CONTEXT Chronic obstructive pulmonary disease (COPD) is a lung disease that is usually caused by smoking. People with COPD feel short of breath and have a chronic cough. The condition worsens steadily, limiting exercise and normal activities. These symptoms are caused by damage to the breathing tubes which carry air into the lungs and to the air sacs where oxygen crosses from the air into the blood. In the UK, COPD affects around 3.7 million people and causes over 30,000 deaths per year. It is the fourth most common cause of death worldwide. From time to time, COPD patients experience attacks, where they feel more breathless or cough up more phlegm (sputum). These attacks are called exacerbations and are often set off by infection. Exacerbations are major events for people with COPD. During an exacerbation, COPD patients need more treatment and may require admission to hospital. It can take weeks to recover fully from an exacerbation and some people never get back to how they were before the exacerbation. Unfortunately, despite current best treatment, many people die during the weeks, months and years after an exacerbation. New treatments are required to prevent deaths and speed up recovery after exacerbations. AIM The overall aim of our research is to see whether a drug called metformin can help COPD patients recover more quickly or survive longer after an exacerbation. Metformin is usually used to lower blood sugar in patients with diabetes. We have found that most patients admitted to hospital for COPD exacerbations have high blood sugar. The higher their blood sugar, the less well they recover from their exacerbation. We therefore think that using metformin to lower blood sugar in COPD patients during exacerbations could improve recovery. Metformin can also dampen down inflammation and mop-up harmful substances called free radicals. These effects could be beneficial for COPD patients with exacerbations. To test our theory we looked back at hospital records of COPD patients. We found that patients leaving hospital on metformin survived longer than those without metformin. This finding is encouraging, but must be interpreted cautiously, as there are several possible explanations. We now need to test the benefits of metformin in clinical trials. THE STUDY Patients admitted to hospital with COPD exacerbations will be invited to take part in the trial. Those who agree will receive all the usual treatments for COPD exacerbations. In addition, they will take a study treatment as a capsule twice daily for 1 month. Participants will be allocated by chance (randomisation) to receive metformin or no medicine (placebo) in the capsule. Neither we nor the participants will know who is taking what. This will allow us to make an unbiased assessment of the effects of metformin. We will assess the benefits of metformin by comparing blood glucose between patients during hospital admission and over the whole study using a test called fructosamine. We will check that people taking metformin don't become more unwell or develop dangerous side effects and that they can tolerate the tablets. We will also get some idea of whether metformin helps them recover more quickly from their COPD exacerbations. However this will need to be tested more thoroughly in the future in a larger group of patients. POTENTIAL BENEFITS At the end of this trial we will know whether metformin can lower blood sugar safely in patients with COPD exacerbations. The next step will be to test metformin in a larger number of COPD patients to see if it can help them to recover more quickly from their exacerbations. Metformin is cheap and widely available. If it works it could quickly be adopted as a new treatment for these patients.

What is this research project about? We will investigate to what extent exposure to air pollution during pregnancy and the first five years of life and poor housing conditions (such as overcrowding and damp/mould) contribute to hospital admissions for respiratory tract infections (RTIs) in children less than five years old. Why are we doing this research? RTIs, including bronchiolitis, pneumonia and croup, are the most common reason for hospital admission in young children in the UK. These admissions are stressful for children, their parents and costly for the National Health Service (NHS). Being admitted to hospital with an RTI during the first few years of life is also associated with the development of chronic respiratory problems, such as asthma, in later childhood. Previous research has found that children from poor backgrounds are more likely to need an RTI admission, but it is not clear which aspects of children's living conditions make the largest contribution to RTI hospital admissions. In this study, we will examine whether exposure to air pollution in the womb or during early childhood, and poor housing conditions are associated with a child's risk of being admitted to hospital with an RTI. Also, we will look at how many RTI admissions could be prevented in the UK if we reduced air pollution and/or improved housing conditions for families with young children. How are we going to do it? We will use data collected from birth certificates, linked to maternity records and hospital admission data for all children born in England between 2005 and 2014, and Scotland between 1997 and 2019: 8 million children in total. We will link in data about children's air pollution exposure during pregnancy and childhood, building characteristics, and information about housing and socio-economic background from the 2011 Census. All data will be kept on secure servers and linked using methods that protect the identities of mothers and children. We will use these data to examine whether exposure to air pollution and poor housing conditions are associated with an increased risk of being admitted to hospital with an RTI during the first five years of life. We will use statistical methods that allow us to take into account whether children have other underlying risk factors for RTI hospital admissions, such as chronic health problems. We will also make sure that other researchers can access these datasets to carry out maternal and child health research in the future.

Mesothelioma is an aggressive and largely untreatable cancer of the lung lining, mainly caused by environmental exposure to asbestos. New treatments, or new approaches to treatment, are urgently required. We can now read detailed information about genetic changes from a small sample of a patient's cancer, which can then be used to make decisions about the most effective anti-cancer drugs to give to an individual patient as "precision medicine". Recent studies have revealed the type and frequency of genetic changes that occur in mesothelioma, which may help in predicting new treatments. In many cancers, genetic changes switch on "oncogenes", which accelerate the speed with which cancer cells divide into two, driving tumour growth. Many cancer treatments use drugs that directly block the activity of oncogenes to prevent this uncontrolled tumour growth. However, mesothelioma is unusual, as there are no common oncogene mutations. Instead, genetic changes mostly occur in "tumour suppressor" genes, disabling proteins that would normally apply a brake to slow down dividing cells and so prevent tumour growth. This presents a difficult challenge for finding ways to treat mesothelioma, as we need to fully understand how each specific tumour suppressor mutation alters the cancerous behaviour of mesothelioma cells, in order to find an Achilles' heel that we might be able to target with drugs. Ultimately, we also need to develop the best laboratory models in which to test the drugs, before they can be given to mesothelioma patients. Disabling mutations of the tumour suppressor BAP1 are found in more than half of all mesotheliomas. Normally, BAP1 controls the production and destruction of other proteins within the cell. Therefore, in mesothelioma without BAP1, there are potentially changes in the amounts of many different proteins that could affect cancerous behaviour. Using cells with gene-edited mutations of BAP1, we identified many of these protein changes. We found that BAP1 mutation not only affects proteins that alter the growth of cancer cells, but also proteins that control how they move, gain access to blood vessels, and spread around the body. We are currently evaluating which of these proteins make mesothelioma cells more sensitive to specific anti-cancer drugs. However, we need to test these drugs in models that can provide a good replica of human mesothelioma growth and spread. To do this, we will develop a chick embryo model of mesothelioma, as a replacement for currently used mouse models. The chick embryo model is classified as non-protected under the Animals Scientific Procedures Act, and so is a useful technique to replace testing in animals. It has many additional advantages over mouse models, including cost effectiveness, accessibility and speed. It is an excellent model to study the growth and spread of tumour cells, as they can be easily engrafted onto the "chorioallantoic membrane". This is an accessible surface, located outside the chick embryo directly beneath the eggshell, with a good supply of blood vessels. Within a few days, a small tumour develops, which can spread across and into the membrane, potentially accessing blood vessels to spread to specific organs. Importantly, new drug treatments can be readily tested in the chick embryo model, and the tumour cells imaged over time to assess their survival and behaviour. We will use the chick embryo model to grow mesothelioma cells, with and without BAP1 mutation, and evaluate therapeutic responses to our candidate drugs. Successful outcomes will suggest new drugs for inclusion in precision medicine trials in mesothelioma patients. During the project, we will develop the first standard operating procedures to generate and monitor mesothelioma tumours in this model. We will make these protocols, and key reagents, available to the mesothelioma research community, encouraging widespread replacement of murine models.

Summary In this proposal, we aim to revolutionise the way that pollen is measured, model the spatial and temporal deposition of different species of grass pollen and identify linkages to human health. In the UK population ~5% suffer from allergic reactions (ranging from hay fever to asthma attacks) and further 22% are sensitised to grass pollen (i.e. they have antibodies capable of causing reactions). Grass pollen is the single most important outdoor aeroallergen closely followed by tree pollen. Similar to tree pollen, sensitivity towards grass pollen varies between species. However, we have no way of detecting, modelling or forecasting the aerial-dispersion of pollen from different species of grass. These limitations are due to complete lack of detailed source maps reflecting both the presence and abundance of different species of grass and because grass pollen, contrary to tree pollen, can not be separated into species using traditional observational methods. Therefore, combinations of the approximately 150 different species of grass pollen that are monitored (using approaches that remain unchanged since World War II) are lumped into a single category and form the foundation of the pollen forecast. In this project we will both develop new models and new methods of detection that address these major shortcomings. The present situation means that hay fever suffers and health practitioners do not know what species, or combination of species cause present symptoms. Individuals can be tested for against particular grass species, but there are ca. 16 million people sensitised to grass pollen, allergic reactions are complex and testing the population against 150 different grass species species is an overwhelming task. The alternative is to take an environmental approach by developing exposure models and identify the environmental conditions that induce the allergic response, which then can be profiled to human health. Recent developments in the generation of a UK plant DNA "barcode" library and DNA sequencing technologies have provided a unique and timely opportunity to identify the species, or combinations of species of grass that are associated with the allergic response. The important development of the UK plant DNA barcode library now gives us the ability to not only target individual species in molecular genetic analyses, but also assign identities to sequences derived from very high throughput molecular meta-analyses of complex mixtures of pollen grains. Similarly, recent developments in next generation air quality models and the advancement of computing power, has enabled the extension of these models into aerobiology in order to study the release, dispersion and transformation of bioaerosols and how this affects the environment. Here, a group of multidisciplinary researchers specialising in aerobiological modelling, DNA barcoding/molecular genetic identification and environmental health have teamed up with the UK Met Office in order to (a.) develop a novel and high-throughput molecular genetic way of measuring the geographical spread and abundance of different allergenic species of grass across the summer months, (b.) develop novel pollen bio-aerosol models and (c.) identify which species, or combinations of species are linked to the most severe public health outcomes of the allergic response (i.e. asthma). The work will provide information that healthcare professionals and charities will be able to translate into helping individuals live healthier and more productive lives. The information will help those with long term health conditions effectively self-manage their conditions, contribute more effectively to the workplace and be less reliant on the health system with accompanied economic benefits. Employers will benefit from greater employer productivity and pharmaceutical companies will be able to better target the distribution of their products and therapies.

As minimally invasive surgery is being adopted in a wide range of surgical specialties, there is a growing trend in precision surgery, focussing on early malignancies with minimally invasive intervention and greater consideration on patient recovery and quality of life. This requires the development of sophisticated micro-instruments integrated with imaging, sensing, and robotic assistance for micro-surgical tasks. This facilitates management of increasingly small lesions in more remote locations with complex anatomical surroundings. The proposed programme grant seeks to harness different strands of engineering and clinical developments in micro-robotics for precision surgery to establish platform technologies in: 1) micro-fabrication and actuation; 2) micro-manipulation and cooperative robotic control; 3) in vivo microscopic imaging and sensing; 4) intra-operative vision and navigation; and 5) endoluminal platform development. By using endoluminal micro-surgical intervention for gastrointestinal, cardiovascular, lung and breast cancer as the exemplars, we aim to establish a strong technological platform with extensive industrial and wider academic collaboration to support seamless translational research and surgical innovation that are unique internationally.