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Abstract Objectives To understand how best to further reduce the inappropriate use of pre‐surgical androgen deprivation therapy (ADT), we investigated the determinants (influences) of ADT prescribing in urologists in two European countries using an established behavioural science approach. Additionally, we sought to understand how resource limitations caused by COVID‐19 influenced this practice. Identification of key determinants, of undistributed and disrupted practice, will aid development of future strategies to reduce inappropriate ADT prescribing in current and future resource‐limited settings. Participants and Methods We conducted semi‐structured qualitative interviews with urologists practicing in Italy and the UK from February to July 2022. Interviews focussed on undisrupted (usual) practice and disrupted practice (changes made during COVID‐19 restrictions). Codes were generated inductively and were mapped to the 14 domains of the Theoretical Domains Framework. Relevant domains of influence were identified, and the similarities and differences between the UK and Italy were distinguished. Results We identified 10 domains that were influential to ADT prescribing in the UK and eight in Italy. The role of guidance and evidence, the cancer care setting, the patients and the urologist's beliefs and experiences were identified as areas that were influential to ADT prescribing before surgery. Twenty‐one similarities and 22 differences between the UK and Italy, for usual and COVID‐19 practice, were identified across these 10 domains. Conclusion Similarities and differences influencing ADT prescribing prior to surgery should be considered in behavioural strategy development and tailoring to reduce inappropriate ADT use. We gained an understanding of usual, undistributed care and resource‐limited or disrupted care due to COVID‐19 in two European countries. This gives an indication of how influences on ADT prescribing may change in future resource‐limited circumstances and where efforts can be focused now and in future.

Abstract Context Prostate‐specific antigen is non‐specific for prostate cancer. This is improved by multiparametric MRI but a significant amount of indolent prostate cancer is detected by the current MRI pathway and data is emerging that clinically significant cancers maybe missed using a standard PSA threshold. Volatile organic compound (VOC) analysis may offer novel biomarkers for prostate cancer and clinically significant disease. Objective To perform a systematic review of the literature to evaluate the current evidence for the use of VOCs as novel biomarkers for prostate cancer and clinically significant prostate cancer. Evidence Acquisition A systematic search of MEDLINE, Scopus, Web of Science and the Cochrane Library was undertaken by two independent reviewers and papers were assessed for inclusion in the review. Study characteristics, sensitivity and specificity of GC–MS or eNose were extracted. Risk of bias and applicability issues were determined using QUADAS 2 and the quality of reporting using the STARD checklist. Evidence Synthesis Nineteen studies were included, of which 6 utilised eNose and 13 GC–MS. eNose sensitivity and specificity were 0.71–0.95 and 0.79–0.96, respectively, and GC–MS found a sensitivity and specificity of 0.66–1.00 and 0.53–0.97, respectively. There were concerns about bias in patient recruitment due to differences in the timing of the index test relative to the reference standard. Conclusion This review has found promising early results for urinary metabolomics in the detection of prostate cancer. However, there is a need for larger, high‐quality studies to validate this. Future work should focus on the detection of clinically significant prostate cancer.

Abstract Keeping up to date with the latest clinical advances in prostate cancer can be challenging. We investigated the impact of guideline use on quality of treatment decisions as well as the impact of a novel, CE-certified clinical decision support tool (Siemens AIPC software) on the amount of time clinicians spend on decision-making in a multicenter setting. Ten urologists assessed ten clinical cases (screening and localized prostate cancer) in three settings: without support, using a digital version of the EAU guidelines, and with the AIPC tool, resulting in 300 clinical decisions. Comparison involved time spent, decision correct- and completeness. Using AIPC compared to digital guidelines led to a significant reduction of expenditure of time at a per case level (3.57 min and 0:14 min, p

Context: Cancer and its treatments cause fatigue in up to 90% of men with advanced prostate cancer. As men with prostate cancer are surviving longer, cancer-related fatigue is becoming increasingly important for clinicians to understand and proactively manage. Objective: The aim of this work is to identify knowledge gaps that may support healthcare professionals to recommend personalised fatigue management strategies. Evidence acquisition: This manuscript is based on a roundtable discussion held during the European Association of Urology 2022 Annual Symposium, combined with a review of the literature. Five core themes were generated from the roundtable: (1) meaning of fatigue in prostate cancer patients, (2) impact of fatigue, (3) association between fatigue and treatment selection, (4) benefits of managing fatigue, and (5) barriers to exercise. Evidence synthesis: Cancer-related fatigue has complex underlying aetiology and is a subjective experience that may be under-reported. Some studies have shown that techniques such as education, cognitive behavioural therapy, guided imagery, and progressive muscle relaxation can result in clinically meaningful improvements in fatigue. However, the largest body of evidence, and a theme echoed in the roundtable discussions, was the benefit of exercise on fatigue. Despite the benefits of exercise, for some men, objective barriers to exercise exist and knowledge of benefits does not automatically translate into implementation and adherence. Conclusions: Understanding the specific health needs of individual patients and their desired health outcomes is essential to identify personalised strategies for minimising fatigue. As an outcome of the roundtable meeting, we developed a quick reference guide for healthcare providers. A high-resolution copy can be downloaded from https://patients.uroweb.org/library/fatigue-in-prostate-cancer-patients-guide/. Patient summary: This article is based on dialogue between a group of specialists, patients, and caregivers, which took place at a roundtable meeting during the European Association of Urology 2022 Annual Symposium. The group discussed how healthcare providers can best support their patients who experience fatigue. The group subsequently developed a guide to help healthcare providers during appointments.

Background and objective: The treatment landscape of metastatic prostate cancer (mPCa) has evolved significantly over the past two decades. Despite this, the optimal therapy for patients with mPCa has not been determined. This systematic review identifies available predictive models that assess mPCa patients’ response to treatment. Methods: We critically reviewed MEDLINE and CENTRAL in December 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Only quantitative studies in English were included with no time restrictions. The quality of the included studies was assessed using the PROBAST tool. Data were extracted following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews criteria. Key findings and limitations: The search identified 616 citations, of which 15 studies were included in our review. Nine of the included studies were validated internally or externally. Only one study had a low risk of bias and a low risk concerning applicability. Many studies failed to detail model performance adequately, resulting in a high risk of bias. Where reported, the models indicated good or excellent performance. Conclusions and clinical implications: Most of the identified predictive models require additional evaluation and validation in properly designed studies before these can be implemented in clinical practice to assist with treatment decision-making for men with mPCa. Patient summary: In this review, we evaluate studies that predict which treatments will work best for which metastatic prostate cancer patients. We found that existing studies need further improvement before these can be used by health care professionals.

Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in “real-life” patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

Human heroin addicts and mice administered morphine for a 2 week period show a greatly increased number of hypothalamic hypocretin (Hcrt or orexin) producing neurons with a concomitant reduction in Hcrt cell size. Male rats addicted to cocaine similarly show an increased number of detectable Hcrt neurons. These findings led us to hypothesize that humans with alcohol use disorder (AUD) would show similar changes. We now report that humans with AUD have a decreased number and size of detectable Hcrt neurons. In addition, the intermingled melanin concentrating hormone (MCH) neurons are reduced in size. We saw no change in the size and number of tuberomammillary histamine neurons in AUD. Within the Hcrt/MCH neuronal field we found that microglia cell size was increased in AUD brains. In contrast, male rats with 2 week alcohol exposure, sufficient to elicit withdrawal symptoms, show no change in the number or size of Hcrt, MCH and histamine neurons, and no change in the size of microglia. The present study indicates major differences between the response of Hcrt neurons to opioids and that to alcohol in human subjects with a history of substance abuse.

Abstract Global mean sea level has risen at an accelerating rate in the last decade and will continue to rise for centuries. The Amundsen Sea Embayment in West Antarctica is a critical region for present and future ice loss, however most studies consider only a worst-case future for the region. Here we use ice sheet model sensitivity experiments to investigate the centennial scale implications of short-term periods of enhanced ocean driven sub-ice shelf melting on ice loss and assess what future reduction in melting is necessary to mitigate ice stream retreat and offset global sea level rise. Our findings reveal that restoring elevated melt rates to present-day levels within 100 years causes rates of ice discharge to immediately decline, thereby limiting the overall sea level contribution from the region. However, while ice stream re-advance and slowed ice discharge is possible with reduced basal melting, a centennial scale increase in accumulation must occur to offset the extensive ice loss.

