For much of European Christian history, asceticism has been associated with the capacity to transform individuals as well as societies. As an organised collaborative exercise in monasteries, asceticism enabled monks not only to live a life preparing for eternal life but also to generate ground-breaking technical and social innovations. Drawing on identity theories and recent developments in the social movement literature, we examine how asceticism has been the impetus for various individual and societal transformations and explore whether asceticism can still unfold such transformative power. In particular, we discuss whether and how ongoing movements for Voluntary Simplicity (VS) and further reflections on that, as found, for example, in the work of the sociologist Ulrich Beck, might assist humans in coping with climate change. Our article contributes to recent environmental ethics research by exploring the role of asceticism in potentially triggering collective climate action and its contribution to helping individuals to live meaningful lives in the face of climate change.
Goal recognition is an important problem in many application domains (e.g., pervasive computing, intrusion detection, computer games, etc.). In many application scenarios, it is important that goal recognition algorithms can recognize goals of an observed agent as fast as possible. However, many early approaches in the area of Plan Recognition As Planning, require quite large amounts of computation time to calculate a solution. Mainly to address this issue, recently, Pereira et al. developed an approach that is based on planning landmarks and is much more computationally efficient than previous approaches. However, the approach, as proposed by Pereira et al., considers trivial landmarks (i.e., facts that are part of the initial state and goal description are landmarks by definition) for goal recognition. In this paper, we show that it does not provide any benefit to use landmarks that are part of the initial state in a planning landmark based goal recognition approach. The empirical results show that omitting initial state landmarks for goal recognition improves goal recognition performance.
Recent successes in image generation, model-based reinforcement learning, and text-to-image generation have demonstrated the empirical advantages of discrete latent representations, although the reasons behind their benefits remain unclear. We explore the relationship between discrete latent spaces and disentangled representations by replacing the standard Gaussian variational autoencoder (VAE) with a tailored categorical variational autoencoder. We show that the underlying grid structure of categorical distributions mitigates the problem of rotational invariance associated with multivariate Gaussian distributions, acting as an efficient inductive prior for disentangled representations. We provide both analytical and empirical findings that demonstrate the advantages of discrete VAEs for learning disentangled representations. Furthermore, we introduce the first unsupervised model selection strategy that favors disentangled representations.
Due to its ability to incorporate and leverage time information in relational data, Temporal Knowledge Graph (TKG) learning has become an increasingly studied research field. To predict the future based on TKG, researchers have presented innovative methods for Temporal Knowledge Graph Forecasting. However, the experimental procedures employed in this research area exhibit inconsistencies that significantly impact empirical results, leading to distorted comparisons among models. This paper focuses on the evaluation of TKG Forecasting models: We examine the evaluation settings commonly used in this research area and highlight the issues that arise. To make different approaches to TKG Forecasting more comparable, we propose a unified evaluation protocol and apply it to re-evaluate state-of-the-art models on the most commonly used datasets. Ultimately, we demonstrate the significant difference in results caused by different evaluation settings. We believe this work provides a solid foundation for future evaluations of TKG Forecasting models, thereby contributing to advancing this growing research area.
