Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Background: Recent rises in many human chronic diseases have been linked with changes in gut bacteria, but we know very little about how human health is influenced by the fungus that lives in our intestine. Children with inflammatory bowel disease (IBD) have increased amounts of fungus in the gut, and patients with genetic problems in anti-fungal immunity suffer from severe intestinal inflammation. Recent work by Dr. Neil McCarthy found that human gut tissue can be protected against fungus by a cell type called 'Vdelta2' which is common in humans but missing in mice. Vdelta2 cells are activated by an immune system protein called BTN which detects a bacterial chemical called HMB-PP. We think this could be an important new type of anti-fungal immune response that may not be working properly in patients with IBD. Hypothesis: Vdelta2 cells prevent fungus growth to protect against human gut inflammation. Aim 1. Identify how Vdelta2 cells restrict growth of Candida fungus. We will add the fungus Candida to human intestinal tissue and investigate how Vdelta2 cells stop fungal growth. Lots of scientific studies have been done on Candida, so this is a good fungus to use when setting-up our tests. We will add chemicals to block different types of Vdelta2 cell response and observe the effect on Candida growth. These experiments will tell us how Vdelta2 cells stop Candida so that we can later test how well this works with real gut fungus. Aim 2. Determine how Vdelta2 cells restrict growth of real human gut fungi. We will use 'dirty' gut tissue biopsies to test whether growth of real intestinal fungus can be blocked by Vdelta2 cells. Fungus experts will help us to identify the species that we collect from these experiments. This will tell us how Vdelta2 cells stop the growth of different types of fungus in the healthy human gut, so that we can next test if this immune response works differently in IBD. Aim 3. Test if Vdelta2 cells can restrict fungal growth in inflamed human gut. We will test whether Vdelta2 cells can control fungus in gut tissue from IBD patients, and whether inflammation changes how the fungus grows. We will also identify the fungal species to see if these differ between healthy and inflamed gut. Other experiments will test whether fungus grows more easily in tissue from IBD patients being treated with drugs that block Vdelta2 cell responses. This will give us important information about how Vdelta2 control of fungi works differently in patients with gut inflammation and how this might be changed by IBD therapies. We will then be in a good position to look for other factors that change the ability of Vdelta2 cells to limit fungal growth in the gut. Aim 4. Examine whether fungi can escape Vdelta2 responses by forming 'biofilms'. Gut fungi can team-up with certain types of bacteria to form thick organic layers called 'biofilms' that are difficult for the immune system to break down. We will therefore test if fungus can 'escape' Vdelta2 cell responses by forming biofilms with gut bacteria. These experiments will also be used to extend our research into other areas where fungal biofilms often cause major problems in human patients (medical implants, tissue transplants, and on plastic tubing used in hospitals). Aim 5. Test if Vdelta2 cells can prevent fungal growth in BTN-deficient patients. Vdelta2 cells are activated by the immune system protein BTN, so we will test whether Vdelta2 cells can still control fungal growth in blood from volunteers with genetic changes in BTN proteins. These experiments will generate important new information about how BTN proteins work in human patients so that we design better treatments in future. New treatments: Several drugs have already been produced that can strongly activate Vdelta2 T-cells in human tissues, so it is highly likely that Vdelta2 cell-targeted therapies could also be developed to increase patient protection against fungi and reduce inflammation in IBD.

Each year around 20,000 patients die after surgery in the UK, although the exact total is unclear. The most common causes of death involve the heart, including heart attack or heart failure. New data, from research using a sensitive blood test, suggest that ~10% of surgical patients suffer damage to the heart muscle (myocardial injury) and are more likely to die. This phenomenon is poorly understood. Urgent research is needed to find out how these complications arise and to develop new treatments to make surgery safer. Until recently some opinion leaders supported giving surgical patients beta-blockers (drugs which primarily lower heart rate). This reduced heart attacks after surgery, but was later found to increase the risk of stroke and death. The reason for this is unknown. One explanation is that elevated heart rate puts strain on the heart, increasing the demand for oxygen, which leads to damage. However, our understanding of how heart rate around the time of surgery relates to myocardial injury is incomplete. Heart rate during surgery has only been examined in a few studies. These looked at general cardiac complications, such as heart attacks, but did not use blood tests to look for myocardial injury. Heart rate before surgery has been linked to outcomes after cardiac operations, but this has not been fully investigated in non-cardiac surgery. Heart rate change during exercise may also be associated with surgical outcomes. However, the evidence is inconsistent. It is assumed that a fast heart rate before or during surgery is associated with myocardial injury. However, little evidence supports this assertion. In order to reduce cardiac complications after surgery, we must have a clear idea of the mechanism of myocardial injury. Understanding the role of heart rate before and during surgery is a crucial step in this process. This work will address an important unanswered question: are changes in heart rate associated with myocardial injury after surgery? Aim: To determine if patients with myocardial injury after surgery share common heart rate characteristics. Objectives: 1. Determine whether patterns of heart rate before or during surgery are associated with subsequent myocardial injury, and to define 'safe' heart rate ranges. 2. Investigate associations between exercise-induced changes in heart rate before surgery and subsequent myocardial injury. 3. Repeat analyses using major cardiac complications as an alternative endpoint to make this work comparable to other studies in the field. 4. Consider possible associations between myocardial injury and long-term outcomes. Methods: These objectives can only be addressed using large multi-centre datasets. Our group has unique access to four studies of surgical patients, making me ideally placed to answer these questions. Much of my work so far has involved collecting additional data for these studies, and adapting the datasets for use as part of my PhD. I will analyse these data using sophisticated statistical modelling. I will develop data management skills, learn complex statistical techniques and continue to conduct exercise tests for the METS study. I will be supported by a full-time statistician. Applications and benefits: 1. Develop a new model for identifying patients at risk of myocardial injury after surgery using pre-operative heart rate at rest and during exercise. This could enhance pre-operative assessment and improve clinical outcomes. 2. Improve clinical care by defining 'safe' heart rate ranges. Clinicians would be better able to identify patients at risk of myocardial injury and target therapy to control heart rate. 3. Develop new treatments to reduce myocardial injury. Heart rate targets could be used in two ways. (a) To improve drug dosing in clinical trials of heart rate treatments during surgery. (b) To improve recruitment to clinical trials by selecting the patients most at risk of myocardial injury.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

In the UK in 2006 coronary heart disease (CHD) caused over 16% of all deaths (94,381 out of 571,034). Of these, 95% (89,817) occurred in people over the age of fifty-five. The cost of health care was estimated at 3.2 billion (50 per capita), the additional economic cost due to lost working days has been estimated at 3.9 billion, and the cost of informal care of patients, at 1.8 billion.Coronary heart disease is an expensive killer. It places a huge burden on the taxpayer, costing nearly 9 billion per year which, with the acknowledged and inexorable trend toward an ageing population, will continue to grow year by year.The term CHD is one of a number that refer to the disease of atherosclerosis, wherein atheromatous plaques (fat and calcium deposits) accumulate in an artery wall to form a partial blockage and thereby cause myocardial ischaemia (inadequate blood flow to the heart muscle). In time, so-called vulnerable plaques undergo a sudden rupture and activate the body's blood-clotting mechanism. This occludes the artery and leads to (the most common form of) myocardial infarction: a 'heart attack'.There is currently no 'standard' screening tool for CHD. Patients who consult their doctor are already in some discomfort and the subsequent diagnosis requires the intervention of, and examination by, highly specialized medical practitioners.We propose a proof-of-concept investigation which connects computational applied mathematics to biotechnology. A successful outcome would provide a relatively cheap screening and diagnosis tool for CHD which could be targeted towards 'at-risk' population groups.An arterial stenosis has an acoustic signature (bruit) which is triggered by the resulting turbulent blood flow impacting on the artery walls. This causes low amplitude displacement waves (shear waves) to travel through the chest, which then manifest themselves as disturbances on the chest surface. These disturbances can be measured non-invasively by placing sensors on the skin.The generation of waves at the artery wall, their transmission through the chest, and their appearance at the chest surface, can all be described by a detailed mathematical model which describes the viscoelastic nature of human tissue (heart, lungs, muscle etc). The entire model can be simulated in software as a virtual chest thus obviating the need, in the early proof-of-concept development stage, for clinical tests on real people.We propose to develop and implement this virtual chest in theory and in software and to validate it by experiment in order to evaluate this approach in terms of an effective 'early days screening process' for an at-risk population. This task consists of two parts (the direct and inverse solver) both of which will be calibrated and tested by experiments on a realistic mechanical model of the chest.Specifically, the virtual chest will be formulated mathematically, implemented computationally and tested experimentally. An initial guess at the arterial disturbance will, via the direct problem, predict the surface disturbances at the chest wall. The difference between these and measured values will form an iterative inverse solver procedure which will modify the arterial disturbance until the difference between the measured and computed values is minimised.Once this direct-inverse solution iteration has finished, the surface measurements have been decoded by the mathematics and software into the arterial impacts. These can, potentially, be used to indicate the presence, size, location and morphology of the stenosis. It is this potential for diagnosis that this project seeks to investigate and evaluate through a fundamental study involving mathematical modelling and analysis, computational simulation, and validation through experimentation on chest phantoms filled with tissue-mimicking gel.