Stress response gene family expansions correlate with invasive potential in teleost fish.

The bluegill sunfish Lepomis macrochirus and the closely related redear sunfish Lepomis microlophus have important ecological and recreational value and are widely used for research and aquaculture. While both species have been introduced outside of their native ranges, only the bluegill is considered invasive. Here, we report de novo transcriptome assemblies for these fish as a resource for sunfish biology. Comparative analyses of the transcriptomes revealed an unexpected, bluegill-specific expansion in the HSP70 and HSP90 molecular chaperone gene families. These expansions were not unique to the bluegill as expansions in HSP70s and HSP90s were identified in the genomes of other teleost fish using the NCBI RefSeq database. To determine whether gene family expansions are specific for thermal stress responses, GST and SOD gene families that are associated with oxidative stress responses were also analyzed. Species-specific expansions were also observed for these gene families in distinct fish species. Validating our approach, previously described expansions in the MHC gene family were also identified. Intriguingly, the number of HSP70 paralogs was positively correlated with thermotolerance range for each species, suggesting that these expansions can impact organismal physiology. Furthermore, fish that are considered invasive contained a higher average number of HSP70 paralogs than non-invasive fish. Invasive fish also had higher average numbers of HSP90, MHC and GST paralogs, but not SOD paralogs. Taken together, we propose that expansions in key cellular stress response gene families represent novel genetic signatures that correlate with invasive potential.

Duration of Exposure to General Endotracheal Anesthesia during Cesarean Deliveries at Term and Perinatal Complications.

OBJECTIVE: To examine whether the duration of time from initiation of general endotracheal anesthesia (GETA) to delivery for cesarean deliveries (CDs) performed is related to perinatal outcomes. STUDY DESIGN: This is a retrospective study of patients with singleton nonanomalous gestations undergoing CD ≥37 weeks of gestation under GETA with reassuring fetal status at a single tertiary care center from 2000 to 2016. Duration from GETA initiation until delivery was calculated as the time interval from GETA induction to delivery (I-D), categorized into tertiles. Outcomes for those in the tertile with the shortest I-D were compared with those in the other two tertiles. The primary perinatal outcome was a composite of complications (continuous positive airway pressure or high-flow nasal cannula for ≥2 consecutive hours, inspired oxygen ≥30% for ≥4 consecutive hours, mechanical ventilation, stillbirth, or neonatal death ≤72 hours after birth). Secondary outcomes were 5-minute Apgar score <7 and a composite of maternal morbidity (bladder injury, bowel injury, and extension of hysterotomy). Bivariable and multivariable analyses were used to compare outcomes. RESULTS: Two hundred eighteen maternal-perinatal dyads were analyzed. They were dichotomized based on I-D ≤4 minutes (those in the tertile with the shortest duration) or >4 minutes. Women with I-D >4 minutes were more likely to have prior abdominal surgery and less likely to have labored prior to CD. I-D >4 minutes was associated with significantly increased frequency of the primary perinatal outcome. This persisted after multivariable adjustment. In bivariable analysis, 5-minute Apgar <7 was more common in the group with I-D >4 minutes, but this did not persist in multivariable analysis. Frequency of maternal morbidity did not differ. CONCLUSION: When CD is performed at term using GETA without evidence of nonreassuring fetal status prior to delivery, I-D interval >4 minutes is associated with increased frequency of perinatal complications. KEY POINTS: · Cesarean delivery under general anesthesia is associated with increased perinatal complications.. · Perinatal complications are increased with increasing duration of exposure to general anesthetics.. · Maternal complications were not increased with shorter duration of exposure to general anesthesia..

UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD.

Ubiquilin (UBQLN) proteins are a dynamic and versatile family of proteins found in all eukaryotes that function in the regulation of proteostasis. Besides their canonical function as shuttle factors in delivering misfolded proteins to the proteasome and autophagy systems for degradation, there is emerging evidence that UBQLN proteins play broader roles in proteostasis. New information suggests the proteins function as chaperones in protein folding, protecting proteins prior to membrane insertion, and as guardians for mitochondrial protein import. In this review, we describe the evidence for these different roles, highlighting how different domains of the proteins impart these functions. We also describe how changes in the structure and phase separation properties of UBQLNs may regulate their activity and function. Finally, we discuss the pathogenic mechanisms by which mutations in UBQLN2 cause amyotrophic lateral sclerosis and frontotemporal dementia. We describe the animal model systems made for different UBQLN2 mutations and how lessons learnt from these systems provide fundamental insight into the molecular mechanisms by which UBQLN2 mutations drive disease pathogenesis through disturbances in proteostasis.

ALS/FTD mutations in UBQLN2 are linked to mitochondrial dysfunction through loss-of-function in mitochondrial protein import.

UBQLN2 mutations cause amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD), but the pathogenic mechanisms by which they cause disease remain unclear. Proteomic profiling identified 'mitochondrial proteins' as comprising the largest category of protein changes in the spinal cord (SC) of the P497S UBQLN2 mouse model of ALS/FTD. Immunoblots confirmed P497S animals have global changes in proteins predictive of a severe decline in mitochondrial health, including oxidative phosphorylation (OXPHOS), mitochondrial protein import and network dynamics. Functional studies confirmed mitochondria purified from the SC of P497S animals have age-dependent decline in nearly all steps of OXPHOS. Mitochondria cristae deformities were evident in spinal motor neurons of aged P497S animals. Knockout (KO) of UBQLN2 in HeLa cells resulted in changes in mitochondrial proteins and OXPHOS activity similar to those seen in the SC. KO of UBQLN2 also compromised targeting and processing of the mitochondrial import factor, TIMM44, resulting in accumulation in abnormal foci. The functional OXPHOS deficits and TIMM44-targeting defects were rescued by reexpression of WT UBQLN2 but not by ALS/FTD mutant UBQLN2 proteins. In vitro binding assays revealed ALS/FTD mutant UBQLN2 proteins bind weaker with TIMM44 than WT UBQLN2 protein, suggesting that the loss of UBQLN2 binding may underlie the import and/or delivery defect of TIMM44 to mitochondria. Our studies indicate a potential key pathogenic disturbance in mitochondrial health caused by UBQLN2 mutations.

Serpin neuropathology in the P497S UBQLN2 mouse model of ALS/FTD.

Accumulating evidence suggests X-linked dominant mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) through both loss- and gain-of-function mechanisms. However, the mechanisms by which the mutations cause disease are still unclear. The goal of the study was to uncover the possible pathomechanism(s) by which UBQLN2 mutations cause ALS/FTD. An analysis of proteomic changes in neuronal tissue was used to identify proteins with altered accumulation in the P497S UBQLN2 transgenic mouse model of ALS/FTD. We then used immunocytochemistry and biochemical techniques to confirm protein changes in the mutant P497S mice. Additionally, we used cell lines inactivated of UBQLN2 expression to determine whether its loss underlies the alteration in the proteins seen in P497S mice. The proteome screen identified a dramatic alteration of serine protease inhibitor (serpin) proteins in the mutant P497S animals. Double immunofluorescent staining of brain and spinal cord tissues of the mutant and control mice revealed an age-dependent change in accumulation of Serpin A1, C1, and I1 in puncta whose staining colocalized with UBQLN2 puncta in the mutant P497S mice. Serpin A1 aggregation in P497S animals was confirmed by biochemical extraction and filter retardation assays. A similar phenomenon of serpin protein aggregation was found in HeLa and NSC34 motor neuron cells with inactivated UBQLN2 expression. We found aberrant aggregation of serpin proteins, particularly Serpin A1, in the brain and spinal cord of the P497S UBQLN2 mouse model of ALS/FTD. Similar aggregation of serpin proteins was found in UBQLN2 knockout cells suggesting that serpin aggregation in the mutant P497S animals may stem from loss of UBQLN2 function. Because serpin aggregation is known to cause disease through both loss- and gain-of-function mechanisms, we speculate that their accumulation in the P497S mouse model of ALS/FTD may contribute to disease pathogenesis through similar mechanism(s).

ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function.

Mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerations. However, the mechanism by which the UBQLN2 mutations cause disease remains unclear. Alterations in proteins involved in autophagy are prominent in neuronal tissue of human ALS UBQLN2 patients and in a transgenic P497S UBQLN2 mouse model of ALS/FTD, suggesting a pathogenic link. Here, we show UBQLN2 functions in autophagy and that ALS/FTD mutant proteins compromise this function. Inactivation of UBQLN2 expression in HeLa cells reduced autophagic flux and autophagosome acidification. The defect in acidification was rescued by reexpression of wild type (WT) UBQLN2 but not by any of the five different UBQLN2 ALS/FTD mutants tested. Proteomic analysis and immunoblot studies revealed P497S mutant mice and UBQLN2 knockout HeLa and NSC34 cells have reduced expression of ATP6v1g1, a critical subunit of the vacuolar ATPase (V-ATPase) pump. Knockout of UBQLN2 expression in HeLa cells decreased turnover of ATP6v1g1, while overexpression of WT UBQLN2 increased biogenesis of ATP6v1g1 compared with P497S mutant UBQLN2 protein. In vitro interaction studies showed that ATP6v1g1 binds more strongly to WT UBQLN2 than to ALS/FTD mutant UBQLN2 proteins. Intriguingly, overexpression of ATP6v1g1 in UBQLN2 knockout HeLa cells increased autophagosome acidification, suggesting a therapeutic approach to overcome the acidification defect. Taken together, our findings suggest that UBQLN2 mutations drive pathogenesis through a dominant-negative loss-of-function mechanism in autophagy and that UBQLN2 functions as an important regulator of the expression and stability of ATP6v1g1. These findings may have important implications for devising therapies to treat UBQLN2-linked ALS/FTD.

Prophylactic Intrathecal Morphine and Prevention of Post-Dural Puncture Headache: A Randomized Double-blind Trial.

BACKGROUND: Prophylactic epidural morphine administration after unintentional dural puncture with a large-bore needle has been shown to decrease the incidence of post-dural puncture headache. The authors hypothesized that prophylactic administration of intrathecal morphine would decrease the incidence of post-dural puncture headache and/or need for epidural blood patch after unintentional dural puncture. METHODS: Parturients with an intrathecal catheter in situ after unintentional dural puncture with a 17-g Tuohy needle during intended epidural catheter placement for labor analgesia were enrolled in this randomized, double-blind trial. After delivery, subjects were randomized to receive intrathecal morphine 150 µg or normal saline. The primary outcome was the incidence of post-dural puncture headache. Secondary outcomes included onset, duration, and severity of post-dural puncture headache, the presence of cranial nerve symptoms and the type of treatment the patient received. RESULTS: Sixty-one women were included in the study. The incidence of post-dural puncture headache was 21 of 27 (78%) in the intrathecal morphine group and 27 of 34 (79%) in the intrathecal saline group (difference, -1%; 95% CI, -25% to 24%). There were no differences between groups in the onset, duration, or severity of headache, or presence of cranial nerve symptoms. Epidural blood patch was administered to 10 of 27 (37%) of subjects in the intrathecal morphine and 11 of 21 (52%) of the intrathecal saline group (difference 15%; 95% CI, -18% to 48%). CONCLUSIONS: The present findings suggest that a single prophylactic intrathecal morphine dose of 150 µg administered shortly after delivery does not decrease the incidence or severity of post-dural puncture headache after unintentional dural puncture. This study does not support the clinical usefulness of prophylactic intrathecal morphine after an unintentional dural puncture.

Lou Gehrig's Disease (ALS): UBQLN2 Mutations Strike Out of Phase.

In this issue of Structure, Dao et al. (2019) report that ALS-linked mutations in the Pxx domain of Ubiquilin 2 (UBQLN2) differentially influence the protein's phase separation abilities. The affect is by reducing the temperature and UBQLN2 concentration necessary for liquid-liquid phase separation droplet formation and by modulating UBQLN2 oligomerization.

Postpartum hemorrhage revisited: new challenges and solutions.

PURPOSE OF REVIEW: Postpartum hemorrhage (PPH) is a leading cause of maternal morbidity and mortality in the United States, and worldwide. Recognition of PPH is challenging, but once hemorrhage is recognized, management needs to focus on achieving adequate uterine tone and maintaining maternal hemodynamic stability. There have been several advances in the management of postpartum hemorrhage, many of which can be implemented at the labor and delivery unit level. RECENT FINDINGS: There have been many advances in the understanding of at-risk parturients, and the use of hemorrhage protocols and safety bundles have been shown to improve patient outcomes. There are many new advances in transfusion management (e.g. fibrinogen concentrate, prothrombin complex concentrate, tranexamic acid) that can compliment traditional component therapy. Consideration should be given to transferring women at high risk for complications (e.g. invasive placentation) to a higher level facility for delivery. SUMMARY: Although postpartum hemorrhage itself may not be preventable, early identification of blood loss, and mobilization of resources may prevent adverse outcomes. Multidisciplinary planning at the system level, ensuring that hemorrhage protocols exist, as well as for management of high-risk patients is important for improving patient outcomes.

The Effect of Prophylactic Phenylephrine and Ephedrine Infusions on Umbilical Artery Blood pH in Women With Preeclampsia Undergoing Cesarean Delivery With Spinal Anesthesia: A Randomized, Double-Blind Trial.

BACKGROUND: Spinal anesthesia for cesarean delivery is associated with a high incidence of hypotension. Phenylephrine results in higher umbilical artery pH than ephedrine when used to prevent or treat hypotension in healthy women. We hypothesized that phenylephrine compared to ephedrine would result in higher umbilical artery pH in women with preeclampsia undergoing cesarean delivery with spinal anesthesia. METHODS: This study was a randomized double-blind clinical trial. Nonlaboring women with preeclampsia scheduled for cesarean delivery with spinal anesthesia at Prentice Women's Hospital of Northwestern Medicine were randomized to receive prophylactic infusions of phenylephrine or ephedrine titrated to maintain systolic blood pressure >80% of baseline. Spinal anesthesia consisted of hyperbaric 0.75% bupivacaine 12 mg, fentanyl 15 µg, and morphine 150 µg. The primary outcome was umbilical arterial blood pH and the secondary outcome was umbilical artery base excess. RESULTS: One hundred ten women were enrolled in the study and 54 per group were included in the analysis. There were 74 and 72 infants delivered in the ephedrine and phenylephrine groups, respectively. The phenylephrine:ephedrine ratio for umbilical artery pH was 1.002 (95% confidence interval [CI], 0.997-1.007). Mean [standard deviation] umbilical artery pH was not different between the ephedrine 7.20 [0.10] and phenylephrine 7.22 [0.07] groups (mean difference -0.02, 95% CI of the difference -0.06 to 0.07; P = .38). Median (first, third quartiles) umbilical artery base excess was -3.4 mEq/L (-5.7 to -2.0 mEq/L) in the ephedrine group and -2.8 mEq/L (-4.6 to -2.2mEq/L) in the phenylephrine group (difference -0.6 mEq/L, 95% CI of the difference -1.6 to 0.3 mEq/L; P = .10). When adjusted for gestational age and infant gender, umbilical artery pH did not differ between groups. There were also no differences in the umbilical artery pH stratified by magnesium therapy or by the severity of preeclampsia. CONCLUSIONS: We were unable to demonstrate a beneficial effect of phenylephrine on umbilical artery pH compared with ephedrine. Our findings suggest that phenylephrine may not have a clinically important advantage compared with ephedrine with regard to improved neonatal acid-base status when used to prevent spinal anesthesia-induced hypotension in women with preeclampsia undergoing cesarean delivery.

Effect of Intrathecal Bupivacaine Dose on the Success of External Cephalic Version for Breech Presentation: A Prospective, Randomized, Blinded Clinical Trial.

BACKGROUND: Breech presentation is a leading cause of cesarean delivery. The use of neuraxial anesthesia increases the success rate of external cephalic version procedures for breech presentation and reduces cesarean delivery rates for fetal malpresentation. Meta-analysis suggests that higher-dose neuraxial techniques increase external cephalic version success to a greater extent than lower-dose techniques, but no randomized study has evaluated the dose-response effect. We hypothesized that increasing the intrathecal bupivacaine dose would be associated with increased external cephalic version success. METHODS: We conducted a randomized, double-blind trial to assess the effect of four intrathecal bupivacaine doses (2.5, 5.0, 7.5, 10.0 mg) combined with fentanyl 15 µg on the success rate of external cephalic version for breech presentation. Secondary outcomes included mode of delivery, indication for cesarean delivery, and length of stay. RESULTS: A total of 240 subjects were enrolled, and 239 received the intervention. External cephalic version was successful in 123 (51.5%) of 239 patients. Compared with bupivacaine 2.5 mg, the odds (99% CI) for a successful version were 1.0 (0.4 to 2.6), 1.0 (0.4 to 2.7), and 0.9 (0.4 to 2.4) for bupivacaine 5.0, 7.5, and 10.0 mg, respectively (P = 0.99). There were no differences in the cesarean delivery rate (P = 0.76) or indication for cesarean delivery (P = 0.82). Time to discharge was increased 60 min (16 to 116 min) with bupivacaine 7.5 mg or higher as compared with 2.5 mg (P = 0.004). CONCLUSIONS: A dose of intrathecal bupivacaine greater than 2.5 mg does not lead to an additional increase in external cephalic procedural success or a reduction in cesarean delivery.

Effect of anesthesia type on perioperative outcomes with a midurethral sling.

INTRODUCTION AND HYPOTHESIS: There is no consensus on the most appropriate type of anesthesia for placement of a midurethral sling. Our objective was to compare intra- and perioperative outcomes for this procedure performed under general anesthesia versus monitored anesthesia care. METHODS: Retrospective cohort analysis of women undergoing outpatient placement of synthetic retropubic midurethral sling under general anesthesia (n = 141) or monitored anesthesia care (n = 84). Patients undergoing concomitant procedures were excluded. Primary outcome was operating room time. Secondary outcomes included surgical and recovery times, cost, discharge home with a catheter, and postoperative pain and/or nausea. RESULTS: In the general anesthesia group, both operating room time (mean ± SD, 67.6 ± 13.3 min vs 56.9 ± 11.8 min, p < 0.001) and recovery room time (240.0 ± 69.8 min vs 190.1 ± 78.3 min, p < 0.001) were longer, whereas there was no difference in surgical time (30.0 ± 8.9 min vs 29.0 ± 9.7 min, p = 0.43). Cost was significantly higher in the general anesthesia group ($4,095 ± 715 vs $3,877 ± 777, p = 0.03). There was no difference in rates of bladder perforation (6.4 % vs 11.9 %, p = 0.33). Patients who underwent general anesthesia had higher rates of discharge with a catheter (27.0 % vs 15.8 %, p = 0.04). CONCLUSION: Monitored anesthesia care may offer significant benefits over general anesthesia in women undergoing retropubic midurethral sling, including shorter operating room and recovery times, lower costs, and less voiding dysfunction in the immediate postoperative period.

The Relationship of Body Mass Index with the Incidence of Postdural Puncture Headache in Parturients.

BACKGROUND: Unintentional dural puncture is a known risk after epidural or combined spinal-epidural procedures, occurring in approximately 1% of labor epidural catheters placed in parturients with normal body habitus but may be as high as 4% in morbidly obese parturients. Anecdotal experience and limited publications suggest that an inverse relationship between body mass index (BMI) and postdural puncture headache (PDPH) may exist. We hypothesized that parturients with increased BMI have a lower incidence of PDPH than those with a lower BMI after unintentional dural puncture. METHODS: After IRB approval, we performed a retrospective cohort study by medical record review. Case logs from our institution were searched for patients with documented unintentional dural puncture during attempted neuraxial analgesia between January 1, 2004, and December 13, 2013. The primary outcome was the incidence of PDPH. The association between BMI and PDPH was assessed using binary logistic regression, and the Wilcoxon-Mann-Whitney odds and confidence intervals (CIs) for a random pair of BMI values from a PDPH subject compared with a non-PDPH subject were calculated from the area under the receiver operator characteristics curve. Classification tree analysis was used to determine the BMI cutoff value for the risk of developing a PDPH. The presence or absence of second-stage labor pushing and placement of an intrathecal catheter after unintentional dural puncture were compared in parturients with and without PDPH using the Fisher exact test. BMI groups were dichotomized at the cutoff value (low and high BMI groups). We compared the incidence of a PDPH between high and low BMI groups using the Fisher exact test after controlling for pushing during labor and placement of an intrathecal catheter at the time of unintentional dural puncture. Secondary analysis evaluated the highest reported numeric rating of pain scores for headache and the need for an epidural blood patch between BMI groups. RESULTS: Unintentional dural puncture was identified in 518 (0.53%) patients (95% CI, 0.48%-0.58%). The overall incidence of PDPH after unintentional dural puncture was 51% (95% CI, 46%-55%). The Wilcoxon-Mann-Whitney odds for a random pair of BMI values from a PDPH subject compared with a non-PDPH subject was 0.74 (95% CI, 0.60-0.90, P = 0.001). The odds ratio for developing a PDPH in women who pushed during delivery was 2.4 (95% CI, 1.2-3.9, P = 0.001) compared with women who did not push. Classification tree analysis identified a BMI cutoff value of 31.5 kg/m for prediction of a PDPH. The incidence of PDPH in parturients with a BMI ≥31.5 kg/m (39%) was lower than in parturients with a BMI <31.5 kg/m (56%; difference -17%; 95% CI, -7% to -26%, P = 0.0004). The odds ratio for a PDPH in the high BMI compared with the low BMI group was 0.36 (95% CI, 0.14-0.92, P = 0.04) in parturients who pushed during labor and 0.62 (95% CI, 0.41-0.97, P = 0. 04) in parturients who did not push. After the unintentional dural puncture, 112 (22%) parturients had an intrathecal catheter placed. The incidence of PDPH in parturients with an intrathecal catheter was 59% (95% CI, 49%-68%) compared with 48% (95% CI, 43%-54%) in women with an epidural catheter (P = 0.06). Median (interquartile range) headache severity (0-10 verbal rating scale) was 8 (6-9) and did not differ between parturients in the high versus low BMI groups (P = 0.61). The rate of epidural blood patch administration for PDPH treatment was similar in BMI groups (difference -12%; 95% CI, 4 to -27, P = 0.13). CONCLUSIONS: The findings are consistent with previous reports of decreased PDPH incidence after unintentional dural puncture in parturients with an increased BMI, even after controlling for pushing during labor. Severity of headache and need for epidural blood patch treatment were similar in low and high BMI groups.

A randomized controlled trial of the impact of simulation-based training on resident performance during a simulated obstetric anesthesia emergency.

INTRODUCTION: The percentage of patients having cesarean delivery (CD) under general anesthesia has decreased, which may have implications for residency training in anesthesiology. We undertook this study to assess the effect of focused simulation-based training on resident performance during a simulated general anesthetic for emergency CD. METHODS: Thirty-two second-year anesthesiology resident volunteers were randomly assigned to one of the two groups: a group trained on the patient simulator performing general anesthesia for emergency CD (CD group) and a control group trained on the simulator using a different general anesthetic scenario unrelated to obstetric anesthesia (SHAM group). Between 6 and 9 weeks, all the residents performed the emergency CD scenario on the simulator and were videotaped. Two blinded observers scored the videotaped performances using a valid and reliable scoring system separately and were blinded to each others score. The time interval from the start of the scenario until the simulated surgical incision was noted. Total scores and component scores in six subcategories were compared between resident groups, as was the start to incision time interval. RESULTS: Residents in the CD group had higher total scores and higher scores in the preoperative assessment, equipment availability check, and intraoperative management before delivery subcategories than residents in the SHAM group. The start to incision time interval did not differ between the groups. CONCLUSIONS: Anesthesiology residents who underwent focused training on a simulator that included performance of a general anesthetic for emergency CD exhibited improved performance during a subsequent simulated anesthetic scenario compared with trainees who did not undergo such instruction.

Acquisition of critical intraoperative event management skills in novice anesthesiology residents by using high-fidelity simulation-based training.

BACKGROUND: Early acquisition of critical competencies by novice anesthesiology residents is essential for patient safety, but traditional training methods may be insufficient. The purpose of this study was to determine the effectiveness of high-fidelity simulation training of novice residents in the initial management of critical intraoperative events. METHODS: Twenty-one novice residents participated in this 6-week study. Three hypoxemia and three hypotension scenarios were developed and corresponding checklists were validated. Residents were tested in all scenarios at baseline (0 weeks) and divided into two groups, using a randomized crossover study design. Group 1 received simulation-based training in hypoxemic events, whereas Group 2 was trained in hypotensive events. After intermediate (3 weeks) testing in all scenarios, the groups switched to receive training in the other critical event. Final testing occurred at 6 weeks. Raters blinded to subject identity, group assignment, and test date scored videotaped performances by using checklists. The primary outcome measure was composite scores for hypoxemia and hypotension scenarios, which were compared within and between groups. RESULTS: Baseline performance between groups was similar. At the intermediate evaluation, the mean hypoxemia score was higher in Group 1 compared with Group 2 (65.5% vs. 52.4%, 95% CI of difference 6.3-19.9, P < 0.003). Conversely, Group 2 had a higher mean hypotension score (67.4% vs. 45.5%, 95% CI of difference 14.6-29.2, P < 0.003). At Week 6, the scores between groups did not differ. CONCLUSIONS: Event-specific, simulation-based training resulted in superior performance in scenarios compared with traditional training and simulation-based training in an alternate event.