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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.

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.

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.

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: 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 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.

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.

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.

Background Uterine-preserving prolapse surgery offers the chance to retain fertility; however, limited data is available for the safety of pregnancy following surgery and the effect of pregnancy on surgical outcome. Our operative technique involves mesh encircling the cervix and uterine arteries, which raises concerns that compromise of uterine blood flow during pregnancy may lead to foetal growth restriction. We also think this necessitates delivery by caesarean section. We report on six pregnancy outcomes following laparoscopic hysteropexy. Primary outcomes were live birth and birth weight. Secondary outcomes were integrity of mesh and immediate effect on prolapse. Results All patients had successful pregnancy outcomes with birth weights on or above the 10th centile. There was no effect on mesh integrity seen in any of the cases. There was no deterioration in apical prolapse when assessed post delivery, but two patients had new onset anterior vaginal wall prolapse. Conclusions We think our technique of hysteropexy is safe for those wishing to conceive. Larger numbers are needed to allow robust evidence-based guidance for patients and clinicians.

A 17-year-old man with no significant past medical history presented with a 2-week history of worsening jaundice, lethargy, anorexia and progressive right upper quadrant abdominal pain. There were no stigmata of chronic liver disease. Initial investigations were suggestive of cholangitis with large intrahepatic and extrahepatic bile duct strictures but otherwise normal hepatic and splenic appearances. A percutaneous transhepatic cholangiogram with the positioning of drains was performed to alleviate the obstructive jaundice. Within 2 weeks of the first presentation, full blood count revealed a significantly raised white blood count and a subsequent peripheral blood smear and bone marrow were consistent with a diagnosis of acute myeloid leukaemia. Chemotherapy was started after partial improvement of his obstructive jaundice. Complete morphological and cytogenetic remission was obtained 4 weeks after the first cycle of chemotherapy (half dose of daunorubicin and full dose of cytarabine, treated off trial) on control bone marrow. The patient remains in remission.

This article analyzes the network of phosphate producing sites in French colonial North Africa in the twentieth century. By tracing phosphate flows across the region between mining sites, and by placing the North African network into imperial and global perspective, the article develops the concept of a phosphate archipelago, capable of recognizing the shared specificities of the phosphate mines as extractive spaces and of describing their insertion into adjacent local and regional dynamics. Drawing on political-economic writings after World War One, the article focuses mainly on phosphates’ role in the colonial politics of economic autarky, but also touches on labour migration, the role of phosphates as an actor, and the trajectory of the phosphate archipelago in North Africa across the watershed of independence in the 1950s and down to the present day, when it plays a key role in the politics of global nutrition and food security.

Key content Management of uterine prolapse is currently heavily influenced by patient and surgeon preferences. The traditional approach to uterine prolapse is vaginal hysterectomy. However, this does not address the underlying deficiency in connective tissue pelvic floor support, and prolapse recurrence is common. Uterine preservation surgery is increasing in popularity, both with surgeons and patients; there is currently little evidence to show superior outcome to hysterectomy. Fertility preservation remains the one absolute indication for hysteropexy. Other potential advantages include stronger apical support and reduced vaginal surgery. Colpocleisis remains a valid option for a small cohort of patients. Learning objectives Options for the management of uterine prolapse. How to help patients decide on a management plan.

Tissue Inhibitor of Metalloproteinase 3 (TIMP3) is a secreted protein that has a great utility to inhibit elevated metalloproteinase (MMP) activity in injured tissues including infarcted cardiac tissue, inflamed vessels, and joint cartilages. An imbalance between TIMP3 and active MMP levels in the local tissue area may cause worsening of disease progression. To counter balance elevated MMP levels, exogenous administration of TIMP3 appeared to be beneficial in preclinical studies. However, the current form of WT‐TIMP3 molecule has a limitation to be a therapeutic candidate due to low production yield, short plasma half‐life, injection site retention, and difficulty in delivery, etc. We have engineered TIMP3 molecules by adding extra glycosylation sites or fusing with albumin, Fc, and antibody to improve pharmacokinetic properties. In general, the C‐terminal fusion of TIMP3 improved expression and production in mammalian cells and extended half‐lives dramatically 5‐20 folds. Of note, a site‐specific glycosylation at K22S/F34N resulted in a higher level of expression and better cardiac function compared to other fusion proteins in the context of left ventricle ejection fraction (LVEF) changes in a rat myocardial infarction model. It appeared that cardiac efficacy depends on a high ECM binding affinity, in which K22S/F34N and N‐TIMP3 showed a higher binding to the ECM compared to other engineered molecules. In conclusion, we found that the ECM binding and sustained residence of injected TIMP3 molecules are important for cardiac tissue localization and inhibition of adverse remodeling activity.

Background Failure to plan and document an appropriate ceiling of care can lead to treatment decisions being made urgently, out of hours, by a team unfamiliar with the patient; unwanted hospital admissions; investigations and treatments which do not contribute positively to the individual’s experience of care. To address this, we developed an electronic Treatment Escalation Plan (TEP) as part of the Electronic Patient Record. TEPs were implemented trust-wide in July 2015. This is part of a wider project to improve end of life care: Poole Hospital is part of ‘Building on the best’ in partnership with NCPC, Macmillan, and locally funded by Forest Holme Hospice Charity. Methods Electronic notes review of 40 consecutive adult inpatients who died within 100 days of hospital admission (index admission October 2015), using a standardised proforma (documentation of TEP or DNACPR, involvement of patients and families in discussions during the index admission). Run chart of TEP documentation showing how many electronic TEPs are created in EPR each month. Comparison with in–hospital mortality review in which notes of people who have died are reviewed by senior clinicians. Results Of 40 patients, 17 died during the index admission, with documented discussion of prognosis for 88%, electronic TEP for 29%, DNACPR for 100%. Of 23 who died subsequently, discussion of prognosis had been documented in the index admission for 17%, electronic TEP for 4%, DNACPR for 30%. There has been a significant increase in the median number of TEPs created: 44 per month (2015/16) to 140 per month (2016/17). In 2017, 90% of adults dying in hospital have a documented ceiling of care. Conclusion Treatment escalation plans are one way to improve decision making and documentation. TEPs are now widely used throughout the hospital, contributing to effective individualised care for people approaching the end of their life.

Background Uterovaginal prolapse in very elderly women is a growing problem due to increased life expectancy. Surgeons and anaesthetists may be wary of performing quality of life surgery on this higher risk group. Where surgery is undertaken, it is commonly performed vaginally; there is a perception that this is better tolerated than abdominal surgery. Little data is published about laparoscopic prolapse surgery tolerability in this population, and laparoscopic surgery is perceived within the urogynaecological community as complex and lengthy and hence inherently unsuitable for the very elderly. In Oxford, UK, laparoscopic abdominal surgical techniques are routinely employed for urogynaecological reconstructive surgery. The authors offer abdominal laparoscopic prolapse surgery to patients suitable for general anaesthesia with apical vaginal prolapse, irrespective of age. We here report outcomes in this elderly patient cohort and hypothesise these to be acceptable. This is a retrospective case note review of all patients aged 79 years old and above undergoing laparoscopic prolapse surgery (hysteropexy or sacrocolpopexy) in two centres in Oxford, UK, over a 5-year period (n = 55). Data were collected on length of surgery, length of stay, intraoperative complications, early and late post-operative complications and surgical outcome. Results Mean age was 82.6 years (range 79–96). There were no deaths. Minor post-operative complications such as UTI and constipation were frequent, but there were no serious (Clavien-Dindo grade III or above) complications; 80% achieved objective good anatomical outcome. Conclusions Laparoscopic prolapse surgery appears well tolerated in the elderly with low operative morbidity and mortality.

