Septic Abortion Complicated by Disseminated Intravascular Coagulation.

Audience: This scenario was developed to educate emergency medicine residents on the diagnosis and management of two concurrent conditions: septic abortion and disseminated intravascular coagulation (DIC). Introduction: Patients with an abortion (spontaneous or induced) of less than twenty weeks gestation may present with concurrent uterine infection, also known as septic abortion. One of the complications of septic abortion is DIC. Early management of both underlying etiology (septic abortion) and subsequent complications (DIC) is crucial to minimize morbidity and mortality. Educational Objectives: At the conclusion of the simulation session, learners will be able to: 1) Obtain a relevant focused history including pregnancy history, medication use, and past medical history. 2) Develop a differential for fever and vaginal bleeding in a pregnant patient. 3) Discuss management of septic abortion, including empiric broad-spectrum antibiotics and obstetric consultation for source control with dilation and curettage (D&C). 4) Discuss expected laboratory findings of disseminated intravascular coagulation (DIC). 5) Discuss management of DIC, including identification of underlying etiology and supportive resuscitation with blood products. 6) Review the components of blood products. 7) Identify appropriate disposition of the patient to the intensive care unit (ICU). Educational Methods: This session was conducted using high-fidelity simulation followed by a debriefing session and discussion about the diagnosis, differential, and management of both septic abortion and DIC. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. In this technique, the facilitator described something they observed in the case, outlined their reasoning as a facilitator why this observation was important or why they had questions, and then asked the learners to share their frame of reference at the time. An example: "I heard the team leader state that the platelets were normal, but then another resident disagreed. No one paused to come to a consensus. I'm wondering why this wasn't explored further in real time. Tell me more." This scenario may also be run as an oral boards case or adapted for other learners such as critical care fellows. Research Methods: Our residents were provided a survey at the completion of the debriefing session so they could rate different aspects of the simulation, as well as provide qualitative feedback on the scenario. The local institution's simulation center's electronic feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form,1 with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7. Results: Thirteen learners completed a feedback form out of seventeen participants. This session received all six and seven scores (consistently effective/very good and extremely effective/outstanding, respectively) other than two isolated 4 scores. Discussion: This is a cost-effective method for reviewing septic abortion and DIC. The case may be modified for appropriate audiences, such as simplifying the case to septic abortion without DIC. You can also consider not showing an initial temperature with the initial set of vitals unless it is specifically asked for by the participants. We encourage readers to utilize bleeding moulage techniques as a visual stimulus to increase psychological buy-in. Topics: Medical simulation, septic abortion, pregnancy complications, hematology emergencies, obstetric emergencies, disseminated intravascular coagulation, emergency medicine.

A Drosophila model to screen Alport syndrome COL4A5 variants for their functional pathogenicity.

Alport syndrome is a hereditary chronic kidney disease, attributed to rare pathogenic variants in either of three collagen genes (COL4A3/4/5) with most localized in COL4A5. Trimeric type IV Collagen α3α4α5 is essential for the glomerular basement membrane that forms the kidney filtration barrier. A means to functionally assess the many candidate variants and determine pathogenicity is urgently needed. We used Drosophila, an established model for kidney disease, and identify Col4a1 as the functional homolog of human COL4A5 in the fly nephrocyte (equivalent of human podocyte). Fly nephrocytes deficient for Col4a1 showed an irregular and thickened basement membrane and significantly reduced nephrocyte filtration function. This phenotype was restored by expressing human reference (wildtype) COL4A5, but not by COL4A5 carrying any of three established pathogenic patient-derived variants. We then screened seven additional patient COL4A5 variants; their ClinVar classification was either likely pathogenic or of uncertain significance. The findings support pathogenicity for four of these variants; the three others were found benign. Thus, demonstrating the effectiveness of this Drosophila in vivo kidney platform in providing the urgently needed variant-level functional validation.

Dissemination, Utilization, and Satisfaction With Emergency Medicine Resident Simulation Curriculum for Pediatrics (EM ReSCu Peds) by North American Residency Programs.

OBJECTIVES: Our research team's primary objective was to investigate how a custom standard simulation curriculum for teaching emergency medicine residents about pediatrics was being used by programs across North America. We also wanted to know if program directors were satisfied with the curriculum and whether they had challenges with implementing it. Our long-term goal is to promote the Emergency Medicine Resident Simulation Curriculum for Pediatrics for use by all programs in the United States. METHODS: We distributed an electronic questionnaire to individuals who have downloaded the Emergency Medicine Resident Simulation Curriculum for Pediatrics in the form of an e-book from the Academic Life in Emergency Medicine Web site. The curriculum was marketed through national emergency medicine (EM) and pediatric emergency medicine (PEM) groups, PEM listserv, and through the International Network for Simulation-Based Pediatric Innovation, Research, and Education. We asked survey recipients how they used the curriculum, plans for future maintenance, satisfaction with curriculum use, and whether they had any challenges with implementation. Finally, we asked demographic questions. RESULTS: Most survey respondents were EM or PEM health care physicians in the United States or Canada. Respondents' primary goal of using the curriculum was resident education. Through assessment with the Net Promoter Score, satisfaction with the curriculum was net positive with users largely scoring as curriculum promoters. We found COVID-19 and overall time limitations to be implementation barriers, whereas learner interest in topics was the largest cited facilitator. Most responders plan to continue to implement either selected cases or the entire curriculum in the future. CONCLUSIONS: Of those who responded, our target audience of EM physicians used our curriculum the most. Further investigation on implementation needs, specifically for lower resource emergency programs, is needed.

Pediatric contributions and lessons learned from the NEPTUNE cohort study.

Primary glomerular diseases are rare entities. This has hampered efforts to better understand the underlying pathobiology and to develop novel safe and effective therapies. NEPTUNE is a rare disease network that is focused on patients of all ages with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. It is a longitudinal cohort study that collects detailed demographic, clinical, histopathologic, genomic, transcriptomic, and metabolomic data. The goal is to develop a molecular classification for these disorders that supersedes the traditional pathological features-based schema. Pediatric patients are important contributors to this ongoing project. In this review, we provide a snapshot of the children and adolescents enrolled in NEPTUNE and summarize some key observations that have been made based on the data accumulated during the study. In addition, we describe the development of NEPTUNE Match, a program that aims to leverage the multi-scalar information gathered for each individual patient to provide guidance about potential clinical trial participation based on the molecular characterization and non-invasive biomarker profile. This represents the first organized effort to apply principles of precision medicine to the treatment of patients with primary glomerular disease. NEPTUNE has proven to be an invaluable asset in the study of glomerular diseases in patients of all ages including children and adolescents.

Diabetes screening outcomes in youth presenting for paediatric weight management: A report of the Paediatric Obesity Weight Evaluation Registry.

OBJECTIVE: Rising prevalence of obesity has led to increased rates of prediabetes and diabetes mellitus (DM) in children. This study compares rates of prediabetes and diabetes using two recommended screening tests (fasting plasma glucose [FPG] and haemoglobin A1c [HbA1c]). STUDY DESIGN: Data were collected prospectively from 37 multi-component paediatric weight management programs in POWER (Paediatric Obesity Weight Evaluation Registry). RESULTS: For this study, 3962 children with obesity without a known diagnosis of DM at presentation and for whom concurrent measurement of FPG and HbA1c were available were evaluated (median age 12.0 years [interquartile range, IQR 9.8, 14.6]; 48% males; median body mass index 95th percentile [%BMIp95] 134% [IQR 120, 151]). Notably, 10.7% had prediabetes based on FPG criteria (100-125 mg/dL), 18.6% had prediabetes based on HbA1c criteria (5.7%-6.4%), 0.9% had DM by FPG abnormality (≥126 mg/dL) and 1.1% had DM by HbA1c abnormality (≥6.5%). Discordance between the tests was observed for youth in both age groups (10-18 years [n = 2915] and age 2-9 years [n = 1047]). CONCLUSION: There is discordance between FPG and HbA1c for the diagnosis of prediabetes and DM in youth with obesity. Further studies are needed to understand the predictive capability of these tests for development of DM (in those diagnosed with prediabetes) and cardiometabolic risk.

Inhalational Injury Secondary to House Fire.

Audience: This scenario was developed to educate emergency medicine residents on the diagnosis and management of patients with an inhalational airway injury secondary to a house fire. Background: Burn injuries are a common occurrence encountered by the emergency physician. According to the National Hospital Ambulatory Medical Care Survey, around 371,000 patients were treated in emergency departments for fire or burn injuries across the United States in 2020. This represents around 1% of emergency department visits related to injury, poisoning, or adverse effects.1 One of the most dangerous and time critical aspects of managing severely burned patients is inhalation injury. Inhalation injury is a relatively vague term which may refer to pulmonary exposure to a wide range of chemicals in various forms. In the context of burn patients, this is most often smoke exposure. It is critical that the emergency medicine provider rapidly identifies the potential for an inhalational injury in order to determine the need for definitive airway management. It is also important that the provider has the necessary skills and systematic approach to manage what is likely to be a difficult airway. Furthermore, providers must then have the knowledge of how to best manage and resuscitate these severely burned patients post-intubation. Educational Objectives: At the conclusion of the simulation session, learners will be able to: 1) recognize the indications for intubation in a thermal burn/inhalation injury patient; 2) develop a systematic approach to an inhalational injury airway; and 3) recognize indications for transfer to burn center. Educational Methods: This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on the diagnosis, differential diagnosis, and management of inhalational airway injury secondary to a house fire. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. This scenario may also be run as an oral board case. Research Methods: Our residents are provided a survey at the completion of the debriefing session so they may rate different aspects of the simulation, as well as provide qualitative feedback on the scenario. The local institution's simulation center's electronic feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form2 with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7. Results: Nine learners completed a feedback form. This session received all 6 & 7 scores (consistently effective/very good and extremely effective/outstanding, respectively) other than one isolated 5 score. Discussion: This is a cost-effective method for reviewing inhalational airway injury diagnosis and management. The case may be modified for targeted audiences, expected resources, and learning objectives, such as removal of a bronchoscope availability in settings which are expected to be resource-limited. Some readers may choose to focus on other aspects of burn management instead of airway securement such as cyanide and/or carbon monoxide toxicity. We encourage readers to limit the number of learning objectives because airway algorithms and troubleshooting for this scenario was a rich, stand-alone debriefing. There was not enough time to review in detail all nuanced aspects of the burned patient, including: Lund-Browder versus rule of 9's, modified Brooke versus Parkland formulas, indications for and completion of escharotomies, and/or identification and treatment of cyanide and carbon monoxide toxicity. Topics: Medical simulation, burns, airway emergencies, emergency medicine.

Ventricular Tachycardia.

