NIHRDataInsights/HRCSData huggingface dataset:
Title: Over two years: Breathe deep – opening up the windpipe in children
Funder: Action Medical Research

Abstract: Background_x000D_ Tracheomalacia is floppiness of the windpipe (trachea) where the throat closes down and restricts the airflow in and out of the lungs. In severe cases, the diameter of the trachea may be reduced to less than 1mm and breathlessness will affect all activities. Sometimes these problems are present from birth (congenital or primary tracheomalacia), in other cases they develop during childhood as result of prolonged infection or damage to the windpipe. The incidence of primary airway malacia in children has been estimated to be one in 2,100.1 Children with tracheomalacia have an increased risk of choking and suffer from recurrent airway infections, leading to frequent hospital admissions and sadly, some will die from complications of this condition. A second and rarer problem is congenital tracheal stenosis where the cartilage rings which support the trachea are complete and thus do not allow expansion and this problem is estimated to occur in 1 in 64,500 births.2 For both these groups of patients the current last resort treatment is an operation to insert an expandable metal mesh tube (stent) that opens up the windpipe and holds it open. The only stents available are intended for use in blood vessels and are therefore not well suited to the windpipe. As the child grows the stent does not, so regular operations under a general anaesthetic are needed to clean and re-expand it. If re-expansion does not work, the stent has to be removed - this is a difficult and complicated procedure and some children have died as a result of undergoing this operation._x000D_ The research project_x000D_ The aims of this project are firstly to investigate the mechanical behaviour of the windpipe in young children and then to develop an implantable stent that will last for about two years before it gradually degrades away. By this age the child has developed enough for the windpipe to remain open of its own accord. The researchers will study two different materials: one which uses slowly degrading glass fibres in a degradable plastic and the second, a metal alloy that dissolves in body fluid. By the end of the project they hope to have developed a biodegradable stent appropriate for the windpipe of infants and young children that is ready to enter clinical trials.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Open-architecture telehealth platform for COPD.
Funder: Department of Health (England)

Abstract: COPD affects 210 million people globally, with 50% of costs (unplanned hospital admissions) that could be avoided with more responsive models of care. 30% of COPD patients in the NHS are re-admitted to hospital once within the year. Within 10 years, COPD will become the third leading cause of death. Even if everyone stopped smoking today, the effect on COPD statistics would not be seen for up to 20 years. We propose to develop an easy-to-use system for patients to monitor their condition, based on mobile communications technology (hence the name of mHealth). The project will make use of the latest generation of smartphones and iPads to enable COPD sufferers to complete patient diaries, respond early to worsening symptoms, and receive support from a respiratory nurse who has access to all of their data. This will lead to improved self-management and a higher quality of life for these patients, with a reduction in the number of severe exacerbations which they experience and which require an unplanned and costly hospital admission. A key goal of our approach is to bring the costs of telehealth technology by at least an order of magnitude to enable it to be adopted on a much larger scale than at present.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: RESPIRATORY
Title: Pregnancy zone protein in the lung – investigating gender differences in development and prognosis of bronchiectaisis
Funder: Chief Scientist Office, Scotland

Abstract: Women are more likely than men to suffer from a number of severe lung conditions. Bronchiectasis, a chronic lung disease causing cough and chest infections, affects around 10,000 people in Scotland and 70% of patients are female. We want to know why women are more likely to get this condition, and why they have a worse prognosis when they do. We have found that pregnancy zone protein (PZP) accumulates in the lung to a much greater degree in women with bronchiectasis. When PZP is high, patients have greater lung bacterial infections. In this study we will look carefully at lung inflammation and lung bacteria in men and women with bronchiectasis. We will then test whether female hormones are making lung disease worse by increasing lung levels of PZP. Finally, we believe it is possible that PZP stops the lung from effectively killing bacteria, and we will test this in the laboratory. Together we hope this study will discover the key differences causing women to have worse lung disease outcomes and lead to better treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Deriving and validating a clinical prediction rule for the diagnosis of asthma in primary care
Funder: Chief Scientist Office, Scotland

Abstract: Asthma is common in Scotland, causing considerable illness, healthcare usage, and public expense. Accurate diagnosis is essential for good asthma management. Yet, uncertainty about the best way to diagnose asthma can lead to missed diagnoses and under-treatment, or over-diagnosis leading to unnecessary treatment and healthcare costs. This project aims to make it easier for doctors and nurses to identify and interpret the important information gathered from a patient suspected of having asthma. Using an existing research database, we can identify which features predict who has asthma and use this information to develop an asthma prediction ‘rule’. The ‘rule’ will be tested using anonymous routine data from UK general practices and a Netherlands-based asthma referral service. The prediction ‘rule’ will help doctors and nurses make sense of information in a standardised way, improving the accuracy with which asthma is diagnosed. Patients will benefit from being accurately diagnosed and receiving appropriate treatment.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: RESPIRATORY
Title: A Qualitative Study Exploring The Acceptability, Facilitators And Barriers To Accessing A Palliative Care Service For People Living With End Stage Chronic Obstructive Pulmonary Disease (COPD).
Funder: Chief Scientist Office, Scotland

