Exploring the interface between adolescent dysmenorrhoea and endometriosis: a protocol for a cohort and nested case–control study within the QResearch Database

Introduction Dysmenorrhoea affects up to 70%–91% of adolescents who menstruate, with approximately one-third experiencing severe symptoms with impacts on education, work and leisure. Dysmenorrhoea can occur without identifiable pathology, but can indicate underlying conditions, including congenital genital tract anomalies or endometriosis. There is a need for evidence about the management and incidence of dysmenorrhoea in primary care, the impact of treatments in adolescence on long-term outcomes and when to consider the possibility of endometriosis in adolescence. Methods and analysis This study aims to improve the evidence base for adolescents presenting to primary care with dysmenorrhoea. It comprises three interlinked studies. Using the QResearch Database, the study population includes all female at birth participants aged 10–19 years any time between 1 January 2000 and 30 June 2021. We will undertake (1) a descriptive study documenting the prevalence of coded dysmenorrhoea in primary care, stratified by demographic variables, reported using descriptive statistics; (2) a prospective open cohort study following an index cohort of all adolescents recorded as attending primary care with dysmenorrhoea and a comparator cohort of five times as many who have not, to determine the HR for a diagnosis of endometriosis, adenomyosis, ongoing menstrual pain or subfertility (considered singly and in combination) anytime during the study period; and (3) a nested case–control study for adolescents diagnosed with endometriosis, using conditional logistic regression, to determine the OR for symptom(s) preceding this diagnosis. Ethics and dissemination The project has been independently peer reviewed and received ethics approval from the QResearch Scientific Board (reference OX46 under REC 18/EM/0400)

Hormone replacement therapy in women with cancer and risk of cancer-specific mortality and cardiovascular disease : A protocol for a cohort study from Scotland and Wales.

Funding This work was supported by Cancer Research UK (reference C37316/A29656). The funder had no role in study design, data collection, data analysis, data interpretation or writing the manuscript.Peer reviewedPublisher PD

Hormone replacement therapy and cancer mortality in women with site specific cancers : A cohort study using linked medical records.

Acknowledgements We would like to acknowledge the support of the eDRIS team (Public Health Scotland) for their involvement in obtaining approvals, provisioning and linking data and the secure analytical platform within the National Safe Haven. We would also like to acknowledge support of SAIL Databank for facilitating access to the dataset from Wales. We acknowledge the contribution of EMIS practices who contribute to the QResearch database and the Chancellor, Masters and Scholars of the University of Oxford for continuing to develop and support the QResearch database. The Hospital Episode Statistics data used in the English portion of this analysis are re438 used by permission from NHS Digital who retain the copyright. We thank the Office for National Statistics (ONS) for providing the mortality data for the English analyses. The ONS bears no responsibility for the analysis or interpretation of the data. The authors would also like to thank the PPI representatives for providing a patient and public perspective on the study design, findings, interpretation of the study and lay summary materials.Peer reviewe

Hormone replacement therapy in women with cancer and risk of cancer-specific mortality and cardiovascular disease: A protocol for a cohort study from Scotland and Wales

Background: Hormone replacement therapy (HRT) is widely used and has proven benefits for women with menopausal symptoms. An increasing number of women with cancer experience menopausal symptoms but the safety of HRT use in women with cancer is unclear. There are particular concerns that HRT could accelerate cancer progression in women with cancer, and also that HRT could increase the risk of cardiovascular disease in such women. Therefore, our primary aim is to determine whether HRT use alters the risk of cancer-specific mortality in women with a range of common cancers. Our secondary objectives are to investigate whether HRT alters the risk of second cancers, cardiovascular disease, venous thromboembolism and all-cause mortality.Methods: The study will utilise independent population-based data from Wales using the SAIL databank and Scotland based upon the national Prescribing Information System. The study will include women newly diagnosed with common cancers from 2000 to 2016, identified from cancer registries. Women with breast cancers will be excluded. HRT will be ascertained using electronic prescribing in Wales or dispensing records in Scotland. The primary outcome will be time to cancer-specific mortality from national mortality records. Time-dependent cox regression models will be used to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) for cancer specific death in HRT users compared with non-users after cancer diagnosis after adjusting for relevant confounders, stratified by cancer site. Analysis will be repeated investigating the impact of HRT use immediately before cancer diagnosis. Secondary analyses will be conducted on the risk of second cancers, cardiovascular disease, venous thromboembolism and all-cause mortality. Analyses will be conducted within each cohort and pooled across cohorts.Discussion: Our study will provide evidence to inform guidance given to women diagnosed with cancer on the safety of HRT use and/or guide modifications to clinical practice

Preexisting Neuropsychiatric Conditions and Associated Risk of Severe COVID-19 Infection and Other Acute Respiratory Infections

Importance Evidence indicates that preexisting neuropsychiatric conditions confer increased risks of severe outcomes from COVID-19 infection. It is unclear how this increased risk compares with risks associated with other severe acute respiratory infections (SARIs).Objective To determine whether preexisting diagnosis of and/or treatment for a neuropsychiatric condition is associated with severe outcomes from COVID-19 infection and other SARIs and whether any observed association is similar between the 2 outcomes.Design, Setting, and Participants Prepandemic (2015-2020) and contemporary (2020-2021) longitudinal cohorts were derived from the QResearch database of English primary care records. Adjusted hazard ratios (HRs) with 99% CIs were estimated in April 2022 using flexible parametric survival models clustered by primary care clinic. This study included a population-based sample, including all adults in the database who had been registered with a primary care clinic for at least 1 year. Analysis of routinely collected primary care electronic medical records was performed.Exposures Diagnosis of and/or medication for anxiety, mood, or psychotic disorders and diagnosis of dementia, depression, schizophrenia, or bipolar disorder.Main Outcomes and Measures COVID-19–related mortality, or hospital or intensive care unit admission; SARI-related mortality, or hospital or intensive care unit admission.Results The prepandemic cohort comprised 11 134 789 adults (223 569 SARI cases [2.0%]) with a median (IQR) age of 42 (29-58) years, of which 5 644 525 (50.7%) were female. The contemporary cohort comprised 8 388 956 adults (58 203 severe COVID-19 cases [0.7%]) with a median (IQR) age of 48 (34-63) years, of which 4 207 192 were male (50.2%). Diagnosis and/or treatment for neuropsychiatric conditions other than dementia was associated with an increased likelihood of a severe outcome from SARI (anxiety diagnosis: HR, 1.16; 99% CI, 1.13-1.18; psychotic disorder diagnosis and treatment: HR, 2.56; 99% CI, 2.40-2.72) and COVID-19 (anxiety diagnosis: HR, 1.16; 99% CI, 1.12-1.20; psychotic disorder treatment: HR, 2.37; 99% CI, 2.20-2.55). The effect estimate for severe outcome with dementia was higher for those with COVID-19 than SARI (HR, 2.85; 99% CI, 2.71-3.00 vs HR, 2.13; 99% CI, 2.07-2.19).Conclusions and Relevance In this longitudinal cohort study, UK patients with preexisting neuropsychiatric conditions and treatments were associated with similarly increased risks of severe outcome from COVID-19 infection and SARIs, except for dementia

Overcoming Ostrea edulis seed production limitations to meet ecosystem restoration demands in the UN decade on restoration

The European flat oyster, Ostrea edulis, is a habitat-forming bivalve which was historically widespread throughout Europe. Following its decline due to overfishing, pollution, sedimentation, invasive species, and disease, O. edulis and its beds are now listed as a threatened and/or declining species and habitat by OSPAR. Increasing recognition of the plight of the oyster, alongside rapidly developing restoration techniques and growing interest in marine restoration, has resulted in a recent and rapid growth in habitat restoration efforts. O. edulis seed supply is currently a major bottleneck in scaling up habitat restoration efforts in Europe. O. edulis has been cultured for centuries, however, research into its culture declined following the introduction of the Pacific oyster, Crassostrea gigas to Europe in the early 1970 s. Recent efforts to renew both hatchery and pond production of O. edulis seed for habitat restoration purposes are hampered by restoration project timelines and funding typically being short, or projects not planning appropriately for the timescales required for investment, research-and-development and delivery of oyster seed by commercial producers. Furthermore, funding for restoration is intermittent, making long-term commitments between producers and restoration practitioners difficult. Long-term, strategic investment in research and production are needed to overcome these bottlenecks and meet current ambitious restoration targets across Europe

Assessing the materiality of nature-related financial risks for the UK

•At least half of global GDP is moderately or highly directly dependent on nature, and ultimately there is no economy without its critical services, including clean and abundant water, clean air and food. Nature across most of the globe has now been significantly altered by multiple human drivers, such as land-use change, pollution, extraction of minerals, abstraction of water and climate change. Statistics on the current state of biodiversity loss and environmental degradation are alarming: the extent and condition of ecosystems has declined in 50% of natural ecosystems, including more than 85% of wetland area lost, and 25% of species are at risk of extinction (IPBES, 2019). The 2019 Global Assessment Report of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) concluded that fourteen of the eighteen ecosystem services that were assessed had declined since the 1970s. The United Kingdom is no exception. The percentage of UK habitats ‘in favourable or improving conservation status’ has been deteriorating since 2007, exacerbating impacts on our soils, pollinators, air and environmental pollution, water and flood protection. Our analyses show that 75% of the United Kingdom is covered by at least one hotspot of natural capital depletion, and 25% is covered by two or more hotspots of natural capital depletion. The UK, with its globally interconnected economy, is also exposed to significant global emerging risks. •The erosion of UK and global natural capital generates significant and long-term risks to society and the UK economy and financial sector. Studies by Central Banks around the world have highlighted the high degree of dependence on nature and the exposure of financial portfolios to nature-related risks. What is not yet clear, is the extent to which this is a material risk to financial stability, on a par with other risks on the radar of Central Banks, and if so, on what timescales this risk could emerge and where it might ‘fall through the cracks’ of current supervision and regulation. •The objective of this project was to assess the materiality of nature-related risks to the UK financial sector both in the near-term and the longer-term. To address this, we develop six innovations: 1.The first Nature-Related Risk Inventory for the UK (UK-NRRI), equivalent in format to the National Risk Register or Climate Change Risk Assessment (CCRA). 2.Dependency analysis with spatial information to track dependencies on international supply and the nature risks therein, alongside transition risk exposures for the seven largest banks. 3.Development of sector-specific nature-related Value at Risk (nVaR) scores. 4.Co-development of three benchmark scenarios of nature-related risks, following the approach outlined by the Taskforce on Nature-Related Financial Disclosures (TNFD 2023). 5.Macroeconomic modelling to gauge the potential impacts on UK prosperity and resilience. 