly lower levels of ALDH1A2 mRNA and other retinoic acid-dependent genes, whereas key inflammatory genes were increased in these individuals. In this project we hypothesise that talarozole, by blocking breakdown of retinoic acid, will enhance retinoic acid-responsive genes and suppress OA chondrocyte inflammatory genes in hand OA. We will conduct a randomised, placebo controlled study of talarozole in 44 patients immediately prior to planned surgery for base of thumb OA. Primary outcome will be mRNA levels for a panel of retinoic acid and inflammatory response genes. This study will (i) provide evidence as to whether systemic administration of this class of drug is able to penetrate the joint and modify the retinoic acid pathway in human chondrocytes in vivo; (ii) establish whether augmenting retinoic acid can suppress chondrocyte inflammatory gene regulation in hand OA as a pre-requisite for suppressing pain and degeneration; (iii) provide preliminary data that will be used to design a full clinical trial of a RAMBA in hand OA.",,6.1 PHARMACEUTICALS,INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL HRCS22_19421,Versus Arthritis,,"Rivaroxaban versus warfarin for stroke patients with antiphospholipid syndrome, with or without SLE (RISAPS): a randomised, controlled, phase II/III, non-inferiority trial","Thrombotic antiphospholipid syndrome (APS), a serious and potentially fatal complication of systemic lupus erythematosus (SLE), is a recognised cause of ischaemic stroke or progressive cognitive impairment, in part due to recurrent cerebral infarction or progression of cerebral white matter hyperintensities (WMH) of presumed vascular origin, on magnetic resonance imaging (MRI). Prevention of stroke is an NHS priority. The current mainstay of the treatment of thrombotic APS is anticoagulation with warfarin, which has many limitations. We propose a phase II/III randomised controlled trial of rivaroxaban in APS stroke patients, with or without SLE, to assess the efficacy of rivaroxaban for the secondary prevention of stroke in these patients. The primary outcome measure will be the rate of change in brain WMH volume on MRI, a surrogate marker of brain vascular tissue damage, as recurrent strokes in APS patients are rare because of effective anticoagulation. Other brain MRI biomarkers, clinical efficacy (thrombotic events), safety (serious adverse events and all bleeding events), the rate of change in cognitive function and quality of life will also be assessed. In addition a Health Economic evaluation will be undertaken. This study should enable identification of the optimal anticoagulation in stroke patients with APS/SLE and thus improved patient care.",,6.1 PHARMACEUTICALS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_03202,Medical Research Council,MRC,Robotics to enhance independence & safety for dementia patients in the home,"The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added from 2020. Interactive ‘social’ robots have laboratory established capacity used to engage and stimulate people living with dementia. They can: (a) undertake diverse behaviours; (b) collect rich data; (c) change the environment and (d) respond appropriately in a flexible, task-dependent manner. They provide a way to continuously monitor the home and engage with people to support behaviour or to provide companionship. However, their clinical potential is untapped and development of robotics for dementia care is at an early stage. We will develop an automated ‘family’ of robotic devices focusing on improving safety in the home and enhancing the quality of life for a person living with dementia. The robotic devices will be designed to be safe, accessible and enjoyable to engage with. A design sprint will be used to define key features and functionality. The team will develop a small number of exemplars providing proof-of-principle. For example, they will develop robotic systems to respond to (a) environmental alerts produced by the Healthy Home (e.g. noting a kitchen spillage or cooker left on); and (b) alerts related to the person with dementia (e.g. responding to signs of agitation or injury). Following an alert, the robot device will engage with the individuals and, guided by information from a smart environment, will act to reduce risks. The simplest solution may be to direct the owner (help to clean a spillage), but it may be possible to deploy automated tools to achieve similar ends. In the case of agitation, for example,, if a cause can be identified such as confusion simple interventions may be effective and interactions through a conversational agent or social robot may be directly beneficial. A related focus for the programme will be to develop effective methods of communication between people with dementia and robotic devices. The design process will evaluate the impact of variations in features such as configurable visual appearance, voice characteristics, movement, and tactile features that are optimal for the individuals involved, and the team will produce ‘lightweight’ prototypes for testing purposes.). Main objectives include 1. To produce robotic devices with elementary AI that are capable of interacting with people living with dementia. 2. To integrate robotic devices within smart living environments to monitor and manage the environment for improved safety and quality of life. 3. Draw from user-centred design to define the characteristics of robotic devices suitable for these tasks",,5.3 MEDICAL DEVICES,NEUROLOGICAL HRCS22_10799,Engineering and Physical Sciences Research Council,EPSRC,Robust manufacturable antibacterial surfaces enabled by superhard plasmon-enhanced photocatalytic materials.,"Untreatable infections are one of the biggest modern-day dangers to society, which the current SARS-CoV-2 pandemic has highlighted. The development of antibiotics has been one of the major medical successes of the last 100 years. However, the capacity of pathogens to evolve and acquire resistance to new antibiotics makes their effectiveness necessarily precarious. Meanwhile, studies on the spread of drug-resistant pathogens such as MRSA, respiratory syncytial virus, norovirus and CoVID-19 suggest that surfaces are a major point of transmission with CoVID-19 remaining infectious on plastic and stainless steel surfaces for up to 6 days. Surfaces with an antimicrobial function that avoid or minimise the use of antibiotics whilst maintaining good efficacy after prolonged use are critically needed in hospitals, living spaces, and on biomedical implants, to reduce healthcare-acquired and public space-acquired infections, reduce healthcare costs, and promote healthier lives. However standard antimicrobial surfaces are not sufficiently robust to withstand the wear and tear encountered in a biomedical implant environment and in public spaces. Sheffield Hallam University and Imperial College London aim to develop superhard nanostructured surfaces with plasmonically-enhanced photocatalysis which will enable microbial inactivation in both illuminated and dark environments whilst retaining their robustness and effectiveness in the long term and which, as a result, will lead to orthopaedic implants and anti-microbial surfaces that are more functional than those produced with the current technologies. The innovative antimicrobial surfaces will be robust due to the use of superhard nanoscale multilayer coatings with wear rates up to 1000 times better than conventional metal alloys. At the same time the robust antimicrobial surfaces will have a dual functionality - (1) active, they will be able to kill microorganisms by photocatalysing the production of highly reactive singlet oxygen - one of the most effective killers of pathogens. The photocatalysis will be activated by visible light from the environment. The light will interact with a carefully prepared coating material to induce plasmonic resonance on its surface and generate high energy electrons which are needed to boost the photocatalytic reaction. (2) passive, mimicking naturally occurring surfaces such as the cicada wing, the surfaces will contain a number of appropriately dimensioned nanopillars which will stretch and mechanically rupture the walls of microorganisms. This functionality is potent in wet, dry, illuminated or dark environments. We have developed a new plasmonic nanoscale multilayer material which activates photocatalysis under standard (visible) light and have developed technology based on high power impulse magnetron sputtering which can produce these materials at room temperature on polymers. We will study the plasma processes needed to produce the materials and nanopillars, their response to light activation and the effect they have on microbials. This will help us to develop a cost-effective manufacturing technology to enable large scale production by upgrading systems which are already available in industry for coating deposition and nanopatterning with a digitalised system control which is driven by artificial intelligence algorithms. Together with the local NHS hospital trust we will trial the material on metal plates for door furniture and polymer sheets to cover surfaces in hospitals (beds, seating areas). When successful we will have some of the most exciting new developments in robust antimicrobial materials and their manufacturing and take a step closer to a world with fully effective infection control.",,1.3 CHEMICAL AND PHYSICAL SCIENCES;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,INFECTION HRCS22_01131,Medical Research Council,MRC,Role and regulation of cyclin F in the cellular responses to ionizing radiation (IR).,"A feature of cells exposed to IR is the activation of a G2/M checkpoint, which controls cell cycle progression, allows damage repair or drives cell death. From work in my laboratory, cyclin F has emerged as a crucial regulator of multiple aspects of the G2 phase (D’Angiolella et al., Trends in Cell Biol, 2013). I found that cyclin F act as an E3 ubiquitin ligase and induces the ubiquitin-mediated proteolysis of the Ribonucleotide Reductase subunit (RRM2) (D’Angiolella et al., Cell, 2012), which controls production of dNTPs, the building blocks of DNA. After the induction of the G2/M checkpoint by IR, cyclin F is proteolyzed to allow production of dNTPs for DNA repair and to modulate multiple aspects of the IR response. How cyclin F activity and levels are regulated by the checkpoint, however, is not understood. We have identified discrete phosphorylation events on cyclin F, which change dynamically upon checkpoint induction and we have shown that cyclin F is phosphorylated directly by cyclin-dependent kinases, Wee1 and Chk1. Furthermore, we have identified the E3 ubiquitin ligase βtrcp as an interacting partner and regulator of cyclin F. We will establish how cyclin F activity and levels are controlled during the checkpoint induced by IR and the impact on the production of dNTPs (Aim1). These studies will reveal how DNA replication and checkpoint responses induced by IR in S and G2 phases of the cell cycle are coordinated with dNTP production. Since altered cyclin F levels have been described in hepatocellular carcinoma and ovarian cancer, where cyclin F levels correlate with survival outcome (Carlucci, D’Angiolella, Br J Cancer, 2015), our studies may also predict patient responses to IR and checkpoint inhibitors in the presence of altered cyclin F levels. In addition to RRM2, preliminary studies from my laboratory have identified Scaper as an additional substrate of Cyclin F. Scaper is a poorly characterized regulator of cell cycle progression that regulates cyclin A localization (Tsang et al., J Cell Biol, 2007). We have observed that Scaper has a crucial role in regulating cell survival after IR. We propose to further investigate the role of Scaper and its regulation by ubiquitin mediated proteolysis mediated by cyclin F and APC/C (Aim2). Interestingly, deletion and mutations of Scaper are frequent in cancer cell lines and tumors. Our studies may predict patient responses to IR and checkpoint inhibitors in cancers bearing Scaper mutations.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_01920,Medical Research Council,MRC,Role of NFAT in the vascular endothelium,"Calcineurin-NFAT signaling plays a crucial role in the regulation of many cellular processes. In the immune system, where it is particularly well studied, it plays a key role in the transcriptional regulation of many cytokines, chemokines and growth factors. However, the role of this pathway in the vasculature is still not fully delineated, although it has been implicated in the maturation of coronary valves and lymphatic vessels. We recently re-examined the consequences of loss of NFAT signaling in the endothelium. This revealed a previously undetected defect in venous development in these mice. Although vein endothelial cells are molecularly and functionally distinct from their arterial and lymphatic counterparts, the signalling and transcriptional pathways controlling of venous differentiation are not well characterized. Analysis of publicly available NFATc1 ChIP-seq data in vein endothelial cells demonstrated direct NFATc1 binding to enhancer regions of numerous key venous differentiation genes, suggesting that NFAT factors may directly regulation venous identity. In the project, we will use a combination of mutational analysis and enhancer characterization in zebrafish, mouse and in vitro models to determine the exact role of calcineurin-NFAT signaling in venous development, identify the direct target and partner proteins of NFATs factors, and establish the upstream regulators controlling vein-specific expression of this transcription factor family.",,5.2 CELLULAR AND GENE THERAPIES,CARDIOVASCULAR HRCS22_02627,Medical Research Council,MRC,Role of glycolysis in mesoderm specification and self-organisation of the anterior posterior axis in the mouse embryo.,"As organs and organisms develop and grow, two cellular processes must be tightly coordinated. In the first, cells must undergo a series of cell specification events to generate the complete array of required cell types. Secondly, progenitor populations must grow and proliferate at the correct rate to generate well-proportioned organs and tissues. Understanding the control mechanism that links growth and differentiation is both essential for a full appreciation of the underlying mechanisms of embryonic development and for the understanding how these cellular behaviours become uncoupled in the transition from homeostasis to cancer pathogenesis. This proposal aims to investigate the molecular mechanisms that lay at the interface between these two processes, as the early mesoderm is specified and expanded during early gastrulation. Given glucose is the most commonly used carbon source for energy production and biosynthetic pathways, we hypothesise that glucose uptake and metabolism is a central component in linking specification and growth during mammalian gastrulation. To test this, we will use and experimental system that enables the alteration of nutrient supply and metabolism in a controlled manner. During the course of development, a pole of mesodermal cells forms and break the symmetry setting up the anterior-posterior axis in gastruloids. We will first determine how glucose import is regulated by the differential expression glucose transporters. Next, we will determine the importance of glucose uptake in growth and specification of early mesoderm. Finally, we will implement state-of-the-art metabolic flux analysis to determine how glucose is metabolised through different biosynthetic pathways. Ultimately, this work will provide improve our ability to manipulate cell types metabolically to obtain specific cell types in vitro for further applications such as regenerative medicine.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_15484,Wellcome Trust,,Role of median eminence oligodendrocytes in the development of obesity,"One’s appetite and body weight are primarily controlled by neurons in a brain region called the hypothalamus, which respond to signals from the organs involved in digestion and metabolism. These signals reach the hypothalamus after being transported through another brain reigon, the median eminence (ME). New evidence suggests that non-neuronal cells, called oligodendrocytes (OL), may contribute to the ME’s control of signal entry to the hypothalamus; OLs intentionally die and are replaced throughout adult life and express receptors for peripheral signals, both behaviours which change based on nutritional status (i.e. when one last ate) and coincide with changes in permeability of the ME.We aim to determine how obesity disrupts the function of OLs in the ME, and how this may alter ME permeability. We will block certain functions of OLs in obese mice and identify the physiological consequences, identifying genes involved in these processes. We will use this data to identify candidate mechanisms which may alter OL function and influence healthy physiology. We will also explore the possibility that a new class of obesity drug, which mimic the signalling of hormones naturally released in the body, have their therapeutic effect by targeting OLs and changing ME permeability.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,METABOLIC AND ENDOCRINE HRCS22_13394,Versus Arthritis,,Role(s) of Fibrillin-1 in post-traumatic osteoarthritis,"Fibrillin-1 is a glycoprotein found in the pericellular matrix of articular cartilage (AC). My studies so far have shown that Fibrillin-1 is lost with osteoarthritis in a spontaneous (Str/ort) and a trauma-induced model of osteoarthritis, as well as in human OA cartilage. In addition, I have now found that abnormal Fibrillin-1, as found in Tight Skin mice, leads to increased OA severity, in particular affecting non-cartilage tissues (ligaments and synovium). The aim of this award is to determine the role of Fibrillin-1 in OA development and potential novel mechanisms involved in joint degeneration. To achieve this, over the next 8 months, I will use transgenic mouse lines with Fibrillin-1 deletion in the whole limb, or in articular cartilage alone, and measure their OA severity in response to trauma (using a non-invasive model of PTOA that I have pioneered). In addition, I will be testing which cell signalling pathways are involved in these effects, in particular integrin activation. This is based on previous work on Fibrillin-1 in non-skeletal tissues. This project will determine the role of Fibrillin-1 in musculoskeletal tissues, in particular in response to mechanical trauma, and whether its downstream signalling are viable targets for therapy against OA.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MUSCULOSKELETAL HRCS22_02585,Medical Research Council,MRC,SAFEguarding children in Substance exPosed fAmilies by supporting the non-using CaregivEr: Safe Space,"Parental substance misuse is a substantial public health and safeguarding issue. Research in this area typically focuses upon developing and evaluating interventions to reduce substance misuse in the misusing parent. The presence of a non-substance misusing parent/caregiver has been found to offer some protection from harm to children in substance exposed families. Despite this, there is a lack of research examining interventions to support the non-substance misusing parent/caregiver to achieve health and well-being outcomes for themselves and their children. Our project aims to develop an intervention for this population. Our specific objectives are: - To understand the real world formal and informal structural, social and individual level systems of care and the impact of these as barriers and facilitators to effective health and social care for dependent age children and families affected by parental substance misuse - To examine the knowledge, skill and support needs of non-substance misusing parents/caregivers of dependent age children affected by parental substance misuse - To co-produce an intervention for non-substance misusing parents which seeks to support them and their children. The methods we will use to achieve our objectives: - Soft-systems methodology to map out the wide range of formal systems and co-construct social reality maps which capture details of health and social care provision for families affected by parental substance misuse - Social Network Analysis to explore the formal and informal care networks accessed by children in substance exposed families and the non-substance using parents/caregivers - In-depth qualitative interviews with non-using parents/caregivers to identify which causal or contextual factors increase the likelihood of harm to the family and which have the greatest scope for change as well as the mechanisms of change - Co-production workshops with practitioners and non-substance misusing parents/caregivers.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,MENTAL HEALTH HRCS22_16866,Wellcome Trust,,SARS-CoV-2 immunoepidemiology in Wellcome-funded urban and rural cohorts in Malawi : generating evidence to inform regional medium and long term decision making,"General population serosurveillance in low-income Africa is fundamental to understanding the population exposure to SARS-CoV-2, to explain the observed epidemiology and to ensure that ongoing control measures in the region are proportionate and are not guided by observations from very different settings. Detailed longitudinal immunological studies of infected individuals will be key to determining the long-term strategy in managing COVID-19 in highly vulnerable African populations. Utilising the longitudinal urban and rural cohorts established by the Malawi Epidemiology and Intervention Research Unit, and supported by international and national expertise, we will undertake population immunoepidemiological surveillance to understand the trends in exposure and transmission of SARS-CoV-2, risk factors for SARS-CoV-2 infection and severe disease, as well as the proportion of asymptomatic or pauci-symptomatic infection in the population to enable an accurate estimate of infection fatality rate. Furthermore, we will recruit individuals with evidence of past SARS-CoV-2 infection to a nested cohort with 3-monthly sampling, to explore the magnitude and duration of antibody response and protective immunity in the Malawian population, and at the same time creating a biorepository for further in-depth virological and immunological studies.",,2.4 SURVEILLANCE AND DISTRIBUTION,INFECTION HRCS22_06168,Health Education England,HEE,SCHEMA - Secure Care Hospital Evaluation of Manualised (interpersonal) Art-Psychotherapy: A Randomised Controlled Trial.,"SCHEMA - Secure Care Hospital Evaluation of Manualised (interpersonal) Art-psychotherapy: A Randomised Controlled Trial. Research questionDoes interpersonal art psychotherapy reduce (i) the frequency and severity of aggressive incidents and/or (ii) patient self-reported distress associated with psychiatric symptoms in adults within secure care who have intellectual disability (ID) or borderline intellectual functioning? AimsTo test the effectiveness, cost-effectiveness, and psychotherapeutic processes of interpersonal art psychotherapy in NHS adult secure care compared to usual care only. ObjectivesTo conduct an RCT of interpersonal art psychotherapy, compared to usual care, in secure care in England.To estimate the subsequent effectiveness and cost-effectiveness of interpersonal art psychotherapy.To report and disseminate outcomes and findings to a wide range of stakeholders.To brief/advise commissioning and policy/programmes as a result of the findings. Inpatient ID mental health and secure careThe presence of co-occurring mental illness can significantly increase the likelihood of people with intellectual disabilities (ID) having both victimisation and offending histories (24). People with ID who are inpatients in NHS services and/or residential care are more likely to have reported aggression compared with people living independently (10). In England, out of a population of 1.2M people with ID 3% are receiving treatment in psychiatric hospitals, with half treated in secure care. Expenditure is estimated at 300M pounds per annum (25). Patients with ID being treated in secure care are routinely in hospital for longer compared to patients on other types of secure mental health wards, >10 years in high secure, 5 years in medium secure or 15 years in a mix of high and medium secure settings (26). Patients in secure care are likely to be more violent than those in other types of psychiatric units (2). Psychological interventions in secure care The most recent systematic review (2019) of RCTs of psychological interventions in secure care (n=9 studies including 523 participants) reported that current practice is based on limited and inconsistent evidence (12). The study sample sizes were small ranging from 14 to 112. No economic evaluations were conducted in the studies. The review concluded that further studies within a standardised framework are needed to clarify the evidence base (29). Feasibility A RCT feasibility study of interpersonal art psychotherapy (n=20) carried out (by the applicant) indicated that a full trial is feasible and signalled moderate to strong effects upon aggressive behaviour and patient reported distress related to psychiatric symptoms (42). DesignThe RCT will utilise a parallel-group participant-randomised design with participants being allocated to interpersonal art psychotherapy and usual care (UC) or a UC delayed interpersonal art psychotherapy treatment control group after 38 weeks. Patient and Public Involvement and Engagement (PPIE) has informed the inclusion of a delayed treatment control group. Timelines for delivery Year 1: Trial development - protocol published, approvals, RCT set-up.Year 2 to 4: RCT effectiveness/cost-effectiveness/psychotherapy process analysis.Year 5: Stakeholder engagement and dissemination. Anticipated impact and disseminationRCT results will inform evidence-based practice/commissioning for the treatment of aggression and psychological distress for people with ID in secure care.","Key Points Some people with learning disabilities who commit a crime and go to court can be sent to prison or to a hospital with secure care. People with learning disabilities in secure care are more likely to stay there longer than people without a learning disability. Records show that people in secure care hurt either themselves or others more often than in other mental health hospitals. People who struggle with reading information and communication can find creative approaches a helpful way to understand and manage their own mental health needs. Art psychotherapy is a psychological therapy where people work with a therapist and make artwork to help them to communicate about any difficulties they are having. It can be helpful for people who find it hard to talk about what they are thinking about, feeling, or struggling with.Who is doing this research? The research team is made up of art psychotherapists and researchers. People with learning disabilities have spoken to us about this research and helped us to design it, plan how to do it, and how we tell people about it when it is finished. Why is this research needed? In the past people who have a learning disability were often excluded from taking part in research. This means that knowing what works well for them is not always clear. Lots of psychotherapies available to help people with mental health difficulties are based on talking, which might not always be the best approach for people with learning disabilities. Doing artwork or creative things within art psychotherapy can be a helpful way for people to communicate about themselves. Interpersonal art psychotherapy has been designed to help people with learning disabilities in secure care. The art psychotherapist encourages people to use creative ways to express the things they are frustrated, angry, or distressed about. What are we aiming to find out? We want to find out if interpersonal art psychotherapy is helpful and value for money for people with learning disabilities who are in secure care. We will be testing if interpersonal art psychotherapy works better than the standard care that is being provided. To do this we will need to recruit 240 people and put them into groups by chance, with half having interpersonal art psychotherapy and half on a waiting list for it. This is called a randomised controlled trial (RCT). Everyone in the study will get a chance to have interpersonal art psychotherapy. How have we involved patients and the public in our research?People who have a learning disability have been advising us on how we should do this research. People helped us to design the study, suggesting using a waiting list. They thought it was important for everyone in the study to have a chance to do art psychotherapy. The therapy manual was developed by an art psychotherapist and people who have a learning disability looked at it and told us what they thought worked well and what could be improved. People with a learning disability will be advising us during the study. A theatre company, run by and for people who have a learning disability, will help share the results of our research through performances. How will people with learning disabilities and secure services benefit from the study?We will find out if interpersonal art psychotherapy can help people who are in secure care to improve their mood, become less distressed, and not hurt themselves or others. We think that this research will give people with a learning disability more choice about accessing psychotherapy in secure care.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_22545,"Department for Environment, Food and Rural Affairs",DEFRA,SE0567: Coronavirus Susceptibility of Deer in Great Britain,"Deer species are variably susceptible to beta-coronavirus infections including SARS-CoV-2, bovine and bovine-like coronaviruses (BoCoVs). Some are zoonotic/reverse zoonotic (e.g. SARS-CoV-2, HuCoV-OC3 of rodent/bovine origin) others cause infection of wild and domestic ruminant’s including deer. Deer species, including those in GB, are known to express the cellular receptor (ACE2) for SARS-CoV-2 indicating possible susceptibility to infection at a cellular level. Our understanding of the role of CoV hazards, threats and risks with respect to wildlife, livestock and humans",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_05323,Department of Health and Social Care,NIHR,SMALL: Open surgery versus minimally invasive vacuum-assisted excision for small screen-detected breast cancer – a phase III randomised multi-centre trial,"Aim_x000D_ This research aims to look at a new treatment for women who have a small breast cancer diagnosed by Breast Screening and compare it with surgery, which has always been used to treat these cancers._x000D_ _x000D_ Background_x000D_ In the NHS Breast Screening Programme, there has been concern about the diagnosis of cancers which would never have been seen if a woman had not had a screening mammogram. This is known as overdiagnosis, and it’s estimated for every breast cancer death prevented by breast screening, about three cancers will be overdiagnosed. These cancers have always been treated with an operation. However, in this research, we plan to look at a new way of removing these small, early-stage breast cancers, using a method called vacuum-assisted excision. This uses a large needle connected to a vacuum device to remove tissue from the breast, and is done under local anaesthetic, under the control of an ultrasound scan. Afterwards, mammograms are done to make sure that the small cancer is completely removed._x000D_ _x000D_ Design and Methods_x000D_ In this research, women with small, early stage breast cancers will be have their cancer removed either with a standard surgical operation (removal of the tumour along with a lymph node from the armpit) under general anaesthetic, or else using the new vacuum-assisted needle method to remove the breast tumour only._x000D_ _x000D_ After standard surgery, up to 1 in 5 women will need to have a follow-up operation, because when the cancer is removed from the breast and examined in the lab, cancer cells are still present at the edge of the piece of tissue that was removed. If we are using the new method to remove cancers, we need to make sure that a larger number of women won’t need a follow-up operation afterwards if the mammogram shows that the cancer is not fully removed. We would accept that a few more women might need a follow-up operation after the new treatment, because many more would benefit from avoiding having standard surgery in the first place. In the research, we will compare the rate of women who need a follow-up operation in both groups to make sure that it is not much higher in women having the vacuum group._x000D_ _x000D_ We also know that after breast cancer treatment there is a very low risk of the cancer coming back in the breast - this happens in about 1 in 100 women. We know when this happens it can be treated with another operation. We will be following women up to make sure that this doesn’t happen more often in women who have the new treatment._x000D_ _x000D_ If this research shows that the new method of removing breast cancers is as safe and as good as an operation, this would have many benefits for patients and their families. They would not need to have their cancer treated with an operation, so they wouldn’t need to have a general anaesthetic and run the risk of having the side effects of surgery. Also, fewer trips to hospital would be needed. There would also be benefits for the NHS as it would mean that fewer people would need to come to hospital for an operation, so there would be more operating theatre time available for other surgery._x000D_ _x000D_ Dissemination of Results_x000D_ Women who take part in this research will be offered the opportunity to be sent a copy of the results. We will also share the results with groups of patients who have an interest in this area, and with the NHS staff who look after women with breast cancer, so that they are aware of the results of the research and can use it to help them offer the best possible treatment.","SMALL is a phase III multi-center randomised trial to assess whether vacuum-assisted excision of biologically-favourable screen-detected breast cancer is as effective as standard surgical excision with sentinel lymph node biopsy in terms of requiring a second surgical procedure, and in achieving acceptable local recurrence rates._x000D_ _x000D_ STUDY DESIGN_x000D_ • Randomised controlled trial with embedded single arm cohort_x000D_ • Patients randomised in a 2:1 ratio in favour of vacuum-assisted excision (VAE)_x000D_ • Single arm analysis of VAE patients to assess local recurrence (LR) rates_x000D_ • LR rate in VAE cohort not to exceed undesirable threshold (3% at 5 years)_x000D_ • LR rate in standard surgical arm to be utilised to aid interpretation of VAE cohort_x000D_ • Internal Pilot Phase to assess feasibility of intervention and recruitment_x000D_ • QuinteT Recruitment Intervention utilised to optimise recruitment_x000D_ _x000D_ _x000D_ STUDY SETTING_x000D_ • Patients identified/approached within the NHS Breast Screening Programme (NHSBSP) _x000D_ • Recruitment and treatment in secondary care specialist Breast Units_x000D_ _x000D_ _x000D_ TARGET POPULATION_x000D_ • Women >50 years_x000D_ • Screen-detected breast cancer <15mm in size, ER/PR positive, HER2 negative_x000D_ _x000D_ _x000D_ HEALTH TECHNOLOGIES BEING ASSESSED_x000D_ VAE_x000D_ • Widely used in NHSBSP for excision of benign lesions, and acceptable to patients_x000D_ • Repurposing for excision of small breast cancers avoiding open surgery_x000D_ _x000D_ VAE Arm_x000D_ • VAE of tumour under local anaesthesia_x000D_ • Post-procedure imaging to determine completeness of excision_x000D_ • Open surgical procedure if incompletely excised_x000D_ _x000D_ Standard Surgery Arm_x000D_ • Surgical excision under general anaesthetic_x000D_ • Further surgery as required to achieve complete resection_x000D_ _x000D_ Both Arms_x000D_ • Adjuvant hormonal and radiotherapy as per local protocol_x000D_ • 5 years mammographic surveillance _x000D_ _x000D_ _x000D_ MEASUREMENT OF COSTS AND OUTCOMES_x000D_ Co-primary Outcomes_x000D_ • Re-excision rate (non-inferiority)_x000D_ • LR rate in VAE cohort_x000D_ _x000D_ Secondary Outcomes_x000D_ • Patient reported outcomes_x000D_ • Complications_x000D_ • Health economic evaluation_x000D_ _x000D_ _x000D_ SAMPLE SIZE_x000D_ 801 patients will be recruited, allowing for a 5% drop out. In the randomised comparison of re-excision rates, the probability of success in both arms is 80%: one-sided 2.5% alpha, 90% power to detect a maximum difference of 10%. 762 patients are required. To exclude an undesirable local recurrence rate of 97% in the VAE cohort at 5 years with one-sided 2.5% alpha and 90% power requires 511 VAE patients to be followed for 3 years. _x000D_ _x000D_ _x000D_ PROJECT TIMETABLE_x000D_ The study duration is 9 years. Recruitment will last 4 years with 18 month internal pilot. At the pilot’s conclusion, 141 patients will be recruited and maximum recruitment achieved, by which time we aim to recruit 22 patients/month from 70 centres. Analysis of the first primary outcome will be carried out once all patients are recruited. Follow-up continues for 5 years and analysis of LR rate in the VAE arm will occur when all patients have 3 years follow up._x000D_ _x000D_ _x000D_ EXPERTISE OF THE SMALL TEAM_x000D_ A multidisciplinary team with a proven track record in breast cancer research will ensure delivery of this practice-changing trial. The clinical and PPI team brings wide experience in treatment de-escalation studies. Methodological and statistical expertise comes from the CR UK Clinical Trials Unit at Birmingham University, as do Health Economic and Trial Management skills. PPI representatives are key members of the trial development group and vital to ensuring it's successful delivery. Finally, the QuinteT Recruitment Intervention team bring extensive experience of addressing and overcoming recruitment difficulties in challenging trials.",6.4 SURGERY,CANCER AND NEOPLASMS HRCS22_06196,Department of Health and Social Care,NIHR,"SMART Schools: Smartphones, social Media and Adolescent mental wellbeing: the impact of school policies Restricting dayTime use","Most adolescents own a smartphone and many use social media. In moderation, these interactive technologies can be advantageous for mental wellbeing. Yet negative wellbeing tends to increase with the increasing amount of time adolescents spend using smartphones and social media. We do not know exactly how much time adolescents spend using smartphones and social media, but we know that use in most adolescents is likely to be at levels that are potentially detrimental to wellbeing. We also have little current understanding of the nature of phone/media use in this age group and how this relates to wellbeing._x000D_ _x000D_ Many secondary schools have introduced policies that restrict phone use during the school day, however some schools have a more permissive approach to phones, allowing use at break and lunchtimes. This provides an opportunity to examine the impact of these restrictive school policies by comparing phone use and mental wellbeing in pupils attending schools restricting phone use, with those attending schools which allow phone use. _x000D_ _x000D_ School phone/media policies are a plausible mental wellbeing intervention. Prior research suggests that schools are effective contexts to deliver health interventions, positively impact mental wellbeing, and support phone/media use behaviours. In addition, the UK government recently reported that schools urgently need evidence-based guidance on phone/media use to help them make informed decisions about how better to support adolescents uses of phones/media and their mental wellbeing._x000D_ _x000D_ This proposed study will build on prior evidence to add new understandings on what types of school policies and phone/media use are optimal for adolescent mental wellbeing. We will work closely with secondary schools, senior leaders, teachers, governors, parents, adolescents and key stakeholders so that across the two school groups (schools that do not permit smartphone use and schools that permit smartphone use) we can:_x000D_ _x000D_ 1. Compare the impacts of the two policy types on mental wellbeing _x000D_ 2. Compare differences in: adolescents’ uses of phones/media (within school, over 24hrs and across 7 days); reasons why adolescents use their phones/media; and levels of addictive use_x000D_ 3. Compare behavioural outcomes that are often associated with mental wellbeing, including sleep, physical activity, classroom behaviour and attainment_x000D_ 4. Talk with school senior leader staff, teachers, parents, and governors to better understand the school phone/media policies that are implemented and what family/home factors influence policy implementation and phone/wellbeing relationships_x000D_ 5. Talk to adolescents to better understand how they experience relationships between their phone/media use, school policies and mental wellbeing_x000D_ 6. Assess the impact of these school policies on teachers’ time use to provide evidence of their value for money in terms of improving adolescent mental wellbeing_x000D_ 7. Engage with policy makers, national agencies and local authorities to communicate the findings to inform national policy and guidance, school policy and curricula, and the design and implementation of future interventions to improve mental wellbeing._x000D_ _x000D_ This study will address current gaps in evidence, identify how to maximise benefits and minimise harms of phones/media for mental wellbeing and inform future school policy.","BACKGROUND_x000D_ Adolescence is a crucial period for developing social and emotional habits important for mental wellbeing. Smartphones and social media (phones/media) is a habitual behaviour during adolescence. Evidence suggests that moderate amounts of time spent on phones/media is beneficial for mental wellbeing, and other wellbeing promoting behaviours: sleep, physical activity, school behaviour and attainment. At higher levels of use the reverse effect is seen, with increasing time on phones/media associated with decreasing levels of mental wellbeing, higher anxiety and depression, and addictive use. Many, but not all schools, are currently altering adolescents’ uses of phones/media through school policies that restrict daytime phone/media use. These policies have the potential to lower the overall time adolescents spend on their phones/media and improve mental wellbeing. However, there is currently no evaluation of the effect of school policies that restrict school time smartphone use and there is limited evidence on how these policies are implemented in schools. _x000D_ _x000D_ AIM_x000D_ To determine the impact of school time restrictions of smartphone use on mental wellbeing (primary outcome), anxiety, depression, sleep, physical activity, classroom behaviour, attainment, and addictive use, and assess the costs of policy implementation from an education sector perspective._x000D_ _x000D_ METHODS_x000D_ This is a natural experimental study using mixed methods to compare the impact of school daytime restrictions on smartphone use on mental wellbeing in 2 secondary school contexts: schools that do not permit phone use (intervention) vs schools that permit phone use (control). The focus is on adolescents aged 11-12 years and 14-15 years (population). The primary outcome will be mental wellbeing, and we will measure secondary outcomes of anxiety, depression, classroom behaviour, attainment, physical activity, sleep, and addictive phone/media use. We will examine how the school environment, individual factors and family/home factors influence relationships between school policies, phone/media use and mental wellbeing._x000D_ _x000D_ Data will be collected from 30 schools (15, intervention, 15 control) and 750 adolescents. To measure the primary and secondary outcomes we will collect data from a student online survey and accelerometers. We will conduct document/website analysis and teacher and senior leadership team surveys to understand how school policies are implemented and to complete an economic analysis. Qualitative data will be collected from 6 case study schools (3 intervention, 3 control) to examine the influence of the school environment, individual factors and family/home factors. 36 focus group interviews will be completed with adolescents (n=12), school staff (n=12) and parents (n=12). _x000D_ _x000D_ TIMELINE_x000D_ This is a 28 month study, starting September 2021._x000D_ _x000D_ IMPACT _x000D_ This study will establish whether restrictive school phone/media use policies are an effective mental wellbeing intervention. We will also determine key features of school phone/media policy implementation that positively influence mental wellbeing and related outcomes, inclusive of associated costs, to facilitate adoption of and adherence to effective policies across school contexts. We will disseminate the outcomes to relevant channels to inform national policy and guidance, school policy and curricula, and the design and implementation of future interventions to improve mental wellbeing.",3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,MENTAL HEALTH HRCS22_14183,Duchenne UK,DUK,SMART Suit,This project aims to develop a transformative medical device to support arm movemnets in boys with DMD who are losing strenghts in their arms. It is a collaborative programme funded by the People Postcode lottery and led by Duchenne UK,,5.3 MEDICAL DEVICES,MUSCULOSKELETAL HRCS22_03895,Medical Research Council,MRC,SOCITS: A SOCial sITuational Systems approach to measuring and modelling influences on adolescent mental health,"This project will establish SOCITS as a readily available framework to allow any research team to adopt a situated systems approach to adolescent mental health, whether from a qualitative, quantitative, simulation or practice background. Through a series of reflective and comparative studies, we will determine the optimal approach for data collection and analysis to support a system-level understanding of how psychosocial constructs operate within SOCially sITuated Systems, and how the experience of the constructs within complex environments influences mental health outcomes. The study will use focal constructs of stress, loneliness and mental health stigma. The SOCITS study will develop a framework to identify the social-situational factors relevant to a specific adolescent environment or 'system of interest (SoI)' by developing methods toolkits for the following work packages. 1. Youth Advisor Investigator led walking interviews to obtain data about situations relevant to focal constructs. 2. Systems thinking workshops tailored to inform survey design and Agent Based Model specification for socially situated constructs. 3. Agent Based Models of socially situated interactions, calibrated to data, and used to explore situational-environmental interventions. 4. Development, testing and deployment of a longitudinal school survey containing socially situated assessment of constructs, and how they relate to mental health. A final work package involves a webinar series throughout the life of the grant to discuss SOCITS concepts with the various research communities relevant to adolescent mental health and systems approaches, and at the end of the workshop, SOCITS useability testing workshops, using Normalisation Process Theory to assess how easily research teams can make use of SOCITS for their own projects.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",GENERIC HEALTH RELEVANCE;MENTAL HEALTH HRCS22_07252,Department of Health and Social Care,NIHR,SOUNDFIELDS: A Virtual Reality Therapeutic Framework for Children with Autistic Spectrum Disorder.,"Virtual reality has been an important tool for delivering therapy to those with autism for over two decades. Advancements in consumer equipment are allowing the technology to become increasingly accessible, facilitating therapy frameworks to be delivered via a fun and motivating format. We have developed a VR experience called 'SoundFields' which is a serious game designed to provide an exposure therapy framework for autistic children with auditory hyper-sensitivities. The VR experience rewards players who interact with problematic auditory stimuli. The game utilises novel immersive spatial audio for creating realistic soundscapes. Our prior research demonstrated that this creates a significant benefit to the effectiveness and duration of the therapy. We have conducted preliminary trials within environments where many participants experience their problematic sounds, such as schools. Such real-world context could potentially influence and improve clinical practice, support treatment in a community setting, and overall improve access to treatment for autistic children. Moreover, our current version of the application is developed for the Oculus Rift S, which requires a PC and is relatively expensive. The goal of this project is to develop the application for more affordable and practical devices, such as the Oculus Quest, thus enabling wider reach. This proposal includes collaboration from the Child Oriented Mental health Intervention Centre (COMIC) at Leeds and York Partnership NHS Foundation Trust, and the AudioLab at the University of York, bringing together clinical autism experience and technical expertise. It will involve co-design from families with lived experience and ASD professionals. The development process will involve stakeholders including children and young people and their families, and academics, teachers and clinicians who work with autistic children. The University of York is the owner of the IP. Our goal is to develop the application so that it can be widely used for therapy worldwide under non-exclusive licensing and via a not-for profit commercial entity.","Virtual reality has been an important tool for delivering therapy to those with autism for over two decades. Advancements in consumer equipment are allowing the technology to become increasingly accessible, facilitating therapy frameworks to be delivered via a fun and motivating format. We have developed a VR experience called 'SoundFields' which is a serious game designed to provide an exposure therapy framework for autistic children with auditory hyper-sensitivities. The VR experience rewards players who interact with problematic auditory stimuli. The game utilises novel immersive spatial audio for creating realistic soundscapes. Our prior research demonstrated that this creates a significant benefit to the effectiveness and duration of the therapy. We have conducted preliminary trials within environments where many participants experience their problematic sounds, such as schools. Such real-world context could potentially influence and improve clinical practice, support treatment in a community setting, and overall improve access to treatment for autistic children. Moreover, our current version of the application is developed for the Oculus Rift S, which requires a PC and is relatively expensive. The goal of this project is to develop the application for more affordable and practical devices, such as the Oculus Quest, thus enabling wider reach. This proposal includes collaboration from the Child Oriented Mental health Intervention Centre (COMIC) at Leeds and York Partnership NHS Foundation Trust, and the AudioLab at the University of York, bringing together clinical autism experience and technical expertise. It will involve co-design from families with lived experience and ASD professionals. The development process will involve stakeholders including children and young people and their families, and academics, teachers and clinicians who work with autistic children. The University of York is the owner of the IP. Our goal is to develop the application so that it can be widely used for therapy worldwide under non-exclusive licensing and via a not-for profit commercial entity.",5.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_16221,Cancer Research UK,CRUK,"STARTER-KIT: A technical, procedural and ethical template for accelerating the start-up of AI multicentre studies requiring data re-use and/or sharing in clinical settings","Background Modern radiotherapy research paradigms often require large or varied datasets that can be assembled only via collaboration between multiple centres and by combining multiple data holdings. Typical use cases include development of artificial intelligence (AI) algorithms; tackling rare cancers or subtypes where the number of cases registered at a single centre is small; gathering a complete, demographically unbiased cross-section of the population; and industry-academia co-production partnerships. There is a great appetite within the research community for findable, accessible, interoperable and reusable (FAIR) data, which has the potential to catalyse a host of new projects in diverse areas. Yet such retrospective data are often “siloed” within institutions or have access restricted for a variety of complicated ethical, procedural and technical reasons. Equally, prospective studies are slowed down by the need to interact with multiple entities in a complex ecosystem of rules and governing authorities. As a result, new multicentre studies involving data sharing take too long to “get off the ground” and repeatedly “reinvent the wheel”. Aims STARTER-KIT will bring together complementary research and expertise, developed separately as part of the CRUK-funded RadNet, ART-NET and NCITA consortia and made available via newly designated CRUK Centres, to create an infrastructure template and worked examples for facilitating multicentre collaborative data analytics projects. Methods Across a range of data-sharing problems, four interconnected work packages will implement a common methodology, viz.: Step 1: Gather input from stakeholders; Step 2: Develop technical solutions; Step 3: Present solutions and seek consensus for future joint work. WP1 will examine the ethics landscape of creating FAIR data, considering particularly HRA databases and ""micro-approvals"" and the extent to which these can be federated, as well as issues of data quality and how to make this ""findable"". WP2 considers technical aspects of data access and federation. WP3 will develop methods of federated identity management and maintenance of catalogues for tools and data, and will map the outputs of WP1 into software to create an electronic approvals workflow tool. WP4 will organise engagement activities with stakeholders (patients and the general public, alongside AI researchers and industry partners), demonstrate the software created in WP2 and WP3 and build consensus on its ethical use. How the results of this research will be used The deliverable of a complete starter-kit will significantly reduce the resource requirement for the setup of new studies and increase our ability to launch new initiatives in a timely fashion.",,5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT),CANCER AND NEOPLASMS HRCS22_05057,Department of Health and Social Care,NIHR,"STIMULATE-ICP (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways)","Background: Long COVID clinics are being implemented as usual care, but clinical characteristics, effective management strategies, recovery pathways, resource needs, and equitable access remain ill-defined. Aim: To develop integrated care pathways (ICPs) for long COVID, and to evaluate effectiveness and cost-effectiveness, compared with usual care. Methods: We will define optimal long COVID care pathways (investigation, treatment, rehabilitation) in an adaptive, 2-year programme with three work packages involving: long COVID clinics in six regions; patient support groups; policymakers; specialist health professionals and academics in long COVID and integrated care. First, we will study patient trajectories, healthcare utilisation, effectiveness and cost of usual long COVID care using: (i)UK linked national records(n=56 million); (ii)prospective cohort study of non-hospitalised long COVID(n=500); (iii)long COVID clinics (n=6); (iv)qualitative interviews(n=30); and (v)”deep phenotyping”(e.g. omics, imaging, physiology) of common symptom groupings(n=300). Second, in a pragmatic cluster (primary care network-level)-randomised trial, we will evaluate ICPs with early, supported investigation (multi-organ MRI with CoverscanTM and clinical decision support) and enhanced rehabilitation (Living with COVID RecoveryTM), compared with usual care(basic investigations and YourCOVIDRecoveryTM self-management), recruiting adults with suspected long COVID at referral(n=4520). In a nested, multi-arm, randomised (patient-level) drug trial, we will assess aspirin, colchicine and loratidine/famotidine versus standard of care. Primary outcome is fatigue assessment scale at three months. We will develop a long COVID core outcome dataset for research and assess cost-effectiveness of interventions. Third, with patients, we will co-develop interventions (enhanced case-finding) to improve access to care and support. In long COVID clinics, our trials and national data, we will investigate inequalities by geographic location, socioeconomic status, ethnicity and pandemic stage. Outputs for long COVID policy and research include: (i)evaluation of current care and clinical trajectory; (ii)effective and equitable care pathways, transferable to other long-term conditions; (iii)platform for future trials; and (iv)biobank for investigating outcome and treatment response(~5000).","Long Covid is affecting over a million people in the UK. The wide-ranging symptoms are disabling, and need joined-up care from specialists, hospitals and community services. Over 80 long COVID clinics have been established but we need to better understand, diagnose and treat the disease. We will design and test the best ways to care for people with long COVID. We will bring together six regions: Derby, Exeter, Hull, Leicester, Liverpool, and London, and include the Royal College of General Practitioners policy team, health professionals and academics. Four patient organisations have helped to develop this proposal. They will be involved across the project from design to dissemination. To improve recovery, we will work out what long COVID is, how to diagnose it and how to manage it. The data and findings will be easily accessible to aid further research and service improvement. We will interview patients and health professionals and analyse data from NHS records. This will inform our understanding of patterns of long COVID and the outcomes of current clinical practice. Usual care involves basic investigations such as blood tests and self-management of rehabilitation using a website https://www.yourcovidrecovery.nhs.uk/ . We will recruit over 4,500 patients in the largest long-COVID trial to-date. We will compare a new pathway including community-based, comprehensive MRI scan (CoverscanTM) and enhanced rehabilitation (Living with COVID RecoveryTM) with usual care. We will also test different drugs, including aspirin, colchicine and loratadine/famotidine. We will measure effects of three months treatment by symptoms, mental health, return to work and other important outcomes. With patients, we will co-develop means to improve patient access to the right care at the right time in the right place, including health professional training. We will consider the aspects of long COVID care which might improve care for patients with multimorbidity and long-term conditions.",6.1 PHARMACEUTICALS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.1 ORGANISATION AND DELIVERY OF SERVICES,INFECTION HRCS22_02648,Medical Research Council,MRC,STRESS-MALAWI: Strengthening Resilience against Sleeping Sickness in Malawi,"Rhodesian human African trypanosomiasis (rHAT) is caused by the protozoan parasite Trypanosoma brucei rhodesiense via the bite of infected tsetse flies. Foci of this disease persist in areas where tsetse and wild reservoir hosts are abundant (e.g. national conservation parks of Central and East Africa). People and livestock living closest to these areas are at the highest risk of contracting rHAT, but due to its zoonotic lifecycle it is extremely difficult to prevent transmission without targeting the vector. The Vwaza Marsh Reserve spans the border of north Malawi and Zambia and experienced an unexpected surge in rHAT cases in 2019-20. The reasons for this rise in rHAT are currently unknown but the majority of cases originated in villages less than 5 km from the park. We hypothesize that evidence-based and spatially explicit targeted vector control surrounding the park edge can reduce the risk of rHAT spilling into neighbouring agricultural areas. To test this hypothesis, we will: 1. Sample tsetse along transects across the wildlife-agriculture interface and other potential tsetse habitat outside of the park and quantify the relationship between abundance and the environment using data captured by satellites and drones. 2. Quantify the human-biting index of local tsetse flies in Vwaza and determine whether exposure to tsetse-bites is greatest either inside or outside households via comparative entomological sampling methods. 3. Compare the genetic structure and parasite virulence of T. brucei rhodesiense circulating in Vwaza with historical samples of the parasite 4. Implement a two-year tsetse control strategy on the borders of the Vwaza Marsh Wildlife Reserve by deploying insecticide-treated targets at optimal densities informed by computational models of tsetse population dynamics.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,INFECTION HRCS22_06579,Department of Health and Social Care,NIHR,SUPPORT TIA: Structured follow-Up Pathway to imProve management Of Residual impairmenTs and patients’ quality of life after Transient Ischaemic Attack and minor stroke: Intervention refinement and feasibility study.,"Background The prevalence of transient ischaemic attack (TIA) and minor stroke in the UK is high; 510,000 and 300,000, respectively. Current long-term management of these conditions focuses on stroke prevention. However, my PhD research found that many TIA/minor stroke patients experience ongoing impairments, for which there are no guidelines or structured pathway of follow-up support. Residual impairments post-TIA/minor stroke could potentially reduce people's quality of life (QoL) and cause economic burden through reduced productivity at work and unplanned health/social care costs.Pilot work identified a demand from TIA/minor stroke patients and stakeholders for a structured pathway of support post-TIA/minor stroke. A preliminary intervention pathway has been informed by the pilot work and comprises: a follow-up appointment to screen for post-TIA/minor stroke impairments and refer patients to appropriate local support services (facilitated by a directory of services). However, further research is required to refine and test the feasibility this intervention pathway. Pilot work is currently underway to identify potential screening tools and time points for screening. The proposed research will identify the setting for the intervention pathway; develop the directory of support services; refine delivery of the intervention pathway; and test the feasibility and acceptability.Aims To (i) refine and (ii) test the feasibility and acceptability of an intervention pathway to improve management of residual impairments and QoL post-TIA/minor stroke.Plan of investigationWP-1: Qualitative interviews One-to-one, semi-structured qualitative interviews will help to understand the context of potential settings to follow-up and screen patients after TIA/minor stroke. Around 10-15 TIA/minor stroke patients will be identified from general practice patient lists and recruited by postal invitations. Around 30-35 healthcare providers will be recruited from TIA clinics, general practices and community/voluntary care.WP-2: Refine the content and delivery of the intervention pathway a) Healthcare professionals and TIA/minor stroke patients will be surveyed to identify local support services relevant for TIA/minor stroke in the West Midlands. Subsequently, an online directory of relevant support services in the West Midlands will be developed. b) The screening tools, time point for screening and setting for the follow-up appointment will be selected using data from the interviews (WP-1), the survey (WP-2a) and consultation with patients and stakeholders. c) A stakeholder engagement event will be held to refine the delivery of the intervention pathway. Behaviour change theories will also be used to inform the delivery and address the barriers to implementation of the pathway identified from the interviews (WP-1) and the survey (WP-2a).WP-3: Feasibility study A study will be conducted to assess the feasibility and acceptability of the intervention pathway. 60 TIA/minor stroke participants will be recruited from TIA clinics in the West Midlands and randomised 1:1 to the intervention pathway or control groups. Participants will be followed-up at three months. Quantitative and qualitative data will be collected to provide information on feasibility and acceptability outcomes.WP-5: Dissemination and grant writing Dissemination will encompass academic and non-academic routes and target key stakeholders and maximise impact. A protocol will be developed for a definitive randomised controlled trial (RCT) and a grant application produced to secure funding for this future research.Potential benefit to patients/the NHS There is potential for immediate benefit to patients/the NHS though dissemination of the online directory of support services. The intervention pathway has further potential to improve healthcare and QoL for TIA/minor stroke patients, which may impact on other important outcome such as return to work/social activities and management of stroke risk factors. There is a direct trajectory to patient/NHS benefit through a future definitive RCT. The proposed research will address research priorities of TIA/minor stroke patients and stakeholders.","What is the aim of the research? To design a care pathway that will help manage long-term problems after mini-stroke. The research will also test if the care pathway works practically to help decide if a larger study can be done.What is the problem and why is this important? Mini-strokes are similar to full strokes, but symptoms last less than 24 hours. Many people (up to 70%) have long-term problems after a mini-stroke, such as anxiety; depression; problems with brain functioning (like memory loss); and fatigue (feeling tired). However, the current healthcare pathway only focuses on preventing another stroke and care for other long-term problems is not routinely given. Without proper treatment, people with long-term problems after a mini-stroke could have worse quality of life and may find it difficult to return to work and their social activities.How will you address the problem? I have designed a new care pathway where people who have a mini-stroke will get a new follow-up appointment. At this appointment, a questionnaire will be used to identify which people have long-term problems and these people will be referred to local support services. More research is needed to help decide where the new follow-up appointment should be; to develop a database of local support services; and to design the details of how the new care pathway will be delivered. I will also test if the new care pathway works practically.There will be four stages to the project:Stage-1: I will interview people who have had a mini-stroke and people who deliver healthcare in hospitals, GP practices and the community. I will ask people about their experiences of the current care available and their opinions on the new care pathway.Stage-2: I will design the details of the new care pathway and how it will be delivered practically. Part a) I will send a survey to people who have had a mini-stroke, doctors, nurses and volunteers to find out what services are available in the West Midlands to support people with anxiety, depression, fatigue and brain functioning. This information will be put on a website so that doctors and nurses can easily search for local services. Part b) I will use the information from the interviews in stage one to decide where the follow-up appointment for the new care pathway should be, e.g. should it be in a hospital or in the community. Part c) I will consider practical issues to help design how the care pathway will be delivered. I will get advice from people who the care pathway is relevant to, including people who will deliver the pathway, people who have had a mini-stroke, stroke doctors, GPs and stroke charities.Stage-3: I will test the new care pathway to see if it works practically. 60 people who have had a mini-stroke will be involved: 30 will get the new care pathway and 30 will get normal care.Stage-4: I will share the findings from stages 1-3 with the general public and people who may want to use the new care pathway in the future, including patients, doctors and nurses, academics and politicians. I will also design a bigger study to test if the care pathway improves people's quality of life and management of long-term problems after mini-stroke.How have you involved patients and the public in your research? To help design the research project, I put together a group of people who have had a mini-stroke and their family members. This group has given advice on what they would want from a new care pathway. They also advised on the methods for the research, including how to recruit mini-stroke patients and if any parts of the research might cause upset or burden to participants. Members of this group (9 people) have agreed to continue to give advice during the research project.How will you share the findings of your research? I will share the findings of my researchers with the following people: Researchers Mini-stroke patients and the general public Healthcare staff: stroke doctors and nurses, GPs, community doctors and nurses, and volunteers. People who make decisions about health care services: politicians, policy makers and commissioners. A meeting will be held at the end of the study where all these groups of people will be invited to discuss the results and the next stages of research. The findings of the research will also be presented at research conferences; published in academic journals; and shared on social media and through summary leaflets.",7.1 INDIVIDUAL CARE NEEDS,STROKE HRCS22_20132,Cancer Research UK,CRUK,"Screening, Prevention and Diagnosis of Colorectal Cancer","Background The CSPRG is a multidisciplinary research team focused on screening and prevention of colorectal cancer (CRC). Aims Our aim is to reduce CRC incidence and mortality. Over the next funding period, we will: • Examine methods to improve the impact of flexible sigmoidoscopy (FS) and faecal immunochemical tests (FIT) for CRC screening. • Evaluate the effectiveness of the current adenoma surveillance guidelines. • Investigate how we can improve screening, surveillance and diagnosis of proximal colon cancer (PCC). • Explore risk factors for PCC. • Build a national Lynch Syndrome (LS) database to improve surveillance in these patients. Methods We will use the UK FS screening trial (UKFSST) to examine the impact of endoscopist performance and patient experience of FS on long-term CRC incidence and future screening participation. We will use data from the FIT for Follow-Up study to understand how endogenous and exogenous factors affect the diagnostic accuracy of FIT. We will conduct a randomised trial within the Bowel Cancer Screening Programme (BCSP) to investigate the impact of different FIT thresholds on CRC incidence and mortality. We will evaluate colonoscopy surveillance in relation to long-term CRC risk in all adenoma risk groups. We will use data from our existing studies to examine the predictive value of distal and proximal lesions for future PCC risk. In addition, we will use GP data linked to cancer registries to identify risk factors and symptoms associated with PCC. We will build a national database of LS patients with functionality to provide call and recall for colonoscopy surveillance. How the results of this research will be used Results from the UKFSST have shown that a single FS screening reduces incidence and mortality of CRC by 35% and 41%, respectively, after 17 years. Our additional analyses will determine how the impact of FS can be further increased. Understanding the sources of variability in FIT results and effects of different thresholds on CRC incidence and mortality will ensure the optimum use of FIT, maximising the efficacy and cost-effectiveness of screening. Our evaluation of adenoma surveillance will provide vital data required to refine the existing guidelines and focus colonoscopy resources where they are really needed. Improving understanding of risk factors, screening and early-detection strategies for PCC will decrease incidence and mortality of this malignancy. The LS database aims to reduce CRC mortality in LS patients by ensuring that they receive the recommended level of colonoscopy surveillance.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING,CANCER AND NEOPLASMS HRCS22_20018,Cancer Research UK,CRUK,Self-DNA Detection in Genome Maintenance and Cancer,"Background Most cancers, either during their development, or during chemotherapy, undergo genotoxic stress and chromosomal instability. While much is known about how classic DNA repair and DNA damage checkpoint machineries respond to such defects, and how these modulate carcinogenesis and chemotherapy, recent work has implicated another player – the innate immune system. Because innate immune signalling can both have important cell-intrinsic effects and regulate immune responses, understanding its response to genotoxic stress may transform our view of cancer development and treatment particularly with the advances being made through immunotherapy. A major trigger for innate immune responses is DNA-dependent activation of the cyclic GMP-AMP synthase cGAS, leading to inflammation, senescence and apoptosis. Under unperturbed conditions, chromosomal self-DNA appears to be shielded from activating cGAS, but this is negated in response to genotoxic stress. Although the mechanistic basis underlying this phenomenon is not yet understood, my recent work showed that the chromatin organization of chromosomal DNA inhibits cGAS, thereby potentially preventing cGAS activation during normal growth. Aims The main purpose of this research plan is to understand how chromatin inhibits cGAS, how this inhibition is relieved in cancer and in response to genotoxic stress, and to reveal the consequences of cGAS activation by self-DNA. Aim 1: Reveal how cGAS activation is controlled by chromatin. Aim 2: Reveal how genotoxic stress activates cGAS. Aim 3: Reveal how cGAS controls cell fate following genotoxic stress. Methods I will apply biochemistry, structural analysis and cell biology to this problem. A unique system of cell-free extracts will be used to investigate cGAS response to self-DNA in a physiological but biochemically tractable environment. Cell culture, automated imaging, and gene editing will reveal cell fates and in vivo mechanisms. Ionising radiation and taxanes will be used as sources of genotoxic stress, both with direct relevance to cancer treatment. How the results of this research will be used. I hope to establish a comprehensive understanding of how cGAS orchestrates the response to genotoxic stress, and establish model systems to dissect other innate immune pathways. In collaboration, I subsequently plan to apply these findings to revealing the role of cGAS activation by self-DNA in cancer development and treatment. The deep mechanistic understanding that I aim to establish should prove valuable to develop approaches for manipulating the cGAS pathway during cancer therapy, as well as utilising it as a biomarker for tumour responses during therapy.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_07097,Department of Health and Social Care,NIHR,Self-Harm in Eating Disorders: A Mixed-Methods Exploratory Study (SHINE Study),"Research Question: What are the psychological, emotional, and social factors that motivate and maintain self-harm in young people aged 16-25 with an eating disorder? Background: Rates of SH in young people with EDs are exceptionally high, ranging between 25.4% and 55.2% (Claes and Muehlenkamp 2014), contrasting to 13.4% in the general population (Swannell et al. 2014). The prevalence of SH in EDs is more than double that in other psychiatric disorders (Solano et al. 2005) and is a risk-factor for suicide (Cucchi et al. 2016). It is not known why a young person may develop both ED and SH, or how these interrelate or impact one another. There are no targeted NHS services or interventions for SH in ED. Aims: Investigate the psychological, emotional and social factors that underlie SH thoughts and behaviours in young people aged 16-25 diagnosed with an ED Explore young people s perspectives of the causes and functions of SH in an ED; and, on the psychological/clinical/social support needed to address SH in ED. Objectives: Phase 1 Examine the frequency, intensity and duration of SH thoughts and behaviours in young people with ED, as they occur in real-time. Examine the context, function and processes surrounding SH thoughts and behaviours in young people with ED. Identify proximal factors predicting transition from SH thoughts to behaviours. Phase 2 Explore young people s perspectives on: Factors that led to the development of SH (thoughts and/or behaviours) and ED. Social and emotional functions of SH and ED; and, their interrelationships. Psychological/clinical/social support needed to address SH in ED. Methods: Sequential explanatory mixed-methods study (Creswell et al. 2003) in two specialist ED outpatient services for young people. Phase 1: 70-100 participants aged 16-25 with an ED and SH thoughts or behaviours will take part in ecological momentary assessment, repeatedly capturing feelings, thoughts, motives, behaviours and experiences of SH in real time over 14 days. Phase 2: 20-30 participants to Phase 1 will also take part in a qualitative interview, exploring: experiences of SH in ED; why and when the ED and SH developed; what functions each serves; support needs. Thematic analysis of data (Clarke and Braun 2013). Timeline for Delivery: 18 months: Pre-award: Set up; recruitment of Research Fellow; HRA and REC submission & approval. 0-8: first YAG consultation; Screening; EMA data collection, analysis; second YAG consultation; 9-16: Qual Data collection, transcribing, analysis; third YAG consultation; 15-18: Data integration; write up; dissemination; fourth YAG consultation; Project close. Anticipated Impact and Dissemination: The study will: Establish why young people with ED also self-harm, and define their social, psychological and clinical support needs; Generate knowledge to inform future NHS interventions for the treatment of SH in ED and pathway restructure within existing CAMHS services; Inform public understandings of SH and ED in young people; Establish the feasibility of combining EMA and qualitative interviews with young people with complex MH comorbidity; Build capacity for young people with lived experience to become future leaders in MH research. Dissemination of findings to: clinical, academic and lived experience audiences.","Aim: This study will investigate the psychological, emotional, and social factors that underlie self-harm (SH) in young people aged 16-25 with an eating disorder (ED). Background: Described during our stakeholder consultations with young people with lived experience as “something that s not talked about enough”, approximately 25%-55% of young people with an eating disorder (ED) self-harm. This is much higher than the estimate of 13% of young people in the general population. Currently, however, there is a lack of knowledge of how best to treat self-harm in the context of eating disorders and there are no NHS targeted services or interventions. This means that a young person with an ED who self-harms is faced with a focus on one diagnosis rather than a holistic approach to their difficulties. This leaves some support needs unmet and risks making ED treatment less effective. This service gap stems from the fact that we do not know enough about the psychological, emotional, and social factors that lead a young person with an ED to self-harm or how these behaviours interact or impact one another on a day-to-day basis. Until we understand this, including from the perspective of young people themselves, there will not be enough evidence to develop targeted interventions or services. Our study will therefore establish what motivates and maintains SH in this group of vulnerable young people, exploring their experiences and defining their support needs. Design and Methods: Set in three specialist outpatient services for young people with eating disorders, this study will sequentially use quantitative and then qualitative methods: Phase 1: 70-100 young people aged 16-25 with an ED and SH thoughts or behaviours will take part in ecological momentary assessment: A downloadable app will repeatedly capture participants current feelings, thoughts, motives, behaviours and experiences of self-harm in real time over 14 days. Phase 2: 20- 30 young people who participated in Phase 1 will be re-approached to invite them to take part in an in-depth qualitative interview. These will sensitively explore with participants: experiences of SH in ED; why and when the ED and SH developed, including the influence of life events; what functions the ED and SH are serving, and how these interrelate; participants support needs. Public and Patient Involvement: The study has been designed with members of an advisory group of young people with lived experiences, who have described it as “really needed” and “ethical.” They have advised us on appropriateness of methods, ethical considerations, the feasibility of recruiting young people, and they have set research priorities. Members involvement will be continued and invaluable. They will review emerging findings, input into the development of qualitative topic guides, be part of accessible dissemination and collaboratively set priorities for follow-on research.","2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",MENTAL HEALTH HRCS22_05675,Department of Health and Social Care,NIHR,Sensorised Micro-Surgical Robot for Safe Regenerative Retinal Therapy Delivery,"Research question Gene and cellular therapies are emerging transformative treatments for blinding retinal diseases. Treatment delivery into delicate retinal tissue layers, some as thin as 10-20um, requires precision and force sensing beyond human capabilities, and calls for robotic assistance. Therefore, we must create systems that augment surgical delivery by offering dexterous assistance and information about tool/tissue interaction. Background Research on robot-assisted vitreoretinal surgery originally focused on vessel cannulation and epiretinal membrane peeling. Research has now pivoted to regenerative therapy delivery, where robotic assistance is critical due to the precision required. However, retrofitting existing systems to adhere to the stricter requirements of therapy delivery cannot lead to optimal performance. The majority of robotic systems under research and development are straight-tool holders that follow conventional surgical protocols. Further, they do not offer simultaneous force and depth-of-implantation sensing due to the challenge of incorporating multi-modal sensors within a sub-millimetre tool. On the contrary, our research focuses from the onset on cellular and gene therapy delivery. Our prototyped telemanipulated system can improve clinical performance near the retina due to its snake-like flexibility, offering both precision and dexterity. Aims and Objectives We will produce a sensorised flexible micro-surgical robot to deliver retinal therapies by: 1. Sensorising a flexible robot with fibre-based force sensing and high-resolution imaging at its tip. 2. Developing algorithms for retina tracking and semi-automated therapy delivery. 3. Compiling documentation in support of first-in-human evaluation of a Minimum Viable Product (MVP). Methods and Timelines The project lasts 12 Quarters (Q). The objectives will be met via 5 development work-packages: WP1 (Q1-Q4) will deliver a flexible submillimetre core that will house five sensing fibres, a therapy delivery channel and a forceps. The core will be embedded within the robot body to maintain the separation of the fibres. It will be created through fibre-pulling technology. WP2 (Q2-Q10) will deliver two optical imagers based on single-fibre OCT. The “S” profiler provides an A-scan that will enable the robot to maintain a safe distance from the retina. The “I” imager will produce a detailed B-scan (series of A-scans) to guide injection thanks to the innovative use of a rotating cleaved fibre. WP3 (Q1-Q10) will develop the first ever Fibre-Bragg grating based force/shape sensor for submillimetre robots. System calibration will be achieved through a bespoke cable-driven force applicator and tailored deep-learning models. WP4 (Q5-Q12) builds on our software to develop “operating room ready” retina and tool tracking algorithms. By detecting the tools and motion of the retina, our robot will be stabilised in lateral dimensions to perform minute-long therapy injection. WP5 (Q1-Q12) will identify desired features of an MVP through interviews with surgeons, redevelop our robot prototype under a Quality Management System, and submit to regulators application for first-in-human consideration. Impact and Dissemination The project de-risks our innovation while generating publications, new knowledge, and IP in support of a multi-stage commercialisation strategy. Robust mechanisms to engage and be informed by public and patients will advise the presentation and orientation of the research, while also broadly disseminating our results.","Age-related macular degeneration (AMD) is one of the commonest irreversible eye diseases, affecting almost a million people in the UK alone. The economic effect of AMD is tremendous, rising to more than £1 Billion of associated costs. The development of novel therapies to reverse AMD is therefore crucial from both a societal and an economic perspective. AMD can be wet , when abnormal blood vessels grow into the seeing nerve layer of the eye and bleed, while dry degeneration occurs when the seeing nerves are spontaneously lost. Both forms eventually lead to vision loss. Laser and injection of drugs into the eye, which destroy or suppress the abnormal vessels, are the only treatment for wet AMD; dry AMD has no treatment. Overall, however, the progress of the disease is slowed but never reversed. Pioneering studies conducted worldwide and in the UK, including a pivotal preliminary clinical trial by the lead clinical investigator within the research team, demonstrated that sight restoration in AMD may be possible with regenerative therapies. The research team evaluated a novel cell-based therapy that replaces the damaged cells in the eye. Promising results showcasing sight restoration were captured within a year of follow-up studies. Delivery of these upcoming treatments, under the retina, is currently performed using a hand-held needle. This manipulation is very demanding for surgeons as it lies at the limit of what humans can achieve. Furthermore, the forces that are applied during these subretinal injections are very low and generally not perceivable. Finally, similar to inserting a hypodermic needle, there is no direct indication of where exactly the needle is within the retina. These factors make the efficacy of novel therapeutics limited by manual skills and adversely affect their success. As one of the major limitations of regenerative therapy is delivery, we have been working on a flexible robotic system to boost the capabilities of surgeons and clinical outcomes. Our new research will endow our system with micro-scale force sensing to enable the surgeon to feel the generally imperceivable forces exercised in retinal microsurgery. Further, we will develop sensors to see through the retina directly from the robot s tip with Optical Coherence Tomography, which is a technology drawing parallels to ultrasound imaging. We will develop a semi-automated stabilisation system to aid when steady prolonged therapy delivery is required. Similar to a lane-following vehicle, the developed algorithms will allow our robot to maintain its targeting at predetermined locations in the retina and account for physiological patient motion. The plurality of sensors will allow for targeted safe delivery of regenerative therapies anywhere within the retina. With our proposed system the success of novel therapies will not be held back by conventional and limited conventional retinal surgery protocols.",5.4 SURGERY,EYE HRCS22_00817,Medical Research Council,MRC,Setting the Standard for Genomics and Health-Related Data Sharing: The Global Alliance for Genomics and Health,"As a consequence of the continued decrease in the cost of genomic sequencing, research cohorts of hundreds of thousands of genomes have become available & millions more samples are anticipated in the coming years from both research & healthcare.However, major barriers in data sharing have hindered effective use of the data including: lack of mandates for data sharing, difficulty in submitting data for sharing, inadequate resources for ingesting & storing datasets, insufficient consent for data sharing, lack of interoperability of datasets due to disparate data models & terminologies, inconsistency in pipelines generating the data & inability to address privacy issues & provide sufficient security.In order to overcome these barriers, make the most use of these data, &fulfill the human right to benefit from scientific advances as stated in the Universal Declaration of Human Rights, the research & healthcare communities must come together to agree on common approaches. The Global Alliance for Genomics and Health (GA4GH) was launched to address this need. GA4GH Technical Work Streams, spanning Large Scale Genomics, Cloud, Data Use & Researcher Identity (DURI), Clinical & Phenotypic Data Capture, Discovery, & Genomic Knowledge Standards, have developed standards & tools that are designed to overcome technical and regulatory hurdles to international genomic data-sharing.Foundational Work Streams provide guidance to both Technical Work Streams & Driver Projects in the areas of regulatory, ethics, & data security in genomics.To date, 13 technical standards &18 policies, papers, & an over-arching data sharing framework to guide regulatory practice have been released by GA4GH & can be found on ga4gh.org. These outputs are developed by GA4GH work streams & have been identified by 23 real-world genomic data initiatives—or GA4GH Driver Projects—as immediately relevant to their community/able to support their existing Driver Project efforts. Driver Projects come from nearly 100 countries & include both national initiatives like Genomics England, GEnome Medical alliance Japan &the US All of Us Research Program as well as research programs like the Human Cell Atlas &EpiShare & programs that support the clinical interface such as ClinGen &the Variant Interpretation for Cancer Consortium.These initiatives advocate, mandate, implement, & use the policies and standards in their local contexts. There are now several examples of research & clinical care being enabled by GA4GH standards, & these numbers continue to increase. Genomics England is using the htsget API to serve all of its data from the 100,000 Genomes Program &the Genomic Medicine Service. Access to large-scale cohorts can now be facilitated by GA4GH-developed Researcher Identity &Data Use standards by automatically matching the researcher’s characteristics to the data access policy.The All of Us Research Program intends to use these standards in conjunction with the NIH eRA Commons to manage data access. Using the GA4GH Workflow Execution Service API, researchers can then execute the analysis method(s) they choose on federated datasets that may not be shareable across international boundaries.This effort can happen at scale, independent of the details of network topology & data location. In summary, a full understanding of the basis of human health & disease will require enormous datasets & global collaboration & data sharing. The GA4GH is enabling this community effort on an international scale.",,8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_01878,Medical Research Council,MRC,Shaping a stem cell into dozens of cell types: A single-cell epigenetic roadmap of planarian stem cell differentiation,"Pluripotent stem cells give rise to multiple lineages of differentiated mature cell types. We currently think that stem cells change their chromatin accessibility patterns in a different manner in each differentiation lineage. The regulation of this process is of fundamental importance for regenerative medicine and reprogramming and its deregulation causes human disease and cancer. However, how stem cells orchestrate these changes to activate multiple differentiation programs into a myriad of cell types is still unknown. Planarians are an ideal model organism to investigate this question as their stem cells constantly differentiate into all cell types to turn over their tissues. The advent of single cell technologies, together with the properties of the planarian model, will enable this research now. We have already applied single cell transcriptomics to planarian stem cell differentiation, revealing for the first time their full differentiation lineage tree. Here I propose to measure chromatin interactions and accessibility at the single cell level in the bulk cell population of the planarian Schmidtea mediterranea. By using and combining Chromatin Conformation Capture techniques to monitor chromatin interactions and single cell ATAC-seq to measure chromatin accessibility we will elucidate the changes in chromatin accessibility that take place during stem cell differentiation into each differentiated cell lineages and their order. By measuring chromatin accessibility after knocking down candidate conserved regulators, we will be able to detect the chromatin changes they induce, the genomic regions where they happen and the differentiation lineages where they are needed. Since many of the genes involved are conserved from humans to planarians, this knowledge will inform human stem cell therapies and regenerative medicine. This will lay a cornerstone into our understanding of the epigenetic bases that regulate stem cell differentiation to multiple cell types.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_19180,Wellcome Trust,,Shared Futures: Codeveloping Medical Humanities in China and the UK,"The programme of exchange and networking proposed here aims to build on preliminary experiences of connecting and co-working between UK and Chinese institutions in order to:   i. Drive the Medical Humanities as a mature disciplinary field in China. ii. Grow collaborative working between an expanding number of Chinese institutions and UK universities in the Medical Humanities. iii. Establish a generation of scholars in the Medical Humanities with experience of research, training and teaching in both academic cultures and the capacity to build the field in China and elsewhere. iv. Equip graduates of the programme with Medical Humanities knowledge and perspectives to enable them to engage in fresh ways with human health problems and challenges as they enter careers and sectors beyond academe around the world.   It will connect the partners at the institutions above as they work together to enable:   i. 18 M.Sc. students from SHU, SASS and Fudan to complete Masters degrees at the CSHHH Glasgow and the CHSTM at Manchester University. ii. 9 one-year Early Career Researcher (ECR) Medical Humanities Fellowships at SHU, SASS and Fudan University. iii. 6 Medical Humanities events (3 workshops in UK and 3 conferences in China) to showcase the network.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_03790,Medical Research Council,MRC,Silicosis and silicotuberculosis amongst small scale gemstone miners in Northern Tanzania,"Artisanal and small scale mining (ASM) provides employment for an estimated 45 million people. Despite known occupational risks, it is a key and underrecognized component of the world economy. There are few studies of the health impact of ASM, particularly regarding silicosis and tuberculosis (TB). Silicosis is contingent on cumulative respirable crystalline silica (RCS) exposure and has only been characterised in one ASM population in Brazil. Rates of TB in miners are high but the impact on community transmission unclear. Whole genome sequencing (WGS) of TB facilitates mapping transmission and drug resistance testing. Tanzanite mining in Mererani, Northern Tanzania, is exclusively small scale. Current evidence suggests silicosis is highly prevalent and presents aggressively after short exposure. TB appears highly prevalent in the community and miners. My primary hypothesis is the rate of silicosis progression and respiratory impairment is high, associated with cumulative RCS dose, and modified by TB. My secondary hypotheses include; that prevalence of TB among miners and the community is high, and transmission occurs within mines and from miners to the community; that miners experience high rates of catastrophic economic loss; and that rates of drug resistant TB transmission are high. To do this, I propose two studies. First, I will establish a prospective cohort of 410 small scale tanzanite miners and record symptoms, respiratory function including spirometry, chest radiography, and prevalence of TB and HIV infection over an 18 month period. Second, I will perform a cross-sectional study on participants identified to have TB during community screening and at baseline in the cohort. I will collect epidemiological data and perform WGS on positive Mycobacterium tuberculosis culture samples. There are cost-effective interventions suitable for interventional studies. Given the lack of research in this area, this study will have global implications.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_03194,Medical Research Council,MRC,Single molecule nucleocytoplasmic transport dynamics in FTD/ALS,"The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. This programme will explore how nucleocytoplasmic transport is affected in FTD and ALS at the single molecule level, and how this links to common disease pathologies. Studies will focus on disease-associated proteins containing LCDs, such as those identified pathologically in individuals carrying C9orf72 mutations. This multidisciplinary work will utilise super resolution microscopy to investigate the dynamics of single molecule cargo through the nuclear pore combined with biophysical studies to study phase transitioning of nuclear pore selection barriers to unveil unique disease pathomechanisms often overlooked from bulk endpoint analyses. Methodologies developed in these studies will be broadly applied across different disease models, from transduced cell lines to patient-derived induced pluripotent stem cells (and adapted for use in Drosophila and mouse models), utilising transcriptomics and proteomics. Key mechanistic findings will be validated in FTD and ALS patient tissues to ensure disease relevance.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_00057,The Francis Crick Institute,Crick,Single molecule studies of cell motility and cell signalling,"My core research interest lies in understanding how mechanical force affects or controls interactions between biological molecules. The energy balance of most biomolecular interactions lies somewhere between thermal energy (kBT=4pN.nm) and the free-energy of ATP hydrolysis (100pN.nm). This means macromolecular assemblies (e.g. the cytoskeleton, multi-subunit protein complexes, protein-DNA transactions) can be readily assembled and disassembled and relatively weak forces can have dramatic effects on these processes. My group uses a variety of optically-based, single-molecule technologies, some of which allow picoNewton forces to be applied or measured (i.e. optical and magnetic tweezers and atomic force microscopy) while others (Total Internal Reflection Fluorescence and super-resolution microscopy) allow single molecule interactions be observed within living cells. A major question in the area of molecular motor research is how chemical energy is transduced to mechanical work. My group have been studying the mechanical properties of actin-myosin, using a combination of single-molecule techniques including optical tweezers and live cell imaging using TIRF microscopy. We are using super-resolution optical microscopy and cryoEM (with Peter Rosenthal, Crick) to map the ultra-structure of microscopic cellular protrusions called filopodia. We want to understand how myosin-10 moves along actin filaments located within filopodia and how malarial class 14 myosins drive parasite invasion into the red blood cell. We are also examining the bundling and cooperative motion of actin filaments driven by myosin motors and how this is modulated by the calcium-calmodulin-dependent kinase CamKII (important in dendritic spine remodelling during Long-Term-Potentiation and learning). Our single molecule studies of bacterial plasmid replication (with Martin Webb) and plasmid transmission (Gabriel Waksman, UCL, London) using magnetic tweezers aim to address how DNA topology (specifically DNA twist and writhe) affect assembly and action of the relaxosome complexes that nick plasmid DNA and initiate its. Specifically we want to know how relaxase enzymes sense DNA supercoiling and how associated helicase activity is affected by DNA tension or torsion. We are also studying how archaeal histone binding to DNA is influenced by topology and transcription factors (with Werner, UCL). We intend to develop more sophisticated magnetic tweezer based approaches with our colleagues at KCL, London (Paula Booth and Sergi Garcia Manyes) in order to manipulate DNA and membrane proteins (see below). Our work on G-protein coupled receptors and ion channels uses a combination of optically-based single-molecule approaches (our expertise) with electrical recording using patch-clamp (with Lucia Sivilotti, UCL).",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_20533,Wellcome Trust,,"Sleep circuitry: linking homeostasis, sedation and stress","This proposal aims to understand: 1) What circuitries sense the inexorable drive to sleep when we are sleep-deprived?  We will investigate if sleep need is sensed locally in the brain by a distributed circuit network that feeds into a central hub, the lateral hypothalamus, providing global restorative sleep. We have identified neurons in the mouse prefrontal cortex, preoptic hypothalamus, and ventral tegmental area (VTA) that sense sleep need and contribute to inducing sleep after sleep deprivation. Learning how responses to sleep deprivation are embedded in distributed sleep circuitry would explain how sleep homeostasis works at the circuit level. 2) Do sedative drugs promote these restorative sleep pathways? How do two important drugs, propofol and dexmedetomidine, intervene in the sleep-homeostasis circuitry? We will search for cells that respond to sedatives to induce restorative  sleep without deleterious effects (hypothermia). Understanding this circuitry may identify new drug targets. 3) What is the significance of sleep-promoting circuitry we have discovered in the basal ganglia and midbrain (globus pallidus to lateral habenula to VTA to lateral hypothalamus), which overlaps with circuitry that responds to aversive outcomes and stress? We will investigate if this basal ganglia-triggered sleep helps offline processing of negative experience.","We sleep for 30% of our lives, but why we do remains a mystery. We will address several questions centred around sleep’s restorative properties: what circuitries sense the inexorable drive to sleep when we are sleep deprived, and do sedative drugs hijack these natural restorative sleep pathways? Why do things feel better after a good night’s sleep - how does sleep mitigate negative experiences? We will use the latest genetic, physiological and behavioural techniques  with mice to identify the circuitries involved. Our work will aid understanding of feedback processes that sense the sleep drive, and identify whether drugs can be developed that provide natural sleep’s restorative benefits; we will determine whether side-effects (e.g. hypothermia) of sedative drugs can be reduced. Finally, our discovery of sleep-promoting circuitry in the basal ganglia, which overlaps with circuitry that controls how we react to negative experiences, could allow new approaches to improve mental health.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;NEUROLOGICAL HRCS22_02781,Medical Research Council,MRC,Sleep regulation by neuron-astrocyte interactions,"A better understanding of neurobiology in sleep is extremely important for our health. However, the regulatory mechanism of REM sleep remains elusive compared to NREM sleep. Previous studies have suggested that the sublaterodorsal nucleus (SLD) plays a central role in REM sleep regulation. However, it remains unclear how SLD neurons are regulated across the sleep-wake cycle in vivo. Although accumulating evidence also suggests that astrocytes are involved in sleep homeostasis as a wakefulness integrator, our preliminary results show higher calcium signals during NREM sleep in SLD astrocytes, implying that SLD astrocytes play a role in NREM sleep maintenance and REM sleep induction. To investigate the regulatory mechanism of calcium signals in SLD astrocytes across the sleep-wake cycle, we will test the hypothesis that activity of GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG) modifies calcium signals in SLD astrocytes across the sleep-wake cycle. By combining optogenetic and calcium imaging approaches in mice, we will investigate how SLD-projecting vlPAG GABAergic neurons ('vlPAG->SLD GABAergic neurons') are active across the sleep-wake cycle, and whether the optogenetic activation of vlPAG->SLD GABAergic neurons can increase calcium level in SLD astrocytes. To explore the functional role of calcium signals in SLD astrocytes, with respect to sleep regulation, we will test the hypothesis that calcium signals in SLD astrocytes play a role in NREM sleep maintenance and REM sleep genesis. By combining chemogenetic, calcium extruder and calcium imaging, we will investigate how artificial manipulations of calcium level in SLD astrocytes affects sleep architecture. This study will shed new light on the importance of astrocyte for sleep regulation.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_13960,Cancer Research UK,CRUK,Smartphone application for effective prostate cancer screening utilising machine learning- enhanced ultrasound PSA-density measurement,"Background Prostate cancer (PCa) is the commonest male cancer. Prostate-specific antigen (PSA) testing is the first-line investigation used for referral to secondary care. Around half of the 120,000 patients/year referred in the UK are ultimately diagnosed with PCa, highlighting the inefficiencies in the current system, including utility of MRI as an expensive resource, and biopsy as an invasive procedure. A common reason for raised PSA levels is benign prostate overgrowth; PSA-density corrects for enlarged gland volume and can therefore better indicate the presence of clinically significant cancer. Ultrasound (US) can measure gland volume, however, US is currently performed in secondary care by specialised practitioners, which increases costs, and may delay cancer pathways. Making US volume calculations automated, cheap, and potentially available in primary care would avoid such limitations. Aims We will perform system optimisation of a prototype device for automated US measurement of prostate volume and validate its performance in a patient cohort. The device will feature: [1] A real-time miniaturised tracker paired with a smartphone to track US-probe position [2] A workflow-optimised smartphone application importing real-time video streaming of US images and presenting them to clinicians [3] A machine learning algorithm that detects, segments, and reconstructs real-time 3D-prostate volume, allowing PSA-density calculation Methods The miniaturised tracking system uses a wireless reusable tracker that integrates with a MEMS-based gyroscope, magnetometer sensor, and tracking software. The tracker will be compact and can be clipped onto any existing US machine/probe. The smartphone application will simultaneously capture positional data from the tracker and prostate images from the US scanner. The utility and workflow of the device will be first optimised on a prostate phantom. A proof-of-principle clinical study will then be performed comparing smartphone/machine learning-derived PSA-density in a 20-patient cohort undergoing clinical MRI, for gold-standard comparison. How the results of this research will be used We will validate our device prototype in a small prospective trial of tertiary-care patients to demonstrate efficacy and to statistically power larger clinical trials in primary care and inform subsequent licensing/commercialisation. Our disruptive technology will potentially allow screening of prostate patients in GP practices, to obtain accurate PSA-density prior to urology referral. This will improve patient management and reduce costs by rationalising MRI use, allowing appropriate avoidance of further investigations in some patients, and triaging other patients for more urgent MRI. This technique offers potential for quick translation into primary-care for screening and optimisation of cancer-care pathways.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_06403,Department of Health and Social Care,NIHR,Social Care Recovery and Resilience: Learning lessons from international responses to the COVID-19 pandemic in long-term care systems,"Research question What can we learn from international evidence and experiences in order to support the recovery of the social care sector and to inform the development of policies to prevent and manage future outbreaks in social care settings in England? Background The first wave of Covid-19 has had an enormous impact on people who use and provide long-term care in England, with substantial excess mortality, compared to previous years, both for people who use home care and who live in care homes, and other impacts on mental and physical health, it has also had a major impact financial impact on care providers. As England faces a second wave and considers the recovery of the sector, there is an opportunity to learn more in-depth from relevant experiences of other countries in implementing measures to prevent and mitigate these impacts in care settings and through taking a systematic and rigorous approach to synthesizing emerging scientific evidence about which measures have worked well or not. Aims and objectives We aim to facilitate learning from the scientific evidence and relevant experiences of other countries in preventing and mitigating Covid, as well as recovering from its impacts in social care setting through: Co-development of a framework to provide strategic direction for how the social care sector in England can recover from, and respond to, Covid-19 (we define the social care sector as care provided in residential and community settings, by paid and unpaid carers) Synthesis of international evidence and lessons learnt that are relevant to the English social care sector Informing the development of policies and practices to support recovery and better prevent and manage future outbreaks Methods We will use situational analysis and Theory of Change (ToC) to establish a framework from which to assess the relevance of international experiences and evidence to the social care system in England. We will then carry out scoping reviews to map and synthesise empirical evidence on measures that can support the social care sector in preventing and mitigating the negative impact of Covid. We will then use a case study approach, including document analysis and interviews, to review in detail the experiences and learnings from 4 countries. Finally, we will apply the framework developed through ToC to synthesise findings from these work streams. Timelines for delivery The project plans to start on the 1st of November and will last for 18 months. The work plan has been organized to deliver outputs in a timely manner as practicable, recognising the critical nature of the Covid pandemic. Anticipated impact and dissemination The project s framework and priorities will be co-developed with stakeholders, to ensure that the research is relevant and useful within an English social care context. The team is well positioned to ensure effective and timely dissemination through their own policy and practice networks, their institutions, relationships with media and the dissemination platforms provided by their respective institutions and the LTCcovid.org website.","This project aims to understand the important areas that need addressing to improve the English social care system s response to the Covid-19 pandemic, support the recovery of the sector and better prevent and manage future outbreaks. It will also seek to learn from the good and bad experiences of other countries and from the scientific evidence. We will do this in four main steps: We will consult with people involved in social care – those using, providing, commissioning and designing services. We will ask them what are the key questions that we should be looking to answer in this project. We will use a structured exercise to map out how to prevent or reduce the severity of future outbreaks, and how to recover from the effects of the first Covid wave. We will search and summarise scientific studies to find out which measures worked, or not, during the pandemic. We will review the experiences of other countries in dealing with Covid-19 in social care settings (not just care homes), identifying which measures were successful in protecting people who use care and why. We will consider how structures already in place in these countries, as well as specific responses to local outbreaks, may have contributed to reducing the impact of the pandemic. Building on existing reports, we will identify four countries with both positive and negative experiences during the pandemic and identify the reasons behind their successes and failures by interviewing people, and reviewing policy documents, in those countries. Finally, we will bring together the learnings from international experiences and the scientific evidence to identify lessons for the recovery of the English social care sector and to inform management of future Covid outbreaks or other infection disease outbreaks. We will again work with those directly involved in social care (as above) to review how these strategies fit onto the route agreed with them in step 1. It is important that our findings are available to national and local decision-makers as quickly as possible. Therefore, we will regularly publish research evidence summaries, targeted briefings and blogs, using social media to disseminate messages. We will use our wide and established networks among policy-makers, government, providers and organizations that represent people who use care and unpaid carers to ensure that findings reach the right people, setting up meetings with key stakeholders. A final output will bring together what we have learnt across the project and summarise the main lessons and recommendations for the recovery from, and future prevention and management of, Covid-19 in the English social care sector, as well as lessons emerging to inform the longer-term future of social care.",8.1 ORGANISATION AND DELIVERY OF SERVICES;7.1 INDIVIDUAL CARE NEEDS,GENERIC HEALTH RELEVANCE HRCS22_20767,Cancer Research UK,CRUK,Southampton Clinical Trials Unit,"The Southampton Clinical Trials Unit (SCTU), at the University of Southampton, is a UKCRC registered CTU which is integrated within the Southampton CRUK Centre, Experimental Cancer Medicine Centre (ECMC) and Centre of Cancer Immunology (CCI) with strong links to the Wessex Investigational Sciences Hub laboratory (a CRUK CDD Biomarker Centre of excellence for immunomonitoring). SCTU has good representation of its statisticians and clinical investigators on all the relevant NCRI Clinical Studies Groups. Patient and public involvement runs through the whole SCTU system, from the initial review of whether to take on a trial, through funding application, delivery of the trial and dissemination of results. SCTU has a highly efficient operational set up and state of the art clinical trial information systems, which has resulted in trial set-up times which are among the best in the UK academic sector. We have a growing portfolio of innovative experimental therapeutic studies and a range of large scale studies combining important clinical questions with extensive correlative science, in order to maximise the information we derive from every study subject. As well as a strong track record of precision medicine studies SCTU has experience of establishing of a nationwide platform for molecular phenotyping in aggressive lymphoma which it plans to mirror in other tumour sites. SCTU's principal tumour sites of interest are upper gastrointestinal cancer, lymphoma and urology, although studies in other sites such as head & neck, breast and mesothelioma are supported, especially if they align with the SCTU expertise and focus in cancer immunology. SCTU supports a number of innovative experimental medicine studies of immune-oncology reagents developed in the laboratories of Southampton CCI/ECMC, with an expanding portfolio in this field working in partnership with industry, spanning all the way from first-in-man to large scale randomised trials. A growth area for SCTU is early detection, increasing links with the NCRI Screening, Prevention and Early Diagnosis CSG and building on successful recruitment of a very large cohort of 20 000 people with potential symptoms of early malignancy, from whom blood samples that have been stored for future analysis in collaborations addressing early cancer detection. SCTUs links to public health and primary care in Southampton will be important assets in this area. Our CRUK core funding will allow us to contribute to CRUK’s vision of bringing forward the day when all cancer is cured and 3 in 4 patients will survive their cancer by 2034.",,4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION),CANCER AND NEOPLASMS HRCS22_09265,"Chief Scientist Office, Scotland",CSO,Spatial and network phylodynamics of COVID-19 in Scotland,"Viral phylogenetic data (i.e. the family trees of viruses obtained from infected individuals) provide unprecedented detail on virus spread and inform our understanding of “who infected whom?” However, data issues, including variations in evolutionary rates and incomplete, biased sampling can hamper their utility, and influence our interpretation of events. For example, the number of transmission events that are deemed to occur before or after a policy change influences our understanding of its efficacy and our estimates of this is skewed by biases. As COVID-19 genetic data relies heavily on self-reported community tests, these biases can be substantial. By combining viral genetic data with Scotland-specific demographic and COVID-19 cases data (including dates and locations of tests, types of test, age and gender), we shall generate analytical tools to account for these issues and ask important questions about the COVID-19 epidemic’s control, including: i) How close did Scottish measures come to eradicating COVID-19 in the summer of 2020, and how important was travel with other countries in perpetuating the epidemic? ii) What impact could long distance movement restrictions have had in slowing down the spread of the Alpha and Delta variants across Scotland? iii) Can we estimate region-specific differences in control measure efficacy? By addressing these questions, we shall be developing methods that will allow us, in future, to robustly inform policy questions in real time. These tools will also be invaluable for analysing other infectious diseases in Scotland such as influenza or future pandemics), further increasing the utility of this project",,2.4 SURVEILLANCE AND DISTRIBUTION,INFECTION HRCS22_14328,Diabetes UK,,Spatiotemporal Control of Signalling of the GLP-1R Variant Ala316Thr in Pancreatic Beta Cells,"The glucagon-like peptide-1 receptor (GLP-1R) is an important target for type 2 diabetes (T2D) therapy that improves beta cell function amongst other beneficial effects. GLP-1R non-synonymous genetic variants are associated with alterations in beta cell responses potentially linked to pharmacogenetic changes GLP-1R agonist effects and/or varying T2D risk. Individuals with the GLP-1R single nucleotide polymorphism Ala316Thr present with decreased T2D and cardiovascular risk, as well as lower fasting glucose without insulin sensitivity changes. As the spatiotemporal regulation of signalling is key to control GLP-1R responses, the student will investigate trafficking and signalling characteristics associated with GLP-1R Ala316Thr to identify specific mechanisms by which this allele reduces T2D risk. We have detected reduced basal clustering, increased lateral diffusion and cAMP versus β-arrestin-2 signal bias for this variant, which correlate with sustained in vitro insulin secretion, reduced trafficking to degradative compartments and increased segregation to perinuclear endosomes. Here, the student will characterise changes in GLP-1R-lipid nanodomain interactions, post-translational modifications, specific binding partners and intracellular signalling signatures for this allele employing state-of-the-art quantitative microscopy, biochemical assays and mass spectrometry-based proteomics. Additionally, they will study in vivo this variant and its regulation by β-arrestin-2 in GLP-1R Ala316Thr knock-in mice ± beta cell-specific β-arrestin-2 knockouts.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,METABOLIC AND ENDOCRINE HRCS22_11637,Economic and Social Research Council,ESRC,Speech Therapy Animation and imaging Resource (STAR),"We will work with qualified Speech and Language Therapists (SLTs), the educational providers registered to license them, and SLT Clients and their carers, to create freely-accessible, online vocal-tract imaging resources and animations to improve pre-registration SLT training, aid continuing professional development (CPD) and provide an engaging visual resource for use in Clinic and at home. Our research aims will address the current debates for SLTs about how best to deliver both SLT training and Speech Therapy in remote/blended forms, especially for paediatric care. Our main aims are to: 1. Create clinically-focussed, online vocal-tract-imaging and animated resources to allow users to view the movements of both the hidden and visible speech organs. Using existing ultrasound tongue imaging (UTI), and magnetic resonance imaging (MRI) vocal-tract research datasets of child and adult speech, we will create resources housed on two connected Websites; one for SLT training and CPD, the other for use in Clinic with paediatric Clients, or for Clients' use at home. 2. In doing this, we aim to extend the reach of audio-visual therapies for remediation of speech delay/disorder to children outside face-to-face clinic sessions, by providing accessible online resources for independent home practice. Our Clinical paediatric Website will contain simplified, but accurate and engaging animations of the vocal-tract during speech-sound production. Key speech sounds will be animated, based on real children's and adults' speech. Animations will demonstrate differences in tongue shape and placement. Interactive exercises for Clients/Client's carers will facilitate aspects of practise homework set by SLTs in Clinic, e.g. speech-articulator identification, speech-sound discrimination tasks. 3. Our training Website aims to promote understanding, familiarity and use of articulatory imaging in (motor-based) Speech and Language Therapy. UTI-based visual biofeedback and visual articulatory animated model (VAAM) based therapies are important specialist tools in speech therapy intervention and clinical diagnosis. By adding dynamic visual material to audible speech recordings, breakthroughs in the treatment of persistent disorders can be achieved. However, imaging technologies are not widely used in general paediatric clinics. Many SLTs are unfamiliar with this technology. Our site will provide introductory explanations and comparison of imaging techniques, demonstrations of use, and links to literature. 4. With both Websites we aim to augment the audio-visual resources currently available to train and support Speech and Language Therapists (SLTs) for both consulting and specialist roles. SLTs will be able to better explain the movements of the hidden, as well as the visible, speech articulators and articulatory movement to Clients with the material on the paediatric clinical Site. The training Web-site will be suitable for preregistration SLT phonetics learning, but also inter-professional education, as well as for reference, revision and CPD. The training Web-site will contain much sought after resources such as (a) a clickable chart containing the extended-International Phonetic Alphabet (ext-IPA) speech symbols linked to MRI, UTI and animated video of performance of extIPA disordered speech sounds (b) a filterable database containing UTI-based recordings of examples of disordered speech sound productions, produced by children (c) a filterable database containing UTI-based recordings of non-disordered adult and child speech. 5. We aim to work with SLTs, trainers, and students, Clients and carers, to evaluate qualitatively and quantitatively the Web resources created. We will determine which resources are most helpful and effective for each user group.","Speech and Language Therapy training and practice is dominated by approaches involving listening to sounds, feeling the movements of the speech organs and verbal descriptions of how speech sounds are produced. However, recent research involving use of visual information about hidden speech organ movement in particular (e.g. tongue movement) has shown that visual approaches to speech therapy can be game changing, providing breakthroughs after years of conventional therapy. One of the main advantages of visual approaches is that viewing dynamic imaging of the hidden speech organs has been shown to be a more intuitive method of demonstrating target speech articulations, particularly for children, avoiding complex, abstract descriptions of how speech organs move. Several technologies can be used to reveal the hidden speech organs. Ultrasound Tongue Imaging (UTI), using standard medical ultrasound machines, has emerged as a promising therapy tool, allowing users to view target tongue movements and compare them to their own. Magnetic Resonance Imaging provides a more comprehensive view, showing all parts of the vocal tract, but is not suitable for use in day-to-day therapy. Costs, training and accessibility prevent the general use of these technologies in Speech Therapy clinics; however, clinical and phonetic researchers have collected a large number of UTI and MRI video recordings of both disordered and non-disordered speech. These represent a valuable training/therapeutic resource, but cannot be accessed in their current form, as most UTI/MRI datasets can be viewed only using expensive and technically-sophisticated specialist software. UTI and MRI reveal a greater variety of strategies for speech-sound production than are generally considered, and therefore provide a greater number of strategies for Clients to try. The benefit for Speech Therapy Clients is a better understanding of tongue movement and placement in speech-sound production, a more intuitive means of understanding vocal-organ movement and visual input, which can be particularly useful for those who learn more effectively through visual demonstration. This project will create bespoke resources for Speech Therapists' training and use in Clinic; the Speech Therapy Animation and imaging Resource (STAR). Existing vocal-tract-imaging recordings from six different clinical and non-clinical speech-research projects will be made available online, in the most accessible formats and user-friendly interfaces. Additionally, MRI recordings of speech will be used to create accurate, simplified vocal-tract animations for use by paediatric Speech Therapy Clients, in Clinic and at home. These animations will show how the vocal organs move in the production of speech sounds. STAR will consist of two Web sites; one for Speech Therapists' training, reference and continuing professional development, and the other for use by paediatric Clients and their families, in Clinic, and at home. The training site will contain vocal-tract animations and explanations of UTI and MRI technology and recording processes. It will contain much needed databases of UTI videos of disordered and non-disordered speech, showing a variety of speech-errors and disorders, as well as normative speech-sound production in a variety of English accents. The clinical site will contain clear and informative animations explaining how the vocal tract works and showing speech-sound production in different syllable positions. It will also contain interactive animated homework exercises to facilitate aspects of practise homework set by Therapists in Clinic. STAR will make available these resources at a time when the need for remote quality clinical teaching has never been greater. The research strand of our project will be to work with the SLT community and Clients, to assess how best to deliver remote and/or blended training and therapy, which meets the challenges of the current and post-COVID-19 environment",5.7 PHYSICAL;8.1 ORGANISATION AND DELIVERY OF SERVICES,MENTAL HEALTH HRCS22_01801,Medical Research Council,MRC,Standardising surgical Interventions and Co-interventions: development of a quality assurance intervention for surgical RCTs (STItCh-IT),"Well designed and conducted surgical RCTs are essential to establish evidence-based practice. Currently, few surgical RCTs are undertaken and existing ones are often methodologically weak. An unaddressed challenge relates to the complexity of surgical interventions, which comprise multiple components and co-interventions that are delivered by surgeons with differing expertise. This complexity can mean interventions are not delivered as intended, creating unexpected differences between and within trial groups. Differences can be further exaggerated through the introduction of performance bias, which occurs if healthcare providers become aware of treatment allocations during the RCT. In pharmaceutical RCTs, performance bias is reduced through blinding staff and care givers; however, this is difficult in surgical settings. Alternative strategies are therefore required. This project will create a 'quality assurance intervention (QAI)' to optimise the quality assurance of surgical interventions and co-interventions in RCTs. This will involve development and use of i) a typology to systematically deconstruct surgical (co-)interventions into their component parts; ii) methods to maximise the efficiency of systematic reviews to summarise existing evidence about how each component of the (co-)interventions should be standardised, thereby identifying evidence gaps; iii) methods to undertake qualitative research in the operating theatre, to address the evidence gaps; and iv) consensus methods for trials teams to agree on the standards of surgery within an RCT. I will pilot the QAI using exemplar cases, create a guidance document and develop an interactive online platform. This will provide a practical solution for optimising the QA of surgical interventions during RCT design, reduce performance bias and improve the transparency of intervention delivery, so surgical procedures can be more accurately replicated in clinical practice.",,8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_21879,Innovate UK,IUK,Steel inclusion detection using high resolution X-ray non-destructive testing,"SilverRay Ltd is a start-up company whose primary goal is to exploit a proprietary technology developed for the production of large area, high sensitivity X-ray detectors for real-world applications. This proprietary technology has demonstrated a 2-3 orders of magnitude higher X-ray detection sensitivity than conventional organic detectors, whilst operating at low voltages and offering excellent shaping to complex surfaces. Further, the technology has detected X-radiation over a broad energy range, from 60 kV to 6 MV, making it applicable for a variety of end applications such as medical radiography, non-destructive testing, and security border controls, amongst others. The current, dominant technology for non-destructive testing (NDT) by radiography is the use of advanced digital X-ray imaging technology based on inflexible flat panel detectors, with outputs displayed directly on to a computer screen. The detectors cannot be flexed, and need to be used in its rigid form with care due to its high expense and fragility. This is in comparison to the traditional and widely used flexible photographic film technology which allows access to complex parts/corners of an object but which does not offer real-time imaging or digital manipulation. At SilverRay Ltd, we have developed a detector active material consisting of a printable 'X-ray sensitive ink' containing two elements: an interpenetrating network of organic material and inorganic nanoparticles. The 'X-ray sensitive ink' can be used to coat X-ray sensitive pixelated films over a wide range of substrates, including the development of flexible detectors. Thus far, small area detectors (<1 cm2) have been successfully developed by SilverRay Ltd. The aim of the current project is to scale up the technology to large area (8x2.5 cm2) conformable, multi-pixel, digital devices suitable for X-ray imaging in NDT applications. Readout electronics will be developed allowing for remote NDT examination in a manufacturing setting. With the project collaborator, Tata Steel, detector performance will be tested in a real world application on safety critical products used in the construction industry. The X-ray imaging system produced as an outcome of this feasibility programme will allow SilverRay to demonstrate their proprietary large area digital film based technology at a scale suitable for many other applications including NDT. This novel breakthrough technology is backed by a US granted patent application, and will be initially adopted to manufacture detectors suitable for NDT applications such as for the safety critical products identified here.",,4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),GENERIC HEALTH RELEVANCE HRCS22_07382,Department of Health and Social Care,NIHR,Stewardship of Antimicrobials using Real-Time Artificial Intelligence (SamurAI) - Phase 1,"Background: 20-30% of patients in hospital are taking antibiotics unnecessarily, or being treated with a suboptimal choice of drug, dose or duration. This increases patients' risk of side-effects and future drug-resistant infections and prolongs hospital stay, which increases healthcare costs. Stopping antibiotics early in patients who no longer need them can reduce antibiotic overuse, but most doctors – except experts in infection - find this challenging. SamurAI s goal is to give every doctor 24/7 access to an infection expert. Aim: To prototype and test an AI device which identifies patients who could stop or change antibiotics, in order to reduce unnecessary antibiotic prescribing. The device will monitor every patient in hospital taking antibiotics, and alert doctors to patients who could stop or change antibiotics so they can be reviewed by an infection expert. Methods: We will create a training dataset which links historic expert antibiotic review decisions to electronic health records for the corresponding prescribing episode. Using the dataset we will train a supervised classification model to predict an experts prescribing review decision (stop, change, continue antibiotics). Model predictions will be validated in 700 randomly sampled cases by comparison with the experts review decision in order to estimate Receiver Operating Characteristics (ROC) Area Under the Curve (AUC). Safety data will also be collected. Timeline: 0-2 months - training dataset; 2-6 months - classification model; 9 months - validation; 9-12 months – dissemination. Impact: This study will provide validation data in a relevant environment (TRL5). Dissemination will focus on raising awareness of SamurAI among clinicians, pharmacists, patients, policy makers, and NHS senior managers) and identifying sites to participate in a future multi-centre clinical evaluation. A patient public involvement group will oversee SamurAI s use of patient data and be involved in all stages of the research project.","The Problem Antibiotics save lives, but the more they are used, the less effective they become. Infections learn how to resist them. More than 50,000 people in the UK have infections that resist antibiotics, and this number will increase if we do nothing. In a typical hospital, around 150 patients are taking antibiotics on any one day. Research suggests that 30-50% of individual prescriptions could be avoided if they were reviewed by a specialist in antibiotics looking at things with the danger of over-use in mind. However, there aren t currently enough of these specialists - microbiologists and antibiotic pharmacists - to review every antibiotic prescription and provide feedback to every doctor. For last 2 years we have been working with infection specialists, health psychologists and designers to solve this problem. The Solution It s simple - use fewer antibiotics. But antibiotics seem so helpful that this hasn t worked, the use of antibiotics in UK hospitals is still growing. Our plan is to develop and test something we call SamurAI. It involves computers working in a way that copies human thinking ( artificial intelligence ) and it takes advantage of the introduction of electronic patient records into UK hospitals. The system will combine historical data for patients prescribed antibiotics with the findings of specialists in infection as they review prescriptions. Under specialist medical supervision, the computer system will learn what works best and when to start, stop or change the use of antibiotics. Once up and running the system should be able to identify and flag patients who should be reviewed by specialists and guide antibiotic treatment for individual patients. The research will start at one hospital in London, but our aim is to roll it out to 3 different hospitals within 4 years. Evaluation and Safeguards First, we will evaluate whether SamurAI can accurately and safely identify patients who can stop, change or switch antibiotics. We will compare SamurAI s predictions to what happens when experts review 200 patients taking antibiotics. If SamurAI s predictions and the experts mainly agree, we will apply for funding to further develop and test SamurAI through carefully designed trials. We expect it can reduce antibiotic use by 10-20%, benefitting patients by reducing their time in hospital and the risk of side-effects from antibiotic treatment. Reduced use will also prolong the lifespan of our existing antibiotics. Once we have tested the system in our three hospitals, we aim to introduce it in new hospitals by 2027. We will involve patients, the public and healthcare workers at all stages of the project, to understand their concerns about using patient data and agree how to protect it. We will hold a workshop to share research findings with patients.",7.3 MANAGEMENT AND DECISION MAKING,INFECTION HRCS22_06595,Health Education England,HEE,Stopping abusive voices from distressing patients with schizophrenia,"Background: The majority of patients with a diagnosis of schizophrenia hear voices (70%). Around half report their voice(s) to be persistently abusive or violent.Hence it is unsurprising that voice hearers experience depression, anxiety, low self-esteem, suicidality and, when acute, hospital admission. Current treatments require substantial improvement: antipsychotic medication is only moderately effective and generic CBT results in only small improvements in voices.Evidence suggests that the diagnosis of schizophrenia is comprised of multiple independent psychotic experiences including hearing voices (as well as for example paranoid and grandiose beliefs). The heritability of these individual experiences differs and there are distinct genetic and environmental contributions to each. The most fruitful approach to improving outcomes will be to use a precision medicine paradigm, understanding the unique psychological mechanisms maintaining each psychotic experience and building a treatment which targets them. Within voices alone there are multiple differing presentations. One of the most successful existing treatments targets just one of these voice presentations: command hallucinations. The current application therefore adopts a similarly focused approach to understanding and treating a different voice presentation: engagement with abusive voices.The applicant has developed a cognitive framework for understanding why patients listen to and believe (i.e. engage with) abusive voices. This proposes that key cognitions (thoughts) drive engagement with voices (e.g. 'the voice has important information'), despite the patient knowing that if they engage with the voices, this will leave them feeling distressed. This framework forms the foundations upon which a cognitive model will be developed, based on qualitative analysis of patient experiences. The components of the model will be empirically tested to inform the development of a targeted intervention.Research aims: There are three aims: i) to develop the first model of engagement with abusive voices ii) to refine the model and gather predictive data (ie. how well do key psychological variables in the model predict engagement with abusive voices?) and iii) develop the model into a targeted treatment which enables patients to disengage from abusive voices.Research questions: i)What psychological variables (i.e. cognitions, cognitive styles, attentional styles and affect) are described by people who have experience of engaging with abusive voices? ii) Which psychological variables predict engagement with voices over time? iii)Is it feasible and acceptable to deliver a CBT treatment protocol, based on the above model of engagement, to patients experiencing abusive voices?Plan of investigation: Study one will build a maintenance model of engagement with voices. This will involve a qualitative study with patients to identify psychological factors which promote engagement with abusive voices. From this a cognitive model of voice engagement will be developed. Study two will i) develop and validate a new measure of voice engagement and ii) test the association between model components and engagement with abusive voices over time, using a longitudinal observational design. The model will be refined in light of results and study three will develop a treatment which manipulates key variables to reduce engagement with distressing voices.Potential benefit to patients and the NHS: This programme of translational research will develop a novel targeted treatment, based on a thorough mechanistic understanding of psychological factors which predict engagement with voices. The targeted treatment for abusive voices can be further evaluated in a randomised controlled trial. Patient involvement will ensure that the treatment is highly acceptable to voice hearers.Manual style workbooks and training workshops delivered by the applicant will enable the treatment to be disseminated easily to NHS clinicians. The treatment could be offered as a stand-alone intervention, or added to treatments for other symptoms such as paranoia.","The problem: 'Some really evil [voices] came and they were trying to convince me to kill myself they made themselves out to sound like people were going to break into my house and kick the hell out of me... With the evil voices comes an overwhelming sense of fear.. a fear I've never experienced before.. the darkest thing I wish I never felt... I felt completely helpless and so vulnerable. I was believing it....'. - Domicile'The voices were quite derogatory and it was a hard time to cope with them. I remember feeling so bad about my situation - the bully voice always making me even more depressed -h; that one day I decided to hang myself, but it was the comforting voices that stopped me.' -h; StewartApproximately 70% of people with a diagnosis of schizophrenia hear voices in the absence of someone speaking. There are many ways that these voices manifest, but this research will focus on one common clinical presentation: abusive voices. These are voices which are derogatory or threatening. Depression, anxiety, suicidal thinking, difficulty maintaining friendships, unemployment and hospitalisation are common in this group. Current treatments group all voice presentations together and don't focus on specific sub-types. Anti-psychotic medication and generic cognitive behavioural therapy (CBT, a talking therapy) are the recommended treatments. These require substantial improvement: medication is only moderately effective and associated with marked side-effects, generic CBT results in only small improvements in voices. Only 14-20% of people make a full recovery. This is not as good as CBT for other difficulties, like anxiety. One way to improve effect sizes is to identify factors which maintain specific voice presentations and build treatments which target them. However there has been no sustained research attention investigating factors which cause people to engage with abusive voices, and hence there is no specific treatment.How beliefs about voices promote engagement with them (a cognitive framework):Through clinical experience the applicant has observed a paradox: patients say the voices are trying to upset them, that the voices are doing it on purpose. Whilst patients are aware of this hostile intent, they still listen to and believe (engage with) the voice's derogatory or threatening comments. This results in depression and anxiety. A novel framework for understanding this paradox has been developed by the applicant, drawing on previous literature on i) why people engage in excessive worry, and ii) why patients comply with commands from voices (another specific voice presentation). Whilst most people say that they would prefer not to listen to the voice, there are clear reasons for listening. These are hypothesised to fall into two groups: i) beliefs about listening to voices (reasons for listening) and ii) beliefs about the person's inability to try out alternative approaches. Examples of beliefs about listening to voices include: because the voices threaten to harm them or have important information. Beliefs about the person's inability to try out alternative approaches may include feeling resigned that they have been changed forever by the voices, so there is no point trying. Or, negative predictions about the consequences of disengaging from voices (e.g. 'It'll get so bad that I won't be able to cope'). Next stepsThe framework needs elaborating and testing through the proposed research programme. A comprehensive theory will be developed to explain why people continue to engage with abusive voices. This will be empirically tested and developed into a CBT treatment. Working alongside people with experience of voices will ensure the model and treatment are relevant and acceptable. The research aims to:1) Interview people with experience of hearing abusive voices to identify the psychological factors (e.g. beliefs, thinking styles, attention styles and emotion) that maintain engagement with voices (a qualitative study).2) Monitor patients who hear abusive voices over three months to test which of these psychological factors predict engagement with abusive voices (a quantitative study).3) Translate the theoretical understanding into a CBT treatment (therapeutic development). Feasibility will be examined by offering it to twelve patients. This is important preparatory work before conducting a larger scale effectiveness trial, which would take place at a later point.Potential benefit to patients and the NHS:The programme will produce a potentially much more effective treatment for abusive voices in schizophrenia. A series of workbook style manuals accompanying the CBT will be produced and disseminated to NHS clinicians to ensure that as many people benefit from the research as possible.","2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL",MENTAL HEALTH HRCS22_05563,Department of Health and Social Care,NIHR,Stopping anticoagulation for isolated or incidental sub-segmental pulmonary embolism (STOPAPE),"Pulmonary embolism (PE) is a potentially serious condition, whereby blood clots cause a blockage of the blood supply to the lungs. PEs are often caused by blood clots in the legs and occasionally the arms (deep vein thrombosis (DVT)) breaking off and travelling to the lungs. A number of risk factors increase the chances of developing PE and/or DVT, including cancer, major surgery, pregnancy, some medications (e.g. the combined oral contraceptive pill or hormone replacement therapy), dehydration, long-distance travel and prolonged immobility. The symptoms of a PE depend on the size and location of the blood clot. A large PE can cause symptoms of breathlessness and chest pain, and the diagnosis is made using blood tests and a scan of the lungs. The treatment of PE includes anticoagulant medication (“blood thinners”) that are taken over months and include: warfarin, an injectable form of heparin and direct oral anticoagulants (DOACs). These medications work by preventing new clots from forming whilst the body’s own mechanisms break down the clots._x000D_ _x000D_ As the scanning technology for PE has become more sensitive, smaller clots are being diagnosed. In addition, small PEs may not cause any symptoms and may be found incidentally on scans performed for other reasons. In these situations, it is unclear whether treatment is required for the PE. These clots in smaller blood vessels away from the centre of the lungs (subsegmental PE) may be removed by the body’s own mechanisms for dissolving clots without needing medications. Anticoagulant medication can cause side effects in some patients such as bleeding. For the anticoagulant medication to be appropriate in these smaller PEs the benefits from preventing future blood clots (PEs and DVTs) would need to outweigh the potential risks from the medication side effects. The study aims to address this question. _x000D_ _x000D_ This trial will enrol 1466 patients who have an isolated or incidental subsegmental PE confirmed on CT scanning of the chest, and are well enough to not need ongoing treatment in hospital. Patients will have an equal chance of receiving the current standard of care (anticoagulant medication) or no anticoagulant treatment for at least 3 months. Follow-up by the researchers will occur for up to 6 months, with further data collection until at least 12 months using routine NHS records. We will assess patient and staff perceptions of the risks and benefits of not providing anticoagulant medication in these types of PEs, by conducting interviews with up to 60 people. Additionally, we will assess how cost-effective the no treatment approach is and perform a safety analysis after 3 months of follow-up._x000D_ _x000D_ Our team includes a patient with experience of blood clots (CR) and a thrombosis expert (SN) who are project officer and medical director of Thrombosis UK respectively, the UK’s leading thrombosis charity. This link with Thrombosis UK will ensure our study is feasible and of relevance to patients, as well as helping us spread the findings through their established communications network. The study team has experience of conducting clinical trials in hospitals, as well as those which enrol patients taking blood thinning treatment. We have designed this study alongside a local patient group who will also remain involved for their views throughout the study. We anticipate the study will be completed in four and a half years.","Research Question: Is withholding anticoagulation for patients with isolated subsegmental pulmonary embolism (SSPE) clinically and cost effective compared with full anticoagulation for three months?_x000D_ Background: The increasing use of computed tomography pulmonary angiography (CTPA) to investigate patients with suspected pulmonary embolism (PE) has led to an increase in the diagnosis of SSPE. The decreased case fatality rate for PE together with an increase in SSPE incidence suggests overdiagnosis and questions the need for anticoagulation treatment in SSPE. There is growing equipoise about the value of full anticoagulation for patients with SSPE who do not have an associated proximal deep vein thrombosis, given the significant side effects of bleeding and the insufficient evidence of improved mortality or reduced VTE recurrence with treatment._x000D_ Objectives: _x000D_ 1. Determine whether or not anticoagulating for incidental/subsegmental PE reduces harm (recurrent VTE and bleeding events) compared with three months of full anticoagulation at 3, 6 and 12 months _x000D_ 2. Determine the rate of complications of anticoagulation therapy in patients with SSPE. _x000D_ 3. Determine whether not treating SSPE is acceptable to patients and clinicians_x000D_ 4. Determine the reclassification rate of SSPE diagnoses made by acute reporting radiologists when reviewed by thoracic radiologists and formulate a set of rules to improve acute reporting radiologists' diagnoses of SSPE._x000D_ 5. Assess cost-effectiveness of the no treatment approach in patients with SSPE, taking a health service perspective._x000D_ 6. Set up an acute PE research network to support follow on research studies._x000D_ Methods: Individual patient randomised open controlled trial with blinded committee adjudicated end point assessment, powered for superiority for bleeding events and non-inferiority for recurrent venous thromboembolism (VTE), including an internal pilot for feasibility and acceptability of the intervention (no anticoagulation). In order to demonstrate non-inferiority for the outcome of recurrent VTE in patients randomised to no anticoagulation at an upper margin of 2.5%, we require 1466 patients which allows for a 10% drop out rate. Superiority for bleeding events in the no anticoagulation arm is needed to change practice and 1338 patients (allowing for 10% drop out) will give us 90% power to detect a reduction in bleeding events (major and CRNMB) from 7% in the anticoagulation arm to 3% in the intervention arm. Our planned recruitment of 1466 patients over a 32 month window from 50 sites, opening 2 new sites per month, ensures we are powered for both outcomes._x000D_ A nested study of all CTPAs will be performed, comparing the SSPE diagnosis made by the acute reporting radiologists with specialist thoracic radiologists. This will allow us to determine safety in the pilot study (patients with larger than subsegmental clot are rapidly identified), appropriate powering and sample size (e.g. patients with breathing artefact may be recruited instead of true SSPE) and develop guidance for SSPE diagnosis in routine clinical practice._x000D_ Timelines: 54 months, with a 12 month internal pilot _x000D_ Impact: If the trial results are positive, this will change National Institute for Health and Care Excellence and British Thoracic Society guidance for VTE treatment.",6.1 PHARMACEUTICALS,BLOOD HRCS22_07737,Department of Health and Social Care,NIHR,Strategic assessment of NIHR investment in Mental Health Research in the North of England,"Overall aim: To describe the mental health research population needs in the North of England, taking account of NIHR national mental health research priorities, to provide a strategic assessment of NIHR investment and inform consideration of future options._x000D_ _x000D_ The specific objectives are to:_x000D_ - Highlight areas of strength and important content gaps in MHR relevant to Northern population needs._x000D_ - Identify future mental health research and capacity development priorities in Northern HEIs._x000D_ - Outline opportunities for increasing the number of clinicians active in mental health research._x000D_ - Explore methods for encouraging interdisciplinary working and better accommodating research collaborations (between, for example, mental health, social care, digital innovations, education, the environment, and disciplines across the arts and humanities) in MH research in the North._x000D_ - Identify mechanisms for encouraging and facilitating different specialities/disciplines to contribute to and get involved in mental health research.","To describe the mental health research population needs in the North of England, taking account of NIHR national mental health research priorities, to provide a strategic assessment of NIHR investment and inform consideration of future options.",8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),MENTAL HEALTH HRCS22_19074,Wellcome Trust,,Stratification and phenotyping of pulmonary vascular disease with imaging,"Pulmonary hypertension is a severe disorder with a poor outcome. The disease is heterogenous even in idiopathic pulmonary arterial hypertension (IPAH) its purest form. There is a grand challenge to link genetic subphenotypes that link genetic mutation data to pathological features and clinical outcomes. COPD is a huge health burden and the need is urgent to better characterise pulmonary vascular disease (PVD) in COPD and identify a subphenotype(s) that responds to therapy. I will use MRI and CT computational imaging models with the following aims: (a) Diagnose, subphenotype and prognosticate patients with pulmonary hypertension. Statistical and computational modeling approaches I have developed in ~1000 patients in the ASPIRE having MRI and right heart catheterisation. (b) Study genetic imaging subphenotypes of IPAH utilising the national IPAH cohort (~n=1000), matching existing and new genetic variants with imaging pathological features and clinical outcome. (c) Investigate the association of PVD and lung structure and function in COPD, employing imaging models in the MESA-lung cohort (n=3000) to probe the associations between genetics, CT lung structure, lung function, PVD and patient outcome. (d) Study PAH therapy response in COPD in the ASPIRE registry on treatment (n=~80, estimated n=15 responders) identifiying imaging subphenotype(s) that responds to therapy.","Pulmonary hypertension (PH) is when a person has high blood pressure in the pulmonary arteries within the lungs; patients are short of breath, fatigued and have poor life expectancy. Even in the pure form called idiopathic pulmonary arterial hypertension there can be big differences in the disease from patient to patient. There is a grand challenge to better understand the different types of disease, particularly IPAH and lung diseases, in terms of genetics, response to treatment and life expectancy. Using computer-based methods to combine information from magnetic resonance images (MRI); together with computed tomography (CT_ scans, I aim to better diagnose patients, identify patients with common clinical and scan features (called phenotypes) and predict life expectancy. Working with the national IPAH cohort (~1000 patients) I will perform a detailed analysis of CT and MRI scans comparing with genetic mutations. In addition, working with researchers in the USA on a group of chronic obstructive pulmonary disease (COPD) patients (~3000 patients) I will use patient images alongside genetic data to investigate which patients are prone to developing PH, how PH is related to the lung disease in COPD (e.g. amount of lung destruction) and the effect on life expectancy.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CARDIOVASCULAR;RESPIRATORY HRCS22_06266,Department of Health and Social Care,NIHR,Strengthening the Implementation and Operationalisation of ‘Open Disclosure’ with Women and Families after Unexpected Harm in NHS Maternity Care,"BACKGROUND: Open Disclosure is the discussion between health providers and the patient, their family, carers and other support people about incidents that result in harm to a patient while receiving health care. This includes expressing regret for what has happened, keeping the patient and family informed, providing feedback on investigations, and the steps taken to prevent a recurrence of the adverse event. _x000D_ _x000D_ It can reduce distress for those harmed and help clinicians and services to learn to prevent this harm happening again. However, there is a lot of variation in how open disclosure is practiced across the NHS and we need to know more about what patients, families and NHS staff find the most helpful. This is particularly notable in NHS maternity care where harm can devastate families and fears of litigation are widespread. There is urgent need to understand how and when some maternity teams are managing to improve the open disclosure process and to what effect. _x000D_ _x000D_ AIMS: We want to find the key factors to support improvements in Open Disclosure within maternity care. We also want to find out the effects that Open Disclosure has for women and families, clinical teams, and service managers. To work with these interest groups to produce guidance on Open Disclosure practices and processes for women, families and NHS staff._x000D_ _x000D_ STUDY PLAN: First, we will develop a framework of the key factors that support Open Disclosure improvements from international literature and in discussions with experts. Second, we will refine this framework by an in-depth study in maternity care. This will involve interviews with senior service, professional and user-group representatives who will also help to identify 3 units or networks where Open Disclosure is practiced for detailed case study. Each case study will include staff interviews, observations of Open Disclosure work routines and effects, and analysis of paperwork. Finally, we will discuss and develop our findings with service-user and senior service and professional representatives to agree the framework for co-designed study outputs. _x000D_ _x000D_ STUDY OUTPUTS: We will include recommendations for managers and policy-makers and filmed and written guidance for staff teams and for women and families on Open Disclosure processes and practices.","Open disclosure [OD], the discussion of harm in healthcare with affected patients or families, is a patient or family entitlement. It may also enhance learning for safety improvement, reduce the distress of those harmed and increase public trust in healthcare. There is often a significant gap between what patients and families want from OD and what clinicians or organisations provide. There are complex barriers to OD: fear of litigation and loss of reputation; lack of skills and effective systems. Despite the legal duty of candour on NHS organisations, disparities in OD between trusts are notable. NHS maternity services are central to policy reform and under public pressure to improve OD. There is limited understanding of how maternity providers can achieve this. This study will examine what improvements are being made, how and their felt effects._x000D_ AIMS: _x000D_ 1.to generate actionable evidence to inform maternity providers and NHS trusts on how to strengthen Open Disclosure in NHS maternity services; _x000D_ 2. to collaborate in the production of outputs to support improvements in OD for the benefit of women and families, staff teams and quality and safety of maternity care. _x000D_ _x000D_ RESEARCH QUESTION: ‘what are the critical factors that can improve the incidence and quality of Open Disclosure in NHS maternity care?’ _x000D_ _x000D_ METHODOLOGY: a realist evaluation to identify the critical factors that contribute to improvements in OD. Approaching OD improvement as a complex social intervention, the evaluation will explore what assumptions underlie these approaches and examine ‘what works, for whom, in what circumstances, in why respects and why’. This approach will establish a transferable theory of critical factors for improving OD. _x000D_ _x000D_ STUDY PLAN: The 36-month, three-phased research plan is: _x000D_ Phase 1 [Months 1-21] to establish working hypotheses of OD improvement and to refine these hypotheses by realist review of the international literature and telephone interviews with national and regional stakeholders [n=60]; _x000D_ Phase 2 [Months 22-30] construct three ethnographic case studies using the methods of observation; return staff interview (with managers, clinicians, administrators, and women/family representatives [n=48]); and documentary analysis of records of OD improvements in the three purposively selected services, trusts or networks to further refine or revise our hypotheses;_x000D_ Phase 3 [Months 29-36], to include 6 interpretive forums for study participants to make sense of findings and advise on the design of some study outputs, and 1 summative forum for dissemination of initial findings, mutual learning and network building among study participants and policy makers. _x000D_ _x000D_ OUTPUTS: briefing documents and tailored recommendations for service, trust and organisation managers; actionable guidance on OD for staff and women and families (written and video); ongoing lay summaries of study progress and findings; in-depth understanding of process of OD improvement (mechanisms and contexts by which they are effective for different participants and service concerns); academic papers and HS&DR report. Tailored dissemination, supported by stakeholder analysis, will ensure that the study has academic and societal impact. _x000D_ The multi-professional/disciplinary research team have extensive experience of research and quality improvement work in OD and in maternity care. The views and interests of women and families have been, and will be, represented at all study stages.",8.1 ORGANISATION AND DELIVERY OF SERVICES,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_15593,Wellcome Trust,,Structural Investigations of Sodium Channel Mutations Associated with Neurological Diseases,"Sodium channels (Navs) are proteins which are found in cells around the body, including the central and peripheral nervous system and heart muscles. These proteins span the cell membrane and form channels which specifically allows sodium ions to cross the membrane under certain conditions. This influx of sodium ions in neurons is responsible for information processing and is critical for nervous system function. Genetic mutations in Navs can cause multiple diseases including epilepsy, chronic pain and cardiac arrhythmias. Generally, these mutations reduce the function of Navs, disrupting the balance of information, for example in the brain sometimes resulting in epilepsy. Specific drugs therefore need to be developed in order to re-establish this balance either by adding to Navs’ functionality or reducing it. We aim to use structural biology techniques, including x-ray crystallography and potentially cryo-EM to visualise potential drug binding sites. We will also look at common disease-causing mutations allowing us to identify drugs which will not only target a specific subtype of Nav but also a specific mutation. In particular we will be looking at repurposing already commercially available drugs. This work has the potential to identify drugs for Nav related diseases and provide new treatment options for patients.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_15383,Wellcome Trust,,Structural and functional characterisation of the fungal proton pump Pma1,"Fungi fuel their nutrient uptake through generating a proton-motive force across their plasma membrane via the membrane protein proton pump Pma1. This proton-motive force is used as an energy source to import nutrients for the cell, and fungi die without the activity of Pma1. To date, knowledge on the molecular structure and function of this protein is limited. I therefore aim to study the structure of Pma1 and understand its molecular function, through the use of structural analyses, including cryoEM and X-ray crystallography and biophysical assays. I will be using protein isolated from the fungus Neurospora crassa and a set of known small molecules that lock the protein in different catalytic conformations to investigate its catalytic cycle. I will also establish a way to produce Pma1 in baker's yeast, allowing me to generate variants of the native protein for functional and structural studies. My findings will broaden our understanding of the structure and function of the protein, opening the possibility of a wide range of secondary research including protein-lipid interaction studies and the possibility of designing novel antifungal agents.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_19746,Cancer Research UK,CRUK,Structural and mechanistic studies of proteins involved in human DNA double-strand break repair,"1) Background DNA damage results in mutations that can lead to cancer. DNA can be damaged in many ways but one of the potentially most serious is double-strand breaks. If these breaks are not repaired correctly, point mutations and/or deletions can occur. In worst cases, re-joining of ends incorrectly can lead to chromosome translocations and other forms of genomic instability that give rise to cancer. Several genes implicated in genome instability are associated with syndromes that have cancer predisposition (e.g. Bloom’s, Werner’s, Fanconi’s). 2) Aims The aims of this proposal are to understand the structure and mechanism of the processing of double-strand DNA breaks as a prelude to recombination repair. Defects in this process cause problems with the repair of DNA damage leading to genomic instability that results in cancer. Our previous work on the RecBCD/AddAB systems have revealed insights into this process in bacteria. Although the RecBCD/AddAB proteins themselves are not conserved in humans, there is an underlying similarity between the process of double-strand break repair in bacteria and humans. Indeed, proteins with the same activities found in the bacterial proteins are present in humans but located within different proteins and protein complexes. This research proposal will be to extend what we have learned from RecBCD/AddAB to the human double-strand break repair system. In particular, I wish to understand how the large human protein complexes interact and cooperate with one another to achieve DNA break repair. which is even more complex and presents some challenging problems in structural biology. However, meeting these challenges is essential if we are to understand fully how these multi-component systems cooperate to repair DNA damage, and hence prevent cancer, in humans. 3) Methods The primary methods used in this study will be structural techniques particularly single particle cryo-electron microscopy but also X-ray crystallography as well as other biophysical techniques such as Small Angle X-ray Scattering (SAXS) and Fluorescence Resonance Energy Transfer (FRET). In addition, biochemical characterisation of the proteins will involve a variety of standard techniques including DNA footprinting, ATPase and helicase assays, site-directed mutagenesis, isothermal titration calorimetry, protein cross-linking and mass spectrometry analysis. 4) How the results of this research will be used The results of this research will be used to improve our understanding of how the interplay between the various protein components leads to double strand-break repair in humans.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_20757,Wellcome Trust,,Structural cell biology of transport vesicle and organelle biogenesis,"Integral membrane protein cargo are constantly moved in coated tubular/vesicluar carriers between the cell's organelles and its limiting membrane in order to maintain membrane identity and function. That these transport processes are of fundamental importance is reflected by the fact that ~30% of mammalian proteins are either components of the vesicle/tubule transport machinery or are its cargo. Coated vesicular/tubular carrier formation including cargo selection requires the interplay of a network of peripheral membrane proteins and membrane components including phospholipids, small GTPases, docking proteins and the cargo itself. The coat must also prepare and facilitate the carrier for fusion with its target. AP2, AP3, COPI and retromer/VARP based coats along with their accessory/regulatory factors are vital for producing a fully functional endosomal system. We will use a combination of X-ray crystallography, NMR and the fast developing techniques of single particle cryoEM and cryo electron tomography allied with biochemical/biophysical studies to formulate theories concerning the architecture, assembly routes and control/regulation of the formation of these four key tubular/vesicular transport carriers. Specific function abolishing mutations designed on the basis of these studies will allow us to test and further explore our theories in cells using a wide range of in vivo techniques.","Every one of the trillions of cells in a human are surrounded by a lipid membrane and contain membrane-bound compartments. Proteins embedded in these membranes mediate cell interactions with the blood and the immune system. They also permit signals and small molecules to cross these membrane barriers. These embedded proteins are moved in the right quantities at the right times to the right membranes in transport vesicles. These are formed when a portion of a donor membrane, into which the correct embedded proteins have been sorted, is pinched off, transported to and fused with its target membrane. Failures in vesicle transport can result in cell death or malfunction leading to diseases including Alzheimers, Parkinsons and cancers. The transport vesicle system can be ‘hijacked’ by pathogens to facilitate their entry into host cells. We aim to determine atomic resolution structures of various protein nano-machines that are recruited onto membranes from inside the cell to drive a transport vesicle’s formation, transport and fusion. This will allow us to explain how these proteins function correctly and how they can go wrong. It will also allow us to design highly specific mutant forms of them to help test theories of vesicle formation/destruction in cells.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;INFECTION;NEUROLOGICAL HRCS22_19477,Wellcome Trust,,Structural mechanics in subcellular structure formation,"A failure to properly build and maintain cellular structures leads to cell-death or disease. Yet, the regulation and mechanisms of the machinery that coordinate such structures are generally poorly understood. The formation and maintenance of many cellular substructures is dependent on the receipt and retention of specific components, selected through tethering complexes. Of particular interest is the exocyst complex, whose role in polarized trafficking leads in part to the spatially and physically distinct cilia and tight junction membrane substructures. I hypothesize that membranes and combinations of their signaling proteins coordinate the mechanics of the polarized trafficking machinery through the exocyst. I will determine how this complex assembles and targets specific membranes through an innovative reconstitution combining biophysical and cell biological approaches. Through synergy with structural methods, the outcome of this approach will be information on the relationship between structure and functional mechanism on membranes, and the cellular consequence of exocyst spatiotemporal regulation. The imbalances of polarized trafficking in both aberrant development and cancers urge a program aimed at resolving the molecular mechanics of this pathway.","Cells harbor structures that define their function. Yet the regulation and mechanisms of the machinery that coordinate such structures are generally poorly understood. I aim to understand the mechanics of this machinery. I will use a reconstitution approach, building the system from minimal components through to its full complexity. This approach harnesses state-of-the-art protein biochemistry and membrane biophysical methods in a unique way, aimed at broad and high-throughput experimentation. I will build synergy of this strategy with experimental cell biology, which provides both validation and new avenues exploring cellular consequences of perturbations to the coordinating machinery. The outcome of these studies will be a comprehensive model for regulation and the structural basis for coordination of subcellular structures. Signaling in both development and cancers result in drastic changes to this aspect of biology, and an understanding of the basic mechanisms has the long-term potential for new opportunities in treatment.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_19729,Wellcome Trust,,"Structure, mechanism and dynamics of recoding in viral infection","Many RNA viruses (e.g. SARS-CoV-2, HIV-1) have evolved ways of reprogramming translation to expand the coding capacity of their small genomes. ‘Recoding’ events such as -1 frameshifting, stop codon read-through and StopGo peptide release are necessary for viral replication, producing viral proteins in optimal ratios for efficient assembly. Recoding is regulated by a complex interplay between the elongating ribosome, cis-acting elements in the mRNA or nascent peptide, and trans-acting protein factors. Elucidating the structural basis of recoding is essential to understand viral pathogenesis. However, classical biochemical approaches cannot accurately capture kinetics or per-ribosome heterogeneity, making it difficult to define a ""window of opportunity"" for structure determination. Recent technological advances allow single-molecule fluorescent imaging of translation in real-time. I will apply these methods to study recoding in vitro and in live cells, starting with -1 frameshifting in SARS-CoV-2, HIV-1 and EMCV, which utilise topologically-distinct stimulatory elements. I will determine the structure of key ribosomal states by time-resolved cryo-EM, and investigate the structure and stability of stimulatory elements using crystallography, single molecule FRET and optical tweezers. Longer-term, this approach will be applied to investigate other recoding events, thus revealing universal and case-specific mechanistic principles, and highlighting new avenues for therapeutic intervention.","Accurate translation of mRNA by the ribosome is essential for all life. It is therefore a high-fidelity process, with spontaneous error rates of only ~ 1 in 100,000 codons. When RNA viruses infect cells they frequently make proteins that differ from the genetically encoded sequences. These highly-regulated ‘recoding’ events are vitally important to viral gene expression, and if disrupted many viruses (e.g. SARS-CoV-2, HIV-1) fail to complete their replication cycles. I aim to use a multidisciplinary approach to better understand recoding, initially focussing on -1 programmed ribosomal frameshifting (PRF) in SARS-CoV-2, HIV-1 and EMCV. Using single-molecule fluorescence microscopy, I will observe PRF in real-time both in vitro and in live cells. I will also reveal mechanistic details by time-resolved cryo-EM, crystallographic and biophysical studies. Together, this work will reveal universal structural and mechanistic principles that govern mammalian recoding, laying the foundations for developing a new class of antiviral drugs.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_07021,Department of Health and Social Care,NIHR,"Suicidal ideation, homicidal ideation, and self-harm in parent carers.","Background Emerging research suggests family carers are a high-risk group for suicide, homicide, and self-harm. Only three studies, however, have focused on parent carers and none were conducted in the UK. More than 800,000 children in the UK have disabilities and long-term illnesses and the majority are cared for by their parents. Aims and Objectives Aim: Conduct the first UK study of suicidal ideation, homicidal ideation, and self-harm in parent carers. Objectives: Estimate the rate of suicidal ideation, suicide attempts, and self-harm. Identify risk and protective factors for suicidal ideation, suicide attempts, and self-harm. Explore the lived experience of suicidal ideation and attempts, homicidal ideation and attempts, and self-harm. Identify carers recommendations for research, practice, and policy. Provide a foundation for sensitive, evidence-based initiatives for at-risk carers and the social care professionals who support them. Methods The study has a sequential explanatory mixed-methods design, with two interrelated stages. It was co-created with parent carers and social care professionals. Four carers are co-investigators. Stage One: A cross-sectional survey of 1,000 parent carers. The survey will include questions on parent and child demographics, the nature and extent of the disability/illness, and the nature and extent of care provision, plus measures of suicidality, self-harm, and psychosocial variables. For legal and ethical reasons, questions about homicidal ideation and attempts will be included in Stage Two only. Descriptive analyses will identify rates of suicidal ideation, suicide attempts, and self-harm. Independent t-tests and chi-square tests will identify differences between suicidal and non-suicidal carers, and self-harming and non-self-harming carers. Regression analyses will identify risk and protective factors. Stage Two: In-depth interviews with 20 parent carers. The topic guide will be informed by existing research and preliminary analysis of the survey data. Interviews will be audio recorded and transcribed verbatim. Transcripts will be analysed using case-centred, narrative thematic analysis to: understand lived experience; identify critical situations and turning points in the caring journey related to suicide, homicide, and self-harm; and, identify carers recommendations for research, practice, and policy. Safeguarding and risk response protocols will ensure the safety and wellbeing of carers, care recipients, and the research team. The team has experience conducting research on sensitive topics and with vulnerable populations, and their previous research has informed policy and practice. Timeline & Support The study will take 24 months. A Parents and Partners Network and an Advisory Group will provide strategic guidance and support. Dissemination & Impact The findings will be published in academic journals and presented at a childhood disability conference. Lay summaries, policy briefings, short films, mainstream media, and social media will be used to disseminate the findings to government departments, clinicians, social care providers, schools, charities, and carers. This will: raise awareness; encourage help-seeking; strengthen advocacy; facilitate reviews of existing policy and practice; and provide justification and recommendations for additional support for at-risk parent carers. A subsequent application for an NIHR Programme Grant will support the development, evaluation, and implementation of sensitive interventions for at-risk carers and training for social care professionals.","Family carers make a valuable social and personal contribution, but they receive little support and the role takes a serious toll on their wellbeing. A growing body of research also suggests that many carers may self-harm and consider killing themselves or the person for whom they care. Only three of these studies, however, have focused on parents caring for children with disabilities or long-term illnesses (DLTI), and none were conducted in the UK. More than 800,000 children in the UK have DLTI and their parents may be at greater risk of suicide, homicide, and self-harm than other family carers. The aim of our project is to estimate how many parent carers in England have thought about and/or attempted suicide, and how many self-harm. We also want to identify the factors that contribute to and protect against these thoughts and behaviours. (Note: For legal and ethical reasons we will not be able to determine how many parent carers have thought about or attempted homicide). Finally, we want to understand the everyday experiences of parent carers who have considered suicide, considered homicide, or self-harmed, and seek their suggestions for research, practice, and policy. This information will ultimately allow us to develop better strategies for supporting carers in crisis. We will conduct an anonymous survey of 1,000 parent carers in England. We will also conduct face-to-face interviews with 20 of these carers. Carers will choose whether they complete the survey online or as a hard copy. Carers will also choose whether the interview is conducted in their home or another quiet location. Carefully developed protocols will ensure parent carers, their children, and the research team are supported and kept safe throughout the project. We have spent the last year working closely with parent carers and social care professionals to develop this project. To ensure the research continues to be informed by their needs and experiences, four of the carers have become co-investigators. They will be equal members of the research team, contributing at every stage. The wider group of carers and professionals have formed a network to oversee the project and will be consulted at regular intervals. Our team has extensive experience conducting research on family care, disability, suicide, homicide, and self-harm. We will share the findings with the wider community – including carers, social care professionals, and policy makers – via easy-to-read summaries, policy briefings, short films, and a project website. We will share the findings with other researchers via academic journal articles and conference presentations. After this study is complete, we will apply for an NIHR Programme Grant for Applied Research to develop sensitive, evidence-based supports for at-risk carers and training for social care professionals.",7.1 INDIVIDUAL CARE NEEDS,MENTAL HEALTH HRCS22_05945,Department of Health and Social Care,NIHR,"SuperResPath-Renal: Quantitative super-resolution technology for a fast, de-centralised clinical diagnosis of renal pathologies","Background Renal pathologies are the most common primary cause of nephrotic syndrome. For diagnosis, a renal biopsy is examined at different levels, including high-resolution electron microscopy (EM) to detect glomerular ultrastructural changes imperceptible by histology. EM is the most expensive single test in histopathology labs, limiting diagnosis of renal pathologies with long turnaround times (2-3 weeks). NHS England spent around £1.45 billion on chronic kidney disease (2009-10), with an average 70% of renal biopsies needing EM studies for diagnosis, costing around £300 each. Aims and Research question Our project aims to combine super-resolution microscopy with advanced data analysis to establish a de-centralised and rapid (2-5 days) platform for routine renal pathology assessment. We intend to detect multiple glomerular podocyte markers in biopsy samples using high-precision dSTORM imaging for an improved renal histopathology diagnosis and patient outcome. Methods Formalin-fixed paraffin-embedded tissue samples will be imaged using ONI s Nanoimager microscope, with cutting-edge super-resolution imaging technology. Machine-learning algorithms will allow detection of features of interest to be imaged with dSTORM to visualise key fluorescently-labelled renal proteins. Multi-parametric cluster-based data analysis will provide a read-out for diseased tissues. Timelines Phase I will validate and optimise the protocol to stain tissue samples for dSTORM imaging, phase II will integrate imaging and automated data analysis into a turn-key workflow, phase III will see the clinical application of ONI's super-resolution microscope into NHS histopathology labs. Our technology should be patient-ready in 3 years. Anticipated impact and dissemination Our technology will allow a larger portion of renal biopsies to be examined, increasing diagnostic sensitivity and specificity, benefiting patients. Replacing EM and reducing labour costs could save money to the NHS (>£10M across UK pathology units, 3 years post-project). Adoption will be ensured through conference presentations, publications, demonstrations at NHS pathology units, and with public and patient involvement.","Kidneys are the organs that filter the blood and produce urine. Conditions are usually identified (diagnosed) by doing a kidney biopsy, a procedure that takes a piece of kidney tissue for examination under a microscope (instrument used to see objects which are too small to be seen by naked eye). Currently, electron microscopes are the only tool able to detect tiny nanoscale (a nanometre is a millionth of a millimetre) changes in kidney tissue. Detecting these tiny changes allows experts to diagnose specific kidney diseases, like Minimal Change Disease and Focal Segmental Glomerulosclerosis (scarring). These affect two components of the kidney filtration barrier: podocytes (cells wrapped around blood vessels) and basement membrane (sitting between cells and vessels). In the last 10 years, a new class of light microscopy that enables imaging at the nanoscale has emerged: super-resolution microscopy, which is able to resolve structures too small to see with normal light microscopes. This type of microscopy can be used to visualise the really small kidney structures that are affected in these diseases. The company Oxford Nanoimaging (ONI) has built one of the world s first desktop super-resolution microscopes, which can sit on a laboratory bench and make advanced imaging more easily usable in clinical practice. The technology can measure data of multiple single molecules (groups of atoms bonded together) with great accuracy. We recognised the need for a faster, simpler, cheaper test that studies the entire kidney biopsy in detail rather than a small part of it. This would increase diagnostic quality and give advantages to patients and the NHS, such as a shorter time to diagnosis in just 2-5 days. To achieve this we will test and confirm a range of kidney markers in renal tissue using the ONI microscope. This information will then be used to build a computer programme for automated imaging analysis (a software to extract data from digital images). Presentations at conferences, publications and technology demonstrations at pathology units and hospitals will encourage adoption. We will engage patients, researchers and clinicians across Leeds Teaching Hospital, to ensure an informed strategy through discussions. Public members will be engaged during the Leeds University open days, National Pathology day and the Thackray Medical Museum. Once commercialised (on sale to hospitals), our super resolution microscope could be used to diagnose other diseases and become a routine NHS test.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,RENAL AND UROGENITAL HRCS22_06615,Health Education England,HEE,Supporting medicines optimisation for people living with dementia: exploring communication between informal carers and people living with dementia in the context of polypharmacy,"Background People with dementia (PwD) who experience polypharmacy often require support to take medicines optimally. Research has shown that carers (family and friends) of PwD provide substantial support with administering and monitoring medicines, involving daily and often difficult negotiations with the PwD. Communication skills have been shown to be crucial in negotiating medicines taking in interactions between healthcare professionals and PwD in hospital. Research is needed to explore similar interactions between carers and PwD at home. Analysis of findings will inform development of resources to support safe, ethical and effective medicines use for PwD and reduce carer burden. Aims To improve medicines optimisation for PwD by: 1: Conducting in-depth analysis of interactions occurring in the home between PwD and their carers when they talk about and manage medicines; 2. Identifying carer communication behaviours (questions, requests, negotiations etc) which support optimal medicines taking by PwD 3. Illuminating how taking multiple medicines is experienced by PwD 4. Building detailed case studies and integrating these into patient and carer resources to inform medicines optimisation for PwD 5. Working with established networks to disseminate findings, patient and carer resources and learning materials Research questions 1. How do PwD and their carers communicate about medicines at home? 2. How and to what extent do PwD-carer interactions support or inhibit medicines optimisation? 3. How is taking multiple medicines experienced by the PwD? 4. How can insights from detailed patient-carer case studies inform improvements in medicines optimisation for PwD? Methods A longitudinal in-depth qualitative study combining observational data, naturally occurring conversations and data generated from participant diaries and interviews. 24 participants, consisting of 12 PwD who take 5 or more medicines and their 12 carers, will be observed over 10-12 months in the home environment. Interactions when participants talk about or use medicines will be video-recorded. Digital recordings will be made by the researcher, or by trained carer-participants, and analysed using Conversation Analysis. I will support PwD to keep verbal, written or photo diaries then conduct individual interviews using the diaries as prompts to discuss feelings, thoughts and beliefs about medicines use. I will integrate data from observations, conversations, diaries and interviews in a narrative synthesis. My analysis will be informed by Burden of Treatment Theory, focusing on the 'work' that patients and carers do as they engage in healthcare treatment.Impact on patients and NHSThis research will: Identify evidence-based strategies to improve medicines conversations in the home and avoid interactional 'troubles' between PwD and carers Make patient and carer 'treatment burden' visible by showing the interactions involved in medicines practices. Findings will highlight where burdens can be reduced in ways that are acceptable to PwD, carers and professionals Develop and disseminate resources to support conversations about medicines optimisation between professionals and PwD, illustrated with case studies Improve carer experience by providing carers with strategies to manage negotiations around medicines","Background570-600,000 people with dementia (PwD) live in their own homes in the UK. Many have support from informal carers, such as a partner or children. PwD are often prescribed many medicines and need help with these from their carer. Research from interviews with carers shows that managing medicines can be a significant source of conflict and worry. Recent research in a hospital analysed video recordings of interactions between professionals and PwD. They showed that the ways in which professionals requested PwD to take medicines made a difference to whether or not they were taken. In this study I will spend time with PwD and their carers at home, observing how they talk about medicines and how they manage medicines together. My analysis of this communication will inform the development of training materials to improve conversations about medicines, supporting PwD and their carers in safe and effective medicines use. AimsTo build a detailed picture of 'communication about medicines' and improve patient care by: Exploring how PwD and carers communicate about medicines and how these conversations influence medicines taking; Following PwD and their carers over time, to understand their experience of taking multiple medicines; Identifying approaches to communication which support optimum medicines use; Developing resources for carers and professionals to help them communicate effectively about medicines. Study design and methods I will use observations, video-recordings and data generated from diaries and interviews to explore medicines use in the home. I will visit 24 people (12 pairs of PwD and their carers) at home over 10-12 months, observing how they manage medicines and video-recording their interactions when they talk about and take medicines. Recordings will be made by me, or by trained carer-participants using iPads. I will also support PwD to record their feelings and experiences of medicines using a combination of spoken, written and photo diaries, then talk to them about their diaries. I will analyse data from recordings to identify communication approaches which best support PwD and their carers to have effective conversations around medicines. I will also combine data collected from diaries and interviews to build rich stories showing the medicines experiences of PwD. Patient and public involvementThe James Lind Alliance has identified that a key priority in dementia research is finding ways of helping PwD be as independent as possible. Safe and effective medicines use at home is a crucial element of maintaining independence. I have improved my project by discussing it with PwD and carers at a discussion group and dementia support groups. For example, PwD highlighted that some crucial medicines interactions may take place late at night so I adapted the protocol to include these (see Project Plan) A lay research panel also gave me feedback on my ideas. My study advisory panel will include PwD and carers to advise on how the study is carried out, including analysis and sharing the results. Outputs Resources for carers, PwD and professionals showing helpful communication strategies, including short films (played by actors) and written resources. These will be freely available on the internet. Anonymised case studies showing the range of medicines experiences of PwD. I will work with established networks (Alzheimer's UK, Opening Doors London) to make these available via the internet, social media and community events as well as academic journals and conferences. Regular updates on a dedicated page on the APOLLO-MM study website (www.polypharmacy.org.uk) Talks and presentations of findings at community dementia groups.",7.1 INDIVIDUAL CARE NEEDS,NEUROLOGICAL HRCS22_19784,Wellcome Trust,,SureChEMBL: open patent data for all,"SureChEMBL is a large-scale, fully automated, chemical-structure-enabled database providing the research community with open, free and FAIR access to the patent literature. SureChEMBL contains ~140 million patents with ~50,000 added monthly. Of these, ~50 million patents are chemically annotated with more than 20 million unique chemical structures. Around 80,000 new compounds are extracted and stored monthly. The data in SureChEMBL can currently be accessed via a web interface that enables users to perform text and chemical structure queries, filter the output and then display the results. The complete set of chemical structures and patent associations are also available for download.  In this proposal we plan to significantly enhance SureChEMBL, enabling a wider selection of questions and use cases to be addressed, by: expanding annotations to include biological entities; developing methods to assess the relevance of information identified in patents and enable more accurate data retrieval and analysis; significantly improving the technical infrastructure and web interface with enhanced stability and usability; providing programmatic access through development of a RESTful application programming interface (API). The new, upgraded SureChEMBL will provide the broader life sciences research community with unparalleled access to a large and rich source of information and knowledge.","Understanding the activity and properties of drug-like molecules is key to the discovery of new medicines. Patents are a valuable source of such information, yet are difficult for many scientists to access. SureChEMBL is a database that enables the scientific community to obtain and analyse data and information from patents. This is important because significant amounts of drug discovery information are first disclosed in patent form and may never be written up in the “traditional” scientific literature. We will make it much easier for scientists to access and use patents for their own projects. We will extend and enhance our annotations of key terms, enabling users to identify those patents most relevant to their research. We will make major improvements to the website and the underlying software infrastructure. All data will be freely accessible to enable drug discovery scientists to be even more effective in their quest for new medicines.",1.3 CHEMICAL AND PHYSICAL SCIENCES;2.4 SURVEILLANCE AND DISTRIBUTION,GENERIC HEALTH RELEVANCE HRCS22_06544,Department of Health and Social Care,NIHR,Sustaining locally-driven social care for those affected by dementia: A realist evaluation of successful Meeting Centres,"Rationale: Social care for people living with dementia, who require support to live at home with a decent quality of life, is in crisis in many parts of the country, particularly in rural areas. The detrimental health impact of social isolation and loneliness is increasingly recognised. Survey data reveals 60% of people living with dementia report loneliness, isolation and losing touch with people in their lives since diagnosis. Around a quarter feel they are not part of their community and that people avoid them. Family carers provide the bulk of support, but there is a growing recognition that carers health and wellbeing is negatively impacted over time. Families need reliable long-term support but may community initiatives struggle to maintain beyond 1-2 years. Scaling up provision of evidence-based community initiatives for people with dementia, and their families, is imperative. Aims: This research will focus on the sustainability of Meeting Centres for people and families living with dementia in rural communities in England and Wales. Meeting Centres (MCs) originated in the Netherlands 20 years ago and there are now 150 Dutch MCs. The first two UK MCs were established in 2015 through the MEETINGDEM research programme, which took learning from the Netherlands and successfully adapted it to the UK, Italy and Poland. MCs provide small-scale, on-going social clubs, staffed by a small permanent team of staff and volunteers. They open 3 days per week, driven by local community groups, and provide activity and support driven by the needs and wishes of members. MEETINDEM demonstrated significant Quality of Life benefit to MC attendees compared with those receiving care as usual. There are now 13 UK MCs established (including Scotland and Wales) with 20 more due by 2021. Many UK community groups find MCs attractive and achievable. However, it is not understood how these diverse communities can ensure they are putting in place strategies that will help them sustain in the longer term, over the initial 1-2 years start-up. This research aims to understand how three well-established rural MCs have achieved this within the current UK context. This knowledge will then be shared with emerging MCs so that scale-up can be accelerated. Methods: Utilising a recently developed programme theory (SCI-Dem) on sustainable adoption and implementation of community dementia interventions, Realist Evaluations of three established UK MCs will be undertaken. Stakeholders from each MC, including members directly affected by dementia, will provide qualitative and quantitative data. Data from all sources will refine the programme theory of how, why, for whom, in what contexts and to what extent MCs are successfully adopted and implemented by diverse communities. Willingness to pay for MC provision will be explored utilising a health economic analysis through a Discrete Choice Experiment. Outcomes: The resulting knowledge will impact on the decision making of those commissioning, planning or implementing Meeting Centres locally, regionally and nationally to accelerate the scale up of Meeting Centres that will sustain into the long term, for the benefit of those living with dementia and those caring for them","Supporting people with dementia and their carers to live well is an international health priority. However, social care is struggling with demand and people living with dementia in the UK will double by 2040. There are big gaps in the support available to help people cope with the condition and support has been described as a post-code lottery. Meeting Centres are local social clubs (3 days per week) for people and families affected by dementia. The first Meeting Centres opened in the UK in 2015. There is good evidence that they help people cope better. They are set up and run by community groups, funded by members subscriptions, fundraising and grants. Meeting Centres are low-cost and provide accessible on-going social care. Our team set up and evaluated Meeting Centres in the UK. Thirteen have been set up, with twenty planned by 2021. There is a danger that Centres may struggle to keep going after 1-2 years particularly in rural areas. Our research needs to move from how to set up a Meeting Centre to how to keep one going long-term . We have already undertaken research to develop a theory (set of ideas) about what needs to be in-place to help Centres thrive long-term. We now want to use a research method known as a Realist Evaluation to see whether this is actually the case in rural Meeting Centres. We will focus on three well-established Meeting Centres that have kept going longer than three years, to see how they have managed to succeed. The Centres include Leominster (rural); Droitwich Spa (semi-rural); and Powys (rural Wales). These are all in rural communities, as these areas are more difficult to sustain compared to towns and cities that often have more resources. We will collect information on the way each Centre is organised and funded and what factors have been important over time. We will interview members (people with dementia and family carers/friends), staff, volunteers, trustees, health and social care staff and volunteers about their views. Importantly, this will also include their views on what they are willing to pay to attend the Centre and the value they place on this. We will use what we learn to develop user-friendly guidance and materials to best help Meeting Centres survive and thrive in the long-term. We will also use this information to help policy makers and government understand what they can do to improve this situation. Our project will support the growth of more Meeting Centres to support people in desperate need. Service users and members of the public are central in guiding this research. Meeting Centre members and staff will be involved in all stages of our project from design to sharing of findings.",8.1 ORGANISATION AND DELIVERY OF SERVICES,NEUROLOGICAL HRCS22_03178,Medical Research Council,MRC,Synaptic and neuronal compensation in Alzheimer’s disease,"Alzheimer’s disease (AD) is characterized by synaptic and neuronal loss at early and late stages in the disease progression, respectively. One of the most puzzling aspect of AD is that the accumulation of amyloid and tau pathology precedes by several decades the onset of clinical dementia. Our research program rests on the notion that this gap corresponds to compensatory mechanisms implemented at all levels: first, at the synaptic level following synapse loss, and then at the neuronal and circuit level - and that the saturation of all these compensatory mechanisms mark the onset of dementia. In this research program, we aim to investigate the nature of these compensatory protective mechanisms, in particularly those implemented at the synaptic and neuronal level. Although much is known about the mechanisms underlying synaptic loss in AD, the compensatory mechanisms implemented following synaptic loss remain unexplored. This is probably due to the inability to predict which synapses will be lost and consequently, which will be compensated. To overcome this hurdle, we are developing optogenetic and chemogenetic tools to artificially eliminate synapses with complete spatio-temporal control in order to monitor the emergence of synaptic compensation over time (days and weeks) both at the structural and functional level using in-vitro and in-vivo two-photon microscopy. Using this targeted approach, we aim to investigate i) the nature of synaptic compensation (e.g., enlargement of surviving synapses and/or synaptic regrowth), ii) the molecular mechanisms underlying compensation using transcriptomics and proteomics approaches, iii) the role of astrocytes and microglia in modulating synaptic compensation, and more importantly iv) the role of synaptic compensation in delaying the onset of cognitive deficits in well-characterized AD animal models (e.g., APP/PS1). As a neurodegenerative disease, AD is also characterized by neuronal loss at the later stages of the disease. In the second part of our research program, we will investigate the compensatory mechanisms implemented at the level of neuronal ensembles following neuronal loss. Using in-vivo two-photon microscopy to identify neuronal ensembles, we will investigate i) the ensemble compensation following the selective photoablation of constituents of the ensemble, ii) the molecular mechanisms underlying neuronal compensation and ultimately, iii) the role of neuronal compensation in improving cognition in AD models associated to neuronal loss. We strongly believe that understanding the molecular mechanisms underlying synaptic and neuronal compensation will be crucial for developing alternative therapeutics to delay the onset of clinical dementia.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_15556,Wellcome Trust,,Synthesis and evaluation of novel antagonists and fluorescent ligands for the human P2Y2 receptor,"The human P2Y2 receptor is one of a large and diverse family of disease-relevant drug targets called G protein-coupled receptors. The P2Y2 receptor is a promising therapeutic target for important conditions, including metastatic cancer. However, no drugs which block the P2Y2 receptor have ever entered clinical trials. The research group recently published an initial study where novel P2Y2 receptor inhibitors, that prevent the action of the receptor, with good biological activity were produced. The project will build on this previous work to design, synthesise and evaluate further inhibitors with improved biological activity and ""drug-like"" properties to make them more clinically viable. The design of these inhibitors will be driven by visualisation of key interactions with the P2Y2 receptor in computational models. Another subsequent part of the project will involve equipping these novel inhibitors with a light emitting fluorescent dye that can be used to investigate their interaction with the P2Y2 receptor in cell and tissue-based experiments with state of the art imaging equipment.  Novel, high affinity and drug-like P2Y2 receptor inhibitors and their fluorescently-labelled counterparts would provide a vital tool to further validate the role of P2Y2 in disease and aid in the development of clinically viable drugs.",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_13335,Wellcome Trust,,Systemic Inflammation and Growth following Acute Illness in Children.,"Medical and nutritional management in acutely-ill undernourished children in developing countries aim to support rapid weight gain. However, such children remain at risk of death and poor catch-up growth post-hospital discharge. Little is known about mechanisms regulating childhood growth after acute illness. I hypothesise that persistent systemic inflammation (SI) is a key determinant of growth post-discharge among undernourished children. SI is associated with reduced linear growth in community cohorts, and is demonstrable at hospital discharge among undernourished children, potentially indicating untreated infections, microbiota dysbiosis, gut-circulation microbial product translocation, or enteric inflammation. My proposed work is nested within the CHAIN cohort that aims to characterise modifiable risks for mortality among acutely-ill children <2 years old in six countries in Africa and Asia. I aim to investigate whether persistent SI is a key determinant of catch-up growth among undernourished children and investigate its causes. I will examine relationships between growth and markers of SI, blood metabolomic profile, growth mediators, and microbial exposures comparing with well community children through a collaborative network between KEMRI-Wellcome; Kenya, the University of Oxford and the Wellcome Sanger Institute. Better understanding of relationships between SI and post-discharge growth is expected to inform therapeutic strategies to improve recovery.","Undernutrition remains a major global health problem that increases risks of infectious diseases, and affects brain development, immunity, cardiovascular and metabolic health. Systemic inflammation (SI) is a natural response to infections and should resolve with recovery. In pilot studies, I have observed high levels of SI among undernourished children when they appear well at the time of discharge from hospital linked to the risk of subsequent death and poor growth. In community studies and in inflammatory diseases, SI has been seen to impair child growth. In this fellowship, I aim to determine whether SI persists after hospital discharge, is greater among undernourished children, if it affects post-discharge growth and identify causes of SI. I will utilise a large set of existing high-quality data and biological samples from a recent large study of children admitted to hospitals in sub-Saharan Africa and South Asia and followed up for 6 months after discharge.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_03030,Medical Research Council,MRC,Systems Neuroscience of Primate Social Cognition,"Primate social cognition involves sophisticated decision-making, observational learning and perspective-taking. To study the underlying neuronal mechanisms, we combine multi-area multi-electrode electrophysiological recordings with reversible interventions and computational modelling while monkeys perform well-established decision tasks in a social context. In a value-guided decision task, two monkeys observe and learn from each other's choices how to obtain subjectively preferred rewards. In a social rule-based decision task, two monkeys observe and learn from each other which of several abstract rules is currently valid and leads to reward. Neuronal recordings in both tasks allow us to identify neuronal signals related to shared, task-general social processes (self-other distinction, observational learning, social choice prediction, perspective-taking) and task-specific signals (subjective valuation and reward processing vs. rule following and conflict processing). We use chronic electrode arrays and semi-chronic multi-electrode drives to target areas previously implicated in social behaviour, including anterior cingulate cortex, amygdala and connected temporal-lobe areas, and prefrontal areas implicated in decision-making and advanced cognition, including frontal pole and dorsolateral prefrontal cortex. Using electrical microstimulation and reversible pharmacological interventions, we disrupt local activities and network interactions before and during task performance to establish which of these brain areas make essential contributions to social task performance. We integrate the neural and behavioural data using biophysically realistic neural-network modelling to build task-specific and task-general computational models, and thereby uncover the mechanisms and circuit architectures underlying primate social cognition.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL,NEUROLOGICAL HRCS22_20924,Cancer Research UK,CRUK,Systems approach to therapeutic combinations for glioblastoma: new targets and agents delivered and sequenced for synergy,"Glioblastoma (GBM) is a dismal disease whose treatment is limited by drug resistance and likely by the blood-brain barrier (BBB). Here we will identify new evidence-led combination therapies and enhance their delivery to GBM cells in vivo, so as to improve patient outcomes. We will address how rewiring of cellular signaling pathways promotes therapeutic resistance, including to standard-of-care therapies. We will combine our complimentary expertise to develop a unique drug-combination discovery and delivery platform, specifically tailored to GBM. We propose a multidisciplinary approach to address 7 key aims:- AIms Aim1: Identification and validation of novel therapeutic targets and agents in combination with standard-of-care radiotherapy and temozolomide. Aim2: Target validation and drug resistance modelling in vivo. Aim3: Pathway profiling following target perturbation. Aim4: Development and application of an interactive computational modelling platform for predicting novel drug combinations and biomarkers in GBM. Aim5: Biological validation and prioritization of drug-target combinations. Aim6: Optimization of functionalized layer-by-layer nanoparticles (LbL NP) for enhanced delivery of novel combination therapies across the BBB. Aim7: In vivo proof-of-concept in animal models of GBM. Methods: We have assembled an international team of leaders in the following: high-content phenotypic screening optimized for target validation and drug combination testing across 2D and 3D human GBM assays; patient-derived cellular and mouse models of GBM combined with non-invasive intravital imaging and immune profiling; protein-level pathway analyses, computational modeling and systems biology to predict changes across cellular signaling networks in response to treatment; and nanoscale material science that has huge potential for targeting multiple agents across the BBB to GBM cells in their microenvironment. Through co-development of state-of-the-art methodologies in an integrated platform, we will establish a novel drug-target combination discovery and delivery platform to develop new therapies for GBM in a rapid translational pathway, with clinical advice at each stage. How the results of the research will be used This project represents a balance of new screening and integrated systems-level approaches to inform new therapeutics and the testing of existing exemplar high-value combination hypotheses that our work has already identified. The results will be exhaustively tested pre-clinically and thereafter compiled into de-risked and prioritised combinations, with mechanism of action/biomarker packages, that can be tested clinically with UK partners. Our team offers new approaches that will be co-developed and aid the wider GBM research community, advancing the field’s understanding of current treatment failures in GBM.",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_01340,Medical Research Council,MRC,"Systems neuroscience of human long-term memory, ageing and dementia","Memory problems are some of the first complaints as we grow older, and can be particularly debilitating following brain injury or neurodegenerative disease. This programme investigates human long-term memory and its disorders using novel psychological tasks, combined with neuroimaging and neuropsychological assessment of patients, in addition to computational modelling, multivariate analyses of large cohorts and advanced methods development. Understanding the neurological bases of memory is vital for developing treatments, and pertinent to the MRC 2019 Delivery Plan priorities of “prevention and early detection”, in terms of promoting healthy ageing and detecting early signs of Alzheimer’s Disease.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MENTAL HEALTH;NEUROLOGICAL HRCS22_21514,Innovate UK,IUK,T Cell Responder,"* Protective immunity to SARS-CoV-2, like other viruses, depends on a combined immune response by specific antibodies and T lymphocytes. As we race to immunise the world and end the pandemic, there is considerable unmet need for better, high-throughput immune monitoring. In diverse settings, from healthcare and public health planning to travel and hospitality, there is demand to know if people are carrying immunity. These answers also impact if and when people will require vaccine boosters. While the increased momentum behind antibody testing has supplied finely-tuned, cost-effective, reliable tests, T lymphocyte assays remain cumbersome, costly and limited to specialist labs. The team at Imperial College are leaders in T lymphocyte immunology and have, since the start of the pandemic, been at the forefront of characterising immunity to the virus. However, the assays involve complex cell separations and equipment. We have invested considerable effort in defining which aspects of immunity are truly specific to SARS-CoV-2 and not the result of cross-reactivity with the related common cold viruses. Recent work has been devoted to reimagining T lymphocyte assays to consider what it would take to demonstrate, rapidly, that a small blood sample contains specific cells responding to the virus - that is, who can be defined as having immune memory for this virus - 'a T cell responder'. We have been able to show novel biomarkers of the response, measurable in immune people in a matter of hours. During this project we plan to refine our observations to the extent of producing a pilot point-of-care test that can be developed as a test of T lymphocyte immunity. We envisage utilisation in many settings: international immunity certificates, management of optimal vaccine schedules in at-risk patient groups, public health decisions on when to boost vaccines. Once optimised, the approach can easily be extended to other settings, from immunity to other pathogens, to monitoring of the anti-tumour response in cancer patients given immunotherapy. For these reasons, we have given the project and proposed kit an easy and self-explanatory name - 'T Cell Responder'.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_20304,Wellcome Trust,,TDP-43 Misregulation in neurodegeneration,"TDP-43 is a conserved RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 normally autoregulates its expression by binding to the 3’UTR of its cognate transcript. We have linked disrupted TDP-43 autoregulation to disease, showing that disease-linked TDP-43 missense mutations disturb TDP-43 autoregulation causing a gain of function, finding that ALS patients harbour non-coding variants in the 5’ and 3’UTRs of TDP-43 that could disturb TDP-43 expression and observing that TDP-43 misregulation in mice causes selective brain atrophy reminiscent of human ALS-FTD. We will follow these leads to understand the causes and consequences of TDP-43 misregulation and elucidate therapeutic targets and biomarkers for ALS-FTD. Specifically, we will dissect the TDP-43 autoregulation protein interactome in wild-type and TDP-43 missense mutant cells by performing in-cell protein-RNA interaction studies and native mass spectrometry. To determine the significance of ALS-linked UTR variants in regulating TDP-43 expression we will perform an in-vitro CRISPR/Cas9 mutagenesis screen with parallel genomic and transcriptomic sequencing. To understand how TDP-43 misregulation causes regional and cell type-specific neurodegeneration we will use in situ sequencing of mouse brain sections to obtain transcriptomic information with single cell resolution.","Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating brain diseases linked to disturbances in the protein TDP-43. TDP-43 tightly autoregulates its expression, but disease-linked mutant TDP-43 escapes this process leading to increased TDP-43 and regional brain atrophy in mice reminiscent of human ALS-FTD. Additionally, ALS patients harbour uncharacterised non-coding mutations in the UTRs of TDP-43, which could directly disturb autoregulation. We will use RNA-protein interaction assays and proteomics to characterise the network of proteins involved in TDP-43 autoregulation. We will recreate UTR variants in human cells using CRISPR and determine their effect on TDP-43 expression and neuronal viability. Finally, we will examine the brain transcriptome in situ in TDP-43 mutant mice to elucidate mechanisms underlying regional brain vulnerability in ALS-FTD. These studies will identify how TDP-43 expression is regulated in health and disease and determine how this ubiquitously expressed protein causes selective vulnerability in the brain.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_01517,Medical Research Council,MRC,TRPA1; a potential therapeutic target in idiopathic pulmonary fibrosis,"General protocols: Primary human lung myofibroblasts (HLMFs) are grown from the lung parenchyma of patients with IPF and healthy non-fibrotic control (NFC) tissue removed at lung resection. AIM 1: The expression of TRPA1 in HLMFs and human lung parenchymal tissue from non-fibrotic control (NFC) and IPF donors TRPA1 expression will be examined in NFC- and IPF-derived HLMFs both at rest and following activation with TGFb1 and H2O2 activation. We will examine mRNA expression (qRT-PCR), protein expression (western blotting), functional expression (patch clamp electrophysiology), tissue expression (immunohistochemistry). AIM 2: The functional role of TRPA1 in HLMF pro-fibrotic activity We will study the effect of TRPA1 blockers/RNA silencing on HLMF function proliferation, wound healing, soluble collagen secretion, aSMA expression/stress fibre formation, and contractility in collagen gels. AIM 3: The mechanistic interactions between ROS, TGFb1, and TRPA1 signalling in HLMFs We will use ratiometric Ca2+ imaging and fluorescent probes to detect intracellular Ca2+ and ROS in HLMFs activated with H202 and TGFb1 +/- TRPA1 antagonists/siRNA. Inhibitors of ROS and NOX4 will be used to investigate ROS-dependency. We will also assess TGFb1-dependent pro-fibrotic signalling (SMAD2/3 phosphorylation and nuclear translocation, phosphorylation of P38 MAPK/JNK) in the presence of ROS inhibitors and TRPA1 antagonists/siRNA. AIM 4: The contribution of TRPA1 to TGFb1-dependent fibrogenesis in a human lung parenchymal tissue ex-vivo model of fibrosis We will study TRPA1 antagonists, anti-oxidants and NOX4 inhibitors in our human lung parenchymal model of lung fibrogenesis, using qRT-PCR profiling arrays and immunohistochemistry. This human lung parenchymal assay avoids the important tissue-dependent heterogeneity applicable to TRPA1 pharmacology, and offers the opportunity to benchmark the potential clinical effectiveness of TRPA1 antagonists against pirfenidone.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,RESPIRATORY HRCS22_07886,Department of Health and Social Care,NIHR,Tafasitamab with lenalidomide for treating relapsed or refractory diffuse large B-cell lymphoma [ID3795],"Lymphomas are cancers of the lymphatic system, which is a part of the immune system. Lymphomas are divided into Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphomas (NHL) are a diverse group of conditions which are categorised according to the cell type affected (B-cell or T-cell), as well as the clinical features and rate of progression of the disease. The most common B-cell lymphomas are follicular lymphoma which is a slow growing, low grade form of NHL and diffuse large B-cell lymphomas (DLBCL), a fast growing, high grade form of NHL. Some follicular lymphomas transform into high grade DLBCL (transformed high grade follicular lymphoma). The symptoms differ depending on which organ or tissues are affected by the lymphoma. NHL often presents as painless lumps (enlarged lymph nodes) in the neck, armpit or groin but sometimes may start in other parts of the body such as the stomach or bowel (extranodal disease). People may also have loss of appetite, tiredness or night sweats._x000D_ _x000D_ There were around 12,065 people diagnosed with NHL in England in 2017.[1] It is estimated that about 53% of people with NHL have DLBCL, which equates to around 6,391 people diagnosed with DLBCL per year.[1]_x000D_ _x000D_ Most people diagnosed with DLBCL are 65 or over.[2] Although most patients are cured with first-line chemotherapy, about 10-15% have primary refractory disease and a further 20-30% relapse.[3] Survival rates at 5 years for DLBCL are around 65- 70% for stage 1 and 2 and around 50% at stages 3 and 4. [4]_x000D_ _x000D_ The most widely used first-line treatment for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone). Sometimes etoposide is added to this regimen. NICE guideline NG52 recommends salvage therapy, a multi-agent chemotherapy with or without rituximab, for relapsed or refractory disease in patients who are fit and eligible for subsequent stem cell transplant. Chemotherapy regimens commonly used in clinical practice include DHAP (dexamethasone, cytarabine, cisplatin), GDP (gemcitabine, dexamethasone, cisplatin), ICE (ifosfamide, carboplatin, etoposide) and IVE (ifosfamide, etoposide, epirubicin)._x000D_ _x000D_ There is no established clinical management for people who have co-morbidities or are not fit enough for stem cell transplant. Further chemotherapy, with or without immunotherapy, may be used. This may include R-GemOx (rituximab, gemcitabine oxaliplatin), R-Gem (rituximab gemcitabine), R-P-MitCEBO (rituximab, prednisolone, mitoxantrone cyclophosphamide, etoposide bleomycin, vincristine), (R-)DECC (rituximab, dexamethasone, etoposide, chlorambucil, lomustine) and BR (bendamustine, rituximab)._x000D_ _x000D_ NICE technology appraisal 306 (TA306) recommends pixantrone monotherapy for people who have multiply relapsed or refractory aggressive non-Hodgkin B cell lymphoma, when they have received previous treatment with rituximab and are in the third or fourth line of treatment. NICE technology appraisal 469 (TA649) recommends polatuzumab vedotin with rituximab and bendamustine as an option for treating relapsed or refractory DLBCL in adults who cannot have a haematopoietic stem cell transplant. NICE technology appraisal 559 (TA559) recommends axicabtagene ciloleucel therapy for use within the Cancer Drugs Fund as an option for treating relapsed or refractory DLBCL in adults after 2 or more systemic therapies. NICE technology appraisal 567 (TA567) recommends tisagenlecleucel therapy for use within the Cancer Drugs Fund as an option for treating relapsed or refractory DLBCL in adults after 2 or more systemic therapies._x000D_ _x000D_ References_x000D_ 1. Office for National Statistics. Cancer registration statistics, England. 2019. Accessed September 2021._x000D_ 2. Lymphoma association. Diffuse Large B-cell lymphoma. Accessed September 2021._x000D_ 3. Chaganti S, Illidge T, Barrington S, McKay P, Linton K, Cwynarski K, et al. Guidelines for the management of diffuse large B-cell lymphoma. British journal of haematology. 2016;174(1):43-56. Available from:_x000D_ https://doi.org/10.1111/bjh.14136_x000D_ 4. Cancer Research UK. Non-Hodgkin lymphoma- Survival. Accessed September 2021.",To appraise the clinical and cost effectiveness of tafasitamab with lenalidomide followed by tafasitamab monotherapy within its marketing authorisation for treating adults with relapsed or refractory diffuse large B-cell lymphoma.,6.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_05177,Department of Health and Social Care,NIHR,Tailoring evidence-based psychological therapY for People with common mental disorder including Psychotic EXperiences (TYPPEX),"Aims and objectives We aim to improve the prospects of recovery for people with common mental disorder including psychotic experiences attending Improving Access to Psychological Therapies (IAPT) services (http://www.iapt.nhs.uk/). Working with our service-user advisory group, our objectives are to: Explore attitudes in IAPT settings towards identification and treatment of people with psychotic experiences; introduce a simple tool to identify them; and measure their outcomes. Tailor evidence-based psychological therapy (TYPPEX) for these people, and develop effective training for higher-tier IAPT therapists. Implement a stepped-wedge cluster-randomised controlled trial (cRCT) of TYPPEX. Define best practice in policy and commissioning regarding care pathways for people with psychotic experiences and ensure its adoption and diffusion. Establish a blueprint for evaluating further innovations in therapies deployed in IAPT. Background and rationale Psychotic experiences are common, often indexing the severity of underlying common mental disorder; only rarely do they indicate incipient psychotic illness. People with common mental disorder including psychotic experiences are poorly served by mental health services, and would prefer to be helped in primary care or IAPT services. Our preparatory work in IAPT services has shown that psychotic experiences are not routinely measured in IAPT services but are common in the people they serve. In addition, psychotic experiences were associated with poor response to conventional IAPT psychological therapies. The lack of effective therapies allows psychopathology and disability to evolve, negating recovery. Research plan We propose five workpackages implemented across 12 separate IAPT teams provided by large IAPT services (provider sites) in Cambridgeshire and Peterborough, Norfolk and Suffolk, and Sussex. We shall: Explore service-users , IAPT therapists and managers views on the identification and treatment of people with “common mental disorder including psychotic experiences” in IAPT services; and conduct a systematic review of psychological therapies for these phenomena. Tailor evidence-based psychological therapY for People with common mental disorder including Psychotic EXperiences (TYPPEX), and develop a training package regarding TYPPEX for IAPT therapists. Determine the prevalence of common mental disorder including psychotic experiences in the higher-tier of IAPT services; establish the response to current treatments; and confirm effectiveness and sample size prior to a stepped-wedge cRCT of TYPPEX. Implement a stepped-wedge cRCT of TYPPEX in the higher-tier of IAPT services. This will also demonstrate a means of evaluating other treatment innovations in IAPT settings. We shall test the hypothesis that TYPPEX is more effective and cost-effective than treatment-as-usual. We shall randomise training in TYPPEX to IAPT teams with ~15 higher-tier IAPT therapists each, measuring patient-reported outcomes within the service-users seen by therapists before and after training. Inclusion criteria for service-users will be age ≥16 years, consenting to additional assessment and possible allocation to a trained higher-tier IAPT therapist, and presence of psychotic experiences. The only exclusion criterion will be mental disorder meriting referral to secondary care (usual IAPT practice). Accordingly, we estimate that at least 2,700 service-users would agree to take part over 20 months of recruitment. Each IAPT therapist will treat at least three at any one time. The primary outcome will be ""Reliable Recovery"" based on the routine IAPT patient-reported outcomes (http://www.iapt.nhs.uk/silo/files/measuring-recovery-2014.pdf/). We shall analyse it at the beginning and end of treatment (last therapy session), and one year after treatment initiation. The primary effectiveness end-point will be obtained at the last therapy session, as per routine practice. In our preparatory work, Reliable Recovery prevalence for service-users with psychotic experiences was 39%, versus 62% for those without them (p=0.008). A stepped wedge design with five steps of 4 months (including a baseline step with all therapists in the control arm) with 2 IAPT teams (clusters) randomised at each step and each team having 5 therapists each seeing 3 service-users per step would have just over 80% power to detect a Reliable Recovery difference in the arms of 0.39 and 0.58 (50% increase) at the 5% level of significance, assuming an intra-cluster correlation of 0.05. This would involve a total of 600 service-users and 8 teams. In order to allow for drop-out and flexibility, the aim is to recruit 10 therapists from each team; this would involve 1200 service-users and 80 therapists. Intention-to-treat analyses will compare Reliable Recovery proportions between service-users treated by therapists before and after training in TYPPEX. We will also conduct economic evaluations. Projected outputs & dissemination plans We shall produce a new tailored therapy to treat people with common mental disorder including psychotic experiences and a training package for higher-tier IAPT therapists. Advised by our service-user group, and exploiting strong partnerships with NIHR CLAHRCs and an established co-production approach with stakeholders, our implementation plans (workpackage 5) run throughout the programme. Benefits to patients and the NHS Our programme aims to increase recovery for people with common mental disorder including psychotic experiences in high-volume IAPT services. Increasing the efficiency of these services underpins wider provision of cost-effective NHS mental health care.","The TYPPEX study (Tailoring evidence-based psychological therapY for People with common mental disorder including Psychotic EXperiences). Too many people with common mental health problems, such as depression or anxiety, do not recover after receiving talking therapy. People usually receive cognitive behavioural therapy (CBT), delivered by Improving Access to Psychological Therapy (IAPT) also called Psychological Wellbeing services. Some people who do not get better are experiencing more severe forms of common mental health problems including psychotic experiences such as paranoia or hearing voices. About one-in-five people using higher-intensity IAPT services have some psychotic experiences, often after traumatic events. Currently, IAPT services do not support these people particularly well. In some cases, they are referred to specialist early intervention in psychosis services. These specialist services tend to focus on psychotic experiences and the risk of people developing more severe mental health conditions such as schizophrenia. This is despite the fact that the vast majority of people who have psychotic experiences do not develop schizophrenia. In addition, such services do not usually address the depression, anxiety, and other problems that affect this group of people. For people experiencing a common mental health disorder as well as psychotic experiences, neither IAPT services nor early intervention services fully meet their needs. One of our service-user advisors said, “It was like being stranded in no-man s-land…there was simply no service that was right for me”. The TYPPEX study will develop a form of talking therapy that will meet the needs of people with a common mental health condition and psychotic experiences. This talking therapy will be offered to service-users in IAPT settings, making it more accessible and less stigmatising than specialist mental health services. We will use a brief questionnaire to help identify people using IAPT services with psychotic experiences. We will use the best research evidence, and the views from service-users and IAPT therapists to design a new therapy for these people. IAPT therapists will then be trained to deliver the new therapy using a specially developed training package. We will then prepare for a large study to test how well this new therapy works. It is possible that the training of therapists will improve with experience. Therefore, the study randomly selects the order that teams of IAPT therapists were trained in the new therapy. We will then check if this therapy helps service-users with psychotic experiences better than standard therapy by comparing how many of them recover before and after the new therapy is introduced, team-by-team. This work should help service-users. It will also support IAPT services to achieve their challenging performance targets, and provide a blueprint for testing other therapies beyond current CBT.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_02418,Medical Research Council,MRC,Targeting New Mechanisms In The Control Of Thymus Function To Restore Balanced T-cell Production,"This proposal continues towards our long-term goal of dissecting mechanisms of thymus function that will inform future therapies to restore and replace defective immunity. To examine the role of thymic epithelial cells (TEC) in T-cell development, we have generated novel TEC reporter tools to dissect poorly understood pathways in TEC development that will lead to a better understanding of how epithelial thymic microenvironments develop and function. Building on our novel observation that eosinophils are essential for thymus regeneration, we will identify mechanisms controlling endogenous recovery of thymus function that following insult, including ablative therapy. We will also examine thymus reconstitution following bone marrow transplant, and identify mechanisms that limit the recovery of self-tolerant T-cell production. Finally, we will develop an in-depth definition of conventional and Foxp3+ regulatory Recent Thymus Emigrants (RTE), to provide accurate qualitative and quantitative measurement of thymus function. By defining mechanisms of thymus function and identifying processes that influence the recovery of thymus function, our findings will be important to inform future strategies that aim to improve thymus-dependent immune reconstitution. Our specific goals are: 1. Use newly produced RANKVenus/CCL21Tomato TEC reporter mice to define developmental pathways controlling the formation of functionally distinct medullary TEC subsets that relate to distinct functions of the thymus medulla. 2. Examine mechanisms that control endogenous thymus recovery following ablative therapy, by focussing on a proposed tuft cell/ILC2/eosinophil axis for thymus regeneration. 3. Identify mechanisms that limit the recovery of self-tolerant T-cell production following bone marrow transplantation. 4. Define a molecular signature for mouse and human conventional and Foxp3+ Regulatory RTE, to enable accurate analysis of how therapeutic interventions impact thymus function.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_20196,Cancer Research UK,CRUK,Targeting RNA metabolism to expand haematopoietic stem cells and eredicate acute myeloid leukaemia,"Background Lifelong haematopoiesis critically depends on haematopoietic stem cells (HSCs) which possess unique self-renewal capacity and multilineage differentiation potential. Due to these properties, allogeneic HSC transplantation, in which HSCs are sourced from adult donors or cord blood (CB), offers optimal treatment for many diseases, including blood malignancies. Given the shortage of suitable donors and low HSC yield from CB, it is essential to efficiently expand HSCs for widespread applications. In acute myeloid leukaemia (AML), HSCs/progenitors acquire mutations disrupting the balance between self-renewal and differentiation, often resulting in the formation of treatment-resistant leukaemic stem cells (LSCs), which initiate and propagate leukaemia. Since current therapies often fail to eradicate LSCs, the surviving LSCs cause severe disease relapses. It is therefore essential to identify efficient means of LSC elimination. Aims We investigated methylation- and uridylation-dependent regulation of RNA metabolism, whose role in haematopoiesis remains unknown. N6-methyladenosine methylation (m6A) and 3’-uridylation are widespread RNA modifications which control transcript degradation. We found that conditional deletion of YTHDF2, an m6A reader which recognises m6A-modified transcripts and accelerates their degradation, or inactivation of terminal uridylyl transferases (TUT4/7) which catalyse RNA 3’-uridylation thus promoting its decay, results in HSC expansion. We discovered that YTHDF2 is highly expressed in AML and is essential for disease initiation. We intend to address the hypothesis that m6A- and 3’-uridylation-dependent regulation of RNA metabolism orchestrates normal and leukaemic/cancer stem cell functions, and target these pathways to expand HSCs and eliminate LSCs. Methods Firstly, using genetic and functional approaches in mouse and human HSCs we will identify the key features of HSCs which are dependent on YTHDF2 and TUT4/7, and establish the therapeutic potential of their inactivation in expanding HSCs. Secondly, we will systematically dissect the requirement for YTHDF2 and TUT4/7 at distinct stages of leukaemogenesis in clinically-relevant mouse AML models and validate them as therapeutic targets in diverse AML subtypes with distinct prognoses. Finally, we will employ state-of-the-art molecular approaches to identify mechanisms through which YTHDF2 and TUT4/7 function and dissect their impact on HSC biology and AML leukaemogenesis. How the results will be used This research programme will establish the therapeutic potential of inactivating YTHDF2, TUT4/7 or their downstream pathways in expanding clinically-relevant HSCs and targeting LSCs in different AML subtypes. We will next launch drug discovery programmes and subsequent clinical trials for HSC expansion and AML therapies. Finally, these investigations will reach beyond haematopoiesis and inform novel therapies for other cancers.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS;BLOOD HRCS22_20908,Cancer Research UK,CRUK,Targeting biological vulnerabilities of glioblastoma (TARGET-GBM),"Background: We focus on primary glioblastoma (GBM), the most common and aggressive form of adult brain cancer. Despite increasing knowledge of the genetic and epigenetic changes that underlie the disease, prognosis for GBM patients remains dismal. A new level of understanding of GBM biology is therefore urgently needed. GBMs are driven by neural stem-like cells that exploit developmental pathways to fuel tumour growth and recurrence. Deciphering and targeting the molecular and cellular mechanisms that control GBM cell fate within these developmental/regenerative-like programmes will lead to improved therapies. However, significant challenges exist: i) The GBM neural stem-like state is sustained by ‘master regulatory’ transcription factors that are thought to be undruggable; ii) GBM stem cells exist in diverse and poorly understood sub-states of quiescence, dormancy and proliferation; iii) Cell fate decisions, dormancy and cell proliferation are regulated by complex and ill-defined microenvironmental signals. The TARGET-GBM team will unite three of the UKs leading brain tumour research centres: University of Edinburgh, University College London (UCL), and Institute for Cancer Research (ICR). University of California San Francisco (UCSF) and The Hospital for Sick Children/University of Toronto, will provide missing expertise. Aims: There are three interlinked Themes: Theme 1 Transcriptional control of ‘stemness’ Theme 2 Intrinsic and extrinsic control of dormancy/quiescence Theme 3 Microenvironmental cues: immune-and mechano-regulation Methods: To tackle these challenges from fresh perspectives we will recruit experts new to the field and leverage our CRUK-funded Brain Tumour Centres of Excellence, and the CRUK-funded Glioma Cellular Genetics Resource (www.gcgr.org.uk). Our vision is to gain a deep integrated understanding of GBM biology and identify new therapeutic targets. We tackle GBM by identifying biological vulnerabilities of GBM across scales (molecular, cell-cell, niche/tissue, physical forces and systemic/immune). This will be achieved by moving back-and-forth between the latest cutting-edge technologies and models (mouse and human), and clinical samples. All investigators in our team will be supported by five innovative cross-theme platforms (CTPs): quantitative digital pathology (CTP1), whole brain imaging (CTP2), informatics (CTP3), genome engineering (CTP4) and immune profiling (CTP5) (Figure 2). These will be all based in our CRUK Centres, and build upon existing infrastructure, to drive new thinking and new capacity in brain tumour research across the UK. Outputs: TARGET-GBM will deliver a new integrated and comprehensive picture of how GBM cell fate is controlled. New biology and new targets will emerge. Ultimately, this provides the best chance to identify new cures.","Background: We focus on primary glioblastoma (GBM), the most common and aggressive form of adult brain cancer. Despite increasing knowledge of the genetic and epigenetic changes that underlie the disease, prognosis for GBM patients remains dismal. A new level of understanding of GBM biology is therefore urgently needed. GBMs are driven by neural stem-like cells that exploit developmental pathways to fuel tumour growth and recurrence. Deciphering and targeting the molecular and cellular mechanisms that control GBM cell fate within these developmental/regenerative-like programmes will lead to improved therapies. However, significant challenges exist: i) The GBM neural stem-like state is sustained by ‘master regulatory’ transcription factors that are thought to be undruggable; ii) GBM stem cells exist in diverse and poorly understood sub-states of quiescence, dormancy and proliferation; iii) Cell fate decisions, dormancy and cell proliferation are regulated by complex and ill-defined microenvironmental signals. The TARGET-GBM team will unite three of the UKs leading brain tumour research centres: University of Edinburgh, University College London (UCL), and Institute for Cancer Research (ICR). University of California San Francisco (UCSF) and The Hospital for Sick Children/University of Toronto, will provide missing expertise. Aims: There are three interlinked Themes: Theme 1 Transcriptional control of ‘stemness’ Theme 2 Intrinsic and extrinsic control of dormancy/quiescence Theme 3 Microenvironmental cues: immune-and mechano-regulation Methods: To tackle these challenges from fresh perspectives we will recruit experts new to the field and leverage our CRUK-funded Brain Tumour Centres of Excellence, and the CRUK-funded Glioma Cellular Genetics Resource (www.gcgr.org.uk). Our vision is to gain a deep integrated understanding of GBM biology and identify new therapeutic targets. We tackle GBM by identifying biological vulnerabilities of GBM across scales (molecular, cell-cell, niche/tissue, physical forces and systemic/immune). This will be achieved by moving back-and-forth between the latest cutting-edge technologies and models (mouse and human), and clinical samples. All investigators in our team will be supported by five innovative cross-theme platforms (CTPs): quantitative digital pathology (CTP1), whole brain imaging (CTP2), informatics (CTP3), genome engineering (CTP4) and immune profiling (CTP5) (Figure 2). These will be all based in our CRUK Centres, and build upon existing infrastructure, to drive new thinking and new capacity in brain tumour research across the UK. Outputs: TARGET-GBM will deliver a new integrated and comprehensive picture of how GBM cell fate is controlled. New biology and new targets will emerge. Ultimately, this provides the best chance to identify new cures.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_12508,Versus Arthritis,,Targeting pathogenic fibroblasts in immune mediated inflammatory disease,"Rheumatoid arthritis (RA) and Sjögren's Syndrome (SjS) are both autoimmune mediated inflammatory diseases characterised by persistent tissue inflammation and damage[1,2]. While in RA, inflammation localises to synovial joints leading to arthritis, cartilage and bone damage, SjS is a disabling systemic disease characterised by pain, fatigue and mucosal dryness, with risk of systemic complications (joints, lungs, skin, and peripheral nerves being the most frequently involved) in 30–50% of patients. In SjS, there is no effective immunomodulatory treatment for disease-related systemic complications. Whilst in RA, the introduction of biological drugs targeting either leucocytes or their derived products has led to a step change in management, however 30-40% of patients do not respond to treatment, regardless of the mechanism of action of the drug used and up to 15% of individuals develop multi-drug resistance (treatment refractory disease). Collectively, these observations suggest the existence of additional pathways of disease persistence that remain to be targeted therapeutically. Fibroblasts are heterogeneous and have diverse effector roles in disease pathology including different immunological properties depending on their tissue of origin. We have recently identified a pathogenic subset of fibroblasts present in the joints of patients with active RA despite treatment and in patients with active SjS. In RA, these immune-modulatory fibroblasts express high levels of the cell-surface glycoprotein fibroblast activation protein-α (FAPα) and contribute to disease pathology by “usurping” the joint microenvironment, producing pathogenic levels of chemokines and cytokines that modify the quality, quantity and duration of leucocyte accumulation. In SjS, the same biomarker (FAPa) identifies a population of immune effector fibroblasts that supports the development and maintenance of ectopic tertiary lymphoid structures, a key pathological feature of the disease. Experimental deletion of FAPa expressing fibroblasts in transgenic mouse models of joint and salivary gland inflammation resulted in attenuated tissue inflammation and damage. These data provide a clear rationale for the therapeutic targeting of FAPα expressing fibroblasts in both RA and SjS using a targeted cell depletion strategy. Recent breakthroughs in cancer therapy have been achieved by redirecting cytotoxic T cells to recognise specific antigens on cancer cells using a chimeric antigen receptor (CAR). The modified T cells effectively eliminate cancer cells, and CAR-T cell therapy has been approved for the treatment of some forms of haematological malignancy and are under investigation for use in autoimmune diseases, such as Lupus. Our project collaborators (JE) have shown that the adoptive transfer of CAR-T cells directed against FAPα leads to a significant reduction in fibrosis and restoration of function after cardiac injury in mice, an effect mediated through the direct ablation of FAPα expressing cardiac fibroblasts. In this project we aim to use FAPα-CAR-T cells to selectively deplete FAPα expressing synovial fibroblasts to attenuate synovial inflammation and damage in arthritis. If successful, this study will provide ‘proof-of-principle’ for the therapeutic efficacy of targeting synovial fibroblasts in RA, using specifically engineered CAR-T cells.",,5.2 CELLULAR AND GENE THERAPIES,MUSCULOSKELETAL HRCS22_03269,Medical Research Council,MRC,Targeting torpor circuits across species: towards translation,"We are interested in torpor as a model of resilience that might be mimicked in an ICU setting. Several lines of evidence recently identified neurons in the preoptic area (POA) of the mouse hypothalamus that are active during torpor, and whose reactivation induces hypothermia and inactivity. This evidence suggests a role for a glutamatergic Adcyap1-expressing projection from the POA to the dorsomedial hypothalamus (DMH). It is not clear whether POA-Adcyap1 neurons generate all the physiological adaptations associated with torpor. We will address this question in mice using a genetic activity dependent TRAP2 strategy to express DREADDs or opsins in POA neurons that are active during torpor (i.e., TRAPed). We will assess in vivo and in the working heart brainstem preparation whether this POA ensemble generates a typical profile of cardiorespiratory, thermal, and metabolic depression. We will compare activating all POA neurons that were TRAPed during torpor with the effects of activating a specific subset of POA Adcyap1-expressing neurons using an Adcyap1-Cre mouse line. Both these will be compared with natural torpor in wild type mice. Rats do not enter torpor, however chemo-activating excitatory neurons in the POA of the rat induces a hypothermic state with reduced oxygen consumption and bradycardia ('synthetic torpor'). We will investigate the degree to which synthetic torpor in the rat recapitulates natural torpor in the mouse, whether synthetic torpor is driven by a glutamatergic projection from the POA to the DMH, and explore the natural drivers for this population of neurons in the rat. We will test whether synthetic torpor is protective in a lung-injury model in the rat, with a 2x2 factorial design with measures of physiological parameters (e.g. SpO2, respiratory rate), lung histology/weights, inflammatory markers, and lactate. This work will inform the approach to be taken towards developing synthetic torpor as a possible therapeutic strategy.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL;RESPIRATORY HRCS22_21836,Innovate UK,IUK,Technical feasibility for the Revive + Adrenaline Auto-injector,"An adrenaline auto-injector (AAI) is prescribed to people who are susceptible to severe allergies that put them at risk of anaphylaxis -- a life threatening allergic reaction. Despite medical advice to carry the injector on person at all times, our user studies show: 1. People do not carry them nearly as much as they should 2. Not receiving adrenaline for an anaphylactic reaction is the biggest common factor in fatalities as adrenaline is the only drug known to prevent death due to anaphylaxis. Revive is a new AAI concept developed as a graduation project at the Royal College of Art (RCA). This project seeks to extend the promising results of this prior phase wherein a proof of concept(PoC) was developed. Designed with the patient at its centre, it's much smaller size makes it easy to carry and its form makes it discreetly fit within a patient's life. These combine like never before to counteract the identified problems of being too large to practically carry continuously and adverse impacts on quality of life from an obvious medical form and associated stigma. Revive achieves this through a fresh examination of how a syringe should be designed for an AAI. The proprietary needle injection system concept has been awarded InnovationRCA's support and is patent pending in the UK. We have developed a PoC where we tested functionality and medicine dosage. Revive also has simplified instructions designed to improve accurate use. Revive, unlike most current offerings in the market, incorporates a variety of needle lengths. Now, the team seeks to extend this achievement by conducting a technical feasibility study through the engineering audit of the concept.",,5.3 MEDICAL DEVICES,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_15459,Wellcome Trust,,Telomeric chromatin and VSG allelic exclusion in African trypanosomes,"Trypanosomes are single-celled parasites that causes lethal diseases in humans and livestock. The parasite is covered in variable surface glycoprotein (VSG) that enables host immune system evasion. VSG is often swapped by ‘antigen switching’, which is central for the parasite’s virulence.My group found that the active VSG suppresses expression of other VSGs. As VSG genes are located near the ends of chromosomes, we hypothesise that the characteristic and highly repetitive sequences at chromosome ends are important for suppression. To facilitate studying this, I will manipulate the dosage of these sequences using new genome editing tools (CRISPR/Cas9).Also, I will explore the function of the proteins that package these regions. Again, I will use CRISPR/Cas9 to create parasites with a single copy of each gene encoding these packaging proteins, allowing me to manipulate those genes as well. These proteins impact DNA repair, DNA replication and gene regulation.This project will provide new insight into how chromosome ‘caps’ function, how VSG genes behave at these locations and may also reveal potential drug targets.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_07724,Department of Health and Social Care,NIHR,Tezepelumab for treating severe asthma [ID3910],"Asthma is a chronic inflammatory disease associated with variable airflow obstruction and airway hyperresponsiveness. It is characterised by exacerbations associated with symptoms such as breathlessness, chest tightness, wheezing, sputum production and cough. Asthma is classified as severe when it does not improve with standard therapy. [1] Eosinophils are thought to play a major role in airway inflammation in asthma. Asthma can also have an allergic component, resulting in over-production of human immunoglobulin E (IgE)._x000D_ _x000D_ People with severe asthma often have a severely impaired quality of life which can lead to fatigue, absence from school or work and psychological problems including stress, anxiety and depression. There were 1,484 deaths from asthma in the UK in 2017. [2] Around 4.8 million people in England and Wales currently have treatment for asthma. [2]_x000D_ _x000D_ NICE guideline [NG80] on asthma: diagnosis, monitoring and chronic asthma management, and guidelines from the Global Initiative for Asthma (GINA)[3] recommend a stepwise approach for treating asthma. Control is maintained by stepping up treatment as necessary using combinations of inhaled corticosteroids (ICS), leukotriene receptor antagonists (LTRAs) and long-acting beta-2 agonists (LABAs), and stepping down when control is good. People whose asthma is inadequately controlled by medium-dose ICS plus a LABA with or without an LTRA should be stepped up to have high-dose ICS or offered a trial of an additional drug (for example, a long-acting muscarinic receptor agonist or theophylline)._x000D_ _x000D_ NICE TA278 recommends omalizumab for treating severe persistent confirmed allergic IgE-mediated asthma as an add-on to optimised standard therapy in people aged 6 and older who need continuous or frequent treatment with oral corticosteroids (4 or more courses in the previous year). Optimised standard therapy is defined as a full trial of and, if tolerated, documented compliance with high-dose ICS, LABAs, LTRAs, theophyllines, oral corticosteroids, and smoking cessation if clinically appropriate._x000D_ _x000D_ NICE TA479 recommends reslizumab as an add-on for treating severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose ICS plus another drug, only if the blood eosinophil count has been recorded as 400 cells per microlitre or more with 3 or more severe asthma exacerbations needing systemic corticosteroids in the past 12 months. _x000D_ _x000D_ NICE TA565 and NICE TA671 recommend benralizumab and mepolizumab in adults as add-ons for treating severe refractory eosinophilic asthma, only if:_x000D_ _x000D_ • the blood eosinophil count has been recorded as 300 cells per microlitre or more with 4 or more exacerbations needing systemic corticosteroids in the previous 12 months, or the person has had continuous oral corticosteroids of at least the equivalent of prednisolone 5 mg per day over the previous 6 months, or _x000D_ • the blood eosinophil count has been recorded as 400 cells per microlitre or more with 3 or more exacerbations needing systemic corticosteroids in the past 12 months._x000D_ _x000D_ References_x000D_ 1. Asthma UK. What is severe asthma? Accessed February 2021_x000D_ 2. Asthma UK. Asthma facts and statistics. Accessed February 2021_x000D_ 3. Global Initiative for Asthma (2019) Global strategy for asthma management and prevention. Accessed February 2021",To appraise the clinical and cost effectiveness of tezepelumab within its marketing authorisation for treating severe asthma.,6.1 PHARMACEUTICALS,RESPIRATORY HRCS22_19398,Wellcome Trust,,Thailand Africa and Asia Programme - PPE Award,"The Wellcome Thailand AAP has conducted high quality impactful research for 40 years on infectious diseases of major public health concern, leading to the widespread adoption of new approaches and treatments for many of them including malaria, melioidosis, and rickettsial infections. In our fifth decade we will focus on ensuring sustainable impact and influence on policymakers by strengthening our research network and developing the capabilities of our partner institutions. Our vision is to: 1. Through research continue to address public health problems with regional and global relevance, using cutting edge approaches to seek affordable and deployable solutions to disease prevention, diagnosis and patient management. 2. Maximise our public health research’s uptake and impact, incorporating health economics analysis and goal-driven engagement with policymakers, national academic institutions, hospitals, industry partners, communities and the general public. 3. Work with our local host institutions to increase their national and global impact by integrating activities including training programmes, joint research projects, and supporting partner-led programmes to translate research into policy and practice. Our goal is to improve life quality and expectancy by reducing the adverse impact of infectious diseases, which account for much of the disparity in health metrics between low and high income countries.",,8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_20801,Wellcome Trust,,"Thanzi La Mawa: Integrated Analysis of Health System Capabilities and Effects on Population Health in Malawi and Eastern, Central and Southern Africa","Those responsible for the healthcare sector in countries in Eastern, Central and Southern Africa must decide what to do with limited resources to generate the greatest possible benefit to the health of the people they serve. We propose to develop new methods and collect new data to characterize the means by which the healthcare system produces health benefits in the context of a complex and evolving pattern of demand for healthcare. Our proposed approach is to build a detailed and theoretically-principled simulation model that couples a ‘Healthcare Production Module’ with an agent-based ‘Epidemiological Module’, that together would represent the mechanisms by which resources create healthcare that lead to health gains. We will use these methods to examine: how can the currently available resources (budgets and non-financial resources) for health be used to generate the greatest health gains; how could greater gains be achieved with more financial resources; and how should the healthcare system adapt in response to evolving burdens of diseases. We will work closely with national and regional institutions to translate the insights into strategic planning and policy and facilitate the routine usage of these methods by governmental analysts throughout the region.","Those responsible for the healthcare sectors in Eastern, Central and Southern Africa must decide what to do with limited resources to create the greatest possible health benefits for people they serve. However, deciding on how and what services should be provided is difficult because healthcare is complex, the needs of the population are many and not every possible service can be afforded. We will build a computer model of the healthcare system, which will help because the effect of different choices can then be examined before they are implemented. We will work with the government of Malawi to tackle the questions it faces and also support analysts in the region to use the computer model to tackle the questions being faced elsewhere. This should lead to better decision making and contribute to improvements in health.",8.1 ORGANISATION AND DELIVERY OF SERVICES;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_19081,Cancer Research UK,CRUK,The Birmingham CRUK Centre Clinical Academic Training and Research Programme / Year 2,"Background: As the practice of oncology becomes ever more complex there is an increasing need for clinicians who have been trained not only to become excellent physicians but also as leading scientists. A rigorous scientific education is essential to ensuring that the UK not only produces top flight academic clinicians at the forefront of innovative clinical trial design, doctors who are able to develop the appropriate translational research programmes but also clinician scientists who have the ability to understand critical clinical questions and design and run laboratory programmes with a view to answering them. An ambitious clinical academic training programme is pivotal to this and at the Cancer Research UK Birmingham Centre we have developed a robust programme to help develop the vision. Aims: To develop and successfully deliver a world class academic training programme for clinical trainees so as to produce first rate clinicians working in the area of cancer management who can think scientifically and maintain the UKs reputation as a beacon of academic excellence. Methods: Building on our established structures that deliver excellent clinical academic training we propose to train 3 MBPhD students per annum to start their PhDs at the completion of their intercalated degree or for graduate entry students after year 1 (of 4 years) of their medical degree. We will also offer scientific training to 3 Clinical Research Training Fellows annually who will enter their PhD during their clinical training as per standard practice. We will develop structures to attract the best young students and trainees including earlier exposure to oncologists and related clinicians to enable individuals to make an informed decision about pursuing a clinical cancer research career. We will develop comprehensive mentorship and support programmes post-PhD to maintain scientific engagement and excellence to ensure that wherever possible candidates become academic clinicians and clinician scientists in oncology and related disciplines. We will also offer shorter research courses such as MSc and MDs. How the results of this research will be used: The main aim of this programme is to increase the number of clinical academics working in cancer related specialities in the next 15 years. It is our belief that these individuals are critical to CRUKs ambition to improve the cure rate of people with cancer from 50% to 75% within the next 20 years, and the ultimate aim of bringing forward the day when all cancers are cured.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_05810,Department of Health and Social Care,NIHR,The Cauda Equina Syndrome Early Recognition (CESER) Study: A mixed-methods study to improve diagnosis of cauda equina syndrome in the Emergency Department.,"Background:Cauda equina syndrome (CES) describes the symptoms caused by compression of multiple sacral and lumbar nerve roots within the vertebral canal. It is a spinal emergency and often leads to irreversible life-changing disability. Delayed decompression is believed to worsen prognosis but the gold standard diagnostic tool (MRI scanning) is not always immediately available.Aim:The aims of this study are to (1) determine whether patients with suspected CES can be risk-stratified using clinical features, (2) report current outcomes for patients with suspected CES, (3) describe variation in pathway design across the NHS, and (4) make recommendations about the optimal design of clinical pathways for patients with suspected CES.Workstream 1:A systematic review of diagnostic studies will synthesise the existing literature and pool data using appropriate techniques for meta-analysis. This will determine to what degree clinical features can predict which patients with low back pain should undergo emergency MRI. Workstream 2:A multi-centre prospective cohort study will be used to evaluate the clinical features identified in Workstream 1 to determine whether or not they can be safely used to risk-stratify patients with suspected CES. This study will also describe variation in the management of patients with suspected CES (e.g. time to imaging, inter-hospital transfer, and decompression) as well as establish the prognosis of patients with CES and those whose symptoms are not explained by the initial MRI. A small subset of patients (30) will undergo qualitative interviews focussed on what is important to patients in relation to their experience of symptoms and health seeking activity, emergency care, diagnosis, treatment and early phase of recovery. Workstream 3:A facilities audit and care pathway mapping exercise will be undertaken using nominated clinicians at each acute NHS hospital. This will map CES pathways and protocols currently in use around the UK to identify unexplained variation and to highlight examples of innovative practice aimed at achieving prompt diagnosis. The different models of evaluating patients with suspected cauda equina syndrome will be categorised and evaluated for cost effectiveness using data from Workstream 2. Workstream 4:A structured guideline development exercise will be undertaken to consider the evidence from Workstreams 1-3 and establish recommendations around which local pathways and national guidelines can be developed. Impact:This programme will improve the assessment of individual patients and the design of clinical pathways for patients with suspected CES. It will therefore facilitate rapid diagnosis of patients with CES, improve patient outcomes, and reduce healthcare costs.","'Cauda equina syndrome' describes symptoms caused by a disc from the spine pushing on the nerves at the end of the spinal cord. These nerves supply the legs, bladder, anus and sexual organs, and can become damaged if compressed for too long. Most patients with cauda equina syndrome require an emergency operation to take pressure off the nerves.Although lots of people attend Emergency Departments with back pain, very few have cauda equina syndrome. Unfortunately, cauda equina syndrome can be difficult to diagnose and we do not know whether any particular pattern of symptoms can help us rule out the diagnosis without a MRI scan. This is a problem as MRI scanning is not available in all hospitals at night and we know that some patients end up waiting too long before getting a diagnosis.This study will try to determine whether any pattern of symptoms can help us identify which patients are very unlikely to have cauda equina syndrome. It will also help determine how patients should be treated when they arrive at an Emergency Department with symptoms that could be caused by cauda equina syndrome.First, we will use data from previous studies to see whether these found that symptoms or signs on a physical examination can show which patients have cauda equina syndrome.Second, we will recruit 2000 patients into a study run across a number of different NHS hospitals. These patients will be examined carefully by a doctor before anyone knows the result of their MRI scan. We will then take the results of the MRI scan and look back to see whether any signs or symptoms were particularly helpful in working out which patients would end up with a final diagnosis of cauda equina syndrome. We will contact all patients at 6-weeks, 6-months, and 12-months to ask whether they still have symptoms. A smaller group of patients will be interviewed to learn more about their experiences of being assessed for cauda equina syndrome.Third, we will ask all NHS hospitals how they manage patients who might have cauda equina syndrome. This will help us determine where there are obvious problems or delays and major differences between hospitals. It will also help us identify hospitals that have found useful ways to diagnose cauda equina syndrome quickly. We will use this information, together with the data from the large study of 2000 patients, to estimate the cost effectiveness of different methods of managing patients with suspected cauda equina syndrome.Finally, we will ask a group of patients and professionals to consider all of this evidence and develop recommendations about how individual clinicians and the systems they work in should act when assessing a patient who might have cauda equina syndrome.These four studies have been designed to help all hospitals provide high-quality care across the NHS for patients that might have cauda equina syndrome. This should make healthcare more efficient (and so possibly cheaper) at the same time as reducing harm to patients.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,MUSCULOSKELETAL;NEUROLOGICAL HRCS22_19956,Wellcome Trust,,The Chemical Probes Portal: An Open Resource Empowering High Quality Chemical Biology,"The Institute of Cancer Research (ICR), in partnership with the Structural Genomics Consortium (SGC), proposes to assume responsibility for the Chemical Probes Portal (http://www.chemicalprobes.org/) (Portal) and move its operations to the UK. We request funds to complement existing in-kind and financial support in order to: maintain, enhance and expand the Portal; ensure its continuation as an invaluable public resource; and implement a sustainability plan for future independence. The Portal is a public online resource created to provide biomedical researchers with expert advice to identify the most appropriate chemical probes for their experiments. Experts rank probes using a star rating and provide advice on their properties and use. It is an innovative, open science solution with a clear aim – to reduce the use of poor quality probes in the literature, and thus increase the quality and reproducibility of scientific research. The Portal is currently supported by small donations from companies and in-kind contributions from a founding set of 146 advisors from academia and industry. We are seeking complementary funding from The Wellcome Trust to enhance, extend and maintain the core infrastructure, to expand the number of probes, and to better communicate the Portal’s offering to funders, scientists and publishers.","Chemical substances that modulate biological systems are widely used by biomedical researchers to understand biological mechanisms, decipher mechanisms of disease, and discover novel drugs. They complement genetic technologies, and the approaches are especially powerful when used together. Chemical tools must be selected and used very carefully. Only specific, highly characterised compounds, called chemical probes, provide interpretable information regarding the biology of proteins. Inappropriate selection and use of chemical probes can lead to misleading results; wasting time and resources. Many researchers lack the expertise to select the most appropriate chemical probes, and relevant expertise often resides in industry. As a solution, the Chemical Probes Portal, an open, web-based community resource, provides trusted, expert advice to help the research community to select and use the right probes. Through our collaborative public-private partnership, we will enhance and significantly increase the content of the Portal and provide a sustainability plan to ensure its continuation.",2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),GENERIC HEALTH RELEVANCE HRCS22_15114,Wellcome Trust,,"The Child's Speech: speech therapy, stammering, and activism in Britain, 1906-2000","This project will produce a cultural and social history of speech therapy in twentieth-century Britain that is ambitious in seeking to account for the entwined relationship of speech therapy to stammering activism, not simply in a relationship of medical professional to patient. Municipalities employed speech therapists from c.1906 to ‘correct’ what (in contemporary language) were considered ‘defects’ of children’s speech. Early therapists were often female, trained in drama-school elocution and only later became medicalised. Consequently, they were as marginalised as the disabled subjects they sought to ‘treat’. Conversely, individuals who stammered long pointed towards the uniqueness of their position and voice to militate for improved therapy. In short, this project allows an ambitious study that cuts across normally polarised voices of ‘medical professional’ and ‘patient experience’ to explore the boundaries of what encompasses ‘the medical’ itself: both as practices (elocution therapeutics and activism) and as theories (what ‘stammering’ meant). ‘The Child’s Speech’ therefore offers a unique case study into the margins of disability studies which can point towards new frameworks for thinking about professionalisation; its relationship to competing, but also harmonising, forms of expertise, patient voice, experience and activism; and wider gender, race, class and disability dynamics within these.","Stammering remains on the margins of disability and disability studies. This project will develop the first history of speech therapy for children who stammered in twentieth-century Britain, explored through the stories of stammering activism and speech therapy which - I argue - are not separate but bound together. Speech therapy as a profession has also historically been marginalised within medicine, mostly on account of gender (its practitioners are overwhelmingly female and have faced discrimination as a consequence) and its historical links to elocution rather than experimental science. Stammering activism has long proceeded alongside the development of therapy – from early twentieth-century therapists who mobilised experiences of being (former) ‘stammerers’ through to the creation of the British Stammering Association in 1978. In exploring these interconnections, I shall address broader questions around what terms 'experience', 'expertise' and even 'the medical' mean in the context of stammering and its therapy.",8.1 ORGANISATION AND DELIVERY OF SERVICES,MENTAL HEALTH HRCS22_14132,Action for A-T,,The David Peake Study to test the feasibility of whole-body MRI for cancer surveillance in children and young people with Ataxia Telangiectasia,This project explores the feasibility of whole-body MRI for cancer surveillance in children and young people with Ataxia Telangiectasia,"Dr Rob Dineen and his team believe that the combination of an MRI scan of the whole body together with a blood test is a good way to find hidden cancers in children and young people with the inherited disease Ataxia Telangiectasia (A-T). In this study which the first of its kind in A-T, they want to see: whether this type of MRI scan is acceptable to the children and young people with A-T and their families whether having the MRI scan and blood test causes any additional stress for the people who take part, and whether the MRI scan and blood test are able to find hidden cancers. They will also contact experts around the world who treat people with A-T to find out their views and current policies on looking for hidden cancers. This study is a relatively small to start but if they find that the combination of whole body MRI scans and blood tests are acceptable to the people who take part and their families, the next step will be to carry out a much larger study to show that this approach is really effective at screening for hidden cancers in children and young people with A-T.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS;CONGENITAL DISORDERS HRCS22_19857,Cancer Research UK,CRUK,The Edinburgh-UCL CRUK Glioma Centre of Excellence,"Adult and paediatric brain cancers now account for more cancer deaths in the under 40’s than any other tumour types, with adult gliomas accounting for the majority of the ~5000 cases of malignant brain tumours in the UK each year. However, translation to the clinic is hampered by both a lack of a community of academic, science-minded specialist clinicians who work in neuro-oncology, and lack of understanding of the key biological vulnerabilities to target therapeutically. At present, for both paediatric and adult glioblastoma (our area of focus), there is little effective translational pipeline from basic research to clinical trials to enable evidence-led ‘smart’ clinical advances in a UK-wide network with global connections. Only by tackling this we will develop new cures for this dismal disease; for this, we will contribute to building a core community of clinical academics that are linked to high-quality discovery science. The mission of the Glioma Centre of Excellence (CoE) will be to tackle the building of a new neuro-oncology community as a priority, with integration into our existing strong research and training infrastructure at both UCL and University of Edinburgh. We will simultaneously establish a new translational pipeline that is built upon a deeper biological understanding of GBM. This will take biological and data-intensive research and phenotypic-led drug discovery (in disease-relevant and predictive pre-clinical models) into a strong clinical community that can perform state-of-the-art adaptive clinical studies. To fuel the pipeline, and with additional funding for science in due course, we will maximise new cross-disciplinary opportunities in data-driven innovation, imaging technologies and growing strengths in phenotypic drug discovery using patient-derived GBM cellular models. Our longer term CoE aims are to improve the landscape across the UK for discovery, and clinical evaluation, of new brain cancer therapeutics.",,5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),CANCER AND NEOPLASMS HRCS22_20578,Wellcome Trust,,The Global Alliance for Genomics and Health: Setting the Standards for Genomics and Health-Related Data Sharing,"The decreasing cost of genomic sequencing will yield millions of samples in the coming years from both research and healthcare. To make the most use of these data, the community must agree on common methods for collecting, storing, transferring, accessing, and analyzing data.  This proposal will support the Global Alliance for Genomics and Health (GA4GH; www.ga4gh.org) as it develops the standards and policies necessary for effective and responsible data sharing. With more than 1,000 active contributors working across more than 30 countries in the areas of healthcare, research, patient advocacy, life science, and information technology, this diverse organization enables broad sharing that transcends the boundaries of any single institution or country.  We envision a future in which the full suite of GA4GH standards enables all clinicians, geneticists, and researchers to search across the world’s collective genomic data to reveal unanticipated gene-disease associations, make otherwise impossible drug-response predictions, and generally participate in genomics at a competitive pace—regardless of their means or location.  The promise of genomic medicine lies at a crossroads that depends on community harmonization and will significantly enhance human health and medicine if we succeed. We believe GA4GH is necessary to that success.",,1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),GENERIC HEALTH RELEVANCE HRCS22_13365,Wellcome Trust,,The Human Behaviour-Change Project: Building the science of behaviour change for complex intervention development,"What the activity will look like: We will bring together health-interested publics and population-health decision-makers for a series of workshops engaging with key aspects of the AI System and co-producing a toolkit of resources to facilitate appropriate trust in AI systems applied to population health.   What we will have achieved 1: Co-produced toolkit of resources Exact nature of the resources will depend on outcomes of the workshops.  We envisage resources that explain and prompt questioning about key features of the AI System and promote consideration of personal values/preferences regarding those aspects to decide upon trust in the System. The toolkit will also be applicable to discussions of trust in other AI systems applied to population health.   2:  Multi-media documentation of discussions in workshops • Developed in partnership with participants • Made publicly available online • Documenting issues raised and providing case studies of public engagement   3: Interactive public talk on facilitating appropriate trust in AI in population health decision-making • With live web video link and video-recording • Opportunities for Q&A’s during and after   4: Additions to the HBCP AI System user interface Toolkit resources will be linked to the System’s online interface and their use promoted to people querying the AI System.   Overarching these achievements will be efforts to achieve long-lasting and widespread reach The dissemination and engagement strategy will be both broad and targeted, maximising exposure to and engagement with the outputs, including a social media campaign. Long-term availability of the outputs will be ensured through hosting them on the HBCP website.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;CARDIOVASCULAR;STROKE;METABOLIC AND ENDOCRINE HRCS22_13183,Barts Charity,,The IDEAL Study: Investigating The DEterminants Of COVID-19 Outcomes Across East London,"People from Black, Asian and minority ethnic (BAME) backgrounds are more likely to become very unwell or die from COVID-19 than those of white ethnicity. COVID-19 has unmasked alarmingly poorer outcomes in BAME communities which are not new and must be urgently addressed. Underlying reasons are unclear; suggestions include an interplay between pre-existing health conditions and socio-economic factors (e.g. occupational or health literacy) which may have compromised social distancing or resulted in delayed presentation for care. COVID-19 has deeply affected the multi-ethnic communities of East London so we believe it is the right place to base this study which aims to examine in detail, if and why these differences exist in BAME communities. We will bring together clinical data of COVID-19 patients from Barts Health hospitals and local authority data to help us identify factors that support people to have better health and those that increase the risk of ill-health. We will then work directly with local BAME residents, in a variety of ways, to understand their life before, and during, COVID-19. This research will help NHS and policymakers develop realistic and effective strategies to reduce the damaging impact of COVID-19 on BAME communities. We hope it will also provide useful insights for other health issues where ethnic differences exist.",,"2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",INFECTION HRCS22_19309,Wellcome Trust,,"The Jalview Resource for Biological Sequence, Structure and Function Analysis: 2019 and Beyond","The Jalview Resource is an open-source, GPL-licenced, graphical multiple sequence alignment editor and analysis workbench, first developed in 1996. It is installed on >57,000 computers in >130 countries and publications describing Jalview have been cited >5,600 times. In addition to sophisticated colouring, filtering, searching, alignment editing and annotation functions for DNA, RNA and Protein sequences, Jalview provides linked views of trees, three-dimensional structures and RNA secondary structure. Eight standard multiple alignment algorithms, four disorder predictors, seventeen conservation methods, the JPred protein secondary structure predictor and RNAalifold RNA structure predictor are freely available in Jalview.  Users can interactively search PDBe and Uniprot, and retrieve alignments and genomic data from the Interpro and Ensembl data resources at the EMBL-EBI.  Wellcome Trust investment since 2014 enabled improvements, including efficient handling of long genes with large numbers of annotations, a linked DNA/RNA/protein multiple alignment window, discovering and displaying genetic variation from Ensembl, extended querying against PDBe and Uniprot EMBL-EBI services and the development of >30 training videos that have received >50,000 views. Here we request support to extend the Jalview Resource to add sophisticated facilities for long RNA-read interpretation, reproducible data analysis, further links with EMBL-EBI, and a new web-friendly JavaScript version: JalviewJS.","This project will enhance a powerful computer application called Jalview that is used by tens of thousands of scientists worldwide to help them understand the function of genes and the effect mutations in DNA have on disease.   Jalview works on Windows, Apple and Linux computers and provides tools to align sequences to see which regions are similar and so help find what their function is.  Jalview links to international databases to extract information and show it graphically on the alignment to help scientists understand their context.  Jalview has features to allow time-consuming calculations to be routed to remote supercomputers that perform these tasks efficiently.  It also has built in functions to calculate and display evolutionary trees and the three-dimensional structures of proteins and other molecules. This project will make Jalview work on iPads and web pages and provide videos to help scientists and school students learn to use it.",1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),GENERIC HEALTH RELEVANCE HRCS22_05444,Department of Health and Social Care,NIHR,The Missing Billion: Using participatory approaches to improve access to healthcare for disabled people in Uganda,"BackgroundParticipatory Learning and Action (PLA) is a community-led participatory strategy to improve healthcare access. Community groups are established. They meet regularly to identify issues, develop and implement solutions, and evaluate results. PLA for women significantly reduces maternal and neonatal mortality, but its impact in other areas is not clear. The study aims to assess whether the PLA for Disability (PLA-D) can reduce mortality and improve health and healthcare access of disabled people in Uganda. Objectives: To use an evidenced-based approach to co-create PLA-D. To assess the feasibility of PLA-D implementation. To undertake a cluster-based Randomised Controlled Trial (RCT) to assess the effectiveness/cost-effectiveness of PLA-D in reducing mortality. To undertake a process evaluation of PLA-D to understand mechanisms for impact and scale-up. To strengthen capacity for informing disability policy and practice through the conduct of high-quality research.MethodPLA adaptation (months 0-24): We will undertake in-depth interviews and analyse existing quantitative data to describe healthcare access and barriers experienced by disabled people in Uganda. We will update relevant systematic reviews and review the PLA literature. A consortium (researchers, implementers, disabled people) will co-create the PLA-D using the formative research. Feasibility of PLA-D will be assessed with 5 groups in Uganda.A two-arm cluster RCT will assess the effectiveness and cost-effectiveness of PLA-D in Luuka district, Uganda (months 24-48). The control arm will receive health system strengthening support (accessibility audit of healthcare facilities; healthcare worker disability training). The intervention arm will additionally receive the PLA-D intervention, with one group established per cluster (village or city block). Groups will target disabled people, but will be open to their family/community members. We will include 64 clusters per arm with approximately 50 disabled people per cluster (Total: 3200 disabled participants per arm). Data collection will occur: 1) pre-randomisation (baseline), 2) after intervention completion (12 months) and 3) endline (24 months post-baseline). Disabled participants will complete a structured questionnaire with a trained researcher covering: healthcare quality and access, morbidity, quality of life, and contextual characteristics (e.g. poverty). Vital status will be recorded at follow-ups and verbal autopsy undertaken for reported deaths. Direct and indirect intervention costs will be collected. A process evaluation will be undertaken to examine the intervention implementation, potential mechanism for action, and consider strategies for scale-up. Ethical procedures will be adhered to throughout. Analysis/dissemination (months 49-60). Intention-to-treat analyses will compare outcomes between control and intervention arms. Incremental cost-effectiveness ratio will be calculated for outcomes. We will disseminate findings to key audiences (communities, disabled people, Ugandan and international policy/programme implementers, academics) through tailored approaches (e.g. policy/evidence briefs, community meetings, individual meetings, journal articles, academic presentations).Anticipated impact PLA-D is anticipated to improve healthcare access and quality for disabled people in the intervention clusters, and thereby reduce morbidity and mortality. Better health will support participation (e.g. education, employment), and so improve quality of life and reduce poverty. If successful, this programme can be scaled in Uganda and other LMICs, extending this impact. Translational research capacity will be strengthened for Professor Kuper and Ugandan partners.","BackgroundThere are one billion disabled people globally. Disabled people, on average, have higher healthcare needs than others. Yet they face barriers in accessing healthcare. As a result, they have worse health outcomes, including 2-3 times higher mortality rates across all ages. Policies and laws supporting the right to healthcare for disabled people are often not put into practice. Evidence is growing that interventions to improve healthcare led by communities are particularly effective. They are low-cost, scalable and address locally relevant concerns. One example is the Participatory Learning and Action (PLA) approach developed to prevent maternal and newborn deaths. In PLA, women's community groups are established and meet monthly to: 1) identify problems, 2) identify solutions, 3) plan and implement solutions, and 4) evaluate their efforts. PLA significantly reduces maternal and newborn deaths, usually by at least 20%, and is endorsed by WHO. The aim of this study is to assess whether the Participatory Learning and Action for Disability (PLA-D) approach can reduce mortality and improve health of disabled people in Uganda. Uganda is the research setting, given my strong networks and partners and the legal commitments on healthcare provision for disabled people.Design and methodResearch will be undertaken by a consortium of UK and Uganda based partners. We will identify the problems facing disabled people in accessing healthcare in Uganda, through: 1) In-depth interviews with key informants (e.g. disabled people, health workers), 2) Analysis of existing numerical data, 3) Updating reviews on access to healthcare for disabled people. We will then collaborate with disabled people and health professionals to use this information to adapt the PLA approach for disabled people. We will decide who should facilitate the groups, where they should meet, and how the PLA delivery and materials need to be adapted. Five PLA-D groups will be established, each including about 20 disabled people, and we will assess whether they are feasible to run and if further adaptations are needed. We will then undertake a trial to assess whether PLA-D is effective. We will identify 128 clusters (villages or city blocks) in Luuka district, and randomly assign them to be in the intervention or control group. In the control group, we will help to strengthen the health system, by undertaking an accessibility audit of health facilities and providing training on disability to healthcare workers. In the intervention group we will establish one PLA-D group per cluster, as well as the health system strengthening activities. We will interview all disabled people in the study about health and healthcare access at baseline and follow-up (1 year and 2 years), and record if any participants had died. The intervention and control groups will be compared to assess whether mortality rates were lower and health/healthcare access better in the intervention groups than among controls, and what the cost was for the outcomes achieved.Community engagement and involvementCommunity engagement is at the heart of PLA as well as the Disability Movement with its ethos 'Nothing about us, without us'. Identification of problems and implementation of solutions is led by disabled people themselves. We will include disabled people as advisors at every stage, and as researchers wherever possible.DisseminationResearch is most worthwhile if it can be used to improve policy and practice. We will develop tailored strategies to reach our key audiences. We will hold community meetings and with disabled people's organisation. We will engage with policy and programme implementers, both in Uganda and internationally, by producing short documents of key findings and holding meetings. We will reach academics through publishing articles in journals and presenting at key meetings and conferences.",7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_13644,Cancer Research UK,CRUK,The MyoScreen Study - Investigating the Utility of Liquid Biopsy as a Method of Early Detection of Idiopathic Inflammatory Myopathy-Associated Cancer,"Background Autoimmune diseases are associated with increased cancer risk and poor outcomes. Early autoimmune-associated cancer diagnosis is vital but under-researched. Blood-based liquid biopsy provides an opportunity for early autoimmune disease-associated cancer diagnosis, potentially improving outcomes. Proof of concept of added benefit of liquid biopsy is vital, however autoimmune disease heterogeneity makes multi-disease research challenging. Idiopathic inflammatory myopathy (IIM) represents an ideal condition in which to investigate proof of concept of utility of liquid biopsy as a method of early autoimmune-associated cancer diagnosis. IIM is a chronic multisystem autoimmune condition predominantly manifesting with muscle inflammation (myositis). One in four adults with IIM are diagnosed with cancer (multiple organs) within three years either side of IIM onset and outcomes are poor (17% remission rate). Research demonstrates significant beneficial survival impact of earlier diagnosis of IIM-associated cancer. Aim The MyoScreen study aims to carry out preliminary investigation into the utility of liquid biopsy as a method of early cancer detection in newly diagnosed IIM patients, thus generating pilot data for grant applications to fund a large international longitudinal study. Methods Cohort Thirty adult participants with new onset (<​6 months) IIM will be recruited from specialist IIM clinics in Salford Royal Hospital, University College London Hospital, and via the National Institute for Health Research Musculoskeletal Translational Research Collaboration (15 UK-wide research active centres). Data collection Participants will undergo blood-based liquid biopsies at the time of recruitment and after six months for circulating tumour DNA detection by the Nucleic Acid Biomarker Team at the CRUK Manchester Institute Cancer Biomarker Centre. Participants will also undergo standard of care ""multi-modality"" cancer screening at recruitment. Analysis Analysis will aim to identify “concordance” of cancer diagnoses between liquid biopsy and conventional ""multi-modality"" screening. Added benefit of liquid biopsy will be assessed by ability of liquid biopsy to identify early-stage cancer in patients where conventional screening has not. How results will be used - Provide preliminary evidence for future grant applications for a longitudinal study in >100 international adult IIM participants. - Stimulate research into liquid biopsy as a method of early autoimmune-associated cancer detection. - Establish a new onset IIM UK-wide recruitment network, facilitating future research. - Earlier IIM-associated cancer diagnosis, thus potentially improving survival. - Establish collaborative partnerships outside non-traditional cancer fields (i.e. IIM, rheumatology, autoimmunity).",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_18247,Wellcome Trust,,The New Jerusalems: post-war New Town archives in Britain and Ireland,"The project will make accessible for research eleven archives from post-war new towns in England, Wales and Ireland.  Eight of these archives will be catalogued and all will be safeguarded through conservation and preservation work.  The new towns included are: Basildon, Bracknell, Crawley, Cwmbran, Newton Aycliffe, Peterlee, Redditch, Runcorn, Shannon, Stevenage and Warrington.The archives are held by nine partner organisations brought together through the Association of New Towns Archives and Museums.  The Association builds on existing academic partnerships, and this project will develop those further.  Key outcomes include not only itemised catalogues and protected collections, but also a collaborative dissemination programme.This project will provide a substantial increase in the evidence base available for researchers seeking to interrogate the new towns’ legacy. The project is particularly timely in the context of the current public health emergency.  New towns have much to contribute to current policy making in urban planning and public health including: new homes to reduce overcrowding; generous public green space; amenities within 15 minutes of the home; and supporting walking and cycling. There is renewed interest in many aspects of new town design as plans are made for social recovery in the aftermath of Covid-19.",,3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS,GENERIC HEALTH RELEVANCE HRCS22_19604,Wellcome Trust,,The Nomenclature of Human and Vertebrate Genes,"As human genomics is already a crucial aspect of biomedicine, with increasing importance in clinical practice and everyday life, communicating in a common language about genes becomes ever more vital. The HUGO Gene Nomenclature Committee (HGNC) is the sole worldwide authority assigning standardised nomenclature to human genes, and maintains a searchable database of over 40,000 named human genes at www.genenames.org. This funding will enable the continuance of the crucial work of the HGNC, in particular naming newly identified protein-coding and RNA genes and pseudogenes. A further key activity will be the reassignment of genes with uninformative identifiers to function-based names as this information is elucidated. The HGNC will also continue to play a pivotal role in consensus annotation of the remaining unresolved gene structures in the human genome. HGNC recently established the Vertebrate Gene Nomenclature Committee (VGNC, vertebrate.genenames.org), a sister project for naming genes in other vertebrates utilising data from phylogenetic resources and in collaboration with specialist advisors for complex gene families","Effective communication between scientists, healthcare professionals and the general public is vital to unlocking the wealth of information encoded in the human genome. Our genome contains thousands of genes, many of which encode proteins, the building blocks of life; each gene needs a unique name and symbol (an abbreviation of the name). The HUGO Gene Nomenclature Committee (HGNC) is the only group worldwide giving names and symbols to human genes. The HGNC's freely available online database (www.genenames.org) lists all human genes with a standardised name; users can find relevant information about these genes and link out to many other online resources, for example to find out the health consequences of alterations in a gene, and identify similar genes in human and other species. As many animal's genomes are being sequenced the HGNC will also name their genes in a similar way (catalogued at vertebrate.genenames.org), to enable comparisons of different genomes.",1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING),GENERIC HEALTH RELEVANCE HRCS22_20255,Wellcome Trust,,The Peek Practice-based Evidence Framework,"Health system strengthening, as endorsed by the WHO’s global action plan for universal eye health, facilitated a 25% reduction in global visual impairment between 1990 and 2015.  New mobile health technologies have potential to greatly enhance systems strengthening, driving further revolutionary improvements in eye care. Currently, lack of detail in health system data and delayed information flows results in sporadic health systems’ improvement rarely founded on locally derived evidence. Testing single changes typically requires classical research studies, often taking years to produce results, by which time the environment may have changed, causing study data not informing change in practice. In the commercial software sector, a variety of testing methodologies are employed to develop and optimise web-based systems. Learning from these, we propose developing a hypothesis-driven, agile health service improvement approach enabling responsive changes to eye care service systems (our specific field) in low- and middle-income countries. This will use techniques including A/B testing and data-driven perpetual optimisation. These hypothesis-driven methodologies will allow quicker testing, analysis and implementation of service improvements with greater potential for translation to other settings.  Used by local health system leaders, the tools could lead to a paradigm change in health system strengthening, improving health for millions.","Worldwide, over 250 million people are blind or have low vision, 90% in low- and middle-income countries.  Yet 75% of cases are avoidable, largely through cost-effective, proven treatments. Why do so many live with poor vision when treatments exist in most cases? One reason is that health services cannot access the information they need to improve.  Understanding the impact of changes requires resource-intensive clinical trials, which can take years.  This leads to entrenched inefficiency and poor outcomes, simply because understanding which improvements work is so challenging. We are developing a new way to test improvements to health services based on strategies from software development.  It will allow services to rapidly test and optimise changes, so their impact can be understood in months, not years.  If successful, this approach will enable eye health services to adapt and improve far quicker than before, ultimately strengthening them and improving outcomes for patients.",8.1 ORGANISATION AND DELIVERY OF SERVICES,EYE HRCS22_01653,Medical Research Council,MRC,The Pluripotent Stem Cells and Engineered Cell (PSEC) Hub,"We will deliver a platform of technologies and expertise that will enable new human pluripotent stem cell (hPSC) based therapies to more readily enter the clinic. This will be done around 2 major therapeutic areas - hPSC derived dopaminergic neurons and megakaryocytes. These exemplars will contextualise the overarching aim of the hub which is to further understand and develop the next generation of genetic and reprogramming tools needed to allow ANY hPSC-based product to progress to clinic. This will be done through 3 major research programmes: THEME 1 - CELL CHARACTERISATION AND STABILITY: We will assess the phenotypic consequences of specific genetic variants using our clinical exemplars, while also developing sensitive high-throughput detection methods for genetically variant cells. We will the use this information to optimise culture conditions to suppress the appearance of concerning genetic variant, while also producing lists of non-consequential genetic variants that we detect which we will then feed into international guidelines for adoption by relevant regulatory agencies. THEME 2 - IDENTIFYING AND MODELLING KEY DETERMINANTS OF MANUFACTURING OUTCOMES FOR HPSC PRODUCTS AND PROVIDING A REGULATORY ROADMAP: We will address issues to do with manufacturing cells in the quantity and the quality required, for clinical adoption using dynamic process models as well as novel protocols and reagents. This will include a pathway for regulatory integration, to facilitate clinical application and first in human studies. THEME 3 - UNDERSTANDING ROUTES TO DIFFERENTIATION: We will develop a new generation of genetically modified hPSCs with improved differentiation capabilities including purity, cell yield and reduced dependence on expensive media and/or complex cytokine cocktails as well as reducing their immunogenicity such that they can more easily be employed in the clinic without the need for major immunosuppressive anti-rejection therapies and their associated risks.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);5.2 CELLULAR AND GENE THERAPIES;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT),NEUROLOGICAL;BLOOD;GENERIC HEALTH RELEVANCE HRCS22_07154,Health Education England,HEE,The RAPID 2 study. Reducing Anxiety in Pregnancy: Intervention Development phase 2. A feasibility study of a midwife facilitated supportive intervention.,"Research aim and objectivesThe aim of the study is to test the feasibility of conducting a trial to examine the effectiveness of a midwife facilitated intervention for pregnant women with symptoms of mild to moderate anxiety. The study objectives are to: To assess rates of participant eligibility, recruitment and retention To assess the recruitment procedures To estimate the standard deviation of the primary outcome measure to estimate the sample size for a definitive cluster trial To conduct a qualitative assessment of women's and facilitators' experiences To investigate participant-related and service-level factors potentially affecting outcomes To estimate the amount of unexplained variability in outcomes between trusts and participants To assess the relevance and acceptability of data collection and outcome measures To identify data collection tools for economic evaluationBackgroundEach year in the UK approximately 750,000 women use midwifery services, and 14% will experience symptoms of anxiety. Anxiety disorders are associated with postnatal depression, low birthweight, premature birth and developmental and behavioural problems in children. For women with mild-moderate anxiety, psychological support may help reduce anxiety and prevent an escalation of symptoms. However, services have not been developed or rigorously tested in pregnancy. Work conducted as a doctoral study included the design and developmental testing of a new intervention (RAPID 1). This was the first midwife-led intervention to be evaluated for this population of pregnant women and the first to included midwifery support workers as co-facilitators. The design followed the MRC framework and informed by psychological theory, systematic review evidence and expert and public involvement. RAPID 1 demonstrated the intervention could be integrated within routine maternity care and women considered that they benefitted from participating. MethodsA cluster RCT to test the feasibility of the intervention (RAPID 2) will be conducted in six NHS trusts. The aim is to recruit 70 nulliparous pregnant women with self-reported symptoms of mild-moderate anxiety. The intervention comprises:( a) One-to-one pre-group midwife meeting (b) Six facilitated group discussion sessions (c) Self-help materials. The intervention will be given to six to eight groups over a twelve-week period. Control group participants will receive usual maternity care. The primary outcome will be GAD-7 anxiety scores. Secondary outcomes include quality of life, social support and birth outcomes. Timelines for deliveryEthical approval will be sought in year 1. Recruitment (70 participants), intervention delivery (across 3 cluster sites) and data collection (baseline, baseline plus 14 weeks) will be completed in year 2. Data analysis, reporting and dissemination will be completed in year 3. Anticipated impact and dissemination Public involvement will assist with dissemination including co-presenting at conferences and social media briefings. Dissemination will include journal submissions, reports and briefings for health providers, commissioners, perinatal mental health and maternity networks. The study will contribute to the knowledge base for the care of women with anxiety in pregnancy and has potential to improve infant and maternal outcomes. The intervention will provide women with access to timely, effective support and provide an evidence-based, cost-effective intervention which can be integrated in maternity care structures.","Aim of the research: To conduct a small research study known as a 'feasibility study' to test a new approach to care for pregnant women with symptoms of mild to moderate anxiety. This approach will be supported by midwives and maternity support workers. The study (called RAPID 2) will find out how many women are interested and willing to take part and test all the steps in a later larger study. Background to the research: Each year around 750,000 UK pregnant women use midwifery services. Around 14% of women will experience symptoms of anxiety. Anxiety in pregnancy is linked to other problems for women and their babies. This includes postnatal depression, babies born early, of lower birthweight than expected and behaviour and development problems for children. For women with mild to moderate anxiety, psychological support may help reduce anxiety and prevent their symptoms becoming worse. It is important that any new services to support pregnant women with anxiety are tested thoroughly. Earlier stages of this work included designing a new approach to care for women with mild to moderate anxiety (RAPID 1 study). The design was based on psychological theory, a review of previous research and the opinions of service users and other experts. This approach to care consists of group sessions, individual midwife support and self-help materials. The RAPID 1 study found that this approach to care could work within maternity care and women felt that they had benefitted from taking part. Design and methods used: A feasibility study is a piece of research done before a main study to answer the question 'Can this study be done?'. The RAPID 2 feasibility study will be conducted in six NHS trusts. The aim is to recruit 70 first-time pregnant women with symptoms of mild to moderate anxiety. Women will be invited to attend six group sessions over 12 weeks, groups will be supported by a trained midwife and a midwifery support worker. Women will be able to discuss their experiences, provide and receive peer support and access midwifery support. Anxiety before and after taking part in the study will be measured by asking women to complete questionnaires about their symptoms. Anxiety symptoms for this group of women will be compared with a group who receive usual current maternity care. Testing this approach to care with a small group of pregnant women will help to plan a larger study. The study will identify how many women would need to be involved to draw overall conclusions, how willing women are to participate and how useful information can be collected and assessed. Patient and public involvement: This new approach to care was designed with advice from women who had experienced anxiety and women who had recent pregnancies. Women decided the format of the groups and the range of self-help materials. Refinements to the design have been made with input from women who recently accessed maternity care and women from minority ethnic groups. This led to changes in the way that participants are introduced and recruited to the study and the location of groups. An advisory panel of five women have agreed to support the study through the three-year process. They will meet at key stages to help with recruitment, interpreting the results and presenting the findings through social media and local networks. Dissemination: The study findings will be published in scientific journal papers and presented at international midwifery and perinatal mental health conferences. Written reports and social media briefings will be prepared for healthcare professionals, perinatal mental health networks, service user groups, maternal and mental health charities and Royal Colleges (GPs, Psychiatrists, Midwives).",6.1 PHARMACEUTICALS;7.1 INDIVIDUAL CARE NEEDS,REPRODUCTIVE HEALTH AND CHILDBIRTH;MENTAL HEALTH HRCS22_13244,Barts Charity,,The Role Of Myosin Light Chain Kinase 3 (Mylk3) In Dilated Cardiomyopathy,"The grant will support a Post Doctoral scientist to further investigate a variant in Myosin light chain kinase 3 (Mylk3), a protein involved in the development of dilated cardiomyopathy (DCM), a condition that reduces the capability of the heart to eject blood and can eventually lead to heart failure. The team has collated preliminary data and hypothesises MYLK3 to be a key regulator of post-translational modifications in many proteins which are known to cause DCM in humans, and presents an exciting potential target for patient therapy. The findings will support an application to the British Heart Fundation to further develop the work.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CARDIOVASCULAR HRCS22_01556,Medical Research Council,MRC,The Role of Membrane Attack Complex in Atypical Haemolytic Uraemic Syndrome,"Atypical haemolytic uraemic syndrome (aHUS) encompasses the triad of; haemolytic anaemia, thrombocytopenia, and renal failure. Tremendous advances led by the Newcastle group has shown aHUS arises due to dysregulation of the alternative pathway of the complement system. The complement system is a complex series of proteins that results in an enzymatic cascade culminating in activation of the terminal pathway, producing C5a and Membrane attack complex (MAC). These two components whilst protecting self can injure cells and local tissues through their pro-inflammatory and lytic roles; thus are implicated in numerous diseases. We know that aHUS is driven by complement dysregulation of the terminal pathway evidenced by the successful treatment of aHUS patients with a C5 convertase inhibitor. However, this treatment silences the terminal pathway in its entirety, predisposing vulnerable patients to infections and the cost of therapy prevents access to all. We do not currently know which protein plays the critical role in the development of aHUS. I have developed a novel murine model of aHUS engineered around a mutation in complement C3 from our aHUS patient cohort. My data clearly shows that my murine model absolutely mirrors aHUS in man, and ongoing experiments confirm the critical nature of C5. I therefore will determine the role of MAC and C5a in aHUS. The increased understanding of MAC and C5a in complement mediated renal disease will enable me to deliver targeted therapies for patients. I seek to investigate the roles of C5a and MAC in aHUS by rescuing the phenotype of the C3 gain of function D1115N mouse model of aHUS by blocking the terminal pathway: a.) by breeding onto the C5-/- strain b.) through the use of a murine C5 inhibitor c.) by breeding onto a C6 deficient mouse (no MAC). I will assess the role C5a in the model: a) through breeding the D1115N mouse with the C5AR1-/- & C5ALR-/- mice b) therapeutic inhibition using the C5aR1 antagonist.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,RENAL AND UROGENITAL HRCS22_07011,Department of Health and Social Care,NIHR,"The Role of Staff and Team Communication in Reducing Seclusion, Restraint and Forced Tranquilisation in Acute Inpatient Mental Health Settings","Research Question: What staff and team communication predicts successful de-escalation of patients displaying aggressive behaviour in acute mental health wards, avoiding the need to use physical restraint (holding to prevent movement), seclusion (locked in isolation) and forced tranquilisation (involuntarily injected with psychotropic medication)? Background: In the U.K. over 100,000 patients with severe mental illness (e.g. psychosis) are admitted to acute mental health wards annually, over 40% admitted involuntarily.1, 2 Patient aggression is managed through communication, known as de-escalation. This usually involves multiple staff (de-escalation team) supporting an individual who communicates directly with the patient (primary de-escalator). Around one third of de-escalations are unsuccessful3 resulting in physical restraint, seclusion, and/or forced tranquilisation. In England, six restraints occur per hour,4 resulting in physical harm, even death,5 and significant psychological distress.6-10 Patients experience trauma, fear, feeling disempowered and dehumanised.5, 10 Staff feel unsafe and anxious, leading to burn out9, 11, 12 costing the NHS £69M annually.13 NICE guidelines recommend de-escalation but it is not evidence based14 and practice varies.3, 15 The importance of staff and team communication in de-escalation is clear16-18 yet no research has examined what specific communication is effective. Our research in psychiatric consultations found patients experience better communication with staff who try to understand them and display pro-social nonverbal communication, designed to encourage conversation (i.e. shared gaze, nodding).19, 20 Clear leadership predicts de-escalation success in simulated de-escalations,21 while on wards, introducing regular, honest discussions about aggression management has led to fewer restraints.22 Aim: To identify the specific staff and team communication that leads to successful de-escalation of patients displaying aggressive behaviour in acute mental health settings, thus avoiding use of restrictive practice. Objectives: Identify the communication displayed by (i) primary de-escalators and (ii) de-escalation teams in successful and unsuccessful de-escalations Observe how patient aggression is anticipated, discussed, planned for and managed on wards, beyond the de-escalation event Explore patient and staff experience of de-escalation and perceptions of aggression management Explore the relationship between staff and team communication during successful and unsuccessful de-escalations and ward approaches to aggression management Methods & Timelines: Observational study conducted in four acute inpatient mental health wards. Sixty-four de-escalation events (32 successful, 32 unsuccessful) will be recorded from body worn cameras [Months 4-11] Three Work Packages will address the objectives: WP1: De-escalation Communication [Months 10-17] Analyse the verbal and nonverbal communication of the primary de-escalator (pro-social nonverbal behaviour and shared understanding) and the de-escalation team (leadership). Mixed model regression analyses will identify the communication that predicts successful de-escalation. WP2: Ward Context [Months 4-16] Conduct ethnographic observations on wards and one-to-one interviews with patients (n=16) and staff (n=20). Qualitative transcripts will be thematically analysed. WP3: Data Synthesis [Months 17-19] Triangulate findings from WP1&2, identifying of the facilitators and barriers to successful de-escalation. Impact and dissemination: A multi-disciplinary de-escalation working group will facilitate translation of findings into policy, training and practice. Research into practice workshops will be delivered at participating Trusts. Results will be disseminated via the project website, Involve and Trust newsletters and peer reviewed publications.","Research aims: The project will identify staff and team communication that lead to successful management of patient aggression in acute mental health settings, avoiding the need to use physical restraint (held to prevent movement), seclusion (locked in isolation), and forced tranquilisation (involuntarily injected with sedating medication). Background: Over 100,000 patients are admitted to acute mental health wards annually, 40% involuntarily. Wards are under incredible pressure due to high bed occupancy rates and staff shortages. Only patients who are extremely unwell are admitted, experiencing symptoms of psychosis (hearing voices), mania or severe depression. In England, 80% of nurses report experiencing patient aggression. Staff manage aggression through communication; talking to patients to try to calm down their aggression. This technique is called de-escalation . However, often de-escalation is unsuccessful, leading to restraint, seclusion and forced tranquilisation of patients. In England 60,000 restraints occur annually causing patient harm (even death), trauma and fear. Staff also experience harm, anxiety and burn out, costing the U.K. £69M annually. De-escalation training is not evidence based and staff practice varies. Communication is clearly important but we don t know what type of communication is most effective in managing patient aggression. This study will analyse how staff communicate when managing patient aggression. Our previous work analysing outpatient psychiatric consultations found that patients experience better communication with doctors who invest effort trying to understand them. Clear leadership and open communication among teams are also linked with better aggression management. This study will be the first to examine staff and team communication in mental health wards, identifying the communication that leads to successful de-escalation. Design and methods Four acute inpatient mental health wards will be recruited; two with low and two with high rates of restraint. Sixty-four de-escalations will be video recorded (32 successful, 32 unsuccessful) Staff and team communication will be analysed from video using established tools. Statistical analysis will identify the specific communication that leads to successful de-escalation. Ward observations will examine how teams discuss and plan for patient aggression. One-to-one interviews with patients (n=16) and staff (n=20) will examine their experience of de-escalation. Patient and public involvement The Service User and carer Group Advising on Research (SUGAR) Group has shaped this study. The lived experience co-applicant will contribute to data collection, analysis, interpretation and dissemination. We will form a working group focused on de-escalation and aggression management in mental health involving, academic, clinical and patient partners. Dissemination The findings will be shared through patient organisation and charity websites and in academic publications. Workshops helping staff apply the findings in their own practice will be held at participating Trusts. We will work closely with clinical education groups to share the content of these workshops with mental health staff more widely.",5.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_02025,Medical Research Council,MRC,The T6SS as a search engine for naturally validated antibacterial targets,"The type VI secretion system (T6SS) is an antimicrobial weapon used by Gram-negative bacteria to inject toxins into competitors, restricting their growth to benefit scarce resources. The T6SS toxins, and their cognate immunities, identified so far are phospholipase, DNase or peptidoglycan hydrolase. We consider the T6SS as a gold mine for the search of novel antimicrobial activities since bacteria competed for billions of years and evolved unexpected strategies. Since toxin/immunity (TI) pair genes are only occasionally found genetically linked to T6SS genes, we developed an unbiased approach using transposon mutagenesis and sequencing (TraDIS) to search for T6SS immunity genes in Pseudomonas aeruginosa and characterize the associated T6SS toxins. This was possible using a mutant systematically activating its 3 T6SSs and all associated TI genes as we published recently (Allsopp et al., PNAS, 2017). Our screen is validated by the identification 12 of the known TI pairs, e.g. Tse2/Tsi2; Tle5a/Tli5a. We started to characterize Tse8/Tsi8, which we propose targets the transamidosome and impairs protein synthesis in organisms using this complex to load Asn/Gln on tRNA. We also point at an extra 7 putative novel TI pairs which we believe have original biochemical activity and would direct us toward novel targets. Our proposal shall provide a global vision of the P. aeruginosa's T6SS toxins and antimicrobial strategy which could be mimicked in treatment of resistant bacteria and thus be in the future considered for antimicrobial research. We took the opportunity of having implemented the TraDIS approach to screen for mutants resistant/sensitive to T6SS attack in an immunity-independent manner. The exploitation of these data combined with a ""resistance"" evolution approach where serial contact of a T6SS-immunity deficient strain with a T6SS attacker result in acquired resistance would take us into an unexplored and ground-breaking area of the T6SS bacterial warfare.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_13201,Guts UK,,The TARGET Study (TArgeted biopsies to Risk Stratify Gastric cancer precursors for tailored Endoscopic surveillance and Treatment),"Background: Despite a precipitous decline in previous decades, gastric adenocarcinoma (GA) incidence and mortality have now plateaued in the UK. Roughly 6700 new cases are diagnosed per year in the UK, on a par with melanoma and oesophageal adenocarcinoma incidence. Only 19% of adults survive their diagnosis at 5 years, with UK survival among the lowest in Europe (average 24- 28% 5-year survival). The main risk factor for developing GA is Helicobacter pylori infection and over 35% of adults in the UK are chronically infected. Patients with extensive metaplastic atrophic gastritis are at greatest GA risk, however our current approach to risk stratification involving random biopsies and histopathology assessment is subjective, imprecise, and unreliable. This situation is unacceptable. Recent evidence (Esposito et al. 2019; Pimentel-Nunes et al. 2016) and 2019 British (Banks et al. 2019) and European guidelines (Pimentel-Nunes et al. 2019) now advocate the use of enhanced imaging endoscopy with a move towards targeted biopsies to more robustly assess disease extent and cancer risk. There is now an urgent clinical need to develop a quantitative understanding of the evolution to gastric cancer in chronic gastritis patients to accurately identify the minority of high-risk individuals. Our group has pioneered a unique targeted spatial analysis of early cancer evolution in chronic gastritis (details in this application). Here we request Guts UK Development Funding to investigate precancerous clonal diversity from targeted endoscopic gastric biopsies within the context of an ongoing prospective clinical study (ESTIMATE study). Aim and deliverables: We aim to develop an objective molecular test that allows accurate stratification of patients with chronic atrophic metaplastic gastritis for future gastric cancer risk. 1. We hypothesise that biopsies targeted to patches of gastric intestinal metaplasia (GIM) enable sensitive detection of clonal genetic abnormalities and represent a superior method for interrogating clonal diversity within the at-risk stomach compared to random biopsies. 2. We hypothesise that copy number alteration (CNA) burden and clonal diversity correlate with markers of cancer progression risk (dysplasia detection, endoscopic and histopathologic staging of atrophy and IM) and could therefore act as an accurate predictor of neoplastic progression risk. Design & Methods: We are currently running an international multicentre study (ESTIMATE study) comparing the current gold standard approach of random biopsies (timepoint 1) to endoscopically targeted biopsies (timepoint 2), in patients with chronic atrophic metaplastic gastritis. Each patient (target recruitment 240 patients, on schedule December 2019) will undergo two endoscopies on separate occasions at least six months apart. At each endoscopy 5 biopsies will be taken and thus 10 biopsies per patient are available from two timepoints, one reference set of random biopsies and a second patient-matched set of targeted biopsies. The ESTIMATE trial will reveal the accuracy and reproducibility of endoscopic risk stratification for chronic gastritis patients. Here we propose to leverage this unique resource to assess the benefit of targeted biopsies to interrogate within-patient clonal diversity as a marker of GC progression risk. We will carry out shallow depth whole genome sequencing (sdWGS) (median depth 0.15x) to reveal clonal diversity and total CNA burden, comparing random gastric biopsies (Timepoint 1, 5 biopsies) to biopsies targeted at clonal metaplastic precursors (Timepoint 2, 5 biopsies) for each of 60 patients (total 600 sdWGS analyses, Work package 1). Our pilot data demonstrate that we can reliably perform sdWGS to map genetic clonal diversity within these patients from routine ESTIMATE formalin-fixed paraffinembedded (FFPE) biopsies (see pilot data below). We will profile the within-patient clonal diversity and CNA burden from multiple individual patches of GIM and correlate these molecular data to clinical markers of progression risk (dysplasia detection, serum atrophy, endoscopic stage of disease, histopathologic OLGIM staging, Work package 2). This will allow us to compare the breadth of GIM clonal diversity in these patients undergoing gastric surveillance (endoscopy cohort) to those that have progressed to gastric cancer (our established surgical cohort) and develop a clinicalmolecular risk prediction model of cancer progression in chronic gastritis. Our proposal benefits from the robust within-patient control design of targeted to random biopsies and the wealth of clinically annotated ESTIMATE study data: histopathology including subtype of GIM (complete vs incomplete) demographics, endoscopy, serology for further risk prediction modeling studies. Clinical & Scientific Summary: By taking a targeted approach to sampling cancer precursor lesions our proposal presents a fundamentally new approach to risk stratification in chronic gastritis patients. This award will allow us to establish proof of principle data that can be tested in future larger prospective clinical trials with dysplasia detection primary endpoints. The ESTIMATE study is part of an international study between the UK and the Netherlands for which collateral funding has been obtained (endoscopy study running costs, €147,807) from the Dutch Gastroenterology Society MLDS.","Project Summary: Stomach cancer has a poor survival rate, particularly in the UK. Accurate identification of changes to the stomach lining in people with chronic gastritis that might be precursors to cancer is essential for earlier detection. This project aims to identify the molecular nature of these changes, to develop an early, easy, and accurate test for early detection of stomach cancer.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_05979,Department of Health and Social Care,NIHR,The Utility Of Frequency-Modulated Electromagnetic Neural Stimulation (FREMS) As A Third Line Treatment In Patients With Painful Diabetes-Related Peripheral Neuropathy: A Randomised Controlled Trial (FREMS-PDPN),"Aims: To evaluate the efficacy of FREMS (Frequency Rhythmic Electrical Modulated System) in patients with painful diabetic peripheral neuropathy (PDPN, painful feet from nerve damages caused by diabetes) who have not responded to the NICE (National Institute for Health and Care Excellence) recommended treatments. FREMS delivers electrical pulses via stickers that are placed on the feet and legs; these pulses can reduce the pain in patients with PDPN._x000D_ _x000D_ Background: PDPN affects a quarter of people with diabetes and 70% of sufferers have moderate-to-severe foot pain. This pain results in in sleep disruption, poor quality of life (QoL), unemployment and depression. The average health care cost for each patient with PDPN in the UK was estimated to be £2,511 per year, which increases with greater pain severity. The burden of PDPN is likely to increase as diabetes becomes more common. NICE guidance 173 recommended certain medications as initial treatments for PDPN. However, using these medications results in 50% reduction in pain in one third of patients at best. These medications also have multiple side effects such as nausea, sedation, dizziness, dry mouth, weight gain, falls, constipation and more. Beyond these drugs, there are no NICE recommended treatments. As a result, many patients receive opioids (43%), which has many unwanted side effects including addiction. _x000D_ _x000D_ Hence, there is a clear need to identify an effective, safe, well-tolerated, non-invasive intervention that is good value for money in those who fail to respond to NICE recommended treatments. This could reduce medications and opioid use & improve QoL._x000D_ _x000D_ Design and methods: We propose a randomised controlled trial to assess the efficacy of FREMS in patients with PDPN who have significant pain despite trying the NICE recommended treatments. Randomised means that the patients will receive a treatment chosen by chance (like flipping a coin). Participants will be randomised to FREMS or TENS (Transcutaneous Electrical Nerve Stimulation). Both FREMS and TENS give electrical pulses delivered through stickers on the skin. The nature of these pulses is different between FREMS and TENS, resulting in different biological effects on pain and different responses (short term pain reductions for TENS, usually days, and 3-4 months for FREMS). In this study, both FREMS and TENS will be delivered using the same device and stickers on the skin, but treatment will be chosen by a keycard with a pre-programmed randomly chosen treatment allocation. This will ensure that neither participants nor researchers can tell which treatment is given, and this will improve the quality of the study results._x000D_ _x000D_ After randomisation, participants will receive 35-minute treatment sessions for 10 consecutive weekdays at the research centre. The main study outcome will be at 3 months with a total follow up of 6 months. During the study, routine care will continue and participants’ medications can be adjusted by their doctors as needed. The main study outcome is pain severity collected by text message from the participants. Other outcomes include QoL, sleep quality, medication changes & value for money._x000D_ _x000D_ Patient and public involvement: Patients have been involved in defining the research question and writing the lay summary. Patients will be involved in the study conduct and oversight, producing patient information, and dissemination._x000D_ _x000D_ Dissemination: The findings will be shared widely, including conferences, patient groups, NICE and local commissioning groups.","Research question: Is Frequency Rhythmic Electrical Modulated System (FREMS) an effective treatment in patients with persistent painful diabetic peripheral neuropathy (PDPN) despite trying at least two PDPN medications?_x000D_ _x000D_ Background: PDPN affects 25% of people with diabetes and 70% of sufferers have moderate-to-severe pain. PDPN is associated with sleep disruption, poor quality of life (QoL), unemployment & depression. The average health care cost of PDPN in the UK is £2,511 per patient per year, which increases with greater pain severity. The burden of PDPN is likely to increase with increasing diabetes prevalence. National Institute for Health and Care Excellence (NICE) guidance 173 recommended certain medications as initial treatments for PDPN. However, using these medications only results in 50% reduction in pain in 33% of patients at best. These medications also have multiple significant side effects (such as weight gain, falls, urinary retention, constipation). Beyond these drugs, there are no NICE recommended treatments. As a result, many patients (43%) receive opioids, which have many unwanted side effects including dependency. There is a clear need to identify an effective, safe, well-tolerated, non-invasive, and cost-effective intervention in those who fail to respond to NICE recommended treatments. This could reduce medication and opioid use and improve QoL._x000D_ _x000D_ Aims and objectives: Efficacy objectives: 1. To evaluate the efficacy of FREMS using 11-point numerical rating scale (NRS) 24-hour pain scores (0 to 10) averaged over the last 7 days (primary outcome). 2. Other outcomes: sleep quality, QoL & medication use amongst others. 3. To evaluate the cost effectiveness of FREMS in PDPN. Safety objectives: To describe Adverse Events and Serious Adverse Events data. Exploratory objectives: To investigate if patient phenotypes predict response to treatment._x000D_ _x000D_ Methods:_x000D_ Design: A multi-centre 2-arm parallel group double blind sham-controlle RCT. The RCT will include an internal pilot with stop/go criteria. _x000D_ Setting: Patients will be recruited from 10 NHS Trusts that have PDPN services and the aligned primary care and podiatry services, as well as social media and Diabetes UK local patient groups. The study device will be placed in the Trusts._x000D_ Population: Adults with PDPN for >=3 months with significant pain (a mean total pain NRS >=4 for the week before randomisation) despite trying at least 2 different classes of medication._x000D_ Intervention: FREMS + standard care. Comparator: TENS (Transcutaneous Electrical Nerve Stimulation) + standard care_x000D_ Outcomes: As above. The primary outcome is at 3 months & study end at 6 months._x000D_ _x000D_ Timelines: Protocol, database & CRFs: months 1-8; HRA, REC, MHRA approvals: 5-9; Site set-up: 8-13; Recruitment: 10-29; Follow-up: 13-35, Data Cleaning: 35-38; Analysis & dissemination: 36-41; Health economic analysis: 36-41; Final report: 41_x000D_ _x000D_ Anticipated impact: The trial is designed to address gaps identified by NICE multiple technology appraisal (MTA) of FREMS in 2017. Hence the outcome of the trial is likely to lead to a NICE technology appraisal_x000D_ _x000D_ Dissemination: Via peer-reviewed articles, national/international presentations, Diabetes UK patients groups and social media. The investigators will liaise with the manufacturer & NICE. Study participants will be informed of the findings.",6.3 MEDICAL DEVICES,METABOLIC AND ENDOCRINE;NEUROLOGICAL HRCS22_06121,Department of Health and Social Care,NIHR,"The VITDALIZE UK Study: Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: UK arm of an international multi-centre, placebo-controlled double-blind trial","Background: Sunlight is the major source of vitamin D. A small proportion comes from the food we eat (e.g. oily fish, fortified cereals). Traditionally, vitamin D has been thought to be primarily important for bone health but the last 20 years of research has revealed important effects of vitamin D on the immune system and health. It has also been found to have potential effects on heart and muscle function. Every type of cell in the human body has the ability to use vitamin D. _x000D_ _x000D_ Vitamin D deficiency is common (up to 70%) in critical illness and has been found to be associated with poor outcomes, death and increase in infection rates. More than 160,000 patients are admitted to intensive care units every year in the UK with a death rate of 15-20%. They are critically unwell for many reasons including serious infections, after surgery or serious accidents and usually require support of at least one major organ function (heart, lung, kidney or brain). For those that do survive, critical illness can be life changing, with long term mental and physical consequences._x000D_ _x000D_ Problems with current treatments: Despite the associations, it is unclear if vitamin D deficiency is a cause or effect of critical illness. Furthermore, there is no clear clinical data from trials, although it is suggested from a previous trial, that the beneficial effects may only be present in those patients with severe deficiency and high doses may therefore be required. Currently there are no guidelines to measure and treat vitamin D deficiency on admission to intensive care. Vitamin D is cheap, safe and readily available in oral form and, if proven, could be quickly introduced into clinical practice._x000D_ _x000D_ Aims: The trial aims to answer if high dose vitamin D replacement in critical illness can improve outcomes. The main outcome will be if the patient has survived to 28 days. The other important outcomes are 90 day and 1-year survival rate, length of hospital stay, physical function (activities of daily living) and recurrent infections. In the UK, we also plan to collect additional data, including information held on national clinical databases to allow us to investigate the effects on the patients’ health and quality of life up to 1 year and to work out the cost effectiveness of the treatment in the NHS._x000D_ _x000D_ Methods: This is an international study aiming to recruit 2400 patients from around the world, including the UK, Austria, Germany and Belgium. The UK study will enrol 25% of those patients. Importantly this will allow much quicker and cost-effective completion of the study. Patients will be randomised (allocated to different treatment groups by chance) to either a single high dose of vitamin D liquid or matching placebo (dummy liquid) on recruitment to the study but only to patients with severe deficiency on the intensive care unit, followed by maintenance daily dose for up to 90 days._x000D_ _x000D_ We have worked closely with our local patient clinical research ambassador group (CRAG) and the charity ICUsteps in developing this UK application. The Chairperson of the CRAG, a former ICU patient and a treated vitamin D deficient patient are co-applicants. Patients and the public will continue to be central in the ongoing design, delivery and reporting of the study._x000D_ _x000D_ Impact: The results of this study will help clinicians working in the NHS to decide if vitamin D should be measured and treated as a standard of care to improve outcomes in critical illness in intensive care.","Vitamin D deficiency (VDD) in critical illness is common and has been found to be associated with poor outcomes. Recently there has been heightened awareness of VDD and its possible treatment amongst ICU physicians. Currently, however there is insufficient evidence of its effectiveness. _x000D_ _x000D_ Research Questions: _x000D_ In adult critically ill patients with severe VDD_x000D_ 1. Does high dose oral vitamin D3 replacement improve 28-day mortality, longer-term mortality, morbidity and patient specific outcomes?_x000D_ 2. Is is cost-effective to test for and treat severe VDD with high dose oral vitamin D3?_x000D_ _x000D_ Design: UK arm of a large international randomised double blind placebo controlled trial._x000D_ _x000D_ Setting: 15 general Intensive Care Units (ICUs) within NHS hospitals with a patient case mix typical of UK critical care practice. _x000D_ _x000D_ Population: Adult critically ill patients admitted to ICU with severe VDD ((25(OH)D=12ng/ml (30nmol/L))_x000D_ _x000D_ Intervention: Single loading high-dose oral/enteral vitamin D3 (540,000IU cholecalciferol, Oleovit™, Fresenius Kabi, Austria, dissolved in 37.5ml of medium chain triglycerides – MCT) followed by 4000IU daily (10 drops) for 90 days._x000D_ _x000D_ Control group treatment: Placebo, identical regime of loading dose of 37.5mls MCT (Fresenius Kabi, Austria) followed by 10 drops of MCT daily for 90 days. _x000D_ _x000D_ Outcomes: _x000D_ Primary outcome is mortality at 28 days after randomisation. _x000D_ Secondary outcomes are: ICU, hospital, 90 day and 1 year mortality; hospital and ICU length of stay (starting at day 0, ending at discharge from the trial site or day 90); change in organ dysfunction on day 5 as measured by Sequential Organ Function Assessment score (SOFA), number of organ failures (0-6; defined as >2 SOFA points in each of the 6 categories); Hospital and ICU readmission until day 90; Discharge destination (home, rehabilitation, other hospital); self-reported infections requiring antibiotics until day 90. _x000D_ Safety outcomes: hypercalcaemia at day 5; self-reported falls, fractures until day 90; new episodes of kidney stones._x000D_ _x000D_ In the UK arm, the following additional secondary outcomes will be evaluated: Health-related Quality of Life (EQ-5D-5L) and Disability assessment (WHODAS 2.0) at 90 days and 1 year; and health care utilisation to 1 year._x000D_ _x000D_ Health Economic evaluation: In this UK arm we will assess the 1-year and life-time cost-effectiveness of screening for and treating severe VDD in critical illness compared to standard care/placebo._x000D_ _x000D_ Follow up: This will be for 12 months after randomisation._x000D_ _x000D_ Sample size: Total sample size of international study n=2400 of whom 25% will be recruited in the UK (sample size in UK n=600)_x000D_ _x000D_ Projected time frames: 6 months for trial set up to obtain all regulatory approvals. We plan for 15 ICUs and estimate 2 patients will be recruited per ICU per month. Assuming a staggered set up of 6 months, 2 years total recruitment is required with a 1-year follow-up period. Recruitment rates are based on our previous ICU trials, the VITdAL-ICU study and a screen failure rate of 2/3 for severe VDD. Allowing for 12 months for health economics analysis and reporting commencing at 36 months, the total duration is 48 months._x000D_ _x000D_ Expertise: Our team includes critical care specialists, endocrinologist, nephrologist, health economists, methodologist, trialists and patient representatives. The team has expertise in running complex multi-centre trials in the ICU setting and performing long-term health economic evaluation",6.1 PHARMACEUTICALS,METABOLIC AND ENDOCRINE HRCS22_22858,The Academy of Medical Sciences,AMS,The association between glycaemic control in young people with Type 1 diabetes mellitus and executive functioning in social contexts: a pilot study,"Type I diabetes mellitus (T1DM) is associated with impairments in multiple cognitive domains including executive functions (working memory, inhibition, cognitive flexibility and decision-making). It is unknown whether these deficits are amplified in social contexts as a result of dysglycaemia affecting both executive functioning and social cognitive skills. Understanding the interplay between these cognitive skills is important for evaluating real-life behaviours and developing interventions to combat the emergence of T1DM-related complications in adolescence and adulthood. This pilot study aims to address this knowledge gap by investigating the association between quality of glycaemic control and executive functioning in neutral and social contexts in adolescents with T1DM. There are three main objectives. Firstly, I will investigate whether glycaemic control indicators (HbA1c, glucose variability, proportion of time with hyperglycaemia) are associated with decrements in executive functioning in 12-16-year-olds with T1DM. Secondly, I will analyse whether these dysglycaemia-related decrements in executive functioning are exacerbated in social compared to neutral contexts. Thirdly, this study will generate pilot data to inform further studies examining T1DM and adolescent neurocognitive development. Participants will be recruited from a hospital-based paediatric diabetes service, whose service users have been involved in study design. Cognitive data will be collected remotely using a secure online testing platform, and glucose data will be collected using continuous glucose monitoring sensors and from hospital records. This study will allow better understanding of the impact of long-term and current glycaemic control on adolescent cognitive development, and inform future studies and interventions aimed at improvingT1DM management for young people.","Managing type 1 diabetes during adolescence can be particularly challenging, and sugar control is often poor, increasing the likelihood of long-term diabetes-related health complications. Poor diabetes control in adolescence is thought to result from disease pathology and suboptimal management as individuals begin assuming responsibility for their diabetes while simultaneously experiencing many biological, psychological and social changes. Understanding adolescent cognitive development may help when developing strategies to facilitate engagement from young people in their own diabetes management by providing insight into their motivations and behaviours. This project will investigate whether quality of sugar control in 12-16 year-olds with diabetes is associated with skills in decision-making, stopping automatic responses, shifting between tasks and manipulating information. These skills, termed ‘executive functions’, together control our behaviours and will be measured using four computer-based tasks via an online secure platform. Each task assesses executive function with neutral objects e.g. shapes and with faces, which require participants to process social information during the task. Diabetes is predicted to impact on both executive functions and social information processing skills. Adolescents with poor sugar control, assessed using continuous glucose monitoring sensors and clinical records, are expected to perform less well on executive functions tests than their peers with better sugar control, and it is expected that these differences will be exacerbated when the tasks also contain social information. Evaluating how adolescents with diabetes process information in social contexts is crucial for understanding real-life behaviours and developing interventions to enhance diabetes management and reduce incidence of long-term complications.",7.1 INDIVIDUAL CARE NEEDS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,METABOLIC AND ENDOCRINE HRCS22_05334,Department of Health and Social Care,NIHR,The clinical and cost-effectiveness of exercise intervention for depression in adolescents: a phased multi-site randomised controlled trial,"Depression in adolescents is a serious problem that can lead to poor mental health and stigma throughout a person’s life. Depression is reported in around 20% of young people by the time they are 18 years of age. Over half continue to be depressed into adulthood, with many attempting suicide. Problems include difficulties at home and school, maintaining friendships and taking part in social activities, including exercise. Young people with depression often delay seeking psychological support. Antidepressants can help some, but they have negative side effects. Research shows that adults with depression benefit from exercise, but it is not known whether exercise is helpful for young people who are depressed. _x000D_ _x000D_ The aim of this research is to find out whether exercise is an effective treatment for young people with depression and whether it is good value for money for the NHS. We will recruit young people, aged 13-17 years, diagnosed with depression, from Child & Adolescent Mental Health Services and GP practices. The young people will continue to receive their usual health care. Those suitable for exercise will be allocated randomly (e.g. throwing a dice) to one of 3 groups:_x000D_ _x000D_ 1. High intensity exercise, through vigorous activities (basketball, football, dance, boxing) _x000D_ 2. Low intensity exercise, through moderate activities (table tennis, yoga, bowling, gymnastics) _x000D_ 3. An active control of social non-exercise based activities (playing games, watching films)_x000D_ _x000D_ Participants in groups 1 & 2 will be offered 2 x 60-minute exercise sessions per week for 12 weeks. All groups will also receive education and support on healthy living. Exercise sessions will be delivered by Registered Exercise Professionals (REPs) supported by Peer Support Workers (PSWs) at local sports and community centres. The research team will collect information from participants at the start, and at 14, 26, and 52 weeks. This will include questionnaires on depression, quality of life, self-esteem, service use, session attendance and changes in physical activity. We will ask some participants, parents/carers, REPs and PSWs about their experience of the exercise sessions and participation. _x000D_ _x000D_ The research will be conducted in 2 phases over 5 years:_x000D_ _x000D_ 1. In the first 18 months we will explore how best to undertake this research (feasibility trial). We will recruit 60 young people (20 per group) from 3 sites to test the recruitment of young people, attendance and exercise achieved and completion of questionnaires. This will help us improve the study design and feasibility. _x000D_ _x000D_ 2. We will then conduct the main study over the next 42 months in 8 locations. In the first 8 months a pilot study with 150 young people will be complete to check that the study procedures are working as expected. Over the next 34 months 1044 young people will be recruited and the data analysed to complete the study at month 60._x000D_ _x000D_ We have talked to young people, some with depression, and a Public Involvement Research group at the University of Hertfordshire (UH) about this research; their advice has shaped the study. We will continue to involve them and various stakeholders including parents/carers, health professionals and policy makers in the research. They will also help us to share our findings at the end of the study. The project will be led by UH in collaboration with the Universities of Bedfordshire and East Anglia, various NHS Mental Health Trusts and County Sports Partnerships.","Existing research demonstrates that depression among young people is highly prevalent and increasing(1–3). Recent research suggests that adolescents who seek help do benefit from contact with mental health services(4,5). Depression among young people presents a significant burden to Health Care Services, the young person and their family, and future potential cost where untreated over the longer term. Provision of care for young people with mental health problems is a current Department of Health priority(6-8)._x000D_ _x000D_ Exercise provides a treatment option for health care services, that avoids problems associated with pharmacological interventions, and does not rely on hard pressed services providing psychological therapy(9,10). There is a growing body of evidence that exercise is potentially an effective treatment intervention for depression in young people, but there remains considerable uncertainty, with poor quality, small scale trials, and little evidence addressing the intensity of exercise required(11-15)._x000D_ _x000D_ The current proposal is for a multi-site, single blinded, superiority, cluster randomised effectiveness RCT with nested process and economic evaluations. The study is designed to address whether:_x000D_ _x000D_ - Physical exercise of a high, or a low intensity compared with an active control improves depression symptoms in young people,_x000D_ - The cost-effectiveness of an exercise interventions delivered in a community setting, and_x000D_ - The extent to which adherence to exercise differs between high and low intensity exercise._x000D_ _x000D_ The study will compare 3 interventions consisting of a high intensity exercise intervention, compared to a low intensity intervention, and an active control group. All intervention groups will include an education component (Healthy Living) with behaviour change techniques facilitating exercise adherence and maintenance over the longer term. The study includes a feasibility randomised trial, and an effectiveness trial including an internal pilot study with appropriate stop-go criteria(16–18)._x000D_ _x000D_ The feasibility randomised trial (N=60) will be undertaken in the first 18 months to evaluate the feasibility of delivering the main trial as planned. Information gained from this study will inform protocol development and demonstrate the ability to recruit sufficient patients into a larger scale trial (with planned stop, revise, go criteria)._x000D_ _x000D_ The main trial (N=1044), with internal pilot study (N=150), will provide definitive evidence of the clinical and cost effectiveness of the intervention for the treatment of depression in young people aged 13 to 17._x000D_ _x000D_ The interventions will be delivered through the national network of County Sports Partnerships in local community settings. Young people seeking support for depression will be referred from GP Practices, and Child and Adolescent Mental Health Services. The interventions will be delivered by Registered Exercise Professionals supported by Peer Support Workers. Young people are followed up at 14, 26 and 52 weeks. This will include questionnaires on depression, quality of life, self-esteem, and service use. Some young people and intervention staff will be interviewed to understand their experience of the exercise sessions and participation._x000D_ _x000D_ Young people (PPI) have influenced the design of the study, and along with parents and other stakeholders, will continue to provide significant input throughout the study, and provide support for dissemination.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_02441,Medical Research Council,MRC,The clinical impact of inherited chromosomally-integrated human herpesvirus 6 (iciHHV-6): a comprehensive analysis using UK Biobank,"Human herpesvirus 6A and 6B have the unusual ability to integrate into telomeres of human chromosomes and, in some people, viral genomes are present in the germline, giving rise to inherited chromosomally integrated HHV-6 (iciHHV-6). iciHHV-6 has the potential to cause disease through viral reactivation and by interfering with telomere function. We know that iciHHV-6 can reactivate in vivo, and analysis of two cohort studies has shown an association with an increased risk of angina. However, the overall impact of iciHHV-6 on health is not clear. We estimate that around 1.2% of the UK population is iciHHV-6-positive and it is, therefore, important to understand the health implications. A large study is required to have the power to detect associations with diseases that are not common, and associations with small effect sizes. This study will investigate the clinical impact of iciHHV-6 through analysis of UK Biobank, a cohort with samples and data from 500,000 individuals. iciHHV-6A and 6B status will be determined using a two-stage strategy involving an initial screen of all samples using a triplex TaqMan assay, and secondary analysis of likely positive samples using droplet digital PCR. Most iciHHV-6 in the UK can be traced to a small number of ancestral viral integrations; we will use complementary approaches to identify these ancestral viral lineages as they may influence disease associations. We will test previously reported disease associations and identify new associations by analysing a wide range of physical and mental health phenotypes in an agnostic fashion. We will investigate the link between iciHHV-6 and angina and determine the consequences using the wealth of cardiovascular data in UK Biobank. Analyses will be performed for iciHHV-6 overall, and for iciHHV-6A and 6B. The findings will provide a solid evidence base for counselling individuals found to be iciHHV-6-positive and potentially lead to improved diagnostics and treatment in the future.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_17764,Dunhill Medical Trust,,The development and feasibility of a post-operative rehabilitation programme to improve walking in older people with neurogenic claudication.,"Neurogenic claudication (NC) affects 1:10 older people and reduces walking and quality of life. It is the main indication for spinal surgery in older people yet following surgery, up to 40% report walking disability and 90% do not achieve physical activity recommendations. Changing behaviour is challenging without appropriate guidance and support. Rehabilitation could improve walking but current provision is inconsistent and ineffective. Modifiable factors that influence post-operative walking in people with NC are unclear but if identified and targeted with theoretically-informed rehabilitation post-operative walking may be improved. Aims: This fellowship was developed collaboratively with patient advisors and aims to i) identify the determinants of post-operative walking; ii) co-design and test the feasibility including acceptability of a theoretically-informed post-operative rehabilitation programme to improve walking in older people post-surgery for NC. Methods: Stage one: This prospective observational study will recruit 122 adults aged ≥60 years, waiting for surgery for NC. Measures (six-minute walk distance (6MWD, dependent variable), daily step count and objective and self-reported physical and psychosocial factors will be assessed pre-operatively and at 6 and 12 weeks post-operatively. Multivariate linear regression analysis will identify predictors of 6MWD at 12 weeks. Stage two: This qualitative interview study will enrol 20 adults aged ≥60 years, 3 months post-surgery for NC. Audio-recorded, semi- structured interviews will explore the experience of walking in the post-operative period. Data will be analysed thematically. Stage three: Building on the findings of the first two stages, patients and other stakeholders will co-design a post-operative rehabilitation programme to target salient determinants of walking in a series of workshops, using an experience based co-design approach. Stage four: A single arm feasibility study will enroll up to 30 adults ≥60 years old, post-surgery for NC. Measures (e.g. 6MWD, daily step count) will be collected before and after participants complete the rehabilitation programme. Recruitment, measure completion rates, and programme attendance will be summarised descriptively. Participants’ experience of the rehabilitation programme and research processes will be explored in an audio-recorded focus group of 8-12 participants and data analysed thematically. Dissemination: A PhD thesis will be produced. Professional journals, clinical and public meetings, scientific conferences, social media, podcasts and patient summaries will be used to disseminate the findings. Patient advisors will help disseminate results. The findings will inform the design of a randomised controlled trial investigating the effect the programme.","Background Lumbar spinal stenosis causes symptoms called neurogenic claudication and prevents people from walking. Lumbar spinal stenosis is the most common reason for spinal surgery but many people do not increase their walking after their operation. We don’t know why this happens. Post-operative rehabilitation may improve walking, but it is not always available and it is not clear what should be included in the rehabilitation programme. Aims: •To identify the key factors which affects walking after surgery in older people with neurogenic claudication; •To develop a post-operative rehabilitation programme that helps these factors; •To assess if the new programme is acceptable and see if it is possible to carry out a larger study in the future looking at whether the rehabilitation programme works. Methods: This fellowship comprises four stages Stage one: 122 adults waiting for surgery for neurogenic claudication, aged over 60 years old, will be invited to attend two appointments, one 8 weeks before surgery and one 12 weeks after surgery. They will be asked to complete a walking test, leg strength and balance tests, complete some questionnaires and wear a step counter on their thigh for 7 days. In addition, people will be asked to complete some questionnaires at home 6 weeks after their operation. The things that have the greatest influence on walking will be identified and used to develop a post-operative rehabilitation programme. Stage two: Up to 20 adults who are over 60 years old, at least 3 months after they have had surgery for neurogenic claudication will be interviewed. Interviews will explore people’s beliefs and their experience of walking after surgery and things that help or hinder walking. Common themes will be identified from the interviews and used to help develop a rehabilitation programme. Stage three: Patients and clinicians will be invited to attend three day workshops over 3 months to co-design a post-operative rehabilitation programme based on the things that influence walking identified in the previous stages. Stage four: In this feasibility study up to 30 adults, who are at least 60 years old and have had surgery for neurogenic claudication, will complete questionnaires and walking tests before and after completing the new programme. Twelve people will be invited to share their experiences of the programme in an audio-recorded focus group. Common themes will be identified and used to refine the programme and inform a trial into the effect of the programme.",6.7 PHYSICAL,GENERIC HEALTH RELEVANCE HRCS22_22624,Welsh Government Office for Science,WGOS,The development of in vitro models of respiratory biofilm assembly to develop novel antimicrobial therapies (PMF),"This multidisciplinary project aims to tackle one of the largest growing global issues, and a clear unmet clinical need i.e. antimicrobial resistance (AMR). The unrestricted use of antibiotics in medicine and animal husbandry has led to the global epidemic of AMR (1). Most recently, the development of resistance to colistin (our ‘last resort’ antibiotic), which can spread directly between bacteria, may herald the end of the antibiotic era (2). With no new treatment strategies in the ‘pipeline’, a government-commissioned report predicts, a crisis, with 300 million premature deaths attributable to AMR and a £64 trillion loss to the global economy by 2050 (3). My previous work, across the University and the NHS sector in Wales, has demonstrated the antimicrobial potential of a novel, low molecular weight (Mn ~3.200) oligosaccharide, OligoG CF-5/20 (Fig 1), derived from seaweed (4). Initial studies showed an ability to increase the effectiveness of antibiotics against highly antibiotic-resistant bacteria (5, 6). Based on this work, OligoG CF-5/20 entered human trials (Phase IIb was completed in Q4 2016) and was awarded Orphan drug status by the US Food and Drug Administration in 2016. It is only by understanding how OligoG CF-5/20 modulates bacterial behaviour, biofilm formation and potentiates antibiotic activity, that we can target therapies to deliver the potential of this exciting technology in the next generation of commercial products. The research outlined in this Fellowship will address the unmet clinical need for novel anti-infective therapies for patients with multi-drug resistant (MDR) lung infections and cystic fibrosis (CF). The key objective of my proposal is to develop a reproducible method to screen the effectiveness of new antimicrobial compounds, and to utilise this model to define the optimum oligomer structural compound to improve our understanding of antimicrobial resistance in, and the treatment of, MDR bacterial biofilm infections.",,5.1 PHARMACEUTICALS,INFECTION HRCS22_12873,Diabetes UK,,The effect of Canagliflozin 300mg on glucose homeostasis in subjects without diabetes after bariatric,The effect of Canagliflozin 300mg on glucose homeostasis in subjects without diabetes after bariatric,,5.1 PHARMACEUTICALS,METABOLIC AND ENDOCRINE HRCS22_17194,Wellcome Trust,,The effect of ageing on inflammation resolution and its causation in age-related immune dysfunction.,"The immune system protects us from infection, however as we age it can weaken and even contribute to age-related diseases such as heart disease, cancer and arthritis. The exact reasons for this are not known, and new treatments could help us fight infection, treat age-related disease, and improve lifespan. This laboratory has discovered that one explanation may be that white blood cells cannot neutralise their targets at sites of infection properly, worsening the inflammatory response and causing excessive tissue damage. Another explanation may be that the management or oversight of the immune response seems to change with time. To examine these two ideas we plan to use a safe and effective model of skin infection in adults to look for subtle differences between the immune systems of young and elderly people, before and after local skin infections. If we find a cause for these differences, we will perform experiments in mice to see if they are a cause of age-related immune dysfunction. These results could then be used to design medications and further experiments to help improve the lives of patients with and without age-related disease.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_06494,Medical Research Council,MRC,The efficacy and mechanisms of action of n-3 poly-unsaturated fatty acid supplementation in people with non-steroidal exacerbated airways disease and uncontrolled asthma,"Some people with asthma are allergic to aspirin and other similar painkillers, like ibuprofen. These make their asthma worse. This type of asthma, known as aspirin sensitive asthma, can be difficult to treat and sometimes requires specialist injections of anti-body type drugs. We know that being allergic to aspirin causes in high levels of inflammatory chemicals (called leukotrienes). Taking fish oil supplements has been shown to change leukotrienes. This may reduce the inflammation in the lungs and improve asthma symptoms. People find it easy to take fish oils and they do not cause side effects. _x000D_ The aim of this research is to test, if fish oil supplements improve asthma symptoms. This will be done by using questionnaires. We will also measure breathing and chemicals in breath, sputum (spit), blood and urine to find out how fish oils may be working. Based on the results of the study, we will be able to recommend whether people who are allergic to aspirin should take fish oils or not._x000D_ We plan to do a small clinical trial involving people from hospitals throughout the UK. We will identify 98 people who have troublesome aspirin sensitive asthma. At the beginning of the study, we will ask patients to complete questionnaires about their asthma symptoms and general well-being, perform routine forced (spirometry) and gentle (exhaled nitric oxide) breathing tests, if possible, and to give blood and urine samples to measure inflammation. Some patients will be asked to produce a sputum sample either spontaneously or after inhaling salty mist to measure standard and new tests of inflammation. We plan to give people either six fish oil capsules, or dummy capsules (placebo), every day for six months, as we think this dose will be effective. We will repeat these tests after 3 months and 6 months (end of the study). We will measure the amount of the fats from fish oils in patients’ blood cells to work out if they have been taking the capsules. The results will tell us if fish oils improve peoples’ asthma symptoms or not and whether they change the inflammatory chemicals. _x000D_ We have consulted people living with asthma in planning this study. Based on this, we have checked that:_x000D_ • measuring the burden of asthma symptoms is important for people with asthma_x000D_ • the questionnaires we will use will be easy to complete._x000D_ • people are happy to provide blood, sputum and urine samples _x000D_ • taking capsules every day is acceptable. _x000D_ _x000D_ Asthma UK Centre for Applied Research (AUKCAR), a national research group which includes people with asthma, will support our study by working with us to make sure it is helpful for people with asthma. Someone living with asthma who cannot take aspirin medication (Olivia Fulton) is an applicant on this grant and will be joined by other people from AUKCAR to provide advice during our study. There will be someone with asthma at all of our decision-making group meetings. _x000D_ The study will be undertaken by doctors and researchers with experience of asthma, aspirin sensitivity, fish oils and inflammatory chemicals. We are confident that we will be able to find out whether fish oils help people who are allergic to aspirin and how they may be working. We will widely publicise our results with the help of AUKCAR. We will write reports for medical publications, media articles and use social media. Hopefully, as a result of the study, asthma treatment guidelines will be changed.","Research question_x000D_ Is omega-3 poly-unsaturated fatty acid (n-3 PUFA) supplementation efficacious in people with non-steroidal exacerbated respiratory disease (N-ERD), and what is its mechanism of action?_x000D_ Background_x000D_ Asthma is a syndrome compromising many phenotypes including N-ERD (caused by increased 4-series leukotriene (LT) production). n-3 PUFA supplementation modulates 4-series LT and has anti-inflammatory effects. However, other than in a pilot study with dietary manipulation, the effects of N-ERD are unknown._x000D_ Aims and Objectives_x000D_ The primary objective is to determine whether n-3 PUFA supplementation in people with N-ERD can improve asthma control using the asthma control questionnaire (ACQ-6). Secondary objectives are to determine whether n-3 PUFA improves asthma and rhinitis symptoms and quality of life and airway calibre. Mechanistic objectives are to assess effects on red blood cell fatty acid composition, cyclooxygenase pathways and airway inflammation._x000D_ Methods_x000D_ This is a placebo controlled randomised controlled parallel multicentre study with of 6g per day of PUFA for 6 months in people with N-ERD and poor asthma control. Ninety-eight people will be included in the study if they have a reliable history of N-ERD or a positive nasal aspirin challenge, an ACQ-6 > 1.5 and are on stable treatment. People with other significant disease, recent respiratory tract infection, receiving aspirin desensitisation, biological asthma therapies will be excluded, as will those with a significant smoking history or alcohol consumption. _x000D_ The intervention will be 6g of n-3 PUFA (EPA and DHA as six (5.04g EPA+DHA) taken once daily, or in divided doses, with food for 6 months. The control will be matched placebo._x000D_ Measurements will be at be made every 6 weeks for ACQ-6. At baseline, 3 months and 6 months exhaled nitric oxide (FeNO), spirometry (where possible), blood for red blood cell fatty acid concentration, blood eosinophil count and safety markers. The following questionnaires will also be undertaken at these time-points: Mini Asthma Quality of Life Questionnaire (mini-AQLQ), and Euroqol 5 dimension 5 level (EQ5D-5L). The food frequency questionnaire will be measured at baseline and 6 months. Urine will be analysed for uLTE4 and prostaglandin D2 at baseline and 6 months. Induced or spontaneous sputum (where possible) will be obtained at baseline and 6 months in a subgroup for differential cell count and specialised pro-resolving mediators._x000D_ Timelines for delivery_x000D_ We will require 9 months to set up the sites. We will require 15 months to recruit the participants. We require four patients per site at the initial phase, and between 0.5 and 1 patient per month for the study as a whole, depending on site involvement. The intervention is for 6 months’ duration. We will require 6 months at the end of the study for analysis, report writing and dissemination._x000D_ Anticipated impact and dissemination_x000D_ We will determine the efficacy of this cheap, novel treatment option and understand its mechanism of action. We will share the findings through the scientific and social media supported by Asthma UK Centre for Applied Research.",5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS,RESPIRATORY HRCS22_20461,Wellcome Trust,,The emergence of GABAergic microcircuits in the cortex,"The wiring of neurons in the brain is a highly dynamic process, where the number and strength of synapses between neurons are in constant flux. This period of brain development neatly encapsulates a central unanswered question in the field: how do circuits remain stable in the face of unrelenting change? This is further complicated by the fact that neurons process information at multiple spatial scales, from the local integration of synaptic inputs along individual dendrites, to the summation of dendritic events at the soma and the emergence of coherent activity in local microcircuits. Therefore, mechanisms that modulate activity across these different spatial domains must be present to control the flow of information in the brain. Here, we will focus on the emergence of GABAergic microcircuits by cortical interneurons, which modulate the ongoing activity of circuits in the brain. We aim to (1) trace the emergence of these circuits during development; (2) uncover the activity rules that controls their wiring and (3) establish the functional role they play keeping cortical circuits stable. Our findings will not only provide a unique description of circuit formation and plasticity, but also shed light on the homeostatic mechanisms employed by the brain to attain stability.","The brain is made up of millions of neurons that form trillions of connections with each other, allowing information to be passed across them. A fundamental question in neuroscience is to understand how these connections are formed, as neurons wire up during development. Neurons in the brain can be broadly divided into excitatory and inhibitory, depending on whether they stimulate or dampen brain activity. It is thought that a tight balance exists between the two, so that the brain is able to process information in a stable manner. Indeed, disruption of this balance has been implicated in many neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. We propose to explore the principles behind the wiring of inhibitory neurons in the brain. In so doing we aim to discover how circuits of connected neurons emerge during development and uncover the mechanisms by which they remain stable over time.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,NEUROLOGICAL HRCS22_15900,Stroke Association,,The eye and brain: Evaluation of the retinal nerve fibres and vessels as markers of small vessel disease progression or regression on neuroimaging.,"We aim to better understand the pathophysiology of small vessel disease (SVD), a cause of stroke and dementia, through use of multi-modal retinal imaging. Research indicates that brain MRI features of SVD not only progress but can also regress, so some of the brain damage may be reversible. However, MRI is not able to demonstrate the tiny brain blood vessels and nerves in detail. The retinal small vessels and nerves are developmentally related to those in the brain and can be seen in fine detail with high definition retinal cameras. We will use multi-modal retinal imaging, including optical coherence tomography (OCT) and OCT angiography, to augment detailed assessments of patients presenting with mild stroke as part of a funded study due to commence in 2018. Patients will undergo brain MRI including blood-brain barrier permeability imaging, cerebrovascular reactivity and diffusion imaging together with clinical assessments, cognitive testing, blood measurements and other tests. Associations between retinal and brain imaging features and other study data will be investigated, at baseline and intensive follow-up over the first year after stroke, and annually thereafter for 4 years. Edinburgh is uniquely placed to conduct this work, having the imaging technology and cross-disciplinary experts in one place.","We aim to better understand the pathophysiology of small vessel disease (SVD), a cause of stroke and dementia, through use of multi-modal retinal imaging. Research indicates that brain MRI features of SVD not only progress but can also regress, so some of the brain damage may be reversible. However, MRI is not able to demonstrate the tiny brain blood vessels and nerves in detail. The retinal small vessels and nerves are developmentally related to those in the brain and can be seen in fine detail with high definition retinal cameras. We will use multi-modal retinal imaging, including optical coherence tomography (OCT) and OCT angiography, to augment detailed assessments of patients presenting with mild stroke as part of a funded study due to commence in 2018. Patients will undergo brain MRI including blood-brain barrier permeability imaging, cerebrovascular reactivity and diffusion imaging together with clinical assessments, cognitive testing, blood measurements and other tests. Associations between retinal and brain imaging features and other study data will be investigated, at baseline and intensive follow-up over the first year after stroke, and annually thereafter for 4 years. Edinburgh is uniquely placed to conduct this work, having the imaging technology and cross-disciplinary experts in one place.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,NEUROLOGICAL;EYE HRCS22_22872,The Academy of Medical Sciences,AMS,The fetal microglial response to glucocorticoid exposure in utero,"The objective is to investigate whether the adverse neurodevelopmental outcomes associated with intrauterine glucocorticoid exposure may be linked to impacts on fetal microglia. We aim to characterise the gene expression profile of murine fetal microglia after glucocorticoid exposure in pregnancy. We also aim to identify and describe the transcriptome of microglial clusters at this gestation. Glucocorticoids (GC) act to increase surfactant production in fetal lungs, thereby reducing the likelihood of several life-threatening conditions at birth. Where delivery is expected to occur within the next 7 days, antenatal maternal glucocorticoid (AMGC) therapy is routinely offered to women before 34 weeks’ gestation. Resultantly, AMGC are given to 7–10% of women in Europe and North America at risk of preterm labour. The potentially deleterious effects of AMGC therapy have been reported for decades using animal models. A recent study of >600,000 children has confirmed earlier concerns regarding the long-term impact of AMGC on cognitive/behavioural control. It was found that AMGC exposure was associated with a higher risk of any mental and behavioural disorder (12.01% vs 6.45%). Microglia account for ~10% of all cells in the CNS and ~80% of the immune cells in the brain. Thought to be key to developmental synaptogenesis, microglial dysfunction has been linked to autism spectrum disorders. Microglial are highly diverse during development and are sensitive to glucocorticoids. They are key to embryonic brain development and in the response to injury/inflammation. The role of these cells in the context of AMGC administration has not previously been investigated.","When babies are expected to be delivered prematurely, pregnant mothers are usually offered a steroid drug to help speed-up the development of their babies’ lungs. This treatment is vital in avoiding many harmful and life-threatening conditions caused by an inability to breathe sufficiently at birth. Steroids are particularly useful in premature deliveries where the babies’ lungs are poorly developed. Towards the end of pregnancy however, the overall benefit of these steroids is reduced and babies may only benefit from avoiding mild or short-term breathing problems. Whilst these drugs work well in helping babies’ lungs to function, they also potentially alter brain development, as the targets of the steroids are also found there. This may have an impact on normal brain development. Whilst experiments in animals have raised these concerns for years, it has recently emerged that there could be long-term behavioural consequences for human babies exposed to these drugs. 
A group of cells which are critically important in controlling brain development, called microglia, are known to be affected by steroid drugs. Thus, it is important to understand the impact of steroids on these cells and the developing brains they usually nurture. Therefore, we will analyse how the microglia genes respond to steroid drugs, and how this may affect their function. This information will help us to better understand the consequences of these drugs, and eventually may lead to new ways of giving steroids which cause less harm to babies’ brains.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_18123,Dunhill Medical Trust,,"The future of older people's housing and living arrangements: matching emerging technologies with needs for independent living and care support in a sustainable and systematic 'living lab' approach","This project aims to: 1) understand the needs and desires of older people with different backgrounds regarding their future care, support, and housing and living arrangements; 2) identify emerging technology-enabled products and services that are likely to have an impact on independent living, care support and the living environment for older people with care and support needs, and develop methods to monitor and influence the development of such products and services, and assess their potential added value on a regular basis, using a multi-stakeholder co-design/co-decide approach; 3) develop a “living lab”, a realistic cyber-socio-physical environment in which new solutions and care concepts can be tested and evaluated and adapted to meet people’s needs. The project consists of five work packages, one focusing on management of the project, three addressing the above-mentioned aims, and one focusing on dissemination and sustainability. WP1 includes all project management activities. In WP2 we will identify and analyse the needs and aspirations of current clients of Johnnie Johnson Housing/Astraline (JJH/A) and clients on their waiting lists. In addition, we will assess the needs/aspirations of communities who currently do not use or have access to such services, whether that be for economic or cultural reasons. We will endeavour to understand how new technologies can be tools for enabling greater inclusivity. We will conduct surveys and in-depth interviews with people drawn from each of these three groups. The result will be an overview of what current and potential future clients find important in terms of housing arrangements and technological support. WP3 will focus on identifying emerging products and services that may have an impact on care, support and housing for older people, and on developing a systematic, critical methodology to monitor, on an ongoing basis, the development of such products and services and to assess their potential added value. We will develop a method to regularly scan the relevant literature, conferences and exhibitions. To assess the potential added value of new products and services, we will develop a set of key criteria that are important for decisions about their introduction, starting with the set of technical criteria JJH/A currently uses for such decisions, augmented with aspects like expected added value, cost-benefit, safety and security, user acceptance, usability, the risk of increasing inequalities, etc. As a third element of this WP we will, together with older people, informal carers, care professionals, housing and health and social care organisations, technology suppliers and other relevant stakeholders, design a co-decision process for assessing the potential of new products and services. In WP4 we develop a “living lab” with JJH/A in which new products and care concepts can be tested/evaluated. Living labs are user-centred ecosystems whereby innovations can be developed and tested in an open and inclusive manner. In this case, the core of this living lab will be a panel of actual clients of JJH/A who are willing to experiment with new products in their own homes. For the evaluation of these new products and services a standardised toolkit with assessment criteria and procedures, linked to the criteria used in WP2, will be developed. Products and services that ‘pass the test’ of the process designed in WP3 will be evaluated in this living lab. As part of this initiative a junior researcher will live in one of the housing facilities as an ‘embedded researcher’. Under appropriate conditions, this living lab will be made available to external parties who would seek to better understand their users and their environments through co-design processes or who wish to have their products and services evaluated in real settings. In WP5 the results of this project will be disseminated. They will directly feed into the work and strategy of JJH/A but will also be made available to other organisations. Findings will be published in a series of scientific publications, including a PhD thesis, and industry publications within the housing, health and care sectors. In addition, we well develop and implement a sustainable and equitable exploitation model for the living lab and assessment methodologies. The ultimate aim of the project is to develop mechanisms to respond to changing care needs and to exploit technical opportunities to meet these needs.","New technologies, and the products and services they enable, hold the promise of improving the care provided to older people, in terms of both its quality and its coverage. However, technical innovation is difficult: most new products/services fail, even when the underlying idea is sound. A chief cause of failure is a lack of understanding of the real needs, wishes and capabilities of target users: new products/services developed in the R&D lab tend not to survive contact with the complexity of people’s everyday lives. This represents a waste of the time, effort and resources as well as a missed opportunity to improve lives. The solution to this problem is, on the face of it, obvious: include end users, and anyone else with an interest, in development, and at as early a stage as possible. In practice, however, this is not as easy as it sounds. Engaging and involving users can be difficult and costly, requiring particular skills and resources and raising ethical concerns, especially when the primary users – the recipients of care – can be ill or vulnerable, and there is a variety of secondary users and interested parties: family, friends and informal carers, health and care professionals, housing providers, care commissioners, and so on. In this project we propose to address this challenge by developing a “living lab” and complementary methods to guide development and testing of new products/services. In contrast to the sterile, closed environment of the R&D lab, a living lab is composed of real people – all potential users of the technology – living their lives in their own homes and places of work and leisure, who participate in all stages of the innovation process to help develop practical solutions to meet their real needs and aspirations. In this way, products/services are developed in an open and inclusive manner with the active input of users. We will develop, with the participants, acceptable methods to identify and appraise promising emerging technologies and candidate products/services in a systematic way. The results of these appraisals will guide selection and purchase decisions, and steer development and support investment. Because this is valuable information, we believe that the living lab can become economically self-sufficient, with an equitable distribution of surplus income. Furthermore, since by its very nature this approach strives to be inclusive, we see it as a means for including those currently excluded or marginalised by existing care provision.",7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_01459,Medical Research Council,MRC,The immunological basis of susceptibility to nontyphoidal Salmonella bacteraemia among HIV-infected adults in Uganda,"Nontyphoidal Salmonellae (NTS) cause fatal bacteraemia among HIV-infected Africans. Surprisingly, susceptibility initially increases on antiretroviral therapy (ART) and, although subsequently diminishes, it remains over 50-fold higher than in HIV-uninfected Africans. Candidate vaccines aim to induce antibodies against Salmonella lipopolysaccharide (LPS) O-antigen. Previously, I found that these antibodies occur in excess in some HIV-infected Africans and block killing of NTS, raising safety concerns. Blocking antibodies may represent one of a number of factors contributing to susceptibility. I propose an integrated hypothesis that NTS bacteraemia in HIV-infected Africans occurs due to: 1. high levels of NTS in the gastrointestinal (GI) tract, 2. translocation of NTS to the circulation secondary to loss of CD4+ Th17 cells and mucosal-associated invariant T (MAIT) cells, 3. dysregulated production of anti-O-antigen antibodies, secondary to translocated LPS and Tfh cell dysregulation; these antibodies are unable to kill translocated bacteria, resulting in bacteraemia. The experimental approach exploits the changes in susceptibility to NTS with ART and investigates blood, GI mucosa collected by endoscopy, and stool in a cohort of treatment-naïve HIV-infected adults in Uganda, immediately before and for 24 months after initiating ART, in comparison with HIV-uninfected adults. I will examine Salmonella in the GI tract by metagenomics, and its translocation to the circulation by 16S qPCR, and immunological and biochemical markers. Concentration and function of blocking antibodies will be determined by ELISA and bactericidal assays, while frequency and function of T cell subsets, focusing on CD4+ Th17 and Tfh, and MAIT cells, will be explored by flow cytometry. I will test for association between these parameters and findings will be correlated with time on ART. The detailed knowledge obtained will help guide the development of appropriate vaccines and therapies.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_11643,Economic and Social Research Council,ESRC,The impact of childhood adversity on violent crime in adolescence and early adulthood,"The aim of this project is to provide a better understanding of the link between childhood adversity and serious violence (defined as violence against the person, possession of an offensive weapon, and homicide) during adolescence and early adulthood. We will consider a wide range of adversities, including those encompassed within the adverse childhood experiences framework (abuse, neglect, domestic violence, parental separation, substance abuse, mental illness and imprisonment) as well as exposure to other traumatic events such as bereavement and bullying. It is known that childhood adversity is associated with an increased risk of being involved in violence and it has rapidly become a central pillar of violence prevention policy and activity. However, our understanding of the causal pathway from adversity to violence is limited. Previous studies have often relied on retrospective reports of childhood adversity and have aggregated these diverse experiences into a sum score. As such, it is not clear whether the associations are causal, which adversities have the largest impact, and the extent to which the timing of exposure to adversity is important. Further, it is unclear what role other factors such as mental health, school attainment and absence, and risk behaviours such as drug use play in this association. The specific objectives of our project are: 1. To establish linkage between the Avon Longitudinal Study of Parents and Children (ALSPAC, comprising longitudinal study data and linked health and education data) and police data on criminal convictions and cautions as a resource for this project and future research. 2. To explore the extent to which self-reported crime and antisocial behaviours and police-recorded crime in ALSPAC are subject to misclassification and missing information in order to derive more accurate measures of the prevalence of serious violence. 3. To understand the relative and temporal contribution of adversity experiences in the emergence of serious violent behaviour during adolescence and early adulthood. 4. To understand the mediating role of school outcomes (attainment, attendance, exclusion), other risk-taking behaviours (smoking, alcohol and illicit drug use), and mental health outcomes (depression, anxiety, ADHD) in the link between adversity and serious violence during adolescence/early adulthood. As part of objective 3 we will investigate the importance of the timing of the adversities in terms of their impact on the risk of perpetrating serious violence. Specifically, we will look at whether the risk depends on when the adversities were first experienced and whether they were experienced throughout childhood or for a limited time only. Our findings will facilitate the design and targeting of appropriate interventions aimed at reducing the risk of serious violence among vulnerable individuals. This is currently a UK Government priority. ALSPAC, together with linked data on crime, education, and health, provides a unique resource for filling knowledge gaps in this area. Firstly, it has detailed information on a wide range of individual and family factors that are potential confounders of the relationship between adversity and violence. Secondly, data on adversities were collected at repeated time points during childhood, allowing us to examine the impact of timing. Thirdly, linking to police records will provide crime data as recorded by the police to complement self-reported crime; it will also give data on individuals who are no longer actively contributing to ALSPAC (in addition to those who are). This is vital because research has shown that individuals who have been lost to follow up are more likely to have experienced adversity during childhood and more likely to be involved in crime. Our methodological work will provide a blueprint for estimating the prevalence of serious violence and other crimes using multiple sources of data.","Even though rates of overall crime have gone down in the UK over the last two decades, levels of serious violence in the past four years indicate a reversal of this trend. As a result, tackling serious violence has become a UK Government priority. One of the main ways to prevent youth involvement in violence is to identify and limit its early causes. It is well-known that individuals who have had traumatic or stressful experiences during childhood (referred to as adverse childhood experiences or childhood adversity) - such as being a victim of child abuse or having a parent who suffers from a mental illness - are more likely to engage in violence during adolescence and early adulthood. However, it is not clear which adverse experiences contribute most to violence nor whether they have a greater or lesser impact if experienced at different ages. The aim of our project is to answer these questions. We will address several research questions about the relationship between childhood adversity and serious violence during adolescence and early adulthood. We will consider a wide range of adversities including (but not restricted to) abuse (emotional, physical, and sexual), bullying, bereavement, and parental substance abuse, mental illness, and criminality. The choice of adversities to include in our analyses will be informed in part by the Ambassadors for Vulnerable Children and Young People on our steering group (these are young people who have experience of adversity in childhood, and who are employed by local authorities as ambassadors). We will identify whether any of these adversities have a particularly large impact on the risk of being involved in violent crime as a teenager or a young adult. Another goal is to determine whether there are critical periods during childhood where exposure to adversity - either in general or to one or more specific adversities - puts a child at particularly high risk. We also plan to investigate what role school attainment and attendance, mental health, and risk-taking behaviours (such as taking drugs) play in the relationship between childhood adversity and violence. To fulfil the goals of our project, we will use data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a world-leading data resource that has recorded extremely detailed information on the health, development and family circumstances of approximately 14,500 families living in the Bristol area since the early 1990s. Data collection started during pregnancy and has continued year on year ever since. The richness of this data resource makes it possible to answer questions that previous studies have been unable to address. We will link ALSPAC to data provided by Avon and Somerset police to generate the richest data set on violence and childhood adversity ever created in the UK, further enhancing this unique resource and enabling other researchers to investigate the causes and consequences of offending in new ways. Our findings will shed light on how and when we can best intervene with children (or families) at risk of violence. Addressing these key questions has the potential to help reduce rates of violent crime and to provide a better understanding of how childhood experience contributes to violence that will benefit perpetrators and their families, victims, practitioners, policy makers and the general public.","2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",MENTAL HEALTH HRCS22_09528,Health and Care Research Wales (Welsh Government),,The impact of mobile technology in hospitals on patient care management and clinical practice,"Staff in some hospitals in Wales are using mobile technology, rather than paper-based forms, to record patient observations. This information, collected at the bedside, can help medical teams to make well-informed decisions about patient care. It can give hospital management staff up-to-the-minute information which can assist them with bed management by tracking patient-flow through the system. Thus, mobile technology has the potential to improve patient care management and clinical practice. However, we don’t actually know what difference it makes. The purpose of this study is to find out whether indeed this technology makes any difference to the management of patient care and how it impacts on professional practice and relationships in the multidisciplinary team. We will do this by supporting a PhD student firstly to find out from the published literature how technology like this is used and evaluated in other places. Then the student will gather and analyse data from two hospitals where the mobile technology and software is used record patient data. Information can be fully anonymised (so no-one knows who any of the patients are) and downloaded from the software. It can be analysed to explore patient-flow between wards and in-and-out of the hospitals. But that is only one source of data for this study. As important is finding out what staff think of using the mobile technology. Through talking to members of the multidisciplinary teams (nurses, doctors, physiotherapists, occupational therapists, ward clerks) and hospital managers, the student will find out how or whether this up-to-the-minute patient data is used to inform their clinical practice and the decisions they make about patient care, and if it makes any difference to their communication with managers. What we learn from this study can help others in hospitals across Wales, and more widely, use this technology to best effect.","Staff in some hospitals in Wales are using mobile technology, rather than paper-based forms, to record patient observations. This information, collected at the bedside, can help medical teams to make well-informed decisions about patient care. It can give hospital management staff up-to-the-minute information which can assist them with bed management by tracking patient-flow through the system. Thus, mobile technology has the potential to improve patient care management and clinical practice. However, we don’t actually know what difference it makes. The purpose of this study is to find out whether indeed this technology makes any difference to the management of patient care and how it impacts on professional practice and relationships in the multidisciplinary team. We will do this by supporting a PhD student firstly to find out from the published literature how technology like this is used and evaluated in other places. Then the student will gather and analyse data from two hospitals where the mobile technology and software is used record patient data. Information can be fully anonymised (so no-one knows who any of the patients are) and downloaded from the software. It can be analysed to explore patient-flow between wards and in-and-out of the hospitals. But that is only one source of data for this study. As important is finding out what staff think of using the mobile technology. Through talking to members of the multidisciplinary teams (nurses, doctors, physiotherapists, occupational therapists, ward clerks) and hospital managers, the student will find out how or whether this up-to-the-minute patient data is used to inform their clinical practice and the decisions they make about patient care, and if it makes any difference to their communication with managers. What we learn from this study can help others in hospitals across Wales, and more widely, use this technology to best effect.",7.3 MANAGEMENT AND DECISION MAKING,GENERIC HEALTH RELEVANCE HRCS22_11635,Economic and Social Research Council,ESRC,The impact of sleep deprivation and anxiety on social understanding and social functioning,"Being able to identify other people's perspectives, beliefs and feelings (SOCIAL UNDERSTANDING) is crucial for everyday social interactions. There is evidence that social understanding is significantly affected by ANXIETY and SLEEP DEPRIVATION. When Anxiety or Sleep Deprivation is induced, people are worse at understanding others. In clinical conditions associated with poor sleep and anxiety, problems with social functioning are observed. We do not know the mechanism through which sleep deprivation and anxiety affect social understanding and we do not know whether social functioning difficulties are mediated by problems with social understanding. 1) My FIRST OBJECTIVE is to map the mechanism for how induced sleep deprivation and anxiety affect social understanding. Work Package 1 includes three studies to address this objective. We will use systematic induction of sleep deprivation and anxiety and measure the impact on belief-reasoning and empathy. At the end of this project, we will know how acute sleep deprivation and anxiety affect different aspects of social understanding, including - (i) global performance, (ii) social motivation and (iii) self-other distinction. 2) My SECOND OBJECTIVE is to model the relationship between individual differences in sleep, anxiety, social understanding and social functioning. Work Package 2 includes large-scale measurement of individual differences in sleep, anxiety, social understanding and social functioning. We will analyse these data using Structural Equation Modelling. At the end of this project, we will know whether longer-term variation in sleep and anxiety relates to social functioning. We will also know whether individual differences in social understanding mediate this relationship. 3) My THIRD OBJECTIVE is to relate the empirical findings of the project to the broader theoretical and practical implications of the relationship between sleep, anxiety and social understanding. This will form the basis of a review paper. At the end of this project, we will have a clear and integrated model for the relationship between sleep, anxiety and social understanding. This model will provide for specific predictions for the neural basis of the relationship between sleep, anxiety and social understanding, and for the impact of sleep and anxiety on social functioning in clinical conditions. As PI, I am in a unique position to understand the methods and theoretical issues in this project. As appropriate for a New Investigator Grant, the project includes specific objectives to progress to independence. 4) My FOURTH OBJECTIVE is to develop specific research skills in sleep deprivation and Structural Equation Modelling. Training in sleep deprivation will be undertaken in a research visit to Monash University, with support from Dr Clare Anderson. Ongoing local support will be provided by Dr Andrew Bagshaw. Training in Structural Equation Modelling will be undertaken in a week-long course. At the end of this project, I will have skills and experience in a new experimental method (sleep deprivation) and a new analytical technique (Structural Equation Modelling). 5) My FIFTH OBJECTIVE is to develop research leadership skills necessary for independence. This will be achieved by a clear mentorship plan with an experienced senior academic - Professor Jane Raymond (see mentor statement). Two research lab visits are included in the project to international collaborators on the grant - Dr Anderson (Monash) and Dr Andrew Todd (University of California - Davis). These collaborations will support international impact, crucial for establishing a world-leading reputation. At the end of the project, I will have the skills and experience to manage large research grants independently.","Poor sleep and anxiety pose significant economic and social challenges. Inadequate sleep costs the UK economy 1.3-1.9% of Gross Domestic Product each year and has significant health and social consequences. Common mental health difficulties, such as anxiety, account for 17.6 million sick days yearly and reduce GDP by around 1.3%. Additional to this are the indirect costs of poor sleep and anxiety - the costs to our social understanding, social interaction and social relationships. Understanding other people's perspectives, beliefs, desires and feelings is important. The sophistication with which humans do this is one of the things that has led to our success as a species. We live in large communities and cooperate to meet shared goals. We learn from others, teach our children and care for those more vulnerable than ourselves. Each of these activities relies on our understanding of what other people see, believe, want or feel. Sometimes others tell us this information, but sometimes we have to infer it from the way they act. Everyday experience suggests poor sleep and anxiety affect our social understanding. Who has not noticed anxious students nervously ignoring each other as they wait for an exam? How many of us have spent time apologizing to our mothers when we forgot to send them a birthday card because we were exhausted after over-working towards a deadline? Emerging experimental evidence supports the suggestion that sleep deprivation and anxiety can change our social understanding and that those with long-term experiences of sleep problems or anxiety experience social difficulties. What is less clear is exactly how sleep and anxiety impact on our social understanding and how variability in these experiences impacts our longer-term social functioning. One hypothesis that is consistent with the literature is that anxiety makes us more selfish, encouraging us to focus on our own point of view at the expense of others. Another is that sleep deprivation makes us more muddled, making it harder to distinguish between our own point of view and other people's. A third is that those with better sleep and lower levels of anxiety will function better in the longer term because they understand people better. To look at the impact of sleep deprivation, we will test people on three tasks, after having them remain awake for a whole night. The tasks will investigate their ability to think about other people's thoughts and feelings. Their responses will be informative as to whether sleep deprivation has caused them to have difficulties in distinguishing between their own thoughts and feelings, and other people's. To look at the impact of anxiety, we will induce anxiety in people and then have them do the very same tasks. People will be made anxious by recalling and writing about a time they felt anxious. Here, we predict people's responses will show evidence of increased selfishness in their judgments. To look at the relationship between long-term, everyday tendencies towards anxiety and poor sleep, and social difficulties, participants will complete a number of questionnaires and short experimental tasks. We will use sophisticated statistical modelling to test the relationship between people's traits in these areas. Each of these experiments will provide exciting new evidence for how everyday experiences impact on our social understanding. They will also open up new avenues for investigation, looking at the impact of these findings. Clearer evidence for the way in which poor sleep and anxiety impact social understanding is highly relevant to clinical populations, such as those with insomnia, generalized anxiety disorder and autism. Further, specialist populations, such as new parents, junior doctors or soldiers in combat have to experience poor sleep and anxiety at the same time as making crucial social judgments. The novel insights offered by our project will provide a model for understanding how their abilities are affected.","1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",MENTAL HEALTH HRCS22_03004,Medical Research Council,MRC,The impact of type 2 immunity on haematopoiesis and consequences for host immune function,"Haematopoietic stem cells (HSCs) sense peripheral inflammation allowing bone marrow immune cell production to adapt to ongoing demands. This is well understood for bacterial and viral infection with key roles for pro-inflammatory cytokines (e.g. type I/II interferons). In contrast, how HSC respond to type 2 inflammation represents a substantial knowledge gap. This is important as type 2 immunity is key for responses to helminth parasites and in allergic disease. Our preliminary studies show chronic infection with Schistosoma mansoni drives a type 2 bone marrow cytokine environment with substantial changes to immune cell progenitors (BM monocytes, LSK cells, HSCs). This is associated with weaker responses to re-infection maintained even after parasite clearance. We propose type 2 inflammation causes sustained alterations to HSCs with wide-ranging implications for both anti-parasite immunity and bystander immune responses to unrelated challenges. We will first characterise how schistosome-induced type 2 inflammation impacts on mouse HSCs using single cell gene expression profiling (10x Chromium) and functional assays. We will assess the persistence of epigenetic changes (ATAC-seq) following parasite clearance. We will also determine if these gene expression signatures are present in schistosome-infected people. Next, we will identify the cytokine signals that drive these changes and test how HSC integrate type 2 (IL-4) and type 1 (IFN-I/g) inflammatory signals. Finally, we will assess the extent to which HSC training by type 2 inflammation underpins parasite immune modulation. We will determine whether infection-induced changes to HSC directly drive weak immune responses in chronic schistosomiasis. Finally, we will test how HSC integrate type 1 and type 2 signals and the consequences of this for trained immunity. To do this, we will test if parasite-induced changes to HSC lead to weaker responses to live vaccines (BCG) in both humans and in mouse models.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES,INFECTION;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_19279,Wellcome Trust,,The interaction of polygenic and monogenic diabetes to unravel new biology and diabetes subtypes,"We are now in the genomics era where clinical and pre-emptive genetic testing is common. This has raised new problems in monogenic disorders such as Maturity-Onset Diabetes of the Young (MODY), a rare genetic form of diabetes: 1) identification of wide variation in the clinical features of people with MODY mutations, including non-diabetic individuals. 2) identification of people who are ‘MODY-like’ (slim, young and not on insulin) but without a MODY mutation and therefore without a known cause for their diabetes. During my fellowship, I will address these new problems using our unique cohort of MODY/MODY-like diabetes and clinical and genetic data on 500,000 people from UK Biobank. I hypothesise that polygenic risk of diabetes-related traits will explain variation in the MODY phenotype and characterise new subtype(s) of diabetes which presents as classic MODY, but is due to extreme polygenic risk of diabetes-related traits (polygenic-phenocopies). The outcomes of this research will be to provide accurate prediction of which people with MODY mutations will get diabetes and when, and define and characterise a new type of diabetes. This work will have important implications for individuals with MODY, for the wider diabetes community and will provide framework for other genetic disorders.","Maturity-Onset Diabetes of the Young (MODY) is a rare genetic form of diabetes. Identifying MODY is important for the correct treatment. We are now doing more genetic testing than ever before. This has led to two new problems: 1) We are now finding people with defective MODY genes but without diabetes and 2) we are finding people who are ‘MODY-like’ but without defective MODY genes. During this fellowship, I will aim to study these two problems in detail. I will develop ways to accurately predict if and when people with defective MODY genes will get diabetes. I will also aim to identify a reason for this MODY-like diabetes and whether it can be treated differently to common forms of diabetes. My work therefore has important implications for individuals with MODY, for the wider diabetes community and is relevant to other genetic disorders.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,METABOLIC AND ENDOCRINE HRCS22_22704,The Academy of Medical Sciences,AMS,The key role of primary cilia in determining tooth morphogenesis,"The loss of teeth not only seriously affects the health of life of patients, but also affects the longevity of elderly people in the long-term. It is one of the most important health problems in the aging society. In the future, the ability to regenerate a tooth as an important digestive organ is a key issue in the field of tissue regeneration and medical health. At present, worldwide scholars are trying to make progress in understanding and promoting tooth development. However, it is worth noting that human teeth are more complex than most animals, including incisors, canines, molars, etc. As an independent organ, how to control the morphology of tooth through development and the principal regulatory mechanisms are still to be disclosed. Therefore, one of the major questions to be answered in this study is how to regulate the development of tooth germs into different morphologies during tooth regeneration, and what the crucial regulatory genes are. More importantly, using this model, this study also helps to understand the principles of morphological control and key molecules in organ regeneration.","Tooth formation is highly regulated multistage process, which includes epithelial-mesenchymal signaling interactions, tooth germ development, crown formation and tooth root development. Among these key steps, many key signalings involved are disclosed, such as WNT and HH. However, during tooth formation, which factors could determine the development direction of tooth germ (to molar, premolar or incisor) are still unclear. Primary cilia are organelles on the cell surface as key coordinators of chemical sensation, signal transduction, and control of cell differentiation during tissue development and homeostasis. Recently, several groups including us found that primary cilia could play a significant role in the development of tooth. IFT140, the core member of intraflagellar transport complex A (IFT-A) of primary cilium, is an essential molecule for signal transduction within the primary cilia. By conditional knocking out IFT140 in mesenchymal stem cells in vivo, it is very interesting that the typical molar (multirooted teeth) transformed into an unirooted teeth, which is similar to the shape of human premolar (schematic 1A&B). Based on the previous investigations and our preliminary evaluation of these critical tooth morphological changing in genetic mouse models (delete IFT140 in different stages of DPSCs/odontoblast differentiation by using Prx1-cre/Osx-cre/Dmp1-cre mice), we look forward to exploring the role of primary cilia and core protein IFT140 involved in tooth formation, especially to answer the key mechanism of the development control of complicated tooth shapes from simple shape of tooth germ.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,ORAL AND GASTROINTESTINAL HRCS22_18253,Wellcome Trust,,The maternal antibody paradox: Characterising mechanisms and devising solutions for rotavirus vaccination,"Maternal antibodies (MA) are transferred to fetus and infant via the placenta and through breast milk, providing protection against pathogens when the immune response is immature. However, MA also suppress the development of B cell responses to pathogens via mechanisms that are not well defined. MA can therefore result in poor vaccine performance in the infant, placing them at risk against potentially life-threatening pathogens such as rotavirus. Rotavirus infection poses a substantial threat to human health globally. The virus is a major cause of acute gastroenteritis in young children, resulting in ~215,000 deaths each year. Rotavirus vaccines have recently been applied with great success in developed countries, however it is unknown why rotavirus vaccines are much less effective in low-income countries. Whilst malnutrition and the gut microbiome may contribute to poor vaccine efficacy, interference by MA is also considered to be a major prohibitive factor. This study aims to unravel the mechanisms by which MA limit development of effective antibody responses to rotavirus vaccination in infants. This project also aims to translate mechanistic results into rational design of improved vaccines. This work has the potential to generate vaccines that induce protection against rotavirus in younger children across all economic areas.","Antibodies are produced by our immune system to protect against infections. Babies are unable to make antibodies when they are born, so antibodies from the mother (‘maternal antibodies’) are transferred to babies through the placenta and breast milk instead. These maternal antibodies provide protection whilst the child’s immune system develops. However, a downside of maternal antibodies is that they can block vaccines. This is especially concerning for the rotavirus vaccine as rotavirus can cause life-threatening diarrhoea in children. Babies with high maternal antibodies are often not protected against rotavirus disease after vaccination. Despite this problem being identified over twenty years ago, how this occurs is not known. This project aims to work out how maternal antibodies block rotavirus vaccines. This knowledge will then be used to design more effective vaccines, which has the potential to save the lives of infants that would otherwise succumb to rotavirus disease.",3.4 VACCINES,INFECTION HRCS22_19353,Cancer Research UK,CRUK,The role of ATRX alterations in the genesis and therapeutic sensitivity of neuroblastoma,"Background: Neuroblastoma is a common tumour of childhood, arising in the developing sympathetic nervous system (SNS). In neuroblastoma, genetic alterations in ATRX define a chemo-resistant, poor-outcome group. ATRX has multiple functions including a critical role in the maintenance of genome stability, in addition to a diverse but incompletely understood role in transcriptional regulation. Despite urgent need for novel therapies, the underlying mechanisms driving oncogenesis in ATRX-neuroblastoma are unknown. I will generate developmental models that re-capitulate SNS development to understand how ATRX alterations contribute to neuroblastoma genesis, and identify directly druggable targets arising as a result of transcriptional dysregulation in ATRX mutant cells. Aims: (1) To generate experimental models that faithfully recapitulate SNS development, and to identify the effects of ATRX-alterations on epigenetic programming/transcriptional regulation during SNS differentiation. (2) To identify the co-operating events that drive oncogenesis in developmental ATRX neuroblastoma models, then to probe the transcriptional landscape of ATRX-neuroblastoma generated in-vivo. (3) To identify and pre-clinically evaluate druggable targets arising as a result of dysregulated transcription in ATRX-neuroblastoma. Methods: (1) I will perform ChIP-sequencing, ATAC-sequencing and RNA-sequencing in isogenic ATRX-mutant/wild-type induced pluripotent stem cells at different stages of SNS development, to identify dynamic genome-wide changes in epigenetic regulation during SNS development, and how these contribute to oncogenesis. (2) I will investigate the tumorigenic potential of ATRX alterations alone, and following induction of chromosomal instability. Based on clinical sequencing data, I will also evaluate whether activating ALK mutations co-operate with ATRX alterations to drive oncogenesis. (3) Based on my published and preliminary data I will focus on combination therapies targeting both transcriptional activation and DNA damage repair pathway vulnerabilities, arising as a result of ATRX alterations. How the results of this research will be used: This research will result in greater insight into the origins of ATRX-neuroblastoma and identify druggable targets and novel combination therapies for this poor outcome group. This will ultimately lead to a programme of laboratory work that will in-turn be translated into innovative clinical trials for children with currently incurable neuroblastoma.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE HRCS22_18688,Versus Arthritis,,The role of Agrin loss in the establishment and treatment of OA pain,"Blocking non-specific pain mechanisms in osteoarthritis such as inhibiting NGF or TrkA improved pain however, in some patients, induced accelerated osteoarthritis (Hochberg, 2015). There is a need for targets that are specific to osteoarthritis-related pain mechanisms, to pathological pain, and ideally which also improve cartilage health and homeostasis. New data from our laboratory and data from the literature suggest that the loss of the proteoglycan Agrin in cartilage and in sensory nerves underpins both cartilage loss and establishment of allodynia in OA and that agrin supplementation will block pathological pain in OA while also inducing cartilage regeneration. Agrin loss in the dorsal root ganglia (DRG) and in the spinal cord dorsal horns (DH) is a general and critical mechanism in neuropathic pain (Cui and Bazan, 2010). Neuropathic pain is highly prevalent in osteoarthritis and is associated with worse quality of life (Valdes et al., 2014). Agrin supplementation removed neuropathic pain in animal models (Cui and Bazan, 2010). We discovered that Agrin is a potent chondrogenic factor and is lost in osteoarthritic cartilage (Eldridge et al., 2015), at least in part through proteolysis. As in other models of neuropathic pain, we demonstrated downregulation of agrin in the ipsilateral DRG of mice which had developed pain post surgical-induction of osteoarthritis. C-terminal agrin fragments induce axon growth (Bergstrom et al., 2007; Kim et al., 2007; Mantych and Ferreira, 2001), thereby possibly contributing to the invasion of nociceptive nerves observed in osteoarthritic cartilage (Bowyer et al.). We hypothesize that agrin loss within the joint, the DRG and the DH is a common mechanism which links cartilage breakdown to the establishment of neuropathic pain in osteoarthritis and that restoration of agrin expression, inhibition of agrin proteolysis or agrin supplementation will reduce neuropathic pain whilst also providing a chondroprotective or even chondro-regenerative effect. In this application we will study: 1) Whether and how C-terminal Agrin degradation products within cartilage contribute to the nociceptive nerve invasion in cartilage in humans and animal models of osteoarthritis; 2) The mechanisms of agrin loss in cartilage, DRG and DH in osteoarthritis; 3) Whether restoration of agrin expression in the DRG, DH and cartilage, using tissue specific transgenics, will decrease neuropathic pain in osteoarthritis models. These studies will further our understanding of the mechanisms of pathological pain in osteoarthritis and will identify, for the first time, a pharmaceutical target that will simultaneously tackle symptoms and structural outcomes; thereby overcoming the limitations of targeting non-specific pain mechanisms.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,MUSCULOSKELETAL HRCS22_02793,Medical Research Council,MRC,The role of GABAergic inhibition in the function and dysfunction of the human binocular visual system,"The ability to see in-depth using two eyes is acquired early in development, and critically requires normal binocular visual experience. Abnormal binocular experience, through a squint or unequal refraction, causes long-lasting and severe deficits in visual perception. This condition called Amblyopia, affects around 3% of the population. As binocular vision is achieved by the brain, amblyopia is a disorder not of the eyes but of the brain. One of the key elements in determining experience-dependent plasticity in the binocular visual system is the inhibitory neurotransmitter GABA. This programme of research is designed to determine the role of GABA in binocular function and dysfunction in the human visual cortex. The proposed research aims to use multi-modal magnetic resonance imaging (MRI) to determine (i) whether pharmacologically modulating GABA levels in the brain interferes with binocular functions; (ii) whether a binocular visual training leads to a reduction in GABA in amblyopes that is correlated with improvement in binocular vision and; (iii) how the visual system of children at risk of amblyopia differs from those without binocular deficits and how patching therapy changes cortical structure and function underlying binocular vision. In combination, we will non-invasively quantify the concentration of GABA in the visual cortex, obtain population receptive field measures of depth and assess binocular vision acuity to determine the relationship between neurochemistry, neural organisation and perception. By performing experiments in healthy adults, adults with amblyopia and children at risk of amblyopia, we aim to build a unifying framework that can account for changes during early development and in adulthood. Not only will these studies provide important data for improving therapy for amblyopia, but the binocular vision system can act as a model for neurodevelopmental disorders of higher cognitive function, such as autism or schizophrenia.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,EYE;NEUROLOGICAL HRCS22_02584,Medical Research Council,MRC,The role of axonal mRNA translation in Amyotrophic Lateral Sclerosis (resubmission),"Dysregulated RNA biology has emerged as a major driving force in the pathogenesis of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. While it is still unclear why motor nerves are particularly vulnerable in ALS, their extreme length further implicates axonal trafficking processes to be involved. The observed 'dying-back' pathology also supports that cellular disruption begins at the distal nerve terminus. Thus, we hypothesise that defects in processes such as transport and translation of certain mRNAs in motor neurons is an important contributor to neurodegeneration in ALS. In this proposal we aim to identify mRNA populations actively undergoing translation (translatome) specifically in the axons and synapses of motor nerves in vivo. We will use the model organism Drosophila to study the disease-relevant neuron type in situ, and to exploit its unparalleled genetic tractability. We have established a novel method to extract tagged ribosomes specifically from motor nerve axons. In this study, we will 1) determine the MN axonal translatome under normal conditions over the fly life-course, 2) investigate how axonal and somal translation is affected by TDP-43 mutations and C9orf72-related repeats during disease progression and 3) determine the relative contribution of different dysregulated axonal mRNAs to pathogenicity by assessing their functional impact on the disease-relevant circuits at an organismal level. The results of this project will provide new insights into how dysregulated RNA biology specifically impacts on motor neuron survival.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES,CONGENITAL DISORDERS;NEUROLOGICAL HRCS22_23184,The British Academy,,The role of family background for individuals’ material and psychological wellbeing,"The extent to which individuals’ life chances depend on family circumstances is a fundamental question of social science. Circumstances of families and their adult children are typically defined in terms of income, social class, or education. Such broad categories, however, might not fully capture how family circumstances define individuals’ life chances. In this project I will extend knowledge on both the types of advantages and disadvantages that are intergenerationally reproduced and through which channels this occurs. First, this study will examine the implications of family background on various dimensions of material and psychosocial wellbeing. Material wellbeing is defined in terms of wealth, financial burdens and financial stress while psychological wellbeing is defined in terms of mental health and life satisfaction. Second, I will take a multidimensional approach to social origin and study what particular dimensions of family context are important for adult wellbeing. The project will focus on the UK in an international comparative perspective.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",MENTAL HEALTH HRCS22_02655,Medical Research Council,MRC,The role of impaired glucagon secretion in life-threatening hypoglycaemia of type 1 diabetes: mechanism and therapeutic potential,"Glucagon is the body's principal hyperglycaemic hormone and acts by stimulating hepatic glucose production. It is released from the alpha-cells of the pancreatic islets in response to neurotransmitters (like adrenaline) and a fall in plasma glucose below the normal 5mM but inhibited by somatostatin (released from neighbouring delta-cells). Type-1 diabetes (T1D) is a bihormonal disorder involving (nearly) complete loss of insulin secretion. Crucially, in T1D glucagon secretion in response to hypoglycemia also becomes defective. This increases the risk of severe hypoglycaemia, a potentially fatal complication of insulin therapy. Hypoglycaemia accounts for 10% of the mortality in patients with T1D. The only effective treatment (apart from reducing insulin) is islet or pancreas transplantation but the requirement for immunosuppression makes this a last resort. We will explore the mechanisms underlying the defective glucagon secretion in T1D using in vivo (insulin tolerance tests) and ex vio techniques (hormone secretion, electrophysiology, imaging, gene expression analysis). For our experiment we will use the NOD mouse model, which previously has been widely used for studies of autoimmune destruction of the beta-cells but with little attention being paid to the alpha- and delta-cells that survive the autoimmune attack. Preliminary data indicate that NOD mice recapitulate the loss of hypoglycaemia-induced glucagon secretion seen in patients wit. We will explore how the autoimmune attack, and/or the subsequent reorganisation of the islet and resultant hyperglycaemia results in dysregulated glucagon secretion. The proposed studies will result in new therapeutic paradigms that reduce the risk of hypoglycaemia, thereby enabling more aggressive insulin therapy that reduce the risk of secondary microvascular complications (including heart/renal failure).",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,METABOLIC AND ENDOCRINE HRCS22_09305,"Chief Scientist Office, Scotland",CSO,The role of serum derived-extracellular vesicles in development and treatment of stroke and cognitive impairment,"Stroke is the 3rd leading cause of death and The leading cause of disability in the UK. Stroke risk increases with age and as we are living longer the number of people living with the consequences of stroke increases. One of the most feared consequences of stroke is memory problems. Our research group looks for new stroke treatments. Extracellular vesicles (EVs) are tiny particles that transport messages around the body. EVs have roles in both health and disease. We have found that EVs in blood from people with stroke differ from those in people without stroke. The main difference is in the types of microRNA (miRNA) they carry. MiRNAs are small pieces of a person's genetic make-up which control the expression of other substances. In this study we will explore how these miRNAs differ in people with stroke. We will particularly focus on those with stroke related memory problems. We will then test whether adding 'healthy' miRNA to EVs can aid recovery in experimental stroke models. If we show that miRNA can lessen the damage from stroke, both physical function but also memory and thinking, there may be scope to develop new treatments.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,STROKE HRCS22_17727,Wellcome Trust,,The systems biology of oncogenic PI3Kα-driven stemness regulation,"Cancer stemness is linked to therapy resistance and metastasis. Emerging evidence suggests that PIK3CA-H1047R, a hotspot mutation in breast cancer and the PIK3CA-related overgrowth spectrum (PROS), elicits a stemness phenotype characterised by dedifferentiation and cell plasticity. Nevertheless, PIK3CA-H1047R does not cause malignancy in PROS, perhaps reflecting molecular differences between mammary (cancer) and endothelial (PROS) cell lineages.  By learning and applying novel systems biology tools, I aim to address the mechanism(s) behind PIK3CA-H1047R-driven stemness in a quantitative manner, taking into account cell type, genetic mosaicism and the strength of genetic PI3K pathway activation. I will generate mosaic cell models with doxycycline-inducible PIK3CA-H1047R expression, focussing on human breast epithelial cells and human endothelial cells due to their relevance for breast cancer and PROS, respectively. The cells will be exposed to short- and long-term PIK3CA-H1047R expression, followed by temporal assessment of: 1.Cell-state-transitions by single-cell RNA sequencing; 2.PI3K signalling dynamics by candidate-based quantitative single-cell imaging. Next, I will use data integration and mathematical modelling to infer the underlying regulatory principles. My ultimate goal is the identification of PIK3CA-mutant- and cell type-specific pharmacological therapies for reversal of aberrant stemness regulation, followed by validation in physiologically-relevant 3D models based on the established mosaic cell systems.","Defects in a gene known as PIK3CA are common in breast cancer and in developmental disorders featuring vascular malformations. In these conditions, cells with a PIK3CA mutation are out of tune with their environment and misinterpret the signals they receive. Research suggests that this misinterpretation may result in a loss of cell identity, whereby a cell becomes more 'plastic' and harder to eradicate with conventional therapies. Taking an engineering view, I propose to study the cell as a 'computational system' in order to understand how PIK3CA is wired to regulate cell plasticity, and how this changes according to different conditions - specifically focussing on models of the breast and the vasculature. To succeed, I will collaborate with drug development experts and computer scientists who will teach me how to analyse new types of experimental data that can be used to predict optimal therapeutic strategies for cells with genetic PIK3CA defects.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_03255,Medical Research Council,MRC,The use of Advanced MRI techniques to evaluate antenatal lung development.,"Pulmonary hypoplasia is a congenital condition in which development of the lungs is incomplete. This results in lungs that are too small for efficient gas exchange in postnatal life. It affects 1:1000 pregnancies and is lethal in over 50% of cases. It is associated with conditions such as second trimester premature rupture of membranes, congenital diaphragmatic hernia or certain congenital heart diseases. At present ultrasound and conventional MRI scans provide the mainstay of antenatal lung assessment and are used to prognosticate whether the child is likely to survive. However these scans only evaluate overall lung size and do not provide insight into tissue microstructure or function. Advanced MRI techniques (deformable slice to volume reconstruction, motion corrected diffusion and T2* imaging) facilitate more accurate assessment of lung size and vasculature, and can assess tissue microstructure and oxygenation potentially reflecting alveolar structure and tissue perfusion. This project aims to evaluate lung development with advanced MRI techniques in uncomplicated pregnancies and those at high risk of pulmonary hypoplasia. Methods 100 women with uncomplicated pregnancies and 70 with conditions at high risk of pulmonary hypoplasia will be recruited from four tertiary referral units. MRI imaging will be undertaken including T2, T2* and diffusion sequences. Outcome data including survival, surgical interventions, surfactant or supplemental oxygen therapy will be recorded. Pulmonary function tests will be performed at term equivalent age from three units. Data will be postprocessed to generate lung volumes, mean T2*, fractional anisotropy and apparent diffusion co-efficients. Normal ranges during gestation for each parameter will be generated and conditions at high risk of pulmonary hypoplasia will then be compared. In the future we hope this knowledge may help improve and individualize counselling, and evaluate surgical and medical interventions.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_15502,Wellcome Trust,,The use of global connectivity estimates in real-time models of international infectious disease spread,"Human mobility plays an important part in the spread of infectious diseases. Mathematical models can assess the risk that an emerging outbreak will spread internationally, providing decision-makers with information to support early surveillance and control measures. In this project I will aim to improve how well these models capture international mobility patterns by exploring the suitability of different measures of connectivity. I will compare flight passenger data (which is commonly used in international infectious disease spread models) with alternative transport passenger statistics and novel data, such as location data from mobile phones. I will use these data sources (both individually and in combination) in models to make predictions of the risks of imported and exported disease cases, and assess how well these different models can retrospectively predict the global spread of COVID-19. I will use these findings to develop a statistical model and tools that are ready in advance of future outbreaks to make rapid assessments of the risks that they will spread geographically. The project will lead to more realistic models of international infectious disease spread and thus improve the information that is available to support decision-makers in controlling future outbreaks before they become widespread.",,2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY),GENERIC HEALTH RELEVANCE;INFECTION HRCS22_07045,Medical Research Council,MRC,Therapeutic targets for the effective psychological treatment of trauma sequelae symptoms and psychosis in patients with comorbid Schizophrenia Spectrum Disorder and Post-Traumatic Stress Disorder: Psychological and neural mechanisms.,"Aims: We will look at a specific talking therapy to help with a mental health problem that can develop following traumatic events, Post-Traumatic Stress Disorder (PTSD), in people with psychosis symptoms (which includes hearing voices and having unusual beliefs). We aim to find out how therapy works by looking at changes in the mind (trauma-related psychological processes) and in the brain (underlying neural pathways). We will also look at whether the therapy works in the same way for PTSD and psychosis symptoms. _x000D_ _x000D_ Background: PTSD symptoms following a trauma include having nightmares and flashbacks, where the event is relived in the here and now, and feeling fearful or on edge. There are four main ways in which PTSD symptoms develop: trauma memories are stored differently to everyday memories, meaning they are very intense and easily triggered; threatening beliefs about the self and others develop (e.g., “I am weak”; “people are dangerous”); being on the look-out for threat increases (called ‘hypervigilance’); and people automatically shut-off from their emotions (called ‘dissociation’), which is a way of protecting ourselves from extreme threat. Talking therapies for PTSD work by changing these four mechanisms._x000D_ _x000D_ Research has shown that a history of trauma (especially abuse and neglect) increases the risk of developing psychosis symptoms, and these are often related to the trauma (e.g., hearing the voice of their past abuser). We have integrated the standard talking therapies for PTSD and for psychosis (trauma-focused cognitive-behaviour therapy for psychosis; TF-CBTp), for people who present with both. We will test if TF-CBTp works in a related study, the STAR (Study of Trauma And Recovery) trial. The current study will allow us to find out if it works by changing the above four mechanisms, and whether those changes lead to a decrease in psychosis as well as PTSD symptoms._x000D_ _x000D_ Design and methods: We will recruit participants from the STAR trial over three years, which will include 300 patients across five sites in the UK. We will measure the four mechanisms in two ways: Experience Sampling Methodology (ESM), which uses a mobile phone app over a six days period to capture people’s symptoms and experiences as they unfold in their daily life; and brain scans (using a technique called functional magnetic resonance imaging, fMRI) to look at which brain processes are involved while patients carry out memory and attention psychological tasks. 200 patients will do the ESM and 80 will do the fMRI, half of whom will be receiving TF-CBTp, lasting nine months, in addition to their usual care, and the other half just their usual care. Patients will do this twice: when they start the STAR trial and nine months later. We will compare the changes in the ESM and fMRI responses over time across the two groups, and how those relate to changes in PTSD and psychosis symptoms._x000D_ _x000D_ PPI, impact and dissemination: PPI in the STAR trial and this study involves consultation with experts-by-experience in the design and delivery of the study, and in making sense of the results and how to share them. We have a long history of PPI in our clinics, research, training, and sharing of our work. Understanding how the therapy works will allow us to improve future interventions to target only those mechanisms that are important. We will share our results in academic journals and clinical training, including a therapy manual, to be published by the STAR trial team.","Research Question: To enhance the effectiveness of psychological therapies for psychosis it is necessary to identify specific targets for therapeutic intervention. We will establish which psychological and neural mechanisms must be targeted to successfully treat the trauma sequelae symptoms of patients suffering from schizophrenia disorders, and whether targeting these mechanisms influences core positive symptoms of psychosis (hallucinations and delusions)._x000D_ _x000D_ Background: Research has shown that traumatic experiences play a causal role in the development of schizophrenia disorders. A substantial minority of schizophrenia patients also suffer from symptoms of post-traumatic stress disorder (PTSD). Studies of PTSD patients without schizophrenia have shown that these symptoms are caused by four neural/psychological mechanisms: abnormal encoding of trauma memories; dysfunctional cognitions, hypervigilance for threat, and dissociation. Psychological treatments that target these mechanisms are effective PTSD treatments._x000D_ _x000D_ Objectives: We will identify which neural and psychological mechanisms must change in dual diagnosis schizophrenia-PTSD patients for the effective treatment of their trauma sequelae symptoms. We will also determine whether influencing these mechanisms impacts on the occurrence of these patients’ psychotic symptoms._x000D_ _x000D_ Methods: We will recruit our participants from the STAR (Study of Trauma And Recovery) trial, which will evaluate the effectiveness of Trauma-Focused Cognitive Behaviour Therapy for psychosis (TF-CBTp) in 300 patients at 5 sites. Half will receive TF-CBTp for 9 months and half will receive usual treatment. In this sub-study we will measure key psychological and neural processes at patients’ inception into the trial and 9-months later (coinciding with the end of therapy in the TF-CBTp group), using two methods:_x000D_ _x000D_ 200 patients will take part in experience sampling, a well-tested and well-tolerated method that allows psychological processes to be measured in everyday life. During testing phases soon at inception and at follow-up they will be issued with smart phones programmed to bleep 10 x a day at pseudorandom intervals over 6 days. On hearing a beep, they will be presented with a series of questions designed to measure recall of traumatic events, negative cognitions, hypervigilance and dissociation._x000D_ _x000D_ 80 patients will undertake an fMRI protocol, with which we will measure neural responses when encoding memories, when seeing cues related to traumatic experiences and while judging threatening faces._x000D_ _x000D_ Our design will allow us to measure how these specific mechanisms change in response to TF-CBTp, the extent to which these changes predict reductions in PTSD symptoms and whether the same processes also influence psychotic symptoms in daily life._x000D_ _x000D_ Timeline: The project will be completed in three years._x000D_ _x000D_ Dissemination and impact: We will be able to devise ways of enhancing TF-CBTp for schizophrenia-PTSD patients; our work will therefore inform future clinical trials in terms of intervention design and outcome variables. Our findings will inform the design of future interventions for the much wider group of schizophrenia spectrum patients who, although experiencing trauma, do not meet full PTSD criteria. We will disseminate our findings in high impact psychiatric journals, at major psychiatric and clinical psychology conferences, and at special dissemination events for people with lived experience of psychosis",5.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_11708,Economic and Social Research Council,ESRC,This is My face: Re-signifying HIV stigma through participatory visual methods,"This ESRC fellowship will consolidate my PhD (and award-winning research outcomes) by strengthening my track record of publications, expanding on existing impact and knowledge transfer of my research and its pioneering method, and by strengthening opportunities for academic continuity. Objectives: 1.To extend my work's reach and impact by completing a manuscript monograph (first draft) which will be pitched to publishers, academics and stakeholders, and with which I will secure a publishing contract. 2.To develop a strong record of publications by producing two journal articles. 3.To produce a multimedia and interactive website to advance my pioneering work. 4.To strengthen networks with relevant stakeholders, by holding workshops and knowledge exchange sessions with a wide range of stakeholders. 5.To lay ground for the co-development of a research grant bid with colleagues at Sussex and Goldsmiths. Details about how these will be met is explained in relation to the outputs: - Visual Monograph: It departs from my PhD photo-book, which contains images and texts created by people living with HIV in Chile, and which revealed the impact of HIV stigma and the centrality of narratives for sense-making. This data is part of my doctoral research and participant consent is already secured. The monograph will offer an anthropological analysis through first-person accounts, which emerged from participants who had lived with HIV for only 6 months up to those who were diagnosed more than 30 years ago. This wide range of narratives will provide opportunities to analyse continuities/discontinuities in terms of stigma, amidst the rapid change in antiretroviral therapy. - Journal articles: I will complete two publications in order to establish my track record at world-leading journals: ""The value of non-disclosure and the risk of silence: HIV as biographical disruption in a post-dictatorship context"", for the Journal of Medical Humanities; and ""From the Field to the Screen: Reflexive Practices and Collaborative Methods"", for the Journal of Visual Anthropology. - Workshops: I will co-design and run 2 workshops with UNAIDS Fast-Track City in the UK (Brighton), with the Association for the Wellbeing of People Living with HIV (AWPHIV) in Chile. This last workshop will take place in Santiago, where I conducted fieldwork and where an ""HIV epidemiological emergency"" has been declared. The events' purposes will be to disseminate findings, knowledge transfer with relevant actors in the field, and strengthening and building networks in order to promote further impact and collaborations to influence policy-making. - Website: The website will showcase outcomes of my pioneering work with participatory visual methods to communicate these research findings in multi-media form. The website will provide space for knowledge exchange in the form of open access contributions-between academics, relevant stakeholders, and people living with HIV and their families. At the same time, it will invite others who are HIV+ to create their own photographic representations of their experiences with HIV and stigma. On this website, researchers and different organisations (University of Sussex, Pontifical Catholic University in Chile; and UNAIDS Fast Track city and AWPHIV, respectively) will strengthen collaborations between Chile and the UK. with the objective of advancing knowledge transfer of my PhD method, linking communities and academic audiences. This will be an important opportunity for knowledge transfer and the impact of my project internationally, with the contribution of UNAIDS Fast-Track City programme. - Research grant bid: With my mentors, we will lay ground for the development of a further long-term proposal to examine the continuities/discontinuities around experiences of people living with HIV from a multi-sited perspective. This grant bid will be presented for an ESRC research grant, significantly extending my academic development.","""This is My face: Re-signifying HIV stigma through participatory visual methods"" explores how people create meaning of the ""biographical disruption"" caused by an HIV diagnosis, within a context that limits opportunities for sense-making. When confronted with ""existential uncertainty"", sharing narratives with others becomes a crucial strategy to understand and create meaning. Although in the UK there is strong advocacy to end HIV stigma, in other countries like Chile, stigma is reinforced; which prevents people from sharing experiences with others. My project explores the possibilities of pioneering visual methods as a way to facilitate the narratives of people living with HIV in contexts where their expression is limited. As part of this PDF, I will produce a series of outcomes around HIV narratives, looking at collaborating with a wide range of audiences, and consolidating my PhD work extensively. First, I will produce a visual monograph (based on my unpublished PhD photo-book) which will weave autobiographical photos and texts created by people living with HIV in Chile as part of my PhD. This monograph will highlight the need of narratives for sense-making and expand existing knowledge on the intersections of visual and medical anthropology. There is no academic text dealing with HIV stigma in Latin America through visual participatory methods. The monograph will be pioneering in this specific field, and will target a wide audience including academics, HIV organisations, and relevant stakeholders. It will be pitched to publishers such as Routledge who can reach with and beyond academia, and later to Verso and Pittsburg. By producing a multimedia website to disseminate research findings, I will create a platform for collaboration between people living with HIV, scholars, and relevant stakeholders. I will mobilise my existing networks to contribute to the website's visibility and content: Global Fund Partnership Forum, UNAIDS, academic research groups, HIV organisations in Chile and the UK, among others. I will co-organise two workshops: one in Chile with Association for the Wellbeing of People Living with HIV, and one in the UK with UNAIDS Fast-Track city in Brighton. The workshops will expand public engagement and promote knowledge exchange, while strengthening local approaches to promote HIV sense-making at national and international levels. I have collaborated extensively with these organisations, and they are keen to co-design the events and welcome a wide range of stakeholders to further influence policy. By producing two journal articles and presenting at world-leading conferences, I will disseminate findings related to my pioneering method, contributing to discussions around methodological approaches to HIV, and offering opportunities for further analysis on HIV narratives. Through the collaboration with the UN Fast-Track City Project for HIV prevention in Brighton, I will produce an important site for knowledge transfer and impact of my work. Additionally-considering the wide work on Medical and Visual Anthropology at Sussex and Goldsmiths-we will lay ground for a multi-sited research grant bid about experiences of illness through participatory methods, bringing together researchers from the Centre for Cultures of Reproduction, Technologies and Health (CORTH), Centre for Innovation and Research in Childhood and Youth (CIRCY) and the Institute for Development Studies (IDS). This project is timely and urgent (see Case for Support), and by connecting a wide range of audiences, I will extend the impact of my public engagement work, expand on knowledge transfer, and lay ground for academic continuity and further research collaborations. Sussex will be the perfect environment to enrich these outcomes, by collaborating with Dr. Paul Boyce and Prof. Day and with other colleagues at Sussex and Goldsmiths who are producing research in the same field, and/or with similar interdisciplinary and ethical considerations.",7.1 INDIVIDUAL CARE NEEDS,INFECTION HRCS22_09286,"Chief Scientist Office, Scotland",CSO,Time critical precision medicine for acute critical illness using treatable trait principles: Data enabled adaptive platform trial with embedded biological characterisation [TRAITS Program],"Our project aims to enable time-critical precision medicine (TCPM) to be used in critically ill patients presenting to emergency departments and Intensive Care Units (ICUs) throughout Scotland. We will develop a collaborative hub based at The University of Edinburgh, to carry out PM Randomised Clinical Trials (RCTs) (supported by data from the NHS). This will mean TCPM can be potentially used at the bedside within 5 years from start of this project. Precision Medicine (PM) refers to treatments that take individual variability into account. PM is growing in use in cancer care, providing precise treatments for patients based on their genetics or proteins. Currently, it isn’t used in ICU because patients admitted to ICU have life threatening illnesses that need treatment immediately and despite current treatment approaches 40% die within 60-days of admission to ICU. In this project, to enable TCPM in ICU, we have designed a novel clinical trial that will use routinely collected data and test multiple treatments simultaneously. To select patients for this TCPM trial, we will use the results of a blood test done routinely in all patients admitted to ICU needing breathing support, namely low lymphocyte counts. We plan to assess whether the two lead treatments (recombinant IL-7 and trimodulin) improve survival when administered with usual care. There is preliminary evidence that reversing the effects low lymphocyte count with these two treatments may improve survival in ICU patients. Consent to participate will be from patients, or their Legal Representative where patients lack capacity. Knowing what happens to participants after they have been recruited is important. Our patient assessments will include short-term outcomes (such as mortality, health related quality of life) and longer-term outcomes such as rehospitalisation. By using routinely collected NHS data to help us understand what happens to patients after they have been discharged from ICU, we will be reducing the burden of trial follow-up for patients.",,6.1 PHARMACEUTICALS,RESPIRATORY HRCS22_20534,Wellcome Trust,,Time to Decide.,"The objective of this proposal is to investigate the temporal dynamics of simple perceptual decisions in Drosophila, with a view toward uncovering general mechanisms of neural information processing at timescales from hundreds of milliseconds to several seconds. In his classical essay The Problem of Serial Order in Behavior, the psychologist Karl Lashley emphasized the ubiquity of brain processes that unfold over time: Temporal integration is not found exclusively in language; the coordination of leg movements in insects, the song of birds, the control of trotting and pacing in a gaited horse, the rat running the maze, the architect designing a house, and the carpenter sawing a board present a problem of sequences of action which cannot be explained in terms of successions of external stimuli. In spite of the ubiquity of the problem, there have been almost no attempts to develop physiological theories to meet it. Although Lashley wrote this passage more than 60 years ago, the fundame ntal problem of how activity sequences are generated remains largely unsolved. Temporal processing is integral also to decision-making because the information necessary to commit to a choice is rarely available all at once but must be gathered over time. A large literature, whose beginnings stretch back to the 19th century, documents systematic variations in the speed of perceptual judgments with stimulus strength: easy decisions, based on strong, unambiguous sensory data, tend to be fast; di fficult decisions, based on weak or conflicting data, tend to be slow. This difficulty-dependent cost of decision time is thought to reflect an underlying need to construct time-averaged sensory representations. Just like engineers average signals over time to reduce the effects of contaminating noise, the brain appears to improve its signal-to-noise ratio by integrating information from sequential samples. The duration of the integration period depends on the quality of the sensory data and the desired response accuracy or confidence. Beautiful as these ideas are, the neural mechanisms that allow neurons to accumulate information, compare the accumulated signal to a response criterion, and discharge behaviour when the criterion is met remain elusive. The complexity of vertebrate brains, the difficulty of molecular interventions in primates, and the effort required to generate and analyse genetic variants have presented serious barriers to progress. These barriers have begun to ero de with our recent discovery that fruit flies, like mammals, take longer to commit to difficult perceptual choices than to easy ones, and that quantitative relationships link speed, accuracy, and task difficulty. The exact mathematical form of these relationships is predicted by integrator models that were originally formulated to describe human behaviour. Drosophila thus appears to accumulate sensory data in the lead-up to a choice, making this type of temporal processing amenable to genetic di ssection. A small screen of candidate genes uncovered an unexpected role for FoxP in decision-making. FoxP mutants are slower to commit than wild-type flies, and, despite taking longer, are also more error-prone - precisely the constellation of symptoms one might expect in an a",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,NEUROLOGICAL HRCS22_07888,Department of Health and Social Care,NIHR,Tofacitinib for treating active ankylosing spondylitis (ID3865),"Axial spondyloarthritis belongs to a clinically heterogeneous group of inflammatory rheumatologic diseases which share common genetic, histological and clinical features (also including psoriatic arthritis, arthritis associated with inflammatory bowel disease, reactive arthritis and undifferentiated spondyloarthritis). Axial spondyloarthritis involves inflammation of the sacroiliac joints and spine. If inflammation is visible on xray (as erosions, thickening of the bone, or fusion of joints), the disease is classified as radiographic axial spondyloarthritis (also known as ankylosing spondylitis). If x-rays of the sacroiliac joints and spine are normal, but there are other objective signs of inflammation (elevated C-reactive protein or evidence on magnetic resonance imaging) the disease is classified as nonradiographic axial spondyloarthritis._x000D_ _x000D_ The clinical symptoms of axial spondyloarthritis can vary from person to person, but usually develop slowly over several months or years. The main symptoms can include back pain, usually inflammatory in nature, arthritis (inflammation of the joints in other parts of the body), enthesitis (inflammation where a bone is joined to a tendon), and fatigue. Extra-articular manifestations include uveitis, inflammatory bowel disease and psoriasis. The onset of symptoms typically occurs in the third decade of life, but it can be 7– 10 years before a diagnosis is made. Many patients with mild disease may remain undiagnosed. _x000D_ _x000D_ Around 200,000 people have been diagnosed as having ankylosing spondylitis in the UK. The prevalence is thought to range from 0.05% to 0.23%, representing approximately 2,300 new diagnoses each year in England and Wales. Ankylosing spondylitis is about 3 times more common in men than in women.[1],[2]_x000D_ _x000D_ Conventional therapy for radiographic axial spondyloarthritis includes antiinflammatory treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy. Tumour necrosis factor-alpha (TNF-alpha) inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab) are typically used when the disease has not responded adequately to conventional therapy. NICE technology appraisal TA383 recommends adalimumab, certolizumab pegol, etanercept, golimumab and infliximab as treatment options for adults with severe active ankylosing spondylitis in adults whose disease has responded inadequately to, or who cannot tolerate NSAIDs. Biosimilar versions of adalimumab, etanercept and infliximab are available. Infliximab is only recommended if the least expensive infliximab product is used. NICE technology appraisal 407 recommends the interleukin17A (IL-17A) inhibitor secukinumab as an alternative to, or after inadequate response to TNF-alpha inhibitors._x000D_ _x000D_ References_x000D_ 1 National Ankylosing Spondyloarthritis Society: Facts & Figures. Available at https://nass.co.uk/about-as/as-facts-and-figures/ Accessed December 2020_x000D_ 2 Department of Health (2006) The musculoskeletal services framework. Accessed December 2020",To appraise the clinical and cost effectiveness of tofacitinib within its marketing authorisation for treating active ankylosing spondylitis.,6.1 PHARMACEUTICALS,MUSCULOSKELETAL HRCS22_03164,Medical Research Council,MRC,Towards an in vivo functional dissection of the role of microglia and macrophages in Alzheimer’s disease aetiology,"The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. In vivo study of microglia/MØ function is essential to understand how alterations in basic physiological processes, mostly implicated by the genetics of disease (from cell signalling, endocytosis and phagocytosis, lysosomal functions, adhesion and migration, proliferation and renewal), contribute to dysfunctions that may predispose to disease. The in vivo context is essential for the study of MØ phenotype (discussed below), provides a bridge between cell culture and 3d models and human disease, and importantly is amenable to study of disease alterations and testing of potential therapeutic interventions. A collaboration has been established with Gareth Howell (GH) at the Jackson Laboratories (Honorary Cardiff Senior Research Fellow), who has a large US National Institute of Ageing-funded AD model generation programme. Based on Prof. Williams’ observations, GH introduced the protective SNP from PLCG2 into the corresponding highly conserved sequenced in mouse Plcg2 using CRISPR technologies in C57BL/6 mice. The fertility of these mice has been confirmed and they should be shipped to Cardiff in Q2 of 2017. Our collaboration places us in a strong position to rapidly move from identification of novel disease associated variants (Prof. Williams’ ongoing independent genetic discovery programme) to generation of novel mouse models for in vivo dissection of their mechanistic role in diseases susceptibility or protection.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_12996,Cancer Research UK,CRUK,Tracking Cancer Evolution through Therapy (Tracer X),"TRACERx is an international prospective observational clinical trial with 6 confirmed participating Experimental Medicine Cancer Centres (ECMCs). TRACERx will study the non-small cell lung cancer (NSCLC) evolutionary mutational landscape and the dynamics of intratumour heterogeneity (ITH) over time combined with detailed clinical and histopathological annotation for each patient. TRACERx will acquire tissue following informed consent from sites of metastatic disease, as part of routine clinical practice, during the disease course for genetic analysis to track the tumour evolutionary dynamics. We anticipate that serial exome re-sequencing technologies together with low coverage whole genome ‘skim’ sequencing, to decipher structural rearrangements such as the EML4-ALK and ROS1 fusion genes, will help decipher the frequency of branched evolutionary growth in NSCLCs, and when in the metastatic process distinct somatic events and the initiation of genomic instability are acquired. Our goal is to identify the impact of ITH upon clinical outcome, trace the dynamics of tumour evolution over time through non-invasive approaches and ultimately through deciphering tumour evolution on a patient-by-patient basis develop a better understanding of the genetic events that contribute to drug resistance, metastases and tumour adaptation. The relationships between heterogeneous tumour neo-antigen expression and immune effector cell tumour infiltration will also be established. Characterising ITH with sequential tumour biopsies and blood-based analyses of tumour DNA over time will enable us to study the capacity of adjuvant therapies to exacerbate genomic instability and to identify novel factors implicated in drug resistance, tumour metastasis and immune cell effector function driven by tumour neo-antigen exposure. Finally, by mapping tumour growth in greater detail and reconstructing evolutionary histories of individual tumours, we hope to identify mechanisms contributing to ITH in NSCLC. Anonymised but clinically annotated data from these analyses will be made publicly available to enable dissemination to the wider scientific community.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_14272,Autistica,,"Tracking and evaluating outcomes from Ambitious about Autism's Education to Employment initiative (Bath)","Evaluating AaA's programme which aims to support autistic people in higher education into employment.","Evaluating AaA's programme which aims to support autistic people in higher education into employment.","8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;7.1 INDIVIDUAL CARE NEEDS",MENTAL HEALTH HRCS22_18714,Cancer Research UK,CRUK,TransRAMPART: Renal Adjuvant MultiPle Arm Randomised Trial - Translational Research,"Background Renal cell cancer (RCC) is the most lethal urological malignancy with 50% of patients dying from their disease. Overall, 30% of patients with initially localised RCC, having seemingly curative surgery, will develop incurable metastatic RCC (mRCC); this proportion increases to 75% in patients with high risk disease. As such, there is considerable interest in adjuvant therapies for post-nephrectomy RCC patients to prevent the development of mRCC. RAMPART is a UK academic-led, international Multi-Arm Multi-Stage (MAMS) platform trial in intermediate and high risk localised RCC patients. Patients are randomised between active monitoring (observation by clinical and radiological means), 1 year of the PD-L1 inhibitor durvalumab or a combination of 1 year of durvalumab and 2 cycles of the CTLA-4 inhibitor tremelimumab. TransRAMPART is the translational study linked to RAMPART. Aims The aim of TransRAMPART is to collect tissue, blood and urine samples from patients randomised to the RAMPART trial for the development of novel molecular markers of prognosis, minimal residual disease, treatment response, resistance and toxicity. Methods A comprehensive, longitudinal sample collection including peripheral blood mononuclear cells (PBMCs), double spun plasma, urine, FFPE tissue blocks and fresh frozen tissue. Samples will be collected at the time of nephrectomy, before first treatment administration and throughout patient follow-up. Additional samples will be collected upon recurrence and development of Grade 3 infusion-related toxicities. Sample sizes have been based on a pre-planned, powered analysis of predictive ability of PD-L1 status for response to adjuvant immune checkpoint inhibitors. How results from this research will be used TransRAMPART will provide a unique opportunity to address which of our RCC patients are most in need of adjuvant checkpoint inhibitors; predict the patients who will respond to these agents, identify when and how resistance may develop and pre-empt patients who will experience significant toxicity. To date a number of biomarkers, including PD-L1 expression and tumour mutational burden, have emerged as predictors of benefit from immune checkpoint blockade in other solid tumour types. Given the size of the TransRAMPART cohort and the comprehensive sampling of tumours we would like to carry out we are in a unique position to identify biomarkers of response in this patient group which could ultimately serve both adjuvant and metastatic RCC populations, as well as to identify recurrent mechanisms of resistance and immune-related adverse events. We have a series of planned scientific approaches for the TransRAMPART biorepository incorporating genomic, transcriptomics, proteomics, metabolomics and immunology.",,4.5 RESOURCES AND INFRASTRUCTURE (DETECTION),CANCER AND NEOPLASMS HRCS22_14893,Versus Arthritis,,"Transcriptomic, Proteomic and Bioinformatics Analyses of Cell-Based Therapies for Cartilage Injuries in Humans","ASCOT is a prospective randomised trial nearing completion, it is designed to determine if the modification of standard autologous chondrocyte implantation (ACI) using other cell types will improve clinical outcome. The trial compares autologous chondrocytes with either autologous bone marrow-derived stromal cells (BM-MSCs) or a combination of the two when implanted beneath either a periosteal or a collagen membrane for the treatment of articular cartilage defects in the knee (Richardson et al., 2017). The key goals for the proposed PhD project will be to: Map the mRNA, miRNA and protein profiles of the ASCOT trial transplanted cell population. Transcriptomic and proteomic data is to be made publicly available on an online repository to enable additive benefit to the broader scientific community. Identify transcriptomic and proteomic signatures and altered biological pathways that relate to functional and structural outcomes in the ASCOT trial cohort. Use a systems biology approach to identify molecular differences (a) between BM-MSCs and chondrocytes and (b) across donors with demographic features known to influence the outcome of these cell-based therapies e.g. between cells from different genders. Training and development of an early career researcher with a desirable, multimodal skillset, which includes innovative scientific approaches to improve cell-based therapies for musculoskeletal injuries and diseases.",,5.2 CELLULAR AND GENE THERAPIES;6.2 CELLULAR AND GENE THERAPIES,MUSCULOSKELETAL HRCS22_22816,The Academy of Medical Sciences,AMS,Transforming diagnostic certainty in developmental disorders using CRISPR-based saturation genome editing,"Aims and objectives: We will apply saturation genome editing to the gene DDX3X to functionally classify all single nucleotide variants (SNV) and improve diagnostic certainty. There is an urgent clinical need to improve the functional interpretation of genetic variants. This is required for the timely genetic diagnosis of developmental disorders. However, for most proteins, we do not know the functional consequence of the majority of genetic variants. This impairs the clinical interpretation of previously unobserved variants. Advances in CRISPR-Cas9 technologies allow us to specifically engineer all possible SNV in a gene at its endogenous locus. We propose to combine these technologies with in vitro massively parallel genetic screens to interrogate the functional significance of hundreds of genetic changes in a single experiment. This is known as Saturation Genome Editing (SGE). The HAP1 cell line is near-haploid and derived from a chronic myeloid leukaemia line. Haploidy simplifies the design and interpretation of genetic screens. From publicly available data we have identified genes in which loss of function mutations cause developmental disorders and are essential in HAP1. We propose to apply SGE to these HAP1-essential genes in order to interrogate the functional consequence of every possible SNV. This grant will fund SGE of DDX3X, an X-linked RNA helicase of the DEAD-box protein family. Heterozygous loss of function mutations in DDX3X are the commonest genetic cause of intellectual disability in females. We will validate our results in a neural cell line, and by comparison with known clinical and population genetic variation.","Genes act as a code which is ‘read’ to make proteins, the building blocks of cells. In 2020, we still do not properly understand our genetic code. We all carry genetic changes, but most do not cause problems. However, in a genetic condition, a change in the genetic code changes the function of a protein and alters a child’s development. We check a person’s genetic code when we suspect that they have a genetic condition. Unfortunately, we cannot always predict which genetic changes will alter a protein’s function. Therefore, it can be difficult to decide whether a child’s difficulties are due to the genetic changes that we have observed. This often makes diagnosis difficult. This is particularly true in young children or unborn babies, as the true extent of their difficulties may not yet be fully known. However, diagnosing children when they are young can improve treatment and reduce the disability caused by a genetic condition. Families tell us that earlier and quicker diagnosis would be useful to them. Our experiment aims to understand better which genetic changes will cause a child difficulties. In our experiment we will artificially change the genetic code in human cells grown in a dish. We will test thousands of changes to identify which ones prevent proteins from working properly. This will help us to understand the impact that these genetic changes could have in a child. This will help doctors to interpret genetic tests and diagnose children earlier.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CONGENITAL DISORDERS HRCS22_06622,Department of Health and Social Care,NIHR,Transforming outcome measures in plastic surgery through computer science,"Background Cleft lip and/or palate (CL/P) affects 1/700 births and has lifelong sequelae even after treatment. There is limited high-quality evidence underpinning CL/P management, and the Eurocleft study showed undesirable treatment variation across Europe. An international consensus-based core outcome set (COS) has been proposed to evaluate CL/P treatments' effectiveness and value. Subscales of CLEFT-Q, a patient-reported outcome measure (PROM) are central to the COS. CLEFT-Q contains 110 questions within 12 subscales, plus a nine-question checklist. Our PPI team felt this is too burdensome, as the PROM is intended for children as young as eight.The rating of facial photographs by a panel of surgeons is considered a robust method of assessing aesthetic outcomes of CL/P surgery in patients too young to complete PROMs. However, this method is expensive and impractical.Research Question/Aim: To improve outcome measurement in CL/P using contemporary psychometrics and computer science. Objectives To develop computerised adaptive testing (CAT) software for CLEFT-Q that accurately predicts respondents' scores from fewer questions To evaluate machine learning models for autonomously grading photographic outcomes of CL/P surgery Methods I have already programmed a pilot unidimensional CAT that reduces the total number of questions from 110 to a mean of 43, predicting scores with a 97% accuracy. Using the international CLEFT-Q field test data, I will further study the structural validity of CLEFT-Q to inform the development of more sophisticated item response theory models (bifactor and second order structural equation models) that could improve these results. Once these models have been optimised, I will evaluate them in simulated trials that compare the number of questions administered in the full-length CLEFT-Q and its CAT counterpart. User interfaces will be developed in Concerto: an open-source CAT testing platform. In a PPI-co-developed workstream, I will use an existing platform (Face++) to process 150,000 pre and post-operative facial photographs of patients with CL/P, which have previously been rated by surgeons. This will return numerical values for each photograph, representing features such as symmetry and distances between facial landmarks. I will analyse this dataset with regularised regression models and test these models' ability to predict surgeon ratings using independent variables derived from photographs.Impact This project will deliver an optimised CLEFT-Q CAT and a platform to run it, which will support the uptake of CLEFT-Q in research and clinical practice, as recommended in the COS, within 5 years. This is expected to raise standards of patient-centred care, research and clinical commissioning internationally. Automating the assessment of facial photographs could provide a cheap and consistent means of assessing surgical outcomes in children too young to complete CLEFT-Q CAT.Dissemination Dissemination will be through scientific meetings and journals, including co-presentation with PPI representatives. Collaboration with ICHOM will support the deployment of our instruments on a global scale. Patients and the public will be updated via the Q-portfolio website, social media and charity newsletters. Our experience of working with patients and the public will be presented at scientific meetings and published on the NIHR INVOLVE website.","Aim The aim of this project is to improve how we measure the outcomes of treatments for cleft lip and/or palate. Background One in 700 babies are born with a gap in their lip and/or the roof of their mouth. This is called cleft lip and/or palate (CL/P). It can cause long-term difficulties with feeding, hearing, speaking, appearance and emotional wellbeing. Clefts are treated in many ways. This typically includes a series of operations as the child grows. Different surgeons recommend different operations, but there is little evidence to tell us which operations are more successful than others. It is important to measure how successful operations are to know which ones work best. So far, this has involved doctors' opinions, which are inconsistent. It can also involve looking at scans and other test results. But this isn't necessarily what matters most to people born with CL/P. Recently, a team of researchers asked people born with CL/P what matters most to them. From this, they made a questionnaire to score these things. It is called CLEFT-Q.Overall, CLEFT-Q has 119 questions. These are arranged into groups, e.g. questions about 'lips' 'speech' 'mood' etc. Some groups of questions are not always suitable. For example, questions about lips are skipped for somebody with only a cleft palate. We discussed this with our research partners (children and adults with CL/P, parents of children with CL/P, and members of the public). They felt CLEFT-Q was still too long. Children under eight are too young to use CLEFT-Q. Instead, their outcomes are often scored by groups of doctors looking at photographs of their face before and after surgery. This is expensive and not always practical. Methods I am making computer programs that shorten CLEFT-Q. These are called computerised adaptive tests (CATs). The programs pick only relevant questions for each person, adjusting based on the answers they've already given. A CAT can predict someone's final CLEFT-Q scores without asking all the questions. This would make CLEFT-Q easier to complete. To make and test the CAT we will study patients' CLEFT-Q answers that were collected around the world by different research teams. I am also making an 'artificial intelligence' computer program that can measure the outcome of surgery by looking at photographs. I think this will be cheaper, quicker and more consistent than doctors' measurements. To do this I will use 150,000 photos of patients with CL/P before and after they had surgery. The photographs have already been studied by surgeons who rated how well they think the surgery went. My program will learn what a good or bad outcome is by measuring different parts of the face and working out patterns that lead to an outcome being considered good or bad.Patient and public involvement My research partners have already been involved in the project design and helped to write this application. I will invite them to contribute to all further stages of this research. This includes making decisions about what I should work on and how I should do it. They will ensure we make the programs as user-friendly as possible. To make this easier for them, most of our meetings will be done over video-calls or at charity events. We will write up our experience of working together. This will be published on the NIHR INVOLVE website, and I will invite research partners to join me in presenting this at relevant meetings. Dissemination I will keep the CL/P community updated through the CLEFT-Q website, social media and charity newsletters. I will also present our findings at scientific meetings and publish the results in scientific journals.",6.4 SURGERY;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),ORAL AND GASTROINTESTINAL HRCS22_01287,Medical Research Council,MRC,Transgenic Modelling of Human Prion Susceptibility and Diseases,"In studies now spanning well over a decade we have developed highly specialised transgenic transmission facilities for comprehensive studies of human prion disease under appropriate biocontainment. Species-barrier-free transmission of many forms of human prion disease is available. While excellent, well characterised models are now in routine use, further improvement to these models, and the development of improved models for the assay of vCJD prions are underway. In addition to ongoing basic research into intermammalian and strain-specific transmission barriers and characterisation of the prion strains causing human disease, this facility is being applied to address key public health issues which require human prion bioassay (tissue distribution of infectivity and human prion decontamination for example) and to study putative prion therapeutics. Animal models of a range of inherited human prion diseases are being studied, in particular to determine if prions are produced spontaneously in such animals. The specific aims of this programme are as follows:- To establish the full range of prion strains causing human disease and to attempt to biologically clone these for biochemical study (with programme 6) - To complete our long-term characterisation of intermammalian prion transmission barriers of relevance to public health and to understand the interaction between prion strain diversity and these barriers - To model the human inherited prion diseases and determine whether prions can be generated spontaneously in these models - To generate new transgenic lines as required to model novel human PrP polymorphisms and candidate prion modifier genes (in conjunction with programmes 1 and 2) - To generate transgenic models of frontotemporal dementia (in conjunction with programme 10) - Development and use of standardised models for evaluation of candidate therapeutics - To continue to provide and update the Units Transgenic Core facility and support animal research throughout the Unit",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,NEUROLOGICAL HRCS22_18501,Wellcome Trust,,Translating the potential of the urine steroid metabolome to stage NAFLD (TrUSt - NAFLD),"Fat deposition in the liver is now the commonest chronic liver condition, affecting one-in-three individuals. It can lead to liver problems including cirrhosis and liver cancer as well as increasing your risk of heart attacks and strokes. Simple blood tests are often normal, and the current gold-standard test for assessing NAFLD severity is a liver biopsy. This is an invasive procedure that is associated with significant complications, including pain and bleeding. We have developed a urine test that measures natural steroid hormones and provides an accurate reflection of how the liver is functioning in patients with NAFLD. We wish to extend our findings to a large cohort of patients with NAFLD to ensure that our test is accurate and reliable. If successful, our urine test could be used by GPs and hospitals reducing liver biopsies and making a significant advance to patient care.","Fat deposition in the liver is now the commonest chronic liver condition, affecting one-in-three individuals. It can lead to liver problems including cirrhosis and liver cancer as well as increasing your risk of heart attacks and strokes.  Simple blood tests are often normal, and the current gold-standard test for assessing NAFLD severity is a liver biopsy. This is an invasive procedure that is associated with significant complications, including pain and bleeding. We have developed a urine test that measures natural steroid hormones and provides an accurate reflection of how the liver is functioning in patients with NAFLD. We wish to extend our findings to a large cohort of patients with NAFLD to ensure that our test is accurate and reliable.  If successful, our urine test could be used by GPs and hospitals reducing liver biopsies and making a significant advance to patient care.",4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,ORAL AND GASTROINTESTINAL;METABOLIC AND ENDOCRINE HRCS22_01208,Medical Research Council,MRC,Translational Applications of New Insights into Immunoreceptor Signalling,"Goals To understand the cell biology of the leukocyte surface and to use the insights to alter the behaviour of leukocytes in autoimmune settings. The T-cell biology group is working towards an understanding of the biology of the leukocyte surface and the mechanism of receptor triggering, both for its intrinsic cell biological interest and as the basis for developing new types of immunotherapy. For the last several years we have focused on understanding the composition of the T-cell surface and how receptors expressed there are organized and then ‘triggered’ by ligand binding (1-3). The expression of transcripts encoding known cell surface molecules by a human CD8+ T-cell clone was characterized by a transcriptomic approach (SAGE) and the results suggested that existing models of receptor triggering are unlikely to be wrong because key components remain to be discovered (1). Determination of an anti-CD28 superagonistic antibody Fab fragment bound to CD28 (2) provided insights as to how antibody superagonists work and incorporated CD28 into the family of receptors triggered via kinase/phosphatase segregation – a family that includes the T cell receptor (for a review see reference 3). Assembly of proteins expressed at the cell surface has been studied by bioluminescence resonance energy transfer (BRET), which has been used to characterize the quaternary structures of cell surface molecules. Our new experimental framework for detecting transfected receptor dimers revealed that most proteins expressed at the cell surface are likely to be monomers, undermining the notion that important groups of receptors inexorably form dimers (4). Together with our collaborators we have established a new method for studying the organization of native receptor complexes (two-colour coincidence detection). Analysis of the composition of protein complexes on the surface of live T cells has shown that the TCR is monovalent (5). Recent work has focused on determination of the stoichiometries of each key component of the T cell triggering apparatus – MHC class II, CD4, CD45 – and these too have been shown to be monovalent (6). Future research plans Future work will concentrate on understanding receptor triggering by native ligands and by antibodies and to use this knowledge in the development of new receptor agonist-based therapeutic antibodies – for example against inhibitory receptors such as PD-1 that suppress immune responses both in vivo and in vitro. A key objective is to target molecules that may offer new opportunities to intervene in autoimmunity. References: (1) Evans et al 2003 Immunity 19: 213 (2) Evans 2005 Nature Immmunol 6: 271 (3) Davis and van der Merwe 2006. Nature Immunol 7: 803 (4) James et al. 2006 Nature Methods 3: 1001 (5) James et al 2007 Proc Natl Acad Sci USA 104: 17662 (6) James et al. 2011 J Biol Chem. 2011 16:31993",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_05464,Department of Health and Social Care,NIHR,Translational Research to Reduce Mortality from CNS Infections in Africa,"Background: Infections of the central nervous system (CNS) are major causes of mortality in low- and middle-income countries. In sub-Saharan Africa CNS infections are a leading cause of death in HIV-infected adults, accounting for up to 30% of early mortality in ART programmes. Detailed understanding of the aetiology of adult meningitis in this setting is of critical importance to inform diagnostic pathways and treatment strategies. Novel affordable point-of-care diagnostic tests for meningitis, with the ability to detect multiple pathogens simultaneously, are urgently needed to facilitate diagnosis, screening and prevention strategies. And effective treatments are required to improve patient outcomes.Aims and objectives: I aim to improve outcomes of adult meningitis in high HIV-prevalence African settings. My specific objectives are to: (1) Develop a meningitis surveillance network using enhanced molecular diagnostics and metagenomic assays to describe meningitis aetiology, and determine the clinical impact of concurrent CNS pathogens;(2) Validate novel multiplex and rapid meningitis diagnostic technologies community and inpatient settings;(3) Evaluate novel short-course liposomal amphotericin B based treatment for HIV-associated CM in a multi-centre phase-III randomized controlled trial;(4) Perform HLA genotyping, KIR genotyping, and a genome wide association study (GWAS) with linked immune phenotyping in a cohort of HIV-infected individuals with CM and controls.Methods: The proposed research builds on my current meningitis surveillance and diagnostic studies, and an ongoing cryptococcal meningitis treatment trial in Botswana, South Africa, Zimbabwe, Malawi, and Uganda.To determine meningitis aetiology a panel of sequential molecular diagnostic assays will be performed in a cohort of patients with suspected meningitis. CSF samples will be bio-banked for subsequent metagenomic analysis and deep-sequencing to identify previously unrecognized or novel pathogens in meningitis cases without confirmed diagnoses.This prospective meningitis surveillance study will serve as a platform to validate a multiplex PCR-based meningo-encephalitis diagnostic and evaluate the performance of the Biosynex CryptoPS, a novel point of care semi-quantitative cryptococcal antigen detection assay.A multi-centre phase-III randomised non-inferiority trial to determine whether a novel single-dose liposomal amphotericin B treatment is as effective as standard therapy in averting all-cause mortality in HIV-associated CM will be performed. This trial is already funded through the the EDCTP and Joint Global Health Trials Scheme, and will recruit 850 patients at 6 African partner-sites.Within the clinical trial we will investigate host genetic susceptibility to cryptococcal meningitis in a large cohort of patients. A GWAS and HLA and KIR genotyping will be performed to identify modifiable risk factors for CM development and poor outcomes that would be amenable to future clinical intervention trials.Anticipated impact and dissemination: The research findings will enable diagnostic and treatment strategies across Africa to be updated, leading to significant improvements in outcomes from meningitis.The results of the treatment trial have the potential to provide a highly effective treatment option for cryptococcal meningitis that is practical and accessible in Africa with the potential to prevent many thousands of deaths. And advances in understanding of the pathophysiology of cryptococcal infection will inform future patient-targeted immune modulation therapy.","Meningitis and other infections of the brain (or 'central nervous system') are extremely difficult to diagnose and treat. Even in resource-rich settings, these infections cause very high rates of death and disability. In low- and middle-income settings central nervous system (CNS) infections are much more common - particularly in regions with high rates of HIV infection. Individuals infected with HIV are at risk from a very wide variety of different CNS infections, and tend to develop extremely severe illness. The highest rates of HIV infection in the world are seen in east and southern Africa, and in these regions meningitis and other brain infections are a leading cause of death. Unfortunately this has remained the case despite the widespread provision of HIV treatment, probably due to the fact that there are still many people who are not diagnosed with HIV until they have very advanced disease, and increasing numbers of people who are dropping out of HIV treatment programmes or developing resistance to the drugs. Up to 200,000 people are estimated to die from just one form of meningitis called cryptococcal meningitis (CM) every year, and overall infections of the CNS cause up to 30% of all deaths in HIV-infected individuals.To reduce this extremely high death rate several different approached are needed. It is currently not known exactly what infections cause much of the meningitis in African patients, so targeted treatment is not possible; therefore research studies to determine the specific causes of meningitis in Africa are urgently required. It is also critically important to provide doctors in Africa with the correct tools to be able to quickly and effectively diagnose CNS infections in order for the correct treatments to be given. New diagnostic tests are needed. Even with the currently available treatments for meningitis, over half of the patients with these diseases in African settings still die, thus developing new effective treatments is a priority. And finally, a better understanding of the body's response to CNS infections, and the risk factors for disease development and death, would enable the development of entirely novel treatment and prevention strategies.I aim to improve management of adult meningitis in African settings with high levels of HIV. My key goals are (1) to collect information on all patients being tested for meningitis at an African hospital, and run very detailed testing to determine the causes; (2) to evaluate new tests for meningitis capable of testing for many different infections at once and diagnosing infection at the bedside; (3) to test a new treatment for CM, the commonest cause of meningitis in this setting, based on a single very high dose of an existing drug called liposomal amphotericin; and (4) to perform a detailed examination of the patients' immune responses and genetic make up to try to find out why some patients develop CM while some do not, and what factors are associated with death from CM.This work will be based on a series of clinical studies and a large trial of new CM treatment in Botswana, South Africa, Zimbabwe, Malawi, and Uganda. The results of this work will allow treatment guidelines for meningitis to be updated based on accurate data about the causes of meningitis, leading to reductions in the high death rates. An effective new treatment for CM that is easy to administer in African hospitals would save many thousands of lives each year. And better understanding the underlying pathological processes that predispose some people to CNS infections and subsequent death could lead to new treatments and prevention strategies to further reduce the severe toll from these infections in Africa.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS,INFECTION HRCS22_19831,Wellcome Trust,,Transmissible cancer evolution and host interaction,"Transmissible cancers are malignant somatic cell lineages that spread between individuals by the allogeneic transfer of living cancer cells. These cancers, whose three known instances in mammals affect dogs and Tasmanian devils, provide a unique perspective on cancer evolution and host interaction. I will investigate this by deeply sequencing whole genomes from 1100 tumours selected from across each cancer’s range, together with matched bulk RNA sequencing and targeted single-cell RNA sequencing. Time-resolved phylogenetic trees for each clone will be annotated with mutation and gene expression data, and the source and consequence of mutation explored. Host cell contribution to the tumour microenvironment, and its variation across hundreds of tumours, will be assessed using allelic and cell-type deconvolution. Combining genetic, microenvironment composition and clinical data, I will explain how the immunological interface between allogeneic cancer and host varies between individuals, and how this interaction controls the outcome of disease. The inherent heterogeneity and short lifespans of most cancers may obscure their underlying biological patterns. By capturing variation in hundreds of clonally derived tumours inhabiting different hosts, I seek to deeply probe the mutational, evolutionary and immunological principles of cancer.","Cancers are outgrowths of abnormal cells driven by a malignant evolutionary programme and supported by a permissive tumour microenvironment. Most cancers arise from and remain within the bodies of their hosts. Rarely, however, cancers may escape their hosts, defy immunological barriers, and spread through populations. Only three such transmissible cancers are known amongst mammals, affecting dogs and Tasmanian devils, and these provide a unique perspective on cancer evolution and host interaction. Here, I outline a plan to sequence the entirety of DNA and RNA from hundreds of tumours, together with targeted single-cell RNA sequencing, in order to understand these cancers’ evolution and mechanisms of immune evasion. I will investigate the source and consequence of mutation and characterise variation in composition and function of the tumour microenvironment. This work will reveal how cancers exploit a transmissible niche, and how the interaction between cancer and immune system controls disease outcome.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_05394,Department of Health and Social Care,NIHR,Treatment of Advanced Glaucoma Study (TAGS): A multicentre randomised controlled trial comparing primary medical treatment with primary trabeculectomy for people with newly diagnosed advanced glaucoma,"Glaucoma is a common potentially blinding disease. It occurs when the intraocular pressure (eye pressure) in the eye is too high. Patients presenting with advanced disease (severe visual field loss on visual field examination) are at high risk of becoming blind despite treatment. It is the second commonest cause for blind registration in the UK. Blindness places a burden on society, patients and their family._x000D_ Glaucoma is treated by using eye drops (medical) or by an operation (surgery) to lower eye pressure. NICE recommends surgery in patients presenting with advanced glaucoma. The operation is called a trabeculectomy, this creates a small hole in the eye which lowers the eye pressure. Medical care starts with eye drops and may require up to 4 different drops. If this fails to control the eye pressure, surgery (trabeculectomy) is required. Surgery is good at lowering eye pressure but there can occasionally be severe side effects. _x000D_ Low eye pressure is the best way to prevent further visual loss and is very important in patients with advanced disease. Surgery is better at lowering eye pressure than drops, but in the short-term it requires intensive post-operative follow-up with frequent hospital visits, adjustments to the surgery and has an increased risk of cataract development and vision threatening complications requiring further surgery. Using drops to lower eye pressure as the first treatment may delay or prevent surgery altogether and maintain a better quality of life for patients. Uncertainty exists as to whether modern medical treatments lower eye pressure sufficiently to reduce the risk of blindness in the future._x000D_ Modern glaucoma drops are better at lowering IOP and have fewer side effects than those available in the past. In addition many of these drops are now available as generic drops and so are much less expensive than in the past. It is possible therefore that using drops will be less expensive than undertaking surgery for this group of patients._x000D_ We want to determine whether medication (drops) or surgery produces better patient health, quality of life, reduced risk of sight loss, and represents a better use of NHS and society resources in people presenting with advanced glaucoma. Our proposed study involves giving either medication (drops) or surgery to 440 people who agree to take part. They will be randomly allocated to have either eye drops or surgery. The study will include a network of hospitals over 73 months with each participant being studied for 2 years. We will measure the impact of the treatments on the health of the participants, their vision and eye pressure and determine which treatment represents best value for money. This information will be collected by asking the participants to complete a series of questionnaires over the 2 years and by staff at the study hospitals completing case report forms._x000D_ Our research team is made up of surgeons (ophthalmologists), lay experts and experts in the design, performance and analysis of clinical trials. The study will be managed by a Clinical Trials Unit which is very experienced at running large multicentre randomised controlled trials within the NHS. We also have the support of the patient organisation, The International Glaucoma Association. We will convene a Trial Steering Committee and Data Monitoring Committee which will meet annually to over see the trial progress and ensure that there are no safety concerns with regards to the treatments being investigated._x000D_ The study will last 73 months. This includes 5 months to set up the study; 36 months to set up centres, recruit participants, a further 26 months to complete the follow up on all participants and 6 months to analyse, write up and close down the study._x000D_ The study will take into account the NHS, patient and society perspectives so that our finding will provide further information for all stakeholders on how best to manage patients presenting with advanced glaucoma. The study will assess relative effectiveness, safety and costs in routine everyday NHS practice to ensure that the results are representative of NHS practice._x000D_ Our proposal specifically fulfils the requirement of the HTA surgery research call. Our study will determine whether there is a need for initial surgery (as recommended by NICE) in patients presenting with advanced glaucoma when alternative effective modern glaucoma medications with fewer side effects have become available. Patient views and experience are an important outcome in our proposal as we use a visual quality of life measure as our main outcome, To further clarify the patients treatment pathways we measure the patients visual health and general health status at frequent intervals to allow “profiling” of the patient experience during their follow-up on._x000D_ ADDENDUM (02-11-2018) - As a result of being given extra funding and ethical and regulatory approval, the study team will ask TAGS participants who consented to longer term follow-up to complete participant questionnaires 3, 4 and 5 years after they joined the study. We will also collect more clinical data at participants’ regular NHS clinical follow-up around 5 years after they joined the study. This is good news for people living with advanced glaucoma. The planned 2-year results will assist clinical and patient decision-making about which treatment has better outcomes. But additional 5-year data will afford more certainty that any differences are consistent in the longer term. This data will more accurately reflect the lifetime outcomes for patients with advanced glaucoma, and that will allow patients newly diagnosed with advanced glaucoma, and their clinicians, to make more informed choices regarding the treatment options.","Design:_x000D_ A pragmatic multicentre randomised controlled trial comparing primary medical treatment with primary trabeculectomy (standard care). Participants will be randomised to medical treatment or trabeculectomy (1:1 allocation minimised by centre and bilateral disease). We will include an internal pilot to confirm the feasibility of recruitment and retention targets._x000D_ Setting:_x000D_ Secondary care (20 centres within the UK; Nottingham; London (x3); Leicester; Sheffield;, Portsmouth; Hinchingbrooke; Huddersfield; Cheltenham; Norwich; Belfast; Edinburgh; Glasgow; Birmingham; Bristol; Manchester; Maidstone; Warrington; Sunderland)_x000D_ Target population:_x000D_ Adults presenting with advanced glaucoma in at least one eye. Advanced disease will be classified as severe glaucoma by the Hodapp classification of glaucoma severity_x000D_ Health technologies being assessed:_x000D_ Primary medication: refers to initial treatment with step wise escalation of medical care (escalating glaucoma drops) to lower intraocular pressure (IOP) according to the following specifications: initially the patient will start on one or more glaucoma drops, if the clinician judges IOP control is inadequate an escalation of medical therapy follows (following NICE guidelines). _x000D_ Primary surgery: Trabeculectomy with mitomycin C (augmented trabeculectomy) is the recommended operation for advanced glaucoma._x000D_ Measurement of Costs and Outcomes:_x000D_ Patient centred outcomes: Vision specific health (NEI VFQ-25) at baseline, 4, 12 and 24 months via participant completed questionnaire. Generic (EQ5D, HUI-3), glaucoma specific (GUI) health status and patient experience questions measured at; baseline, 1, 3, 6, 12, 18 and 24 months post randomisation and immediately prior to trabeculectomy._x000D_ Clinical outcomes: Humphrey visual fields Mean Defect; Intraocular pressure; LogMAR visual acuity, measured at; baseline, 4, 12 and 24 months post randomisation and recorded on a case report form (CRF). Complications of surgery and medical treatments and therapy changes will be recorded, also need for cataract surgery by 24 months, eligibility for registration as visually impaired and evaluation of legal driving status at 24 months._x000D_ Economic outcomes: Costs of initial treatments including time in hospital and secondary care use will be based on data collected in CRFs. Primary care, personal social service use and patient costs will be collected via questionnaire at 4, 12 and 24 months post randomisation. These data will be combined with both standard (NHS reference costs) and study specific unit costs. Responses to the EQ5D; HUI-3 and GUI will be combined with relevant tariffs to produce QALYs. Costs and QALYs will be combined in a within trial cost-utility analysis, incorporating deterministic and stochastic sensitivity analysis. _x000D_ The cost-utility will also be modelled over the patient’s lifetime._x000D_ The scoring system for the GUI was developed from a sample of glaucoma sufferers, a comparatively small number of whom had advanced glaucoma. In order to tailor this tool for the trial population a discrete choice experiment whose responses formed the basis of the GUI scoring system will be administered to trial participants. This questionnaire has already undergone extensive piloting. _x000D_ Sample size: _x000D_ The primary patient reported outcome is the health status measured by the NEI-VFQ-25 assessment at 24 months. A study with 190 participants in each group will have 90% power at 5% significance level to detect a difference in means of 0.33 of a standard deviation (SD), this translates to 6 points on the NEI-VFQ-25 assuming a common SD of 18 points observed in previous work which is a clinically relevant effect size in patients with advanced glaucoma. Assuming a drop-out rate of 13.5% due to declining further follow-up and death, a total of 440 participants will need to be randomised to be able to detect this difference. The primary outcome will be analysed using linear regression correcting for baseline VFQ-25, EQ5D, HUI-3 and MD. _x000D_ Project timetable including recruitment rates:_x000D_ The projected start date for the study is 1 January 2014: the study duration will be 73 months. Milestones are: prefunding: protocol development; multicentre research ethics, central R&D approvals; Months: 1-5 Study initiation; set up office, assemble team NHS approvals, start site set up Months 6 -17: establish study in all 20 centres; months 6-41: identify and recruit 440 participants; months; Months 42-67: complete 24 month follow up; Months 68-73: complete DCE, close down, analysis, report writing._x000D_ All participating centres have indicated a throughput of at least 20 eligible patients annually. The recruitment projection is based on 20 sites recruiting approximately 9-11 patients per year, with a staggered start of recruiting sites, allowing 440 participants to be recruited over 3 years._x000D_ Expertise: _x000D_ The applicants comprise a strong multidisciplinary research team of ophthalmologists, patient representatives and methodologists. The study will be co-ordinated by the Centre for Health and Randomised Trials (CHaRT) an established clinical trials unit with expertise in running surgical randomised trials and specifically glaucoma studies._x000D_ ADDENDUM (02-11-2018) - Funding has been secured and regulatory approval given to follow TAGS participants who consented to longer term follow-up for up to 5 years post-randomisation. This includes a participant questionnaire at 3, 4 and 5 years as well as a clinic visit at 5 years. This visit should coincide with participants’ regular NHS clinical follow-up.",6.1 PHARMACEUTICALS;6.4 SURGERY,EYE HRCS22_02455,Medical Research Council,MRC,Treatment of osteoarthritis by inhibition of aggrecanases using targeted delivery of engineered TIMP-3,"Joints affected by osteoarthritis (OA) have increased levels of matrix-degrading enzymes such as matrix metalloproteinases (MMP) and aggrecanases that can degrade the articular cartilage and result in joint damage and pain. TIMP-3 is a potent endogenous inhibitor of MMPs and aggrecanases. However, attempts to harness the therapeutic potential of TIMP-3 have been prevented by technical challenges associated with protein production and by observations that synthetic broad-spectrum inhibitors of MMPs caused unwanted side-effects. In this project, TIMP-3 molecules that have been engineered to narrow their inhibitory activity to aggrecanases but not MMPs, will be produced and delivered to sites of arthritic disease. Targeting of these proteins to arthritic joints will be achieved by producing TIMP-3 in fusion with the latency-associated peptide (LAP) of TGF-beta1. This renders the protein biologically inactive until it reaches the site of disease where TIMP-3 is released from the LAP by MMPs present in arthritic joints. The effect of delivery of engineered TIMP-3 on the course of disease in vivo will be assessed by measuring cartilage degradation and subchondral bone thickening by a combination of histology, immunohistochemistry and micro computed tomography. The inhibitory effects of engineered TIMP-3 on various members of the ADAM and ADAMTS families of matrix-degrading enzymes will also be assessed in vitro to provide insight into the potential benefits of this therapeutic strategy. Knowledge of the targeting potential of this approach in OA and of the effects of inhibition of aggrecanases in joints affected by OA could pave the way for a novel treatment for OA that could be used alone or in combination with existing therapies.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MUSCULOSKELETAL HRCS22_06773,Department of Health and Social Care,NIHR,Trial design and analysis methods to incorporate the complexities of surgery - Evaluating the individual and combined effects of the constituent components of surgical interventions and the effects of surgical learning curves.,"BACKGROUND: Current approaches to trial design and analysis for evaluating surgical interventions do not sufficiently account for the fact that surgery is a complex intervention. The trial designs/analyses often mirror pharmaceutical trials, answering black-and-white, 'A-vs-B'-style questions, without addressing specifically how the treatments should be performed, or how their effectiveness changes as the surgeons are learning them. This causes limited influence of trial results, perpetuation of the large-scale heterogeneity of surgical care delivery, the delayed roll-out of beneficial surgical techniques and the sub-optimal implementation of new interventions. A paradigm shift is required, moving beyond conventional parallel-group trial designs that ignore complexities of an intervention such as surgery. AIM: Enhance the value and impact of surgical trials by developing and extending existing surgical trial designs and analyses. OBJECTIVES: Review existing methodologies for trial design and analysis of complex interventions which can be used to meet the needs in the surgical setting for addressing learning effects and analysing the individual components of an intervention. Develop, evaluate and illustrate surgical trial designs able to estimate surgeon learning curves. Extend existing statistical methods to estimate the effects of mandatory and optional components of surgical interventions on patient outcomes in the context of conventional parallel-group designs. Develop, evaluate and illustrate trial designs for estimating the individual and combined effects of mandatory and optional intervention components on patient outcomes. Provide practical guidance for the use of these design and analysis methods, ensuring clear communication of results to non-statisticians, to maximise impact. METHODS: Qualitative synthesis of surgical literature to illustrate the need in the surgical setting for the proposed research. Targeted literature reviews and snowballing to relate these needs to relevant methodologies from design of experiments and causal inference. Design of experiments approach to develop a design incorporating learning effects, adapting the replicated-crossover design. Evaluate the design via simulation studies. Output methodological paper and software for implementation of new design. Extend causal inference methodologies to evaluate the effects of mandatory/optional components of a surgical intervention. Illustrate the methods on trial datasets. Output guidance paper and example code for statisticians. Same approach as that outlined in 2, but drawing from designs which use multiple, conditional randomisations. Workshop to discuss practical implications of 2-4. Output a practical guidance paper to augment the more methodological papers. IMPACT: The methodological papers and practical guidance will facilitate the uptake of the proposed designs and analyses in surgical trials by making them accessible to all stakeholders. Once in use, these designs and analyses will allow trials to be commenced sooner, to be more inclusive for surgeons and to produce a more detailed evidence base to inform surgeons/policymakers not only about which intervention leads to better patient outcomes on average, but also specific details of how best to deliver the intervention. This will lead to improved reproducibility of results in wider practice, faster and wider adoption of beneficial techniques, considerable reduction in the inequality of care that patients currently receive and the development of evidence-based, tailored interventions for different subpopulations of patients.","Background: Before a new surgical intervention can be adopted into practice, it must be determined that patients would benefit more from receiving the new intervention than receiving the current intervention. The randomised controlled trial (RCT) is accepted as the best approach for doing this. There are many different RCT designs, and surgical research has embraced the conventional 'parallel-group' design typically used to test pharmaceuticals. However, this design cannot handle the complex nature of a surgical intervention and so common features of surgery often render surgical RCTs invalid. Learning effects: One such feature is that surgeons need time to learn the new technique. The conventional RCT involves randomising a large number of patients from multiple hospitals to either receive a new technique ('Surgery A') or the current technique ('Surgery B'), and then comparing patient outcomes between the two groups. Many surgeons in the trial will be unfamiliar with 'Surgery A', and it is expected that for these surgeons there will be a period of learning during which time the technique will be less effective than it is when performed by an expert. In contrast, 'Surgery B' is typically a well-established technique that most of the surgeons in the trial will already be very familiar with. This can lead to an unfair comparison between a 'Surgery B' at full potential and a 'Surgery A' at less than full potential. Component effects: Another feature is that surgical interventions are made up of many different components (e.g. operating surgeon, the wider surgical team, the specific equipment available, the local policy on post-operative care, etc.). These components determine what version of the intervention a patient receives, and they can all vary considerably from patient to patient. Patients receiving 'Surgery A', for example, may all receive different antibiotic regimes depending on their hospital. Furthermore, these differences in technique can affect patient outcomes e.g. maybe certain antibiotic regimes for 'Surgery A' lead to lower rates of infection. We need to be able to perform analyses that evaluate whether different versions of an intervention lead to different patient outcomes and, if so, then which versions lead to the best outcomes. Aims: The first aim is to develop new RCT designs which can provide relevant, precise and fair comparisons between surgical interventions even when learning effects are present. The newly developed designs will be evaluated via simulation studies to see how capable they are of producing quality results under various common real-life scenarios. The second aim is to develop new RCT designs that allow for analyses that explore how choices of the components (e.g. which antibiotic regime to use) affect patient outcomes, and to explore how best to communicate the results from these more complex analyses. Analysis methods will be explored by using data from existing trials where lots of information about how the surgical interventions were delivered was collected. PPI: I will seek patient and surgeon input to my project relating to acceptability and practicality of the new RCT designs during their development. My advisory group, which will meet biannually, includes PPI and surgeon representatives. I will also have regular contact with surgeons and PPI representatives through my trials work at Leeds CTRU. Furthermore, I plan to hold two workshops to discuss the new designs with PPI groups and with surgeons. Outputs: Outputs from this project will include methodological papers and software for researchers to use the new designs and papers summarising practical considerations as discussed with PPI reps and surgeons. Dissemination will be through the surgical and UK clinical trials unit network, presentations and discussion at relevant surgical and methodological conferences, and the PPI workshop.",6.4 SURGERY,GENERIC HEALTH RELEVANCE HRCS22_23240,Royal Academy of Engineering,,Triboelectrically Powered Super-Smart Textiles for Remote Health Monitoring,"In the future, wearable healthcare technologies will require efficient, autonomous and sustainable energy sources. Dr Dharmasena investigates nanogenerator technology to develop super-smart textiles that use electro-static interactions of textile yarns to generate electricity from human body movements. These smart textiles function as energy generators and self-powered sensors for remote rehabilitation monitoring.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,GENERIC HEALTH RELEVANCE HRCS22_19105,Cancer Research UK,CRUK,Tumour Cell Death,"Macroautophagy (autophagy) is a catabolic membrane-trafficking process that delivers cytoplasmic constituents to lysosomes. The process is active in multiple tissues and contributes to cellular fidelity and viability. As a result, autophagy is implicated in a variety of diseases including cancer and there is clear evidence that it plays important roles in both the prevention of tumour development and in the establishment and maintenance of malignant disease. Moreover, as certain tumours are autophagy-dependent, autophagy has become an attractive target for cancer therapy. My laboratory has made a number of significant discoveries regarding autophagy in cancer and we are one of the leading teams in this area. In our proposed plan of investigation we aim to build on our previous discoveries and to advance the state of the art in three main areas: 1) We are widely recognized for our work on DRAM family proteins and autophagy in cancer. We have discovered a molecular function of DRAM-1 that is highly relevant to tumour development and we will explore this mechanism in greater detail. In addition, using DRAM1-deficient mice we will explore a role we have found for the protein in tumour progression. These studies will be undertaken alongside further studies into the role of autophagy during tumour development in vivo. 2) Through RNAi screens we have discovered that a transcriptional regulator important for cancer is a novel autophagy regulator. We plan to explore how this regulator affects autophagy genes and in what contexts. To this end, we have established collaborations to look at autophagy regulation by this factor in vivo and we aim to examine how this factor selectively regulates different forms of autophagy. 3) Changes in glysosylation are an extremely frequent event in cancer and yet their contribution to the aetiology of the disease is poorly understood. We have found that a key enzyme involved in glycosylation is required for successful autophagy. Moreover, we have also discovered that perturbation of this enzyme enhances pancreatic tumour development in a mouse model. We aim to define the role played by this enzyme in the regulation of autophagy and delineate its contribution to tumour development in pancreas and other tumour types. These studies will lead to a greater understanding of the role of autophagy and its regulators in cancer and we hope they will lead to the improved application of existing cancer therapies and to the identification of potential new targets for therapeutic intervention.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_01370,Medical Research Council,MRC,"Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for drug-sensitive Tuberculosis: the ""TRUNCATE-TB"" trial","TRUNCATE-TB is a randomized, open-label, parallel group, non-inferiority trial testing a new strategic approach to the treatment of drug-sensitive pulmonary TB. Patients will be randomized to receive 6 months' initial standard-of-care treatment, or to one of several strategy arms comprising 2 months' treatment with a novel combination followed by 6 months' re-treatment with the standard-of-care combination for those who relapse. A multi-arm multi-stage (MAMS) design will be used that allows multiple regimens to be tested against a single control group and which allows for treatment arms to be dropped or added during the trial. This represents an efficient and cost-effective approach to evaluating several candidate regimens that may provide high rates of sterilization after 2 months' treatment. The trial will have a pilot phase in which 300 patients will be enrolled to gather detailed initial safety data, as well as test feasibility of recruitment and follow-up and allow an initial intermediate assessment for efficacy and possible arm drop. The definitive phase of the trial will complete the recruitment of a total of 1300 patients. Eligible patients must have a pulmonary TB confirmed by molecular test, without rifampicin resistance. HIV infected participants will be eligible (recruited only in the definitive phase), but must have a CD4 above 200 cells/mm3 and be off anti-retroviral therapy at study entry. Patients will be followed for 96 weeks (prolonged if late-re-treatment). The primary endpoint is TB sputum culture status at 96 weeks after randomization. Secondary endpoints include drug resistance, treatment failure or relapse, programme resource use and cost and the safety of the treatment regimens. The trial will be conducted at approximately 12 sites in Asia, forming a sustainable Asian TB clinical trials network that will make a significant future contribution to the urgent need for increased TB clinical trials capacity.",,6.1 PHARMACEUTICALS,INFECTION HRCS22_11480,Economic and Social Research Council,ESRC,UK Data Service (2017-2022),"Primary objective is to provide users with access to easily discoverable and relevant data for social and economic research. In order to achieve this objective we shall: * To act as a trusted national digital repository for a wide range of data providers and users * To provide a single point of access and enhanced support to a broad range of quality assured economic and social data, including controlled access to sensitive and/or disclosive personal or organisational information * To extend use of its data holdings to the widest possible academic, policy and practitioner communities for generating greater impact. We shall also: * Develop and promote common standards and agreed strategies for data preparation, processing, documentation and preservation * Integrate data services (but not necessarily making model less distributed) through the development of a universal single point of access and simple registration procedures and common conditions of use * Enhance underlying data sources and promote increased re-use and re-purposing of datasets * Help build up capacity within the social science community through the development of programme for user support and training, including support in data management planning and in close cooperation with the ESRC * Engage on a regular basis with a wide range of stakeholders in the UK and overseas, including data suppliers, data funders and users * Ensure regular and transparent service evaluation, reflection and business development process to stimulate the most efficient delivery of the service for the benefit of the widest-range of users. * Promote behavioural changes in approach to data sharing and re-use among social science researchers * Increase the number of users who do not require formal authentication process to access and use data held by the UK Data Service * Ensure that all our activities provide value-for-money","The UK Data Service will provide an easy to use, trusted, one-stop shop for * owners of data which have potential for re-use for social and economic research * users of these types of data Users are expected to come to the UK Data Service's website to search and browse for data collections created by a wide range of suppliers, including government data, data from ESRC-funded research projects, and will be able to access or download these data for their own use. The Service will rely on user registration to enhance our ability to tailor the needs of users and to ensure that licensing arrangements are correctly managed. (In the intervening period between the submission of this proposal and the new award, there will be a complete review of all the data collections currently held under the ONS-Special Licence. This review will remove this form of licence, therefore, all data currently available through this mechanism will either be available through our near-Open End User Licence or controlled through Secure Lab.) We shall continue to advocate Open access to relevantly classified datasets, while ensuring that access to personal data is maintained through the provision of secure access to sensitive data for trusted and Approved Researchers. The five years of this award, are likely to see some of the most significant changes in sharing government data --- all of which have a significant impact on the UK Data Service --- the review of the Approved Researcher status has the potential to broaden use of our Secure Lab; the Digital Economy Bill (currently in Parliament) is likely to widen the range of data we have deposited from government and the change of policy of the ADRN to allow the retention of data means that the UK Data Service is one of the most likely places for these data to be maintained. The timescale for some of these activities is clear and we can plan for; for others, we shall have to be responsive to external factors. For the Service to provide long-term access to data, the highest levels of digital repository and digital preservation techniques will be applied; and the Service shall conform to the relevant national and international standards to ensure the highest quality service. Audience Stakeholders Public - protection of data.",2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),GENERIC HEALTH RELEVANCE HRCS22_20660,Wellcome Trust,,UK Prevention Research Partnership (UKPRP) - call 2 consortium and network grants,"The UKPRP is an inter-disciplinary national initiative supported by an alliance of UK charities, Research Councils and the UK Health Departments, and established in recognition of the need for research into population-level strategies that will prevent non-communicable diseases (NCDs) and reduce inequalities in health.",,3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION),GENERIC HEALTH RELEVANCE HRCS22_13086,Versus Arthritis,,UK Research in Musculoskeletal Epidemiology - UK-RIME,"The 1st term of the Epidemiology Centre Award (UK Research in Musculoskeletal Epidemiology (UK-RiME) partnership) was established with funds within the 1st term of funding for the Centre for Epidemiology. It is a partnership bringing national collaboration between msk epidemiology centres: For the 2nd term an Annual Research Showcase is supported. The annual showcase provides an opportunity for face-to face meetings between members of the UK-RIME centres and others interested in MSK epidemiology. The showcase is planned and organised by a junior organising committee from all eight UK-RIME centres and typically includes brief presentations from each Centre, ‘elevator pitch' presentations by ECRs and break-out sessions to discuss methodological and clinical topics related to MSK epidemiology. This organising committee also acts as a successful communications network, distributing information and opportunities to all sites.",,2.4 SURVEILLANCE AND DISTRIBUTION;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL HRCS22_01971,Medical Research Council,MRC,UK:Brazil Joint Centre Partnership in leishmaniasis,"Leishmaniasis is a devastating parasitic disease that targets the poorest of society and is the 9th largest global infectious disease burden (WHO). It is truly a Neglected Infectious Disease as the combined financial support of basic and clinical research equates to <2% of infectious disease R&D resources available. Consequently, there are no vaccines available currently and the limited available treatments are repurposed from other applications, have severe side effects; including anaphylaxis, growing drug resistances and are inappropriate for the primarily juvenile leishmaniasis patients. Disease pathologies range from tegumental (mucocutaneous and cutaneous leishmaniasis) to visceral and cases in Brazil alone range from 20,000 TL to 3,500 VL per annum. The JCPiL will fund five inter-related projects and 3 workshops to promote research at the interface of basic and clinical science, to extend existing collaborations between UK and Brazil and to develop new partnerships and interdisciplinary ways of working. Travel will be used to cross train PIs, PDRAs and PhD students in the foremost technologies and expertise available worldwide. Studies will be focused on understanding parasite genetic diversity in the context of variations of Leishmania infectivity and virulence factor expression, mechanisms of immune evasion, diversity of host response, resultant immunopathology and sustained activation that drives chronic disease. We will investigate novel molecular targets of vulnerable pathways that are essential to Leishmania viability, optimise techniques and diagnostic markers to predict and definitively categorize patient pathology profiles to inform more bespoke, effective treatment design. Our JCPiL will create new collaborations in order to build sustainable, fundable future projects and make an impact on this deadly disease.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_02806,Medical Research Council,MRC,UKPRP Community of Practice,"Five Development Themes will launch at the outset of the CoP. 1. UKPRP Networks Aim: to develop the Network's capabilities by exchanging knowledge and developing best practice, and to explore solutions to common network issues (e.g. building cross-sector research capacity). Outputs: to include best practice guidelines, case studies, and identification of potential projects for Networks to progress based on initial discussion around shared priorities. 2. Consortium and Network Management Aim: to share learning around the formation, implementation and operation of effective multi-sector collaborative groups. Outputs: to include a toolkit for and guidance on the management of large-scale collaborative projects, including evaluation. 3. Impact-Oriented Research Aim: to co-develop a shared understanding of approaches to impact-oriented prevention research, and to critically assess different approaches to impact. Outputs: to include an impact report comparing approaches across the Networks and Consortia and an understanding of how the DT has helped strengthen impact strategies. 4. Commercial Sector Interactions Aim: to share, compare and reflect on Network and Consortia approaches to managing interactions with and interference by commercial sector organisations. Outputs: to include guidance on issues and approaches for the management of commercial interactions, and/or attempted interference with the conduct or impact of prevention research. 5. Meta-Research Aim: to collect, review and evaluate the approaches UKPRP projects are taking to reflect on and continually improve their research, stakeholder engagement, knowledge exchange and impact realisation processes and practices, and to seek to enhance the outcomes of our research by sharing know-how across the portfolio of participating UKPRP projects. Outputs: to include a 'playbook' as a knowledge base for future researchers and research funders to use when developing research calls and bids.",,3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION),GENERIC HEALTH RELEVANCE HRCS22_01646,Medical Research Council,MRC,UKRMP Hub: The Engineered Cell Environment.,"The UKRMP Engineered Cell Environment Hub (ECEH) aims create a platform, linking excellence in the regenerative biology of the stem cell niche with experimental medicine to translate regenerative therapies to the clinic. We will bring together leading scientists in regenerative biology, stem cells, niche biology, phenotypic screening, safety and transplant immunity with clinician scientists working in regenerative medicine in a highly collaborative network. We will develop two linked translational regenerative strategies: (1) Developing Cell Therapies for Damaged Organs: We will use our knowledge of niche biology to optimise cells for therapy. Artificial niches will be constructed that mimic healthy tissue and facilitate effective cell therapy. Pluripotent and adult human stem cell sources will be optimised in vitro and tested in our pre-clinical models of liver, joint and lung repair. Immune responses to the transplanted cells will be assayed in relevant humanized mouse models. (2) Promoting endogenous repair of damaged organs:Using stem cells in vitro, we will create high content 2D and 3D phenotypic screens for liver, cartilage and lung repair. We will study the behaviour of stem cells in their niche aiming towards optimising endogenous repair and use FDA approved compound libraries to identify potential drugs and biological agents for translation. The Hub is structured with 3 basic underpinning scientific areas and technologies: (a) Understanding and improving the physical properties of Aged and Injured Tissue Niches; (b) Developing Artificial Wnt Niches to act as regenerative signals for tissue formation and repair; (C) High content phenotypic screening for the discovery of novel targets for endogenous repair. We have 3 clinical translational exemplars: liver (WP1), joint (WP2), lung (WP3) repair. Each theme is led by a pair of investigators with complimentary expertise, common underpinning biology and enabling technologies that span the WPs.",,5.2 CELLULAR AND GENE THERAPIES,ORAL AND GASTROINTESTINAL;MUSCULOSKELETAL;RESPIRATORY HRCS22_09452,"Public Health Agency, NI",PHA,US Ireland Partnership Professor Alan Stitt Targeting the compromised brain endothelial barrier function during cerebral malaria with AT2 receptor agonists,"Strengthening of inter-cellular junctions of endothelial cells would facilitate important translational applications for a variety of diseases where endothelial integrity is compromised. As a first model, we have chosen cerebral malaria (CM), which remains the deadliest manifestation of malaria. It is caused by Plasmodium falciparum infected erythrocytes (iRBC) adhering to host brain endothelial cells and compromising the blood brain barrier. While anti-malarial drugs clear parasites from the blood, they do not have specific effects against CM. We have found that P. falciparum-iRBC-induced disruption of human brain microvascular endothelial cell junctions and development of CM in mice was prevented by the activation of the angiotensin (Ang) II receptor type 2 (AT2). Ang II is only a biased agonist of the G-protein coupled receptor AT2, since it does not activate G-proteins via the receptor. We have discovered the real endogenous agonist for AT2 (EA), which activates Gs and protects against disruption of endothelial integrity. Based on in silico modelling and in vitro experiments, we have also identified a first AT2-specific non-peptidic receptor agonist (SNPA) that also activates Gs. We hypothesize that activation of specific intracellular signaling pathways of AT2 protects human brain and retinal endothelial cells from P. falciparum-induced disruption of inter-endothelial junctions, thus maintaining endothelial function, reducing/preventing edema and hemorrhages and thus CM and related retinopathy. We will first identify which AT2-mediated intracellular signaling pathways are key in the protection of endothelial integrity, by testing 4 differently acting compounds: Ang II, EA, SNPA and the non-specific agonist C21, in AT2-transfected cells and in human and murine brain endothelial cells and quantifying intracellular signaling molecules important in barrier integrity. A pharmacological approach and targeted inhibition of AT2 by siRNA in primary human (brain, retina) and mouse (wild-type and AT2-deficient) endothelial cells will identify the most efficient agonist in brain endothelial protection. We will determine the specific effects of the agonists interacting with AT2 on endothelial activation, junction integrity, and on selected second messengers. Finally, we will test how treatment with the different agonists affects the outcome of CM and related retinopathy in wild-type and AT2-deficient mice, whereby analysis of the retina offers scope for investigation of brain microvascular function. The main goal of this project is to identify a lead compound, which can stimulate specific intracellular signaling at the AT2 receptor to mediate essential protection of endothelial integrity. Our experiments will lay the foundation for the development of a small molecule drug to be immediately tested in clinical trials for the treatment of the life-threatening pathology of CM, with possible future applications in other hemorrhagic diseases. This proposal is submitted under the US-Ireland R&D Partnership Programme, which is focused on the development of new therapeutic approaches. Funding is requested only for the US component, since the Irish funding agencies have already committed their financial support conditional on a positive NIH funding decision.",,5.1 PHARMACEUTICALS,INFECTION HRCS22_19905,Wellcome Trust,,"Understanding Chemotaxis Towards Self-Generated Gradients Using Computational Models, Model Organisms and T cells","Cell migration is essential to processes throughout biology, especially embryonic development and immune function. Migration must be steered to be physiologically effective. Steering cues are not well understood; we know a lot about how cells interpret them, but relatively little about how they are generated. The basic premise of this work is that the cells often generate their own cues, by breaking down attractants that are widely present (and thus initially give no steering information) into local gradients. Attractant breakdown and migration happen simultaneously. This mechanism - chemotaxis up self-generated gradients (SGGs) - is hard to dissect because it is complex, and based on positive feedback loops. We therefore propose a four-pronged, iterative approach, in which we combine less challenging components to create an understanding of the underlying biology. Key goals are: (1) explore possible mechanisms and new extensions using computational models; (2) test outcomes using chemotactic Dictyostelium in custom microfluidic devices; (3) verify these data by establishing cultured T cells chemotaxing to CCL19 as a model SGG; (4) combine findings from parts 1-3 to make a 3D, SGG-based model of a lymph node. Together they will illuminate chemotactic steering in general, by focussing on one physiologically important system.","When immune cells find disease in the body, they take evidence to a centre of operations called a lymph node. Many different cells of the immune system need to communicate there. They therefore need an effective way of navigating to the lymph node, and finding one another after they arrive. We have shown that this navigation is an active process - cells create a pathway by changing their environment. The way they do this is complex, and almost impossible to study with simple experiments. We deal with this complexity by combining different simpler experiments - computer models let us explore a range of possible conditions; amoebas are good navigators and easy to study; and single isolated immune cells. Ultimately, we will make a functioning 3D model of a lymph node, to show exactly how different kinds of immune cell navigate around it in order to find each other.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_05607,Department of Health and Social Care,NIHR,Understanding Mechanisms of Thrombosis and Thrombocytopenia in COVID-19 and with SARS-CoV-2 Vaccines,"Background to the research_x000D_ The vast majority of people who have a COVID-19 vaccine experience only mild side effects lasting for two or three days. However, in March 2021 reports of a small number of people being admitted to hospital with what could potentially be a very rare side effect of vaccination began to emerge. These people had blood clots in the major veins in the brain or in the abdomen, but at the same time a low level of platelets – which are responsible for clotting – in the blood. The blood clots varied in severity, and sadly, some of the individuals affected by this side effect died. The combination of blood clots with low platelet levels is very uncommon. Although it has been reported previously (even before the pandemic), the clusters of cases were unusual and an association with the vaccines was suggested. It is important to note that the vast majority of individuals given the vaccine do not develop this complex of problems (clots together with low platelets – for which we are using the name thrombotic thrombocytopenia syndrome, or TTS), but about 1 in 100,000 to 1 in a million do. We do not understand why a vaccine that is safe for almost everyone can cause TTS in particular individuals._x000D_ _x000D_ Aims_x000D_ We aim to: _x000D_ • Investigate how common TTS was: before COVID-19; in those who have been vaccinated against COVID-19 and in those suffering from COVID-19. _x000D_ • Understand why a very small number of those vaccinated against COVID-19, and also those with COVID-19 itself, develop blood clotting disorders. _x000D_ • Investigate the changes in the body that lead to the unique combination of blood clots and low platelet count seen in TTS._x000D_ _x000D_ Approach_x000D_ We have brought together researchers and doctors from across the UK with expertise in many different areas. These include: using information in electronic health records to understand disease; vaccine safety and effectiveness; understanding how the immune system and the genes controlling the immune system respond to viral infection and vaccination; treating people who have blood clots and understanding how and why blood clots form. Our team will work together to understand the biology behind TTS and develop solutions to prevent and treat TTS._x000D_ _x000D_ Patient and public involvement_x000D_ We will work with people who have recovered, or are recovering from TTS, and their families to make sure that their voice is heard. We will also engage those with those who have been vaccinated but without side effects. Our PPI group will work closely with each of our groups of researchers to create a shared understanding of the most important research questions, to interpret the experimental results and to create plain language summaries to share the research findings._x000D_ _x000D_ Impact_x000D_ Our research will discover why COVID-19 vaccines can lead to TTS in rare cases. This will be important for redesigning COVID-19 vaccines to avoid TTS and for development of new vaccines in any future pandemics and against existing diseases for which there is no vaccine. The benefit-risk ratio of the COVID-19 vaccines is highly beneficial. Understanding how TTS develops has the potential to further improve the safety of current and future vaccines.","Background_x000D_ Clusters of cases of cerebral venous sinus thrombosis (CVST) or thrombosis in other major veins, together with thrombocytopenia (thrombotic thrombocytopenia syndrome (TTS)) began to emerge following roll-out of SARS-CoV-2 vaccines. Although a mechanistic link is not yet proven, there is strong epidemiological evidence that TTS is a very rare adverse effect of SARS-CoV-2 vaccines, and in particular, adenoviral vectored vaccines. The incidence of vaccine-induced TTS is thought to range between 1 in 100,000 and 1 in 1,000,000 with a fatal outcome in up to 20% of cases._x000D_ _x000D_ Research question_x000D_ We aim to investigate the mechanisms underlying TTS in response to SARS-CoV-2 vaccination with the ultimate goal of developing novel preventive and interventional strategies. _x000D_ _x000D_ Aims _x000D_ • Evaluate SARS-CoV-2 vaccine safety using real world epidemiology data._x000D_ • Understand the prevalence of anti-platelet factor 4 (PF4) antibody positivity._x000D_ • Understand the relationship between the immune response initiated by COVID-19, vaccines and haemostatic dysfunction including the underlying genetic factors._x000D_ • Develop in vitro platelet models to understand mechanisms of vaccine associated adverse events, and identify potential therapeutic interventions._x000D_ _x000D_ Timelines for delivery_x000D_ We expect important findings of relevance to public health to be delivered during the funding period (before August 2022). Our expected outcomes are:_x000D_ • Epidemiological data that provides robust evidence of background rates of thrombocytopenia, thrombosis and TTS, and whether TTS is associated with any of the COVID-19 vaccines, including the magnitude of the effect._x000D_ • Robust laboratory data to show the background rates of anti-PF4 antibodies, and whether they are sensitive and specific indicators of TTS._x000D_ • Novel methods for preventing TTS including potential avenues to modify the vaccines to prevent TTS._x000D_ • Development of a clinical assay for TTS._x000D_ • Identification of improved treatment approaches for TTS to improve its prognosis._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ Our work will enable regulatory authorities to assess the relative risk of developing TTS in response to SAR-CoV-2 vaccine against that of becoming seriously ill with COVID-19. This understanding is important to ensure that populations worldwide receive maximum benefit from vaccination programmes. Understanding the mechanism for vaccine-induced TTS will inform development of second-generation COVID-19 vaccines and help to identify new therapies to reduce the case fatality rate associated with TTS._x000D_ _x000D_ Our outputs will be of national and international importance. Initially, we will share new findings with the Vaccine Task Force (VTF), the Joint Committee on Vaccination and Immunisation, and other representatives of the Department of Health and Social Care (DHSC) . The DHSC will determine whether the findings are of ministerial interest. Press releases will be cleared with NIHR, DHSC and the VTF._x000D_ _x000D_ Investigating the Genetic basis for TTS_x000D_ Genomics England, part of the consortium, is leading and funding complementary work investigating the genomics of thrombosis and thrombocytopenia related to COVID-19 and SARS-CoV-2 vaccines. The whole consortium will work together, and collaborate with other researchers worldwide, to develop a better understanding of TTS and maximise public health impact.",3.4 VACCINES,CARDIOVASCULAR;INFECTION HRCS22_13608,Cancer Research UK,CRUK,"Understanding Tobacco Industry Pricing, Profits, and Taxation in Low and Middle-Income Countries","Tobacco tax increases are the most effective way of reducing tobacco use and addressing the inequalities inherent to tobacco use. Past research has found that the Tobacco Industry (TI) uses its pricing strategies to undermine the impacts of tobacco taxes in high income countries such as the UK. What isn’t currently known is if the TI also uses the same tactics in Low and Middle Income Countries (LMIC), whether they are adjusted for local market conditions, and what other strategies are used in such settings in order to maintain or enhance industry profitability. Similarly, little is known about tobacco industry profitability in these countries, or the accuracy of industry reporting on this issue. The goal of this PhD to understand how the industry prices and profits from its products in a variety of LMIC, and hence how policy makers should appropriately respond to address the actions of tobacco companies that are increasingly focusing on LMIC.",,3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING,CANCER AND NEOPLASMS;CARDIOVASCULAR;RESPIRATORY;STROKE HRCS22_15402,Wellcome Trust,,Understanding actin-dependent chromosome cohesion in mammalian eggs,"Every human life starts when an egg is fertilised by a sperm. For poorly understood reasons, eggs frequently contain an incorrect number of chromosomes. This chromosomal abnormality is a leading cause of embryo deaths in humans – it accounts for nearly 35% of miscarriages. Chromosomal abnormality in embryos also leads to genetic disorders such as Down’s syndrome, which affects about 1 in 1,000 live births worldwide. My PhD project is aimed at understanding which cellular processes protect eggs from having an incorrect number of chromosomes before fertilisation. In this regard, I will investigate a recently discovered and unexpected function of the actin cytoskeleton in preventing chromosomal abnormality in eggs. In the future, knowledge obtained from my research project could be exploited to improve the outcomes of fertility treatments as well as prevent pregnancy loss.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_20084,Wellcome Trust,,Understanding and exploiting Group A streptococcal anti-chemotactic proteases in vaccines for infection,"Streptococcus pyogenes is a major human pathogen responsible for a significant global disease burden.  Despite a century of research, there is no effective vaccine, in part due to the existence of multiple serotypes that vary worldwide. Notably, S. pyogenes produces two surface-associated serine proteases that inactivate specific neutrophil chemotactic signalling families. SpyCEP cleaves and inactivates the entire family of neutrophil-active CXC-chemokines including IL8/CXCL8, while C5a peptidase (ScpA) cleaves and inactivates both C5a and C3a. Both SpyCEP and ScpA are major, yet fully conserved, targets in the protective human antibody response against S. pyogenes and are therefore leading candidate vaccine targets. There is, however, minimal structural information to indicate how these proteases function to recognise or cleave their substrates, nor factors that influence activity. We will undertake • Comprehensive evaluation of the structures of each enzyme complexed with substrate • Detailed examination of enzymology and substrate specificity • Systematic study of the expression and role of the enzymes in vivo • Use the above data to develop and design hybrid vaccine antigens to evaluate in vivo   Such information would greatly advance our fundamental understanding about this family of enzymes, providing a platform for novel vaccine antigen design, and future opportunities for drug development.","Group A Streptococcus – also known as Strep A- causes over half a million deaths annually, by triggering rheumatic heart disease in children with repeated minor streptococcal infections, and also by causing more lethal infections and sepsis. These could all be prevented if there was a vaccine active against all types of Strep A. Two enzymes made by Strep A are known to fight the immune response by cutting immune system chemical messengers in two. Understanding how the enzymes work could help design better drugs to fight unwanted inflammation in the future. Most importantly, we know that these enzymes can be used as vaccines against Strep A, but do not understand their structure. In this project we will work out how these two enzymes interact with the chemical messengers, and work out how to adapt the enzymes’ structures to make the best possible vaccine against Group A Streptococcus.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_20575,Cancer Research UK,CRUK,Understanding and harnessing the antigenicity and adjuvanticity of combination oncolytic virus and targeted drug immunotherapy,"Background: during our current programme we have investigated combination immunovirotherapy, including with targeted small molecules. We have uncovered immune-mediated enhancement of the oncolytic viruses (OV) reovirus and herpes simplex virus (HSV), in combination with inhibitors of BRAF, poly(ADP)-ribose polymerase 1 (PARP-1) and CDK4/6. These studies have predominantly focused on tumour cell-intrinsic immune mechanisms, including i) reovirus-mediated activation of cellular PARP1 and PARylation of cellular proteins, leading to enhanced extrinsic apoptosis dependent on nucleic acid sensing mechanisms mediated by RIG-I and TLR3, and ii) combination reovirus/palbociclib augmentation of the endoplasmic reticulum stress/unfolded protein response, leading to increased IFN signalling and endogenous retroviral transcripts. Critically, these combination strategies did not rely on increase in viral replication, supporting the paradigm whereby OV primarily act as immunotherapy. Aims: this proposal builds on our OV/targeted drug data to test immunogenicity in whole animal and human multicellular models. We propose that an increased understanding of both antigenicity and adjuvanticity, which together determine therapy, will inform better design of combination immunotherapy strategies of OV/targeted drugs for clinical testing. To achieve this, we will elucidate the tumour associated antigens (TAA) and tumour immune microenvironment (TIME) changes which are associated with successful combination treatment. Methods: we will focus on melanoma and head and neck cancer, and the immunogenicity of reovirus and HSV in combination with targeted drugs. As TAA, we will investigate i) cancer testis antigens, ii) human papilloma virus proteins, and iii) APOBEC-driven neoepitopes, as a type of neoantigen we have shown to be induced by OV. In addition to established immune readouts of anti-tumour immune activation, we will apply and develop novel assays comprising: i) bioinformatic prediction of TAA immunogenicity using population-based, as well as class I-specific approaches, ii) measurement of epitope presentation by immunopeptidomics (direct by tumour cells and cross-presented by antigen presenting cells), and iii) functional T cell stimulation and priming assays based on predicted/presented epitopes. Testing of therapy in mice will include application of the murine ‘Timer of cell kinetics and activity’ (Tocky) system, to elucidate temporal and dynamic changes in T cell signalling (including antigen specific), which are central to shaping a beneficial treatment response. How the results of this research will be used: this proposal will inform rational strategies, based on detailed mechanistic understanding, of OV/drug combinations to take forward into clinical testing. Our integrated mouse/human antigen/adjuvant pipeline platform can also be applied for mechanistic testing of wider immunotherapy strategies.",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_23303,The Health Foundation,THF,Understanding and learning from the impact of changes in colorectal cancer care delivery in light of COVID-19 and their interplay with socioeconomic inequalities,"The COVID-19 pandemic has resulted in rapid changes to health service delivery, with important implications for cancer care. These changes influence the way in which someone can contact their GP, how people are tested for cancer, how teams come together to determine the best treatment plan, and what type of treatment is offered. Some of these changes will be advantageous to patients (for example, more flexibility), but there are also challenges, and some changes may be beneficial for some and not others. For example, being able to access health care remotely requires a smartphone or a computer, which many do not possess or cannot fully use. Another important consideration is that people from more deprived areas of the UK have worse cancer outcomes than people in less deprived areas (the deprivation gap). There is concern that the rapid changes in care during COVID-19 could have increased the deprivation gap in cancer care. This research project will use colorectal cancer as an exemplar to help understand the impact of changes in cancer care on patient experience and outcomes. The project team will hold interviews with patients from high and low deprivation areas of the UK who have contacted their GP with a concerning symptom during the pandemic, and with health professionals in community and hospital settings. This evidence, combined with information from national guidance documents, will be used to develop recommendations on optimal practice to manage care and protect patients in the context of similar pandemics.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;8.1 ORGANISATION AND DELIVERY OF SERVICES",CANCER AND NEOPLASMS HRCS22_06252,Department of Health and Social Care,NIHR,Understanding and using people’s experiences of social care to guide service improvements:could an effective and efficient co-design approach be translated from health to social care using the exemplar of loneliness?,"Local authorities need to find new ways of collecting and using data on people’s experiences of social care to improve service design and quality. We propose to adapt and test a service improvement approach successfully used in health care settings. We will use loneliness as our focus. Loneliness affects many people and is important to local policy makers. Based on rigorous qualitative research the approach will use carefully selected extracts of people describing their social care experiences in the form of a 20-25 minute film to prompt discussions about how services can be improved. Importantly these discussions involve local authority staff and lay people working as equal partners. _x000D_ _x000D_ There are two stages: 1. DISCOVERY. Interviews with a national sample of 40-50 people exploring their experiences of loneliness and social care, and with 20 social care staff to explore opportunities for service improvement around loneliness. Interviews will be filmed or audio recorded if the person prefers, typed in full and analysed for ‘touch points’ which show positive care moments or areas where services could be improved. A 'touch points' film will be produced. 2. CO-DESIGN involves separate feedback workshops with staff and social care users followed by a joint meeting where the film is shown to both. Participants work together to agree a list of priorities to put in place for improving services._x000D_ _x000D_ Interviews will include those who are less often heard in research e.g. learning disabled people and people from black and minority ethnic groups. Doncaster will be the test site for stage 2 because loneliness is a high risk in many parts of the city and tackling it is a priority for the local authority. Given the challenges that social care research faces in engaging practice and the time it can take to build and sustain links with local authorities it is important to have a willing organisation who are interested in research and are committed to the topic area._x000D_ _x000D_ Working with social care service improvement colleagues from adult social care and Doncaster residents who experience loneliness, we will use observations and interviews to study how improvements are made over a nine month period. Key questions will include i) whether this approach using a film based on a national interview study of social care users and staff perspectives of loneliness would work in a local setting and ii) whether this quality improvement approach is acceptable, or needs adapting, for wider use in social care. _x000D_ _x000D_ Outputs: a section on loneliness based on analysis of the interviews with around 250 film, audio and text extracts published on a new website Socialcaretalk.org; recommendations for the use of this service improvement approach in social care; conference presentations; a new interview collection for the Health Experiences Research Group data archive for secondary analysis; end of project event; three academic papers._x000D_ _x000D_ Anticipated impact: Local authorities need new ways of collecting and using data on people's experiences of social care to improve service design and quality. Our study will draw on and adapt as appropriate an approach from the healthcare improvement field to address this need. The touch point film will be transferable for use in improvement initiatives across other local authority settings. The project will provide valuable learning beyond the immediate project outcomes through a wider engagement strategy with social care partners.","BACKGROUND:Local authorities (LAs) need to find new ways of collecting and using data on social care users' experiences to improve service design and quality. Our study will draw on and adapt as appropriate an approach from the healthcare improvement field to address this need using loneliness as a focus. Loneliness can have a well documented and recognised significant negative impact on the health and quality of life. As a result many and varied preventative and case finding activities are being instigated in the community however there is little evidence to support their effectiveness. Exploring how evidence is created and considered is therefore of great importance._x000D_ _x000D_ AIMS: to assess whether an effective and efficient co-design approach ‘accelerated experience based co-design'(AEBCD) can be translated from health to social care. _x000D_ OBJECTIVES:_x000D_ 1.To understand how loneliness is i) characterised and experienced by people who are in receipt of social care in England and ii) characterised by social care staff and the voluntary sector_x000D_ 2.To identify how services might be changed to help tackle the problem of loneliness experienced by users of social care_x000D_ 3.To test with one LA whether an approach to service improvement, known to be effective in health care, could be adapted for use in social care_x000D_ 4.To disseminate all study outputs and publish resources on a newly established Socialcaretalk.org platform for public, family carers, service users, voluntary organisations, researchers, teachers, policy makers and providers and wider._x000D_ _x000D_ METHODS: In-depth interview study involving a national sample of 40-50 social care users who experience loneliness and 20 social care staff who provide support or manage these services with a remit to tackle loneliness from LAs, private/voluntary sectors. Data will be analysed thematically using a grounded theory approach. A catalyst film will be co-produced capturing touch points (good practice points or examples where services could be improved) from the interview data. Doncaster will be used as the test site for the AEBCD process which will involve workshops with service users, staff and the identification of service improvement priorities. Evaluation of this approach will adopt methods used successfully in the evaluation of AEBCD in health settings including ethnographic observation, attending planning meetings and co-design groups. Our focus will include the acceptability of the approach to social care staff and what adaptations might be needed for future use in social care._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION: Outputs include a new section on loneliness on Socialcaretalk.org; recommendations using AEBCD in social care; and a catalyst film for use across LA settings. Dissemination via social media, conference presentations, third sector organisations and end of project event. Outputs will be relevant to service users,families, health and social care professionals and students, commissioners and service providers. Social care research is somewhat in its infancy in terms of funding beyond NIHR School for Social Care Research. We know that engagement with NIHR agendas in practice has been limited therefore we feel the project will provide valuable learning over and above the immediate project outcomes in terms of a wider engagement strategy with social care partners.",8.1 ORGANISATION AND DELIVERY OF SERVICES,GENERIC HEALTH RELEVANCE HRCS22_20118,Cancer Research UK,CRUK,Understanding evolutionary constraints in sporadic and inherited renal cell cancers,"Background In the interim analysis of the TRACERx Renal study (Tx100) (1, 2), we detected conserved patterns of mutation ordering, co-occurrence and mutual exclusivity, and repeat parallel evolution, in primary tumours, while route to metastases converged on a common genomic solution, copy number alterations. These findings illustrate that cancer evolution is highly constrained by selection. However, the impact of mutation supply, tumour microenvironment (TME) and therapeutic intervention on the opportunity and strength of selection is unknown. ccRCC is an excellent model to explore these questions. Aims 1. Resolving clonal dynamics 2. Understanding the fitness landscape 3. Investigating evolution of von Hippel Lindau Disease 4. Evaluating clonal dynamics through representative sequencing Methods 1. micro-clonal dynamics will be resolved through a mini-bulk sequencing approach 2. the role of TME will be evaluated through immuno-histochemistry and RNA sequencing 3. the evolution of VHL disease will be analysed through bulk DNA sequencing and immunohistochemistry 4. representative sequencing will be performed on homogenised surgical to derive pervasive patterns of clonal evolution. Outputs This programme will derive a fitness landscape map that reveals the most critical steps in tumour evolution, especially triggers of progression, and provide a standardised approach to understanding clonal dynamics and their impact on clinical phenotypes.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_03927,Medical Research Council,MRC,Understanding excess child and adolescent mortality in the United Kingdom compared with EU15+ countries,"The rate at which children die in the United Kingdom is higher than in many other developed countries. I will investigate why this occurs, and thus inform policies to improve UK child survival. In the 1970s UK child mortality rates (the number of child deaths per 100,00 population) were similar to those in comparable wealthy nations, and in many areas the UK performed well. However, although UK child mortality has been falling since then, the rate of decline has been slower than in other countries, and the UK now has one of the highest child mortality rates in Europe. If the UK had a mortality rate similar to Sweden (the best performing country), about 2000 fewer children would die each year, or 5 fewer a day. I will establish an up to date picture of child mortality compared with similar wealthy nations, and then investigate where the UK performs badly - i.e. identify which causes of death and age groups show the greatest difference. The comparator group I will use is the EU15+ - meaning the countries of the EU before 2004 plus Canada, Australia and Norway. Previous studies have shown a high risk of dying around the time of birth in the UK, which has been explained by high rates of early delivery and low birth weights. My project will concentrate on causes of death after the newborn period, where the UK also performs poorly but about which little is known. Previous studies have shown that many outcomes (including mortality) for long-term conditions (also known as non-communicable diseases (NCDs)) such as asthma, diabetes and cancer, are worse in the UK than other wealthy nations. I will look at these causes of death in much greater detail than has been done previously, to identify which causes contribute to the high rates of child mortality in the UK. Because many of these conditions affect teenagers and young adults, the project will focus on deaths in young people to age 24 years as well as in younger children. I will also examine where in the UK children are more likely to die. I will examine whether some of the high child death rates are due to high levels of poverty, social exclusion, and other markers of deprivation which are known to affect child health. Previous research has shown that poverty in the UK is more concentrated among children than adults, in contrast to other European countries, and I will explore if this a factor in high UK child mortality rates. This part of the project looking at social determinants of health will help identify which groups will need particular attention to reduce child mortality, and identify particular policy areas outside of health where intervention could save lives. Finally, I will look at how health services are used in the years before children die in the UK. Previous studies have shown wide variation in the care that children receive for common illnesses in different parts of the country. I will explore whether access to and use of health care services such as outpatient clinics, attendances to Accident and Emergency departments, and rates of missed appointments prior to death, and the way these vary across England, may be related to greater risk of dying. I will use data on causes of death collected routinely by national statistics offices in England, Wales, Northern Ireland and Scotland. These organisations also provide data on levels of poverty and inequality needed for my analysis. This information can be linked with data collected by hospitals on which children were admitted, had clinic appointments, or attended emergency department, to describe use of health services before death. I will describe patterns of UK child mortality in detail and identify which groups are at greatest risk and how much deprivation and healthcare factors are related to this risk. My findings may enable effective policies to be developed to reduce child deaths in the UK, a key healthcare priority. Technical Summary Background: There is growing concern that mortality outcomes for children and young people (CYP) in the UK have lagged behind other wealthy countries, and the UK now has one of the highest CYP mortality rates in Europe. Aims: To investigate the causes of excess UK CYP mortality outcomes by 1) updating international comparisons of CYP mortality trends 2008 - 2015 between the UK and EU15+ countries (the pre-2004 European Union plus Norway, Canada, Australia); 2) identifying causes of deaths with excess CYP mortality relative to EU15+ nations; 3) understanding demographic, socioeconomic and regional variation in excess UK CYP mortality; 4) assessing the contribution of health systems factors to explain variation in UK CYP mortality. Methods: Data sources: WHO World mortality database for international comparisons (grouped and primary cause of death). Mortality and socioeconomic variables from Office for National Statistics (ONS) (England and Wales), and equivalent national databases for Northern Ireland and Scotland. ONS data will be linked with Hospital Episodes Statistics (HES) to analyse healthcare utilisation in domains of excess CYP mortality in England. Analyses: Study(S)1: Compare trends in UK total and cause mortality by 5-year age group (0-24) and sex, to EU15+ countries 2008-2015 S2: Identify groups of causes of CYP mortality (post-neonatal to 24 years) where the UK has excess mortality compared with the EU15+ from 2000-2015. S3: Analyse variation in CYP mortality within the UK for groups of causes by level of deprivation and local measures of income inequality. S4: Explore the contribution of health service utilisation prior to death and individual demographic factors (as exposures) to mortality risk in England (as outcome) in groups of causes where the UK has excess mortality.",,2.4 SURVEILLANCE AND DISTRIBUTION,GENERIC HEALTH RELEVANCE HRCS22_07004,Health Education England,HEE,Understanding factors which affect willingness to self-manage a pessary for pelvic organ prolapse: A mixed methods study aiming to improve access to pessary self-management.,"Pelvic organ prolapse is descent of the uterus, vaginal compartments and/or neighbouring organs which causes bothersome symptoms for 10% of UK women. While surgical management is an option, mechanical support from a vaginal pessary provides alternative, effective management. Pessary follow-up tends to be biannual which requires significant healthcare resources and is burdensome for women. Self-management is the woman's ability to remove and reinsert her pessary. In addition to reducing hospital appointments, self-management offers women autonomy regarding how to use their pessary. Pessary self-management was identified by patients and healthcare professionals as a James Lind Alliance priority for research in 2017. There is currently an NIHR funded study exploring whether pessary self-management improves quality of life. Recruitment has highlighted many women are unwilling to self-manage their pessary. At present there is a dearth of evidence regarding factors which affect willingness to self-manage. Barriers previously reported include; physical inability; preference for clinician-led care; difficulty; the intimate nature of pessary self-management; pain; emotional barriers; age; insufficient cognitive ability; inability to attend self-management teaching, personal circumstances and lacking willingness. Further exploration is required to understand causes of the lack of willingness and whether this can be overcome. Research aims To determine whether women can remove and insert their shelf or gell-horn pessary To gain a deeper understanding of factors affecting willingness to self-manage a pessary for prolapse To investigate the presence of these factors in a larger population of pessary users and prioritise the influence of factorsClinical aims To develop a questionnaire for clinical practice to help women identify and communicate concerns about pessary self-management To develop resources to help women overcome factors that influence their willingness to self-manageExploratory sequential mixed methods underpinned by a pragmatic paradigm will be used. The methods will incorporate quantitative findings which inform sampling, qualitative interview and quantitative questionnaire data collected using The Delphi technique. Work package 1- Study of 45 shelf and gell-horn users at Manchester University NHS Foundation Trust (MFT) to determine whether women are able to insert and remove these pessaries. Work package 2- Grounded theory exploration of factors which affect willingness to self-manage a pessary. Data will be collected through semi-structured interviews with 20-30 women with the initial sample recruited at MFT. Work package 3- Delphi survey questionnaires completed by 30 women who don't self-manage their pessary from 5 UK hospitals. Respondents will quantify and prioritise factors which affect willingness to self-manage. Work package 4- Creation of a clinical questionnaire and resources to support women to overcome factors which affect willingnessIf factors negatively affecting willingness to self-manage a pessary can be overcome through support or education, this may increase the number of women empowered to self-manage. Findings will be submitted for presentation at conferences and publication. The applicant will utilise her position on the National Pessary Best Practice Group to ensure findings are disseminated to clinical leaders. Findings will also be shared via Facebook support groups for women with prolapse, on Twitter, in an e-newsletter and a webinair.","Pelvic organ prolapse caused by weakness in pelvic floor muscles causes bothersome symptoms for 1 in 10 UK women who have given birth. Symptoms include a bulge protruding into or outside the vagina, dragging discomfort and difficulty emptying the bladder or bowels. Prolapse can be managed with a mechanical device called a pessary (Appendix 1-image of pessaries) or by surgery. Comparisons of surgery versus pessary show both options improve quality of life. A pessary is inserted while the woman is awake in clinic and needs to be removed on a regular basis. At each appointment, the doctor or nurse removes the pessary, checks the skin inside the vagina and inserts a new pessary. In the UK, pessary follow-up is usually performed every 3-6 months. In other countries, women are taught to remove and reinsert their pessary independently; however a survey of practice in the UK showed only 17% of women are offered this. A project in Cambridge suggested some women prefer self-management. There is no published research on reasons women may or may not be willing to self-manage pessaries. It is important to understand this so we can develop ways of enabling women. Therefore this study plans to research factors affecting willingness to self-manage a pessary for prolapse. There are 4 work packages: 1-Investigating whether women are able to remove and reinsert shelf and gell-horn pessaries 2-Qualitative in-depth exploration of factors affecting willingness to self-manage a pessary will be undertaken by conducting semi-structured interviews with pessary users. 3-Using data from interviews, a list of factors that affect willingness to self-manage a pessary for prolapse will be generated. Using consensus technique, a questionnaire will be developed and sent to pessary users across the UK to evaluate whether these concerns and fears are issues for them and score the factors in terms of influence. Agreement on factors will be achieved by repeated rounds of questionnaires. 4-A further clinical questionnaire will be developed based on information collected in work packages 2 and 3. The questionnaire will be completed in clinic by women who have concerns but wish to self-manage. Women will complete the questionnaire to identify and communicate their specific areas of concern. Resources will be developed to support women to overcome their specific barriers to self-management. This research aims to support and facilitate woman-centred care; therefore collaboration with pessary users is essential. Two pessary users will be invited to be members of the project steering committee to offer guidance and support throughout the study. They will also contribute to questionnaire design, revision and data analysis to ensure themes and concepts important to pessary users are prioritised and analysed from the perspective of a service user. In addition, patients attending a service user group meeting at Saint Mary's Hospital and members of a national patient group will be asked to advise upon study literature, the research proposal and development of the clinical questionnaire and resources to support self-management. Findings of the study will be submitted for presentation at national and international conferences and for publication within relevant journals. Findings will also be posted out to all study participants and shared using social media targeted at women with an interest in prolapse and pessary care. Results will also be disseminated to appropriate clinical forums including The Pessary Best Practice Guideline Group, which the applicant is a member of, to ensure findings are translated into practice and benefit future women.",7.1 INDIVIDUAL CARE NEEDS,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_01933,Medical Research Council,MRC,Understanding individual differences in facial emotion perception and their association with psychiatric risk indicators,"The aim of this project is to understand why atypical processing of emotional facial expressions is associated with many clinical disorders. Although it is well established that atypical processing is associated with increased psychiatric risk, the cognitive basis of atypical processing is not known, and this has prevented progress in diagnosis and treatment. Knowing why some people show atypical processing requires knowing what emotional expressions look like to different people, but technical limitations have previously made it impossible to establish what an emotional expression looks like to an individual. We have now overcome this limitation by combining ground breaking computer graphics techniques and state-of-the-art behavioural methods. The new tools use genetic algorithms that allow individuals to create the facial expressions that they associate with particular emotions. In each iteration of the algorithm, selected characteristics are bred to create a new 'generation' of facial expressions. The process is repeated until convergent on an expression associated with a particular emotion ('happy', 'sad', 'angry'). We propose to use these 'evolved' faces to gain knowledge about emotion expression recognition in typical and high trait populations, thereby improving clinical and pre-clinical studies of emotional processing. We will use the new tools to allow participants to create their own facial expressions. We will then use machine-learning techniques to quantify and characterise the facial configurations created by typical and by individuals with high trait anxiety or psychopathy. We will use these evolved expressions to establish the role of perceptual differences in atypical emotional processing in high trait groups, by using them in conventional clinical and pre-clinical emotional tests instead of standard faces. We will ensure maximum uptake of our toolkit by making it open access, and easy to use.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,MENTAL HEALTH HRCS22_13432,Wellcome Trust,,Understanding mechanisms that drive pain perception in early human development,"Pain in infancy has negative long-term consequences and its prevention is a clinical priority, but adequate treatment requires mechanistic understanding of the structural and functional development of human nociceptive circuitry. Recent scientific and technological advances provide insights into how noxious information is transmitted to the infant brain, providing a platform to ask how intrinsic brain network connectivity and the environment affect noxious-evoked brain activity, behaviour and ultimately pain perception in the developing infant nervous system. The fellowship goal is to understand the mechanisms that drive and modulate pain perception in early human development. I will ask whether inherent differences in how the brain behaves at rest influence variability in noxious-evoked activity, and will determine how this relationship is altered by environmental factors and pathology. I will establish how the development of structural and functional network connectivity alters noxious-evoked brain activity, and influences the dynamic relationship between brain activity and behaviour. I will translate this mechanistic understanding into clinical practice by conducting a clinical trial of an analgesic (fentanyl) during a minor surgical procedure, and will establish whether our newly-developed measures of noxious-evoked brain activity are suitable for use in infant analgesic dose-finding studies.","Thirty years ago, it was commonly believed that infants do not feel pain. Surgeries were carried out without adequate pain relief, based on the misconception that the infant nervous system is too immature to process pain and on concerns about side-effects of pain relieving drugs. Happily, this has changed, and infants now routinely receive pain-relief during surgery. However, there is still an acceptance that medical procedures – such as taking blood samples, vaccinations, or tongue-tie division – will be performed without pain medication. For a hospitalised infant, medical procedures are an everyday occurence, and the youngest and sickest infants may experience more than 50 painful procedures per day. Given the negative consequences associated with early life pain, which include long-term changes in brain development that are linked to reduced academic performance in school-aged children, improving pain treatment in infants is central to our responsibility to protect children in our care. However, as infants cannot describe their pain, we are reliant on alternative methods to measure pain experience. The fellowship goal is to understand how brain development leads to pain perception; to investigate the consequences of early life pain on brain development; and to develop new pain treatment options for infants.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,MENTAL HEALTH;NEUROLOGICAL HRCS22_23279,The Health Foundation,THF,Understanding nurse retention and its impact on patient outcomes in secondary care,"The rate at which nursing and ambulance staff are leaving the NHS is increasing. The number of nurse vacancies has risen to over 40,000 – a record high. The ambulance service has recorded an 80 per cent increase in staff leaving the profession since 2010. These rates are unequally distributed across professions, specialties and geographical regions, introducing inevitable inequalities in patient care. This Efficiency Research project aims to use this variation to detect underlying contributory factors for better or worse nurse and ambulance staff retention, and determine its effect on patient outcomes. A research team from Staffordshire University will use their experience of applying ‘big data’ analytics and unifying large datasets from three previous studies on the effect of nurse staffing on patient safety. There are three work programmes to explore workforce retention and configuration in health care. The first programme will combine and align multiple large datasets from 20 NHS trusts across secondary care and mental health and 10 ambulance trusts. This will enable the analysis of multiple variables and their effect on workforce retention, and how these variables, in combination with workforce retention, subsequently impact patient outcomes. The second work programme will involve designing and testing an infrastructure for the routine extraction, combination and analysis of these large datasets. This will enable the adoption of these techniques across the NHS. The nursing element (NuRS) will start first, with the ambulance staff (AmReS) element following approximately six months later. A third programme will examine the effect of the COVID-19 pandemic on patient safety in terms of reporting behaviours, for example; and will explore how nursing and ambulance workforce configuration in response to a pandemic affects patient safety and quality of care. This project is a unique opportunity to unlock the key underlying drivers of nurse and ambulance retention and determine their impact on care quality, helping to tackle the challenge of supply in the NHS and ensure that high quality, sustainable care is available to all.",,8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),GENERIC HEALTH RELEVANCE HRCS22_15670,Wellcome Trust,,Understanding potential candidates for malarial transmission-blocking vaccines,"Malaria is a deadly infectious disease caused by a parasite called Plasmodium. It has a complex life cycle that involves sexual and asexual stages and can live in both the human host and the mosquito vector. It is challenging to search for effective malarial vaccines as the Plasmodium surface proteins can adapt rapidly and hide from the host’s immune system. Hence, an effective vaccine will require multiple antigens that present on the surface of the parasites at different stages. Transmission-blocking vaccines aim to reduce the infectivity of parasites and prevent the spreading of the disease. The potential candidates for transmission-blocking vaccines are proteins located on the surface of Plasmodium gametocytes, the specialised sexual cells that can be transmitted from human host to the mosquito. We aim to see what candidates for transmission-blocking vaccines look like, using X-ray crystallography and cryo-EM. Together with biochemical and biophysical methods, we are able to investigate their interactions with monoclonal antibodies and understand how these proteins regulate the fertility of the parasites. These studies will provide structural information for developing transmission-blocking vaccines.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_17703,Wellcome Trust,,Understanding signal modulation by the inhibitory immune checkpoints,"Immune checkpoint proteins expressed on the surface of T-cells fine-tune signaling from the T-cell receptor by providing co-stimulatory and inhibitory signals. The manipulation of the receptors that provide the inhibitory signals (‘inhibitory receptors’), using interaction-blocking and agonistic antibodies, holds great promise for treating cancer and autoimmunity. Remarkably little is known, however, about the signaling pathways initiated by the inhibitory receptors, or how their expression at the cell surface is regulated following signaling. Important, unanswered questions therefore are: (1) what makes inhibitory receptors inhibitory - are there shared or convergent inhibitory pathways that can be targeted systematically; and (2) if we want to agonize these receptors, can their downregulation be prevented so that signaling is sustained? This proposal aims to characterize the signaling and surface-modulatory behavior of a set of five immune checkpoints using systematic genetic screens. I will use reporter cell-lines generated to study inhibitory signaling pathways in T-cells to identify the genetic regulators of inhibitory signaling and receptor down-modulation induced by native ligands and by antibody agonists, using a CRISPR/Cas9-based, genome-scale loss-of-function screening approach. The project should yield new insights into how inhibitory signals are generated, and how they might be better harnessed for treating malignancies and autoimmunity.","When specialized white blood cells recognize the signatures of pathogens and cancer, proteins expressed on their surfaces instruct the immune system to clear the threat. Other, inhibitory, proteins expressed by these cells can override these instructions, however, to prevent over-reactions. Recent years have witnessed great excitement over the therapeutic potential of these inhibitory proteins: by blocking their activity, the immune system can be primed to attack cancer cells, whereas enhancing their effects allows unwanted immune responses (e.g. colitis) to be switched off. Despite this excitement, important questions remain: what makes the inhibitory proteins inhibitory, and how is their expression regulated after they exert their inhibitory effects. Using advanced ‘gene-editing’ methods and new assays that I will develop, I will address these questions in ways that haven't been possible previously. A deeper understanding of how these inhibitory proteins work should allow us to build upon the recent, remarkable developments in immunotherapy.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,CANCER AND NEOPLASMS HRCS22_17927,Cancer Research UK,CRUK,Understanding the Global Gist Signal as a Risk Marker for Early Cancer Detection,"Background Humans are experts at the rapid perception of the broad meaning of ‘gist’ of a scene (forest, beach, etc). Medical images are the ‘scenes’ processed by expert radiologists. We have shown that expert radiologists can distinguish normal from abnormal mammograms at above chance levels after viewing them for just 500 msec even when the signs of cancer are quite subtle. We have shown that the signal is not dependent on breast density or symmetry. The gist signal is strongest in the high spatial frequencies and is detectable in images from the otherwise ‘normal’ breast contralateral to the breast with overt signs of cancer. These results suggest that radiologists are detecting a ‘global gist signal’ in the texture of the breast tissue as a whole and not simply fixating on the lesion by chance on a few images. Critical for this proposal, two of our studies show that experts can detect the signal in precancerous images taken 3 years before the onset of cancer itself. Aims A gist signal that is detectable in prior exams could be an imaging risk marker. Our goal is to understand the signal and establish how it might be exploited as a perceptual ‘risk factor’. There are 3 aims. 1) Understand the nature of the gist signal by isolating visual features (spatial frequency and texture descriptors) that support classification with gist and testing its relationship to ‘complexity’ measures estimated using validated quantitative computer methods. 2) Assess the use of the global gist signal as an imaging risk marker that when combined with deep learning methodology can augment deep learning breast cancer risk assessment. 3) Determine if the global gist signal reflects the phenotype of a specific subtype or subtypes of cancer. We will also explore the existence of similar gist signals in cervical, lung, and prostate cancer screening. Method We will use behavioural studies of radiologists and radiographers viewing mammograms. Experimental protocols will include rapid image assessment and self-paced report protocols administered to expert radiologists and radiographers. We will also use image-analysis and pattern-recognition capabilities provided by deep convolutional neuronal networks (CNN) and machine learning. How the results of this research will be used A reliable gist signal could serve as an early warning for breast cancer. It could be used to guide screening and to improve early diagnosis combined with CNN’s into a variety of cancer screening modalities.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_14883,Cancer Research UK,CRUK,Understanding the association between adiposity and aggressive prostate cancer,"Background: Prostate cancer accounted for over 11,000 deaths in the UK in 2016 but there are no established modifiable risk factors for the disease. There is some evidence that relates adiposity (excessive fat accumulation) to aggressive prostate cancer (fast-growing with lethal progression). However, it is unknown if adiposity or its distribution (visceral [fat around internal organs] or subcutaneous fat), promote metabolic and hormonal dysfunction that stimulates the growth of prostate cancer cells, or if late detection explains these associations. Genetic data and better measurements of body composition in large population studies and international consortia now give us the opportunity to assess these associations more reliably. Aims: The main aim is to understand how adiposity and its distribution relate to aggressive prostate cancer. For this, I will study whether men with genetic predisposition to higher total adiposity or a specific fat distribution (alleles associated with decreased subcutaneous but increased visceral fat and insulin levels, or vice versa) have a higher risk of aggressive prostate cancer. I will also investigate potential metabolic and hormonal pathways that may underlie these associations. Methods: I will use data from two large international consortia and from UK Biobank, the largest population study using gold standard methods to quantify body fat. I will first determine whether men with genetic predisposition to higher adiposity or a specific fat distribution (visceral or subcutaneous) have a higher risk of aggressive prostate cancer, using data from the PRACTICAL consortium. Secondly, I will assess the relationship of blood biomarkers related to adiposity (i.e. C-peptide, glucose), including their genetic determinants, with the risk of aggressive prostate cancer using individual participant data from the EHNBPCCG prostate cancer consortium and PRACTICAL. Finally, I will investigate how adiposity and its distribution (using phenotypic and genetic data) relate to other biomarkers previously linked to prostate cancer development (i.e. insulin-like growth factor-I, C-reactive protein, sex hormone-binding globulin, oestradiol, free testosterone) in UK Biobank. How the results of this research will be used: Identification of adiposity or its distribution as the only modifiable risk factor to prevent aggressive prostate cancer should promote the development of clinically-based and public health interventions to tackle obesity. This study will inform which biological pathways should be examined in more detail to increase our understanding of this complex relationship, which may help to identify new targeted preventive interventions for men with excess adiposity and/or clinical prognostication in men with prostate cancer.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,CANCER AND NEOPLASMS HRCS22_07083,Department of Health and Social Care,NIHR,Understanding the factors that shape care homes’ responses to Government COVID-19 guidance on visiting arrangements,"Background While effective in limiting Covid-19 transmission, restrictions on family visits to care homes for older people can negatively impact residents emotional, cognitive and physical health and cause distress for families.1,2 Government has published guidance for care homes on establishing visiting policies that balance these risks, subject to local-area risk assessments from Public Health Directors.3 The guidance states, the first priority must remain preventing infections and visiting policy should still be restricted with alternatives sought wherever possible. However, it guides homes to develop a policy for limited visits which is made available and/or communicated to residents and families. This is challenging and potentially sensitive, with significant lobbying for increased access on compassionate and human rights grounds.4,5,6 Experience is evolving and care homes will manage these challenges differently.7,8,9,10 Research aims and objectives We will identify: range and diversity in care homes interpretation and implementation of guidance how scope for personalisation afforded by the guidance is reflected in policies need for, and use of, support (guidance, tools, assistance) to develop and implement policies perspectives on how policies are working; including feasibility, acceptability, equity and other impacts consultation with families and other stakeholders, including challenges, achievements and influence on policies how policies are communicated to residents, families and others; perspectives on how well this worked and why whether family members find policies understandable, fair and proportionate, and why how characteristics and circumstances of care homes, and contextual factors, influence all of the above The evidence generated by our study is intended to inform ongoing policy and practice during the current pandemic and be of relevance in the event of future epidemics and pandemics. Methods Stage one (months 1-6): To understand range and diversity and generate theory, we will administer a semi-structured questionnaire to care home managers or nominated senior staff (20 minutes; online or telephone) and review policy documents across 200 care homes, purposively-sampled. This provides sufficient breadth and depth and a sampling pool for later stages. Stage two (months 6-12): We will further develop explanatory analyses using twenty cases theoretically-sampled from the participating homes, involving 1-3 in-depth interviews with care home managers and nominated senior staff. Stage three (months 6-15): Thirty to thirty-five in-depth interviews with family carers, purposively-sampled to reflect diversity, will be conducted to explore understanding and views of care home policies. In all stages, data from will be thematically-analysed using NVivo; range and diversity will be fully described and patterns in the data identified and articulated.16,17,18 Findings will be refined and interpreted, and policy implications considered in consultation with our expert advisors and experts-by-experience. Supported by LSE and Care England s media and communications teams, we will monitor updates to Government guidance and key developments throughout to inform data-collection, analysis and interpretation. Three policy briefings and three peer-reviewed journal articles will be produced and promoted through our websites, professional networks, social media and public platforms. We will run joint webinars, give presentations and produce lay summaries.","During the pandemic, many families have been unable to visit relatives living in care homes. This is to prevent the spread of Covid-19 but can be harmful for care home residents emotional, mental and physical health and distressing for families. Government has recently published guidance for care homes. This states, the first priority must remain preventing infections and visits should still be restricted with alternatives sought wherever possible, but recommends care homes develop a policy for limited visits, to be made available and/or communicated to residents and families. Care homes must follow advice from their local Public Health Director and the guidance tells them what factors to consider but care homes otherwise choose their own policies. It is extremely difficult to strike the right balance, and many carers and organisations are arguing for more in-person visiting on compassionate and human rights grounds. Our study will find out: how care homes have applied the guidance to develop their policies how personalisation, encouraged in the guidance, is reflected in policies what help, other than the guidance, care homes have used or needed whether managers and staff think their policies are workable, acceptable and fair what consultation has been carried out with residents, families and others, and how this has influenced policies how policies are communicated, how well this has worked and why whether family members find policies understandable, fair and proportionate, and why the most important factors that influence all of the above We will select 200 diverse care homes, review and compare their written policies and, using a questionnaire (completed online or by telephone), ask care home managers (or a senior staff member) about using the guidance and their policies. Based on what we find out, we will choose twenty of the homes and speak in more depth with the care home manager and other staff. We will also interview 30 family carers to find out about their views and experiences. We will consult an expert advisory group and a group of five experts-by-experience (two of whom input into this proposal) at three stages in the project to help us refine and better understand the implications of emerging findings. Two of our research team are experts-by-experience. Margaret is an ex-carer for her husband who had dementia, a trustee and volunteer with carers support organisations. She will support the experts-by-experience group. Sarah is a family carer for her mother who lives in a nursing home and will work as a researcher on all aspects of the study. Study outputs (briefings, summaries and timely journal papers) will be promoted through our websites, professional networks, social media and public platforms. We will run joint webinars, give presentations and produce lay summaries.","8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_18411,Cancer Research UK,CRUK,Understanding the impact of hypoxia dynamics on therapeutic response in breast cancer,"Background: Hypoxia, resulting from an imbalance between oxygen delivery and consumption, is a common feature of most solid tumours that is clinically associated with therapeutic resistance. It is also a highly dynamic feature, with fluctuations recorded on time scales ranging from seconds to days. Current knowledge of the magnitude, timescale and spatial distribution of hypoxia dynamics is fundamentally limited by our inability to visualise hypoxia in vivo at adequate resolution and derive mechanistic insight into the relationship between haemoglobin oxygen delivery and tumour tissue hypoxia. Aims: Our aim is to better understand hypoxia dynamics in vivo and evaluate whether this knowledge can be used to aid precision therapy in breast cancer. The workflow of the proposal runs through 4 objectives: 1) Develop and validate photoacoustic imaging (PAI) assessment of hypoxia dynamics based on transient blood flow changes in vivo; 2) Establish a computational framework for modelling hypoxia dynamics in silico; 3) Test the relationship between the observed magnitudes and timescales of oxygenation changes and therapeutic response in vitro; 4) Apply the integrated framework from objectives 1 – 3 to precision therapy in mouse models. Methods: Our multidisciplinary team brings together the required expertise of in vivo imaging, in silico modelling and in vitro cell culture studies to tackle the challenge of understanding the magnitude, timescale and spatial distribution of hypoxia dynamics and their impact on cancer therapeutic response. We propose to use observational data of tumour haemoglobin concentration and oxygenation dynamics measured using PAI to inform mathematical models that can reveal mechanistic causes of dynamic behavior and predict the resulting tissue oxygen saturation. Our predictions can then be tested and refined using in vitro and in vivo studies. How the results of this research will be used: The framework developed here will provide us with fundamental insight into the magnitudes, timescales and spatial distributions of hypoxia dynamics in breast cancer. It will also allow us to test the interaction of novel therapies with the hypoxic solid tumour microenvironment. The framework could, in the future, be applied to a range of other cancer models in which hypoxia is also known to be a key factor in therapeutic response, including head and neck, and colorectal cancers. Future work should examine how the identified PAI techniques could be practically adapted to clinical implementations of the modality with appropriate validation and how they might be integrated into the clinical pathway for improved patient management.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_12940,Cancer Research UK,CRUK,Understanding the impact of immune tolerance within the liver microenvironment on efficacy of immune checkpoint inhibitors,"Background Patients with melanoma liver metastases have inferior response to checkpoint inhibitors (CPI) compared to those without, resulting in decreased survival. Aim To assess whether cross-talk between melanoma cells and cells within the liver microenvironment alters the milieu of inflammatory modulators/immune infiltrates and thereby efficacy of CPI. Methods To use reductionist in vitro models combining melanoma cells with liver stromal cells in parallel with in vivo studies and analysis of patient biopsies. How the results of this research will be used Data from these studies will provide rationale for drug development programmes or re-purposing of drugs to use in combination with checkpoint inhibitors in order to increase their efficacy in patients with liver metastases.",,5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_22844,The Academy of Medical Sciences,AMS,Understanding the impact of the Covid-19 pandemic on the mental health of children and young people with pre-existing mental health conditions.,"Understanding the impact of the Covid-19 pandemic on the mental health of children and young people (CYP) with pre-existing psychiatric conditions is crucial to provide preventive and early interventions, plan mental health services, and influence policy makers. In this cohort study I will investigate how the different aspects of the pandemic, from social distancing restrictions to the effects on family economics and education, interplay with pre-Covid individual and socio-demographic characteristics, at present and as the pandemic evolves, to differentially impact on the mental health of CYP attending Child and Adolescent Mental Health Services (CAMHS). I will use the innovative My-Health-E system to contact the over 4000 families attending CAMHS at South London and Maudsley (SLaM) NHS Foundation Trust with a unique link to the gold standard questionnaire CoRonavIruS health Impact Survey (CRISIS), which we have adapted to the CAMHS clinical population for use in 8 Countries in Europe and Oceania. I will integrate survey data collected every three months with in-depth clinical and service information as extracted from our electronic health records. Finally, I will innovate the way we bring information technology into clinical practice by nesting individual survey reports into the child’s care records to enable timely clinical follow-up; and by measuring how survey responses impact on care provision and support an efficient service planning. The data I can gather with this study are pivotal to effectively respond to the current emergency and to plan for any future scenarios.","The Covid-19 pandemic has created an unprecedented health crisis. Together with social distancing and lockdown, this has caused many psychological and financial problems for children and their families. Children that already have mental health problems may have found that these have worsened. A family's circumstances and services' reduced ability to provide face to face support may make the situation more difficult. In Child and Adolescent Mental Health Services (CAMHS) we have observed that children and young people with pre-existing mental health problems have been affected in different ways, and to different degrees, and yet at present very little research has been completed. As a result, clinicians do not know which patients are at greatest risk and whether the care they provide meets their needs. In this study, I will use an innovative online system to contact over 4000 families attending CAMHS at South London and Maudsley NHS Foundation Trust, and ask parents and young people to complete a survey on how they are coping with the pandemic. I will collect further data at three-month intervals. I will then combine the survey data with clinical and service information to try and understand which factors may cause children and young people to worsen. Finally, I will provide clinicians with a summary of survey answers for each child under their care, to help them provide the right follow-up. This study will provide a clearer picture of which patients may need more clinical support, and will help clinicians meet their needs.","2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;7.1 INDIVIDUAL CARE NEEDS",INFECTION;MENTAL HEALTH HRCS22_19075,Wellcome Trust,,Understanding the impact of ‘near-coding’ variation in human disease,"Rare diseases (prevalence <1/2000) collectively affect >250 million people globally. Current approaches for identifying the genetic cause of a disease focus on regions of the genome that code directly for protein, finding a disease-causing variant in only ~50% of cases. My aim is to identify novel genetic variants outside of these protein-coding regions that lead to disease, and the mechanisms through which they do so. I will do this by applying computational and statistical methods to pioneering large-scale genomic datasets, totalling ~700,000 individuals.  My approach will focus on ‘near-coding’ regions, defined as those directly adjacent to protein-coding sequence that have important functions regulating protein expression. I will use complementary approaches that (a) look for near-coding variants in rare disease patients without a causative coding variant and (b) assess the strength of negative selection acting on categories of near-coding variants to predict which are deleterious and cause disease. The findings from my work will be translated into clinical care to enable more patients to receive a valuable genetic diagnosis. In addition, increasing our understanding of the near-coding variant types that are deleterious will inform on genetic mechanisms underlying disease and suggest novel therapeutic strategies.","Over 250 million people globally have a rare disease. For these individuals, and their families, identifying the exact genetic variant that causes the disease has enormous value for diagnosis, screening and personalised treatment. This knowledge can also reveal the biology behind why the disease developed, suggesting new therapeutic strategies. Current clinical screening approaches are limited in the regions of DNA they assess, only looking at those that directly encode proteins. These methods identify disease-causing variants in only ~50% of patients. I aim to improve our understanding of genetic variants outside of these protein-coding regions to identify those that cause rare disease. I will do this by applying state-of-the-art statistical and computational approaches to large datasets of individuals with and without rare disease. This work will inform clinical genetic testing guidelines, enable more patients to receive a valuable genetic diagnosis, and improve our understanding of the genetic mechanisms leading to disease.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE HRCS22_19251,Cancer Research UK,CRUK,Understanding the mechanisms how long noncoding RNAs control genome stability in cancer,"Genome stability is paramount to cellular homeostasis throughout the human lifespan. Cells have developed several surveillance mechanisms to protect the genome from mutations and ensure faithful duplication and transmission of the genetic material. Defects in any of these mechanisms leads to genome instability, which drives cancer evolution and contributes to tumour heterogeneity, drug resistance and poor prognosis. Protein-mediated mechanisms controlling genome stability are well described, however, the biological and regulatory function of RNA-based mechanisms in this context, and in particular the contribution of long noncoding RNAs (lncRNAs), is largely unknown. With an RNAi-based phenotypic screen, I identified novel lncRNAs linked to chromosome mis-segregation, a process common to different types of cancer. I will focus on two nuclear-localised lncRNAs whose expression is altered in renal cell carcinoma (RCC), and investigate the mechanisms through which lncRNAs regulate genome stability and their relevance to cancer. Aims (1) Functionally analyse the lncRNA loci (DUBR, PP7080) involved in chromosome segregation fidelity and determine the nature of chromosome segregation errors (CSE) in lncRNA-depleted cells; (2) Identify the mechanisms underlying the role of these lncRNAs in genome stability; (3) Determine whether lncRNA dysregulation contributes to genome instability in RCC. Methods Aim 1. I will employ different loss-of- and gain-of-function methods to functionally analyse lncRNA loci and ascertain whether CSE in lncRNA-depleted cells arise from pre-mitotic and/or mitotic events. I will investigate the impact of lncRNA absence on aneuploidy (unbalanced karyotype) and genome instability by analyzing p53 activity, DNA damage response and chromosome alterations in normal diploid human cell lines. Aim 2. I will use complementary systems-wide approaches to identify the role of lncRNA-regulatory networks in genome stability. I will profile the transcriptome of lncRNA-depleted cells and identify lncRNA-DNA and lncRNA-protein interactions. I will investigate the functions of lncRNA interactors through rescue experiments and determine long-term consequences of lncRNA depletion on genome stability. Aim 3. I will test the role of DUBR and PP7080 in maintaining genome stability in normal renal cell lines, and translate in vitro findings into a mechanistic understanding how lncRNAs contribute to genome stability in RCC. How the results of this research will be used My research will provide fundamental mechanistic insights into the role of lncRNAs as important yet unexplored guardians of genome integrity. Understanding how defects in RNA-mediated mechanism contribute to genome instability in cancer will pave the way for novel RNA-based strategies to improve diagnosis and treatment of cancer patients.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_19622,Cancer Research UK,CRUK,Understanding the multicellular dynamics of clear cell renal cell carcinoma from initiation to the response to systemic therapy,"Background Half of all patients diagnosed with clear cell renal cell carcinoma (ccRCC) will succumb to the disease. This is despite the extremely long latency period with the first mutation acquired many decades prior to diagnosis. As a surgeon, I am particularly motivated to help improve the risk stratification and direct therapy for those patients who appear to present with localised disease only to relapse with metastasis after surgical resection. Aims This research proposal aims to discover the functional dynamics of ccRCC; from the initiating events, to small renal masses, through to higher risk tumours and their response to systemic therapy. I will also seek to understand the functional heterogeneity in the multi-cellular microenvironment of a range of ccRCCs, focussing on the differences between high-risk and low risk disease. Methods The transforming events that underpin the development of clear cell renal cell carcinoma will be quantified through the functional interrogation of early cancer cell clusters and the non-cancerous at risk cell population with chromosome 3p loss. Multiregional single cell RNA sequencing with bulk whole exome sequencing of low versus high risk renal cell carcinomas will allow us to chart the functional changes throughout a tumour’s evolution and delineate the trajectory from indolence to metastasis. These methods will also be applied to patients undergoing neo-adjuvant therapy, comparing the single cellular function microenvironment from pre-treatment biopsies and post-treatment nephrectomy specimens. How the results of this research will be used Understanding initiating events may inform possible preventative strategies, particularly for those patients with familial renal cancer in whom the penetrance of cancer approached 80%. The discovery of key functional differences between high and low risk disease will aid the applicability of molecular based decision making to help reduce the incidence of relapsed disease following surgery with curative intent. Examining the response to systemic therapy will help aid our understanding of tumour sensitivity or resistance, paving the way for intelligent design of combinatorial treatments.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS,CANCER AND NEOPLASMS HRCS22_13321,Marie Curie,,Understanding the number of people who die in poverty,"A crude analysis of poverty risks and mortality rates suggests that around one in five people are likely to die in poverty. However, a more complete picture needs to take account of how costs and incomes change at the end of life, how pathways into poverty at the end of life develop, and how this varies for different population subgroups. This project seeks to address these issues using secondary analysis of quantitative data. A key aim will be to produce ‘headline statistics’ of the number of people dying in poverty, and in hardship, taking account of the additional costs of terminal illness. This will be accompanied by more detailed findings to provide a deeper understanding of how the relationship between poverty and mortality differs according to key characteristics such as age, sex, ethnicity, location, and socioeconomic position. Analysis of administrative data, including mortality and life-expectancy statistics, as well as small-area data on income/poverty, will provide a starting point in comparing geographical areas with different socio-economic profiles. The relationships between poverty and mortality at an individual level will be explored in more detail using data from large household surveys, including Understanding Society and the English Longitudinal Study of Ageing. The latter includes longitudinal information on finances and is linked to mortality statistics, so will be particularly valuable for the proposed project. This analysis will likely involve multiple regression to explore associations between poverty and mortality controlling for other factors, and more complex methods such as survival analysis and selection modelling to refine these estimates. The findings will add significant value to Marie Curie’s work to address poverty and hardship at the end of life, Specifically, the research could potentially feed into the charity’s ‘Scrap Six Months’ campaign to remove restrictions on terminally ill patients’ access to benefits.","A diagnosis of terminal illness is devastating for anybody. But the impact can be compounded by the stress of financial hardship and its consequences, such as poor housing and fuel poverty. This can be further exacerbated by the (often substantial) financial impact of having a diagnosed terminal illness – whether through direct costs such as residential care and transport to hospital or, for working age people, through loss of income. This project seeks to find out just how common it is to die in poverty in the UK, particularly after being diagnosed with a terminal illness. A rough estimate based on official mortality and poverty rates suggests that around one in five people are likely to die in poverty. However, this doesn’t give us the full picture. We know that costs and income change at the end of life, and that the route into poverty is not the same for everyone who experiences financial hardship. We also need to consider the ways in which key characteristics such as age, sex, ethnicity and location might influence the risk and experience of poverty at the end of life. To address these issues, we will carry out statistical analysis using information collected routinely by the NHS and the Government on mortality rates and poverty in the UK. We will also use information from large household surveys that collect information on both health and financial circumstances, to increase our understanding of how poverty and mortality are linked in different groups within the population, and how the financial costs of ill health might vary. We hope the findings will help charities like Marie Curie continue to campaign to reduce poverty and hardship at the end of life, for example by removing restrictions on terminally ill patients’ access to benefits.",7.2 END OF LIFE CARE,GENERIC HEALTH RELEVANCE HRCS22_23194,The British Academy,,Understanding the psychological risk factors for believing political misinformation by merging neural network and multiple regression models.,"In the last few years, work has begun to diagnose the individual risk factors associated with believing political misinformation. However, many of these factors have been considered in isolation. Since many psychological factors covary, it is vital to understand which factors predict vulnerability to misinformation above and beyond other factors. Historic techniques for evaluating the most important predictors in a dataset have some limitations. Multiple regression is prone to overfitting, reducing the likelihood of replicability. Machine learning techniques (i.e. neural networks) are criticized for their lack of transparency. This work will use state-of-the-art techniques to merge the outputs of neural networks and multiple regressions to better understand the combination of features which best predict vulnerability to misinformation. This project will find a model with the (out-of-sample) predictive power of a neural network and the transparency of a multiple regression model.",,1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES,GENERIC HEALTH RELEVANCE;MENTAL HEALTH HRCS22_02079,Medical Research Council,MRC,Understanding the relationship between depression and trajectories of physical multimorbidity accrual: longitudinal analysis of UK Biobank data,"Importance and aim. Multimorbidity poses major challenges to researchers and to health systems. Physical condition-depression multimorbidity is particularly interesting because it is common, appears to have a bidirectional relationship, and is associated with worse outcomes. The aim of this study is to use UK Biobank data to identify trajectories of physical condition accrual in middle and older age, and examine how associations with depression at both baseline and follow-up. In objective 1, we will build on our previous work to define which conditions we are going to count, and define trajectories of physical condition accrual in three ways: (1) Unweighted counts of number of conditions incident during follow-up; (2) Latent class trajectory modelling to classify patients in terms of the count trajectory, and; (3) Agglomerative hierarchical and k-means clustering to classify patients in terms of the types of conditions they accrue during follow-up. We will additionally define a number of measures of depression at both baseline and follow-up. In objective 2, we will examine how baseline depression (and sociodemographic, lifestyle and risk factor characteristics) is associated with subsequent physical condition accrual using Poisson regression and multiple event survival analysis (outcome = condition count) and multinomial regression (outcomes = count trajectory and trajectory-by-condition-cluster cross-classification). In objective 3, we will examine how physical condition accrual during follow-up is associated with subsequent incident and recurrent depression using logistic regression for multiple depression phenotypes. Outputs. The substantive findings will be of widespread interest, but the derived variables (individual morbidities, trajectories and condition clusters) and methods will also support future studies in Biobank using blood assay and genotype data, and implementation in other datasets.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",GENERIC HEALTH RELEVANCE HRCS22_06442,Department of Health and Social Care,NIHR,Understanding the role of intravenous iron to treat anaemia in survivors of critical illness,"Background Approximately 30-50% of intensive care unit (ICU) survivors leave hospital with a haemoglobin (Hb) of 100 g.L-1 which equates to 'moderate / severe anaemia'. Patients surviving ICU often experience poor health-related quality of life, high levels of fatigue and weakness. Anaemia could be causing some of these symptoms, but the precise contribution it makes, over and above other causes such as deconditioning, muscle wasting and nerve damage, remains unclear.Iron restriction is a major factor underlying anaemia in ICU either because of absolute iron deficiency, iron sequestration (impaired iron trafficking) or functional iron deficiency (imbalance between iron requirements of the bone marrow and availability. Standard biochemistry tests are unable to identify specific causes because of inflammation - which is present in nearly all ICU patients. The discovery of the iron hormone hepcidin has improved our understanding of iron metabolism. Hepcidin is elevated in inflammation where it blocks the duodenal absorption of iron (thereby limiting the efficacy of oral iron) and release from macrophages. Conversely, low hepcidin levels facilitate the absorption of iron and release of iron from body stores. Evidence from other patient groups has shown it can identify absolute iron deficiency in spite of inflammation and it can also predict responsiveness (increase in haemoglobin) to iron (i.e. lower the hepcidin the more likely a response).Available evidence so far has not demonstrated any benefit in using iron to treat anaemia in ICU. This can partly be explained by study limitations but also becuase patients may have simply been too sick to utilise the iron. No trials have attempted to treat anaemia after critical illness where it is plausible that iron utilisation will be greater as inflammation regresses.Aims The overall aim of this fellowship is to undertake a feasibility study to determine whether or not a large multicentre trial of intravenous iron versus placebo in ICU survivors with anaemia can be carried out. Research obejctives to be address in this fellowship 1) To estimate important feasibility and clinical outcomes, such as number of eligible participants, recruitment rates, follow-up rates, metrics of changes in haemoglobin concentration and quality of life scores, which would be required for the larger study.2) To identify the patient characteristics and biological profiles of patients who respond to intravenous iron and whether or not biomarkers such as hepcidin predict response to iron.Research methods To answer these objectives I will use the following methods.1) A feasibility open-label randomised trial of intravenous iron versus no iron (control) in ICU survivors with anaemia. Participants will receive a one-off dose of 1000mg of ferric carboxymaltose within 72 hours of leaving ICU. This contains the equivalent of 2-3 months of oral iron. Intravenous iron is also more efficacious than oral iron as it bypasses the hepcidin-block created by inflammation. Participants will be followed up at 4 weeks, 3 month and 6 months post-randomisation. 2) For all participants, I will analyse their biological (biochemistry, iron, inflammatory and bone marrow) profiles. Novel techniques developed in our institution are now able to provide a functional quantitative result of bone marrow function from a blood test, thereby avoiding the need for a bone marrow aspirate which is invasive and painful. In the group that received iron, I will explore if hepcidin can predict a rise in haemoglobin. Analysis of the control group will help determine which biological factors, if any, are associated with a spontaneous improvement (or lack of) in haemoglobin.Potential impact This research has the potential to treat a common and potentially easily reversible condition, which could alleviate symptoms and improve quality of life in ICU survivors.","Background of the research Anaemia is also known as low red blood cell count or low haemoglobin. Haemoglobin carries oxygen and therefore anaemia reduces the amount of oxygen that is available to the body. Anaemia is very common in intensive care unit (ICU) patients and also in those who leave ICU alive. 164,000 patients are admitted to ICU per year in the United Kingdom. Nearly half of these who survive ICU will leave with a haemoglobin of less than 100 grams per liter (g/L), which is termed 'moderate-severe' anaemia.The body reacts to infection or injury by producing inflammation (an attempt to heal or mend the body). Inflammation is present in nearly all ICU patients. However, whilst doing this, the body is unable to use available iron to make haemoglobin resulting in anaemia because iron is essential to make haemoglobin. Current blood tests are not able to reliably tell us how much iron is available because of inflammation. A new blood test of the main hormone that controls iron in body - hepcidin, has become recently available and may be a better test.Patients who survive ICU often experience high levels of tiredness and weakness resulting in a poor quality of life. These could be symptoms of anaemia, but may also relate to other complications the patient may have experienced during their illness such as muscle wasting and nerve damage. Given that so many patients leave ICU with anaemia, it is important to see whether treating this aspect of their ill health improves their symptoms. To our knowledge, there is no research that has investigated treating anaemia with iron after the patient has left ICU.Aims The aim of this research is to understand the role of intravenous ('through a drip') iron in treating anaemia in patients who are recovering from intensive care.Study design Currently, patients do not routinely receive intravenous iron to treat anaemia after intensive care. I will compare a group of patients who have survived ICU to receive intravenous iron (treatment group) to a group that will not recieve iron (control or 'usual care' group). My objective is to see if this study is feasible. If so, the results would be used to facilitate a larger study involving other hospitals where we would investigate whether treating anaemia with intravenous iron after intensive care improves quality of the life after hospital by treating the symptoms mentioned above. I am using intravenous iron because it works more effectively than oral iron. A one-off injection, lasting 15 minutes, contains the equivalent of 2-3 months of oral iron. Oral iron also has unpleasant side effects such as constipation and nausea. Furthermore, the body is not able to use oral iron because of inflammation whereas it can use intravenous iron. In patients with cancer or kidney problems, who also have inflammation, intravenous iron has been shown to work very well. In this study, a computer will decide randomly (based on chance) which group a patient will be allocated to (randomisation). The control group will not receive any treatment from us. The treatment group will receive the intravenous iron within 72 hours of leaving ICU. I will collect information on how many patients are eligible for the study, how many agree to participate and how many I am able to follow-up after ICU. I will take blood tests, which will include hepciidn, prior to and 4 weeks, 3 months and 6 months after randomisation. These will be looking at the levels of inflammation and iron stores in the body which will further develop our understanding of anaemia after ICU. Patients in both groups will also be asked about symptoms of faitgue and their quality of life using validated questionnaires.Patient and public involvement I have spoken to ICU survivors from our hosptial's ICU support group. Many of them felt weak and tired for a long time after leaving ICU. They were not aware of how common anaemia is after intensive care, the negative impact it could have and what little research into treatment exists for it. They understood why undertaking this research to treat a potentially easily treatable condition has the potential to improve quality of life after ICU.Dissemination of findings of this research The findings of this research will be shared with regional research groups, the local and international academic community through forums and conferences, and to our local and national patient groups. The findings will also be published in highly read intensive care medical journals.",6.1 PHARMACEUTICALS,BLOOD HRCS22_14873,Versus Arthritis,,Understanding the role of messenger RNA regulation in pain nerves during osteoarthritis,"Hyperalgesia is a recognised feature of osteoarthritis which is at least in part due to changes in nociceptor neurons that innervate the joint. Regulation of local protein synthesis by mRNA localisation and cytoplasmic polyadenylation have recently been implicated in nociceptor plasticity. Indeed, we have shown that the polyadenylation inhibitor cordycepin affects pain behaviour in rodent models of osteoarthrits. There is as yet very little knowledge on which mRNAs are localised and polyadenylated in nociceptor neurons and their role in hyperalgesia. In this mulitdisciplinary PhD project, the student will use mRNA tagging, RNAseq and knockdown techniques to: 1) Identify regulated mRNAs in axons of nociceptors during pain signalling in culture system 2) Determine the role of polyadenylation and translation regulation on nociceptor excitability in culture 3) Investigate the role of mRNA regulation in pain signalling using an in vivo mouse model of osteoarthritis. 4) Identify nociceptor axon branch-specific mRNAs and their changes in a mouse model of osteoarthritis This work will improve our understanding of nociceptor function and aid the development of polyadenylation inhibitors as medicines for osteoarthritis pain. It will provide excellent training in advanced RNA biology, microfluidic culturing of neurons and animal models of osteoarthritis for a talented student.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MUSCULOSKELETAL HRCS22_02000,Medical Research Council,MRC,Understanding the structural basis of specificity in mitochondrial lipid transport and its role in drug resistance,"Mitochondrial membrane lipids are either imported from the endoplasmic reticulum (ER) or synthesized at the mitochondrial inner membrane from ER-derived precursor lipids. Recent studies have identified a conserved class of lipid transfer proteins in the intermembrane space, namely the Ups/PRELI family, which ensure intramitochondrial lipid distribution and synthesis by shuttling phospholipids between both mitochondrial membranes. Remarkably, they do this in a highly lipid-specific manner allowing defined alterations in the membrane lipid composition by regulated lipid transfer. Disturbances in the PRELI system play active roles in regulating apoptosis and driving drug resistance in cancer as well as being implicated in other human disease. The crystal structure of the phosphatidic acid transporter revealed some of the basic features of phospholipid recognition, but the basis for lipid specificity of Ups/PRELI proteins and the transport process remained enigmatic. In this new proposal we will apply interdisciplinary approach to understand fully the mechanism of lipid transport and specificity within mitochondria. Advance structural biology methods together with gain-of-function genetic screens in yeast and biochemical assays will uncover the critical determinants that drive specific lipid transport. This proposal will complete our understanding of the molecular mechanism of lipid transfer between mitochondrial membranes and how the lipid homeostasis of mitochondrial membranes is maintained. Using our insight, we will also discover novel ways of manipulating the process, which will new ideas for treating dysregulation but are of broad relevance for other cellular lipid transport processes.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_02903,Medical Research Council,MRC,Understanding the unique properties of the Sin3A histone deacetylase complex in transcription and cell viability,"Histone deacetylase 1 and 2 (HDAC1/2) regulate global histone-acetylation levels as common components of four distinct multi-protein complexes: Sin3A, NuRD, CoREST and MiDAC. These complexes have definitive roles in all nuclear processes, including DNA repair, DNA synthesis and gene expression. Pan-HDAC inhibitors (HDACi) are used in the clinic to treat cancer and depression, although their use is associated with several debilitating side-effects. Our goal is to develop small-molecule inhibitors against each of the four HDAC1/2 complexes using a PROTAC approach, to understand their function in cells and develop novel therapeutics. PROTACs are small hetero-bifunctional molecules which incorporate a known binding moiety to the protein of interest (POI, e.g. an inhibitor), coupled to a ligand for an E3 ubiquitin ligase. Direct recruitment of the E3 ligase to the POI via the PROTAC, targets it for ubiquitination and ultimately degradation. As a proof-of-concept, we have tagged both alleles of Sin3A in embryonic stem cells (ESCs) with an FKBP12-F36V domain, so that it can be degraded by a known PROTAC, dTAG-13. Addition of dTAG-13 to the culture media results in loss of Sin3A protein within 2 hours and a loss of ESC viability by 72 hours. Loss of viability is unique to Sin3A among the range of HDAC1/2 complexes and we would like understand why, at molecular level. Using Sin3A-FKBP12-F36V cells, we now have the ability to address absolutely fundamental questions of Sin3A biology for the first time: (i) what are the direct transcriptional targets of Sin3A and how do these contribute to active transcription; (ii) understand the requirement for Sin3A/HDAC1 in DNA replication and genome stability; and (iii) define specific sites of Lys-acetylation regulated by Sin3A/HDAC1. Furthermore, by using a comprehensive range of deletion mutants we can identify the critical Sin3A domains (PAH1, HID, etc.), and protein-protein interactions they mediate, required for these activities.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,GENERIC HEALTH RELEVANCE HRCS22_14896,Cancer Research UK,CRUK,Unravelling cancer stem cell heterogeneity in myeloproliferative neoplasms,"Background Intratumoural heterogeneity (ITH) underlies many of the challenges we face in cancer medicine, including therapy-resistance, disease progression/evolution and relapse after seemingly effective therapy. New techniques that resolve heterogeneity at the single-cell level are ideally placed to unravel ITH and provide entirely new insights into cancer biology, accelerating the development of new approaches to improve outcomes for patients. The existence of rare cancer stem cells (CSCs) in certain tumours has important implications for ITH, as it is ultimately CSCs that are the unit of evolution and selection by therapy. Arguably, the best characterised CSC-propagated malignancies are chronic myeloid neoplasms, which are excellent tractable disease models for cancer biology. The focus of this proposal is to apply single-cell genomics to study ITH of CSCs in chronic myeloid neoplasms associated with poor prognosis, high rates of clonal evolution and therapy-resistance. Aims To resolve CSC heterogeneity in paediatric myelodysplasia (PMDS), juvenile myelomonocytic leukaemia (JMML) and U2AF1-mutant myeloproliferative neoplasms (MPN) with the ultimate objective of improving precision medicine and therapeutic/biomarker discovery. Methods PMDS: We will analyse PMDS haematopoietic stem and progenitor cells (HSPCs) pre- and post-allogeneic transplantation using high-throughput single-cell RNA-seq (scRNA-seq) combined with a novel method for combined scRNA-seq and mutation analysis we developed (TARGET-seq). Analysis of serial samples will identify HSPC/CSC subpopulations associated with therapy-resistance. Presence of novel HSPC/CSC subpopulations will be correlated with clinical characteristics, follow-up data and laboratory findings to classify patients into distinct disease groups. Identification of CSC subpopulations that predict disease relapse/progression (including after AHSCT) will facilitate therapeutic/biomarker discovery. U2AF1-mutant MPN: We will apply TARGET-seq to analyse HSPCs from a cohort of patients with U2AF1-mutant MPN. Understanding the mechanisms by which such mutation exert clonal dominance in human HSPCs is restricted by the marked heterogeneity found in this compartment, including mRNA-splicing heterogeneity caused by the U2AF1- spliceosome mutation itself. We will combine this large-scale scRNA-seq analysis with state-of-the-art molecular biology and stem-cell assays to identify and validate candidate biomarkers and therapeutic targets, including immunotherapy targets. Potential impact of this research The most tangible impact of this work on patient outcomes is likely to come from better approaches to diagnose, monitor (biomarkers of early relapse) and treat patients with PMDS and MPN.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS HRCS22_01794,Medical Research Council,MRC,"Unravelling signatures of clonal response, resistance and evolution of high-risk essential thrombocythaemia at single-cell resolution","Single-cell genomics techniques have enormous potential to resolve intratumoural heterogeneity, of importance for precision medicine in cancer. However, translating this powerful new technology through to direct clinical application requires evidence that such an approach might benefit patients in specific disease area. The overarching aim of this research is to provide this proof of principle of the clinical utility of single-cell genomic analysis in a disease with an unmet need: high-risk essential thrombocythaemia (ET). We hypothesise that single-cell analysis of haematopoietic stem and progenitor cells (HSPCs) in hydroxycarbamide-resistant/intolerant ET patients in the MAJIC study will reveal considerable heterogeneity reflecting distinct molecular signatures, not detected by mutation screening of bulk cell populations, and will therefore facilitate the identification of novel biomarkers and therapeutic targets. We will use a novel technique developed in the Mead laboratory (TARGET-seq) to carry out this analysis. This technique allows ultrasensitive mutation analysis (with allelic dropout rates <3%) combined with unbiased whole transcriptome analysis of the same cell. No currently published method allows this combined analysis and we believe that this will prove to be an extremely powerful method for precision medicine. The technique also allows identification on non-clonal HSPCs to provide insights into cell-extrinsic disruption in the bone marrow microenvironment in high-risk ET. I am committed to a career as an academic haematologist and am excited about the potential application of single-cell genomics technologies in clinical medicine. This innovative technology is likely to move towards wider clinical application in the coming years and I anticipate that the state-of-the-art training in this field that I will receive, as described in this proposal, will set the foundation for a career as a clinician scientist working in this exciting area of research.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,BLOOD;GENERIC HEALTH RELEVANCE HRCS22_23045,The British Academy,,Unsilencing Sexualised Torture: Identifying and Responding to Sexual Torture Amongst Refugee Survivors of Torture,"Torture is a serious violation of human dignity, but one which remains peripheral to mainstream sociology, often situated instead in psychological studies or international relations. Sexual torture, and sexualised torturous violence (Canning, 2016), is further silenced in all realms of study, in part due to the complexity in identifying or defining what sexual constitutes sexual torture, and in part due to social silencing inherent to the shame and stigma associated with sexual violence more broadly. Using narrative oriented inquiry of 10% of a 1500 case dataset of survivors of torture (n = 150) based at the Danish Institute Against Torture, and focus groups with practitioners, this study aims to: explore documentation of sexualised violence amongst torture survivors; develop an epidemiological dataset on forms of violence inflicted, who by, where (spatially and geographically) and when; and how best to name, respond and address sexual torture amongst survivors of torture generally.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",DISPUTED AETIOLOGY AND OTHER HRCS22_22605,UK Space Agency,UKSA,Unsolved Issues for the Skeleton and role of FGF23-Klotho axis; Contribution of a Bone Digital Twin [Bone On ISS,"Prediction of fracture risk relies on measures of gross bone mass, but bone strength is also determined by bone size, shape, and material properties. This study will investigate the effect of space flight on the material properties of bone using a novel reference point indentation method in the human tibia. Reference point indentation is a novel, minimally invasive, method of measuring bone material properties in vivo at the tissue level by testing the resistance of the outer cortex of the tibia to penetration. A small needle is placed on the bone surface and a micro-indentation (<0.3 mm depth) is made in the cortex in response to a fixed level of force (40 N). By producing a small fracture, the properties of the collagen matrix (alongside other material characteristics) can be tested. Reference point indentation distinguishes between osteoporotic fracture cases and stress fracture cases compared with controls, and is sensitive to changes in bone strength with drug treatments and exercise, even in the absence of changes with state-of-the-art imaging. State-of-the art imaging techniques of weight-bearing and non-weight-bearing bone and analyses of novel blood and urine markers will help us to better characterise the bone response to spaceflight. Measurements will be taken before and serially for up to 2 years after spaceflight on the International Space Station. The aim of this approach is to improve monitoring of skeletal health in response to, and recovery from, space flight. This trial is a collaborative trial and is sponsored by the Europen Space Agency (ESA), the Italian Space Agency (ASI), the German Space Agency (DLR), and the French Space Agency (CNES) and approved to start by ESA on astronauts on-board the International Space Station","Prediction of fracture risk relies on measures of gross bone mass, but bone strength is also determined by bone size, shape, and material properties. This study will investigate the effect of space flight on the material properties of bone using a novel reference point indentation method in the human tibia. Reference point indentation is a novel, minimally invasive, method of measuring bone material properties in vivo at the tissue level by testing the resistance of the outer cortex of the tibia to penetration. A small needle is placed on the bone surface and a micro-indentation (<0.3 mm depth) is made in the cortex in response to a fixed level of force (40 N). By producing a small fracture, the properties of the collagen matrix (alongside other material characteristics) can be tested. Reference point indentation distinguishes between osteoporotic fracture cases and stress fracture cases compared with controls, and is sensitive to changes in bone strength with drug treatments and exercise, even in the absence of changes with state-of-the-art imaging. State-of-the art imaging techniques of weight-bearing and non-weight-bearing bone and analyses of novel blood and urine markers will help us to better characterise the bone response to spaceflight. Measurements will be taken before and serially for up to 2 years after spaceflight on the International Space Station. The aim of this approach is to improve monitoring of skeletal health in response to, and recovery from, space flight. This trial is a collaborative trial and is sponsored by the Europen Space Agency (ESA), the Italian Space Agency (ASI), the German Space Agency (DLR), and the French Space Agency (CNES) and approved to start by ESA on astronauts on-board the International Space Station",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MUSCULOSKELETAL HRCS22_02761,Medical Research Council,MRC,Untangling gene regulatory networks controlling host-pathogen interactions of the antimicrobial-resistant human pathogen Klebsiella pneumoniae,"Klebsiella pneumoniae (Kp) is an important cause of nosocomial and community-acquired infections. Treatment is hindered by the global spread of multidrug-resistant strains, and of special concern are carbapenem-resistant isolates of sequence type ST258. Although Kp is well-characterised from a genomic perspective, our knowledge of the molecular mechanisms underpinning its pathogenicity is still limited. Our aim is to define these mechanisms underpinning Kp infections of eukaryotic immune cells through four complementary work packages. WP 1 will simultaneously profile the transcriptome of ST258 isolate RH201207 during macrophage infection and of the host in response by dual RNA-seq. WP 2 will reconstruct the gene regulatory networks responsible for the transcriptional responses of Kp to macrophage invasion using the complementary functional genomics approaches of ChIP-seq and TraDISort. It will be possible to fully determine the upstream and downstream regulatory pathways of key regulators and reconstruct the complete transcriptional networks. WP 3 will identify the transcriptomic changes under infection-relevant conditions to compare RH201207 to other pathogens such as S. Typhimurium and E. coli as well as a previously published Kp strain. WP 4 will examine the diversity of host interaction within large collections of fully sequenced clinical Kp isolates by analysing their capacity to replicate inside macrophages using fluorescence dilution. This will allow us to perform exploratory genome wide association studies to test the association of mutations and the gene presence between each variant and the potential for intramacrophage replication. The knowledge gained has great potential to establish broadly applicable technologies for studies of bacterial gene regulation networks, identify genes necessary to infect and manipulate host cells which could act as novel antibacterial and antivirulence drug targets and discover pathways of the immune response to Kp exposure",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFECTION HRCS22_03898,Medical Research Council,MRC,Untangling the mechanistic links between heart and brain health in older populations: An AI assisted toolkit for assessing dementia risk,"Dementia is a global public health priority. There is abundant evidence of a strong association between cardiovascular diseases (CVD) and associated risk factors (e.g. hypertension) with dementia risk. Yet, knowledge of the mechanistic pathways linking CVD and brain health is limited. Further, there is a lack of screening instruments to reliably assess risk of dementia and suggest possible interventions for further study. To date, dementia treatment, prevention and risk reduction trials have shown limited success. This is largely due to inadequate knowledge of the disease pathways underlying dementia. Therefore, using Artificial Intelligence (AI) methods synthesising clinical, lifestyle, and socio-demographic data from the Cohort Studies of Memory in an International Consortium (COSMIC), the Emerging Risk Factors Collaboration (ERFC), and UK Biobank, we aim to develop, in people with CVD, novel models for predicting the risk of (1) incident dementia; and (2) dementia-related mortality. The project will be completed in two phases. The first (Months 1-5) will involve secondary data analysis. The aim will be to develop and incorporate novel techniques for advanced analytics, including machine learning architectures, to enhance knowledge regarding correlations between dementia and CVD to establish a better patient-centric disease prediction methodology. We will answer questions like: What are the disadvantages and limitations of current approaches to calculate risk; what are the most important factors driving risk for a particular individual or data cohort; and, how can we incorporate knowledge domain to improve predictions? The second (Month 6) involves dissemination including knowledge sharing and design of a full application focused on translating the models into electronic toolkits. The timing of the study is critical as new approaches are needed to accelerate the development and delivery of precision interventions for dementia risk reduction and prevention.",,2.4 SURVEILLANCE AND DISTRIBUTION;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;7.1 INDIVIDUAL CARE NEEDS,CARDIOVASCULAR;NEUROLOGICAL HRCS22_07730,Department of Health and Social Care,NIHR,Upadacitinib for treating active non-radiographic axial spondyloarthritis [ID3958],"Axial spondyloarthritis belongs to a clinically heterogeneous group of inflammatory rheumatologic diseases which share common genetic, histological and clinical features (also including psoriatic arthritis, arthritis associated with inflammatory bowel disease, reactive arthritis and undifferentiated spondylarthritis). Axial spondyloarthritis involves inflammation of the sacroiliac joints and spine. If inflammation is visible on x-ray (as erosions, thickening of the bone, or fusion of joints), the disease is classified as radiographic axial spondyloarthritis (also known as ankylosing spondylitis). If x-rays of the sacroiliac joints and spine are normal, but there are other objective signs of inflammation (elevated C-reactive protein or evidence on magnetic resonance imaging) the disease is classified as nonradiographic axial spondyloarthritis. _x000D_ _x000D_ The clinical symptoms of axial spondyloarthritis can vary from person to person, but usually develop slowly over several months or years. The main symptoms can include back pain, which will be inflammatory in nature, peripheral arthritis (inflammation in the joints in other parts of the body), enthesitis (inflammation where a bone is joined to a tendon), and fatigue. Extra-articular manifestations include uveitis, inflammatory bowel disease and psoriasis. The average age of onset of symptoms is 24 years, with an average of 8.5 years before a diagnosis is made, by which time damage to the spine which can be irreversible may have occurred. [1] _x000D_ _x000D_ Around 220,000 adults have been diagnosed as having axial spondyloarthritis and an estimated 1 in 200 of the adult population in the UK is affected. [1] Non-radiographic axial spondyloarthritis affects approximately equal numbers of men and women, but there are limited data on the prevalence of the condition. _x000D_ _x000D_ Conventional therapy for non-radiographic axial spondyloarthritis includes antiinflammatory treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy. NICE technology appraisal guidance 383 and 497 recommend tumour necrosis factor-alpha inhibitors adalimumab, certolizumab pegol, etanercept and golimumab as treatment options in people with disease that does not respond adequately to or cannot tolerate NSAIDs. Biosimilar versions of adalimumab, etanercept and golimumab are now available. _x000D_ _x000D_ NICE technology appraisals 719 and 718 recommend secukinumab and ixekizumab as options for treating active non-radiographic axial spondyloarthritis with objective signs of inflammation (shown by elevated C-reactive protein or MRI) that is not controlled well enough with non-steroidal anti-inflammatory drugs (NSAIDs) only if tumour necrosis factor (TNF)-alpha inhibitors are not suitable or do not control the condition well enough._x000D_ _x000D_ References_x000D_ 1 National Axial Spondyloarthritis Society. What are the issues in axial SpA (AS)? Available from: https:// nass.co.uk/about-as/as-facts-and-figures/",To appraise the clinical and cost effectiveness of upadacitinib within its marketing authorisation for treatment of active non-radiographic axial spondyloarthritis.,6.1 PHARMACEUTICALS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_07122,Department of Health and Social Care,NIHR,Update of DG23 PlGF-based testing to help diagnose suspected pre-eclampsia,"Pre-eclampsia is a serious condition that some people develop during pregnancy, usually in the second or third trimesters. It is important that it is timely and accurately diagnosed, as, without treatment, it can lead to significant health risks to mothers and foetuses. In routine antenatal care pregnant people are assessed for their level of risk for and signs of pre-eclampsia. People with suspected pre-eclampsia undergo further tests and if they are diagnosed with the condition they are closely monitored, and sometimes may be admitted to hospital. A type of test, known as the placental growth factor (PlGF) test, is available for use with or without soluble fms-like tyrosine kinase (sFlt), alongside standard assessments and clinical follow-up to help doctors to ‘rule in’ (i.e. to diagnose pre-eclampsia) or ‘rule out’ the condition (i.e. pre-eclampsia is not diagnosed). The PlGF test measures the amount of placental growth factor in a person’s blood. If levels are low, this may indicate pre-eclampsia. Use of this test may provide more accurate and timely diagnosis of preeclampsia and help identify people at lower risk of developing the condition, which could help avoid admission to hospital._x000D_ _x000D_ In 2016 the National Institute for Health and Care Excellence (NICE) recommended two types of PlGF tests - the Triage PlGF test and the Elecsys immunoassay sFlt 1/PlGF ratio - for use in the NHS in England, for ruling out pre-eclampsia between 20 weeks and 34 weeks plus 6 days of gestation. NICE did not recommend two other available tests - The DELFIA Xpress PlGF 1-2-3 test and BRAHMS sFlt-1 Kryptor/BRAHMS PlGF plus Kryptor PE ratio - for routine use. Currently no test is recommended for ruling in pre-eclampsia. NICE’s guidance suggests that further research is done to find out if the DELFIA and BRAHMS tests are accurate in diagnosing pre-eclampsia. The guidance also recommends more research to find out if the Triage PIGF test and the Elecsys immunoassay sFlt-1/PIGF ratio test can accurately rule in pre-eclampsia. Since 2016 new research evidence has become available which potentially addresses NICE’s recommendations._x000D_ _x000D_ We previously carried out a review of the available research evidence and constructed an economic model to determine the benefits and costs of these tests to patients and the NHS to inform the NICE guidance. In our current project, we will be updating the review and the economic model. We will search medical research databases to find new, relevant studies. We will then review the studies in detail, in an organised way using standard research methods. We will summarise and critically appraise the methods and results of the studies and judge whether any of them might be biased, and whether we can trust the results they give.","Pre-eclampsia is a serious condition that can occur during pregnancy, mostly in the second and third trimesters. Without timely and accurate diagnosis, monitoring and intervention it can lead to significant health risks to the mother and fetus. Pre-eclampsia is a heterogeneous and unpredictable condition, and the established method of diagnosis is assessment of standard key clinical signs and symptoms, including blood pressure measurement for hypertension, urinalysis to detect proteinuria and foetal monitoring for evidence of uteroplacental dysfunction with fetal growth restriction. People with suspected pre-eclampsia may be admitted to acute maternity units for initial evaluation and monitoring._x000D_ _x000D_ Tests are available that measure the amount of placental growth factor (PlGF) in blood plasma or serum during pregnancy. PlGF is a protein involved in placental angiogenesis (the development of new blood vessels) and levels rise during the course of pregnancy, reaching a plateau at 26 to 30 weeks gestation. Abnormally low levels of PlGF during pregnancy may indicate placental dysfunction associated with pre-eclampsia. Some PlGF tests measure soluble FMS-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic protein which disables proteins, such as PlGF, which are associated with blood vessel formation. In cases of pre-eclampsia levels of sFlt-1 are higher than normal._x000D_ _x000D_ Use of PlGF-based tests (i.e. PlGF or sFlt-1/PlGF tests) to aid standard clinical assessments may provide an earlier and more accurate diagnosis in people who have signs and symptoms of possible pre-eclampsia. In turn, this can inform care decisions, such as avoiding hospital admission in people with low risk of developing pre-eclampsia.",6.3 MEDICAL DEVICES,REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_06496,Department of Health and Social Care,NIHR,Use of fractional exhaled nitric oxide (FeNO) to guide monitoring of asthma treatment in primary care,"Background to the research Acute exacerbations of asthma place considerable burden on health care resources, with hospitalisations accounting for 52% to 86% of total asthma-related costs. Inhaled corticosteroids are the mainstay of treatment to prevent acute exacerbations. However, standard methods of monitoring asthma in primary care, including spirometry and reversibility assessments, have limited value in predicting future exacerbations. This may result in inaccurate targeting and dosing of inhaled corticosteroids in patients with asthma. Fractional exhaled nitric oxide (FeNO) is an objective marker of steroid-responsive eosinophilic airway inflammation, which may allow for a more targeted and personalised treatment approach. Raised FeNO levels have been shown to be associated with increased risk of asthma exacerbations. However, although NICE already recognises the value of using FeNO to aid diagnosis of asthma, it has highlighted the need for more robust evidence to guide health care professionals in how to use and interpret FeNO measurements when monitoring asthma treatment in patients who have already been diagnosed. Aims of the work My proposed programme of research aims to:Establish optimal FeNO thresholds for monitoring treatment of asthma.Explore health care professionals' views and experiences of using FeNO to monitor asthma treatment in primary care.Plan of investigation To establish optimal FeNO thresholds for stepping up and stepping down treatment in patients with asthma, I propose to conduct a systematic review and individual patient data (IPD) meta-analysis of data from observational studies and randomised controlled trials. For my primary analysis, I will conduct a one-stage meta-analysis. I will use mixed effects Poisson regression to examine the association between FeNO measurements and incidence of acute asthma exacerbations, adjusting for potential baseline confounders, including age, sex, smoking status and co-morbidities. I will construct Receiver Operator Characteristic (ROC) curves and explore different strategies for determining optimal decision thresholds on the ROC curve, including weighted comparison measures and average overall costs of performing FeNO measurements. To explore health care professionals' views and experiences of using FeNO to monitor asthma treatment in primary care, I will conduct semi-structured interviews with a maximum variation sample of 15 to 20 health care professionals based on video-recorded primary care asthma monitoring consultations conducted by study participants. I will lend study participants a FeNO analyser (NIOX VERO, Aerocrine) to use during one or two video-recorded asthma clinics and train them in how to obtain and interpret FeNO measurements according to a FeNO-guided management algorithm whose decision thresholds will be informed by the findings of the systematic review and IPD meta-analysis. I will watch two or three contrasting consultations with each study participant and ask them to talk me through their thought process during each consultation. Data will be analysed using thematic analysis to allow an inductive approach, whereby emerging themes will be grounded in the data collected rather than derived from previous research or researchers' preconceptions. Data collection, analysis and coding will proceed alongside each other until data saturation is reached. Summary of potential benefits to patients and the NHS My proposed research will produce an evidence-based algorithm for FeNO-guided monitoring of asthma treatment in primary care. The systematic review and IPD meta-analysis, whose findings will be available by the end of year 3, will establish optimal FeNO decision thresholds for adjusting treatment. The qualitative study, whose findings will be available by the end of year 5, will inform strategies for implementing FeNO-guided monitoring of asthma treatment in primary care. These research findings will help inform NICE and BTS/SIGN guidance on monitoring asthma treatment and have strong potential for rapid translation into clinical practice within five years of this fellowship being completed.","BackgroundAsthma is a common condition which affects the airways of the lungs. In people with asthma, swelling (also known as inflammation) can occur in the linings of the airways. This inflammation can cause mucus (phlegm) to build up and make the airways narrower than usual. This can lead to symptoms such as wheezing, coughing, chest tightness and shortness of breath. If these symptoms flare up very badly, people may need treatment with medicines to help reduce inflammation in the airways (such as antibiotics or steroids) or even admission to hospital. To try and prevent serious 'flare-ups' from happening, health care professionals may advise people with asthma to take inhaled steroids to keep the inflammation in their airways under control.Most patients with asthma have asthma check-ups at least once a year in their GP surgery. However, the tests used during these asthma check-ups are not always helpful in predicting how likely someone is to have a serious 'flare-up' of their asthma (also known as an exacerbation). Fractional exhaled nitric oxide (FeNO) is a quick and easy breath test which measures inflammation in the airways and predicts more accurately how likely someone is to have an exacerbation of their asthma. However, at the moment, most GP surgeries do not measure patients' FeNO levels during asthma check-ups. The National Institute for Health and Clinical Excellence (NICE) already recognises the value of FeNO in helping health care professionals diagnose asthma. However, NICE has also highlighted the need for clearer guidance on how to use FeNO to make sure that the right people receive treatment with inhaled steroids, and that treatment doses are correctly adjusted in order to minimise the risk of future exacerbations. Aims and proposed methods My proposed research aims to: 1) Find out which FeNO levels should prompt health care professionals to consider adjusting a patient's asthma treatment. I will study the relationship between FeNO levels and risk of future exacerbations by combining the results of several different studies on this subject. Combining these results will help me draw more definite conclusions by allowing me to apply the same definition of exacerbations across all studies, consider the predictive value of individual FeNO measurements (rather than categories or ranges of FeNO measurements), and take into account other factors which might influence the risk of exacerbations, such as age, smoking and other medical conditions. 2) Find out how health care professionals feel about using FeNO to help them decide how to adjust patients' asthma treatment during asthma check-ups.Using the findings of my first study, I will train 15 to 20 health care professionals who perform asthma check-ups in GP surgeries in how to measure and use FeNO to adjust asthma treatment. I will then lend them a machine for measuring FeNO to use during one or two asthma clinics, which I will ask them to record on video. For each health care professional, I will select two or three different video-recorded consultations, and ask them to watch these consultations with me while talking me through their thought process during each consultation.Patient and public involvement I plan to recruit an advisory group of six patient representatives, consisting of people with asthma and carers of people with asthma. The group will meet once during year 3 to help me prepare information leaflets for patients about my proposed study with health care professionals, and ensure that procedures for seeking consent to video-record consultations are acceptable to patients. The group will meet again during year 5 to help me summarise the findings of my research in terms which patients will understand and help me find ways of informing relevant patient groups and the wider public about these findings. Between meetings, I will keep the group updated on emerging findings from my study with health care professionals. Dissemination I will aim to publish my research findings in high quality and widely read medical and scientific journals.I will also aim to present my research at national and international meetings attended by health care professionals who are mainly responsible for monitoring and adjusting treatment in patients with asthma. I will work closely with my research mentors, Professors Ian Pavord and Mike Thomas, to incorporate my research findings into national asthma management guidelines for health care professionals. I will also aim to promote uptake of my research findings into clinical practice by working with a regional network of academics and clinicians based in Oxford, which has links to patients, universities, industry, and health service providers and commissioners.",4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,RESPIRATORY HRCS22_12611,Cancer Research UK,CRUK,Use of structural variants to detect recurrence of renal cancer via blood,"Background Renal cancer has the poorest survival of any urological malignancy, with only around half survive 5 years, with the poorest survival amongst those with widespread or recurrent disease. The disease returns in around a third of patients who have curative surgery, half of whom are potentially curable when identified. Current strategies for detection of recurrent disease are estimated to miss one-third of patients and attempts to improve this have failed. We propose the use of genetic rearrangements seen in clear cell renal cancer called structural variants to detect those patients with recurrent disease earlier and potentially curable. Aims To verify and refine methods using the detection of structural variants in circulating tumour DNA (ctDNA) via blood in clear cell renal cell carcinoma (ccRCC). To validate the effectiveness of these methods for detection of recurrence/metastasis in ccRCC via peripheral samples. To the ability of electrophoresis to provide validation for the detection of circulating tumour DNA To develop a clinic based workflow to enable the use of these methods to facilitate widespread change in clinical practice and patient outcomes via clinical trial. Methods Subjects Fresh frozen tumour samples and matched longitudinal blood and urine samples of ccRCC patients including patients with known recurrent disease. Techniques: The use of sequencing of tumour samples to identify structural variants. The design of primers targeting these structural variants. Identification the presence or absence of tumour DNA in blood and/or urine samples using targeted two step PCR amplicon sequencing. How the results of this research will be used. This research will enable the validation of a method allowing rapid cost-effective detection of recurrent ccRCC after surgery. If successful it will lead to prospective clinical trial with the ultimate aim of widespread implementation and improvement in survival rates and wider economic and social costs.",,4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_03058,Medical Research Council,MRC,Using data to improve public health: COVID-19 secondment,"Events following SARS-CoV-2 infection in the era of delta - Technical Summary Aim: The aim of this project is to understand the risk of adverse health events following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the era of delta among the fully vaccinated and the electively unvaccinated. Research Questions: 1. Among vaccinated individuals in the era of the delta variant of SARS-CoV-2, are there higher rates of an incident outcome in those with and without SARS-CoV-2 infection, before and after adjustment for potential confounders? 2. Among electively unvaccinated individuals (individuals eligible for vaccination that have chosen not to receive it) in the era of the delta variant of SARS-CoV-2, are there higher rates of an incident outcome in those with and without SARS-CoV-2 infection, before and after adjustment for potential confounders? Methods: This research will be conducted using the OpenSafely electronic health records data source, with a start date of 01-06-2021 (when delta was thought to be ubiquitous) and end date corresponding to date of most recent data collection. Individual follow-up will end at the earliest date of outcome event, death, or study end date. Exposure to SARS-COV-2 infection will be defined as the first date of a confirmed COVID event after index date. Each outcome will be defined as the first event occurring within the follow-up period, the events of interest are; Acute myocardial infarction, Ischaemic stroke, Pulmonary embolism, Deep vein thrombosis, Transient ischaemic attack, Subarachnoid haemorrhage and haemorrhagic stroke, Heart failure, Angina, Arterial thrombosis events, and Venous thromboembolism events. Cox regression models with a calendar time scale will be fitted to ensure analyses account for changes with calendar time in rates of the outcome event. Hazard ratios will be estimated for events of different types before and after exposure, and by time since exposure. Results will be adjusted for potential confounders including Sex, Age, Ethnicity, Deprivation, Region, Consultation rate, Number of regular medications, Smoking status, Obesity, previous events, Combined oral contraceptive pill, and Hormone replacement therapy.",,2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES),INFECTION HRCS22_22953,The Academy of Medical Sciences,AMS,Using genetics to understand changes in body weight over time and links to disease.,"My research will go beyond existing studies to establish a better understanding of the relationship between weight fluctuation and diseases linked to obesity, including type 2 diabetes, cardiovascular disease, and stroke. Weight-fluctuations are common in people living with obesity. My project is important because I will assess the contribution of patterns of weight fluctuation derived from longitudinal population data. My project will be a major advance compared to previous studies that have focussed only on establishing links between one measure of weight and disease. I will perform four sets of analysis that address the following questions: 1)What patterns of weight fluctuation occur in a population setting? 2)How does pattern and severity of weight fluctuation correlate with disease risk and mortality? 3)Are there genetic factors associated with variability in weight fluctuation and do these differ from those associated with single time-point measures of weight? 4)Is weight fluctuation causal for disease when accounting for current BMI? I will use primary care data, lifestyle data, and genetic data from 500,000 individuals from the UK Biobank, with follow-up in 23,000 individuals from the Women’s Genome Health Study. Analyses will focus on weight change prior to developing a disease based on longitudinal primary care data. The identification of causal associations between weight-fluctuation and disease will have important implications for public health strategies. For example, if “yoyo” weight trajectories are causally associated with increased disease risk, these findings may help inform future intervention strategies by targeting individuals who experience weight-cycling.","In the UK, over half of all adults are currently overweight, with £10 billion spent each year on treating diseases that are common in people living with obesity, such as type 2 diabetes. While previous research has focussed on links between weight and disease, less is known about the importance of weight-change over time. For example, one person’s weight may increase slowly while another person’s weight “yo-yos” up and down. The limited availability of data in large numbers of people means we know little about the link between weight fluctuation and disease that is independent from a single measure of a person’s weight. My project is novel because I will combine people’s DNA data, health-care records, and lifestyle information to investigate weight-changes. I will test whether or not different patterns of weight-change make getting type 2 diabetes, for example, more likely, or whether simply being overweight is the main driver of increasing disease risk. My project is novel in scale – I will use information from 500,000 individuals that live in the UK. This data will be used to test 1) patterns of weight-change over time and links to disease, and 2) whether our DNA influences how much our weight changes over time. If patterns of weight-change are found to increase disease risk, then this work may help healthcare professionals and patients understand the importance of weight-change. It will also inform future studies that aim to prevent groups of people at risk of developing disease, such as type 2 diabetes.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE HRCS22_17731,Wellcome Trust,,"Using genetics, neurophysiology and longitudinal data to disentangle the complex relationship between sleep and mood disorders.","Emerging evidence suggests that sleep traits could be useful indicators of risk, relapse and potential treatment targets for mood disorders. However, the longitudinal and genetic relationships between sleep and mood disorders are complex and remain poorly understood. In this fellowship, I will address these gaps and build on my previous work by using cutting edge methods in genetic epidemiology, sleep neurophysiology and longitudinal data analysis.   Key goals:   (1) Determine the neurophysiological correlates of genetic liability to sleep traits and mood disorders using polysomnography – the gold-standard objective measure of sleep. Examining this in healthy populations will circumvent medication effects and bidirectionality, major confounds in existing polysomnography research.   (2) Examine genetic and longitudinal relationships between adolescent sleep and depression to determine whether genetic variants for sleep traits in adult populations also influence sleep in younger populations, and delineate prospective associations between sleep and depression onset.   (3) Investigate whether sleep disturbances can be used as an indicator of liability to relapse in bipolar disorder. Using in-depth longitudinal data from digital technologies will elucidate the role of sleep in predicting mood episodes in bipolar disorder.   This work will inform sleep interventions and further knowledge on the role of sleep in mood disorders.","Sleep could be a cause or precursor of mood disorders such as depression and bipolar disorder (a mood disorder with periods of high and low mood). However, there is still much we do not understand about the complex relationship between sleep and mood. For example, are sleep problems a cause or effect of mood disorders? Why do sleep problems affect mood in some people more than others? Can we use information on sleep to predict if or when someone will become unwell? To investigate these questions, I will analyse genetic, sleep and mood data from large populations of people with and without mood disorders. This will involve cutting-edge methods for measuring sleep (polysomnography) and mood (digital technology). Results from this work will impact our current understanding of the role sleep disturbance plays in the onset and recurrence of mood disorders, in addition to informing mental health interventions and treatments.",2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,MENTAL HEALTH HRCS22_01979,Medical Research Council,MRC,"Using host-responses and pathogen genomics to improve diagnostics for tuberculosis in Bandung, Indonesia","Tuberculosis disease (TB), caused by M. tuberculosis (Mtb), is an important global public health issue. Indonesia remains one of the 22 high-TB burden countries in the world. Improving diagnostic tools for TB could assist the identification of active disease and evaluation of the response of anti-tuberculosis treatments, ultimately leading to disease control. Our study aims to use next-generation sequencing and bioinformatic techniques to characterise the human response to Mtb infection, which has previously been shown to offer an accurate and sensitive diagnostic for active TB. However, previous work has not assessed the impact of Mtb strain on diagnostic ability, or converted these signatures into useable in-house assays, such as PCR. In this project, we will seek to generate a human blood transcriptome based risk score, measured by a PCR assay that can be used in Indonesia across their strain diversity and local environments. Insights from this work could lead new diagnostics and control policy. This project will also capacity build in Indonesia for genomic technologies and analysis.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,INFECTION HRCS22_02071,Medical Research Council,MRC,Using smartphone-based personal sensing to understand and predict risk of psychotic relapse at the individual level,"Despite the efficacy of antipsychotic medication in the acute phase of psychosis, around 80% of patients experience at least one psychotic relapse. Predicting risk of relapse, and using this information to stratify treatment, is a key clinical challenge in the management of the illness. In other to address this challenge, we have developed a smartphone app which allows close monitoring of daily social stress - a strong candidate mechanism for psychosis based on animal and human models - across multiple contexts, time-points and locations (Urban Mind; www.urbandmind.info). Firstly, we will use an adapted version of the Urban Mind app to monitor daily social stress in 225 patients with first episode psychosis recruited from the South London & Maudsley NHS Foundation Trust. Secondly, we will develop a predictive model which links daily social stress with risk of future psychotic relapse, by integrating the data collected via our app with clinical data over a 12-month follow-up period. Thirdly, we will validate our predictive model in an independent group of 225 patients with first episode psychosis recruited from a different NHS Trust (Barnet Enfield and Haringey Mental Health Trust). A key aim of the project will be to examine the extent to which, within our predictive model, ""passive"" data generated via continuous background monitoring of phone usage (i.e. personal sensing), can be used as a proxy for ""active"" data which require patients to log their responses into their phone (i.e. experience sampling). Our predictive model will generate an individualised report which includes a prognostic risk score for psychotic relapse. In the final stage of the project, we will pilot the integration of this report in the electronic database nested within routine clinical care, which we are currently developing as part of an existing MRC-funded Mental Health Data Pathfinder programme. This could improve clinical outcomes and have major health economic benefits for society.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,MENTAL HEALTH HRCS22_13471,Coeliac UK,,Using software to improve the long-term management of people affected by coeliac disease,"Cievert is a digital health SME specialising in designing innovative software for the health sector. Established in 2011 by a former NHS radiographer, Cievert software can now be found in NHS Trusts across England, Scotland and Northern Ireland. This industrial research will be conducted in conjunction with the Academic unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, which is the largest centre for gluten-related diseases in the UK. Coeliac disease affects one in 100 people, however only 24% of these people have been diagnosed*. The mainstay of treatment is strict adherence to a Gluten Free Diet (GFD), allowing restoration of the structure and function of the small intestine. Despite national and international guidelines advocating follow-up of coeliac disease, there remains significant differences in how individuals are supported and followed up. For example, some patients have regular follow-up consultations with their GPs, others see Gastroenterologists or Dietitians, and others have no follow-up at all. Ideally, long-term care should be tailored to the individual need of the patient. Some patients will adapt well to the dietary modification and require minimal ongoing support or care, whilst others may require significantly greater intervention. This project has two broad aims. Firstly, to improve how coeliac patients are followed up by using Cievert’s software, called Penguin, to remotely monitor how patients are living with their coeliac disease and automatically use this information to tailor clinical need to the individual. Secondly, using this improved data collection to help better identify those responding to a GFD, without the need for invasive biopsies of the gut. To achieve these aims, we will trial the software with patients that have coeliac disease and assess: • Which patients use the software and why/why not • The frequency of use and compliance over time • The effect on referral rates within primary and secondary care • How Penguin affects outcomes for patients by comparing adherence to a GFD and biochemical/serological markers Functionally, Penguin allows for clinical teams to pose pre-determined questions to patients at set intervals about their clinical condition. Once the patient answers these questions, the software then automatically assesses the answers looking for any response out of tolerance. Any answer out of tolerance is then flagged to the most appropriate clinical team for follow-up. This means that patients requiring support are identified more quickly and those that are doing fine receive reassurance without unnecessarily consuming finite clinical resource.","Currently, the only treatment for coeliac disease is strict adherence to a Gluten Free Diet (GFD). Clinical best practice states that every patient living with coeliac disease should be clinically reviewed at least once a year, to assess how they are and how they are managing with their GFD. There is, though, huge variation in how, when and by whom patients are followed up. Some patients are reviewed annually by a consultant gastroenterologist, others by a dietician or clinical nurse specialist. Others still are followed up by their GP and some are discharged with no follow-up at all. For some patients, adapting to a GFD is relatively simple and annual follows-up serves little purpose; for others, adapting to a GFD can be difficult and they require much greater support. The goal of this project is to better identify those patients with coeliac disease that require additional clinical support, compared to those that are living well. This project will utilise software to pose personalised online questionnaires to patients to assess how they are living and coping with their GFD. Patients will be able to record blood results and urine results in the software as well. Importantly, the software will then automatically assess the patient’s answers, against clinical best practice, to identify those patients that require additional support and the type of support they require compared to those that are living well. The result will be that patients who are living well continue to have the assurance of being clinically followed up without the inconvenience of hospital appointments, whilst patients requiring additional care are identified quickly and easily, whenever the need may arise. If successful, this software will be extremely cost effective at following up large numbers of patients. By doing so, the software will also collect outcome data on large numbers of patients living with coeliac disease. This could also lead to further research and insight into how best to manage the disease and support patients. The software will not replace any clinical activity, instead it will support existing clinical pathways and decision-making only.",7.1 INDIVIDUAL CARE NEEDS,ORAL AND GASTROINTESTINAL;INFLAMMATORY AND IMMUNE SYSTEM HRCS22_05600,Department of Health and Social Care,NIHR,Using the Person-Based Approach to design novel Virtual Reality treatments for eating disorders,"Research Question: Can novel Virtual Reality treatments be developed for eating disorders, and are such treatments acceptable to young people with ED? A person-based approach Background: Eating disorders are serious mental illnesses with significant associated mortality and morbidity. Most eating disorders begin during adolescence, and they affect 1 in 20 adolescent girls and 1 in 50 adolescent boys. Rates of hospital admission with an eating disorder have more than doubled since 2016. However existing treatments do not work for as many as half of those with an eating disorder, and people often relapse following treatment, particularly if they have residual symptoms of dissatisfaction with their weight and shape.Aims and objectives: The overarching aim is to use the Person-Based Approach to co-design a suite of novel Virtual Reality interventions for use alongside the usual treatment of 14-25-year-olds with eating disorders for whom an overvaluation of shape and weight is a key part of their illness(Anorexia Nervosa, Bulimia Nervosa, and the related Other Specified Feeding and Eating Disorders). As part of the Fellowship, I will then design a study protocol and apply for funding for a feasibility trial of their use. Ultimately, the aim is to test effectiveness of the intervention in real-world settings, and working alongside experienced therapists will ensure that the resulting interventions will be appropriate for use within the NHS.Specific Objectives: Use the Person-Based Approach to co-develop the following interventions within Virtual Reality: a graded-exposure scenarioto practice a challenging real-life situation, of ordering in a caf. a gamified attentional re-training taskto train attention away from underweight bodies. an intervention to explore inhabiting and viewing different versions of one's body in Virtual Reality, to address the overvaluation of shape and weight. Bring together the most successful aspects of Objectives 1(i) to 1(iii) into a single novel intervention and test its acceptabilityin a separate group. Design a study protocol and apply for further funding for a feasibility studyof this novel treatment.Methods: I will use the Person-Based Approach (a methodology developed by my research mentor Prof Yardley) to enable the existing evidence base to be combined with qualitative work with people with lived experience. The iterativeintervention design and optimisation process that is central to the Person-Based Approach will ensure that the resulting interventions are engaging and acceptable for people with eating disorders, as well as drawing on the existing evidence base.Timelines for delivery: The process of iterative co-design is necessary but time-intensive, and I envisage that Objectives 1(i, ii and iii) will be complete around 3.5 years into the project. Objective 2 will draw the most successful elements together over the following year. The final six months will be spent applying for funding and IRAS to conduct a feasibility study. Anticipated impact and dissemination: This work will result in a novel intervention as an adjunctive treatment for eating disorders which has potential for a significant positive impact on patients. It will be widely disseminated including via peer-reviewed literature, conferences social media and via charity collaborators.","Eating disorders are serious mental illnesses which have significant consequences, including on physical health. Having an eating disorder increases the risk of early death between two to six times. Eating disorders affect over 1 in 20 adolescent girls, and almost 1 in 50 adolescent boys. Rates of admission to hospital with an eating disorder have more than doubled since 2016. Current treatments work for under half those affected, and many people relapse. Feeling unhappy with one's body is associated with being less likely to recover, and more likely to relapse with an eating disorder.This project will develop novel treatments using Virtual Reality (VR), for eating disorders where diagnosis includes a 'disturbance of the way in which body weight or shape is experienced', or 'undue influence of body weight or shape on self-evaluation' - that is, Bulimia Nervosa, Anorexia Nervosa, and other similar eating disorders. The project will use the 'Person-Based Approach' to design and optimise three novel VR-based treatments for eating disorders. This method combines existing research evidence with qualitative feedback from people with personal experience of an eating disorder. Results are used to design novel interventions, which will then be tried by a new group of people with an eating disorder. This group will be recorded whilst they 'think aloud' during their experience of the new interventions, and during detailed qualitative interviews. Their feedback will be used to refine the interventions. The final stage will involve a third group of people with eating disorders trying and giving feedback on the VR intervention as a further check of its acceptability and potential usefulness. I will collaborate with a VR company whose previous work has involved developing software that enables people to experience what it might be like to have a different-sized body, and to view their own body from an external perspective, and they will programme the novel VR interventions.The novel VR-based treatments will address different aspects of eating disorders, selected on the basis of the existing evidence and the views of PPI groups conducted as part of the preparatory work for this application. Three treatments will be developed: A caf environment -h; this will enable people with an eating disorder to practice a situation that many find challenging, of visiting a caf; they will be able to work through increasing levels of difficulty. An attention-retraining game -h; this will aim to shift attention away from smaller bodies, at which eye tracking studies suggest people with eating disorders spend more time looking. Experiencing different bodies -h; this will enable people to have the experience of being in a different-sized body (1stperson perspective), of viewing their own body from the outside (3rdperson perspective), or of being in an abstract representation of a body. Following the design of these three treatments, the next stage will be to combine the most successful elements. This process will also use the Person-based Approach to make sure the final treatment is as accessible and engaging as possible for people with an eating disorder. The final stage of the project will be to apply for NHS ethics and further funding to enable me to test the feasibility of using the final intervention alongside existing ED treatments in the NHS. Throughout the project, the PPI group will support the design of study materials, the interpretation of results, and the dissemination of findings. The project is also supported by a group of clinician experts, by parents and carers of people with eating disorders, and by the eating disorders charity, Beat.",6.6 PSYCHOLOGICAL AND BEHAVIOURAL,MENTAL HEALTH HRCS22_06220,Department of Health and Social Care,NIHR,Vaccination in older adults: understanding how to do it better and knowing when to stop,"We have an aging population in the UK thus there is a need to focus efforts on how to keep older people fit and well, and given NHS pressures, help them avoid attending primary care and hospital. Vaccination is a primary means of disease prevention used by the NHS, but evidence is lacking in several areas used to inform vaccine policy decisions in older adults. This research aims to enhance vaccination policy for older adults in England, through better evidence and stronger decision-making structures, to ultimately improve the health of older people. The objectives are: (1)To assess the heterogeneity in vaccine uptake in the 65+ population (2)To explore knowledge, attitudes and perceptions of routine vaccines for 65+ year olds and of other programmes that could offer this group protection against infectious diseases (3)To estimate social contacts and mixing patterns in older people (50+ population) (4)Valuing the impact of potentially vaccine preventable disease on health and capability to determine potential gains from vaccination in people aged 65+ years (5)To develop a methodological guideline for reassessing, including withdrawing, routine vaccine programmesStatistical analysis of secondary data (primary care records) will be used in objective 1 (completion 07/2020). Focus groups with the public will be used in objective 2 (completion 06/2022). For objective 3 a survey will be administered to the public and data statistically analysed (completion 10/2020). A longitudinal study will be used in objective 4 with data statistically analysed (completion 06/2022). For objective 5 a methodological guideline will be developed through a process of initial scoping of key questions, literature review, gaining evidence from stakeholders, and consultation (completion 11/2022). Patient and Public involvement (PPI) will be embedded throughout the research with four consultation events with a panel of PPI contributors informing study document design, analysis and interpretation of results, and dissemination plans. Two PPI contributors will also be part of the advisory group, which will also seek to include GPs, and individuals with a national/international profile in vaccine policy, guideline development, qualitative research, and health economics.Research summaries will be shared with participants and GP practices and at wider public engagement events. Results will be published in peer-reviewed journals and at conferences (including at a PPI conference for which an abstract will be co-produced with a PPI representative). The methodological guideline will be sent to organisations with an interest in vaccine policy and delivery (all of whom will be invited to be stakeholders in the guideline development) including the Joint Committee on Vaccination and Immunisation, Department of Health, NHS England, Public Health England and patient groups. The findings of the research can be used to improve vaccine uptake and modify vaccine strategies in older adults, reducing ill health (and the requirement of antibiotics to treat infectious disease), pressures on healthcare services and allow scarce resources to be spent in the best possible way. Ultimately the impact of this research will be the improvement of health in older adults through improved decision making around the use of vaccines in this age group.","We have an aging population in the UK. This means that we need to focus on preventing disease by keeping older people fit and well, which will also help take pressure off healthcare services. One way of preventing disease is vaccination. Three vaccines are currently offered to people aged 65+ in the UK, against flu, shingles and pneumococcal disease. More vaccines are being developed. Decision making around which vaccines are offered to the public rely on understanding how infections spread and the benefits that could be gained by preventing disease. Policies must also take into account current uses of and attitudes to vaccination. However, better evidence is needed for older adults.This research aims to improve the health of older adults through producing better evidence to influence vaccine decisions and designing a method for reassessing vaccine strategies. The research is divided into five areas of work: (1)We will look at GP records (we will not have access to identifiable information) to find out how many older people choose to be vaccinated and what might affect these rates. (2)We will do 8 focus groups with older people to look at why people get vaccinated or not and find out how they feel about other ways they could be protected by vaccinations (for example other people they meet being vaccinated). (3)We will survey 1000 older adults living in the community, and assisted living, and ask them about who they come into contact with to understand how infection can be spread. (4)We will survey older people who have had a disease that could have been prevented through vaccination and ask them about their health and quality of life over time, so that we can better understand the benefits of vaccination. (5)We will develop a guideline for reassessing, including stopping, vaccine programmes. We will bring together results from the other work packages, decide on an initial list of questions to consider, look at the existing research, gain opinions from people with an interest in vaccines (for example members of the public, Department of Health, Public Health England) and hold a consultation on the guideline.Patients and members of the public have informed the design of the areas of work. Two patient/public members will sit on an advisory committee, meeting 8 times over 4 years. A patient/public panel of 8-10 people will meet four times over the project to help us develop study materials, feedback on findings, advise on other angles to explore and discuss how best to share findings. Support will be given to members of the public who contribute to the study.Findings will be shared in different ways to ensure the research has impact. This will include sending a short report to people taking part in the research and speaking at events where members of the public can discuss research (such as the Pint of Science festival). Results will be shared with clinicians through sending reports to GP practices and seeking to work with the Royal College of General Practitioners. We will share our results with researchers through publications in journals and conference presentations and will seek to work with a member of the public to share our results at a public involvement conference. We will promote our guideline to organisations responsible for vaccination in the UK (for example Department of Health and the Joint Committee on Vaccination and Immunisation) and will produce a short report with PolicyBristol who share these with Parliamentary contacts and senior civil servants.Ultimately this research will affect policy decisions about infectious disease control in older adults to improve the health of older people in England.",3.4 VACCINES,GENERIC HEALTH RELEVANCE;INFECTION HRCS22_03924,Medical Research Council,MRC,Vaccines and Immunity,"Too many young children continue to die of diseases that can potentially be prevented by vaccines, and we want to optimise the use of this potentially lifesaving intervention. In order to make the safest and most efficient vaccines, we have to understand well how the immune system of small children works, and we now have the tools to gather much deeper insights. We use sophisticated technologies such as flow cytometry (to study cells), gene expression and proteomics (to study proteins) in the labs to analyse small blood samples taken during the conduct of our clinical studies. We can now study cells and blood components in great detail to understand their complex interactions and the impact of age on their composition. This is likely to matter for the way we design our vaccines. The team is also exploring the safe use of vaccines in pregnant women as a tool to decrease illness and deaths in their newborn babies through the antibodies that get transmitted during pregnancy. We want to know, which germs make the babies ill, where they come from and how vaccines might be able to prevent these infections, for example Group B strep infection, which causes meningitis and blood poisoning. A lot of children also suffer from TB, and we are working to make better diagnostics and to make sure that preventive measures that we already know can work are also actually implemented. Technical Summary The overarching aim of Prof Kampmann’s research is to improve the development and deployment of life-saving vaccines, in particular for the prevention of early life morbidity and mortality, but increasingly across the life-course of vaccination, with a specific focus on vaccination in pregnancy. As one of the three theme leaders at the MRC Unit in The Gambia, Prof Kampmann oversees all research activities in infant immunology, childhood tuberculosis and molecular diagnostics. The research ranges from basic laboratory research studying innate and acquired immune responses to infection and vaccination in pregnant women and infants through a systems biology approach to the conduct of clinical trials of novel vaccines, adjuvants and administration modalities. We are currently evaluating vaccines against pneumococcus, pertussis, meningococcus, HPV, Yellow Fever, malaria in a large number of phase 2,3 and 4 clinical trials. Our aim is to embed as much discovery science in the conduct of these clinical trials as feasible, and we have pioneered the use of small blood samples to derive big data in Africa. In addition, our work includes social science research into factors influencing uptake of vaccines in the African context and evaluation of tools for improving understanding and uptake of vaccines. As the director of IMPRINT- the IMmunising PRegnant women and INfants network, one of the 5 MRC-funded networks for vaccines (www.imprint-network.co.uk), and the Vaccine Centre at the LSHTM in the UK (https://www.lshtm.ac.uk/research/centres/vaccine-centre), Prof Kampmann has forged links with a growing number of vaccinology investigators in Africa. We are also working with WHO and UNICEF to investigate additional factors influencing maternal and neonatal health, such as investigating the aetiology of neonatal infections and their potential prevention through novel vaccines, such as against Group B streptococcus and other emerging pathogens. Our childhood TB program currently extends into 4 African countries and employs transcriptomic and proteomic methodologies to advance novel diagnostics for childhood TB as well as forming closer interactions with national TB programs to enhance knowledge about childhood TB and implementation of preventive measures. It is closely aligned with the work on adult TB at the MRC Unit, which aims at the discovery of predictive biomarkers of risk to progression from TB infection to TB disease and studies of long-term outcome of TB patients.",,2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES,INFECTION HRCS22_16468,Barts Charity,,Vagal Regulation of RvDn-3 DPA in Cardiovascular Protection during Inflammatory Arthritis,"Rheumatoid arthritis (RA) does not only lead to joint inflammation and pain, it is also linked with a higher chance of developing blood vessel disease (CVD), which in RA is one of the main causes of death. The applicants recently found that the body produces molecules termed resolvins that regulate white blood cell responses and vessel inflammation. Results from ongoing studies indicate that the production of these molecules in the blood stream and in other tissues is controlled by the nervous system, specifically the vagus nerve. In RA patients, they found a marked reduction in the resolvin production, in particular those produced from the fatty acid n-3 docosapentaemoic acid (RvDn-3 DPA) in the blood stream. In the proposed studentship they will explore whether impaired neuronal control of these molecules results in increased CVD in patients with RA and whether these molecules can be used to treat blood vessel and joint inflammation.",,1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,INFLAMMATORY AND IMMUNE SYSTEM HRCS22_09069,Department of Health and Social Care,NIHR,Velmanase alfa for treating alpha-mannosidosis [ID800] - Part 2,"Alpha-mannosidosis is a rare genetic disease caused by the deficiency of an enzyme called alpha-mannosidase. It is inherited as an autosomal recessive disorder, which means that both chromosome copies carry mutations in the alpha-mannosidase gene MAN2B1, and both parents may be unaffected carriers. Alpha-mannosidase breaks down oligosaccharides and in the absence of this, oligosaccharides accumulate inside cells, resulting in damage of tissues and organs and leading to cell death. This is characterised by skeletal changes, deterioration of bones and joints, muscle weakness, hearing loss, recurring infections and developmental impairment._x000D_ _x000D_ Alpha-mannosidosis can present at infancy, childhood or early adolescence. The onset and severity of symptoms varies widely across a broad spectrum. The most severe forms of alpha-mannosidosis manifest during infancy and are typically characterised by enlargement of the liver, severe infections and poor survival rates. More moderate disease is associated with slow progression but the characteristics of alpha-mannosidosis are evident and have a substantial impact on physical and mental wellbeing. These characteristics may be absent in people with mild disease. [1]_x000D_ _x000D_ The exact prevalence of alpha-mannosidosis is not known, but has been estimated to be approximately 1 in 500,000. [2] The MPS Society has identified 30 people with alpha-mannosidosis in the UK, although it is expected that there may be more patients whose disease has not been diagnosed.[3]_x000D_ _x000D_ There are currently no pharmacological treatments for alpha-mannosidosis. Treatment options are aimed at managing symptoms, delaying progression and improving quality of life. Allogeneic haematopoietic stem cell transplant (HSCT) from a family member or unrelated donor is a treatment option for some patients when clinically indicated, although there are significant risks associated with allogeneic HSCT._x000D_ _x000D_ References_x000D_ 1. Beck, M. et al. (2013). Natural history of alpha mannosidosis a longitudinal study. Orphanet Journal of Rare Disease 8:88._x000D_ 2. Malm, D. (2008). Alpha-mannosidosis. Orphanet Journal of Rare Disease 3:21._x000D_ 3. The MPS society. What is Mannosidosis? http://www.mpssociety.org.uk/diseases/related-diseases/mannosidosis/ Accessed October 2017",To evaluate the benefits and costs of velmanase alfa within its licensed indication for treating alpha-mannosidosis for national commissioning by NHS England.,6.1 PHARMACEUTICALS,CONGENITAL DISORDERS HRCS22_01358,Medical Research Council,MRC,Virus Structures,"The virus structure programme aims to integrate structural biology, imaging, proteomics and molecular biological techniques to address key questions concerning the biology of medically important viruses. In the forthcoming quinquennium we aim to develop two exciting new avenues of research: in-situ structural biology – structure analysis of macromolecular assemblies within the virus infected cell, and viral proteomics – characterisation of the protein content of purified virions. Several viruses of medical and veterinary importance will be considered, including respiratory syncytial virus (RSV), herpes simplex virus and Zika virus, and structural and proteomic approaches will be applied to study filamentous influenza A viruses (IAV). Our investigations will address fundamental questions in IAV biology, including the importance of host proteins in virion infectivity and morphology and the function of viral filaments in the infectious process. The capacity to determine structures for virus-associated macromolecular assemblies within the infected cell has huge potential to revolutionise our understanding of virus biology by providing detailed insights into the molecular interactions that underpin critical stages of viral replication cycles. Integration of proteomics into a programme of virus structure research combined with the shared focus on IAV of the two lead investigators presents exciting opportunities for exchange of knowledge, ideas and expertise that will drive our research to address key biological aspects of this important pathogen.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT,INFECTION HRCS22_03755,Medical Research Council,MRC,Volatile hypoxia signatures in oesophageal adenocarcinoma,"Oesophageal adenocarcinoma (OAC) has poor survival rates (<15% at 5 years) and there is an urgent need to develop more effective therapies to improve clinical outcomes. Tumour hypoxia is druggable, but hypoxia stratification and monitoring are needed to advance clinical trials of hypoxia-modifying therapy (HMT). Mass spectrometric analysis of exhaled volatile organic compounds (VOCs) is a promising approach to diagnose OAC non-invasively. Our recent work has shown that exhaled VOCs reflect deregulated volatile carbonyl (VC) chemistry in OAC and can be influenced by hypoxia. By comprehensively characterizing volatile signatures of hypoxia targeted at the carbonyl chemistry of OAC, we hypothesize that exhaled VOCs could be used to predict and monitor the response to HMT non-invasively. This will be investigated by developing a VOC signature of hypoxia using human and model systems with mechanistic understanding and examining the VOC signature in response to HMT. The VC chemistry of OAC will be analysed using quantitative MS and validated methods in (i) breath and tumour samples stratified by a rationally selected hypoxia gene signature and (ii) cell lines under hypoxic and oxic conditions to evaluate kinetics. Genetically constrained cell models and stable isotope tracing will be used for mechanistic evaluation. Hypoxia-targeting drugs will be evaluated in OAC cell lines with serial VOC measurement. The influence of hypoxia and VCs on therapeutic targets will be assessed, focusing on the hypoxic DNA damage response. Finally, patients participating in an HMT trial will be recruited for a 'proof-of-principle' study of response prediction and therapeutic monitoring using breath analysis. The proposed scientific work will develop for the first time the VOC signature of hypoxia in OAC. This innovative approach will provide the opportunity to use breath testing as a non-invasive tool to monitor the response to targeted cancer therapy.",,4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES,CANCER AND NEOPLASMS HRCS22_11626,Economic and Social Research Council,ESRC,WHO CARES? REBUILDING CARE IN A POST-PANDEMIC WORLD,"The pandemic highlighted the centrality of care. COVID-19 heightened awareness of the myriad forms of social connections in care as essential work crucial to the functioning of society. Care work has never been so visible, yet so precarious and vulnerable. Abundant evidence reveals the disproportionately negative consequences of COVID-19 on women, particularly women of color, migrants, and refugees, both as essential care workers and as recipients of care. The pandemic also revealed the limitations of care systems, exacerbating the care crisis worldwide with a greater impact in vulnerable territories. The project seeks to uncover and understand the matrix of care provision that is fragmented and uncoordinated, and the resultant overlapping, inconsistent and at times competing polices and regulations shaping care work and its provision at different levels of governance. Rebuilding a robust and more resilient care organization requires a comprehensive understanding of the care economy and entails learning from innovative initiatives in different countries. Our transnational team, extending previous comparative research networks, will bring together experts on care studies to analyze six countries with differing welfare regimes, level of inequalities, social organization of care, and health systems in Brazil, Canada, Colombia, France, United Kingdom and United States. We can gain a better understanding of vulnerabilities and capacities for responding to care crises from cross-national comparative research. Comparisons will proceed along four main axes: (i) the impact of the pandemic on needs and modalities of care provision: surveying alternative methodologies to harmonize data in a transnational perspective. (ii) labor conditions and rights in a post pandemic world: transnational analysis of/with paid care workers. (iii) care as a strategic dimension and pillar for public policies on social infrastructure rebuilding: comparing national experiments. (iv) caring strategies when the state fails: qualitative analysis of care provision on vulnerable communities.","The pandemic has highlighted the centrality of care as a necessary service performed by care workers that affects everyone. Our proposal will analyze how this focus on care has affected the practices of both care providers and care recipients, and how it has influenced social policies. Broadening our focus through international comparisons reveals how the Covid experience provides lessons in the medium and long-term. Comparisons will proceed along four main axes, comprising different dimensions and approaches, reflecting the interdisciplinary team profile: (i) The impact of the pandemic on needs and modalities of care provision: surveying alternative methodologies to harmonize data in a transnational perspective. (ii) Labor conditions and rights in a post pandemic world: transnational analysis of/with paid care workers. (iii) Care as a strategic dimension and pillar for public policies on social infrastructure rebuilding: comparing national and urban experiments. (iv) Caring strategies when the state fails: qualitative analysis of care provision on vulnerable communities. Defining axes is a way to intersect and integrate the research agendas from the different national teams, taking advantage of their competences to achieve an organized cross- fertilization of ideas and methods. Our selection of countries and teams will achieve two main goals. First, Brazil, Colombia, Canada, France, UK and the US provide enough variation in societal characteristics crucial to understanding the different configurations of care across national governance, welfare regime, health-care system institutionalization and jurisdiction over health policy, care employment, working conditions of care workers, level of labor market informality, home health-care policies, and Covid-19 pandemic policies. Second, the principal researchers of each national team have national and comparative care expertise and previous experience in collaborative research. The project leverages the local relevance of the foci from different axes as a strength of the research design. While each country team takes responsibility for an in-depth analysis of one main axis, our cross-cutting research strategy uncovers the mechanisms that reveals significant differences in the observed situations","8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE;INFECTION HRCS22_21952,Innovate UK,IUK,Walkable area and pavement anomaly segmentation for MSVI-supervised autonomous pedestrian navigation,"Theia is an orientation and mobility device for people with visual impairments. BBC Science Focus Magazine named it as the number one invention that will shape the future (2020). Anthony Camu, Theia's inventor, was named as Innovate's Young Innovator of the Year 2021/22\. Think of it as a guide dog helping Visually Impaired users to navigate. Our patent pending device scans the ground and generates a 3D map of the user's environment. It then uses forces to guide user's hands -- similar to a guide dog pulling on its leash. We have already developed a prototype of our product and tested it extensively with users in Alpha and Beta phases. It is able to successfully support VI people in identifying obstacles and navigating safely. This is potentially good news for the 350,000 blind and partially sighted people in the UK and approximately 300 million worldwide. In the UK, 95% of blind and partially sighted people have collided with an obstacle in their neighbourhood within a three-month period with a third suffering injuries (RNIB, 2017). The most effective support is a guide dog, but there simply are not enough of them. Only 1 in 72 eligible VI people receive a guide dog, leaving a large proportion of VI's requiring alternative support and guidance. That is where Theia can help! However, to make our product more effective a new R&D project is required to look at how to improve the way Theia helps users understand their immediate environment whilst being guided autonomously. To help us get this right, we will be working with Vista Blind, a Leicester-based charity supporting those with visual impairments. Vista Blind will support user-led design workshops with visually impaired users to shape our solution around user experience. At the end of this project, we will have a tested prototype that is ready to help visually impaired people live safer lives.",,5.3 MEDICAL DEVICES,EYE HRCS22_20930,Wellcome Trust,,Wellcome Centre for Mitochondrial Research,"Our mission is to transform the lives of patients with mitochondrial disease To achieve this mission we will build on progress made since the start of the Centre in May 2012 and combine: Three core scientific research themes • Understanding clinical mitochondrial disease: we will expand our unparalleled cohort of mitochondrial patients through extensive deep phenotyping, identifying key disease mechanisms at a clinical (whole patient) and organ level, and developing models of specific clinical features to enable improved treatment for patients with mitochondrial disease. • Understanding the genetic mechanisms underlying mitochondrial disease: we will elucidate genetic factors responsible for mitochondrial disease, exploring the mechanisms underlying the tissue specificity that characterises clinical disease and delineating the pathways underlying mitochondrial translation. • Prevention and treatment of mitochondrial disease: we will optimise the prevention of mitochondrial disease, developing novel therapies targeted at the mitochondrial genome and identifying new compounds to treat mitochondrial disease. We will ensure that every patient with mitochondrial disease has the opportunity to be involved in a clinical trial. Training the next generation of clinical and basic mitochondrial scientists. Engaging with patients to evolve our research focus and with policy makers to ensure our research findings improves care for patients with mitochondrial disease.",No Data Entered,2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY),GENERIC HEALTH RELEVANCE;NEUROLOGICAL HRCS22_07249,Department of Health and Social Care,NIHR,What is the best second line therapy for people aged 65 years or over with type 2 diabetes?: systematic review and network meta-analysis,"Research question What is the most effective and safe second line therapy for people aged 65-years and over with type 2 diabetes(T2DM)? Background One-in-six people aged 65-years or over has T2DM and over half of prevalent T2DM cases are in this age group. Older adults have a higher risk of adverse cardiovascular and renal outcomes, and potentially more adverse-effects from drugs. Evidence suggests that the relationships between therapy and outcome may differ between older and younger people so the common approach of trial participant selection (recruiting people with a wide range of ages) may not allow a full description of the responses in this age group. Aims and Objectives To perform a systematic review and network meta-analysis (NMA) using either stratified summary data or individual patient data (IPD) of all relevant randomised controlled trials to determine the rankings of second line therapies for patients aged 65-years or over with T2DM. Objective 1. Calculate the relative effectiveness of drugs and combinations of drugs in patients aged 65-years or over who are also receiving metformin. Objective 2. Calculate the relative effectiveness of drugs and combinations of drugs in patients aged 65-years or over who are not receiving metformin Methods We will update the search in a recent NMA and perform risk of bias assessments on newly identified studies. We will obtain individual patient data (IPD) for all relevant studies using 5 different processes. Including data repositories, contacting data owners, and authors of papers. The statistical analysis will be a two-stage process. First, IPD will be analysed independently for each trial using appropriate regression models for each outcome. Models will adjust for variables that were stratified by in randomisation. We will also adjust for baseline values of HbA1c, sex, BMI, presence of cardio-vascular disease, presence of chronic kidney disease in all models. Second, these summary treatment effect estimates and their standard errors will be used in a NMA to synthesise the evidence in a single mathematically coherent model. This will allow us to rank treatments by efficacy and safety, and then estimate the relative effectiveness of all treatments with confidence intervals. Timelines for delivery Pre-grant phase(12/19-05/20): Update literature search, apply to trial portals and request data from study teams, develop protocol. 05/20-01/21: Finalise protocol, continue data acquisition and develop computer code for evidence synthesis. 11/20-06/21: Clean data, quality assess newer studies and analyse data 07/21-10/21: Update database and perform NMA. Write-up study and disseminate. Many processes overlap during these phases. PPI will be throughout the project. Anticipated Impact and Dissemination We will identify the best second line treatments for patients with T2DM who are 65-years or older. Findings will be disseminated to patients in collaboration with (e.g. Foundation for Diabetes Research in Older People); to clinicians via diabetes, older people and general practice conferences, networks and publications; policy makers through the NICE diabetes management guidelines committees. We envisage the results will change practice by impacting on evidence-based prescribing for older people, reduce adverse effects, and potentially improved cardiovascular health, and quality of life.","Background Almost half of people with type 2 diabetes are aged above 65 years. One in six people aged above 65 years have type-2-diabetes. This is expected to increase as people live longer. Currently experts recommend metformin as the first drug of choice for people with type-2-diabetes to control their blood sugar. When metformin alone does not control blood sugar, we need to give an additional drug or replace metformin. This is known as second-line treatment. There are many drugs to choose from at this stage, but doctors do not know which is the best for people aged over 65 years. Most research studies only include a small number of older people which does not allow us to identify the best choice of drug for them. This is unfortunate, because older people are more likely than younger people to have other health problems like heart disease and kidney disease, which could affect the choice of which drug to use as a second-line treatment; particularly that we now have newer drugs that improve glucose levels and at the same time prevent heart and kidney disease. On the other hand, we need to be careful with our choice of drugs because older people are also more likely to experience side effects. Aims We will identify then combine all evidence regarding older people from different research studies comparing different treatments. Then we will do a new analysis using these data to identify the best second-line treatments for older patients with type 2 diabetes, in terms of their ability to improve the blood sugar control, prevent diabetes complications and reduce side effects. Methods We will identify all of the scientific evidence by searching all published studies. For each study, we will attempt to obtain data specific for patients age 65 and over. We will do this by searching data storage sites which hold anonymised patient data and by contacting authors of published studies. We will use established analytical methods to combine this information and achieve the above mentioned aims. Patient and public involvement (PPI) We have discussed this research with patients who are aged 65 or over with type 2 diabetes. They were enthusiastic about the project and its potential benefits. Many of them reported issues with side effects from their current treatments such as low blood sugar. They were unaware about potential benefits towards the health of their heart and kidneys. Dissemination We will make these results available freely to as many people as possible by publishing papers in journals and on websites, and by talking to doctors, researchers, and patients. We will also work with the Diabetes UK charity, Diabetes Frail organisation and will involve Clinical Commissioning Groups and NICE guidelines committee.",6.1 PHARMACEUTICALS,METABOLIC AND ENDOCRINE HRCS22_20216,Wellcome Trust,,What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping.,"BMI is a simplified measure of body composition/fatness based on your weight adjusted for height and there are clear correlations between BMI and health. However, it is extremely difficult to change BMI in many people and we still do not understand why BMI is a risk factor. The processes of our bodies leave behind chemical bi-products which can be measured easily and efficiently. They provide a snap-shot of health status and the relationships between these “metabolites” and BMI can help understand the biological implications of being leaner or larger. Using collections of metabolites measured in very different studies, I will characterise the downstream effects of BMI on a broad range of biological processes. I will then use very large studies of the general population to bring together evidence and generate a list of metabolites which are affected by BMI. Once done, I will use publicly available genetic studies of disease to help ask the really important question; if BMI has an effect on metabolites, then what do these do to disease risk? Where I find metabolites that do alter disease risk, this will inform future work looking closely at those metabolites rather than attempting to change BMI alone.",,2.1 BIOLOGICAL AND ENDOGENOUS FACTORS,CARDIOVASCULAR;ORAL AND GASTROINTESTINAL;METABOLIC AND ENDOCRINE;GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS HRCS22_18591,Wellcome Trust,,What makes us human?,"The Human Developmental Biology Initiative (HDBI) will deliver a step-change in fundamental knowledge about human development leading to improved health outcomes in fertility, birth conditions and regenerative medicine.  What makes us human? will enable a culture of engagement and new ways of working, allowing the science to anticipate, include and respond to a broad range of insights and perspectives. Importantly, this includes consideration of embryo and fetal donors, and staff - including the Human Developmental Biology Resource (HDBR) - who make our research possible, those who consider and regulate our work, and people and patients who (stand to) benefit from our progress.  What makes us human? focuses on developing knowledge, skills and confidence of HDBI researchers and Public Engagement (PE) practitioners through an ongoing programme of training and support. It develops a significant long-term relationship with a multi-stakeholder Insights Group to inform and improve our research, engagement and communications. Built in is provision for responsive dialogue, to be identified by horizon scanning the emerging needs of our research, or changes in the healthcare policy or practice landscape. What makes us human? will raise awareness of and trust in HDB research with a range of public audiences across the UK.",,"8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_18963,Wellcome Trust,,"What’s at stake in the fake? Indian pharmaceuticals, African markets and global health","For the past several decades, global health researchers and policy-makers have raised the alarm about the growing threat that fake pharmaceuticals pose to global health. Often these concerns are framed in terms of particular places and people, for example, fake drugs from India imperil Africans’ health. We subjected these high-profile and oft-repeated claims to scrutiny. This exercise produced some unexpected findings. Across scientific, policy and popular literature, we found substantial misalignments between (1) the strength of claims about fakes alongside (2) the relative weakness of these claims’ evidence. Scientific literature in particular raised questions about apparent certainties, such as: What, exactly, are fake drugs? Are fake drugs necessarily dangerous? Where do they come from? When the global supply of life-saving medicines is beset by worries about safety, governments and citizens face difficult decisions about how to allocate scarce resources. By asking questions about these worries, we hypothesize that the problem of fake drugs is not solely a pharmacological problem; it is also a social problem. Two questions guide our project’s historical and ethnographic research 1. What accounts for the rise of fake-talk—the wide-spread and urgently-reiterated set of concerns about the dangers that fake drugs present? 2. What are the effects of fake-talk?","Today, the idea that fake drugs threaten global health has become almost common-sensical. Often, these concerns are voiced in relation to how, for example, Africans’ already poor health is further imperilled by fake Indian drugs. Yet when we looked closely at the scientific literature backing up these claims, we found that they were based on unexpectedly weak evidence. This project responds to this puzzle by critically re-examining our collective common-sense about fake drugs and global health. Initial research suggests that, addition to the world of pharmacology, worries about fake drugs may be based in social worlds. When the world’s supply of live-saving drugs is beset by worries about safety, governments and citizens face difficult decisions about how to allocate scarce resources. Our project’s historical and ethnographic enquiries seek to understand the emergence and circulation of worries about fake drugs for global health, as well as to understand these worries’ effects.","8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",GENERIC HEALTH RELEVANCE HRCS22_06288,Department of Health and Social Care,NIHR,"Why are we stuck in hospital? Understanding service user, family and staff perspectives when transforming care for people with learning disabilities and/or autism","In recent years, there has been growing concern about the number of people with learning disabilities and/or autism living in long-stay hospitals. Although the UK decided to close asylums for people with learning disabilities from the 1960s onwards, there has been a growth in people admitted to so-called ‘assessment and treatment units’, with allegations that some people stay here for far too long, with little ‘assessment’ or ‘treatment’ that could not be provided elsewhere. Other people live in secure units or in an NHS campus where the previous hospital is still in the process of closing. Over 2,100 people live like this at the moment (despite repeated policies to help people leave hospital and live in the community). This is a real problem as these services struggle to help people to lead ordinary lives, are very expensive, can be a long way from people’s homes and families, and have seen a number of abuse scandals – just as was the case with the asylums of the 1960s._x000D_ _x000D_ Despite this, there has been little research on why people with learning disabilities are delayed in such settings. In particular, previous debates have often failed to talk directly to people with learning disabilities, their families and front-line staff about their experiences of living or working in such settings, what they see as the main barriers and what would help more people to leave hospital. In other research with older people, we have looked at these issues from the perspective of older people themselves, their families and care staff, as each group has a unique view on what is happening and might make a difference. Unless we listen to these voices we will not find solutions to these problems, and too many people will remain in hospital unnecessarily. Our aim here is to do the same with people with learning disabilities, their families and care staff, so that their voices are heard too. This will increase the chance that people can leave hospital in a timely way and lead more ordinary lives in the community._x000D_ _x000D_ This is sensitive work, requiring skills in working with people who may not communicate verbally, where there is a risk that some people can be violent (as all of us can when we’re scared and distressed), and where there can be tensions around what is best. We have therefore included a skilled, experienced team who can carry out such in-depth work in a way that suits the needs of the individual. We also have strong relationships with local services, national policy and voluntary agencies working with people with learning disabilities in long-stay hospitals – and these will be crucial for the study’s success._x000D_ _x000D_ We will produce a report and articles so that people can read what we have found. We will also produce a good practice guide (based on the experiences of people with learning disabilities and their families) and send this to every health and social care leader in the country. We will also produce a free training video for care staff who may not have access to as much training/support as they need. We will ensure our research is conducted well and produces helpful findings by working with a group of national advisors, chaired by a person with a learning disability. We will design our research materials with a group of people with learning disabilities and families, so that the questions we ask, how we get to know people and how we share our findings work really well for people with learning disabilities and their families.","Transforming care so that people with learning disabilities and/or autism can receive support at home rather than in inpatient units, secure settings or assessment and treatment units is a key government priority, which has significant implications for people’s quality of life as well as for public finances. Recently we have witnessed a series of abuse scandals and significant public anger at such outmoded service models, often provided out-of-area and in the commercial sector at significant expense and with poor outcomes. A key aim of the ‘Building the Right Support’ and ‘Transforming Care’ programmes is to enhance community capacity and reduce inappropriate hospital admissions/length of stay. In spite of this some 2,185 people with learning disabilities and/or autism were hospital inpatients at the end of January 2020, 58% of whom had a hospital stay of over 2 years, and progress on discharge has been slow._x000D_ _x000D_ Despite significant national debate, very little previous research has engaged directly with people with learning disabilities or their families to understand the issues from their perspective. In research into older people’s hospital admissions and discharge, there has been a similar failure to consider the lived experience of older people and their families and our recent NIHR study (‘Who Knows Best’) is believed to be the first research to meaningfully consider these issues from the perspectives of older people themselves. Whilst professionals often see the individual at a particular point in time (often in a crisis), it is only the person and their family who have a longitudinal sense of how their story has unfolded: their informal networks; their contacts over time with formal services; their experience of hospital; the different options considered; and what has ultimately helped/hindered in securing desired outcomes. Failing to take into account this lived experience is not only morally wrong, but also deprives us of a major source of expertise with which to improve services. Similarly, there has been little consideration of the perspectives of front-line staff, who are being asked to practise in very different ways in a difficult environment, arguably without the support needed to do this well. This was also challenged in our ‘Who Knows Best’ research, seeking to value staff experience as a key resource to help develop better services/outcomes._x000D_ _x000D_ Against this background, the University of Birmingham and the rights-based organisation, Changing Our Lives, are conducting joint research to better understand the experiences of people with learning disabilities who have been stuck in long-stay hospital settings, their families and front-line staff – using this knowledge to create practice guides and training materials to support new understandings and new ways of working. Our aims are to:_x000D_ _x000D_ • Review the rate and causes of delayed hospital discharges of adults with learning disabilities from specialist inpatient units, NHS campuses and assessment and treatment units (referred to as ‘long-stay hospital settings’ as a shorthand)_x000D_ • More fully understand the reasons why some people with learning disabilities are unable to leave hospital, drawing on multiple perspectives (including the lived experience of people with learning disabilities and their families, and the tacit knowledge of front-line staff)_x000D_ • Identify lessons for policy/practice so that more people can leave hospital and lead a more ordinary life in the community.",8.1 ORGANISATION AND DELIVERY OF SERVICES;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES),MENTAL HEALTH HRCS22_22631,The Academy of Medical Sciences,AMS,Why do some children find language hard to learn? A crosslinguistic comparison of learning processes,"The goal of the study is to pinpoint the underlying cognitive deficit in children who have difficulties learning their native language. Language impairment (LI) in children has been much studied in English, where difficulties particularly affect learning of grammar. I propose a cross-linguistic investigation, comparing LI in English and Tamil. English-speaking children with LI are poor at procedural learning, even when no language is involved. This is evident in weak sensitivity to statistical patterns in a sequential input. Very little is known about LI in Tamil, an agglutinative language where word order is relatively unimportant. I will study procedural and declarative learning in LI children, predicting that the pattern of deficits will relate to the language being learned. I will use a new method to test learning of language-like transitions. The project will also give deliverable products such as language assessment tools in Tamil, and a child-friendly procedural memory task.",,"2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS",MENTAL HEALTH HRCS22_02378,Medical Research Council,MRC,Work productivity effects of HIV prevention and treatment interventions on populations from endemic settings,"HIV is a threat to sustainable development and top of the global health research agenda. My research will focus on South Africa which has the largest HIV epidemic in the world and where HIV accounted for about 50% of all life years lost due to illness in 2010. As a major contributor to the burden of disease and for being concentrated in the working age population, HIV comes at large socio-economic cost. Understanding work productivity effects of HIV prevention and treatment interventions (HIVPTI) is thus important for policy makers in their decision to allocate scarce resources most effectively. The impact of HIVPTI on HIV and work productivity can work along several pathways: Healthier individuals are more effective in producing and delivering goods and services both in households and at the workplace. This has social and economic returns, in the form of monetary and wider societal value added. Moreover, as health can be considered an investment good, the prospect of prolonged life lived in better health leads to higher monetary returns of investments into education, hence incentivising individuals to invest in human capital with positive social and economic returns in the long-term. However, the exact consequences of HIVPTI on work productivity and long-term economic development are unknown. Existing evidence on Anti-Retroviral Therapy (ART) effects on work productivity is promising and shows positive correlations of ARTs with economic activities however limited to small-scale observations of unrepresentative sub-population groups. These findings cannot answer the essential questions of productivity effects in the long-term considering HIV-dynamics. Neither provide these studies any basis for generalising findings to the wider public which is the important piece of information required by policy makers deciding on allocating scarce resources in health. My research project will address these gaps in the literature.",,8.2 HEALTH AND WELFARE ECONOMICS,INFECTION HRCS22_01705,Medical Research Council,MRC,"YATHU YATHU (""For us by us""): A Cluster Randomised Trial of community-based SRH and HIV services for adolescents and young people in Zambia","Yathu Yathu (""For us by us"") is a two-arm cluster-randomised trial that will evaluate community-based, peer-led sexual and reproductive health services (SRH), including HIV prevention and treatment for adolescents and young people (AYP), in 2 urban communities in Lusaka, Zambia. SRH services will be established in community spaces in collaboration with adolescent community advisory boards who will advise on the location, content and running of the services. Services offered will include contraception, condoms, HIV testing, STI screening and treatment, VMMC information and referral, ART support groups (face-to-face and via mobile phone), PEP/PrEP services and support groups (by mobile phone), menstrual hygiene products as well as information and support on a range of other subjects requested by young people. The 2 communities are divided into 20 clusters that will be randomized to intervention or control arms. Each intervention cluster will have one community centre with services accessed either at the centre or the health facility. In the control clusters, services can be accessed at the health facility as per the national standard of care. The primary outcomes will be knowledge of HIV status, measured via a cross-sectional survey, and an indicator of coverage measured using an electronic prevention points ""Yathu card"" provided to all AYP, aged 15-24 years, living in the study communities. Secondary outcomes will include uptake and adherence of specific services such as ART, PreP, or modern contraceptives. In addition economic and qualitative enquiry will provide data on the costs and inputs required to establish the services, barriers and enablers to the use of the services and the experience of AYP in both control and intervention arms. The study findings will help inform policy-makers on how to best provide SRH services for AYP.",,"3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE",INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH HRCS22_19755,Wellcome Trust,,"mRNA cap regulation of gene expression, cell function and fate","Human life utilises hundreds of cell types with massive diversity in function defined largely by which proteins they express. We will determine how regulation of the mRNA cap modification coordinates the gene expression required in different cell types. The cap protects mRNA from degradation and recruits processing and translation factors. The enzymes which catalyse cap formation were perceived as acting on all genes, in every cell. Our research reveals that the capping enzyme complexes are differentially expressed in different tissues and have gene-specific impacts. During cell differentiation, we demonstrate that changes in capping enzyme complexes result in coregulation of gene families, which we hypothesise co-ordinates the gene regulation required for new cell identities to emerge.Key goals are to determine: 1. mechanisms governing capping enzyme gene-specificity  2. how co-factors influence capping enzyme functionality 3. the impact of mRNA cap regulation in differentiation In pluripotent cells, the components of mRNA capping enzyme complexes will be characterised and their impact on enzyme kinetics, cap formation and sequence-specific RNA selection determined. During differentiation, how mRNA capping enzyme regulation impacts on enzyme function and gene expression will be investigated. This project will determine the dynamic impact of mRNA capping enzyme regulation. Keywords: gene regulation; mRNA; cell function","Humans contain hundreds of different cell types, whose function depends on the proteins they contain. Each human cell contains over 25000 genes which are the instructions for making proteins. We want to understand how cells control which proteins are made and how this process changes in different types of cell.We discovered that a structure called the mRNA cap controls which proteins are selected for production in the cell.  When cells develop, we found that how the mRNA cap is made changes and this alters which proteins are made. We aim to discover how the mRNA cap controls which proteins are made in a cell. When cells develop, we will investigate how changes in the cap influence which proteins are made and how this helps produce new types of cell.This project will indicate potential ways that we could influence which proteins are made in cells in medical therapies.",1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING,GENERIC HEALTH RELEVANCE HRCS22_17186,Wellcome Trust,,novel labelling and tracking strategies to understand mesenchymal stem/stromal cell populations relevant to musculoskeletal regenerative therapy,"Bone marrow-derived MSCs can exert strong therapeutic effects in the musculoskeletal system and cell therapies have developed to regenerate and repair cartilage defects. However, our understanding of the biology of this heterogeneous group of cells is incomplete and there are still many hurdles to their wide application in the clinic. We will use a combination of labelling techniques and novel cell markers developed in Cambridge to track labelled cells in vivo to determine their survival, engraftment and distribution. The biology of unlabelled and labelled MSCs will be studied in vitro to confirm that the labelling does not affect the cells’ function. Labelled cells will be injected into a mouse knee (after creation of a cartilage defect) and repeated imaging will be used to track the distribution of these cells to study their biology in greater detail. With the current focus on moving cell therapies to the clinic, in vivo tracking of these cells is critical in assessing their homing and proliferative potential over time. The novel genetic labelling strategies used will provide important information regarding graft behaviour in small animal models, offering both fast readouts of longitudinal cell survival and low costs per imaging study.",,5.2 CELLULAR AND GENE THERAPIES,MUSCULOSKELETAL HRCS22_07209,Department of Health and Social Care,NIHR,toothPASTE - emPowering fAmilies of young children with autiSm to esTablish good oral hEalth habits,"BACKGROUND:Preventing tooth decay is the top dental research priority. In England, approximately a quarter of children with autism have decay by five-years-old. Frequently their dental treatment is provided under general anaesthetic at significant costs to the NHS, morbidity to the child and impact on family-life. Tooth decay is preventable. National guidelines recommend twice-daily toothbrushing with fluoride toothpaste and limiting sugar consumption. Good habits in early childhood provide lifelong protection from decay. For families of children with autism, however, establishing good habits can be complex because of communication, altered sensitivity and rigid behaviour patterns. Attending the dentist is challenging and often an unsuitable setting for meaningful support. Frequently families feel overwhelmed, isolated and uncertain who to ask. While families may receive support from early-years services, oral health is rarely discussed and professionals are uncertain of what advice to give. AIM: To empower families of young children with autism to establish good oral health habits OBJECTIVES: STAGE ONE (Month 1-12) - Understanding the problem and context in West Yorkshire [1A] A scoping review of the literature to identify the barriers and facilitators to good oral health behaviours. [1B] Qualitative interviews with families of children with autism (n=25) to explore their current oral health behaviours, the challenges involved, their experiences of navigating early-years services and ideas of support. [1C] Qualitative interviews with professionals working in health, education and care services (n=30) to explore their current practice, their opportunities, capabilities and motivations for providing oral health support and their views on the design of such support. Using framework analysis, combined with the Theoretical Domains Framework and COM-B model, we will synthesise our findings to understand the barriers and facilitators to good oral health behaviours. We will map out the support available across different local authority areas, identify commonalities and opportunities for new or enhanced oral health interventions. STAGE TWO (Month 12-18) – Development of the toothPASTE intervention With our Patient and Public Involvement panel, professionals and stakeholders as equal partners, we will co-design the toothPASTE intervention. Using a series of workshops and participatory activities (Experience-Based Co-Design approach), we will finalise the toothPASTE intervention prototype, including content and format, who will deliver it, when, how often and a training package to enable delivery. To understand the mechanism of action for toothPASTE, we will iteratively tailor a pre-existing oral health logic model to reflect the study findings and refine the theory of change. Impact and dissemination: Development of the toothPASTE intervention ready for feasibility testing, before progressing to a definitive study with the aim of reducing tooth decay in children with autism. Our findings will inform commissioning within West Yorkshire and national commissioning guidance for children and young people in residential special educational settings. Our dissemination strategy is tailored to families, policymakers, commissioners, stakeholders and professionals. Outputs include a short video summarising our results, support maps for children with autism living in different local authorities, study website, social media, conference presentations and publications submitted to high impact academic journals.","Why is this research important? Tooth decay is a major health problem. A quarter of five-year-olds have tooth decay. For children with autism, especially those with little or no verbal communication, tooth decay can lead to self-harm, impaired sleep and disrupted routines. Children with autism find it more difficult to go to a dentist or accept dental treatment. Frequently their dental treatment is provided under general anaesthetic. Tooth decay is preventable. Twice daily toothbrushing with fluoride toothpaste and limiting sugary foods and drinks helps prevent tooth decay. These good habits should start in early childhood. For families of children with autism, establishing good habits can be complex, owing to extra challenges, such as communication, altered sensitivity and rigid behaviour patterns. What we plan to do: We will work with families of young children with autism and the professionals who care for them. Together we will explore the barriers and facilitators to good oral health habits and design a support package. This package will help families to be confident in looking after their child s teeth. This study will identify what support they need, who could provide it and the best times to provide support. Study plan: This research study has two stages: Stage 1: To find out what advice families currently receive about looking after their child s teeth; what works well and not so well. We will search for published research studies and talk to families and professionals. Stage 2: We will work with families and professionals, to develop a support package that they would be pleased to use and would empower families to look after their child s teeth. Patient and Public Involvement (PPI): Families of children with autism have been involved from the start of the study. They have identified this as an important topic and shaped the design of the study to ensure it helps families. Nikki Pickles, a parent of a child with autism and family support coordinator for a local autism charity, has agreed to lead our PPI group. Nikki will collaborate with other families throughout the study. Sharing our findings: We will summarise our results in a short video. Two autism charities based in West Yorkshire will share the video and our findings on their social media pages. This allows families who have not been involved in the study to learn about it. We will work with professionals, the National Autistic Society, Autistica and government bodies to publicise our findings and discuss future plans. For professionals, we will present the results at conferences and in publications. Outcome: We will test the support package in a feasibility trial. This will check that it is acceptable to families, feasible to professionals and has the potential to prevent decay.",7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES,ORAL AND GASTROINTESTINAL;MENTAL HEALTH