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Purpose: There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%). Results: A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001). Conclusions: Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.

BackgroundInnovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence.ObjectiveTo present the voting results of the APCCC 2022.Design, setting, and participantsThe experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions.Outcome measurements and statistical analysisThe panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions.Results and limitationsThe voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer.ConclusionsThese voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials.

Predictive maintenance is essential for complex industrial systems to foresee anomalies before major system faults or ultimate breakdown. However, the existing efforts on Industry 4.0 predictive monitoring are directed at semi-supervised anomaly detection with limited robustness for large systems, which are often accompanied by uncleaned and unlabeled data. We address the challenge of predicting anomalies through data-driven end-to-end deep learning models using early warning symptoms on multivariate time series sensor data. We introduce AnoP, a long multi-timestep anomaly prediction system based on unsupervised attention-based causal residual networks, to raise alerts for anomaly prevention. The experimental evaluation on large data sets from detector health monitoring of the Hadron Calorimeter of the CMS Experiment at LHC CERN demonstrates the promising efficacy of the proposed approach. AnoP predicted around 60% of the anomalies up to seven days ahead, and the majority of the missed anomalies are abnormalities with unpredictable noisy-like behavior. Moreover, it has discovered previously unknown anomalies in the calorimeter’s sensors.

The human epidermal growth factor receptor 2 (HER2, ERBB2) is amplified or overexpressed in approximately 20% of breast cancers. HER2 amplification results in increased homodimerization and HER3 heterodimerization, with HER2/HER3 heterodimers promoting cell proliferation via the mitogen-activated protein kinase/AKT pathway and also evasion of apoptosis via the phosphatidylinositol 3-kinase (PI3K) signaling cascade. Oncogenic mutations in PI3KCA render tumor cells resistant to drugs that block HER2 dimerization, thereby promoting cell survival. Although several approved HER2-directed agents have shown significant survival improvements for HER2-positive patients, in the metastatic setting, nearly all of these patients will ultimately progress and die of their disease.

Representativeness of Study Participants

CONSORT Diagram

Purpose:There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).Patients and Methods:This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%).Results:A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001).Conclusions:Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.

Slow-wave sleep (SWS) is a fundamental physiological process, and its modulation is of interest for basic science and clinical applications. However, automatised protocols for the suppression of SWS are lacking. We describe the development of a novel protocol for the automated detection (based on the whole head topography of frontal slow waves) and suppression of SWS (through closed-loop modulated randomised pulsed noise), and assessed the feasibility, efficacy and functional relevance compared to sham stimulation in 15 healthy young adults in a repeated-measure sleep laboratory study. Auditory compared to sham stimulation resulted in a highly significant reduction of SWS by 30% without affecting total sleep time. The reduction of SWS was associated with an increase in lighter non-rapid eye movement sleep and a shift of slow-wave activity towards the end of the night, indicative of a homeostatic response and functional relevance. Still, cumulative slow-wave activity across the night was significantly reduced by 23%. Undisturbed sleep led to an evening to morning reduction of wake electroencephalographic theta activity, thought to reflect synaptic downscaling during SWS, while suppression of SWS inhibited this dissipation. We provide evidence for the feasibility, efficacy, and functional relevance of a novel fully automated protocol for SWS suppression based on auditory closed-loop stimulation. Future work is needed to further test for functional relevance and potential clinical applications.

Northern Germany is a weak seismicity region with low level of exposure to seismic hazard. Accordingly, seismic hazard assessment has been pursued with low priority in the past. Rather poor observational conditions in the North German Basin are also a limiting factor for seismic monitoring. In a multi-institutional collaboration, we have been able to increase the number of permanent broadband stations in the North German Federal States of Schleswig-Holstein and Mecklenburg-Vorpommern from previously four in the year 2013 to currently fifteen. All data of the network are freely available through the EIDA node at the Federal Institute for Geosciences and Natural Resources (BGR) in Hannover.Three complementary seismic arrays, notably on the islands of Heligoland in the North Sea and on Rügen in the Baltic Sea, improve monitoring capabilities of offshore areas. Data from these seismic arrays also provide an opportunity to investigate properties of oceanic microseism in epicontinental seas.In addition to the development and operation of the seismic network, continuous event detection and analysis routines have been established at Kiel University. Besides low magnitude earthquakes, other natural phenomena like rockslides on cliffs or subrosion events have been repeatedly detected. Known controlled explosions provide an opportunity to quantify detection and location capabilities of the network. The recent destruction of the Nord Stream gas pipelines proved the importance of ongoing network expansion, and the need and reliability of routine seismic monitoring in this region., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

Cybersecurity planning is challenging for digitized companies that want adequate protection without overspending money. Currently, the lack of investments and perverse economic incentives are the root cause of cyberattacks, which results in several economic impacts on companies worldwide. Therefore, cybersecurity planning has to consider technical and economic dimensions to help companies achieve a better cybersecurity strategy. This article introduces SECAdvisor, a tool to support cybersecurity planning using economic models. SECAdvisor allows to (a) understand the risks and valuation of different businesses' information, (b) calculate the optimal investment in cybersecurity for a company, (c) receive a recommendation of protections based on the budget available and demands, and (d) compare protection solutions in terms of cost-efficiency. Furthermore, evaluations on usability and real-world training activities performed using SECAdvisor are discussed., Comment: 12 pages, 7 figures, 2 tables, 9 equations

Contains fulltext : 291600.pdf (Publisher’s version ) (Open Access) BACKGROUND: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management. OBJECTIVE: To present consensus voting results for select questions from APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. RESULTS AND LIMITATIONS: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis. CONCLUSIONS: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions.

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence. Objective: To present the results from the APCCC 2019. Design, setting, and participants: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naive prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions. Outcome measurements and statistical analysis: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process. Results and limitations: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material. Conclusions: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials. Patient summary: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.

PURPOSE To describe a newly established international registry recruiting diverse patients with advanced prostate cancer across academic and community practices to address unmet needs in this population. PATIENTS AND METHODS Initiated in 2017, IRONMAN (International Registry for Men with Advanced Prostate Cancer) is a prospective cohort of patients with advanced prostate cancer. The study will enroll 5,000 patients with metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC), recruited from Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, the United Kingdom, and the United States. The study is collecting datatypes to study variation in care and treatment of advanced prostate cancer across countries and across academic, community-based, and government practices with a focus on clinical outcomes, patient-reported outcomes, epidemiologic data, biologic subtypes, and clinician questionnaires. RESULTS Through July 2022, 2,682 eligible patients were enrolled in 11 of 12 active countries. Sixty-six percent of patients have mHSPC, and 34% have CRPC. On the basis of self-report, 11% of patients are Black and 9% are Hispanic. Five Veterans Affairs Medical Centers are enrolling patients. Globally, 23% of patients report being veterans of military service. CONCLUSION To our knowledge, this is the first international cohort of people newly diagnosed with advanced prostate cancer designed to describe variations in patient management, experiences, and outcomes. IRONMAN aims to identify optimal treatment sequences to improve survival, understand patient-reported outcomes, and explore novel biomarkers to understand treatment resistance mechanisms. Insights from IRONMAN will inform and guide future clinical management of people with mHSPC and CRPC. This cohort study will provide real-world evidence to facilitate a better understanding of the survivorship of people with advanced prostate cancer.

Patients with advanced prostate cancer (APC) may be at greater risk for severe illness, hospitalisation, or death from coronavirus disease 2019 (COVID-19) due to male gender, older age, potential immunosuppressive treatments, or comorbidities. Thus, the optimal management of APC patients during the COVID-19 pandemic is complex. In October 2021, during the Advanced Prostate Cancer Consensus Conference (APCCC) 2021, the 73 voting members of the panel members discussed and voted on 13 questions on this topic that could help clinicians make treatment choices during the pandemic. There was a consensus for full COVID-19 vaccination and booster injection in APC patients. Furthermore, the voting results indicate that the expert’s treatment recommendations are influenced by the vaccination status: the COVID-19 pandemic altered management of APC patients for 70% of the panellists before the vaccination was available but only for 25% of panellists for fully vaccinated patients. Most experts (71%) were less likely to use docetaxel and abiraterone in unvaccinated patients with metastatic hormone-sensitive prostate cancer. For fully vaccinated patients with high-risk localised prostate cancer, there was a consensus (77%) to follow the usual treatment schedule, whereas in unvaccinated patients, 55% of the panel members voted for deferring radiation therapy. Finally, there was a strong consensus for the use of telemedicine for monitoring APC patients. Patient summary In the Advanced Prostate Cancer Consensus Conference 2021, the panellists reached a consensus regarding the recommendation of the COVID-19 vaccine in prostate cancer patients and use of telemedicine for monitoring these patients.

BACKGROUND: Over recent years, the incidence of renal cell carcinoma (RCC) has remained unchanged in Switzerland and is low compared with other European countries. Partial or radical nephrectomy is the mainstay of treatment in patients with localised disease. METHODS: We conducted an analysis of data from the cancer registry of Eastern Switzerland on patients with surgery for RCC from 2009 to 2018, focusing on a comparison of surgical technique and outcome in tertiary and non-tertiary hospitals. RESULTS: 492 nephrectomies were performed. Out of 441 curative procedures, 226 were radical and 195 partial nephrectomies (20 unknown). At the tertiary hospital, statistically significantly more partial nephrectomies were performed in non-metastatic patients than at non-tertiary hospitals. We demonstrate a trend towards better disease-free survival after partial compared with radical nephrectomy. The 5-year overall survival for patients diagnosed between 2009 and 2013 was 85%, 83%, and 70% in stage I, II, and III, respectively, compared with 96%, 78%, and 72% for patients diagnosed between 2014 and 2018. CONCLUSION: RCC incidence in Switzerland has been stable during the past decade in contrast to other European countries, and no stage migration occurred. We demonstrated that patients with localised renal cancer at our tertiary centre were more likely to be treated with renal preserving surgery compared with non-tertiary hospitals. This analysis underlines the importance of local cancer registries in the comparison of treatment and outcome over time.

The management of advanced prostate cancer has changed substantially with the availability of multiple effective novel treatments, which has led to improved disease survival. In the era of personalized cancer treatments, more precise imaging may help physicians deliver better care. More accurate local staging and earlier detection of metastatic disease, accurate identification of oligometastatic disease, and optimal assessment of treatment response are areas where modern imaging is rapidly evolving and expanding. Next-generation imaging modalities, including whole-body MRI and molecular imaging with combined PET and CT and combined PET and MRI using novel radiopharmaceuticals, create new opportunities for imaging to support and refine management pathways in patients with advanced prostate cancer. This article demonstrates the potential and challenges of applying next-generation imaging to deliver the clinical promise of treatment breakthroughs.

Zusammenfassung Hintergrund Die Förderung psychischer Gesundheit im Jugendalter ist eine zentrale Aufgabe von Gesundheitsämtern. Die im Kanton Zug bewährten „10 Schritte für psychische Gesundheit“ sollten deshalb jugendgerecht angepasst werden. Im Artikel wird anhand des partizipativen Forschungs- und Entwicklungsprojekts exemplarisch aufgezeigt, dass und wie partizipative Angebotsentwicklung in Gesundheitsämtern gelingen kann. Die methodischen Zugänge, die Ergebnisse und die Förderfaktoren und Stolpersteine in der Umsetzung werden beschrieben. Methodik Die jugendgerechte Anpassung der 10 Schritte wurde 2018 bis 2019 von Präventionsfachpersonen des Amts für Gesundheit im Kanton Zug mit Beteiligung von Jugendforschenden (6 Mädchen, 4 Jungen), einem Texter, einem Grafiker und zwei Wissenschaftler*innen vorgenommen. Es wurden Methoden der partizipativen Qualitätsentwicklung und der partizipativen Forschung eingesetzt. Ergebnisse Die 10 Schritte konnten basierend auf der partizipativen Studie und bestehenden wissenschaftlichen Erkenntnissen zu einer jugendgerechten Kampagne mit 4 Tipps für psychische Gesundheit („Kennsch es?“) weiterentwickelt werden. Die dabei verwendeten partizipativen Methoden Photovoice, Blitzbefragung, Brainstorming, „design thinking“ und der Einbezug Jugendlicher als Forschende erzielten gute Ergebnisse (zielgruppengerechte massenmediale Kampagne, Schulworkshops). Schlussfolgerung Partizipative Angebotsentwicklung in Ämtern ist unter Beachtung gewisser Förderfaktoren und Stolpersteine gut machbar. Praktiker*innen von Gesundheitsämtern können die dafür notwendigen partizipativen Prozesse initiieren, steuern und nachhaltig in einem Amt verankern.

Previous research shows that experimental sleep deprivation alters emotion processing, suggesting a potential mechanism linking sleep disruption to mental ill-health. Extending previous work, we experimentally disrupted sleep continuity in good sleepers and assessed next-day emotion processing and regulation using tasks with established sensitivity to depression. In a laboratory-based study, 51 good sleepers (37 female; mean age = 24 years, SD= 3.63) were randomized to one night (23:00-07:00) of uninterrupted sleep (n=24) or sleep continuity disruption (n=27). We assessed emotion perception, attention, and memory the following day. Participants also completed an emotion regulation task and measures of self-reported affect, anxiety, sleepiness, overnight declarative memory consolidation, and psychomotor vigilance. Confirming the effects of the manipulation, sleep continuity disruption led to a marked decrease in polysomnography-defined total sleep time (229.98 mins vs 434.57 mins), increased wake-time after sleep onset (260.66 mins vs 23.84 mins) and increased sleepiness (d=0.81). Sleep continuity disruption led to increased anxiety (d=0.68), decreased positive affect (d=-0.62), reduced overnight declarative memory consolidation (d=-1.08) and reduced psychomotor vigilance [longer reaction times (d=0.64) and more lapses (d=0.74)], relative to control. However, contrary to our hypotheses, experimental sleep disruption had no effect on perception of, or bias for, emotional facial expressions, emotional memory for words, or emotion regulation following worry induction. In conclusion, one night of sleep continuity disruption had no appreciable effect on objective measures of emotion processing or emotion regulation in response to worry induction, despite clear effects on memory consolidation, vigilance, and self-reported affect and anxiety.

The evolution of glaciers and ice sheets depends sensitively on the processes occurring at their boundaries such as, e.g., the ice-bedrock interface or shear margins. These boundary regions share as common characteristics the transition from flow to no flow over a relatively short distance, resulting in a complex and fundamentally non-hydrostatic stress field. The localised intense shearing may further induce weakening of the ice owing to thermomechanical interactions, ultimately accelerating and potentially destabilising the bulk of the ice. Better understanding the sensitivity of these near-boundary processes is vital and challenging as it requires non-linear and coupled full Stokes models that can afford very high resolution in three-dimensions.We present recent development of a thermomechanical coupled numerical model that leverages graphical processing units (GPUs) acceleration to resolve the instantaneous stress and velocity fields within ice flow over complex topography in three dimensions. We apply the model to various glaciers of the Swiss Alps resolving the complex flow field in three dimensions and at very high spatial resolution. We further use the model to assess the competition between basal sliding and internal sliding, the latter referring to the formation of a near-basal internal shear zone within the ice owing to thermomechanical feedback. We finally provide some insights in GPU-based high-performance computing model development using the Julia language and the ongoing development of efficient implicit iterative solvers based on the accelerated pseudo-transient method.

