NIHRDataInsights/HRCSData huggingface dataset:
Title: Multi-species transmission of Echinococcus on the Tibetan Plateau.
Funder: Wellcome Trust

Abstract: Human echinococcosis or hydatidosis is a neglected chronic debilitating and potentially fatal parasitic disease that causes cysts or tumour-like lesions in the human liver. It is contracted from dogs or foxes which harbour the gut stage adult tapeworm. On the Tibetan Plateau three types of the Echinococcus parasite occur in wildlife and/or domestic mammals, with E.granulosus and E.multilocularis causing a serious public health problem of cystic (CE) and alveolar (AE) echinococcosis amongst Tibet an herders. A third species E.shiquicus has been described in wildlife populations only. Understanding the role of dogs (and foxes) in transmission of E.multilocularis is a key objective to be investigated by undertaking natural reinfection studies in owned dogs using non-invasive lab based tests for faecal samples. Identification of the dominant parasite strains involved will be investigated. Importantly the project will assess the impact of ongoing interventions on the frequency of canine and human echinococcosis and help to predict outcome of current and future control strategies in Tibetan and other CE/AE co-endemic communities in Asia.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Advances in Veterinary Telemedicine: A mobile phone-based tool to diagnose Mastitis.
Funder: Wellcome Trust

Abstract: Small-scale dairy farmers in India produce 80% of the country s milk and meat (Gautam et al., 2009). Dairy production is considered by the Indian government as a critical pathway out of poverty for the estimated 40 million farmers living on less than $2 dollars/day (see GoI 6th-11th Development Plans, 1985-2009). Nevertheless, livestock disease is a major constraint to livelihood security. Mastitis, a disease of cattle, is rapidly spread through herds due to poor hygiene when milking. However, many poor farmers in India do not seek the help of a veterinarian due to social barriers. Therefore, knowledge regarding the disease is low and appropriate prevention strategies rare. To address this issue, the study is further developing and field-testing a mobile phone application to enable poor farmers to diagnose mastitis prior to the advent of severe clinical signs. Based on pattern recognition, the simple and easy to use tool supports rapid diagnosis and better communication with local an imal healthcare providers. The application will also transfer basic information regarding mastitis diagnosis, prevention and treatment to aid farmer understanding of the disease. Overall, the project will greatly enhance the lives and livelihoods of an estimated 5,000 poor dairy producers in India.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: microRNAs and drug resistance in parasitic nematodes.
Funder: Wellcome Trust

Abstract: Many domestic animals reared for food are infected with parasitic nematodes or roundworms There are no vaccines for such parasites, therefore control is based upon the use of drugs. The development of drug resistance in roundworms that infect livestock is a major problem for farmers worldwide. Some parasites of sheep and goats are resistant to all three commonly used drugs, making the rearing of these animals increasingly difficult. Drug resistance is also a problem in some roundworms of horses , cattle and humans. There are few new drugs in development, so extending the useable life of existing drugs is very important. However the mechanisms by which drug resistance develops in parasitic nematodes are not properly understood. In this application we propose a novel mechanism of drug resistance based on the altered activity of microRNAs in resistant worms microRNAs are small non-coding RNA molecules that bind to other genes and regulate their expression. They are known to be involved i n drug resistance in many different types of tumour and we believe they may play a role in resistance in parasitic nematodes. Additionally, by studying the signature of microRNAs, we hope to develop a test for the presence of resistant worms in livestock.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Developing treatments for mitochondrial DNA diseases.
Funder: Wellcome Trust

Abstract: One in 400 people has a maternally inherited, mitochondrial DNA (mtDNA) disease mutation, causing a range of illnesses, including deafness, blindness, diabetes, loss of skills, heart and liver failure. We will study mitophagy (the body s system for mitochondrial quality control) in cell lines from severely affected patients, and attempt to modulate it to favour healthy cells. Mitochondria are essential for generating cellular energy. Mitochondrial failure occurs in both catastrophic chil dhood diseases and the commonest disease of all, ageing. Despite 2 decades of active research, we still do not understand why two affected individuals with the same mtDNA mutation may have very different problems We now propose that these differences are due to mitophagy. We already have a high-tech machine that can easily detect recycling of damaged mitochondria (mitophagy) in cultured cells. We will develop this to study drug treatments that prevent or ameliorate mitophagy. Such treatm ents will be useful for studying other severe conditions in which mitophagy may be important. These include brain damage due to poor circulation of oxygen (hypoxic ischaemic encephalopathy), brian damage due to head injury (traumatic brain injury) and juvenile Parkinson s disease.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Fundamental limits on muscle-actuated locomotor tasks.
Funder: Wellcome Trust

