2.1 Unmet Clinical Need Bronchiectasis (BE) is a progressive respiratory (lung) disease characterised by cough, mucus and severe, recurrent bacterial chest infections with high rates of ill health, time off work and marked reductions in health-related quality-of-life. In almost half of cases, the cause of bronchiectasis is unknown (idiopathic) and treatment in these patients remains "best guess" or symptom driven. Bronchiectasis presents a huge challenge to patients and doctors because no effective treatment is available. Both the world's first national guidelines (authored by coapplicants of this proposal) and Cochrane "best evidence" review of Bronchiectasis confirms this situation, reporting that small single-centre studies with ill-defined patient groups have hampered the few attempts to study clinical interventions /drug trials, rendering them of unproven use. Previously the MRC sponsored UK trials in Bronchiectasis in the 1950s: Since then major developments have been sorely lacking. This partly reflects a feeling that BE is rare. However recent evidence is against this: In the UK and the US healthcare demands due to BE and mortality rates are increasing with 70,000+ hospital admissions in the UK 2011. Based on projections from US health insurance claims there are 100,000 US patients. We have limited UK data on how common this bronchiectasis is: Experts have however estimated 30-60,000 patients are affected in the UK but recent research suggests over 100,000 are affected. Whilst the small case series reported so far demonstrate that "unknown cause" (idiopathic) and post-infectious bronchiectasis are the leading causes, bronchiectasis can also complicate common lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) or immune problems e.g. Rheumatoid arthritis. Cystic Fibrosis is an inherited (genetic) form of bronchiectasis which like COPD associated bronchiectasis has different outcomes, microbiology and management needs from Bronchiectasis. Cystic fibrosis is rare (10,000 cases in the UK) yet has made significant gains through multicentre working and coordinating research. To date no large studies of the genetic causes of idiopathic bronchiectasis have been conducted as this requires large numbers of patients beyond that a single centre can provide. There is currently no registry of well characterised patients with Bronchiectasis anywhere outside the US. The US national registry was commenced recently and has 1200 patients that differ to UK patients. There is an urgent need to build a large cohort of UK patients with Bronchiectasis in which large enough studies can be undertaken; adding in a biobank is a key additional strength. Brief description of the Cohort and Partnership The cohort will comprise 3500 symptomatic adult patients with a High Resolution CT scans demonstrating bronchiectasis. Patients will be characterised on the basis of clinical history, clinical examination and detailed investigations that are already part of routine clinical care with yearly reviews. A DNA biobank (from a blood sample) will be collected and will form a world's first in bronchiectasis providing a unique resource allowing future genetic studies to identify underlying genetic causes & new targets for treatment. The partnership links 9 recruiting centres with established clinics & track records in Bronchiectasis research spread across the UK that have never had funding to work together. Additionally ground-breaking scientific partners with expertise in relevant areas will for the first time allow comprehensive mapping of the knowledge gaps. Future research will be able to use the strength of the assembled cohort; we can deliver a programme of clinical trials that address fundamental issues. We will therefore tackle three major unmet needs 1) Lack of expertise in the area, 2) Lack of a clinical evidence base 3) Basic science- attracting skilled scientists to work in the area.

Clinical pharmacologists are physicians and scientists whose focus is developing and understanding existing and new drug therapies; they work in a variety of settings in academia, the NHS, industry and government. In the clinical setting, they work directly with patients, participate in trials, and investigate how patients respond to drugs, including why certain patients develop side effects to drugs. The total number of academic clinical pharmacologists trained in the UK is small, and there is an imperative to continue to train more clinical pharmacologists and other specialists with expertise in clinical pharmacology who can work between academia, healthcare and industry. In 2010, the Government recognised that the provision of high quality-care and better interaction with Industry requires clinicians to be familiar with the relevant practices in clinical pharmacology. The universities of Liverpool and Manchester, in collaboration with industry partners, were awarded funding from the MRC to address this unmet need in clinical pharmacology: The North West England MRC Clinical Research Training Fellowship Programme in Clinical Pharmacology and Therapeutics. This programme has allowed 13 clinical fellows (high flying trainee doctors), rigorously selected from across all medical specialties e.g. dermatology, rheumatology, paediatrics etc., to study for PhDs on a variety of clinical pharmacology related research topics such as drug safety and stratified medicine - matching the right drug to the right patient. In addition to their research work the fellows received without walls training with industry and modular training in key aspects of clinical pharmacology. The programme has been a tremendous success with 56 scientific journal publications, 21 conference presentations, 13 prizes and interactions with 61 NHS Trusts. All fellows will also get a PhD. We now wish to renew the scheme with the MRC and with 4 industry partners - Lilly, Novartis, Roche and UCB Pharma, to appoint 13 more fellows. The previous successful format and structure will be retained as will joint leadership from the two universities. Refinements to the programme include: increasing the number of industry partners thereby allowing us to cover more therapeutic areas including cancer; lengthening of the recruitment process to give potential fellows, their supervisors and industry representatives more time to develop research projects with strong alignment; identification of a lead industry partner for each fellow from the beginning of the programme to develop a partnership from the outset; ensuring, where possible, that fellows can spend up to one year with the industry partner at their site(s) performing different aspects of their project. These changes will enhance fellows' training with industry, and also increase the input provided by industry in individual projects. There will be very strong patient and public engagement (as in the current scheme) with involvement of patients in the planning of research proposals, a number of public lectures and involvement of fellows at events such as the Manchester Science Spectacular. The Fellowship Programme will go some way to producing academics with expertise in clinical pharmacology and helping to optimise the safe, targeted prescribing of existing drugs and the development of new therapies for human disease.

