NIHRDataInsights/HRCSData huggingface dataset:
Award Title: SOCITS: A SOCial sITuational Systems approach to measuring and modelling influences on adolescent mental health
Funder: Medical Research Council

Abstract: This project will establish SOCITS as a readily available framework to allow any research team to adopt a situated systems approach to adolescent mental health, whether from a qualitative, quantitative, simulation or practice background. Through a series of reflective and comparative studies, we will determine the optimal approach for data collection and analysis to support a system-level understanding of how psychosocial constructs operate within SOCially sITuated Systems, and how the experience of the constructs within complex environments influences mental health outcomes. The study will use focal constructs of stress, loneliness and mental health stigma. The SOCITS study will develop a framework to identify the social-situational factors relevant to a specific adolescent environment or 'system of interest (SoI)' by developing methods toolkits for the following work packages. 1. Youth Advisor Investigator led walking interviews to obtain data about situations relevant to focal constructs. 2. Systems thinking workshops tailored to inform survey design and Agent Based Model specification for socially situated constructs. 3. Agent Based Models of socially situated interactions, calibrated to data, and used to explore situational-environmental interventions. 4. Development, testing and deployment of a longitudinal school survey containing socially situated assessment of constructs, and how they relate to mental health.   A final work package involves a webinar series throughout the life of the grant to discuss SOCITS concepts with the various research communities relevant to adolescent mental health and systems approaches, and at the end of the workshop, SOCITS useability testing workshops, using Normalisation Process Theory to assess how easily research teams can make use of SOCITS for their own projects.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: GENERIC HEALTH RELEVANCE;MENTAL HEALTH
Award Title: STARTER-KIT: A technical, procedural and ethical template for accelerating the start-up of AI multicentre studies requiring data re-use and/or sharing in clinical settings
Funder: Cancer Research UK

Abstract: Background
Modern radiotherapy research paradigms often require large or varied datasets that can be assembled only via collaboration between multiple centres and by combining multiple data holdings. Typical use cases include development of artificial intelligence (AI) algorithms; tackling rare cancers or subtypes where the number of cases registered at a single centre is small; gathering a complete, demographically unbiased cross-section of the population; and industry-academia co-production partnerships.

There is a great appetite within the research community for findable, accessible, interoperable and reusable (FAIR) data, which has the potential to catalyse a host of new projects in diverse areas. Yet such retrospective data are often “siloed” within institutions or have access restricted for a variety of complicated ethical, procedural and technical reasons. Equally, prospective studies are slowed down by the need to interact with multiple entities in a complex ecosystem of rules and governing authorities. As a result, new multicentre studies involving data sharing take too long to “get off the ground” and repeatedly “reinvent the wheel”.

Aims
STARTER-KIT will bring together complementary research and expertise, developed separately as part of the CRUK-funded RadNet, ART-NET and NCITA consortia and made available via newly designated CRUK Centres, to create an infrastructure template and worked examples for facilitating multicentre collaborative data analytics projects. 

Methods
Across a range of data-sharing problems, four interconnected work packages will implement a common methodology, viz.: Step 1: Gather input from stakeholders; Step 2: Develop technical solutions; Step 3: Present solutions and seek consensus for future joint work.

WP1 will examine the ethics landscape of creating FAIR data, considering particularly HRA databases and "micro-approvals" and the extent to which these can be federated, as well as issues of data quality and how to make this "findable". 

WP2 considers technical aspects of data access and federation.

WP3 will develop methods of federated identity management and maintenance of catalogues for tools and data, and will map the outputs of WP1 into software to create an electronic approvals workflow tool. 

WP4 will organise engagement activities with stakeholders (patients and the general public, alongside AI researchers and industry partners), demonstrate the software created in WP2 and WP3 and build consensus on its ethical use.

How the results of this research will be used
The deliverable of a complete starter-kit will significantly reduce the resource requirement for the setup of new studies and increase our ability to launch new initiatives in a timely fashion.


Research Activity Codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health Categories: CANCER AND NEOPLASMS
Award Title: STRESS-MALAWI: Strengthening Resilience against Sleeping Sickness in Malawi
Funder: Medical Research Council

Abstract: Rhodesian human African trypanosomiasis (rHAT) is caused by the protozoan parasite Trypanosoma brucei rhodesiense via the bite of infected tsetse flies. Foci of this disease persist in areas where tsetse and wild reservoir hosts are abundant (e.g. national conservation parks of Central and East Africa). People and livestock living closest to these areas are at the highest risk of contracting rHAT, but due to its zoonotic lifecycle it is extremely difficult to prevent transmission without targeting the vector. The Vwaza Marsh Reserve spans the border of north Malawi and Zambia and experienced an unexpected surge in rHAT cases in 2019-20. The reasons for this rise in rHAT are currently unknown but the majority of cases originated in villages less than 5 km from the park. We hypothesize that evidence-based and spatially explicit targeted vector control surrounding the park edge can reduce the risk of rHAT spilling into neighbouring agricultural areas.  To test this hypothesis, we will: 1. Sample tsetse along transects across the wildlife-agriculture interface and other potential tsetse habitat outside of the park and quantify the relationship between abundance and the environment using data captured by satellites and drones.  2. Quantify the human-biting index of local tsetse flies in Vwaza and determine whether exposure to tsetse-bites is greatest either inside or outside households via comparative entomological sampling methods. 3. Compare the genetic structure and parasite virulence of T. brucei rhodesiense circulating in Vwaza with historical samples of the parasite    4. Implement a two-year tsetse control strategy on the borders of the Vwaza Marsh Wildlife Reserve by deploying insecticide-treated targets at optimal densities informed by computational models of tsetse population dynamics.


Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health Categories: INFECTION
Award Title: Screening, Prevention and Diagnosis of Colorectal Cancer
Funder: Cancer Research UK

Abstract: Background
 The CSPRG is a multidisciplinary research team focused on screening and prevention of colorectal cancer (CRC).

Aims
Our aim is to reduce CRC incidence and mortality. Over the next funding period, we will:
• Examine methods to improve the impact of flexible sigmoidoscopy (FS) and faecal immunochemical tests (FIT) for CRC screening.
• Evaluate the effectiveness of the current adenoma surveillance guidelines.
• Investigate how we can improve screening, surveillance and diagnosis of proximal colon cancer (PCC).
• Explore risk factors for PCC.
• Build a national Lynch Syndrome (LS) database to improve surveillance in these patients.

Methods
We will use the UK FS screening trial (UKFSST) to examine the impact of endoscopist performance and patient experience of FS on long-term CRC incidence and future screening participation.

We will use data from the FIT for Follow-Up study to understand how endogenous and exogenous factors affect the diagnostic accuracy of FIT.

We will conduct a randomised trial within the Bowel Cancer Screening Programme (BCSP) to investigate the impact of different FIT thresholds on CRC incidence and mortality.

We will evaluate colonoscopy surveillance in relation to long-term CRC risk in all adenoma risk groups.

We will use data from our existing studies to examine the predictive value of distal and proximal lesions for future PCC risk. In addition, we will use GP data linked to cancer registries to identify risk factors and symptoms associated with PCC.

 We will build a national database of LS patients with functionality to provide call and recall for colonoscopy surveillance.

How the results of this research will be used
Results from the UKFSST have shown that a single FS screening reduces incidence and mortality of CRC by 35% and 41%, respectively, after 17 years. Our additional analyses will determine how the impact of FS can be further increased.

Understanding the sources of variability in FIT results and effects of different thresholds on CRC incidence and mortality will ensure the optimum use of FIT, maximising the efficacy and cost-effectiveness of screening.

Our evaluation of adenoma surveillance will provide vital data required to refine the existing guidelines and focus colonoscopy resources where they are really needed.

Improving understanding of risk factors, screening and early-detection strategies for PCC will decrease incidence and mortality of this malignancy.

The LS database aims to reduce CRC mortality in LS patients by ensuring that they receive the recommended level of colonoscopy surveillance.


Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health Categories: CANCER AND NEOPLASMS
Award Title: Self-DNA Detection in Genome Maintenance and Cancer
Funder: Cancer Research UK

Abstract: Background
Most cancers, either during their development, or during chemotherapy, undergo genotoxic stress and chromosomal instability. While much is known about how classic DNA repair and DNA damage checkpoint machineries respond to such defects, and how these modulate carcinogenesis and chemotherapy, recent work has implicated another player – the innate immune system. Because innate immune signalling can both have important cell-intrinsic effects and regulate immune responses, understanding its response to genotoxic stress may transform our view of cancer development and treatment particularly with the advances being made through immunotherapy.
A major trigger for innate immune responses is DNA-dependent activation of the cyclic GMP-AMP synthase cGAS, leading to inflammation, senescence and apoptosis. Under unperturbed conditions, chromosomal self-DNA appears to be shielded from activating cGAS, but this is negated in response to genotoxic stress. Although the mechanistic basis underlying this phenomenon is not yet understood, my recent work showed that the chromatin organization of chromosomal DNA inhibits cGAS, thereby potentially preventing cGAS activation during normal growth.

Aims
The main purpose of this research plan is to understand how chromatin inhibits cGAS, how this inhibition is relieved in cancer and in response to genotoxic stress, and to reveal the consequences of cGAS activation by self-DNA.

Aim 1: Reveal how cGAS activation is controlled by chromatin.
Aim 2: Reveal how genotoxic stress activates cGAS.
Aim 3: Reveal how cGAS controls cell fate following genotoxic stress.

Methods
I will apply biochemistry, structural analysis and cell biology to this problem. A unique system of cell-free extracts will be used to investigate cGAS response to self-DNA in a physiological but biochemically tractable environment. Cell culture, automated imaging, and gene editing will reveal cell fates and in vivo mechanisms. Ionising radiation and taxanes will be used as sources of genotoxic stress, both with direct relevance to cancer treatment.

How the results of this research will be used.
I hope to establish a comprehensive understanding of how cGAS orchestrates the response to genotoxic stress, and establish model systems to dissect other innate immune pathways. In collaboration, I subsequently plan to apply these findings to revealing the role of cGAS activation by self-DNA in cancer development and treatment. The deep mechanistic understanding that I aim to establish should prove valuable to develop approaches for manipulating the cGAS pathway during cancer therapy, as well as utilising it as a biomarker for tumour responses during therapy.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Shaping a stem cell into dozens of cell types: A single-cell epigenetic roadmap of planarian stem cell differentiation
Funder: Medical Research Council

Abstract: Pluripotent stem cells give rise to multiple lineages of differentiated mature cell types. We currently think that stem cells change their chromatin accessibility patterns in a different manner in each differentiation lineage. The regulation of this process is of fundamental importance for regenerative medicine and reprogramming and its deregulation causes human disease and cancer. However, how stem cells orchestrate these changes to activate multiple differentiation programs into a myriad of cell types is still unknown. Planarians are an ideal model organism to investigate this question as their stem cells constantly differentiate into all cell types to turn over their tissues. The advent of single cell technologies, together with the properties of the planarian model, will enable this research now. We have already applied single cell transcriptomics to planarian stem cell differentiation, revealing for the first time their full differentiation lineage tree. Here I propose to measure chromatin interactions and accessibility at the single cell level in the bulk cell population of the planarian Schmidtea mediterranea. By using and combining Chromatin Conformation Capture techniques to monitor chromatin interactions and single cell ATAC-seq to measure chromatin accessibility we will elucidate the changes in chromatin accessibility that take place during stem cell differentiation into each differentiated cell lineages and their order. By measuring chromatin accessibility after knocking down candidate conserved regulators, we will be able to detect the chromatin changes they induce, the genomic regions where they happen and the differentiation lineages where they are needed. Since many of the genes involved are conserved from humans to planarians, this knowledge will inform human stem cell therapies and regenerative medicine. This will lay a cornerstone into our understanding of the epigenetic bases that regulate stem cell differentiation to multiple cell types.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Shared Futures: Codeveloping Medical Humanities in China and the UK
Funder: Wellcome Trust

Abstract: The programme of exchange and networking proposed here aims to build on preliminary experiences of connecting and co-working between UK and Chinese institutions in order to:       i. Drive the Medical Humanities as a mature disciplinary field in China.   ii. Grow collaborative working between an expanding number of Chinese institutions and UK universities in the Medical Humanities.   iii. Establish a generation of scholars in the Medical Humanities with experience of research, training and teaching in both academic cultures and the capacity to build the field in China and elsewhere.   iv. Equip graduates of the programme with Medical Humanities knowledge and perspectives to enable them to engage in fresh ways with human health problems and challenges as they enter careers and sectors beyond academe around the world.       It will connect the partners at the institutions above as they work together to enable:       i. 18 M.Sc. students from SHU, SASS and Fudan to complete Masters degrees at the CSHHH Glasgow and the CHSTM at Manchester University.   ii. 9 one-year Early Career Researcher (ECR) Medical Humanities Fellowships at SHU, SASS and Fudan University.   iii. 6 Medical Humanities events (3 workshops in UK and 3 conferences in China) to showcase the network.


Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Silicosis and silicotuberculosis amongst small scale gemstone miners in Northern Tanzania
Funder: Medical Research Council

Abstract: Artisanal and small scale mining (ASM) provides employment for an estimated 45 million people. Despite known occupational risks, it is a key and underrecognized component of the world economy.  There are few studies of the health impact of ASM, particularly regarding silicosis and tuberculosis (TB). Silicosis is contingent on cumulative respirable crystalline silica (RCS) exposure and has only been characterised in one ASM population in Brazil. Rates of TB in miners are high but the impact on community transmission unclear. Whole genome sequencing (WGS) of TB facilitates mapping transmission and drug resistance testing.  Tanzanite mining in Mererani, Northern Tanzania, is exclusively small scale. Current evidence suggests silicosis is highly prevalent and presents aggressively after short exposure. TB appears highly prevalent in the community and miners.  My primary hypothesis is the rate of silicosis progression and respiratory impairment is high, associated with cumulative RCS dose, and modified by TB. My secondary hypotheses include; that prevalence of TB among miners and the community is high, and transmission occurs within mines and from miners to the community; that miners experience high rates of catastrophic economic loss; and that rates of drug resistant TB transmission are high. To do this, I propose two studies. First, I will establish a prospective cohort of 410 small scale tanzanite miners and record symptoms, respiratory function including spirometry, chest radiography, and prevalence of TB and HIV infection over an 18 month period. Second, I will perform a cross-sectional study on participants identified to have TB during community screening and at baseline in the cohort. I will collect epidemiological data and perform WGS on positive Mycobacterium tuberculosis culture samples.  There are cost-effective interventions suitable for interventional studies. Given the lack of research in this area, this study will have global implications.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION
Award Title: Single molecule nucleocytoplasmic transport dynamics in FTD/ALS
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK.  Funding details for UK DRI programmes will be added in 2019. This programme will explore how nucleocytoplasmic transport is affected in FTD and ALS at the single molecule level, and how this links to common disease pathologies. Studies will focus on disease-associated proteins containing LCDs, such as those identified pathologically in individuals carrying C9orf72 mutations. This multidisciplinary work will utilise super resolution microscopy to investigate the dynamics of single molecule cargo through the nuclear pore combined with biophysical studies to study phase transitioning of nuclear pore selection barriers to unveil unique disease pathomechanisms often overlooked from bulk endpoint analyses. Methodologies developed in these studies will be broadly applied across different disease models, from transduced cell lines to patient-derived induced pluripotent stem cells (and adapted for use in Drosophila and mouse models), utilising transcriptomics and proteomics. Key mechanistic findings will be validated in FTD and ALS patient tissues to ensure disease relevance.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Single molecule studies of cell motility and cell signalling
Funder: The Francis Crick Institute

Abstract: My core research interest lies in understanding how mechanical force affects or controls interactions between biological molecules. The energy balance of most biomolecular interactions lies somewhere between thermal energy (kBT=4pN.nm) and the free-energy of ATP hydrolysis (100pN.nm). This means macromolecular assemblies (e.g. the cytoskeleton, multi-subunit protein complexes, protein-DNA transactions) can be readily assembled and disassembled and relatively weak forces can have dramatic effects on these processes. My group uses a variety of optically-based, single-molecule technologies, some of which allow picoNewton forces to be applied or measured (i.e. optical and magnetic tweezers and atomic force microscopy) while others (Total Internal Reflection Fluorescence and super-resolution microscopy) allow single molecule interactions be observed within living cells.  A major question in the area of molecular motor research is how chemical energy is transduced to mechanical work. My group have been studying the mechanical properties of actin-myosin, using a combination of single-molecule techniques including optical tweezers and live cell imaging using TIRF microscopy. We are using super-resolution optical microscopy and cryoEM (with Peter Rosenthal, Crick) to map the ultra-structure of microscopic cellular protrusions called filopodia. We want to understand how myosin-10 moves along actin filaments located within filopodia and how malarial class 14 myosins drive parasite invasion into the red blood cell. We are also examining the bundling and cooperative motion of actin filaments driven by myosin motors and how this is modulated by the calcium-calmodulin-dependent kinase CamKII (important in dendritic spine remodelling during Long-Term-Potentiation and learning).  Our single molecule studies of bacterial plasmid replication (with Martin Webb) and plasmid transmission (Gabriel Waksman, UCL, London) using magnetic tweezers aim to address how DNA topology (specifically DNA twist and writhe) affect assembly and action of the relaxosome complexes that nick plasmid DNA and initiate its. Specifically we want to know how relaxase enzymes sense DNA supercoiling and how associated helicase activity is affected by DNA tension or torsion. We are also studying how archaeal histone binding to DNA is influenced by topology and transcription factors (with Werner, UCL). We intend to develop more sophisticated magnetic tweezer based approaches with our colleagues at KCL, London (Paula Booth and Sergi Garcia Manyes) in order to manipulate DNA and membrane proteins (see below). Our work on G-protein coupled receptors and ion channels uses a combination of optically-based single-molecule approaches (our expertise) with electrical recording using patch-clamp (with Lucia Sivilotti, UCL).


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE