NIHRDataInsights/HRCSData huggingface dataset:
Title: Digital Spatial Profiling in biomedical research
Funder: Wellcome Trust

Abstract: The key aim of this application is to provide capacity for medium throughput targeted transcriptomic and protein expression analysis appropriate for, but not limited to, analysis of scarce and challenging clinical samples. Capital equipment costs are requested for the purchase of a Nanostring Digital Spatial Profiler (DSP) Instrument together with a nCounter Max Analysis System. The DSP will become available commercially in late 2018 and provides a unique approach to non-destructive multiplexed immunohistochemistry and gene expression profiling. Maintenance costs for a five-year period are also requested. To ensure effective, open access to this equipment for researchers across the region, salary support for a dedicated technician for a period of five years will be provided in kind by the University of York. This new 5 year post will be based in the Dept. of Biology’s Biosciences Technology Facility, a core facility with an international reputation for training and technology development in the area of imaging and cytometry. Continuation of this post beyond 5 years will be funded through new grant applications based on the use the instrumentation.

Lay abstract: Maximising the use of samples donated by patients and volunteers as well as those derived from animal studies has important cost and ethical benefits. Although technology has been available for examining isolated cells for their expression of multiple different proteins and / or genes has been available for many years, until recently it has been difficult to apply such multiplex techniques to cells in a way that provides information about their position within a healthy or diseased tissue. The new technology we propose to purchase now makes this possible. We expect to be able to make significant gains in our understanding of the development of a range of infectious and non infectious diseases by having access to this technology and we will use this information to help develop new diagnostic and therapeutic tools to improve patient health.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION;CANCER AND NEOPLASMS
Title: A randomized controlled pilot study to assess the feasibility of the Ultimate Cholesterol Lowering Plan (UCLP) in cardiovascular risk reduction in HIV dyslipidaemia
Funder: Department of Health (England)

Abstract: Aim: to test the feasibility and acceptability of the Ultimate Cholesterol Lowering Plan.Design: 50 adults with HIV infection and raised cholesterol levels will be randomly allocated to receive dietary advice on either: reducing saturated fat alone, or together with increasing intake of nuts, plant stanols, soya protein, beans and oats (components of UCLP) for 6 months. Results from blood tests, questionnaires and interviews will inform the design of a larger definitive trial assessing the impact of UCLP on risk of heart disease in adults with HIV infection on anti-retroviral therapy. Also providing information on UCLP feasibility for other populations.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFECTION;CARDIOVASCULAR
Title: 2018 Doctoral Fellowship: Endodontic infections and CardiOvascular disease risk (ECO): A prospective study of a possible link?
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Although major risk factors such as hypertension, diabetes, smoking and hyperlipidaemia have been strongly linked to cardiovascular disease (CVD), the effects of other conditions contributing to chronic systemic inflammation have been studied less widely. The emerging evidence suggests an association between dental disease particularly chronic marginal periodontitis (CMP), systemic inflammation and CVD risk. Similar to but distinct from CMP, endodontic infections have a mixed poly-microbial aetiology and are highly prevalent in western populations, however, links between endodontic infections, systemic inflammation and CVD are not well established. The aim of this study is to investigate whether endodontic infection is predictive of incident coronary heart disease (CHD), independent of established risk factors, in a cohort of 60-70 year-old men enrolled in the PRIME (Prospective Epidemiological Study of Myocardial Infarction) study. A subsidiary aim is to explore whether specific bacterial species associated with endodontic infection can affect the risk for CHD. The study will employ a blend of clinical and laboratory investigations to achieve the following objectives (1) Determine the prevalence of endodontic infections among PRIME subjects. (2) Quantify specific endodontic pathogens in plaque samples obtained from PRIME subjects. (3) Quantify the association of endodontic infections with systemic inflammation and biomarkers of CVD in PRIME subjects. (4) Determine whether or not endodontic infection and/or specific endodontic pathogenic species are predictive of incident CHD independent of established risk factors. (5) Determine whether a combined oral inflammatory burden, combining endodontic infections with measures of periodontal disease severity, will improve the prediction of the risk for the development of CHD. Expected outcomes: We will determine whether presence of endodontic infections and specific endodontic pathogens are associated with systemic inflammation and risk of incident CHD. We will further determine whether oral inflammatory burden combining endodontic infections and CMP is associated with increased risk of incident CHD.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION;CARDIOVASCULAR
Title: The role of macrophages in the development of the atherosclerotic plaque after pneumonia.
Funder: Medical Research Council

