97 results on '"Weitkamp JH"'
Search Results
2. Placenta and Intestinal Injury in Preterm Infants.
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Garg P, Weitkamp JH, McDonald AG, Cilvik SN, Mir I, Shenberger JS, Olaloye O, Konnikova L, Kallapur SG, and Garg PM
- Abstract
Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal conditions affecting 6 to 10% of low-birth-weight infants and remains a leading cause of death. The risk factors associated with NEC are complex and multifactorial, including preterm birth and intrauterine exposure to inflammation and hypoxia. Chorioamnionitis has been associated with intestinal injury in animal and human clinical studies. This review presents current evidence about the clinical impact of the intrauterine environment on intestinal injury during pregnancy and postpregnancy. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus. Prospective multicenter studies, including accurate and precise clinical, maternal, and laboratory predictors (e.g., inflammatory biomarkers), will help identify the mechanisms associated with the placental pathology, the development of NEC, and the impact of in utero-triggered inflammation on the clinical outcomes. Filling the knowledge gap to link the inflammatory surge to postnatal life will aid in identifying at-risk infants for NEC in a timely manner and facilitate the development of novel immunomodulatory treatments or interventions to improve the outcomes of these vulnerable infants. KEY POINTS: · Placental inflammatory and vascular lesions are associated with NEC severity.. · Higher grade chorioamnionitis with a fetal response is associated with an increased risk of surgical NEC.. · There is a need for routine bedside utilization of placenta pathology in clinical decision-making.., Competing Interests: None declared., (Thieme. All rights reserved.)
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- 2024
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3. Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy.
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Morell AS, Monsell SE, Cornet MC, Wisnowski JL, McKinstry RC, Mathur AM, Li Y, Glass HC, Gonzalez FF, Mayock DE, Benninger KL, Van Meurs KP, Lampland AL, Wu TW, Riley D, Mietzsch U, Chalak L, Flibotte J, Weitkamp JH, Ahmad KA, Yanowitz TD, Baserga M, Merhar S, Rao R, Sokol GM, Comstock BA, Heagerty PJ, Juul SE, and Wu YW
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- Infant, Child, Humans, Child, Preschool, Magnetic Resonance Imaging methods, Brain, Hypoxia-Ischemia, Brain complications, Hypoxia-Ischemia, Brain diagnostic imaging, Hypoxia-Ischemia, Brain genetics, Cerebral Palsy complications, Hypothermia, Induced methods
- Abstract
Background: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE., Methods: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years., Results: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies., Conclusions: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)
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- 2024
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4. Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.
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Blakely ML, Krzyzaniak A, Dassinger MS, Pedroza C, Weitkamp JH, Gosain A, Cotten M, Hintz SR, Rice H, Courtney SE, Lally KP, Ambalavanan N, Bendel CM, Bui KCT, Calkins C, Chandler NM, Dasgupta R, Davis JM, Deans K, DeUgarte DA, Gander J, Jackson CA, Keszler M, Kling K, Fenton SJ, Fisher KA, Hartman T, Huang EY, Islam S, Koch F, Lainwala S, Lesher A, Lopez M, Misra M, Overbey J, Poindexter B, Russell R, Stylianos S, Tamura DY, Yoder BA, Lucas D, Shaul D, Ham PB 3rd, Fitzpatrick C, Calkins K, Garrison A, de la Cruz D, Abdessalam S, Kvasnovsky C, Segura BJ, Shilyansky J, Smith LM, and Tyson JE
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- Female, Humans, Infant, Infant, Newborn, Male, Asian statistics & numerical data, Bayes Theorem, Gestational Age, Patient Discharge, Age Factors, Hispanic or Latino statistics & numerical data, White statistics & numerical data, United States epidemiology, Black or African American statistics & numerical data, Hernia, Inguinal epidemiology, Hernia, Inguinal ethnology, Hernia, Inguinal surgery, Infant, Premature, Herniorrhaphy adverse effects, Herniorrhaphy methods, Herniorrhaphy statistics & numerical data
- Abstract
Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial., Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia., Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023., Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age., Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period., Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup)., Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit., Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.
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- 2024
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5. Effects of pasteurization on osteopontin concentrations in human breastmilk.
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McClanahan KG, Reese J, Weitkamp JH, and Olivares-Villagómez D
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- Humans, Infant, Infant, Newborn, Infant, Premature, Osteopontin, Pasteurization methods, Milk, Human
- Abstract
Background: Osteopontin (OPN) is an important breastmilk protein involved in infant intestinal, immunological, and brain development. However, little is known about how common milk pasteurization and storage techniques affect this important bioactive protein., Methods: Human milk osteopontin concentration was measured in single-donor fresh (n = 1) or frozen (n = 20) breastmilk, pooled Holder-pasteurized donor breastmilk (n = 11), and a shelf-stable (retort pasteurized) breastmilk product (n = 2) by ELISA. Single-donor breastmilk samples were subjected to pasteurization and/or freezing before measuring osteopontin concentrations., Results: Holder pasteurization of breastmilk resulted in an ∼50% decrease in osteopontin concentration within single-donor samples. Breastmilk from mothers of preterm infants trended toward higher osteopontin concentration than mothers of term infants; however, samples from preterm mothers experienced greater osteopontin degradation upon pasteurization. A commercial breastmilk product that underwent retort pasteurization had lower osteopontin concentration than a Holder-pasteurized pooled breastmilk product. Finally, freezing breastmilk prior to Holder pasteurization resulted in less osteopontin degradation than Holder pasteurization prior to freezing., Conclusions: Commonly used breastmilk pasteurization and storage techniques, including freezing and Holder pasteurization, decrease the concentration of the bioactive protein osteopontin in human breastmilk. Holder pasteurization reduced osteopontin concentration by an average of 63%, while freezing resulted in an 8-12% decrease., Impact: Pasteurization of human breastmilk significantly decreases the concentration of the bioactive protein osteopontin. Use of both pasteurization and freezing techniques for breastmilk preservation results in greater loss of osteopontin. This study presents for the first time an analysis of osteopontin concentrations in single-donor pasteurized milk samples., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)
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- 2024
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6. Multidrug-Resistant Bacterial Infections Among Very Low Birthweight Infants With Late-Onset Sepsis in Johannesburg, South Africa.
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Licona G, Ballot D, Moon TD, Banerjee R, Amorim G, Agthe AG, and Weitkamp JH
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Background: An estimated 2.4 million babies died within the first 28 days of life in 2020. The third leading cause of neonatal death continues to be neonatal sepsis. Sepsis-causing bacterial pathogens vary temporally and geographically and, with a rise in multidrug-resistant organisms (MDROs), pose a threat to the neonatal population., Methods: This was a single-center, retrospective study of very low birth weight (VLBW) infants with late-onset sepsis (LOS) admitted to a neonatal unit in South Africa. We aimed to calculate the prevalence of multidrug-resistant (MDR) infections in this population. The data collected included demographic and clinical characteristics, length of hospital stay, risk factors for MDRO and mortality, and microbiology results. Logistic regression was used to assess the association between prespecified risk factors with MDR infections and mortality., Results: Of 2570 VLBW infants admitted, 34% had LOS, of which 33% was caused by MDROs. Infection with Acinetobacter spp., Pseudomonas spp., extended-spectrum beta-lactamase Klebsiella spp., or Escherichia coli was associated with the highest mortality in the LOS cohort. Infants with congenital infections (adjusted odds ratio [aOR], 5.13; 95% CI, 1.19-22.02; P = .028) or a history of necrotizing enterocolitis (aOR, 2.17; 95% CI, 1.05-4.49; P = .037) were at significantly higher risk for MDR infections., Conclusions: More than one-third of LOS cases in VLBW infants were caused by MDROs in this study. MDR infections cause substantial neonatal mortality. Antimicrobial stewardship programs, infection control protocols, and ongoing surveillance are needed to prevent further emergence and spread of MDR infections worldwide., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2023
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7. Bronchopulmonary dysplasia is associated with polyhydramnios in a scan for novel perinatal risk factors.
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Campbell MS, Bastarache LA, Van Driest SL, Adgent MA, Goldstein JA, Weitkamp JH, Ransom MA, Lister RL, Shelton EL, and Sucre JMS
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- Infant, Pregnancy, Female, Infant, Newborn, Humans, Gestational Age, Risk Factors, Retrospective Studies, Bronchopulmonary Dysplasia etiology, Polyhydramnios diagnostic imaging, Premature Birth
- Abstract
Background: The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial, and there are limited data about prenatal exposures and risk of BPD., Study Design: Our study performed parallel analyses using a logistic regression model in a cohort of 4527 infants with data from a curated registry and using a phenome wide association study (PheWAS) based on ICD9/10-based phecodes. We examined 20 prenatal exposures from a neonatal intensive care unit (NICU) curated registry database related to pregnancy and maternal health as well as 94 maternal diagnosis phecodes with a PheWAS analysis., Result: In both the curated registry and PheWAS analyses, polyhydramnios was associated with an increased risk of BPD (OR 5.70, 95% CI 2.78-11.44, p = 1.37 × 10
-6 )., Conclusion: Our data suggest that polyhydramnios may be a clinical indicator of premature infants at increased risk for bronchopulmonary dysplasia. Combining curated registry data with PheWAS analysis creates a valuable tool to generate hypotheses., Impact: Polyhydramnios was significantly associated with bronchopulmonary dysplasia in both a curated registry and by ICD coding analysis with a phenome wide association study (PheWAS). Preterm polyhydramnios may be a clinical indicator of infants at increased risk for developing bronchopulmonary dysplasia after preterm birth. Combining curated registry with PheWAS analysis creates a valuable tool to generate hypotheses about perinatal risk factors and morbidities associated with preterm birth., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)- Published
- 2023
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8. Clinical impact of NEC-associated sepsis on outcomes in preterm infants.
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Garg PM, Paschal JL, Ansari MAY, Block D, Inagaki K, and Weitkamp JH
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- Infant, Infant, Newborn, Humans, Infant, Premature, Birth Weight, Gestational Age, Retrospective Studies, Sepsis complications, Enterocolitis, Necrotizing complications, Enterocolitis, Necrotizing surgery, Ileus
- Abstract
Objective: To determine risk factors and outcomes of necrotizing enterocolitis (NEC)-associated sepsis in infants with NEC., Methods: A retrospective review comparing demographic and clinical information in infants with and without NEC-associated sepsis (defined as positive blood culture at the time of NEC onset)., Results: A total of 209 infants with medical (n = 98) and surgical NEC (n = 111) had a median gestational age of 27 weeks (IQR 25; 30.5) and a median birth weight of 910 g [IQR 655; 1138]. Fifty of 209 (23.9%) infants had NEC-associated sepsis. Infants with NEC-associated sepsis had lower median GA (26.4 vs. 27.4 weeks; p = 0.01), lower birth weight (745 vs. 930 g; p = 0.009), were more likely mechanically ventilated [p < 0.001], received dopamine [p < 0.001], had more evidence of acute kidney injury [60% vs. 38.4%, p = 0.01], longer postoperative ileus (16 [13.0; 22.0] vs. 12 [8; 16] days; p = 0.006), higher levels of C-reactive protein, lower platelet counts, longer hospitalization compared to infants without NEC-associated sepsis. On multivariate regression, cholestasis was an independent risk factor for NEC-associated sepsis (OR 2.94; 95% CI 1.1-8.8, p = 0.038)., Conclusion: NEC-associated sepsis was associated with greater hemodynamic support, acute kidney injury, longer postoperative ileus, and hospitalization on bivariate analysis, and cholestasis was associated with higher odds of sepsis on multi regression analysis., Impact: NEC-associated sepsis was present in 24% of infants with NEC. Gram-positive bacteria, Gram-negative bacteria, and Candida were found in 15.3%, 10.5%, and 2.8% of cases, respectively. Infants with NEC-associated sepsis had a greater inflammatory response (CRP levels), received more blood transfusion before NEC onset, frequently needed assisted ventilation ionotropic support, and had acute kidney injury after NEC onset. NEC infants with Gram-negative sepsis had higher portal venous gas, received more platelet transfusions before NEC onset, and had higher CRP levels and lower median lymphocyte counts at 24 h after NEC onset than those with Gram-positive sepsis., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)
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- 2022
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9. Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.
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Wu YW, Comstock BA, Gonzalez FF, Mayock DE, Goodman AM, Maitre NL, Chang T, Van Meurs KP, Lampland AL, Bendel-Stenzel E, Mathur AM, Wu TW, Riley D, Mietzsch U, Chalak L, Flibotte J, Weitkamp JH, Ahmad KA, Yanowitz TD, Baserga M, Poindexter BB, Rogers EE, Lowe JR, Kuban KCK, O'Shea TM, Wisnowski JL, McKinstry RC, Bluml S, Bonifacio S, Benninger KL, Rao R, Smyser CD, Sokol GM, Merhar S, Schreiber MD, Glass HC, Heagerty PJ, and Juul SE
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- Administration, Intravenous, Cerebral Palsy etiology, Double-Blind Method, Humans, Infant, Infant, Newborn, Erythropoietin administration & dosage, Erythropoietin adverse effects, Erythropoietin therapeutic use, Hypothermia, Induced methods, Hypoxia-Ischemia, Brain complications, Hypoxia-Ischemia, Brain drug therapy, Hypoxia-Ischemia, Brain therapy, Neuroprotective Agents administration & dosage, Neuroprotective Agents adverse effects, Neuroprotective Agents therapeutic use
- Abstract
Background: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown., Methods: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition., Results: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57)., Conclusions: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.)., (Copyright © 2022 Massachusetts Medical Society.)
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- 2022
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10. Development of a mobile phone camera-based transcutaneous bilirubinometer for low-resource settings.
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Harrison-Smith B, Dumont AP, Arefin MS, Sun Y, Lawal N, Dobson D, Nwaba A, Grossarth S, Paed AM, Farouk ZL, Weitkamp JH, and Patil CA
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Newborns in high-income countries are routinely screened for neonatal jaundice using transcutaneous bilirubinometery (TcB). In low-and middle-income countries, TcB is not widely used due to a lack of availability; however, mobile-phone approaches for TcB could help expand screening opportunities. We developed a mobile phone-based approach for TcB and validated the method with a 37 patient multi-ethnic pilot study. We include a custom-designed snap-on adapter that is used to create a spatially resolved diffuse reflectance detection configuration with the illumination provided by the mobile-phone LED flash. Monte-Carlo models of reflectance from neonatal skin were used to guide the design of an adapter for filtered red-green-blue (RGB) mobile-phone camera reflectance measurements. We extracted measures of reflectance from multiple optimized spatial-offset regions-of-interest (ROIs) and a linear model was developed and cross-validated. This resulted in a correlation between total serum bilirubin and mobile-phone TcB estimated bilirubin with a R
2 = 0.42 and Bland-Altman limits of agreement of +6.4 mg/dL to -7.0 mg/dL. These results indicate that a mobile phone with a modified adapter can be utilized to measure neonatal bilirubin values, thus creating a novel tool for neonatal jaundice screening in low-resource settings., Competing Interests: The authors declare that they have no conflict of interest., (Published by Optica Publishing Group under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.)- Published
- 2022
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11. Randomized trial of azithromycin to eradicate Ureaplasma respiratory colonization in preterm infants: 2-year outcomes.
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Viscardi RM, Terrin ML, Magder LS, Davis NL, Dulkerian SJ, Waites KB, Allen M, Ajayi-Akintade A, Ambalavanan N, Kaufman DA, Donohue P, Tuttle DJ, and Weitkamp JH
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- Double-Blind Method, Humans, Infant, Infant, Newborn, Placebos, Anti-Bacterial Agents therapeutic use, Azithromycin therapeutic use, Infant, Premature, Lung microbiology, Ureaplasma Infections drug therapy
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Background: To assess the potential impact of azithromycin treatment in the first week following birth on 2-year outcomes in preterm infants with and without Ureaplasma respiratory colonization who participated in a double-blind, placebo-controlled randomized controlled trial., Methods: Respiratory morbidity was assessed at NICU discharge and at 6, 12, and 22-26 months corrected age using pulmonary questionnaires. Comprehensive neurodevelopmental assessments were completed between 22 and 26 months corrected age. The primary and secondary composite outcomes were death or severe respiratory morbidity and death or moderate-severe neurodevelopmental impairment, respectively, at 22-26 months corrected age., Results: One hundred and twenty-one randomized participants (azithromycin, N = 60; placebo, N = 61) were included in the intent-to-treat analysis. There were no significant differences in death or serious respiratory morbidity (34.8 vs 30.4%, p = 0.67) or death or moderate-severe neurodevelopmental impairment (47 vs 33%, p = 0.11) between the azithromycin and placebo groups. Among all trial participants, tracheal aspirate Ureaplasma-positive infants experienced a higher frequency of death or serious respiratory morbidity at 22-26 months corrected age (58%) than tracheal aspirate Ureaplasma-negative infants (34%) or non-intubated infants (21%) (p = 0.028)., Conclusions: We did not observe strong evidence of a difference in long-term pulmonary and neurodevelopment outcomes in preterm infants treated with azithromycin in the first week of life compared to placebo., Impact: No strong evidence of a difference in long-term pulmonary and neurodevelopment outcomes was identified at 22-26 months corrected age in infants treated with azithromycin in the first week of life compared to placebo. The RCT is the first study of 2-year pulmonary and neurodevelopmental outcomes of azithromycin treatment in ELGANs. Provides evidence that ELGANs with lower respiratory tract Ureaplasma have the most frequent serious respiratory morbidity in the first 2 years of life, suggesting that a Phase III trial of azithromycin to prevent BPD targeting this population is warranted., (© 2021. The Author(s).)
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- 2022
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12. Parental Enrollment Decision-Making for a Neonatal Clinical Trial.
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Weiss EM, Guttmann KF, Olszewski AE, Magnus BE, Li S, Kim SYH, Shah AR, Juul SE, Wu YW, Ahmad KA, Bendel-Stenzel E, Isaza NA, Lampland AL, Mathur AM, Rao R, Riley D, Russell DG, Salih ZNI, Torr CB, Weitkamp JH, Anani UE, Chang T, Dudley J, Flibotte J, Havrilla EM, O'Kane AC, Perez K, Stanley BJ, Shah SK, and Wilfond BS
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- Cross-Sectional Studies, Humans, Infant, Infant, Newborn, Intensive Care Units, Neonatal statistics & numerical data, Randomized Controlled Trials as Topic, Surveys and Questionnaires, Decision Making, Parents psychology, Patient Selection
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Objective: To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial., Study Design: This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision., Results: In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P < .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status., Conclusions: Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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13. Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy.
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Chalak L, Redline RW, Goodman AM, Juul SE, Chang T, Yanowitz TD, Maitre N, Mayock DE, Lampland AL, Bendel-Stenzel E, Riley D, Mathur AM, Rao R, Van Meurs KP, Wu TW, Gonzalez FF, Flibotte J, Mietzsch U, Sokol GM, Ahmad KA, Baserga M, Weitkamp JH, Poindexter BB, Comstock BA, and Wu YW
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- Acute Disease, Chronic Disease, Cohort Studies, Double-Blind Method, Erythropoietin therapeutic use, Female, Gestational Age, Humans, Hypothermia, Induced, Hypoxia-Ischemia, Brain therapy, Infant, Newborn, Male, Pregnancy, Risk Factors, Hypoxia-Ischemia, Brain pathology, Placenta Diseases diagnosis, Placenta Diseases epidemiology
- Abstract
Objective: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE., Study Design: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system., Results: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities., Conclusions: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE., Trial Registration: ClinicalTrials.gov: NCT02811263., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2021
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14. Blood metabolomics in infants enrolled in a dose escalation pilot trial of budesonide in surfactant.
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Ballard PL, Torgerson D, Wadhawan R, Hudak ML, Weitkamp JH, Harris J, Asselin J, Chapin C, Ballard RA, and McEvoy CT
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- Chromatography, Liquid methods, Dose-Response Relationship, Drug, Dried Blood Spot Testing, Humans, Infant, Limit of Detection, Pilot Projects, Tandem Mass Spectrometry methods, Anti-Inflammatory Agents administration & dosage, Budesonide administration & dosage, Infant, Premature, Metabolomics, Pulmonary Surfactants administration & dosage
- Abstract
Background: The pathogenesis of BPD includes inflammation and oxidative stress in the immature lung. Corticosteroids improve respiratory status and outcome, but the optimal treatment regimen for benefit with low systemic effects is uncertain., Methods: In a pilot dose escalation trial, we administered ≤5 daily doses of budesonide in surfactant to 24 intubated premature infants (Steroid And Surfactant in ELGANs (SASSIE)). Untargeted metabolomics was performed on dried blood spots using UPLC-MS/MS. Tracheal aspirate IL-8 concentration was determined as a measure of lung inflammation., Results: Metabolomics data for 829 biochemicals were obtained on 121 blood samples over 96 h from 23 infants receiving 0.025, 0.05, or 0.1 mg budesonide/kg. Ninety metabolites were increased or decreased in a time- and dose-dependent manner at q ≤ 0.1 with overrepresentation in lipid and amino acid super pathways. Different dose response patterns occurred, with negative regulation associated with highest sensitivity to budesonide. Baseline levels of 22 regulated biochemicals correlated with lung inflammation (IL-8), with highest significance for sphingosine and thiamin., Conclusions: Numerous metabolic pathways are regulated in a dose-dependent manner by glucocorticoids, which apparently act via distinct mechanisms that impact dose sensitivity. The findings identify candidate blood biochemicals as biomarkers of lung inflammation and systemic responses to corticosteroids., Impact: Treatment of premature infants in respiratory failure with 0.1 mg/kg intra-tracheal budesonide in surfactant alters levels of ~11% of detected blood biochemicals in discrete time- and dose-dependent patterns. A subset of glucocorticoid-regulated biochemicals is associated with lung inflammatory status as assessed by lung fluid cytokine concentration. Lower doses of budesonide in surfactant than currently used may provide adequate anti-inflammatory responses in the lung with fewer systemic effects, improving the benefit:risk ratio., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)
- Published
- 2021
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15. The Role of Biomarkers in Suspected Neonatal Sepsis.
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Weitkamp JH
- Subjects
- Biomarkers, C-Reactive Protein analysis, Humans, Infant, Newborn, Procalcitonin, Neonatal Sepsis diagnosis, Sepsis diagnosis
- Published
- 2021
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16. Antibiotic Safety and Effectiveness in Premature Infants With Complicated Intraabdominal Infections.
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Smith MJ, Boutzoukas A, Autmizguine J, Hudak ML, Zinkhan E, Bloom BT, Heresi G, Lavery AP, Courtney SE, Sokol GM, Cotten CM, Bliss JM, Mendley S, Bendel C, Dammann CEL, Weitkamp JH, Saxonhouse MA, Mundakel GT, Debski J, Sharma G, Erinjeri J, Gao J, Benjamin DK Jr, Hornik CP, Smith PB, and Cohen-Wolkowiez M
- Subjects
- Humans, Infant, Infant, Newborn, Infant, Premature, Intraabdominal Infections complications, Intraabdominal Infections mortality, Prospective Studies, Treatment Outcome, Anti-Bacterial Agents standards, Anti-Bacterial Agents therapeutic use, Intraabdominal Infections drug therapy
- Abstract
Background: In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population., Methods: Infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3) at doses stratified by postmenstrual age. Due to slow enrollment, a protocol amendment allowed eligible infants already receiving study regimens to enroll without randomization. The primary outcome was mortality within 30 days of study drug completion. Secondary outcomes included adverse events, outcomes of special interest, and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion., Results: One hundred eighty infants [128 randomized (R), 52 nonrandomized (NR)] were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 [95% confidence interval (CI): 1.39-12.13], 4.53 (95% CI: 1.21-15.50), and 4.07 (95% CI: 1.22-12.70) for groups 1, 2, and 3, respectively., Conclusions: Each of the antibiotic regimens are safe in premature infants with cIAI., Clinical Trial Registration: NCT0199499., Competing Interests: The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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17. Gut-derived T cells might cause brain injury in NEC.
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Weitkamp JH
- Subjects
- Animals, Brain, Humans, Infant, Newborn, Infant, Premature, T-Lymphocytes, Brain Injuries etiology, Enterocolitis, Necrotizing
- Published
- 2021
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18. Parental Factors Associated With the Decision to Participate in a Neonatal Clinical Trial.
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Weiss EM, Olszewski AE, Guttmann KF, Magnus BE, Li S, Shah AR, Juul SE, Wu YW, Ahmad KA, Bendel-Stenzel E, Isaza NA, Lampland AL, Mathur AM, Rao R, Riley D, Russell DG, Salih ZNI, Torr CB, Weitkamp JH, Anani UE, Chang T, Dudley J, Flibotte J, Havrilla EM, Kathen CM, O'Kane AC, Perez K, Stanley BJ, Wilfond BS, and Shah SK
- Subjects
- Female, Humans, Infant, Newborn, Male, Surveys and Questionnaires, Trust, Biomedical Research, Clinical Trials as Topic, Parental Consent psychology, Parents psychology, Refusal to Participate psychology
- Abstract
Importance: It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation., Objective: To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial., Design, Setting, and Participants: This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units included parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial or who were eligible but declined enrollment. Data were analyzed October 2019 through July 2020., Exposure: Parental choice of enrollment in neonatal clinical trial., Main Outcomes and Measures: Percentages and odds ratios (ORs) of parent participation as categorized by demographic characteristics, self-assessment of child's medical condition, study comprehension, and trust in medical researchers. Survey questions were based on the hypothesis that parents who enrolled their infant in HEAL differ from those who declined enrollment across 4 categories: (1) infant characteristics and parental demographic characteristics, (2) perception of infant's illness, (3) study comprehension, and (4) trust in clinicians and researchers., Results: Of a total 387 eligible parents, 269 (69.5%) completed the survey and were included in analysis. This included 183 of 242 (75.6%) of HEAL-enrolled and 86 of 145 (59.3%) of HEAL-declined parents. Parents who enrolled their infant had lower rates of Medicaid participation (74 [41.1%] vs 47 [55.3%]; P = .04) and higher rates of annual income greater than $55 000 (94 [52.8%] vs 30 [37.5%]; P = .03) compared with those who declined. Black parents had lower enrollment rates compared with White parents (OR, 0.35; 95% CI, 0.17-0.73). Parents who reported their infant's medical condition as more serious had higher enrollment rates (OR, 5.7; 95% CI, 2.0-16.3). Parents who enrolled their infant reported higher trust in medical researchers compared with parents who declined (mean [SD] difference, 5.3 [0.3-10.3]). There was no association between study comprehension and enrollment., Conclusions and Relevance: In this study, the following factors were associated with neonatal clinical trial enrollment: demographic characteristics (ie, race/ethnicity, Medicaid status, and reported income), perception of illness, and trust in medical researchers. Future work to confirm these findings and explore the reasons behind them may lead to strategies for better engaging underrepresented groups in neonatal clinical research to reduce enrollment disparities.
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- 2021
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19. Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial.
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Cummings JJ, Gerday E, Minton S, Katheria A, Albert G, Flores-Torres J, Famuyide M, Lampland A, Guthrie S, Kuehn D, Weitkamp JH, Fort P, Abu Jawdeh EG, Ryan RM, Martin GC, Swanson JR, Mulrooney N, Eyal F, Gerstmann D, Kumar P, Wilding GE, and Egan EA
- Subjects
- Administration, Oral, Aerosols, Cohort Studies, Female, Gestational Age, Humans, Infant, Newborn, Intensive Care Units, Neonatal statistics & numerical data, Intubation, Intratracheal statistics & numerical data, Male, Nebulizers and Vaporizers, Prospective Studies, Biological Products administration & dosage, Pulmonary Surfactants administration & dosage, Respiratory Distress Syndrome, Newborn drug therapy
- Abstract
Background: Exogenous surfactants to treat respiratory distress syndrome (RDS) are approved for tracheal instillation only; this requires intubation, often followed by positive pressure ventilation to promote distribution. Aerosol delivery offers a safer alternative, but clinical studies have had mixed results. We hypothesized that efficient aerosolization of a surfactant with low viscosity, early in the course of RDS, could reduce the need for intubation and instillation of liquid surfactant., Methods: A prospective, multicenter, randomized, unblinded comparison trial of aerosolized calfactant (Infasurf) in newborns with signs of RDS that required noninvasive respiratory support. Calfactant was aerosolized by using a Solarys nebulizer modified with a pacifier adapter; 6 mL/kg (210 mg phospholipid/kg body weight) were delivered directly into the mouth. Infants in the aerosol group received up to 3 treatments, at least 4 hours apart. Infants in the control group received usual care, determined by providers. Infants were intubated and given instilled surfactant for persistent or worsening respiratory distress, at their providers' discretion., Results: Among 22 NICUs, 457 infants were enrolled; gestation 23 to 41 (median 33) weeks and birth weight 595 to 4802 (median 1960) grams. In total, 230 infants were randomly assigned to aerosol; 225 received 334 treatments, starting at a median of 5 hours. The rates of intubation for surfactant instillation were 26% in the aerosol group and 50% in the usual care group ( P < .0001). Respiratory outcomes up to 28 days of age were no different., Conclusions: In newborns with early, mild to moderate respiratory distress, aerosolized calfactant at a dose of 210 mg phospholipid/kg body weight reduced intubation and surfactant instillation by nearly one-half., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Drs Cummings and Wilding are contracted consultants to ONY Biotech. Dr Egan is chief medical officer of ONY Biotech; the other authors have indicated they have no financial relationships relevant to this article to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)
- Published
- 2020
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20. Randomised trial of azithromycin to eradicate Ureaplasma in preterm infants.
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Viscardi RM, Terrin ML, Magder LS, Davis NL, Dulkerian SJ, Waites KB, Ambalavanan N, Kaufman DA, Donohue P, Tuttle DJ, Weitkamp JH, Hassan HE, and Eddington ND
- Subjects
- Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents pharmacokinetics, Azithromycin administration & dosage, Azithromycin pharmacokinetics, Bronchopulmonary Dysplasia etiology, Double-Blind Method, Drug Administration Schedule, Female, Gestational Age, Humans, Infant, Extremely Premature, Infant, Newborn, Intensive Care Units, Neonatal, Intention to Treat Analysis, Male, Prospective Studies, Respiratory Tract Infections complications, Risk Factors, Ureaplasma Infections complications, Anti-Bacterial Agents therapeutic use, Azithromycin therapeutic use, Infant, Premature, Diseases drug therapy, Respiratory Tract Infections drug therapy, Ureaplasma Infections drug therapy
- Abstract
Objective: To test whether azithromycin eradicates Ureaplasma from the respiratory tract in preterm infants., Design: Prospective, phase IIb randomised, double-blind, placebo-controlled trial., Setting: Seven level III-IV US, academic, neonatal intensive care units (NICUs)., Patients: Infants 24
0 -286 weeks' gestation (stratified 240 -266 ; 270 -286 weeks) randomly assigned within 4 days following birth from July 2013 to August 2016., Interventions: Intravenous azithromycin 20 mg/kg or an equal volume of D5W (placebo) every 24 hours for 3 days., Main Outcome Measures: The primary efficacy outcome was Ureaplasma -free survival. Secondary outcomes were all-cause mortality, Ureaplasma clearance, physiological bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age, comorbidities of prematurity and duration of respiratory support., Results: One hundred and twenty-one randomised participants (azithromycin: n=60; placebo: n=61) were included in the intent-to-treat analysis (mean gestational age 26.2±1.4 weeks). Forty-four of 121 participants (36%) were Ureaplasma positive (azithromycin: n=19; placebo: n=25). Ureaplasma -free survival was 55/60 (92% (95% CI 82% to 97%)) for azithromycin compared with 37/61 (61% (95% CI 48% to 73%)) for placebo. Mortality was similar comparing the two treatment groups (5/60 (8%) vs 6/61 (10%)). Azithromycin effectively eradicated Ureaplasma in all azithromycin-assigned colonised infants, but 21/25 (84%) Ureaplasma -colonised participants receiving placebo were culture positive at one or more follow-up timepoints. Most of the neonatal mortality and morbidity was concentrated in 21 infants with lower respiratory tract Ureaplasma colonisation. In a subgroup analysis, physiological BPD-free survival was 5/10 (50%) (95% CI 19% to 81%) among azithromycin-assigned infants with lower respiratory tract Ureaplasma colonisation versus 2/11 (18%) (95% CI 2% to 52%) in placebo-treated infants., Conclusion: A 3-day azithromycin regimen effectively eradicated respiratory tract Ureaplasma colonisation in this study., Trial Registration Number: NCT01778634., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2020
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21. Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE).
- Author
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McEvoy CT, Ballard PL, Ward RM, Rower JE, Wadhawan R, Hudak ML, Weitkamp JH, Harris J, Asselin J, Chapin C, and Ballard RA
- Subjects
- Anti-Inflammatory Agents pharmacology, Birth Weight, Budesonide blood, Cytokines metabolism, Dose-Response Relationship, Drug, Female, Humans, Hydrocortisone blood, Infant, Extremely Premature, Infant, Newborn, Infant, Premature, Male, Risk, Treatment Outcome, Bronchopulmonary Dysplasia drug therapy, Budesonide administration & dosage, Surface-Active Agents administration & dosage
- Abstract
Background: Initial trials of lung-targeted budesonide (0.25 mg/kg) in surfactant to prevent bronchopulmonary dysplasia (BPD) in premature infants have shown benefit; however, the optimal safe dose is unknown., Methods: Dose-escalation study of budesonide (0.025, 0.05, 0.10 mg/kg) in calfactatant in extremely low gestational age neonates (ELGANs) requiring intubation at 3-14 days. Tracheal aspirate (TA) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. Outcomes were compared with matched infants receiving surfactant in the Trial Of Late SURFactant (TOLSURF)., Results: Twenty-four infants with mean gestational age 25.0 weeks and 743 g birth weight requiring mechanical ventilation were enrolled at mean age 6 days. Budesonide was detected in the blood of all infants with a half-life of 3.4 h. Of 11 infants with elevated TA cytokine levels at baseline, treatment was associated with sustained decrease (mean 65%) at all three dosing levels. There were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. Respiratory outcomes did not differ from the historic controls., Conclusions: Budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated ELGANs. One-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action.
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- 2020
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22. Meningitis, urinary tract, and bloodstream infections in very low birth weight infants enrolled in a heart rate characteristics monitoring trial.
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Weitkamp JH, Aschner JL, Carlo WA, Bancalari E, Perez JA, Navarrete CT, Schelonka RL, Whit Walker M, Porcelli P Jr, O'Shea TM, Palmer C, Grossarth S, Lake DE, and Fairchild KD
- Subjects
- Cohort Studies, Female, Humans, Infant, Newborn, Infant, Very Low Birth Weight, Male, Meningitis microbiology, Urinary Tract Infections microbiology, Heart Rate, Meningitis complications, Sepsis complications, Urinary Tract Infections complications
- Abstract
Background: Displaying heart rate characteristic (HRC) scores was associated with lower sepsis-associated mortality in very low birth weight (VLBW) infants in a multicenter randomized controlled trial (HeRO trial). The aim of this study was to test whether HRC indices rise before diagnosis of urinary tract infection (UTI) or meningitis, with and without concomitant BSI., Methods: Blood, urine, and cerebrospinal fluid (CSF) culture data after 3 days of age and within 120 days of study enrollment were analyzed from 2989 VLBW infants. The HRC index was analyzed 12 h prior to positive cultures compared to 36 h prior, using paired signed-rank tests., Results: UTI, meningitis, and BSI were diagnosed in 10%, 2%, and 24% of infants, respectively. The mean hourly HRC index was significantly higher 12 h prior to diagnosis of UTI and BSI compared to 36 h prior (UTI 2.07 versus 1.81; BSI 2.62 versus 2.25, both p < 0.0001). The baseline HRC index was higher for meningitis, compared to UTI or BSI, but without a statistically significant rise in the day prior to meningitis diagnosis., Conclusions: In a large cohort of VLBW infants enrolled in the HeRO trial, the HRC index increased in the 24-h period prior to diagnosis of UTI and BSI but not meningitis.
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- 2020
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23. Case 3: Abdominal Distention in a Preterm Infant.
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Sanlorenzo LA, Grossarth S, and Weitkamp JH
- Subjects
- Diseases in Twins diagnosis, Female, Humans, Infant, Newborn, Infant, Premature, Abdomen pathology, Digestive System Abnormalities diagnosis, Infant, Newborn, Diseases diagnosis, Infant, Premature, Diseases diagnosis
- Published
- 2020
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24. Osteopontin and iCD8α Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis.
- Author
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Nazmi A, Greer MJ, Hoek KL, Piazuelo MB, Weitkamp JH, and Olivares-Villagómez D
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, Epithelium immunology, Female, Humans, Hyaluronan Receptors immunology, Killer Cells, Natural immunology, Male, Mice, Mice, Inbred C57BL, Receptors, Antigen, T-Cell, gamma-delta immunology, Th17 Cells immunology, CD8-Positive T-Lymphocytes immunology, Homeostasis immunology, Intestines immunology, Intraepithelial Lymphocytes immunology, Osteopontin immunology
- Abstract
Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes, ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses, such as survival of Th17 cells and homeostasis of NK cells among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. In this study, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCRγδ
+ , TCRβ+ CD4+ , TCRβ+ CD4+ CD8α+ , and TCRβ+ CD8αα+ cells in comparison with wild-type mice. For some IEL subpopulations, the decrease in cell numbers could be attributed to apoptosis and reduced cell division. Moreover, we show in vitro that exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8α IEL but not TCRγδ+ IEL, TCRβ+ IEL, or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8α cells in the homeostasis of IEL., (Copyright © 2020 by The American Association of Immunologists, Inc.)- Published
- 2020
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25. Procalcitonin versus C-reactive protein: review of kinetics and performance for diagnosis of neonatal sepsis.
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Eschborn S and Weitkamp JH
- Subjects
- Bacteria pathogenicity, Biomarkers blood, C-Reactive Protein pharmacokinetics, Humans, Infant, Low Birth Weight blood, Infant, Newborn blood, Neonatal Sepsis blood, Procalcitonin pharmacokinetics, Severity of Illness Index, Virulence, C-Reactive Protein analysis, Neonatal Sepsis diagnosis, Procalcitonin blood
- Abstract
Procalcitonin (PCT) and C-reactive protein (CRP) are commonly used biomarkers, but their diagnostic advantage for neonatal early-onset (EOS) or late-onset (LOS) sepsis is controversial. In a comprehensive literature review we found significant heterogeneity between studies in sample timing, cut-off values, consideration of blood culture results for sepsis classification, and definition of EOS versus LOS. We identified 39 studies directly comparing PCT with CRP, but only four in very low birth weight (VLBW) neonates. The mean sensitivity for EOS, LOS, and EOS + LOS was 73.6%, 88.9%, and 76.5% for PCT, compared to 65.6%, 77.4%, and 66.4% for CRP, respectively. Mean specificity of PCT and CRP was 82.8% versus 82.7% for EOS, 75.6% versus 81.7% for LOS, and 80.4% versus 91.3% for EOS + LOS. More studies directly comparing both biomarkers for EOS and LOS, especially in extremely and very-low-birth-weight infants, are needed to determine their clinical value for guidance of antibiotic therapy in neonatal sepsis.
- Published
- 2019
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26. Innate and adaptive immunity in necrotizing enterocolitis.
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Mara MA, Good M, and Weitkamp JH
- Subjects
- Humans, Infant, Newborn, Infant, Premature, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Toll-Like Receptors metabolism, Adaptive Immunity immunology, Enterocolitis, Necrotizing immunology, Immunity, Innate immunology
- Abstract
Necrotizing enterocolitis (NEC) is the most frequent and devastating gastrointestinal disease of premature infants. Although the precise mechanisms are not fully understood, NEC is thought to develop following a combination of prematurity, formula feeding, and adverse microbial colonization. Within the last decade, studies increasingly support an important role of a heightened mucosal immune response initiating a pro-inflammatory signaling cascade, which can lead to the disruption of the intestinal epithelium and translocation of pathogenic species. In this review, we first describe the cellular composition of the intestinal epithelium and its critical role in maintaining epithelial integrity. We then discuss cell signaling during NEC, specifically, toll-like receptors and nucleotide oligomerization domain-like receptors. We further review cytokines and cellular components that characterize the innate and adaptive immune systems and how they interact to support or modulate NEC development., (© 2018 Published by Elsevier Ltd.)
- Published
- 2018
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27. Variability in Immunization Practices for Preterm Infants.
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Gopal SH, Edwards KM, Creech B, and Weitkamp JH
- Subjects
- Apnea etiology, Birth Weight, Bradycardia etiology, Gestational Age, Humans, Infant, Infant, Low Birth Weight, Infant, Newborn, Intensive Care Units, Neonatal statistics & numerical data, Neonatologists, United States epidemiology, Vaccination adverse effects, Immunization Schedule, Infant, Premature, Practice Patterns, Physicians'
- Abstract
Introduction: The Advisory Committee on Immunization Practices and the American Academy of Pediatrics (AAP) recommend the same immunization schedule for preterm and term infants. However, significant delays in vaccination of premature infants have been reported., Objective: The objective of this study was to assess the variability of immunization practices in preterm infants., Study Design: We conducted an online survey of 2,443 neonatologists in the United States, who are members of the Section for Neonatal-Perinatal Medicine of the AAP. Questions were targeted at immunization practices in the neonatal intensive care unit (NICU)., Results: Of the 420 responses (17%) received, 55% of providers administer the first vaccine at >2-month chronological age. Most providers (83%) surveyed reported delaying vaccines in the setting of clinical illness. Sixty percent reported increasing frequency of apnea-bradycardia events following immunization. More than half administer the initial vaccines over several days despite lack of supporting data. Reported considerations in delaying or spreading out 2-month vaccines were clinical instability, provider preference, lower gestational age, and lower birth weight., Conclusion: This survey substantiates the variability of immunizations practices in the NICU and identifies reasons for this variability. Future studies should inform better practice guidance for immunization of preterm NICU patients based on vaccine safety and effectiveness., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)
- Published
- 2018
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28. Distinct mucosal microbial communities in infants with surgical necrotizing enterocolitis correlate with age and antibiotic exposure.
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Romano-Keeler J, Shilts MH, Tovchigrechko A, Wang C, Brucker RM, Moore DJ, Fonnesbeck C, Meng S, Correa H, Lovvorn HN 3rd, Tang YW, Hooper L, Bordenstein SR, Das SR, and Weitkamp JH
- Subjects
- Age Factors, Anti-Bacterial Agents pharmacology, Biodiversity, Enterocolitis, Necrotizing drug therapy, Female, Humans, Infant, Infant, Newborn, Male, Microbiota drug effects, Pregnancy, Anti-Bacterial Agents therapeutic use, Enterocolitis, Necrotizing microbiology, Enterocolitis, Necrotizing surgery, Intestinal Mucosa drug effects, Intestinal Mucosa microbiology
- Abstract
Objective: Necrotizing enterocolitis (NEC) is the most common surgical emergency in preterm infants, and pathogenesis associates with changes in the fecal microbiome. As fecal samples incompletely represent microbial communities in intestinal mucosa, we sought to determine the NEC tissue-specific microbiome and assess its contribution to pathogenesis., Design: We amplified and sequenced the V1-V3 hypervariable region of the bacterial 16S rRNA gene extracted from intestinal tissue and corresponding fecal samples from 12 surgical patients with NEC and 14 surgical patients without NEC. Low quality and non-bacterial sequences were removed, and taxonomic assignment was made with the Ribosomal Database Project. Operational taxonomic units were clustered at 97%. We tested for differences between NEC and non-NEC samples in microbiome alpha- and beta-diversity and differential abundance of specific taxa between NEC and non-NEC samples. Additional analyses were performed to assess the contribution of other demographic and environmental confounding factors on the infant tissue and fecal microbiome., Results: The fecal and tissue microbial communities were different. NEC was associated with a distinct microbiome, which was characterized by low diversity, higher abundances of Staphylococcus and Clostridium_sensu_stricto, and lower abundances of Actinomyces and Corynebacterium. Infant age and vancomycin exposure correlated with shifts in the tissue microbiome., Conclusion: The observed low diversity in NEC tissues suggests that NEC is associated with a bacterial bloom and a distinct mucosal bacterial community. The exact bacterial species that constitute the bloom varied by infant and were strongly influenced by age and exposure to vancomycin., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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29. Monitoring neonates for ototoxicity.
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Garinis AC, Kemph A, Tharpe AM, Weitkamp JH, McEvoy C, and Steyger PS
- Subjects
- Age Factors, Child, Preschool, Dose-Response Relationship, Drug, Drug Interactions, Early Diagnosis, Hearing Loss diagnosis, Hearing Loss physiopathology, Hearing Loss therapy, Humans, Infant, Infant, Newborn, Intensive Care Units, Neonatal, Predictive Value of Tests, Risk Assessment, Risk Factors, Drug Monitoring methods, Hearing drug effects, Hearing Loss chemically induced, Hearing Tests
- Abstract
Objectives: Neonates admitted to the neonatal intensive care unit (NICU) are at greater risk of permanent hearing loss compared to infants in well mother and baby units. Several factors have been associated with this increased prevalence of hearing loss, including congenital infections (e.g. cytomegalovirus or syphilis), ototoxic drugs (such as aminoglycoside or glycopeptide antibiotics), low birth weight, hypoxia and length of stay. The aetiology of this increased prevalence of hearing loss remains poorly understood., Design: Here we review current practice and discuss the feasibility of designing improved ototoxicity screening and monitoring protocols to better identify acquired, drug-induced hearing loss in NICU neonates., Study Sample: A review of published literature., Conclusions: We conclude that current audiological screening or monitoring protocols for neonates are not designed to adequately detect early onset of ototoxicity. This paper offers a detailed review of evidence-based research, and offers recommendations for developing and implementing an ototoxicity monitoring protocol for young infants, before and after discharge from the hospital.
- Published
- 2018
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30. Why are preterm newborns at increased risk of infection?
- Author
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Collins A, Weitkamp JH, and Wynn JL
- Subjects
- Adaptive Immunity physiology, B-Lymphocytes immunology, Humans, Immunity, Cellular physiology, Immunity, Innate physiology, Immunoglobulins immunology, Infant, Premature, Infant, Premature, Diseases immunology, Infections immunology, Sepsis immunology
- Abstract
One in 10 newborns will be born before completion of 36 weeks' gestation (premature birth). Infection and sepsis in preterm infants remain a significant clinical problem that represents a substantial financial burden on the healthcare system. Many factors predispose premature infants for having the greatest risk of developing and succumbing to infection as compared with all other age groups across the age spectrum. It is clear that the immune system of preterm infants exhibits distinct, rather than simply deficient, function as compared with more mature and older humans and that the immune function in preterm infants contributes to infection risk. While no single review can cover all aspects of immune function in this population, we will discuss key aspects of preterm neonatal innate and adaptive immune function that place them at high risk for developing infections and sepsis, as well as sepsis-associated morbidity and mortality., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2018
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31. Bacterial DNA is present in the fetal intestine and overlaps with that in the placenta in mice.
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Martinez KA 2nd, Romano-Keeler J, Zackular JP, Moore DJ, Brucker RM, Hooper C, Meng S, Brown N, Mallal S, Reese J, Aronoff DM, Shin H, Dominguez-Bello MG, and Weitkamp JH
- Subjects
- Animals, Female, Mice, Pregnancy, RNA, Ribosomal, 16S genetics, Vagina metabolism, Vagina microbiology, Amniotic Fluid metabolism, DNA, Bacterial analysis, Intestinal Mucosa metabolism, Intestines embryology, Placenta metabolism, Placenta microbiology
- Abstract
Bacterial DNA has been reported in the placenta and amniotic fluid by several independent groups of investigators. However, it's taxonomic overlap with fetal and maternal bacterial DNA in different sites has been poorly characterized. Here, we determined the presence of bacterial DNA in the intestines and placentas of fetal mice at gestational day 17 (n = 13). These were compared to newborn intestines (n = 15), maternal sites (mouth, n = 6; vagina, n = 6; colon, n = 7; feces, n = 8), and negative controls to rule out contamination. The V4 region of the bacterial 16S rRNA gene indicated a pattern of bacterial DNA in fetal intestine similar to placenta but with higher phylogenetic diversity than placenta or newborn intestine. Firmicutes were the most frequently assignable phylum. SourceTracker analysis suggested the placenta as the most commonly identifiable origin for fetal bacterial DNA, but also over 75% of fetal gut genera overlapped with maternal oral and vaginal taxa but not with maternal or newborn feces. These data provide evidence for the presence of bacterial DNA in the mouse fetus., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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32. Antimicrobial and Antibiofilm Activity of Human Milk Oligosaccharides against Streptococcus agalactiae, Staphylococcus aureus, and Acinetobacter baumannii.
- Author
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Ackerman DL, Craft KM, Doster RS, Weitkamp JH, Aronoff DM, Gaddy JA, and Townsend SD
- Subjects
- Acinetobacter baumannii growth & development, Anti-Bacterial Agents isolation & purification, Biofilms growth & development, Biological Products isolation & purification, Biological Products pharmacology, Female, Humans, Microbial Sensitivity Tests, Oligosaccharides isolation & purification, Staphylococcus aureus growth & development, Streptococcus agalactiae growth & development, Acinetobacter baumannii drug effects, Anti-Bacterial Agents pharmacology, Biofilms drug effects, Milk, Human chemistry, Oligosaccharides pharmacology, Staphylococcus aureus drug effects, Streptococcus agalactiae drug effects
- Abstract
In a previous study, we reported that human milk oligosaccharides (HMOs) isolated from five donor milk samples possessed antimicrobial and antibiofilm activity against Streptococcus agalactiae, also known as Group B Streptococcus or GBS. Herein, we present a broader evaluation of the antimicrobial and antibiofilm activity by screening HMOs from 14 new donors against three strains of GBS and two of the ESKAPE pathogens of particular interest to child health, Staphylococcus aureus and Acinetobacter baumannii. Growth and biofilm assays showed that HMOs from these new donors possessed antimicrobial and antibiofilm activity against all three strains of GBS, antibiofilm activity against methicillin-resistant S. aureus strain USA300, and antimicrobial activity against A. baumannii strain ATCC 19606.
- Published
- 2018
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33. The Marshall Klaus Research Award and Tribute to a Trailblazing Neonatologist.
- Author
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Grossarth SN, Coggins SA, Tune A, Ariagno RL, Fanaroff AA, and Weitkamp JH
- Subjects
- History, 20th Century, History, 21st Century, Research, United States, Awards and Prizes, Neonatologists history
- Published
- 2018
- Full Text
- View/download PDF
34. In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4 + T Lymphocytes.
- Author
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Matta P, Sherrod SD, Marasco CC, Moore DJ, McLean JA, and Weitkamp JH
- Subjects
- Biomarkers metabolism, Chorioamnionitis pathology, Enterotoxins pharmacology, Female, Humans, Infant, Newborn, Infant, Premature, Male, Pregnancy, Th1 Cells pathology, Chorioamnionitis immunology, Chorioamnionitis metabolism, Th1 Cells immunology, Th1 Cells metabolism
- Abstract
Histological chorioamnionitis (HCA) is an intrauterine inflammatory condition that increases the risk for preterm birth, death, and disability because of persistent systemic and localized inflammation. The immunological mechanisms sustaining this response in the preterm newborn remain unclear. We sought to determine the consequences of HCA exposure on the fetal CD4
+ T lymphocyte exometabolome. We cultured naive CD4+ T lymphocytes from HCA-positive and -negative preterm infants matched for gestational age, sex, race, prenatal steroid exposure, and delivery mode. We collected conditioned media samples before and after a 6-h in vitro activation of naive CD4+ T lymphocytes with soluble staphylococcal enterotoxin B and anti-CD28. We analyzed samples by ultraperformance liquid chromatography ion mobility-mass spectrometry. We determined the impact of HCA on the CD4+ T lymphocyte exometabolome and identified potential biomarker metabolites by multivariate statistical analyses. We discovered that: 1) CD4+ T lymphocytes exposed to HCA exhibit divergent exometabolomic profiles in both naive and activated states; 2) ∼30% of detected metabolites differentially expressed in response to activation were unique to HCA-positive CD4+ T lymphocytes; 3) metabolic pathways associated with glutathione detoxification and tryptophan degradation were altered in HCA-positive CD4+ T lymphocytes; and 4) flow cytometry and cytokine analyses suggested a bias toward a TH 1-biased immune response in HCA-positive samples. HCA exposure primes the neonatal adaptive immune processes by inducing changes to the exometabolomic profile of fetal CD4+ T lymphocytes. These exometabolomic changes may link HCA exposure to TH 1 polarization of the neonatal adaptive immune response., (Copyright © 2017 by The American Association of Immunologists, Inc.)- Published
- 2017
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35. Human Milk Oligosaccharides Exhibit Antimicrobial and Antibiofilm Properties against Group B Streptococcus.
- Author
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Ackerman DL, Doster RS, Weitkamp JH, Aronoff DM, Gaddy JA, and Townsend SD
- Subjects
- Anti-Bacterial Agents isolation & purification, Biofilms growth & development, Breast Feeding, Female, Humans, Microscopy, Electron, Scanning methods, Oligosaccharides isolation & purification, Postpartum Period, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Streptococcus agalactiae growth & development, Streptococcus agalactiae ultrastructure, Anti-Bacterial Agents pharmacology, Biofilms drug effects, Milk, Human chemistry, Oligosaccharides pharmacology, Streptococcus agalactiae drug effects
- Abstract
Streptococcus agalactiae (Group B Streptococcus, GBS) is a Gram-positive bacterial pathogen that causes invasive infections in both children and adults. During pregnancy, GBS is a significant cause of infection of the fetal membranes (chorioamnionitis), which can lead to intra-amniotic infection, preterm birth, stillbirth, and neonatal sepsis. Recently, breastfeeding has been thought to represent a potential mode of GBS transmission from mother to newborn, which might increase the risk for late-onset sepsis. Little is known, however, about the molecular components of breast milk that may support or prevent GBS colonization. In this study, we examine how human milk oligosaccharides (HMOs) affect the pathogenesis of GBS. HMOs from discrete donor samples were isolated and profiled by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). Growth and biofilm assays show that HMOs from mothers of specific milk groups can modulate the growth and biofilm formation of GBS. High-resolution field-emission gun scanning electron microscopy (SEM) and confocal laser scanning microscopy confirmed the quantitative biofilm assays and demonstrated cell arrangement perturbations in bacterial cultures treated with specific oligosaccharides. These findings demonstrate that HMOs affect the growth and cell biology of GBS. Finally, this study provides the first example of HMOs functioning as antibiofilm agents against GBS.
- Published
- 2017
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36. Congenital Cutaneous Candidiasis: Prompt Systemic Treatment Is Associated With Improved Outcomes in Neonates.
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Kaufman DA, Coggins SA, Zanelli SA, and Weitkamp JH
- Subjects
- Adolescent, Adult, Antifungal Agents therapeutic use, Candida drug effects, Candida isolation & purification, Candidiasis microbiology, Candidiasis, Cutaneous blood, Candidiasis, Cutaneous diagnosis, Drug Administration Routes, Female, Gestational Age, Humans, Infant, Newborn, Infant, Premature, Diseases microbiology, Intensive Care Units, Neonatal, Male, Medical Records, Nystatin administration & dosage, Nystatin adverse effects, Nystatin therapeutic use, Pregnancy, Skin microbiology, Treatment Outcome, Young Adult, Candidiasis prevention & control, Candidiasis, Cutaneous congenital, Candidiasis, Cutaneous drug therapy, Infant, Premature, Diseases drug therapy
- Abstract
Background: Congenital cutaneous candidiasis (CCC) is a challenging diagnosis due to various rash presentations. Inadequate early treatment is associated with high rates of dissemination and death. The effects of early diagnosis, dermatologic presentation, and antifungal treatment on outcomes are lacking., Methods: CCC cases were reviewed from 2 academic neonatal intensive care units (NICUs) from 2004 to 2015. We defined CCC as a diffuse rash involving the body, extremities, face or scalp, and/or funisitis, presenting in the first week (≤7 days), with identification of Candida species from skin or mucous membrane cultures, and/or by culture or staining of the placenta or umbilical cord., Results: CCC occurred in 0.1% of all NICU admissions (21 of 19 303) and 0.6% of infants <1000 grams birth weight. Median gestational age of CCC infants was 26 3/7 (range, 23 0/7-40 4/7) weeks. Skin findings were commonly present on the day of birth [median (range): 0 (0-6) days], appearing most frequently as a desquamating, maculopapular, papulopustular, and/or erythematous diffuse rash. When systemic antifungal therapy was started empirically at the time of rash presentation and continued for a median (interquartile range) of 14 (14-15) days, all patients survived and none developed dissemination. Delaying systemic treatment, exclusive use of nystatin, and treating for <10 days was associated with Candida bloodstream dissemination., Conclusions: CCC is an invasive infection that presents as a diffuse rash in preterm and term infants. Prompt systemic antifungal treatment at the time of skin presentation for ≥14 days prevents dissemination and Candida-related mortality., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2017
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37. Erythematous plaques and papules on a premature infant.
- Author
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Riemenschneider K, Redenius R, Reese J, Fine JD, Weitkamp JH, and Tkaczyk E
- Subjects
- Apgar Score, Biopsy, Needle, Female, Follow-Up Studies, Gestational Age, Humans, Immunohistochemistry, Impetigo congenital, Impetigo drug therapy, Infant, Newborn, Male, Pregnancy, Pregnancy Complications, Infectious microbiology, Respiratory Distress Syndrome, Newborn physiopathology, Respiratory Distress Syndrome, Newborn therapy, Streptococcal Infections drug therapy, Treatment Outcome, Anti-Bacterial Agents therapeutic use, Impetigo pathology, Infant, Premature, Pregnancy Complications, Infectious drug therapy, Streptococcal Infections transmission
- Abstract
A 2240 gram boy was born at 33.2 weeks gestation with nonblanching, deeply erythematous plaques and papules on the back, flanks, and scalp (Figure 1). His mother was GBS positive and on antibiotic suppression for prior cutaneous MRSA and urinary tract infections. Intrapartum intravenous Penicillin G was administered, and the amniotic sac was artificially ruptured 4 hours prior to delivery to facilitate labor. The delivery was uncomplicated without concern for chorioamnionitis, but the patient initially required CPAP for respiratory distress with 1-minute and 5-minute Apgar scores of 7 and 8, respectively. A skin punch biopsy is shown (Figure 2)., Competing Interests: The authors do not have any conflicts of interest to disclose.
- Published
- 2017
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38. Surgical necrotizing enterocolitis.
- Author
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Robinson JR, Rellinger EJ, Hatch LD, Weitkamp JH, Speck KE, Danko M, and Blakely ML
- Subjects
- Biomarkers metabolism, Enterocolitis, Necrotizing physiopathology, Fatty Acid-Binding Proteins metabolism, Feces, Humans, Infant, Extremely Premature, Infant, Newborn, Infant, Premature, Diseases physiopathology, Infant, Very Low Birth Weight, Leukocyte L1 Antigen Complex metabolism, Patient Selection, Predictive Value of Tests, S100A12 Protein metabolism, Treatment Outcome, Drainage, Enterocolitis, Necrotizing surgery, Enterostomy, Infant, Premature, Diseases surgery, Laparotomy
- Abstract
Although currently available data are variable, it appears that the incidence of surgical necrotizing enterocolitis (NEC) has not decreased significantly over the past decade. Pneumoperitoneum and clinical deterioration despite maximal medical therapy remain the most common indications for operative treatment. Robust studies linking outcomes with specific indications for operation are lacking. Promising biomarkers for severe NEC include fecal calprotectin and S100A12; serum fatty acid-binding protein; and urine biomarkers. Recent advances in ultrasonography make this imaging modality more useful in identifying surgical NEC and near-infrared spectroscopy (NIRS) is being actively studied. Another fairly recent finding is that regionalization of care for infants with NEC likely improves outcomes. The neurodevelopmental outcomes after surgical treatment are known to be poor. A randomized trial near completion will provide robust data regarding neurodevelopmental outcomes after laparotomy versus drainage as the initial operative treatment for severe NEC., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
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39. Oral colostrum priming shortens hospitalization without changing the immunomicrobial milieu.
- Author
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Romano-Keeler J, Azcarate-Peril MA, Weitkamp JH, Slaughter JC, McDonald WH, Meng S, Latuga MS, and Wynn JL
- Subjects
- Administration, Oral, Adult, Bacteria classification, Colostrum immunology, Female, Humans, Immunoglobulin A analysis, Infant, Newborn, Infant, Premature immunology, Lactoferrin analysis, Length of Stay, Male, Muramidase analysis, Pregnancy, Prospective Studies, RNA, Ribosomal, 16S genetics, Saliva chemistry, United States, Young Adult, Colostrum chemistry, Hospitalization statistics & numerical data, Microbiota, Mouth microbiology, Saliva immunology
- Abstract
Objective: Oral colostrum priming (OCP) after birth in preterm infants is associated with improved weight gain and modification of the oral immunomicrobial environment. We hypothesized that OCP would modify salivary immune peptides and the oral microbiota in preterm infants., Study Design: We conducted a prospective, randomized clinical trial to determine the effects of OCP on salivary immune peptide representation in preterm infants (<32 weeks completed gestation at birth). Saliva samples were collected before and after OCP. Salivary immune peptide representation was determined via mass spectroscopy. Oral microbiota representation was determined via sequencing of the 16S rRNA gene., Results: Neonates who received OCP (n=48) had a 16-day reduction in the median length of hospitalization as compared with infants who did not receive OCP (n=51). No differences in salivary immune peptide sequence representation before OCP between groups were found. Longitudinal changes in peptides were detected (lysozyme C, immunoglobulin A, lactoferrin) but were limited to a single peptide difference (α-defensin 1) between primed and unprimed infants after OCP. We found no difference in microbial diversity between treatment groups at any time point, but diversity decreased significantly over time in both groups. OCP treatment marginally modified oral taxa with a decline in abundance of Streptococci in the OCP group at 30 days of life., Conclusions: OCP had neither an effect on the salivary peptides we examined nor on overall oral bacterial diversity and composition. Infants who received OCP had a reduced length of hospitalization and warrants further investigation., Competing Interests: The authors have no conflicts of interest relevant to this paper.
- Published
- 2017
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40. Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection.
- Author
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Cohran V, Managlia E, Bradford EM, Goretsky T, Li T, Katzman RB, Cheresh P, Brown JB, Hawkins J, Liu SXL, De Plaen IG, Weitkamp JH, Helmrath M, Zhang Z, and Barrett TA
- Subjects
- Animals, Blotting, Western, Class Ia Phosphatidylinositol 3-Kinase, Digestive System Surgical Procedures adverse effects, Disease Models, Animal, Enterocolitis, Necrotizing surgery, Extracellular Matrix Proteins metabolism, Gene Expression Regulation, Humans, Immunohistochemistry, Infant, Infant, Newborn, Inhibitor of Apoptosis Proteins biosynthesis, Mice, Mice, Inbred C57BL, Real-Time Polymerase Chain Reaction, Repressor Proteins biosynthesis, Short Bowel Syndrome etiology, Survivin, Adaptation, Physiological physiology, Inhibitor of Apoptosis Proteins metabolism, Phosphatidylinositol 3-Kinases metabolism, Short Bowel Syndrome metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial Pik3r1 (p85α)-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of β-catenin target gene expression, activated caspase-3, survivin, p85α, and Trp53. Healthy and post-resection human infant small-bowel sections were analyzed for survivin, Ki-67, and TP53 by immunohistochemistry. Five days after ileocecal resection, epithelial levels of survivin increased relative to sham-operated on mice, which correlated with reduced cleaved caspase-3, p85α, and Trp53. At baseline, p85α-deficient intestinal epithelial cells had less Trp53 and more survivin, and relative responses to resection were blunted compared with wild-type. In infant small bowel, survivin in transit amplifying cells increased 71% after SBR. Resection increased proliferation and decreased numbers of TP53-positive epithelial cells. Data suggest that ileocecal resection reduces p85α, which lowers TP53 activation and releases survivin promoter repression. The subsequent increase in survivin among transit amplifying cells promotes epithelial cell proliferation and lengthens crypts. These findings suggest that SBR reduces p85α and TP53, which increases survivin and intestinal epithelial cell expansion during therapeutic adaptation in patients with short bowel syndrome., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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41. Histological chorioamnionitis shapes the neonatal transcriptomic immune response.
- Author
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Weitkamp JH, Guthrie SO, Wong HR, Moldawer LL, Baker HV, and Wynn JL
- Subjects
- Adaptive Immunity, Biomarkers blood, Chemokine CCL2 blood, Chorioamnionitis blood, Chorioamnionitis pathology, Cytokines blood, Female, Humans, Immunity, Innate, Infant, Newborn, Infant, Premature blood, Male, Matrix Metalloproteinase 9 blood, MicroRNAs genetics, MicroRNAs metabolism, Pregnancy, Chorioamnionitis immunology, Transcriptome
- Abstract
Background: Histologic chorioamnionitis (HCA) is commonly associated with preterm birth and deleterious post-natal outcomes including sepsis and necrotizing enterocolitis. Transcriptomic analysis has been used to uncover gene signatures that permit diagnosis and prognostication, show new therapeutic targets, and reveal mechanisms that underlie differential outcomes with other complex disease states in neonates such as sepsis., Aims: To define the transcriptomic and inflammatory protein response in peripheral blood among infants with exposure to histologic chorioamnionitis., Study Design: Prospective, observational study., Subjects: Uninfected preterm neonates retrospectively categorized based on placental pathology with no HCA exposure (n=18) or HCA exposure (n=15)., Outcomes Measures: We measured the transcriptomic and inflammatory mediator response in prospectively collected whole blood., Results: We found 488 significant (p<0.001), differentially expressed genes in whole blood samples among uninfected neonates with HCA exposure that collectively represented activated innate and adaptive immune cellular pathways and revealed a potential regulatory role for the pleotropic microRNA molecule miR-155. Differentially secreted plasma cytokines in patients with HCA exposure compared to patients without HCA included MCP-1, MPO, and MMP-9 (p<0.05)., Conclusions: Exposure to HCA distinctively activates the neonatal immune system in utero with potentially long-term health consequences., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
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42. Heart rate characteristic index monitoring for bloodstream infection in an NICU: a 3-year experience.
- Author
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Coggins SA, Weitkamp JH, Grunwald L, Stark AR, Reese J, Walsh W, and Wynn JL
- Subjects
- Bacteremia diagnosis, Bacteremia physiopathology, Blood Culture methods, Blood Culture statistics & numerical data, Cohort Studies, Electronic Health Records statistics & numerical data, Female, Humans, Infant, Newborn, Infant, Premature, Intensive Care Units, Neonatal statistics & numerical data, Male, Monitoring, Physiologic methods, Monitoring, Physiologic statistics & numerical data, Retrospective Studies, Statistics as Topic, United States, Heart Rate, Neonatal Sepsis blood, Neonatal Sepsis diagnosis, Neonatal Sepsis physiopathology
- Abstract
Background: Bloodstream infection (BSI) among neonatal intensive care unit (NICU) infants is a frequent problem associated with poor outcomes. Monitoring for abnormal heart rate characteristics (HRCs) may decrease infant mortality by alerting clinicians to sepsis before it becomes clinically apparent., Methods: HRC scores were acquired using the HRC (HeRO) monitor system from Medical Predictive Science Corporation and entered into the electronic medical record by bedside staff. We retrospectively analysed HRC scores recorded twice daily in the medical record during a 30-month period (1 January 2010 through 30 June 2012) for infants in the NICU at the Monroe Carell Jr. Children's Hospital at Vanderbilt. We identified infants that met Centers for Disease Control criteria for late-onset BSI (>3 days of life) during the study period., Results: During the study period, we recorded 127 673 HRC scores from 2384 infants. We identified 46 infants with BSI. Although 8% (9701/127 673) of the HRC scores were ≥2 and 1% (1387/127 673) were ≥5, BSI (at any time) was observed in just 5% of patients with HRC scores ≥2, and 9% of patients with HRC scores ≥5. Of infants with BSI, 5/46 (11%) had at least one HRC score ≥5 and 17/46 (37%) had at least one score ≥2 recorded in the 48 h period prior to the evaluation that resulted in the first positive blood culture of the episode., Conclusions: In our single-centre retrospective study, elevated HRC scores had limited ability to detect BSI. BSI was infrequent at any time during hospitalisation in infants with significantly elevated HRC scores., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Published
- 2016
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43. Answers to Epilogue questions.
