This project will connect a large number of transnational academic resources to investigate the transmission success of the Escherichia coli ST131 clone. E. coli is the most common cause of urinary tract and bloodstream infections worldwide. A recent WHO report states that resistance to one of the most widely used antibiotic classes (fluoroquinolones [FQs]) is very widespread. In many parts of the world, FQs are now ineffective in more than half of patients. A single E. coli clone, ST131, is predominantly responsible for this global FQ-R and cephalosporin-R pandemic causing millions of antibiotic-resistant infections annually. It remains unclear which features of ST131 had resulted in the biggest antimicrobial resistance succes of the 2000s. We propose a combined European-Canadian consortium that will investigate the transmission dynamics of ST131. This study will explore the vertical and horizontal transmission of resistance and virulence genes and how they contributed to the transmission success of ST131 among humans, animals and different environments. The broad goal is to improve human health by better understanding managing infections due to multidrug resistant E. coli. The study will explore explanations for the high transmission rates and success of ST131. A famous quote from Stephen Hawking; "Intelligence is the ability to adapt to change". ST131 adapted rapidly to environmental changes; we need to know why and how. This project will serve as a model to predict what can possibly happen in the future with the continuing emergence of multidrug resistant clones among bacteria.

The three important things that are urgently required to fight SARS-CoV-2 are prevention, and protection & treatment. Prevention is being implemented by screening and self isolation but as the number of countries reporting cases has risen to 29, the lack of a licenced vaccine or therapeutic to protect patients is increasingly important. PHE propose to develop a model of infection to evaluate interventions. Additionally, we need to develop a model to assess safety as there are concerns that some vaccines or treatments may accidentally enhance the disease. We cannot ethically test this in humans and we cannot risk using vaccines without checking that the vaccine or therapy is safe. We know whole virus vaccines against SARS can accidentally make things worse and that vaccines need to be carefully designed to avoid this risk. This project will test if this complication is relevant for SARS-CoV-2 as well as SARS-CoV-1. Once we have established this, we will be able to offer the ability to test for this problem to all vaccine developers or authorities wishing to check this before use in humans.

Even though rates of overall crime have gone down in the UK over the last two decades, levels of serious violence in the past four years indicate a reversal of this trend. As a result, tackling serious violence has become a UK Government priority. One of the main ways to prevent youth involvement in violence is to identify and limit its early causes. It is well-known that individuals who have had traumatic or stressful experiences during childhood (referred to as adverse childhood experiences or childhood adversity) - such as being a victim of child abuse or having a parent who suffers from a mental illness - are more likely to engage in violence during adolescence and early adulthood. However, it is not clear which adverse experiences contribute most to violence nor whether they have a greater or lesser impact if experienced at different ages. The aim of our project is to answer these questions. We will address several research questions about the relationship between childhood adversity and serious violence during adolescence and early adulthood. We will consider a wide range of adversities including (but not restricted to) abuse (emotional, physical, and sexual), bullying, bereavement, and parental substance abuse, mental illness, and criminality. The choice of adversities to include in our analyses will be informed in part by the Ambassadors for Vulnerable Children and Young People on our steering group (these are young people who have experience of adversity in childhood, and who are employed by local authorities as ambassadors). We will identify whether any of these adversities have a particularly large impact on the risk of being involved in violent crime as a teenager or a young adult. Another goal is to determine whether there are critical periods during childhood where exposure to adversity - either in general or to one or more specific adversities - puts a child at particularly high risk. We also plan to investigate what role school attainment and attendance, mental health, and risk-taking behaviours (such as taking drugs) play in the relationship between childhood adversity and violence. To fulfil the goals of our project, we will use data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a world-leading data resource that has recorded extremely detailed information on the health, development and family circumstances of approximately 14,500 families living in the Bristol area since the early 1990s. Data collection started during pregnancy and has continued year on year ever since. The richness of this data resource makes it possible to answer questions that previous studies have been unable to address. We will link ALSPAC to data provided by Avon and Somerset police to generate the richest data set on violence and childhood adversity ever created in the UK, further enhancing this unique resource and enabling other researchers to investigate the causes and consequences of offending in new ways. Our findings will shed light on how and when we can best intervene with children (or families) at risk of violence. Addressing these key questions has the potential to help reduce rates of violent crime and to provide a better understanding of how childhood experience contributes to violence that will benefit perpetrators and their families, victims, practitioners, policy makers and the general public.

