John Oehlert

Postural balance in children with cerebral palsy

Postural control deficits have been suggested to be a major component of gait disorders in cerebral palsy (CP). Standing balance was investigated in 23 ambulatory children and adolescents with spastic diplegic CP, ages 5 to 18 years, and compared with values of 92 children without disability, ages 5 to 18 years, while they stood on a force plate with eyes open or eyes closed. The measurements included center of pressure calculations of path length per second, average radial displacement, mean frequency of sway, and Brownian random motion measures of the short-term diffusion coefficient, and the long-term scaling exponent. In the majority of children with CP (14 of 23) all standing balance values were normal. However, approximately one-third of the children with CP (eight of 23) had abnormal values in at least two of the six center of pressure measures. Thus, mean values for path length, average radial displacement, and diffusion coefficient were higher for participants with CP compared with control individuals with eyes open and closed (p<0.05). Mean values for frequency of sway and the long-term scaling exponent were lower for participants with CP compared with control participants (p<0.05). Increased average radial displacement was the most common (nine of 23) postural control deficit. There was no increase in abnormal values with eyes closed compared with eyes open for participants with CP, indicating that most participants with CP had normal dependence on visual feedback to maintain balance. Identification of those children with impaired standing balance can delineate factors that contribute to the patients gait disorder and help to guide treatment.

Tissue oxygen distribution in head and neck cancer patients

The importance of hypoxia in limiting the sensitivity of tumor cells to ionizing radiation has long been known.

A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia

OBJECTIVE: Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD. METHODS: The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 250–296/7 weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks’ postmenstrual age. At 36 weeks’ postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip. RESULTS: Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10−8) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative. CONCLUSIONS: We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

Diagnostic Testing by CFTR Gene Mutation Analysis in a Large Group of Hispanics: Novel Mutations and Assessment of a Population-Specific Mutation Spectrum

Characterization of CFTR mutations in the U.S. Hispanic population is vital to early diagnosis, genetic counseling, patient-specific treatment, and the understanding of cystic fibrosis (CF) pathogenesis. The mutation spectrum in Hispanics, however, remains poorly defined. A group of 257 self-identified Hispanics with clinical manifestations consistent with CF were studied by temporal temperature gradient electrophoresis and/or DNA sequencing. A total of 183 mutations were identified, including 14 different amino acid-changing novel variants. A significant proportion (78/85) of the different mutations identified would not have been detected by the ACMG/ACOG-recommended 25-mutation screening panel. Over one third of the mutations (27/85) occurred with a relative frequency >1%, which illustrates that the identified mutations are not all rare. This is supported by a comparison with other large CFTR studies. These results underscore the disparity in mutation identification between Caucasians and Hispanics and show utility for comprehensive diagnostic CFTR mutation analysis in this population.

Clinical variability in congenital fiber type disproportion

Congenital Fiber Type Disproportion (CFTD) has recently been described as a consistent and stereotyped clinicopathological entity, including congenital nonprogressive hypotonia and weakness, contractures, kyphoscoliosis, high arched palate, dislocated hips, short stature, and feet deformities. Our personal experience with this condition suggests a wider disparity in the physical appearance and associated abnormalities of affected individuals than the well-defined clinical syndrome previously described. We are presenting 5 cases, including 2 siblings, whose muscle biopsies satisfy the major histological and statistical criteria for the diagnosis. Although each child clearly had hypotonia and weakness consistent with a congenital myopathy, only 3 had a sufficient number of other similarities to establish the diagnosis clinically. The clinical spectrum of the other cases ranged from one infant whose only abnormality was mild hypotonia in the legs to another whose problems included severe motor impairment, marked mental retardation, growth failure, frontal bossing, abnormal hair, and scoliosis. Even in retrospect, the diagnosis of CFTD could not have been supported on clinical grounds alone. Therefore, CFTD is a congenital myopathy whose diagnosis can be made only by muscle biopsy, rather than a distinct syndrome whose diagnosis can be assumed on the basis of clinical characteristics alone.

Exome Sequencing of Neonatal Blood Spots and the Identification of Genes Implicated in Bronchopulmonary Dysplasia

RATIONALE Bronchopulmonary dysplasia (BPD), a prevalent severe lung disease of premature infants, has a strong genetic component. Large-scale genome-wide association studies for common variants have not revealed its genetic basis. OBJECTIVES Given the historical high mortality rate of extremely preterm infants who now survive and develop BPD, we hypothesized that risk loci underlying this disease are under severe purifying selection during evolution; thus, rare variants likely explain greater risk of the disease. METHODS We performed exome sequencing on 50 BPD-affected and unaffected twin pairs using DNA isolated from neonatal blood spots and identified genes affected by extremely rare nonsynonymous mutations. Functional genomic approaches were then used to systematically compare these affected genes. MEASUREMENTS AND MAIN RESULTS We identified 258 genes with rare nonsynonymous mutations in patients with BPD. These genes were highly enriched for processes involved in pulmonary structure and function including collagen fibril organization, morphogenesis of embryonic epithelium, and regulation of Wnt signaling pathway; displayed significantly elevated expression in fetal and adult lungs; and were substantially up-regulated in a murine model of BPD. Analyses of mouse mutants revealed their phenotypic enrichment for embryonic development and the cyanosis phenotype, a clinical manifestation of BPD. CONCLUSIONS Our study supports the role of rare variants in BPD, in contrast with the role of common variants targeted by genome-wide association studies. Overall, our study is the first to sequence BPD exomes from newborn blood spot samples and identify with high confidence genes implicated in BPD, thereby providing important insights into its biology and molecular etiology.

The accuracy of human senses in the detection of neonatal heart rate during standardized simulated resuscitation: Implications for delivery of care, training and technology design

AIM Auscultation and palpation are recommended methods of determining heart rate (HR) during neonatal resuscitation. We hypothesized that: (a) detection of HR by auscultation or palpation will vary by more than ± 15BPM from actual HR; and (b) the inability to accurately determine HR will be associated with errors in management of the neonate during simulated resuscitation. SUBJECTS AND METHODS Using a prospective, randomized, controlled study design, 64 subjects participated in three simulated neonatal resuscitation scenarios. Subjects were randomized to technique used to determine HR (auscultation or palpation) and scenario order. Subjects verbalized their numeric assessment of HR at the onset of the scenario and after any intervention. Accuracy of HR determination and errors in resuscitation were recorded. Errors were classified as errors of omission (lack of appropriate interventions) or errors of commission (inappropriate interventions). Cochrans Q and chi square test were used to compare HR detection by method and across scenarios. RESULTS Errors in HR determination occurred in 26-48% of initial assessments and 26-52% of subsequent assessments overall. There were neither statistically significant differences in accuracy between the two techniques of HR assessment (auscultation vs palpation) nor across the three scenarios. Of the 90 errors in resuscitation, 43 (48%) occurred in association with errors in HR determination. CONCLUSIONS Determination of heart rate via auscultation and palpation by experienced healthcare professionals in a neonatal patient simulator with standardized cues is not reliable. Inaccuracy in HR determination is associated with errors of omission and commission. More reliable methods for HR assessment during neonatal resuscitation are required.

Comparison of Umbilical Venous and Intraosseous Access During Simulated Neonatal Resuscitation

OBJECTIVE: Emergent umbilical venous catheter (UVC) placement for persistent bradycardia in the delivery room is a rare occurrence that requires significant skill and involves space constraints. Placement of an intraosseous needle (ION) in neonates has been well described. The ION is already used in the pediatric population and is placed at an anatomic location distant from where chest compressions are performed. In this study we compared time to placement, errors in placement, and perceived ease of use for UVCs and IONs in a simulated delivery room. SUBJECTS AND METHODS: Forty health care providers were recruited. Subjects were shown an instructional video of both techniques and allowed to practice placement. Subjects participated in 2 simulated neonatal resuscitations requiring intravenous epinephrine. In 1 scenario they were required to place a UVC and in the other an ION. Scenarios were recorded for later analysis of placement time and error rate. Subjects were surveyed regarding the perceived level of difficulty of each technique. RESULTS: The average time required for ION placement was 46 seconds faster than for UVC placement (P < .001). There was no significant difference in the number of errors between UVC and ION placement or in perceived ease of use. CONCLUSIONS: In a simulated delivery room setting, ION placement can be performed more quickly than UVC insertion without any difference in technical error rate or perceived ease of use. ION insertion should be considered when rapid intravenous access is required in the neonate at the time of birth, especially by health care professionals who do not routinely place UVCs.

Therapeutic hypothermia during neonatal transport: data from the California Perinatal Quality Care Collaborative (CPQCC) and California Perinatal Transport System (CPeTS) for 2010

Objective:To evaluate cooling practices and neonatal outcomes in the state of California during 2010 using the California Perinatal Quality Care Collaborative and California Perinatal Transport System databases.Study Design:Database analysis to determine the perinatal and neonatal demographics and outcomes of neonates cooled in transport or after admission to a cooling center.Result:Of the 223 infants receiving therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) in California during 2010, 69% were cooled during transport. Despite the frequent use of cooling in transport, cooling center admission temperature was in the target range (33–34 °C) in only 62 (44%). Among cooled infants, gestational age was <35 weeks in 10 (4.5%). For outborn and transported infants, chronologic age at the time of cooling initiation was >6 h in 20 (11%). When initiated at the birth hospital, cooling was initiated at <6 h of age in 131 (92.9%).Conclusion:More than half of the infants cooled in transport do not achieve target temperature by the time of arrival at the cooling center. The use of cooling devices may improve temperature regulation on transport.

Copy number variation in bronchopulmonary dysplasia.

Copy Number Variation in Bronchopulmonary Dysplasia Thomas J. Hoffmann, Gary M. Shaw, David K. Stevenson, Hui Wang, Cecele C. Quaintance, John Oehlert, Laura L. Jelliffe-Pawlowski, Jeffrey B. Gould, John S. Witte, and Hugh M. O’Brodovich* Department of Epidemiology and Biostatistics and Institute for Human Genetics, University of California San Francisco, San Francisco, California Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California California Genetic Disease Screening Program of the California Department of Public Health, Richmond, California Department of Epidemiology and Biostatistics, Division of Preventive Medicine and Public Health, University of California San Francisco School of Medicine, San Francisco, California California Perinatal Quality Care Collaborative, Stanford, California