Cincinnati Children Research Articles

Prevalence of delayed puberty and low bone density in patients with epidermolysis bullosa: Insight from a large single center's experience.

Epidermolysis bullosa (EB) is a group of rare genetic skin conditions that result in skin fragility. EB can be quite severe with chronic inflammation and malnutrition impairing growth and pubertal development. These factors have potential consequences for skeletal health. We aimed to determine the prevalence of delayed puberty and low bone mineral density (BMD) for age in children and young adults with EB. Electronic medical records (EMR) of patients with confirmed EB <30 years of age at time of initial encounter at Cincinnati Children's Hospital Medical Center between January 1, 2010 and September 30, 2020 were reviewed. Natural language processing software was used to categorize pubertal status of patients with EB as early, normal or delayed. BMD was measured by dual energy x-ray absorptiometry and categorized as low if height adjusted Z-score was <-2.0 using age, sex and race specific reference ranges. 29% of individuals with EB had low BMD with most cases occurring prior to 10 years of age. Of patients who reached adolescence, 23% failed to develop any signs of puberty in the normal range (before age 13 in females or 14 in males) and BMD Z-scores further declined in these individuals. Delayed puberty is an under-recognized comorbidity of individuals with EB, especially in those with recessive dystrophic EB, and can have a significant impact on BMD.

Using deep learning and electronic health records to detect Noonan syndrome in pediatric patients

PurposeThe variable expressivity and multisystem features of Noonan syndrome (NS) make it difficult for patients to obtain a timely diagnosis. Genetic testing can confirm a diagnosis, but underdiagnosis is prevalent owing to a lack of recognition and referral for testing. Our study investigated the utility of using electronic health records (EHRs) to identify patients at high risk of NS. MethodsUsing diagnosis texts extracted from Cincinnati Children’s Hospital’s EHR database, we constructed deep learning models from 162 NS cases and 16,200 putative controls. Performance was evaluated on 2 independent test sets, one containing patients with NS who were previously diagnosed and the other containing patients with undiagnosed NS. ResultsOur novel method performed significantly better than the previous method, with the convolutional neural network model achieving the highest area under the precision-recall curve in both test sets (diagnosed: 0.43, undiagnosed: 0.16). ConclusionThe results suggested the validity of using text-based deep learning methods to analyze EHR and showed the value of this approach as a potential tool to identify patients with features of rare diseases. Given the paucity of medical geneticists, this has the potential to reduce disease underdiagnosis by prioritizing patients who will benefit most from a genetics referral.

Pancreatitis in the Complex Care Population: Presentation, Incidence, and Severity.

To describe the incidence and presentation of pancreatitis in Children with Medical Complexity (CMC) while evaluating severity of disease and outlining risk factors. This was a retrospective chart review between January 2010 and December 2019 of patients seen in the complex care clinic at Nationwide Children's Hospital (NCH) and Cincinnati Children's Hospital Medical Center (CCHMC). Data collected included sex, underlying diagnosis, family history of pancreatitis, type of pancreatitis, signs/symptoms, abdominal imaging, severity of attack, and presence of various risk factors associated with pancreatitis. Severity and diagnosis of pancreatitis was determined based on North American Society for Pediatric Gastroenterology, Hepatology and Nutrition criteria. One hundred and twelve patients from both institutions were included, 62% from NCH, median age 11.5 [interquartile range (IQR): 5-16 years], 50% male. Most patients were less than 18 years of age with a median age of 8 years (IQR: 4-13 years). Underlying diagnoses included seizures (67%), cerebral palsy/spastic quadriplegia (65%), diabetes (3.6%), and mitochondrial disease (3%). Majority of patients were found to have multiple underlying diagnoses (88%). Incidence of pancreatitis for both institutions was 336 of 100,000 patients/year which is significantly higher than the general pediatric population ( P < 0.0001). Majority of first episodes of pancreatitis were mild (82%) with abdominal pain as the predominant symptom (50%). Adult patients were more likely to have pancreatitis related to medication use than pediatric patients (70% vs 38%, respectively P = 0.007). Individuals in the CMC population at our institutions have a high incidence of pancreatitis with unique risk factors compared to the general pediatric/young adult populations.

First Author Spotlight

AnnouncementFirst Author SpotlightPublished Online:09 Sep 2022https://doi.org/10.1152/ajprenal.2022.323.3.AUMoreSectionsPDF (285 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat RAWAN ALMUTLAQCardiorenal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AlabamaFigure 1.Rawan AlmutlaqDownload figureDownload PowerPointRawan Almutlaq is a PhD student in the Department of Integrative Biology and Physiology at the University of Minnesota, mentored by Dr. Louise Evans. She earned her BS in Biochemistry from King Abdulaziz University and her MS in Biotechnology from the University of Alabama at Birmingham. Her research interest focuses on salt-sensitive hypertension. In her spare time, she likes to bake [Photo: Fig. 1].https://doi.org/10.1152/ajprenal.00055.2022DENISE C. HASSONDivision of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioFigure 2.Denise HassonDownload figureDownload PowerPointDenise Hasson was born and raised in a suburb of Los Angeles, CA. She graduated from Dartmouth College and then earned her medical degree at Keck School of Medicine at the University of Southern California. She completed an Internal Medicine-Pediatrics Residency at the University of Colorado Hospital/Children's Hospital Colorado. She moved to Cincinnati, OH, to pursue research mentorship from Dr. Steve Standage, Dr. Hector Wong, and Dr. Stuart Goldstein in the laboratory of Dr. Steve Standage at Cincinnati Children's Hospital Medical Center. She finished a Pediatrics Critical Care Fellowship and a Critical Care Nephrology Fellowship. Her research interests focus on the improvement of pediatric acute kidney injury outcomes with a translational approach to nutritional/metabolic optimization. She has accepted a position as a Clinical Assistant Professor in the Department of Pediatrics at NYU Langone Health/NYU Grossman School of Medicine. Denise enjoys traveling, biking, swimming, and she is a loyal Dodgers fan [Photo: Fig. 2].https://doi.org/10.1152/ajprenal.00033.2022SOPHIA M. SEARSDepartment of Pharmacology and Toxicology, University of Louisville, Louisville, KentuckyFigure 3.Sophia SearsDownload figureDownload PowerPointSophia Sears recently earned her PhD in Pharmacology and Toxicology from the University of Louisville. During her graduate studies, she was awarded an F31 predoctoral fellowship from the National Institute of Diabetes and Digestive and Kidney Diseases under the mentorship of Dr. Leah Siskind. She then became a postdoctoral associate in Dr. Siskind's laboratory. Her research interests include chronic kidney disease and inflammation. In her spare time, she enjoys exercising and playing with her dog [Photo: Fig. 3].https://doi.org/10.1152/ajprenal.00097.2022This article has no references to display. Download PDF Back to Top Next FiguresReferencesRelatedInformationRelated ArticlesAromatase inhibition increases blood pressure and markers of renal injury in female rats 23 Aug 2022American Journal of Physiology-Renal PhysiologyCholine supplementation attenuates experimental sepsis-associated acute kidney injury 17 Aug 2022American Journal of Physiology-Renal PhysiologyPharmacological inhibitors of autophagy have opposite effects in acute and chronic cisplatin-induced kidney injury 17 Aug 2022American Journal of Physiology-Renal Physiology More from this issue > Volume 323Issue 3September 2022Pages i-i Crossmark Copyright & PermissionsCopyright © 2022 the American Physiological Society.https://doi.org/10.1152/ajprenal.2022.323.3.AUHistory Published online 9 September 2022 Published in print 1 September 2022 Metrics

Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations.

Mutations in the SF3B1 splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood. RNA-seq data from SF3B1 mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 (IRAK4) isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in preclinical models of MDS/AML. RNA-seq splicing analysis of SF3B1 mutant MDS samples revealed retention of full-length exon 6 of IRAK4, a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteasomal degradation. Expression of IRAK4-long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models. SF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models. This work was supported by Cincinnati Children's Hospital Research Foundation, Leukemia Lymphoma Society, and National Institute of Health (R35HL135787, RO1HL111103, RO1DK102759, RO1HL114582), Gabrielle's Angel Foundation for Cancer Research, and Edward P. Evans Foundation grants to DTS. AV is supported by Edward P. Evans Foundation, National Institute of Health (R01HL150832, R01HL139487, R01CA275007), Leukemia and Lymphoma Society, Curis and a gift from the Jane and Myles P. Dempsey family. AP and JB are supported by Blood Cancer UK (grants 13042 and 19004). GC is supported by a training grant from NYSTEM. We acknowledge support of this research from The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health Contract C34874GG. MS is supported by a National Institute of Health Research Training and Career Development Grant (F31HL132420).

Brief Report: Telehealth Satisfaction Among Caregivers of Pediatric and Adult Psychology and Psychiatry Patients with Intellectual and Developmental Disability in the Wake of Covid-19.

Telehealth has been shown to be both acceptable and effective in many areas of healthcare, yet it was not widely adopted prior to the SARS-CoV-2 (COVID-19) pandemic. Additionally, previous evaluations of telehealth for autism spectrum condition (ASC) and intellectual and developmental disability (IDD) populations are limited in both number and scope. Here, we investigated satisfaction amongst Psychology and Psychiatry patient caregivers at Cincinnati Children’s Hospital Medical Center (CCHMC) after the onset of the COVID-19 pandemic. Results (640 responses) showed high rates of satisfaction across departments, appointment types, and diagnoses, with 92% indicating overall satisfaction with their appointment. There were, however, notable decreases in satisfaction among Group Therapy respondents, and those whose diagnosis was classified as Other.

Understanding racial disparities in childhood asthma using individual- and neighborhood-level risk factors

Racial disparities in childhood asthma outcomes result from a complex interplay of individual- and neighborhood-level factors. We sought to examine racial disparities in asthma-related emergency department (ED) visits between African American (AA) and European American (EA) children. This is a retrospective study of patients younger than 18 years who visited the ED at Cincinnati Children's for asthma from 2009 to 2018. The outcome was number of ED visits during a year. We assessed 11 social, economic, and environmental variables. Mediation and mixed-effects analyses were used to assess relationships between race, mediators, and number of ED visits. A total of 31,114 children (46.1% AA, 53.9% EA) had 186,779 asthma-related ED visits. AA children had more visits per year than EA children (2.23 vs 2.15; P< .001). Medicaid insurance was associated with a 7% increase in rate of ED visits compared with commercial insurance (1.07; 95% CI, 1.03-1.1). Neighborhood socioeconomic deprivation was associated with an increased rate of ED visits in AA but not in EA children. Area-level particulate matter with diameter less than 2.5 μm, pollen, and outdoor mold were associated with an increased rate of ED visits for both AA and EA children (all P< .001). Associations between race and number of ED visits were mediated by insurance, area-level deprivation, particulate matter with diameter less than 2.5 μm, and outdoor mold (all P< .001), altogether accounting for 55% of the effect of race on ED visits. Race was not associated with number of ED visits (P= .796) after accounting for mediators. Racial disparities in asthma-related ED visits are mediated by social, economic, and environmental factors, which may be amenable to interventions aimed at improving outcomes and eliminating inequities.

Frequency and Severity of Hypothyroidism During TKI Therapy in the Pediatric and Young Adult Population.

Tyrosine kinase inhibitors that target vascular endothelial growth factor receptor [VEGFR-TKI] are a class of targeted therapies approved for treatment of several malignancies and are increasingly used in the pediatric population. Development of hypothyroidism during VEGFR-TKI therapy is well described in adults; however, there are no available data in children. Importantly, hypothyroidism during childhood can negatively impact growth and neurodevelopment. This retrospective study is the first to document frequency and severity of VEGFR-TKI induced hypothyroidism in pediatric and young adult patients. Patients included were ≤25 years of age and treated with at least one VEGFR-TKI between 2010 and 2018 at Cincinnati Children's Hospital Medical Center. After review of clinical and demographic data, 69 patients were identified. Of these, 19 (27.5%) developed thyroid dysfunction defined as Thyroid-stimulating hormone≥5mIU/mL during therapy. Twelve of those patients had overt hypothyroidism with documentation of low free thyroxine and/or levothyroxine initiation. Mean exposure time to VEGFR-TKI before thyroid dysfunction was 2.8 (0.5-10.4) months. These results suggest moderate risk of developing thyroid dysfunction during VEGFR-TKI therapy in pediatric and young adult patients. Baseline thyroid hormone screening should be performed and repeated frequently during the first year of therapy in the pediatric population.

Factors Associated With Fertility Preservation in a Pediatric, Adolescent and Young Adult Population.

To determine the patient characteristics associated with pursuing fertility preservation (FP) before gonadotoxic therapy in a pediatric, adolescent and young adult patient population. This is a retrospective cohort study of patient data at Cincinnati Children's Hospital Medical Center. Demographics, clinical diagnoses, and treatment characteristics were compared between participants that selected FP versus those that declined. Variables were analyzed separately for males and females by logistic regression. Patients with a hematologic cancer were less likely to be eligible for preservation: 53.9% of ineligible males, P <0.001, and 51.8% of ineligible females, P <0.0001. Among patients who were candidates for FP, those receiving high-risk therapy were more likely to elect for FP (65.3% males, P <0.0001, and 87.5% of females, P <0.0001). Pubertal males were more likely to undergo preservation than prepubertal males (70.5% vs. 29.5%, P <0.0001; however, this trend was not demonstrated among female patients. In both males and females, race, ethnicity, religion, primary language, and insurance status were not shown to be statistically significant factors in predicting utilization of FP. Risk of infertility, type of cancer, and developmental status influenced decisions on pursuing FP in pediatric, adolescent and young adult patients facing iatrogenic infertility.

'Form fruste' Aortoventricular Tunnel: Preoperative Computed Tomographic Virtual Dissection Defines This Unusual Variant.

HomeCirculation: Cardiovascular ImagingVol. 15, No. 9‘Form fruste’ Aortoventricular Tunnel: Preoperative Computed Tomographic Virtual Dissection Defines This Unusual Variant No AccessCase ReportRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialNo AccessCase ReportRequest AccessFull Text‘Form fruste’ Aortoventricular Tunnel: Preoperative Computed Tomographic Virtual Dissection Defines This Unusual Variant Justin T. Tretter, MD, Eric J. Crotty, MD and David G. Lehenbauer, MD Justin T. TretterJustin T. Tretter Correspondence to: Justin T. Tretter, MD, Pediatric and Congenital Heart Center, Cleveland Clinic, 9500 Euclid Ave, M-41, Cleveland, OH, 44195. Email E-mail Address: [email protected] https://orcid.org/0000-0001-8926-3752 Department of Pediatrics, Cincinnati Children’s Hospital Medical Center (J.T.T.), Heart Institute, University of Cincinnati College of Medicine, OH. Search for more papers by this author , Eric J. CrottyEric J. Crotty Department of Radiology, Cincinnati Children’s Hospital Medical Center, OH (E.J.C.). Search for more papers by this author and David G. LehenbauerDavid G. Lehenbauer https://orcid.org/0000-0001-7417-727X Department of Surgery, Division of Cardiothoracic Surgery (D.G.L.), Heart Institute, University of Cincinnati College of Medicine, OH. Search for more papers by this author Originally published8 Jul 2022https://doi.org/10.1161/CIRCIMAGING.122.014092Circulation: Cardiovascular Imaging. 2022;15FootnotesSupplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.122.014092.For Sources of Funding and Disclosures, see page 693 & 694.Correspondence to: Justin T. Tretter, MD, Pediatric and Congenital Heart Center, Cleveland Clinic, 9500 Euclid Ave, M-41, Cleveland, OH, 44195. Email [email protected]org

Baricitinib in COVID-19: a coming-of-age from artificial intelligence to reducing mortality

Baricitinib in COVID-19: a coming-of-age from artificial intelligence to reducing mortality

Adaptive Hearing Aid Benefit in Children With Mild/Moderate Hearing Loss: A Registered, Double-Blind, Randomized Clinical Trial.

We completed a registered double-blind randomized control trial to compare acclimatization to two hearing aid fitting algorithms by experienced pediatric hearing aid users with mild to moderate hearing loss. We hypothesized that extended use (up to 13 months) of an adaptive algorithm with integrated directionality and noise reduction, OpenSound Navigator (OSN), would result in improved performance on auditory, cognitive, academic, and caregiver- or self-report measures compared with a control, omnidirectional algorithm (OMNI). Forty children aged 6 to 13 years with mild to moderate/severe symmetric sensorineural hearing loss completed this study. They were all experienced hearing aid users and were recruited through the Cincinnati Children's Hospital Medical Center Division of Audiology. The children were divided into 20 pairs based on similarity of age (within 1 year) and hearing loss (level and configuration). Individuals from each pair were randomly assigned to either an OSN (experimental) or OMNI (control) fitting algorithm group. Each child completed an audiology evaluation, hearing aid fitting using physically identical Oticon OPN hearing aids, follow-up audiological appointment, and 2 research visits up to 13 months apart. Research visit outcome measures covered speech perception (in quiet and in noise), novel grammar and word learning, cognition, academic ability, and caregiver report of listening behaviors. Analysis of outcome differences between visits, groups, ages, conditions and their interactions used linear mixed models. Between 22 and 39 children provided useable data for each task. Children using the experimental (OSN) algorithm did not show any significant performance differences on the outcome measures compared with those using the control (OMNI) algorithm. Overall performance of all children in the study increased across the duration of the trial on word repetition in noise, sentence repetition in quiet, and caregivers' assessment of hearing ability. There was a significant negative relationship between age at first hearing aid use, final Reading and Mathematical ability, and caregiver rated speech hearing. A significant positive relationship was found between daily hearing aid use and study-long change in performance on the Flanker test of inhibitory control and attention. Logged daily use of hearing aids related to caregiver rated spatial hearing. All results controlled for age at testing/evaluation and false discovery rate. Use of the experimental (OSN) algorithm neither enhanced nor reduced performance on auditory, cognitive, academic or caregiver report measures compared with the control (OMNI) algorithm. However, prolonged hearing aid use led to benefits in hearing, academic skills, attention, and caregiver evaluation.

A Large Naturalistic Study on the BRACHA: Confirmation of the Predictive Validity.

Aggression is a major challenge on child/adolescent inpatient psychiatric units. A screening instrument to accurately identify risk is urgently needed. To determine the predictive validity of the Brief Rating of Aggression by Children and Adolescents (BRACHA). Prospective cohort study.BRACHA is administered by clinical staff in the emergency department (ED) prior to inpatient psychiatric admission.A consecutive sample of 10,054 admitted patients from 2010-2021. No patients refused screening nor were excluded.BRACHA administered to patients in the ED prior to admission at Cincinnati Children's Hospital Medical Center (CCHMC).Patient behavioral outcomes measured by Overt Aggression Scale (OAS), categorizing aggression as verbal or physical, then as towards self, others, or objects.Female patients comprised 53.6% (n = 5,386) of the sample. Most patients were white (n = 6,556, 65.2%). Patients ranged in age from 4 to 18years, with a mean age of 13.6 ± 3.1years. A single biological parent (n = 5,317, 52.9%) was the predominant living arrangement among patients. The Area Under the Curve (AUC), as an assessment of predictive validity across all possible cut-offs of BRACHA scores ranged from 0.640 (aggression to self) to 0.758 (physical aggression towards others).Our findings support the BRACHA as a useful predictive instrument for aggression in inpatient psychiatric admissions from ED regardless of length of stay. Treating staff are then able to immediately classify risk level and inform care plans for all lengths of hospitalization. Applies to potential risk for aggression, except for self-aggression. Future data analyses will evaluate demographic factors to determine which improve predictive power of the BRACHA and can be used to create a BRACHA calculator. To our knowledge, this naturalistic outcomes study is one of the largest in psychiatry. The BRACHA will continue to be studied to evaluate risk for aggression on inpatient units and aim to assist in keeping unit staff and patients safe.

Prednisone and deflazacort in Duchenne muscular dystrophy: a patient perspective and plain language summary publication of the Cincinnati study.

