[CAR-T therapy for autoimmune diseases]. / Thérapie cellulaire CAR-T dans le traitement des maladies auto-immunes.

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.

La thérapie cellulaire à base de lymphocytes T génétiquement modifiés exprimant des récepteurs synthétiques ou CAR (récepteur antigénique chimérique) a révolutionné le traitement de certaines maladies hémato-oncologiques. Ce succès a conduit à l'exploration de la même approche dans le traitement de maladies auto-immunes sévères et réfractaires aux thérapies conventionnelles. Les premiers résultats obtenus dans le lupus érythémateux systémique ont montré des rémissions complètes semblant persister dans le temps. Nous assistons donc actuellement à une prolifération importante d'essais cliniques. Dans cet article, nous abordons le rationnel derrière l'utilisation des thérapies CAR-T, les maladies auto-immunes ciblées, mais aussi les risques associés.

Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma.

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.

Patient-reported outcomes in adoptive cell-therapy trials: mind the gap.

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.

Development of an optimized closed and semi-automatic protocol for Good Manufacturing Practice manufacturing of tumor-infiltrating lymphocytes in a hospital environment.

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.

Guillain-Barré syndrome after adoptive cell therapy with tumor-infiltrating lymphocytes.

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.

[Side effects of immune checkpoint inhibitors: diagnosis and management]. / Effets indésirables des inhibiteurs de points de contrôle immunitaire : diagnostic et prise en charge.

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.

Les nouvelles thérapies oncologiques, dont les inhibiteurs de points de contrôle immunitaire, permettent une stimulation lymphocytaire antitumorale. Ces traitements ont amélioré de manière significative le pronostic oncologique de nombreux patients, mais présentent néanmoins un nouveau spectre de toxicités, d'ordre immunologique. Les toxicités immunes les plus fréquentes sont le rash cutané, la colite, la dysthyroïdie, l'hypophysite, l'hépatite et la pneumonie. Une détection précoce de ces effets secondaires est cruciale afin de réaliser un bilan étiologique adéquat puis d'introduire un traitement immunosuppresseur temporaire, qui permet une résolution de la toxicité dans la grande majorité des cas. Une évaluation multidisciplinaire est souvent indispensable pour une prise en charge optimale.

Safety and Tolerability of Adoptive Cell Therapy in Cancer.

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.

Differences in triage category, priority level and hospitalization rate between young-old and old-old patients visiting the emergency department.

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.

Mushroom poisoning: a retrospective study concerning 11-years of admissions in a Swiss Emergency Department.

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.

Emergency department management of body packers and body stuffers.

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: the essential of 2015 guidelines]. / Réanimation cardiopulmonaire: l'essentiel des recommandations 2015.

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.

Characterizing the vulnerability of frequent emergency department users by applying a conceptual framework: a controlled, cross-sectional study.

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.

[Emergency medicine: updates 2014]. / Médecine d'urgence.

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.

[Management of severe sepsis and septic shock]. / Prise en charge initiate du sepsis sévère et du choc septique.

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.

Missed opportunities: evolution of patients leaving without being seen or against medical advice during a six-year period in a Swiss tertiary hospital emergency department.

AIM: The study aimed at describing the evolution over a 6-year period of patients leaving the emergency department (ED) before being seen ("left without being seen" or LWBS) or against medical advice ("left against medical advice" or LAMA) and at describing their characteristics. METHODS: A retrospective database analysis of all adult patients who are admitted to the ED, between 2005 and 2010, and who left before being evaluated or against medical advice, in a tertiary university hospital. RESULTS: During the study period, among the 307,716 patients who were registered in the ED, 1,157 LWBS (0.4%) and 1,853 LAMA (0.9%) patients were identified. These proportions remained stable over the period. The patients had an average age of 38.5±15.9 years for LWBS and 41.9±17.4 years for LAMA. The median time spent in the ED before leaving was 102.4 minutes for the LWBS patients and 226 minutes for LAMA patients. The most frequent reason for LAMA was related to the excessive length of stay. CONCLUSION: The rates of LWBS and LAMA patients were low and remained stable. The patients shared similar characteristics and reasons for leaving were largely related to the length of stay or waiting time.

Emergency department use by oldest-old patients from 2005 to 2010 in a Swiss university hospital.

BACKGROUND: Aging of the population in all western countries will challenge Emergency Departments (ED) as old patients visit these health services more frequently and present with special needs. The aim of this study is to describe the trend in ED visits by patients aged 85 years and over between 2005 and 2010, and to compare their service use to that of patients aged 65-84 years during this period and to investigate the evolution of these comparisons over time. METHODS: Data considered were all ED visits to the University of Lausanne Medical Center (CHUV), a tertiary Swiss teaching hospital, between 2005 and 2010 by patients aged 65 years and over (65+ years). ED visit characteristics were described according to age group and year. Incidence rates of ED visits and length of ED stay were calculated. RESULTS: Between 2005 and 2010, ED visits by patients aged 65 years and over increased by 26% overall, and by 46% among those aged 85 years and over (85+ years). Estimated ED visit incidence rate for persons aged 85+ years old was twice as high as for persons aged 65-84 years. Compared to patients aged 65-84 years, those aged 85+ years were more likely to be hospitalized and have a longer ED stay. This latter difference increased over time between 2005 and 2010. CONCLUSIONS: Oldest-old patients are increasingly using ED services. These services need to adapt their care delivery processes to meet the needs of a rising number of these complex, multimorbid and vulnerable patients.

Characteristics of highly frequent users of a Swiss academic emergency department: a retrospective consecutive case series.

OBJECTIVES: The aim of this study was to describe the demographic, social and medical characteristics, and healthcare use of highly frequent users of a university hospital emergency department (ED) in Switzerland. METHODS: A retrospective consecutive case series was performed. We included all highly frequent users, defined as patients attending the ED 12 times or more within a calendar year (1 January 2009 to 31 December 2009). We collected their characteristics and calculated a score of accumulation of risk factors of vulnerability. RESULTS: Highly frequent users comprised 0.1% of ED patients, and they accounted for 0.8% of all ED attendances (23 patients, 425 attendances). Of all highly frequent users, 87% had a primary care practitioner, 82.6% were unemployed, 73.9% were socially isolated, and 60.9% had a mental health or substance use primary diagnosis. One-third had attempted suicide during study period, all of them being women. They were often admitted (24.0% of attendances), and only 8.7% were uninsured. On average, they cumulated 3.3 different risk factors of vulnerability (SD 1.4). CONCLUSION: Highly frequent users of a Swiss academic ED are a highly vulnerable population. They are in poor health and accumulate several risk factors of being even in poorer health. The small number of patients and their high level of insurance coverage make it particularly feasible to design a specific intervention to approach their needs, in close collaboration with their primary care practitioner. Elaboration of the intervention should focus on social reinsertion and risk-reduction strategies with regard to substance use, hospital admissions and suicide.

Nitric oxide mediates the blood pressure response to mental stress in humans.

OBJECTIVE: Nitric oxide (NO) regulates arterial pressure by modulating peripheral vascular tone and sympathetic vasoconstrictor outflow. NO synthesis is impaired in several major cardiovascular disease states. Loss of NO-induced vasodilator tone and restraint on sympathetic outflow could result in exaggerated pressor responses to mental stress. METHODS: We, therefore, compared the sympathetic (muscle sympathetic nerve activity) and haemodynamic responses to mental stress performed during saline infusion and systemic inhibition of NO-synthase by NG-monomethyl-L-arginine (L-NMMA) infusion. RESULTS: The major finding was that mental stress which during saline infusion increased sympathetic nerve activity by ~50 percent and mean arterial pressure by ~15 percent had no detectable sympathoexcitatory and pressor effect during L-NMMA infusion. These findings were not related to a generalised impairment of the haemodynamic and/or sympathetic responsiveness by L-NMMA, since the pressor and sympathetic nerve responses to immersion of the hand in ice water were preserved during L-NMMA infusion. CONCLUSION: Mental stress causes pressor and sympathoexcitatory effects in humans that are mediated by NO. These findings are consistent with the new concept that, in contrast to what has been generally assumed, under some circumstances, NO has a blood pressure raising action in vivo.

Social and medical vulnerability factors of emergency department frequent users in a universal health insurance system.

OBJECTIVES: The objectives were to identify the social and medical factors associated with emergency department (ED) frequent use and to determine if frequent users were more likely to have a combination of these factors in a universal health insurance system. METHODS: This was a retrospective chart review case-control study comparing randomized samples of frequent users and nonfrequent users at the Lausanne University Hospital, Switzerland. The authors defined frequent users as patients with four or more ED visits within the previous 12 months. Adult patients who visited the ED between April 2008 and March 2009 (study period) were included, and patients leaving the ED without medical discharge were excluded. For each patient, the first ED electronic record within the study period was considered for data extraction. Along with basic demographics, variables of interest included social (employment or housing status) and medical (ED primary diagnosis) characteristics. Significant social and medical factors were used to construct a logistic regression model, to determine factors associated with frequent ED use. In addition, comparison of the combination of social and medical factors was examined. RESULTS: A total of 359 of 1,591 frequent and 360 of 34,263 nonfrequent users were selected. Frequent users accounted for less than a 20th of all ED patients (4.4%), but for 12.1% of all visits (5,813 of 48,117), with a maximum of 73 ED visits. No difference in terms of age or sex occurred, but more frequent users had a nationality other than Swiss or European (n = 117 [32.6%] vs. n = 83 [23.1%], p = 0.003). Adjusted multivariate analysis showed that social and specific medical vulnerability factors most increased the risk of frequent ED use: being under guardianship (adjusted odds ratio [OR] = 15.8; 95% confidence interval [CI] = 1.7 to 147.3), living closer to the ED (adjusted OR = 4.6; 95% CI = 2.8 to 7.6), being uninsured (adjusted OR = 2.5; 95% CI = 1.1 to 5.8), being unemployed or dependent on government welfare (adjusted OR = 2.1; 95% CI = 1.3 to 3.4), the number of psychiatric hospitalizations (adjusted OR = 4.6; 95% CI = 1.5 to 14.1), and the use of five or more clinical departments over 12 months (adjusted OR = 4.5; 95% CI = 2.5 to 8.1). Having two of four social factors increased the odds of frequent ED use (adjusted = OR 5.4; 95% CI = 2.9 to 9.9), and similar results were found for medical factors (adjusted OR = 7.9; 95% CI = 4.6 to 13.4). A combination of social and medical factors was markedly associated with ED frequent use, as frequent users were 10 times more likely to have three of them (on a total of eight factors; 95% CI = 5.1 to 19.6). CONCLUSIONS: Frequent users accounted for a moderate proportion of visits at the Lausanne ED. Social and medical vulnerability factors were associated with frequent ED use. In addition, frequent users were more likely to have both social and medical vulnerabilities than were other patients. Case management strategies might address the vulnerability factors of frequent users to prevent inequities in health care and related costs.

High-fidelity simulation in the nonmedical domain: practices and potential transferable competencies for the medical field.

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.