Focus: Lessons learned on diabetes pathogenesis based on human pancreas/isletsTitle:Designing a cell culture model to study the effects of ER stress involved in the pathogenesis of type 2 diabetes.Background:Diabetes is a debilitating disease that afflicts millions of individuals worldwide, and the statistics rise each year. Diabetes is associated with various ailments which reduce the quality of life, and has been shown to be associated with seemingly unrelated diseases or conditions. Finding an effective treatment for diabetes requires efficacious treatments that could be studied and screened in a model that closely resembles the pathogenesis of the disease.Aims:An INS-1E cell line model was investigated to study ER stress in the development of type 2 diabetes, with the potential to evaluate the efficacy of treatments associated with both ER stress and diabetes simultaneously.Methods:Pancreatic beta-cells (INS-1E) were treated with high glucose (33.3 mM) media with the natural ER stress inducer (interleukin-1beta) or synthetic compounds known to induce ER stress (tunicamycin, brefeldin-A, and thapsigargin) to evaluate the development of ER stress and its effect on insulin production. The MTT assay was used to assess the effect of the high glucose and ER stress inducers on cell viability, and cell electrical impedance using the Roche xCelligence system was used as a secondary cell viability assay. Nitric oxide was quantified to provide an indirect link between glucotoxicity and ER stress in the natural model involving the elevated interleukin-1beta levels. Flow cytometric analysis using Annexin-V and propidium iodide was used to validate the time points used for the model. An insulin ELISA was performed to determine the effect of hyperglycaemia and ER stress on the cells ability to produce and secrete insulin.Results:Data obtained from MTT, cell electrical impedance, and flow cytometric analysis of high glucose indicated that high glucose appeared to confer an initial protective feature to the cells, which later became deleterious to the cells as the high glucose became chronic. The ER stress inducers showed a gradual decline in cell viability over time; however, the synthetic ER stress inducers appeared to display far more potent cytotoxicity effects on the pancreatic beta cells than interleukin-1beta. Nitric oxide was only present when the cells were treated with interleukin-1beta, with high glucose exacerbating the production of nitric oxide. Insulin levels were markedly decreased with hyperglycaemia and the synthetic ER stress inducers, but retained normal levels when cultured with interleukin-1beta.Discussion:While each of the assays described give similar categories of results (i.e. cell viability), they address different aspects involved in biological systems, and each have their own advantages and disadvantages. The MTT data gave insight into cellular metabolism that is important to consider when studying metabolic diseases such as diabetes; however, the assay is an endpoint assay. The cell electrical impedance assay addresses this by providing real-time data of cells attaching and detaching from the surface of the plate, providing both cell viability and cell proliferation data, but lacking additional biochemical information such as pathways activated or modes of potential cell death. The flow cytometric analysis provides much needed data regarding the mode of cell death cells may experience in the presence of high glucose and/or ER stress inducers, as well as size dimension variations of the cells, but is again an endpoint assay that lacks real-time factors. Nitric oxide quantification gives an indication of potential inflammation within the model, which is a pivotal aspect to be considered when studying diabetes and ER stress. The insulin ELISA data answered the vital diabetes-related question of how the model, or any treatments screened in the model, influenced the production and secretion of insulin, the absence of which is often indicative of diabetes. Using these methods to build the foundation of an optimal cell culture model to study diabetes and various related conditions associated with diabetes and ER stress, the researcher is able investigate more specific biochemical pathways and processes much quicker and more efficiently.

Research on perceptions of discrimination has focused on group-based differential treatment that is widely accepted as being illegitimate (e.g., based on race or gender). The present research investigates how individuals interpret less obvious forms of group-based exclusion based on age (Study 1) and vision correction status (Study 2). We propose that individuals will not question the legitimacy of such treatment, unless they are provided with explicit cues to do so. Participants who merely encountered exclusion (baseline control) did not differ from those who were directed to consider the legitimate reasons for this treatment, with respect to perceived legitimacy, felt anger, and collective action intentions. In contrast, individuals who were directed to consider the illegitimate reasons for the exclusion perceived it to be less legitimate, felt more anger, and reported higher collective action intentions. Participants’ own status as potential victims or mere observers of the exclusion criterion did not influence their legitimacy perceptions or felt anger. Results suggest that when confronted with forms of group-based exclusion that are not commonly defined as discrimination, people do not perceive an injustice unless explicitly directed to seek it out.

Lipoprotein (a) [Lp(a)] is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions [with and without correction for Lp(a)-cholesterol] at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced.

