NIHRDataInsights/HRCSData huggingface dataset:
Title: Replacing rodent models for investigating the influence of the microbiome upon innate immune responses and resistance to pathogens
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: We propose to replace the use of rodents with a zebrafish larval model, to study the influence of the microbiome upon immune responses to pathogenic Streptococcus infection. Zebrafish have a number of advantages: they are translucent, their gut physiology is similar to mammals, they develop a gut microbiome by 3 days post fertilisation and the fish pathogen, S. iniae, mimics much of the pathology found in humans. As in other vertebrates, the microbiome is important in stimulating immune responses and some gut microbes are protective against particular bacterial pathogens. Germ-free (Gf) zebrafish can be easily generated and maintained and new microbiotic colonisers can be non-invasively introduced into these Gf larvae. We will characterise the influence of the microbiota upon streptococcal infection outcome in a clinically-predictive replacement model using Gf larval zebrafish colonised with specific microbiota. We hypothesise that Gf fish will be more susceptible to incoming streptococcal infection than conventionally reared fish or Gf fish given specific probiotic replacements. Furthermore we will use live imaging of larvae infected with fluorescent-tagged bacteria to follow dissemination of infection in individual larvae with / without a specific microbiome over time. We will also use fish with fluorescent protein (FP) labeled inflammatory cells to visualise phagocytic capability and cell migration of neutrophils and macrophages to sites of streptococcal infection. Studies using fluorescent bacteria and FP immune cell larvae will allow the immune and infection status of individual fish to be measured in vivo over time and directly related to the presence and/or absence of specific protective microbiota. Some mammalian non-pathogenic bacteria from probiotics and faecal material are able to colonise zebrafish. In the long-term therefore this model is likely to indicate probiotics that can be used both to alter immune status and to combat Streptococcal infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Molecularly Imprinted Nanoparticles (MIP NPs) as non-animal antibodies substitutes for detection of viruses
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: This Fellowship proposal aims to determine if artificial antibodies - molecularly imprinted nanoparticles (MIP NPs) - can be developed as new diagnostic/therapeutic entities in veterinary medicine to directly replace bioassays for a very important infectious disease, avian influenza, which possesses an immense potential for harm to poultry, and also a dangerously high chance to spread from poultry and pigs to humans. To date, the molecular imprinting of polymers represents the most generic, versatile, scalable and cost-effective approach to the creation of synthetic molecular receptors. Recent developments in the automated synthesis of MIP NPs using an immobilised template approach pioneered in the group of Prof. Piletsky mean that for the first time a reliable supply of "soluble" synthetic nanoparticles with pre-determined molecular recognition and/or catalytic properties with sub-nanomolar affinities, defined size and surface chemistry can be made available for testing as potential bioactives. These bioactives may have the potential to detect viruses that are widely circulating in farm animals and indeed humans. Early and accurate identification of the infectious agent will expedite appropriate control and even treatment measures. Therefore, the research into the development of MIP NPs with high affinity coupled with diagnostic technology could be a significant contribution to the scientific advancement and cost effective diagnosis at global scale.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: HYDROMAL: Hydro-dynamic drivers of malaria transmission hazard in Africa
Funder: Natural Environment Research Council

Abstract: HYDROMAL: Hydro-dynamic drivers of human malaria transmission hazard in Africa. Thomas, Macklin, Smith and Gamarra Summary Malaria is a vector borne disease - we become infected by the bite of an infected mosquito. There is currently great concern that climate change may improve conditions for many disease vectors, such as mosquitoes, and that diseases like malaria will increase. The main burden of this disease falls in Africa, where changes in rainfall and temperature are projected to occur over the next century. While we have a reasonably good understanding, from laboratory studies, of how changed temperature may effect mosquito populations, we have very little on the effect of changed rainfall, which controls the availability of mosquito breeding sites. The distribution of these breeding sites in relation to human hosts is the main driver of local epidemiology, and in many locations across Africa it is likely that changes in precipitation, not temperature, will drive changes in transmission. This is the critical gap our project aims to fill, not by developing new science, but by adding value to existing knowledge by coupling different disciplines. Modern challenges require interdisciplinary thinking, and our project is an example of this. We aim to link well-established tools from geophyscial hydrology with mathematical models of malaria transmission, models that have been around for over 50 years. To quantify this relationship we will spend a year in the field in Tanzania, with a parallel program of hydrology and entomology, working in a large valley with the highest levels of malaria transmission in the world. We will then spend a further year analyzing the data and linking the mathematics. Our idea is that if we can predict where the breeding sites for vector mosquitoes will be at any given time, based on rainfall and terrain, we can estimate the malaria transmission. If we can prove this simple idea works, it will pave the way for future studies linking climate change projections to impact on this disease in Africa. It may also prove useful for health planners: it may prove more effective to target resources in key locations, and it may be that different interventions are more effective in different landscapes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: C2C CLOUD TO COAST: Integrated assessment of environmental exposure, health impacts and risk perceptions of faecal organisms in coastal waters
Funder: Natural Environment Research Council

Abstract: Health impacts from pathogens indexed by faecal indicator organisms (FIOs) arise from water contact and food consumption derived from catchments, rivers, estuaries and coastal waters. However, the risks associated with these exposures are often highly episodic and determined by rates of pathogen shedding, tides, weather and seasons, all of which are impacted by changing climate, and particularly when storminess is included. Point sources include sewage effluents, intermittent discharges from combined sewer overflows, agricultural point sources such as manure stores, and diffuse sources. Faecal loads are attenuated during the soil - fresh water (including groundwater and/or river water) - estuarine - coastal pathway. Better predictions of the fate and transport of these pollutants along their pathways from sources to receptors would inform several health, policy and operational issues, including: - Whether to manage health risks by restricting access to receiving waters or by management of potential sources of pollutants; - When to declare coastal waters closed, and when to reopen them, trading off the health risks against the economic and social impacts; - What further sewage/intermittent discharge treatment to deploy, which involves trading off the financial and carbon costs against the infrequent health improvements; - What agricultural management options to impose, trading off the financial and food security impacts against the potential health improvements? - How better to optimise health and risk-management processes based on scientific evidence vis-a-vis public perception. The proposed research seeks to develop a new integrated model to predict the exposure to and the health impact assessment of pathogen risks, as indexed by FIOs, in near-shore coastal waters. The approach will be to build and validate a FIO fate and transport model which incorporates rainfall and catchment sources to coastal receiving waters, to use this model together with enhanced disease burden modelling and quantitative microbial risk assessment procedures to produce a dynamic quantitative health impact assessment. The overall model will then be used to analyse policy options for range of future scenarios, including climate change (in terms of changes in rainfall), and to relate the outcomes to actual and perceived health risks. The outputs of the research will inform identified policy gaps and afford improved decision making to minimise health risk from FIO.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Improving the evidence base for the control of nosocomial Norovirus infection using next generation sequencing methods
Funder: Department of Health (England)

Abstract: To control the spread of norovirus infection, known as winter vomiting disease, it is important to know where the virus is coming from, how it’s being transmitted, and which patients are at risk. To provide evidence for this we will develop new methods for sequencing norovirus from patients and the environment in hospitals and identify sources of infection, areas that need extra cleaning or patients that can be screened to prevent spread of infection. We will determine the burden of norovirus infection in immunosuppressed patients to provide evidence for how they can managed clinically, including those who shed norovirus asymptomatically.


Research activity codes: 4.3 INFLUENCES AND IMPACT;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: A randomised placebo controlled trial of “follow on” Rifaximin for the prevention of relapse of Clostridium associated diarrhoea
Funder: Department of Health (England)

Abstract: Background Clostridium Difficile infection is a significant cause of in-hospital morbidity, mainly affecting frail and elderly patients. While existing treatments are reasonably effective with initial success rates around 80% there is an unacceptably high incidence of recurrence of up to 30%. Rifaximin is a poorly absorbed antibiotic with an excellent safety record, used to treat Traveller's Diarrhoea. It achieves high concentrations in the bowel, easily exceeding the MIC for C. difficile infection but disturbs the normal colonic bacteria less than metronidazole and vancomycin, and may actually increase some favourable bacteria which may reduce recurrence rates of C difficile infection. Recent reports suggest a tailing dose of Rifaximin can successfully treat patients with relapsing C difficile Aims .We aim to test the effectiveness of a 4 week “follow on “ treatment with Rifaximin in reducing the relapse rate of CDAD by means of a randomised placebo controlled trial. We will also examine the initial disturbance and subsequent recovery of faecal microbiota in patients given Rifaximin versus placebo and attempt to develop a surrogate marker for colonisation resistance to predict why some patients relapse Plan of Investigation Study: a multi-centre, randomised, placebo controlled trial Setting: Nottingham University Hospital, Nottingham City Hospital, Kings Mill Hospital and Derby Royal Infirmary. 158 patients who have had a successful treatment of C difficile associated diarrhoea (CDAD) will be randomised to receive either Rifaximin 200mg or Placebo tablets, 2 t.d.s for 2 weeks followed by 1 t.d.s. for 2 weeks . Patients or their carers will keep a daily stool dairy (Bristol Stool Form Score) during the duration of the study. Samples: Stool for microbiological assessment at week 1, 4 & 12 or at relapse . Blood to confirm safety of treatment and to assess antibody response will be obtained at week 1 & 12 A final telephone contact will be made at 6 months to document any further episode of CDAD.???.??? Potential Impact The health protection agency's data in the UK demonstrate an increasingly serious clinical problem with C difficile infection with increasing morbidity and mortality associated with more virulent epidemic strains. Reducing the relapse rate from 30% to 10% will significantly reduce the burden of this disease in hospitals and the community and provide an inexpensive solution to this serious and debilitating illness. The incremental cost for CDAD has been calculated at £9100 for recurrent cases and £5710 for initial cases(1). The cost of the proposed treatment would be £ 210 and the potential savings of £206.50 per patient treated if it reduced the relapse rate from 30% to 5% or £161.00 if it reduced the relapse rate to 10%. (1) Ghantoji et al . J Hosp Infect 2010; 74(4):309-318.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Adressing HIV literacy and inequalities in an era of biomedical HIV prevention: supporting the well being of communities most affected by HIV in Scotland
Funder: Chief Scientist Office (Scotland)

Abstract: HIV continues to disproportionately affect populations who are also more likely to experience other forms of ill-health and social disadvantage. Men who have sex with men (MSM) and migrant African communities represent the majority of new and existing HIV diagnoses. New biomedical options to prevent HIV are emerging as recent clinical trials have demonstrated the effectiveness of using existing HIV treatment for prevention. This means that preventing the sexual transmission of HIV is no longer only about enabling the reduction of risky sexual practices. It is also reliant on increasingly complex prevention methods such as the use of clinical biomarkers (viral loads), monitoring and supporting treatment adherence, and engaging communities at risk more generally with this new biomedical technology. This complex HIV prevention landscape requires improved capacity in clinical HIV literacy, yet evidence has identified inequalities in HIV literacy amongst those most affected by HIV. This fellowship aims to improve HIV literacy amongst MSM and African communities within the context of biomedical HIV prevention. This will be achieved through the development and feasibility testing of an HIV literacy intervention programme. This intervention will be developed in collaboration with practitioner and community stakeholders and delivered through a programme of techniques and tools tailored to target groups (MSM and African peer groups and sero-discordant couples). Intervention development will consider how social and structural inequalities affect HIV literacy, and how improving HIV literacy can enable resilience in a dynamic sexual health environment. Outcomes of this feasibility study will inform larger evaluation and implementation.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION
Title: Applied mathematical and economic modelling for the evaluation and optimisation of the effectiveness of public health interventions against sexually transmitted infections.
Funder: Department of Health (England)

Abstract: Gonorrhoea and chlamydia present a significant public health burden, and are the leading cause of preventable infertility. Mathematical models, economic analysis and parameter estimation will be used to address questions relating to sexual health service provision: 1) What is the probability of progression from chlamydia infection to complications? 2) What is the effect of heterogeneity in sexual behaviour and health care access on chlamydia screening? 3) What are the cost and reliability implications of dual testing (chlamydia/gonorrhoea)? The applicant will develop skills in economic analysis and public health commissioning and delivery while integrating into the existing STI research programme.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: INFECTION
Title: The HCV treatment journey
Funder: Department of Health (England)

Abstract: HCV is a major cause of end-stage liver disease, cancer, and transplantation. Over 185,000 people live with chronic HCV in the UK. Prevalence and associated mortality are predicted to rise exponentially unless HCV treatment uptake increases. Antiviral therapies work in 50-80% of cases, yet only 3% of diagnosed UK patients receive treatment each year. This mixed-methods study explores the barriers and facilitators to HCV treatment uptake and completion from patient, provider and ‘system’ perspectives in order to improve HCV treatment uptake. Outcomes include: information and decision-making resources, a quantitative survey instrument, and recommendations for HCV provider training, interventions and aftercare.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFECTION
Title: Interventions to reduce hepatitis C virus transmission amongst injecting drug users in England
Funder: Department of Health (England)

Abstract: Hepatitis C virus (HCV) antiviral treatment is effective at clearing the disease, but few injecting drug users (IDUs) are treated. We believe antiviral treatment can act as prevention for HCV amongst IDUs. To examine this hypothesis, we will develop mathematical models of HCV transmission, incorporating current interventions, heterogeneity in risk and treatment accessibility, and new IDU specific data. We aim to: determine why current interventions have failed to control HCV, project the impact and cost-effectiveness of current and future treatments given heterogeneity, and optimise combination interventions with budget restrictions. This research will guide the development of effective and cost-effective HCV health policy.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION
Title: Investigating the potential benefit of enhanced or alternative interventions for infectious disease control: a focus on adolescent vaccination and contact tracing
Funder: Department of Health (England)

Abstract: Infectious diseases are important causes of infant illness and death, so vaccination campaigns are often targeted at this age-group. However, adolescents are also vulnerable to disease and may act as reservoirs for transmitting infections to children. Using two infections, meningococcal disease and whooping cough, this work investigates whether changing vaccination schedules, placing greater emphasis on adolescents, and/or contact tracing practices, may prevent more disease in England than current strategies. Mathematical and economic models will be developed, using recent data, to predict the impact (disease avoided and cost-effectiveness) of different strategies. This research will guide policy decisions about infectious disease control


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Impact of conjugate vaccination on population immunity to pneumococcal and meningococcal disease in England: immunosero-epidemiological analysis
Funder: Department of Health (England)

Abstract: Pneumococcal disease and meningitis C are serious bacterial infections that can cause severe illness and death. Although current conjugate vaccines are effective, certain pneumococcal variants not covered by conjugate vaccine have increased and are causing concern; and the meningitis C vaccine mainly provides short-lasting protection. Therefore, this research entails analysis of specific antibody levels in blood samples from different age groups in England, to assess how well-protected people are against these diseases. This evidence will enhance understanding of the vaccines’ influence on immunity in the population, and help in guiding national immunisation policy decisions.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);3.4 VACCINES
Health categories: INFECTION
Title: Using routine health data to target preventive strategies for severe influenza in children
Funder: Department of Health (England)

Abstract: Children experience high rates of influenza infection, which can lead to hospital admission and critical illness. To prevent severe cases, we need to understand the characteristics of children affected by severe influenza and determine if vaccines and treatments are effective. Electronic GP and hospital records will be used to: i) estimate how many children are admitted to hospitals and intensive care units with influenza and describe their characteristics; ii) describe how access to vaccinations and drug treatments vary between children and iii) explore whether vaccines, antibiotics and antivirals reduce the risk of severe influenza symptoms in children.


Research activity codes: 6.1 PHARMACEUTICALS;3.4 VACCINES
Health categories: INFECTION