NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the mechanisms involved in HIV infection and cerebral endothelial dysfunction in a 3D human brain neurovascular spheroid.
Funder: Wellcome Trust

Abstract: Despite successfully suppressing HIV infection with antiretroviral therapy (ART), cerebrovascular disease, including stroke and cognitive impairment, remains a dominant complication in this population. I have shown that HIV is a leading risk factor of stroke in the young and can contribute to 15-30% of overall stroke presentations in endemic regions. There is good evidence that atherogenesis is part of the mechanism. Chronic inflammation and antiretrovirals are amongst confounders that obscure delineating the exact pathway to atherogenesis. The Neurovascular Unit (NVU) which consists of the cerebrovascular endothelium supported by astrocytes and pericytes is pivotal to maintaining blood vessel function and impeding HIV to enter the brain. To date, scientific advancement has been limited by developing experimental systems that replicates the NVU in its normal environment. My fellowship proposes to use a powerful new in vitro multicellular 3D model of the NVU, with blood brain barrier (BBB) properties similar to those found in vivo, to investigate how HIV crosses the BBB, establishes NVU infection, and triggers endothelial dysfunction, a precursor for atherogenesis. Finally, I will exploit an established cohort of HIV patients with ART and phenotyped for cerebrovascular disease in Malawi, to verify the mechanistic insights from my in vitro findings.

Lay abstract: nowadays HIV patients are no longer dying from advanced disease but instead, live longer due to effective treatment. However, owing to reasons yet to be fully explained, we see more patients suffering from neurological complications such as stroke and cognitive impairment, that have brain blood vessel dysfunction at their origin. The blood vessel wall is composed of endothelium. This layer of cells closely interacts with other surrounding cells to form a functional unit that controls brain vascular function. It creates a barrier against HIV. Therefore, for HIV to cause vascular complications in the brain, it needs to penetrate this barrier and dysregulate the endothelium. We will assemble a 3D system that mimics the brain environment, and test how HIV penetrates this barrier, establishes infection and causes dysfunction of the endothelium. This study will give insight into the mechanism of vascular disease in the brain and identify potential targets for treatment.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;INFECTION
Title: Defining pathways of infection induced inflammation in the CNS
Funder: Wellcome Trust

Abstract: While the importance of smallest cells in blood, namely platelets, in blood clotting is well understood, there is increasing interest in their role in regulating the inflammatory response. Our preliminary observations have revealed platelet aggregation and recruitment within the meninges following infection with the fungus Cryptococcus neoformans, the main causative agent of cryptococcal meningitis. Meningeal inflammation is one of the main contributors towards death in patients with cryptococcal meningitis, and thus targeting this is a potential therapeutic strategy for a disease which kills over 180,000 people every year. This project aims to understand how platelets and leukocytes (e.g. meningeal macrophages) drive inflammation and disease progression within the central nervous system during fungal meningitis. Using techniques such as flow cytometry and microscopy, we will determine platelet-leukocyte interactions during fungal infection in the CNS and define the molecular mechanisms governing these responses. Previous studies have shown disrupting platelet-macrophage interactions worsens disease outcome in sepsis, thus there is scope for targeting these interactions therapeutically. The results from this project will significantly advance our understanding of the pathology of cryptococcal meningitis, a disease associated with high morbidity and mortality, whilst providing novel insights into the immune functions of platelets which are poorly understood.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Novel methods in data science to quantify viral and environmental triggers of chronic disease exacerbations
Funder: Medical Research Council

Abstract: This project focuses on exacerbations (periods of worsening) of three major diseases in the UK: asthma, chronic obstructive pulmonary disease, and coronary heart disease. People with these chronic diseases are at risk of early death, and suffer significant morbidity as a result of their conditions. Viral infections are known to trigger exacerbations from individual-level studies, but there is limited understanding of how circulation of triggering viruses impacts population-level patterns of exacerbations. A key tool for interrogating infectious disease dynamics - infectious disease modelling - has not been used to understand the role of infections in population-level patterns of chronic disease exacerbations. Current methods either inaccurately include infectious variables, or use statistical smoothing to remove their effect, leading to unreliable estimation of other triggers. Reliable estimation of the effect of risk factors is crucial for policymakers, and for patients. The accepted best tool for understanding infectious disease dynamics is transmission modelling. I aim to close this gap in our knowledge by using state of the art transmission modelling techniques to better quantify the burden of infectious disease on chronic conditions. By bringing together two disciplines and using novel methods, this project will strengthen the evidence base for possible interventions, such as vaccinations, preventive care, risk awareness, and treatment options.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: CARDIOVASCULAR;INFECTION;RESPIRATORY
Title: A randomised controlled trial comparing rituximab to standard immunosuppression as maintenance therapy in ANCA associated vasculitis (RITAZAREM)
Funder: Versus Arthritis

Abstract: There is an unmet need for improved maintenance therapy for ANCA-associated vasculitis (AAV), to reduce relapse rates and thereby reduce disease related damage and exposure to immunosuppressives and glucocorticoids. Rituximab and glucocorticoids are effective induction therapy for AAV, and a potential role for rituximab in maintaining remission for patients at high relapse risk has emerged from retrospective surveys.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;INFLAMMATORY AND IMMUNE SYSTEM
Title: The Role of Epicardial Adipose Tissue Inflammation in Post-Operative Atrial Fibrillation
Funder: Medical Research Council

Abstract: Despite being the most common cardiac surgical complication, there have been few new strategies over the last 30 years to tackle the development of post-operative atrial fibrillation (POAF). POAF carries significant short and long-term morbidity and mortality in addition to increasing the financial costs of cardiac surgery. One area of growing interest is in the fat depot directly overlying the heart and coronary arteries, namely epicardial adipose tissue (EAT). EAT hosts an array of immune cells and inflammatory mediators that can infiltrate the myocardium given the lack of fascial boundaries between the tissues. Numerous imaging studies have demonstrated an independent association between EAT volume and AF risk. However, the exact mechanism for this association remains poorly understood. My preliminary data implicates memory T cell populations and specific cytokines (IL-17/CCL-17) in the EAT of POAF patients, which are not seen in the blood (systemic control) or subcutaneous fat (control adipose tissue). In this project, I will verify the memory T cell population implicated in POAF is producing these cytokines and perform RNA sequencing analysis of inflammatory mediators that could be implicated in the EAT-POAF association. Second, I will perform immunohistochemistry analysis on the atrial appendage tissue samples from the same patient cohort to confirm whether the infiltration of immune cells and cytokines reflects the inflammatory profile of EAT. I will go on to evaluate the direct contribution of the identified T cell subset mediators on parameters increasing AF vulnerability in a human atrial cardiomyocyte cell line. Throughout the project, I will seek to clinically correlate the immunological findings with detailed patient demographic and clinical characteristics. Ultimately, the project should form the basis of novel risk stratification tools and yield new immune therapeutic targets for POAF prevention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;INFLAMMATORY AND IMMUNE SYSTEM
Title: The WARMER (Wearable Ambulatory RAynaud's Measurement Recorder) Project
Funder: Scleroderma & Raynaud's UK

Abstract: The award will be used to bring together a project team comprising patients, scleroderma experts, designers, biosensor experts, software developers and textile engineers to design and build a wearable medical device that shall remotely assess finger blood flow. The funding shall primarily be used to provide resources for our external partner Thrive Wearables who are specialists in developing wearable technology.

Lay abstract: Aiming to develop a prototype product to measure the perfusion of blood in the hands of people with Raynaud’s, in real time. The University of Bath, in collaboration with commercial partner THRIVE Wearables, will develop a wearable glove which integrates a series of sensors that measure a person’s blood flow through the capillaries of their hand. The glove will also monitor the external temperature the wearer is exposed to. SRUK’s funding covers the process of developing a working prototype that can be tested in ‘healthy’ volunteers. Data from this study will be used to seek further funding, and approval for WARMER as a registered medical device. It is hoped that this glove could be worn in clinical trials to assess the effectiveness of new treatments, bringing new therapeutics closer to the people who need them.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;INFLAMMATORY AND IMMUNE SYSTEM
Title: Cardiac Electrophysiological and structural changes in systemic sclerosis.
Funder: Scleroderma & Raynaud's UK

Abstract: Evaluation of an implantable loop recorder in those with SSc to assess if their heart is involved, as cardiovascular dysfunction is a primary process.

