Mutated SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms.

Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of patients with CNL also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutated leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutated hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs, most strongly upregulating Myc and Myc target genes. This upregulation of Myc can be reversed by LSD1 inhibitors. In summary, we found that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutated CSF3R through the upregulation of Myc-associated gene expression programs.

Evidence-Based Guideline for Prehospital Airway Management.

Airway management is a cornerstone of emergency medical care. This project aimed to create evidence-based guidelines based on the systematic review recently conducted by the Agency for Healthcare Research and Quality (AHRQ). A technical expert panel was assembled to review the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The panel made specific recommendations on the different PICO (population, intervention, comparison, outcome) questions reviewed in the AHRQ review and created good practice statements that summarize and operationalize these recommendations. The recommendations address the use of ventilation with bag-valve mask ventilation alone vs. supraglottic airways vs. endotracheal intubation for adults and children with cardiac arrest, medical emergencies, and trauma. Additional recommendations address the use of video laryngoscopy and drug-assisted airway management. These recommendations, and the associated good practice statements, offer EMS agencies and clinicians an opportunity to review the available evidence and incorporate it into their airway management strategies.

Evaluation of Posttraumatic Stress Disorder Screening Measures of Emergency Medical Services Clinicians in Urban and Suburban New York During the Coronavirus Disease 2019 Pandemic.

OBJECTIVE: The objective of this study was to assess the psychological impact of the coronavirus disease 2019 (COVID-19) pandemic on the self-reported rates of posttraumatic stress disorder (PTSD) among emergency medical services (EMS) clinicians in urban and suburban settings that were one of the primary epicenters during the first wave of the COVID-19 pandemic. METHODS: Anonymous surveys containing the PTSD Checklist-Specific (PCL-S) were sent electronically between November 2020 and April 2021 to EMS clinicians working in 2 EMS agencies. A threshold score ≥ 36 was considered a positive screen for PTSD symptomology; a score ≥ 44 was considered a presumptive PTSD diagnosis. RESULTS: Of the 214 surveys sent, 107 responses were returned. The total PCL-S scores suggested PTSD symptoms were present in 33% of responding EMS clinicians (95% confidence interval [CI], 24.1%-42.5%), and 25% (95% CI, 17.6%-34.7%) met the criteria for a presumptive diagnosis of PTSD. Regression revealed increasing PCL-S scores were associated with thoughts of job resignation (+3.8; 95% CI, 1.1-6.4; P = .006), whereas lower PCL-S scores were related to the degree that respondents believed emotional support was available at their institution (-3.6; 95% CI, -6.8 to -0.4; P = .03). CONCLUSION: Sixth months after the first wave of the COVID-19 pandemic, one third of participating EMS clinicians screened positive for PTSD symptoms. Pandemic planning must address the mental health of EMS clinicians to reduce subsequent burnout and maintain a healthy workforce.

Informal Peer Support and Intentional Acts of Kindness May Attenuate the Impact of Work-Related Stressors on Compassion Satisfaction, Secondary Traumatic Stress, and Burnout of Emergency Medical Services Clinicians.

OBJECTIVE: Emergency medical services (EMS) Code Lavender was developed to support EMS clinicians after stressful events via consistent recognition of events, informal peer support, and intentional acts of kindness. This study evaluated changes in burnout screening tool responses of EMS clinicians in response to program implementation and the coincidental start of coronavirus disease 2019. METHODS: Anonymous surveys with demographic questions and 2 burnout screening tools were distributed before program implementation (spring 2020) and 20 months later (fall 2021). Analysis included t-tests, Fisher exact tests, and multivariable linear regression. RESULTS: Seventy-seven preprogram (59% response rate) and 108 intraprogram (88% response rate) survey responses were included. No changes existed between preprogram and intraprogram responses across all subscale scores. Sex was associated with depersonalization subscale scores, with men having scores 1.53 (95% confidence interval [CI] 0.11-2.95) higher than women. Compared with emergency medical technicians, paramedics had higher compassion satisfaction (OR 3.50; 95% CI 1.79-5.70) and personal accomplishment scores (OR 2.40; 95% CI 1.08-3.71). Transport nurses had higher personal accomplishment (OR 3.29; 95% CI 1.18-5.40), depersonalization (OR 3.73; 95% CI 1.19-6.26), and rates of burnout symptoms (OR 0.54; 95% CI 0.09-0.98) than emergency medical technicians. CONCLUSION: The organizational commitment, peer support, and authentic leadership of EMS Code Lavender may attenuate work-related stressors among EMS clinicians.

Supporting Emergency Medical Services Clinicians Through Acute and Sustained Crises With Informal Peer Support and Intentional Acts of Kindness: The Emergency Medical Services Code Lavender Program.

OBJECTIVE: Given the recommendations against the use of critical incident stress debriefing, the emergency medical services (EMS) Code Lavender program was created as a mechanism to consistently recognize and reach out to EMS clinicians after acute crisis events, offer nonintrusive informal peer support and acts of kindness, and provide stepwise support via mental health professionals as needed. The study aimed to assess program utilization and evaluate the program's impact on EMS clinicians' perceptions of support and resources available to them after an acute crisis event. METHODS: Anonymous surveys were distributed before program implementation and 18 months later. Program utilization was tracked using REDCap (Vanderbilt University, Nashville, TN). Fisher exact tests and logistic regression were used to analyze the survey results. RESULTS: Within 30 months, 87 referrals were made. Seventy-seven preprogram (59% response rate) and 104 intraprogram (88% response rate) surveys were collected. There were no differences between respondents by sex or role. There were significant improvements in knowing where to go for help (from 40% to 85%, P < .001) and willingness to seek help if needed (from 40% to 59%, P = .02). CONCLUSION: The implementation of an EMS Code Lavender program led to significant increases in EMS clinician self-reported knowledge of where to go and willingness to seek help after acute crisis events.

Incidence and management of pleural effusions in patients with Wilms tumor: A Pediatric Surgical Oncology Research Collaborative study.

Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.

Use of gelatin puzzle phantoms to teach medical students isolated ultrasound transducer movements and fundamental concepts.

BACKGROUND: Psychomotor skills related to the use of medical ultrasound are a fundamental, but often overlooked component of this ubiquitous medical imaging technology. Although discussions of image production/orientation, sonographic planes, and imaging/scanning techniques are common in existing literature, these discussions rarely address practical skills related to these basic concepts. The cognitive load of transducer movements and machine operation, in conjunction with learning the ultrasound representation of anatomy, may overwhelm a novice learner. Our goal was to develop and evaluate a set of ultrasound puzzle phantoms for students to use as they learn isolated, specific transducer movements and sonographic concepts. We intentionally created phantoms that contain objects that are likely familiar to students to reduce the cognitive load associated with simultaneously learning the ultrasound interpretation of anatomy. METHODS: This preliminary evaluation of our novel, homemade, gelatin ultrasound puzzle phantoms was performed using pretests and posttests obtained by scanning an assessment phantom, and student questionnaires. Two phases of training and testing occurred with feedback from Phase 1 allowing for refinement of the puzzles and techniques for testing. Skills taught and evaluated included probe rotation, depth assessment, sliding, and tilting. RESULTS: Twenty-eight students attended the Phase 1 training session with positive trends in students' abilities to use rotation, sliding, and tilting to answer questions, while only depth showed statistically significant improvements (p = 0.021). Overall students agreed the experience a productive use of time (86%), was beneficial (93%), and would recommend to others (93%). Fifteen (54%) students returned 3 months later. There was no significant decay in skills obtained from the prior training session. In Phase 2, 134 medical students participated, and 76 (57%) completed an online questionnaire. A majority of students agreed they had a better understanding of rotation (83%), depth (80%), sliding (88%) and tilting (55%). Similar to Phase 1, many students (75%) felt the experience was beneficial. CONCLUSIONS: This preliminary study gave us insight into student opinions, as well as information to guide future scalability and development of additional ultrasound puzzle phantoms to aid in medical student education of isolated transducer movements and sonographic concepts prior to imaging human anatomy.

Prehospital Naloxone and Emergency Department Adverse Events: A Dose-Dependent Relationship.

BACKGROUND: The purpose of this study was to evaluate prehospital and emergency department (ED) interventions and outcomes of patients who received prehospital naloxone for a suspected opioid overdose. OBJECTIVES: The primary objective was to evaluate if the individual dose, individual route, total dose, number of prehospital naloxone administrations, or occurrence of a prehospital adverse event (AE) were associated with the occurrence of AEs in the ED. Secondary objectives included a subset analysis of patients who received additional naloxone while in the ED, or were admitted to an intensive care or step-down unit (ICU). METHODS: This was a retrospective, observational chart review of adult patients who received prehospital naloxone and were transported by ambulance to a suburban academic tertiary care center between 2014 and 2017. Descriptive, univariate, and multivariate statistics were used, with p < 0.05 indicating significance. RESULTS: There were 513 patients included in the analysis, with a median age of 29 years, and median total prehospital naloxone dose of 2 mg. An increasing number of prehospital naloxone doses, an occurrence of a prehospital AE, and a route of administration other than intranasally for the first dose of prehospital naloxone were significantly associated with an increased likelihood of an ED AE. Patients who received < 2 mg of prehospital naloxone had the least likelihood of being admitted to an ICU, whereas patients who received at least 6 mg had a dramatically increased likelihood of ICU admission. CONCLUSIONS: Our results suggest that an increasing number of prehospital naloxone doses was significantly associated with an increased likelihood of an ED adverse event.

Integration of a Low-Cost Introductory Ultrasound Curriculum Into Existing Procedural Skills Education for Preclinical Medical Students.

We evaluated integration of an introductory ultrasound curriculum into our existing mandatory procedural skills program for preclinical medical students. Phantoms consisting of olives, pimento olives, and grapes embedded in opaque gelatin were developed. Four classes encouraged progressive refinement of phantom-scanning and object identification skills. Students improved their ability to identify hidden objects, although each object type achieved a statistically significant improvement in correct identification at different time points. The total phantom cost per student was $0.76. Our results suggest that short repeated experiences scanning simple, low-cost ultrasound phantoms confer basic ultrasound skills.

High cell density attenuates reactive oxygen species: implications for in vitro assays.

In vitro cell-based assays are an essential and universally used step in elucidation of biological processes as well as in drug development. However, results obtained depend on the validity of protocols used. This statement certainly pertains to in vitro assays of oxidative stress. The holy grail of in vitro models is reliability and predictability of outcomes that relate to a single variable like addition of hydrogen peroxide or xanthine oxidase. Without such validated outcomes, comparison of results among different laboratories is not possible. Achieving this goal requires a thorough understanding of the complex interplay between the cells, their environment, and the experimental assays. Furthermore, as this knowledge is attained, it must be disseminated and used to update and standardize existing protocols. Here, we confirm and extend the effect of pyruvate and cell density on in vitro oxidative stress assays. Cell viability was assessed using a colorimetric assay measuring the reduction of a tetrazolium salt (XTT) into a colored formazan dye. Extracellular hydrogen peroxide concentrations were measured using the foxp3 assay. We confirmed a previously reported finding that pyruvate, a common ingredient in cell culture media, acts as an extracellular scavenger of reactive oxygen species. We also demonstrated that cell density directly correlates with resistance to oxidative stress in tissue culture. It is theorized that the protective effect due to cell density predominantly relates to intracellular factors such as reduced glutathione and extracellular factors such as catalase.

Meconium Ileus, Distal Intestinal Obstruction Syndrome, and Other Gastrointestinal Pathology in the Cystic Fibrosis Patient.

Cystic fibrosis is an autosomal-recessive defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on chromosome 7 that affects 1 in 2500 live White births. Defects in the gene lead to abnormally thick secretions causing chronic obstruction in the respiratory and gastrointestinal tracts. Common gastrointestinal pathology in children with cystic fibrosis includes meconium ileus in infancy and distal intestinal obstruction syndrome in childhood and exocrine pancreatic insufficiency, constipation, and rectal prolapse. This article describes the presentation, diagnosis, and management of these conditions in patients with cystic fibrosis, from birth to adulthood.

Learning the Language of Medical Device Innovation: A Longitudinal Interdisciplinary Elective for Medical Students.

PROBLEM: Physicians are playing a growing role as clinician-innovators. Academic physicians are well positioned to contribute to the medical device innovation process, yet few medical school curricula provide students opportunities to learn the conceptual framework for clinical needs finding, needs screening, concept generation and iterative prototyping, and intellectual property management. This framework supports innovation and encourages the development of valuable interdisciplinary communication skills and collaborative learning strategies. APPROACH: Our university offers a novel 3-year-long medical student Longitudinal Interdisciplinary Elective in Biodesign (MSLIEB) that teaches medical device innovation in 4 stages: (1) seminars and small-group work, (2) shared clinical experiences for needs finding, (3) concept generation and product development by serving as consultants for biomedical engineering capstone projects, and (4) reflection and mentorship. The MSLIEB objectives are to: create a longitudinal interdisciplinary peer mentorship relationship between undergraduate biomedical engineering students and medical students, and encourage codevelopment of professional identities in relation to medical device innovation. OUTCOMES: The MSLIEB enrolled 5 entering cohorts from 2017 to 2021 with a total of 37 medical student participants. The first full entering cohort of 12 medical students produced 8 mentored biomedical engineering capstone projects, 7 of which were based on clinical needs statements derived from earlier in the elective. Medical student participants have coauthored poster and oral presentations; contributed to projects that won WolfieTank, a university-wide competition modeled after the television show Shark Tank; and participated in the filing of provisional patents. Students reflecting on the course reported a change in their attitude towards existing medical problems, felt better-equipped to collaboratively design solutions for clinical needs, and considered a potential career path in device design. NEXT STEPS: The MSLIEB will be scaled up by recruiting additional faculty, broadening clinical opportunities to include the outpatient setting, and increasing medical student access to rapid prototyping equipment.

Angiotensin receptor blockade and stereotactic body radiation therapy for early stage lung cancer ARB & SBRT for early stage lung cancer.

Stereotactic body radiotherapy (SBRT) demonstrates excellent local control in early stage lung cancer, however a quarter of patients develop recurrence or distant metastasis. Transforming growth factor-beta (TGF-ß) supports metastasis and treatment resistance, and angiotensin receptor blockade (ARB) indirectly suppresses TGF-ß signaling. This study investigates whether patients taking ARBs while undergoing SBRT for early stage lung cancer exhibited improved overall survival (OS) or recurrence free survival (RFS) compared to patients not taking ARBs. This was a single institution retrospective analysis of 272 patients treated with SBRT for early stage lung cancer between 2009 and 2018. Patient health data was abstracted from the electronic medical record. OS and RFS were assessed using Kaplan-Meier method. Log-rank test was used to compare unadjusted survival between groups. Univariable and multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs). Of 247 patients analyzed, 24 (10%) patients took ARBs for the duration of radiotherapy. There was no difference in mean age, median tumor diameter, or median biologic effective dose between patients taking ARBs or not. Patients taking ARBs exhibited increased OS (ARB = 96.7 mo.; no ARB = 43.3 mo.; HR = 0.25 [95% CI: 0.10 to 0.62, P = .003]) and increased RFS (median RFS, ARB = 64.3 mo.; No ARB = 35.1 mo.; HR = 0.26 [95% CI: 0.10 to 0.63, P = .003]). These effects were not seen in patients taking angiotensin converting enzyme inhibitors (ACEIs) or statins. ARB use while undergoing SBRT for early stage lung cancer may increase OS and RFS, but ACEI use does not show the same effect.

Safety and Efficacy of Pembrolizumab in Combination with Acalabrutinib in Advanced Head and Neck Squamous Cell Carcinoma: Phase 2 Proof-of-Concept Study.

PURPOSE: Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival. RESULTS: Seventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4-6.8] months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size. CONCLUSIONS: Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.

HLH-Like Syndrome and Rhabdomyolysis in an Adolescent Patient.

Hemophagocytic lymphohistiocytosis (HLH) is a rare heterogeneous group of disorders characterized by immune overactivation. It can occur because of primary genetic mutations or secondary to almost any inflammatory or infectious process. The clinical manifestations of this syndrome are varied and life-threatening and resemble those of many malignancies, infections, sepsis, and multisystem inflammatory syndrome in children. Laboratory abnormalities often are not diagnostic for HLH until late in the disease course, and the laboratory studies are send-out tests at most institutions. Thus, quickly and accurately diagnosing pediatric patients with HLH presents significant challenges to the clinician. Furthermore, there has been recent discussion in the literature regarding the use of diagnostic criteria for HLH. In this case report, we detail an adolescent male individual who developed persistent unexplained fever, rhabdomyolysis, and regional ischemic immune myopathy. To our knowledge, there is no previous report of a pediatric patient with this rare myopathy or HLH presenting with persistent rhabdomyolysis in the literature. The patient was hospitalized for a total of 61 days, with multiple treatments attempted throughout during his course of illness. In this report, we highlight the importance of using diagnostic flexibility when HLH is suspected in pediatric patients and provide insight into the unique challenges of identifying this condition.

12-Lead Electrocardiograms Acquired and Transmitted by Emergency Medical Technicians are of Diagnostic Quality and Positively Impact Patient Care.

INTRODUCTION: Existing peer-reviewed literature describing emergency medical technician (EMT) acquisition and transmission of 12-lead electrocardiograms (12L-ECGs), in the absence of a paramedic, is largely limited to feasibility studies. STUDY OBJECTIVE: The objective of this retrospective observational study was to describe the impact of EMT-acquired 12L-ECGs in Suffolk County, New York (USA), both in terms of the diagnostic quality of the transmitted 12L-ECGs and the number of prehospital percutaneous coronary intervention (PCI)-center notifications made as a result of transmitted 12L-ECGs demonstrating a ST-elevation myocardial infarction (STEMI). METHODS: A pre-existing database was queried for Emergency Medical Services (EMS) calls on which an EMT acquired a 12L-ECG from program initiation (January 2017) through December 31, 2019. Scanned copies of the 12L-ECGs were requested in order to be reviewed by a blinded emergency physician. RESULTS: Of the 665 calls, 99 had no 12L-ECG available within the database. For 543 (96%) of the available 12L-ECGs, the quality was sufficient to diagnose the presence or absence of a STEMI. Eighteen notifications were made to PCI-centers about a concern for STEMI. The median time spent on scene and transporting to the hospital were 18 and 11 minutes, respectively. The median time from PCI-center notification to EMS arrival at the emergency department (ED) was seven minutes (IQR 5-14). CONCLUSION: In the event a cardiac monitor is available, after a limited educational intervention, EMTs are capable of acquiring a diagnostically useful 12L-ECG and transmitting it to a remote medical control physician for interpretation. This allows for prehospital PCI-center activation for a concern of a 12L-ECG with a STEMI, in the event that a paramedic is not available to care for the patient.

Disparity in Gender Representation of Speakers at National Emergency Medical Services Conferences: A Current Assessment and Proposed Path Forward.

INTRODUCTION: Gender disparities between Emergency Medicine physicians with regards to salary, promotion, and scholarly recognition as national conference speakers have been well-documented. However, little is known if similar gender disparities impact their out-of-hospital Emergency Medical Services (EMS) colleagues. Although there have been improvements in the ratio of women entering the EMS workforce, gender representation has improved at a slower rate for paramedics compared to emergency medical technicians (EMTs). Since recruitment, retention, and advancement of females within a specialty have been associated with the visibility of prominent, respected female leaders, gender disparity of these leaders as national conference speakers may contribute to the "leaky pipeline effect" seen within the EMS profession. Gender representation of these speakers has yet to be described objectively. STUDY OBJECTIVE: The primary objective of this study was to determine if disparity exists in gender representation of speakers at well-known national EMS conferences and trade shows in the United States (US) from 2016-2020. The secondary objective was to determine if males were more likely than females to return to a conference as a speaker in subsequent years. METHODS: A cross-sectional analysis of programs from well-known national conferences, specifically for EMS providers, which were held in the US from 2016-2020 was performed. Programs were abstracted for type of conference session (pre-conference, keynote, main conference) and speakers' names. Speaker gender (male, female) was confirmed via internet search. RESULTS: Seventeen conference programs were obtained with 1,709 conference sessions that had a total of 2,731 listed speaker names, of whom 537 (20%) were female. A total of 30 keynote addresses had 39 listed speaker names of whom six (15%) were female. No significant difference was observed in the number of years males returned to present at the same conference as compared to females. CONCLUSION: Gender representation of speakers at national EMS conferences in the US is not reflective of the current best estimate of the US EMS workforce. This disparity exists not only in the overall percent of female names listed as speakers, but also in the percent of individual female speakers, and is most pronounced within keynote speakers. Online lecture platforms, as an unintentional consequent of the COVID-19 pandemic, coupled with intentional speaker development and mentorship initiatives, may reduce barriers to facilitating a new pipeline for more females to become speakers at national EMS conferences.

Utility of Different Lung Ultrasound Simulation Modalities Used by Paramedics during Varied Ambulance Driving Conditions.

INTRODUCTION: Prehospital use of lung ultrasound (LUS) by paramedics to guide the diagnoses and treatment of patients has expanded over the past several years. However, almost all of this education has occurred in a classroom or hospital setting. No published prehospital use of LUS simulation software within an ambulance currently exists. STUDY OBJECTIVE: The objective of this study was to determine if various ambulance driving conditions (stationary, constant acceleration, serpentine, and start-stop) would impact paramedics' abilities to perform LUS on a standardized patient (SP) using breath-holding to simulate lung pathology, or to perform LUS using ultrasound (US) simulation software. Primary endpoints included the participating paramedics': (1) time to acquiring a satisfactory simulated LUS image; and (2) accuracy of image recognition and interpretation. Secondary endpoints for the breath-holding portion included: (1) the agreement between image interpretation by paramedic versus blinded expert reviewers; and (2) the quality of captured LUS image as determined by two blinded expert reviewers. Finally, a paramedic LUS training session was evaluated by comparing pre-test to post-test scores on a 25-item assessment requiring the recognition of a clinical interpretation of prerecorded LUS images. METHODS: Seventeen paramedics received a 45-minute LUS lecture. They then performed 25 LUS exams on both SPs and using simulation software, in each case looking for lung sliding, A and B lines, and seashore or barcode signs. Pre- and post-training, they completed a 25-question test consisting of still images and videos requiring pathology recognition and formulation of a clinical diagnosis. Sixteen paramedics performed the same exams in an ambulance during different driving conditions (stationary, constant acceleration, serpentines, and abrupt start-stops). Lung pathology was block randomized based on driving condition. RESULTS: Paramedics demonstrated improved post-test scores compared to pre-test scores (P <.001). No significant difference existed across driving conditions for: time needed to obtain a simulated image; clinical interpretation of simulated LUS images; quality of saved images; or agreement of image interpretation between paramedics and blinded emergency physicians (EPs). Image acquisition time while parked was significantly greater than while the ambulance was driving in serpentines (Z = -2.898; P = .008). Technical challenges for both simulation techniques were noted. CONCLUSION: Paramedics can correctly acquire and interpret simulated LUS images during different ambulance driving conditions. However, simulation techniques better adapted to this unique work environment are needed.

An Evolving Clinical Need: Discordant Oxygenation Measurements of Intubated COVID-19 Patients.

Since the first appearance of the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) earlier this year, clinicians and researchers alike have been faced with dynamic, daily challenges of recognizing, understanding, and treating the coronavirus disease 2019 (COVID-19) due to SARS-CoV-2. Those who are moderately to severely ill with COVID-19 are likely to develop acute hypoxemic respiratory failure and require administration of supplemental oxygen. Assessing the need to initiate or titrate oxygen therapy is largely dependent on evaluating the patient's existing blood oxygenation status, either by direct arterial blood sampling or by transcutaneous arterial oxygen saturation monitoring, also referred to as pulse oximetry. While the sampling of arterial blood for measurement of dissolved gases provides a direct measurement, it is technically challenging to obtain, is painful to the patient, and can be time and resource intensive. Pulse oximetry allows for non-invasive, real-time, continuous monitoring of the percent of hemoglobin molecules that are saturated with oxygen, and usually closely predicts the arterial oxygen content. As such, it was particularly concerning when patients with severe COVID-19 requiring endotracheal intubation and mechanical ventilation within one of our intensive care units were observed to have significant discordance between their predicted arterial oxygen content via pulse oximetry and their actual measured oxygen content. We offer these preliminary observations along with our speculative causes as a timely, urgent clinical need. In the setting of a COVID-19 intensive care unit, entering a patient room to obtain a fresh arterial blood gas sample not only takes exponentially longer to do given the time required for donning and doffing of personal protective equipment (PPE), it involves the consumption of already sparce PPE, and it increases the risk of viral exposure to the nurse, physician, or respiratory therapist entering the room to obtain the sample. As such, technology similar to pulse oximetry which can be applied to a patients finger, and then continuously monitored from outside the room is essential in preventing a particularly dangerous situation of unrealized hypoxia in this critically-ill patient population. Additionally, it would appear that conventional two-wavelength pulse oximetry may not accurately predict the arterial oxygen content of blood in these patients. This discordance of oxygenation measurements poses a critical concern in the evaluation and management of the acute hypoxemic respiratory failure seen in patients with COVID-19.

Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia.

Mutations in SET-binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging preclinical data for the use of trametinib in SETBP1-mutant disease.