• 2021-2021close
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• 2019 close

Our long-term vision is that AVATAR therapy is optimised for delivery in clinical settings, with the impact that a novel effective treatment for distressing voices is readily adopted in UK and international clinical settings. As a result of the current study we expect the impact to be: - Software platform tested and optimised for use in NHS settings - Further evidence of effectiveness and the relative cost effectiveness of two therapy levels, including a further elaboration of the participants for whom the simpler phase 1 approach would be sufficient. The advantage of this being that the therapy would be more rapidly disseminated as the more straightforward skills needed for this phase are widely available and at lower cost both in the UK and internationally compared to the specialised psychological therapy skills necessary for phase 2 - Clarity about optimal therapy content and training, with published therapy operational and clinical manuals - Evidence sufficient for a NICE recommendation of AVATAR as a treatment in the NHS. This is a key next step in the wider dissemination of this therapy in the UK and will also be helpful data for similar clinical guideline and policy recommendations in the US and elsewhere AVATAR therapy is a brief intervention aimed at reducing the frequency of auditory verbal hallucinations (AVH, henceforth ‘voices’). It involves the use of a digital simulation (avatar) of the entity the person believes is the source of the voice in a three-way discussion between participant, avatar and therapist, focussing initially on managing anxiety and helping the participant to stand up to the avatar (phase 1) followed by a realistic enactment of the ascribed character of the voice, targeting processes that are specific to an individualised formulation (phase 2). The first fully powered RCT found AVATAR therapy resulted in a rapid and substantial fall in frequency and associated distress of voices that was superior to a supportive counselling control condition at 12 weeks. In the current study we have four main goals. First, a multicentre RCT to examine the effects of high and low intensity AVATAR therapy (where high intensity involves both phases and low intensity only phase 1) by comparing each to a treatment as usual comparator, and to identify who would be likely to benefit from the high intensity therapy versus those for whom low intensity alone would be sufficient. Second, to examine the relative cost-effectiveness of the two levels of AVATAR therapy and routine treatment. Third, to broaden the availability of AVATAR therapy by expanding the number of staff trained in geographically dispersed NHS settings. Finally, to provide the evidence on effects and cost-effectiveness necessary to take AVAVAR therapy to recommendation by guideline bodies such as NICE.

Many greenhouse gas mitigation actions also benefit air quality and health. However, progress incorporating co-benefits assessments into climate mitigation planning has been limited. Over the next several years, C40 Cities is working with city governments to develop climate action plans. We aim to develop methods to integrate PM2.5 and associated health co-benefits into the climate action planning tool these cities will use, thereby building a bridge between the scientific evidence on co-benefits to the largest urban climate action planning effort worldwide. Specifically, we will: 1) Develop, evaluate, and integrate a screening-level air quality model (focusing on fine particulate matter, PM2.5) into C40’s climate action planning tool, Pathways, for at least three pilot cities; 2) With local partners, test the tool to explore air quality and health co-benefits of climate action pathways in the pilot cities; and 3) Assess the potential for quantifying additional health co-benefits in Pathways, such as changes in ozone, nitrogen dioxide, physical activity, noise, and green space. Data and tools will be publicly available to support additional research into climate/health linkages. C40 will maintain Pathways beyond the project’s end, creating a platform to study more cities and enabling long-term integration of co-benefits into city climate action planning. Many actions cities can take to reduce greenhouse gas emissions would also improve air quality and therefore also human health. This project develops a decision-support tool that helps cities explicitly recognize the nexus between climate action and air quality and public health benefits. We will add a new screening-level air quality and health assessment capability to an existing greenhouse gas planning tool that is maintained by C40 Cities and used in cities worldwide. We will then work with local officials in three pilot cities to test the tool to explore the air quality and health implications of specific climate action pathways that these cities can take. We will also assess the potential for including additional health co-benefits such as from increased physical activity and green space.

Bacterial secretion systems release effectors into the extra-cellular milieu or directly into foreign cells. They represent fundamental mechanisms by which bacteria modulate their environment and induce human infection. Here we study two related and complementary secretion systems, the bacterial type II secretion system (T2SS) and the Tad secretion system (TdSS). The T2SS secretes effectors and toxins involved in cell adherence, biofilm formation and host cell death. The TdSS drives cell adherence and colonization through extra-cellular pilus formation. Both secretion systems constitute multi-component complexes with many shared components that span the cell envelope of Gram-Negative bacteria. The overall goal is to determine the molecular mechanism underlying T2SS and TdSS operation. Key aims for the T2SS include showing how substrate is recruited, how inner membrane components are organised, and how pseudo-pilus assembly is coordinated. The repertoire of K. pneumoniae T2SS virulence factors will also be expanded. For the TdSS, key aims include structure-function studies on the outer membrane secretin with its associated pilotin and pilus. Comparison of T2SS and TdSS structures will reveal common mechanistic and evolutionary principles. By understanding how the T2SS and TdSS function and promote pathogenesis, this research has the potential to facilitate drug development and combat anti-microbial resistance. Some bacteria cause infections in humans that kill millions of people annually. To trigger the infection, the bacteria contain nanomachines within their cell surface that act like miniature pumps. These are secretion systems. One role of secretion systems is to deliver harmful proteins from inside the bacteria to outside environments like your cells. These harmful proteins act as molecular weaponry in many ways. They can form grappling hooks to help the bacteria attach to environments like your intestine or as molecular malware that maliciously reprogram your cells. We use a powerful technique called cryo-electron microscopy, which allows us to visualize the precise position of the atoms within the secretion systems. In this way we can learn the 3D structure and chemistry of the secretion systems. By understanding how the secretion systems work we have a much greater chance of developing medicines that stop the secretion systems from causing human illness.

Blood vessels, including arteries and capillaries, are equipped to constrict and dilate in response to changes in their environment. Importantly, vessels are known to respond to pH. A key example is in the lungs, where lung damage prevents these regions from taking up oxygen, making the area hypoxic and acidic. This causes vessels in the damaged area to constrict, reducing blood flow. However, the ways by which vessels respond to pH are not fully understood. Recently, the gene encoding a pH-sensing protein named PAC has been identified. PAC is an ion channel, forming a gated pore in cell membranes which opens in response to acidic pH and allows movement of chloride ions. Here we propose that PAC is important for vessels to respond to acidity. We will investigate this by measuring chloride currents in vascular cells, and by using a technique called myography which allows us to observe vessel constriction. We will apply these techniques to study channel structure, and explore potential drugs which target the channel. Overall, this will further our understanding of how blood vessels respond to pH. The long-term goal is enabling PAC to become a target for diseases of the lungs and other organs.

The transcription of almost all genes occurs via random transitions between active and inactive gene states. The net mRNA production is determined by the frequency and size of the resulting random bursts of mRNA synthesis, making gene expression a stochastic process. As a consequence, responses of individual immune cells upon bacterial infection are highly variable, resulting in different infection outcomes. For example, only a subset of innate immune macrophages may accurately recognize and kill invading bacteria. In this project, using mathematical modelling of transcriptional bursting, inference of single-cell genomics and live-cell imaging data, I aim to understand mechanisms involved in coordination of the innate immune responses to pathogen stimulation. In particular, I will study how the foodborne Listeria monocytogenes manipulates the host cell’s gene expression and signalling responses in order to establish a successful infection. I hypothesise that modulation of transcriptional bursting characteristics is a key control mechanism that allows the host to fine-tune its response to pathogen infection, and in turn enables the pathogen to implement its infection strategy. Mechanistic understanding of transcriptional dynamics induced by bacterial infection will inform strategies to improve infection outcomes in the future.

The dominantly inherited spinocerebellar ataxias (SCAs) are rare neurodegenerative disorders which primarily affect the cerebellum, the area of the brain responsible for motor coordination. Patients suffering from SCAs experience a progressive loss of coordination as the cerebellum degenerates. Key cerebellar cells known as Purkinje cells (PCs) are particularly affected, but not enough is known about the disease mechanisms and there is currently no cure. This project aims to investigate the role of two key proteins – TRPC3 and mGluR1 – in the molecular pathways underlying these disorders. mGluR1 is a cell-surface membrane protein which responds to the neurotransmitter glutamate at synapses and leads to activation of TRPC3, an ion channel which allows positively charged ions such as calcium into the cell. Mutations in both proteins have been identified in different subtypes of SCA; these mutations lead to increased protein activity and a subsequent toxic increase of intracellular calcium. Using computational techniques, in vitro studies, and a novel mGluR1 mutant mouse model, I will investigate the impact of mutant TRPC3 and mGluR1 on PCs, as well as the effects of novel TRPC3 inhibitors, to better understand the molecular mechanisms underlying SCAs and work towards new therapeutic approaches.

I will use routine healthcare data to undertake feasibility work to inform novel clinical trial design and trial populations in heterogeneous populations. There is an unmet need for this in intensive care research. I will frame this around critically ill patients with CVD following on from my PhD, however this will be applicable to other disease/pathologies with heterogeneous populations. I hypothesise that critically ill patients with co-existing CVD may benefit from higher oxygen delivery to the myocardium during critical illness, preventing myocardial infarction and subsequent cardiovascular mortality. Key goals: 1. Identification of current outcomes for critically ill patients with CVD. I will link high quality Scottish routine healthcare datasets for all admissions to Scottish ICUs 2010-2018. I will characterise cardiovascular and non-cardiovascular outcomes and healthcare trajectories for these patients. 2. Identification of patients in whom CVD has the highest attributable mortality. This group would be the target population for a cardiovascular intervention trial. I will use prediction modelling, latent variable analysis and propensity score analysis to address this. 3. Identification of intermediate short-term outcomes using both routinely collected time series ICU physiological data, national datasets and existing trial datasets. 4. Development of efficient trial methodology, including Bayesian adaptive trial designs. Novel clinical trial design is needed to reduce the burden of research on patients, reduce costs, and improve efficiency. High quality routine healthcare data can help identify at risk groups and quantify important outcomes. This work is framed around critically ill patients with cardiovascular disease (CVD), following on from my PhD. Patients with CVD have a vulnerable heart muscle at risk of damage due to lack of oxygen. Interventions to increase oxygen delivery may benefit these patients. I will describe critically ill patients with CVD using data routinely collected in all Scottish hospitals. I will explore rates of cardiovascular events and mortality, and identify groups where the cardiovascular risk is greatest, and therefore where cardiovascular interventions are most likely to be beneficial. I will explore the relationship between routinely collected "vital-signs" data in ICU and longer-term outcomes, and I will develop my expertise in efficient trial methodology.

Haematopoietic stem cells (HSCs) have been used for the treatment of diseases including immune deficiencies and metabolic disorders, as well as bone marrow repair after radiation treatment. In order to harvest their full potential, it is essential that we expand our understanding of HSC development and function. A vital part of HSC generation in the developing embryo is the transition of a subset of endothelial cells into blood cells. This occurs under the control of a multitude of factors within the cell and those present in the surrounding environment, the hematopoietic niche. The cell cycle has been shown to be an important involved in the cellular differentiation process, as some cells need to exit the cell cycle in order to undergo the transcriptional and morphological changes associated with differentiation. In my project I will investigate the impact of various factors as cell cycle regulators in this early differentiation of endothelial cells into haematopoietic cells. These studies will employ genetically modified mice, alongside state-of-the-art in-vitro and transcriptional profiling techniques such as single-cell RNA-sequencing. We expect our research to help elucidate the origin of HSCs and therefore contribute to our understanding of how to generate these cells in-vitro.

Malaria continues to pose a huge burden on African communities and hospitals. Despite scaled mosquito vector control coverage, many children across the central belt of Africa continue to be infected with the malaria parasite every year. Despite improved access to effective malaria medicines and diagnostics, malaria remains the leading cause of admission to paediatric wards at many hospitals, with children often admitted with life-threatening illness. New evidence is required to understand the relationship between rates of infection exposure and severe malaria in childhood and how these children reach emergency services. I propose to use a network of hospitals in Africa, to answer two related questions: a) how does the incidence and phenotype of severe malaria vary between malaria ecologies, at a time of increased control coverage? and b) what are the pathways to hospitalization with severe malaria? This work is intended to improve our ability to predict impacts of current and new tools aimed at reducing parasite exposure, identify points of improved referral care and demonstrate how upgraded hospital data can be used as epidemiological surveillance instruments to measure impacts of community-based control. Malaria continues to pose a huge burden on African communities and hospitals. Despite scaled mosquito vector control coverage, many children across the central belt of Africa continue to be infected with the malaria parasite every year. Despite improved access to effective malaria medicines and diagnostics, malaria remains the leading cause of admission to paediatric wards at many hospitals, with children often admitted with life-threatening illness. Work will take place at 16 hospitals in Kenya and Uganda and 20 additional hospitals in the Africa region, to define the relationship between how often a child is infected with the malaria parasite and the chances of being hospitalized with different forms of severe malaria; how children with severe malaria reach hospital; and how these surveillance data might lead to a best-practice model for future surveillance of severe disease, allowing countries to measure control impact.