NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Developing a school-based, transdiagnostic, preventative intervention for adolescent mental health
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;7.1 INDIVIDUAL CARE NEEDS
Health Categories: MENTAL HEALTH
Award Title: Developing and commercialising a non-invasive test of adrenal insufficiency for children on steroids.
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Developing and implementing machine learning driven analytics for quality improvement in health care
Funder: The Health Foundation

Abstract: 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.


Research Activity Codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health Categories: GENERIC HEALTH RELEVANCE;STROKE
Award Title: Developing contextually specific interventions to reduce alcohol consumption amongst increasing and higher risk drinkers within the Drink Less App
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health Categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;GENERIC HEALTH RELEVANCE;ORAL AND GASTROINTESTINAL;STROKE
Award Title: Developing mechanistic understanding to improve the activity of bicyclic peptides as novel antimicrobials
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: INFECTION
Award Title: Developing personalised risk prediction for women at increased risk of Vulval Cancer
Funder: Cancer Research UK

Abstract: 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.


Research Activity Codes: 2.4 SURVEILLANCE AND DISTRIBUTION;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: CANCER AND NEOPLASMS
Award Title: Development and Evaluation of a Training Package to support the Remote Assessment and Management of People with Movement Impairment and Disability
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 7.3 MANAGEMENT AND DECISION MAKING;7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health Categories: INFECTION
Award Title: Development and testing of a high resolution respirometry protocol to define T cell mitochondrial fitness in health and disease.
Funder: Cancer Research UK

Abstract: 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.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health Categories: CANCER AND NEOPLASMS
Award Title: Development of a digital intervention to promote healthy growth during the first 2 years of life
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health Categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE
Award Title: Development of a patient-derived, mucosoid-microbiota model to identify novel gastric adenocarcinoma biomarkers triggered by the intestinal metaplasia-associated microbiota
Funder: Cancer Research UK

Abstract: 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.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS