NIHRDataInsights/HRCSData huggingface dataset:
Title: Hydroxysteroid Dehydrogenase activity and the vitamin D axis in acute lung injury - mechanistic and functional importance.
Funder: Medical Research Council

Abstract: Objectives: We study why vitamin D levels are low in HSD-1 KO mice and its functional importance in terms of calcium metabolism, bone density and innate immunity. We test the ability of HSD-1 KO mice to resist infectious models of pneumonia and peritonitis following caecal ligation and puncture as clinically relevant models of infection/sepsis. We will replace the vitamin D deficiency in the HSD-1 KO mice to establish if this can both attentuate lung and systemic injury injury. We will establish whether there is a link between urinary measures of HSD-1 activity in a cohort with or at risk of ALI (expected low HSD-1 activity markers in urine). Methodology: We have an existing colony of HSD-1 KO mice. We have experience of manipulating vitamin D levels in wild type mice by using cholecalciferol liquid (Vigantol) or making mice deficient using diet lacking vitamin D. We have expertise in the animal models of pneumonia (Mitchell) and caecal ligation and puncture (Thickett / Lax). We will utilise standard markers of lung injury and quantitative microbiology culture to assess the impact of these models. Sample and effect size calculations are based on robust data about from these models in wild type animals. For the observational clinical studies we will utilise cohorts of patients that are currently being recruited or archived samples, as well as recruiting ALI patients in a prospective manner. Exploitation: data generated will be published in high citation peer reviewed journals. We will use the data about vitamin D replacement to plan further clinical trials in humans with ALI .


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Epigenetic regulation of GR function in pulmonary inflammation: the role of MERM1
Funder: Medical Research Council

Abstract: Pulmonary inflammation is a major human health concern, for which glucocorticoids (Gc) are the major treatment. However, Gc exert variable effects, for reasons which remain unclear. We have discovered that in inflammation MERM1, an important epigenetic regulator of GR function is degraded. This is due to cytokine induction of MERM1 ubiquitinylation, and proteasome digestion. The same cytokines impair GR function. GR function is rescued by restoration of MERM1 expression, by mutating the ubiquitinylation sites. The importance of MERM1 to human lung disease is exemplified by finding loss of MERM1 protein expression across a panel of human inflammatory lung disease histological sections. The mechanisms underlying MERM1 action in the lung will be explored using human bronchial epithelial cells, and macrophages in-vitro. The impact of MERM1 loss on responses to inflammatory challenge and Gc treatment will be measured. The broader actions of MERM1 will be measured using RNA-Seq and ChIP-Seq protocols targeting both MERM1, and GR under conditions of induced inflammation, and Gc exposure. These datasets will be subject to detailed bioinformatics analysis to reveal other MERM1 dependent transcription factors operative in these cells under inflammatory challenge, and to define the spectrum of Gc targets that are MERM1 regulated. We now seek to make a bronchial epithelium-targeted MERM1 deletant mouse, and compare this to littermate controls in a series of pulmonary inflammatory challenges, including allergic, and rhinoviral infection protocols. The impact of MERM1 loss in the bronchial epithelium will be determined on elaboration, and resolution of inflammation. In particular we will investigate the impact of MERM1 loss on the anti-inflammatory actions of Gc. The gene target and pathway discovery approaches above will be tested in primary human lung tissue and cells from patients with Gc resistant asthma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: BRONCH-UK a multicentre and multidisciplinary partnership grant tackling unmet needs in bronchiectasis
Funder: Medical Research Council

Abstract: 3.1 Technical summary ; Our methodology is to 1) Set up a world leading multi-disciplinary partnership, that addresses translational gaps through collective, but never before, assembled expertise. 2) Develop industry & academia pre-competitive space workshops to define consensus statements, new mechanistic studies/ grants and clinical trials. 3) Biobank DNA & serum from 3500 well characterised databased patients with CT proven BE. 4) Create a large database of well-characterised BE patients to facilitate translational research and clinical trials. Databasing will include multiple fields aligned to national standards of care and additional fields (developed from the US Bronchiectasis database allowing international comparisons). Tagging of records to Office of National Statistics and HES data will allow prognostic indices to be developed. 5) Three Partnership pilot projects will focus on important events that have important mechanistic or pathfinding potential and mandate multicentre & multi-disciplinary approaches: i) A clinimetrics study of outcome measures in BE Identify and define/ validate clinical outcome measures & biomarkers in an intensive pilot study of 100 patients including lung function (spirometry, lung clearance index), quality of life (QOL-B), culture and quantitative counts with exploratory biomarkers in blood & sputum (as compared to sputum 16SRNA microbiome). ii) A pilot randomised placebo controlled trial of Pseudomonas aeruginosa bacterial eradication in patients who develop their first infection. This is cross-cutting and studies both patient and bacterial factors involved in P. aeruginosa persistence (16S microbiome analysis & virulence marker expression and human exome sequencing) to help identify vaccine targets. iii) Identify the prevalence of P. aeruginosa epidemic strains and compare their phenoytpe and genotypes to non-epidemic / BE adapted strains, linking to an international genome project for additional comparative power.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: RESPIRATORY
Title: New diagnostic tools for Primary Ciliary Dyskinesia
Funder: Department of Health (England)

Abstract: Primary Ciliary Dyskinesia (PCD) is an inherited condition diagnosed by the examination of cells under a powerful electron microscope. In 30% of children who have PCD the cells look normal. The purpose of this study is to test new microscopy methods, electron tomography and immunofluorescence, to make a diagnosis. Our group has tried out both of these novel techniques and found differences in cilia in PCD patients compared to healthy controls that can be used for diagnosis of disease. We now wish to assess a large number of patients to determine the usefulness of these approaches and if they prove successful to integrate them into the national NHS diagnostic service


Research activity codes: 4.3 INFLUENCES AND IMPACT;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Respiratory monitoring by pulse oximetry waveform analysis in infants and children
Funder: Department of Health (England)

Abstract: Background Respiratory monitoring is central to the care of children with a wide variety of health problems Direct observation of breathing pattern by nurses is time-consuming, inaccurate, and can only be intermittent. Current technologies for monitoring breathing are invasive, poorly tolerated by young children, and unsuitable for prolonged continuous monitoring. We have developed, validated (RfPB grant PB-PG-0706-10504) and published [1] a method for extracting respiratory data by analysis of the plethysmograph waveform of a standard pulse oximeter. We have demonstrated that this reliably records respiratory rate and respiratory pattern in healthy newborn infants, infants with lung disease, and wheezy preschool children. This technique has considerable promise for monitoring sick children. Aims The aim of the proposed study is to apply the technique of Respiratory Analysis of Oximetry (RAO) in clinical practice and assess its value in a range of common paediatric care situations. Specific objectives are: 1) to assess the feasibility and accuracy of overnight respiratory monitoring of children using RAO: a) in hospital b) at home 2) to assess the ability of RAO to detect apnoea a) in neonates with apnoea of prematurity b) in children with obstructive sleep apnoea 3) to assess the utility of RAO as a marker of the severity of acute wheezing illness Plan of Investigation Objective 1: a) the accuracy of RAO in overnight monitoring will be assessed in stable preterm infants on the neonatal unit, using two existing respiratory monitoring systems (impedance pneumography and a volumetric vest system) as comparators. b) feasibility of home monitoring will be assessed in healthy term infants, infants with chronic lung disease, and children being investigated for possible obstructive sleep apnoea (OSA). Objective 2: comparing RAO, clinical observations, and impedance pneumography in a) otherwise stable neonates with recurrent apnoea b) post-tonsillectomy children with a history of OSA. Objective 3: assessing the ability of RAO to predict the need for admission of children with acute wheezing respiratory disease seen on the Children's Assessment Unit. Potential Impact The outcome of this research could have the following benefits for patient care: - safer monitoring of neonates at risk of apnoea - accurate screening for obstructive sleep apnoea in the home, avoiding the need for overnight inpatient assessment - more accurate triage of children with acute respiratory disease - more efficient use of skilled nursing time


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Evaluation of bronchodilator response by interrupter technique as a way of improving the management of wheezy preschool children
Funder: Department of Health (England)

Abstract: Background Whilst there is broad consensus on asthma management in schoolchildren, management of wheezy preschool children is difficult and controversial. Some such children have asthma, and require inhaled corticosteroids (ICS). Others have viral-induced wheezing, and ICS may be ineffective and undesirable, with potential side effects. It is very difficult to distinguish these 2 groups clinically. Above 5 years, measuring bronchodilator response (Bdr) is used to guide treatment decisions, but until recently this was impossible under 5. Interrupter resistance (Rint) can now be measured reliably in preschool children, and Bdr using Rint appears able to distinguish children with clinical asthma. The predictive value of these measurements in guiding treatment has not been assessed. Aims To determine whether a positive bronchodilator response (Bdr), as measured by a significant fall in interrupter resistance (Rint), is predictive of a clinical response to asthma therapy in wheezy preschool children referred for assessment: a) does a positive Bdr predict clinical response to inhaled corticosteroid treatment? b) does a positive Bdr predict clinical response to bronchodilator treatment? Plan of Investigation Inclusion criteria: 160 preschool children (age 2 to 5 years) referred to hospital for assessment and treatment of recurrent wheezing, in whom the clinican intends to start a trial of inhaled corticosteroid. Measure baseline Rint and change with beta-agonist bronchodilator (Bdr) - parent and clinician blinded to these data.Parent records symptoms and quality of life (QOL) score for 2 weeks baseline, then for 6 weeks after starting inhaled corticosteroid. Clinical response to bronchodilator is assessed by parental report. Clinical response to inhaled corticosteroid assessed by change in symptom and QOL scores, clinician assessment and repeat Rint measurement at 6 weeks. Potential Impact Currently, many preschool children who do not have asthma are started on regular bronchodilators and inhaled corticosteroids both in secondary and primary care, and may remain on treatment for prolonged periods without obvious benefit, and with the possibility of side effects. If we can demonstrate that a positive Bdr using Rint predicts a positive response to asthma treatment, clinicians can avoid treating children inappropriately whilst concentrating treatment efforts on those children likely to benefit from asthma therapy. The equipment is portable and relatively simple to use, so potentially this technology could be used in primary as well as secondary care.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Reducing costs in asthma management - a pilot study
Funder: Department of Health (England)

Abstract: Background Many patients start corticosteroid treatment for asthma based on their history alone. As a consequence up to 40% of patients treated for asthma have no evidence that this treatment is required. Patients are therefore taking an unnecessary treatment which is costing the NHS millions of pounds. Measuring nitric oxide is simple and has been shown in research studies to reliably predict a poor short term response to inhaled corticosteroids. We wish to determine whether its introduction into routine clinical practice is feasible and can be used as a screening test to reliably and safely identify a group of patients who will not benefit from starting an inhaled corticosteroid and a group who are unlikely to benefit but need further investigation to safely withhold inhaled corticosteroids. Aims The main aims of this initial study are to determine the feasibility of introducing a single measure of exhaled nitric oxide into routine clinical practice at the point a prescription for an inhaled corticosteroid is prescribed. It will also provide data on the number of new prescriptions for inhaled corticosteroids for suspected asthma in a 12 month period and provide crucial data on the negative predictive value of a low exhaled nitric oxide level for predicting the short term response to corticosteroids. Plan of Investigation Ten general practices in Nottinghamshire will participate. Consecutive patients suspected of having asthma will be evaluated by the General Practitioners using their normal approach but at the point of writing a prescription for an inhaled corticosteroid exhaled nitric oxide will be measured. Using the cut point of 47 ppm, patients with a value below this will be offered the opportunity to visit the Nottingham Biomedical Research Unit for further evaluation of their airways and enter a randomised controlled trial in which they will receive an inhaled corticosteroid or placebo inhaler in a 2:1 ratio. The benefit of corticosteroid over placebo at various nitric oxide cut points can then be estimated and the response to corticosteroid by baseline variable analysed. Potential Impact If exhaled nitric oxide can be shown to identify a group of symptomatic patients who will not benefit and a group who are unlikely to benefit from inhaled corticosteroids we can start to develop and evaluate a new diagnostic pathway that will reduce the use of expensive and ineffective medication. The next step will be to determine whether this can be rolled out across the NHS in a cost-effective way and determine the long term consequences of withholding corticosteroids in this group of patients.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Individually Ventilated Cages in laboratory animal facilities and the prevention of laboratory animal allergy; a proof-of concept study
Funder: Department of Health (England)

Abstract: Laboratory animal asthma (LAA) occurs in people who inhale animal (usually mouse) proteins at work and can have serious health and employment consequences. This project aims to determine whether, with recent improvements in laboratory animal housing (introduction of individually ventilated cages (IVCs)), LAA can be prevented. Several hundred scientists and animal carers from UK research organisations will be tested for LAA (using questionnaires, ‘skin prick’ and blood tests), their work environments examined, and rates of LAA in IVC-only and traditional facilities compared. The aim is to develop a code of practice to prevent or minimise future occurrence of LAA.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;4.4 POPULATION SCREENING
Health categories: RESPIRATORY
Title: Right ventricular outflow limitation and capacity for exertion associated with age and iron status
Funder: The Dunhill Medical Trust

Abstract: The quality of life for older people depends upon their physical ability to undertake their normal daily activities. Exercise capacity and cardiac output can be limited in the elderly by right ventricular afterload, which itself is determined by the pulmonary vascular resistance (PVR). This resistance is dependent upon oxygen levels, which fall with age, and is under the control of the hypoxia-inducible factor transcription-activation system, which itself is iron dependent. We have shown that PVR depends upon iron status. Administration of iron reduces PVR in hypoxia (both in the laboratory and at high altitude) in both healthy volunteers and patients with chronic lung disease. This study aims to examine in 50-80 year olds: (1) the relationship between exercise capacity and iron status, (2) whether iron therapy improves exercise capacity, and (3) the extent to which improvements in exercise capacity can be attributed to a reduction in right ventricular afterload.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: The K+ channel KCa3.1 as a novel target for idiopathic pulmonary fibrosis.
Funder: The Dunhill Medical Trust

Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown etiology1 that occurs primarily in older adults. In the UK the overall incidence of IPF is 4.6 per 100,000 person-years, and is increasing by 11% annually. Median survival is only 3 years with patients dying from respiratory failure. There is no effective treatment and thus an urgent need to find new therapies. Irrespective of the factors involved in IPF initiation and progression, we hypothesise that KCa3.1 K+ channel-dependent cell processes are a common denominator in IPF pathophysiology. Our preliminary data support this. Our aims are to further delineate the role of KCa3.1 channels in IPF, using in vitro human cell and tissue explant models to examine the role of KCa3.1 in the fibrotic process. We expect this work to provide the rationale for a clinical trial of an existing KCa3.1 blocker in this terrible disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Validation of biomarkers for chronic obstructive pulmonary disease (COPD) in a prospective study
Funder: The Dunhill Medical Trust

Abstract: COPD is the fourth leading cause of morbidity and mortality worldwide with high prevalence in old age. It represents a substantial economic and social burden. Clinical presentation is often late in the disease course with limited therapeutic options. COPD is largely irreversible airway obstruction determined by spirometry. COPD is a heterogeneous disease and spirometry is overall a poor predictor of disease severity, rate of progression and as a marker for response to therapy. We have identified three specific informative markers for COPD with 80% predictive power for distinguishing the disease group compared to non-diseased smoking controls by using a combination of mass spectrometry and artificial neural networks. We will: assess the validity of these biomarkers prospectively in a longitudinal study of 29 well- characterised COPD patients and 30 non-disease smoking controls with clinical endpoints including one year follow up to monitor changes in the biomarkers in relation to disease.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Reviews of current treatment for BRONCHO and Asthma in adults and children
Funder: Department of Health (England)

Abstract: Long-acting bronchodilators (with and without inhaled corticosteroids) are increasingly being used in the care of adults and children with asthma and in adults with COPD. Whilst symptomatic benefit may be assessed on an individual patient basis (using a short-term trial of treatment) the longer term risks and benefits (in relation to death admission to hospital and exacerbations requiring oral corticosteroids) require evidence from large numbers of patients.We are therefore working on a set of Cochrane protocols and then systematic reviews and overviews to compare and contrast the different possible combinations of treatment in COPD and asthma with a particular focus on safety and long-term outcomes.The reviews and overviews will be published on the Cochrane Database of Systematic Reviews.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: ‘Medical versus surgical interventions for nasal polyps’ and ‘Surgical interventions for nasal polyps’
Funder: Department of Health (England)

Abstract: Chronic rhinosinusitis (CRS) is highly prevalent affecting 11% of UK adults1. Nasal polyps are a clinical feature of CRS (CRSwNP) causing nasal obstruction purulent nasal discharge anosmia facial pain and headaches2 significantly impacting patients’ quality of life3. Treatment aims to reduce symptoms and recurrences and is primarily medical with surgery reserved for unresponsive patients.There is insufficient evidence on treatment options to allow definitive recommendations. Uncertainty regarding the role of surgery leads to five-fold practice variation across the UK4. This resulted in sinus surgery being deemed of ‘limited clinical effectiveness’5. Specialists believe this is a mistake risking restricting patient access and increasing geographical variation. Recent NICE Commissioning Guidance highlights the need for further trials in this area and better systematic review of the available literature6.An HTA review7 of endoscopic sinus surgery for CRSwNP identified three RCTs and 39 case series which suffered from serious methodological flaws; there have been at least 5 new RCTs. A previous Cochrane review has addressed the effectiveness of surgery for CRS as a whole8. International Guidelines9 now recognise CRSwNP as a distinct entity responding differently to treatment. This review addresses the needs of policy makers clinicians and patients and will inform a proposal for an HTA funded randomised controlled trial being submitted by the senior author.


Research activity codes: 6.3 MEDICAL DEVICES;6.4 SURGERY
Health categories: RESPIRATORY
Title: Enabling Award: Venovenous extracorporeal carbon dioxide removal (W-ECCO2R) in adults with respiratory failureS
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: However, viral load rebounded much more frequently in the monotherapy group ( 35% vs 3.2%; difference 31.8% [95%CI 24.5% to 39.0%], p < 0.001). Patients with viral rebound all became undetectable again, either spontaneously or after the addition of two NRTIs.


Research activity codes: 6.7 PHYSICAL
Health categories: RESPIRATORY