Whereas rhinoplasty with a reduction of the dorsum and modification of the tip is a common procedure among Caucasians, augmentation of the dorsum remains a challenge in Asians. Choice of the ideal grafting material for dorsal augmentation is a matter of preference and remains under discussion. Autologous and alloplastic materials have their advantages and disadvantages. We report our experiences of the extrusion of alloplastic materials and their management. We report of 18 patients, who had rhinoplasty in the past for dorsal augmentation with alloplastic material. Augmentation rhinoplasty was performed in Asia (n = 15) and Germany (n = 3). All cases showed recurrent signs of foreign body infection and/or partial extrusion and therefore underwent revision surgery in our centers. Once all patients had been successfully treated with antibiotics, we performed a one-stage revision rhinoplasty with explantation of the alloplastic material and subsequent reconstruction with autologous rib cartilage. The nasal dorsum was augmented with either solid rib cartilage grafts, diced cartilage in fascia, or free diced cartilage in platelet-rich fibrin. All patients received pre-, peri-, and postoperative antibiotics. The outcome was screened via clinical examination, ultrasound examination pre- and postoperatively, two-dimensional/three-dimensional (3D) imaging, and magnetic resonance imaging scans. Alloplastic augmentation of the nasal dorsum runs the risk of foreign body reaction, recurrent infections, uncontrolled scarring, and unsatisfying long-term results. We have obtained a series of aesthetically and functionally satisfying results after single-stage revision surgery with autologous cartilage and demonstrate a variety of novel postoperative screening tools including 3D imaging and high-frequency ultrasound. Level of Evidence N/A
Background Alcohol consumption to facilitate social interaction is an important drinking motive. Here, we tested whether alcohol influences trust in others via modulation of oxytocin and/or androgens. We also aimed at confirming previously shown alcohol effects on positive affect and risk-taking, because of their role in facilitating social interaction. Methods This randomized, controlled, within-subject, parallel group, alcohol-challenge experiment investigated the effects of alcohol (versus water, both mixed with orange juice) on perceived trustworthiness via salivary oxytocin (primary and secondary endpoint) as well as testosterone, dihydrotestosterone, positive affect, and risk-taking (additional endpoints). We compared 56 male participants in the alcohol condition (1.07 ± 0.18 per mille blood alcohol concentration) with 20 in the control condition. Results The group (alcohol versus control condition) × time (before [versus during] versus after drinking) interactions were not significantly associated with perceived trustworthiness (η ² < 0.001) or oxytocin (η ² = 0.003). Bayes factors provided also substantial evidence for the absence of these effects (BF 01 = 3.65; BF 01 = 7.53). The group × time interactions were related to dihydrotestosterone (η ² = 0.018 with an increase in the control condition) as well as positive affect and risk-taking (η ² = 0.027 and 0.007 with increases in the alcohol condition), but not significantly to testosterone. Discussion The results do not verify alcohol effects on perceived trustworthiness or oxytocin in male individuals. However, they indicate that alcohol (versus control) might inhibit an increase in dihydrotestosterone and confirm that alcohol amplifies positive affect and risk-taking. This provides novel mechanistic insight into social facilitation as an alcohol-drinking motive.
Background Electroanatomical mapping (EAM)-guided stereotactic arrhythmia radioablation (STAR) is a novel noninvasive therapy option for patients with monomorphic ventricular tachycardia (VT) refractory to antiarrhythmic drugs and/or urgent catheter ablation (CA). Data on success rates in an emergency situation such as electrical storm (ES) are rare. We present a case of a patient with an initially very poor life expectancy after extensive myocardial infarction with therapy–resistant ES, not amendable for further antiarrhythmic drug therapy, implantable cardioverter-defibrillator implantation, or repeated CA who was introduced to the radiation oncology department for emergency STAR as a bail-out therapy. Methods Target volume definition and transfer from EAM to CT were validated and quality assured with a semi-automatic, dedicated visualization tool (CARDIO-RT). Emergency STAR was performed with 25 Gy in the framework of the RAVENTA study. The VT burden gradually decreased after STAR; however, a second VT morphology occurred, which was successfully treated with EAM-guided CA 12 days after STAR. Results The second EAM-guided CA showed areas of low voltage in the irradiated segments, indicating a precise targeting and early functional response to STAR. The patient remained free of any VT recurrence or any radiation-related toxicities and in good general condition during the recent follow-up of 18 months. Conclusion The case highlights the possible approach, caveats, difficulties, and prognosis of a patient severely affected by therapy-resistant VT in whom CA could not lead to VT suppression. Further studies of putative mechanisms of STAR in the acute and chronic phase of this novel therapy are warranted.
This paper is a cross fertilization of ideas about the importance of molecular aspects of breast cancer metastasis by basic scientists, a pathologist, and clinical oncologists at the Henry Ford Health symposium. We address four major topics: (i) the complex roles of lymphatic endothelial cells and the molecules that stimulate them to enhance lymph node and systemic metastasis and influence the anti-tumor immunity that might inhibit metastasis; (ii) the interaction of molecules and cells when breast cancer spreads to bone, and how bone metastases may themselves spread to internal viscera; (iii) how molecular expression and morphologic subtypes of breast cancer assist clinicians in determining which patients to treat with more or less aggressive therapies; (iv) how the outcomes of patients with oligometastases in breast cancer are different from those with multiple metastases and how that could justify the aggressive treatment of these patients with the hope of cure.
Purpose Botulinum toxin injections in the anal sphincter apparatus (Botox) and enteral neuromodulation (ENM) are options for treatment of refractory chronic constipation. We present a retrospective comparative observational study. Patients and methods From 2014 to 2022, pediatric patients with chronic constipation were either treated with Botox or ENM with continuation of conservative treatment. Comparison was conducted regarding the primary outcome variables defecation frequency, stool consistency, and abdominal pain. Secondary outcomes were fecal incontinence, enuresis, change of medication and safety of treatment. Results 19 Botox patients (10 boys, 9 girls, 12 patients with Hirschsprung disease (HD), 7 patients with functional constipation (FC)) were compared to 24 ENM patients (18 boys, 6 girls, 12 HD patients, 7 FC patients). Groups differed significantly in age (5.0 years (Botulinum toxin) and 6.5 years (ENM), mean values, p-value 0.008). Improvement of constipation was seen in 68% (n = 13/19) of Botox and 88% (n = 21/24) of ENM patients (p = 0.153). Influence of etiology on therapeutic effects was not observed. Complications were minor. Conclusions Botox and ENM can be considered as valuable and effective treatment options in refractory chronic constipation. Prospective, large-population studies should be designed to enable improved evidence.
BACKGROUND Distinctive genetic changes can identify various types of gliomas. However, acquiring tumor material via surgery in the central nervous system (CNS) can pose the danger of neurological impairments, especially if the tumor is located near critical areas or in the brain stem. Gliomas discharge tumor DNA into the cerebrospinal fluid (CSF), where it mixes with circulating DNA from normal cells to generate cell-free DNA (cfDNA). Analyzing cfDNA via next-generation sequencing (NGS) is a substitute method for genomic assessments. MATERIAL AND METHODS We conducted targeted next-generation sequencing (NGS) of cerebrospinal fluid (CSF) cell-free DNA (cfDNA) using a panel that encompasses 130 genes from 81 patients with MRI detected suspicion of a primary (n = 69) or recurrent (n = 12) glioma. The library preparation and raw read data preprocessing were tailored specifically for cfDNA samples. To identify single nucleotide variants (SNVs) and small insertions and deletions (Indels), a classifier based on machine learning (somaticseq) was trained using cfDNA reference standards. The on- and off-target reads were employed to develop profiles of copy-number variations (CNVs) (cnvkit). RESULTS The sensitivity and specificity of short variant (SNV + Indel) calling were determined to range between 36.1% - 93.3% and 66.5% - 87.1%, respectively, depending on the input amounts (2ng to 4ng) of cfDNA reference material and the circulating tumor DNA (ctDNA) content (1% to 5%). In a group of 20 CSF samples from glioblastoma patients, the detected mutations and CNVs corresponded to those found in solid tissue samples. Furthermore, two additional patients with glial tumors in the brain stem that could not be accessed surgically were found to have an IDH:p.R132C mutation and a histone H3.3:p.K28M mutation, respectively. CONCLUSION A clinical workflow was developed with specific sensitivity and specificity values for sequencing cerebrospinal fluid (CSF) cell-free DNA (cfDNA). This workflow was tested on a group of glioblastoma patients with matched solid tumor tissue. In two patients with suspected glial tumors but no accessible tissue, the diagnosis was confirmed by identifying characteristic mutations.
