NIHRDataInsights/HRCSData huggingface dataset:
Title: In Situ Structural and Mechanistic Interrogation of dsDNA Synthesis in Hepatitis B Virus
Funder: Medical Research Foundation

Abstract: Hepatitis B Virus (HBV) is a global pathogen estimated to have infected >2 billion people, ~350 million of whom are chronic sufferers, at major risk of developing liver cancer and cirrhosis. Chronic infections of HBV are a major unmet medical need. The costs of treating these diseases is high. The only treatment options are antiviral drugs, which are becoming less effective due to an increased number of resistant HBV strains, or liver transplantation which is prohibitively expensive. These facts illustrate the desperate need for novel antivirals and drug targets, the goal of this proposal. HBV is a para-retrovirus, a dsDNA virus which packages a pre-genomic ssRNA (pgRNA) into a nucleocapsid (NC), along with the virally-encoded polymerase (P). The pgRNA is used as a template for reverse transcription, which occurs concomitantly with RNA degradation in the first round of replication. Each of these nucleic acid copying and degradation activities occurs within the confines of the NC. There are large pores through the protein shell of NC through which presumably dNTPs and NMPs move in and out during replication. Previous EM structures suggest that the pgRNA is arrayed within the NC with multiple contacts to the inner surface of the core protein. We have recently shown that these protein-RNA contact sites are likely sequence-specific and mimic the multiple, dispersed Packaging Signals (PSs) that the Stockley laboratory has helped identify in a wide range of positive-sense ssRNA viruses. For HBV these contacts likely order the pgRNA as a track, preventing the formation of tangles and facilitating the movement of the P enzyme. Similar replication steps must occur for all retroviruses, but little is known about the precise mechanistic events occurring inside their NCs. In part this is due to the complexity of most of these viruses. HBV represents a unique opportunity to study these processes for a major pathogen with a very simple genome (~3500nts long). In addition, accurate replication in this case requires a series of exquisitely precise template switches, without which no infectious virion could be produced. Thus these studies will contribute to both fundamental knowledge and open up possible new drug targets. This proposal will combine several techniques for the first time, using single molecule fluorescence spectroscopy, X-ray foot printing and cryo-electron microscopy techniques to investigate the mechanistic and structural detail of the reverse transcription and RNase functions in situ within the NC of HBV. The results will clarify whether the NC uses PSs during assembly, how the P integrates its activities with this process, and potentially identify new drug targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Reducing toxicity liability in the treatment on malaria
Funder: Medical Research Foundation

Abstract: Currently malaria is one of the world’s most prevalent diseases with more than 300 million people infected with P. falciparum, the most virulent species of malaria parasite (1). Despite the proven efficacy of artemisinin based combination therapies (ACTs), currently the front-line treatment for malaria (2, 3), still over 0.6 million deaths a year are attributable to the disease (4). Furthermore, with evidence of the emergence of resistance to ACTs there is now an urgent need for a novel anti-malaria treatments (2). One of the central issues with delivering the next generation of anti-malaria treatments is the issue of human toxicity. New guidelines issued by the Bill and Melinda Gates funded Medicines for Malaria Venture (MMV) state that new treatments have to consist of a single dose, costing no more than a dollar a dose and be safe to administer to millions of people including children and pregnant women. Thus high efficacy and low toxicity (and low cost) is of the essence. This proposal addresses these issues by developing predictive methods for human toxicity of novel molecular entities, to define processes in the parasite that can be targeted to provide high clinical efficacy and to develop novel clinical protocols that will reduce the toxicity of a known low cost anti-malarial treatment.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Studies of Antibody binding, Sialic Acid Receptor binding, and the three-dimensional structures of Influenza Virus Haemagglutinins.
Funder: Medical Research Foundation

Abstract: Studies of Antibody binding, Sialic Acid Receptor binding, and the three-dimensional structures of Influenza Virus Haemagglutinins.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Childhood uveitis not associated with juvenile idiopathic arthritis (JIA): Incidence, initial management and one-year outcomes
Funder: Moorfields Eye Charity

