Low back pain affects 80% of the population at some point in their lives, costing millions to the UK economy. Approximately 40% of all low back pain cases are caused by disease in the joints in the spine, known as the intervertebral discs. These discs enable the spine to move, bend and flex and act to absorb load during normal daily activities. Intervertebral discs are similar in structure to a jam doughnut, containing a soft gel (like the jam) surrounded by a stiffer elastic ring (like the dough in the doughnut). Disease of these spinal discs which is known as disc degeneration, is the result of abnormal cell behaviour and mechanical damage, which results in an increased production of natural chemicals which can damage the disc and stimulate local nerves, making the back very painful. Current treatments for low back pain do not target the cause of disc degeneration so they do not cure the patient, they simply treat the symptoms to make it less painful. Right now, the only successful approach surgeons use is the removal of disc material (the jam) which has squeezed out of the disc which presses nearby nerves. This surgery prevents further compression of the nerve root, making it less painful, however this is only a suitable treatment for a small proportion of sufferers where the middle of the disc has squeezed out and compresses the nerves. Most patients with low back pain without nerve compression currently have very limited treatment options. We have developed a new material (NPgel) which is a liquid outside of the body and can be injected directly into the disc via a needle without the need for major surgery. Following the injection into the disc the material becomes a gel, with similar mechanical properties to intervertebral disc tissue. In addition the material can be mixed with stem cells taken from the patient's own bone marrow, which will allow the growth of healthy new disc material in the diseased discs. The material can also be mixed with chemicals that prevent the native diseased cells of the disc from causing any further damage. Our material has the potential to stop the disease getting worse, whilst helping the growth of new disc tissue using the stem cells we inject into the disc. We have previously tested our gel material and shown it has similar mechanical properties to intervertebral disc tissue, and does not kill human bone marrow stem cells when they are mixed together. In addition we have previously shown that cells taken from healthy people and mixed into the NPgel change their behaviour and start producing the materials from which the spinal disc is made. Before we are allowed to perform clinical trials in humans, a series of laboratory and animal experiments are essential. We have completed initial animal safety studies showing our gel is not toxic. Here, we aim to complete mechanical tests and determine the behaviour of the gel and injected cells in a laboratory set-up which mimics the environment of the human disc. Once successful, we aim to begin studies on large animals, which is necessary before we can conduct clinical trials of our gel on people. If all this goes well, it could be used as a treatment to cure disc disease in less than 10 years.

People with diabetes have more heart attacks and strokes than people without diabetes. The risk of heart disease and stroke is worse if diabetic control is poor. In diabetes, the level of sugar (glucose) in the blood tends to go very high, and is brought back to normal by tablets or injections of insulin. We already know that inadequate control of glucose levels tends to cause inflammation in the blood vessels, which results in furring up of these vessels, and causes strokes and heart attacks. Because of that clear link between poor control of diabetes and heart attacks, we've been focusing treatment on getting ever better control of sugar levels in the blood in our patients. However, we've started to realise that where the sugar level goes too low, this is also harmful. Acute drops in sugar levels are very unpleasant for patients, and are also associated with heart attacks and heart damage. We are beginning to understand that low blood sugar may cause inflammation in a similar way to high blood sugar levels. I want to see if this is true and if I can do things to prevent the harmful effects of low blood sugar. To do this, I'm going to set up an experiment in otherwise healthy people where we deliberately make their blood sugar low, then expose them to material purified from dead bacteria. This will test how low blood sugars affect the inflammatory response, and look at how the immune system handles stress and infection after episodes of low blood sugar. I will also set up models where I can see the exact mechanism of inflammation. I will look in mice that are prone to furring up of the arteries, and see if low blood sugars makes this artery damage worse. I will see whether, as I suspect, the low blood sugars cause the immune system to become overactive. Finally, I will see if I can prevent this low blood sugar-associated damage and help to develop treatments that could be used in humans to reduce heart attack risks. These studies together will work to show why and how low blood sugars are harmful to the heart and circulation. I hope that they will help us understand the very best levels of blood sugar to aim for in people with diabetes, and help us to understand how to minimise any harm that might occur when sugar levels go too low.

Platelets are the main type of blood cell involved in the formation of blood clots that cause heart attacks. We give antiplatelet drugs (aspirin, for example) to reduce the risk of another clot forming and causing another heart attack. Platelets are also known to have a role in inflammation and infection. In a recent large clinical trial of patients with heart attacks, known as the PLATO study, it was shown that patients treated with a new antiplatelet medication (ticagrelor) developed fewer lung infections, as well as fewer heart attacks, compared to the previous standard treatment (clopidogrel). There was evidence that this might partly explain the reduced risk of death after a heart attack when ticagrelor is used instead of clopidogrel. I therefore hypothesise that ticagrelor and clopidogrel have different effects on the immune response, which is, in part, due to their differing effect on platelet receptors and, in part, due to mechanisms unrelated to platelet receptors. I therefore plan to study the effect of ticagrelor and other antiplatelet agents on the immune response. This may help us to further improve the treatment of patients after a heart attack with the prospect of developing new drugs that have a better effect on the immune response. To date, no studies have been published that directly investigate the effect of ticagrelor on the immune response. In the first study, I will take blood from healthy volunteers and examine the effects of antiplatelet agents on white blood cells in detail, as they are the main type of cell involved in the immune response. I will study whether adding these antiplatelet agents to the blood affects white blood cell surface markers of activation and their ability to localise towards areas of infection. I will also study whether antiplatelet agents affect the ability of white blood cells to consume and kill bacteria. I will assess whether or not the antiplatelet agents interfere with platelets interactions with white blood cells. I will determine whether ticagrelor affects white blood cells through its known mechanisms of action by comparing its effects to other agents that also affect the same pathways. By performing the experiments in the presence and absence of platelets, I will also determine whether ticagrelor's effects are due to its effects on platelets and their subsequent interaction with white blood cells or whether it acts directly on white blood cells. In the second study, I will investigate the effect of antiplatelet medications on the immune response of healthy volunteers. Thirty healthy volunteers will be randomised to take ticagrelor, clopidogrel or no antiplatelet medication for one week (ten participants in each group). They will then attend the Sheffield Clinical Research Facility where I will use the safe, well-established method of injection of a very low dose of endotoxin (a component of bacteria rather than actual bacteria) into the bloodstream to stimulate an immune response. I will study whether ticagrelor or clopidogrel affect this immune response by measuring their effect on inflammatory markers, white blood cell function and the interaction of platelets with white blood cells. I will use the findings from my first study to guide which aspects of white blood cell function to examine in detail. The third study will involve patients with coronary artery disease who are due to undergo a stenting procedure to treat their narrowed coronary arteries. These patients are often started on clopidogrel prior to the procedure. I will take blood before and one week after the initiation of clopidogrel. I will study whether initiating clopidogrel causes any changes in patients' immune response, particularly the function of white blood cells and their interactions with platelets. I will also explore effects on white blood cell function in detail, guided by the findings from my first study.

Although people do not usually talk at the same time, simultaneous speech by two or more speakers is surprisingly frequent. In the typical conversations recorded for our recent AHRC -funded project it occupies 16% of total talking time, 41% of speaker turns being overlapped by another speaker. Simultaneous or overlapping talk is known to be a particular problem for individuals who have a hearing loss, even when using a conventional hearing aid or cochlear implant. Until recently, even in one-to-one settings many users would need optimum conditions in order to hold a satisfactory conversation, e.g. a quiet environment and the communication awareness of both participants that they should avoid talking at the same time. Professionals have steered clear of advising cochlear implant users about how to deal with situations of overlapping talk, on the basis that such a situation would be just too hard to handle. However, recent improvements in the signal processing strategies used in cochlear implants mean that it is now more realistic for users to attempt to engage in conversations where overlapping talk occurs. The aim of this follow-on project is to engage with a group of adult users of cochlear implants in order to develop useful training materials for handling overlapping talk in conversation. These materials will draw mainly on the outputs from our earlier project on overlapping talk, where we have developed a unique corpus and some key findings about overlapping talk in normal conversation. To the best of our knowledge, these will be the first materials that specifically address the problems raised by overlapping talk. The main objectives of this project are: 1. To identify the specific issues that overlapping talk raises for cochlear implant users This will be accomplished by direct questioning, via focus group and questionnaire survey; observation of recorded naturalistic conversations; and by exploring linguistic and cultural differences. 2. To develop ways of improving the experience of cochlear implant users This will involve devising training software and activities for cochlear implant users, in close collaboration with a group of cochlear implant users. The idea is that the implant user will be able to work with the materials on their own, and with their family members, at home. The software will make use of real examples from our collection of recorded conversations, where people are quite often talking in overlap. The software will focus on both listening and speaking. On the listening side, for example, it will allow users to simultaneously hear and visualise the flow of a conversation over time, by presenting speaker activity on a graphical timeline. On the speaking side, it will provide learning tasks that allow users to practise producing cues in their own speech. 3. To promote and disseminate the training software through a special event, a dedicated website and through existing channels for cochlear implant users and professionals. This project will engage with a small number of cochlear implant users initially, in order to develop software materials that can assist cochlear implant users when dealing with overlapping talk. The project is embedded in the local NHS cochlear implant service, in which two project team members are employed. Initially the outputs of the project will benefit users of that service. They will be disseminated more widely in the UK through the final dissemination event, and through participation in established national meetings for professionals and for cochlear implant users. Other team members will disseminate results at national and international conferences, which will raise awareness of the work within relevant academic communities. The project website will provide global access to the software materials: the project therefore has the potential to enhance the social participation of more than a quarter of a million cochlear implant users worldwide.

Medical diagnostic tests performed in high throughput, time critical NHS hospital laboratories are key to ensuring that clinicians can deliver high quality patient care. An important type of test, providing diagnosis for a wide range of diseases and illnesses, including cancer and heart problems, are immunoassays. These assays are based on nature's exquisite recognition apparatus: anti-bodies. Immunoassays involve attaching anti-bodies to a detector surface, waiting for the analyte (e.g. protein biomarkers or specific cells) of interest to become bound at the surface, and finally using electrical or optical methods to read-out the test result. However, due to the low concentration of many diagnostic analytes, the time spent waiting for sufficient amounts of analyte to diffuse to the detector to enable read-out can be significant. The consequence of these long incubation times is severe: for example automated hospital instruments that can handle thousands of samples per hour are rate limited by up to twenty minute waits for the immunoassay process to complete. As well as reducing throughput for routine analysis, these delays hamper the task of returning time critical diagnostic information to clinicians, such as screening for heart problems in patients with chest pain. Slow accumulation of analyte at an anti-body detector also limits developing methods that rely on isolating rare cells, such as circulating tumour cells to indicate the progression of cancer and enable personalised medicine. In this context, it is clear that the challenge of speeding up the rate at which analytes reach the detector is great, and that successfully achieving this can have significant Healthcare impact. Here we propose to develop a new approach to achieve rapid analyte detection, by exploiting micro-rockets; small scale devices that can generate rapid motion within fluids. Micro-rockets are powered by the asymmetrical release of bubbles from their surface. These bubbles are generated by enzymes decomposing fuel molecules in the surrounding solution. Micro-rockets will be used to speed up immunoassays in two ways. Firstly, micro-rockets' rapid motion and bubble generation stirs solutions, which is otherwise hard to achieve at small scales. This will be used to reduce the incubation times for immunoassays where anti-bodies are attached to the inside surfaces of a "micro-well" containing the analytical solution. By agitating the solution with micro-rockets, analytes will contact the well surfaces more frequently, speeding up detection. In the second method, the micro-rockets themselves will be covered with anti-bodies and used as a mobile detector, rapidly moving throughout the analytical sample. The fast motion will allow dilute quantities of analyte to be rapidly located. Analyte binding rate to anti-bodies and selectivity will also be improved by using a rapidly moving detector surface. At the end of the incubation period, magnets will be used to retrieve the dispersed rockets to enable analyte concentration to be determined using existing optical or electrical methods. Efficiently developing new micro-rockets with the required functions of analyte recognition and magnetic control will be aided by using ink-jet printing to allow micro-rocket composition, size, shape to be easily controlled and optimised. To demonstrate the utility of micro-rockets, experiments will be conducted to compare the speed at which micro-rockets can acquire analytes, compared to the existing diagnostic methods used by hospitals. Two diagnostic tests will be considered: one for protein molecules called "Troponins" that signal recent cardiac damage, and the second for circulating tumour cells. Establishing proof of micro-rocket effectiveness in this way will be a key step to attract interest from industrial partners who can assist the development of this technology to allow eventual deployment in hospitals.