Background—: The adaptive growth of blood vessels is an important protective mechanism in cardiovascular disease. However, the underlying regulatory mechanisms of this process are only partly understood. Recently, small endogenous RNAs (microRNAs [miRNAs]) were found to play an important role in embryonic and postnatal vascular development. Here, we used miRNA transcriptome analysis after induction of hind-limb ischemia in mice to screen for miRNAs involved in adaptive blood vessel growth following arterial occlusion. Methods and Results—: Using miRNA arrays, we explored the miRNA expression profile during adaptive neovascularization. We describe specific changes in miRNA expression patterns and show that miRNA-100 is significantly downregulated after induction of hind-limb ischemia in mice. Our data demonstrate that miR-100 modulates proliferation, tube formation, and sprouting activity of endothelial cells and migration of vascular smooth muscle cells and functions as an endogenous repressor of the serine/threonine protein kinase mammalian target of rapamycin (mTOR). Whereas miR-100 inhibition increased mTOR levels in endothelial cells, overexpression of miR-100 reduced mTOR expression and consequently attenuated cellular proliferation. Supporting this notion, overexpression of an mTOR construct lacking the miRNA binding site rescued the inhibitory effect of miR-100 on cell proliferation. Accordingly, miR-100 inhibition by specific antagomirs in vivo stimulated angiogenesis and resulted in functional improvement of perfusion after femoral artery occlusion in mice. In contrast, treatment with the mTOR inhibitor rapamycin had the opposite effect. Conclusions—: Our data demonstrate that miR-100 has an antiangiogenic function and represses mTOR signaling in endothelial and vascular smooth muscle cells. Inhibition of miR-100 could be a novel approach for the modulation of blood vessel growth and other mTOR-dependent processes.

Forkhead box (Fox) transcription factors are important regulators of cardiovascular development and several Fox-proteins have recently been shown to modulate embryonic and post-natal angiogenesis. However, the role of the FoxP subfamily, which is highly expressed in cardiovascular tissue, has not been investigated so far. Here, we show that the transcription factor FoxP1 is the highest expressed FoxP-protein in endothelial cells and that it is upregulated at the site of neovascularization during hindlimb ischemia in mice. Silencing of FoxP1 results in a strong inhibition of proliferation, tube formation and migration of cultured endothelial cells. Accordingly, knockdown of FoxP1 in zebrafish was followed by a disruption of intersomitic vascular formation. Using gene expression profiling, we show that FoxP1 induces a specific change of the endothelial transcriptome and functions as a suppressor of semaphorin 5B, which has previously been described as a neuronal inhibitory factor. Our findings now demonstrate that semaphorin 5B also acts as a FoxP1- dependent suppressor of endothelial cell proliferation, migration and sprouting, mediating the effects of FoxP1. In summary, our data indicate that the transcription factor FoxP1 is essential for the angiogenic function of endothelial cells and functions as a suppressor of the inhibitory guidance cue semaphorin 5B, suggesting an important function of FoxP1 in the regulation of neovascularization.

Background: Medical staff are regularly confronted with workplace violence (WPV), which poses a threat to the safety of both staff and patients. Structured de-escalation training (DET) for Emergency Department (ED) staff has been shown to positively affect the reporting of WPV incidents and possibly reduce its impact. This study aimed to describe the development of incidence rates, causes, means, targets, locations, responses, and the time of WPV events. Additionally, it explored the effect of the staff trained in DET on the objective and subjective severity of the respective WPV events. Methods: In a retrospective, single-center cohort study, we analyzed ten years of WPV events using the data of Staff Observation Aggression Scale-Revised (SOAS-R) score (ranging from 0 to 22) in a tertiary ED from 2014 to 2023. The events were documented by ED staff and stored in the electronic health record (EHR). Results: Between 2014 and 2023, 160 staff members recorded 859 incidents, noting an average perceived severity of 5.78 (SD = 2.65) and SOAS-R score of 11.18 (SD = 4.21). Trends showed a non-significant rise in incident rates per 10,000 patients over time. The WPV events were most frequently reported by nursing staff, and the cause of the aggression was most often not discernible (n = 353, 54.56%). In total, n = 273 (31.78%) of the WPV events were categorized as severe, and the most frequent target of the aggressive behavior was the staff. WPV events occurred most frequently in the traumatology section and the detoxification rooms. While the majority of events could be addressed with verbal interventions, more forceful interventions were performed significantly more often for higher severity WPV events. More WPV events occurred during off-hours and were of a significantly higher objective and subjective severity. Overall, the presence of staff with completed DET led to significantly higher SOAS-R scores and higher perceived severity. Conclusion: The findings underline the relevance of WPV events in the high-risk environment of an ED. The analyzed data suggest that DET significantly fostered the awareness of WPV. While most events can be addressed with verbal interventions, WPV remains a concern that needs to be addressed through organizational measures and further research.

Background: The GPT-4 is a large language model (LLM) trained and fine-tuned on an extensive dataset. After the public release of its predecessor in November 2022, the use of LLMs has seen a significant spike in interest, and a multitude of potential use cases have been proposed. In parallel, however, important limitations have been outlined. Particularly, current LLMs encounter limitations, especially in symbolic representation and accessing contemporary data. The recent version of GPT-4, alongside newly released plugin features, has been introduced to mitigate some of these limitations. Objective: Before this background, this work aims to investigate the performance of GPT-3.5, GPT-4, GPT-4 with plugins, and GPT-4 with plugins using pretranslated English text on the German medical board examination. Recognizing the critical importance of quantifying uncertainty for LLM applications in medicine, we furthermore assess this ability and develop a new metric termed “confidence accuracy” to evaluate it. Methods: We used GPT-3.5, GPT-4, GPT-4 with plugins, and GPT-4 with plugins and translation to answer questions from the German medical board examination. Additionally, we conducted an analysis to assess how the models justify their answers, the accuracy of their responses, and the error structure of their answers. Bootstrapping and CIs were used to evaluate the statistical significance of our findings. Results: This study demonstrated that available GPT models, as LLM examples, exceeded the minimum competency threshold established by the German medical board for medical students to obtain board certification to practice medicine. Moreover, the models could assess the uncertainty in their responses, albeit exhibiting overconfidence. Additionally, this work unraveled certain justification and reasoning structures that emerge when GPT generates answers. Conclusions: The high performance of GPTs in answering medical questions positions it well for applications in academia and, potentially, clinical practice. Its capability to quantify uncertainty in answers suggests it could be a valuable artificial intelligence agent within the clinical decision-making loop. Nevertheless, significant challenges must be addressed before artificial intelligence agents can be robustly and safely implemented in the medical domain.

Hintergrund Das neue, pandemische Coronavirus SARS-CoV-2 und die damit einhergehende Erkrankung COVID-19 (Coronavirus Disease 2019) stellt die medizinischen Versorgungssysteme vor große Herausforderungen. Die vorliegende Arbeit fasst die Strategie, Organisation und Maßnahmen der COVID-Taskforce des Universitätsklinikums Freiburg zusammen und berichtet über Erfahrungen und Behandlungsergebnisse von der Versorgung der ersten 115 COVID-19-Patienten. Methoden Retrospektive, narrative Prozessbeschreibung und -analyse des Zeitraums Ende Januar bis Anfang April 2020, durchgeführt unter Mitwirken der beteiligten Departments, Kliniken und Institute des Universitätsklinikums Freiburg. Ergänzend erfolgte eine retrospektive Beobachtungsstudie mit deskriptiver statistischer Auswertung der epidemiologischen und klinischen Daten aller bis 31. März 2020 hospitalisierten COVID-19-Patienten. Ergebnisse Durch eine interdisziplinär zusammengesetzte Taskforce Coronavirus wurden Maßnahmen in den Bereichen ambulante Testung und Beratung, Separierung der Patientenströme sowie Eskalation der Versorgungskapazitäten auf Normal- und Intensivstationen im Sinne eines dynamischen Stufenmodells angeregt und umgesetzt. Die Versorgung der ersten 115 Patienten gelang somit ohne Entstehung von Engpässen. Diskussion Durch Zusammenwirken sämtlicher Disziplinen und Abteilungen des Universitätsklinikums Freiburg konnte eine adäquate Versorgung von COVID-19-Patienten sichergestellt und die Handlungsfähigkeit des Klinikums in der aktuellen Ausbruchsituation erhalten werden. Background The new pandemic coronavirus SARS-CoV-2 causing coronavirus disease-2019 (COVID-19) poses immense challenges to health care systems worldwide. In the current manuscript we summarize the strategies, organisational approaches and actions of the Task-force Coronavirus at the University Medical Center Freiburg. We also report on experiences with implementation of these approaches and treatment outcomes in the first 115 COVID patients. Methods Retrospective, narrative process description and analysis of the time period between end of January and beginning of April 2020, performed by representatives of the involved departments and institutes. Additionally a retrospective observational cohort study with descriptive analysis of epidemiological and clinical data of COVID patients admitted until March 31st was performed. Results A multidisciplinary Task-force Coronavirus initiated measures concerning outpatient testing and counseling, reorganisation and separation of patient flow processes alongside with substantial escalation of inpatient capacities on regular wards and intensive care units. Within the framework of the resulting dynamic care model, 115 patients suffering from COVID could be treated without shortages in staff or bed capacities. Dicussion In the upcoming pandemic, adequate COVID management and care could be secured by a collaborative approach with inclusion of administrative departments, clinical disciplines and theoretical institutes of the University Medical Center Freiburg.