Abstract: Childhood uveitis is a rare condition with high risk of loss of vision (17-­‐30%). Management and referral pathways vary throughout the country, making service planning and commissioning of specialized services difficult. One local study reported an incidence of 4.85/100,000 children age 0-­‐ 16 years per year, but national incidence data are lacking. Up to 47% of cases of childhood uveitis may occur in the context of juvenile idiopathic arthritis (JIA) [1]. Whilst some epidemiological data are present on JIA-­‐associated uveitis, far less is known about incidence and initial management of non-­‐JIA-­‐associated uveitis. We propose to carry out a prospective observational national ascertainment study of new cases through BOSU (British Ophthalmological Surveillance Unit) to determine incidence, regional patterns of presentation, ophthalmic referral and management, and systemic associations of this condition. The expected number of cases of around 250 over one year fits within the BOSU remit.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case control study identifying contributing risk factors
Funder: Moorfields Eye Charity

Abstract: New research from Moorfields Eye Hospital and the UCL Institute of Ophthalmology has identified a 3-fold increase of Acanthamoeba keratitis cases, amongst contact lens users in South-East England, since 2011. The findings can probably be extrapolated to the rest of the UK. This study also identified Risk factors for the development of the disease included disinfection of contact lenses (CL) with a contact lens solution containing Oxipol as the principal disinfecting agent, poor contact lens hygiene, poor hand hygiene, and the use of CLs whilst swimming or bathing. AK is a largely preventable disease. The current outbreak is unlikely to be due to any one of the identified risk factors in isolation. However, improving CL and hand hygiene, avoiding CLs contamination with water, and use of effective CL disinfection solutions, or daily disposable CLs, ca be expected to reduce the incidence of AK. In the longer-term water avoidance publicity for CL users can be expected to reduce the incidence further.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Letermovir for treating cytomegalovirus infection during blood and bone marrow transplant - [ID1153]
Funder: Department of Health and Social Care

Abstract: To appraise the clinical and cost effectiveness of letermovir within its marketing authorisation for preventing cytomegalovirus reactivation or disease in people with sero-positive-CMV who have had an allogeneic haematopoietic stem cell transplant.

Lay abstract: Cytomegalovirus (CMV) is a common viral infection. Once a person is infected, CMV stays in the body for life and the person will have CMV antibodies (known as ‘seropositive’). The virus is carried by around 50–80% of the population (1). For healthy people, CMV usually remains dormant and does not cause symptoms. However, for people undergoing haematopoietic stem cell transplantation (HSCT) the virus can become active again (reactivation) because of a weakened immune system. CMV infection in this population can cause serious complications and increased mortality. In 2015, 1,610 patients received allogeneic haematopoietic stem cell transplants in the UK (2). It is reported that up to 50% of CMV seropositive recipients of allogeneic HSCT experience CMV reactivation, regardless of the donor’s serostatus (3). Prophylactic antiviral strategies aim to reduce CMV incidence. Monitoring of CMV levels in the blood is essential. Antivirals for primary or secondary prophylaxis may include aciclovir, valaciclovir, valganciclovir (4) and foscarnet. Use of ganciclovir is limited due to toxicity (4). References 1. Medscape. Heuman DM, et al. Cytomegalovirus Colitis. Accessed May 2017 2. British Society of Blood and Marrow Transplantation. 2015 activity. Accessed May 2017. 3. George B, Pati N, Gilroy N et al. Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivations after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transplant Infectious Disease 2010;12:322-329. Accessed June 2017. 4. Management of cytomegalovirus infection in haemopoietic stem cell transplantation. British Journal of Haematology. Accessed June 2017

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Developing a valid and acceptable psychosocial index of women's sexual health risk to enable targeting of interventions in community settings
Funder: Department of Health and Social Care

Abstract: A range of community-based services now provide (or refer to) sexual healthcare, but are currently vulnerable to missed opportunity and poor resource allocation. To target services an evidence-based means of identifying women at risk of sexually transmitted infections (STI) acquisition and unintended pregnancy is needed. Assessment based on sexual behaviour self-report may feel stigmatising in community-based services - leading women to under-report risk. Evidence suggests psychosocial variables may be acceptable as risk assessment questions and effective in predicting STI acquisition and unintended pregnancy. This study will develop a psychosocial index for assessing sexual health risk in women attending community-based services.

