NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Use of structural variants to detect recurrence of renal cancer via blood
Funder: Cancer Research UK

Abstract: 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.


Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Using data to improve public health: COVID-19 secondment
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health Categories: INFECTION
Award Title: Using genetics, neurophysiology and longitudinal data to disentangle the complex relationship between sleep and mood disorders.
Funder: Wellcome Trust

Abstract: 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.

Lay Abstract: 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.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: MENTAL HEALTH
Award Title: Using host-responses and pathogen genomics to improve diagnostics for tuberculosis in Bandung, Indonesia
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: INFECTION
Award Title: Using smartphone-based personal sensing to understand and predict risk of psychotic relapse at the individual level
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: MENTAL HEALTH
Award Title: Vagal Regulation of RvDn-3 DPA in Cardiovascular Protection during Inflammatory Arthritis
Funder: Barts Charity

Abstract: 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.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Velmanase alfa for treating alpha-mannosidosis [ID800] - Part 2
Funder: Department of Health and Social Care

Abstract: 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_
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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_
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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_
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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_
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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

Lay Abstract: To evaluate the benefits and costs of velmanase alfa within its licensed indication for treating alpha-mannosidosis for national commissioning by NHS England.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: CONGENITAL DISORDERS
Award Title: Virus Structures
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION
Award Title: Volatile hypoxia signatures in oesophageal adenocarcinoma
Funder: Medical Research Council

Abstract: 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.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Walkable area and pavement anomaly segmentation for MSVI-supervised autonomous pedestrian navigation
Funder: Innovate UK

Abstract: 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.


Research Activity Codes: 5.3 MEDICAL DEVICES
Health Categories: EYE
Award Title: Wellcome Centre for Mitochondrial Research
Funder: Wellcome Trust

Abstract: 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.

Lay Abstract: No Data Entered

Research Activity Codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health Categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL