Depression is a very common illness in people of all ages and many people with severe (clinically relevant) depression (called major depression) remain unwell after standard treatments with antidepressant drugs and talking therapies. The persistence of key symptoms of depression in these people makes it very difficult for them to function normally in their daily lives at work or at home and consequently contributes a lot to the high cost of looking after people with depression. Two types of persistent symptom are those related to mood (such as reduced ability to enjoy oneself) and those related to memory ('memory problems' such as forgetting things and difficulty in reasoning). There is therefore a great need to find new types of treatment. Since depression seems to be an illness with different causes and patterns of symptoms then it seems unlikely that a single new treatment will help everyone. A different approach is to find subgroups of people who seem to share the same cause of their illness. One such subgroup is people with high blood pressure (hypertension) since there is evidence that hypertension causes changes in the brain which may be an important cause of persisting symptoms in middle-aged and older people with major depression. Poorly treated hypertension is common since about a half of middle aged and older people have hypertension and half of these are not properly treated. Such hypertension changes the blood vessels which supply the brain and makes them more likely to fail to adequately supply the blood the brain needs. This is thought to cause parts of the brain not to function normally and lead to the persistent symptoms of depression and the disability this produces. Previous research shows that treating hypertension much more rapidly (over a few weeks) and with more drugs than usual can be done safely and leads not only to better control of blood pressure but to improved bloodflow in the brain. This is called rapid intensive BP lowering. The increase in bloodflow in the brain with this treatment might allow improvement of these persistent symptoms so people get completely well from their depression. However, this intensive BP lowering treatment has not been tried before in depression and so we don't know if doing this will help treat depression. We therefore propose to test this by comparing those who have normal treatment for their hypertension with people receiving the intensive BP lowering regime. We will recruit 60 people who have persistent symptoms of major depression and hypertension that needs better treatment. We will recruit people aged 50 to 80 because such hypertension is more common in this age group (about a quarter of such older adults have inadequately treated hypertension). These people will be randomly allocated to a standard hypertension treatment group (following NICE recommendations) or intensive hypertension treatment group. They will be seen regularly by a study doctor who will monitor their BP, check for any side-effects and alter their treatment depending on which treatment group they are in. Before beginning treatment and at the end of the 12 week study period different research staff, who do not know which treatment patients are receiving, will ask questions to rate patients' mood and 'memory symptoms' to compare the effects of intensive BP lowering with the standard hypertension treatment. They will also have a special brain scan to measure bloodflow in the brain before treatment and after 12 weeks and the scientist rating this again will not know which treatment they have had. We have chosen 12 weeks because studies of depression treatments usually allow 6 weeks to look for benefits and we know it takes 6 weeks to have a significant improvement in bloodflow in the brain with the rapid intensive BP lowering treatment.

Bacterial infections have great public health and economic impact. While at present most can be treated with antibiotics, doing so requires cases of bacterial infections to be recognised early so that they can be treated with the right drugs, while ensuring that antibiotics are not given unnecessarily. With the growth in antibiotic resistance, it is becoming essential that we use these drugs appropriately. At present growth of organisms from patient samples (e.g. urine), a process which takes 18 hours or more, is usually required before specific infecting bacteria can identified. A device able to rapidly detect the presence of bacteria in such samples, and identify which species are present, without this growth step would enable doctors to make rapid and informed decisions about when antibiotic treatment is necessary and which drug should be used. Here we propose to develop and evaluate a technology for identifying bacteria in patient samples. We will combine a novel series of chemical probes (fluorescent carbon dots, FCDs) that can attach to bacteria to make them fluorescent, with an ultra-sensitive quantum photonic sensor (QPS) developed by our industrial partner, FluoretiQ Ltd., that is able to detect these fluorescent bacteria in patient samples. In order to identify individual species of bacteria we will attach specific sugars (glycans) to the surface of FCDs, exploiting the fact that different bacteria recognise particular sugar molecules as part of the process of binding to the cells of their host. We base our trials around E coli bacteria causing urinary tract infections as these are common conditions that create high workloads for NHS laboratories (our clinical partner processes up to 1000 urine samples per day) and if improperly treated can lead to severe conditions such as sepsis. We will test this methodology by assessing in the laboratory whether specific bacteria can bind to specific glycan-FCDs. A second series of laboratory experiments will then seek to replicate patient samples by suspending bacteria derived from patients, and cultured human cells, in liquid media designed to mimic the composition of human urine and testing whether glycan-FCDs bind bacteria under these conditions. Finally, with support from clinical microbiologists, we will test whether the glycan-FCD/QPS method can detect and identify bacteria in urine samples from human patients and evaluate its effectiveness compared to methods currently in use. As future users they will also help us to optimise the method and associated instrumentation to ensure that this can be used easily in the clinical laboratory, and provide guidance on how to ensure that our method can be validated against appropriate comparators and demonstrated to comply with NHS quality management systems. In parallel we will test whether glycan-FCDs can be used as the basis for new treatments for bacterial infections. We have already demonstrated that FCDs can bind to and enter bacteria; preliminary experiments show that they can also kill bacteria, in a light-dependent process. Hence we will investigate whether our modified glycan-FCDs retain the ability to kill bacteria, and whether this killing is specific to the species targeted by the particular surface sugar. We will also attach antibiotics to the surface of FCDs to test whether this represents a method to deliver drugs to specific bacteria, many of which are difficult to kill with antibiotics because the drug is unable to enter the bacterial cell. The project will establish whether glycan-FCDs can form the basis of a rapid method for detecting infecting bacteria in patient samples in the clinical microbiology laboratory, and whether these can also be used to improve the effectiveness of antibiotics against many of these organisms. In so doing we will also develop new methods for synthesising complex sugar molecules that may be applied in multiple other research areas including drug and vaccine development.