Lay abstract: A range of community-based services now provide (or refer to) sexual healthcare, but are currently vulnerable to missed opportunity and poor resource allocation. To target services an evidence-based means of identifying women at risk of sexually transmitted infections (STI) acquisition and unintended pregnancy is needed. Assessment based on sexual behaviour self-report may feel stigmatising in community-based services - leading women to under-report risk. Evidence suggests psychosocial variables may be acceptable as risk assessment questions and effective in predicting STI acquisition and unintended pregnancy. This study will develop a psychosocial index for assessing sexual health risk in women attending community-based services.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFECTION
Title: Inflammation, Infection and Immunotherapeutics
Funder: Department of Health and Social Care

Abstract: Our objectives are: Short-term:  enhance capacity for immunophenotyping, including through the NIHR Cambridge BRC Cell Phenotyping Hub by providing analytical capability for acute and out-of-hours patient samples;  deliver single cell technologies;  build capacity to oversee assay development and experimental design, and an enhanced technical and scientific educational role; Medium-term  support integration of the Cambridge Institute for Therapeutic Immunology and Infectious Diseases;  develop a GLP-accredited immunophenotyping service;  ensure technology remains cutting-edge;  develop and standardise a range of in vitro functional immune assays;  consolidate a diagnostic and research-focussed adult primary immunodeficiency service;  foster opportunities to develop shared infrastructure with industry; Long-term:  develop clinical immunoassays that inform diagnosis and treatment pathways, and identify drug targets that are translated into new immunotherapeutics. Over the course of the next 5 years ‘Inflammation, Infection, Immunotherapeutics’ aims to have validated the efficacy of at least four new drug targets, and to have brought at least two diagnostic or prognostic tests to the clinic, in its own disease area


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION
Title: Reducing the burden of undiagnosed STIs and BBVs.
Funder: Department of Health and Social Care

Abstract: The overarching aim of this theme is to inform the development of interventions and diagnostic tools that will facilitate effective and efficient early access to care and treatment for STIs and BBVs, thus reducing morbidity, mortality and transmission of STIs/BBVs.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION
Title: Improving the care and management of people with STIs and BBVs.
Funder: Department of Health and Social Care

Abstract: The overarching aim of this research theme is to identify, understand and manage factors that influence the uptake of healthcare interventions, continuity in care and outcomes in persons with HBV, HCV and HIV.


Research activity codes: 7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: INFECTION
Title: WS4: Evidence Synthesis
Funder: Department of Health and Social Care

Abstract: We will undertake evaluation of interventions in primary care and community settings based on PHE’s priorities. Short term (1-2 years) objectives Short term objectives will provide the evidence base necessary for intervention development to be evaluated in future studies. · To conduct a feasibility cohort study of paediatric RTI microbiology surveillance among 300 children registered at 12 GP practices in Bristol as an exemplar project on antibiotic prescribing and antibiotic resistance (and including nested randomised controlled feasibility trials of real-time feedback of microbiology results to clinicians and parents to improve use the of antibiotics and primary care services) · To evaluate the effectiveness of interventions which increase Chlamydia and HIV testing in primary care, to improve rates of diagnosis and reduce late-HIV diagnosis. · Evaluate methods to increase the effectiveness of case management for Chlamydia including retesting positive cases and partner management for cases diagnosed in primary care Medium and long term (3-5 years) objectives, contingent on 2016 to 2019 PHE priorities · To conduct a Bristol city-wide enhanced paediatric RTI microbiology surveillance study, with genome wide sequencing, among a prospectively recruited, representative cohort of children with RTI living within 10 miles of the centre of Bristol to: (i) evaluate the burden and transmission of antibiotic resistant bacteria associated with RTIs in children; (ii) describe the clinical and economic burden of vaccine and non-vaccine preventable RTIs in children and their household contacts, and evaluate the impact of new vaccine strategies (e.g. paediatric influenza); (iii) describe the movement of microbes associated with paediatric RTIs from the community into primary and secondary care, using genome wide sequencing; and (iv) investigate the relative contribution of clinical and microbiological factors to primary care (WICs, OOH primary care centres, Emergency Departments and GP practices) utilisation. Using evaluative RCTs embedded in the above prospective cohort study, we will evaluate the effectiveness of real time enhanced paediatric RTI microbiological surveillance results on primary and secondary care utilisation for paediatric RTI, given to: parents and primary care clinicians (GPs and nurse practitioners) to improve their use of antibiotics and primary care services. · Understand wider effects of interventions on risk and sexual behaviour such as normalisation of STI/HIV testing, effectiveness and ease of partner notification in primary care · Develop robust methods for the holistic evaluation of effectiveness and cost-effectiveness of health protection interventions for STIs, especially those aimed at reducing late HIV diagnosis and increasing Chlamydia case finding in primary care


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: INFECTION
Title: Emerging Threats
Funder: Department of Health and Social Care

