Urine biomarkers of acute kidney injury and association with brain MRI abnormalities in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: Determine whether urine biomarkers NGAL (neutrophil gelatinase-associated lipocalin), KIM-1 (kidney injury molecule 1) and IL-18 (interleukin-18) are associated with abnormal MRI findings in neonates with hypoxic-ischemic encephalopathy (HIE) who underwent therapeutic hypothermia (TH). STUDY DESIGN: Secondary analysis of a multicenter, prospective study of neonates with HIE requiring TH. Urine biomarkers were obtained at 12 and 24 h of life (HOL). Brain MRI was scored per NICHD criteria. Association between biomarkers and MRI stage was determined. RESULTS: In 57 neonates with HIE, only IL-18 at 24 HOL was significantly increased in neonates with MRI Stage 2B or greater, compared to Stage 2A or less (mean 398.7 vs. 182.9 pg/mL, p = 0.024.) A multivariate model including IL-18 at 24 HOL and 5-min Apgar performed best, with an AUC of 0.84 (SE = 0.07, p = 0.02). CONCLUSIONS: Elevated urine IL-18 at 24 HOL was associated with more severe brain MRI abnormalities among neonates with HIE.

Minimum Effective Dose of Clemastine in a Mouse Model of Preterm White Matter Injury.

Background: Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification if the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day. Methods: Mouse pups were exposed to normoxia or hypoxia (10% FiO 2 ) from postnatal day 3 (P3) through P10. Vehicle or clemastine fumarate at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given orally to hypoxia-exposed pups. At P14, myelination was assessed by immunohistochemistry and electron microscopy to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment. Results: Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed C max 44.0 ng/mL, t 1/2 4.6 hours, and AUC 24 280.1 ng*hr/mL. Conclusion: Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI. Key Points: Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates.Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment.The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials.We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.

Acute kidney injury in neonates with hypoxic ischemic encephalopathy based on serum creatinine decline compared to KDIGO criteria.

BACKGROUND: Neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia (HIE + TH) are at risk for acute kidney injury (AKI). The standardized Kidney Disease Improving Global Outcomes (KDIGO) criteria identifies AKI based on a rise in serum creatinine (SCr) or reduced urine output. This definition is challenging to apply in neonates given the physiologic decline in SCr during the first week of life. Gupta et al. proposed alternative neonatal criteria centered on rate of SCr decline. This study aimed to compare the rate of AKI based on KDIGO and Gupta in neonates with HIE and to examine associations with mortality and morbidity. METHODS: A retrospective review was performed of neonates with moderate to severe HIE + TH from 2008 to 2020 at a single center. AKI was assessed in the first 7 days after birth by KDIGO and Gupta criteria. Mortality, brain MRI severity of injury, length of stay, and duration of respiratory support were compared between AKI groups. RESULTS: Among 225 neonates, 64 (28%) met KDIGO, 69 (31%) neonates met Gupta but not KDIGO, and 92 (41%) did not meet either definition. Both KDIGO-AKI and GuptaOnly-AKI groups had an increased risk of the composite mortality and/or moderate/severe brain MRI injury along with longer length of stay and prolonged duration of respiratory support compared to those without AKI. CONCLUSIONS: AKI in neonates with HIE + TH was common and varied by definition. The Gupta definition based on rate of SCr decline identified additional neonates not captured by KDIGO criteria who are at increased risk for adverse outcomes. Incorporating the rate of SCr decline into the neonatal AKI definition may increase identification of clinically relevant kidney injury in neonates with HIE + TH.

The contribution of neutrophils to bacteriophage clearance and pharmacokinetics in vivo.

With the increasing prevalence of antimicrobial-resistant bacterial infections, there is great interest in using lytic bacteriophages (phages) to treat such infections. However, the factors that govern bacteriophage pharmacokinetics in vivo remain poorly understood. Here, we have examined the contribution of neutrophils, the most abundant phagocytes in the body, to the pharmacokinetics of intravenously administered bacteriophage in uninfected mice. A single dose of LPS-5, an antipseudomonal bacteriophage recently used in human clinical trials, was administered intravenously to both wild-type BALB/c and neutropenic ICR mice. Phage concentrations were assessed in peripheral blood and spleen at 0.5, 1, 2, 4, 8, 12, and 24 hours after administration by plaque assay and qPCR. We observed that the phage clearance is only minimally affected by neutropenia. Indeed, the half-life of phages in blood in BALB/c and ICR mice is 3.45 and 3.66 hours, respectively. These data suggest that neutrophil-mediated phagocytosis is not a major determinant of phage clearance. Conversely, we observed a substantial discrepancy in circulating phage levels over time when measured by qPCR versus plaque assay, suggesting that substantial functional inactivation of circulating phages occurs over time. These data indicate that circulating factors, but not neutrophils, inactivate intravenously administered phages.

Resource Utilization and Costs Associated with Approaches to Identify Infants with Early-Onset Sepsis.

Objective. To compare resource utilization and costs associated with 3 alternative screening approaches to identify early-onset sepsis (EOS) in infants born at ≥35 wk of gestational age, as recommended by the American Academy of Pediatrics (AAP) in 2018. Study Design. Decision tree-based cost analysis of the 3 AAP-recommended approaches: 1) categorical risk assessment (categorization by chorioamnionitis exposure status), 2) neonatal sepsis calculator (a multivariate prediction model based on perinatal risk factors), and 3) enhanced clinical observation (assessment based on serial clinical examinations). We evaluated resource utilization and direct costs (2022 US dollars) to the health system. Results. Categorical risk assessment led to the greatest neonatal intensive care unit usage (210 d per 1,000 live births) and antibiotic exposure (6.8%) compared with the neonatal sepsis calculator (112 d per 1,000 live births and 3.6%) and enhanced clinical observation (99 d per 1,000 live births and 3.1%). While the per-live birth hospital costs of the 3 approaches were similar-categorical risk assessment cost $1,360, the neonatal sepsis calculator cost $1,317, and enhanced clinical observation cost $1,310-the cost of infants receiving intervention under categorical risk assessment was approximately twice that of the other 2 strategies. Results were robust to variations in data parameters. Conclusion. The neonatal sepsis calculator and enhanced clinical observation approaches may be preferred to categorical risk assessment as they reduce the number of infants receiving intervention and thus antibiotic exposure and associated costs. All 3 approaches have similar costs over all live births, and prior literature has indicated similar health outcomes. Inclusion of downstream effects of antibiotic exposure in the neonatal period should be evaluated within a cost-effectiveness analysis. Highlights: Of the 3 approaches recommended by the American Academy of Pediatrics in 2018 to identify early-onset sepsis in infants born at ≥35 weeks, the categorical risk assessment approach leads to about twice as many infants receiving evaluation to rule out early-onset sepsis compared with the neonatal sepsis calculator and enhanced clinical observation approaches.While the hospital costs of the 3 approaches were similar over the entire population of live births, the neonatal sepsis calculator and enhanced clinical observation approaches reduce antibiotic exposure, neonatal intensive care unit admission, and hospital costs associated with interventions as part of the screening approach compared with the categorical risk assessment approach.

A Population Model of Time-Dependent Changes in Serum Creatinine in (Near)term Neonates with Hypoxic-Ischemic Encephalopathy During and After Therapeutic Hypothermia.

The objective was to apply a population model to describe the time course and variability of serum creatinine (sCr) in (near)term neonates with moderate to severe encephalopathy during and after therapeutic hypothermia (TH). The data consisted of sCr observations up to 10 days of postnatal age in neonates who underwent TH during the first 3 days after birth. Available covariates were birth weight (BWT), gestational age (GA), survival, and acute kidney injury (AKI). A previously published population model of sCr kinetics in neonates served as the base model. This model predicted not only sCr but also the glomerular filtration rate normalized by its value at birth (GFR/GFR0). The model was used to compare the TH neonates with a reference full term non-asphyxiated population of neonates. The estimates of the model parameters had good precision and showed high between subject variability. AKI influenced most of the estimated parameters denoting a strong impact on sCr kinetics and GFR. BWT and GA were not significant covariates. TH transiently increased [Formula: see text] in TH neonates over the first days compared to the reference group. Asphyxia impacted not only GFR, but also the [Formula: see text] synthesis rate. We also observed that AKI neonates exhibit a delayed onset of postnatal GFR increase and have a higher [Formula: see text] synthesis rate compared to no-AKI patients. Our findings show that the use of [Formula: see text] as marker of renal function in asphyxiated neonates treated with TH to guide dose selection for renally cleared drugs is challenging, while we captured the postnatal sCr patterns in this specific population.

Rectal administration of tacrolimus protects against post-ERCP pancreatitis in mice.

OBJECTIVE: There is an unmet clinical need for effective, targeted interventions to prevent post-ERCP pancreatitis (PEP). We previously demonstrated that the serine-threonine phosphatase, calcineurin (Cn) is a critical mediator of PEP and that the FDA-approved calcineurin inhibitors, tacrolimus (Tac) or cyclosporine A, prevented PEP. Our recent observations in preclinical PEP models demonstrating that Cn deletion in both pancreatic and hematopoietic compartments is required for maximal pancreas protection, highlighted the need to target both systemic and pancreas-specific Cn signaling. We hypothesized that rectal administration of Tac would effectively mitigate PEP by ensuring systemic and pancreatic bioavailability of Tac. We have tested the efficacy of rectal Tac in a preclinical PEP model and in cerulein-induced experimental pancreatitis. METHODS: C57BL/6 mice underwent ductal cannulation with saline infusion to simulate pressure-induced PEP or were given seven, hourly, cerulein injections to induce pancreatitis. To test the efficacy of rectal Tac in pancreatitis prevention, a rectal Tac suppository (1 mg/kg) was administered 10 min prior to cannulation or first cerulein injection. Histological and biochemical indicators of pancreatitis were evaluated post-treatment. Pharmacokinetic parameters of Tac in the blood after rectal delivery compared to intravenous and intragastric administration was evaluated. RESULTS: Rectal Tac was effective in reducing pancreatic injury and inflammation in both PEP and cerulein models. Pharmacokinetic studies revealed that the rectal administration of Tac helped achieve optimal blood levels of Tac over an extended time compared to intravenous or intragastric delivery. CONCLUSION: Our results underscore the effectiveness and clinical utility of rectal Tac for PEP prophylaxis.

Incidence of Neonatal Hypothermia in the Newborn Nursery and Associated Factors.

Importance: Thermoregulation is a key component of well-newborn care. There is limited epidemiologic data on hypothermia in late preterm and term infants admitted to the nursery. Expanding on these data is essential for advancing evidence-based care in a population that represents more than 3.5 million births per year in the US. Objective: To examine the incidence and factors associated with hypothermia in otherwise healthy infants admitted to the newborn nursery following delivery. Design, Setting, and Participants: A retrospective cohort study using electronic health record data from May 1, 2015, to August 31, 2021, was conducted at a newborn nursery at a university-affiliated children's hospital. Participants included 23 549 infants admitted to the newborn nursery, from which 321 060 axillary and rectal temperature values were analyzed. Exposures: Infant and maternal clinical and demographic factors. Main Outcomes and Measures: Neonatal hypothermia was defined according to the World Health Organization threshold of temperature less than 36.5 °C. Hypothermia was further classified by severity (mild: single episode, temperature 36.0-36.4 °C; moderate/severe: persistent or recurrent hypothermia and/or temperature <36.0 °C) and timing (early: all hypothermic episodes occurred within the first 24 hours after birth; late: any episode extended beyond the first 24 hours). Results: Of 23 549 included infants (male, 12 220 [51.9%]), 5.6% were late preterm (35-36 weeks' gestation) and 4.3% were low birth weight (≤2500 g). The incidence of mild hypothermia was 17.1% and the incidence of moderate/severe hypothermia was 4.6%. Late hypothermia occurred in 1.8% of infants. Lower birth weight and gestational age and Black and Asian maternal race and ethnicity had the highest adjusted odds across all classifications of hypothermia. The adjusted odds ratios of moderate/severe hypothermia were 5.97 (95% CI 4.45-8.00) in infants with a birth weight less than or equal to 2500 vs 3001 to 3500 g, 3.17 (95% CI 2.24-4.49) in 35 week' vs 39 weeks' gestation, and 2.65 (95% CI 1.78-3.96) in infants born to Black mothers and 1.94 (95% CI 1.61-2.34) in infants born to Asian mothers vs non-Hispanic White mothers. Conclusions and Relevance: In this cohort study of infants in the inpatient nursery, hypothermia was common, and the incidence varied by hypothermia definition applied. Infants of lower gestational age and birth weight and those born to Black and Asian mothers carried the highest odds of hypothermia. These findings suggest that identifying biological, structural, and social determinants of hypothermia is essential for advancing evidence-based equitable thermoregulatory care.

Impact of model-informed precision dosing on achievement of vancomycin exposure targets in pediatric patients with cystic fibrosis.

BACKGROUND: Vancomycin is commonly used to treat acute pulmonary exacerbations in pediatric patients with cystic fibrosis (CF) and a history of methicillin-resistant Staphylococcus aureus. Optimizing vancomycin exposure during therapy is essential and area under-the-curve (AUC)-guided dosing is now recommended. Model-informed precision dosing (MIPD) utilizing Bayesian forecasting is a powerful approach that can support AUC-guided dose individualization. The objective of the current study was to examine the impact of implementing an AUC-guided dose individualization approach supported via a MIPD clinical decision support (CDS) tool on vancomycin exposure, target attainment rate, and safety in pediatric patients with CF treated with vancomycin during clinical care. METHODS: A retrospective chart review was performed in patients with CF at a single children's hospital comparing pre- and post-implementation of a MIPD approach for vancomycin supported by a cloud-based, CDS tool integrated into the electronic health record (EHR). In the pre-MIPD period, vancomycin starting doses of 60 mg/kg/day (<13 years) or 45 mg/kg/day (≥13 years) were used. Dose adjustment was guided by therapeutic drug monitoring (TDM) with a target trough 10-20 mg/L. In the post-MIPD period, starting dose and dose adjustment were based on the MIPD CDS tool predictions with a target 24 h AUC (AUC24 ) 400-600 mg*h/L. Exposure and target achievement rates were retrospectively calculated and compared. Rates of acute kidney injury (AKI) were also compared. RESULTS: Overall, 23 patient courses were included in the pre-MIPD period and 21 patient courses in the post-MIPD period. In the post-MIPD period, an individualized MIPD starting dose resulted in 71% of patients achieving target AUC24 compared to 39% in the pre-MIPD period (p < 0.05). After the first TDM and dose adjustment, target AUC24 achievement was also higher post-MIPD versus pre-MIPD (86% vs. 57%; p < 0.05). AKI rates were low and similar between periods (pre-MIPD 8.7% vs. post-MIPD 9.5%; p = 0.9). CONCLUSION: An MIPD approach implemented within a cloud-based, EHR-integrated CDS tool safely supported vancomycin AUC-guided dosing and resulted in high rates of target achievement.

Renal Oxygen Saturations and Acute Kidney Injury in the Preterm Infant with Patent Ductus Arteriosus.

OBJECTIVE: Decreased near-infrared spectroscopy (NIRS) measures of renal oxygen saturation (Rsat) have identified preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA). NIRS may further identify infants at risk for acute kidney injury (AKI) in a population with concern for hsPDA. STUDY DESIGN: Review of infants ≤29 weeks' gestation undergoing NIRS and echocardiography due to concern for hsPDA. The hsPDA was defined by two of the following: moderate-large size, left to right shunt, aortic flow reversal, left atrial enlargement. AKI was defined by neonatal modified Kidney Disease Improving Global Outcomes (KDIGO). Rsat and cerebral saturation (Csat), averaged over 1 hour, were evaluated for the 24-hour period around echocardiography. RESULTS: Among 77 infants, 29 (38%) had AKI by neonatal modified KDIGO criteria. hsPDA was found on echocardiography in 59 (77%). There were no differences in hsPDA in infants with and without AKI (p = 0.1). Rsat was not associated with AKI (p = 0.3). Infants on dopamine had less Rsat variability (p < 0.01). CONCLUSION: Rsat prior to echocardiography did not discriminate AKI in this cohort of preterm infants at risk for hsPDA; however, data may not capture optimal timing of Rsat measurement before AKI. KEY POINTS: · No Rsat value was found to be associated with the development of AKI.. · The optimal timing of Rsat measurement should be evaluated in infants at risk for hsPDA.. · NIRS bedside monitoring of Csat and Rsat measures may be useful in trending perfusion patterns.. · Identification of those at high risk for AKI may allow for more careful kidney function monitoring..

Fewer glucose checks and decreased supplementation using dextrose gel for asymptomatic neonatal hypoglycemia.

OBJECTIVE: Evaluate the impact of a neonatal hypoglycemia (NH) clinical pathway implementing buccal dextrose gel in late preterm and term infants. STUDY DESIGN: Quality improvement study at a children's hospital associated birth center. Number of blood glucose checks, use of supplemental milk, and need for IV glucose were followed for 26-months after implementation of dextrose gel and compared to previous 16-month period. RESULTS: After QI implementation, 2703 infants were screened for hypoglycemia. Of these, 874 (32%) received at least one dose of dextrose gel. Special cause shifts with reductions in mean number of blood glucose checks per infant (pre 6.6 vs. post 5.6), use of supplemental milk (pre 42% vs. post 30%), and need for IV glucose (pre 4.8% vs. post 3.5%) were found. CONCLUSION: Incorporating dextrose gel into a clinical pathway for NH was associated with a sustained reduction in number of interventions, use of supplemental milk and need for IV glucose.

Renal oximetry for early acute kidney injury detection in neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia.

BACKGROUND: Neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia are at high risk of acute kidney injury (AKI). METHODS: We performed a two-site prospective observational study from 2018 to 2019 to evaluate the utility of renal near-infrared spectroscopy (NIRS) in detecting AKI in 38 neonates with HIE receiving therapeutic hypothermia. AKI was defined by a delayed rate of serum creatinine decline (< 33% on day 3 of life, < 40% on day 5, and < 46% on day 7). Renal saturation (Rsat) and systemic oxygen saturation (SpO2) were continuously measured for the first 96 h of life (HOL). Renal fractional tissue oxygen extraction (RFTOE) was calculated as (SpO2 - Rsat)/(SpO2). Using renal NIRS, urine biomarkers, and perinatal factors, logistic regression was performed to develop a model that predicted AKI. RESULTS: AKI occurred in 20 of 38 neonates (53%). During the first 96 HOL, Rsat was higher, and RFTOE was lower in the AKI group vs. the no AKI group (P < 0.001). Rsat > 70% had a fair predictive performance for AKI at 48-84 HOL (AUC 0.71-0.79). RFTOE ≤ 25 had a good predictive performance for AKI at 42-66 HOL (AUC 0.8-0.83). The final statistical model with the best fit to predict AKI (AUC = 0.88) included RFTOE at 48 HOL (P = 0.012) and pH of the infants' first postnatal blood gas (P = 0.025). CONCLUSIONS: Lower RFTOE on renal NIRS and pH on infant first blood gas may be early predictors for AKI in neonates with HIE receiving therapeutic hypothermia. A higher resolution version of the Graphical abstract is available as Supplementary information.

Evaluation of Neonatal and Paediatric Vancomycin Pharmacokinetic Models and the Impact of Maturation and Serum Creatinine Covariates in a Large Multicentre Data Set.

BACKGROUND AND OBJECTIVE: Infants and neonates present a clinical challenge for dosing drugs with high interindividual variability due to these patients' rapid growth and the interplay between maturation and organ function. Model-informed precision dosing (MIPD), which can account for interindividual variability via patient characteristics and Bayesian forecasting, promises to improve individualized dosing strategies in this complex population. Here, we assess the predictive performance of published population pharmacokinetic models describing vancomycin in neonates and infants, and analyze the robustness of these models in the face of clinical uncertainty surrounding covariate values. METHODS: The predictive precision and bias of nine pharmacokinetic models were compared in a large multi-site data set (N = 2061 patients, 5794 drug levels, 28 institutions) of patients aged 0-365 days. The robustness of model predictions to errors in serum creatinine measurements and gestational age was assessed by using recorded values or by replacing covariate values with 0.3, 0.5 or 0.8 mg/dL or with 40 weeks, respectively. RESULTS: Of the nine models, two models (Dao and Jacqz-Aigrain) resulted in predicted concentrations within 2.5 mg/L or 15% of the measured values for at least 60% of population predictions. Within individual models, predictive performance often 2 differed in neonates (0-4 weeks) versus older infants (15-52 weeks). For preterm neonates, imputing gestational age as 40 weeks reduced the accuracy of model predictions. Measured values of serum creatinine improved model predictions compared to using imputed values even in neonates ≤1 week of age. CONCLUSIONS: Several available pharmacokinetic models are suitable for MIPD in infants and neonates. Availability and accuracy of model covariates for patients will be important for guiding dose decision-making.

Serum Creatinine Patterns in Neonates Treated with Therapeutic Hypothermia for Neonatal Encephalopathy.

INTRODUCTION: There is large variability in kidney function and injury in neonates with neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH). Acute kidney injury (AKI) definitions that apply categorical approaches may lose valuable information about kidney function in individual patients. Centile serum creatinine (SCr) over postnatal age (PNA) may provide more valuable information in TH neonates. METHODS: Data from seven TH neonates and one non-TH-treated, non-NE control cohorts were pooled in a retrospective study. SCr centiles over PNA, and AKI incidence (definition: SCr ↑≥0.3 mg/dL within 48 h, or ↑ ≥1.5 fold vs. the lowest prior SCr within 7 days) and mortality were calculated. Repeated measurement linear models were applied to SCr trends, modeling SCr on PNA, birth weight or gestational age (GA), using heterogeneous autoregressive residual covariance structure and maximum likelihood methods. Findings were compared to patterns in the control cohort. RESULTS: Among 1,136 TH neonates, representing 4,724 SCr observations, SCr (10th-25th-50th-75th-90th-95th) PNA centiles (day 1-10) were generated. In TH neonates, the AKI incidence was 132/1,136 (11.6%), mortality 193/1,136 (17%). AKI neonates had a higher mortality (37.2-14.3%, p < 0.001). Median SCr patterns over PNA were significantly higher in nonsurvivors (p < 0.01) or AKI neonates (p < 0.001). In TH-treated neonates, PNA and GA or birth weight explained SCr variability. Patterns over PNA were significantly higher in TH neonates to controls (801 neonates, 2,779 SCr). CONCLUSIONS: SCr patterns in TH-treated NE neonates are specific. Knowing PNA-related patterns enable clinicians to better assess kidney function and tailor pharmacotherapy, fluids, or kidney supportive therapies.

Oral hymecromone decreases hyaluronan in human study participants.

BACKGROUNDHyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODSWe conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum.RESULTSHymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA.CONCLUSIONAfter 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT02780752.FUNDINGStanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970.

Epidemiology and trends in neonatal early onset sepsis in California, 2010-2017.

OBJECTIVE: This study evaluated patterns of neonatal early onset sepsis (EOS) disease burden to guide approaches to EOS management. STUDY DESIGN: Retrospective cohort. RESULT: A total of 1535 EOS cases were identified amongst 2,872,964 neonates born between 2010 and 2017 at 136 NICUs within the California Perinatal Quality Care Collaborative. EOS incidence was 7.4 per 1000 (E coli: 4.3, GBS: 1.1) in preterm, 0.76 per 1000 (E coli: 0.29, GBS: 0.22) in late preterm, and 0.31 per 1000 (E coli: 0.07, GBS 0.13) in term neonates. There was no significant change in overall incidence, though an increase in E coli (p < 0.001) and decrease in GBS (p = 0.04) incidence were noted. After adjusting for gestational age, there was no difference in the odds of death by pathogen (p > 0.2). CONCLUSION: The overall EOS incidence remained steady in California NICUs from 2010-2017, though an increase in E coli and decrease in GBS EOS incidence was noted.

Urine Biomarkers for the Assessment of Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia.

OBJECTIVE: To evaluate the predictive performance of urine biomarkers for acute kidney injury (AKI) in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia. STUDY DESIGN: We performed a multicenter prospective observational study of 64 neonates. Urine specimens were obtained at 12, 24, 48, and 72 hours of life and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, interleukin-18 (IL-18), tissue inhibitor of metalloproteinases 2 (TIMP2), and insulin-like growth factor-binding protein 7 (IGFBP7). Logistic regression models with receiver operating characteristics for area under the curve (AUC) were used to assess associations with neonatal modified KDIGO (Kidney Disease: Improving Global Outcomes) AKI criteria. RESULTS: AKI occurred in 16 of 64 infants (25%). Neonates with AKI had more days of vasopressor drug use compared with those without AKI (median [IQR], 2 [0-5] days vs 0 [0-2] days; P = .026). Mortality was greater in neonates with AKI (25% vs 2%; P = .012). Although NGAL, KIM-1, and IL-18 were significantly associated with AKI, the AUCs yielded only a fair prediction. KIM-1 had the best predictive performance across time points, with an AUC (SE) of 0.79 (0.11) at 48 hours of life. NGAL and IL-18 had AUCs (SE) of 0.78 (0.09) and 0.73 (0.10), respectively, at 48 hours of life. CONCLUSIONS: Urine NGAL, KIM-1, and IL-18 levels were elevated in neonates with HIE receiving therapeutic hypothermia who developed AKI. However, wide variability and unclear cutoff levels make their clinical utility unclear.

A population physiologically-based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab.

AIMS: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in paediatric patients, there is a need to develop systems PK models that integrate ontogeny-related changes in human physiological parameters. METHODS: A population-based physiological-based PK (PBPK) model to characterize antibody PK in paediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose-exposure relationships for infliximab. RESULTS: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two paediatric cohorts (n = 141, 4-19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody. CONCLUSION: The paediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in paediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

A Clinical Monitoring Approach for Early Onset Sepsis: A Community Hospital Experience.

BACKGROUND: A serial clinical examination approach to screen late preterm and term neonates at risk for early onset sepsis has been shown to be effective in large academic centers, resulting in reductions in laboratory testing and antibiotic use. The implementation of this approach in a community hospital setting has not been reported. Our objective was to adapt a clinical examination approach to our community hospital, aiming to reduce antibiotic exposure and laboratory testing. METHODS: At a community hospital with a level III NICU and >4500 deliveries annually, the pathway to evaluate neonates ≥35 weeks at risk for early onset sepsis was revised to focus on clinical examination. Well-appearing neonates regardless of perinatal risk factor were admitted to the mother baby unit with serial vital signs and clinical examinations performed by a nurse. Neonates symptomatic at birth or who became symptomatic received laboratory evaluation and/or antibiotic treatment. Antibiotic use, laboratory testing, and culture results were evaluated for the 14 months before and 19 months after implementation. RESULTS: After implementation of the revised pathway, antibiotic use decreased from 6.7% (n = 314/4694) to 2.6% (n = 153/5937; P < .001). Measurement of C-reactive protein decreased from 13.3% (n = 626/4694) to 5.3% (n = 312/5937; P < .001). No cases of culture-positive sepsis occurred, and no neonate was readmitted within 30 days from birth with a positive blood culture. CONCLUSIONS: A screening approach for early onset sepsis focused on clinical examination was successfully implemented at a community hospital setting resulting in reduction of antibiotic use and laboratory testing without adverse outcomes.