Abstract: Clinical and epidemiological data suggests that community-acquired pneumonia triggers acute coronary syndromes (ACS). The mechanistic basis of this association is not established and there are few models of post-pneumonic atherosclerotic plaque formation. I predict that pneumonia induces localised inflammatory changes in the atherosclerotic plaque and that plaque-associated macrophages mediate the alterations in plaque composition. I will test this hypothesis in a unique murine model of post-pneumonic plaque formation that I have developed. I will use ApoE-/- mice fed a Western diet and establish a resolving model of bacteraemic S. pneumoniae infection to create a model of the post-pneumonic plaque. Using this model, my objectives will be: 1. To investigate the effect of pneumonia on plaque size, inflammatory cell composition, smooth muscle content and macrophage transcriptome and phenotype using advanced histopathological techniques including laser-capture microdissection. 2. To determine the role of plaque macrophages in post-pneumonic plaque formation using diphtheria toxin (DT) inducible or anti-CCR2 antibody mediated macrophage depletion in this murine model. 3. To establish whether initiation of statin therapy at the time of pneumonia reverses the changes that characterise the post-pneumonic plaque. The scientific opportunities which this work will create will arise from the identification of a mechanistic basis for the association of ACS with pneumonia, which has the potential to identify novel aspects of the pathogenesis of atherosclerotic plaques applicable in other clinical settings as well. The medical potential will stem from the identification of new therapeutic strategies to reverse changes in the atherosclerotic plaque and from the identification of a major clinical indication that should lead to implementation of this preventive strategy.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;CARDIOVASCULAR
Title: The role of CMV-specific immunity in the association between CMV infection and vascular complications with old age
Funder: The Dunhill Medical Trust

Abstract: Numerous publications suggest an association between Cytomegalovirus (CMV) infection, older-age vascular morbidity, and reduced survival in CMV-infected older people. However, no study has ever been conducted specifically to confirm or refute this potentially very important link. Thanks to DMT funding we have recently established a research-interested cohort of 130 older people (60 – 85 years of age, 50% CMV-positive) of good general health and well characterised in terms of CMV-specific immunity. Based on this ideally suited cohort and additional participants we now wish to answer if CMV-infection is linked to a decrease in vascular compliance (a highly sensitive and early parameter of cardiovascular risk), and increased blood pressure. We will also measure key parameters of CMV-infection and specific immunity (T-cell responses and antibody levels), which we believe might identify those most at risk. This study is a critical step towards understanding the role of CMV-infection in reducing survival at older ages


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;CARDIOVASCULAR
Title: The impact of HIV and antiretroviral therapy on the cardiovascular system in HIV-infected children.
Funder: Wellcome Trust

Abstract: Antiretroviral (ARV) medicines have substantially reduced death, and severe illnesses in adults and children with HIV infection. However research has shown that adults with HIV have higher risks of vascular disease (heart attacks, hypertension, and strokes). Both the HIV virus and ARV medication appear to contribute to these risks. There is limited research on vascular disease in HIV-infected children, who are infected for longer than adults and will need ARV treatment for most of their lives . Recently simple ultrasound techniques have been developed to look at blood vessel walls and measure evidence of early damage. Coupled with blood tests these enable early signs of vascular damage to be detected. I plan to use these measures in groups of HIV infected children in Africa on different ARV regimes and compare the findings to uninfected children to determine to what extent the disease and the treatment have on their arteries. This will allow the development of treatment regime s that will not only suppress the viral infection but also prevent the development of arterial disease which is likely to be the cause of substantial clinical problems when they are older.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;CARDIOVASCULAR
Title: Mouth to Heart: Mechanism of Oral Bacteria-Induced Platelet Activation.
Funder: Wellcome Trust

Abstract: There are small disc shaped fragments in blood known as platelets that play a crucial role in blood clotting and tissue repair. At sites of tissue damage, platelets become activated, aggregate and form a dense mat to prevent blood loss. However, they can also become activated by mistake, by bacteria that have got into the blood stream. The accumulations of bacteria and platelets can lead to intravascular coagulation (blood clot) or infective endocarditis (heart valve disease), and to certain dea th in the absence of treatment. A new molecule that activates platelets has been identified on the surfaces of Streptococcus and Enterococcus bacteria, which grow inside the mouth. This discovery was made possible by using a sophisticated flow chamber apparatus in the laboratory to pass blood over immobilized bacteria. Without the presence of this molecule, the bacteria failed to induce thrombus formation. This project will study in molecular detail the mechanism of interaction between this bact erial factor and human platelets. Understanding the precise nature of this reaction may enable development of new drugs that prevent blood clots or heart disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;CARDIOVASCULAR
Title: Does CMV reactivation cause functional impairment of CMV specific CD4+ T-cells? The potential for valaciclovir to prevent CMV-mediated adverse modulation of the immune system in patients with ANCA-associated vasculitis.
Funder: Wellcome Trust

Abstract: Cytomegalovirus (CMV) is a common virus that tends not to cause symptoms in healthy individuals. Research has shown that the virus remains in the body for life and undergoes periods of reactivation. The immune system trys to keep the virus in-check. However this means that a large proportion of T-cells, part of the immune system important for fighting infection, is 'committed' to responding to CMV. Some of these committed T cells do not appear to work well. This is particularly evident in the elderly where previous CMV infection is linked with poor outcomes. Similar changes have been shown to occur in patients with autoimmune disease such as vasculitis. Vasculitis is a disease of the blood vessels that causes lung and kidney damage. CMV infection in these patients is linked with an increase in 'committed' T-cells and increased number of infections and poor outcomes. This study will involve investigating the nature of CMV specific T cells and treating vasculitis patients with chronic CMV infection with an anti-CMV drug, valaciclovir, to determine whether treatment reduces reactivation of virus and improves function of 'committed T-cells'. This may lead to improved therapy for vasculitis patients and also the ageing population with chronic CMV infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: INFECTION;CARDIOVASCULAR
Title: RAPID point-of-care infection detection and antibiotic-resistance TESTing enabled with laser-patterned microfluidic devices (RAPID-TEST)
Funder: Cystic Fibrosis Trust

Abstract: Developing a quick, point of care system to assist decision-making by clinical teams on when and how to intervene to preserve lung function.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION;CONGENITAL DISORDERS
Title: Development of robust analytical pipelines for the analysis of microbial community data from clinical samples
Funder: Medical Research Council

Abstract: Cystic fibrosis (CF) affects around 9,000 people in the UK and is one of the most common inherited causes of premature death in adults. CF is inherited recessively from mutations found in the gene encoding for the CF transmembrane conductance regulator (CFTR), an epithelial chloride ion channel. In the respiratory tract, defective chloride ion transport leads to dehydration of the mucosal surface and consequent failure of the mucociliary escalator and plugging of the airways by hyperviscous mucus. Although, without treatment, premature death is inevitable, in developed countries management of the condition has resulted in a dramatically increased life expectancy with most patients now surviving into adult life. However, still only half of CF patients survive into their 40s. During this fellowship, I aim to answer several key questions relating to chronic lung infection in cystic fibrosis, particularly: - Is there a typical CF microbiota, and what is it like? - How does the CF microbiota vary according to disease severity? - Why has the Pseudomonas aeruginosa Midlands-1 clone established itself in our local cohort, and what are the routes of transmission? - How does Pseudomonas and other species evolve to adapt to the host during colonisation? Answering these questions requires the concurrent addressing of important technical questions, specifically: - Which benchtop instrument (Ion Torrent and Illumina MiSeq) performs best for 16S phylogenetic surveys? - How well does whole-genome shotgun metagenomics perform compared to 16S analysis for phylogenetic surveys? - What other information does whole-genome shotgun metagenomics provide compared to 16S? - Are these methods statistically robust enough to enter clinical practice? - Can 16S and metagenomics data be presented in a way useful for clinicians? The methods employed will include use of 16S amplicon sequencing, whole-genome shotgun sequencing and whole-genome metagenomics (see case for support).


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;CONGENITAL DISORDERS
Title: Microbial community ecology of chronic respiratory infections
Funder: Natural Environment Research Council

Abstract: The World Health Organisation has identified respiratory illness as one of the leading global causes of human morbidity and mortality. Set within an ecological framework, this CASE studentship will focus on the community ecology of microbial infections within the lungs of cystic fibrosis (CF) patients; where morbidity and mortality in CF patients is primarily caused by chronic microbial infections and concomitant airway inflammation. CF makes an ideal paradigm for chronic respiratory infections as it is a well defined disorder and typically has a more rapid decline in lung function (due to infection) than other respiratory illnesses. The microbiological analysis of clinical specimens has relied traditionally upon culture dependent methods prior to identification and research has focused upon only a few targeted bacterial pathogenic species including; Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae and Burkholderia cepacia complex (BCC). The use of molecular biological approaches, developed and widely used in environmental microbiology, promise to provide fresh insights into infections that have previously been considered well characterised. For example, recent molecular biological based studies have shown that the level of bacterial diversity in CF sputum was much higher than previously accepted. Although known pathogens clearly are important, it is only now being recognised that chronically colonized CF airways represent a surprisingly complex and diverse ecosystem and understanding the CF lung in terms of its community ecology could benefit our understanding of disease progression and influence treatment regimens. Here the PhD student will be provided with training in ecological modelling and statistics, molecular microbial ecology, clinical microbiology, and the latest cutting edge genomic sequencing techniques. This innovative inter-disciplinary training will allow the student to gain an entirely new level of understanding in CF microbiology and to address the following fundamental questions: (1) What are the diversity, abundance and distribution of bacterial taxa across clinically stable patients? (2) How do those community characteristics compare and contrast when patients suffer pulmonary exacerbations? (3) Are there regional differences in the bacterial community ecology for groups of CF patients attending different centres for CF excellence? (4) Do archaeal and eukaryotic organisms also have a role to play in disease in pulmonary exacerbations?


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;CONGENITAL DISORDERS
Title: US-Ireland R&D Partnership - Cystic Fibrosis: The role of anaerobic bacterial infection in Cystic Fibrosis
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Participants in the monotherapy arm were restarted on triple therapy if they had three viral load results >50 copies/mL (including a retested sample), or due to side effects or patient choice. Approximately 80% of people in the boosted PI monotherapy arm used darunavir/r, with 14% using lopinavir/r and 7% using another PI. Baseline characteristics included median age 44 years (IQR 38-49), 23% women, 60% gay men; 68% white, 28% black, 4% other. Baseline CD4 count and CD4 nadir were 513 cells/mm3 (IQR 392 – 682) and 178 cells/mm3 (IQR 86 – 250), respectively. Median time on ART was 4.0 years (IQR 2.2 – 6.7), having used a median of 4 individual drugs (IQR 3 – 6). Approximately half of participants were using PI-based and half using NNRTI-based treatment at enrolment. Although loss of treatment options was low in both arms, more people lost treatment options on the PI/r vs the triple therapy arm. These results were 6 (2.1%) vs 2 (0.7%) people [difference 1.4% (95%CI -0.4 to 3.4%), p = 0.15] after 36 months and 6 (2.1%) vs 4 (1.8%) people [difference -0.2% (95%CI -2.5 to 2.46%), p = 0.85] at the end of the trial.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;CONGENITAL DISORDERS
Title: Genetic diversification and within-host evolution of chronic Pseudomonas aeruginosa infections in cystic fibrosis patients.
Funder: Wellcome Trust

Abstract: Cystic fibrosis (CF) patients are particularly prone to bacterial infections of the lungs. The most important species of bacterium in this respect is Pseudomonas aeruginosa, which, once established, proves impossible to clear and causes a major deterioration of lung function and patient health. We have recently generated a unique resource of multiple samples from multiple patients infected with the same P. aeruginosa strain. Unexpectedly, we found that chronic infections diversify into hundreds of distinct genotypes when we looked at clinically important traits of the bacteria, such as antibiotic resistance. Moreover, we found that a molecule produced by the bacteria was linked to episodes of acute symptoms in the patients. Here we wish to use the latest advances in DNA sequencing technologies to provide a comprehensive picture of diversity within P. aeruginosa infections. Specifically we wish to identify genes that are evolving rapidly and involved in adaptation to the CF lung, an d to identify genes associated with acute clinical symptoms Doing so will help us to understand the ability of chronic P. aeruginosa infections to persist within CF patients and the harm that they cause to CF patients.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;CONGENITAL DISORDERS
Title: Calprotectin is released in neutrophil extracellular traps in response to infection and is central to CF lung inflammation.
Funder: Wellcome Trust

Abstract: Cystic fibrosis is a universally fatal genetic disease characterised by lung infection and inflammation. CF effects 1 in every 2000 live births with 1 in 25 of the population being carriers. Most sufferers die by their mid thirties, the only cure being lung transplant, which will on average only prolong life for a further 5 years. I have demonstrated that a protein, calprotectin, is present in lung fluid in CF and changes in relation to how bad lung disease is, decreasing when patients are be tter. I have also demonstrated that calprotectin stimulates blood cells to cause inflammation and therefore may make lung disease worse in CF. Calprotectin is released when white blood cells die in a certain way forming what are known as neutrophil extracellular traps (NETs) which are collections of DNA and proteins. In this study we will investigate the release of calprotectin on NETs following infection, and how this is involved in inflammation and lung damage. We will demonstrate that cal protectin is an important cause of inflammation in the CF lung and that decreasing the activity of calprotectin in the lung will improve inflammation.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;CONGENITAL DISORDERS