Background and objective: The ability of health care professionals to communicate with patients compassionately and effectively is crucial for shared decision-making, but little research has investigated patient-clinician communication. As part of PIONEER—an international Big Data Consortium led by the European Association of Urology to answer key questions for men with prostate cancer (PCa), funded through the IMI2 Joint Undertaking under grant agreement 777492— we investigated communication between men diagnosed with PCa and the health care professional(s) treating them across Europe. Methods: We used the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Communication 26, which was shared via the PIONEER and patient organisations on March 11, 2022. We sought men who spoke French, Italian, Spanish, German, Dutch, or English who were diagnosed with PCa and were undergoing or had already received treatment for their PCa. Results and limitations: A total of 372 men reported that they communicated with their clinician during either the diagnostic or the treatment period. Overall, the majority of participants reported positive experiences. However, important opportunities to enhance communication were identified, particularly with regard to correcting misunderstandings, understanding the patient’s preferred approach to information presentation, addressing challenging questions, supporting the patient’s comprehension of information, attending to the patient’s emotional needs, and assessing what information had already been given to patients about their disease and treatment, and how much of it was understood. Conclusions and clinical implications: These results help us to identify gaps and barriers to shared treatment decision making. This knowledge will help devise measures to improve patient-health care professional communication in the PCa setting. Patient summary: As part of the PIONEER initiative, we investigated the communication between men diagnosed with prostate cancer and their health care professionals across Europe. A total of 372 men from six different countries participated in the study. Most participants reported positive experiences, but areas where communication could be improved were identified. These included addressing misunderstandings, tailoring the presentation of information to the patient’s preferences, handling difficult questions, supporting emotional needs, and assessing the patient’s understanding of their diagnosis and treatment.

We observe the evacuation of 11-year-old landfast sea ice in the Larsen B embayment on the East Antarctic Peninsula in January 2022, which was in part triggered by warm atmospheric conditions and strong offshore winds. This evacuation of sea ice was closely followed by major changes in the calving behaviour and dynamics of a subset of the ocean-terminating glaciers in the region. We show using satellite measurements that, following a decade of gradual slow-down, Hektoria, Green, and Crane glaciers sped up by approximately 20 %–50 % between February and the end of 2022, each increasing in speed by more than 100 m a−1. Circumstantially, this is attributable to their transition into tidewater glaciers following the loss of their ice shelves after the landfast sea ice evacuation. However, a question remains as to whether the landfast sea ice could have influenced the dynamics of these glaciers, or the stability of their ice shelves, through a buttressing effect akin to that of confined ice shelves on grounded ice streams. We show, with a series of diagnostic modelling experiments, that direct landfast sea ice buttressing had a negligible impact on the dynamics of the grounded ice streams. Furthermore, we suggest that the loss of landfast sea ice buttressing could have impacted the dynamics of the rheologically weak ice shelves, in turn diminishing their stability over time; however, the accompanying shifts in the distributions of resistive stress within the ice shelves would have been minor. This indicates that this loss of buttressing by landfast sea ice is likely to have been a secondary process in the ice shelf disaggregation compared to, for example, increased ocean swell or the drivers of the initial landfast sea ice disintegration.

BackgroundIntradural extramedullary teratomas in the cervical or cervicomedullary region are rare in adults.Case descriptionWe report a symptomatic, mature teratoma at the cervicomedullary junction in a 52-year-old Hispanic female who also has a type I diastematomyelia in the thoracolumbar spine. The patient underwent surgical resection of the lesion with the resolution of presenting symptoms. Histopathology of the lesion revealed a mature cystic teratoma with pulmonary differentiation.ConclusionWe discuss the case along with a review of pertinent literature and considerations with regard to the diagnosis, etiology, prognosis, and management of this unusual pathology.

Mass loss from the Amundsen Sea Embayment of the West Antarctic Ice Sheet is a major contributor to global sea-level rise (SLR) and has been increasing over recent decades. Predictions of future SLR are increasingly modelled using ensembles of simulations within which model parameters and external forcings are varied within credible ranges. Accurately reporting the uncertainty associated with these predictions is crucial in enabling effective planning for, and construction of defences against, rising sea levels. Calibrating model simulations against current observations of ice-sheet behaviour enables the uncertainty to be reduced. Here we calibrate an ensemble of BISICLES ice-sheet model simulations of ice loss from the Amundsen Sea Embayment using remotely sensed observations of surface elevation and ice speed. Each calibration type is shown to be capable of reducing the 90% credibility bounds of predicted contributions to SLR by 34 and 43% respectively.

BackgroundNemaline myopathies are congenital or acquired muscle disorders that typically present in childhood but can occasionally occur in adults with underlying malignant, infectious or autoimmune disorders. There is a great genetic heterogeneity as well as clinical variability among the disease.Case presentationHere, we present a case of nemaline myopathy in a young woman who was newly diagnosed with systemic lupus erythematosus (SLE) and Sjögren's overlap syndrome complicated by macrophage activation syndrome (MAS). She had no personal or family history of myopathy and was reporting progressive thigh weakness. A muscle biopsy revealed type 1 myofiber predominance with granular material in atrophic myocytes consistent with nemaline myopathy. Her symptoms markedly improved with immunotherapy for her SLE and MAS supporting the diagnosis of sporadic late-onset nemaline myopathy (SLONM) associated with her autoimmune disease.ConclusionsSLONM is a type of nemaline myopathy that presents in adults and can occasionally be associated with autoimmune disease. In these cases, treatment of the underlying disorder with immunosuppression appears to improve symptoms of myopathy.

Rationale and objectives: The potential of breast microcalcification chemistry to provide clinically valuable intelligence is being increasingly studied. However, acquisition of crystallographic details has, to date, been limited to high brightness, synchrotron radiation sources. This study, for the first time, evaluates a laboratory-based system that interrogates histological sections containing microcalcifications. The principal objective was to determine the measurement precision of the laboratory system and assess whether this was sufficient to provide potentially clinical valuable information. Materials and methods: Sections from 5 histological specimens from breast core biopsies obtained to evaluate mammographic calcification were examined using a synchrotron source and a laboratory-based instrument. The samples were chosen to represent a significant proportion of the known breast tissue, mineralogical landscape. Data were subsequently analysed using conventional methods and microcalcification characteristics such as crystallographic phase, chemical deviation from ideal stoichiometry and microstructure were determined. Results: The crystallographic phase of each microcalcification (e.g., hydroxyapatite, whitlockite) was easily determined from the laboratory derived data even when a mixed phase was apparent. Lattice parameter values from the laboratory experiments agreed well with the corresponding synchrotron values and, critically, were determined to precisions that were significantly greater than required for potential clinical exploitation. Conclusion: It has been shown that crystallographic characteristics of microcalcifications can be determined in the laboratory with sufficient precision to have potential clinical value. The work will thus enable exploitation acceleration of these latent microcalcification features as current dependence upon access to limited synchrotron resources is minimized.

The fracturing of glaciers and ice shelves in Antarctica influences their dynamics and stability. Hence, data on the evolving distribution of crevasses are required to better understand the evolution of the ice sheet, though such data have traditionally been difficult and time-consuming to generate. Here, we present an automated method of mapping crevasses on grounded and floating ice with the application of convolutional neural networks to Sentinel-1 synthetic aperture radar backscatter data. We apply this method across Antarctica to images acquired between 2015 and 2022, producing a 7.5-year record of composite fracture maps at monthly intervals and 50 m spatial resolution and showing the distribution of crevasses around the majority of the ice sheet margin. We develop a method of quantifying changes to the density of ice shelf fractures using a time series of crevasse maps and show increases in crevassing on Thwaites and Pine Island ice shelves over the observational period, with observed changes elsewhere in the Amundsen Sea dominated by the advection of existing crevasses. Using stress fields computed using the BISICLES ice sheet model, we show that much of this structural change has occurred in buttressing regions of these ice shelves, indicating a recent and ongoing link between fracturing and the developing dynamics of the Amundsen Sea sector.

Antarctica's ice shelves modulate the grounded ice flow, and weakening of ice shelves due to climate forcing will decrease their 'buttressing' effect, causing a response in the grounded ice. While the processes governing ice-shelf weakening are complex, uncertainties in the response of the grounded ice sheet are also difficult to assess. The Antarctic BUttressing Model Intercomparison Project (ABUMIP) compares ice-sheet model responses to decrease in buttressing by investigating the 'end-member' scenario of total and sustained loss of ice shelves. Although unrealistic, this scenario enables gauging the sensitivity of an ensemble of 15 ice-sheet models to a total loss of buttressing, hence exhibiting the full potential of marine ice-sheet instability. All models predict that this scenario leads to multi-metre (1-12 m) sea-level rise over 500 years from present day. West Antarctic ice sheet collapse alone leads to a 1.91-5.08 m sea-level rise due to the marine ice-sheet instability. Mass loss rates are a strong function of the sliding/friction law, with plastic laws cause a further destabilization of the Aurora and Wilkes Subglacial Basins, East Antarctica. Improvements to marine ice-sheet models have greatly reduced variability between modelled ice-sheet responses to extreme ice-shelf loss, e.g. compared to the SeaRISE assessments.

Abstract Background The association of testicular microlithiasis with testicular tumour and the need for follow-up remain largely unclear. Methods We conducted a national questionnaire survey involving consultant BAUS members (BAUS is the official national organisation (like the AUA in USA) of the practising urologists in the UK and Ireland), to provide a snapshot of current attitudes towards investigation and surveillance of patients with testicular microlithiasis. Results Of the 464 questionnaires sent to the BAUS membership, 263(57%) were returned. 251 returns (12 were incomplete) were analysed, of whom 173(69%) do and 78(31%) do not follow-up testicular microlithiasis. Of the 173 who do follow-up, 119(69%) follow-up all patients while 54(31%) follow-up only a selected group of patients. 172 of 173 use ultra sound scan while 27(16%) check tumour makers. 10(6%) arrange ultrasound scan every six months, 151(88%) annually while 10(6%) at longer intervals. 66(38%) intend to follow-up these patients for life while, 80(47%) until 55 years of age and 26(15%) for up to 5 years. 173(68.9%) believe testicular microlithiasis is associated with CIS in < 1%, 53(21%) think it is between 1&10% while 7(3%) believe it is > 10%. 109(43%) believe those patients who develop a tumour, will have survival benefit with follow-up while 142(57%) do not. Interestingly, 66(38%) who follow-up these patients do not think there is a survival benefit. Conclusion There is significant variability in how patients with testicular microlithiasis are followed-up. However a majority of consultant urologists nationally, believe surveillance of this patient group confers no survival benefit. There is a clear need to clarify this issue in order to recommend a coherent surveillance policy.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Structured-grid adaptive mesh refinement (SAMR) is an approach to mesh generation that supports structured access to data and adaptive mesh refinement for discretized partial differential equations (PDEs). Solution algorithms often require that an inverse of an operator be applied, a system of algebraic equations must be solved, and this process is often the primary computational cost in an application. SAMR is well suited to geometric multigrid solvers, which can be effective, but often do not adapt well to complex geometry including material coefficients. Algebraic multigrid (AMG) is more robust in the face of complex geometry, in both boundary conditions and internal material interfaces. AMG requires a stored matrix linearization of the operator. We discuss an approach, and an implementation in the Chombo block-structured AMR framework, for constructing composite grid matrices from a SAMR hierarchy of grids for use in linear solvers in the PETSc numerical library. We consider a case study with the Chombo-based BISICLES ice sheet modeling application.

Structured-grid adaptive mesh refinement (SAMR) is an approach to mesh generation that supports structured access to data and adaptive mesh refinement for discretized partial differential equations (PDEs). Solution algorithms often require that an inverse of an operator be applied, a system of algebraic equations must be solved, and this process is often the primary computational cost in an application. SAMR is well suited to geometric multigrid solvers, which can be effective, but often do not adapt well to complex geometry including material coefficients. Algebraic multigrid (AMG) is more robust in the face of complex geometry, in both boundary conditions and internal material interfaces. AMG requires a stored matrix linearization of the operator. We discuss an approach, and an implementation in the Chombo block-structured AMR framework, for constructing composite grid matrices from a SAMR hierarchy of grids for use in linear solvers in the PETSc numerical library. We consider a case study with the Chombo-based BISICLES ice sheet modeling application.

The Antarctic Ice Sheet (AIS) remains the largest uncertainty in projections of future sea level rise. A likely climate-driven vulnerability of the AIS is thinning of floating ice shelves resulting from surface-melt-driven hydrofracture or incursion of relatively warm water into subshelf ocean cavities. The resulting melting, weakening, and potential ice shelf collapse reduces shelf buttressing effects. Upstream ice flow accelerates, causing thinning, grounding-line retreat, and potential ice sheet collapse. While high-resolution projections have been performed for localized Antarctic regions, full-continent simulations have typically been limited to low-resolution models. Here we quantify the vulnerability of the entire present-day AIS to regional ice shelf collapse on millennial timescales treating relevant ice flow dynamics at the necessary ∼1-km resolution. Collapse of any of the ice shelves dynamically connected to the West Antarctic Ice Sheet (WAIS) is sufficient to trigger ice sheet collapse in marine-grounded portions of the WAIS. Vulnerability elsewhere appears limited to localized responses.

Ice shelves play a key role in the dynamics of marine ice sheets by buttressing grounded ice and limiting rates of ice flux to the oceans. In response to recent climatic and oceanic change, ice shelves fringing the West Antarctic Ice Sheet (WAIS) have begun to fragment and retreat, with major implications for ice-sheet stability. Here, we focus on the Thwaites Eastern Ice Shelf (TEIS), the remaining pinned floating extension of Thwaites Glacier. We show that TEIS has undergone a process of fragmentation in the last 5 years, including brittle failure along a major shear zone, formation of tensile cracks on the main body of the shelf, and a release of tabular bergs on both the eastern and western flanks. Simulations with the Helsinki Discrete Element Model (HiDEM) show that this pattern of failure is associated with high backstress from a submarine pinning point at the distal edge of the shelf. We show that a significant zone of shear, upstream of the main pinning point, developed in response to the rapid acceleration of the shelf between 2002 and 2006, seeding damage on the shelf. Subsequently, basal melting and positive feedback between damage and strain rates weakened TEIS, allowing damage to accumulate. Thus, although backstress on TEIS has likely diminished over time as the pinning point shrunk, accumulation of damage has ensured that the ice in the shear zone remained the weakest link in the system. Experiments with the BISICLES ice-sheet model indicate that additional damage to or unpinning of TEIS is unlikely to trigger significantly increased ice loss from WAIS, but the calving response to the loss of TEIS remains highly uncertain. It is widely recognised that ice-shelf fragmentation and collapse can be triggered by hydrofracturing and/or unpinning from ice-shelf margins or grounding points. Our results indicate a third mechanism, backstress triggered failure, that can occur if and when an ice shelf is no longer able to withstand stress imposed by pinning points. In most circumstances, pinning points are essential for ice-shelf stability, but as ice shelves thin and weaken, the concentration of backstress in damaged ice upstream of a pinning point may provide the seeds of their demise.

Summary:. Knee arthroplasty, both total knee and unicompartmental, has had a significant impact on millions of patients globally. Although satisfaction is usually high, complications such as periprosthetic fracture are increasingly common. Distal femur periprosthetic fractures are relatively well researched and understood in comparison with periprosthetic proximal tibia fractures (PTFs). The management of PTFs is essentially an evidence-free area. This review explores the literature (or lack thereof) and integrates cases from Australia and Japan. As it stands, there is scant literature relating to all facets of PTFs, including, most concerningly, the management of them. Larger studies are required to help further investigate this important interface between arthroplasty and orthopaedic trauma. As a guide, those with loose prostheses will likely benefit most from revision total knee arthroplasty, while those with well-fixed prostheses can be managad according to the fracture with homage paid to the presence of the prosthesis. The use of periarticular locked plates is likely a better option over conventional large or small fragment plates. Nonoperative management is a viable option for selected individuals and can be associated with favorable outcomes.

The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.

The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.

