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Pierre-Nicolas Carron, Lionel Trueb, Bertrand YersinEmergency Service, University Hospital Center, Lausanne, SwitzerlandAbstract: Simulation is a promising pedagogical tool in the area of medical education. High-fidelity simulators can reproduce realistic environments or clinical situations. This allows for the practice of teamwork and communication skills, thereby enhancing reflective reasoning and experiential learning. Use of high-fidelity simulators is not limited to the medical and aeronautical fields, but has developed in a large number of nonmedical organizations as well. The techniques and pedagogical tools which have evolved through the use of nonmedical simulations serve not only as teaching examples but also as avenues which can help further the evolution of the concept of high-fidelity simulation in the field of medicine. This paper presents examples of high-fidelity simulations in the military, maritime, and aeronautical fields. We compare the implementation of high-fidelity simulation in the medical and nonmedical domains, and discuss the possibilities and limitations of simulators in medicine, based on recent nonmedical applications.Keywords: high-fidelity simulation, crew resource management, experiential learning

Background: Adverse environmental events occurring early in life have received little attention as predictors of disease in the later stages of life. At birth, the transition from gas exchange by the placenta to gas exchange by the lungs requires dramatic changes in the pulmonary circulation, which during this period is particularly vulnerable to noxious stimuli. We measured pulmonary-artery pressure responses to high-altitude exposure, a stimulus that causes pronounced pulmonary vasoconstriction, in young adults who had had transient perinatal hypoxic pulmonary hypertension and in controls of similar age and sex distribution. Methods: Review of neonatal-care records at the Lausanne University Hospital for Children identified 15 individuals who met the eligibility criteria (birth at > or = 34 weeks of gestation, persistence of hypoxaemia during ventilation with oxygen during the first week of life, and persistence of fetal circulation). Ten of these individuals agreed to take part; the control group was ten volunteers without any history of perinatal complications. Systolic pulmonary-artery pressure (by echocardiography) and arterial oxygen saturation were measured at baseline and at high altitude (4559 m). Findings: The mean increase in pulmonary-artery pressure at high altitude was significantly greater (p=0.01) in the participants who had had perinatal pulmonary hypertension (from 26.2 mm Hg [SD 2.1] to 62.3 mm Hg [7.3]) than in the controls (from 25.8 mm Hg [2.3] to 49.7 mm Hg [11.3]). The fall in arterial oxygen saturation was similar in the two groups. Interpretation: These findings suggest that a transient perinatal insult to the pulmonary circulation leaves a persistent and potentially fatal imprint, which when activated in adult life predisposes to a pathological response. Survivors of perinatal pulmonary hypertension may be at risk of developing this disorder in later life. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8 + cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization., Competing Interests: Declaration of interests G.C. has received grants, research support, or has been coinvestigator in clinical trials by Bristol-Myers Squibb, Tigen Pharma, Iovance, F. Hoffmann-La Roche AG, and Boehringer Ingelheim. The Lausanne University Hospital (CHUV) has received honoraria for advisory services G.C. has provided to Genentech, AstraZeneca AG, and EVIR. G.C. has previously received royalties from the University of Pennsylvania for CAR-T cell therapy licensed to Novartis and Tmunity Therapeutics. D.D.L., S.B., A.H., and G.C. are inventors on patent applications filed by the Ludwig Institute for Cancer Research Ltd. on behalf of the University of Lausanne and the CHUV pertaining to the subject matter disclosed herein, and such patent applications have been licensed to Tigen Pharma SA. S.Z. is currently an employee of F. Hoffmann-La Roche. O.M. has consulting/advisory roles for Bristol Myers Squibb, MSD, Roche, Novartis, Amgen, Pierre Fabre, and Neracare; research grants from Bristol Myers Squibb, MSD, Amgen, and PCL; was a consultant advisor or paid speaker for Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Amgen, and Nektar; and has received research funding from Bristol Myers Squibb and Pierre Fabre and is the cofounder of a cell therapy company called Cellula., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Experience-Based Co-Design (EBCD) is a multi-stage participatory action research process which was developed originally to increase patient involvement in service improvement initiatives. This viewpoint article serves as a reflection on the researchers' experiences, focusing on the application and feasibility of participatory approaches, particularly co-design, in the specific context of early-phase clinical trials., Methods: We reflect on the opportunities and challenges of applying EBCD in a new context of early-phase clinical trials in oncology where experimental treatments are increasingly perceived as a therapeutic option and, in certain instances, their efficacy may lead to accelerated approval facilitating a swifter integration into standard care., Results: We propose that the opportunity of applying EBCD in such trials lies in improving the delivery of person-centered care, care coordination, and support during the transition from experimental to standard care. Three potential challenges when applying EBCD in early-phase clinical trials are discussed related to: the need for standardization in trial processes; planning EBCD in a context of high uncertainty; and vulnerability of patient populations., Conclusion: Integrating EBCD into early-phase oncology trials presents an opportunity to enhance person-centered care and can lead to simultaneous improvements in care processes and therapeutic development., Patient or Public Contribution: This article has been developed with the collaboration of a patient partner who serves on the advisory board of our ongoing EBCD study in early clinical trials., (© 2024 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Cellular therapy using genetically modified T lymphocytes expressing synthetic receptors, known as CAR (Chimeric Antigen Receptor), has revolutionized the treatment of certain hematologic malignancies. This success has led to exploring the same approach in the treatment of severe autoimmune diseases refractory to conventional therapies. Initial results in systemic lupus erythematosus have shown complete remissions that appear to persist over time. Consequently, there is a growing number of ongoing clinical trials. In this review, we discuss the rationale behind the use of CAR-T therapies, the targeted autoimmune diseases, and the associated risks., Competing Interests: Le Pr Y. D. Müller est inventeur d’une licence sur les CAR-T (US 2023/0340068 A1) et responsable de site d’une étude CAR-T (NCT05798117). Les autres auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell-intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8 + TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor-reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

Adoptive cell therapies (ACT) have demonstrated promise in the treatment of patients with cancer, leading to long-lasting responses and, in some cases, even cure. Technological advances have brought these individualized therapies closer to reality, establishing them as credible therapeutic option. However, to date, few efforts have been made to understand patients' experience during ACT trials. Patient-reported outcomes (PROs) and patient-reported outcome measures (PROMs), which are instruments used to report PROs, are increasingly being used in oncology to capture patients' perspective, provide real-world data on treatment safety, and support decision-making processes, such as health economic decisions. Due to the inherent complexity of ACT, the inclusion of PROMs in this field remains limited. In this commentary, we discuss the benefit of capturing PROs in ACT trials, the challenges of PROM administration and collection, and we propose simple and actionable recommendations to promote their adoption in ACT trials., Competing Interests: Competing interests: GC reports grants from Celgene, grants from Boehringer-Ingelheim, personal fees from Genentech, grants from Roche, personal fees from Roche, grants from BMS, personal fees from BMS, personal fees from AstraZeneca, grants from Iovance Therapeutics, grants from Kite Pharma, personal fees from NextCure, personal fees from Geneos Tx, and personal fees from Sanofi/Aventis. MDM received grants or contracts to his institution from Tesaro and GSK, consulting fees from Novartis, Roche, AstraZeneca, Merck Serono, Pfizer, Merck Sharp & Dohme, Janssen, Eisai, Takeda, Boehringer Ingelheim, Servier; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, Roche, AstraZeneca, Pfizer, Merck Sharp & Dohme, Janssen, Astellas, Boehringer Ingelheim; participation on a Data Safety Monitoring Board or Advisory Board for Merck Sharp & Dohme, Janssen, Astellas and Amgen. ME reports grants or contracts to her institution from Kaiku Health, Novartis, Roche, Vifor, BMS and Payment or honoraria for lectures, presentations from Roche, BMS and Vifor. The other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Aims: Several studies report on Good Manufacturing Process (GMP)-compliant manufacturing protocols for the ex vivo expansion of tumor-infiltrating lymphocytes (TILs) for the treatment of patients with refractory melanoma and other solid malignancies. Further opportunities for improvements in terms of ergonomy and operating time have been identified., Methods: To enable GMP-compliant TILs production for adoptive cell therapy needs, a simple automated and reproducible protocol for TILs manufacturing with the use of a closed system was developed and implemented at the authors' institution., Results: This protocol enabled significant operating time reduction during TILs expansion while allowing the generation of high-quality TILs products., Conclusions: A simplified and efficient method of TILs expansion will enable the broadening of individualized tumor therapy and will increase patients' access to state-of-the-art TILs adoptive cell therapy treatment., (Copyright © 2020. Published by Elsevier Inc.)

Background: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a promising experimental immunotherapy that has shown high objective responses in patients with melanoma. Current protocols use a lymphodepletive chemotherapy before infusion of ex vivo expanded TILs, followed by high-dose interleukin-2 (IL-2). Treatment-related toxicities are mainly attributable to the chemotherapy regimen and to the high-dose IL-2 and are generally reversible. Neurological side effects have rarely been described. Nevertheless, due to improvements in cell production techniques and due to combinations with other immunomodulating molecules, side effects not previously described may be encountered., Case Presentation: We report the case of a 53-year-old heavily pretreated patient with melanoma who developed Guillain-Barré syndrome (GBS) 19 days after ACT using autologous TILs, given in the context of a phase I trial. He presented with dorsal back pain, unsteady gait and numbness in hands and feet. Lumbar puncture showed albuminocytological dissociation, and nerve conduction studies revealed prolonged distal motor latencies in median, ulnar, tibial and peroneal nerves, compatible with a GBS. The patient was treated with intravenous immunoglobulins and intensive neurological rehabilitation, with progressive and full recovery at 21 months post-TIL-ACT. Concomitant to the onset of GBS, a cytomegalovirus reactivation on immunosuppression was detected and considered as the most plausible cause of this neurological side effect., Conclusion: We describe for the first time a case of GBS occurring shortly after TIL-ACT for melanoma, even though we could not identify with certainty the triggering agent. The report of such rare cases is of extreme importance to build on the knowledge of immune cellular therapies and their specific spectrum of toxicities., Competing Interests: Competing interests: GC has received grants or research support from or is coinvestigator in clinical trials by BMS, Celgene, Boehringer Ingelheim, Roche, Iovance and Kite, and has received honoraria for consultations or presentations by Roche, Genentech, BMS, AstraZeneca, Sanofi-Aventis, Nextcure and GeneosTx. SZ reports travel grants by AstraZeneca in the last 12 months., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Taxon names are at the core of communication related to biodiversity. Thus, systems that regulate such names should prevent unnecessary changes. Unfortunately, the current regulatory codes have some articles that produce confusion or, even, generate name instability. To promote nomenclatural stability, while maintaining a system that effectively conveys information about biological diversity and its evolution, we argue in favor of emendations to the current International Code of Zoological Nomenclature (ICZN). We propose that taxon names should be created within an evolutionary framework; ideally, this would mean including a phylogenetic tree or, at the very least, formulating a hypothesis in words based on explicit arguments (homologous traits) for the evolutionary relatedness of taxa, avoiding subjective perceptions. Additionally, we consider that some relatively minor changes of the ICZN would greatly increase name stability; the most relevant modifications that would facilitate long-term stability are: (i) immutability of the species epithet of species names, (ii) intercalation of unranked taxa between formal Linnaean ranks, (iii) elimination of homonyms in taxon names at the genus-group level, and (iv) inclusion of flexible phylogenetic definitions when supraspecific taxa are named.

New oncological approaches using immune checkpoint inhibitors aim to reinvigorate lymphocytes against the tumor. The prognosis of cancer has been significantly improved by these treatments, which nonetheless lead to a new spectrum of immune-related side effects. The most frequent are skin rash, colitis, thyroid dysfunction, hypophysitis, hepatitis and pneumonitis. Early detection of these toxicities is crucial to determine the etiology and to introduce a temporary immunosuppressive therapy, allowing resolution of toxicity in most of cases. A multidisciplinary team is essential for optimal management., Competing Interests: Les auteurs ne déclarent aucun conflit d’intérêt en lien avec cet article.

Adoptive T cell therapy (ACT) is a safe and effective personalized cancer immunotherapy that can comprise naturally occurring ex vivo expanded cells (e.g., tumor-infiltrating lymphocytes [TIL]) or T cells genetically engineered to confer antigen specificity (T-cell receptor [TCR] or chimeric antigen receptor [CAR] engineered T cells) to mediate cancer rejection. In recent years, some ACTs have produced unprecedented breakthrough responses: TIL therapy has moved from melanoma to solid tumor applications, TCR-engineered cells are developed for hematologic and solid tumors, and CAR-engineered T cells have received Food and Drug Administration (FDA) approval for the treatment of patients with certain B-cell malignancies. Although results are encouraging, to date, only a small percentage of patients with advanced malignancies can benefit from ACT. Besides ACT availability and accessibility, treatment-related toxicities represent a major hurdle in the widespread implementation of this therapeutic modality. The large variety of observed toxicities is caused by the infused cell product or as side effects of accompanying medication and chemotherapy. Toxicities can occur immediately or can be delayed. In order to render those highly promising therapeutic approaches safe enough for a wider pool of patients outside of clinical trials, an international consensus for toxicity management needs to be established.

Background: Emergency Department (ED) are challenged by the increasing number of visits made by the heterogeneous population of elderly persons. This study aims to 1) compare chief complaints (triage categories) and level of priority; 2) to investigate their association with hospitalization after an ED visit; 3) to explore factors explaining the difference in hospitalization rates among community-dwelling older adults aged 65-84 vs 85+ years., Methods: All ED visits of patients age 65 and over that occurred between 2005 and 2010 to the University of Lausanne Medical Center were analyzed. Associations of hospitalization with triage categories and level of priority using regressions were compared between the two age groups. Blinder-Oaxaca decomposition was performed to explore how much age-related differences in prevalence of priority level and triage categories contributed to predicted difference in hospitalization rates across the two age groups., Results: Among 39'178 ED visits, 8'812 (22.5%) occurred in 85+ patients. This group had fewer high priority and more low priority conditions than the younger group. Older patients were more frequently triaged in "Trauma" (20.9 vs 15.0%) and "Home care impossible" (10.1% vs 4.2%) categories, and were more frequently hospitalized after their ED visit (69.1% vs 58.5%). Differences in prevalence of triage categories between the two age groups explained a quarter (26%) of the total age-related difference in hospitalization rates, whereas priority level did not play a role., Conclusions: Prevalence of priority level and in triage categories differed across the two age groups but only triage categories contributed moderately to explaining the age-related difference in hospitalization rates after the ED visit. Indeed, most of this difference remained unexplained, suggesting that age itself, besides other unmeasured factors, may play a role in explaining the higher hospitalization rate in patients aged 85+ years.

Wild mushroom intoxication is an unusual cause of toxic ingestion in Europe. A great diversity of clinical symptoms may arise depending on the variety of wild mushrooms ingested. These initial symptoms are often non-specific, with frequent gastrointestinal symptoms, and have no direct correlation with the outcome. Therefore, management of mushroom poisoning and risk evaluation are a challenge for emergency clinicians. We retrospectively reviewed all cases of mushroom poisoning identified in the ED database spanning 11 years. Demographic and clinical data, time from consumption to symptoms, type of mushrooms, the number of patients presenting at the same time, treatment(s) provided, length of stay, discharge diagnosis, in-hospital mortality, and serious complications were evaluated. We identify 87 cases of mushroom poisoning. The most common symptoms are nausea and vomiting (71 cases, 82%), followed by diarrhea (68%), syncope (10%), abdominal pain (8%), and hallucinations (7%). Sixty-four patients (74%) exhibited early symptoms (appearance <6 h after ingestion) and 23 (26%) late symptoms (appearance >6 h after ingestion). Eleven patients (13%) required hospitalization over 24 h. Patients with late symptoms tended to have longer in-hospital lengths of stay. Only one patient had Amanita phalloides intoxication, with a favorable outcome. Thirty-eight patients (44%) were involved in cluster presentations. Mushroom poisoning is an unusual but potentially severe form of intoxication. Patients presenting with late-appearing symptoms (>6 h) are associated with a higher risk of A. phalloides intoxication, and therefore require specific investigation and management.

Trafficking and sale of narcotics frequently involves the intra-abdominal transport of large quantities of drugs, usually cocaine or heroin ("body packing"), or, when there is a risk of being arrested, the oral ingestion of minor quantities of narcotics dedicated for immediate resale ("body stuffing"). This study aimed to describe the characteristics, complications and medical follow through of 132 cases of body packing (n = 36), cases of body stuffing (n = 83) or mixed cases (n = 13), referred by the authorities to our emergency department over the course of 12 years. Analysis of these 132 cases did not reveal any intra-abdominal rupture or leak of the packaging, or any case of acute intoxication. Nevertheless, a surgical intervention was required in three of the body packers (2.3%) owing to stasis of the packages inside the stomach. The mean length of stay was longer when the packets were located in the stomach at time of diagnosis than when they were lower in the gastrointestinal tract (61.9 vs 43.8 hours, respectively), but this was not statistically significant (p = 0.13). Length of stay was not associated with the presence of (nonspecific) symptoms or the total number of packs ingested. In conclusion, the study of this cohort of 132 body packers and body stuffers permits us to state that the medical management of these patients is rarely associated with serious complications, and that their length of stay is generally long, averaging 2 days before complete elimination of the drug packages.

Cardiopulmonary resuscitation (CPR) guidelines have been updated in October 2015. The 2010 guidelines are reaffirmed: immediate call for help via the local dispatch center, high quality CPR (frequency between 100 and 120/min, compression depth between 5 and 6 cm) and early defibrillation improve patient's survival chances. This article reviews the essential elements of resuscitation and recommended advanced measures.

Background: Frequent emergency department (ED) users meet several of the criteria of vulnerability, but this needs to be further examined taking into consideration all vulnerability's different dimensions. This study aimed to characterize frequent ED users and to define risk factors of frequent ED use within a universal health care coverage system, applying a conceptual framework of vulnerability., Methods: A controlled, cross-sectional study comparing frequent ED users to a control group of non-frequent users was conducted at the Lausanne University Hospital, Switzerland. Frequent users were defined as patients with five or more visits to the ED in the previous 12 months. The two groups were compared using validated scales for each one of the five dimensions of an innovative conceptual framework: socio-demographic characteristics; somatic, mental, and risk-behavior indicators; and use of health care services. Independent t-tests, Wilcoxon rank-sum tests, Pearson's Chi-squared test and Fisher's exact test were used for the comparison. To examine the -related to vulnerability- risk factors for being a frequent ED user, univariate and multivariate logistic regression models were used., Results: We compared 226 frequent users and 173 controls. Frequent users had more vulnerabilities in all five dimensions of the conceptual framework. They were younger, and more often immigrants from low/middle-income countries or unemployed, had more somatic and psychiatric comorbidities, were more often tobacco users, and had more primary care physician (PCP) visits. The most significant frequent ED use risk factors were a history of more than three hospital admissions in the previous 12 months (adj OR:23.2, 95%CI = 9.1-59.2), the absence of a PCP (adj OR:8.4, 95%CI = 2.1-32.7), living less than 5 km from an ED (adj OR:4.4, 95%CI = 2.1-9.0), and household income lower than USD 2,800/month (adj OR:4.3, 95%CI = 2.0-9.2)., Conclusions: Frequent ED users within a universal health coverage system form a highly vulnerable population, when taking into account all five dimensions of a conceptual framework of vulnerability. The predictive factors identified could be useful in the early detection of future frequent users, in order to address their specific needs and decrease vulnerability, a key priority for health care policy makers. Application of the conceptual framework in future research is warranted.

The year 2014 was marked by new therapeutic acquisitions in emergency medicine. Nephrolithiasis likelihood estimation should avoid imaging in patients at high risk. Therapeutic hypothermia post cardio-respiratory arrest has no benefit compared to a strategy of controlled normothermia. Treatment of acute bronchitis with no signs of severity by coamoxicillin or NSAIDs is useless. Adding colchicine to standard treatment of acute pericarditis reduces the rate of recurrence. The D-dimerthreshold adjustment by age reduces the number of imaging in case of low or intermediate risk of pulmonary embolism. Finally, the speed of the initial management of septic shock is crucial to the outcome of patients, but an early invasive monitoring provides no benefit.

Severe sepsis and septic shock are systemic manifestations of the host response to infection. Mortality remains high despite advances in pathophysiological knowledge. Hemodynamic and respiratory management is largely supportive, while early antibiotics administration and source of infection's control are crucial for patient outcome. We review the principles guiding the initial management of these patients in emergency situation.