Abstract: In order to explore the acceptability of using palliative care services, the clinical respiratory team will identify potential participants for interview. We will conduct 20 interviews with people who have experience of the respective outpatient services provided in their area. That is, in the south of Glasgow interviewing ten people who have accessed the palliative care clinic, and interviewing ten people in the north west of Glasgow who have accessed generic outpatient services. The aim of interviewing people using different outpatient services is to capture any differences or similarities in experiences between those who have accessed the palliative care service and those who have not. A maximum variation sampling strategy will be used to identify patients with a range of experiences. Interviews will be recorded and transcribed verbatim. The data will be analysed using framework analysis. NVIVO software will be used manage the data and analysis.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: RESPIRATORY
Title: Early-life effects on host-microbiome interactions:identification of ecological drivers that are key to short- and long-term respiratory problems in pre-term born children
Funder: Chief Scientist Office, Scotland

Abstract: Respiratory health problems such as infections and asthma are leading causes of morbidity and mortality worldwide in young children, and responsible for a majority of doctor’s visits and health care costs. Prematurely born children are especially at risk of recurrent and severe respiratory infections in the first years of life. They also have a significantly increased risk of developing asthma in the following years. Respiratory infections are actually caused by pathobionts, i.e. bacteria and viruses that are common members of the respiratory microbiome. Interestingly, early presence of these pathobionts is also associated with development of asthma over time. In recent years it has become clear that the human microbiome plays an important role in pathogen-resistance, immune-maturation and –modulation/inflammation and mucosal barrier function. We recently identified in infants/toddlers distinct microbiota profiles, each associated differently with pathogen overgrowth and containment, as well as with development of acute infections and wheezing episodes over time. Moreover, my work and that of others has shown that ‘beneficial’ microbiota, associated with reduced risk of infections and wheezing, were also associated with vaginal delivery and breastfeeding. These beneficial profiles, however, were quickly eradicated by early antibiotic treatment. Moreover, it has been shown in separate studies that early-life infections lead to epigenetic modifications of immunomodulating genes, and in other studies that epigenetic modifications of immunomodulating genes are associated with asthma. What is lacking is knowledge on how accumulating harmful early-life events drive the microbiome composition in preterm infants. Furthermore, no single study has investigated the individual links A. early environmental effects, B. microbiome development, C. development of acute/recurrent respiratory infections in the first years of life, D. epigenetic modifications and E long-term development of preschool wheeze in premature and term infants in a single cohort, although this would be the most sensible approach to unravel cause-effect relationships and to determine the independent contribution of each link to the proposed chain of events


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Therapeutic targeting of AMP-activated protein kinase to enhance airway bacterial clearance in bronchiectasis
Funder: Chief Scientist Office, Scotland

Abstract: The lung is the major interface between the body and the environment. A normal person breathing at a normal rate will inhale more than 1,000,000 bacteria per day. As a result, the lung needs to have an effective method of removing bacteria and other inhaled particles to prevent lung damage. This involves the action of lung immune cells which eat bacteria and other particles, as well as the action of tiny hairs called cilia, which “flick” particles that are trapped in lung mucus out of the lungs. In patients with lung disease, these natural defences against infection fail. In a particularly severe form of chronic lung disease called bronchiectasis, the airways widen, leading to a failure to clear mucus. The cilia are damaged and slow and fail to clear infection from the lungs and we and others have shown that the immune cells in the lungs fail to eat bacteria effectively. As a result, patients suffer from frequent respiratory infections, chronic cough and poor quality of life. There are no effective treatments and as a result patients are treated mostly with frequent courses of antibiotics. The cause of the disease is unknown but our studies are beginning to unravel what happens to cause immune and cilia dysfunction in bronchiectasis. Our studies have identified a critical energy regulator called AMP-activated protein kinase (AMPK) as an important contributor to the disease. AMPK senses when cells need more energy and responds by suppressing energy consuming process (to preserve energy). The converse is also true when energy is abundant. AMPK affects multiple cellular processes including being a very powerful regulator of how the immune system functions. We and others have found in the laboratory that drugs that activate AMPK, some of which are already in use in the clinic, can reduce inflammation and promote the clearance of bacteria. In this project, we will test whether AMPK activators could become a new therapy for bronchiectasis and other lung conditions. We will use AMPK activator drugs to stimulate immune cells, aiming to improve their ability to clear bacterial infections. We will also study whether AMPK activators can enhance the movement of cilia, helping to clear mucus from the lungs. Finally, we will conduct studies in patients that will provide the proof of concept needed to target medications in the right way at the right time. This work therefore aims to further our understanding of chronic lung disease and to potentially develop a completely novel treatment approach.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Immunglobulin Replacement Therapy Immunglobulin G sub class 2 Deficient Patients with Bronchiectasis: A proof of concept study
Funder: Chief Scientist Office, Scotland

Abstract: Bronchiectasis is a common chronic lung condition with over 1,000 patients attending secondary care in NHS Lothian. Such patients have permanent airways damage leading to daily symptoms of cough, sputum production and recurrent respiratory tract infections. We have found a severe deficiency of the immune system as a rare cause of bronchiectasis (called immunoglobulin G subclass 2 deficiency) and occurs in about 1 in 20 bronchiectasis patients. Our pilot work shows these patients have more chest infections and their lung function deteriorates more rapidly. There are no trials to date to guide doctors to decide whether we should replace this deficiency from donated blood or not. The aim with treatment is to prevent disease progression and avoid the need for long term antibiotics. This proof of concept trial will help us understand how this treatment works and its acceptability to patients. This study will help us decide whether we should pursue a future formalised randomised controlled trial in many centres throughout the UK and how we should evaluate such a treatment.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: RESPIRATORY
Title: Rheological measurement of abnormal blood clot microstructures: A novel marker for predicting embolic risk
Funder: Health and Care Research Wales (Welsh Government)

Abstract: The proposed research aims to explore the potential of a novel biomarker in predicting the risk of an embolic event in patients diagnosed with Deep Vein Thrombosis (DVT). Venous Thomboembolism (VTE) encompasses a progression of diseases where initially a blood clot is formed in the deep veins i.e. a DVT. The clot can break off, travel in the bloodstream and lodge in the pulmonary arteries leading to a lack of blood supply to the lungs. This embolic event known as pulmonary embolism, or PE, which can often be fatal. Early intervention and prevention of an embolic event is critical. However, the management of VTE patients has been reported as inconsistent and there is a lack of markers available for predicting the likelihood of a PE in DVT patients. Clinicians are often unaware of the risk of an embolic event. The project stems from exploiting our recent advances, at the NISCHR Haemostasis Biomedical Research Unit, that have shown that blood obtained from patients with VTE produce clots with abnormal structures. Clots that are very stiff could be more friable or clots that are more stringy could have a lesser tendency to break away from the vessel. We aim to validate a novel biomarker of clot structure by investigating the link between abnormal clotting and the propensity of clots to embolise. The biomarker with improved monitoring, assessment and prediction capabilities arising from this work will underpin (i) a screening tool for patients with DVT to assess risk of PE, (ii) improved monitoring of clotting responses to therapeutics and other medicines (e.g. heparin, warfarin), benefiting the patient and reducing the burden on the NHS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Investigation of glycosylation patterns by optical spectroscopy for diagnosis of COPD and exacerbation
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Chronic obstructive pulmonary disease (COPD) is a lung disease that severely restricts normal breathing where ~90% of patients are current/ex-smokers. COPD will become the third most common cause of death by 2020. Direct/indirect annual costs to the NHS are over £1 billion. In Wales, there are 57,500 known cases with 10,000 hospital admissions, 90,000 bed days and 1,500 deaths per year. The majority of people with COPD remain undiagnosed. The annual cost of COPD to NHS Wales is £60 million. At least 60% of costs are for treating acute exacerbations – an increase in inflammation and deterioration in lung function leading to mortality and impaired quality of life. Surprisingly, there are currently no diagnostic tests for the early diagnosis of COPD or to detect exacerbation using biomarkers with good sensitivity and specificity. We lead a national study called Medlung that involves hospitals across England and Wales who recruit, in addition to lung cancer, COPD patients to provide sputum for our research into developing a technology for early diagnosis of COPD and to detect when a patient exacerbates. This studentship will evaluate the diagnostic technology called Fourier transform infrared spectroscopy (FTIR), on a large set of samples and help us elucidate the different biochemicals that are changed in sputum between COPD patients and non-COPD smokers. The student will fully evaluate a cost-effective, easy to use hand-held device for diagnosing COPD at the point-of-care. The student will also develop the technology to detect when a patient is exacerbating through sampling their sputum. Other technologies will be used to confirm the biochemical changes detected by FTIR. The data produced by this PhD could lead to significant changes to the way COPD patients are managed and treated.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Molecular mechanisms of toxicity from exposure to biofuel emissions
Funder: Medical Research Council

Abstract: In response to concerns over fossil fuel consumption, combustion of biomass and biofuel alternatives has been encouraged in Europe. While cleaner than fossil diesel emissions in terms of sulphur, CO and hydrocarbons, biodiesel emissions are rich in ultrafine particles and NOx and targeted studies indicate that they induce stronger inflammation and oxidative stress. Early omics screens demonstrated that the molecular interactions that drive pulmonary responses to biodiesel emissions differ from those caused by fossil-diesel exhaust. Combining mRNA and miRNA sequencing with epigenomic arrays, my research aims to characterise transcriptional dysregulation in the lungs of individuals who have been exposed to biodiesel emissions under controlled chamber conditions. This work is accompanied by a multi-platform metabonomic urinalysis, which explores non-invasively accessible signatures of susceptibility to biodiesel emission toxicity. Relatively little is known of wood smoke toxicity, but exposure has been shown to induce inflammation, cell death and genotoxicity in airway models. Mirroring my biodiesel study, I aim to characterise transcriptional dysregulation in the pulmonary tissue and activated inflammatory cells of exposed volunteers.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Public Health Initiative on LMIC Air Pollution (PHILAP)
Funder: Medical Research Council

Abstract: The PHILAP proposal brings together a multidisciplinary team with a range of expertise to bear on the problem of health effects of air pollution in Delhi, India which is not only a critical case but also a microcosm of a wider global health concern in low and middle income countries, tied up with questions of social justice and equity. In particular, PHILAP seeks to characterise the burden of asthma in adolescents living in the slums of Delhi - a marginalised section of the population who have dropped out of the school system and are engaged in ad-hoc work in the informal sector. PHILAP will employ stateof-the-art miniature wearable sensors currently deployed in Delhi in the MRC-/NERC-funded (2016-21) DAPHNE (Delhi Air Pollution: Health and Effects) as part of the Air Pollution and Human Health (APHH) - Delhi programme, to measure actual personal exposure to particulate pollution and contemporaneously recording its physiological effects, such as changes in the respiratory rate/flow and physical activity levels, with the aim of correlating disease control of asthma with air pollution exposure. These measurements will be situated, and made sense of, in the social and cultural contexts of people's everyday lives through ethnographic fieldwork and interviews. By engaging the ethnographic data in dialogue with the scientific data of urban air pollution and exposure and its clinical effects, we hope to unpick the multiple strands in the entwined health dimensions of breathing and living with air pollution. PHILAP will harness these vast data-sets, produced and mobilised across the work-packages, into a series of public facing visual narratives that seek to foster dialogue at the interface of science, arts and humanities research.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: RESPIRATORY
Title: Investigation of REVERBalpha as a therapeutic target in pulmonary fibrosis
Funder: Medical Research Council

Abstract: Pulmonary fibrosis (IPF) kills 5,000 people a year in the U.K. I have discovered that REVERBalpha prevents myofibroblast differentiation, critical for fibrosis. I propose that REVERBalpha inhibits pulmonary fibrosis by inhibiting myofibroblast differentiation. Aim1: The role of REVERBalpha in pulmonary fibrosis development I will repress the exprssion of REVERBalpha, in two distinct fibrosis models. I will investigate how REVERBalpha affects fibrosis development and resolution. Based on these studies I will proceed to target REVERBalpha expression in specific lung cell types, to identify which cells are mediating the fibrotic effects. In parallel studies I will test the therapeutic effects of novel REVERBalpha ligands in a lung fibrosis model. Finally I will compare REVERBalpha expression between human fibrotic explants and healthy lung explants. Aim2: Examine the pulmonary fibrotic pathological changes in the BAL metabolome I have developed a metabolomics approach capable of detecting differences between fibrotic and control human lungs sampled in-vivo. I will apply this discovery platform to identify metabolites that predict fibrosis development, and progression in the murine studies above. I will develop this approach further, analysing additional human samples, and applying a bioinformatics approach to find metabolites for functional analysis below. Aim3: Analysis of the metabolomic and transcriptional changes through which REVERBalpha alters the pulmonary fibrotic phenotype I will use ChIP-SEQ and RNA-SEQ to identify the REVERBalpha cistrome, and the network of REVERBalpha effects, in the cell-types identified above. This powerful approach, coupled with targeted validation using siRNA, and pharmacological inhibition, will discover new control points for fibrosis regulation. In addition I will identify the function of candidate metabolites identified from aim 2 using in vitro cell culture models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY