Cincinnati Children's Hospital Medical Center Research Articles

OR07-6 Integrating Targeted Bioinformatic Searches of the Electronic Health Records and Genomic Testing Identifies a Molecular Diagnosis in Three Patients with Undiagnosed Short Stature

Background: Short stature is a common reason for referral to a pediatric endocrinologist. Despite adequate evaluation, a pathological diagnosis is not identified in the vast majority of patients. It is often difficult to determine which of these many patients have an undiagnosed genetic cause. The electronic health record (EHR) improves our ability to identify cohorts of patients with a specific phenotype of interest, and it has become a valued tool for the augmentation of clinical characterization to drive discovery of phenotype-genotype associations. The aim of our study was to assess the feasibility of using dense phenotypic information from the EHR to systematically identify a distinct cohort of patients with short stature who have a high probability of harboring a monogenic etiology for their short stature. Methods/Results: As an initial proof of principle, we chose to focus on patients with Insulin-like growth factor I (IGF-I) resistance. We performed a targeted bioinformatics search of the EHR at three leading pediatric endocrine departments (Boston Children’s Hospital (BCH), Children’s Hospital of Philadelphia (CHOP) and Cincinnati Children’s Hospital Medical Center (CCHMC)). Inclusion criteria were height below -2 SD (for age and sex) and an IGF-I level above the 90thpercentile. Patients with known underlying genetic conditions, other chronic illnesses, or precocious puberty were excluded. All eligible patients were approached by mail or telephone to participate in the study. Whole exome sequencing (WES) was performed on DNA extracted from whole blood or saliva samples from ten patients and their immediate family members. The targeted bioinformatics search identified a total of 234 patients (104 at CCHMC, 64 at CHOP and 62 in BCH). Of these, 39 patients were eligible for recruitment and 10 were successfully recruited for genetic testing. WES identified two novel pathogenic variants in IGF1R including a novel missense variant (p.Val1013Phe) and a maternally inherited single amino acid deletion (p.Thr28del) in two patients. In addition, a third patient was found to have a novel missense variant in CHD2 (p.Val540Phe). Functional analyses confirmed the pathogenicity of the p.Val1013Phe variant, and are ongoing for the other two variants. Conclusion: This novel approach combining bioinformatics and modern genetics successfully led to the identification of a genetic etiology in 3 of 10 patients, giving a yield of 30% including identification of two patients with novel pathogenic mutations in IGFIR. Notably, these patients were otherwise missed clinically as having a genetic condition. Similar algorithms can be designed to identify diverse cohorts of patients likely to have genetic conditions. This approach can be integrated into the EHR to generate best practice advisories to advance our ability to diagnose rare genetic conditions and improve patient care.

Ibrutinib for the Treatment of Chronic Graft Versus Host Disease in Pediatric Patients

Background Ibrutinib, a Bruton's Tyrosine Kinase inhibitor, is FDA approved for the treatment of chronic graft versus host disease (cGVHD) in adults. No data exist for the use of ibrutinib in pediatric patients. Methods We conducted a retrospective review on the use of ibrutinib for cGVHD at Cincinnati Children's Hospital Medical Center (CCHMC). All patients received an initial dose of 250 mg/m2 orally, once daily (max 420 mg), rounded to the nearest 70 mg for ease of administration. The ibrutinib dose was halved if patients were also on a strong concomitant CYP3A4 inhibitor. Responses were measured at 6 months after drug initiation using the 2014 NIH consensus panel response criteria. Plasma IL6 and CXCL9 before and after ibrutinib initiation were analyzed as surrogate markers of effectiveness. Results Twelve patients, median age 11 years (range 3-19), received ibrutinib between August 2017- October 2018 at CCHMC (Figure 1). Chronic GVHD grades were severe (n=8), moderate (n=1) and mild (n=3) at ibrutinib initiation. Ten patients had ≥2 organs involved, with skin being the predominant organ (n=9) followed by lung (n=6) and eyes (n=7). Two patients had steroid dependent cGVHD, while the rest were steroid-refractory. Eight patients were on a median steroid dose of 0.9 mg/kg/day at ibrutinib initiation. Median number of systemic cGVHD medications prior to ibrutinib was 2 (range 1-5). The median dose of ibrutinib was 140 mg (range 70-420 mg) daily, and median duration was 170.5 days (range 28-341 days). Four patients stopped ibrutinib on 28, 41, 54 and 82 days due to adverse events or death and could not be evaluated for 6-month response. Adverse events leading to discontinuation included recurrent fevers without a source (n=1), bleeding mouth sores (n=1), gastrointestinal distress with mouth sores (n= 1) and death due to pneumococcal sepsis(n=1) Of the 8 evaluable patients, 8 achieved a partial response at 6 months. Four of 6 patients with lung involvement had stable (n=2), improved (n=1) or recovered (n=1) lung function at 6 months. One patient had EBV reactivation, and 1 patient developed pneumococcal sepsis despite appropriate prophylactic therapy while on ibrutinib therapy. No fungal infections occurred while on ibrutinib. Additional adverse events reported included thrombocytopenia, neutropenia, muscle spasms and fatigue. Steroids were weaned in 8 patients to 50% of pre-ibrutinib dose (n=5), physiologic steroids (n=2) or discontinued (n=1) by 6 months. A decline in plasma IL-6 and CXCL9 levels was noted in all but one patient (Figure 2A and B). Interestingly, the patient with increasing cytokine levels was the patient discontinued from therapy early for recurrent fevers. Conclusion Ibrutinib administration at our proposed dosing regimen shows promising responses in cGVHD as salvage therapy. Larger studies are needed to establish dosing and efficacy in children

Interleukin-27 as a candidate diagnostic biomarker for bacterial infection in immunocompromised pediatric patients.

BackgroundImmunocompromised pediatric patients constitute a growing population that is particularly vulnerable to bacterial infection, necessitating prompt recognition and treatment. This study assessed the utility of interleukin-27 (IL-27) and procalcitonin (PCT) as biomarkers of bacterial infection among immunocompromised pediatric subjects.MethodsThis is a single-center prospective cohort study conducted from July 2016 through September 2017, drawing subjects from the inpatient units at Cincinnati Children’s Hospital Medical Center (CCHMC), a large, tertiary care children’s hospital. Patients were included if they fit the definition of immunocompromised and were under clinical suspicion for infection, defined by the acquisition of a blood culture at any point during the admission. The primary analysis assessed the accuracy of IL-27 to diagnose bacterial infection in immunocompromised pediatric patients, using PCT as a comparator.Results293 patients were recruited, representing 400 episodes of suspected bacterial infection. The median age was 7.8 years (IQR 3.1–13.8 years). Fifty-three percent (n = 213) of the population had a primary oncologic diagnosis, 24% (n = 95) had received a bone marrow transplant, and 21% (n = 85) had received a solid organ transplant. The overall infection rate was 37%, with 70% of those patients having some form of culture positivity. Twenty-eight-day mortality was 5%, 60-day mortality was 9%, with 87% of patients surviving to hospital discharge. The AUC’s of the ROC curve to diagnose bacterial infection were 0.62 (0.5–0.68) for IL-27 and 0.65 (0.6–0.73) for PCT. Using the previously determined cutoff of 5.0 ng/mL, the specificity of IL-27 to diagnose bacterial infection reached 94%, with a negative predictive value of 64%.ConclusionsDespite prior work demonstrating IL-27 and PCT as possible biomarkers of bacterial infection in immunocompromised pediatric patients, we were unable to validate these findings. This illustrates the challenges associated with developing reliable biomarkers of bacterial infection in this vulnerable population.

EEG endophenotypes in autism spectrum disorder

ObjectivesThe association between autism spectrum disorder (ASD) and epilepsy is well-known. Abnormalities on electroencephalography (EEG) results have been reported in patients with ASD without a history of seizures. However, little is known about the relationship between abnormalities on EEG results and the core features of ASD. The purpose of the study was to determine the relationship between the presence of epilepsy and/or abnormalities on EEG results and disease-associated impairments in young children with ASD. MethodsData were collected from medical records at Cincinnati Children's Hospital Medical Center (CCHMC) of patients with well-characterized ASD. Patients were subdivided into three groups: ASD without epilepsy but with abnormal EEG results, ASD without epilepsy and normal EEG results, and ASD with epilepsy. Developmental (Mullen Scales of Early Learning (MSEL)), adaptive (Vineland Adaptive Behavior Scales (VABS)), behavioral (Child Behavior Checklist), and language (Preschool Language Scales (PLS)) assessments, along with birth and developmental histories, medications, and medical comorbidities were collected. Electroencephalography data were abstracted from reports and included presence, characterization, and location of abnormalities. ResultsAnalysis was performed on 443 patients with ASD. Seventy patients (15.8%) had epilepsy at the time of ASD diagnosis. Out of 372 patients with ASD and no epilepsy, 95 (25.5%) had an abnormal EEG result (67.4% epileptiform, 36.8% other abnormalities). Majority of epileptiform discharges were focal (83%) and most commonly seen in the left temporal region. The group with abnormal EEG results exhibited more impaired adaptive functioning when compared with the group with normal EEG results (p < 0.05). The group with abnormal EEG results was more similar to the group with epilepsy, differing only in expressive language (p < 0.01) and fine motor (p < 0.05) skills on the Mullen Scales. The group with epilepsy exhibited lower scores in all areas of developmental and adaptive functioning compared with the group with normal EEG results (p < 0.05). At the time of analysis, 13 patients (8 in the group with abnormal EEG results, 5 in the group with normal EEG results) developed epilepsy at a mean age of 10.5 years ± 3.3 years. ConclusionsThe presence of an abnormal EEG result or epilepsy in the setting of ASD suggests worse developmental and adaptive functioning. Further analysis will help to clarify associations and offer insight into treatment for this subpopulation without epilepsy but with abnormal EEG results.

Implementation of Pharmacogenetics at Cincinnati Children's Hospital Medical Center: Lessons Learned Over 14 Years of Personalizing Medicine.

Significant inter-individual variability in medication response can result in adverse drug reactions (ADRs) and increased health care costs. Based on ADR prevalence and mounting evidence linking genetics and pharmacokinetic variability, Cincinnati Children’s Hospital Medical Center (CCHMC) launched the Genetic Pharmacology Service (GPS) in 2004 and has since performed >25,000 tests. Herein, we describe how the service developed, launched, and has been updated along with how it is currently utilized, and key lessons learned.

Developing Resident-Sensitive Quality Measures: A Model From Pediatric Emergency Medicine.

To begin closing the gap with respect to quality measures available for use among residents, the authors sought to identify and develop resident-sensitive quality measures (RSQMs) for use in the pediatric emergency department (PED) setting. In May 2016, the authors reviewed National Quality Measures Clearinghouse (NQMC) measures to identify resident-sensitive measures. To create additional measures focused on common, acute illnesses (acute asthma exacerbation, bronchiolitis, closed head injury [CHI]) in the PED, the authors used a nominal group technique (NGT) and Delphi process from September to December 2016. To achieve a local focus for developing these measures, all NGT and Delphi participants were from Cincinnati Children's Hospital Medical Center. Delphi participants rated measures developed through the NGT in two areas: importance of measure to quality care and likelihood that measure represents the work of a resident. The review of NQMC measures identified 28 of 183 as being potentially resident sensitive. The NGT produced 67 measures for asthma, 46 for bronchiolitis, and 48 for CHI. These were used in the first round of the Delphi process. After two rounds, 18 measures for asthma, 21 for bronchiolitis, and 21 for CHI met automatic inclusion criteria. In round three, participants categorized the potential final measures by their top 10 and next 5. This study describes a template for identifying and developing RSQMs that may promote high-quality care delivery during and following training. Next steps should include implementing and seeking validity evidence for the locally developed measures.

Ocular Vestibular Evoked Myogenic Potentials: Normative Findings in Children.

To add to the limited body of literature on ocular vestibular evoked myogenic potential (oVEMP) responses in children and to assess a different montage for oVEMP recording. To evaluate the characteristics of the oVEMP response in children and compare the results with that of a group of healthy adults. Prospective descriptive study from a tertiary referral center. Twenty-two children (mean age = 6.3 yr, standard deviation = ±1.5, range = 3.5-8.9 yr) were recruited from families whose parent(s) were employed by the Cincinnati Children's Hospital Medical Center (CCHMC). Pediatric participants were categorized by age into three groups for data analysis. The comparison adult group of ten participants were members of the employee staff at CCHMC. Audiometric assessment was completed in all participants. The latency, amplitude, and threshold of the oVEMP responses were recorded using a modified electrode montage with reference at the chin and compared between the pediatric and adult participants. All participants completed testing and had bilateral measurable oVEMP responses using a 105-dB nHL, 500-Hz tone burst stimulus. Comparison between right and left ears across all participants for each oVEMP characteristic found no statistically significant difference. oVEMP testing showed no significant differences with respect to latency, amplitude, interaural amplitude asymmetry, and threshold of response as a function of age. oVEMP responses for ages ≥3 did not differ from responses in adults.

Automated Risk Assessment for School Violence: a Pilot Study

School violence has increased over the past ten years. This study evaluated students using a more standard and sensitive method to help identify students who are at high risk for school violence. 103 participants were recruited through Cincinnati Children's Hospital Medical Center (CCHMC) from psychiatry outpatient clinics, the inpatient units, and the emergency department. Participants (ages 12-18) were active students in 74 traditional schools (i.e. non-online education). Collateral information was gathered from guardians before participants were evaluated. School risk evaluations were performed with each participant, and audio recordings from the evaluations were later transcribed and manually annotated. The BRACHA (School Version) and the School Safety Scale (SSS), both 14-item scales, were used. A template of open-ended questions was also used. This analysis included 103 participants who were recruited from 74 different schools. Of the 103 students evaluated, 55 were found to be moderate to high risk and 48 were found to be low risk based on the paper risk assessments including the BRACHA and SSS. Both the BRACHA and the SSS were highly correlated with risk of violence to others (Pearson correlations>0.82). There were significant differences in BRACHA and SSS total scores between low risk and high risk to others groups (p-values <0.001 under unpaired t-test). In particular, there were significant differences in individual SSS items between the two groups (p-value <0.001). Of these items, Previous Violent Behavior (Pearson Correlation = 0.80), Impulsivity (0.69), School Problems (0.64), and Negative Attitudes (0.61) were positively correlated with risk to others. The novel machine learning algorithm achieved an AUC of 91.02% when using the interview content to predict risk of school violence, and the AUC increased to 91.45% when demographic and socioeconomic data were added. Our study indicates that the BRACHA and SSS are clinically useful for assessing risk for school violence. The machine learning algorithm was highly accurate in assessing school violence risk.

P.21 - Genotype-phenotype associations in a large cohort of Duchenne muscular dystrophy patients

Phenotype heterogeneity within the DMD population has long been noted but until recently there has been a relative dearth of understanding of the relationship between genotype and phenotype. Prior studies have suggested some genotype-specific phenotypic variations (exon 3–7 deletions, exon 44 skippable genotypes, exon 53 skippable genotypes). Genotype-phenotype associations were evaluated with regard to age at loss of ambulation within the Cincinnati Children's Hospital Medical Center (CCHMC) DMD Natural History Database (n = 574) with focus on genotypes amenable to exon skipping therapies and genotypes with significant patient numbers. Survival analysis was performed comparing genotypes of interest against the rest of the cohort. Kaplan-Meier curves were generated and log-rank tests were performed. Specific genotype groups analyzed included exon skippable genotypes (44, 45, 50, 51, 53, 55), deletions (exons 3–7, 8–11), duplications (exon 2), splice mutations, nonsense mutations and non-stop codon point mutations. Deletion of exons 3–7 (80% ambulating >17 years, CI 9.8-∞, p = 0.004) and exon 44 skippable genotypes (median age 20.5, CI 11.9-∞, p = 0.005) were associated with a later age of loss of ambulation. Exon 51 skippable genotypes (median age 11.0, CI 9.5–12.5, p = 0.0001) were associated with an earlier age of loss of ambulation. Exon 8–11 deletions, exon 2 duplications, splice mutations, non-sense mutations, non-stop codon point mutations and genotypes amenable to skipping of exons 45, 50, 53, 55 were not significantly different from the rest of the cohort (respectively). In conclusion, deletion of exons 3–7 and exon 44 skippable genotypes are associated with a later age of loss of ambulation. Exon 51 skippable genotypes are associated with an earlier age of loss of ambulation. These genotype-specific phenotypic variations can have significant impact on the success of future DMD clinical trials.

Reducing Parental Uncertainty Around Childhood Cancer: Implementation Decisions and Design Trade-Offs in Developing an Electronic Health Record-Linked Mobile App.

BackgroundParents of children newly diagnosed with cancer are confronted with multiple stressors that place them at risk for significant psychological distress. One strategy that has been shown to help reduce uncertainty is the provision of basic information; however, families of newly diagnosed cancer patients are often bombarded with educational material. Technology has the potential to help families manage their informational needs and move towards normalization.ObjectiveThe aim of this study was to create a mobile app that pulls together data from both the electronic health record (EHR) and vetted external information resources to provide tailored information to parents of newly diagnosed children as one method to reduce the uncertainty around their child’s illness. This app was developed to be used by families in a National Institutes of Health (NIH)-funded randomized controlled trial (RCT) aimed at decreasing uncertainty and the subsequent psychological distress.MethodsA 2-phase qualitative study was conducted to elicit the features and content of the mobile app based on the needs and experience of parents of children newly diagnosed with cancer and their providers. Example functions include the ability to view laboratory results, look up appointments, and to access educational material. Educational material was obtained from databases maintained by the National Cancer Institute (NCI) as well as from groups like the Children’s Oncology Group (COG) and care teams within Cincinnati Children’s Hospital Medical Center (CCHMC). The use of EHR-based Web services was explored to allow data like laboratory results to be retrieved in real-time.ResultsThe ethnographic design process resulted in a framework that divided the content of the mobile app into the following 4 sections: (1) information about the patient’s current treatment and other data from the EHR; (2) educational background material; (3) a calendar to view upcoming appointments at their medical center; and (4) a section where participants in the RCT document the study data. Integration with the NCI databases was straightforward; however, accessing the EHR Web services posed a challenge, though the roadblocks were not technical in nature. The lack of a formal, end-to-end institutional process for requesting Web service access and a mechanism to shepherd the request through all stages of implementation proved to be the biggest barrier.ConclusionsWe successfully deployed a mobile app with a custom user interface that can integrate with the EHR to retrieve laboratory results and appointment information using vendor-provided Web services. Developers should expect to face hurdles when integrating with the EHR, but many of them can be addressed with frequent communication and thorough documentation. Executive sponsorship is also a key factor for success.Trial RegistrationClinicalTrials.gov NCT02505165; https://clinicaltrials.gov/ct2/show/NCT02505165 (Archived by WebCite at http://www.Webcitation.org/6r9ZSUgoT)

Prenatal, intrapartum, and postnatal factors are associated with pediatric eosinophilic esophagitis

Multiple lines of evidence point to the potential importance of early-life environmental factors in the rapid increase in the incidence of eosinophilic esophagitis (EoE), but potential exposures have not been extensively studied. We sought to assess the association between prenatal, intrapartum, and postnatal factors and the development of pediatric EoE using a case-control study. Patients with EoE were recruited from an existing registry at Cincinnati Children's Hospital Medical Center (CCHMC). Population-based community control subjects were identified from a separate CCHMC registry. Mothers of study subjects were contacted and completed a Web-based questionnaire. Crude and adjusted models were used to estimate associations. Mothers of 127 cases and 121 control subjects were included. We observed a positive association between several early-life factors and EoE, including prenatal (maternal fever: adjusted odds ratio [aOR], 3.18; 95% CI, 1.27-7.98; preterm labor: aOR, 2.18; 95% CI, 1.06-4.48), intrapartum (cesarean delivery: aOR, 1.77; 95% CI, 1.01, 3.09), and infancy (antibiotic use: aOR, 2.30; 95% CI, 1.21-4.38; use of an acid suppressant: aOR, 6.05; 95% CI, 2.55-14.40) factors. We observed an inverse association between having a furry pet in infancy and EoE (aOR, 0.58; 95% CI, 0.34-0.97). No associations were observed for breast-feeding or maternal multivitamin or folic acid supplement use. Early-life factors, including maternal fever, preterm labor, cesarean delivery, and antibiotic or acid suppressant use ininfancy, were associated with risk of pediatric EoE; having apet in the home was protective. These results add to growing evidence that implicate early-life exposures in EoE pathogenesis.

Stroke Avoidance for Children in REpública Dominicana (SACRED): Protocol for a Prospective Study of Stroke Risk and Hydroxyurea Treatment in Sickle Cell Anemia

BackgroundIn the Dominican Republic, where the burden of sickle cell anemia (SCA) is high, many children lack access to routine screening and preventative care. Children with SCA are at risk for stroke, an event that leads to significant morbidity and mortality. In the United States, screening via transcranial Doppler (TCD) identifies children with SCA at highest stroke risk, allowing early intervention with blood transfusions. The need for indefinite transfusions for primary stroke prevention limits their practicality in limited-resource countries. Hydroxyurea has been shown to lower TCD velocities and to prevent conversion from conditional (170 to 199 cm/sec) to abnormal (greater than or equal to 200 cm/sec) velocities. In resource-limited settings, implementation of a TCD screening program, coupled with hydroxyurea therapy, could reduce the burden of SCA and stroke.ObjectiveThe aims of the Stroke Avoidance for Children in REpública Dominicana (SACRED) trial are (1) to screen children with SCA for stroke risk using TCD and to determine the prevalence of elevated velocities in a cross-sectional sample; (2) to identify clinical and laboratory correlates of elevated velocities; and (3) to obtain longitudinal data on the natural history of TCD velocities and to measure therapeutic effects of hydroxyurea.MethodsThis prospective trial, designed and conducted by Cincinnati Children’s Hospital Medical Center (CCHMC) and Hospital Infantil Robert Reid Cabral (HIRRC) with Centro de Obstetricia y Ginecología, includes a baseline cross-sectional epidemiological survey of the distribution of TCD velocities across a large cohort of children with SCA in the Dominican Republic. Children with conditional velocities are eligible to begin protocol-directed hydroxyurea if laboratory criteria are met. The treatment schedule begins with a fixed-dose of approximately 20 mg/kg/day for 6 months, after which it escalates to maximum tolerated dose (MTD). All participants undergo longitudinal annual TCD evaluation, while those on hydroxyurea have semi-annual evaluations during the 3-year study period. Data are collected using an Internet-based Research Electronic Data Capture (REDCap) system with forms translated into Spanish; both remote and on-site monitoring are used.ResultsTo date, 122 children with SCA have enrolled in SACRED including 85 (69.7%, 85/122) with normal, 29 (23.8%, 29/122) with conditional, 5 (4.1%, 5/122) with abnormal, and 3 (2.5%, 3/122) with inadequate TCD velocities. Of the 29 children with conditional TCD velocities, 17 (59%, 17/29) have initiated hydroxyurea per protocol, with plans for escalation to MTD.ConclusionsThe SACRED trial will provide novel epidemiologic data about the prevalence of children with SCA and increased stroke risk in the Dominican Republic. The study also includes an investigation of the impact of hydroxyurea at MTD on elevated TCD velocities, as well as clinical and laboratory parameters. The design and implementation of SACRED reflect a successful international institutional partnership, one that features local capacity building and training in research methods and clinical care. The trial’s results have important implications for screening and prevention of primary stroke in children with SCA living in resource-limited settings.Trial RegistrationClinicalTrials.gov NCT02769845; https://www.clinicaltrials.gov/ct2/show/NCT02769845 (Archived by WebCite at http://www.webcitation.org/6qf6n0Egh)

Impact of a formal human papilloma virus (HPV) education program in a childhood cancer survivor center.

10568 Background: The HPV vaccine has proven efficacy in preventing secondary cancers. It was approved for females age 11-26 in 2006 and for males age 11-21 in 2011. Despite this, vaccination rates in the US have been poor. The Cancer Survivorship Center (CSC) at Cincinnati Children’s Hospital Medical Center (CCHMC) instituted an education program in July, 2016 to improve education and vaccination rates in a childhood cancer survivor population. The following is a summary of program effectiveness. Methods: Providers in the CSC identified females age 11-26, and males age 11-21, presenting for annual visit from 7/1/16 thru 12/31/16. Patients received HPV education materials published by the CDC at registration. Materials were also displayed in exam and waiting rooms. During the visit, providers reviewed and documented vaccination history and discussed the importance of the HPV vaccine in preventing cancer. Patients interested in starting the vaccine series received the first vaccine in clinic and a follow-up schedule for further vaccination. Education and immunization status was documented in the electronic medical record using smart phrase trackable format. All patients were asked to sign a release to obtain vaccine records from the primary physician. A comparison group consisted of HPV eligible patients seen in the CSC during the six months prior to program initiation. Groups were compared for education completed and vaccination rate. Results: A total of 156 eligible patients were seen in the comparison group. None received HPV-directed education during their visit. Only 37 (23.7%) had any HPV vaccine, with 5 given during the clinic visit (13.5%). By comparison, 176 eligible patients were seen after initiation of the education program. All patients received materials at registration and 89% had documented education completed by a health care provider. Ninety one (55%) had any HPV vaccine, with 30 given during the clinic visit (33%). Conclusions: Through the implementation of a standardized education program in the CSC, we saw more than a 200% increase in rate of HPV vaccination. This demonstrates the importance of knowledgeable providers and the value of a dedicated HPV education program.

Natural history of aortic root dilation through young adulthood in a hypermobile Ehlers-Danlos syndrome cohort.

Hypermobile Ehlers-Danlos syndrome (hEDS) is a common inherited connective tissue disorder characterized by joint hypermobility. The natural history of aortic root dilation (AoD), a potential complication of EDS, has not been well characterized in this population. We describe the natural history of aortic root size in a large cohort of patients with hEDS. A cohort of 325 patients with HEDS was identified at Cincinnati Children's Hospital Medical Center (CCHMC), including 163 patients from a previous study. Medical records were reviewed and each participant's height, weight, and aortic dimensions from up to four echocardiograms were documented. Aortic root z-scores were calculated using two established formulas based on age (Boston or Devereux). Overall prevalence of AoD and prevalence by age were calculated and longitudinal regression was performed. The prevalence of AoD with a z-score ≥ 2.0 was 14.2% (46/325) and with a z-score of ≥3.0 was 5.5% (18/325). No significant increases in z-score were seen over time for patients with multiple echocardiograms. Participants under the age of 15 years had an average decline of 0.1 standard deviations (SDs)/year. No significant change was found after 15 of age. Between the ages of 15 and 21 years, Boston z-scores were 0.96 higher than Devereux z-scores. The nearly 1 z-score unit difference between formulas indicates caution prior to diagnosing AoD in patients with hEDS. In light of the low prevalence and lack of progression of AoD, routine echocardiograms may not be warranted for pediatric patients with hEDS.

Risk Stratification for Opioid Misuse in Children, Adolescents, and Young Adults: A Quality Improvement Project.

The Pediatric Palliative and Comfort Care Team (PACT) at Cincinnati Children's Hospital Medical Center (CCHMC) provides opioids to a large population of patients in the ambulatory setting. Before this project, PACT had no reliable system to risk stratify patients for opioid misuse. The global aim was safe opioid prescribing by the palliative care team. The specific, measurable, achievable, realistic, and timely aim was as follows: "In patients who present for follow up with PACT, we will use the "opioid bundle" to increase risk stratification for opioid misuse from 0% to 90% over 5 months." The opioid bundle includes a urine drug screen, Ohio Automated Rx Reporting System report, pill count, and screening history for drug abuse and mental health disorders. The setting was multiple CCHMC ambulatory clinics. Participants included all PACT members. Since implementing the new system, we have increased risk stratification for opioid misuse among outpatients from 0% to >90%. Results have been sustained for 12 months. Key processes have become reliable: obtaining informed consent and controlled substance agreements for all new patients and obtaining the opioid bundle to enable risk stratification in a consistent and timely fashion. A total of 34% of patients have been stratified as high risk, and an additional 27% have been stratified as moderate risk. A system to ensure safe opioid prescribing practices to all patients is critical for providers. Identifying key processes and executing them reliably has enabled the palliative care team at CCHMC to risk stratify >90% of patients receiving opioids in the ambulatory setting for opioid misuse.

A prognostic tool to predict severe acute pancreatitis in pediatrics.

Approximately 15-20% of pediatric patients with acute pancreatitis (AP) develop severe disease. Severity scoring tools were developed for adult patients, but have limitations when applied in children. We aimed to identify early predictors of severe acute pancreatitis (SAP) on hospital admission for early risk stratification of patients. Retrospective review of AP admissions was conducted. The derivation cohort included cases at Cincinnati Children's Hospital Medical Center (CCHMC) between 2009 and 2013. Clinical data collected during the first 24h of admission were analyzed and a predictive model was derived through statistical analysis. The performance of the model was evaluated in a validation cohort from 2 more institutions other than CCHMC. In the derivation cohort 19% of the 284 admissions were SAP. A generalized linear mixed effect model analysis revealed that lipase, albumin and white blood count (WBC) play a role in the development of SAP (area under the receiver operating curve (AUROC 0.76)). In the validation cohort of 165 AP cases, SAP ranged from 8 to 20% at the three institutions. Performance of the model in this cohort was comparable to the derivation model (AUROC 0.77). There were 369 encounters in the combined derivation and validation pool (AUROC 0.76). The prognostic severity tool with 3 variables (lipase, albumin, and WBC) obtained within 24h of admission can be applied to predict SAP in pediatric patients.

Improving Access to Care at Autism Treatment Centers: A System Analysis Approach.

The prevalence of autism spectrum disorder is steadily increasing and placing more demands on already overburdened diagnostic and treatment systems. A thoughtful, systematic reorganization of autism service delivery may reduce delays and better meet the growing need. Two clinical centers in the Autism Intervention Research Network on Physical Health, Cincinnati Children's Hospital Medical Center (CCHMC) and Nationwide Children's Hospital (NCH), undertook a year-long access improvement project to reduce delays to care by using system analysis to identify sources of delay and to target changes by using a set of defined access principles. Although both sites addressed access, they focused on slightly different targets (reducing number of patients with autism spectrum disorders waiting for follow-up appointments at NCH and reducing delay to new diagnosis at CCHMC). Both sites achieved dramatic improvements in their complex, multidisciplinary systems. A 94% reduction in number of patients on the waitlist from 99 to 6 patients and a 22% reduction in median delay for a new ongoing care appointment were realized at NCH. A 94% reduction in third next available appointment for new physician visits for children 3 to 5 years old was realized at CCHMC. This article demonstrates that 2 different clinical systems improved access to care for autism diagnosis and follow-up care by identifying sources of delay and using targeted changes based on a set of access change principles. With appropriate guidance and data analysis, improvements in access can be made.

A quality improvement project to reduce the intraoperative use of single-dose fentanyl vials across multiple patients in a pediatric institution.

The use of a single-dose vial across multiple patients presents a risk to sterility and is against CDC guidelines. We initiated a quality improvement (QI) project to reduce the intraoperative use of single-dose vials of fentanyl across multiple patients at Cincinnati Children's Hospital Medical Center (CCHMC). The initial step of the improvement project was the development of a Key Driver Diagram. The diagram has the SMART aim of the project, key drivers inherent to the process we are trying to improve, and specific interventions targeting the key drivers. The number of patients each week receiving an IV dose of fentanyl, from a vial previously accessed for another patient was tracked in a high turnover operating room (OR). The improvement model used was based on the concept of building Plan-Do-Study-Act (PDSA) cycles. Tests of change included provider education, provision of an increased number of fentanyl vials, alternate wasting processes, and provision of single-use fentanyl syringes by the pharmacy. Prior to initiation of this project, it was common for a single fentanyl vial to be accessed for multiple patients. Our data showed an average percentage of failures of just over 50%. During the end of the project, after 7 months, the mean percentage failures had dropped to 5%. Preparation of 20 mcg single-use fentanyl syringes by pharmacy, combined with education of providers on appropriate use, was successful in reducing failures to below our goal of 25%. Appropriately sized fentanyl syringes prepared by pharmacy, education on correct use of single-dose vials, and reminders in the OR, reduced the percentage of patients receiving a dose of fentanyl from a vial previously accessed for another patient in a high-volume otolaryngology room.

Factors Influencing Migraine Recurrence After Infusion and Inpatient Migraine Treatment in Children and Adolescents.

To evaluate factors that influence migraine recurrence after outpatient infusion or inpatient treatment for intractable migraine. Recurrence of migraine after acute treatment in an infusion center or an inpatient setting is not well documented in children and adolescents. Given the multifactorial pathogenesis of migraines, multiple factors may influence migraine recurrence. It has been reported that treatment with steroids may reduce the risk of migraine recurrence. The efficacy of steroids as a therapeutic adjunct has not been established. Studies in the adult population have yielded conflicting results. This study is a retrospective chart review of patients presenting for treatment of an intractable migraine to the outpatient infusion unit or inpatient unit at Cincinnati Children's Hospital Medical Center (CCHMC). Data collected included: age, gender, location of treatment (outpatient, inpatient), migraine duration, diagnosis, severity, the addition of steroids to treatment protocols, and recurrence of migraine at 48 and 72 hours after discharge. Data were analyzed using Fisher's exact tests, logistic regression with backward elimination for variable selection, and least squares means slicing with associated odds ratios. Charts from 207 pediatric patients were analyzed. Using logistic regression analysis: location, gender, diagnosis, and age were all found to be significant predictors of migraine recurrence (P < .05). Patients treated in the inpatient setting were significantly less likely to experience recurrence compared to patients treated in an outpatient infusion unit (OR = 0.32; 95% CI 0.17-0.61, P = .0002). Male patients with a diagnosis of episodic migraine were significantly less likely to experience recurrence than male patients with chronic migraine (OR 0.17; 95% CI 0.04-0.73; P = .0074). The inclusion of steroids in this study population showed no significant reduction in migraine recurrence. The probability of recurrence decreased with age for episodic migraine patients, while the probability increased with age for chronic migraine patients. Recurrence is an important consideration when treating intractable migraines. Age, gender, diagnosis, and location of treatment correlate with migraine recurrence, but the inclusion of steroids does not. Considering these factors in the management of migraines may improve the outcome of these patients and reduce the risk of recurrence.

Late-Onset Hypoglycemia in Term Newborns With Poor Breastfeeding.

Brain injury as a result of significant neonatal hypoglycemia has been recognized for many years. Recently, several case reports from around the world have documented that neonatal hypoglycemia in term infants can result from inadequate intake related to breastfeeding.1 Clinical manifestations can vary from no symptoms, to hypotonia and lethargy, to seizures.2 The blood glucose level and duration of hypoglycemia that lead to neurodevelopmental sequelae have not been established.3 For many years, it was thought that hypoglycemic brain injury was localized to the occipital lobes; however, more recent research has shown that the damage can occur anywhere in the brain.4,5 There have been minimal follow-up data in this patient population to determine long-term prognosis.6 We report a cohort of 11 term neonates who were admitted to the Cincinnati Children’s Hospital Medical Center (CCHMC) NICU for treatment of hypoglycemia that was not due to endocrinopathies, sepsis, hypoxic-ischemic encephalopathy, or maternal medical problems such as diabetes. All of the infants were discharged from their birth hospitals and within a few days were admitted to the NICU with hypoglycemia. A retrospective search was conducted to identify all neonates admitted to the CCHMC NICU from January 2010 to December 2013 with the following diagnosis codes: “neonatal convulsions” and/or “neonatal hypoglycemia.” The research was conducted with approval of the CCHMC Institutional Review Board (Protocol 2014-0607). A chart review was performed for all 47 patients identified. Patients were excluded if they had any other diagnosis that could cause hypoglycemia such as: hypoxic-ischemic encephalopathy, meconium aspiration syndrome, sepsis, prematurity, micropenis, ambiguous genitalia, intrauterine growth restriction, small for gestational age, or those who were hypoglycemic immediately …