6.Preliminary financial ‘stress test’ for the domestic lending of the UK’s seven largest banks. The analyses focus on physical nature-related risks, with exposure analysis or transition risks. The findings demonstrate that biodiversity loss and environmental degradation create material risks for the UK economy and financial sector, in addition to their wider social and biodiversity impacts. These impacts are near and present. We find that the deterioration of our natural environment could slow economic growth and result in UK Gross Domestic Product (GDP) being 6% lower than it would have been otherwise by the 2030s under two scenarios (domestic and international) and 12% lower under an AMR-pandemic scenario. These are greater than the impact on GDP experienced in the Global Financial Crisis, in which UK GDP fell by around 4% to 6%, and - for the AMR-pandemic scenario – greater than the GDP impact of the COVID-19 pandemic when GDP fell 11% over 2020. While these findings are preliminary, all the evidence points to them being conservative. This study focussed on quantifying near- to medium-term risks, but the evidence clearly demonstrates these risks will increase over time with the potential for crossing tipping points. •The compounding impacts of climate and nature loss would have a very material impact on UK GDP; equivalent to several lost years of growth. It is not realistic to consider nature in isolation as climate change and environmental degradation are occurring in parallel and are interconnected. Environmental degradation increases the likelihood and severity of an acute climate or health shock, and the combined effect would have a very material impact on the economy. For this reason, we also draw upon the NGFS climate scenarios to explore the compounding impacts of climate and nature. We find that in our acute shock scenarios, these compounding impacts can lead to a UK GDP that is 8% lower than it would be otherwise, with a peak shock that wipes out around £200 billion from UK GDP and persists for several quarters, equivalent to 4 – 7 years of lost growth over the period. •The gradual impacts of environmental degradation on the economy are as detrimental or more so than climate change in the near-term - and the chronic year-to-year changes lead to losses that are as important as more sudden shocks. We find that the impact to GDP of chronic year-on-year environmental degradation is at least on par with that from physical climate change risks in the coming decade and for acute shocks, can be far greater than climate impacts alone. In effect, the impacts of environmental degradation are doubling or more the impact of climate change. Antimicrobial resistance (AMR) and zoonotic diseases are closely linked with deforestation and habitat destruction which can bring humans and wild animals into closer contact and have been shown to lead to greater abundance of antibiotic resistance genes in soil. Chronic nature-related risks associated with soil degradation, water provisioning, pollution and pollination services have material impacts on agriculture, manufacturing, construction, utilities and key supply chains. •Around half of UK nature-related risks come from overseas, through supply chains and financial exposures, pointing toward the importance of working internationally to close the gaps in disclosures and risk management. The four trillion GBP of financial assets assessed are dependent upon many trillions more of assets globally. Analyses of UK financial exposures suggest that 56% of the total upstream financial exposures have a High or Very High dependence on ecosystem services. Exposures to overseas risks are most material (in financial terms) for the services and manufacturing sectors, with highest risks related to water. The agricultural sector is most at risk in percentage terms, but the largest risks in monetary terms are to the services and manufacturing sectors. Agriculture can be impacted by disruption to several ecosystem services, with potential reductions in output (the nature-related value at risk – or nVaR) up to 15% of total annual production for disruption of any one service, albeit multiple ecosystem services at risk and impacts occur simultaneously, with risks to related to pollination services, soil quality and invasive species. Looking across the UK economy, we find that the nVaR associated with disruption to ecosystem services is in the hundreds of billions and equivalent to several percentage points of GDP; water risks alone are equivalent to around 13% UK GDP (for an extreme 1-in-100 year risk). The agricultural sector is also the most exposed to transition risks and opportunities. •Looking across the portfolios of the seven largest UK banks, the analyses indicate possible adjustments in the valuations of domestic holdings (excluding finance) of up to 4 – 5% over the coming decade from physical nature-related risks. Depending on the bank, the most at-risk sectors include agriculture, utilities, real-estate and manufacturing. Preliminary analyses suggest that between 8% and 53% of the portfolios of the seven largest banks are exposed also to transition risks. Firms could also derive opportunities from the nature-positive transition; including new demand for nature-positive products and services. The findings of this study take us further than previous studies to-date by clearly demonstrating the materiality of nature-related risks and the potential for compounding risks with climate change. Further work is needed to assess the implications for regulation, policy and supervision. Based upon the findings presented here and elsewhere, we believe there is a case for action by Central Banks, regulators and governments to assess if and where nature may be falling through the cracks of current frameworks and where this could lead to financial stability risks that justify explicit changes to those frameworks. We make a series of arguments based on the evidence for why nature may present new challenges that necessitate action. It is clear, for example, from other work (e.g. GARP 2024 and TNFD 2023), that there are sizeable information asymmetries created by the lack of disclosures of nature-related risks and impacts that mean that risks are currently under-priced. This may lead to an accumulation of systemic risk that goes undetected. We also lay out how nature-related risks suffer from the same ‘tragedy of the horizon’ issue identified by Mark Carney in 2015, but also additional challenges of a ‘tragedy of scale’ and unique drivers and risk transmission channels that are not captured within current climate-related risk assessments. •This study adds further evidence to support the conclusion from the Dasgupta Review and others that an early orderly transition toward a nature-positive economy brings significant benefits for UK prosperity and financial stability, through reducing both transition and physical risks, as well as for people and planet. Actions that could be considered by regulators and supervisors to mitigate risks to financial stability include advancing disclosures, broadening supervisory statements on climate to explicitly include environmental risks and introducing a simple nature-risk scenario within exploratory scenario exercises. There are many low-regrets measures that could be taken now, including supporting capability building through fora such as the Climate Financial Risk Forum and working with the scientific community to advance a set of benchmark scenarios, building upon those developed here. Regulators should also take timely opportunities to incorporate nature alongside climate into emerging frameworks, for example on transition plans, ISSB standards and taxonomies. •For financial institutions, the findings should motivate action to assess and manage nature-related financial risks, build capability, and begin to incorporate nature into emerging transition plans. These preliminary results suggest that even in the short-term nature-related risk is not negligible, especially if the losses are considered in relative terms to specific fractions of a lending portfolio. Financial institutions can manage risks to their own portfolios through working with their clients to reduce risks through supporting their transition and resilience. Importantly the transition toward a nature-positive economy presents opportunities as well as risks. With early action, UK firms – both financial and real-economy – can capture these opportunities. •For government, the materiality of nature-related risks demonstrated in this study add additional urgency to put in place the mechanisms, domestically and globally, to meet the goals and targets of the Kunming-Montreal Global Biodiversity Framework (GBF), as well as domestic policies such as the Environmental Improvement Plan (2023). This includes engaging internationally to ensure that emerging sustainable finance frameworks incorporate nature and nature related, including the IFRS Foundation’s ISSB. There is also an urgent rationale for investment and closer working with the scientific community to improve data and analytics as a public good to underpin the UK's transition to a resilient, nature-positive economy. •To continue to advance this area, strengthening collaboration between financial institutions and the scientific community is essential. Nature-related financial risk assessment is in its infancy, but risks are significant. This study has revealed several gaps in knowledge and approaches that require further study. It has also produced a series of tools that can be advanced today: •A Nature-Related Risk Inventory (UK-NRRI) that includes 29 key risks to the UK, with zoonotic diseases and antimicrobial resistance, soil health decline and global repercussions of food insecurity emerging as highest risks in terms of likelihood and impacts. •A set of benchmark narrative and quantitative scenarios that could form the basis for the further co-development of a set of scenarios for financial institutions, through fora such as the Climate Financial Risk Forum and UK Integrating Finance and Biodiversity network. There is a need to build platforms for collaboration and an opportunity to build upon existing fora such as the Climate Financial Risk Forum. The new £7m UKRI Integrating Finance and Biodiversity network, bringing together 17 research institutions, provides a ready venue to deepen collaborations. •Finally, while our focus has been on nature-related risks, the findings have implications for climate change given the strong interconnections between climate and nature The findings suggest that incorporating nature-related risk amplifications in climate scenarios would double the estimated impact of climate change on the UK economy, beyond what is currently predicted by the NGFS