The threat posed by tick-borne diseases (TBD) in temperate regions such as the UK is growing rapidly. Human exposure is often linked to woodlands that support high densities of tick vectors and key wildlife hosts of these pathogens, and are intensively used by people. Climate change and government policies to increase woodland connectivity and improve human recreational access are highly likely to increase risks of TBD in the UK. To mitigate this threat we need to better understand effects of landscape structure on the movement and habitat use of those wildlife species which are key hosts for ticks and zoonotic pathogens. We also need to understand how humans use landscapes, where they are most at risk of exposure to tick bites and whether exposure could be prevented by habitat and host management. Given recent shifts across Europe in the distributions of TBD and tick populations, it is also critical to understand how longer term climate and land use changes may affect the introduction, establishment and spread of TBDs. Bringing together researchers from ecology, epidemiology, public health, and social science, TICKSOLVE aims to address these gaps. We will provide evidence for optimal greening and woodland restoration policies that will maximise benefits to biodiversity and human wellbeing while minimising human risks from current and future tick-borne diseases by: 1. Bringing together key national and regional level actors in health, land and biodiversity policy that interact with landscapes and TBD systems, to frame key risk scenarios and feasible environmental interventions for TBDs. 2. Better understanding how landscape structure shapes wildlife host distribution, habitat selection and movements and consequently impacts on ticks and TBD risk combining ecological surveys, pathogen genetics and computer modelling 3. Mapping how people use woodland landscapes and how this interacts with risk of encountering infected ticks to identify high risk areas for human exposure 4. Modelling how potential environmental barriers and interventions could reduce human exposure, integrating this knowledge of ecological interactions across the landscapes 5. Predicting how changes in woodland area and climate and patterns of bird migration may change TBD risks in the future 6. Co-developing interventions to minimise current and future TBD risks with stakeholders and policymakers that are locally appropriate. The research will focus on three emerging pathogens that pose a risk to the UK. Firstly Lyme disease (LD) which is currently present in the UK and can cause long-term debilitation. Reported cases of LD have increased 10-fold since 2000, probably linked to an expanding distribution of its main tick vector, Ixodes ricinus. Secondly, tick-borne encephalitis (TBE) which has been recently detected in ticks in the UK with evidence of suspected human cases in 2019. TBE uses the same tick vector and can cause severe neurological damage and death with some 5,000 to 12,000 reported cases each year in mainland Europe. Thirdly, Crimean Congo Haemorrhagic Fever (CCHF), caused by a WHO priority pathogen CCHF virus, with epidemic potential, is expanding north-westward in Europe. It's tick vector, Hyalomma spp., was found recently on migratory birds arriving in the UK. The TICKSOLVE project platform and approach of co-developing research, models and risk communication materials with stakeholders, accounting for diverse land management priorities, will enable formulation of future-proofed woodland and greening policies that minimise risks of these diverse TBDs. Furthermore, engagement with key global partners and networks through webinars and meetings will facilitate transfer of TICKSOLVE inter-disciplinary approaches to other rapidly changing tick-borne disease systems worldwide.

Bacterial infection is an increasing problem, even in the developed world. Over the past 60 years antibiotics have been used to treat bacterial infections with good success. Treating a disease is much easier, and cheaper, if we can detect its presence early in the lifecycle. Detecting a bacterial disease requires specialist systems such as diagnostic instrumentation and diagnostic kits. As new strains of bacteria emerge scientists need to develop new kits to detect these new pathogens, a process which is very time consuming. The EPSRC i-sense IRC is a multidisciplinary collaboration that aims to speed up the time it takes to diagnose infectious disease and is developing a range of novel diagnostic technology for both bacteria and viruses. The IRC is currently seeking "Next Steps" Core funding to extend the lifetime of the IRC by creating an "i-sense2" IRC with the ultimate aim of becoming a sustainable Centre of Excellence. Recently, the effectiveness of antibiotics has begun to decline due the emergence of bacterial strains that are resistant to the commonly used, or even all, antibiotics. In order to effectively treat diseases caused by antibiotic resistant bacteria it is not enough to simply diagnose the identity of the bacterial species. It is also necessary to know whether the causative bacteria are resistant to the antibiotics that would usually be prescribed to the patient to treat the disease. Allied with the i sense2 Core IRC, and dependent upon the outcomes described in that proposal, this "Next Steps" Plus project, "u-Sense", aims to build on the success of the i-sense IRC, to develop a new type of diagnostic system that will not only detect whether a patient sample contains a particular type of harmful bacterium but will also determine rapidly which antibiotics the bacterium is resistant to. Detecting antibiotic resistance in bacteria is complicated as there are many ways in which the bacteria can modify its physiology to become resistant. In the u-Sense Plus project we will capitalise on the fact that bacterial antibiotic resistance is encoded in certain genes, or gene modifications, in the organism's genome. We will modify a novel bioinformatics system that has been developed as part of the i-sense IRC, termed IDRIS, so that is able to pinpoint the genetic features in bacteria that encode the antibiotic resistance traits, by searching through genomic sequences. The system will also generate the sequences necessary for the production of new diagnostic technologies to find these bacteria in future, without the need to carry out DNA sequencing. This new diagnostic technology will be based on a technique known as recombinase polymerase amplification (RPA) which is able to specifically amplify and detect the DNA sequences necessary to establish whether the organism is resistant to a given antibiotic. The format of the test will be in the form of a paper or plastic strip, much like a pregnancy test, to which the test sample is applied. To ensure that the system is sensitive enough to detect low numbers of resistant organisms we will investigate a novel method of detecting DNA that indicates resistance using a method called Surface-Enhanced Raman Scattering (SERS). SERS has the potential to detect rapidly and simultaneously, in a multiplexed format, a number of potential DNA sequences which are responsible for conferring resistance. While SERS normally requires expensive laboratory equipment for the test format, we will research and develop a miniaturised, cost-effective device that will ultimately allow the SERS detection system to be used outside of the laboratory in the hospital, GP surgery or even in the home. Overall, the project will result in a rapid, cost effective system that can be used in a variety of settings and ultimately promises to have a major impact on human health and disease management in developed and developing countries alike.