Depression is a very common and potentially severe disorder. There are some treatments already available for depression, like the SSRI ("Prozac") class of anti-depressants. However, not all patients respond well to SSRI treatment: about a third of patients remain depressed. This is an area of medicine where there is a strong need to do a better job therapeutically. But there has been relatively slow progress in delivering new medicines in the last 15 years. We propose to explore and test a radically innovative approach to finding new drug treatments for depression (and potentially other psychiatric disorders). In this project, we will focus on the idea of using anti-inflammatory drugs (like aspirin) to treat depression, especially in patients who have not responded well to SSRI treatment. Recent scientific research has highlighted that inflammation is a major risk factor for depression. Some degree of depression is very common among patients with medical inflammatory disorders, like rheumatoid arthritis. Patients who are primarily depressed, and do not have a medical inflammatory disorder, generally have somewhat higher blood levels of inflammatory markers than non-depressed people. There is already some evidence that inflammation can block the therapeutic effects of SSRI anti-depressant drugs. And there have been some reports that anti-inflammatory drugs can have anti-depressant effects, at least in some patients with depression. On this basis, we will address 4 key questions that need to be answered more clearly and completely before we can consider potentially more serious investment in clinical development of new anti-inflammatory drugs for depressive symptoms linked to abnormal states of the immune system. 1) Is inflammation linked to SSRI treatment resistance? 2) Do anti-inflammatory drugs have anti-depressant effects? These questions will be addressed mainly by analysis of several, large, prior datasets. For example, we will use anonymised NHS data as well as clinical trial data released by the industrial partners (GlaxoSmithKline and Johnson & Johnson) to look for new evidence linking inflammation to depressive symptoms that respond poorly to SSRI treatment. To test a particular mechanistic reason why inflammation might cause SSRI treatment failure, we will also do a number of small lab experiments, using blood samples from healthy volunteers (University of Edinburgh and GSK). 3) Can we validate immune biomarkers for depression and treatment resistance? 4) Can we use biomarkers of depression to predict which anti-inflammatory drugs are most likely to be anti-depressant? Essentially what we mean by these questions is can we develop a blood test that we can use to predict which patients with depressive symptoms are most likely to benefit from which anti-inflammatory drug? To address these questions we will again priortise analysis or re-analysis of existing data including several large biomarker collections (released by GSK) and major studies conducted by the academic partners (University College London, King's College London). We will also conduct some additional lab experiments on human blood samples. We aim to complete this project within 2 years and then review the case for further investment in direct clinical trials of new anti-inflammatory drugs for treatment of depression in patients who have a blood test result indicating that they are inflamed and unlikely to respond well to existing anti-depressant drugs.

Immediate release (IR) tablets manufactured via direct compression are the most popular oral solid dosage forms to deliver active pharmaceutical ingredients (APIs) to patients. In order to absorb the drug molecues, the tablet needs to be disintegrated in the gastrointestinal (GI) tract to release the API crystals for dissolution. In vitro dissolution testing plays a vital role throughout the IR tablet product development life-cycle, aiming to probe API release profile to inform selection of formulation candidates and identify the impact of variants of the formulation and/or manufacturing processes on in vivo performance. Current compendial dissolution tests can neither reflect the actual conditions of the GI tract of a patient nor are they suitable to predict the drug release performance in vivo. The best way to achieve this is to model the tablet drug release profile based upon a thorough understanding of the underlying physics. However, the current dissolution model cannot predict the drug release from an IR tablet accurately because it assumes the spherical shape of the dissolving particles, without considering crystal morphology and its face specific dissolution properties. There is no direct connection between the disintegration and dissolution models, where the disintegration process is simply treated as a time delay function to initiate API dissolution, although IR tablet disintegration is considered as the key step in controlling API dissolution. Additionally, there is no mathematical model available which can accurately capture the overall physics of an IR tablet disintegration. The situation is further complicated by diversity of excipients used in the formulation, processing and manufacturing facilities and dissolution environments. This proposal will explore how the drug release profile of an IR tablet in the GI tract can be predicted based on the integrated mechanistic models for disintegration and novel API dissolution models, leading to a step change in our ability to model, analyse, and predict API release profiles. The challenges will be tackled by two leading research groups from De Montfort University and University of Surrey, representing a new multidisciplinary collaboration. The group brings together essential expertise in crystallisation science, molecular dynamics, formulation science, pharmaceutical manufacturing, and Raman spectroscopy/imaging. Through experimental and computational efforts, we will develop a modelling framework that accurately predicts the drug release behaviours of IR tablets in the GI tract. This will enable IR tablets to be designed and tested virtually to provide clinically relevant dissolution specifications for the desired clinical performance, having potential to revolutionise IR product design as well as the opportunity to speed up innovation to bring pharmaceuticals to market more quickly and cost-effectively and save lives.

Psoriasis is a common, chronic, potentially disfiguring disease that affects more than 1 million people in the UK. It can cause considerable psychological and social disability. In the past 10 years there has been a dramatic improvement in clinical outcomes for patients with severe psoriasis due to the introduction of a new class of injectable drugs called biologics. These work by targeting specific parts of the immune system which are important in causing psoriasis. However, these drugs are very expensive (estimated annual cost is £10,000) and it remains the case that a significant number of patients fail to respond adequately. If we could predict which patients will do well with a particular biologic drug then we could devise new treatment plans that would be personalised for each patient rather than the current system of "trial and error" prescribing. This would be of added benefit to society as a whole since it could result in significant cost savings to the NHS and aid the pharmaceutical industry in development of new drugs. The programme of research in the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium aims to use existing knowledge about psoriasis, both clinical and scientific, our unparalleled patient base coupled to involvement of patient organisations and state-of -the-art investigative tools to develop tests that we can use in the clinic to help direct personalised treatments. Specific questions we will ask are: i) do levels of a drug in the blood and a patient's immune response to that drug effect outcome; ii) are there specific changes in the skin and blood that predict which drug is likely to be more useful in a particular patient; iii) is there variation in a patient's genetic make-up, linked to psoriasis and how drugs work, that may predict response to treatment; and iv) does bringing all the information collected in i-iii above, though computer based data analysis, have more power to predict response to treatment? Successfully achieving such a goal requires a number of important criteria to be met. Perhaps most importantly we need consent from large numbers of patients to enter studies and provide samples of blood and skin. From the start of the study, we have engaged with the Psoriasis Association (patient organisation) to ensure the study met with their approval. As a consequence of patient engagement, in the UK we have arguably the world's leading safety registry for patients receiving biologic drugs for psoriasis. During the lifetime of our proposal, it will have accumulated comprehensive information on 7,000 patients including responses (good and bad) to biologics. The PSORT consortium includes representatives from 4 of the largest psoriasis clinics in the UK. These will provide the source for patient recruitment. The experiments will take advantage of several factors. First, in contrast to many other chronic diseases, change in psoriasis severity is simple and accurate to determine after starting therapy. Second, target organ tissue (i.e. skin) can be sampled in a minimally invasive way by skin biopsy (patient feedback tells us that this is acceptable to them). Third, internationally competitive expertise exists across the consortium between investigators and collaborators in all of the scientific disciplines required to successfully deliver the programme. Fourth, appropriate research infrastructure exist at each of the three main centres namely Manchester, Newcastle and London. This includes the registry itself (Manchester) and NHS funded facilities (Newcastle and London). Finally, we have developed an extensive network of pharmaceutical company partners who bring specific expertise and resources to the programme. Not only will this help in achieving the short term goals but it will also provide the necessary platform for translating the outcomes into clinically useful tests.

The Health e-Research Centre (HeRC) will turn under-used electronic health data in Northern England into new knowledge and improved healthcare. The under-used data sources include NHS and health science databases. HeRC will develop Health Informatics (HI) methods to clean up and link up the different data sources in ways that give a bigger picture of patterns of health and how patients respond to treatments. As well as linking data to data, HeRC will link data, analytical methods and experts together in order to make more timely and accurate findings. HeRC seeks to unlock the potential in the current islands of data, methods and expertise by joining them in three streams of work: 1) researching and developing HI methodology to make linked health data more available for analysis; 2) applying HI and related methodology, such as computational statistics, to solve previously intractable health science and service questions; and 3) training a new cadre of health informaticians to drive their methodology and its support of cutting-edge research. In contrast to data captured purely for research, data generated during the provision of healthcare are incomplete, inaccurate and subject to variation in recording. HeRC will explore the effects of patients and clinicians recording health and healthcare information together, for example where patients have on-line access to their GP records. HeRC will also prepare for the deluge of patient reported data from technologies such as smartphones. The practical questions that researchers face when using health records will be addressed, for example: Which data are available and where? Do I have permission to use the data? What can I learn from other who used similar data? Software will be developed to provide a research environment that embeds key methods so that they can be learnt and used. The research environment will also embed datasets, making them discoverable, whilst maintaining high standards of information governance. Five research programmes will maximise the value of using linked health data for research: The CoOP (Co-producing Observations with Patients) programme will consider how technologies can be made sufficiently 'engaging' for patients to use them frequently enough to provide important signals that are missing from usual healthcare records. The MOD (Missed Opportunities Detector) will enable linked data to be used to answer questions such as "for these patients who were admitted to hospital with a heart attack, was a prevention opportunity missed somewhere in the system, in public health, general practice or more specialist care?" Such information can be used to target resources to where a community needs them most. The SEA-3 (Scalable Endotypes of Allergies, Asthma and Andrology) will use HI and advanced statistics to help identify patients who appear to have a different form of asthma etc. where different kinds of prevention or treatment are needed. The DOT (Diabesity Outcome Translator) is about speeding up the answering of important questions by getting researchers in different places to work on different kinds of linked data together at the same time - tackling questions such as "what is the cancer risk of common drug treatments for diabetes?". The FIN (Feasibility Improvement Network) will look at how clinical trials for testing new treatments can be better planned so that the numbers of people who actually take part over a particular time period match the estimates that are made using linked data before the trial starts. To deliver HeRC, the consortium will integrate Northern England's top centres for statistics at Lancaster, public health at Liverpool, computer science at Manchester, and health economics/services research at York. This integration will extend to the NHS, building on a promising model (NHS e-lab) of patient, public and community involvement in the trustworthy reuse of health data for research.

Humanity faces critical global challenges in supplying clean energy, food, medicines and materials for a population forecast to reach 10 billion by 2050. Chemical synthesis will play a central role in addressing these challenges, as organic molecules are the fundamental building blocks of drugs, agrochemicals, and materials. However, the synthesis of most chemicals remains energy intensive, requiring fossil fuel feedstocks and endangered metal catalysts, and produces huge levels of waste - far from what is needed for a net-zero future. The essential transition to a circular chemistry economy will materialise only with a total re-think of organic synthesis: a 'Chemical Revolution' is urgently needed, for which Industry users will require a 'next generation' of suitably trained graduates. Without such change, the chemical industry will not be able to sustain the necessary pace of innovation in new chemical technologies, in the face of rapidly changing chemical regulation and policy, thus rendering this CDT crucial for the future of UK PLC. The Oxford-York ESPRC CDT in Chemical Synthesis for a Healthy Planet will deliver world-leading, ground-breaking training to a next generation of synthetic chemists, developing a sustainable, innovative chemistry culture that equips them to address major emerging and future global challenges in Human Health, Energy and Materials, and Food Security. In doing so, we meet a critical User Need, by supplying the workforce that is essential to create the innovative solutions UK chemical industries urgently require. Our overarching objective is to train students to supersede current practices for the synthesis of functional organic molecules by developing sustainable, field-advancing synthetic pathways to the complex targets needed in drug discovery, agrochemistry, and materials development. Our student cohorts will work together in a training period at both Oxford and York, before engaging with industry co-supervised projects in four research fields that develop innovative, sustainable transformations and synthetic strategies, and apply them in pharma, agro and materials chemistry contexts. With around a third of projects supervised jointly at Oxford and York, we will ensure a strong cross-institute connection; whole programme meetings and research field seminars will enable students across multiple cohorts to contribute to and elevate each others' science. Our association with the Eur1.25bn Center for the Transformation of Chemistry brings a unique connection for our students to a major initiative that is aiming to revolutionise chemical synthesis, as well its >140 chemical organisations across Europe. Our partnership with >10 SMEs and their Entrepreneurs-in-Residence will develop entrepreneurial skills and ensure students are exposed to the cutting-edge of chemical innovation in UK PLC. The applications and benefits from the CSHP CDT are many: Primarily, we will develop a UK-wide network of sustainably-minded, innovative chemists ready to meet the urgent User Needs of the UK chemical industry, bolstering this major sector of UK PLC. The scientists graduating from the CSHP CDT, the high-level science they produce, along with the related tools and technologies, will all contribute to the UK's ambitions as a Physical and Mathematical Sciences Powerhouse. We will set new benchmarks for graduate training by ensuring sustainability is embedded and visible in all research and its outputs, as well as influencing and connecting to graduates across the UK through biennial symposia. Our cohorts' work as Sustainability Ambassadors will permeate our exciting discoveries and the message of the future role of synthetic chemistry throughout society - from school to the general public. Above all, we believe this rigorous and inspirational programme is utterly essential if the UK is to remain globally competitive in the rapidly evolving chemistry landscape.