TEAMs go VR-validating the TEAM in a virtual reality (VR) medical team training.

BACKGROUND: Inadequate collaboration in healthcare can lead to medical errors, highlighting the importance of interdisciplinary teamwork training. Virtual reality (VR) simulation-based training presents a promising, cost-effective approach. This study evaluates the effectiveness of the Team Emergency Assessment Measure (TEAM) for assessing healthcare student teams in VR environments to improve training methodologies. METHODS: Forty-two medical and nursing students participated in a VR-based neurological emergency scenario as part of an interprofessional team training program. Their performances were assessed using a modified TEAM tool by two trained coders. Reliability, internal consistency, and concurrent validity of the tool were evaluated using intraclass correlation coefficients (ICC) and Cronbach's alpha. RESULTS: Rater agreement on TEAM's leadership, teamwork, and task management domains was high, with ICC values between 0.75 and 0.90. Leadership demonstrated strong internal consistency (Cronbach's alpha = 0.90), while teamwork and task management showed moderate to acceptable consistency (alpha = 0.78 and 0.72, respectively). Overall, the TEAM tool exhibited high internal consistency (alpha = 0.89) and strong concurrent validity with significant correlations to global performance ratings. CONCLUSION: The TEAM tool proved to be a reliable and valid instrument for evaluating team dynamics in VR-based training scenarios. This study highlights VR's potential in enhancing medical education, especially in remote or distanced learning contexts. It demonstrates a dependable approach for team performance assessment, adding value to VR-based medical training. These findings pave the way for more effective, accessible interdisciplinary team assessments, contributing significantly to the advancement of medical education.

Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping.

The circadian clock, a fundamental biological regulator, governs essential cellular processes in health and disease. Circadian-based therapeutic strategies are increasingly gaining recognition as promising avenues. Aligning drug administration with the circadian rhythm can enhance treatment efficacy and minimize side effects. Yet, uncovering the optimal treatment timings remains challenging, limiting their widespread adoption. In this work, we introduce a high-throughput approach integrating live-imaging and data analysis techniques to deep-phenotype cancer cell models, evaluating their circadian rhythms, growth, and drug responses. We devise a streamlined process for profiling drug sensitivities across different times of the day, identifying optimal treatment windows and responsive cell types and drug combinations. Finally, we implement multiple computational tools to uncover cellular and genetic factors shaping time-of-day drug sensitivity. Our versatile approach is adaptable to various biological models, facilitating its broad application and relevance. Ultimately, this research leverages circadian rhythms to optimize anti-cancer drug treatments, promising improved outcomes and transformative treatment strategies.

Epigenetic control of metabolic identity across cell types.

Constraint-based network modelling is a powerful tool for analysing cellular metabolism at genomic scale. Here, we conducted an integrative analysis of metabolic networks reconstructed from RNA-seq data with paired epigenomic data from the EpiATLAS resource of the International Human Epigenome Consortium (IHEC). Applying a state-of-the-art contextualisation algorithm, we reconstructed metabolic networks across 1,555 samples corresponding to 58 tissues and cell types. Analysis of these networks revealed the distribution of metabolic functionalities across human cell types and provides a compendium of human metabolic activity. This integrative approach allowed us to define, across tissues and cell types, i) reactions that fulfil the basic metabolic processes (core metabolism), and ii) cell type-specific functions (unique metabolism), that shape the metabolic identity of a cell or a tissue. Integration with EpiATLAS-derived cell type-specific gene-level chromatin states and enhancer-gene interactions identified enhancers, transcription factors, and key nodes controlling core and unique metabolism. Transport and first reactions of pathways were enriched for high expression, active chromatin state, and Polycomb-mediated repression in cell types where pathways are inactive, suggesting that key nodes are targets of repression. This integrative analysis forms the basis for identifying regulation points that control metabolic identity in human cells.

Epidemiology of maxillofacial trauma in elderly patients receiving oral anticoagulant or antithrombotic medication; a Swiss retrospective study.

BACKGROUND: The percentage of elderly trauma patients under anticoagulation and antiplatelet agents has been rising lately. As newer agents are introduced, each comes with its own advantages and precautions. Our study covered elderly patients admitted to the ED with maxillofacial trauma while on anticoagulation (AC) or antiplatelet therapy (APT). We aimed to investigate the demographic characteristics, causes, and types of maxillofacial trauma, along with concomitant injuries, duration of hospitalisation, haemorrhagic complications, and the overall costs of care in the emergency department (ED). METHODS: Data were gathered from the ED of Bern University Hospital. In this retrospective analysis, patients over 65 of age were included, who presented at our ED with maxillofacial trauma between 2013 and 2019 while undergoing treatment with therapeutic AC/APT. RESULTS: The study involved 188 patients with a median age of 81 years (IQR: 81 [74; 87]), of whom 55.3% (n=104) were male. More than half (54.8%, n=103) were aged 80 years or older. Cardiovascular diseases were present in 69.7% (n=131) of the patients, with the most common indications for AC/APT use being previous thromboembolic events (41.5%, n=78) and atrial fibrillation (25.5%, n=48). The predominant cause of facial injury was falls, accounting for 83.5% (n=157) of cases, followed by bicycle accidents (6.9%, n=13) and road-traffic accidents (5.3%, n=10). The most common primary injuries were fractures of the orbital floor and/or medial/lateral wall (60.1%, n=113), zygomatic bone (30.3%, n=57), followed by isolated orbital floor fractures (23.4%, n=44) and nasal bone fractures (19.1%, n=36). Fractures of the mandible occurred in 14.9% (n=28). Facial hematomas occurred in 68.6% of patients (129 cases), primarily in the midface area. Relevant facial bleeding complications were intracerebral haemorrhage being the most frequent (28.2%, n=53), followed by epistaxis (12.2%, n=23) and retrobulbar/intraorbital hematoma (9%, n=17). Sixteen patients (8.5%) experienced heavy bleeding that required emergency treatment. The in-hospital mortality rate was 2.1% (4 cases). CONCLUSIONS: This study indicates that falls are the leading cause of maxillofacial trauma in the elderly, with the most common diagnoses being orbital, zygomatic, and nasal fractures. Haemorrhagic complications primarily involve facial hematomas, especially in the middle third of the face, with intracerebral haemorrhage being the second most frequent. Surgical intervention for bleeding was required in 8.5% of cases. Given the aging population, it is essential to improve prevention strategies and update safety protocols, particularly for patients on anticoagulant/antiplatelet therapy (AC/APT). This can ensure rapid diagnostic imaging and prompt treatment in emergencies.

Effects of interacting with a large language model compared with a human coach on the clinical diagnostic process and outcomes among fourth-year medical students: study protocol for a prospective, randomised experiment using patient vignettes.

INTRODUCTION: Versatile large language models (LLMs) have the potential to augment diagnostic decision-making by assisting diagnosticians, thanks to their ability to engage in open-ended, natural conversations and their comprehensive knowledge access. Yet the novelty of LLMs in diagnostic decision-making introduces uncertainties regarding their impact. Clinicians unfamiliar with the use of LLMs in their professional context may rely on general attitudes towards LLMs more broadly, potentially hindering thoughtful use and critical evaluation of their input, leading to either over-reliance and lack of critical thinking or an unwillingness to use LLMs as diagnostic aids. To address these concerns, this study examines the influence on the diagnostic process and outcomes of interacting with an LLM compared with a human coach, and of prior training vs no training for interacting with either of these 'coaches'. Our findings aim to illuminate the potential benefits and risks of employing artificial intelligence (AI) in diagnostic decision-making. METHODS AND ANALYSIS: We are conducting a prospective, randomised experiment with N=158 fourth-year medical students from Charité Medical School, Berlin, Germany. Participants are asked to diagnose patient vignettes after being assigned to either a human coach or ChatGPT and after either training or no training (both between-subject factors). We are specifically collecting data on the effects of using either of these 'coaches' and of additional training on information search, number of hypotheses entertained, diagnostic accuracy and confidence. Statistical methods will include linear mixed effects models. Exploratory analyses of the interaction patterns and attitudes towards AI will also generate more generalisable knowledge about the role of AI in medicine. ETHICS AND DISSEMINATION: The Bern Cantonal Ethics Committee considered the study exempt from full ethical review (BASEC No: Req-2023-01396). All methods will be conducted in accordance with relevant guidelines and regulations. Participation is voluntary and informed consent will be obtained. Results will be published in peer-reviewed scientific medical journals. Authorship will be determined according to the International Committee of Medical Journal Editors guidelines.

Virtual reality simulation to enhance advanced trauma life support trainings - a randomized controlled trial.

BACKGROUND: Advanced Trauma Life Support (ATLS) is the gold standard of initial assessment of trauma patients and therefore a widely used training program for medical professionals. Practical application of the knowledge taught can be challenging for medical students and inexperienced clinicians. Simulation-based training, including virtual reality (VR), has proven to be a valuable adjunct to real-world experiences in trauma education. Previous studies have demonstrated the effectiveness of VR simulations for surgical and technical skills training. However, there is limited evidence on VR simulation training specifically for trauma education, particularly within the ATLS curriculum. The purpose of this pilot study is to evaluate the feasibility, effectiveness, and acceptance of using a fully immersive VR trauma simulation to prepare medical students for the ATLS course. METHODS: This was a prospective randomised controlled pilot study on a convenience sample of advanced medical students (n = 56; intervention group with adjunct training using a commercially available semi-automated trauma VR simulation, n = 28, vs control group, n = 28) taking part in the ATLS course of the Military Physician Officer School. Feasibility was assessed by evaluating factors related to technical factors of the VR training (e.g. rate of interruptions and premature termination). Objective and subjective effectiveness was assessed using confidence ratings at four pre-specified points in the curriculum, validated surveys, clinical scenario scores, multiple choice knowledge tests, and ATLS final clinical scenario and course pass rates. Acceptance was measured using validated instruments to assess variables of media use (Technology acceptance, usability, presence and immersion, workload, and user satisfaction). RESULTS: The feasibility assessment demonstrated that only one premature termination occurred and that all remaining participants in the intervention group correctly stabilised the patient. No significant differences between the two groups in terms of objective effectiveness were observed (p = 0.832 and p = 0.237 for the pretest and final knowledge test, respectively; p = 0.485 for the pass rates for the final clinical scenario on the first attempt; all participants passed the ATLS course). In terms of subjective effectiveness, the authors found significantly improved confidence post-VR intervention (p < .001) in providing emergency care using the ATLS principles. Perceived usefulness in the TEI was stated with a mean of 4 (SD 0.8; range 0-5). Overall acceptance and usability of the VR simulation was rated as positive (System Usability Scale total score mean 79.4 (SD 11.3, range 0-100). CONCLUSIONS: The findings of this prospective pilot study indicate the potential of using VR trauma simulations as a feasible and acceptable supplementary tool for the ATLS training course. Where objective effectiveness regarding test and scenario scores remained unchanged, subjective effectiveness demonstrated improvement. Future research should focus on identifying specific scenarios and domains where VR can outperform or enhance traditional learning methods in trauma simulation.

AMBRA1 levels predict resistance to MAPK inhibitors in melanoma.

Intrinsic and acquired resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma remains a major therapeutic challenge. Here, we show that the clinical development of resistance to MAPKi is associated with reduced tumor expression of the melanoma suppressor Autophagy and Beclin 1 Regulator 1 (AMBRA1) and that lower expression levels of AMBRA1 predict a poor response to MAPKi treatment. Functional analyses show that loss of AMBRA1 induces phenotype switching and orchestrates an extracellular signal-regulated kinase (ERK)-independent resistance mechanism by activating focal adhesion kinase 1 (FAK1). In both in vitro and in vivo settings, melanomas with low AMBRA1 expression exhibit intrinsic resistance to MAPKi therapy but higher sensitivity to FAK1 inhibition. Finally, we show that the rapid development of resistance in initially MAPKi-sensitive melanomas can be attributed to preexisting subclones characterized by low AMBRA1 expression and that cotreatment with MAPKi and FAK1 inhibitors (FAKi) effectively prevents the development of resistance in these tumors. In summary, our findings underscore the value of AMBRA1 expression for predicting melanoma response to MAPKi and supporting the therapeutic efficacy of FAKi to overcome MAPKi-induced resistance.

Physician wellbeing and burnout in emergency medicine in Switzerland.

Emergency physicians are the most at-risk medical specialist group for burnout. Given its consequences for patient care and physician health and its resulting increased attrition rates, ensuring the wellbeing of emergency physicians is vital for preserving the integrity of the safety net for the healthcare system that is emergency medicine. In an effort to understand the current state of practicing physicians, this study reviews the results of the first national e-survey on physician wellbeing and burnout in emergency medicine in Switzerland. Addressed to all emergency physicians between March and April 2023, it received 611 complete responses. More than half of respondents met at least one criterion for burnout according to the Maslach Burnout Inventory - Human Services Survey (59.2%) and the Copenhagen Burnout Inventory (54.1%). In addition, more than half reported symptoms suggestive of mild to severe depression, with close to 20% screening positively for moderate to severe depression, nearly 4 times the incidence in the general population, according to the Patient Health Questionnaire-9. We found that 10.8% of respondents reported having considered suicide at some point in their career, with nearly half having considered this in the previous 12 months. The resulting high attrition rates (40.6% of respondents had considered leaving emergency medicine because of their working conditions) call into question the sustainability of the system. Coinciding with trends observed in other international studies on burnout in emergency medicine, this study reinforces the fact that certain factors associated with wellbeing are intrinsic to emergency medicine working conditions.

Metabolic models predict fotemustine and the combination of eflornithine/rifamycin and adapalene/cannabidiol for the treatment of gliomas.

Gliomas are the most common type of malignant brain tumors, with glioblastoma multiforme (GBM) having a median survival of 15 months due to drug resistance and relapse. The treatment of gliomas relies on surgery, radiotherapy and chemotherapy. Only 12 anti-brain tumor chemotherapies (AntiBCs), mostly alkylating agents, have been approved so far. Glioma subtype-specific metabolic models were reconstructed to simulate metabolite exchanges, in silico knockouts and the prediction of drug and drug combinations for all three subtypes. The simulations were confronted with literature, high-throughput screenings (HTSs), xenograft and clinical trial data to validate the workflow and further prioritize the drug candidates. The three subtype models accurately displayed different degrees of dependencies toward glutamine and glutamate. Furthermore, 33 single drugs, mainly antimetabolites and TXNRD1-inhibitors, as well as 17 drug combinations were predicted as potential candidates for gliomas. Half of these drug candidates have been previously tested in HTSs. Half of the tested drug candidates reduce proliferation in cell lines and two-thirds in xenografts. Most combinations were predicted to be efficient for all three glioma types. However, eflornithine/rifamycin and cannabidiol/adapalene were predicted specifically for GBM and low-grade glioma, respectively. Most drug candidates had comparable efficiency in preclinical tests, cerebrospinal fluid bioavailability and mode-of-action to AntiBCs. However, fotemustine and valganciclovir alone and eflornithine and celecoxib in combination with AntiBCs improved the survival compared to AntiBCs in two-arms, phase I/II and higher glioma clinical trials. Our work highlights the potential of metabolic modeling in advancing glioma drug discovery, which accurately predicted metabolic vulnerabilities, repurposable drugs and combinations for the glioma subtypes.

Contrast-enhanced point of care ultrasound for the evaluation of stable blunt abdominal trauma by the emergency physician: A prospective diagnostic study.

Objectives: Clinical examination alone cannot reliably rule out significant traumatic abdominal injury. Computed tomography (CT) has become the primary method for evaluating blunt abdominal trauma and clinicians rely heavily on it to rule out abdominal injury. Ultrasound examination may miss significant abdominal injury particularly in stable patients. The use of a contrast agent improves ultrasound sensitivity to visceral abdominal injuries. The objective of this diagnostic study is to compare bedside contrast enhanced ultrasound (CEUS) performed by emergency physicians to CT in hemodynamically stable adults for the assessment of blunt abdominal trauma and evaluate CEUS accuracy outcomes. Methods: Hemodynamically stable patients with blunt trauma were prospectively enrolled in the trauma bay. After initial evaluation, we included patients at risk of abdominal injury and for whom an abdominal CT was planned by the trauma leader. Ultrasonography was performed prospectively and at the bedside by the emergency physician followed by abdominal CT used as a reference standard. Results: Thirty-three patients were enrolled in the study; among them, 52% showed positive traumatic findings in abdominal CT scans, and 42% were diagnosed with solid organ lesions. Compared to CT, a focused abdominal sonography (FOCUS) examination, looking for free fluid or perirenal hematoma, showed limited performance for traumatic findings with a sensitivity of 65% (95% confidence interval [CI]: 38%-86%), a specificity of 75% (95% CI: 48%-93%), a negative likelihood ratio (NLR) of 0.47 (95% CI: 0.23-0.95), and a positive likelihood ratio (PLR) of 2.59 (95% CI: 1.03-6.48). When combining FOCUS with CEUS, the sensitivity of the sonography increased to 94% (95% CI: 71%-100%) with a specificity of 75% (95% CI: 48%-93%). The PLR was 3.76 (95% CI: 1.6-8.87) and the NLR was 0.08 (95% CI: 0.01-0.54). In our population, abdominal sonography with contrast failed to identify a single positive abdominal CT with a grade 1 kidney injury. Conclusions: A FOCUS examination shows limited sensitivity and specificity to detect positive abdominal CT in stable adults with abdominal trauma. With the addition of contrast and careful inspection of solid organs, abdominal sonography with contrast performed by the emergency physician improves the ability to rule out traumatic findings on abdominal CT. CEUS performed by emergency physicians may miss injuries, especially in the absence of free fluid, in cases of low-grade injuries, simultaneous injuries, or poor-quality examinations.

Acceptance, Satisfaction, and Preference With Telemedicine During the COVID-19 Pandemic in 2021-2022: Survey Among Patients With Chronic Pain.

BACKGROUND: The COVID-19 pandemic has forced many health care providers to make changes in their treatment, with telemedicine being expanded on a large scale. An earlier study investigated the acceptance of telephone calls but did not record satisfaction with treatment or patients' preferences. This warranted a follow-up study to investigate acceptance, satisfaction, and preferences regarding telemedicine, comprising of phone consultations, among health care recipients. OBJECTIVE: The primary aim was to assess the acceptance and satisfaction of telemedicine during the subsequent months of 2021-2022, after the initial wave of the COVID-19 pandemic in Switzerland. Furthermore, we aimed to assess patients' preferences and whether these differed in patients who had already experienced telemedicine in the past, as well as correlations between acceptance and satisfaction, pain intensity, general condition, perception of telemedicine, and catastrophizing. Finally, we aimed to investigate whether more governmental restrictions were correlated with higher acceptance. METHODS: An anonymous cross-sectional web-based survey was conducted between January 27, 2021, and February 4, 2022, enrolling patients undergoing outpatient pain therapy in a tertiary university clinic. We conducted a descriptive analysis of acceptance and satisfaction with telemedicine and investigated patients' preferences. Further, we conducted a descriptive and correlational analysis of the COVID-19 stringency index. Spearman correlation analysis and a chi-square test for categorical data were used with Cramer V statistic to assess effect sizes. RESULTS: Our survey was completed by 60 patients. Telemedicine acceptance and satisfaction were high, with an average score of 7.6 (SD 3.3; on an 11-point Numeric Rating Scale from 0=not at all to 10=completely), and 8.8 (SD 1.8), respectively. Respondents generally preferred on-site consultations to telemedicine (n=35, 58% vs n=24, 40%). A subgroup analysis revealed that respondents who already had received phone consultation, showed a higher preference for telemedicine (n/N=21/42, 50% vs n/N=3/18, 17%; χ22 [N=60]=7.5, P=.02, Cramer V=0.354), as well as those who had been treated for more than 3 months (n/N=17/31, 55% vs n/N=7/29, 24%; χ22 [N=60]=6.5, P=.04, Cramer V=0.329). Acceptance of telemedicine showed a moderate positive correlation with satisfaction (rs{58}=0.41, P<.05), but there were no correlations between the COVID-19 stringency index and the other variables. CONCLUSIONS: Despite high acceptance of and satisfaction with telemedicine, patients preferred on-site consultations. Preference for telemedicine was markedly higher in patients who had already received phone consultations or had been treated for longer than 3 months. This highlights the need to convey knowledge of eHealth services to patients and the value of building meaningful relationships with patients at the beginning of treatment. During the COVID-19 pandemic, the modality of patient care should be discussed individually.

Perceptions and needs of an outpatient palliative care team regarding digital care conferences in palliative care: a mixed-method online survey.

BACKGROUND: Telemedicine in palliative care (PC) is increasingly being used, especially in outpatient settings with large geographic distances. Its proven benefits include improved communication, coordination quality and time savings. However, the effect on symptom control is less evident. Whether these benefits apply to the Swiss setting and the needs of healthcare professionals (HCPs) is unknown. OBJECTIVES: To identify the perceptions and needs of healthcare professionals (nurses and physicians) regarding telemedicine (generally and specifically for care conferences) in a Swiss outpatient palliative care network. METHODS: We conducted a cross-sectional, mixed-method online survey with purposefully sampled healthcare professionals from an outpatient palliative care team as baseline data during the planning phase of a quality improvement project (digital care conferences). FINDINGS/RESULTS: Of the 251 HCPs approached, 66 responded, including nurses (n = 37) and physicians (n = 29), with an overall response rate of 26.6%. These were distributed into two groups: general palliative care HCPs (n = 48, return rate 21.3%) and specialised palliative care HCPs (n = 18, return rate 69.2%). Generally, telemedicine was perceived as useful. Potential easy access to other HCPs and hence improved communication and coordination were perceived as advantages. Barriers included a lack of acceptance and physical contact, unsolved questions about potential data breaches and technical obstacles. Regarding digital care conferences, the perceived acceptance and feasibility were good; preferred participants were the specialised palliative care HCPs (nurses and physicians), primary physicians and home care nurses, as well as the leadership of a nurse. The needs of the HCPs were as follows: (a) clear and efficient planning, (b) usability and security and (c) visual contact with the patient. CONCLUSION: Digital care conferences are perceived as a feasible and useful tool by healthcare professionals in a local palliative care network in Switzerland. A pilot phase will be the next step towards systematic integration of this telemedicine modality into outpatient palliative care.

Time for "code ICH"? - Workflow metrics of hyperacute treatments and outcome in patients with intracerebral haemorrhage.

INTRODUCTION: Knowledge about uptake and workflow metrics of hyperacute treatments in patients with non-traumatic intracerebral haemorrhage (ICH) in the emergency department are scarce. METHODS: Single centre retrospective study of consecutive patients with ICH between 01/2018-08/2020. We assessed uptake and workflow metrics of acute therapies overall and according to referral mode (stroke code, transfer from other hospital or other). RESULTS: We enrolled 332 patients (age 73years, IQR 63-81 and GCS 14 points, IQR 11-15, onset-to-admission-time 284 minutes, IQR 111-708minutes) of whom 101 patients (35%) had lobar haematoma. Mode of referral was stroke code in 129 patients (38%), transfer from other hospital in 143 patients (43%) and arrival by other means in 60 patients (18%). Overall, 143 of 216 (66%) patients with systolic blood pressure >150mmHG received IV antihypertensive and 67 of 76 (88%) on therapeutic oral anticoagulation received prothrombin complex concentrate treatment (PCC). Forty-six patients (14%) received any neurosurgical intervention within 3 hours of admission. Median treatment times from admission to first IV-antihypertensive treatment was 38 minutes (IQR 18-72minutes) and 59 minutes (IQR 37-111 minutes) for PCC, with significant differences according to mode of referral (p<0.001) but not early arrival (≤6hours of onset, p=0.92). The median time in the emergency department was 139 minutes (IQR 85-220 minutes) and among patients with elevated blood pressure, only 44% achieved a successful control (<140mmHG) during ED stay. In multivariate analysis, code ICH concordant treatment was associated with significantly lower odds for in-hopsital mortality (aOR 0.30, 95%CI 0.12-0.73, p=0.008) and a non-significant trends towards better functional outcome measured using the modified Rankin scale score at 3 months (aOR for ordinal shift 0.54 95%CI 0.26-1.12, p=0.097). CONCLUSION: Uptake of hyperacute therapies for ICH treatment in the ED is heterogeneous. Treatment delays are short but not all patients achieve treatment targets during ED stay. Code ICH concordant treatment may improve clinical outcomes. Further improvements seem achievable advocating for a "code ICH" to streamline acute treatments.

Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation.

Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson's disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) human iPSC reporter line, we here generate time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicts novel regulators of mDAN differentiation and super-enhancers are used to identify key TFs. We find LBX1, NHLH1 and NR2F1/2 to promote mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. A more detailed investigation of TF targets reveals that NHLH1 promotes the induction of neuronal miR-124, LBX1 regulates cholesterol biosynthesis, and NR2F1/2 controls neuronal activity.

[Medical extended reality in digital emergency medicine : From education to clinical application]. / Medical Extended Reality in der digitalen Notfallmedizin : Von der Ausbildung zur klinischen Anwendung.

BACKGROUND: Emergency medicine faces the challenge of providing optimal care with limited resources. Especially in rare but critical situations (high-acuity low occurrence [HALO] situations), sound expertise is essential. Previous training approaches are time-limited and resource-intensive. AIM OF THE WORK: Medical extended reality (MXR) offers promising solutions. This article gives insight into the different areas of MXR and shows the application of MXR in emergency medicine using the HALO-MXR concept as an example. RESULTS AND DISCUSSION: MXR encompasses augmented reality (AR), virtual reality (VR) and mixed reality (MR). AR overlays digital information on the real world, enhancing perception and enabling interactive elements. VR creates an artificial three-dimensional (3D) environment in which the user is immersed. MR combines real and virtual elements. MXR offers advantages such as location-independent learning, virtual mentoring and scalability. However, it cannot replace existing training formats, but should be embedded in an overall concept. The HALO-MXR concept at Inselspital Bern includes e­learning, simulation-based training in VR and on-site, and HALO-Assist support through augmented reality. HALO-Assist provides around-the-clock AR support for HALO procedures via audio and video communication as well as overlayed annotations, objects and flowcharts. CONCLUSION: The integration of MXR into emergency medicine promises more efficient use of resources and enhanced training opportunities. The HALO-MXR concept demonstrates how MXR effectively combines simulation-based training in VR and AR assist to enhance the application of HALO procedures.

Do monosymptomatic stroke patients with dizziness present a vestibular syndrome without nystagmus? An underestimated entity.

BACKGROUND AND PURPOSE: Vestibular symptoms are common in emergency department (ED) patients and have various causes, including stroke. Accurate identification of stroke in patients with vestibular symptoms is crucial for timely management. We conducted a prospective cross-sectional study from 2015 to 2019 to determine stroke prevalence and associated symptoms in ED patients with vestibular symptoms, aiming to improve diagnosis and outcomes. METHODS: As part of the DETECT project, we screened 1647 ED patients with acute vestibular symptoms. Following a retrospective analysis of 961 head and neck magnetic resonance imaging (MRI) scans, we included 122 confirmed stroke cases and assessed them for vestibular signs and symptoms. RESULTS: Stroke prevalence in dizzy patients was 13% (122/961 MRI scans). Most patients (95%) presented with acute vestibular symptoms with or without nystagmus, whereas 5% had episodic vestibular syndrome (EVS). Nystagmus was present in 50% of stroke patients. Eighty percent had a purely posterior circulation stroke, and nystagmus was absent in 46% of these patients. Seven patients (6%) had lesions in both the anterior and posterior circulation. Vertigo was experienced by 52% regardless of territory. CONCLUSIONS: A stroke was identified in 13% of ED patients presenting with acute vestibular symptoms. In 5%, it was EVS. Most strokes were in the posterior circulation territory; vertigo occurred with similar frequency in anterior and posterior circulation stroke, and absence of nystagmus was common in both.

2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition.

2-Hydroxyglutarate (2-HG) is an oncometabolite that accumulates in certain cancers. Gain-of-function mutations in isocitrate dehydrogenase lead to 2-HG accumulation at the expense of alpha-ketoglutarate. Elevated 2-HG levels inhibit histone and DNA demethylases, causing chromatin structure and gene regulation changes with tumorigenic consequences. We investigated the effects of elevated 2-HG levels in Saccharomyces cerevisiae, a yeast devoid of DNA methylation and heterochromatin-associated histone methylation. Our results demonstrate genetic background-dependent gene expression changes and altered H3K4 and H3K36 methylation at specific loci. Analysis of histone demethylase deletion strains indicated that 2-HG inhibits Rph1 sufficiently to induce extensive gene expression changes. Rph1 is the yeast homolog of human KDM4 demethylases and, among the yeast histone demethylases, was the most sensitive to the inhibitory effect of 2-HG in vitro. Interestingly, Rph1 deficiency favors gene repression and leads to further down-regulation of already silenced genes marked by low H3K4 and H3K36 trimethylation, but abundant in H3K36 dimethylation. Our results provide novel insights into the genome-wide effects of 2-HG and highlight Rph1 as its preferential demethylase target.

Impaired neuron differentiation in GBA-associated Parkinson's disease is linked to cell cycle defects in organoids.

The mechanisms underlying Parkinson's disease (PD) etiology are only partially understood despite intensive research conducted in the field. Recent evidence suggests that early neurodevelopmental defects might play a role in cellular susceptibility to neurodegeneration. To study the early developmental contribution of GBA mutations in PD we used patient-derived iPSCs carrying a heterozygous N370S mutation in the GBA gene. Patient-specific midbrain organoids displayed GBA-PD relevant phenotypes such as reduction of GCase activity, autophagy impairment, and mitochondrial dysfunction. Genome-scale metabolic (GEM) modeling predicted changes in lipid metabolism which were validated with lipidomics analysis, showing significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids exhibited a decrease in the number and complexity of dopaminergic neurons. This was accompanied by an increase in the neural progenitor population showing signs of oxidative stress-induced damage and premature cellular senescence. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology.

Exploring objective measures for assessing team performance in healthcare: an interview study.

Introduction: Effective teamwork plays a critical role in achieving high-performance outcomes in healthcare. Consequently, conducting a comprehensive assessment of team performance is essential for providing meaningful feedback during team trainings and enabling comparisons in scientific studies. However, traditional methods like self-reports or behavior observations have limitations such as susceptibility to bias or being resource consuming. To overcome these limitations and gain a more comprehensive understanding of team processes and performance, the assessment of objective measures, such as physiological parameters, can be valuable. These objective measures can complement traditional methods and provide a more holistic view of team performance. The aim of this study was to explore the potential of the use of objective measures for evaluating team performance for research and training purposes. For this, experts in the field of research and medical simulation training were interviewed to gather their opinions, ideas, and concerns regarding this novel approach. Methods: A total of 34 medical and research experts participated in this exploratory qualitative study, engaging in semi-structured interviews. During the interview, experts were asked for (a) their opinion on measuring team performance with objective measures, (b) their ideas concerning potential objective measures suitable for measuring team performance of healthcare teams, and (c) their concerns regarding the use of objective measures for evaluating team performance. During data analysis responses were categorized per question. Results: The findings from the 34 interviews revealed a predominantly positive reception of the idea of utilizing objective measures for evaluating team performance. However, the experts reported limited experience in actively incorporating objective measures into their training and research. Nevertheless, they identified various potential objective measures, including acoustical, visual, physiological, and endocrinological measures and a time layer. Concerns were raised regarding feasibility, complexity, cost, and privacy issues associated with the use of objective measures. Discussion: The study highlights the opportunities and challenges associated with employing objective measures to assess healthcare team performance. It particularly emphasizes the concerns expressed by medical simulation experts and team researchers, providing valuable insights for developers, trainers, researchers, and healthcare professionals involved in the design, planning or utilization of objective measures in team training or research.