BACKGROUND Glioblastoma (GBM) is characterized by a low mutational burden limiting the number of neoantigen targets for cancer vaccines. Vaccination against tumor-associated antigens over-presented via MHC class I and II in GBM is an alternative that has shown promise in previous trials. One cancer vaccine containing peptides presented by HLA-A*02-01 (class I) and some DR alleles (class II), showed evidence of peripheral vaccine-induced immune response against these peptides in patients with GBM. Our study will assess the safety and immunogenicity of the messenger ribonucleic acid (mRNA)-based multiepitope vaccine CV-GBM, an investigational therapeutic mRNA vaccine, encoding eight of these peptides that have demonstrated immunogenicity as peptide vaccines. CV-GBM consists of a mRNA with unmodified nucleotides formulated with lipid nanoparticles. MATERIAL AND METHODS CV-GBLM-001 is a first-in-human, open-label, international, dose-escalation phase 1 trial. HLA-A*02:01-positive patients with newly diagnosed MGMT-unmethylated GBM (CNS WHO Grade 4), including IDH-wildtype astrocytoma with a molecular signature of unmethylated MGMT-GBM who have had a gross total or partial resection and who completed post-surgery radiotherapy with or without chemotherapy, are eligible to receive CVGBM. The trial comprises a dose-escalation part (Part A) followed by a dose-expansion part (Part B). In Part A, the starting dose is 12 µg mRNA, which may be escalated to 25 µg, 50 µg and 100 µg, with 3 to 6 patients per dose level. Dose escalation will be guided by a Bayesian logistic regression model. Patients will receive 7 doses of CVGBM by intramuscular injection on Days 1, 8, 15, 29, 43, 57, and 71, followed by 6 optional doses at 6-week intervals, up to 1 year after the first dose or until disease progression or intolerable toxicity. An independent Data and Safety Monitoring Board will recommend the dose for expansion in Part B in which about 20 patients will be enrolled. Biomarkers and vaccine-induced innate and adaptive immunogenicity, including, but not limited to, systemically induced cytokines and chemokines and antigen-specific CD4+ and CD8+ T cells, will be monitored in the blood, and optionally in vaccine-draining lymph nodes and relapsed tumor. In addition to the primary safety objectives, secondary objectives of efficacy (progression-free survival, overall survival) and patient-reported quality of life outcomes will be assessed. Trial sponsor: CureVac SE, Germany.
Many measurement designs produce domain factors with small variances and factor loadings. The current study investigates the cause, prevalence, and problematic consequences of such domain factors. We collected a meta-analytic sample of empirical applications, conducted a simulation study on statistical power and estimation precision, and provide a reanalysis of an empirical example. The meta-analysis shows that about a quarter of all standardized domain factor loadings is in the range of -.2<λ<.2 and about a third of all domains is measured by five or fewer indicators, resulting in small factor variances. The simulation study examines the associated difficulties concerning statistical power, trait recovery, irregular estimates, and estimation precision for a range of such realistic cases. The empirical example illustrates the challenge to develop measures that produce clearly interpretable domain factors. Study planning and interpretation need to take the (expected) sum of squared factor loadings per domain factor into account. This is relevant even if influences of domain factors are desired to be small, and equally applies to different model variants. We propose several strategies for how researchers may better unlock the bifactor model's full potential and clarify its interpretation.
Administrative burdens appear to influence citizens' perceptions of welfare policies and attitudes toward beneficiaries. However, empirical evidence that has disentangled different state actions' effects on policy perceptions is scarce. We applied a 2 × 2 × 2 factorial survey experiment and manipulated the conceptually distinct state actions implemented in German unemployment benefits. We investigated whether and how exposure to learning demands, compliance demands, and sanctions affected citizens' prejudices against beneficiaries, policy support, and perceived legitimacy. The results from a sample of 1602 German citizens indicate that those confronted with program sanctions exhibit less policy support and expect higher policy spending. Similarly, sanctions decreased the Federal Employment Agency's perceived legitimacy. These results have implications for administrative burden and policy feedback research. Distinguishing different state actions provides nuances to assess policy feedback effects. Practitioners should consider whether program sanctions are necessary because they evoke unintended policy feedback effects.
