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The Met Office in the United Kingdom has developed a completely new probabilistic postprocessing system called IMPROVER to operate on outputs from its operational numerical weather prediction (NWP) forecasts and precipitation nowcasts. The aim is to improve weather forecast information to the public and other stakeholders while better exploiting the current and future generations of underpinning kilometer-scale NWP ensembles. We wish to provide seamless forecasts from nowcasting to medium range, provide consistency between gridded and site-specific forecasts, and be able to verify every stage of the processing. The software is written in a modern modular framework that is easy to maintain, develop, and share. IMPROVER allows forecast information to be provided with greater spatial and temporal detail and a faster update frequency than previous postprocessing. Independent probabilistic processing chains are constructed for each meteorological variable consisting of a series of processing stages that operate on predefined grids and blend outputs from several NWP inputs to give a frequently updated, probabilistic forecast solution. Probabilistic information is produced as standard, with the option of extracting a most likely or yes–no outcome if required. Verification can be performed at all stages, although it is only currently switched on for the most significant stages when run in real time. IMPROVER has been producing real-time output since March 2021 and became operational in spring 2022.

Epigenetic DNA methylation plays an important role in bacteria by influencing gene expression and allowing discrimination between self-DNA and intruders such as phages and plasmids. Restriction–modification (RM) systems use a methyltransferase (MTase) to modify a specific sequence motif, thus protecting host DNA from cleavage by a cognate restriction endonuclease (REase) while leaving invading DNA vulnerable. Other REases occur solitarily and cleave methylated DNA. REases and RM systems are frequently mobile, influencing horizontal gene transfer by altering the compatibility of the host for foreign DNA uptake. However, whether mobile defence systems affect pre-existing host defences remains obscure. Here, we reveal an epigenetic conflict between an RM system (PcaRCI) and a methylation-dependent REase (PcaRCII) in the plant pathogen Pectobacterium carotovorum RC5297. The PcaRCI RM system provides potent protection against unmethylated plasmids and phages, but its methylation motif is targeted by the methylation-dependent PcaRCII. This potentially lethal co-existence is enabled through epigenetic silencing of the PcaRCII-encoding gene via promoter methylation by the PcaRCI MTase. Comparative genome analyses suggest that the PcaRCII-encoding gene was already present and was silenced upon establishment of the PcaRCI system. These findings provide a striking example for selfishness of RM systems and intracellular competition between different defences.

Described by one contemporary as the 'sweet singer of The Temple', George Herbert has long been recognised as a lover of music. Nevertheless, Herbert's own participation in seventeenth-century musical culture has yet to be examined in detail. This is the first extended critical study to situate Herbert's roles as priest, poet and musician in the context of the musico-poetic activities of members of his extended family, from the song culture surrounding William Herbert and Mary Sidney to the philosophy of his eldest brother Edward Herbert of Cherbury. It examines the secular visual music of the Stuart court masque as well as the sacred songs of the church. Arguing that Herbert's reading of Augustine helped to shape his musical thought, it explores the tension between the abstract ideal of music and its practical performance to articulate the distinctive theological insights Herbert derived from the musical culture of his time.

Introduction and hypothesis Laparoscopic mesh sacrohysteropexy offers a uterine-sparing alternative to vaginal hysterectomy with apical suspension, although randomised comparative data are lacking. This study was aimed at comparing the long-term efficacy of laparoscopic mesh sacrohysteropexy and vaginal hysterectomy with apical suspension for the treatment of uterine prolapse. Methods A randomised controlled trial comparing laparoscopic mesh sacrohysteropexy and vaginal hysterectomy with apical suspension for the treatment of uterine prolapse was performed, with a minimum follow-up of 7 years. The primary outcome was reoperation for apical prolapse. Secondary outcomes included patient-reported mesh complications, Pelvic Organ Prolapse Quantification, Patient Global Impression of Improvement in prolapse symptoms and the International Consultation on Incontinence Questionnaire Vaginal Symptoms, Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) and PISQ-12 questionnaires. Results A total of 101 women were randomised and 62 women attended for follow-up at a mean of 100 months postoperatively (range 84–119 months). None reported a mesh-associated complication. The risk of reoperation for apical prolapse was 17.2% following vaginal hysterectomy (VH) and 6.1% following laparoscopic mesh sacrohysteropexy (LSH; relative risk 0.34, 95% CI 0.07–1.68, p = 0.17). Laparoscopic sacrohysteropexy was associated with a statistically significantly higher apical suspension (POP-Q point C −5 vs −4.25, p = 0.02) and longer total vaginal length (9 cm vs 6 cm, p p = 0.59). Conclusion Laparoscopic sacrohysteropexy and vaginal hysterectomy with apical suspension have comparable reoperation rates and subjective outcomes. Potential advantages of laparoscopic sacrohysteropexy include a lower risk of apical reoperation, greater apical support and increased total vaginal length.

Micro and nanosize plastic polymers degrading from large plastic compounds are accumulating in the natural environment and expose potential biological threats to human health. These particles are largely persistent and consequently accumulate in the exposed individuals. The presence of microplastics has already been demonstrated in various human organs including the lung, the gastrointestinal system and the blood raising concerns about their possible harmful effects. The chemical composition, size and shape of microplastics as well as their weathering status represent important factors influencing the potential impact of microplastics on tissues. In addition, microplastics can function as vectors for adsorbed chemical compounds and may harbour and deliver live microbial pathogens or their ligands. In vitro and in vivo animal studies demonstrated that microplastics are taken up to cells in a size and cell type dependent manner. Once inside the targeted cell they activate oxidative processes, mitochondrial dysfunction and ER-stress. These molecular processes result in the activation or repression of cell type specific functions and potentially in the induction of cytotoxicity. The microplastic elicited events may result in inflammation, organ damage and fibrosis of the targeted organs as well as in systemic immunological and metabolic conditions. In addition, microplastics may impact on the gut microbiota which may exert further gastrointestinal and systemic metabolic and immunological effects. In this minireview, we evaluate the factors and mechanisms that influence potential microplastic induced cellular and organ pathologies in humans and discuss limitations of current understanding regarding microplastic elicited conditions as well as future perspectives for research.

Introduction: When intubation is required during a neonatal emergency, it is imperative there are no delays in collecting equipment. Current practice is for the Intubation Assistant to gather intubation equipment with no memory adjuncts. This study aimed to develop a Neonatal Intubation Flowchart (NIF) and test whether it improves performance in equipment collection. Methodology: Using simulation, a control group (n = 21) was compared to an intervention group (utilizing prototype NIF 1) (n = 24), with both groups consisting of neonatal nurses, midwives, and junior and senior pediatric doctors. The simulation involved a neonate requiring emergency intubation and the participant was tasked to collect the intubation equipment. The outcomes measured were Percentage of Equipment Collected, Time to Collect Equipment, and Amount of Questions Asked. Following post-simulation feedback, the NIF 2 was developed. The same simulation was repeated to an intervention group (n = 28) which utilized NIF 2. Results: The NIF 2 displayed a significantly better Time to Collect Equipment compared to control and NIF 1 (Mean [M] = 64.3-102.0 and 150.8 s, respectively). The NIF 2 had a significantly better Percentage of Equipment Collected compared to the control and NIF 1 (M = 96%-59% and 87%, respectively). The NIF 2 demonstrated significantly less Amount of Questions Asked compared to the control and NIF 1 groups (Median = 0-1 and 2, respectively). Conclusion: The NIF 2 provides a significantly superior method to collect equipment, in a quicker time, with less distracting questions asked, compared to current practice.

IMPROVER (Integrated Model Post-Processing and Verification) has been developed by the Met Office as an open-source probability-based post-processing system to fully exploit our convection permitting, hourly cycling ensemble forecasts. Post-processed MOGREPS-UK model forecasts are blended with deterministic UKV model forecasts and data from the coarser resolution global ensemble, MOGREPS-G, to produce seamless probabilistic forecasts from now out to 7 days ahead. For precipitation, an extrapolation nowcast is also blended in at the start. Forecasts are converted to probabilities at the start, and all initial stages of post-processing are performed on gridded data, with site-specific forecasts extracted as a final step, helping to ensure consistency. Data are processed on a 10km global grid and on a 2km UK-centred grid.This talk will briefly describe the post-processing sequence from raw NWP model data to fully-blended, gridded and spot forecasts as probabilities and percentiles of a broad range of meteorological diagnostics, with the application of physical and statistical post-processing techniques. The system became operational in early May 2022, and the this talk will focus on some of the work that has been undertaken in the last year to achieve this, including ensemble calibration of temperature and wind speed data at observed and non-observed sites. There will be discussion of some of the verification used to prove this system, as well as a brief look at the technical aspects of this complex system, the initial customers and collaborators and the planned future work, including the use of ECMWF forecast data to extend the range of IMPROVER out to 14 days.

1. Determining when animal populations have experienced stress in the past is fundamental to understanding how risk factors drive contemporary and future species’ responses to environmental change. For insects, quantifying stress and associating it with environmental factors has been challenging due to a paucity of time-series data and because detectable population-level responses can show varying lag effects. One solution is to leverage historic entomological specimens to detect morphological proxies of stress experienced at the time stressors emerged, allowing us to more accurately determine population responses. 2. Here we studied specimens of four bumblebee species, an invaluable group of insect pollinators, from five museums collected across Britain over the 20th century. We calculated the degree of fluctuating asymmetry (FA; random deviations from bilateral symmetry) between the right and left forewings as a potential proxy of developmental stress. 3. We: i) investigated whether baseline FA levels vary between species, and how this compares between the first and second half of the century; ii) determined the extent of FA change over the century in the four bumblebee species, and whether this followed a linear or non-linear trend; iii) tested which annual climatic conditions correlated with increased FA in bumblebees. 4. Species differed in their baseline FA, with FA being higher in the two species that have recently expanded their ranges in Britain. Overall, FA significantly increased over the century but followed a non-linear trend, with the increase starting c. 1925. We found relatively warm and wet years were associated with higher FA. 5. Collectively our findings show that FA in bumblebees increased over the 20th century and under weather conditions that will likely increase in frequency with climate change. By plotting FA trends and quantifying the contribution of annual climate conditions on past populations, we provide an important step towards improving our understanding of how environmental factors could impact future populations of wild beneficial insects.

This paper uses a novel and practical probabilistic approach to assess the risk of a compressor blade HCF failure in the gas turbine. For a specific design case, the tip timing tests for a newly designed gas turbine compressor blade successfully passed HCF design criteria during engine operation when operated over a wide speed range. However, on a later test high amplitude responses were seen under a VGV configuration which was different from that used during normal operation. Firstly, the gas turbine operational data and blade bench test data are used by the probabilistic assessment to identify the characteristics of the HCF problem. The resonance counting is carried out by the Monte Carlo simulations. The simulation indicates that the HCF endurance limit for the alternating stress is required to be satisfied for this blade. Secondly, the material test data, blade tip timing data and finite element (FE) results are used to build a HCF endurance stress probabilistic model, following which the probability of blade HCF failure was estimated. The Monte Carlo simulations are used for the probabilistic model. The simulation results show that the probability of HCF failure per blade and the risk of HCF failure for any blade of the stage are very small and acceptable.

Machine learning has gone way beyond a ground-breaking technology a few decades ago to now taken for granted in many day-to-day activities. It is now providing new ways for manufacturing, assembling, operating, monitoring, and maintaining products. Typical application areas include performance optimization, quality improvements, fault detection and predictive maintenance. In this paper application of machine learning algorithms to forced response prediction during the design and analysis of a typical gas turbine compressor blade is reported. The forced response prediction process typically involves utilizing harmonic or time domain computational fluid dynamics (CFD) analyses to compute the forcing and the aero damping, to calculate reserve factors that represent the high cycle fatigue life of the blade. This time-consuming process is generally limited to the later phases of the design cycle and can lead to hundreds of calculations if one must address all the resonances in a typical twin shaft running range. A neural network trained using historical data is used to directly predict the reserve factor with high confidence without the need for costlier high fidelity CFD by using just the finite elements (FE) predicted parameters. This allows to perform high-fidelity aero-mechanical assessment at an early stage in the design process. Further, application of image recognition using a convoluted neural network to aid in the identification of FE predicted Modeshapes is also demonstrated, which can also improve the quality of the reserve factor predictions.

The UK Met Office is developing an open-source probability-based post-processing system called IMPROVER to exploit convection permitting, hourly cycling ensemble forecasts. The system is tasked with blending these forecasts with both deterministic nowcast data, and coarser resolution global ensemble model data, to produce seamless probabilistic forecasts from the very short to medium range.A majority of the post-processing within IMPROVER is performed on gridded forecasts, with site-specific forecasts extracted as a final step, helping to ensure consistency. IMPROVER delivers a wide range of probabilistic products to both operational meteorologists and as input to automated forecast production. and this presentation will detail some of the work that has been undertaken in the past year to prepare, with a focus on the use of statistical post-processing.Statistical post-processing plays two complimentary roles within IMPROVER; ensuring forecasts better reflect reality, and in so doing, bringing different models into better alignment, which improves the seamlessness of model transitions. For a selection of diagnostics, the gridded forecasts from different source models are calibrated independently using ensemble model output statistics (EMOS). Results of experiments looking at the calibration of gridded forecasts will be discussed briefly.More recently calibration of site forecasts has been introduced as a final step for temperature and wind speed forecasts. Results of experiments using EMOS to perform calibration in a variety of different ways will be presented, including justifications and trade-offs made in choosing a final approach.This will include some discussion of the remaking of weather symbol products as period, rather than instantaneous, forecasts and the implications for their verification.

SUMMARYWhen a patient in an in-patient psychiatric setting allegedly commits a crime, psychiatrists are sometimes asked to assess their fitness to be interviewed by the police. This article describes how to conduct this assessment, outlines the criminal justice process leading to police interviews (with particular reference to the legal system in England and Wales) and highlights practical issues to consider when assessing fitness to be interviewed in this context.

Cardiac rehabilitation programs across Canada have suspended in-person services as a result of large-scale physical distancing recommendations designed to flatten the COVID-19 pandemic curve. Virtual cardiac rehabilitation (VCR) offers an alternate mechanism of care delivery, capable of providing similar patient outcomes and safety profiles compared to centre-based programs. In order to minimize care gaps, all centres should consider developing and implementing a VCR program. The process of this rapid implementation however can be daunting. Centres should initially focus on the collation, utilization and re-purposing of existing resources, equipment, and technology. Once established, programs should then focus on ensuring that quality indicators are met and care processes are protocolized. This should be followed by the development of sustainable VCR solutions to account for care gaps that existed prior to COVID-19, and to improve cardiac rehabilitation delivery moving forward. This article reviews the potential challenges and obstacles of this process and aims to provide pragmatic guidance to aid clinicians and administrators during this challenging time., Virtual cardiac rehabilitation offers an alternate mechanism of care delivery to ensure cardiovascular patients receive this guideline-based therapy during the COVID-19 pandemic. The challenges and obstacles associated with implementation of virtual cardiac rehabilitation program are reviewed and pragmatic guidance to aid clinicians and administrators is provided.

The COVID-19 pandemic has raised ethical questions for the cardiovascular leader and practitioner. Attention has been redirected from a system that focuses on individual patient benefit towards one that focuses on protecting society as a whole. Challenging resource allocation questions highlight the need for a clearly articulated ethics framework that integrates principled decision making into how different cardiovascular care services are prioritized. A practical application of the principles of minimizing harm, fairness, proportionality, respect, reciprocity, flexibility and procedural justice is provided, and a model for prioritization of the restoration of cardiovascular services is outlined. The prioritization model may be used to determine how and when cardiovascular services should be continued or restored. There should be a focus on an iterative and responsive approach to broader healthcare system needs, such as other disease groups and local outbreaks., for online listing: This paper provides an overview and application of relevant ethical principles in resource allocation decisions during the COVID-19 pandemic. A model for prioritization of cardiovascular services restoration is outlined. The model provides guidance on how and when cardiovascular services should be continued or restored, in an iterative and responsive fashion with the perspective of broader healthcare system needs.

Objective To understand health-related issues in women following mesh-augmented prolapse surgery. Design Inductive thematic analysis of free-text comments from participants in a cross-sectional study of laparoscopic mesh sacrohysteropexy. Setting Tertiary urogynaecology centres, United Kingdom. Population Women who underwent laparoscopic mesh sacrohysteropexy by surgeons based at two tertiary urogynaecology centres between 2010 and 2018. Methods A total of 1766 potential participants were contacted by post and invited to complete paper, online or telephone questionnaires containing a free-text comments section. Of 1121 participants (response proportion 63.5%), 752 (67.1%) provided such comments. These were analysed with a six-stage inductive thematic analysis, using NVivo 11® software. Main outcome measures Themes developed from free-text comments. Results Following familiarisation, 29 codes and 189 sub-codes were identified. These defined six themes: pelvic floor symptoms, health status, treatment success, mesh, pain and care received. The majority of comments centred on the first of these six themes. There were concerns about mesh use and a desire for more information. A range of pain symptoms were mentioned, often associated with pelvic floor symptoms, prolapse surgery or mesh. Conclusions Despite the mesh controversy, pelvic floor symptoms and their impact on quality of life remain the principle concern of women following mesh-augmented prolapse surgery. There is a need for quality, accessible and evidence-based information sources for those women with concerns, and for those considering such surgery in the future, particularly regarding mesh safety and postoperative recovery. The relationships between pain, prolapse, mesh and pelvic floor surgery require further study. Tweetable abstract Following mesh-augmented prolapse surgery, pelvic floor symptoms remain women's main focus; pain deserves further research.

Background Clopidogrel and other P2Y12 inhibitors have become the standard of care among patients presenting with acute coronary syndromes. A substantial proportion of these patients require surgical revascularization during index hospitalization. Hypothesis Guidelines recommend a 5-day waiting period off clopidogrel before coronary artery bypass grafting (CABG) to reduce hemorrhagic complications. These recommendations are not routinely followed in clinical practice, while recent studies also propose shorter waiting periods off clopidogrel for patients awaiting in-hospital CABG. Methods A preliminary PubMed search was conducted using the following MeSH terms under the publication type "Hemorrhage:" "Clopidogrel," AND "Coronary Artery Bypass." Relevant studies and guidelines were then reviewed and selected based on a predetermined criteria. Studies that formulated the current recommendations for stopping clopidogrel preoperative to CABG are discussed in detail this review. Results A comprehensive review of recent evidence illustrates mixed bleeding and transfusion outcomes among CABG patients with preoperative exposure to clopidogrel in less than 5 days. Conclusions The optimal discontinuation time of clopidogrel before CABG is still poorly defined. The recommendation of a 5-day washout period for clopidogrel should be reconsidered to be on par with current clinical practice.

Silyane Larcher, L’Autre Citoyen: L’idéal républicain et les Antilles après l’esclavage (Paris: Armand Colin, 2014).Elizabeth Heath, Wine, Sugar, and the Making of Modern France: Global Economic Crisis and the Racialization of French Citizenship, 1870–1910 (Cambridge: Cambridge University Press, 2014).Rebecca Scales, Radio and the Politics of Sound in Interwar France, 1921–1939 (Cambridge: Cambridge University Press, 2016).Claire Zalc, Dénaturalisés: Les retraits de nationalité sous Vichy (Paris: Éditions du Seuil, 2016).Bertram M. Gordon, War Tourism: Second World War France from Defeat and Occupation to the Creation of Heritage (Ithaca: Cornell University Press, 2018).Shannon L. Fogg, Stealing Home: Looting, Restitution, and Reconstructing Jewish Lives in France, 1942–1947 (Oxford: Oxford University Press, 2017).Sarah Fishman, From Vichy to the Sexual Revolution: Gender and Family Life in Postwar France (New York: Oxford University Press, 2017).Frederick Cooper, Citizenship between Empire and Nation: Remaking France and French Africa, 1945–1960 (Princeton: Princeton University Press, 2014).Jessica Lynne Pearson, The Colonial Politics of Global Health: France and the United Nations in Postwar Africa (Cambridge, MA: Harvard University Press, 2018). Darcie Fontaine, Decolonizing Christianity: Religion and the End of Empire in France and Algeria (New York: Cambridge University Press, 2016).

Background: Poor air quality is associated with poor health. Little attention is given to the complex array of environmental exposures and air pollutants that affect mental health during the life course. Aims: We gather interdisciplinary expertise and knowledge across the air pollution and mental health fields. We seek to propose future research priorities and how to address them. Method: Through a rapid narrative review, we summarise the key scientific findings, knowledge gaps and methodological challenges. Results: There is emerging evidence of associations between poor air quality, both indoors and outdoors, and poor mental health more generally, as well as specific mental disorders. Furthermore, pre-existing long-term conditions appear to deteriorate, requiring more healthcare. Evidence of critical periods for exposure among children and adolescents highlights the need for more longitudinal data as the basis of early preventive actions and policies. Particulate matter, including bioaerosols, are implicated, but form part of a complex exposome influenced by geography, deprivation, socioeconomic conditions and biological and individual vulnerabilities. Critical knowledge gaps need to be addressed to design interventions for mitigation and prevention, reflecting ever-changing sources of air pollution. The evidence base can inform and motivate multi-sector and interdisciplinary efforts of researchers, practitioners, policy makers, industry, community groups and campaigners to take informed action. Conclusions: There are knowledge gaps and a need for more research, for example, around bioaerosols exposure, indoor and outdoor pollution, urban design and impact on mental health over the life course. Natural Environment Research Council (NERC): NE/V002171/1; Engineering and Physical Sciences Research Council (EPSRC): EP/V052462/1; EP/W001411/1; EP/T003189/1