Lay abstract: Evaluating the success of an implantable loop recorder to gauge whether the heart is involved in scleroderma and to detect potentially fatal conditions before they become life threatening. 15-35% of SSc patients have cardiac disease and there is currently no clear way of identifying at risk patients. This research project aims to test the feasibility and use of an implantable loop recorder in a SSc cohort to determine the parameters that can be monitored, and how they correlate with fibrosis.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;INFLAMMATORY AND IMMUNE SYSTEM
Title: Dissecting the role of multinucleated giant cells in the pathogenesis of Giant Cell Arteritis
Funder: Wellcome Trust

Abstract: Giant cell arteritis (GCA) is the commonest form of primary systemic vasculitis. A characteristic feature of GCA is the presence of multinucleated giant cells (MGCs). They are not uniformly present but only develop at high numbers in a limited group of often poorly understood diseases. The common immune pathways that lead to their differentiation in these seemingly disparate diseases is unclear, as is the benefit they provide to host immunity. In GCA they are concentrated at the primary site of vessel damage in close proximity to damage mediated by reactive oxygen species (ROS). In this study, MGCs from unfixed temporal artery biopsy material will be isolated and interrogated by single cell RNA sequencing with findings validated at the protein level by imaging mass cytometry. Analyses of chromatin accessibility will be performed to determine the gene regulatory networks underlying their development. Because it is not technically possible to perform functional analyses on primary MGCs due to low cell numbers an in vitro model will be validated and used to explore how MGCs contribute to vessel damage, including expanding upon preliminary data suggesting that MGCs adapt their metabolism to support production of damaging mitochondrial ROS and testing potentially clinically relevant inhibitors.

Lay abstract: Giant cell arteritis (GCA) is a condition caused by inflammation of blood vessels, particularly those in the head. It causes symptoms including headaches and scalp tenderness. It is important to treat it early as it can result in swelling of blood vessels leading to complications including sight loss and strokes. Around one fifth of those affected permanently lose vision in one or both eyes. This research focuses on Giant Cells that gives GCA its name. They develop in the walls of affected blood vessels where they produce factors that cause damage. When the body tries to repair this it leads to the arteries thickening and blocking. We aim to look at why these cells develop in this disease and how they cause damage to blood vessels. If we knew more about these cells we hope we could develop treatments targeted to them that would prevent complications such as sight loss.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding the excess risk of cardiometabolic disease in individuals with serious mental illness
Funder: Medical Research Council

Abstract: An urgent question facing health researchers is why individuals with serious mental illness have not benefited in recent advances in cardiovascular prevention. My research investigates possible reasons for this by combining health, genetic and social/lifestyle data with statistical and genetic approaches. Firstly, I will determine whether there are common mechanisms underlying the increased risk of cardiometabolic disease in people with mood disorders. Secondly, I will assess the extent to which low socioeconomic status interacts with these mechanisms. Finally, I will explore whether genetic predisposition to serious mental illness can identify subsets of individuals with distinct cardiovascular risk profiles. I will utilise European research cohorts, as well as real-world data. The research cohorts (specifically the IMPROVE (European high cardiovascular risk cohort) and PROCARDIS (European coronary artery disease case-control) studies) have been extensively phenotyped for cardiometabolic metabolic variables. The real-world data (specifically PsyCIS (an ongoing study of >10,000 individuals with serious mental illness and/or psychosis within the NHSGGC Safe Haven) and UK Biobank (a population study of ~500,000 individuals with genetic, clinical and lifestyle/social data as well as linkage to NHS records) allow for long-term follow-up. The UKBiobank is particularly valuable for analyses of lifestyle and socioeconomic data. Standard genetic and epidemiological methods will be used for objectives 1 and 2 respectively. Objective 3 will repurpose quality control methodology in an innovative manner.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;MENTAL HEALTH
Title: Better Parks, Healthier for All?
Funder: Medical Research Council

Abstract: Both experimental and observational studies suggest that contact with nature reduces risk of poor mental health and also cardio-metabolic disease. This effect operates via a variety of aetiological pathways, including increased physical activity and stress reduction via psycho-neuro-endocrine routes. Urban green spaces (the primary exposure to nature for an increasing proportion of humanity) have a variety of designs, facilities, features, vegetation structure and biodiversity levels which plausibly influence the strength and effectiveness of their influence on NCDs. We refer to these as 'qualities'. There has been no systematic, longitudinal assessment of associations between a range of green space qualities, and robust NCD risk factors or outcomes. We will test the hypothesis that higher quality green spaces drive reductions in the risk of, and inequalities in, mental ill-health and cardiometabolic diseases; and a well-connected network of nearby green spaces with diverse qualities and sizes will be a more effective community health intervention than any single high-quality green space. Whilst the state and third sectors in Australia and the UK have blueprints for what to capture in measuring qualities, there are no spatially comprehensive validated secondary measures of green space quality available. We will therefore first co-produce measures of urban green space qualities for 4 cities in Scotland and Australia, using remote imagery including Google earth, Lidar and secondary crowd-sourced biodiversity measures. These will be validated via primary survey. We will then assess, via data linkage, association between green space qualities and robust measures of mental health, cardiometabolic diseases, biomarkers, hospitalisations and risk factors. The health data will come from the 45 and Up Study in Sydney and Wollongong and the UK Biobank in Edinburgh and Glasgow. Co-design of policy options with a multisector advisory group will be informed by our new evidence.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: CARDIOVASCULAR;MENTAL HEALTH
Title: Using the body to calm the mind: An examination of heart rate variability biofeedback as a tool to reduce generalised anxiety disorder symptoms
Funder: Medical Research Council

Abstract: Generalised anxiety disorder (GAD) is a common and debilitating illness. A key cognitive symptom of GAD is uncontrollable worry. Physiologically, GAD is typified by low resting heart rate variability (HRV; the time between consecutive heartbeats). Left untreated, GAD is associated with cardiovascular disease. Cognitive behavioural therapy (CBT) is the psychological treatment of choice for GAD, but only 50% of people recover after CBT. It is thus crucial that we develop alternative methods of symptom reduction for use in primary care. One physiological mechanism showing clinical promise is heart rate variability biofeedback (HRVB). Here, real-time feedback that tracks the relationship between respiration and heart rate is used to increase HRV. HRVB has shown promise as a mechanism for reducing anxiety. Yet, extant research lacks clinical samples and robust methodologies. There is a paucity of knowledge on the causal mechanisms through which HRVB has its effects and the extent to which HRVB reduces symptoms of GAD. Aims: 1. Establish the relationship between increased HRV and cognitive processes known to underpin pathological worry. 2. Determine the extent to which HRVB multi-session training reduces symptoms of GAD as a standalone intervention, or as a multi-modal intervention targeting both physiological and cognitive symptoms of GAD Objectives 1. Examine whether increasing HRV in a single session improves performance on executive function tasks and the ability to disengage from worry. 2. Examine the effects of multi-session HRVB on symptoms of GAD as a standalone intervention and in conjunction with a cognitive training intervention. This research will provide new knowledge of the causal relationship between HRV and cognitive processes impaired in GAD. If HRVB is effective as a standalone intervention or in conjunction with a cognitive intervention, individuals with GAD will benefit from a new treatment approach, offering greater patient choice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: CARDIOVASCULAR;MENTAL HEALTH
Title: Interventions for older people in sub-Saharan Africa
Funder: Economic and Social Research Council

Abstract: Between 2015 and 2050 the number of people aged 60 or more in sub-Saharan Africa is projected to roughly quadruple, reaching over 160 million. Hitherto, international development priorities have focussed on people at younger ages. There is now an urgent need to address this new challenge. It should not be assumed that policies for older people that proved effective in other world regions will be suited to sub-Saharan Africa. Current knowledge about "what works for older people" in the region is very limited. We plan to address this knowledge gap by looking at the effects of three different policies for older people (screening for chronic health conditions, providing basic pensions and extending health insurance coverage) in two quite different countries: Ghana and South Africa. Using survey data that permit analysis over time, we plan to assess impacts of these policies on different aspects of older people's health and well-being. We will pay particular attention to high blood pressure (hypertension) and depression, as these conditions are closely linked to older people's general health and quality of life. Rather than collect our own information, we will make use of a number of existing surveys. Building on insights we generated in a previous study, we will: 1) Examine and seek to explain changing patterns of hypertension among older people in Ghana and South Africa. Hypertension is the leading cause of death and serious illness among this group: understanding these patterns will support the development of more appropriate policy responses. We will look at who has hypertension, who is aware they have the condition and who is effectively managing it. 2) Assess the impact of screening for hypertension in South Africa on older people's awareness, treatment and control of the condition. 3) Assess the impact of Ghana's expanding national health insurance scheme on older people's health and wellbeing, including hypertension and depression. 4) Assess the impact of South Africa's old age grant on the health and wellbeing of older people, with a particular focus on depression and risk of death. Our overall aims are to generate valuable research insights and to ensure these are effectively communicated to appropriate policy-makers. As such, a large part of the project will involve engaging with key global, regional and national policy-makers, including workshops, briefing papers and interaction through social media.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: CARDIOVASCULAR;MENTAL HEALTH;GENERIC HEALTH RELEVANCE