Every six minutes a mother dies from excessive bleeding after childbirth in low-resource countries, in the prime of her life and often leaving behind a young family. When a mother dies in childbirth, her infant has less than a 20% chance of surviving past the first month. Excessive bleeding after childbirth, or postpartum haemorrhage (PPH), is the commonest reason why mothers die worldwide. Effective treatment can stop bleeding in most women. However, those who continue to bleed despite 'first response' treatment are thought to have refractory PPH and are the women who die or suffer major complications. We have developed a provisional management package for these women, called the 'PPH ReAct' package. We wish to refine this management package, develop an implementation strategy for this, field-test these and finally pilot the approach in 5 health facilities in Kenya. The WHO published "Recommendations for the Prevention and Treatment of Postpartum Hemorrhage" in 2012 to provide evidence-informed recommendations for managing PPH. However, adherence to these recommendations is currently limited by a number of challenges. Challenges and proposed solutions 1) Many women continue to bleed despite 'first response' management of PPH --> Solution: A refractory PPH treatment package 2) Delayed or inconsistent use of treatments for refractory PPH management --> Solution: A refractory PPH management (the PPH ReAct) package that uses simplified approaches and a checklist to ensure consistent and timely assessments and treatments. 3) Many care providers and organisations struggle to provide effective care for women with refractory PPH, despite treatments being available --> Solution: Deeper understanding of challenges, and a strategy for changing behaviours of healthcare professionals and organisations using behavioural science frameworks. 4) Lack of evidence and confidence that the proposed approach can improve usage of effective treatments for treatment of refractory PPH --> Solution: A study for the refractory PPH treatment package to ensure an increase usage of life-saving treatment by the healthcare professionals and organisations. This study could generate the necessary evidence that will give healthcare practitioners and policy makers the confidence to implement and scale-up the programme. 5) Limited scale-up and coverage --> Solution: Engagement of strong partners: World Health Organisation, Jhpiego, Behavioural Scientists, Health Ministries and Concept Foundation Our aim is to develop, refine and evaluate an effective approach to managing refractory PPH. Despite concentrated efforts, PPH remains the leading cause why mothers die or suffer major complications during childbirth. Most women with PPH respond to initial treatments. However, a substantial number of women do not, and these are the women who suffer die or suffer major complications. There is an unmet need to define the optimal approach for managing refractory PPH. Furthermore, a management approach could achieve its intended goals only if it is widely accepted and used in everyday practice; thus a meaningful strategy for implementing this approach is necessary. We therefore propose the development, refinement and piloting of a refractory PPH management package and implementation strategy.

While the immune system protects us from infection by viruses and bacteria, the weapons used to destroy such pathogens can also attack our own bodies resulting in autoimmune diseases. Collectively, these diseases are relatively common and include type 1 diabetes, rheumatoid arthritis and multiple sclerosis along with numerous other conditions. Genetic evidence suggests that these diseases are regulated by common pathways. We are trying to understand how a key mechanism, involving a protein called CTLA-4, works to control the immune system. People with a faulty CTLA-4 gene have poorly controlled immune systems and can develop multiple autoimmune diseases. However, our understanding of exactly what CTLA-4 does is still limited. In this proposal we will increase our knowledge of how CTLA-4 works and test ways to improve its function so we can develop better treatments for autoimmune diseases. CTLA-4 works together with 3 other molecules (CD28, CD80, CD86) that are expressed on cells of the immune system, forming a type of thermostat for controlling immune activity. Preventing CTLA-4 function "turns up" the immune response and has generated a major breakthrough in cancer therapy, where the immune system can be used to attack cancer. However, the side effects of this treatment are autoimmune responses that can damage the body. We wish to develop a better understanding of how we might enhance CTLA-4 function and "turn down" the immune response to treat autoimmune conditions. Both CD28 and CTLA-4 are expressed on T cells, specialised white blood cells that play a key role in triggering immune responses. CD28 promotes T cell activation and without it immune responses are feeble. On the other hand, CTLA-4 regulates T cell responses, to prevent them getting out of hand. A precise understanding of how CTLA-4 works with its partners would enable us to change the strength of immune responses as desired, for example increasing immune responses against tumours or decreasing unwanted immune responses in autoimmune conditions. The challenge we face is that the pathway is complex. Although CD28 and CTLA-4 have opposing functions, they share the same binding partners, CD80 and CD86. In our previous work we found that CTLA-4 behaves in an unusual way, essentially "eating" CD80 and CD86 so they cannot promote immune responses via CD28. This "eating" behaviour has been difficult to study, but with previous funding we have now generated novel research tools that allow us to visualise it in a different way. These tools will be used in the present proposal to allow us to see for the first time how CTLA-4 captures its ligands at different places in the body, both under normal conditions and during the course of an autoimmune disease. We have also discovered key differences in how the two binding partners, CD80 and CD86, affect CTLA-4 behaviour during the "eating" process. We now plan to use this understanding to test ways to improve CTLA-4 function and enhance immune suppression. We will also investigate how the upregulation of CD86 and CD80 is controlled, looking at how cells communicate between each other to collectively reach a decision. This cooperation between cells may affect CTLA-4 function and could explain why regulation sometimes fails. Lastly, soluble CTLA-4 (abatacept) is used clinically in rheumatoid arthritis but performs rather poorly in other autoimmune diseases. Our work has generated new ideas on how to overcome this limitation and we will test these with the goal of generating more effective immune suppression. Overall, this programme will help us to develop better therapies for autoimmune conditions, at a time when these diseases are affecting more and more individuals.