Abstract: The aim of this proposal is to advance the basic science that underlies our understanding of animal locomotion. Specifically, I aim to investigate how animal legs and wings provide both the motive power and the weight support required for locomotion. From an engineering viewpoint, animals would fly more efficiently if they flapped faster, and would run more efficiently if their legs could produce enormous forces. However, this is not practically possible since it would require huge, inefficient, muscles. So, there is a compromise between mechanical and muscular demands for efficiency. In order to explore factors determining this balance, I propose to measure the way in which animals use their muscles when they flap, walk, run and hop under a range of effective gravities. Effective gravity and so body weight will be manipulated with centrifugal forces due to circle-flying (pigeons) and voluntary or treadmill-locomotion in a bespoke low-speed centrifuge (mice, quail, kangaroo rat s). Using centrifugal forces has several practical advantages over adding mass, e.g.: (i) higher force alterations can be induced while maintaining locomotor capability; (ii) many aspects of gait selection whether to walk or run are predicted to be related to gravity rather than mass.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Unravelling The Molecular Genetics of Dupuytren's Disease.
Funder: Wellcome Trust

Abstract: Dupuytren's Disease (DD) is a very common hand condition which causes the fingers to curl up into the palm. This leads to considerable functional problems for patients. The incidence of DD increases with age, so with the demographic change in society it is becoming more common. Half of patients present before age 60, and those who present at a younger age often have a more severe and agressive form of the disease. This leads to increased costs for society in general. Surgery is the mainstay of treatment for DD, but complication rates and recurrence after surgery are both high. Sometimes, the contracture is so bad, the only option is to amputate the affected finger. We know that DD is a complex disease, with both genetic and environmental influences. We aim to understand the genetic basis of DD, and the effects of genetic variants on the proteins and cells in DD. This will help us to understand what goes wrong in DD, and in the future lead to the development of new treatments, reduc ing the need for and recurrence after surgery.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Improving Health Outcomes for Looked After Children and Young People: A multi-method exploration.
Funder: Wellcome Trust

Abstract: This research will adopt a mixed methods approach. This will include quantitative analyses of the Children Looked After dataset (www.data.gov.uk/dataset/children-looked-after-data), an audit of statutory health assessment forms, and qualitative interviews with LACYP and health and social care professionals. The project will be aided by an advisory panel compiled of LACYP, health and social care professionals, and academics who work in this field. Timeline for the research: Year one: o The y outh panel will be developed. o A review of the literature will be conducted. o The introductory background and methods chapters of the thesis will be drafted. o Research and ethical approval will be sought from authorities as required. o Participants will be recruited. o Planning and organising of field work. o Descriptive statistical analyses of the Children Looked After Database. o An audit of the health assessment forms will be started. Year two: o Quantitative analysis. o Qualit ative data collection; o Initial qualitative data analysis will be conducted concurrently with interviewing. Year three: o Data Analysis and write up. o If appropriate, revisit quantitative analysis to further investigate issues that have been raised in interviews.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: The convergence of complement and coagulation in atypical haemolytic uraemic syndrome.
Funder: Wellcome Trust

Abstract: Haemolytic Uraemic Syndrome (HUS) is a severe complication of infection with the bacteria E.Coli O157. In ~10% of patients kidney failure occurs, due to a toxin released by the bacteria. Atypical HUS is a rarer form of the disease which is not associated with these bacteria. In both forms of HUS clots form in the area of the kidney which filters blood, preventing the kidney functioning. In many cases there is a genetic predisposition to the disease. Previously we have demonstrated that abnorma lities in genes for complement proteins predispose to disease in around 50% of cases. The complement system plays an important role in allowing the body to differentiate between its own and foreign cells. If these proteins are faulty then the body's own cells can be damaged by mechanisms designed to destroy foreign cells. Despite this, we do not yet fully understand why these mutations result in clots forming in the kidney. In this project we shall examine how the changes in complement prot eins affect the formation of clots and determine whether changes in genes involved in clot formation may predispose to atypical HUS. We will use this data to develop new drugs to treat patients with HUS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: DISPUTED AETIOLOGY AND OTHER;BLOOD
Title: Structure Mechanics and Regulation Of The Vacuolar ATPase.
Funder: Medical Research Council

Abstract: The vacuolar H+-ATPase (V-ATPase) is an ATP-driven proton pump essential for the function of virtually all eukaryotic cells. It is a membrane-bound rotary motor, larger and more complex than the related ATPase synthase, and is responsible for acidifying intracellular compartments, energising membrane transport and pH homeostasis. Mutations in V-ATPase genes cause osteopetrosis, kidney disease and autophagic myopathy, and its involvement in osteoporosis and metastatic cancer means that controlling its activity with drugs has therapeutic potential. Despite its importance, our understanding of the V-ATPase mechanism and regulation is poor and is a major block in therapeutic development, since structural data often underpins therapeutic drug design. This project aims to produce a high resolution structure of the native V-ATPase (at resolution <10?), combining techniques in single particle cryo-electron microscopy and X-ray crystallography. This will allow for previously unresolved features of this rotary motor family to be seen. In particular it will provide information about the organisation of subunit a, which is poorly defined in both the F and V-ATPase family and is a target for a number of potent inhibitors. This will be complemented by both kinetic analysis and time-resolved cryo-EM, to trap the V-ATPase in conformational states, providing insights into the rotary mechanism. This complex motor is regulated in response to physiological signals indicating low energy, leading to reversible domain dissociation. The nature of the structural changes that occur in response to these signals will also be studied by single particle cryo-EM and, where appropriate, crystallography. Time-resolved single particle cryo-EM is the only general purpose method that can give high spatial (<10?) and time (<5ms) resolution, but despite the power of this technique it is infrequently used. I aim to further develop the general utility of this technique and become a leading expert in what promises to become an important general-purpose method in structural biology. A proven key to success in structural biology is having access to the right material. By having access to an excellent V-ATPase preparation which is homogeneous, stable and able to be highly concentrated, combined with access to one of only a handful of time-resolved apparatus worldwide, I am uniquely placed to carry out this work. This proposed research will further our understanding of a complicated molecular motor and will aid the development of the time-resolved cryo-EM technique. Greater understanding of the structure, mechanism and regulation of the V-ATPase may provide a springboard for therapeutic design.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: DISPUTED AETIOLOGY AND OTHER;CANCER AND NEOPLASMS;RENAL AND UROGENITAL
Title: Reducing unnecessary admissions for chest pain with the Manchester Acute Coronary Syndromes (MACS) decision rule: a feasibility study
Funder: Department of Health (England)

Abstract: Objective: We recently developed a decision rule to reduce unnecessary hospital admissions for chest pain. Now, We aim to evaluate whether using the rule in practice leads to real benefits for patients and the health service. Design: We will run an initial pilot trial comparing the effects of using the decision rule with standard care. If we demonstrate that it is feasible, we will proceed to run a larger trial to definitively answer our question. Anticipated benefits: The decision rule could avoid admission for 30% of patients with chest pain with probable substantial economic benefits and less inconvenience for patients.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: DISPUTED AETIOLOGY AND OTHER;CARDIOVASCULAR
Title: The development of next generation DNA sequencing technologies for the diagnosis of genetic disease.
Funder: Department of Health (England)

Abstract: The diagnosis and management of patients with rare genetic disorders is clinically demanding and resource and time intensive. Multi-disciplinary teams of experts provide life-long care and support, which requires a significant health economic resource. The ability to provide a definitive clinical and molecular diagnosis is psychologically important to patients and families and enables the development of an informed care management pathway. Genotypic information is increasingly used to direct targeted treatments, to prevent severe adverse events and to predict clinical outcome. Until recently, cost and resource pressures dictated that genetic testing was restricted to the analysis of known mutations or sequential screening (often partial) of a limited set of genes. The introduction of next generation sequencing into the NHS means that patients can now be tested for mutations in a large number of genes all at once. ln some cases this enables us to offer tests that simply Weren’t available before and increases the likelihood of reaching a confirmed genetic diagnosis much more quickly. This leads to improvements in the care, treatment and counselling of patients and families, as Well as improving our understanding ofthe biology behind the diseases. The diagnosis and management of patients with rare genetic disorders is clinically demanding and resource and time intensive. Multi-disciplinary teams of experts provide life-long care and support, which requires a significant health economic resource. The ability to provide a definitive clinical and molecular diagnosis is psychologically important to patients and families and enables the development of an informed care management pathway. Genotypic information is increasingly used to direct targeted treatments, to prevent severe adverse events and to predict clinical outcome. Until recently, cost and resource pressures dictated that genetic testing was restricted to the analysis of known mutations or sequential screening (often partial) of a limited set of genes. The introduction of next generation sequencing into the NHS means that patients can now be tested for mutations in a large number of genes all at once. ln some cases this enables us to offer tests that simply Weren’t available before and increases the likelihood of reaching a confirmed genetic diagnosis much more quickly. This leads to improvements in the care, treatment and counselling of patients and families, as Well as improving our understanding ofthe biology behind the diseases.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: DISPUTED AETIOLOGY AND OTHER;CONGENITAL DISORDERS
Title: Understanding the causal pathways for persistent speech disorder in children with and without cleft palate
Funder: Department of Health (England)

Abstract: This programme will investigate persistent speech disorder (PSD) in order to provide clinicians with information to prioritise resources for those at high risk for PSD and subsequent poor life outcomes and reduce unnecessary intervention for those who resolve early. Three studies are planned: the first will use existing data from a longitudinal prospective population study; the second will collect new data within a cohort study of children with cleft palate; and the third will use qualitative techniques to develop and pilot an assessment protocol which will provide data on level of risk plus facilitate the collection of national outcomes.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: DISPUTED AETIOLOGY AND OTHER;CONGENITAL DISORDERS
Title: Child & Adolescent Health
Funder: Department of Health and Social Care

Abstract: We will focus on common risk factors and conditions. We aim to improve outcomes and experiences of children and young people (CYP); and to reduce use of primary and secondary care, and health/health care inequalities.


Research activity codes: 7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: DISPUTED AETIOLOGY AND OTHER;GENERIC HEALTH RELEVANCE
Title: Centre for Macaques (CFM)
Funder: Medical Research Council

Abstract: The MRC Centre for Macaques is a primate breeding unit established in 2003 to house and breed rhesus macaques, funded by the MRC with support from the Wellcome Trust. The unit houses about 250 animals, which includes breeding stock and youngsters. The breeding programme is carefully planned so that supply and demand are matched. By maintaining breeding families of macaques at CFM it is not necessary to import animals for UK research and therefore guarantee high husbandry and care standards. The staff and collaborators of CFM are also engaged in many studies of the behaviour of macaques aimed at not only improving macaques welfare and husbandry standards but informing future primate scientific studies . Primates are sourced from CFM by UK universities and primate tissue samples are also available for academic and commercial collaborators.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: DISPUTED AETIOLOGY AND OTHER;GENERIC HEALTH RELEVANCE
Title: Goal-oriented and model-based pharmokinetic dosing of voriconazole in immunocompromised patients
Funder: Department of Health (England)

Abstract: Dosage individualisation represents an important means of optimising therapeutic outcome. A stochastic controller is complex software which enables the individualisation of dosages to attain predefined therapeutic drug concentrations and optimise patients therapeutic outcome. The proposal applies these concepts to voriconazole, a drug used extensively in the NHS to treat immunocompromised patients with invasive fungal infections. The specific aims are: (1) Identify a therapeutic concentration range for voriconazole (2) construct and validate stochastic controllers for paediatric and adult patients receiving voriconazole (3) conduct a proof-of-principle trial to examine whether the stochastic controllers can be used to attain therapeutic drug concentrations in patients in a more accute and timely manner than current care. (4) refine and further develop tools which can be broadly used in the NHS and which could also be used in a definative clinical trial. An effective and non-toxic concentration range for voriconazole will be identified using existing logistic regression and population pharmacokinetic models. Stochastic controllers for adults and children will be developed using pharmacokinetic data from adults and children and their performance validated using computer simulation. A randomised trial in 72 adults and children (36 per arm) receiving voriconazole as part of their routine care will compare real-time dosage adjustment versus-standard care for the attainment of therapeutic drug concentrations. Pharmacogenetic data will be analysed to examine if this improves controller performance. These data will then be used to design a definitive clinical trial to investigate whether individualisation of therapy improves patient outcomes.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: DISPUTED AETIOLOGY AND OTHER;INFECTION