Overview Some people have a weakened immune system due to certain treatments, medicines or illnesses. A weakened immune system can make it more difficult to fight infections caused by viruses, meaning infections can persist for a long time. We have found some individuals can become persistently infected for many months with the virus that causes COVID-19 (also known as SARS-CoV-2). As the virus reproduces in our bodies it can mutate, which is where changes occur in the genetic code of the virus. These mutations cause 'variants' of the virus. Some variants of the virus may spread more easily, cause more severe disease, or make treatments and vaccination less effective. Persistent infection in individuals with a weakened immune system may allow variants to arise in their body, as the virus continues to reproduce and because their weakened immune system cannot kill new variants as they arise. As the virus develops new variants we can investigate how each sequential mutation changes the properties of the virus. Specifically this research will investigate how mutations change how the virus interacts with parts of our immune system. Genome sequencing to identify variants arising during persistent infection. We will use genome sequencing to identify the mutations that arise during persistent infection, especially looking for variants that are known to make the virus spread more easily or more deadly. Using deep genome sequencing we will look at the different variants that exist in persistently infected individuals, even those variants that exist only at low levels in the infected individual. This technique will allow us to see which variants arise over time and in response to different treatments for COVID-19 or medicines for other conditions affecting their immune system. Laboratory experiments with variants of the virus. From the patients' samples we can grow the virus in the laboratory to investigate how different variants behave in experiments. This will include experiments to see how variants escape control of the immune system, allowing a better understanding of the properties of different variants and how the variants interact with our bodies. We will use samples collected longitudinally from persistently infected individuals to see how each new mutation changes the properties of the variants, giving us insight into how the virus interacts with our cells and immune system. First we will investigate if mutations that arise during persistent infection decrease the ability of antibodies to inactivate the virus. This will use antibodies from the persistently infected individual, from others who recover from the virus, and from antibodies produced by vaccination. Second, we will see if variants that occur over time in persistently infected individuals increase resistance of the virus to immune responses in cells that limit infection, called interferon. By using virus from the same individuals but at different timepoints when there are new mutations it will allow us to investigate which variants confer the ability to escape these immune responses. More treatments for COVID-19 may become available in the coming months, such as antibody therapies. By following individuals over time we will be able to see if these treatments lead to new variants being produced. Scientists and clinicians carrying out this research. The research will be conducted by clinicians and scientists working at King's College London, Guy's and St. Thomas NHS Foundation Trust, and University College London. Summary We aim to understand how variants of the virus that causes COVID-19 develop by investigating the virus in individuals persistently infected. We will investigate which variants develop in these individuals, and then grow these variants in the laboratory to study how mutations affect immune responses.

Newborn infants are extremely vulnerable to brain injury. The cause and nature of newborn brain injuries varies widely, but one common factor is that infants who suffer a brain injury at birth often go on to develop cerebral palsy. Cerebral palsy is a group of permanent movement disorders that can severely limit the control of the muscles, and can have a devastating impact on quality of life. Cerebral palsy is the most common form of childhood disability in Europe and every year, approximately 1800 children in the UK are diagnosed with the condition. Cerebral palsy also has a significant impact on families and on society. It is estimated that the costs of care and support for people with cerebral palsy exceeds £1.4 Billion per year in the UK. The early diagnosis of cerebral palsy is critical. While there is no cure for the condition, there are a number of treatments that can improve an infant's long-term motor ability. During the first few weeks and months of life the brain is highly adaptable, which means it is likely to be at its most susceptible to treatment. If infants with abnormal motor development could be identified early, these treatments would have the greatest chance of success. At present, the majority of infants with cerebral palsy are not diagnosed until 1 or 2 years-of-age. By this point it is likely too late for treatment to have the best possible impact. In 2015, the government held an inquiry into issues surrounding cerebral palsy in the UK and highlighted the urgent need for more research to support the early and objective diagnosis of the condition. In healthy children and adults, the parts of the brain that control movement and receive somatosensory input (such as touch sensation) are organized like a map of the body. It has been shown that this organization is disrupted in children and adults with cerebral palsy. If we could monitor this disruption in the infant at the cot-side, it would be possible to provide an early and objective identification of infants who are developing abnormally. At present, there is no technology that can provide the precision, resolution, patient comfort or motion tolerance necessary to achieve this. The aim of this fellowship is to address these challenges and develop a new wearable functional brain imaging technology that will allow infant somatosensory and motor organization to be mapped at the cot-side. I will use flexible electronics to construct a miniaturized imaging array that will incorporate hundreds of emitters and detectors of near-infrared light to safely monitor infant brain function. This imaging array will be fixed into a soft, elastic head-cap that can be worn comfortably by a newborn baby. By designing and integrating an advanced form of motion tracking, and by developing novel signal processing approaches, I will maximize the precision and motion tolerance of this imaging technology to allow brain function to be mapped during touch stimulation and during natural movement. I will then validate this system using carefully controlled laboratory experiments and a comprehensive functional imaging study in healthy adults. Finally, I will translate this technology to the neonatal clinic and investigate the development of somatosensory and motor function in both healthy and brain-injured infants from preterm through to 6 months-of-age. In doing so, I aim to demonstrate a new approach to the objective identification and monitoring of infants with cerebral palsy.

