NIHRDataInsights/HRCSData huggingface dataset:
Title: Partnership for a cross-disciplinary approach to the ecology of antimicrobial drug resistance in Kenya
Funder: Medical Research Council

Abstract: In Kenya and elsewhere, the antibiotic landscape for healthcare and livestock production is shaped by poor regulation and irrational drug use. There is a need for related evidence-based policy and the implementation plans for such policy. We will conduct in depth research in clinical and community settings to understand patterns of resistance, transmission of bacteria and their resistance determinants and genome based studies of resistance evolution. This will be combined with social and economic approaches to quantify the burden of antibacterial infection, the behavioural aspects of drug prescribing and use and the risks of mixing of bacterial populations between clinical settings, the community and the food systems that link them. Our approach is to build a strong network of antibacterial surveillance to monitor microbial ecology, and identify hotspots of selective pressure. Our objectives are: 1) Surveillance in health care settings. We will establish longitudinal and cross sectional surveillance in clinical settings and explore changes in the diversity of bacterial flora with differing care pathways and drug exposure. 2) Community based longitudinal monitoring of ABR in livestock producers. We will recruit commercial farmers in to a series of longitudinal cohorts and monitor their bacterial ecology over time. 3) Microbiological dynamics within the household. We will explore the longitudinal dynamics of bacterial populations in humans, their animals and the immediate farm environment, as well as the products leaving the farms for market. 4) Microbiology and sequencing. We will develop robust microbiological and sequence-based approaches to quantifying bacterial diversity and drug sensitivity 5) Human behaviour and decision-making. We will emphasise the study of the social and economic environment in which antibiotic use takes place, both in domestic animals and humans and develop policy frameworks to limit irrational use.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Towards controlling antimicrobial resistance in global aquatic animal food systems by enhancing collective resilience (AMFORA)
Funder: Medical Research Council

Abstract: Aquaculture is an important protein source for the growing world population but its development is constrained by infectious diseases, which are responsible for the annual loss of 10% of all farmed aquatic animals, amounting to >10 billion USD. Fish are often intensively farmed with heavy antibiotic (AB) use, but there are alternatives as shown by the drastic reduction of AB use in Atlantic salmon production in UK and Norway through vaccination. Aquatic animals are traded worldwide, but their contribution to the burden of consumer exposure to AB resistance genes is not being addressed because of the complexity of global food systems, the lack of knowledge of the drivers of resistance in aquatic systems and the fragmented responsibilities in global food systems. Our vision for the full proposal is to apply innovative systems-based research to implement and evaluate strategies that have the potential of reducing vulnerability of fish farming to the threat of AB resistance. In the development phase we will establish robust foundations for these activities working with strategic partners (World Fish, FAO, ILRI) in 3 LMIC that contribute to 9% of global aquaculture production: Bangladesh, Egypt and Vietnam. Through a combination of desk research (literature review, data synthesis), two workshops (Vietnam and Egypt) and stakeholder interviews we will identify i) drivers of AB usage in fish farming systems and ways in which they impact on resistance development and global public health, ii) knowledge gaps that currently preclude assessment of the consequences of AB usage in fish farming and iii) candidate interventions with the potential of enhancing resilience of the fish farming system to the threat of AB resistance. Building on the consortium's expertise we will expand classical risk assessment to develop a framework (to be used in the full proposal) suitable to assess resilience of of the fish farming system and the consequences of AB usage and resistance development.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Containing antimicrobial resistance in rural Cambodia: a one-health multi-disciplinary intervention to improve village healthcare and farming practice
Funder: Medical Research Council

Abstract: The study proposed is directly and primarily relevant to the development challenges of Cambodia. In particular, it addresses health and agriculture systems needs that have been identified by the Ministry of Health/communicable disease division (MoH/CDC) and Family Welfare (MOHFW) and Ministry of Agriculture, Forestry and Fisheries (MOAFF). Our CAmBR consortium has been formed after consultations by the Malaria Consortium (MC) Cambodia country office, and London/Leeds (by skype) with MOH/CDC and MOAFF. They have agreed to join the consortium for the development stage proposal, and possible full stage activity. The intervention will develop guides, training and monitoring meetings to improve the quality of the health services provided within the community facilities public and private in northern Cambodia to reduce antibiotic prescribing. The intervention will include working through agriculture extension workers, vets and farmers to reduce prescribing, and community dialogues to improve knowledge, attitude and practice of community members for improving the rational use of antibiotics. We will embed the intervention within the existing health and agriculture systems in order to maximise the potential for impact, replicability, sustainability and value for money.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: PET imaging of PARP using 18F-olaparib
Funder: Medical Research Council

Abstract: Given the increasing number of cancer drugs exploiting DNA damage repair defects in tumour tissue, such as PARP inhibitors, there is a clear need for patient stratification, therapy prediction and evaluation tools. Previously, our group has developed several methods for visualising DNA damage and genetic instability (a key hallmark of cancer), based on medical imaging techniques used in routine clinical practice, such as positron emission tomography (PET). Poly ADP ribose polymerase (PARP) is critical in the repair of DNA damage and is expressed to high levels in many tumours. Currently, PARP inhibitors are being studied in >100 clinical trials as a single agent or in combination with both chemo- and radiation therapy. To date, no companion biomarkers exist that predict the pharmacokinetic/dynamic behaviour of the most studied PARP inhibitor, olaparib (Lynparza), in individual patients. Such a tool would nonetheless be exceedingly useful to select patients that may or may not respond to the treatment. Therefore, to olaparib, we have tagged a radioactive isotope, 18F, while retaining its original chemical structure, to allow visualisation of olaparib biodistribution and PARP expression using a PET scanner. We hypothesize that PET imaging with radiolabelled olaparib can be used to determine the response to chemo- and radiotherapy of pancreatic cancers. Molecular information about the response to treatment will allow much faster decision making regarding treatment, compared to the anatomical changes such as tumour shrinkage that is used routinely. Also, 18F-olaparib may be used as an early diagnosis system, detecting the increased genomic instability that accompanies tumorigenesis. Although here we are using PDAC and glioma cells in vitro and in vivo as a model system, given applications of PARP inhibitors in many other tumour types, the approach may be expanded to other disease sites.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Maximising the potential of laboratory mice for understanding the genetic basis for disease
Funder: Medical Research Council

Abstract: Mouse models have long been used to gain a greater understanding of human disease genetics. In mouse genetics, decoding the genome of one strain (C57BL/6J) had a profound impact on our ability to relate sequence to function. There are more than two dozen different laboratory mouse strains used as models for human disease. In the Mouse Genomes Project, we have sequenced the genomes of 36 mouse strains to produce the first comprehensive public catalogs of genetic variation (single nucleotide, short insertion/deletions, and large multi-kilobase copy number changes or rearrangements), and studied its effect on phenotypes. This public resource has been invaluable to the mouse genetics community, and has been cited over 1,200 times since 2011. In 2016, we completed the first draft assembled genome sequences for these strains using second generation short-read sequencing technologies and long range libraries. We have identified over 5,144 loci in the mouse genomes where there is evidence that more complex strain specific alleles or haplotypes are present. These loci are enriched for genes involved in immunity, sensory, and kin recognition functions. These regions are enriched for highly identical repeat sequences which likely promotes recombination at these loci, and therefore pose a particular challenge for genome assembly. We propose to use long read technologies to create reference quality assemblies and genome annotation for 16 mouse strains, and develop and apply a set of quality control measures to assess the accuracy of the strain specific alleles. We will use the genome sequences to study the genome structure of these complex loci that have already been associated with disease phenotypes in QTLs from genetic reference panels such as the Collaborative Cross and Diversity Outbred Cross. All data from this project will be freely available via the Ensembl and UCSC genome browsers and the Mouse Genome Informatics database at the Jackson Laboratory.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Re-defining the paradigm of X-chromosome inactivation
Funder: Medical Research Council

Abstract: A hallmark of naïve cell identity is the presence of two active X-chromosomes in females. However, it was unknown if the naïve gene network prevented the initiation of X-chromosome-inactivation (XCI). In work currently under review at Cell Stem Cell we demonstrated that robust naïve pluripotent stem cell (nPSC) self-renewal abolishes expression of Xist, the master regulator of XCI. Intriguingly, at the onset of differentiation when nPSCs become Nanog-negative, they activate Xist biallelically in females and monoallelically in males. Surprisingly, we found that XCI occurs in males, as characterised by Xist RNA spreading, appearance of a repressive chromatin signature and partial X-linked gene silencing, albeit transiently and rapidly. We proposed that initiation of XCI is gender independent and triggered by the destabilization of the naïve identity, which suggests that gender-specific mechanisms follow rather than precede XCI initiation. Because of its impact for the paradigm of XCI the work under review opens new avenues to investigate how this fundamental process in biology is regulated. The pertinent questions I now want to address include: 1- Using Xist reporter cell lines I want to define what are the expression dynamics of Xist in self-renewing or differentiating mouse and human naïve pluripotent stem cells? 2- What are the molecular events and mechanisms associated with Xist upregulation? 3- I also want to define what are the molecular events associated to the reactivation of the male inactive X. In conclusion, the overarching goal of the proposed research project is to re-define the paradigm of X-chromosome inactivation (XCI).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Nuclear Envelope Directed Genome Organization in Myogenesis and Emery-Dreifuss Muscular Dystrophy
Funder: Medical Research Council

Abstract: One of the least understood remaining aspects of genome regulation to decipher is how tissue-specific patterns of spatial genome organisation are established and the mechanism by which they alter gene expression. Though general genome organisation derives from heterochromatin interactions with lamins and nuclear envelope transmembrane proteins (NETs), the genome changes orchestrated by tissue-specific NETs do not target heterochromatin. Several recent studies found that defective spatial genome organisation can lead to developmental defects or disease and we recently found that Emery-Dreifuss muscular dystrophy (EDMD) patients with no mutations in previously linked proteins have mutations in muscle specific NETs (mNETs) that direct muscle-specific genome organisation patterns. Thus we propose both to study these mutations in context of the disease and use EDMD as a model to study mechanisms of spatial genome organisation. Specifically, we will engineer candidate mNET mutations into the C2C12 myogenesis system to study their effect on genome organisation, gene expression and differentiation in a readily manipulable tissue culture experimental system. The strongest mutations will be engineered into mice to study systemic and metabolic effects and the penetrance of genome organisation effects in situ. Of note, our preliminary studies found both myogenic genes and several loci for regulatory RNAs repositioning during myogenesis in a manner dependent on mNET function. Regulatory RNAs have not been investigated with respect to EDMD and we will analyse miRNAs and lncRNAs for positioning, expression and effects on myogenesis and pathology in our experimental system and in patient biopsies if available. Finally, we will investigate how nuclear envelope tethering of genome regions can influence internal nuclear organisation by specifically modifying adjacent sequences to shorten or extend the length between a tether site and activated gene in the nuclear interior.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Development and evaluation of an integrated early childhood development and violence prevention teacher-training intervention in Jamaican preschools
Funder: Medical Research Council

Abstract: Aim: To integrate an instructional support component into the 'Irie Classroom Toolbox' (a universal, violence prevention, preschool teacher-training programme) and to conduct an on-going evaluation to ensure the intervention is acceptable, feasible and effective in improving teacher practices and child development. Sample: 20 preschools in Kingston, Jamaica, whose teachers have been trained in the 'Irie Classroom Toolbox', will be randomly assigned to intervention (n=10) or control (n=10). Each preschool consists of three classrooms (one 3,4 and 5 year old class) and all teachers and classrooms will be included in the study (30 teachers per group). In addition, a random sample of 5 children from each class will be selected for evaluation of child-level outcomes (150 per group). Intervention: The intervention involves training teachers in strategies to promote children's cognitive and language skills. Training is delivered through 2 full-day workshops and 4 in-class coaching sessions. Measurements: The primary outcome measure is observations of teachers' use of appropriate instructional strategies in a structured book sharing session and in everyday teaching and learning activities. Secondary outcomes are child school readiness and language skills. Measures will also include observations of teachers' use of violence against children and teacher-reported child behaviour difficulties to ensure the additional training does not have a negative effect on teachers' previous training in behaviour management. Process evaluation: An on-going process evaluation will be conducted to examine teachers' engagement with the training and the barriers and enablers to implementation both in terms of teachers implementation of the strategies and the facilitators' delivery of the training. Outputs: The information from the study will be used to develop intervention materials suitable for use in national dissemination including materials i) for teachers and ii) for facilitators.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: GENERIC HEALTH RELEVANCE
Title: Role of Nurses in the delivery of quality care: understanding the workforce deficit
Funder: Medical Research Council

Abstract: There is growing consensus that achieving Sustainable Development Goal 3(SDG 3) on healthy lives and well-being through universal health coverage (UHC) requires a critical focus on human resources for health (HRH). In developing countries, the shortage of health workers is estimated to be over 7 million, with the worst shortages experienced in the poorest countries in Africa. In Kenya, nursing densities in the public sector range between 1.2 to 0.008 per 1000 population across counties, compared to an internationally suggested minimum health workforce threshold of 2.5/1000 population. Nurses form the largest component of the health professional workforce and are recognized as essential to the delivery of safe and effective care and should be key players in promoting and shaping effective health policy. However, we suggest nurses are often undervalued and their contribution underestimated with their 'voice' in discussions on major HRH issues and on quality of care (QoC) often lacking. Increasingly availability of good information is used to provide evidence and advocacy in policy and management debates with measures of quality of care being of a particular focus. We will explore how measures of quality that are more specific to nursing care might be adapted and implemented in an African context. We will develop and pretest tools, co-designed with the nursing community, to produce metrics of nursing quality to inform debate on policy and practice. We will use identity theory as a lens to examine how the identity of nurses as professionals is created and its potential influence on their ability to exert power and agency in management and policy roles and how it also influences the quality of nursing care delivered.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: When there is not enough telomerase: telomerase insufficiency and genome integrity
Funder: Medical Research Council

Abstract: Telomeres are the natural ends of eukaryotic chromosomes evolutionarily conserved from unicellular organisms to humans and important for chromosome integrity. Most human cells express very little telomerase and due to the resultant telomerase insufficiency (TI) our telomeres become shorter with age. This telomere erosion has been linked to impaired tissue homeostasis, wound healing and immune response in the elderly. Furthermore, mutations in human telomerase genes result in accelerated telomere shortening, developmental syndromes and cancer predisposition. Therefore, studying how cells deal with TI and critically short telomeres is important for our understanding of human disease and ageing. To understand how cell populations respond to TI, we will: 1. Dissect cellular responses and telomere dynamics in cells with TI. We will perform genetic screens to identify factors essential for survival of cells with TI, monitor events taking place at critically short telomeres and analyse populations of cells with TI at the single-cell level in order to understand how critically short telomeres affect cell proliferation and population composition. 2. Elucidate the molecular mechanisms of suppression of TI. To gain molecular insights into TI suppression via aneuploidy, we will compare the dynamics of different telomerase components and their assembly into telomerase complexes in euploids and aneuploids. 3. Identify factors and networks important for switch to aneuploidy in response to TI by using a genetic approach. 4. Uncover the molecular dynamics at critically short telomeres upon DNA damage response (DDR) activation by addressing how DDR and DNA repair affect telomerase and telomeres, particularly during TI. Because all the key proteins and pathways under study are highly conserved from yeast to humans our findings will be relevant to research on human ageing and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: UKCRC Tissue Directory & Co-ordination Centre Phase II
Funder: Medical Research Council

Abstract: The Directory has been populated with over 100 HTRs and we are now able to evidence examples of research that have been directly enabled by the Directory. This objective will drive evolutionary change in the Directory, such as modifying the search and/or the data collection strategies. The drivers for change, however, will be an understanding and interaction with the views and behaviour of researchers, and this work will be led by UCL with the necessary technical support provided by the PDRA4 in Nottingham. The task of data entry and manipulation remains a very labour-intensive process for HTRs, with the provision of even basic information such as age, gender and disease beyond the reach of many organisations. This underlying technical challenge can prevent HTRs from registering with the Centre and creates a significant restriction on their ability to respond to queries from researchers. The Centre is one piece of a complex puzzle within the UK's governance, ethical and funding framework surrounding HTRs. There must be effective engagement and collaboration with the various bodies (Human Tissue Authority, Health Research Authority, UK Ethics Committee Authority, UKCRC Funders) in order to ensure that the change we believe is necessary can be achieved. The most effective route would be with agreement and support from these organisations. Our engagement strategy, within this objective, will focus on utilising these influencers to drive key messages into the community, but also seek opportunities where policy change could assist in delivering the Funders' vision. The Centre will develop a business case examining funding opportunities, and options for generating income to prepare the Centre for a self-sustaining future. The day- to-day costs of the Directory will be made self-sustaining by 2020. This is required to ensure that the Centre is removed from the reliance on one group of funders.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE