NIHRDataInsights/HRCSData huggingface dataset:
Title: 2017 Doctoral Fellowship: Petechiae in Children (PIC) Study - Defining a clinical decision rule for the management of non-blanching rashes in children including the role of rapid point of care testing for procalcitonin and neisseria meningitides DNA
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: A fever and a non-blanching rash is a common presentation in the paediatric emergency department (ED). While most children have a self-limiting viral illness there remains concern that this may be the prodromal phase of potentially fatal meningococcal septicaemia. Thus a cautious approach has developed with many admitted to hospital and treated with broad-spectrum antibiotics just in case. Despite this, some children are diagnosed late often having been falsely reassured the previous day by their doctor. Current management is based on research performed before the introduction of the meningococcal B and C vaccines and before the availability of point of care testing (POCT) for procalcitonin (PCT) and N. meningitidis DNA. NICE and the Paediatric Emergency Research UK and Ireland (PERUKI) network have both called for further research into the management of fever and a non-blanching rash including a call for a new clinical decision rule and for research into the role of PCT. This PIC study is a single centre cross sectional study evaluating the diagnostic value of rapid POCT for PCT and N. meningitidis DNA in children with fever and a non-blanching rash. In this cross-sectional study all children presenting to the paediatric ED with a fever and a non-blanching rash will be eligible for inclusion. All children will continue to be managed as per NICE guidance with a detailed clinical record and standard tests (differential blood count and CRP). In addition, a throat swab and 0.5ml of blood taken for rapid POCT. The study will run for 2 years and aims to recruit 250-300 children. A clinical decision rule will be produced and its diagnostic utility (sensitivity, specificity, predictive values, etc) will be studied according to the STARD criteria for diagnostic tests. An economic evaluation of the diagnostic testing strategies assessed will be undertaken with a cost-effectiveness analysis.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Tackling Antimicrobial Resistance: Engineering New Microsystems for Rapid Bacteria Purification
Funder: Royal Academy of Engineering

Abstract: The latest estimates, published by the Government and The Wellcome Trust, predictthat by 2050 antimicrobial resistance (AMR) could claim one life every three seconds, higher than the current death rates for cancer (http://amr-review.org). A major limitation, evidenced through the recent launch of the £10M Longitude Prize (2015-2019), is the lack of fast and reliable diagnostic technologies. For example, current methods to identify an infection in blood are based on bacteria culture and require several days to establish a positive result. During this interim period, potentially ineffective broad-spectrum antibiotics are often administered that may leadto the emergence of resistant bacteria. Consequently, the development of new diagnostic tools is now seen as one of the four main priorities to address AMR (the others being increasing public awareness, developing new drugs and decreasing the use of antibiotics in agriculture). My Fellowship aims to tackle the challenge of rapid diagnosis by engineering a suite of new microsystems capable of performing fast, user-friendly purification of bacteria. Recognised as a key enabling step within the diagnostic workflows (before detection), purification remains a challenge due to i) the low concentration of bacteria in bodily fluids, ii) the difficulty in processing often complex fluids (e.g. blood) and iii) the wide range of bacteria species to be detected. I will combine new microfluidic-based separation approaches with innovative concentration technologies to isolate harmful bacteria in volumes of fluids that are small enough to promote the use of currently limited, advanced bacteria detection and characterisation assays. These technologies have the potential to reduce unnecessary administration of inappropriate antibiotics, enabling a targeted and personalised approach to therapy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Worldwide Influenza Centre (WIC)
Funder: The Francis Crick Institute

Abstract: The Worldwide Influenza Centre (WIC) acts as a WHO Collaborating Centre (WHO CC) for Reference and Research on Influenza, one of six in the world. The WHO CC works within the WHO Global Influenza Surveillance and Response System (GISRS). The object of the work is though detailed analysis of influenza viruses from humans (seasonal influenza viruses, zoonotic influenza viruses and pandemic influenza viruses) to assess on a global scale the likely impact of any newly emerging influenza virus for its impact on humans, to address whether there is a need to modify recommendations for vaccines (seasonal and pre-pandemic), to monitor the resistance of viruses in circulation to antiviral medicines and to carry out risk assessments associated with these viruses. In WIC we collaborate with in the order of 50% of the WHO National Influenza Centres in GISRS receiving both clinical samples and cultured viruses. We perform antigenic and genetic analysis of viruses we propagate and monitor the drug sensitivity of all propagated viruses. Over the last 18 months we have developed a Next Generation Sequencing Pipeline and now can examine whole genome sequences for about 90% of all propagated viruses and full genome sequencing is also performed on some of the clinical samples we receive – notably those from samples of zoonotic influenza (e.g. H5N1 viruses). To exemplify, between 1 January 2016 and 31 December 2016 over 2600 samples were received from 73 National Influenza Centres, four WHO Collaborating Centres, and from two laboratories generating high growth reassortants. WIC also prepares viruses suitable for development for inclusion in influenza vaccines. Currently, because most influenza vaccines are produced in hens’ eggs, these viruses are isolated and propagated exclusively in hens’ eggs. Viruses of the influenza A(H3N2) subtype have proved increasingly difficult to isolate in hens’ eggs but WIC has successfully propagated viruses suitable for inclusion into vaccines. Selected clones of these viruses are sent to National Institute for Biological Standards and Control, to the New York Medical College, and to Seqirus (Melbourne) for development of high growth reassortant viruses to be considered as candidate vaccine viruses. The currently recommended prototype vaccine virus for the H3N2 subtype is a virus from the National Influenza Centre in Hong Kong China SAR and isolated and propagated in WIC (A/Hong Kong/4081/2014).


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Cellular and molecular mechanisms of B cell activation
Funder: The Francis Crick Institute

Abstract: B cells are important immune cells. They produce antibodies against foreign molecules on pathogens, and in this way they protect us against disease. In our laboratory, we are interested in both the cellular and the molecular events that lead to the activation of B cells. We want to understand how these events affect the ability of B cells to produce antibodies. To do this, we work both in vivo and in vitro by combining state-of-the-art imaging technology with biochemistry and genetic models. For example: by following B cells in vivo we can better understand where and when they are activated (Carrasco & Batista 2007; Gaya et al. 2015). By tracking single B cell receptor (BCR) molecules we have shown how the cortical cytoskeleton network regulates receptor signalling (Mattila et al. 2013; Treanor et al. 2011; Treanor et al. 2010). Similarly, by studying actin regulators such as Cdc42 or Nck we have shown that they play a major role in B cell activation and antibody production (Burbage et al. 2014; Castello et al. 2013). We have therefore been, and continue to work towards, a clearer understanding of B cell activation and antibody production at a cellular and molecular level with our innovative approach. This knowledge will aid us in the fight against infectious diseases and cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Mycobacterium tuberculosis systems and chemical biology
Funder: The Francis Crick Institute

Abstract: Despite significant progress in tuberculosis research in the last decades we still fail to understand basic principles of the disease. Lack of basic understanding of Mycobacterium tuberculosis is thought to be one of the main reasons why we experience a number of difficulties in developing new drugs and new vaccine candidates. As tuberculosis continues to kill nearly 2 million people per year and multi-drug resistance is on the rise, we urgently need new research approaches to accelerate the development of novel treatments to revert this epidemic. We aim to uncover and characterize metabolic components from M. tuberculosis responsible for its unique ability to survive in humans and cause disease. In addition, we are interested in understanding how antibiotics act against M. tuberculosis, how is resistance developed and how we can accelerate the discovery of novel and improved antibiotics. To do this in an effective and unbiased fashion we take advantage of liquid chromatography-mass spectrometry metabolomics, as our chief experimental technique. Metabolomics allows simultaneous, unbiased, and quantitative interrogation of hundreds of small molecules in parallel, which in turn allow us to examine mycobacterial metabolism at very high resolution. Enzymes are responsible for most of the activities in any cell, from bacteria to man. We are particularly interested in novel enzymes from M. tuberculosis that likely belong to novel metabolic pathways. In addition, some of these essential enzymes will lack counterparts in humans and therefore might represent attractive new targets for antibiotic development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: A new perspective on anti-toxoplasma gondii immunity
Funder: The Francis Crick Institute

Abstract: Toxoplasma gondii, the causative agent of toxoplasmosis, is the most prevalent persistent human parasitic infection. The obligate intracellular parasite can invade any nucleated cell residing as a tachyzoite in a parasitophorous vacuole (PV). Gamma interferon (IFNγ) is the major cytokine controlling Toxoplasma by upregulating host effector defences. While effector mechanisms are better-defined in mice, we have a limited understanding of the fate of the Toxoplasma PV and host defence molecules in humans. We focus on understanding the IFNγ-stimulated host defence mechanisms that restrict Toxoplasma in both human and murine cells and in vivo in mice. Specifically, we study how ubiquitin-mediated pathways restrict Toxoplasma and how host guanylate binding proteins (GBPs) orchestrate host responses to the parasite. We are probing our findings with other pathogen infections in collaborative efforts and our discoveries are likely to translate to more general pathogen-pattern induced phenomena. We have discovered a novel cellular pathway in which Toxoplasma PVs are ubiquitinated to facilitate their fusion with the endo-lysosomal system, resulting in acidification and parasite destruction. We term this compartment the acidic PV (APV). To define the fate of the PV in IFNγ-simulated human cells, we will determine the composition, pathway and kinetics of Toxoplasma APV formation. Since ubiquitination is a pre-requisite for APV formation, we will identify ubiquitinated cellular proteins driving APV formation. We have shown that GBP1 and GBP4 are not recruited to the PV, yet both restrict Toxoplasma replication in epithelial cells. In macrophages, infection shifts GBP4 from the nucleus to the cytoplasm for degradation. Building on these findings we aim to identify the nuclear function(s) of GBP4 in Toxoplasma control in both epithelial cells and macrophages. Other GBPs mediating Toxoplasma control will be discovered by employing siRNA-based high throughput microscopy assays in THP1 human macrophage cell lines. We have additionally found an extracellular ubiquitin-like protein, ISG15, through their cysteine residues to control IL1 levels during Toxoplasma infection in vivo in mice. This study presents the first evidence of multimerisation of ISG15 being important in driving its cytokine function. To mimic human infection as closely as possible, we have set up human induced pluripotent stem (iPS) cells as a source of macrophages for the study of anti-Toxoplasma pathways. Using state-of-the-art technology including CRISPR, automated and super-resolution microscopy, ubiquitinated substrate identification by mass spectrometry and human iPS cells, we will be able to unravel novel interactions between Toxoplasma and the human host.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Parasite host-cell interactions
Funder: The Francis Crick Institute

Abstract: The aim of our research is to identify how apicomplexan parasites establish their niche in the respective host-cell. In the instance of the malaria parasite Plasmofium falciparum we are looking into a family of exported kinases and identify their function through the generation of conditional KO lines. We identify signalling pathways they control using quantitative phosphoproteomics and use cell biological assays to monitor the function consequences of kinase deletion. In the case of Toxoplasma we are interested in how exported proteins intersect with those of the host-cell, and vice versa, if host-cell proteins interact with parasite exported proteins. We are specifically interested in phosphorylation which we observed occurs on parasite exported proteins after they have entered the host-cell. We also generate Toxoplasma CRISPR screen to identify novel genes important for Toxoplasma virulence.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: From thermometers to thermostats: taking control of preventable harm from urinary catheters
Funder: The Health Foundation

Abstract: Infections caused by catheters are one of the most common types of healthcare-associated infections. Up to 56% of all hospital UTIs are associated with the presence of an indwelling urinary catheter. CAUTIs can cause serious harm and are a common cause of bloodstream infections, linked with up to 20% of hospital-associated bacteraemia. The Health Innovation Network worked with a dozen NHS trusts to deliver a catheter quality improvement programme that reduced CAUTIs in hospital by 30%.Each pillar (see diagram in method tab) consists of a set of traditional improvement and implementation-based activities that creates an effective catheter care bundle of good practice. However, there remains room for improvement. The bundle predominantly appeals to clinicians’ rational decision-making processes. Behavioural science reveals that most human behavior is driven by automatic, instinctive and intuitive thought processes where even important decisions are influenced more by context than by consciously thinking something through.This project will provide behavioural science and communications expertise to enhance the efficacy and scale of the catheter care bundle.A comprehensive mixed-methods evaluation will be carried out led by Revealing Reality an insight and innovation agency with considerable experience of carrying out impactful evaluations in NHS.

Lay abstract: Infections caused by catheters are one of the most common types of healthcare-associated infections. Up to 56% of all hospital UTIs are associated with the presence of an indwelling urinary catheter. CAUTIs can cause serious harm and are a common cause of bloodstream infections, linked with up to 20% of hospital-associated bacteraemia. The Health Innovation Network worked with a dozen NHS trusts to deliver a catheter quality improvement programme that reduced CAUTIs in hospital by 30%.Each pillar (see diagram in method tab) consists of a set of traditional improvement and implementation-based activities that creates an effective catheter care bundle of good practice. However, there remains room for improvement. The bundle predominantly appeals to clinicians’ rational decision-making processes. Behavioural science reveals that most human behavior is driven by automatic, instinctive and intuitive thought processes where even important decisions are influenced more by context than by consciously thinking something through.This project will provide behavioural science and communications expertise to enhance the efficacy and scale of the catheter care bundle.A comprehensive mixed-methods evaluation will be carried out led by Revealing Reality an insight and innovation agency with considerable experience of carrying out impactful evaluations in NHS.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFECTION
Title: Challenging the unknown: using metagenomics to determine viral causes of encephalitis.
Funder: UK Clinical Virology Network

Abstract: The list of infectious agents able to cause encephalitis is long and continues to grow, but because current assays are pathogen-specific, laboratories are able to test only for the most common of these. It is thus unsurprising that in up to half of all cases in which an autoimmune cause has been discounted, the aetiological agent remains undiagnosed. Next-generation sequencing technologies are beginning to revolutionise clinical diagnostics, and not only by replacing existing Sanger-based assays. Metagenomics, where the totality of nucleic acid in a sample is simultaneously sequenced in parallel, presents one such opportunity. Preliminary work in our laboratory has led to the development of a method that is able to overcome the technical limitations of high host background and ultra-low target frequency. In combination with a bioinformatic pipeline wrapping freely-available software packages in a simple script, we have demonstrated the ability both to detect and to characterise diverse RNA and DNA viruses in human clinical substrates. As all assay components are commercially available and the technology is becoming widespread throughout the UK, we intend to further develop this workflow to enable the single-assay detection of viral agents in cerebro-spinal fluid and blood samples. We anticipate that it will form part of the portfolio of NGS assays serving the future needs of NHS virology departments.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Characterisation of the genome diversity of influenza virus associated with complicated Influenza A(H1N1) pdm09 in adults in NHS Lothian 2015-16.
Funder: UK Clinical Virology Network

Abstract: RNA viruses, including influenza, have high mutation rates, due to RNA-dependent low fidelity, leading to important genetic diversity. Viral quasispecies, resulting from these mutations, have been associated with rapid replication kinetics and have many important implications for virus replication and pathogenesis. Reduction of genomic viral diversity of poliovirus and chickunguya in animal models has been associated with reduced clinical severity, suggesting that a higher biodiversity may affect viral pathogenesis. While epidemiological and molecular studies have demonstrated that different influenza virus genotypes co-circulate and assessed antigenic modifications with time, little is known about their consequences on clinical outcomes. Some studies are investigating the association of genomic diversity and disease outcome in paediatric population but no data is currently available about influenza virus biodiversity in immunocompetent adults.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Respiratory virus dynamics amongst British Antarctic Survey personnel – a model for respiratory virus turnover in indoor viral transmission
Funder: UK Clinical Virology Network

Abstract: The contribution of the various modes of transmission (short-range large droplets, long-range aerosols, direct contact or indirect contact via fomites) of respiratory viruses is still unclear, despite numerous studies. The Antarctic winter during which a small community of research scientists is confined in a research base for up to 7 months, offers another opportunity to investigate this phenomenon further. The British Antarctic Survey (BAS) Rothera Research Station houses 40-50 people for an isolated period between when the last planes leave and the final ship call and then 15-20 people over the Antarctic winter. Baseline nasal/throat swabs will be taken upon entry into the closed-base and over-wintering period by the base doctors. Swabs will then be taken from any symptomatic (flu-like illness, with or without fever), consenting individuals/participants, together with any consenting close contacts. The swabs will be transported to the BAS Medical Unit at Plymouth then to Derriford Hospital Clinical Microbiology to arrange respiratory virus testing via Leicester Royal Infirmary Virology using a multiplex respiratory virus (influenza A/B, RSV A/B, parainfluenza 1-4, adenoviruses, entero/rhinoviruses, human metapneumovirus, coronaviruses) PCR assay. If this pump-priming grant application is successful, additional funding will be sought for the study to be extended over more seasons and for viral sequencing to demonstrate a more definitive epidemiological linkage between cases. The outcome of this study is relevant to long submarine, ship, space-station voyages, as well as shorter-duration encounters with infected individuals in confined environments, e.g. cars, taxis, trains, planes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Population impact of conjugate vaccine on pneumococcal transmission and disease in Kenya.
Funder: Wellcome Trust

Abstract: I propose that the breadth, duration and integration of existing surveillance systems in Kilifi can be used to provide a comprehensive assessment of the impact of Pneumococcal Conjugate Vaccine (PC) in Kenya. We have mortality surveillance, morbidity surveillance and vaccine-delivery surveillance, linkedto a single population register of 250,000 people. We also have the most detailed epidemiological studies of pneumococcal transmission prior to vaccineintroduction. Having integrated these systems I now proposed to concentrate onanalyses to evaluate the effectiveness of PCV against invasive pneumococcal disease, pneumonia and mortality. I am to measure the magnitude of indirect protection, monitor for serotype replacement disease and compare the genetic features of new invasive strains against a well-characterized baseline population. I will evaluate the safety of PCV and other vaccines. In new fieldwork I will estimate the epidemiology of serotype replacement carriage and examine whether multiple-serotype carriage confounds these studies. Using observations from Kilifi, and Science insights from mathematical models, I am to predict theimmediate impact of PCV in Kilifi, test these predictions through observation,and then predict the evolution of serotype replacement carriage and disease. If such models work they could be used in other settings which lack surveillance data.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION