Long-Term Functional Outcomes at 1-Year After Hospital Discharge in Critically Ill Neonates With Congenital Diaphragmatic Hernia.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) is a birth defect associated with long-term morbidity. Our objective was to examine longitudinal change in Functional Status Scale (FSS) after hospital discharge in CDH survivors. DESIGN: Single-center retrospective cohort study. SETTING: Center for comprehensive CDH management at a quaternary, free-standing children's hospital. PATIENTS: Infants with Bochdalek CDH were admitted to the ICU between January 2009 and December 2019 and survived until hospital discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred forty-two infants (58% male, mean birth weight 3.08 kg, 80% left-sided defects) met inclusion criteria. Relevant clinical data were extracted from the medical record to calculate FSS (primary outcome) at hospital discharge and three subsequent outpatient follow-up time points. The median (interquartile range [IQR]) FSS score at hospital discharge was 8.0 (7.0-9.0); 39 patients (27.5%) had at least moderate impairment (FSS ≥ 9). Median (IQR) FSS at 0- to 6-month ( n = 141), 6- to 12-month ( n = 141), and over 12-month ( n = 140) follow-up visits were 7.0 (7.0-8.0), 7.0 (6.0-8.0), and 6.0 (6.0-7.0), respectively. Twenty-one patients (15%) had at least moderate impairment at over 12-month follow-up; median composite FSS scores in the over 12-month time point decreased by 2.0 points from hospital discharge. Median feeding domain scores improved by 1.0 (1.0-2.0), whereas other domain scores remained without impairment. Multivariable analysis demonstrated right-sided, C- or D-size defects, extracorporeal membrane oxygenation use, cardiopulmonary resuscitation, and chromosomal anomalies were associated with impairment. CONCLUSIONS: The majority of CDH survivors at our center had mild functional status impairment (FSS ≤ 8) at discharge and 1-year follow-up; however, nearly 15% of patients had moderate impairment during this time period. The feeding domain had the highest level of functional impairment. We observed unchanged or improving functional status longitudinally over 1-year follow-up after hospital discharge. Longitudinal outcomes will guide interdisciplinary management strategies in CDH survivors.

Longitudinal Analysis of Ventilation Perfusion Mismatch in Congenital Diaphragmatic Hernia Survivors.

OBJECTIVE: To determine the natural history of pulmonary function for survivors of congenital diaphragmatic hernia (CDH). STUDY DESIGN: This was a retrospective cohort study of survivors of CDH born during 1991-2016 and followed at our institution. A generalized linear model was fitted to assess the longitudinal trends of ventilation (V), perfusion (Q), and V/Q mismatch. The association between V/Q ratio and body mass index percentile as well as functional status was also assessed with a generalized linear model. RESULTS: During the study period, 212 patients had at least one V/Q study. The average ipsilateral V/Q of the cohort increased over time (P < .01), an effect driven by progressive reduction in relative perfusion (P = .012). A higher V/Q ratio was correlated with lower body mass index percentile (P < .001) and higher probability of poor functional status (New York Heart Association class III or IV) (P = .045). CONCLUSIONS: In this cohort of survivors of CDH with more severe disease characteristics, V/Q mismatch worsens over time, primarily because of progressive perfusion deficit of the ipsilateral side. V/Q scans may be useful in identifying patients with CDH who are at risk for poor growth and functional status.

Longitudinal Analysis of Pulmonary Function in Survivors of Congenital Diaphragmatic Hernia.

OBJECTIVE: To analyze longitudinal trends of pulmonary function testing in patients with congenital diaphragmatic hernia (CDH) followed in our multidisciplinary clinic. STUDY DESIGN: This was a retrospective cohort study of CDH patients born between 1991 and 2013. A linear mixed effects model was fitted to estimate the trends of percent predicted forced expiratory volume in 1 second (FEV1pp), percent predicted forced vital capacity (FVCpp), and FEV1/FVC over time. RESULTS: Of 268 patients with CDH who survived to discharge, 119 had at least 1 pulmonary function test study. The FEV1pp (P < .001), FVCpp (P = .017), and FEV1/FVC (P = .001) decreased with age. Compared with defect size A/B, those with defect size C/D had lower FEV1pp by an average of 11.5% (95% CI, 2.9%-20.1%; P = .010). A history of oxygen use at initial hospital discharge also correlated with decreased FEV1pp by an average of 8.0% (95% CI, 1.2%-15.0%; P = .023). CONCLUSIONS: In a select cohort of CDH survivors, average pulmonary function declines with age relative to expected population normative values. Those with severe CDH represent a population at risk for worsening pulmonary function test measurements who may benefit from recognition and monitoring for complications.

Calculation of posterior chamber intraocular lens (IOL) size and dioptric power for use in pet rabbits undergoing phacoemulsification.

OBJECTIVES: To calculate the size and dioptric power of a posterior chamber intraocular lens (IOL) to achieve emmetropia in adult rabbits and to compare the dioptric power calculation results using a proprietary predictive formula to a retinoscopy-based method. ANIMALS STUDIED: Three wild rabbit cadavers, seven pet rabbits with cataracts and ten healthy pet rabbits. MATERIALS AND METHODS: Implant size was calculated using a capsular tension ring (CTR) (Acrivet® , Berlin, Germany). Published and cadaveric biometric data were used in the predictive formula. An IOL power-escalation study compared the predicted values to the refraction results of one pet rabbit (P1) fitted with a + 41D canine IOL (Acrivet® ) and six pet rabbits (P2-P7) fitted with prototype IOLs (Acrivet® ). Retinoscopy of 10 healthy pet rabbits served as controls. RESULTS: A 13.5 mm CTR fitted in all rabbits and permitted the use of a 13 mm IOL. The predicted IOL power ranged between +24D and +25D. The +41D IOL resulted in a refraction error of +8D. Progressive recalculation through a calibration formula led to the insertion of three +49D IOLs in two pet rabbits and a refraction of +6D to +8D, followed by seven +58D IOLs in four pet rabbits and a refraction median of 0D (range: -1.5D to +1D). CONCLUSIONS: A 13 mm prototype IOL of +58D achieves emmetropia and is of adequate size for rabbits. The combined use of a CTR and retinoscopy is a useful method to calculate the size and refractive power of a new, species-specific, veterinary IOL.

Disparities in Healthcare Utilization: An Analysis of Disease Specific and Patient Level Factors in a Congenital Diaphragmatic Hernia Clinic.

OBJECTIVES: Our study examines if the disease severity profile of our Congenital Diaphragmatic Hernia (CDH) patient cohort adherent to long-term follow-up differs from patients lost to follow-up after discharge and examines factors associated with health care utilization. METHODS: Retrospective review identified CDH survivors born 2005-2019 with index repair at our institution. Primary outcome was long-term follow-up status: "active" or "inactive" according to clinic guidelines. Markers of CDH disease severity including CDH defect classification, oxygen use, tube feeds at discharge, and sociodemographic factors were examined as exposures. RESULTS: Of the 222 included patients, median age [IQR] was 10.2 years [6.7-14.3], 61% male, and 57 (26%) were insured by Medicaid. Sixty-three percent (139/222) of patients were adherent to follow-up. Seventy-six percent of patients discharged on tube feeds had active follow-up compared to 55% of patients who were not, with similar findings for oxygen at discharge (76% vs. 55%). Kaplan-Meier analysis showed patients with smaller defect size had earlier attrition compared to patients with larger defect size. Other race (Hispanic, Asian, Middle Eastern) patients had 2.87 higher odds of attrition compared to white patients (95% CI 1.18-7.0). Medicaid patients had 2.64 higher odds of attrition compared to private insurance (95% CI 1.23-5.66). CONCLUSION: Loss to follow-up was associated with race and insurance type. Disease severity was similar between the active and inactive clinic cohorts. Long-term CDH clinic publications should examine attrition to ensure reported outcomes reflect the discharged population. This study identified important factors to inform targeted interventions for follow-up adherence. LEVEL OF EVIDENCE: Level III.

Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.

Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 x 10(-7)). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders.

Quantitative Evaluation of Content and Age Concordance Across Developmental Milestone Checklists.

OBJECTIVE: Clinicians and caregivers rely on milestone checklists as tools for tracking a child's development. In addition, medical students and residents use milestone checklists to learn about normal child development. However, there are multiple published milestone checklists that vary qualitatively in structure and content, hindering their effective use in developmental surveillance and medical education. This project systematically evaluated the consistency and variability between commonly used milestone checklists. METHODS: A team of child psychologists and developmental pediatricians reviewed a total of 1094 milestones derived from 4 published checklists (2 developed for providers, 2 developed for caregivers) to create a comprehensive set of 728 discrete developmental observations, with each observation mapped to corresponding milestones. This observation-milestone relational database was then used to determine the degree of content overlap and milestone age range concordance across milestone checklists. RESULTS: Of the 728 discrete developmental observations, 40 (5.5%) were mapped to milestones in all 4 milestone checklists, and an additional 90 (12.4%) were mapped to 3 checklists. Among these 40 "universal" observations, most (42.5%) were in the motor domain. Of those 130 observations mapped to milestones in at least 3 of the 4 checklists, 26.9% (35/130) were mapped to milestones that were discordant in their associated age range. CONCLUSION: Four commonly used developmental milestone checklists were found to have limited overlap in content, and those that overlapped were inconsistent in their associated age ranges. The resulting observation-milestone relational database could be used to further validate age estimates of milestones and facilitate milestone surveillance through the electronic health record.

Insomnia of childhood.

PURPOSE OF REVIEW: Insomnia is a major public health problem and is the most common sleep disturbance in both adults and children. The causes of sleeplessness are age-dependent and have potentially enormous effects on cognitive development, behavior, family dynamics, and the metabolic health of children. Here we review the epidemiology, cause, pathophysiology, and clinical approach to pediatric insomnia. RECENT FINDINGS: Normal sleep is crucial for brain function, behavior, and normal metabolism. Consistently, sleep loss has been linked to behavioral and attention problems, impaired learning and memory, obesity, and psychiatric disorders. The neurological mechanisms that govern sleep initiation and maintenance are poorly understood. The types of insomnia are age-dependent and can occur as primary disorders, or in the context of another primary sleep disorder such as restless legs syndrome, or secondary to another underlying medical condition. Children with chronic diseases and especially children with neurodevelopmental disorders are at particular risk of insomnia. SUMMARY: Pediatric insomnia is common and is a source of potential psychophysiological stress to both children and their caregivers. The causes of insomnia are various. Pediatricians should have a working knowledge of the causes of sleeplessness in order to promptly curtail the chronic effects of sleep loss and effectively screen for underlying, potentially treatable disorders.

Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change morbidity outcomes for high-risk congenital diaphragmatic hernia survivors?

PURPOSE: In high-risk congenital diaphragmatic hernia (CDH), significant barotrauma or death can occur before extracorporeal membrane oxygenation (ECMO) can be initiated. We previously examined ex utero intrapartum treatment (EXIT)-to-ECMO in our most severe CDH patients, but demonstrated no survival advantage. We now report morbidity outcomes in survivors of this high-risk cohort to determine whether EXIT-to-ECMO conferred any benefit. METHODS: All CDH survivors with <15% predicted lung volume (PPLV) from September 1999 to December 2010 were included. We recorded prenatal imaging, defect size, and pulmonary, nutritional, cardiac, and neurodevelopmental outcomes. RESULTS: Seventeen survivors (8 EXIT-to-ECMO, 9 non-EXIT) had an average PPLV of 11.7%. Eight of 9 non-EXIT received ECMO within 2days. There were no significant defect size differences between groups, mostly left-sided (13/17) and type D (12/17). Average follow-up was 6.7years (0-13years). There were no statistically significant differences in outcomes, including supplemental oxygen, diuretics, gastrostomy, weight-for-age Z scores, fundoplication, pulmonary hypertension, stroke or intracranial hemorrhage rate, CDH recurrence, and reoperation. No survivor in our cohort was neurologically devastated. All had mild motor and/or speech delay, which improved in most. CONCLUSIONS: In this pilot series of severe CDH survivors, EXIT-to-ECMO confers neither significant survival nor long-term morbidity benefit. LEVEL OF EVIDENCE: Level III treatment study.

Relationship of serum ferritin levels to sleep fragmentation and periodic limb movements of sleep on polysomnography in autism spectrum disorders.

OBJECTIVE: Although children with autism spectrum disorders experience a range of sleep disturbances, exact mechanisms are not well-characterized. We investigated the association of serum-ferritin to sleep fragmentation and periodic limb movements of sleep using polysomnography in children with autism spectrum disorders. METHODS: We conducted a retrospective chart review of children with autism spectrum disorders followed from 1990 to 2010. Inclusion criteria were availability of polysomnography data and ferritin levels within 12 months of each other. The following variables on polysomnography characterized sleep fragmentation: increased arousal index, alpha intrusions, and reduced sleep efficiency. The data were compared with age- and gender-matched controls. RESULTS: Of 9791 children with autism spectrum disorders identified, 511 had a ferritin level, 377 had polysomnography data, and 53 had both ferritin and polysomnography data. As compared with the controls (86 ng/mL), the median ferritin level was 27 ng/mL in the study autism spectrum disorders population (53 patients) (P < 0.01), 27 ng/mL in autism spectrum disorder subjects with periodic limb movements of sleep (25 patients) (P = 0.01), and 24 ng/mL in autism spectrum disorders subjects with sleep fragmentation (21 patients) (P = 0.02). Within the autism spectrum disorders population, median ferritin levels were significantly lower in patients with poor sleep efficiency (7 ng/mL) versus those with normal sleep efficiency (29 ng/mL) (P = 0.01). The prevalence of periodic limb movements of sleep was 47% in autism spectrum disorders compared with 8% in controls (P < 0.01). CONCLUSION: Children with autism spectrum disorders had significantly lower ferritin levels compared with controls. In addition, they experience a higher prevalence of sleep fragmentation, obstructive sleep apnea, and periodic limb movements of sleep than children with ASD and no sleep complaints. Our preliminary observations, which have not been described before, need to be validated in multicenter prospective studies.

Managing behavior for a child with autism in a body cast.

CASE: : Elisa is a 6 ½-year-old white female who has a follow-up appointment in the Developmental Clinic where she is seen for autism, developmental delay, and significant behavioral problems. Her grandparents, who are her legal guardians, request an opinion on a proposed surgery for developmental dysplasia of the hip that will require several months in a whole body cast. Reconstruction of the hip was recommended by 2 pediatric orthopedic surgeons to prevent later disability and pain.Elisa was born following a 41-week gestation. She sat without support at 7 months, but she did not walk until 23 months of age. An evaluation at the Developmental Clinic at 28 months of age documented gross and fine motor delays, cognitive impairment, and autism. A karyotype, fragile X, and microarray were normal. Elisa has a brother with autism and a maternal cousin with mental retardation. After her mother's death from meningitis 2 years ago, her maternal grandparents became her legal guardian.Behavior problems include significant hyperactivity, impulsivity, and aggressive behaviors. She seldom sits still. She also has frequent stereotypies, such as jumping and arm flapping when she is excited or upset. Methylphenidate was associated with increased hyperactivity and irritability.Physical examination demonstrates that she can walk with a very wide gait and swings her right foot out. A magnetic resonance imaging of her brain, acoustic brain response audiometry, and metabolic studies are normal. Other medical issues include gastroesophageal reflux, recurrent pneumonia, and ear infections. Radiographs of the hip reveal a steep acetabulum and a hip that easily dislocates. A magnetic resonance imaging of the hip shows early formation of a pseudoarthrosis. Her grandparents and pediatrician are concerned about managing her behavior after the surgery when she will be in a body cast.

Clinical genetic testing for patients with autism spectrum disorders.

BACKGROUND: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. PATIENTS AND METHODS: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. RESULTS: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. CONCLUSIONS: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

Solitary fibrous tumor of pleura: a case report and review of clinical, radiographic and histologic findings.

We present a case of solitary fibrous tumor of pleura (SFTP) in a 63-year-old male. Clinical manifestations of this entity, including paraneoplastic syndromes, are discussed, albeit absent in our presented case. Furthermore radiographic findings and pathologic correlations are provided. SFTP remains a rare neoplasm for which radiographic features are suggestive yet nonspecific, and immunohistochemistry remains as the diagnostic method of choice.