Julia(https://julialang.org) recently emerged as a very powerful high-level computer language for (parallel) scientific computing, which allows you to “write codes like in MATLAB”, while “achieving the speed of Fortran/C”. A particular strength of Julia is that it is easy to write composable software packages that talk to each other. Here we will discuss our efforts in making Julia a development platform for geodynamic applications that significantly simplifies the process of going from a working solver to a production code which runs on massively parallel (GPU) machines. We are working on a number of open-source packages that simplify certain steps that many geodynamics codes have in common:GeoParams.jl (https://github.com/JuliaGeodynamics/GeoParams.jl) is a package in which you can specify constitutive relationships (e.g., creeplaws). It automatically handles the (non-)dimensionalization of all input parameters, includes pre-defined creep laws (e.g., dislocation and diffusion creep laws), plotting routine and includes computational routines that can be directly integrated in your code. PETSc.jl (https://github.com/JuliaParallel/PETSc.jl) is the main interface from Julia to PETSc, including MPI support and automatic installations of PETSc (one of the main hurdles that existing users faced). We have recently extended the package to include an interface to DMSTAG, such that you create a staggered finite difference grid and assemble the stiffness matrix in a straightforward manner. You can use automatic differentiation tools in Julia to create the Jacobians for nonlinear equations, which again minimizes the required lines of code (compared to their C counterparts). At the same time, the full range of (nonlinear multigrid) PETSc solvers is available. This is thus very well suited to write implicit solvers. ParallelStencil.jl (https://github.com/omlins/ParallelStencil.jl) and ImplicitGlobalGrid.jl (https://github.com/eth-cscs/ImplicitGlobalGrid.jl) are packages that are devoted to solving stencils in a very efficient manner on (parallel) GPU or CPU machines, which scales to very large GPU-based computers. It is particularly efficient in combination with pseudo-transient iterative solvers and allow running codes on modern architectures. GeophysicalModelGenerator.jl (https://github.com/JuliaGeodynamics/GeophysicalModelGenerator.jl) is a package that gives you a simple way to collect geophysical/geological data of a certain region and combine that to construct a 3D geodynamic input model setup. Ongoing efforts include the development of a grid generation and a marker and cell advection package that work, seamlessly with both ParallelStencil and PETSc. This will allow developers to apply both direct-iterative and pseudo-transient implicit solvers to the same problem, while only having to make minimal changes to the model setup. Combined, these packages will make the step from developing a new (nonlinear) solver to having an efficient (3D) production code much easier.

Both sudden and continuous subsidence of the earth’s surface pose a geohazard to the population and infrastructure, especially in urban areas. In Northern Germany, sinkholes occur often at salt dome highs, where dissolution affects the caprock, creating mass deficits in the shallow subsurface. Gravitationally driven subsidence of the overburden subsequently leads to both slow and sudden deformations of the surface.The city of Elmshorn, situated partly on the top of a shallow salt dome structure of nearly 30-40 m below surface, has to deal with such surface deformations which have been the motivation of several investigations in recent decades. Existing geologic data based on drillings has recently been extended by a shear wave seismic 2D profile grid, to support mapping of the spatial course of the salt structures and overlying sediments in high resolution, and to identify areas prone to subrosion more precisely. The seismic profiles were acquired using an Elvis shear wave vibrator (source signal: 20-160 Hz sweep) and a land streamer attached with 10 Hz horizontal geophones in 1 m spacing. High-resolution stacked sections of 0.5 m CMP spacing were generated using shot spacing of 2-4 m. The profile grid shows that the shear wave reflection methodology is suitable to image the heterogeneous caprock surface and the fine structure of the overlaying Quaternary sediments. Strong topographic variations in the caprock surface and strongly heterogeneous lithology of both caprock and overlying sediments occur over short lateral distances less than 100 m, reinforcing the requirements for a close-meshed profile grid. Different caprock lithologies can be distinguished by changes in reflectivity and wavelength. Further, derived physical parameters based on full waveform inversions enable the characterization of the caprock surface and the integrity of the overlying sediments to estimate areas affected by subrosion.The results highlight the structural information capabilities of the shear wave reflection method for the investigation of subrosion-prone areas as well as the further potential of the methodology to improve the knowledge of subrosion process sequences.

Previous research shows that experimental sleep deprivation alters emotion processing, suggesting a potential mechanism linking sleep disruption to mental ill-health. Extending previous work, we experimentally disrupted sleep continuity in good sleepers and assessed next-day emotion processing and regulation using tasks with established sensitivity to depression. In a laboratory-based study, 51 good sleepers (37 female; mean [SD] age 24 [3.63] years), were randomised to 1 night of uninterrupted sleep (n = 24) or sleep continuity disruption (n = 27). We assessed emotion perception, attention, and memory the following day. Participants also completed an emotion regulation task and measures of self-reported affect, anxiety, sleepiness, overnight declarative memory consolidation, and psychomotor vigilance. Confirming the effects of the manipulation, sleep continuity disruption led to a marked decrease in polysomnography-defined total sleep time (229.98 versus 434.57 min), increased wake-time after sleep onset (260.66 versus 23.84 min), and increased sleepiness (d = 0.81). Sleep continuity disruption led to increased anxiety (d = 0.68), decreased positive affect (d = -0.62), reduced overnight declarative memory consolidation (d = -1.08), and reduced psychomotor vigilance (longer reaction times [d = 0.64] and more lapses [d = 0.74]), relative to control. However, contrary to our hypotheses, experimental sleep disruption had no effect on perception of, or bias for, emotional facial expressions, emotional memory for words, or emotion regulation following worry induction. In conclusion, 1 night of sleep continuity disruption had no appreciable effect on objective measures of emotion processing or emotion regulation in response to worry induction, despite clear effects on memory consolidation, vigilance, and self-reported affect and anxiety.

Background: Exergames have attracted growing interest in the prevention and treatment of neurocognitive disorders. The most effective exergame and training components (ie, exercise and training variables such as frequency, intensity, duration, or volume of training and type and content of specific exergame scenarios) however remain to be established for older adults with mild neurocognitive disorders (mNCDs). Regarding the design and development of novel exergame-based training concepts, it seems of crucial importance to explicitly include the intended users' perspective by adopting an interactive and participatory design that includes end users throughout different iterative cycles of development. Objective: This study aimed to determine the capabilities, treatment preferences, and motivators for the training of older adults with mNCD and the perspectives of individuals on training goals and settings and requirements for exergame and training components. Methods: A qualitative study including expert focus groups and individual semistructured in-depth patient interviews was conducted. Data were transcribed to a written format to perform qualitative content analysis using QCAmap software. Results: In total, 10 experts and health care professionals (80% females) and 8 older adults with mNCD (38% females; mean age 82.4, SD 6.2 years) were recruited until data saturation was observed. Conclusions: The psychosocial consequences of patients' self-perceived cognitive deterioration might be more burdensome than the cognitive changes themselves. Older adults with mNCD prefer integrative forms of training (such as exergaming) and are primarily motivated by enjoyment or fun in exercising and the effectiveness of the training. Putting the synthesized perspectives of training goals, settings, and requirements for exergames and training components into context, our considerations point to opportunities for improvement in research and rehabilitation, either by adapting existing exergames to patients with mNCDs or by developing novel exergames and exergame-based training concepts specifically tailored to meet patient requirements and needs., JMIR Serious Games, 11, ISSN:2291-9279

The development of highly efficient, robust and scalable numerical algorithms lags behind the rapid increase in massive parallelism of modern hardware. We address this challenge with the accelerated pseudo-transient iterative method and present here a physically motivated derivation. We analytically determine optimal iteration parameters for a variety of basic physical processes and confirm the validity of theoretical predictions with numerical experiments. We provide an efficient numerical implementation of pseudo-transient solvers on graphical processing units (GPUs) using the Julia language. We achieve a parallel efficiency over 96 % on 2197 GPUs in distributed memory parallelisation weak scaling benchmarks. 2197 GPUs allow for unprecedented terascale solutions of 3D variable viscosity Stokes flow on 49953 grid cells involving over 1.2 trillion degrees of freedom. We verify the robustness of the method by handling contrasts up to 9 orders of magnitude in material parameters such as viscosity, and arbitrary distribution of viscous inclusions for different flow configurations. Moreover, we show that this method is well suited to tackle strongly nonlinear problems such as shear-banding in a visco-elasto-plastic medium. A GPU-based implementation can outperform CPU-based direct-iterative solvers in terms of wall-time even at relatively low resolution. We additionally motivate the accessibility of the method by its conciseness, flexibility, physically motivated derivation and ease of implementation. This solution strategy has thus a great potential for future high-performance computing applications, and for paving the road to exascale in the geosciences and beyond., Geoscientific Model Development Discussions, ISSN:1991-962X, ISSN:1991-9611