Previous human genetic studies have provided insight into the genes and pathways involved in atherosclerotic CAD, however, there remains an incomplete understanding of the precise cell types that drive disease pathogenesis. To generate a cellular atlas for CAD, we performed CITE-seq on left human coronary arteries with obstructive CAD (n=5), CAD with coronary stenting (n=4), or controls without CAD (n=5); single-nuclei RNA sequencing was performed on a subset (n=4) of these samples. Standard histopathology was used to assess the degree of atherosclerotic plaque burden and annotate disease status (Fig b). Sequencing yielded 65,437 cells with 23 distinct cell types (Fig a) and canonical marker genes (Fig c). Within the stroma we found prominent transcriptional changes in endothelial cells and fibroblasts along with the emergence of a modulated smooth muscle cell (SMC) state in CAD tissue. The modulated SMC cells were enriched with fibroblast activator protein surface expression. Additionally, we noted the emergence of a proliferative SMC population in stented arteries. Two distinct fibroblast populations were present: one was specific to coronary arteries in GTEx and this population was enriched for SVEP1 expression in the CAD samples. Furthermore, pseudotime analysis and integration of published single-cell SMC lineage tracing data in atherosclerotic mice show that this population is SMC-derived. Within the immune cells, we find expansion of B- and T-cell populations with transcriptional changes within myeloid subsets. We found 4 distinct macrophage populations: inflammatory, TREM2, HLA-II high, and resident-like macrophages. CAD macrophages had enriched inflammatory and foam-cell like signatures compared to controls. Furthermore, foam cell genes were localized to the inflammatory and TREM2 macrophages. Together, our results provide the first multi-omic single cell atlas of human coronary artery tissue with insights into disease pathogenesis.

In this paper, research that was carried out to optimise an initial variable guide vane schedule of a high-pressure ratio, multistage axial compressor is reported. The research was carried out on an extensively instrumented scaled compressor rig. The compressor rig tests carried out employing the initial schedule identified regions in the low speed area of the compressor map that developed rotating stall. Rotating stall regions that caused undesirable non-synchronous vibration of rotor blades were identified. The variable guide vane schedule optimisation carried out balancing the aerodynamic, aero-mechanical and blade dynamic characteristics gave the ‘Silent Start’ variable guide vane schedule, that prevented the development of rotating stall in the start regime and removed the non-synchronous vibration. Aerodynamic performance and aero-mechanical characteristics of the compressor when operated with the initial schedule and the optimised ‘Silent Start’ schedule are compared. The compressor with the ‘Silent Start’ variable guide vane schedule when used on a twin shaft engine reduced the start time to minimum load by a factor of four and significantly improved the operability of the engine compared to when the initial schedule was used.

In Industrial Design, new design visualisation tools are emerging offering significant benefits to the designers. However, studies show alongside some benefits, new tools can also inhibit designers' creativity or cause time inefficiency if used in the wrong context. Thus, understanding which tools to use and when during the design process is increasingly necessary to ensure the best use of resources in design practice. Existing research on understanding the performance of design tools and the resulting frameworks for comparing tools are either specific to certain tools or highly generalised making evaluation across different design tools challenging. As such, this paper reports the creation of a more comprehensive framework of design tool characteristics to facilitate a better understanding of design tools and their uses. Demonstration of application of the framework is also given in the form of a case study on the use of Digital Sketching and its comparable tools with four practising designers. In conclusion, we show how the Design Tool Characteristics (DTCs) framework is an effective way to understand design tools, with further implications for design tool development.

This essay introduces a special section dedicated to examining the history and culture of automobility, considering a quartet of essays on Saudi Arabia, Egypt, Libya and Algeria, and Syria. Jumping off from the work of Palestinian artist Jumana Manna to examine the motor vehicle as a multifaceted and ambiguous site of social experience and analytical possibility, the essay then sets the four essays that compose the section into the extant literature.

Introduction and hypothesis Apical vaginal support for post-hysterectomy vault prolapse can be provided by vaginal, abdominal, or laparoscopic routes. Sacrocolpopexy is associated with higher satisfaction rates and a lower re-operation rate than vaginal sacrospinous fixation. The laparoscopic approach can reduce hospital stay and blood loss. There are concerns about the use of mesh in urogynaecological procedures, but limited data indicate a low mesh complication rate with sacrocolpopexy (0-5%). This study was aimed at establishing the incidence of complications following laparoscopic sacrocolpopexy. Methods We carried out a retrospective cohort study of patients who underwent laparoscopic sacrocolpopexy at a large tertiary hospital. Cases were identified from coding data, theatre logs and the national urogynaecology procedure database. Data were gathered from theatre records, patient notes and the national database. Demographic data, concomitant procedures performed, duration of surgery, intra-operative complications, change in pelvic organ prolapse quantification point C, duration of stay, late complications and further urogynaecological surgery were assessed. Results A total of 660 patients underwent laparoscopic sacrocolpopexy between 2005 and 2017 (median time from surgery 4 years 3 months). Five cases (0.7%) developed vaginal mesh exposure. Two were successfully managed conservatively with topical oestrogen. Three required surgical excision of the mesh. Four patients (0.6%) presented with erosion of non-absorbable vaginal sutures. Two were successfully managed conservatively with topical oestrogen and oral antibiotics. Two were managed with vaginal suture excision. Conclusions This large series suggests that laparoscopic sacrocolpopexy might confer a low risk of mesh exposure. Together with good anatomical and patient-reported outcomes, laparoscopic sacrocolpopexy is a safe option for patients presenting with post-hysterectomy vault prolapse.

Individuals harboring the loss-of-function (LOF) proprotein convertase subtilisin/kexin type 9 Gln152His variation (PCSK9(Q152H)) have low circulating low-density lipoprotein cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of proPCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes, where it would be expected to contribute to ER storage disease (ERSD), a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9(Q152H) variation. We report that PCSK9(Q152H) carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9(Q152H) using adeno-associated viruses in male mice greatly increased the stability of key ER stress-response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than inducing them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress–driven conditions of the liver. In summary, we have uncovered a cochaperone function for PCSK9(Q152H) that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.

Hospitals and ambulatory facilities significantly reduced cardiac care delivery in response to the first wave of the COVID-19 pandemic. The deferral of elective cardiovascular procedures led to a marked reduction in healthcare delivery with a significant impact on optimal cardiovascular care. International and Canadian data have reported dramatically increased wait-times for diagnostic tests and cardiovascular procedures, as well as associated increased cardiovascular morbidity and mortality. In the wake of the demonstrated ability to rapidly create critical care and hospital ward capacity, we advocate a different approach during the second and possible subsequent COVID-19 pandemic waves. We suggest an approach, informed by local data and experience, which balances the need for an expected rise in demand for healthcare resources to ensure appropriate COVID-19 surge capacity, with continued delivery of essential cardiovascular care. Incorporating cardiovascular care leaders into pandemic planning and operations will help healthcare systems minimize cardiac care delivery disruptions, while maintaining critical care and hospital ward surge capacity and continuing measures to reduce transmission risk in healthcare settings. Specific recommendations targeting the main pillars of cardiovascular care are presented: ambulatory, inpatient, procedural, diagnostic, surgical and rehabilitation., Cardiovascular care delivery was significantly reduced during the first wave of the COVID-19 pandemic, leading to reports of increased wait-times, with associated cardiovascular morbidity and mortality. Recommendations are presented advocating for a different approach in the second and subsequent waves of COVID-19 to balance surge capacity while preserving delivery of essential cardiovascular care.