Expo ’67, Montreal, was the first international exhibition Australia had attended since the 1939 New York World’s Fair. In New York, Australia promoted its export industries in timber and wool in an annex next to the British pavilion. In Montreal, Australia contributed its own major pavilion, a simple, rectangular box of glass and steel. Inside, the pavilion contained few actual exhibits. The main feature of its spacious interior was a salon-style arrangement of two hundred and forty lounge chairs created by the Australian designers Grant and Mary Featherston from an idea by the exhibit designer Robin Boyd. Visitors sat in the chairs to activate short, taped interviews with prominent Australians on aspects of Australian life and achievement, delivered though stereophonic speakers in the chairs’ headrests. Occasional tables stood nearby, bearing books on Australian society and ashtrays of a modern Australian design. One wall of the main exhibition hall featured a row of modernist paintings by leading Australian artists. Natural light streamed into the pavilion through its glazed north and south faces, which provided sweeping views across the exhibition site. Quality Australian wool carpet covered the pavilion’s floors and some internal walls, muffling incoming noise and adding to the general feeling of repose. Aspects of the pavilion’s interior suggest a range of architectural types: a hotel lobby, a corporate foyer, a gallery of modern art, and the living room of a large, modern home. The priority of modern design over specific symbols of Australian nationhood was unprecedented, its origin was in the government’s newfound eagerness to stress Australia’s modernization. Such progress was emphasized in Prime Minister Harold Holt’s four-minute interview on industrialization as a significant but little known feature of contemporary Australia. When questioned on the scale of Australian manufacturing in comparison to its more familiar rural sector, Holt described employment in industry as roughly equivalent to the USA, and higher than other recognized industrial nations such as Canada, France, and Japan.1 He identified Australia’s automobile, electrical, engineering, petroleum, mining, and steel industries as all experiencing rapid growth since 1939, and being “much more advanced and sophisticated than most people would realize.”2 The Prime Minister highlighted Australian inventions such as transistorized aviation beacons, radio telephone equipment, a 1 “Expo 67 Sound Chair Scripts. Notes for Interview with Prime Minister—Final Reading Text,” undated, National Archives of Australia (NAA): A463/1966/2141: 1. 2 Ibid., 3. © 2009 Massachusetts Institute of Technology

SummaryProprotein convertase subtilisin kexin type 9 (PCSK9) has been shown to be involved in the regulation of extracellular levels of the low-density lipoprotien receptor (LDLR). Although PCSK9 is a subtilase, it has not been shown to degrade the LDLR, and its LDLR-lowering mechanism remains uncertain. Here we report the crystal structure of human PCSK9 at 2.3 Å resolution. PCSK9 has subtilisin-like pro- and catalytic domains, and the stable interaction between these domains prevents access to PCSK9's catalytic site. The C-terminal domain of PCSK9 has a novel protein fold and may mediate protein-protein interactions. The structure of PCSK9 provides insight into its biochemical characteristics and biological function.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an attractive therapeutic target for cardiovascular disease. Monoclonal antibodies (mAbs) that bind PCSK9 and prevent PCSK9:low-density lipoprotein receptor complex formation reduce serum low-density lipoprotein-cholesterol (LDL-C) in vivo. PCSK9-mediated lysosomal degradation of bound mAb, however, dramatically reduces mAb exposure and limits duration of effect. Administration of high-affinity mAb1:PCSK9 complex (1:2) to mice resulted in significantly lower mAb1 exposure compared with mAb1 dosed alone in normal mice or in PCSK9 knockout mice lacking antigen. To identify mAb-binding characteristics that minimize lysosomal disposition, the pharmacokinetic behavior of four mAbs representing a diverse range of PCSK9-binding affinities at neutral (serum) and acidic (endosomal) pH was evaluated in cynomolgus monkeys. Results revealed an inverse correlation between affinity and both mAb exposure and duration of LDL-C lowering. High-affinity mAb1 exhibited the lowest exposure and shortest duration of action (6 days), whereas mAb2 displayed prolonged exposure and LDL-C reduction (51 days) as a consequence of lower affinity and pH-sensitive PCSK9 binding. mAbs with shorter endosomal PCSK9:mAb complex dissociation half-lives (

LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting LDL-C clearance. The therapeutic potential for PCSK9 inhibitors is highlighted by the fact that PCSK9 loss-of-function carriers exhibit 15-30% lower circulating LDL-C and a disproportionately lower risk (47-88%) of experiencing a cardiovascular event. Here, we utilized pcsk9(-/-) mice and an anti-PCSK9 antibody to study the role of the LDL receptor (LDLR) and ApoE in PCSK9-mediated regulation of plasma cholesterol and atherosclerotic lesion development. We found that circulating cholesterol and atherosclerotic lesions were minimally modified in pcsk9(-/-) mice on either an LDLR- or ApoE-deficient background. Acute administration of an anti-PCSK9 antibody did not reduce circulating cholesterol in an ApoE-deficient background, but did reduce circulating cholesterol (-45%) and TGs (-36%) in APOE*3Leiden.cholesteryl ester transfer protein (CETP) mice, which contain mouse ApoE, human mutant APOE3*Leiden, and a functional LDLR. Chronic anti-PCSK9 antibody treatment in APOE*3Leiden.CETP mice resulted in a significant reduction in atherosclerotic lesion area (-91%) and reduced lesion complexity. Taken together, these results indicate that both LDLR and ApoE are required for PCSK9 inhibitor-mediated reductions in atherosclerosis, as both are needed to increase hepatic LDLR expression.

BACKGROUND: Patients with atrial switch (Mustard or Senning) repair of D-transposition of the great arteries (D-TGA) are at increased risk for atrial arrhythmias, systemic right ventricular (RV) dysfunction and late mortality. OBJECTIVES: To evaluate case series from a single-centre experience with beta-blocker use in adult, post atrial switch, simple D-TGA patients. METHODS: The Adult Congenital Heart Disease Clinic (Halifax, Nova Scotia) database was used to identify patients with post atrial switch, simple D-TGA. Treatment effect of beta-blockade was evaluated. RESULTS: Eight patients were treated with beta-blockers for systemic RV dysfunction (n=2), arrhythmia (n=2) or both (n=4). Median follow-up was three years, at which time seven of eight patients were still on beta-blockade. Of those patients with complete data, two of five had improved systemic ventricular dysfunction, two of four had improved tricuspid regurgitation and four of six had improved functional capacity, as determined by history or exercise testing. Betablockade was well tolerated in seven of eight patients without any significant clinical deterioration. CONCLUSIONS: Beta-blockade was used infrequently in patients with a prior Mustard procedure. When beta-blockade was prescribed to patients with a prior atrial switch procedure, the drugs were well tolerated and were associated with trends toward improved symptoms, less tricuspid regurgitation and improved functional status in patients with reduced systemic RV function. These data support the need for a randomized trial of beta-blockade in patients with a previous Mustard or Senning operation and RV dysfunction.

OBJECTIVE: To determine the relative admission rates of Asian and non-Asian patients to intensive therapy units (ITUs) in Coventry and to explore the implications of these rates for the transplantation of organs to Asian people. DESIGN: Examination of 1991 census data and a retrospective review of ITU admissions books. Data were collected on ethnic background, presenting diagnosis, and clinical outcome for each admission. SETTING: The three ITUs in Coventry. PATIENTS: All admissions to the ITUs from 1990-93 inclusive. RESULTS: Asian patients were admitted to ITUs disproportionately to their numbers in the Coventry population. Members of the Asian community were less than half as likely to be admitted to an ITU (p < 0.001) and more likely to die while there (p = 0.007) than members of the non-Asian population in Coventry. The proportions of patients referred to the transplant unit and the rates of subsequent donation do not seem to differ significantly for Asian and non-Asian patients (p = 0.26 in both cases). CONCLUSIONS: There are clear implications for the availability of cadaveric kidney transplantation to Asian patients, given that few kidneys from non-Asian donors are histocompatible with Asian recipients. Indeed, in Asians, promotion of living related donation may be more effective in countering the organ shortfall than efforts to increase consent to cadaveric transplantation. However, it may be valuable to investigate any patterns of morbidity or social or cultural factors that might explain the initial low admissions rates to ITUs for Asian patients.