We present a straightforward approach for distributed parallelization of stencil-based xPU applications on a regular staggered grid, which is instantiated in the package ImplicitGlobalGrid.jl. The approach allows to leverage remote direct memory access and enables close to ideal weak scaling of real-world applications on thousands of GPUs. The communication costs can be easily hidden behind computation., Comment: submitted to JuliaCon Proceedings 2022

Background:Innovations in treatments, imaging and molecular characterisationhave improved outcomes for people with advanced prostate cancer; however, many aspectsof clinical management are devoid of high-level evidence. At the Advanced Prostate CancerConsensus Conference (APCCC) 2019, many of these topics were addressed, and consensuswas not always reached. The results from clinical trials will most reliably plus the gaps.Methods:An invited panel of 57 experts voted on 123 multiple-choice questions on clinicalmanagement at APCCC 2019. No consensus was reached on 88 (71.5%) questions definedas

Author's accepted manuscript. © 2020 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works. The application of AI in finance is increasingly dependent on the principles of responsible AI. These principles-explainability, fairness, privacy, accountability, transparency and soundness form the basis for trust in future AI systems. In this empirical study, we address the first principle by providing an explanation for a deep neural nenvork that is trained on a mixture of numerical, categorical and textual inputs for financial transaction classification. The explanation is achieved through (1) a feature importance analysis using Shapley additive explanations (SHAP) and (2) a hybrid approach of text clustering and decision tree classifiers. We then test the robustness of the model by exposing it to a targeted evasion attack, leveraging the knowledge we gained about the model through the extracted explanation.

The purpose of applying reinforcement learning (RL) to portfolio management is commonly the maximization of profit. The extrinsic reward function used to learn an optimal strategy typically does not take into account any other preferences or constraints. We have developed a regularization method that ensures that strategies have global intrinsic affinities, i.e., different personalities may have preferences for certain asset classes which may change over time. We capitalize on these intrinsic policy affinities to make our RL model inherently interpretable. We demonstrate how RL agents can be trained to orchestrate such individual policies for particular personality profiles and still achieve high returns.

Crowd anomaly detection is one of the most popular topics in computer vision in the context of smart cities. A plethora of deep learning methods have been proposed that generally outperform other machine learning solutions. Our review primarily discusses algorithms that were published in mainstream conferences and journals between 2020 and 2022. We present datasets that are typically used for benchmarking, produce a taxonomy of the developed algorithms, and discuss and compare their performances. Our main findings are that the heterogeneities of pre-trained convolutional models have a negligible impact on crowd video anomaly detection performance. We conclude our discussion with fruitful directions for future research.

Machine ethics has received increasing attention over the past few years because of the need to ensure safe and reliable artificial intelligence (AI). The two dominantly used theories in machine ethics are deontological and utilitarian ethics. Virtue ethics, on the other hand, has often been mentioned as an alternative ethical theory. While this interesting approach has certain advantages over popular ethical theories, little effort has been put into engineering artificial virtuous agents due to challenges in their formalization, codifiability, and the resolution of ethical dilemmas to train virtuous agents. We propose to bridge this gap by using role-playing games riddled with moral dilemmas. There are several such games in existence, such as Papers, Please and Life is Strange, where the main character encounters situations where they must choose the right course of action by giving up something else dear to them. We draw inspiration from such games to show how a systemic role-playing game can be designed to develop virtues within an artificial agent. Using modern day AI techniques, such as affinity-based reinforcement learning and explainable AI, we motivate the implementation of virtuous agents that play such role-playing games, and the examination of their decisions through a virtue ethical lens. The development of such agents and environments is a first step towards practically formalizing and demonstrating the value of virtue ethics in the development of ethical agents., Comment: Premature submission of revised revision

The proliferation of artificial intelligence is increasingly dependent on model understanding. Understanding demands both an interpretation - a human reasoning about a model's behavior - and an explanation - a symbolic representation of the functioning of the model. Notwithstanding the imperative of transparency for safety, trust, and acceptance, the opacity of state-of-the-art reinforcement learning algorithms conceals the rudiments of their learned strategies. We have developed a policy regularization method that asserts the global intrinsic affinities of learned strategies. These affinities provide a means of reasoning about a policy's behavior, thus making it inherently interpretable. We have demonstrated our method in personalized prosperity management where individuals' spending behavior in time dictate their investment strategies, i.e. distinct spending personalities may have dissimilar associations with different investment classes. We now explain our model by reproducing the underlying prototypical policies with discretized Markov models. These global surrogates are symbolic representations of the prototypical policies.

Next-generation sequencing (NGS) of tumor cell-derived DNA/RNA to screen for targetable genomic alterations is now widely available and has become part of routine practice in oncology. NGS testing strategies depend on cancer type, disease stage and the impact of results on treatment selection. The European Society for Medical Oncology (ESMO) has recently published recommendations for the use of NGS in patients with advanced cancer. We complement the ESMO recommendations with a practical review of how oncologists should read and interpret NGS reports. A concise and straightforward NGS report contains details of the tumor sample, the technology used and highlights not only the most important and potentially actionable results, but also other pathogenic alterations detected. Variants of unknown significance should also be listed. Interpretation of NGS reports should be a joint effort between molecular pathologists, tumor biologists and clinicians. Rather than relying and acting on the information provided by the NGS report, oncologists need to obtain a basic level of understanding to read and interpret NGS results. Comprehensive annotated databases are available for clinicians to review the information detailed in the NGS report. Molecular tumor boards do not only stimulate debate and exchange, but may also help to interpret challenging reports and to ensure continuing medical education.

353 Background: Pre-clinical and retrospective clinical data support an interaction of metformin (MET) and radiotherapy. Thus, MET may represent a cost-effective means to improve radiotherapy outcomes. We sought to investigate whether MET increases time to progression (TTP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP). Methods: Non-diabetic men with biochemical recurrence after RP were enrolled into an open label, randomized, phase 2 study in 17 hospitals in Switzerland, France, and Germany. The randomization (1:1) was stratified by Gleason score ( 0.5 vs ≤ 0.5 ng/mL), ADT use, and evidence of local recurrence. Following randomization, patients received either prostate bed SRT (70Gy) or prostate bed SRT (70Gy) + MET. MET 850mg PO QD was given for 4 weeks before SRT, then 850mg PO QD for 48 weeks. The primary endpoint was TTP. Secondary endpoints were progression-free survival, undetectable PSA under normal testosterone levels, 50% PSA response, clinical progression-free survival, time to further systemic therapy, prostate cancer-specific survival, overall survival, and adverse events (AE). The trial design was powered for a HR 0.65 with planned enrollment of 170 patients. The trial was prematurely closed by the sponsor due to financial reasons. Data is reported after patients reached a minimum follow-up of 12 months after SRT and corresponds to the final analysis. Results: A total of 111 patients were randomized (106 evaluable) between 10/2017 and 11/2020. The median PSA at randomization was 0.3 ng/mL (range, 0.03-1.5 ng/mL), 19 patients (17.9%) had Gleason ≥8, 54 (50.9%) pT3 disease, and 50 (47.2%) positive surgical margins. Twenty-four patients (22.6%) used short-term ADT. Trial arms were well balanced. At a median follow-up of 27.1 months (95% CI: 26.7-27.8), a total of 16 progression events occurred. The median TTP was not reached in either treatment arm. The hazard ratio adjusted by stratification factors was 1.25 (95% CI: 0.40-3.94; one-sided 80% CI: 2.05; log-rank p=0.62). Two-year TTP was 89% (95% CI: 76%-96%) in the SRT arm vs 82% (95% CI: 67%-91%) in the SRT + MET arm. No statistically significant differences were found for the secondary endpoints. Most common AE during treatment was grade 1-2 diarrhea (24.1% SRT vs 54.6% SRT + MET). Grade 2 and 3 AE (gastrointestinal and/or urinary) were 25.9% and 3.7% with SRT vs 34.5% and 7.3% with SRT + MET (p=0.41 and p=0.68), respectively. Conclusions: Adding MET to SRT did not result in a significant improvement in TTP in non-diabetic men with recurrent prostate cancer post-RP. Because of early trial closure and fewer than expected events, the trial may have been underpowered for this endpoint. Additional correlative studies will be pursued. Clinical trial information: NCT02945813 .