Introduction and hypothesis The paucity of long-term safety and efficacy data to support laparoscopic mesh sacrohysteropexy is noteworthy given concerns about the use of polypropylene mesh in pelvic floor surgery. This study is aimed at determining the incidence of mesh-associated complications and reoperation following this procedure. Methods This was a cross-sectional postal questionnaire study of women who underwent laparoscopic mesh sacrohysteropexy between 2010 and 2018. Potential participants were identified from surgical databases of five surgeons at two tertiary urogynaecology centres in the UK. The primary outcome was patient-reported mesh complication requiring removal of hysteropexy mesh. Secondary outcomes included other mesh-associated complications, reoperation rates and Patient Global Impression of Improvement (PGI-I) in prolapse symptoms. Descriptive statistics and Kaplan–Meier survival analyses were used. Results Of 1,766 eligible participants, 1,121 women responded (response proportion 63.5%), at a median follow-up of 46 months. The incidence of mesh complications requiring removal of hysteropexy mesh was 0.4% (4 out of 1,121). The rate of chronic pain service use was 1.8%, and newly diagnosed systemic autoimmune disorders was 5.8%. The rate of reoperation for apical prolapse was 3.7%, and for any form of pelvic organ prolapse it was 13.6%. For PGI-I, 81.4% of patients were “much better” or “very much better”. Conclusions Laparoscopic mesh sacrohysteropexy has a low incidence of reoperation for mesh complications and apical prolapse, and a high rate of patient-reported improvement in prolapse symptoms. With appropriate clinical governance measures, the procedure offers an alternative to vaginal hysterectomy with apical suspension. However, long-term comparative studies are still required.

Texturally complex monazite grains within two granulite-facies pelitic migmatites from southern Baffin Island, Arctic Canada, were mapped by laser ablation-inductively coupled plasma-mass spectrometry to quantitatively determine the spatial variation in trace element chemistry with a 4-5 μm resolution (with up to 1883 analyses per grain). The maps demarcate growth zones, some of which were cryptic with conventional imaging, highlighting the 3-D complexity of monazite grains that have experienced multiple episodes of growth and resorption during high-grade metamorphism. Associated monazite trace element systematics are highly variable, both within domains interpreted to have grown in a single event, and between samples that experienced similar metamorphic conditions and mineral assemblages. This result cautions against generalised petrological interpretations being made about monazite trace element signatures as it suggests sample-specific controls. Nevertheless, by quantifying monazite textures, a related U-Pb dataset is re-interpreted, allowing ages to be extracted from a continuum of concordant data. The results reveal a ~45 Myr interval between prograde metamorphism and retrograde melt crystallisation in the study region, emphasising the long-lived nature of heat flow in high-grade metamorphic terranes. Careful characterisation of monazite grains suggests that continuum-style U-Pb datasets can be decoded to provide insights into the rates of metamorphic processes.

The global politics of sovereignty that developed after the Cold War, together with the catastrophic United States led invasions of Afghanistan and Iraq after 2001, have furnished international, imperial and diplomatic historians with good, grim reasons to return to the interlocked histories of empire, internationalism and international institutions. A torrent of work on the Geneva based League of Nations (LON) has been one result, alongside writing on the United Nations (UN). In particular, scholars such as Susan Pedersen, Patricia Clavin and Glenda Sluga, already well versed in the archives and literature of European empires and their gender and economic politics, have led a systematic reappraisal of internationalism and international institutions after the First World War. They brought to this campaign heuristic tools sharpened in the 1990s, in the cultural historiography of empire, and they aimed broadly to understand the League's workings and variety, rather than to reassert its political failures. The parallel – and often intersecting – rise of historiographies on the modern and contemporary histories of economic development, human rights and humanitarianism, with their frequent attention to the role of international institutions, has further catalysed this renewal.

To demonstrate a novel technique for complete laparoscopic removal of a transobturator sling for mesh erosion involving a large area of the urethra and bladder neck, without the need for concomitant vaginal dissection. A 56-year-old woman had a transobturator sling inserted for stress urinary incontinence (SUI) in 2009. In 2017, 8 years following surgery, she experienced groin pain, exacerbated by exercise, and developed recurrent urinary tract infections with dysuria and urethral pain. A cystoscopy demonstrated mesh erosion from the midurethra to bladder neck with a 2-cm calculus formed around the mesh. After careful counselling and discussion at a multi-disciplinary meeting, a decision was made to proceed with laparoscopy with a view to remove the mesh completely. The mesh was removed from the points of erosion into the urethra through a total laparoscopic procedure. The patient made a good recovery with no ongoing pain or voiding difficulties. Combined approaches for complete excision of transobturator slings, including bilateral inguinal dissection, are relatively morbid with prolonged recovery time and in most centres will require involvement of plastic surgeons. The laparoscopic approach not only allows for the mesh to be removed in total (including the intramural portion of the mesh), but also provides magnified views compared with open surgery and thus allows for better identification of planes and dissection. It also has the added benefit of avoiding vaginal incisions and therefore reducing the risk of fistula formation between the urethra/bladder and vagina.