This is a summary of an article about the Cincinnati study, which was published in the Journal of Comparative Effectiveness Research in January 2020. The Cincinnati study reviewed data from 435 males with Duchenne muscular dystrophy, also known as DMD, who were treated at the Cincinnati Children's Hospital Medical Center. DMD is a rare disease that worsens over time. People with DMD experience inflammation in their muscles and muscle loss over time. They also experience bone problems such as an abnormally bent spine, also known as scoliosis, as well as heart and lung problems. Prednisone and deflazacort are steroids that help to reduce muscle inflammation and are used as treatments for DMD. The study researchers wanted to further understand the differences between using prednisone and deflazacort in males with DMD by reviewing data from past medical records of patients seen in clinics rather than in clinical studies. This is known as gathering real-world evidence. In the Cincinnati study, the researchers compared males with DMD who started taking prednisone as their first steroid treatment with males who started taking deflazacort as their first steroid treatment. Overall, the researchers found that the participants who took deflazacort were able to walk until a later age before they needed to use a wheelchair, compared with those who took prednisone. They also had a lower risk of scoliosis and developed it at a later age. These results helped the researchers to learn more about the differences between how well prednisone and deflazacort work in males with DMD based on their medical records.

Defining Normal Ranges of Skeletal Muscle Area and Skeletal Muscle Index in Children on CT Using an Automated Deep Learning Pipeline: Implications for Sarcopenia Diagnosis.

BACKGROUND. Skeletal muscle area (SMA), representing skeletal muscle cross-sectional area at the L3 vertebral level, and skeletal muscle index (SMI), representing height-normalized SMA, can serve as markers of sarcopenia. Normal SMA and SMI values have been reported primarily in adults. OBJECTIVE. The purpose of this study was to use an automated deep learning (DL) pipeline for muscle segmentation on abdominal CT to define normative age- and sex-based values for pediatric muscle cross-sectional area as a guide for diagnosis of sarcopenia in children. METHODS. This retrospective study reviewed records of patients who underwent abdominal CT at Cincinnati Children's Hospital Medical Center from January 1, 2009, to January 3, 2019. Patients were excluded on the basis of age outside of the eligible range (2.00-18.99 years), body mass index (BMI) outside of 5-95% age-based percentiles using CDC and WHO growth charts, known medical condition, medication use, support devices, surgery, or missing axial images at the L3 level. A previously validated automated DL pipeline was used to identify an axial slice at L3 and segment skeletal muscle to generate SMA and SMI. Pearson correlation coefficients were computed. Quantile regression analysis was used to plot SMA and SMI as functions of age and sex and to determine age- and sex-based percentile values. RESULTS. Of 8817 patients who underwent abdominal CT during the study period, 2168 (mean age, 12.3 ± 4.3 [SD] years; 1125 female patients, 1043 male patients) met inclusion criteria. Mean BMI-for-age percentile based on CDC and WHO growth charts was 64.8% ± 25.3% for female patients and 61.4% ± 25.8% for male patients. SMA showed strong correlation with weight, height, age, and BMI for male (0.79-0.94) and female (0.75-0.90) patients; SMI showed weak-to-moderate correlation with weight, height, age, and BMI for male (0.25-0.57) and female (0-0.43) patients. Normal SMA and SMI ranges for age and sex were expressed as curves and as a lookup table, identifying 54 male and 59 female patients with muscle measurements below the 5th percentile regression curve. CONCLUSION. By using an automated DL pipeline in a large sample of carefully selected children, normal ranges for SMA and SMI were calculated as functions of age and sex. CLINICAL IMPACT. The normative values should aid the diagnosis of sarcopenia in children.

QOL-23. Expanded protocols for hearing loss related cisplatin-based therapy in childhood cancer patients.

Abstract BACKGROUND: Most children who require cisplatin chemotherapy incur hearing loss. The basal end of the cochlea, corresponding to high frequency sound perception, is typically affected first, with progression along the basilar membrane and to lower frequencies over time. Typical audiologic protocols for children are often restricted to the speech frequencies (500-4000Hz). However, reliable responses to higher frequencies can be obtained using specialized electrophysiologic measures or adapted behavioral test procedures, which may lead to earlier identification of hearing loss during ototoxicity monitoring. METHODS: Auditory Brainstem Response (ABR) and behavioral threshold assessments were completed for patients during cisplatin treatment at Cincinnati Children’s Hospital between 2017 and 2021. High frequency ABR protocols were established to include 6000 and 8000 Hz and behavioral testing protocols were expanded to include frequencies 8000 through 16000 Hz. Hearing loss was defined as &amp;gt;20 dB eHL at any frequency. The typical and high frequency protocols were compared to determine if higher frequency measurement provides a more sensitive means to detect the onset of hearing loss. RESULTS: One-hundred and fifty-three patients receiving cisplatin were assessed audiometrically. For patients who required ABR evaluations, 38% were identified with hearing loss when using the typical test protocol, where 79% of the patients were identified with hearing loss when using the high frequency protocol. For patients who were able to complete behavioral audiometric evaluations, 42% were identified with hearing loss with the typical protocol while 84% were identified with the high frequency protocol. CONCLUSIONS: The addition of higher frequencies to audiologic evaluation protocols for both ABR and behavioral audiometry significantly increases sensitivity to detect hearing loss during ototoxicity monitoring of cisplatin treatment and is a feasible strategy in pediatric cancer patients. Audiologically, the increased sensitivity to detect hearing loss may lead to earlier intervention regarding hearing and communication for the patient/family.

NFB-04. Evaluating focal areas of signal intensity (FASI) in children with neurofibromatosis type-1 (NF1) treated with selumetinib on PBTC-029B

BACKGROUND: Focal Areas of Signal Intensity (FASI) are T2 hyperintense benign lesions in children with NF1. They can mimic the appearance of low-grade glioma (LGG). Selumetinib has shown efficacy in treatment of NF1-associated LGG but treatment effects on FASI have not yet been described. METHODS: Patients with NF1-associated LGG treated with selumetinib on Stratum 3 of PBTC-029B were compared to age-matched untreated children with NF1-associated LGG at Cincinnati Children’s Hospital Medical. FASI were defined by published criteria as T2 hyperintense lesions lacking mass effect, enhancement or T1 hypointensity. Lesion size was determined by cross-product of perpendicular measures in LGG and 1-3 FASI per subject. When multiple FASI were present, the sum of FASI cross-products was used. Change between baseline and the latest available measure within 4 months of control was assessed, insuring that selumetinib-treated subjects were still receiving therapy. RESULTS: Fifteen age-matched pairs were assessed (2.8-16.9 years and 60% were male). Initial FASI size was not different between groups (p=0.98; median [IQR]: 138.7mm2 [88.4-182.0] for treated subjects versus 121.6mm2 [79.6-181.9] for untreated subjects). Lesion change was measured over mean follow up of 18.9 + 5.9 months. Spider plots show decreased LGG size over time during treatment, but there was no consistent change in size among treated or untreated FASI. Comparing FASI size between paired timepoints showed no difference in change from baseline for treated subjects versus for untreated subjects (two-sided test; p=0.08). In subjects who received selumetinib, there was no correlation between change in LGG and change in FASI (r=-0.04, p=0.88). Using RANO criteria for FASI lesions, 2/30 (6.7%) subjects had partial response, 26/30 (86.7%) subjects had stable disease, and 2/30 (6.7%) subjects had progressive disease. CONCLUSIONS: While the sample size was limited, treatment with selumetinib did not reduce overall FASI size in children with NF1 and LGG.

Influence of albumin and methotrexate clearance on high-dose methotrexate-induced mucositis.

e15081 Background: Methotrexate (MTX) is a cornerstone of therapy for several types of cancer. HDMTX-induced mucositis can impact quality of life and delay subsequent chemotherapy. Objective: The objective of this study was to understand the factors increasing risk for mucositis in patients receiving HDMTX in a multicenter cohort. Methods: A multi-center retrospective study collected data on pediatric and young adult patients ages 0-32 years at diagnosis who received at least one dose of HDMTX (&gt;500 mg/m2) at Children’s Healthcare of Atlanta or Cincinnati Children’s Hospital Medical Center from January 2010 through December 2020. Demographic and clinical variables were manually abstracted, while medications and lab values were electronically pulled from the electronic medical record. Common Terminology Criteria for Adverse Events v5 was used to identify the presence and grade of mucositis after HDMTX administration. Institutional review board approval was obtained at each site. Chi-square and t-tests, as appropriate, were calculated using GraphPad Prism v9. MTX concentrations were fit to a published pharmacokinetic model to estimate clearance using NONMEM. Results: The cohort is described in Table. The rate of mucositis was highest after the first HDMTX administration (54.6%), when the MTX clearance is slowest (30.1%&lt;10 L/hr/1.73m2 and albumin was lowest (14.3%&lt;2.5g/dL). Mucositis was significantly more likely in patients with hypoalbuminemia and in patients with MTX clearance &lt;10 L/hr/1.73m2 (OR 1.75 (CI: 1.503 to 2.028), p&lt;0.0001 and OR 1.43 (CI: 1.236 to 1.653), p&lt;0.0001, respectively). Conclusions: Mucositis after administration of HDMTX is common, with 72% of patients experiencing at least grade 1 mucositis and a third of HDMTX administrations leading to mucositis. Chart abstraction is ongoing at a third hospital to increase the sample size, particularly those of Hispanic/Latino ethnicity, in order to investigate differences by race and ethnicity. In addition, current analyses are evaluating the impact of changes in supportive care on HDMTX-induced mucositis and other adverse events. The results of this study will demonstrate who is at highest risk for adverse events so supportive care can be tailored during this potentially toxic chemotherapy.[Table: see text]

1382-P: Novel Mechanisms to Reconvert Glucocorticoids into Pro-Metabolic Agents through Adiponectin

Adiponectin is the most abundant adipokine in our circulation and regulates inter-tissue communication like the adipose-muscle axis. Pharmacological modulation of this crosstalk is beneficial in promoting exercise tolerance in metabolic stress conditions like obesity. Endogenous glucocorticoids regulate metabolic function and stress response, but chronic daily intake of exogenous glucocorticoids produces or exacerbates metabolic stress. However, in stark contrast to daily intake, we discovered that intermittent regimens of glucocorticoids, e.g. once-weekly, improves exercise tolerance. However, the mechanisms underlying the differential regimen-specific effects of glucocorticoids in obesity remain unknown. Here we investigated the mechanisms differentiating once-weekly versus once-daily regimens of the same glucocorticoid prednisone in obesity. In mice with diet-induced obesity, once-weekly prednisone stimulated total and high-molecular weight adiponectin levels, improving exercise tolerance and energy expenditure. These effects were dependent upon adiponectin and were blocked by genetic ablation of the adipokine. Upregulation of Adipoq occurred through the adipose-specific glucocorticoid receptor (GR) , as this effect was blocked in mice with inducible GR ablation in adipose tissue. In contrast, once-daily prednisone decreased adiponectin levels through upregulation of known repressors of adiponectin expression in adipose tissue. The drug regimens remodeled in opposite ways also transcriptome and function in skeletal muscle after onset of obesity. Particularly, once-weekly prednisone treatment increased the muscle metabolic response to adiponectin through the CAMKK2-AMPK cascade. Our study demonstrates that intermittent glucocorticoids produce healthful metabolic remodeling in diet-induced obesity through direct upregulation of adiponectin expression in adipose tissue and adiponectin-dependent signaling in skeletal muscle. Disclosure M.Wintzinger: Employee; Cincinnati Children's Hospital. K.Miz: None. M.Panta: None. H.Durumutla: None. A.Pragasam: None. M.Quattrocelli: None. Funding National Institutes of Health grant DK121875National Institutes of Health grant HL158531CCHMC Trustee AwardCCHMC Heart Institute Translational Grant

Signature for Pain Recovery IN Teens (SPRINT): protocol for a multisite prospective signature study in chronic musculoskeletal pain

IntroductionCurrent treatments for chronic musculoskeletal (MSK) pain are suboptimal. Discovery of robust prognostic markers separating patients who recover from patients with persistent pain and disability is critical for developing patient-specific...