Immune-mediated inflammatory diseases (IMIDs) are common medical conditions that cause substantial pain, distress, loss of function and early death. They are clinically diverse e.g. by variously targeting the skin, joints, or kidneys, but share some common genetic features, environmental triggers and inflammatory pathologic mechanisms. The IMIDs include rheumatoid arthritis (RA), psoriasis, systemic lupus erythematosus (SLE), Sjogren's syndrome, autoimmune hepatitis and primary biliary cirrhosis. Since the 1990s, biologic drugs and improved treatment strategies have revolutionised the treatment of a significant proportion of people with some IMIDs. However some IMIDs have not really progressed and even in those in which advances are notable, many patients do not yet respond to treatment or lose their responses over time - this in life long incurable diseases. Therefore, there remains great unmet clinical need in the IMID field. One exciting approach to improving outcomes is to apply the principles of precision medicine whereby patients will receive the 'right drug at the right time at the right dose' with minimal chance of having significant toxicity. Bringing precision medicine to IMIDs will require large datasets that integrate clinical information together with complex molecular datasets that can now be generated from the blood and damaged tissues that occur in IMIDs. In theory, by putting this information together we can create a 'molecular map' of a patient that allows very precise treatment decisions to be made that will bring better outcomes at reduced risk. Thus far however most IMID collections of such data have been specified for only one disease leading to a rather narrow approach to the broader inflammation medicine field. This proposal will revolutionise this scenario by bringing together many UK biobank and clinical cohort datasets into one single searchable and analysable entity, lead and coordinated by a consortium called IMIDBio-UK. IMIDBio-UK will generate a virtual information superhighway that will allow unprecedented access to information about IMIDs across the UK. The vision of the IMID-Bio-UK consortium is to harness the power of a rich reserve of biosamples, deeply phenotyped clinical cohorts, and high quality multi-omic data formed from a group of highly successful national stratified medicine programmes. These resources will be made available to researchers to study IMID biology and predict drug response, using molecular markers (biomarkers) to define common and unique mechanisms (endotypes) of disease progression and drug action. This will enable wider, safer use of biologics and new medicines across the IMID spectrum. By bringing together IMID samples and comparing data and clinical practice, we will optimise clinical pathways for common IMIDs, and provide much needed insight into biologic use in rarer or poorly characterised IMIDs, ultimately delivering patient benefit and health care savings.

While bulk chemicals are generally manufactured in efficient continuous processes, generating relatively little waste (E-factor <1-5), high value chemical products (fine chemicals, agrochemicals, pharmaceuticals) are usually manufactured in batch units, generating enormous waste (E-factor ca. 25-100). There is therefore a clear business advantage, if continuous manufacturing techniques could be adapted for use in these industries. Continuous processing can facilitate safe manipulation of potentially hazardous reagents that can nevertheless effect low-waste transformations, e.g. by efficient heat-transfer in very exothermic processes & minimising local inventory of hazardous material. Whilst most oxidations of bulk chemicals can be performed continuously using molecular oxygen in the gas phase, safety considerations (exotherm, formation of explosive mixtures) preclude its use in batch processes, particularly for thermally sensitive, involatile substrates found in fine chemical manufacture. This leads to two undesirable behaviours: a) adoption of costly, atom inefficient, waste-generating stoichiometric oxidants, with consequent negative environmental impact, and b) a tendency to avoid oxidative transformations by using inevitably less efficient 'workarounds'. It is therefore clear that oxidation is a potentially key enabling technology. The demonstration of cost-effective, safe, and efficient use of aerobic oxidation in an organic solvent would be transformative since a wide and increasing range of catalytic organic transformations would be considered seriously by industry, and not avoided due to safety concerns. The potential to drive further efficiency by 'telescoping' subsequent transformations would also be facilitated by continuous, work-up free oxidation. Thus, this project aims to instigate a step change in efficiency in the manufacture of many products by developing safe continuous oxidative transformations.

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.