Audience: This scenario was developed to educate emergency medicine residents on the diagnosis and management of ventricular tachycardia (VT) that is refractory to single dose anti-arrhythmic management. Background: Electrical storm, defined as three or more episodes of sustained VT, ventricular fibrillation, or appropriate shocks from an implantable cardioverter defibrillator within 24 hours,1 has a mortality rate up to 14% in the first 48 hours.2 Ventricular tachycardia may present in a heterogenous fashion, not only with stable versus unstable clinical presentations, but also with different electrocardiographic morphologies and etiologies.1 Understanding how to rapidly diagnose, treat, and utilize second or third-line treatments is vital in the setting of refractory ventricular tachycardia rather than relying on the success of first-line agents. Appreciation for what medications are readily available in your crash cart and medication dispensing cabinet is critical for timely management for refractory ventricular tachycardia. Educational Objectives: At the conclusion of the simulation session, learners will be able to: 1) identify the different etiologies of VT, including structural heart disease, acute ischemia, and acquired or congenital QT syndrome; 2) describe confounding factors of VT, such as electrolyte abnormalities and sympathetic surge; 3) describe how to troubleshoot an unsuccessful synchronized cardioversion, including checking equipment connections, increasing delivered energy, and changing pad placement; 4) compare and contrast treatments of VT based on suspected underlying etiology; 5) describe reasons to activate the cardiac catheterization lab other than occlusive myocardial infarction; and 6) identify appropriate disposition of the patient to the cardiac catheterization lab. Educational Methods: This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on the diagnosis, differential diagnosis, and management of VT. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. This scenario may also be run as an oral board case. Research Methods: Our residents are provided a survey at the completion of the debriefing session so they may rate different aspects of the simulation, as well as provide qualitative feedback on the scenario. Results: The local institution's simulation center's electronic feedback form is based on the Center of Medical Simulation's Debriefing Assessment for Simulation in Healthcare (DASH) Student Version Short Form3 with the inclusion of required qualitative feedback if an element was scored less than a 6 or 7. Twelve learners completed a feedback form. This session received 6 and 7 scores (consistently effective/very good and extremely effective/outstanding, respectively) other than three isolated 5 scores. The lowest average score was 6.67 for "Before the simulation, the instructor set the stage for an engaging learning experience." The highest average score was 7 for "The instructor helped me see how to improve or how to sustain good performance." The form also includes an area for general feedback about the case at the end. Illustrative examples of feedback include: "Excellent care and debrief." Specific scores are available upon request. Discussion: This is a cost-effective method for reviewing VT diagnosis and management. The case may be modified for appropriate audiences, such as describing what medications may be readily available in a free-standing emergency department or pre-hospital setting. Topics: Medical simulation, ventricular tachycardia, cardiac emergencies, dysrhythmias, cardiology, emergency medicine.

High-Throughput Splicing Assays Identify Known and Novel WT1 Exon 9 Variants in Nephrotic Syndrome.

Introduction: Frasier syndrome (FS) is a rare Mendelian form of nephrotic syndrome (NS) caused by variants which disrupt the proper splicing of WT1. This key transcription factor gene is alternatively spliced at exon 9 to produce 2 isoforms ("KTS+" and "KTS-"), which are normally expressed in the kidney at a ∼2:1 (KTS+:KTS-) ratio. FS results from variants that reduce this ratio by disrupting the splice donor of the KTS+ isoform. FS is extremely rare, and it is unclear whether any variants beyond the 8 already known could cause FS. Methods: To prospectively identify other splicing-disruptive variants, we leveraged a massively parallel splicing assay. We tested every possible single nucleotide variant (n = 519) in and around WT1 exon 9 for effects upon exon inclusion and KTS+/- ratio. Results: Splice disruptive variants (SDVs) made up 11% of the tested point variants overall and were tightly concentrated near the canonical acceptor and the KTS+/- alternate donors. Our map successfully identified all 8 known FS or focal segmental glomerulosclerosis (FSGS) variants and 16 additional novel variants which were comparably disruptive to these known pathogenic variants. We also identified 19 variants that, conversely, increased the KTS+/KTS- ratio, of which 2 are observed in unrelated individuals with 46,XX ovotesticular disorder of sex development (46,XX OTDSD). Conclusion: This splicing effect map can serve as functional evidence to guide the clinical interpretation of newly observed variants in and around WT1 exon 9.

The Significance of Hematuria in Podocytopathies.

BACKGROUND: Hematuria is frequently present in podocytopathies, but its significance and prognostic value is not well described in these proteinuric kidney diseases. This study describes the prevalence and association between hematuria and kidney-related outcomes in these disorders. METHODS: Hematuria was assessed at the initial urinalysis in participants with the following podocytopathies, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis, in the Nephrotic Syndrome Study Network (NEPTUNE) and Cure Glomerulonephropathy (CureGN) cohorts with >24 months of follow-up. Multivariable Cox proportional hazards models were fit for time to composite outcome (end-stage kidney disease or 40% decline in estimated glomerular filtration rate (eGFR) and eGFR <60 ml/min/1.73 m2) and proteinuria remission (UPCR <0.3 mg/mg). RESULTS: Among the 1,516 adults and children in the study, 528 (35%) participants had focal segmental glomerulosclerosis, 499 (33%) had minimal change disease, and 489 (32%) had membranous nephropathy. Median (IQR) time from biopsy until the initial study urinalysis was 260 days (49, 750), and 498 (33%) participants were positive for hematuria. Participants with hematuria compared to those without, were older (37 [16, 55] vs 33 years [12, 55]), more likely to have an underlying diagnosis of membranous nephropathy (44% vs 27%), had shorter time since biopsy (139 [27, 477] vs 325 [89, 878] days) and higher UPCR (3.8 [1.4, 8.0] vs 0.9 [0.1, 3.1]g/g). After adjusting for diagnosis, age, sex, UPCR, eGFR, time since biopsy, and study cohort, hematuria was associated with a higher riskof reaching the composite outcome (HR 1.31 [1.04, 1.65], p-value 0.02) and lower rate of reaching proteinuria remission (HR 0.80 [0.65-0.98], p-value 0.03). CONCLUSIONS: Hematuria is prevalent among participants with the three podocytopathies and is significantly and independently associated with worse kidney-related outcomes, including both progressive loss of kidney function remission of proteinuria.

Algorithms for Treating Dyslipidemia in Youth.

PURPOSE OF REVIEW: The goal of this article is to review algorithms for treating dyslipidemia in youth, discuss pitfalls, propose enhanced algorithms to address pitfalls, and consider future directions. RECENT FINDINGS: The presence of modifiable and non-modifiable cardiovascular disease (CVD) risk factors during childhood is associated with CVD-related events in adulthood. Recent data has shown that childhood initiation of statin therapy in youth < 18 years of age with familial hypercholesterolemia reduces the risk of adult CVD. However, pediatric dyslipidemia remains undertreated in part due to a lack of primary health care providers with adequate understanding of screening guidelines and pediatric lipidologists with experience in treatment and follow-up of this unique population. Management algorithms have been published by the National Heart, Lung, and Blood Institute and American Heart Association as tools to empower clinicians to manage dyslipidemia. We propose enhanced algorithms, which incorporate recently approved pharmacotherapy to address the management gaps. Future algorithms based upon clinical risk scores may enhance treatment and improve outcomes. Algorithms for dyslipidemia management which target youth < 18 years of age are tools which empower clinicians to manage dyslipidemia in this unique population. Enhanced algorithms may help address pitfalls. We acknowledge the need for further risk assessment tools in pediatrics for tailored dyslipidemia management.

Care of Transgender and Gender-Diverse Children and Adolescents.

Children and adolescents may present with transgender or gender diverse (TGD) identity during the course of development. Pediatricians may be the first health care providers to whom TGD identity is revealed. Pediatricians can optimize health care outcomes by promoting a gender-affirming clinical environment, initiating the evaluation for gender incongruence, supporting social transition, and initiating medical interventions. Clinical practice guidelines are available from the World Professional Association for Transgender Health (WPATH, Standards of Care, version 8, 2022) and the Endocrine Society (2017). This article outlines a general approach to providing social and medical affirming care from the pediatrician's office.

Botulism due to Injection Drug Use.

Audience: This scenario was developed to educate emergency medicine residents on the diagnosis and management of wound botulism secondary to injection drug use. Introduction: Botulism is a relatively rare cause of respiratory failure and descending weakness in the United States, caused by prevention of presynaptic acetylcholine release at the neuromuscular junction. This presentation has several mimics, including myasthenia gravis and the Miller-Fisher variant of Guillain-Barré. It may be caused by ingestion of spores (infant), ingestion of pre-formed toxin (food-borne), formation of toxin in vivo (wound-associated cases), through weaponized sources, or through inappropriately administered injections (iatrogenic). Cases of black tar heroin injection have been associated with botulism. Regardless of the etiology, prompt assessment and support of respiratory muscle strength and ordering antidotal therapy is key to halting further muscle weakness progression. Educational Objectives: At the conclusion of the simulation session, learners will be able to: 1) Identify the different etiologies of botulism, including wound, food-borne, infant, iatrogenic, and inhalational sources, 2) describe the pathophysiology of botulism toxicity and how it prevents presynaptic acetylcholine release at the neuromuscular junction, 3) develop a differential for bilateral descending muscle weakness, 4) compare and contrast presentations of myasthenia gravis, botulism, and the Miller-Fisher variant of Guillain-Barré syndrome, 5) describe measurement of neurologic respiratory parameter testing, such as negative inspiratory force, 6) outline treatment principles of wound-associated botulism, including antitoxin administration, wound debridement, tetanus vaccination, and evaluation for the need of antibiotics, and 7) identify appropriate disposition of the patient to the medical intensive care unit (ICU). Educational Methods: This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on the diagnosis, differential diagnosis, and management of botulism secondary to injection drug use. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. This scenario may also be run as an oral board case. Research Methods: Our residents are provided a survey at the completion of the debriefing session so they may rate different aspects of the simulation, as well as provide qualitative feedback on the scenario. Results: Sixteen learners completed a feedback form. This session received all six and seven scores (consistently effective/very good and extremely effective/outstanding, respectively) other than three isolated five scores. The form also includes an area for general feedback about the case at the end. Illustrative examples of feedback include: "Really awesome debrief, breakdown of pathophysiology and clinical applications. Great work!"; "Great case with awesome learning points," and "Loved this session. Rare case but very great learning." Specific scores are available upon request. Discussion: This is a cost-effective method for reviewing botulism diagnosis and management. The case may be modified for appropriate audiences, such as using classic illness scripting (eg, ingestion of canned foods). We encourage readers to utilize a standardized patient to demonstrate extraocular muscle weakness and bulbar symptoms to increase psychological buy-in. Topics: Medical simulation, botulism, toxicologic emergencies, toxicology, neurology, emergency medicine.

A First-Class Simulation: In-Situ In-Flight Medical Emergencies Curriculum for Emergency Medicine Residents Aboard a Commercial Airliner.

INTRODUCTION: In-flight medical emergencies occur in an estimated one out of 604 flights. Responding in this environment poses a unique set of challenges unfamiliar to most emergency medicine (EM) providers, including physical space and resource limitations. We developed a novel high-fidelity in-situ training curriculum focused on frequent or high-risk in-flight medical scenarios while replicating this austere environment. METHODS: Our residency program coordinated with our local airport's chief of security and an airline-specific station manager to arrange the use of a grounded Boeing 737 commercial airliner during late evening/early morning hours. Eight stations reviewing in-flight medical emergency topics were reviewed, five of which were simulation scenarios. We created medical and first-aid kits that reflect equipment used by commercial airlines. Residents' self-assessed competency and medical knowledge were assessed both initially and post-curriculum using a standardized questionnaire. RESULTS: Forty residents attended the educational event as learners. Self-assessed competency and medical knowledge increased after curriculum participation. All tested aspects of self-assessed competency had a statistically significant increase from a mean of 15.04 to 29.20 out of a maximum score of forty. The mean medical knowledge score increased from 4.65 to 6.93 out of 10 maximum points. CONCLUSION: A five-hour in-situ curriculum for reviewing in-flight medical emergencies increased self-assessed competency and medical knowledge for EM and EM-internal medicine residents. The curriculum was overwhelmingly well-received by learners.

A knockout-first model of H3f3a gene targeting leads to developmental lethality.

Histone variant H3.3 is encoded by two genes, H3f3a and H3f3b, which can be expressed differentially depending on tissue type. Previous work in our lab has shown that knockout of H3f3b causes some neonatal lethality and infertility in mice, and chromosomal defects in mouse embryonic fibroblasts (MEFs). Studies of H3f3a and H3f3b null mice by others have produced generally similar phenotypes to what we found in our H3f3b nulls, but the relative impacts of the loss of either H3f3a or H3f3b have varied depending on the approach and genetic background. Here we used a knockout-first approach to target the H3f3a gene for inactivation in C57BL6 mice. Homozygous H3f3a targeting produced a lethal phenotype at or before birth. E13.5 null embryos had some potential morphological differences from WT littermates including smaller size and reduced head size. An E18.5 null embryo was smaller than its control littermates with several potential defects including small head and brain size as well as small lungs, which would be consistent with a late gestation lethal phenotype. Despite a reduction in H3.3 and total H3 protein levels, the only histone H3 post-translational modification in the small panel assessed that was significantly altered was the unique H3.3 mark phospho-Serine31, which was consistently increased in null neurospheres. H3f3a null neurospheres also exhibited consistent gene expression changes including in protocadherins. Overall, our findings are consistent with the model that there are differential, cell-type-specific contributions of H3f3a and H3f3b to H3.3 functions in epigenetic and developmental processes.

An addiction-based digital weight loss intervention: A multi-centre randomized controlled trial.

OBJECTIVE: This randomized clinical trial tested the effectiveness of an addiction-based digital weight-loss intervention, focusing on withdrawal/abstinence from self-identified problem foods, snacking and excessive amounts at meals, and discomfort displacement, with and without coaching, compared to an in-person, multi-disciplinary, care model among adolescents with obesity. We hypothesized that the digital intervention with coaching would yield greater weight loss and lower delivery burden than the standard clinical arm, and greater participant engagement than the digital arm without coaching. METHODS: Adolescents were randomized to app intervention, with or without coaching, or in-person multidisciplinary obesity intervention for 6 months. The primary outcome was change in %BMIp95 at weeks 12 and 24. A mixed-effects linear regression model was used to assess the association between change in %BMIp95 and intervention arm. We were also interested in assessing delivery burden, participant engagement and evaluating the relationships between weight change and demographic characteristics, mood, executive function and eating behaviours. RESULTS: All adolescents (n = 161; BMI ≥95th%, age 16 ± 2.5 year; 47% Hispanic, 65% female, 59% publicly insured) lost weight over 24-weeks (-1.29%, [-1.82, -0.76], p < 0.0001), with no significant weight loss difference between groups (p = 0.3). Girls lost more weight than boys, whereas binge eating behaviour at baseline was associated with increase in %BMIp95 when controlling for other covariates. There was no association between ethnicity, mood, timing of intervention in relation to the pandemic, or executive function and change in %BMIp95 . CONCLUSIONS: Contrary with our hypothesis, our results showed no difference in the change in BMI status between treatment arms. Since efficacy of this digital intervention was not inferior to in-person, multi-disciplinary care, this could offer a reasonable weight management option for clinicians, based on youth and family specific characteristics, such as accessibility, resources, and communication styles. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT035008353.

Physical Activity Counseling and Documentation by Pediatric Residents in Primary Care: Before and After Introduction of the FITT Principle.

Physician training on physical activity (PA) counseling in patient care is highly variable. The objective of this study was to improve PA counseling by pediatric residents through introduction of the four components of PA, called the FITT principle (frequency, intensity, time, type). Pediatric residents (n=30) received lectures, curriculum content, and an electronic smart-phrase addressing PA in obesity, including the FITT principle. Surveys assessed resident attitudes, and chart reviews (n = 423 over 16 months) identified evidence of PA counseling including FITT principle components preintervention and postintervention. Survey results showed positive attitudes and confidence regarding primary care provider roles in counseling on PA, with no differences postintervention. Chart reviews demonstrated increased documentation on PA frequency postintervention (pre 31.9% vs post 50.9%, P=.00006), but no significant changes in intensity, time or type. In conclusion, a focused PA curriculum promoted PA counseling by pediatric residents, with increased documentation of one component of the FITT principle.

Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis.

Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials. Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS. Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022. Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy. Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria. Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50). Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.

Building a RAFFT: Impact of a professional development program for women faculty and residents in emergency medicine.

Background: Women comprise 28% of faculty in academic departments of emergency medicine (EM) and 11% of academic chairs. Professional development programs for women are key to career success and to prevent pipeline attrition. Within emergency medicine, there is a paucity of outcomes-level data for such programs. Objectives: We aim to measure the impact of a novel structured professional development curriculum and mentorship group (Resident and Faculty Female Tribe, or RAFFT) within an academic department of EM. Methods: This prospective single-center curriculum implementation and evaluation was conducted in the academic year 2020-2021. A planning group identified potential curricular topics using an iterative Delphi process. We developed a 10-session longitudinal curriculum; a postcurriculum survey was conducted to assess the perceived benefit of the program in four domains. Results: A total of 76% of 51 eligible women attended at least one session; for this project we analyzed the 24 participants (47%) who attended at least one session and completed both the pre- and the postsurvey. The majority of participants reported a positive benefit, which aligned with their expectations in the following areas: professional development (79.2%), job satisfaction (83.3%), professional well-being (70.8%), and personal well-being (79.2%). Resident physicians more often reported less benefit than expected compared to fellow/faculty physicians. Median perceived impact on career choice and trajectory was positive for all respondents. Conclusions: Success of this professional development program was measured through a perceived benefit aligning with participant expectations, a positive impact on career choice and career trajectory for participants in each career stage, and a high level of engagement in this voluntary program. Recommendations for the successful implementation of professional development programs include early engagement of stakeholders, the application of data from a program-specific needs assessment, early dissemination of session dates to allow for protected time off, and structured discussions with appropriate identification of presession resources.

Histone H3.3 K27M chromatin functions implicate a network of neurodevelopmental factors including ASCL1 and NEUROD1 in DIPG.

BACKGROUND: The histone variant H3.3 K27M mutation is a defining characteristic of diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG). This histone mutation is responsible for major alterations to histone H3 post-translational modification (PTMs) and subsequent aberrant gene expression. However, much less is known about the effect this mutation has on chromatin structure and function, including open versus closed chromatin regions as well as their transcriptomic consequences. RESULTS: Recently, we developed isogenic CRISPR-edited DIPG cell lines that are wild-type for histone H3.3 that can be compared to their matched K27M lines. Here we show via ATAC-seq analysis that H3.3K27M glioma cells have unique accessible chromatin at regions corresponding to neurogenesis, NOTCH, and neuronal development pathways and associated genes that are overexpressed in H3.3K27M compared to our isogenic wild-type cell line. As to mechanisms, accessible enhancers and super-enhancers corresponding to increased gene expression in H3.3K27M cells were also mapped to genes involved in neurogenesis and NOTCH signaling, suggesting that these pathways are key to DIPG tumor maintenance. Motif analysis implicates specific transcription factors as central to the neuro-oncogenic K27M signaling pathway, in particular, ASCL1 and NEUROD1. CONCLUSIONS: Altogether our findings indicate that H3.3K27M causes chromatin to take on a more accessible configuration at key regulatory regions for NOTCH and neurogenesis genes resulting in increased oncogenic gene expression, which is at least partially reversible upon editing K27M back to wild-type.

Novel technique for continuous pressure monitoring of esophageal balloon in balloon tamponade device for acute variceal bleed.

Acute variceal bleeding is a life-threatening emergency associated with high mortality. Balloon tamponade is required for refractory bleeding to allow stabilization for definitive therapy. Unfortunately, these devices are associated with iatrogenic complications such as esophageal necrosis and perforation. It is imperative to accurately measure the esophageal balloon pressure to limit these complications. We describe a novel technique for both initial and continuous pressure monitoring of the esophageal balloon.