Cigarette smoking and harmful use of alcohol are major preventable causes of early death, disease, accidents and injury in the UK. Although the health effects of smoking have been widely recognised for decades, active and passive smoking still kill over 100,000 people and cause over 160,000 new cases of illness in children each year. Half of the 10 million smokers in the UK today will be killed by their smoking unless they stop. In contrast to smoking, alcohol consumption in the UK has increased markedly in the last thirty years. Ten million people in the UK now drink alcohol to harmful levels, and alcohol causes over 15,000 deaths, 1 million hospital admissions, and accidents and violence that together cost our society more than £20 billion each year. Like the effects of smoking, these harms affect the poorest in society most. Also like tobacco, alcohol consumption is driven by very powerful multinational industries with substantial political influence. It is therefore essential to find better ways to prevent smoking and harmful use of alcohol, now and in the future, and to prevent commercial interests from undermining these actions. Much has been learnt from the successes of reducing smoking prevalence, and many successful tobacco strategies can be applied to prevent alcohol harm. However, alcohol strategies must also take account of the fact that while smoking is dangerous at all levels, low levels of alcohol consumption do not have equivalent health harms to tobacco. So while tobacco policy can be pursued with the aim of eradicating smoking from society, alcohol policy has to aim to prevent consumption to levels that cause significant harm to the user, or to others. This proposal aims to address these problems by bringing together leading tobacco and alcohol researchers to build on success in tobacco research over the past five years by creating a new research centre, the UK Centre for Tobacco and Alcohol Studies (UKCTAS), to study new ways to prevent tobacco and alcohol-related harm, and promote their implementation. Since 2008 we have applied this approach in smoking prevention through the existing UK Centre for Tobacco Control Studies (UKCTCS), and achieved significant impacts on tobacco policy and practice (see www.ukctcs.org). We now propose to continue our tobacco work and to establish a major new focus on alcohol, by incorporating leading international alcohol researchers into the new Centre. Our work will aim to: 1. Understand and identify preventable reasons why people smoke or use alcohol to a harmful degree, and improve understanding of the health impacts of these behaviours 2. Understand and develop better population measures to to reduce smoking and harmful use of alcohol 3. Develop and implement better individual health interventions to prevent smoking and harmful use of alcohol 4. Develop and apply harm reduction strategies for those otherwise likely to continue to smoke or sustain harm from alcohol 5. Understand the tactics of the industry to encourage tobacco and alcohol consumption and thus undermine health policy and practice 6. Use the outcomes of our research to work, with other professional and public groups and individuals, to improve UK and international action to prevent smoking and harm from alcohol We will also aim to further develop our training and development of academic, policymaker and practitioner capacity for tobacco and alcohol work in the future, and to establish UKCTAS as a self sustaining Centre by the end of the five-year funding period. The main benefits of the Centre will be the achievement of sustained reductions in harms to individuals and society from tobacco and alcohol use.

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.

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.

The Government's 'Future of Mobility' and 'Road to Zero' strategies outline a second UK transport revolution, characterised by rapid decarbonisation, increased automation and enhanced connectivity. This radical transformation presents both opportunities and challenges for improving air quality over the next two decades, occurring in the context of disruptive changes in transport technology, increasing public environmental awareness and evolving transport behaviours. In this context, actions taken during the emerging transition phase will influence air pollutant sources and exposure patterns across indoor (i.e. vehicle, rail/bus) and outdoor (i.e. pavement, platform, bus station) land transport environments, with profound future implications for public health. We recognise this critical opportunity for encouraging policy foresight, cultivating scientific advancement and stimulating citizen engagement at the air quality, climate and health nexus. Our vision is to establish a diverse interdisciplinary network, connecting researchers across nine UK higher education and research institutions with >20 network partners, comprising commercial, public sector and non-profit organisations. We will establish sustainable connections to undertake co-definition of issues and opportunities and co-delivery of innovative, evidence-based solutions. We will deliver a varied portfolio of network activities including TRANSITION summits, problem-solving workshops, hackathons, discovery studies, site visits, policy engagement events and creative outreach activities at transport locations. Thus the network partners will achieve the ambitious but achievable goal of directly shaping future air quality, climate and transport policy, reflecting the ambitions of the UKRI SPF Clean Air Analysis and Solutions programme.

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.