A Deep Intronic PKHD1 Variant Identified by SpliceAI in a Deceased Neonate With Autosomal Recessive Polycystic Kidney Disease.

The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans with a pathogenic missense variant (p.Thr36Met), in a newborn who died of autosomal recessive polycystic kidney disease at age 2 days. We validated the deep intronic variant's impact in maternal urine-derived cells expressing PKHD1. Reverse transcription polymerase chain reaction followed by Sanger sequencing showed that the variant causes inclusion of 147bp of the canonical intron between exons 29 and 30 of PKHD1 into the mRNA, including a premature stop codon. Allele-specific expression analysis at a heterozygous site in the mother showed that the mutant allele completely suppresses canonical splicing. In an unrelated healthy control, there was no evidence of transcripts including the novel splice junction. We returned a diagnostic report to the parents, who underwent in vitro embryo selection.

Diagnosis-Related Group Weight and Derived Case Mix Index to Assess the Complexity among Twins.

OBJECTIVE: Diagnosis-related groups (DRGs) are used to summarize hospital morbidity and mortality. Each DRG has a weight which is important in calculating the case mix index (CMI), a numeric summary of disease complexity in a population of patients. We utilized DRG weight and resultant CMI to compare postnatal outcomes among singletons versus monochorionic and monoamniotic, monochorionic diamniotic, and dichorionic diamniotic twins. STUDY DESIGN: This single-center and retrospective cohort study evaluated DRGs assigned by the investigators, birth weight, gestational age, length of stay (LOS), NICU admission rate, and mortality in twin births between 2014 and 2016. Twins were analyzed depending on chorionicity and amnionicity. Overall, 3 months of singleton births served as the control. The CMI derived from DRG weights were compared across groups. RESULTS: Twins (n = 288) had lower gestational ages and birth weights and higher mortality, LOS, NICU admission rates and DRG weights/CMI compared with singletons (n = 327; p < 0.001 for each). The LOS was no different between twin subtypes; monochorionic monoamniotic twins had the highest mortality and DRG weight (p < 0.001). CONCLUSION: DRG weight and CMI values summarize in-hospital complexity and can be a useful tool to evaluate differences in care complexity among groups of patients. KEY POINTS: · Using diagnosis-related group and case mix index to assess morbidities.. · Morbidities of twins are monochorionic-monoamniotic versus monochorionic-diamniotic versus dichorionic-diamniotic twins.. · Only seven diagnosis-related group in neonatology make it a valuable tool for clinicians..

Model-Based Approach for Optimizing Ceftobiprole Dosage in Pediatric Patients.

Ceftobiprole is an advanced-generation cephalosporin for intravenous administration with activity against Gram-positive and Gram-negative organisms. A population pharmacokinetic (PK) model characterizing the disposition of ceftobiprole in plasma using data from patients in three pediatric studies was developed. Model-based simulations were subsequently performed to assist in dose optimization for the treatment of pediatric patients with hospital-acquired or community-acquired pneumonia. The population PK data set comprised 518 ceftobiprole plasma concentrations from 107 patients from 0 (birth) to 17 years of age. Ceftobiprole PK was well described by a three-compartment model with linear elimination. Ceftobiprole clearance was modeled as a function of glomerular filtration rate; other PK parameters were scaled to body weight. The final population PK model provided a robust and reliable description of the PK of ceftobiprole in the pediatric study population. Model-based simulations using the final model suggested that a ceftobiprole dose of 15 mg/kg of body weight infused over 2 h and administered every 12 h in neonates and infants <3 months of age or every 8 h in older pediatric patients would result in a ceftobiprole exposure consistent with that in adults and good pharmacokinetic-pharmacodynamic target attainment. The dose should be reduced to 10 mg/kg every 12 h in neonates and infants <3 months of age who weigh <4 kg to avoid high exposures. Extended intervals and reduced doses may be required for pediatric patients older than 3 months of age with renal impairment.

Pharmacokinetics and Safety of Ceftobiprole in Pediatric Patients.

BACKGROUND: Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced-generation, broad-spectrum, intravenous cephalosporin, which is currently approved for the treatment of adults with hospital-acquired or community-acquired pneumonia. METHODS: Noncompartmental pharmacokinetics and safety were analyzed from 2 recently completed pediatric studies, a single-dose, phase 1 study in neonates and infants up to 3 months of age (7.5 mg/kg) and a phase 3 study in patients 3 months to 17 years of age with pneumonia (10-20 mg/kg with a maximum of 500 mg per dose every 8 hours for up to 14 days). RESULTS: Total ceftobiprole plasma concentrations peaked at the end of infusion. Half life (median ranging from 1.9 to 2.9 hours) and overall exposure (median AUC ranging from 66.6 to 173 µg•h/mL) were similar to those in adults (mean ± SD, 3.3 ± 0.3 hours and 102 ± 11.9 µg•h/mL, respectively). Calculated free-ceftobiprole concentrations in the single-dose study remained above a minimum inhibitory concentration (MIC) of 4 mg/L (fT > MIC of 4 mg/L) for a mean of 5.29 hours after dosing. In the pneumonia study, mean fT > MIC of 4 mg/L was ≥5.28 hours in all dose groups. Ceftobiprole was well tolerated in both studies. CONCLUSIONS: Pharmacokinetic parameters of ceftobiprole characterized in the pediatric population were within the range of those observed in adults. In the pneumonia study, the lowest percentage of the dosing interval with fT > MIC of 4 mg/L was 50.8%, which suggests that pharmacokinetic-pharmacodynamic target attainment can be sufficient in pediatric patients. Ceftobiprole was well tolerated.

Is friday the busiest for late preterm delivery?

BACKGROUND: As a level Illc NICU serving north central West Virginia, we have observed that many of our admissions of infants GA 33-37 weeks occurred on Friday. OBJECTIVE: To investigate the distribution of delivery days for infants with GA between 33-37 wk. DESIGN/METHODS: Data of admitted infants are tracked through medical record from January 2002 to September 2006. The deliveries per day of the week (DOW) were compared. RESULTS: Of 1471 admission, the highest rate of delivery occurring on Fridays; lowest on Sundays. An unequal distribution of delivery DOW in infant GA 33-35 was observed, with the highest rate of delivery occurring on Wednesday. An unequal distribution of delivery DOW was also noted in infants with GA 36-37. However, Friday was noted as the most frequent DOW for delivery in this group. CONCLUSIONS: This Friday delivery phenomenon suggests delivery practices that may affect premature delivery, their morbidity and increased NICU occupancy.

Clinical trial of safety and efficacy of INH-A21 for the prevention of nosocomial staphylococcal bloodstream infection in premature infants.

OBJECTIVE: To determine if INH-A21, an intravenous immune globulin (IGIV) derived from donors with high titers of antibody to surface adhesins of Staphylococcus epidermidis and S. aureus prevents late-onset sepsis (LOS) in very low birth weight (VLBW) infants. STUDY DESIGN: In this double-blind, placebo-controlled study, infants with birth weights 500 to 1250 g were randomized to receive up to four doses of INH-A21 (Veronate) or placebo. The primary objective was to determine the safety and efficacy of INH-A21 versus placebo for prevention of S. aureus LOS in VLBW infants. RESULTS: A total of 1983 infants from 95 neonatal intensive care units were randomized, and received at least one dose of study drug. S. aureus LOS developed in 50 of 989 (5%) and 60 of 994 (6%) infants who received placebo or INH-A21, respectively (P = .34). No differences were found in the frequencies of LOS caused by coagulase-negative staphylococci (CoNS), Candida spp, or overall mortality. No adverse events were statistically significantly associated with INH-A21 infusions compared with placebo. CONCLUSION: INH-A21 failed to reduce the incidence of staphylococcal LOS or candidemia in premature infants.

A proposed classification for the spectrum of vanishing gastroschisis.

Infants born with gastroschisis in association with intestinal atresia are well described. We are the proposing the classification of vanishing gastroschisis. In this series of six cases, at one end of the spectrum is an infant having gastroschisis with a much narrower defect on the right side of umbilicus. The ischemic bowel loops were connected to bowel inside the abdomen by a fibrous band compressing the exposed bowel mesentery. On the other end of spectrum, an infant having extensive bowel atresia and complete closure of abdominal wall defect (gastroschisis) detected on antenatal ultrasound. These cases should raise awareness of this devastating complication in prenatal management of gastroschisis.

Management strategies for neonatal hypoglycemia.

While hypoglycemia occurs commonly among neonates, treatment can be challenging if hypoglycemia persists beyond the first few days of life. This review discusses the available treatment options for both transient and persistent neonatal hypoglycemia. These treatment options include dextrose infusions, glucagon, glucocorticoids, diazoxide, octreotide, and nifedipine. A stepwise, practical approach to the management of these patients is offered.

Cost-effectiveness analysis of palivizumab among pre-term infant populations covered by Medicaid in the United States.

OBJECTIVE: Medicaid infants are at high risk of severe respiratory syncytial virus (RSV) disease. The study objective was to estimate the cost-effectiveness of palivizumab in a Medicaid population. METHODS: A societal cost-utility analysis was conducted of prophylaxis with palivizumab vs no prophylaxis among four groups of premature infants: (1) <32 weeks gestational age (wGA) and ≤ 6 months chronologic age (CA); (2) 32-34 wGA, ≤ 3 months CA with 2009 American Academy of Pediatrics (AAP) risk factors (RF); (3) 32-35 wGA, ≤ 6 months CA with 2006 AAP RF; and (4) 32-35 wGA, ≤ 6 months CA with ≤ 1 RF. Full dosing of palivizumab was assumed throughout the RSV season (consistent with the FDA-approved label). All costs were in 2010 US dollars. The societal public payer spend for palivizumab was estimated using Medicaid reimbursement methodologies for the top 10 palivizumab-using states in 2010 minus mandatory manufacturer rebates. This study reports the incremental cost-effectiveness ratios (ICERs) in cost per quality-adjusted life-year (QALY) gained. Sensitivity and probabilistic analyses were also conducted. RESULTS: Palivizumab saved costs and improved QALYs among infants <32 wGA. Palivizumab was cost-effective in infants 32-34 wGA with 2009 AAP RF ($16,037 per QALY) and in infants 32-35 wGA with 2006 AAP RF ($38,244 per QALY). The ICER for infants 32-35 wGA with ≤ 1 RF was $281,892 per QALY. Influential variables in the sensitivity analysis included the background rate of RSV hospitalization, the cost of palivizumab, and the efficacy of palivizumab. KEY LIMITATIONS: These results are not generalizable to commercially insured infants or infants outside of the US. CONCLUSIONS: This is the first cost-utility analysis of palivizumab in a Medicaid population. Palivizumab, when dosed consistent with the FDA-approved labeling, was either cost-saving or cost-effective among current guideline-eligible infants in the Medicaid population. Palivizumab did not demonstrate cost-effectiveness in 32-35 wGA infants with ≤ 1 RF.

Cost utility of palivizumab prophylaxis among pre-term infants in the United States: a national policy perspective.

OBJECTIVE: The cost-effectiveness of palivizumab has previously been reported among certain guideline-eligible, high-risk premature infants in Medicaid. Because guideline authorities base decisions on a national perspective, the economic model of palivizumab was adapted to include all infants, that is, public and privately insured patients (60% of palivizumab use is public, 40% is private). METHODS: This study examined four groups of premature infants without chronic lung disease of prematurity or congenital heart disease: (1) <32 weeks gestational age (wGA) and ≤ 6 months chronologic age (CA); (2) 32-34 wGA, ≤ 3 months CA, with 2009 American Academy of Pediatrics (AAP) risk factors (RFs); (3) 32-35 wGA, ≤ 6 months CA, with 2006 AAP RFs; and (4) 32-35 wGA, ≤ 6 months CA, with ≤ 1 RF. An average estimate was used between public and private payors for (1) background rates of respiratory syncytial virus hospitalization (RSV-H), (2) direct medical costs associated with RSV-H, and (3) cost of palivizumab. Incremental cost-effectiveness ratios (ICERs) are reported in cost per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed. RESULTS: Palivizumab saved costs and improved QALYs among infants <32 wGA. Palivizumab was cost-effective in infants 32-34 wGA with 2009 AAP RFs ($44,774 per QALY) and in infants 32-35 wGA with 2006 AAP RFs ($79,477 per QALY). The ICER for infants 32-35 wGA with ≤ 1 RF was $464,476 per QALY. Influential variables in the sensitivity analysis included background rate of RSV-H and cost and efficacy of palivizumab. LIMITATIONS: The results are not generalizable to populations outside of the US. The model did not examine all RFs. The wholesale acquisition cost was used as a payment benchmark; actual price paid by end providers varies. CONCLUSIONS: From a national policy perspective, palivizumab remained cost-effective for publically and commercially insured, guideline-eligible, high-risk premature infants. Palivizumab was not cost-effective in infants of 32-35 wGA with ≤ 1 RF.

Sleep-disordered breathing symptoms frequency and growth among prematurely born infants.

BACKGROUND: Children who were born prematurely are at higher risk for sleep-disordered breathing (SDB) compared to their same-age peers who were born fullterm. OBJECTIVE: The objective of the present study was to assess the frequency of SDB symptoms and effects on growth among preterm infants while they are still infants, with a goal of identifying risk factors to facilitate prevention and early intervention. METHODS: The Louisville pediatric SDB risk survey was administered to the primary caretakers of prematurely born infants attending the Neonatal Follow-Up Clinic at West Virginia University Children's Hospital. RESULTS: Participation was 100% among 173 consecutive patients invited to participate in the study. At 9.13 months corrected age, 8.1% of infants born at a mean of 31.6 weeks gestation were reported to snore > or = 3 days/week, a rate consistent with diagnosis of sleep-disordered breathing among older children. A composite of nine parent-reported symptoms was created based on factor analysis. Birth weight and size for gestational age at birth did not differ between snoring groups or correlate with the composite score. But a significant negative correlation between the composite risk for SDB score and current weight for adjusted age percentile score indicate that infants with higher SDB symptom profiles have lower weight for age (r=-.18, p=.028). CONCLUSIONS: SDB symptoms are detectable among infants born preterm, while they are still infants. Because of their preferential risk for SDB and its somatic consequences, a primary research goal should be description of the natural history of SDB and identification of modifiable risk factors and treatment options.

Oropharyngeal tumor in the newborn: a case report.

BACKGROUND: An oropharyngeal tumor presenting as a protruding mass from the mouth of the newborn infant is very rare. This mass has the potential to obstruct the airway and requires urgent medical management, diagnosis and appropriate surgical management. OBJECTIVES: To report a case of a newborn with an oropharyngeal mass presenting at birth and focus on key clinical issues for the physician faced with the care of such an infant. METHODS AND RESULTS: We describe a newborn infant who was born with a large mass protruding from the oral cavity at birth, without respiratory distress. The mass was surgically removed with no complications. The histology of the mass revealed it to be a pharyngeal dermoid polyp, also called 'hairy polyp'. The infant did well after tumor removal and was discharged home within a couple of days. CONCLUSIONS: We report a case of a newborn with a pharyngeal dermoid polyp presenting as an oropharyngeal mass.

The effect of dopamine on glomerular filtration rate in normotensive, oliguric premature neonates.

We examined the effect of dopamine on glomerular filtration rate (GFR) at infusion rates of 0.5, 2.5, and 7.5 micro g/kg per min in 15 premature neonates. Study infants (mean gestational age 34+/-2 weeks, mean birth weight 2.43+/-0.6 kg) had respiratory distress, were normotensive, and had a low urine output (0.9+/-0.1 ml/kg per hour). GFR was determined by the plasma clearance of inulin after a single bolus injection (200 mg/kg). Four hours after inulin administration, dopamine infusion was begun and continued over 6 h. GFR was estimated before and after beginning the dopamine infusions from the slope of the log of plasma inulin concentration versus time. Gestational age, weight, and baseline GFR were similar in all three groups. With a dopamine infusion rate of 0.5 micro g/kg per min there were no changes in GFR, urine output, heart rate, or blood pressure. At an infusion rate of 7.5 micro g/kg per min there was no change in GFR, although urine output, heart rate, and blood pressure all increased. At 2.5 micro g/kg per min there were significant increases in GFR and urine output, with no changes in blood pressure or heart rate. In oliguric, non-hypotensive neonates, GFR increased significantly at 2.5 micro g/kg per min of dopamine. This probably reflects the effects of afferent vasodilatation and may be important clinically when enhancement of GFR is the major treatment objective.

Nmda alters the development of hypoxic pulmonary vasoconstriction and nitric oxide synthetase activity in the isolated perfused rat lung.

Using an isolated salt-perfused rat lung model, the authors investigated whether N-methyl-D-aspartate (NMDA) (1 mM) in the pulmonary circulation effects the pulmonary vascular responses to an acute stimulus of hypoxic insult under baseline, nitric oxide synthetase (NOS)-blocked conditions (N-omega-nitro-L arginine methyl ester; L-NAME, 2 mM), and with an NMDA receptor blocker, MK-801 (0.3 microM) added. NOS activity at baseline, and in response to hypoxia, NMDA, L-NAME, and a combination of these stimuli were also assessed. NMDA did not in itself alter hypoxic pulmonary vasoconstriction (HPV), but did significantly attenuate HPV during VOS blockade. This effect of NMDA was erased by MK-801. Assessment of NOS activity showed that hypoxia alone caused a doubling of NO production within the lung. This effect was erased by the addition of L-NAME. NMDA alone caused a significant, 3-fold increase in NOS activity, which was not further affected by hypoxic chalenge. L-NAME did not depress NOS activity in the hypoxia + NMDA group. These data suggest that NMDA receptor activation results in increased NOS activity and presumably increased production of NO. The increased NOS activity induced by NMDA receptor stimulation is resistant to the blockade effect of L-NAME. The actions of NMDA receptor activation may represent a natural protective mechanism, at least within the pulmonary vasculature, in face of acute, abnormal stimuli such as hypoxia.