Introduction: Climate change is a health emergency. Health organizations have a responsibility to engage with this crisis via advocacy, education, research, divestment and by rapidly reducing their carbon emissions. This report aims to establish what progress has been made by UK health organizations and identify areas requiring further action. Methodology: A cross-sectional survey examined four domains: internal operations; education and training; divestment; and advocacy. Scores were presented according to rank in scorecard format. Results: 28 UK health organizations were asked to participate, with a 39% response rate. Total scores ranged from 13 to 41.75 out of 64 points. The Royal College of Paediatrics and Child Health achieved the highest score (41.75) followed by the Royal College of Psychiatrists (39.5) and the Royal College of General Practitioners (38.5). Discussion: Health organizations are well-placed to: educate their members on the health impacts of climate change; advocate for legal and political change; lead by example by enacting their own decarbonization plans and minimizing their carbon emissions; and by divesting financially from fossil fuels. Organizations showed varying levels of action, with many not participating or scoring poorly. However, there was evidence of some excellent work and growing levels of engagement. Conclusion: This report identifies positive climate action alongside opportunities for growth among UK health organizations. Although considerable advances are being made, these are not to the scale or speed required to secure a liveable future for all. We hope that this work will support organizations in taking further action.

A glacial origin for cirque-like hollows cut into the western escarpment of the Usk valley near Abergavenny, South Wales has become widely accepted. Associated supposed extensive moraine 'festoons' have been depicted merging and contemporaneous with Last Glacial Maximum (LGM) deposits formed by ice occupying the adjacent Usk valley. We re-interpret these festoons as the product mainly of rock slope failures (RSFs) emanating from the hollows. A cirque glacier origin is preferred to account for a compact double-ridge feature in one of the hollows. The equilibrium-line altitude (ELA) of the reconstructed glacier (357 m) is > 60 m lower than all similarly small, presumed Younger Dryas Stadial (YDS; c. , 12.9–11.7 ka) glaciers elsewhere in South Wales. To test whether this glacier nevertheless might date from the YDS, we apply three approaches to reconstruct annual palaeo-precipitation amounts at the ELA, two based on relationships between accumulation and ablation for modern glaciers and the third on a simple degree-day model (DDM) using likely climatic characteristics for this event. The DDM can be tailored to represent the recognised large-amplitude YDS annual temperature range rather than the much smaller one experienced by modern glaciers, making it our preferred approach. Although conditions along the Usk valley escarpment during the LGM would have been well suited to cirque glacier formation, the DDM approach, using the large-amplitude annual temperature ranges, suggests that a YDS age might also be possible. The results have implications for re-assessing the likely ages of some former small glaciers in South Wales. [ABSTRACT FROM AUTHOR]

Antarctica's ice shelves modulate the grounded ice flow, and weakening of ice shelves due to climate forcing will decrease their ‘buttressing’ effect, causing a response in the grounded ice. While the processes governing ice-shelf weakening are complex, uncertainties in the response of the grounded ice sheet are also difficult to assess. The Antarctic BUttressing Model Intercomparison Project (ABUMIP) compares ice-sheet model responses to decrease in buttressing by investigating the ‘end-member’ scenario of total and sustained loss of ice shelves. Although unrealistic, this scenario enables gauging the sensitivity of an ensemble of 15 ice-sheet models to a total loss of buttressing, hence exhibiting the full potential of marine ice-sheet instability. All models predict that this scenario leads to multi-metre (1–12 m) sea-level rise over 500 years from present day. West Antarctic ice sheet collapse alone leads to a 1.91–5.08 m sea-level rise due to the marine ice-sheet instability. Mass loss rates are a strong function of the sliding/friction law, with plastic laws cause a further destabilization of the Aurora and Wilkes Subglacial Basins, East Antarctica. Improvements to marine ice-sheet models have greatly reduced variability between modelled ice-sheet responses to extreme ice-shelf loss, e.g. compared to the SeaRISE assessments.

At least in conventional hydrostatic ice-sheet models, the numerical error associated with grounding line dynamics can be reduced by modifications to the discretization scheme. These involve altering the integration formulae for the basal traction and/or driving stress close to the grounding line and exhibit lower - if still first-order - error in the MISMIP3d experiments. MISMIP3d may not represent the variety of real ice streams, in that it lacks strong lateral stresses, and imposes a large basal traction at the grounding line. We study resolution sensitivity in the context of extreme forcing simulations of the entire Antarctic ice sheet, using the BISICLES adaptive mesh ice-sheet model with two schemes: the original treatment, and a scheme, which modifies the discretization of the basal traction. The second scheme does indeed improve accuracy - by around a factor of two - for a given mesh spacing, but km resolution is still necessary. For example, in coarser resolution simulations Thwaites Glacier retreats so slowly that other ice streams divert its trunk. In contrast, with km meshes, the same glacier retreats far more quickly and triggers the final phase of West Antarctic collapse a century before any such diversion can take place.

Coupled ice sheet-ocean models capable of simulating moving grounding lines are just becoming available. Such models have a broad range of potential applications in studying the dynamics of marine ice sheets and tidewater glaciers, from process studies to future projections of ice mass loss and sea level rise. The Marine Ice Sheet-Ocean Model Intercomparison Project (MISOMIP) is a community effort aimed at designing and coordinating a series of model intercomparison projects (MIPs) for model evaluation in idealized setups, model verification based on observations, and future projections for key regions of the West Antarctic Ice Sheet (WAIS). Here we describe computational experiments constituting three interrelated MIPs for marine ice sheet models and regional ocean circulation models incorporating ice shelf cavities. These consist of ice sheet experiments under the Marine Ice Sheet MIP third phase (MISMIP+), ocean experiments under the Ice Shelf-Ocean MIP second phase (ISOMIP+) and coupled ice sheet-ocean experiments under the MISOMIP first phase (MISOMIP1). All three MIPs use a shared domain with idealized bedrock topography and forcing, allowing the coupled simulations (MISOMIP1) to be compared directly to the individual component simulations (MISMIP+ and ISOMIP+). The experiments, which have qualitative similarities to Pine Island Glacier Ice Shelf and the adjacent region of the Amundsen Sea, are designed to explore the effects of changes in ocean conditions, specifically the temperature at depth, on basal melting and ice dynamics. In future work, differences between model results will form the basis for the evaluation of the participating models.

Coupled ice sheet-ocean models capable of simulating moving grounding lines are just becoming available. Such models have a broad range of potential applications in studying the dynamics of marine ice sheets and tidewater glaciers, from process studies to future projections of ice mass loss and sea level rise. The Marine Ice Sheet-Ocean Model Intercomparison Project (MISOMIP) is a community effort aimed at designing and coordinating a series of model intercomparison projects (MIPs) for model evaluation in idealized setups, model verification based on observations, and future projections for key regions of the West Antarctic Ice Sheet (WAIS). Here we describe computational experiments constituting three interrelated MIPs for marine ice sheet models and regional ocean circulation models incorporating ice shelf cavities. These consist of ice sheet experiments under the Marine Ice Sheet MIP third phase (MISMIP+), ocean experiments under the Ice Shelf-Ocean MIP second phase (ISOMIP+) and coupled ice sheet-ocean experiments under the MISOMIP first phase (MISOMIP1). All three MIPs use a shared domain with idealized bedrock topography and forcing, allowing the coupled simulations (MISOMIP1) to be compared directly to the individual component simulations (MISMIP+ and ISOMIP+). The experiments, which have qualitative similarities to Pine Island Glacier Ice Shelf and the adjacent region of the Amundsen Sea, are designed to explore the effects of changes in ocean conditions, specifically the temperature at depth, on basal melting and ice dynamics. In future work, differences between model results will form the basis for the evaluation of the participating models.

PurposeRising complexity of patients and the consideration of heterogeneous information from various IT systems challenge the decision-making process of urological oncologists. Siemens AI Pathway Companion is a decision support tool that provides physicians with comprehensive patient information from various systems. In the present study, we examined the impact of providing organized patient information in comprehensive dashboards on information quality, effectiveness, and satisfaction of physicians in the clinical decision-making process.MethodsTen urologists in our department performed the entire diagnostic workup to treatment decision for 10 patients in the prostate cancer screening setting. Expenditure of time, information quality, and user satisfaction during the decision-making process with AI Pathway Companion were recorded and compared to the current workflow.ResultsA significant reduction in the physician's expenditure of time for the decision-making process by -59.9% (p < 0,001) was found using the software. System usage showed a high positive effect on evaluated information quality parameters completeness (Cohen's d of 2.36), format (6.15), understandability (2.64), as well as user satisfaction (4.94).ConclusionThe software demonstrated that comprehensive organization of information improves physician's effectiveness and satisfaction in the clinical decision-making process. Further development is needed to map more complex patient pathways, such as the follow-up treatment of prostate cancer.