A vital challenge for modern engineering is the modelling of the multiscale complex particle-liquid flows at the heart of numerous industrial and physiological processes. Industries dependent on such flows include food, chemicals, consumer goods, pharmaceuticals, oil, mining, river engineering, construction, power generation, biotechnology and medicine. Despite this large range of application areas, industrial practice and processes and clinical practice are neither efficient nor optimal because of a lack of fundamental understanding of the complex, multiscale phenomena involved. Flows may be turbulent or viscous and the carrier fluid may exhibit complex non-Newtonian rheology. Particles have various shapes, sizes, densities, bulk and surface properties. The ability to understand multiscale particle-liquid flows and predict them reliably would offer tremendous economic, scientific and societal benefits to the UK. Our fundamental understanding has so far been restricted by huge practical difficulties in imaging such flows and measuring their local properties. Mixtures of practical interest are often concentrated and opaque so that optical flow visualisation is impossible. We propose to overcome this problem using the technique of positron emission particle tracking (PEPT) which relies on radiation that penetrates opaque materials. We will advance the fundamental physics of multiscale particle-liquid flows in engineering and physiology through an exceptional experimental and theoretical effort, delivering a step change in our ability to image, model, analyse, and predict these flows. We will develop: (i) unique transformative Lagrangian PEPT diagnostic methodology for engineering and physiological flows; and (ii) innovative Lagrangian theories for the analysis of the phenomena uncovered by our measurements. The University of Birmingham Positron Imaging Centre, where the PEPT technique was invented, is unique in the world in its use of positron-emitting radioactive tracers to study engineering processes. In PEPT, a single radiolabelled particle is used as a flow follower and tracked through positron detection. Thus, each component in a multiphase particle-liquid flow can be labelled and its behaviour observed. Compared with leading optical laser techniques (e.g. LDV, PIV), PEPT has the enormous and unique advantage that it can image opaque fluids, and fluids inside opaque apparatus and the human body. To make the most of this and image fast, complex multiphase and multiscale flows in aqueous systems, improved tracking sensitivity and accuracy, dedicated new radiotracers and simultaneous tracking of multiple tracers must be developed, and new theoretical frameworks must be devised to analyse and interpret the data. By delivering this, we will enable multiscale complex particle-liquid flows to be studied with unprecedented detail and resolution in regimes and configurations hitherto inaccessible to any available technique. The benefits will be far-reaching since the range of applications of PEPT in engineering and medicine is extremely wide. This multidisciplinary Programme harnesses the synergy between world-leading centres at Birmingham (chemical engineering, physics), Edinburgh (applied maths) and King's College London (PET chemistry, biomedical engineering) to develop unique PEPT diagnostic tools, and to study experimentally and theoretically outstanding multiscale multiphase flow problems which can only be tackled by these tools. The advances of the Programme include: a novel microPEPT device designed to image microscale flows, and a novel medical PEPT validated in small animals for translation to humans. The investigators' combined strengths and the accompanying wide-ranging industrial collaborations, will ensure that this Programme leads to a paradigm-shift in complex multiphase flow research.