Abstract: The research for this theme focuses on maximising the utility of data collected using new technology (internet-based outbreak mapping and healthcare provision, mobile phones) to improve the Health Protection response to emerging infectious disease (EID) epidemics and deliberate releases of biological agents. In an emergency we need to rapidly detect the pathogen and determine its severity, transmissibility and its geographic distribution and anticipate the potential for future geographic spread. Short term: • Develop a generalised model framework to improve early estimation of disease severity in an international EID outbreak from its geographic extent (countries affected). • Develop a protocol and seek ethical approval for collation of detailed mobile phone usage data from the first cases arising from a covert release of a biological agent to rapidly infer release time and location, and to identify other potentially exposed individuals requiring treatment/prophylaxis. Medium term: • Develop methods for rapid severity estimation in EID outbreaks from sub-national spatially stratified incidence data and data on population mobility. • Trial the collection and analysis of detailed mobile phone/tablet data to for use in detecting and responding to a covert release of a biological agent. • Evaluate and improve the performance of EpiCollect (www.EpiCollect.net), a mobile-phone- and tablet- based data collection system, to improve the quality and speed of data collected for emergency response compared to traditional paper based systems. Long term: • Develop an integrated spatiotemporal model of EID spread nationally and internationally and accompanying inferential methods (e.g. particle MCMC) to allow rapid assessment of EID transmissibility and severity. • Raise grant funding for large-scale studies of the use of mobile phone data for detection and assessment of covert select agent releases. • Routine use of EpiCollect for data collection in PHE outbreak investigations with public health staff trained in use of its analysis tools and having been involved in the development of the system.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Lessons for the future: Qualifying and quantifying South Asia's first widespread ciguatera poisoning outbreak
Funder: Natural Environment Research Council

Abstract: Lessons for the future: Qualifying and quantifying South Asia's first widespread ciguatera poisoning outbreak South Asia has long had a fish eating tradition as well as a growing domestic and export fishing industry. However, recently there have been sporadic reports of ciguatera fish poisoning (CFP) from this region. This is a circumtropical disease transmitted by eating carnivorous fishes that contain toxins accumulated from their food and is characterised by gastrointestinal and neurological symptoms which may result in disablement and/or death. Despite the known presence of the dinoflagellate Gambierdiscus spp., one of the most common causative agents of CFP, in the region (Indian Ocean and Arabian Sea) there has been no previously recorded large-scale CFP incident in this area until now. On 1st October 2016 South Asia's first widespread CFP outbreak occurred in the city of Mangalore, Karnataka, on the coast of SW India, resulting in several hundred hospital attendances and admissions. This is believed to be as a result of the consumption of locally caught carnivorous fish, such as the red snapper, Lutjanus bohar, contaminated with ciguatera toxins. These fish were originally intended for a fish processing plant in the city but were also sold at the Mangalore fish market. This recent outbreak presents a unique opportunity to qualify and quantify the presence of the causative algal species, whilst at the same time conduct state-of-the-art toxin analysis of contaminated seafood samples in a region of the world currently underrepresented both in terms of sampling coverage and technological analysis of an algal-born toxin outbreak event. Increased seawater temperatures and lowered salinity are known to favour the regional dinoflagellate community in general, and specifically Gambierdiscus spp. The previous 12 months have seen sea surface temperatures in the Indian Ocean consistently 0.5-1.0 degrees C above average coinciding with the ongoing El Niño Southern Oscillation and this season's monsoon has been particularly sustained, lowering coastal salinity. Data gathered during the proposed study will allow us to make predictions for the occurrence of further outbreaks of CFP along the South Asian coastline and elsewhere, including in the face of global climate change. Our aim to implement a rapid response screening and management programme in response to future CFP events will help to ensure the health and wellbeing of those who depend on fishing as a protein and/or economic resource.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Invention for Innovation Project 20009: Breath Analysis in Intensive Care: Proof of Concept for non-invasive diagnosis of Ventilator-associated pneumonia
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: This award is to facilitate the involvement of BHSCT as a site in an NIHR-funded i4i award to Dr Stephen Fowler, University of Manchester. Funding is provided for Dr Ronan McMullan’s time as a CI for 36 months. The study relates to early identification of patients with ventilator-associated pneumonia using a biochemical breath test to distinguish patients with pathogenic microorganisms in their lower respiratory tract. It is a proof of concept study involving some in silico developments and preliminary clinical work to look at the ability of the test to distinguish between patients with and without pneumonia.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION