NIHRDataInsights/HRCSData huggingface dataset:
Title: Consensus group on the design, analysis and reporting of antibiotic stewardship trials
Funder: Medical Research Council

Abstract: The primary goal of antibiotic stewardship is to reduce use of inappropriate antibiotics while ensuring non-inferior clinical outcome. The highest level of evidence is provided by antibiotic stewardship trials (ASTs). Currently, up to 80% of the publications on ASTs are of insufficient methodological quality to provide interpretable conclusions (Molina 2015). This results - at least in part - from the absence of guidelines and standardized methods on how to design ASTs. To ensure that ASTs do not negatively affect the quality of patient care, non-inferiority designs are often used. However, predefined non-inferiority margins are subjective and non-inferiority designs require large sample sizes, increasing the risk of underpowered studies (Schulz, 2005). As a result, many ASTs are descriptive and not sufficiently powered for evidence-based policymaking. A new alternative method using a composite endpoint of antibiotic use and clinical outcome was recently proposed for evaluating ASTs; the RADAR method (Evans, 2015). This method uses a superiority design, requiring smaller sample sizes. However, with this method outcomes are difficult to interpret and susceptible to subjective choices in the analysis (Phillips, 2016; Schweitzer, in preparation). It is therefore fair to conclude that a consensus on how to properly design and analyse ASTs is lacking. We will establish an international working group consisting of experts on trial methodology and antibiotic stewardship with the aim to establish a best-practice guideline for designing, analysing and reporting ASTs. The working group will evaluate existing methods, develop new methods or improve existing methods, evaluate which settings are important to consider and define the optimal methods for the design and analysis of ASTs per relevant setting. The final product will be a best-practice guideline containing recommendations for designing, analysing and reporting ASTs.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: INFECTION
Title: Dynamics of Antimicrobial Resistance in the Urban Water Cycle in Europe
Funder: Medical Research Council

Abstract: While therapeutic antibiotic use directly impacts the evolution of AntiMicrobial Resistance (AMR), it has become increasingly clear that the environmental dimension of AMR is also of great importance. We postulate that urban water systems (UWS), which are our receptacle for excreted antimicrobials, AMR organisms and AMR genes, are central conduits of AMR to and from pathogens and environmental strains. This is because of high microbial densities and the co-mingling of different wastes, which promotes accelerated AMR gene transfer (HGT) and multi-resistance due to the co-occurrence of antibiotics, biocides, metals and microbes. In DARWIN, we will undertake a never-previously-performed pan-European examination of the fate of key AMR organisms and genetic determinants in UWSs resulting from discharged hospital and community wastes, including transmission mechanisms in different stages of sewer catchments and receiving waters. We focus on the spread of AMR genes encoding clinically relevant extended spectrum b-lactam (ESBL) and carbapenem resistance in three countries with differing AMR profiles and sewage management practices. We posit that AMR genes readily transmit in UWSs from pathogens and commensal hosts in human wastes (after antibiotic use) to environmental strains better adapted to migrate through the sewer environment, which is driven by local ecologies, conjugal plasmid transfer and phage-mediated transduction. Hence, we will, for the first time, determine specific bacterial hosts that carry AMR genes across UWSs, and identify where key HGT events occur with the ultimate goal of assessing the relative risk of AMR genes returning back to humans due to environmental exposure to AMR in urban environments. To guide risk assessments, a predictive dynamic mathematical model for UWSs will be developed to assist in health and sewage management decisions.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: MRC Centre for Molecular Bacteriology and Infection
Funder: Medical Research Council

Abstract: Imperial College will provide three new academic posts to expand research capacity (two Lectureships and one Senior Lectureship). Two posts are to study complementary aspects of AMR and one post will be used to appoint a specialist on the microbiota. An underlying theme of the Centre is the study of bacteria at the single cell level. Most bacteriology research involves studying bacteria as populations - either during growth on lab media or during infection studies. However, it is clear that even though these populations can be genetically identical, individual bacterial cells within them behave differently, and this variability has very significant implications for the outcome of infections and the development of antibiotic resistance. To accelerate work at this level, we wish to establish a high throughput single cell analysis (HTSCA) facility, which will comprise an existing, MRC-funded BD Aria III cell sorter, a BD FACSCalibur analyser, and new equipment that we request from the MRC, comprising a Zeiss Z1 microscope, CellASIC ONIX2 microfluidic system and LionheartTM FX Automated Live Cell Imager. We also request funding from the MRC for a facility manager to maintain, train and help CMBI users with experiments and data analysis. A major component of this proposal is a continuation of our successful PhD training programme. This will consist of 16 studentships, of which 12 (nine MRC and three Imperial contributions) will be non-clinical three and a half year studentships and four will be clinical research training fellowships (three MRC and one Imperial contributions). We also request support for our Centre manager and a small budget for other Centre activities.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Combating MRSA; combining and increasing our understanding on colonisation, transmission and reservoirs will lead to control of infections by MRSA
Funder: Medical Research Council

Abstract: MACOTRA will, for the first time, bring together a range of relevant information on MRSA across three countries, including - - Phenotypic and genotypic characteristics for transmission and resistance - The epidemiology of these strains, including incidence and reservoirs. - Antibiotic and antiseptic usage policies, protocols and real-world evidence - Relative fitness of different clones, in models relevant to their niche in the host, and pressures such as microbiome competition and antibiotic/antiseptic exposure - Potential host-specific interactions impacting on survival. The collection of all of this data will then be incorporated into mathematical models to understand why different countries have different clones and epidemiology, and to predict the impact of changes in antibiotic/antiseptic on MRSA incidence and reservoir In the epidemiology of MRSA, the clone, the host and the environment, including selection and prevention measures all need to be studied for it to be understand. We believe that by combining, the understanding of the epidemiology will be better, and thus prevention measures can be developed more focused. The project is well feasible as 1. Reference laboratories are included of all countries, 2. all participating centres have many years of experience in this field and are proven successful in MRSA research 3. The mathematical modellers are well experienced in their field and have proven to successfully publish their work on different infectious disease topics. The partners and their colleagues have known each other for several years in the field of MRSA research.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Risk of companion animal to human transmission of antimicrobial resistance during different types of animal infection
Funder: Medical Research Council

Abstract: The close contact of pets with humans provides excellent opportunities for interspecies transmission of resistant bacteria and their resistance genes in either direction. Infections in humans due to antimicrobial resistant bacteria originating from pets are becoming a concern. While any animal-human contact offers a chance of transmission, it is generally accepted that a high bacterial burden and high antimicrobial resistance gene copy numbers are present during an active infection. There is a gap of knowledge on the dynamics of transmission and selection of antimicrobial resistance at the pet-human interface. Animals may exchange antimicrobial-resistant bacteria and resistance genes with humans, but the extent to which this happens is unknown. PET-Risk will evaluate the transfer of antimicrobial resistance between pets and household members during animal infections and determine which type of infection (skin and soft tissue vs. urinary tract infections) presents a higher risk of transmission to humans. Furthermore, in a longitudinal study we will collect samples of infected animals under antimicrobial treatment, and their household members at several time points, which will allow the assessment of critical control points at which interventions could substantially affect the spread of resistance. The causality and directionality of pet-human spread of resistance genes will be established by using state-of-the-art techniques in order to design and evaluate preventive and intervening measures for reducing the public health risks of antimicrobial resistance.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Selection and Transmission of Antimicrobial Resistance in Complex Systems
Funder: Medical Research Council

Abstract: The STARCS consortium will (i) develop and implement innovative metagenomic methodologies to map the expression of AMR genes and their linkage to bacterial hosts and mobile genetic elements in human, animal and environmental samples, (ii) use relevant animal models (using mice and ducks) and observational studies (in hospitals and in dogs and their owners) to analyse and quantify the processes of selection and transmission of drug-resistant Enterobacteriaceae (specifically Extended Spectrum Beta-Lactamase producing Escherichia coli) and (iii) implement state-of-the-art epidemiological modelling to quantify the spread of ESBL-producing E. coli between humans and animals. STARCS will develop technological breakthroughs to assess selection and transmission dynamics on the level of the resistance gene, the mobile genetic element, the bacterium, the human-animal-environment interface and in clinical settings. This project will deliver important knowledge into selection and transmission of AMR, will provide the scientific community with novel tools to study selection and transfer of AMR in complex systems and will result in much-needed guidance towards policy decisions by international and national institutions. Ultimately the results from STARCS will form an evidence-based foundation for the development of new regulations, aimed at curbing the spread of AMR.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Structure and function of Heparin Binding Hemagglutinin from Mycobacterium tuberculosis
Funder: Medical Research Council

Abstract: This project aims at an interdisciplinary study of the structural basis of the epithelial cell adhesion by Mycobacterium tuberculosis (MTB) by the heparin-binding haemagglutinin adhesin (HBHA), a homodimeric protein localised at the surface of MTB. The challenging aspect of this ambitious characterisation is associated with the structural complexity of HBHA, which is composed of a membrane-associated domain (residues 1-25), a coiled coil region (residues 26-110) and an intrinsically disordered region (residues 111-199) having the function of sensing and binding epithelial cells via its heparin binding domain (residues 161-199). To characterise this key protein, we will carry out an integrated investigation of solution and solid-state NMR (ssNMR) that will provide high-resolution data to refine the structures of the three HBHA domains (phase I). The membrane associated region will be studied using solid-state NMR, whereas coiled coil and heparin-binding domains will be investigated using solution NMR experiments that are tailored to the characterisation of folded and disordered protein states, respectively. These sparse NMR data will be integrated in an advanced refinement protocol that integrates tools tailored to the characterisation of the structure and dynamics of protein states (phase II). Finally, in phase III we will probe the specific interaction of HBHA with epithelial cells using advanced NMR methods to characterise in detail weak and transient interactions between disordered proteins and complex cellular surfaces (Nature Communications, 2016, 7:12563). This study will identify the relationship between structure, dynamics and functional mechanism of HBHA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Dynamics of bacterial killing by the membrane attack complex
Funder: Medical Research Council

Abstract: Complement is a key part of the innate immune system. Its activation can lead to the formation of pore forming membrane attack complexes (MACs) to lyse bacteria. Much of our current understanding of the MAC results from studies of the MAC perforating single membrane model systems such as synthetic lipid bilayers and red blood cells. However, in physiological context, the MAC targets the much more complex and composite bacterial envelope, and - while of great medical relevance - its mechanisms of (anti)bacterial attack remain unclear. With this project we aim to understand the sequence of events from MAC formation on the bacterial envelope to bacterial killing, presumably by lysis. To this end, we will carry out atomic force microscopy experiments, resolving the MAC as it is assembling and the bacterial envelope as it is degraded, and identify the different steps in membrane pore formation and bacterial killing by the MAC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Dissecting the role of the Leishmania flagellum in pathogenicity
Funder: Medical Research Council

Abstract: The protist Leishmania is an obligate intracellular parasite that infects macrophages and causes disease in humans. Leishmania have a single flagellum required for motility and attachment of promastigote forms in the insect vector. Surprisingly, promastigotes are viable in culture even if they build no flagellum, yet intracellular amastigote forms, whose short flagellum was long considered non-functional, cannot survive in macrophages if protein trafficking to the flagellar membrane is disrupted. This points to a role for the flagellum in infection. We previously showed that the short amastigote flagellum structurally resembles sensory cilia and observed that the flagellum tip forms a junction with the parastiophorous vacuole membrane. Cilia and flagella are organelles found on diverse cell types, from protists to cells in the human body, acting as motile appendages or antenna-like signal transducers and we hypothesise that the flagellum of intracellular Leishmania is a sensory organelle. The flagellum is a complex organelle composed of hundreds of proteins. We have developed a new method for rapid generation of gene knockouts (KO) using CRISPR-Cas9 tools which enable us for the first time to conduct a systematic KO screen to test which types of flagellar mutants (cytoskeletal, membrane, tip defects) lose the ability to infect macrophages. We will also use biochemical methods to discover new proteins localized to the flagellum for inclusion in the KO screen. Mutants that fail to survive in macrophages will be subjected to detailed phenotype analysis. This research will uncover new information about the role of the Leishmania flagellum in infection and test the hypothesis that a physical connection between flagellum tip and host cell contributes to virulence. We will use pluripotent stem cell-derived human macrophages as in vitro infection models which allow us to dissect molecular mechanisms of host-pathogen interactions with relevance to human disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Genomic approach to transmission and compartmentalization of extended-spectrum cephalosporin resistance in Enterobacteriaceae from animals and humans
Funder: Medical Research Council

Abstract: Resistance to extended-spectrum cephalosporins (ESC) in Enterobacteriaceae is a major challenge for public health worldwide. Its international presence in almost every ecological niche and biological compartment with still ongoing dynamic expansion makes it an ideal target to study the spread of antimicrobial resistance (AMR). This project intends to use genomic, evolutionary, transcriptomics, proteomics and experimental approaches to assess the similarities between a variety of ecological niches and biological compartments formed by Enterobacteriaceae species, host species/source (humans, dogs, cattle, swine, chicken, meat products) and geography (Europe: Germany and France, and North America: Canada). These similarities will serve as a basis to identify and focus further on clonal lineages and plasmids able to spread across compartments, using whole genome and plasmid sequencing. A combination of phylogenetic and epidemiologic analyses will allow an assessment of the directionality of transmission between compartments. These analyses will be complemented by series of experiments on transmission of ESC resistance plasmids in vivo in two animal models (chicken and cattle) and on effects of ESC resistance plasmids on the bacterial transcriptome and proteome and its association with plasmid maintenance. These experiments will help to identify major transmission pathways between animals and humans and potential new intervention targets for the control of ESC resistance. The team assembled for this project consists of experienced researchers with a wide spectrum of expertise ideal for the successful completion of a study of antimicrobial resistance in the context of One Health.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Investigating Matrix Degradation Products in Tuberculosis
Funder: Medical Research Council

Abstract: Innovative approaches are required to control the global tuberculosis pandemic. In the absence of an efficacious vaccine to prevent lung disease, identifying and treating individuals with pulmonary disease who drive transmission is the best way to reduce incidence. However, current diagnostic tests are not suitable for population screening. We have shown that matrix degradation products released by TB-induced immunopathology are plasma correlates of lung disease using a hypothesis-driven approach. Lung disease differs between men and women, and between TB in immunocompetent and HIV-infected individuals. Matrix destruction will release many peptide fragments but only a fraction of these have been analysed. This project will perform the first unbiased analysis of matrix degradation products in TB across all the key patient groups using a unique non-depletion based proteomic strategy developed in Southampton by Dr Spiro Garbis. First we will analyse archived samples from a South African cohort, studying healthy controls and TB patients including men and women and HIV-uninfected and HIV-infected individuals in equal number. Subsequent bioinformatic processing of the raw proteomic datasets will be supervised by Dr Christopher Woelk. Next, once key matrix fragments are identified, we will study these in a much larger cohort by Parallel Reaction Monitoring (PRM), Luminex array and ELISA, including the control group of respiratory symptomatics with TB symptoms but alternative final diagnoses. Finally, we will investigate matrix turnover in a UK cohort of mixed ethnicity and diverse clinical manifestation of TB. I will perform the first systematic analysis of matrix degradation in TB, based on clinical observations and strong published and unpublished data. It will provide me with a broad training in widely applicable research methodology, including proteomics, bioinformatics, Luminex arrays and the statistical integration of clinical and laboratory data.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: The role of commensal organisms as pro-infectious agents in Staphylococcus aureus infection dynamics.
Funder: Medical Research Council

Abstract: S. aureus is able to cause a wide range of diseases, with no vaccine available and antibiotic resistance common. It is therefore crucial to understand how S. aureus infection is initiated and progresses in order to identify novel clinical interventions. We have made the exciting discovery that skin commensal organisms, and even their isolated cell walls, can augment S. aureus infection. We have called the augmenting material "pro-infectious agents" and have shown its addition to result in a massive decrease in the inoculum of S. aureus required to cause serious disease. These findings are extremely pertinent to human infection, as this will always occur from within a polymicrobial milieu. It is important now to capitalize on our initial results to understand the breadth and basis of the augmentation phenomenon and how this might be exploited in the development of new approaches to tackle S. aureus. The project will take an interdisciplinary approach, with global partners, using a combination of in vivo and in vitro analyses. We will investigate the molecular basis of pro-infectious agents in terms of those organisms and components able to augment S. aureus disease, coupled with an elucidation of the host response to pro-infectious agents from the molecular, through cellular to the whole host level. This will be set within a determination of the progression of S. aureus infection to understand how disease is established as a complex interaction between host and pathogen and how this dynamic is altered by the presence of pro-infectious agents. Finally, we will examine how our discovery of pro-infectious agents can be utilized in the design of a vaccine and other immunological interventions. Such ambitious goals, from fundamental understanding to translation, can only be achieved via an integrated team of investigators and partners, providing molecular understanding of host:pathogen interaction with important ramifications for human disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION