NIHRDataInsights/HRCSData huggingface dataset:
Title: Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillatioN
Funder: Stroke Association

Abstract: SCIENTIFIC: Background: Direct oral anticoagulants (DOACs) are at least as effective as vitamin K antagonists in preventing recurrent stroke in patients with prior ischaemic stroke and atrial fibrillation (AF). They also give lower rates of symptomatic intracerebral haemorrhage (ICH). Clinicians are weary of using anticoagulants very early after stroke due to risk of ICH but early use may be more effective at stroke prevention. We do not know the safest time to start anticoagulants after stroke. Aims: This trial aims to investigate if earlier initiation of DOACs is feasible and safe and prevents recurrent stroke in patients with AF related stroke without increasing the risk of symptomatic intracerebral haemorrhage. Methods: This is an international, multicentre, randomized-controlled, assessor-blinded trial of 600 participants. We aim to recruit 150 in the UK. All DOACs licensed in the EU may be utilised in the trial Participants will be stratified by stroke size (minor, moderate, major) then randomised to standard or early (minor: <​48hrs, major: 6days) initiation of DOACs. Patients will be followed up by telephone interviews at 30 days and a clinical visit at 90 days. The primary trial outcome is occurrence of major bleeding after 30 days. Secondary outcomes include efficacy measures.

Lay abstract: SCIENTIFIC: Background: Direct oral anticoagulants (DOACs) are at least as effective as vitamin K antagonists in preventing recurrent stroke in patients with prior ischaemic stroke and atrial fibrillation (AF). They also give lower rates of symptomatic intracerebral haemorrhage (ICH). Clinicians are weary of using anticoagulants very early after stroke due to risk of ICH but early use may be more effective at stroke prevention. We do not know the safest time to start anticoagulants after stroke. Aims: This trial aims to investigate if earlier initiation of DOACs is feasible and safe and prevents recurrent stroke in patients with AF related stroke without increasing the risk of symptomatic intracerebral haemorrhage. Methods: This is an international, multicentre, randomized-controlled, assessor-blinded trial of 600 participants. We aim to recruit 150 in the UK. All DOACs licensed in the EU may be utilised in the trial Participants will be stratified by stroke size (minor, moderate, major) then randomised to standard or early (minor: <​48hrs, major: 6days) initiation of DOACs. Patients will be followed up by telephone interviews at 30 days and a clinical visit at 90 days. The primary trial outcome is occurrence of major bleeding after 30 days. Secondary outcomes include efficacy measures.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;STROKE
Title: Next Generation Flow Diverter for the Treatment of Intracranial Aneurysms
Funder: Innovate UK

Abstract: Annually 6,600 UK citizens suffer a subarachnoid haemorrhage (SAH) resulting from the rupture of an intracranial aneurysm (IA), of whom 40% will die and 40% will suffer severe disabilities. However, SAH's are entirely avoidable through early intervention. Over the last decades clinical interventions have increasingly moved from invasive, risky, and expensive open surgeries (clipping) to less risky and cheaper minimally invasive endovascular coiling. Here coils are used to fill the aneurysm and prevent growth/rupture. However, for wide necked aneurysms, coils can dislodge and migrate into the parent artery leading to risk of thrombosis and stroke. To address this challenge stents are placed over the aneurysm neck. However, this is expensive, has limited efficacy and introduces new risks (clot formation). Flow diverters (FDs) are an emerging endovascular device (mesh structure) that is placed over the aneurysm to divert blood flow away, thereby prevent growth/rupture and enabling natural healing. By their nature, FD have the potential to effectively treat complex and wide-necked aneurysms. However, existing FDs have failed to live up to expectations, reporting performance inferior to coiling. Limitations are inherent to the FD mesh design that drives weak and non-uniform radial forces, resulting in incomplete opening, poor vessel apposition, variable porosity and device coning, and leading to suboptimal IA occlusion, FD migration and risk of thrombosis/stroke. OE seek to overcome these challenges through development of a novel 'origami inspired' engineered FD.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR;STROKE;BLOOD
Title: Over two years to study whether new born screened babies with cystic fibrosis still have normal lung function when they go to school.
Funder: Action Medical Research

Abstract: Background Cystic fibrosis (CF) is the UK's commonest life-threatening inherited disease, with approximately one in 25 people in the UK carrying the affected gene. CF mainly affects the lungs and digestive system causing them to become clogged with thick sticky mucus. Symptoms of CF include persistent cough, recurrent chest infections and poor weight gain. Although many children with CF live through into adulthood, life expectancy is significantly shorter than that of healthy individuals. Not all people with CF develop lung disease at the same rate so it is important to be able to identify at an early stage children who are at risk of doing badly. These children can then be treated more intensively to try and delay the onset of serious lung damage. The London CF Collaboration (LCFC) is a study that has run for 14 years, following babies with CF to identify markers of early lung disease. In one part of this study, a group of 75 babies diagnosed by newborn screening were treated with standardised therapy and had their lung function monitored. After one year, these children had much better lung function than expected. The research project These children are now at preschool age (three to five years). The researchers intend to reassess lung function using highly sensitive but safe methods developed in their own laboratory during previous stages of the LCFC. They will then compare these results to the children's previous measurements, to their need for therapy and to the results of healthy children. This study should help identify those children who are likely to get into difficulty in the future, those who will benefit from intensified therapy now and those who will benefit from being entered into research studies for new treatments in the future. The results could have implications for cystic fibrosis treatment around the world. In addition, it will provide an opportunity to test new equipment which should allow CF centres elsewhere to use the sensitive tests developed by this team.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CONGENITAL DISORDERS
Title: Over three years for translational therapy development for Smith-Lemli-Opitz syndrome a common under-diagnosed childhood malformation syndrome
Funder: Action Medical Research

Abstract: Background Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic disorder occurring in one in 50,000 live births. However, the incidence of the condition is likely to be much higher as 80 per cent of babies with SLOS are thought to die during pregnancy. Babies with severe SLOS are born with birth defects such as cleft palate, microcephaly (small head) extra or webbed toes or fingers and fail to grow normally. Children with SLOS often have learning difficulties and all have autistic spectrum disorders. Severely affected children often die at a young age, usually as a result of heart problems Milder cases of SLOS may have minor birth defects coupled with behavioural and learning disorders and can go undiagnosed as children, living through into adulthood. Biochemically, SLOS is caused by an inability of the body to make its own cholesterol but giving extra cholesterol in the diet is of little or no benefit as the patient's cells are not able to use it correctly. There are currently no treatments for SLOS. The research project These researchers want to develop treatments for SLOS. They have discovered that cells from people with SLOS have similar problems as cells from patients with another genetic disease called Niemann-Pick C (NPC). NPC disease has a different genetic cause and people with NPC disease can make their own cholesterol but cannot distribute it around the cell. This failure of the cells to redistribute cholesterol is also a problem in SLOS and is thought to be the reason why adding cholesterol to the diet doesn't help. This research will investigate the cellular changes in SLOS and in particular the role of a substance related to cholesterol which accumulates in cells. The researchers hope to establish exactly why dietary cholesterol is of no benefit in SLOS and evaluate other therapies which could improve quality of life and survival for children with these devastating inherited diseases. Treatments could also be of benefit to adults with SLOS.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Testing the effects of drugs used in the clinic on the genomic health of cells from children suffering with the premature ageing disease Hutchinson-Gilford Progeria Syndrome
Funder: SPARKS

Abstract: Progeria is a severe premature ageing syndrome where children appear to age 8x faster than normal. They suffer from age-related issues such as atherosclerosis and die in their teens from heart attack or stroke. The protein associated with the disease is normally found in cells as a scaffolding protein that allows chromosomes to function correctly. In the disease, the mutant version of the protein affects chromosome behaviour. We have perfected a series of assays to analyse complex chromosome mis-behaviour in cells. We wish to use these assays to determine how well drugs could restore healthy chromosome function in Progeria children.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS
Title: Clinician Scientist: Investigating regulation and effects of Matrix Metalloproteinase secretion in Cystic Fibrosis
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Cystic fibrosis (CF) is characterised by chronic infection and tissue destruction with cystic dilatation of airways and fibrotic remodelling of normal lung tissue. Other destructive lung diseases are associated with excessive matrix metalloproteinase (MMP) secretion. Recently MMPs have been implicated in epithelial to mesenchymal transition (EMT) where injury to epithelial cells causes transformation to a mesenchymal cell type, with invasion beneath the basement membrane and resultant fibrosis. The limited MMP studies in CF suggest upregulated MMP-8/-9. This study will -comprehensively assess MMP activity and regulation in response to infection with Pseudomonas aeruginosa in vitro in a CF model, using bronchial epithelial cell line (NHBE), CF epithelial lines, NHBE cells with CFTR siRNA or a CFTR inhibitor (measuring MMP protein by bead array/ zymography/ western blot and ELISA, mRNA by RT-PCR, signal transduction by western blot/specific inhibitors, transcriptional regulation by western blot, EMSA and transcription factor assays). -correlate this with ex vivo CF lung epithelium and biopsy samples obtained at bronchoscopy. -compare MMP secretion by CF epithelial cells and inflammatory leukocytes with normal human bronchial epithelium and inflammatory leukocytes (healthy volunteers). -assess functional effect of excessive MMP activity on lung matrix degradation (loss of tight junctions –immunocytochemistry-, epithelial potential difference, degradation of matrix proteins by fluorokine assay). -investigate EMT and its regulation in CF epithelium (biopsy samples, cellular model, proteomics). -investigate the role of MMP inhibitors in reducing matrix degradation and EMT in vitro. Data will define the role of MMPs in CF and will set the scene for inhibitor studies in animal models.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Development of an intervention to increase physiotherapy adherence among young children with cystic fibrosis: a Medical Research Council complex intervention framework development and feasibility study
Funder: Chief Scientist Office (Scotland)

Abstract: Cystic fibrosis (CF) is an inherited, life-threatening disorder of the lungs and digestive system affecting approximately 1 in 2,500 children. Chest physiotherapy is a major component in the respiratory management of CF to help prevent lung damage. Adherence in young children is important because damage occurs rapidly and can be irreversible. However, only 50% of parents and young children adhere to their recommended regimen. Interventions to address this significant problem are lacking. We will develop and feasibility test a theoretically- and empirically-informed, multi-professional intervention for parents/carers to increase physiotherapy adherence among 0-8 year olds comprising of two components: -An audio-visual support resource to enhance parental intentions to adhere to physiotherapy. -A family-specific adherence plan to facilitate the translation of intentions into behavioural change. This will lead to a trial that should impact on patient outcomes such as decreasing the likelihood of lung damage thus potentially extending life.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CONGENITAL DISORDERS
Title: Developing and evaluating novel gene therapy approaches in Rett syndrome
Funder: Chief Scientist Office (Scotland)

Abstract: Rett syndrome (RTT) accounts for more female patients with severe intellectual disability than any disorder except Down syndrome. RTT results from loss-offunction mutations in the MECP2 gene and causes lifelong cognitive and motor disabilities. MeCP2 protein is abundant in brain where its role may be to suppress transcription. It likely plays a very similar role in mice as knocking out the gene recapitulates most key features of RTT. Using novel lines of mice that accurately model RTT through the introduction of common human RTT-causing mutations, the proposed study aims to test the effectiveness of AAV vector-based gene therapy approaches in ameliorating and/or reversing RTT-like pathologies. Whilst a number of points support the concept of gene therapy in RTT, the study will also address significant challenges including the cellautonomous effects of MeCP2 deficiency and the fact that ensuring MeCP2 levels within each cell are within physiological bounds may be critical.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CONGENITAL DISORDERS
Title: Dissecting the role of sonic hedgehog signalling during development of the secondary palate: a systems-level approach
Funder: Medical Research Council

Abstract: Cleft palate is a common congenital malformation that affects up to 1 in 2000 live births resulting in approximately 320 new cases each year in the UK alone. Cleft palate leads to distressing problems with obstructive apnoea, feeding, speaking, hearing and social adjustment. Treatment of cleft palate constitutes a heavy burden to affected individuals and their next-of-kin as well as to society more generally as the therapy requires several years and the input of multidisciplinary teams including surgeons, orthodontists, speech therapists and psychologists. Identification of the molecules that are crucial for development of the secondary palate and knowledge of their downstream cascades is imperative to improve diagnosis, prophylaxis, genetic counselling and care for affected individuals and their families. Appropriate specification, growth, elevation, adhesion and fusion of the palatal shelves are essential mechanisms involved in formation of the secondary palate and failure of these processes leads to cleft palate. Recent research has indicated that Sonic Hedgehog (Shh)-mediated signalling plays a fundamental role in ensuring appropriate palatal development; however, the downstream regulatory networks remain uncharacterised. The recent development of resources for defining the complete set of binding sites for Gli transcription factors, the effectors of Shh signalling, has provided a unique opportunity to dissect the Shh signalling cascade during development of the secondary palate In this project, we will use a systems-level approach to dissect the cis-regulatory circuitry underlying Shh-mediated palatal development. The first aim will utilise expression profiling of the palatal shelves of mice carrying loss-of-function or gain-of-function mutations in Smoothened, an obligatory component of Shh signal transduction in responding tissues, to identify genes downstream of Shh signalling. In the second aim, the resulting dataset will be filtered by comparison with a palate-specific database of Gli binding sites generated using ChIP-seq thereby selecting for genes directly regulated by Shh signalling. To prioritise these targets for subsequent analyses, we will filter our data further by intersecting them with a ChIP-seq dataset generated using antibodies specific for the transcriptional co-activator protein p300 to identify a genome-wide catalogue of enhancers active in the developing secondary palate. The presumed direct targets of Shh signalling will then be verified using expression analyses, bio-informatics, independent ChIP-qPCR, and luciferase reporter assays. This analysis will provide crucial insights into the fundamental molecular events driving palatal development and result in the identification of genes that can be screened for mutations in families with a history of cleft palate.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: The Role of Meckel-Gruber Syndrome Proteins in Cell Migration
Funder: Medical Research Council

Abstract: In recent years, many inherited diseases, of previously unknown aetiology, have been shown to be ciliopathies (diseases of cilium dysfunction) and there is considerable worldwide interest in elucidating the role of cilia in human development. Meckel-Gruber syndrome (MKS) is a lethal autosomal recessive disorder that represents the most common syndromic cause of neural tube defects in man; yet the reason for the neural tube defect is unknown. We and others have provided compelling evidence that MKS is a ciliopathy by showing that MKS proteins are required for centrosome polarisation during ciliogenesis, and this remains their only published role. However, MKS mutant cells also show aberrant actin polymerisation that is expected to have a profound effect on cell shape, polarity and migration. Neural tube defects can arise from defective cell migration or cell fate determination and our preliminary data demonstrate that there is a cell migration defect in MKS. The actin and microtubule cytoskeletons cooperate in polarised cell migration and understanding their mechanics in MKS is key to understanding the migration defect. How does cilium loss affect the organisation and dynamics of the actin cytoskeleton and cell adhesions? How do mutations in MKS proteins affect cell shape? How readily do MKS cells polarise towards a target? Why do MKS mutant cells migrate slower? Our overall aim is to use cell biology and genetics to give insight into how MKS proteins function in cell migration. We will image cell polarisation and formation and remodelling of actin networks and cell adhesions in MKS patient-derived immortalised fibroblast cell lines. We will use phase contrast and fluorescence microscopy of live and fixed cells in combination with assays designed to test the effect of mutations in MKS proteins on (a) initiation of polarity, (b) maintenance of polarity and directional cell migration, and (c) organelle polarisation and organisation of the actin cytoskeleton. Specifically, we aim to understand the following questions: 1. How do MKS fibroblasts behave during cell migration? 2. Are the dynamics and organisation of actin perturbed in MKS mutant cells? These studies will increase our knowledge of the basic biology of ciliopathy, critical if these devastating disorders are ever to be treatable, and will facilitate further studies on the role of MKS proteins in migration in a developmental context.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: RNA interference of ENaC as a therapy for cystic fibrosis
Funder: Action Medical Research

Abstract: Background Cystic fibrosis (CF) is an inherited disease that damages the lungs, the digestive system and other organs due to a build up of thick, sticky mucus which prevents these organs from working properly. It is the UK's commonest life-threatening inherited disease with approximately one in 25 people carrying the faulty gene. Around 9,000 people in the UK are living with cystic fibrosis and one in every 2,500 babies born is affected. One effect of the faulty gene is to cause the lining of the lungs, which is normally quite moist, to become dehydrated, allowing bacteria to flourish and cause further damage. Previous attempts at gene therapy for cystic fibrosis have focused on replacing the CF gene itself, but so far with limited success. The research project Rather than trying to replace the CF gene, these researchers are planning to develop a new type of gene therapy which will switch off a gene called ENaC. By switching the gene off, they hope to protect the lung from the dehydration process and reduce the risk of bacterial infections. The drug they plan to develop is a small, synthetic molecule called an siRNA which will be mixed with a lipid/protein substance. The mixture forms very small particles (nanoparticles) that package and protect the siRNA, so that when it is inhaled, it can enter the cells lining the lung and switch off the ENaC gene. The team will test the drug in cells taken from the lungs of people with cystic fibrosis and also in a rodent model. The ultimate aim is to develop a drug which can be given regularly by inhalation to reduce the thickness of mucus in the lungs, improve ease of breathing and reduce bacterial infections. Action Medical Research and the Cystic Fibrosis Trust are together funding this study.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CONGENITAL DISORDERS
Title: Deciphering Developmental Disorders.
Funder: Department of Health (England)

Abstract: Thousands of babies are born each year in the UK who fail to develop normally because of errors in their genetic makeup. Currently, diagnosis is restricted to a small minority of children and requires the clinician to recognise the appearance of the child and the pattern of symptoms, supplemented by the use of microscopes to identify large rearrangements of the genetic material in chromosomes. Research shows that the latest molecular testing methods identify previously undetectable changes in chromosomes allowing new diagnoses to be made. However, clinical use is hampered by the limited availability and inconsistent application of these technologies, and by lack of basic knowledge to link genetic changes directly to symptoms The consequence is that clinical diagnoses remain impossible except for a small number of children. We propose to apply state of the art molecular testing to 12,000 UK children with abnormal development. The results will provide a unique, on-line catalogue of genetic changes linked to symptoms that will enable clinicians to diagnose developmental disorders. Furthermore, we will design more efficient and cheaper diagnostic assays for relevant genetic testing to be offered to all such patients in the UK and so transform clinical practice for children with abnormal development.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CONGENITAL DISORDERS