Increasing equity in science requires better ethics training: A course by trainees, for trainees.

Despite the profound impacts of scientific research, few scientists have received the necessary training to productively discuss the ethical and societal implications of their work. To address this critical gap, we-a group of predominantly human genetics trainees-developed a course on genetics, ethics, and society. We intend for this course to serve as a template for other institutions and scientific disciplines. Our curriculum positions human genetics within its historical and societal context and encourages students to evaluate how societal norms and structures impact the conduct of scientific research. We demonstrate the utility of this course via surveys of enrolled students and provide resources and strategies for others hoping to teach a similar course. We conclude by arguing that if we are to work toward rectifying the inequities and injustices produced by our field, we must first learn to view our own research as impacting and being impacted by society.

Educational Strategies in Pediatric Trauma Resuscitation Across Disciplines: A Scoping Review.

INTRODUCTION: Trauma is the leading cause of death and disability in children. Differences in mechanism, injury pattern, severity, and physiology in this population distinguish pediatric trauma patients from adults. Educational techniques including simulation and didactics may improve pediatric readiness in this setting. We summarize the literature across disciplines, highlighting the curricular approaches, target provider population, educational content, content delivery method, and Kirkpatrick level for pediatric trauma resuscitation education. METHODS: The MEDLINE (via Ovid), Embase (via Elsevier), Cumulative Index to Nursing & Allied Health Literature Complete (via EBSCO), Education Database (via ProQuest), and Web of Science Social Science Citation Index and Science Citation Index (via Clarivate) were searched. We reviewed 90 manuscripts describing pediatric trauma resuscitation education programs. When available, target provider population, curricular content, delivery method, and Kirkpatrick level were obtained. RESULTS: Nurses (50%), residents (45%), and attending physicians (43%) were the most common participants. Airway management (25%), shock (25%), and general trauma (25%) were the most frequently taught concepts, and delivery of content was more frequently via simulation (65%) or didactics (52%). Most studies (39%) were Kirkpatrick Level 1. CONCLUSIONS: This review suggests that diverse strategies exist to promote pediatric readiness. Most training programs are interdisciplinary and use a variety of educational techniques. However, studies infrequently report examining the impact of educational interventions on patient-centered outcomes and lack detail in describing their curriculum. Future educational efforts would benefit from heightened attention to such outcome measures and a rigorous description of their curricula to allow for reproducibility.

Use of pediatric trauma simulations to facilitate exposure to pediatric trauma resuscitations during training.

BACKGROUND: Pediatric traumas are often high-acuity but are low-frequency compared to adult trauma activations. This is reflected in the relatively limited experience with these events during training. Although some principles of trauma resuscitation are similar between adults and children, there are also important differences in physiology, injury patterns, and presentation. Therefore, simulation can be used to supplement trainee exposure and enhance their ability to respond to these high-stakes events. METHODS: We developed a multidisciplinary pediatric trauma resuscitation simulation curriculum to increase exposure to pediatric traumas at our institution. The intervention includes monthly sessions in the pediatric resuscitation bays, during which multidisciplinary teams complete 2 full pediatric trauma resuscitation simulations. This is supplemented with formal debriefing, simulation-specific teaching, and standardized trauma cognitive aids. The comprehensiveness of trauma evaluations and resuscitation efforts are evaluated using our institutional structured trauma resuscitation observation tool, and post-simulation surveys are used to assess the impact of the teaching interventions. RESULTS: Nine simulation sessions were conducted with more than 100 participants, including surgical residents, emergency medicine residents, nursing staff, respiratory therapists, and medical students. Completeness of resuscitation efforts improved from 55% to 82% (P < .01) between initial and repeat simulations. Surveyed participants reported improvement in overall team performance on the Team Emergency Assessment Measure (P < .01). CONCLUSION: Implementing a multidisciplinary pediatric trauma simulation curriculum with structured teaching interventions and standardized trauma scripts promotes teamwork and strengthens trainees' ability to conduct comprehensive evaluations required for high-acuity pediatric traumas.

A National Comparison of Volume and Acuity for Adult and Pediatric Trauma: A Trauma Quality Improvement Program Cohort Study.

