Research context: Unlike other cancer types, which have recently seen significant improvements in their treatments and survival, pancreatic cancer continues to have extremely poor patient outcomes. Less than ten percent of patients diagnosed with pancreatic cancer survive more than five years after diagnosis. A major contributing factor is that pancreatic cancer is often detected at an advanced (incurable) stage. In the United Kingdom, nearly half of patients have Stage 4 disease at the time of diagnosis, which has a profound effect on treatment options and, ultimately, survival. Improving early detection of cancer is essential for improving survival, by providing patients with a window of opportunity to undergo treatment with curative intent. However, diagnosing pancreatic cancer at an early stage remains a challenge, as the signs and symptoms of early pancreatic cancer are often similar to those of many common illnesses. This makes it hard for doctors to identify which patients should be tested for pancreatic cancer. One solution for improving early detection of pancreatic cancer, being developed by our laboratory, is a simple breath test that detects small molecules, called volatile organic compounds (VOCs), which are different in the breath of patients with and without pancreatic cancer. This breath test could be offered to patients visiting a General Practitioner with non-specific symptoms, which for many patients will be due to one of a number of common illnesses, but in a minority may be due to undiagnosed pancreatic cancer. Challenge this project addresses: An important aspect in developing this breath test is to identify how the breath VOCs that are used to detect pancreatic cancer are produced within the cancer environment. This project aims to address this by studying VOC production from pancreatic cancer using a laboratory model. This will help us to identify specific VOCs produced from pancreatic cancer, even when occurring at very low concentrations in breath, thus making the breath test more accurate. To ensure the model is as representative of pancreatic cancer as possible, it will contain both cancer cells and the surrounding cells that are known to promote the growth and spread of these cancers. This allows the model to resemble more closely the interactions occurring between these cells in the human body, which may influence VOC production. Overall aim: To study VOC production from pancreatic cancer using a laboratory model. This model will use cells from 15 human pancreatic cancer samples and 5 normal human pancreas samples that are grown as groups of cells (organoids), as well as their surrounding supporting cells (cancer-associated fibroblasts) to mirror their interactions in the human body. This project will be based at Imperial College, with additional work taking place at the Cancer Research UK Convergence Science Centre. Objectives: To identify pancreatic cancer specific VOCs, compared with normal pancreas VOCs, using groups of pancreatic cells. To grow groups of pancreatic cancer cells together with supporting cells found inside the pancreatic cancer environment, to see whether this affects overall VOC production. To use the above laboratory model to identify biological pathways contributing to VOC production in pancreatic cancer. Potential applications and benefits: Alongside the results of parallel clinical studies, this research will support a future breath test that will offer an opportunity to improve earlier detection of pancreatic cancer, with benefits to both patients and the health service.

It is widely assumed that physical activity affects weight loss outcomes for severely obese patients, but there is a scarcity of robust research on this subject. We propose to use smartphone sensors and advanced data mining techniques to conduct detailed investigations addressing this important question. The research participants will be obese people having bariatric (or weight-loss) surgery (e.g. gastric bypass), but our results will also benefit other people with weight problems and patients with other conditions where exercise is helpful. In England just over a quarter of adults were classified as obese in 2010. This group is more likely to suffer from a range of illnesses (e.g. type-2 diabetes) and to have a lower life expectancy. Surgery is recommended for those with severe and complex obesity that has not responded to other therapies, and is highly cost effective in achieving weight loss, overcoming associated illnesses and promoting longer term health. However long-term success is far from guaranteed, with up to 15% of gastric bypass and 50% of gastric band procedures being ultimately unsuccessful. Obese people often lead very sedentary lives, both before and after surgery. Research has shown that even small long-term increases in routine physical activity could be very significant for weight loss, so we are very interested in how we can motivate people to do that little bit more in their daily lives. Patients attending the Imperial Weight Centre (IWC) are reminded to exercise during their hospital visits, but what they ideally need is a personal trainer to encourage them every day. Recognising this, patients have asked us if there are any devices that can help, and so we began our research into how sensors and mobile phones can seamlessly track activity and deliver timely, personalised feedback and encouragement. IWC Patients have tried wristbands such as the Nike Fuelband - but despite initial enthusiasm the novelty soon wears off. These devices do not provide sufficiently detailed or meaningful information. Smartphone apps such as MyFitnessPal are also popular, but soon become tedious since users must log everything they eat or do: many trying them did not persevere for more than a few days. With the advent of new apps it is now possible to track physical activity effortlessly just by carrying around one's smartphone, using its inbuilt sensors. Data is processed in the "internet cloud" where it can be analysed by new software we are developing. These apps also produce a complete daily "storyline" detailing a user's travels, and the amount and type of activity at each location. Our pilot users have been delighted to be able to see their physical activity progress and said that they felt motivated to challenge themselves to do more each day. This project sets out to objectively monitor physical activites on a daily basis so that we can follow almost 1000 patients over protracted periods of time and throughout their weight loss journey. We will use advanced data mining tools to understand individual differences and responses to surgery in terms of physical activity and how these relate to weight loss and weight maintenance over time. We shall use our analysis and understanding of behaviour change methods to devise ways to encourage users to do better and thereby achieve longer and healthier lives. For example, individualised prompts could incorporate weather and location information to suggest suitable walks on fine days, support positive goal setting or inspire competition with other users. This project will pave the way for further behavioural studies, for example using emerging wearable-sensor technologies and should offer long-term benefits for obese people and others with many different types of health problems, where exercise helps - lifestyle recommendations and advice can be produced that will be more personalised and useful for individuals looking to optimise their health.

Cancer is derived from a single cell that carries mutations that drive an uncontrolled increase in cell number. Recent research has revealed that a surprisingly high number of mutations also accumulate in healthy tissues as we age. For example, by the age of 50, the genetic material of the average white blood cell has accumulated between 800-1,600 mutations. It is thought that mutations that cause cancer have a more profound impact on cell behaviour than mutations found in healthy tissue; however, research is ongoing, and many open questions remain. Viruses cause around 10% of cancers. Therefore, it is vital to investigate how viral infection impacts the burden of mutations in healthy tissue and virus-related cancer. This has been technically challenging to do in humans, as it requires obtaining samples at different stages of infection and cancer development. In this project, I will investigate the consequences of persistent infection with of a cancer-causing virus, Human T cell leukaemia virus type-1 (HTLV-1), on the genetic material of human blood cells. Because HTLV-1 infects cells that circulate in the blood, they can be easily collected and grown in the lab, enabling us to map the locations where mutations occur in each cell's genes. We will study cells from healthy carriers of the virus and cells from people who are in the process of developing Adult T cell Leukaemia/Lymphoma. This analysis will reveal whether the virus changes the type of mutations and the rate at which mutations occur within infected cells, identify if certain mutations are associated with changes in cell behaviour, and can indicate which cellular processes caused the mutations. This research will allow us for the first time to gain direct insight into how HTLV-1 disrupts the genetic material of otherwise healthy cells which it infects, and is key to understanding how HTLV-1 and other similar viruses cause cancer.

Context: Menopausal symptoms have a marked impact on women's lives with approximately 50% suffering from low sexual desire (LSD) with a large proportion distressed by this and seeking medical help. Indeed, the WHO strongly recognises the crucial positive influences of fulfilling sexual experiences on well-being throughout life. In the UK, menopause has been placed at the forefront of the healthcare agenda by the Department of Health following its publication of the Women's Health Strategy in 2022. This identified research into menopause treatments and psychosexual wellbeing as a key priority. Collectively, this aligns with priority 5.1 of the UKRI Strategy: 'Securing better health, ageing and wellbeing'. Challenge: Despite the high global health and social burden of menopausal LSD, the available therapeutic approaches are unsatisfactory due to their very limited efficacy and side-effect profiles. Crucially, a significant number of women suffer with persistent LSD despite first-line hormone replacement therapy (HRT), which only consistently improves pain during sex, but not sexual desire and arousal. Taken together, there is a significant unmet need to identify novel, safer, and more effective treatments to address the considerable burden of LSD in postmenopausal women. Kisspeptin and our pilot data: We have recently shown that administration of the reproductive neuropeptide kisspeptin to men and premenopausal women with LSD robustly modulates sexual brain processing with associated improvements in sexual desire/arousal (independent of downstream sex-steroids). To explore the potential benefit of kisspeptin in postmenopausal women with LSD (despite HRT) and provide mechanistic insight, we have undertaken an in vivo pilot study in ovariectomised (OVX) female mice with oestradiol (E2) replacement (as a rodent model to mimic the postmenopausal state on HRT treatment). This demonstrated that whereas E2 alone does not restore sexual motivation (akin to human sexual desire) in OVX mice, the addition of kisspeptin fully restored sexual motivation. Collectively, this pilot data in animals and our previous clinical findings suggests that kisspeptin administration may augment sexual behaviour in postmenopausal women with LSD and so serves as the timely research theme for this application.

Motivation: The provision of healthcare is highly labour intensive, requiring a multi-disciplinary workforce with many years of training. Quality of care provided to patients depends crucially on both the availability and quality of individual staff and how they work together in teams. The NHS is the largest employer in England, employing more than a million people at a cost of more than £50 billion in 2016 (Department of Health, 2017). But NHS pay review bodies and the UK National Audit Office have noted that evidence on the efficient allocation of existing workers is scarce and long-term workforce planning is lacking (NHS Pay Review Body, 2017; Review Body on Doctor's and Dentist's Remuneration, 2017; National Audit Office, 2016). Such evidence and planning are important in order to contain costs and ensure that patients receive the highest possible quality of care. Aims and methodology: Our proposed research will use econometric techniques and rich administrative data to identify the causal effects of the way in which the health care workforce is organised on healthcare use and patient outcomes. Our first project explores the determinants of variation in the quality and productivity of the most senior doctors (NHS consultants). It is becoming clear that there is wide variation across doctors in their patient outcomes, even within the same hospital. Some of this may be due to patient allocation across doctors, for example, giving the most experienced harder to treat patients. But this does not appear to be the only driver. Our research will seek to quantify this variation and to determine what factors associated with the doctors are associated with this variation. We will use large scale data in order to separate out the effect of the individual doctor and the hospitals in which they work by exploiting movement in doctors across hospitals during their careers. Our second and third projects examine team production. Teams are the dominant form of organisation of staff in healthcare and it is therefore important to understand the causal effects of changes to teams. Project two examines explores the impacts of anticipated and unanticipated disruptions to nursing teams on patient care and costs. To do so, we will exploit new data sources that provide detailed data on staff rotas across all wards in 5 hospitals, which can be linked to treatments and patient outcomes. Project three will explore the relationship between doctor seniority, productivity and patient outcomes by analysing a series of strikes by junior doctors in 2016 and 2017. These strikes changed the mix of staff treating patients, leading to a temporarily higher proportion of senior staff (NHS consultants) working in these teams. To conduct our research we will exploit several data sources, including rich administrative data from the Hospital Episode Statistics and newly available, highly granular, data from one large London NHS hospital group. Applications, benefits and impact: Our ultimate aim is to allow policymakers to better understand the role of the workforce in variation in productivity, hospital utilisation and patient outcomes. Our findings will provide information and tools that help policymakers improve the efficiency of the existing workforce, raise the quality of patient care, and inform future workforce planning. We will maximise impact by producing a range of outputs that communicate the results to multiple audiences. We will submit a series of academic articles to top economic journals. We will also produce a number of press-released non-technical reports, which summarise the key findings directed at journalists, policymakers and other non-academic users. In particular, we will target national policymakers, including the Department of Health and Social Care and Health Education England, and health care providers, such as individual Acute Trusts. We will also engage with health care workers and their representatives.