Cincinnati Children's Hospital Medical Research Articles

Development of a multimodal geomarker pipeline to assess the impact of social, economic, and environmental factors on pediatric health outcomes.

We sought to create a computational pipeline for attaching geomarkers, contextual or geographic measures that influence or predict health, to electronic health records at scale, including developing a tool for matching addresses to parcels to assess the impact of housing characteristics on pediatric health. We created a geomarker pipeline to link residential addresses from hospital admissions at Cincinnati Children's Hospital Medical Center (CCHMC) between July 2016 and June 2022 to place-based data. Linkage methods included by date of admission, geocoding to census tract, street range geocoding, and probabilistic address matching. We assessed 4 methods for probabilistic address matching. We characterized 124244 hospitalizations experienced by 69842 children admitted to CCHMC. Of the 55684 hospitalizations with residential addresses in Hamilton County, Ohio, all were matched to 7 temporal geomarkers, 97% were matched to 79 census tract-level geomarkers and 13 point-level geomarkers, and 75% were matched to 16 parcel-level geomarkers. Parcel-level geomarkers were linked using our exact address matching tool developed using the best-performing linkage method. Our multimodal geomarker pipeline provides a reproducible framework for attaching place-based data to health data while maintaining data privacy. This framework can be applied to other populations and in other regions. We also created a tool for address matching that democratizes parcel-level data to advance precision population health efforts. We created an open framework for multimodal geomarker assessment by harmonizing and linking a set of over 100 geomarkers to hospitalization data, enabling assessment of links between geomarkers and hospital admissions.

Bivalirudin Monitoring in Pediatric Ventricular Assist Device and Extracorporeal Membrane Oxygenation: Analysis of Single-Center Retrospective Cohort Data 2018-2022.

The activated partial thromboplastin time (aPTT) is the most frequently used monitoring assay for bivalirudin in children and young adults on mechanical circulatory support including ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO). However, intrinsic variability of the aPTT complicates management and risks bleeding or thrombotic complications. We evaluated the utility and reliability of a bivalirudin-calibrated dilute thrombin time (Bival dTT) assay for bivalirudin monitoring in this population. Retrospective analysis of clinical data (including aPTT, dilute thrombin time [dTT]) and results of residual plasma samples from VAD patients were assessed in two drug-calibrated experimental assays. One assay (Bival dTT) was validated for clinical use in VAD patients, and subsequently used by clinicians in ECMO patients. Pearson correlation and simple linear regression were used to determine R2 correlation coefficients between the different laboratory parameters using Statistical Package for Social Sciences (Armonk, NY). ICUs at Cincinnati Children's Hospital Medical Center. Children on VAD or ECMO support anticoagulated with bivalirudin. None. One hundred fifteen plasma samples from 11 VAD patients were analyzed. Both drug-calibrated experimental assays (anti-IIa and Bival dTT) showed excellent correlation with each other (R2 = 0.94) and with the dTT (R2 = 0.87), but poor correlation with aPTT (R2 = 0.1). Bival dTT was selected for validation in VAD patients. Subsequently, clinically ordered results (105) from 11 ECMO patients demonstrated excellent correlation between the Bival dTT and the standard dTT (R2 = 0.86) but very poor correlation with aPTT (R2 = 0.004). APTT is unreliable and correlates poorly with bivalirudin's anticoagulant effect in ECMO and VAD patients. A drug-calibrated Bival dTT offers superior reliability and opportunity to standardize results across institutions. Additional studies are needed to determine an appropriate therapeutic range and correlation with clinical outcomes.

Reprint of: How He Did It – The James S. Tweddell Approach to Single Ventricle Palliation in Patients With Hypoplastic Left Heart Syndrome

This article will detail Dr. James Tweddell's operative technique and considerations for 26 all three stages of SVP in patients with HLHS. This will include the Norwood Procedure with 27 Right-Ventricle-to-Pulmonary-Artery Conduit (Sano Modification), Bidirectional Glenn 28 (Superior Cavopulmonary Connection), and Extracardiac, Fenestrated Fontan Completion (Total 29 Cavopulmonary Connection). These techniques are the culmination of over 20 years of experience 30 and represent the final techniques he employed at both Children's Hospital of Wisconsin and 31 Cincinnati Children's Hospital Medical Center.

Impact of inflammation and steroids on anti-coagulation in children supported on a ventricular assist device.

Critically ill pediatric patients supported on ventricular assist devices (VADs) are increasingly being anticoagulated on bivalirudin, but with difficulty monitoring anticoagulation. Activated partial thromboplastin time (aPTT) has recently been shown to poorly correlate with bivalirudin plasma concentrations, while dTT had excellent correlation. However, aPTT is the more common monitoring test and dTT testing is rarely used. In addition, effects of frequent clinical VAD scenarios (such as inflammation) on the accuracy of aPTT and dTT testing remains uncertain. We reviewed the effects of clinical scenarios (infection/inflammation, chylothorax, and steroids administration) on anticoagulation monitoring in 10 pediatric VAD patients less than 3years at Cincinnati Children's Hospital Medical Center from 10/27/2020 to 5/6/2022 using bivalirudin for anticoagulation. There were 16 inflammation/infection, 3 chylothorax, and 6 steroids events. Correlation between dTT and aPTT was significantly lower after infection/inflammation, with dTT increasing prior to inflammation/infection while aPTT remained unchanged. In addition, steroids are administered to VAD patients to reduce inflammation and thus additionally stabilize anticoagulation. However, this anticoagulation stabilization effect was reflected more accurately by dTT compared to aPTT. In children requiring VAD support utilizing bivalirudin anticoagulation, inflammation/infection is a common occurrence resulting in anticoagulation changes that may be more accurately reflected by dTT as opposed to aPTT.

The society for craniofacial genetics and developmental biology 46th annual meeting.

The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 46th Annual Meeting at Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio on October 10th-12th, 2023. On the first day of the meeting, Drs. Sally Moody and Justin Cotney were each honored with the SCGDBDistinguished Scientist Awards for their exceptional contributions to the field of craniofacial biology. The following two days of the meeting featured five sessions that highlighted new discoveries in signaling and genomic mechanisms regulating craniofacial development, human genetics, translational and regenerative approaches, and clinical management of craniofacial differences. Interactive workshops on spatial transcriptomics and scientific communication, as well as a poster session facilitated meaningful interactions among the 122 attendees representing diverse career stages and research backgrounds in developmental biology and genetics, strengthened the SCGDB community.

Learning competing risks across multiple hospitals: one-shot distributed algorithms.

To characterize the complex interplay between multiple clinical conditions in a time-to-event analysis framework using data from multiple hospitals, we developed two novel one-shot distributed algorithms for competing risk models (ODACoR). By applying our algorithms to the EHR data from eight national children's hospitals, we quantified the impacts of a wide range of risk factors on the risk of post-acute sequelae of SARS-COV-2 (PASC) among children and adolescents. Our ODACoR algorithms are effectively executed due to their devised simplicity and communication efficiency. We evaluated our algorithms via extensive simulation studies as applications to quantification of the impacts of risk factors for PASC among children and adolescents using data from eight children's hospitals including the Children's Hospital of Philadelphia, Cincinnati Children's Hospital Medical Center, Children's Hospital of Colorado covering over 6.5 million pediatric patients. The accuracy of the estimation was assessed by comparing the results from our ODACoR algorithms with the estimators derived from the meta-analysis and the pooled data. The meta-analysis estimator showed a high relative bias (∼40%) when the clinical condition is relatively rare (∼0.5%), whereas ODACoR algorithms exhibited a substantially lower relative bias (∼0.2%). The estimated effects from our ODACoR algorithms were identical on par with the estimates from the pooled data, suggesting the high reliability of our federated learning algorithms. In contrast, the meta-analysis estimate failed to identify risk factors such as age, gender, chronic conditions history, and obesity, compared to the pooled data. Our proposed ODACoR algorithms are communication-efficient, highly accurate, and suitable to characterize the complex interplay between multiple clinical conditions. Our study demonstrates that our ODACoR algorithms are communication-efficient and can be widely applicable for analyzing multiple clinical conditions in a time-to-event analysis framework.

Impact of a relocation to a new critical care building on pediatric safety events.

Cincinnati Children's Hospital Medical Center (CCHMC) relocated the pediatric, cardiac, and neonatal intensive care units (PICU, CICU and NICU) to a newly constructed critical care building (CCB) in November 2021. Simulation and onboarding sessions were implemented before the relocation, aimed at mitigating latent safety threats. To evaluate the impact of ICU relocation to the CCHMC CCB on patient safety as measured by the quantity, rate, severity score, and category of safety reports. This retrospective, cross-sectional, observational study compared safety reports filed in a 90-day period before and following the CCB relocation. The primary outcome was pre- and postrelocation safety report rates per 100 patient-days. Secondary outcomes included safety report severity, category, and rate of hospital acquired conditions (HACs). Total safety report incidence increased by 16% across all ICUs postrelocation with no difference in post- versus prerelocation odds ratio between ICUs. Three isolated instances of special cause variation were found, one in NICU and two in CICU. No special cause variation was found in the PICU. There were no statistical differences in assigned safety report severity pre- to postrelocation for all ICUs, and only lab specimen/test related safety reports showed a statistically significant increase postrelocation. Overall rates of HACs were low, with six occurring prerelocation and eight postrelocation. All three ICUs were relocated to the new CCB with minimal changes in the incidence, severity, or category of safety reports filed, suggesting staff training and preparations ahead of the relocation mitigated latent safety threats.

Incidence, risk factors, and management following cardiac catheterization via carotid and axillary artery approaches: A single-center experience on pseudoaneurysms in young infants.

Use of alternate access for complex neonatal interventions has gained acceptance with carotid and axillary artery access being used for ductal and aortic interventions. This study was a retrospective, single-center study at Cincinnati Children's Hospital Medical Center. The study included infants, aged ≤90 days, who underwent cardiac catheterization with either carotid or axillary artery access between 2013 and 2022. Data encompassing demographics, clinical information, catheterization data, and the incidence of pseudoaneurysm as a procedural complication were collected. Among 29 young infants (20 males, 69%), 4 out of 15 patients (27%) who underwent the carotid approach developed pseudoaneurysms, while 1 out of 14 patients (7.1%) who underwent the axillary approach developed one. Two patients required transcatheter intervention due to enlargement of pseudoaneurysms, involving the placement of transarterial flow-diverting stent and occlusion of left common carotid artery. Longer sheath in-to-out time (135 vs. 77 min, p = 0.001), and higher closing activated clotting times (ACT) (268 vs. 197 s, p = 0.021) were observed among patients with pseudoaneurysms compared to those without. Young infants with alternative access via the carotid and axillary arteries may be at risk of pseudoaneurysm formation during longer procedures and with higher ACTs for closure. Ultrasound-guided compression can be employed to prevent the progression and in resolution of these lesions.

The Phenotype of a Bone Marrow Transplant Nurse: Survival of the Fittest

There is a need for proficient nursing practice in specialized critical care settings, such as a pediatric Bone Marrow Transplant (BMT) Unit. The staffing crisis continues to be problematic for areas around the country. Nursing tenure has been positively correlated with improving patient outcomes and confidence in giving care, so efforts must be made to retain pediatric BMT nurses. The purpose of this study was to investigate factors of resilience and how it pertains to the retention of pediatric BMT nurses through 1) Understanding current BMT nursing turnover and trend why nurses are leaving; 2) Measure resilience throughout BMT nursing cohort, covering all tenure of nurses; and 3) Interview senior nurses within the cohort to identify themes relating to retention and resilience using grounded theory methodology. This research was carried out in the Bone Marrow Transplant (BMT) Unit at Cincinnati Children's Hospital Medical Center (CCHMC). The study spanned from 2014 to 2019, during which researchers gathered extensive data to evaluate the turnover risk among BMT nurses. A detailed follow-up was conducted in 2019 to further assess this risk. To measure resilience levels, a group of 115 nurses in the unit completed the Connor Davidson Resilience Scale (CD-RISC). Additionally, in-depth interviews were conducted with nine senior nurses in the cohort, continuing until theoretical saturation was reached, ensuring a comprehensive understanding of the factors influencing nurse turnover in the unit. Researchers looked retrospectively at nursing turnover from 2014-2019. Investigators determined the risk of new nurses leaving was between 22 and 24 months (HR 0.025). Further, follow-up was conducted for data points between 2019-present time, which showed a drastic change in the hazard rate curvature. However, the risk remained relatively the same at 22-24 months (HR 0.03). There was no statistical significance found between CD-RISC results and age (p=0.465), gender (p=0.725), working experience (p=0.15), or education (p=0.14). Through a constant comparative process, several themes were identified as positive, negative, and ambiguous contributions to the retention of nurses. The risk of nurses leaving after two years decreases significantly; therefore, we determined that a nurse with a commitment to pediatric BMT occurs with two years' experience. Although our initial hypothesis was that senior nurses had greater resilience than less tenured nurses, there was no statistical significance as the effect of resilience is small. However, we identified several additional factors pertinent to the pediatric BMT field which may be associated with nursing retention.

Red cell abnormalities characterized by ektacytometry in children with cholestasis.

Spur-cell anemia sometimes accompanies cholestasis. We postulated that even in the absence of spur-cells, cholestasis might alter red blood cell (RBC) osmotic fragility and deformability. Therefore, we assessed these RBC measures by ektacytometry in pediatric patients. We conducted a single center, prospective, cross-sectional investigation of RBC membrane characteristics by ektacytometry in pediatric patients with intra- and extrahepatic cholestasis followed at Cincinnati Children's Hospital Medical Center. We measured red cell membrane fragility and deformability in 17 patients with cholestasis and 17 age-matched controls without cholestasis. Patients with cholestasis had decreased RBC osmotic fragility compared to controls, with a significant left shift in Omin, indicating increased RBC surface-to-volume ratio. One showed spur cell morphology. However, the other 16 had no spurring, indicating that ektacytometry is a sensitive method to detect RBC membrane abnormalities. Left shift of Omin positively correlated with serum conjugated bilirubin levels and even more negatively with serum vitamin E concentration. This study suggests that subclinical red blood cell membrane abnormalities exist in most pediatric patients with cholestasis, increasing risk for hemolysis when subjected to oxidative stress. Hence minimizing pro-oxidants exposure and maximizing antioxidant exposure is advisable for this group. NCT05582447 https://clinicaltrials.gov/ct2/show/NCT05582447?cond=Cholestasis&cntry=US&state=US%3AOH&city=Cincinnati&draw=2&rank=2 . Spur cell anemia due to decreased red cell osmotic fragility and decreased deformability has been reported among patients with cholestasis. Ektacytometry is a reliable, reproducible method to measure red cell osmotic fragility and deformability. Few data describe red cell osmotic fragility or deformability in patients with cholestasis who may or may not have spur cell anemia. Ektacytometry shows that red cell osmotic fragility and deformability are decreased in many children with cholestasis even when spur cell anemia has not yet occurred. Factors associated with decreased osmotic fragility include elevated serum bilirubin, elevated serum bile acids, and decreased serum vitamin E.

Patterns of Nonadherence to Hydroxyurea in Pediatric Sickle Cell Disease

Background: Sickle cell disease (SCD) affects an estimated 100,000 American children and adults (CDC, 2017). Hydroxyurea is the first-line disease-modifying treatment for SCD. Daily oral hydroxyurea significantly reduces the frequency of pain and serious medical complications associated with SCD, including dactylitis and acute chest syndrome (Wang et al., 2011). However, adherence to hydroxyurea is less than optimal at 74% among pediatric patients, with 20% of children who are prescribed hydroxyurea taking less than 50% of their prescribed doses (Louiselle et al., 2016). Suboptimal hydroxyurea adherence is associated with increased risk for medical complications, diminished quality of life, and higher health care costs and utilization (e.g., Badawy et al., 2017; Thornburg et al., 2010). Factors associated with hydroxyurea nonadherence in pediatric SCD include female sex, older age, more adherence barriers (e.g., difficulty obtaining refills), lower socioeconomic status, and lower parent treatment knowledge. Purpose: This study aims to characterize trajectories of pediatric hydroxyurea adherence to identify subgroups that may be at highest risk for hydroxyurea nonadherence (e.g., sociodemographic factors), critical time periods for adherence support interventions (e.g., adolescence), and minimal adherence thresholds to optimize hydroxyurea efficacy. Methods: Retrospective chart review across two institutions (i.e., Cincinnati Children's Hospital Medical Center and Nemours Children's Hospital, Delaware) are ongoing. Participants will include patients with SCD ages 2 to 21 years who were prescribed hydroxyurea from March 2007 to February 2017. Researchers are extracting the following data from patient electronic medical records (EMRs) to estimate hydroxyurea adherence: hemoglobin F levels (HbF), mean corpuscular volume (MCV), and absolute neutrophil count (ANC). Additional clinical information will be extracted from patient EMRs including demographic information, SCD genotype, SCD complications, acute care utilization, medical and social complexity, and concomitant medication use. Descriptive statistics will be used to summarize demographic and clinical characteristics of the sample. MCV will be the primary measure of hydroxyurea adherence and Hgb F and ANC will be secondary measures. If the final sample size is sufficiently large, we will conduct group-based trajectory modeling (GBTM) to analyze patterns of hydroxyurea adherence changes over time and identify hydroxyurea adherence trajectory subgroups. Multinomial logistic regression analyses will be used to analyze potential predictors of hydroxyurea adherence trajectory subgroup membership. Results: Preliminary results revealed that as of February 2017, 88% of eligible patients (based on age) were prescribed hydroxyurea.Data from the first 30 completed chart reviews indicates that half of the sample was female (sex assigned at birth), all identified as Black or African American, all but two participants had HbSS, and the mean age 13.0 years ( SD=8.0, range=2.47 to 26.81). Average MCV across an average of 21 time points ( SD=14.2, range=5-74) was 94.3 ( SD=11.2, range=58.4-114.2). As of February 2017, 53% of individuals had MCV values at or above 100. Specifically, 60% of 5-9 year olds, 47% of 10-15 year olds, and 46% of 16+ year olds had MCV values at or above 100. Average Hgb F across an average of 21 time points ( SD=15.3, range=3-81) was 22.9 ( SD=9.3, range=2.6-44.8). As of February 2017, 50% of individuals had HbF values at or above 20.0. Specifically, 55% of 5-9 year olds, 32% of 10-15 year olds, and 55% of 16+ year olds had HbF values at or above 20.0. Average ANC (at non-ill visits) across an average of 20.0 time points ( SD=13.6, range=5-71) was 3,965 ( SD=1,227; range=1,600-6,910). As of February 2017, 31% of individuals had ANC values less than 3,000. Specifically, 20% of 5-9 year olds, 34% of 10-15 year olds, and 30% of 16+ year olds had ANC values less than 3,000. Discussion:Results from this study have the potential to help researchers and clinicians better understand patterns and correlates of hydroxyurea adherence in pediatric SCD patients that can be targeted in future interventions.

Attitudes of Hematologists in the Midwestern United States Toward Evaluating and Managing Thrombosis Risk in Transgender Youth Starting Gender Affirming Hormone Therapy

Background: Transgender and gender nonconforming (TG) youth who are at increased risk of thrombosis may be evaluated by a hematologist to discuss thromboprophylaxis prior to starting gender-affirming hormone therapy (GAHT). However, in the absence of guidelines to inform the delivery of hematologic care to such youth, variations in practice patterns may lead to suboptimal care for these individuals. Aim: Determine hematologists' recommendations about which TG youth should be considered at higher risk of thrombosis, laboratory evaluation and medical management of such youth, and which youth should be referred for hematologic evaluation prior to starting GAHT. Methods: From 6/2022-2/2023, we recruited hematologists caring for patients 13-22 years-old and practicing in the Midwestern U.S. for individual semi-structured interviews. Hematologists were recruited from the institutions in the footprint of the Midwest Transgender Research Collaborative. Interviews assessed demographics, practice characteristics, comfort recommending and prescribing thromboprophylaxis to TG youth, and recommendations for 1) which youth TG youth would be considered at higher risk of thrombosis; 2) laboratory evaluation; 3) recommended thromboprophylactic medication and duration; and 4) which TG youth should undergo hematologic evaluation prior to GAHT. Transcripts were analyzed using team-based framework analysis. The study was IRB approved; informed consent was obtained. Results: Eleven hematologists from 4 academic centers participated. Mean age was 50.5 years (SD 7.2); 9 participants identified as white; 2 were Latino/a. Ten participants had provided care to TG adolescents (13-17 years-old); all 11 had provided care to TG young adults (18-22 years-old). Participants reported on average 2.8 (SD 3.3) TG adolescents and 2.5 (SD 2.9) TG young adults in their practices. Ten participants reported comfort with recommending and prescribing thromboprophylaxis to patients at higher risk of thrombosis starting estrogen for GAHT; counseling about knowledge gaps and engaging in shared decision making were important elements in the process. One participant reported preference for non-medication interventions, such as compression stockings and using lower doses or transdermal formulations of estrogen. There was less consensus around attitudes toward prophylaxis for youth starting testosterone for GAHT: 4 participants reported lower likelihood of recommending thromboprophylaxis due to low risk of thrombosis with testosterone use; 3 participants discussed risk of erythrocytosis/polycythemia due to testosterone use (although there was no consensus on whether prophylaxis would be recommended); 3 participants reported comfort prescribing prophylaxis to youth starting testosterone; and 2 participants reported insufficient knowledge about the thrombotic risks of testosterone. Hematologists reported various factors that would lead to TG youth being considered high risk, as well as recommended lab testing (Table 1). If prophylaxis is needed, 10 participants would recommend a direct anticoagulant, while 1 would recommend aspirin. Five participants anticipated that long term prophylaxis would be needed for the duration of GAHT, while 6 reported duration would be individualized. Ten participants would not recommend against estrogen due to thrombosis risk, emphasizing the importance of gender care and the role of the hematologist in making GAHT as safe as possible. No participant would recommend against testosterone. Participants offered recommendations for which TG youth should be evaluated by a hematologist prior to starting GAHT (Table 2). Conclusion: Overall, hematologists voiced comfort with recommending and prescribing thromboprophylaxis to TG youth at higher risk of thrombosis starting estrogen. However, there was lack of consensus about evaluation of youth at higher risk of thrombosis starting testosterone and whether mitigation of risk would be needed. Developing guidance for gender care teams for which youth should be considered at higher risk of thrombosis and referred for hematologic evaluation would help optimize the safe delivery of gender-affirming hormone care. Additional data and guidance about the thrombosis risks associated with GAHT is needed to better inform hematologic care. Funding: NIH R01HL161153; Cincinnati Children's Hospital Medical Center Gap Funding

Carbonic anhydrase inhibitors limit complications in X-linked retinoschisis.

Carbonic anhydrase inhibitors (CAIs) reduce macular schisis in patients with X-linked retinoschisis (XLRS). The purpose of this study was to determine if CAIs reduce the incidence of complications from XLRS, including macular atrophy, retinal tears, and retinal detachment (RD), the most common causes of vision loss in patients with XLRS. For this retrospective interventional case series, a chart review of patients examined at Cincinnati Children's Hospital Medical Center [CCHMC] and Cincinnati Eye Institute [CEI] between 1/1/2015 and 1/16/2023 was performed. Male patients were included based on genetically-confirmed RS1 or typical clinical presentation with known family history of XLRS with at least two follow-up visits. Twenty-eight patients (56 eyes) with XLRS were included. There were 10 RS1 variants among the 21 genotyped patients. Median age at clinical diagnosis was 10.4 years old (range: 0.4-55.7 years) with median follow-up time of 4.7 years (range: 0.2-38.3 years). Median presenting Snellen visual acuity was 20/60 (logMAR 0.48, range: 0.18-3). In 26 eyes of 15 patients treated with CAIs, median CST pre-treatment was 416 microns (range: 198-701 microns), and median percentage decrease in CST on treatment was 21.8% (range: 0-74.5%) from highest pre-treatment CST. Reduction in CST with CAI use was statistically significant (p = 0.02), but not logMAR VA (p = 0.64). There was no significant difference in CST between patients treated with topical vs. oral CAI (p = 0.95) or between patients with partial or complete CAI adherence (p = 0.60). Ten eyes of seven patients had an RD requiring surgical intervention. No treated eyes developed new macular atrophy, peripheral retinoschisis, retinal tears, or RD; two eyes on topical CAIs had spontaneous resolution of bullous peripheral retinoschisis. During the follow-up period, patients taking CAIs reduced macular schisis and did not experience new complications of macular atrophy, retinal tears, or RD. This is a relatively large cohort with long-term follow-up periods for patients with XLRS. Reduced macular schisis may not require perfect adherence with CAIs. A large, prospective, randomized, controlled clinical trial is needed to determine the potential of CAIs to improve visual function, reduce retinoschisis, and prevent RD.

Genetic counseling clinic model expansion: Impact on access for general genetics clinic.

Cincinnati Children's Hospital Medical Center (CCHMC) implemented a Genetic Counseling Clinic (GCC), where the appointment for a general genetics indication is conducted solely by a genetic counselor (GC). We conducted a retrospective chart review of 211 patient encounters scheduled in the GCC between January 1, 2022 and June 30, 2022 and collected patient demographics, wait time, appointment characteristics, referral indication, and clinical recommendations. To study impact on patient access, we compared patient demographics and appointment characteristics with 912 patient encounters scheduled in the General Genetics Clinic with a geneticist during the same time period. We found that there were not significant differences in patient demographics scheduled in the GCC as compared with the General Genetics Clinic with the exception of insurance type, where patients scheduled in the GCC were more likely to have private insurance. Patients scheduled in the GCC had a significantly shorter wait time, were more likely to complete their appointment, were more often new to the genetics division, and were more likely to be seen via telehealth (audio plus video or audio-only) as compared with patients scheduled in the General Genetics Clinic. The most common indications for patients scheduled in the GCC were post-test counseling (36.0%) followed by pre-test counseling and coordination of testing (22.3%), and first-line testing for autism, intellectual disability, and developmental delay (13.7%). Completed appointments in the GCC often resulted in the GC ordering genetic testing (67.5%). After genetic testing results were received, most patients (72.7%) did not require subsequent follow-up with the genetics division, thereby reducing burden to the medical genetics team. Our GCC increased access to genetic services and allowed GCs and clinical geneticists to better work at the top of their scope of practice.

THU233 Reduction Of Overutilization Of 1,25-Dihydroxyvitamin D

Abstract Disclosure: J. Brown: None. M. Dewan: None. J. Courter: None. A. Spooner: None. J. Treasure: None. K. Kaplan: None. N.A. Crimmins: None. Unnecessary testing may lead to patient harm, inappropriate treatments, and/or increased cost. Per the Endocrine Society, in conjunction with Choosing Wisely, 1,25-dihydroxyvitamin D (1,25-OH D) should not be measured unless a patient has hypercalcemia or decreased kidney function. This study sought to evaluate overutilization of 1,25-OH D at Cincinnati Children's Hospital Medical Center. We queried EPIC for all 1,25 OH vitamin D tests drawn in all patients (inpatient and outpatient) between 01/01/2021 and 12/31/2021. We then cross-referenced each test with all patient ICD10 codes associated with each patient’s chart. Appropriate ordering was defined as the patient having an ICD10 code related to calcium disorders or renal disease (531 codes included, data not shown). Out of a total of 1,057 1,25-OH D tests ordered, we found that only 19.4 percent were in patients whose chart contained a code that clinically would indicate testing. Further analysis showed most of these tests were obtained by psychiatry (22.7%) and community general pediatricians (14.6%) and not by endocrinology (12.5%) or nephrology (2.2%) providers. We will use this as baseline data to design quality improvement interventions to reduce unnecessary ordering of 1,25 OH vitamin D, including an ordering pathway in Epic to provide point of care education and guidance regarding appropriate Vitamin D test selection. In summary, inappropriate ordering of 1,25 vitamin D is common, likely due to misunderstanding of the best test to determine vitamin D sufficiency. Presentation: Thursday, June 15, 2023

An evaluation of clinical presentation and genetic testing approaches for patients with neuromuscular disorders.

Inherited neuromuscular disorders (NMDs) are a large group of genetic conditions characterized by impaired peripheral nerve, motor neuron, neuromuscular junction, or skeletal muscle function. These conditions are also known to have clinical and genetic heterogeneity and variable ages of onset. Clinical evaluation for NMDs has increasingly incorporated molecular genetics. However, genetic testing is complicated by the variety of testing options and the ambiguity of NMD phenotypes. Examining test selection and yield may elucidate testing recommendations and improve the diagnostic journey for these patients. This retrospective chart review evaluated the clinical presentations, genetic testing approaches, and diagnostic outcomes of 155 patients with suspected NMDs at Cincinnati Children's Hospital Medical Center. A total of 262 individual tests were ordered, averaging 1.7 tests per patient. The clinic utilized 26 separate genetic tests, with test yields ranging from 0% to 66%. Overall, 21% of patients received a genetic diagnosis. Of all the clinical findings evaluated, elevated CPK levels with or without muscle weakness were the most informative symptoms correlated with a diagnostic result. This study highlights several genetic testing considerations for NMDs, including the variability of diagnostic outcomes. This knowledge is relevant to clinicians and patients, especially during the pretest counseling and consenting process.

Benralizumab for eosinophilic gastritis: a single-site, randomised, double-blind, placebo-controlled, phase 2 trial

In eosinophilic gastrointestinal diseases, the role of eosinophils in disease pathogenesis and the effect of eosinophil depletion on patient outcomes are unclear. Benralizumab, an eosinophil-depleting monoclonal antibody that targets the interleukin-5 receptor α, might eliminate gastric tissue eosinophils and improve outcomes in eosinophilic gastritis. We aimed to assess the efficacy and safety of benralizumab in patients with eosinophilic gastritis. We conducted a single-site, randomised, double-blind, placebo-controlled, phase 2 trial at Cincinnati Children's Hospital Medical Center (Cincinnati, OH, USA). Individuals aged 12-60 years with symptomatic, histologically active eosinophilic gastritis (peak gastric eosinophil count ≥30 eosinophils per high-power field [eos/hpf] in at least five hpfs) and blood eosinophilia (>500 eosinophils per μL [eos/μL]) were randomly assigned (1:1, block size of four) to benralizumab 30 mg or placebo, stratified by the use of glucocorticoids for gastric disease. Investigators, study staff, and study participants were masked to treatment assignment; statisticians were unmasked when analysing data. Treatments were administered subcutaneously once every 4 weeks for a 12-week double-blind period (three total injections). The primary endpoint was the proportion of patients who achieved histological remission (peak gastric eosinophil count <30 eos/hpf) at week 12. Key secondary endpoints were the changes from baseline to week 12 in peak gastric eosinophil count, blood eosinophil count, eosinophilic gastritis histology (total, inflammatory, and structural feature scores), Eosinophilic Gastritis Endoscopic Reference System (EG-REFS) score, and patient-reported outcome symptom measures (Severity of Dyspepsia Assessment [SODA] and Patient-Reported Outcome Measurement Information System [PROMIS] short-form questionnaire). After the 12-week double-blind period, patients were eligible for entry into two open-label extension (OLE) periods up to week 88, in which all patients received benralizumab. Efficacy was analysed in the intention-to-treat (ITT) population and safety was assessed in all patients who received at least one dose of study drug. The trial was registered on ClinicalTrials.gov, NCT03473977, and is completed. Between April 23, 2018, and Jan 13, 2020, 34 patients were screened, and 26 were subsequently randomly assigned to benralizumab (n=13) or placebo (n=13) and included in the ITT and safety populations (mean age 19·5 years [SD 7·3]; 19 [73%] male patients and seven [27%] female patients). At week 12, ten (77% [95% CI 50 to 92]) of 13 patients who received benralizumab and one (8% [1 to 33]) of 13 who received placebo achieved histological remission (difference 69 percentage points [95% CI 32 to 85]; p=0·0010). Changes from baseline to week 12 were significantly greater in the benralizumab group versus the placebo group for peak gastric eosinophil counts (mean -137 eos/hpf [95% CI -186 to -88] vs -38 eos/hpf [-94 to 18]; p=0·0080), eosinophilic gastritis histology total score (mean -0·31 [-0·42 to -0·20] vs -0·02 [-0·16 to 0·12]; p=0·0016), histology inflammatory score (mean -0·46 [-0·60 to -0·31] vs -0·04 [-0·22 to 0·13]; p=0·0006), and blood eosinophil counts (median -1060 eos/μL [IQR -1740 to -830] vs -160 eos/μL [-710 to 120]; p=0·0044). Changes were not significantly different between the groups for eosinophilic gastritis histology structural score (mean -0·07 [95% CI -0·19 to 0·05] vs 0·03 [-0·09 to 0·15]; p=0·23), EG-REFS score (mean -1·0 [-2·3 to 0·3] vs -0·5 [-2·0 to 1·0]; p=0·62), or in patient-reported outcomes (SODA and PROMIS). During the double-blind period, treatment-emergent adverse events occurred in 11 (85%) of 13 patients in the benralizumab group and six (46%) of 13 in the placebo group; the most common treatment-emergent adverse events were headache (six [46%] vs two [15%] patients), nausea (three [23%] vs two [15%]), and vomiting (two [15%] vs three [23%]). There were no treatment-related deaths. Two patients had serious adverse events (dizziness and rhabdomyolysis in one patient; aspiration in one patient) during the OLE periods, which were considered unrelated to study treatment. Benralizumab treatment induced histological remission, as defined by absence of tissue eosinophilia, in most patients with eosinophilic gastritis. However, the persistence of histological, endoscopic, and other features of the disease suggest a co-existing, eosinophil-independent pathogenic mechanism and the need for broader targeting of type 2 immunity. AstraZeneca and the Division of Intramural Research (National Institute of Allergy and Infectious Diseases, US National Institutes of Health).

Age-related trajectory of bone density in children with intestinal failure: A longitudinal retrospective cohort study.

Longitudinal changes in bone health in children with intestinal failure (IF) are unclear. We aimed to better understand the trajectory of bone mineral status over time in children with IF and identify clinical factors that influence the trajectory. Clinical records of patients attending the Intestinal Rehabilitation Center of Cincinnati Children's Hospital Medical Center between 2012 and 2021 were reviewed. Children diagnosed with IF before age 3 years with at least two lumbar spine dual-energy x-ray absorptiometry scans were included. We abstracted information on medical history, parenteral nutrition, bone density, and growth. We calculated bone density z scores with and without adjustment for height z scores. Thirty-four children with IF met inclusion criteria. Children were shorter than average with a mean height z score of -1.5 ± 1.3. The mean bone density z score was -1.5 ± 1.3 with 25 of the cohort having a z score < -2.0. After height adjustment, the mean bone density z score was -0.42 ± 1.4 with 11% below -2.0. Most dual-energy x-ray absorptiometry scans (60%) had a feeding tube artifact. Bone density z scores increased slightly with age and lower parenteral nutrition dependency and were higher in scans without an artifact. Etiologies of IF, line infections, prematurity, and vitamin D status were not associated with height-adjusted bone density z scores. Children with IF were shorter than expected for age. Deficits in bone mineral status were less common when adjusting for short stature. Etiologies of IF, prematurity, and vitamin D deficiency were not associated with bone density.

Chronic Mucosal Inflammation in Pediatric Intestinal Failure Patients-A Unique Phenomenon.

As intestinal failure (IF) management improves and long-term survival rate increases, its physiological complications have become more apparent. The development of chronic intestinal inflammation resembling inflammatory bowel disease (IBD) in this population has been reported, but the literature describing it in detail is sparse. The present study was designed to characterize children with IF who developed chronic intestinal inflammation and identify the potential predisposing clinical factors. This retrospective study was based on the electronic medical records of pediatric patients seen at the Cincinnati Children's Hospital Medical Center between January 2000 and July 2022. Demographic and medical history data were collected and compared between children with IF that developed chronic intestinal inflammation and children with IF that did not develop chronic intestinal inflammation. During the follow-up period, 23 children were diagnosed with chronic intestinal inflammation. Of these, 12 (52%) were males, with a median age of 4.5 (3-7) years at diagnosis. Nearly one-third of the patients had gastroschisis (31%), followed by necrotizing enterocolitis (26%), and malrotation and volvulus (21.7%). More children in the chronic intestinal inflammation group lacked an ileocecal valve (ICV) and adjoining distal ileum as compared to the short bowel syndrome (SBS)-IF control group (15 patients, 65% vs 8 patients, 33%). Moreover, more children in the chronic intestinal inflammation group had undergone a prior lengthening procedure than the SBS-IF control group (5 patients, 21.7% vs. 0, respectively). SBS patients are at risk of relatively early onset chronic intestinal inflammation. The absence of an ICV (and adjoin ileum) and prior lengthening procedures emerge as factors associated with the risk of IBD in these patients.

The people behind the papers - Kelsey Elliott and Samantha Brugmann.

The genes encoding proteins involved in cilia formation and function are thought to be well conserved, but ciliopathies are associated with a broad range of tissue-specific phenotypes. A new paper in Development investigates differences in ciliary gene expression across different tissues and developmental stages. To hear more about the story, we caught up with first author Kelsey Elliott and her doctoral supervisor Samantha Brugmann, Professor at Cincinnati Children's Hospital Medical Center.