INTRODUCTION: Most injured children receive trauma care outside of a pediatric trauma center. Differences in physiology, dosing, and injury pattern limit extrapolation of adult trauma principles to pediatrics. We compare US trauma center experience with pediatric and adult trauma resuscitation. MATERIALS AND METHODS: We queried the 2019 Trauma Quality Improvement Program to describe the experience of US trauma centers with pediatric (<15 y) and adult trauma. We quantified blunt, penetrating, burn, and unspecified traumas and compared minor, moderate, severe, and critical traumas (ISS 1-8 Minor, ISS 9-14 Moderate, ISS 15-24 Severe, ISS 25+ Critical). We estimated center-level volumes for adults and children. Institutional identifiers were generated based on unique center specific factors including hospital teaching status, hospital type, verification level, pediatric verification level, state designation, state pediatric designation, and bed size. RESULTS: A total of 755,420 adult and 76,449 pediatric patients were treated for traumatic injuries. There were 21 times as many critical or major injuries in adults compared to children, 17 times more moderate injuries, and 6 times more minor injuries. Children and adults presented with similar rates of blunt trauma, but penetrating injuries were more common in adults and burn injuries were more common in children. Comparing center-level data, adult trauma exceeded pediatric for every severity and mechanism. CONCLUSIONS: There is relatively limited exposure to high-acuity pediatric trauma at US centers. Investigation into pediatric trauma resuscitation education and simulation may promote pediatric readiness and lead to improved outcomes.

Use of a Structured Observation Tool to Promote Medical Student Engagement in Trauma Resuscitations.

OBJECTIVE: We describe a novel approach to promoting medical student learning and engagement during trauma resuscitation with implementation of a structured observation and debriefing tool. DESIGN: In the context of a multifaceted quality improvement effort in our emergency room, we implemented a structured trauma observation tool (SOT) for medical students based on ATLS trauma guidelines. The SOT reflects the American College of Surgeons and Association for Surgical Education (ACS/ASE) trauma evaluation module for medical students. Two medical students from our quality improvement working group undertook a proof-of-concept study to determine whether the SOT facilitated accurate observations of trauma resuscitations and promoted educational debriefs with precepting providers. Results were encouraging, so the tool was implemented for elective use on surgical clerkships. Clerkship students who used the SOT were given the opportunity to share its impact on their experience. Institutional Review Board approval was obtained under Pro00109569. SETTING: A large level 1 trauma center at an academic hospital in the southeastern United States. PARTICIPANTS: An interdisciplinary working group including surgeons, emergency medicine physicians, nurses, and students developed the observation tool. Two medical students from this team showed that the tool was effective at guiding observations and facilitating debriefs prior to its broader implementation on the general surgery clerkship. RESULTS: A total of 630 resuscitation tasks were observed during 15 trauma activations prior to implementation on the surgery clerkship. There was over 97% agreement between students observations and evaluating physicians self-reporting on which tasks were completed. Tasks on which there was disagreement were discussed to aid student learning. The tool was implemented for elective use on the surgery clerkship where students reported positive experiences. CONCLUSIONS: Early data suggest that this structured observation tool facilitates accurate trauma assessment observations and provides an opportunity for high-yield debriefs with the evaluating physician. This promotes student comprehension of ATLS principles. The SOT is being implemented as a pedagogic tool for students on the surgery clerkship to guide their observations, improve comprehension of decisions made in a hyperacute setting, and offer real time feedback as part of their learning in the trauma bay. The tool appears to be a valuable supplement which supports the ACS/ASE curriculum.

Multiple causal variants underlie genetic associations in humans.

Associations between genetic variation and traits are often in noncoding regions with strong linkage disequilibrium (LD), where a single causal variant is assumed to underlie the association. We applied a massively parallel reporter assay (MPRA) to functionally evaluate genetic variants in high, local LD for independent cis-expression quantitative trait loci (eQTL). We found that 17.7% of eQTLs exhibit more than one major allelic effect in tight LD. The detected regulatory variants were highly and specifically enriched for activating chromatin structures and allelic transcription factor binding. Integration of MPRA profiles with eQTL/complex trait colocalizations across 114 human traits and diseases identified causal variant sets demonstrating how genetic association signals can manifest through multiple, tightly linked causal variants.

Transgenic Drosophila lines for LexA-dependent gene and growth regulation.

Conditional expression of short hairpin RNAs with binary genetic systems is an indispensable tool for studying gene function. Addressing mechanisms underlying cell-cell communication in vivo benefits from simultaneous use of 2 independent gene expression systems. To complement the abundance of existing Gal4/UAS-based resources in Drosophila, we and others have developed LexA/LexAop-based genetic tools. Here, we describe experimental and pedagogical advances that promote the efficient conversion of Drosophila Gal4 lines to LexA lines, and the generation of LexAop-short hairpin RNA lines to suppress gene function. We developed a CRISPR/Cas9-based knock-in system to replace Gal4 coding sequences with LexA, and a LexAop-based short hairpin RNA expression vector to achieve short hairpin RNA-mediated gene silencing. We demonstrate the use of these approaches to achieve targeted genetic loss-of-function in multiple tissues. We also detail our development of secondary school curricula that enable students to create transgenic flies, thereby magnifying the production of well-characterized LexA/LexAop lines for the scientific community. The genetic tools and teaching methods presented here provide LexA/LexAop resources that complement existing resources to study intercellular communication coordinating metazoan physiology and development.

Evaluating a longitudinal point-of-care-ultrasound (POCUS) curriculum for pediatric residents.

BACKGROUND: POCUS is a growing field in medical education, and an imaging modality ideal for children given the lack of ionizing radiation, ease of use, and good tolerability. A 2019 literature review revealed that no US pediatric residency programs integrated obligatory POCUS curricula. Our objective was to provide a formalized POCUS curriculum over multiple years, and to retrospectively assess improvement in resident skills and comfort. METHODS: During intern year, pediatric residents received didactics and hands-on scanning opportunities in basic POCUS applications. Their evaluation tools included pre- and post-surveys and tests, and a final performance exam. In the second and third years of residency, all participants were required to complete 8 hours per year of POCUS content review and additional hands-on training. An optional third-year curriculum was offered to interested residents as career-focused education elective time. RESULTS: Our curriculum introduced POCUS topics such as basic and advanced cardiac, lung, skin/soft tissues and procedural based ultrasound to all pediatric residents. Among first-year residents, application-specific results showed POCUS comfort level improved by 61-90%. Completed evaluations demonstrated improvement in their ability to recognize and interpret POCUS images. Second- and third-year residents reported educational effectiveness that was rated 3.9 on a 4-point Likert scale. Four third-year residents took part in the optional POCUS elective, and all reported a change in their practice with increased POCUS incorporation. CONCLUSIONS: Our longitudinal pediatric residency POCUS curriculum is feasible to integrate into residency training and exhibits early success.

Pediatric Sepsis in Community Emergency Care Settings: Guideline Concordance and Outcomes.

OBJECTIVES: Bundled pediatric sepsis care has been associated with improved outcomes in tertiary pediatric emergency departments. Sepsis care at nontertiary sites where most children seek emergency care is not well described. We sought to describe the rate of guideline-concordant care, and we hypothesized that guideline-concordant care in community pediatric emergency care settings would be associated with decreased hospital length of stay (LOS). METHOD: This retrospective cohort study of children with severe sepsis presenting to pediatric community emergency and urgent care sites included children 60 days to 17 years with severe sepsis. The primary predictor was concordance with the American College of Critical Care Medicine 2017 pediatric sepsis resuscitation bundle, including timely recognition, vascular access, intravenous fluids, antibiotics, vasoactive agents as needed. RESULTS: From January 1, 2015, to December 31, 2017, 90 patients with severe sepsis met inclusion criteria; 22 (24%) received guideline-concordant care. Children receiving concordant care had a median hospital LOS of 95.3 hours (50.9-163.8 hours), with nonconcordant care, LOS was 88.3 hours (57.3-193.2 hours). In adjusted analysis, guideline-concordant care was not associated with hospital LOS (incident rate ratio, 0.99 [0.64-1.52]). The elements that drove overall concordance were timely recognition, achieved in only half of cases, vascular access, and timely antibiotics. CONCLUSIONS: Emergency care for pediatric sepsis in the community settings studied was concordant with guidelines in only 24% of the cases. Future study is needed to evaluate additional drivers of outcomes and ways to improve sepsis care in community emergency care settings.

Transcriptomic signatures across human tissues identify functional rare genetic variation.

Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.

Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance.

Aggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, forms large aggregate-like assemblies visualized as nuclear foci. Here we demonstrate that Aire utilizes its caspase activation recruitment domain (CARD) to form filamentous homo-multimers in vitro, and this assembly mediates foci formation and transcriptional activity. However, CARD-mediated multimerization also makes Aire susceptible to interaction with promyelocytic leukemia protein (PML) bodies, sites of many nuclear processes including protein quality control of nuclear aggregates. Several loss-of-function Aire mutants, including those causing autoimmune polyendocrine syndrome type-1, form foci with increased PML body association. Directing Aire to PML bodies impairs the transcriptional activity of Aire, while dispersing PML bodies with a viral antagonist restores this activity. Our study thus reveals a new regulatory role of PML bodies in Aire function, and highlights the interplay between nuclear aggregate-like assemblies and PML-mediated protein quality control.

An origin of the immunogenicity of in vitro transcribed RNA.

The emergence of RNA-based therapeutics demands robust and economical methods to produce RNA with few byproducts from aberrant activity. While in vitro transcription using the bacteriophage T7 RNA polymerase is one such popular method, its transcripts are known to display an immune-stimulatory activity that is often undesirable and uncontrollable. We here showed that the immune-stimulatory activity of T7 transcript is contributed by its aberrant activity to initiate transcription from a promoter-less DNA end. This activity results in the production of an antisense RNA that is fully complementary to the intended sense RNA product, and consequently a long double-stranded RNA (dsRNA) that can robustly stimulate a cytosolic pattern recognition receptor, MDA5. This promoter-independent transcriptional activity of the T7 RNA polymerase was observed for a wide range of DNA sequences and lengths, but can be suppressed by altering the transcription reaction with modified nucleotides or by reducing the Mg2+ concentration. The current work thus not only offers a previously unappreciated mechanism by which T7 transcripts stimulate the innate immune system, but also shows that the immune-stimulatory activity can be readily regulated.

The Sensitivity of Clinician Diagnosis of Sepsis in Tertiary and Community-Based Emergency Settings.

OBJECTIVES: To assess whether the risk of missed clinician diagnosis of pediatric sepsis requiring care in the intensive care unit (ICU) was greater in community vs tertiary pediatric emergency care settings with sepsis pathways. STUDY DESIGN: An observational cohort study in a tertiary pediatric emergency department (ED) staffed by pediatric emergency physicians and 4 affiliated community pediatric ED/urgent care sites staffed by general pediatricians. Use of an institutional sepsis order set or pathway was considered clinician diagnosis of sepsis. Risk of missed diagnosis was compared for 2 outcomes: suspected infection plus ICU admission (sepsis-ICU) and suspected infection plus vasoactive agent/positive-pressure ventilation (sepsis-VV). RESULTS: From January 1, 2014 to December 31, 2015, there were 141 552 tertiary and 139 332 community emergency visits. Clinicians diagnosed sepsis in 1136 visits; median age was 5.7 (2.4, 12.0) years. In the tertiary ED, there were 306 sepsis-ICU visits (0.2%) and 112 sepsis-VV visits (0.08%). In community sites, there were 46 sepsis-ICU visits (0.03%) and 20 sepsis-VV visits (0.01%). The risk of missed diagnosis in community vs tertiary sites was significantly greater for sepsis-ICU (relative risk 4.30, CI 2.15-8.60) and sepsis-VV (relative risk 14.0, CI 2.91-67.24). Sensitivity for sepsis-ICU was 94.4% (91.3%-96.5%) at the tertiary site and 76.1% (62.1%-86.1%) at community sites. CONCLUSIONS: The risk of missed diagnosis of sepsis-ICU was greater in community vs tertiary emergency care settings despite shared pathways and education, but with differences in resources, providers, and sepsis incidence. More research is needed to optimize diagnostic approaches in all settings.

Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation.

Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral dsRNA sensor that induces antiviral immune response. Using a newly developed RNase-protection/RNA-seq approach, we demonstrate here that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNAs because of its limited filament formation on imperfect duplexes, AGS variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNAs. Moreover, we identified an unexpected role of an RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context dependence of self versus non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 in recognizing dsRNA comes at a cost of self-recognition and implicates a unique role of Alu-dsRNAs as virus-like elements that shape the primate immune system.

A translational consideration of intercellular adhesion molecule-1 biology in the perioperative setting.

Intercellular adhesion molecule-1 (ICAM-1) is a critical adhesion molecule involved in leukocyte recruitment. Since its discovery in 1986, a large number of studies have been performed to elucidate its role in vitro and in vivo. Here, we review its role in leukocyte recruitment and consider future steps to take that will enhance our understanding of ICAM-1 biology and its translational application in the perioperative setting.

Bury My Documents in Lenexa, Kansas: Expert Witness Work and the American Indian Records Repository.

Restricted access to the American Indian Records Repository (AIRR) poses significant problems for expert witness historians working outside the federal government, as well as for academic historians and tribes. The authors discuss the creation of the AIRR in 2004, the records housed there, and the challenges they have experienced as expert witnesses seeking access to the AIRR. Although the AIRR preserves a far greater volume of federal records than might have otherwise occurred, the lack of public access may ultimately impede historians' ability to examine modern topics in Native American history and United States-tribal relations.

Medical students' reactions to anatomic dissection and the phenomenon of cadaver naming.

The teaching of gross anatomy has, for centuries, relied on the dissection of human cadavers, and this formative experience is known to evoke strong emotional responses. The authors hypothesized that the phenomenon of cadaver naming is a coping mechanism used by medical students and that it correlates with other attitudes about dissection and body donation. The authors developed a 33-question electronic survey to which 1,156 medical students at 12 medical schools in the United States voluntarily responded (November 2011-March 2012). They also surveyed course directors from each institution regarding their curricula and their observations of students' coping mechanisms. The majority of students (574, 67.8%) named their cadaver. Students most commonly cited the cadaver's age as the reason they chose a particular name for the cadaver. A minority of the students who did not name the cadaver reported finding the practice of naming disrespectful. Almost all students indicated that they would have liked to know more about their donor, particularly his or her medical history. Finally, students who knew the birth name of the donor used it less frequently than predicted. The authors found that the practice of naming cadavers is extremely prevalent among medical students and that inventive naming serves as a beneficial coping mechanism. The authors suggest that developing a method of providing students with more information about their cadaver while protecting the anonymity of the donor and family would be useful.