We study the impact of unilateral economic disintegration, such as Brexit, on national and international policies. We introduce firm mobility and business‐tax policies into a general‐equilibrium trade model and analyze the effects of disintegration on tax policies of asymmetric countries. Whereas the disintegrating country taxes less, business taxes converge in the remaining economic area. We highlight important differences with existing two‐country models. Moreover, we predict a realignment of trade policies with a deeper integration inside the union and lower tariffs worldwide. The leaving country's endogenous integration response with other countries may fully compensate for the disintegration‐induced welfare losses. This article is protected by copyright. All rights reserved
We document the consequences of losing a job across countries using a harmonized research design applied to seven matched employer-employee datasets. Workers in Denmark and Sweden experience the lowest earnings declines following job displacement, while workers in Italy, Spain, and Portugal experience losses three times as high. French and Austrian workers face earnings losses somewhere in between. Key to these differences is that southern European workers are less likely to find employment following displacement. Loss of employer-specific wage premiums explains a substantial portion of wage losses in all countries. (JEL J31, J63, J64)
This report demonstrates a novel class of innate immune cells designated "variable immunoreceptor-expressing myeloids" (VIREMs). Using single-cell transcriptomics and genome-wide epigenetic profiling, we establish that VIREMs are myeloid cells unrelated to lymphocytes. We visualize the phenotype of B-VIREMs that are capable of genetically recombining and expressing antibody genes, the exclusive hallmark function of B lymphocytes. These cells, designated B-VIREMs, display monoclonal antibody cell surface signatures and regularly circulate in the blood of healthy individuals. Single-cell data reveal clonal expansion of circulating B-VIREMs as a dynamic response to disease stimuli. Live-cell imaging models suggest that B-VIREMs load their own Fc receptors with endogenous antibodies during vesicle transport to the cell surface. A first cloned B-VIREM-derived antibody (Vab1) specifically binds stomatin, a ubiquitous scaffold protein that is strictly expressed intracellularly, allowing Vab1-bearing macrophages to phagocytose cell debris without requiring prior opsonization. Our results suggest important antigen-specific tissue maintenance functionalities in these innate immune cells.
Importance: Alcohol misuse in adolescence is a leading cause of disability and mortality in youth and is associated with higher risk for alcohol use disorder. Brain mechanisms underlying risk of alcohol misuse may inform prevention and intervention efforts. Objective: To identify neuromarkers of alcohol misuse using a data-driven approach, with specific consideration of neurodevelopmental sex differences. Design, setting, and participants: Longitudinal multisite functional magnetic resonance imaging (fMRI) data collected at ages 14 and 19 years were used to assess whole-brain patterns of functional organization associated with current and future alcohol use risk as measured by the Alcohol Use Disorder Identification Test (AUDIT). Primary data were collected by the IMAGEN consortium, a European multisite study of adolescent neurodevelopment. Model generalizability was further tested using data acquired in a single-site study of college alcohol consumption conducted in the US. The primary sample was a developmental cohort of 1359 adolescents with neuroimaging, phenotyping, and alcohol use data. Model generalizability was further assessed in a separate cohort of 114 individuals. Main outcomes and measures: Brain-behavior model accuracy, as defined by the correspondence between model-predicted and actual AUDIT scores in held-out testing data, Bonferroni corrected across the number of models run at each time point, 2-tailed α < .008, as determined via permutation testing. Results: Among 1359 individuals in the study, the mean (SD) age was 14.42 (0.40) years, and 729 individuals (54%) were female. The data-driven, whole-brain connectivity approach identified networks associated with vulnerability for future and current AUDIT-defined alcohol use risk (primary outcome, as specified above, future: ρ, 0.22; P < .001 and present: ρ, 0.27; P < .001). Results further indicated sex divergence in the accuracies of brain-behavior models, such that female-only models consistently outperformed male-only models. Specifically, female-only models identified networks conferring vulnerability for future and current severity using data acquired during both reward and inhibitory fMRI tasks. In contrast, male-only models were successful in accurately identifying networks using data acquired during the inhibitory control-but not reward-task, indicating domain specificity of alcohol use risk networks in male adolescents only. Conclusions and relevance: These data suggest that interventions focusing on inhibitory control processes may be effective in combating alcohol use risk in male adolescents but that both inhibitory and reward-related processes are likely of relevance to alcohol use behaviors in female adolescents. They further identify novel networks of alcohol use risk in youth, which may be used to identify adolescents who are at risk and inform intervention efforts.
Survey experiments that investigate how voting procedures affect voting behavior and election outcomes use hypothetical questions and non-representative samples. We present here the results of a novel survey experiment that addresses both concerns. First, the winning party in our experiment receives a donation to its campaign funds inducing real consequences for voting. Second, we run an online experiment with a Dutch national representative sample ( N = 1240). Our results validate previous findings using a representative sample, in particular that approval voting leads to a higher concentration in votes for smaller parties and strengthens centrist parties in comparison to plurality voting. Importantly, our results suggest that voting behavior is not affected by voting incentives and can be equally reliably elicited with hypothetical questions.
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