A Security Framework for Distributed Ledgers

In the past few years blockchains have been a major focus for security research, resulting in significant progress in the design, formalization, and analysis of blockchain protocols. However, the more general class of distributed ledgers, which includes not just blockchains but also prominent non-blockchain protocols, such as Corda and OmniLedger, cannot be covered by the state-of-the-art in the security literature yet. These distributed ledgers often break with traditional blockchain paradigms, such as block structures to store data, system-wide consensus, or global consistency. In this paper, we close this gap by proposing the first framework for defining and analyzing the security of general distributed ledgers, with an ideal distributed ledger functionality, called $\mathcal{F}_\text{ledger}$, at the core of our contribution. This functionality covers not only classical blockchains but also non-blockchain distributed ledgers in a unified way. To illustrate $\mathcal{F}_\text{ledger}$, we first show that the prominent ideal blockchain functionalities $\mathcal{G}_\text{ledger}$ and $\mathcal{G}_\text{PL}$ realize (suitable instantiations of) $\mathcal{F}_\text{ledger}$, which precisely captures their security properties. This immediately implies that their respective implementations, including Bitcoin, Ouroboros Genesis, and Ouroboros Crypsinous, realize $\mathcal{F}_\text{ledger}$ as well. Secondly, we demonstrate that $\mathcal{F}_\text{ledger}$ is capable of precisely modeling also non-blockchain distributed ledgers by performing the first formal security analysis of such a distributed ledger, namely the prominent Corda protocol. Due to the wide spread use of Corda in the industry, in particular the financial sector, this analysis is of independent interest. These results also illustrate that $\mathcal{F}_\text{ledger}$ not just generalizes the modular treatment of blockchains to distributed ledgers, but moreover helps to unify existing results

ChatGPT’s performance in German OB/GYN exams – paving the way for AI-enhanced medical education and clinical practice

BackgroundChat Generative Pre-Trained Transformer (ChatGPT) is an artificial learning and large language model tool developed by OpenAI in 2022. It utilizes deep learning algorithms to process natural language and generate responses, which renders it suitable for conversational interfaces. ChatGPT’s potential to transform medical education and clinical practice is currently being explored, but its capabilities and limitations in this domain remain incompletely investigated. The present study aimed to assess ChatGPT’s performance in medical knowledge competency for problem assessment in obstetrics and gynecology (OB/GYN).MethodsTwo datasets were established for analysis: questions (1) from OB/GYN course exams at a German university hospital and (2) from the German medical state licensing exams. In order to assess ChatGPT’s performance, questions were entered into the chat interface, and responses were documented. A quantitative analysis compared ChatGPT’s accuracy with that of medical students for different levels of difficulty and types of questions. Additionally, a qualitative analysis assessed the quality of ChatGPT’s responses regarding ease of understanding, conciseness, accuracy, completeness, and relevance. Non-obvious insights generated by ChatGPT were evaluated, and a density index of insights was established in order to quantify the tool’s ability to provide students with relevant and concise medical knowledge.ResultsChatGPT demonstrated consistent and comparable performance across both datasets. It provided correct responses at a rate comparable with that of medical students, thereby indicating its ability to handle a diverse spectrum of questions ranging from general knowledge to complex clinical case presentations. The tool’s accuracy was partly affected by question difficulty in the medical state exam dataset. Our qualitative assessment revealed that ChatGPT provided mostly accurate, complete, and relevant answers. ChatGPT additionally provided many non-obvious insights, especially in correctly answered questions, which indicates its potential for enhancing autonomous medical learning.ConclusionChatGPT has promise as a supplementary tool in medical education and clinical practice. Its ability to provide accurate and insightful responses showcases its adaptability to complex clinical scenarios. As AI technologies continue to evolve, ChatGPT and similar tools may contribute to more efficient and personalized learning experiences and assistance for health care providers

ETMR-05: Single-cell transcriptomics of ETMR reveals developmental cellular programs and tumor-pericyte communications in the microenvironment [Abstract]

BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are pediatric brain tumors bearing a grim prognosis, despite intensive multimodal therapeutic approaches. Insights into cellular heterogeneity and cellular communication of tumor cells with cells of the tumor microenvironment (TME), by applying single-cell (sc) techniques, potentially identify mechanisms of therapy resistance and target-directed treatment approaches. MATERIAL AND METHODS: To explore ETMR cell diversity, we used single-cell RNA sequencing (scRNA-seq) in human (n=2) and murine ETMR (transgenic mode; n=4) samples, spatial transcriptomics, 2D and 3D cultures (including co-cultures with TME cells), multiplex immunohistochemistry and drug screens. RESULTS: ETMR microenvironment is composed of tumor and non-tumor cell types. The ETMR malignant compartment harbour cells representing distinct transcriptional metaprograms, (NSC-like, NProg-like and Neuroblast-like), mirroring embryonic neurogenic cell states and fuelled by neurogenic pathways (WNT, SHH, Hippo). The ETMR TME is composed of oligodendrocyte and neuronal progenitor cells, neuroblasts, microglia, and pericytes. Tumor-specific ligand-receptor interaction analysis showed enrichment of intercellular communication between NProg-like ETMR cells and pericytes (PC). Functional network analyses reveal ETMR-PC interactions related to stem-cell signalling and extracellular matrix (ECM) organization, involving factors of the WNT, BMP, and CxCl12 networks. Results from ETMR-PC co-culture and spatial transcriptomics pointed to a pivotal role of pericytes in keeping ETMR in a germinal neurogenic state, enriched in stem-cell signalling. Drug screening considering cellular heterogeneity and cellular communication suggested novel therapeutic approaches. CONCLUSION: ETMR demonstrated diversity in the microenvironment, with enrichment of cell-cell communications with pericytes, supporting stem-cell signalling and interfering in the organization of the tumor extracellular matrix. Targeting ETMR-PC interactions might bring new opportunities for target-directed therapy

Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors

Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Smarcb1 Loss Results in a Deregulation of esBAF Binding and Impacts the Expression of Neurodevelopmental Genes

The murine esBAF complex plays a major role in the regulation of gene expression during stem cell development and differentiation. As one of its core subunits, Smarcb1 is indispensable for its function and its loss is connected to neurodevelopmental disorders and participates in the carcinogenesis of entities such as rhabdoid tumours. We explored how Smarcb1 regulates gene programs in murine embryonic stem cells (mESC) and in this way orchestrates differentiation. Our data underline the importance of Smarcb1 expression and function for the development of the nervous system along with basic cellular functions, such as cell adhesion and cell organisation. Using ChIP-seq, we were able to portray the consequences of Smarcb1 knockdown (kd) for the binding of esBAF and PRC2 as well as its influence on histone marks H3K27me3, H3K4me3 and H3K27ac. Their signals are changed in gene and enhancer regions of genes connected to nervous system development and offers a plausible explanation for changes in gene expression. Further, we describe a group of genes that are, despite increased BAF binding, suppressed after Smarcb1 kd by mechanisms independent of PRC2 function

Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1

Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome

Exploring the current state of clinical and practical teaching in obstetrics and gynecology in the era of competency-based education: a nationwide survey among German teaching coordinators

Abstract Background Obstetrics and gynecology (OB/GYN) is an essential medical field that focuses on women’s health. Universities aim to provide high-quality healthcare services to women through comprehensive education of medical students. In Germany, medical education is undergoing a phase of restructuring towards the implementation of competency-based learning. The objective of the current survey was to gain insights into the teaching methods, resources, and challenges at German medical universities in the field OB/GYN. This aims to document the current state of medical education and derive potential suggestions for improvements in the era of competency-based learning. The survey was conducted with teaching coordinators from the majority of OB/GYN departments at German universities. Methods A questionnaire was sent to the teaching coordinators in all 41 OB/GYN departments at German university hospitals. The survey was delivered via email with a link to an online survey platform. Results The study received 30 responses from 41 universities. Differences were observed in the work environment of teaching coordinators concerning release from clinical duties for teaching purposes and specialized academic training. Overall, medical education and student motivation were perceived positively, with noticeable gaps, particularly in practical gynecological training. Deficiencies in supervision and feedback mechanisms were also evident. Subfields such as urogynecology and reproductive medicine appear to be underrepresented in the curriculum, correlating with poorer student performance. E-learning was widely utilized and considered advantageous. Conclusion The present study provides valuable insights into the current state of medical education in OB/GYN at German universities from the perspective of teaching experts. We highlight current deficits, discuss approaches to overcome present obstacles, and provide suggestions for improvement