Minnesota West Community & Technical College

e22007 Background: CBFA2T3::GLIS2 (CBF/GLIS2) rearranged AML is a highly refractory AML subtype arising in infants and young children. The CBF/GLIS2 fusion is associated with overexpression of FRα. Luveltamab tazevibulin (luvelta) is an anti–FRα-targeting antibody-drug conjugate with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR = 4), which induces cytotoxic and immunologic cell death. Since 2021, luvelta was used alone or in combination with AML therapy to treat children with CBF/GLIS2 AML in the context of a compassionate use program. Data from the first 25 children were reported in December 2023 Blood 142 (Supplement 1): 4295. These children represent a heterogenic group with varying prior treatments and disease burden. They included 17 children who started luvelta with ≥5% bone marrow (BM) blasts and 8 children who had < 5% BM blast with persistent MRD positivity. Luvelta was mostly given at doses of 4.3 or 5.2 mg/kg every 2-4 weeks (4 received fractionated doses on days 1, 3, 5 per cycle). Out of 25 children, 21 received ≥ 1 dose of monotherapy initially, while 4 received combination with AML chemotherapy. All participants were followed for long-term survival. Objectives: Determine long-term overall survival (OS) in the first 25 children who received luvelta for CBF/GLIS2 AML. Methods: All clinical data was reported by compassionate use Investigators. OS was calculated from the date of the first dose of luvelta. Results: As of July 15, 2024, 7 of 25 children were alive, with a median OS of 8.8 months (95% confidence interval [CI] 5.3 -20.4). Among the 7 surviving children, 2 received luvelta as monotherapy while 5 received luvelta in combo either from the beginning of treatment or after failing monotherapy. Most of the deaths occurred in children who did not respond (N = 11) or recurred after luvelta (N = 5); two occurred post-transplant, 1 from progression and 1 from infection. Median OS was 9.7 months (95% CI 5.7-29.8) in the 21 children who received non-fractionated doses every 2 to 4 weeks. Overall, MRD negativity was achieved in 10 of the 25 children: the median OS was 29.8 months (95% CI 6.2-Not Reached [NR]) in those who became MRD negative and 5.3 months (95% CI 1.5-8.6) in those who did not. Nine children received hematopoietic stem cell transplants after morphologic and/or molecular response to luvelta. Post transplant median OS was 22.1 months (95% CI 1.8-NR). Five children received post-transplant maintenance. Conclusions: Luvelta alone or in combination with AML chemotherapy could achieve MRD negativity in more than one third of CBF/GLIS2 AML patients, allowing transplant and resulting survival of more than 2 years. Additional children have received luvelta through compassionate use since 2023 and the pivotal phase 1/2 trial for these patients is now open and enrolling (clinicaltrials.gov NCT06679582).

ObjectiveTo study postoperative pain control differences between liposomal bupivacaine (LB) and immediate-release bupivacaine (IRB) as measured by the use of narcotics after iliac crest graft harvesting for alveolar bone grafting (ABG).DesignA retrospective review was completed at a single-site pediatric stand-alone hospital of patients undergoing ABG with iliac crest bone grafting (ICBG) between May 1, 2020, through May 31, 2023.Patients, ParticipantsPatients who underwent ABG with ICBG were split into three cohorts: LB monotherapy, IRB monotherapy, or LB with IRB.InterventionsAll ABG and ICBG procedures were completed by a single surgeon who is a member of our dedicated cleft lip and palate team.Main Outcome MeasuresThe primary outcome was the difference in oral morphine equivalent (OME) requirements from the immediate postoperative time period to the time of discharge.ResultsPatients treated with LB monotherapy required significantly less OME during their inpatient stay, with an average of 0.21 mg/kg ± 0.15 mg/kg in the LB group, 0.67 mg/kg ± 0.37 mg/kg in the IRB group, and 0.28 mg/kg ± 0.07 mg/kg in the LB with IRB group (P = .001). There was no significant difference in the total number of analgesic medication doses administered throughout the hospitalization among the three groups.ConclusionsUtilization of LB intraoperatively may decrease the need for postoperative opioid treatment for postoperative pain control when harvesting ICB for ABG in the cleft lip and palate population compared to alternative local anesthetics.