Hormone replacement therapy and cancer mortality in women with 17 site-specific cancers: a cohort study using linked medical records

Background: There is limited evidence on the safety of Hormone Replacement Therapy (HRT) in women with cancer. Therefore, we systematically examined HRT use and cancer-specific mortality in women with 17 site-specific cancers. Methods: Women newly diagnosed with 17 site-specific cancers from 1998 to 2019, were identified from general practitioner (GP) records, hospital diagnoses or cancer registries in Scotland, Wales and England. Breast cancer patients were excluded because HRT is contraindicated in breast cancer patients. The primary outcome was time to cancer-specific mortality. Time-dependent Cox regression models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (95% CIs) for cancer-specific mortality by systemic HRT use. Results: The combined cancer cohorts contained 182,589 women across 17 cancer sites. Overall 7% of patients used systemic HRT after their cancer diagnosis. There was no evidence that HRT users, compared with non-users, had higher cancer-specific mortality at any cancer site. In particular, no increase was observed in common cancers including lung (adjusted HR = 0.98 95% CI 0.90, 1.07), colorectal (adjusted HR = 0.79 95% CI 0.70, 0.90), and melanoma (adjusted HR = 0.77 95% CI 0.58, 1.02). Conclusions: We observed no evidence of increased cancer-specific mortality in women with a range of cancers (excluding breast) receiving HRT

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Algebraic synthesis and logic filter approach for the control of cyber-physical manufacturing systems

Cette thèse propose une méthodologie de conception de la commande des systèmes de production cyber-physiques pour l’automaticien 4.0. Cette méthodologie doit permettre de définir des lois de commande fiables, flexible, économe en énergie avec un temps de développement faible en étant acceptable par le milieu industriel. Pour répondre à ces contraintes, nos travaux sont basés sur deux approches originales : la synthèse algébrique et le filtre logique de contraintes. La première est basée sur la résolution de systèmes d’équations booléennes pour obtenir les lois de contrôle. La seconde approche est basée sur l'introduction d'un filtre pour corriger les sorties en fonction de contraintes de sécurité logiques. De plus, afin de conserver un lien avec les outils industriels et de faciliter l’implémentation des lois de commande dans des Automates Programmables Industriels, le GRAFCET a été retenu comme outil de spécification et des procédures de génération automatique de programme de commande ont été intégrées.Cette thèse se concentre sur la formalisation de la phase de conception du mode de fonctionnement normal de la commande. Pour cela, une méthode de conception de la commande basée sur la synchronisation de tâches a été développée, la commande algébrique structurée. La synthèse algébrique est également utilisée comme outil de spécification et de résolution pour les contraintes de sûreté de fonctionnement permettant de définir les filtres algébriques. Cette nouvelle approche des filtres conduit à la définition des filtres algébriques. Enfin, un outil de génération de programme API, ST2UNITY, a été développé pour convertir l’ensemble des spécifications définies en langage ST.This thesis proposes a design methodology for the control of cyber-physical production systems for the automation engineer 4.0. This methodology must enable the definition of reliable, flexible and energy-efficient control laws with a low development time, while being acceptable to the industrial environment. To meet these constraints, our work is based on two original approaches: algebraic synthesis and constraint logic filtering. The first is based on solving systems of Boolean equations to obtain control laws. The second approach is based on the introduction of a filter to correct the outputs according to logical safety constraints. Furthermore, in order to maintain a link with industrial tools and facilitate the implementation of control laws in PLCs, GRAFCET has been retained as a specification tool and procedures for automatic control program generation have been integrated.This thesis focuses on formalizing the design phase of the control's normal operating mode. For this purpose, a control design method based on task synchronization has been developed, the structured algebraic control. Algebraic synthesis is also used as a tool for specifying and solving dependability constraints, enabling logic filters to be defined. This new approach to filters leads to the definition of algebraic filters. Finally, a PLC program generation tool, ST2UNITY, has been developed to convert all the defined specifications into ST language.The methodology proposed in this thesis focuses on formalizing the design phase of the control's normal operating mode. For this purpose, a control design method based on task synchronization has been developed, the structured algebraic control (SAC). This allows extremely simple task GRAFCET to be defined, using synchronization constraints to define complex behaviors. Algebraic synthesis is also used as a specification and resolution tool for safety constraints to define logic filters. This new approach to filters leads to the definition of two types of filters: universal algebraic filters, which are associated with a system and can be used to ensure operational safety for any control law, and specific algebraic filters, which are associated with a given control, thereby simplifying the specification of the latter. Finally, a PLC program generation tool, ST2UNITY, has been developed to convert all defined specifications into ST language