A living cell, e.g. a bacterium, is an information-processing machine. It is composed of a series of sub-systems that work in concert by sensing external stimuli, assessing its own internal states and making decisions through a network of complex and interlinked biological regulatory networks (BRN) motifs that act as the bacterium neural network. A bacterium's decision making processes often result in a variety of outputs, e.g. the creation of more cells, chemotaxis, bio-film formation, etc. It was recently shown that cells not only react to their environment but that they can even predict environmental changes. The emerging discipline of Synthetic Biology (SB), considers the cell to be a machine that can be built -from parts- in a manner similar to, e.g., electronic circuits, airplanes, etc. SB has sought to co-opt cells for nano-computation and nano-manufacturing purposes. During this leadership fellowship programme of research I will aim at making E.coli bacteria much more easily to program and hence harness for useful purposes. In order to achieve this, I plan to use the tools, methodologies and resources that computer science created for writing computer programs and find ways of making them useful in the microbiology laboratory.

Older age groups are the fastest growing sector of the population because of the post-war baby boom population and increased life expectancy. Neurological changes are commonly observed in ageing populations including Alzheimer's Disease (AD) and other dementias. AD patients tend to become withdrawn and depressed due to communication problems and loss of confidence. However memory loss in people with AD occurs in reverse chronological order so that pockets of long-term memory remain accessible even as the disease progresses. AMPER's main technological challenge is the development of an agent with a novel human-like autobiographical memory model that tells stories to encourage reminiscing using individualised repositories of life experiences in real-world social contexts. AMPER will apply user-centred design with AD individuals and their carers to create such an agent. This will perform a carer-assisted intervention for personalised reminiscence, telling stories and bringing to the surface memories residing in the still viable regions of the brain. The project will collect both generationally relevant and personally relevant multi-media materials organised and reorganised by the agent's autobiographical memory. It will test the acceptability and effectiveness of both graphical and table-top robot agents. Autobiographical memory provides a reflection of "self" enabling an individual to relive an event. By building a technological bridge to unique life experiences and aiding recollection, an AD individual's sense of value, importance and belonging may be restored. The project aims to create a meaningful technology that is accessible as well as responsive to an individual's changing needs and experiences. The project will work with the charity Sporting Memories, already involved in reminiscence support, with the NHS Scotland Neuroprogressive and Dementia Network, the University of Edinburgh Centre for Dementia Prevention, and the Latin American Network for Dementia Research, forming its Steering Committee. Craig Ritchie, of the Centre for Dementia Prevention partner, will also bring in Scottish Dementia Research Consortium and Brain Health Scotland as Steering Committee members.

WHO and the G20 have identified the growing threats of Anti-Microbial resistance (AMR) as a major concern that will define the future of global health. Despite these urgent calls, the emergence of AMR in settings of war and distress migration has not been systematically explored. Case reports from Syria, Iraq, Libya, Yemen, and Afghanistan have shown the proliferation of AMR in combatants and civilians injured in these protracted conflicts. With regional conflicts spreading across state borders as well as one of the largest global refugee crises in decades, AMR in the context of conflict has come to pose a serious threat both regionally and internationally. So began penicillin in the Second World War: antibiotics arose in war. Today, in the context of long-running military conflicts we see harbingers of the end of antibiotics. The core question underpinning this proposal is how war, particularly weapons and the industrialised, urbanised context of contemporary conflicts, drives antibiotic resistance by contaminating the environment and the human and non-human organisms that live there. So far, there has been no systematic or holistic consideration of the environmental health impacts of contemporary conflicts conducted in cities. Our program draws together scholars working in the fields of medicine, anthropology, history of science, ethics, epidemiology, microbiology, molecular biology, and environmental sciences to examine the specific intersection of antibiotic resistance and war. Rather than focus on antibiotic resistance as a universal problem afflicting modern societies in general, we focus first on the impact of global conflict on antibiotic resistance more holistically, and second on the case of multi-drug resistant Acinetobacer baumanii (MDRAB), initially reported by American military surgeons under the moniker Iraqibacter, and that has been identified recently by the WHO as a "critical pathogen" for research and the development of new antibiotics. We will focus on a number of specific countries - Iraq, Syria, Palestine, Yemen, and Lebanon-places with history of protracted conflicts and with different, yet overlapping, ecologies of war. The potential global health significance of conflict-related heavy metal mediated antimicrobial resistance is enormous and warrants further study. It will contribute to the field of environmental pathways for antimicrobial resistance more broadly as well as informing the specific intersection of war and antibiotic resistance.