Abstract Intentional injury and violence affect lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI) populations globally and have a detrimental impact on their health and well-being. Elevated levels of injury and violence have been documented in LGBTQI populations relative to heterosexual, cisgender populations. Moreover, LGBTQI individuals experience unique forms of victimization, including hate-motivated violence and criminalization of LGBTQI identities. This chapter provides a broad overview of the literature addressing injury and victimization in LGBTQI populations worldwide, with an emphasis on the Global South. Topics include relevant frameworks, the various manifestations of injury and victimization, and antecedents, consequences, and interventions within interpersonal, institutional, community, and societal domains. Implications for intersections of social identities (e.g., ethno-racial, gender, age) and sub-populations (e.g., people engaged in sex work) are discussed. There remains a critical need for in-depth research and intervention development for many forms of violence that impact LGBTQI populations worldwide. Particular emphasis on addressing subpopulations such as transgender, non-binary, bisexual, intersex, LGBTQI elders, and populations of color is needed. Future research and development of interventions should center on perspectives from the Global South and employ de-colonial and post-colonial frameworks.

This white paper provides clinicians and hospital leaders with practical guidance on the prevention and control of viral respiratory infections in the neonatal intensive care unit (NICU). This document serves as a companion to Centers for Disease Control and Prevention Healthcare Infection Control Practices Advisory Committee (HICPAC)'s "Prophylaxis and Screening for Prevention of Viral Respiratory Infections in Neonatal Intensive Care Unit Patients: A Systematic Review." It provides practical, expert opinion and/or evidence-based answers to frequently asked questions about viral respiratory detection and prevention in the NICU. It was developed by a writing panel of pediatric and pathogen-specific experts who collaborated with members of the HICPAC systematic review writing panel and the SHEA Pediatric Leadership Council to identify questions that should be addressed. The document has been endorsed by SHEA, the American Hospital Association (AHA), The Joint Commission, the Pediatric Infectious Diseases Society (PIDS), the Association for Professionals in Infection Control and Epidemiology (APIC), the Infectious Diseases Society of America (IDSA), and the National Association of Neonatal Nurses (NANN).

Complex regions in the human genome such as repeat motifs, pseudogenes and structural (SVs) and copy number variations (CNVs) present ongoing challenges to accurate genetic analysis, particularly for short-read Next-Generation-Sequencing (NGS) technologies. One such region is the highly polymorphic CYP2D loci, containing CYP2D6, a clinically relevant pharmacogene contributing to the metabolism of >20% of common drugs, and two highly similar pseudogenes, CYP2D7 and CYP2D8. Multiple complex SVs, including CYP2D6/CYP2D7-derived hybrid genes are known to occur in different configurations and frequencies across populations and are difficult to detect and characterize accurately. This can lead to incorrect enzyme activity assignment and impact drug dosing recommendations, often disproportionally affecting underrepresented populations. To improve CYP2D6 genotyping accuracy, we developed a PCR-free CRISPR-Cas9 based enrichment method for targeted long-read sequencing that fully characterizes the entire CYP2D6-CYP2D7-CYP2D8 loci. Clinically relevant sample types, including blood, saliva, and liver tissue were sequenced, generating high coverage sets of continuous single molecule reads spanning the entire targeted region of up to 52 kb, regardless of SV present (n = 9). This allowed for fully phased dissection of the entire loci structure, including breakpoints, to accurately resolve complex CYP2D6 diplotypes with a single assay. Additionally, we identified three novel CYP2D6 suballeles, and fully characterized 17 CYP2D7 and 18 CYP2D8 unique haplotypes. This method for CYP2D6 genotyping has the potential to significantly improve accurate clinical phenotyping to inform drug therapy and can be adapted to overcome testing limitations of other clinically challenging genomic regions.

Studies in critically ill adults demonstrate associations between serum renin concentrations (a proposed surrogate for renin-angiotensin-aldosterone system dysregulation) and poor outcomes, but data in critically ill children are lacking. We assessed serum renin + prorenin concentrations in children with septic shock to determine their predictive ability for acute kidney injury (AKI) and mortality. We conducted a secondary analysis of a multicenter observational study of children aged 1week to 18years admitted to 14 pediatric intensive care units (PICUs) with septic shock and residual serum available for renin + prorenin measurement. Primary outcomes were development of severe persistent AKI (≥ KDIGO stage 2 for ≥ 48h) in the first week and 28-day mortality. Among 233 patients, day 1 median renin + prorenin concentration was 3436pg/ml (IQR 1452-6567). Forty-two (18%) developed severe persistent AKI and 32 (14%) died. Day 1 serum renin + prorenin predicted severe persistent AKI with an AUROC of 0.75 (95% CI 0.66-0.84, p < 0.0001; optimal cutoff 6769pg/ml) and mortality with an AUROC of 0.79 (95% CI 0.69-0.89, p < 0.0001; optimal cutoff 6521pg/ml). Day 3/day 1 (D3:D1) renin + prorenin ratio had an AUROC of 0.73 (95% CI 0.63-0.84, p < 0.001) for mortality. On multivariable regression, day 1 renin + prorenin > optimal cutoff retained associations with severe persistent AKI (aOR 6.8, 95% CI 3.0-15.8, p < 0.001) and mortality (aOR 6.9, 95% CI 2.2-20.9, p < 0.001). Similarly, D3:D1 renin + prorenin > optimal cutoff was associated with mortality (aOR 7.6, 95% CI 2.5-23.4, p < 0.001). Children with septic shock have very elevated serum renin + prorenin concentrations on PICU admission, and these concentrations, as well as their trend over the first 72h, predict severe persistent AKI and mortality. A higher resolution version of the Graphical abstract is available as Supplementary information.

Abstract ObjectiveThrombosis is a major complication after cardiac surgery in children with congenital heart disease (CHD). The mechanisms underlying thrombosis development remain poorly understood. We aimed to identify novel circulating metabolites before cardiac surgery that are associated with the development of thrombosis after surgery in children with CHD.Approach and resultsAll blood samples were drawn right before surgical incision and after the induction of anesthesia, and plasma was separated immediately under 4 °C. Untargeted metabolomic data were measured by Metabolon in plasma from children (age range: 0 days-18 years) with CHD undergoing cardiac surgery. The primary outcome was thrombosis within 30 days of surgery or before discharge. Associations of individual metabolites with thrombosis were assessed with logistic regression with false discovery rate (FDR) correction for multiple comparison and adjustment for clinical characteristics; elastic net regression was used to select a prediction model. Out of 1,115 metabolites measured in samples from 203 children, 776 met the quality control criteria. In total, 26 children (12.8%) developed thrombosis. Among the 776 metabolites, 195 were significantly associated with thrombosis (FDR q-value &lt; 0.05). The top three metabolites showing the strongest associations with thrombosis were eicosapentaenoate, steroid monosulfate C19H28O6S, and formiminoglutamate (FDR = 0.01 for all). Pathway analysis showed that the pathways of nicotinate and nicotinamide metabolism (P = 0.0007) and glycerophospholipid metabolism (P = 0.002) were enriched and had significant impacts on the development of thrombosis. In elastic net regression analysis, the area under the receiver operating-characteristic curve of a prediction model for thrombosis was 0.94 in the training sample (70% of the total sample) and 0.84 in the testing sample (the remaining 30%).ConclusionWe have identified promising novel metabolites and metabolic pathways associated with thrombosis. Future studies are warranted to confirm the findings and examine the mechanistic pathways to thrombosis.