BACKGROUND: Respiratory syncytial virus (RSV) is worldwide the most common cause of a type of chest infections in babies and toddlers called bronchiolitis, which can cause severe disease and occasionally death. Vaccination or specific treatment is not available. Due to treatment costs and costs for the wider society (e.g. days lost at work for parents/ carers) RSV is responsible for a major financial burden. 2% of all babies in the UK have to be admitted to hospital with RSV bronchiolitis and some of them develop very severe and sometimes life threatening disease which causes breathing to fail. These babies require breathing support where a machine inflates their lungs. This is usually only required for a few days, but in a third of these very severe cases the disease fails to improve quickly making longer machine breathing support necessary. Breathing problems in RSV bronchiolitis are thought to be due to very severe inflammation of the small ends of the breathing tubes in the lung. The mechanisms that maintain this inflammation and delay improvement of disease are not well understood. Work in mouse models suggests that two types if immune cells have important roles in lung inflammation after RSV infection; one of these are called T cells and the other dendritic cells (DCs) which are the main activators of T cells. PILOT DATA: In a pilot study of infants with RSV bronchiolitis who were on machine breathing support, we have recently detected substantial numbers of DCs and T cells in small lung washes. Lung washes of infants with healthy uninfected lungs do not contain these cells. HYPOTHESIS AND PROJECT PLaN: We hypothesise that activated lung DCs and T cells which can lead to inflammation, are responsible for continuing inflammation and the delay in improvement of disease in babies with longer lasting severe RSV bronchiolitis. We will take small lung washes from babies with severe RSV disease who are on machine breathing support comparing those who only need this support briefly to those who require it for a longer time. In the lung washes we will count DCs and different groups of T cells, measure the activation of DCs and their ability to activate T cells and we will find out if signal substances in the wash fluid are able to cause the development and / or activation of DCs. We will then use the mouse model of RSV infection to prove or disprove that DCs are required to maintain inflammation by taking DCs out of the mouse and then replacing them. OUTLOOK: If we find that activated lung DCs and associated T cells are responsible for maintaining inflammation and delaying improvement of disease in severe long lasting RSV bronchiolitis, these studies will identify lung DCs as a promising target for the development of new anti-inflammatory therapies for this condition. In addition numbers and properties of lung DC may also be useful as a marker to predict delayed resoltion of severe RSV disease.

Taking an overdose of paracetamol is very common. There are around 100,000 cases of overdose that attend Emergency Departments in the UK every year. Of these, around half need emergency treatment with an antidote to prevent liver damage. The number of patients needing treatment in the UK is similar to the number of people who break their hips, another very common medical emergency. Paracetamol is directly responsible for the deaths of 100-150 people per year in the UK, predominately young people with no significant co-morbidity. The antidote to paracetamol is called acetylcysteine. There are problems with its use: (i) it is only fully effective when administered within around 8 h of taking the overdose. It is ineffective if treatment is delayed more than about 20 h. Therefore, treatment must be started as quickly as possible in those patients at risk of liver damage (ii) Adverse drug reactions (ADRs): nausea/vomiting occurs in more than half of recipients and allergic reactions in about a third. (iii) Prolonged duration: The regime is time consuming, taking at least 21 h to complete, leading to significant hospital bed occupancy. The blood tests used by doctors to identify which patients need treatment with acetylcysteine are currently not optimal. In this project we will develop a new test that will rapidly identify patients who need treatment following paracetamol overdose. The key advantages of our new test are: 1. The marker of liver damage we will measure (cytokeratin-18, (K18)) is more sensitive than the current tests when the patient first arrives at hospital meaning doctors can pick up liver damage more quickly and start treatment promptly in those patients who need it. 2. Our assay is rapid (time to result 20 minutes) 3. Our assay works with a finger prick of blood rather than needing blood from a vein. 4. The assay is point of care which means the test is done in the Emergency Department rather than being sent to the hospital lab. This speeds up the process and eliminates the risk of blood samples being lost. 5. The assay is cheap, which means it can be used widely, including in low and middle income countries. In this project we will develop our K18 assay then perform a proof-of-concept clinical study in Emergency Departments to determine the accuracy of our unique solution to a common, but neglected, clinical problem.

40% of all patients in the intensive care unit (ICU) need a ventilator to support their lungs, with many associated complications. Currently the main indication of clinical deterioration is the presence/spreading of shadowing on the chest x- ray. This has many different causes (all requiring different treatments). There is a pressing need for rapid bedside tests to provide definitive diagnostic information about what is happening in the lungs themselves. Many studies have used blood markers, but in patients with multi-system disease these are not specific for the lung and the results are too slow to be useful in the rapidly-changing ICU setting. We will employ cutting-edge technology to pass a tiny optical fibre deep into the lungs of ventilated patients and spray a 'microdose' of an imaging agent that will tell us the reasons for the lung deterioration. This approach has the potential to rapidly determine, at the bedside, if the lung shadowing is due to inflammation. Such an approach could revolutionise the way we deal with the critically ill patient and provide rapid, point of care diagnostics that would help tailor the patient's management.

Most of the time, prescribing means getting medication from a doctor. Green health prescribing is becoming more popular across the UK as a new way that doctors and other healthcare staff help people of all ages improve their health and wellbeing. Instead of giving tablets for problems like depression or joint and muscle pains, green health prescribing links people to 'nature-based' outdoor activities they like that will benefit both their physical and mental health. Some activities are walking in woodlands, gardening, social community projects that link people together to help reduce loneliness, and open-air art classes to name a few. All activities are based on the preferences and appropriate fit for the individual. Thinking about more ways to get outside and enjoy fresh air is especially important as people age and find it more difficult to be active. And yet, very often people from poorer areas are not considered when creating new ways to improve health and green health prescribing is not easily accessible to all. This project will bring many people together, including experts, GPs, patients, and others who are interested in expanding green health prescribing for older people and especially for those who live in economically challenged areas. Research in this field shows many health benefits of engaging in 'nature-based' activities yet many healthcare workers, including GPs, lack knowledge of how to refer people to such activities. Therefore, our overall aim is to develop and test an easy to use, digital toolkit to help healthcare staff working in primary care to refer more older patients living in deprived areas to 'nature-based' activities. To do this we will hold workshops and talk with people covering a wide variety of perspectives to better understand what needs to be considered to develop the toolkit. We will develop the digital toolkit together with patients and healthcare workers and monitor the use of the toolkit in primary care. We will talk to patients who are referred to 'nature-based' activities to understand their views and monitor any changes in their health before and after they are referred. The goal is to make it easier for general practice staff to use green health prescribing and in the longer term to allow more older people from deprived areas to experience the health benefits that 'nature-based' activities provide.

The EPSRC IRC Proteus is made up of a group of world-leading scientists, engineers and clinicians. Interdisciplinarity is at our heart - we work across traditional boundaries linking together disciplines such as optical physics, chemical biology, biology and engineering to name but a few. The ambition and desire is to translate technologies to help patients - empowering clinicians to "see disease" in front of their eyes at the bedside and help them to make the right decisions and give the right treatments at the right time. This highly interdisciplinary collaboration driven by clinical need and pull, has led to the design, fabrication and testing in patients of a number of world-leading bedside-based technology platforms. Our technology platform combines advanced fibre optic technology (that can be readily be passed into the lung of patients) and highly sensitive detectors in association with highly sensitive fluorescent chemical reagents to diagnose disease. This allows clinicians to "view" inside the lung to detect bacteria or aberrant disease signatures of disease. Clinical pull: Intensive care unit (ICU) patients suffer high death and disability rates and are responsible for a disproportionate financial burden on the health service (the equivalent of 1% of USA GDP is spent on patients in intensive care). Potentially fatal lung complications are a common problem in ventilated ICU patients and doctors caring for these patients in the ICU face many challenges, often needing to make snap decisions without the information necessary to properly inform those decisions. The new technology platforms being developed by Proteus are helping doctors in the intensive care unit to make rapid and accurate diagnoses of patients, allowing them to direct and inform therapy and ensure patients get the right treatment, at the right time and quickly. Although our technology platforms have a focus at this time on being used in the intensive care unit, it is widely applicable to a wide range of lung conditions and other healthcare situations, such as bowel or pancreatic cancer. The next steps for the IRC are to take our technology into a new area in which different flavours of light can be used to diagnose disease - using the teams' highly advanced light sensors (that are able to count a single photon). In addition the proposal moves the IRC towards sustainability, creating a legacy from the EPSRC investment - accelerating the pathways to take new technology into patients, while developing commercial opportunities. In summary the EPSRC IRC Proteus has generated a new cohort of young interdisciplinary scientists trained in physical and biological sciences and engineering that have a full appreciation and practical experience of clinical translational and commercialisation pathways. They will be able to meet the challenges of converting advances in science and engineering into healthcare benefits with the development of a number of cutting-edge bedside technology platforms which will help doctors make rapid and accurate diagnoses. The team, in association with the partner Universities, have also begun to make major strides towards full sustainability of the IRC - making major impacts in the areas of clinical and commercial translation, with significant academic outputs and public engagement activities.