NIHRDataInsights/HRCSData huggingface dataset:
Award Title: 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
Funder: Public Health Agency, NI

Abstract: 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.


Research Activity Codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health Categories: ORAL AND GASTROINTESTINAL;CANCER AND NEOPLASMS
Award Title: A Study of COVID-19 Social Media Infodemic in the Retail Pharmacy Industry
Funder: The British Academy

Abstract: 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.


Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: INFECTION
Award Title: A UK/Canada Collaboration on the genetics of long-term diabetes complications and their risk factors among people with type 1 diabetes
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: METABOLIC AND ENDOCRINE
Award Title: A bespoke Pharmacist-Clinical Assessment Platform (Ph-CAP) for minor illnesses, designed for and with Community Pharmacists.
Funder: Department of Health and Social Care

Abstract: 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.


Research Activity Codes: 7.3 MANAGEMENT AND DECISION MAKING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: A cluster randomized trial of an mHealth integrated model of hypertension, diabetes and antenatal care in primary care settings in India and Nepal
Funder: Medical Research Council

Abstract: 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


Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Award Title: A cross-species, cross-modal approach to computational neuroanatomy
Funder: Wellcome Trust

Abstract: 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.

Lay Abstract: 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.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: NEUROLOGICAL
Award Title: A highly sensitive replacement assay for botulinum neurotoxin type B
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: 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.


Research Activity Codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);5.1 PHARMACEUTICALS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: A newly discovered protein-coding ORF in enteroviruses: from mechanism to application
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: INFECTION
Award Title: A prospective randomised trial comparing radiofrequency ablation With laparoscopic Adrenalectomy as an alternatiVE treatment for unilateral primary aldosteronism (WAVE)
Funder: Barts Charity

Abstract: 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.


Research Activity Codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health Categories: CARDIOVASCULAR;METABOLIC AND ENDOCRINE
Award Title: A systems approach for understanding cell surface dynamics in trypanosomes
Funder: Wellcome Trust

Abstract: 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.

Lay Abstract: 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.

Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION