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Background and Objectives: Despite the neonatal opioid withdrawal syndrome (NOWS) epidemic in the United States, evidence is limited for pharmacologic management when first-line opioid medications fail to control symptoms. The objective with this study was to evaluate outcomes of infants receiving secondary therapy with phenobarbital compared with clonidine, in combination with morphine, for the treatment of NOWS., Methods: We performed a retrospective cohort study of infants with NOWS from 30 hospitals. The primary outcome measures were the length of hospital stay, duration of opioid treatment, and peak morphine dose. Outcomes were compared by group by using analysis of variance and multivariable linear regression controlling for relevant confounders., Results: Of 563 infants with NOWS treated with morphine, 32% ( n = 180) also received a secondary medication. Seventy-two received phenobarbital and 108 received clonidine. After adjustment for covariates, length of hospital stay was 10 days shorter, and, in some models, duration of morphine treatment was 7.5 days shorter in infants receiving phenobarbital compared with those receiving clonidine, with no difference in peak morphine dose. Infants were more likely to be discharged from the hospital on phenobarbital than clonidine (78% vs 29%, P < .0001)., Conclusions: Among infants with NOWS receiving morphine and secondary therapy, those treated with phenobarbital had shorter length of hospital stay and shorter morphine treatment duration than clonidine-treated infants but were discharged from the hospital more often on secondary medication. Further investigation is warranted to determine if the benefits of shorter hospital stay and shorter duration of morphine therapy justify the possible neurodevelopmental consequences of phenobarbital use in infants with NOWS., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Whalen is a codeveloper of the ESC Care Tool; Children’s Hospital at Dartmouth-Hitchcock is one of the institutions on the ESC Care Tool copyright; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Trace element selenium (Se) is incorporated as the 21st amino acid, selenocysteine, into selenoproteins through tRNA [Ser]Sec . Selenoproteins act as gatekeepers of redox homeostasis and modulate immune function to effect anti-inflammation and resolution. However, mechanistic underpinnings involving metabolic reprogramming during inflammation and resolution remain poorly understood. Bacterial endotoxin lipopolysaccharide (LPS) activation of murine bone marrow-derived macrophages cultured in the presence or absence of Se (as selenite) was used to examine temporal changes in the proteome and metabolome by multiplexed tandem mass tag-quantitative proteomics, metabolomics, and machine-learning approaches. Kinetic deltagram and clustering analysis indicated that addition of Se led to extensive reprogramming of cellular metabolism upon stimulation with LPS enhancing the pentose phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation, to aid in the phenotypic transition toward alternatively activated macrophages, synonymous with resolution of inflammation. Remodeling of metabolic pathways and consequent metabolic adaptation toward proresolving phenotypes began with Se treatment at 0 h and became most prominent around 8 h after LPS stimulation that included succinate dehydrogenase complex, pyruvate kinase, and sedoheptulokinase. Se-dependent modulation of these pathways predisposed bone marrow-derived macrophages to preferentially increase oxidative phosphorylation to efficiently regulate inflammation and its timely resolution. The use of macrophages lacking selenoproteins indicated that all three metabolic nodes were sensitive to selenoproteome expression. Furthermore, inhibition of succinate dehydrogenase complex with dimethylmalonate affected the proresolving effects of Se by increasing the resolution interval in a murine peritonitis model. In summary, our studies provide novel insights into the role of cellular Se via metabolic reprograming to facilitate anti-inflammation and proresolution., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Bile acids are important end products of cholesterol metabolism, having been shown to serve as signaling molecules and intermediates between the host and the gut microbiota. Here we describe a robust and accurate method using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) for the quantification of bile acids in stool/cecal and tissue samples.

Objectives: Investigate characteristics of term infants culture-evaluated for early-onset sepsis (EOS) in neonatal intensive care units (NICUs), frequencies of organisms causing EOS, and factors associated with EOS., Study Design: Using a cohort design, we identified term infants evaluated for EOS with blood, cerebrospinal fluid, or urine cultures in 326 NICUs (2011-2016). Using multivariable logistic regression, we investigated the association between EOS and demographic characteristics., Results: Of 142,410 infants, 1197 (0.8%) had EOS, most commonly caused by group B Streptococcus (GBS; 40.6%). Lower EOS risk was associated with low Apgar score, Cesarean delivery, small for gestational age, prenatal antibiotic exposure, and positive or unknown maternal GBS screening result. Increased risk was associated with prolonged rupture of membranes, maternal age <19 years, vasopressor treatment, and ventilator support., Conclusion(s): GBS was the most frequent cause of EOS. Early risk factor recognition may help daily management of term infants in NICUs.

Background and Objectives: Variation in pediatric medical care is common and contributes to differences in patient outcomes. Site-to-site variation in the characteristics and care of infants with neonatal opioid withdrawal syndrome (NOWS) has yet to be quantified. Our objective was to describe site-to-site variation in maternal-infant characteristics, infant management, and outcomes for infants with NOWS., Methods: Cross-sectional study of 1377 infants born between July 1, 2016, and June 30, 2017, who were ≥36 weeks' gestation, with NOWS (evidence of opioid exposure and NOWS scoring within the first 120 hours of life) born at or transferred to 1 of 30 participating hospitals nationwide. Site-to-site variation for each parameter within the 3 domains was measured as the range of individual site-level means, medians, or proportions., Results: Sites varied widely in the proportion of infants whose mothers received adequate prenatal care (31.3%-100%), medication-assisted treatment (5.9%-100%), and prenatal counseling (1.9%-75.5%). Sites varied in the proportion of infants with toxicology screening (50%-100%) and proportion of infants receiving pharmacologic therapy (6.7%-100%), secondary medications (1.1%-69.2%), and nonpharmacologic interventions including fortified feeds (2.9%-90%) and maternal breast milk (22.2%-83.3%). The mean length of stay varied across sites (2-28.8 days), as did the proportion of infants discharged with their parents (33.3%-91.1%)., Conclusions: Considerable site-to-site variation exists in all 3 domains. The magnitude of the observed variation makes it unlikely that all infants are receiving efficient and effective care for NOWS. This variation should be considered in future clinical trial development, practice implementation, and policy development., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Emerging evidence supports that exposure to persistent organic pollutants (POPs) can impact the interaction between the gut microbiota and host. Recent efforts have characterized the relationship between gut microbiota and environment pollutants suggesting additional research is needed to understand potential new avenues for toxicity. Here, we systematically examined the direct effects of POPs including 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), and polychlorinated biphenyls (PCB-123 and PCB-156) on the microbiota using metatranscriptomics and NMR- and mass spectrometry-based metabolomics combined with flow cytometry and growth rate measurements (OD 600 ). This study demonstrated that (1) POPs directly and rapidly affect isolated cecal bacterial global metabolism that is associated with significant decreases in microbial metabolic activity; (2) significant changes in cecal bacterial gene expression related to tricarboxylic acid (TCA) cycle as well as carbon metabolism, carbon fixation, pyruvate metabolism, and protein export were observed following most POP exposure; (3) six individual bacterial species show variation in lipid metabolism in response to POP exposure; and (4) PCB-153 (non-coplanar)has a greater impact on bacteria than PCB-126 (coplanar) at the metabolic and transcriptional levels. These data provide new insights into the direct role of POPs on gut microbiota and begins to establish possible microbial toxicity endpoints which may help to inform risk assessment.

Commensal microbiota-dependent tryptophan catabolism within the gastrointestinal tract is known to exert profound effects upon host physiology, including the maintenance of epithelial barrier and immune function. A number of abundant microbiota-derived tryptophan metabolites exhibit activation potential for the aryl hydrocarbon receptor (AHR). Gene expression facilitated by AHR activation through the presence of dietary or microbiota-generated metabolites can influence gastrointestinal homeostasis and confer protection from intestinal challenges. Utilizing untargeted mass spectrometry-based metabolomics profiling, combined with AHR activity screening assays, we identify four previously unrecognized tryptophan metabolites, present in mouse cecal contents and human stool, with the capacity to activate AHR. Using GC/MS and LC/MS platforms, quantification of these novel AHR activators, along with previously established AHR-activating tryptophan metabolites, was achieved, providing a relative order of abundance. Using physiologically relevant concentrations and quantitative gene expression analyses, the relative efficacy of these tryptophan metabolites with regard to mouse or human AHR activation potential is examined. These data reveal indole, 2-oxindole, indole-3-acetic acid and kynurenic acid as the dominant AHR activators in mouse cecal contents and human stool from participants on a controlled diet. Here we provide the first documentation of the relative abundance and AHR activation potential of a panel of microbiota-derived tryptophan metabolites. Furthermore, these data reveal the human AHR to be more sensitive, at physiologically relevant concentrations, to tryptophan metabolite activation than mouse AHR. Additionally, correlation analyses indicate a relationship linking major tryptophan metabolite abundance with AHR activity, suggesting these cecal/fecal metabolites represent biomarkers of intestinal AHR activity.

Importance: Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required., Objective: To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment., Design, Setting, and Participants: Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population., Interventions: Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies., Main Outcomes and Measures: The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration., Results: For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL)., Conclusions and Relevance: This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.

Although acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) is a manageable disease for many, it is still a source of significant morbidity and economic hardship for many others. The predominant mode of transmission of HIV/AIDS is sexual intercourse, and measures to reduce transmission are needed. Previously, we showed that caerin 1 antimicrobial peptides (AMPs) originally derived from Australian amphibians inhibited in vitro transmission of HIV at relatively low concentrations and had low toxicity for T cells and an endocervical cell line. The use of AMPs as part of microbicidal formulations would expose the vaginal microbiome to these agents and cause potential harm to protective lactobacilli. Here, we tested the effects of caerin 1 peptides and their analogs on the viability of two species of common vaginal lactobacilli ( Lactobacillus rhamnosus and Lactobacillus crispatus ). Several candidate peptides had limited toxicity for the lactobacilli at a range of concentrations that would inhibit HIV. Three AMPs were also tested for their ability to inhibit growth of Neisseria lactamica, a close relative of the sexually transmissible Neisseria gonorrhoeae. Neisseria lactamica was significantly more sensitive to the AMPs than the lactobacilli. Thus, several candidate AMPs have the capacity to inhibit HIV and possible N. gonorrhoeae transmission at concentrations that are significantly less harmful to the resident lactobacilli.

Background: Metronidazole is frequently used off-label in infants with complicated intra-abdominal infections (cIAI) to provide coverage against anaerobic organisms, but its safety and efficacy in this indication are unknown., Methods: In the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections open-label multicenter trial infants ≥34 weeks gestation at birth and <121 days postnatal age with cIAIs were administered metronidazole as part of multimodal therapy. Metronidazole safety was evaluated by reporting of adverse events (AEs) and safety events of special interest. Cure from disease was determined by blood cultures and a clinical cure score >4. A blinded adjudication committee reviewed all safety events of special interest., Results: Fifty-five infants were included, median gestational age was 36 weeks (range: 34-41) and postnatal age was 7 days (0-63). The most common additional antibiotics received included gentamicin, piperacillin-tazobactam, ampicillin and vancomycin. Only one AE, a candidal rash, was identified to be potentially caused by metronidazole administration. One infant died of cardiopulmonary failure, which was deemed unrelated to metronidazole. The most common events of special interest included feeding intolerance in 18 (33%) infants, and exploratory laparotomy in 10 (18%) requiring intestinal anastomosis in 7 (13%) infants. There was 1 (2%) intestinal stricture. Fifty-three infants (96%) achieved overall therapeutic success, 54 (98%) were alive through 30 days post-study therapy, and 54 (98%) had 30-day clinical cure score >4., Conclusions: In a cohort of late pre-term and term infants with cIAIs, combination antibiotic therapy that included metronidazole was safe, and therapeutic success was high.

Background: We sought to compare meropenem and fluconazole dosing in the neonatal intensive care unit with recommendations based on published pharmacokinetic (PK) studies in infants., Methods: We performed an observational cohort study of infants <90 days postnatal age who received a course of meropenem or fluconazole who were treated in neonatal intensive care units managed by the Pediatrix Medical Group (1997-2016). We defined any dose amount from 80% to 120% of the published recommendation to constitute an appropriate dose of either antimicrobial. We calculated the percentage of appropriately dosed courses overall and by discharge year. We then evaluated the change in appropriate dosing over time using a nonparametric test of trend to evaluate the proportion of appropriately dosed courses of each antimicrobial by discharge year., Results: A total of 3608 infants were administered 2025 courses of meropenem and 1201 courses of fluconazole. Of all meropenem courses, 32% were dosed appropriately (increased significantly over time; P = 0.01), while 17% of fluconazole courses were dosed appropriately (increased significantly over time; P = 0.01). Median dosing for both meropenem and fluconazole was at or below recommendations; therefore, under-dosing was more common., Conclusions: There was marked discordance between actual fluconazole and meropenem dosing and dosing recommendation in PK publications, yet adherence to PK-based doses showed improvement over time.

Background: Clinical trials for antibiotics designed to treat hospital-acquired and ventilator-associated bacterial pneumonias (HABP/VABP) are hampered by making these diagnoses in a way that is acceptable to the United States Food and Drug Administration and consistent with standards of care. We examined laboratory and clinical features that might improve pediatric HABP/VABP trial efficiency by identifying risk factors predisposing children to HABP/VABP and describing the epidemiology of pediatric HABP/VABP., Methods: We prospectively reviewed the electronic medical records of patients <18 years of age admitted to intensive and intermediate care units (ICUs) if they received qualifying respiratory support or were started on antibiotics for a lower respiratory tract infection or undifferentiated sepsis. Subjects were followed until HABP/VABP was diagnosed or they were discharged from the ICU. Clinical, laboratory and imaging data were abstracted using structured chart review. We calculated HABP/VABP incidence and used a stepwise backward selection multivariable model to identify risk factors associated with development of HABP/VABP., Results: A total of 862 neonates, infants and children were evaluated for development of HABP/VABP; 10% (82/800) of those receiving respiratory support and 12% (103/862) overall developed HABP/VABP. Increasing age, shorter height/length, longer ICU length of stay, aspiration risk, blood product transfusion in the prior 7 days and frequent suctioning were associated with increased odds of HABP/VABP. The use of noninvasive ventilation and gastric acid suppression were both associated with decreased odds of HABP/VABP., Conclusions: Food and Drug Administration-defined HABP/VABP occurred in 10%-12% of pediatric patients admitted to ICUs. Risk factors vary by age group.

Background: High doses of ampicillin are often used to achieve therapeutic drug concentrations in infants. A paradoxical antibiotic effect, often called the Eagle effect, occurs when increasing concentrations of antibiotic above a threshold results in decreased efficacy. It is unknown if infants treated with ampicillin are at risk for this paradoxical effect., Methods: We identified infants <28 days of age with Escherichia coli, Enterococcus or Streptococcus agalactiae (group B streptococcus) bloodstream infections from 1997 to 2012 and previously included in an ampicillin pharmacokinetic (PK) modeling study. We compared the odds of death for ampicillin dose, estimated time above the minimum inhibitory concentration (T > MIC) and PK parameters using separate logistic regression models. Adjusted logistic regression and Poisson models were used to calculate the odds of prolonged bacteremia ≥3 days and the duration of bacteremia, respectively, for dose, T > MIC and multiple PK parameters., Results: Among 1272 infants meeting inclusion criteria, odds of death 7 or 30 days after the positive blood culture were not consistent with a paradoxical effect across any of the dosing regimens or PK parameters evaluated. The odds of prolonged bacteremia was lowest at the lowest dose category and the lowest daily dose category but not associated with the area-under-the-concentration time curve from 0 to 24 hours, or the maximum or minimum concentrations at steady state. T > MIC of ≥50% of the dosing interval was associated with decreased duration of bacteremia and odds of prolonged bacteremia., Conclusions: It is unlikely that a paradoxical antibiotic effect will have a clinical correlate when ampicillin is used for neonatal bacteremia. A T > MIC ≥50% decreased both duration of bacteremia and odds of prolonged bacteremia.

Bile acids are potent antibacterial compounds and play an important role in shaping the microbial ecology of the gut. Here, we combined flow cytometry, growth rate measurements (OD 600 ), and NMR- and mass spectrometry-based metabolomics to systematically profile the impact of bile acids on the microbiome using in vitro and in vivo models. This study confirmed that (1) unconjugated bile acids possess more potent antibacterial activity than conjugated bile acids; (2) Gram-positive bacteria are more sensitive to bile acids than Gram-negative bacteria; (3) some probiotic bacteria such as Lactobacillus and Bifidobacterium and 7α-dehydroxylating bacteria such as Clostridium scindens show bile acid resistance that is associated with activation of glycolysis. Moreover, we demonstrated that (4) as one of most hydrophobic bile acids, lithocholic acid (LCA) shows reduced toxicity to bacteria in the cecal microbiome in both in vivo and in vitro models; (5) bile acids directly and rapidly affect bacterial global metabolism including membrane damage, disrupted amino acid, nucleotide, and carbohydrate metabolism; and (6) in vivo, short-term exposure to bile acids significantly affected host metabolism via alterations of the bacterial community structure. This study systematically profiled interactions between bile acids and gut bacteria providing validation of previous observation and new insights into the interaction of bile acids with the microbiome and mechanisms related to bile acid tolerance.

The role of pregnant adolescents as perpetrators of intimate partner violence (IPV) is not well understood. Socioecological factors associated with IPV (physical assault and injury, and psychological aggression) perpetrated by pregnant adolescents and the association between IPV and attitudes toward the use of physical punishment to discipline children were examined among 246 pregnant adolescents. Pregnant adolescents were more likely to report perpetrating both physical assault (24%) and psychological aggression (52.7%) than being the recipient (12.2% and 38.6%, respectively) and having been physically injured (7%) than inflicting injury (4.1%). Risk factors for perpetrating physical assault included prior assault by partner, being African American, exposure to community violence, being in trouble with the police, and multiple lifetime drug use. IPV perpetrators had more favorable attitudes toward the use of physical punishment. Interventions should address IPV and parenting attitudes in young couples to maximize the health and safety of both mother and unborn child.

Perfluorooctane sulfonate (PFOS) is a persistent environmental chemical whose biological effects are mediated by multiple mechanisms. Recent evidence suggests that the gut microbiome may be directly impacted by and/or alter the fate and effects of environmental chemicals in the host. Thus, the aim of this study was to determine whether PFOS influences the gut microbiome and its metabolism, and the host metabolome. Four groups of male C57BL/6 J mice were fed a diet with or without 0.003 %, 0.006 %, or 0.012 % PFOS, respectively. 16S rRNA gene sequencing, metabolomic, and molecular analyses were used to examine the gut microbiota of mice after dietary PFOS exposure. Dietary PFOS exposure caused a marked change in the gut microbiome compared to controls. Dietary PFOS also caused dose-dependent changes in hepatic metabolic pathways including those involved in lipid metabolism, oxidative stress, inflammation, TCA cycle, glucose, and amino acid metabolism. Changes in the metabolome correlated with changes in genes that regulate these pathways. Integrative analyses also demonstrated a strong correlation between the alterations in microbiota composition and host metabolic profiles induced by PFOS. Further, using isolated mouse cecal contents, PFOS exposure directly affected the gut microbiota metabolism. Results from these studies demonstrate that the molecular and biochemical changes induced by PFOS are mediated in part by the gut microbiome, which alters gene expression and the host metabolome in mice., Competing Interests: Declaration of Competing Interest John L. Butenhoff, Shu-Ching Chang, were or are employees of 3 M Company, a former manufacturer of PFOS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To assess site variability and concomitant respiratory support related to the timing of caffeine discontinuation, and compare clinical characteristics of infants who discontinued caffeine before vs. within the last week of hospitalization., Study Design: Cohort study of 81,110 infants <35 weeks gestational age and <1500 g birth weight discharged from 304 neonatal intensive care units from 2001-2016., Results: The mean postmenstrual age at caffeine discontinuation ranged from 32 to 37 weeks among sites. Respiratory support at the time of discontinuation was common, but variable, with 0-57% of infants receiving positive airway pressure at caffeine discontinuation by site. Infants who discontinued caffeine within the last week of hospitalization had longer total duration of caffeine, but were discharged from the hospital at an earlier postmenstrual age., Conclusion: There was substantial variability among sites in the timing of caffeine discontinuation before discharge and respiratory support at the time of caffeine discontinuation.

Background: Gastrostomy tube (G-tube) placement is a long-term alternative to oral or nasogastric feeding for premature infants who cannot safely feed orally or need supplemental nutrition for adequate growth., Methods: We compared daily weight changes for G-tube infants 14 and 30 days preplacement and postplacement, excluding the first 7 days post-G-tube insertion. Infants <37 weeks of gestation without major congenital anomalies and discharged from 327 United States neonatal intensive care units (2004-2013) were included. Incidence of in-hospital outcomes including hypoxic ischemic encephalopathy, intraventricular hemorrhage grade 3 or 4, necrotizing enterocolitis, and patent ductus arteriosus ligation was examined. Additionally, we estimated a treatment effect model in which infants with a G-tube were matched 1:1 to untreated controls based on propensity scores; main outcome was the average treatment effect (weight gain) for treated infants during the 7, 14, or 30 days immediately prior to discharge., Results: Of 329,254 infants, 1393 (0.4%) received a G-tube, increasing from 0.2% in 2004 to 0.6% in 2013. Daily weight gain was significantly less during days 8-14 postplacement compared with 14 days preplacement but was similar between 30 days preplacement and 8-30 days postplacement. After matching, G-tube infant weight gain during the 7 days predischarge was less than among controls, but there was no difference in weight gain between treated and control patients for 14 days and 30 days predischarge., Conclusions: The prevalence of G-tube placement has increased. G-tube use in infants was not associated with improved short-term daily weight gain., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Background: Furosemide is commonly used off-label in the neonatal intensive care unit (NICU), but current dosing practices vary widely., Objectives: To describe dosing practices including route, dose, and duration of exposure to furosemide in a large number of community and tertiary NICUs across North America., Method: Using the Pediatrix Medical Group Clinical Data Warehouse, we identified infants who received ≥1 dose of furosemide between 1997 and 2016. We excluded infants with incomplete dosing data. We calculated average daily furosemide dose, cumulative dose, total days of exposure, and maximum daily dose. We compared dosing between infants born at <32 weeks gestational age (GA) and ≥32 weeks GA., Results: A total of 18,572 infants had complete dosing data. The median (interquartile value) postnatal age at first exposure was 11 days (4, 26), the median maximum daily dose was 1.0 mg/kg (0.97, 1.6), the median average daily dose was 1.0 mg/kg (0.88, 1.1), and the median cumulative dose was 2.0 mg/kg (1.0, 4.5). The median total duration of exposure was 2 days (1, 4). A total of 177 (1%) infants received ≥4 mg/kg/day of furosemide. Infants born <32 weeks GA were an older age at initial furosemide exposure compared to those born ≥32 weeks GA: 19 versus 4 days, p < 0.001., Conclusions: Most infants received short courses of furosemide within the labeled dosing parameters. Further studies are needed to assess the safety and efficacy of furosemide in the NICU., (© 2020 S. Karger AG, Basel.)

Background: Given the limited available evidence on chloral hydrate safety in neonatal populations and the discrepancy in chloral hydrate acceptance between the US and other countries, we sought to clarify the safety profile of chloral hydrate compared to other sedatives in hospitalized infants., Methods: We included all infants <120 days of life who underwent a minor procedure and were administered chloral hydrate, clonidine, clonazepam, dexmedetomidine, diazepam, ketamine, lorazepam, midazolam, propofol, or pentobarbital on the day of the procedure. We characterized the distribution of infant characteristics and evaluated the relationship between drug administration and any adverse event. We performed propensity score matching, regression adjustment (RA), and inverse probability weighting (IPW) to ensure comparison of similar infants and to account for confounding by indication and residual bias. Results were assessed for robustness to analytical technique by reanalyzing the main outcomes with multivariate logistic regression, a doubly robust IPW with RA model, and a doubly robust augmented IPW model with bias-correction., Results: Of 650 infants, 497 (76%) received chloral hydrate, 79 (12%) received midazolam, 54 (8%) received lorazepam, and 15 (2%) received pentobarbital. Adverse events occurred in 41 (6%) infants. Using propensity score matching, chloral hydrate was associated with a decreased risk of an adverse event compared to other sedatives, risk difference (95% confidence interval) of -12.79 (-18.61, -6.98), p <  0.001. All other statistical methods resulted in similar findings., Conclusion: Administration of chloral hydrate to hospitalized infants undergoing minor procedures is associated with a lower risk for adverse events compared to other sedatives.

Persistent organic pollutants (POPs) are important environmental chemicals and continued study of their mechanism of action remains a high priority. POPs, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), and polychlorinated biphenyls (PCBs), are widespread environmental contaminants that are agonists for the aryl hydrocarbon receptor (AHR). Activation of the AHR modulates the gut microbiome community structure and function, host immunity, and the host metabolome. In the current study, male C57BL6/J mice were exposed, via the diet, to 5 µg/kg body weight (BW) TCDF or 24 µg/kg BW of TCDF every day for 5 days. The functional and structural changes imparted by TCDF exposure to the gut microbiome and host metabolome were explored via 16S rRNA gene amplicon sequencing, metabolomics, and bacterial metatranscriptomics. Significant changes included increases in lipopolysaccharide (LPS) biosynthesis gene expression after exposure to 24 µg/kg BW of TCDF. Increases in LPS biosynthesis were confirmed with metabolomics and LPS assays using serum obtained from TCDF-treated mice. Significant increases in gene expression within aspartate and glutamate metabolism were noted after exposure to 24 µg/kg BW of TCDF. Together, these results suggest that after exposure to 24 µg/kg BW of TCDF, the gut microbiome increases the production of LPS and glutamate to promote localized gut inflammation, potentially using glutamate as a stress response.

Objective: Characterize frequency and volume of blood draws and transfusions in extremely low birth weight infants in the first 10 weeks of life., Study Design: We included infants with a birth weight <1000 g born 23 0/7-29 6/7 weeks gestational age (GA) and with a length of stay ≥10 weeks, admitted between 2014 and 2016 to a single neonatal intensive care unit., Results: Of 54 infants, median (25th, 75th percentile) GA and birth weight were 25 weeks (24, 26) and 665 g (587, 822), respectively. Median number of blood draws per infant decreased from 57 (49, 65) in week 1 to 12 (8, 22) in week 10. Median volume of blood extracted was 83 mL (70, 97), and median number of blood transfusions was 8 (5, 10)., Conclusions: This cohort experienced a high number and volume of blood draws. Draw frequency and transfusions decreased over the first 10 weeks of life.

Background: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states., Methods: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events., Results: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1-34.0 months) and underwent CPB for 161 minutes (63-394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6-24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7-45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 µg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 µg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13)., Conclusions: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL.

Aims: To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants., Methods: We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM®., Results: We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro., Conclusions: We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study., (© 2019 The British Pharmacological Society.)

Valid understanding of the relationship between cultures and persons requires an adequate conceptualization of the many contexts within which individuals work and live. These contexts include the more distal features of the individual's birth ecology and ethno-national group history. These features converge more proximally upon individual experience as "process" variables, through the institutional-normative constraints and affordances encountered through socialization into a diverse set of cultural groupings. This enculturation is then revealed in the individual's response profile of values, beliefs, choices, and behaviors at any given time. Cross-cultural psychologists have typically compared these encultured responses cross-nationally by averaging the scores of equivalent groups of persons across national groups, terming these average differences "cultural differences." This procedure has generated considerable resistance, primarily due to careless over-generalization of results to all members of a given cultural group. Critics of nation-based characterizations have challenged their methodological and conceptual inadequacies, but we now know better how to address the measurement-related aspects of culture-level "psychological" variables, such as individualism-collectivism. In challenging the accuracy of these measures, critics have also neglected to acknowledge the continuing predictive and discriminant validity of these dimensions of national culture. We here review the utility of more recent measurements. We then show how nation-level comparisons can be used by psychologists to improve our understanding of individual, rather than group, outcomes. Nations are heterogeneous amalgams of ethnicities, social classes, organizations, school systems, and families. Individuals' socialization into these groups affects their functioning at any given point in life. These enculturations are further dependent on their gender, age, and education. Assessment of culture's relation with individual functioning requires adequate measurement of both personality and normative aspects of situations in which behavior is enacted. Once this integration of cultural influences is achieved, the logic and methodology for integrating national culture into psychological models of individual behavior can be applied within any nation where research focuses on how within-nation cultural variation affects individual functioning. Culture, conceptualized as normative group constraints, becomes more widely amenable to study, and the hard lessons learned from cross-national research can be used to guide the practice of more locally sensitive research., (Copyright © 2019 Smith and Bond.)

Objective: To assess the frequency of gastrostomy tube (GT) placement in extremely low birth weight (ELBW) infants, associated comorbidities, and long-term outcomes., Study Design: Analysis of ELBW infants from 25 centers enrolled in the National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-up Registry from 2006 to 2012. Frequency of GT placement before 18-22 months, demographic and medical factors associated with GT placement, and associated long-term outcomes at 18-22 months of corrected age were described. Associations between GT placement and neonatal morbidities and long-term outcomes were assessed with logistic regression after adjustment for center and common co-variables., Results: Of the 4549 ELBW infants included in these analyses, 333 (7.3%) underwent GT placement; 76% had the GT placed postdischarge. Of infants with GTs, 11% had birth weights small for gestational age, 77% had bronchopulmonary dysplasia, and 29% severe intraventricular hemorrhage or periventricular leukomalacia. At follow-up, 56% of infants with a GT had weight <10th percentile, 61% had neurodevelopmental impairment (NDI), and 55% had chronic breathing problems. After adjustment, small for gestational age, bronchopulmonary dysplasia, intraventricular hemorrhage/periventricular leukomalacia, poor growth, and NDI were associated with GT placement. Thirty-two percent of infants with GTs placed were taking full oral feeds at follow-up., Conclusions: GT placement is common in ELBW infants, particularly among those with severe neonatal morbidities. GT placement in this population was associated with poor growth, NDI, and chronic respiratory and feeding problems at follow-up. The frequency of GT placement postneonatal discharge indicates the need for close nutritional follow-up of ELBW infants., Trial Registration: ClinicalTrials.gov: NCT00063063., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Quantify the risk of treatment for retinopathy of prematurity (ROP) among infants meeting current U.S. screening guidelines., Study Design: Among infants ≤1500 g birth weight or ≤30 weeks gestation screened for ROP from 2006-2015, we developed a risk prediction model to identify infants treated for ROP. We applied our model to a separate infant cohort discharged in 2016., Result: Seventy-five thousand eight hundred and twenty one infants met inclusion criteria; 2306 (3%) were treated for ROP. Infants with several risk factor combinations (no ventilator support or oxygen on postnatal day 28, no history of necrotizing enterocolitis, and no intraventricular hemorrhage) were at low risk of ROP. Applied to 6127 infants discharged in 2016, our model had 97.9% sensitivity, 63.3% specificity, positive predictive value of 4.0%, and negative predictive value of 99.9%., Conclusion: Large numbers of infants at low risk of developing ROP are required to undergo screening. Refining current ROP guidelines may reduce unnecessary examinations.

Study Objective: Although long-acting reversible contraceptives (LARC) such as intrauterine devices and subdermal implants remain the most effective methods of contraception for teenagers, most adolescents continue to use less reliable methods. The purpose of this study was to determine: (1) the distribution of contraceptive type according to age of the patients in our clinic system (Baylor Teen Health Clinic); and (2) the differences in this distribution over the past decade., Design: This study was a comprehensive chart review of at least 15,500 charts for the years 2005 to 2014., Setting: Baylor Teen Health Clinic., Participants, Interventions, and Main Outcome Measures: Charts of patients less than 25 years of age who attended one of the 9 Baylor Teen Health Clinics were reviewed. Contraceptive uptake by age and year was the main outcome measured., Results: The percentage of women younger than age 25 years who used LARC increased for all age groups from 2005 to 2014, with the greatest increase for women 20-24 years old (<1% to 9%). The percentage of women using no method decreased for all age groups from 2005 to 2014 with the greatest decrease for women 15-19 years old (9% to 5%). The percentage of women using less effective methods decreased for teenagers younger than 18 years old, but increased for women 20-24 years old and remained the same for women 18-19 years old. Use of pills/patches/rings decreased for all age groups and use of hormonal injections increased for all age groups, with the greatest increase for teenagers younger than 15 years of age (35% to 68%). Our clinic population has a greater proportion of teenagers and young women using LARC than the national average, possibly because of the increased access to LARC when these women enter our clinic system. Nevertheless, less than 10% of all age groups studied used LARC, with the proportion being lowest in teenagers younger than 18 years., Conclusion: More efforts need to be placed on determining the reasons for low LARC uptake despite greatest efficacy in this young, vulnerable population., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To describe the variation in surgical gastrostomy tube (SGT) placement in premature infants among neonatal intensive care units (NICUs) in the United States., Study Design: We identified 8,781 premature infants discharged from 114 NICUs in the Pediatrix Medical Group from 2010 to 2012. The outcome of interest was SGT placement prior to discharge home from an NICU. Unadjusted proportions and adjusted risk estimates were calculated to quantify variation observed among individual NICUs., Results: SGT placement occurred in 360 of 8,781 (4.1%) of infants. Across NICUs, any gastrostomy tube placement ranged from none in 45 NICUs up to 19.6%. Adjusted risk estimates for factors associated with SGT placement included gestational age at birth (odds ratio [OR]: 0.7/week, 95% confidence interval[CI]: [0.65, 0.75]), small for gestational age status (OR: 2.78 [2.09, 3.71]), administration of antenatal steroids (OR: 0.69 [0.52, 0.92]), Hispanic ethnicity (OR: 0.54 [0.37, 0.78]), and higher 5-minute Apgar scores (7-10, OR: 0.54 [0.37, 0.79])., Conclusion: Individual NICU center has a strong clinical effect on the probability of SGT placement relative to other medical factors. Future work is needed to understand the cause of this variation and the degree to which it represents over or under use of gastrostomy tubes., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: Pharmacokinetic (PK) data to guide cefazolin dosing in premature infants are virtually non-existent. Therefore, we aimed to characterize cefazolin PK in infants aged ≤32 weeks of gestation at birth., Study Design: We conducted a prospective, open-label PK and safety study of cefazolin in infants ≤32 weeks gestation from a University Medical Center. We administered intravenous cefazolin and collected both timed and scavenged blood samples. We analyzed data using non-linear mixed effect modeling and simulated several dosage regimens to achieve target concentrations against methicillin-susceptible Staphylococcus aureus., Results: We analyzed 40 samples from nine infants and observed that premature infants had lower clearance and greater volume of distribution for cefazolin compared to older children. The median (range) individual Bayesian estimates were 0.03 L/h/kg (0.01-0.08) for clearance and 0.39 L/kg (0.31-0.52) for volume., Conclusion: Simulations suggested reduced cefazolin dosing based on postmenstrual age achieve target concentrations and potentially reduce unnecessary exposure.

The aryl hydrocarbon receptor (AHR) mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity that can lead to chloracne in humans. A characteristic of chloracne, in contrast to acne vulgaris, is shrinkage or loss of sebaceous glands. Acne vulgaris, on the other hand, is often accompanied by excessive sebum production. Here, we examined the role of AHR in lipid synthesis in human sebocytes using distinct classes of AHR ligands. Modulation of AHR activity attenuated the expression of lipogenic genes and key proinflammatory markers in the absence of canonical DRE-driven transcription of the AHR target gene CYP1A1. Furthermore, topical treatment with TCDD, which mediates DRE-dependent activity, and SGA360, which fails to induce DRE-mediated responses, both exhibited a decrease in the size of sebaceous glands and the number of sebocytes within each gland in the skin. To elucidate the mechanism of AHR-mediated repression of lipid synthesis, we demonstrated that selective AHR modulators, SGA360 and SGA315 increased the protein turnover of the mature sterol regulatory element-binding protein (mSREBP-1), the principal transcriptional regulator of the fatty acid synthesis pathway. Interestingly, selective AHR ligand treatment significantly activated the AMPK-dependent kinase (AMPK) in sebocytes. Moreover, we demonstrated an inverse correlation between the active AMPK and the mSREBP-1 protein, which is consistent with the previously reported role of AMPK in inhibiting cleavage of SREBP-1. Overall, our findings indicate a DRE-independent function of selective AHR ligands in modulating lipid synthesis in human sebocytes, which might raise the possibility of using AHR as a therapeutic target for treatment of acne., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The objectives describe the frequency that inadequate oral feeding (IOF) is the reason why moderately preterm (MPT) infants remain hospitalized and its association with neonatal morbidities., Study Design: Prospective study using the NICHD Neonatal Research Network MPT Registry. Multivariable logistic regression was used to describe associations between IOF and continued hospitalization at 36 weeks postmenstrual age (PMA)., Result: A total of 6017 MPT infants from 18 centers were included. Three-thousand three-seventy-six (56%) remained hospitalized at 36 weeks PMA, of whom 1262 (37%) remained hospitalized due to IOF. IOF was associated with RDS (OR 2.02, 1.66-2.46), PDA (OR 1.86, 1.37-2.52), sepsis (OR 2.36, 95% 1.48-3.78), NEC (OR 16.14, 7.27-35.90), and BPD (OR 3.65, 2.56-5.21) compared to infants discharged and was associated with medical NEC (OR 2.06, 1.19-3.56) and BPD (OR 0.46, 0.34-0.61) compared to infants remaining hospitalized for an alternative reason., Conclusion: IOF is the most common barrier to discharge in MPT infants, especially among those with neonatal morbidities.

Natural aryl hydrocarbon (AHR) ligands have been identified in food and herbal medicines, and they may exhibit beneficial activity in humans. In this study, white button (WB) feeding significantly decreased AHR target gene expression in the small intestine of both conventional and germ-free mice. High-performance liquid chromatography (HPLC) fractionation and ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) combined with an AHR-responsive cell-based luciferase gene reporter assay were used to isolate and characterize benzothiazole (BT) derivatives and 6-methylisoquinoline (6-MIQ) as AHR modulators from WB mushrooms. The study showed dose-dependent changes of AHR transformation determined by the cell-based luciferase gene reporter assay and transcription of CYP1A1 in human Caco-2 cells by BT derivatives and 6-MIQ. These findings suggested that WB mushroom contains new classes of natural AHR modulators and demonstrated HPLC fractionation and UHPLC-MS/MS combined with a cell-based luciferase gene reporter assay as a useful approach for isolation and characterization of the previously unidentifed AHR modulators from natural products.

Objective: To characterize the dosing and safety of off-label caffeine citrate in a contemporary cohort of extremely premature infants., Study Design: We used electronic health records (2010-2013) from 4 neonatal intensive care units to identify infants of ≤28 weeks of gestational age exposed to caffeine citrate. Safety outcomes included death, bronchopulmonary dysplasia, necrotizing enterocolitis, spontaneous intestinal perforation, intraventricular hemorrhage, patent ductus arteriosus ligation, seizures, and arrhythmias. We used multivariable logistic regression to evaluate the association of caffeine citrate exposure with clinical events., Results: Of 410 infants with a median (IQR) gestational age of 26 (24-27) weeks, 95% received caffeine citrate for >0 days. Infants received a median (IQR) daily dose of 8 (5-10) mg/kg/day. Incidences of clinical events on day of caffeine citrate exposure were death 2%, patent ductus arteriosus ligation 12%, and medical and surgical necrotizing enterocolitis 5% and 4%, respectively. Bronchopulmonary dysplasia occurred in 37% of infants and was not associated with caffeine dose. Increased caffeine citrate dose was associated with lower odds of patent ductus arteriosus ligation and necrotizing enterocolitis., Conclusions: Caffeine citrate was used in extremely premature infants at younger gestation, at higher doses, and for longer durations than recommended on the drug label. Increased caffeine citrate exposure, dose, or therapy duration was not associated with increased risk of necrotizing enterocolitis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The Gram-negative bacterium Erwinia amylovora causes fire blight disease of apples and pears. While the virulence systems of E. amylovora have been studied extensively, relatively little is known about its parasitic behavior. The aim of this study was to identify primary metabolites that must be synthesized by this pathogen for full virulence. A series of auxotrophic E. amylovora mutants, representing 21 metabolic pathways, were isolated and characterized for metabolic defects and virulence in apple immature fruits and shoots. On detached apple fruitlets, mutants defective in arginine, guanine, hexosamine, isoleucine/valine, leucine, lysine, proline, purine, pyrimidine, sorbitol, threonine, tryptophan, and glucose metabolism had reduced virulence compared to the wild type, while mutants defective in asparagine, cysteine, glutamic acid, histidine, and serine biosynthesis were as virulent as the wild type. Auxotrophic mutant growth in apple fruitlet medium had a modest positive correlation with virulence in apple fruitlet tissues. Apple tree shoot inoculations with a representative subset of auxotrophs confirmed the apple fruitlet results. Compared to the wild type, auxotrophs defective in virulence caused an attenuated hypersensitive immune response in tobacco, with the exception of an arginine auxotroph. Metabolomic footprint analyses revealed that auxotrophic mutants which grew poorly in fruitlet medium nevertheless depleted environmental resources. Pretreatment of apple flowers with an arginine auxotroph inhibited the growth of the wild-type E. amylovora , while heat-killed auxotroph cells did not exhibit this effect, suggesting nutritional competition with the virulent strain on flowers. The results of our study suggest that certain nonpathogenic E. amylovora auxotrophs could have utility as fire blight biocontrol agents. IMPORTANCE This study has revealed the availability of a range of host metabolites to E. amylovora cells growing in apple tissues and has examined whether these metabolites are available in sufficient quantities to render bacterial de novo synthesis of these metabolites partially or even completely dispensable for disease development. The metabolomics analysis revealed that auxotrophic E. amylovora mutants have substantial impact on their environment in culture, including those that fail to grow appreciably. The reduced growth of virulent E. amylovora on flowers treated with an arginine auxotroph is consistent with the mutant competing for limiting resources in the flower environment. This information could be useful for novel fire blight management tool development, including the application of nonpathogenic E. amylovora auxotrophs to host flowers as an environmentally friendly biocontrol method. Fire blight management options are currently limited mainly to antibiotic sprays onto open blossoms and pruning of infected branches, so novel management options would be attractive to growers., (Copyright © 2019 American Society for Microbiology.)

Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically-based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24-50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24-33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration-time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children., (© 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

A hydrophilic interaction liquid chromatography (HILIC)-ultra high-pressure liquid chromatography (UHPLC) coupled with tandem mass spectrometry (MS/MS) method was developed and applied to profile metabolite changes in human Huh-7 cells exposed to the potent aryl hydrocarbon receptor (AHR) ligand 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). Comparisons of sensitivity (limit of detection as low as 0.01 µM) and reproducibility (84% of compounds had an interday relative standard deviation (RSD) less than 10.0%; 83% of compounds had an intraday RSD less than 15.0%) were assessed for all the metabolites. The exposure of Huh-7 cells to the hepatotoxic carcinogen TCDD at low doses (1 nM and 10 nM for 4 h and 24 h, respectively) was reflected by the disturbance of amino acid metabolism, energy metabolism (glycolysis, TCA cycle), and nucleic acid metabolism. TCDD caused a significant decrease in amino acids such as serine, alanine, and proline while promoting an increase in arginine levels with 24 h treatment. Energy metabolism intermediates such as phosphoenolpyruvate and acetyl-CoA and nucleosides such as UMP, XMP, and CMP were also markedly decreased. These results support the application of HILIC-UHPLC-MS/MS for robust and reliable analysis of the cellular response to environmentally relevant toxicants at lower doses.

Objective: The main purpose of this article is to determine parental consent rates in neonatal drug trials and describe trial characteristics associated with higher rates., Study Design: We included neonatal drug trials published between 2009 and 2014 and compared parental consent rates among the following characteristics: phase type, gestational age, randomization type, drug administration route, drug dosing frequency, blood sampling, control type, length of study, funding source, and length of treatment. We compared characteristics using chi-square, Fisher's exact, one-way analysis of variance or Kruskal-Wallis tests., Results: We identified 52 trials: 38 trials (73%) reported data of parental consent. Median percentage (interquartile range) of parental consent was 79% (62, 89). Higher rates were observed in studies that used active comparators (87%) and shorter study lengths (81% for studies <24 hours)., Conclusion: Parental consent rates for neonatal drug trials varied by study characteristics. Information on proportion of parents consented is valuable to assess generalizability of trial results and for preparing trial protocols., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Prolonged early antibiotics in extremely premature infants may have negative effects. We aimed to assess prevalence and outcomes of provision of prolonged early antibiotics to extremely premature infants in the absence of culture-confirmed infection or NEC., Methods: Cohort study of infants from 13 centers born without a major birth defect from 2008-2014 who were 401-1000 grams birth weight, 22-28 weeks gestation, and survived ≥5 days without culture-confirmed infection, NEC, or spontaneous intestinal perforation. We determined the proportion of infants who received prolonged early antibiotics, defined as ≥5 days of antibiotic therapy started at ≤72 h of age, by center and over time. Associations between prolonged early antibiotics and adverse outcomes were assessed using multivariable logistic regression., Results: A total of 5730 infants were included. The proportion of infants receiving prolonged early antibiotics varied from 30-69% among centers and declined from 49% in 2008 to 35% in 2014. Prolonged early antibiotics was not significantly associated with death (adjusted odds ratio 1.17 [95% CI: 0.99-1.40], p = 0.07) and was not associated with NEC., Conclusions: The proportion of extremely premature infants receiving prolonged early antibiotics decreased, but significant center variation persists. Prolonged early antibiotics were not significantly associated with increased odds of death or NEC.

Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA). We enrolled 27 infants; the median (range) gestational age was 26 weeks (23 to 41 weeks), and the median PNA was 10 days (0 to 84 days). We collected 102 plasma PK samples from 22 of the infants and analyzed safety data from all 27 infants. We analyzed the data using a population PK approach. Rifampin PK was best characterized by a one-compartment model; drug clearance increased with increasing size (body weight) and maturation (PNA). There were no adverse events related to rifampin. Simulated weight and PNA-based intravenous dosing regimens administered once daily (<14 days PNA, 8 mg/kg; ≥14 days PNA, 15 mg/kg) in infants resulted in comparable exposures to adults receiving therapeutic doses of rifampin against staphylococcal infections and TB. (This study has been registered at ClinicalTrials.gov under identifier NCT01728363.)., (Copyright © 2019 American Society for Microbiology.)

Ticarcillin-clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants <30 weeks gestational age, pharmacokinetic data to guide ticarcillin-clavulanate dosing are lacking. We enrolled 15 premature infants <30 weeks gestational age, determined pharmacokinetic parameters, and performed dosing simulations to determine optimal dosing for ticarcillin-clavulanate. The infants had a median (range) postnatal age (PNA) of 18 days (6-44 days) and gestational age of 25 weeks (23-28 weeks). Clearance was lower in infants with a PNA <14 days (0.050 L/kg/h [range 0.043-0.075]) compared with a PNA ≥14-45 days (0.078 L/kg/h [0.047-0.100]), consistent with maturation of renal function. Dosing simulations determined that ticarcillin 75 mg/kg q12h (PNA <14 days) or q8h (PNA ≥ 14-45 days) achieved the target exposure for organisms with a minimum inhibitory concentration ≤16 μ/mL in >90% of simulated infants. For highly resistant organisms (minimum inhibitory concentration 32 μg/mL), increased dosing frequency or extended infusion are necessary., (© 2019 The British Pharmacological Society.)

Objective: To evaluate the association between furosemide exposure and risk of bronchopulmonary dysplasia (BPD)., Study Design: This retrospective cohort study included infants (2004-2015) born at 23-29 weeks gestational age and 501-1249 g birth weight. We compared the demographic and clinical characteristics of infants exposed and not exposed to furosemide between postnatal day 7 and 36 weeks postmenstrual age. We examined the association between furosemide exposure and 2 outcomes: BPD and BPD or death. We performed multivariable probit regression models that included demographic and clinical variables in addition to 2 instrumental variables: furosemide exposure by discharge year, and furosemide exposure by site., Results: Of 37 693 included infants, 19 235 (51%) were exposed to furosemide; these infants were more premature and had higher respiratory support. Of 33 760 infants who survived to BPD evaluation, 15 954 (47%) had BPD. An increase in the proportion of furosemide exposure days by 10 percentage points was associated with a decrease in both the incidence of BPD (4.6 percentage points; P = .001), and BPD or death (3.7 percentage points; P = .01)., Conclusions: More days of furosemide exposure between postnatal day 7 and 36 weeks was associated with decreased risk of BPD and a combined outcome of BPD or death., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate how frequently surfactant is used off-label in preterm infants., Study Design: We conducted a retrospective cohort analysis of prospectively collected administrative data for 2005-2015 from 348 neonatal intensive care units in the US. We quantified off-label administration of poractant alfa, calfactant, or beractant in inborn infants born at <37 weeks of gestational age (GA). Off-label surfactant administration was defined according to the Food and Drug Administration (FDA) label., Results: Of a total of 110 822 preterm infants who received surfactant, 68 226 (62%) received the surfactant off-label. The majority of infants who received surfactant off-label had a higher birth weight than those who received surfactant on-label (40 716 [37%]), had an older GA than those who received surfactant on-label (35 191 [32%]), or were treated with intubation and surfactant administration followed by immediate extubation (INSURE) (32 310 [29%]). Poractant alfa was administered via INSURE more frequently than beractant or calfactant (16 688 [38%], 7137 [20%], and 8485 [27%], respectively). An increasing number of infants received surfactant via INSURE from 2005 to 2015 (from 1697 [19%] to 3368 [36%])., Conclusions: The majority of surfactant given to preterm infants is administered off-label. The uptrend in administration via INSURE coincides with increased supporting evidence. The gap between FDA labeling and current clinic practice exemplifies an opportunity for label expansion, which may require additional prospective or retrospective safety and/or effectiveness data for infants of older GA and higher birth weight., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The aryl hydrocarbon receptor (AHR) is a major regulator of immune function within the gastrointestinal tract. Resident microbiota are capable of influencing AHR-dependent signaling pathways via production of an array of bioactive molecules that act as AHR agonists, such as indole or indole-3-aldehyde. Bacteria produce a number of quinoline derivatives, of which some function as quorum-sensing molecules. Thus, we screened relevant hydroxyquinoline derivatives for AHR activity using AHR responsive reporter cell lines. 2,8-Dihydroxyquinoline (2,8-DHQ) was identified as a species-specific AHR agonist that exhibits full AHR agonist activity in human cell lines, but only induces modest AHR activity in mouse cells. Additional dihydroxylated quinolines tested failed to activate the human AHR. Nanomolar concentrations of 2,8-DHQ significantly induced CYP1A1 expression and, upon cotreatment with cytokines, synergistically induced IL6 expression. Ligand binding competition studies subsequently confirmed 2,8-DHQ to be a human AHR ligand. Several dihydroxyquinolines were detected in human fecal samples, with concentrations of 2,8-DHQ ranging between 0 and 3.4 pmol/mg feces. Additionally, in mice the microbiota was necessary for the presence of DHQ in cecal contents. These results suggest that microbiota-derived 2,8-DHQ would contribute to AHR activation in the human gut, and thus participate in the protective and homeostatic effects observed with gastrointestinal AHR activation.

Micafungin is used off-label in the United States to treat invasive candidiasis in neonates. We used an established pharmacokinetic model to determine micafungin exposures for 46 courses in 39 hospitalized infants. In this small cohort of infants, micafungin exposure was not associated with laboratory markers of liver toxicity, death or failure of microbiologic clearance.

Objective: Pulmonary hypertension causes substantial morbidity and mortality in infants. Although Food and Drug Administration approved to treat pulmonary arterial hypertension in adults, sildenafil is not approved for infants. We sought to describe sildenafil exposure and associated diagnoses and outcomes in infants., Study Design: Retrospective cohort of neonates discharged from more than 300 neonatal intensive care units from 2001 to 2016., Results: Sildenafil was administered to 1,336/1,161,808 infants (0.11%; 1.1 per 1,000 infants); 0/35,977 received sildenafil in 2001 versus 151/90,544 (0.17%; 1.7 per 1,000 infants) in 2016. Among infants <32 weeks' gestational age (GA) with enough data to determine respiratory outcome, 666/704 (95%) had bronchopulmonary dysplasia (BPD). Among infants ≥32 weeks GA, 248/455 (55%) had BPD and 76/552 (14%) were diagnosed with meconium aspiration. Overall, 209/921 (23%) died prior to discharge., Conclusion: The use of sildenafil has increased since 2001. Exposed infants were commonly diagnosed with BPD. Further studies evaluating dosing, safety, and efficacy of sildenafil are needed., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

The constitutive androstane receptor (CAR; NR1I3) contributes important regulatory roles in biotransformation, xenobiotic transport function, energy metabolism and lipid homeostasis. In this investigation, global serum and liver tissue metabolomes were assessed analytically in wild type and CAR-null transgenic mice using NMR, GC-MS and UPLC-MS/MS-based metabolomics. Significantly, CAR activation increased serum levels of fatty acids, lactate, ketone bodies and tricarboxylic acid cycle products, whereas levels of phosphatidylcholine, sphingomyelin, amino acids and liver glucose were decreased following short-term activation of CAR. Mechanistically, quantitative mRNA analysis demonstrated significantly decreased expression of key gluconeogenic pathways, and increased expression of glucose utilization pathways, changes likely resulting from down-regulation of the hepatic glucose sensor and bidirectional transporter, Glut2. Short-term CAR activation also resulted in enhanced fatty acid synthesis and impaired β-oxidation. In summary, CAR contributes an expansive role regulating energy metabolism, significantly impacting glucose and monocarboxylic acid utilization, fatty acid metabolism and lipid homeostasis, through receptor-mediated regulation of several genes in multiple associated pathways.