Osama E Elkhateeb Iqbal Bata Simon JacksonDalhousie University, Halifax, Nova Scotia, CanadaBackground: B-type natriuretic peptide (BNP) is a neurohormone released from the left ventricle in response to ventricular wall stress and pressure overload. BNP testing has been developed, and aids in identification of patients with suspected congestive heart failure (CHF). The objective of this study was to evaluate the role of BNP as a diagnostic marker of CHF, and determine its value in different clinical settings.Methods: A systematic review and meta-analysis of clinical studies regarding BNP and CHF was conducted. A comprehensive search of Medline, the Cochrane Library, and the reference sections of the primary studies was done. The methodologic quality of each study that met the inclusion criteria was assessed. The results of individual studies were described. The pooled sensitivity and specificity were calculated. Estimation of the diagnostic accuracy was done using meta-regression of the diagnostic odds ratio and summarized by a summary receiver-operating curve (S-ROC).Results: In total, 32 studies (n = 11054) met the inclusion criteria. The overall sensitivity and specificity at the optimum cutoff point are 81% (95% confidence interval: 0.76–0.86) and 86% (95% confidence interval: 0.81–0.89), respectively. The area under the S-ROC for all studies is 0.92. Nine papers included patients with dyspnea. The pooled negative likelihood ratio for this group was 0.12. Five studies included patients with chronic CHF and another seven studies included patients who were referred for echocardiography. The remaining studies were patients from the general population, patients with stable coronary artery disease, and patients referred for cardiac catheterization.Conclusion: BNP is a valuable tool in the diagnosis of CHF. It should be applied in the appropriate clinical setting. The strongest evidence of benefit for use of BNP is in patients presenting to the emergency room with dyspnea.Keywords: B-type natriuretic peptide, congestive heart failure, neurohormone, summary receiver-operating curve, dyspnea

'Britain's Farm' and 'America's Junior Partner': that's what Australia was labelled around the WWII period. Prior to WWII it is argued Australia was largely an agrarian nation serving the interests of the British Empire, while the threats posed by WWII marked the nation's transformation in becoming industrialised and 'Americanised'. The key themes of this paper will be exploring the industrialisation of Australia, and the cultural pull for Australian industrial designers between their country's old cultural and economic allegiances to Britain and the increasing post-WWII dominance of America.

Editor—Moller et al did not describe in detail the questionnaire that they used in their longitudinal study of lower urinary tract symptoms in women,1 but it seems to have been based on two different instruments.2,3 The Bristol female lower urinary tract symptoms questionnaire uses a five point scale for reporting symptoms.3 Respondents can reply “never,” “occasionally,” “sometimes,” “most of the time,” or “all of the time” when asked whether they have a particular symptom; when asked about frequency they can reply “never,” “once or less a week,” “2-3 times a week,” “once a day,” or “several times a day.” This raises the issue of reproducibility when the questionnaire is completed on more than one occasion. Reproducibility of our instrument was good when a test-retest analysis was performed with a two week interval, there being no apparent change in the underlying condition during that time; 78% of symptom questions were answered identically on both occasions, with no responses changing by more than two categories. The instrument used by Moller et al is reported to have fair to excellent reproducibility, but details are not supplied. The definition used for incidence in the authors' paper was “the proportion of women in whom symptoms arise or increase from sometimes to weekly or more.” Remission was defined as “the proportion of women with symptoms occurring weekly or more in whom symptoms decreased to less than weekly.” Thus, seemingly, a change in questionnaire response by one category could be recorded as incidence or remission. If reproducibility is similar to that of the Bristol female lower urinary tract symptoms questionnaire over 20% of women in whom there has been no apparent change in their underlying condition will change their response by one category or more over two weeks. Standardised questionnaires that have been tested for validity and reliability should be used whenever possible so that these types of measurement errors can be calculated. Moller et al may simply be confirming test-retest error, and the conclusion that there is an incidence and remission rate of 10.0% and 27.8% for female lower urinary tract symptoms over one year should be interpreted with caution.