- Author
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Maalouf FI, Coggins SA, Phillips JA 3rd, Stefanescu BM, and Weitkamp JH
- Subjects
- Humans, Alkaline Phosphatase blood, Alkaline Phosphatase genetics, Calcification, Physiologic genetics, Hypophosphatasia diagnosis, Hypophosphatasia genetics, Mutation
- Published
- 2016
- Full Text
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44. A newborn with severe skeletal dysplasia.
- Author
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Maalouf FI, Coggins SA, Phillips JA 3rd, Stefanescu BM, and Weitkamp JH
- Subjects
- Bone Diseases, Developmental genetics, Calcification, Physiologic, Extremities diagnostic imaging, Humans, Infant, Newborn, Male, Skull diagnostic imaging, Thorax diagnostic imaging, Treatment Outcome, Bone Diseases, Developmental diagnosis, Bone Diseases, Developmental therapy
- Published
- 2016
- Full Text
- View/download PDF
45. Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18.
- Author
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Wynn JL, Wilson CS, Hawiger J, Scumpia PO, Marshall AF, Liu JH, Zharkikh I, Wong HR, Lahni P, Benjamin JT, Plosa EJ, Weitkamp JH, Sherwood ER, Moldawer LL, Ungaro R, Baker HV, Lopez MC, McElroy SJ, Colliou N, Mohamadzadeh M, and Moore DJ
- Subjects
- Animals, Animals, Newborn, Antibodies, Monoclonal therapeutic use, Female, Male, Mice, Mice, Inbred C57BL, Molecular Targeted Therapy methods, Neonatal Sepsis pathology, Treatment Outcome, Interleukin-17 antagonists & inhibitors, Interleukin-17 immunology, Interleukin-18 immunology, Neonatal Sepsis immunology, Neonatal Sepsis therapy, Survival Rate
- Abstract
Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18-null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G(+) myeloid cells, and blocking IL-17A reduced IL-18-potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18-mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis.
- Published
- 2016
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46. Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development.
- Author
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Fung CM, White JR, Brown AS, Gong H, Weitkamp JH, Frey MR, and McElroy SJ
- Subjects
- Animals, Apoptosis, Birth Weight, Cell Proliferation, Female, Gene Expression, Goblet Cells pathology, Goblet Cells physiology, Humans, Ileum growth & development, Infant, Newborn, Mice, Inbred C57BL, Organ Size, Paneth Cells pathology, Paneth Cells physiology, Pregnancy, Fetal Growth Retardation pathology, Ileum pathology
- Abstract
Infants with intrauterine growth restriction (IUGR) are at increased risk for neonatal and lifelong morbidities affecting multiple organ systems including the intestinal tract. The underlying mechanisms for the risk to the intestine remain poorly understood. In this study, we tested the hypothesis that IUGR affects the development of goblet and Paneth cell lineages, thus compromising the innate immunity and barrier functions of the epithelium. Using a mouse model of maternal thromboxane A2-analog infusion to elicit maternal hypertension and resultant IUGR, we tested whether IUGR alters ileal maturation and specifically disrupts mucus-producing goblet and antimicrobial-secreting Paneth cell development. We measured body weights, ileal weights and ileal lengths from birth to postnatal day (P) 56. We also determined the abundance of goblet and Paneth cells and their mRNA products, localization of cellular tight junctions, cell proliferation, and apoptosis to interrogate cellular homeostasis. Comparison of the murine findings with human IUGR ileum allowed us to verify observed changes in the mouse were relevant to clinical IUGR. At P14 IUGR mice had decreased ileal lengths, fewer goblet and Paneth cells, reductions in Paneth cell specific mRNAs, and decreased cell proliferation. These findings positively correlated with severity of IUGR. Furthermore, the decrease in murine Paneth cells was also seen in human IUGR ileum. IUGR disrupts the normal trajectory of ileal development, particularly affecting the composition and secretory products of the epithelial surface of the intestine. We speculate that this abnormal intestinal development may constitute an inherent "first hit", rendering IUGR intestine susceptible to further injury, infection, or inflammation.
- Published
- 2016
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47. Oligodendroglial maldevelopment in the cerebellum after postnatal hyperoxia and its prevention by minocycline.
- Author
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Scheuer T, Brockmöller V, Blanco Knowlton M, Weitkamp JH, Ruhwedel T, Mueller S, Endesfelder S, Bührer C, and Schmitz T
- Subjects
- Age Factors, Animals, Animals, Newborn, Apoptosis drug effects, Cell Communication drug effects, Cell Death drug effects, Cell Proliferation drug effects, Cells, Cultured, Cerebellum drug effects, Cerebellum growth & development, Cytokines metabolism, Disease Models, Animal, Embryo, Mammalian, Nerve Tissue Proteins metabolism, Oligodendroglia drug effects, Oligodendroglia ultrastructure, Oxidative Stress drug effects, Rats, Rats, Sprague-Dawley, Rats, Wistar, Stem Cells drug effects, Cerebellum pathology, Hyperoxia pathology, Hyperoxia prevention & control, Minocycline therapeutic use, Oligodendroglia pathology
- Abstract
According to recent research, brain injury after premature birth often includes impaired growth of the cerebellum. However, causes of cerebellar injury in this population are poorly understood. In this study, we analyzed whether postnatal hyperoxia perturbs white matter development of the cerebellum, and whether cerebellar glial damage can be prevented by minocycline. We used a hyperoxia model in neonatal rats providing 24 h exposure to fourfold increased oxygen concentration (80% O2) from P6 to P7, followed by recovery in room air until P9, P11, P15, P30. Injections with minocycline were performed at the beginning and 12 h into hyperoxia exposure. Hyperoxia induced oxidative stress in the cerebellum at P7 as evidenced by increased nitrotyrosine concentrations. Numbers of proliferating, NG2+Ki67+ oligodendroglial precursor cells were decreased at P7 after hyperoxia and at P11 following recovery in room air. Numbers of mature, CC1+ oligodendrocytes were diminished in recovering hyperoxia rats, and myelin basic protein expression was still decreased at P30. Electron microscopy analysis of myelinated fibers at P30 revealed thinner myelin sheath after hyperoxia. Long-term injury of the cerebellum by neonatal hyperoxia was confirmed by reduced volumes in MRI measurements at P30. In response to 80% O2, expression of platelet-derived growth factor (PDGF)-A was largely reduced in cerebellar tissue and also in cultured cerebellar astrocytes. Treatment with minocycline during hyperoxia prevented oxidative stress, attenuated oligodendroglial injury, and improved astroglial PDGF-A levels. In conclusion, early hyperoxia causes white matter damage in the cerebellum with astroglial dysfunction being involved, and both can be prevented by treatment with minocycline. Neonatal exposure to hyperoxia causes hypomyelination of the cerebellum. Reduced astroglial growth factor production but not microglial inflammation seems to contribute to oligodendroglial damage, and minocycline rescues oligodendroglia development in the cerebellum after hyperoxia., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
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48. Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality.
- Author
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Wynn JL, Scumpia PO, Stocks BT, Romano-Keeler J, Alrifai MW, Liu JH, Kim AS, Alford CE, Matta P, Weitkamp JH, and Moore DJ
- Subjects
- Adoptive Transfer, Animals, Antibodies immunology, CD11b Antigen metabolism, Endotoxins pharmacology, Female, Fetal Blood cytology, Fetal Blood immunology, Humans, Male, Mice, Mice, Inbred C57BL, Reticulocytes immunology, Spleen cytology, Spleen immunology, Antigens, CD immunology, Bone Marrow Cells immunology, Erythroid Cells immunology, Receptors, Transferrin immunology, Sepsis immunology
- Abstract
Sepsis is a major cause of neonatal mortality and morbidity worldwide. A recent report suggested that murine neonatal host defense against infection could be compromised by immunosuppressive CD71(+) erythroid splenocytes. We examined the impact of CD71(+) erythroid splenocytes on murine neonatal mortality to endotoxin challenge or polymicrobial sepsis and characterized circulating CD71(+) erythroid (CD235a(+)) cells in human neonates. Adoptive transfer or an Ab-mediated reduction in neonatal CD71(+) erythroid splenocytes did not alter murine neonatal survival to endotoxin challenge or polymicrobial sepsis challenge. Ex vivo immunosuppression of stimulated adult CD11b(+) cells was not limited to neonatal splenocytes; it also occurred with adult and neonatal bone marrow. Animals treated with anti-CD71 Ab showed reduced splenic bacterial load following bacterial challenge compared with isotype-treated mice. However, adoptive transfer of enriched CD71(+) erythroid splenocytes to CD71(+)-reduced animals did not reduce bacterial clearance. Human CD71(+)CD235a(+) cells were common among cord blood mononuclear cells and were shown to be reticulocytes. In summary, a lack of effect on murine survival to polymicrobial sepsis following adoptive transfer or diminution of CD71(+) erythroid splenocytes under these experimental conditions suggests that the impact of these cells on neonatal infection risk and progression may be limited. An unanticipated immune priming effect of anti-CD71 Ab treatment, rather than a reduction in immunosuppressive CD71(+) erythroid splenocytes, was likely responsible for the reported enhanced bacterial clearance. In humans, the well-described rapid decrease in circulating reticulocytes after birth suggests that they may have a limited role in reducing inflammation secondary to microbial colonization., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
49. Infectious causes of necrotizing enterocolitis.
- Author
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Coggins SA, Wynn JL, and Weitkamp JH
- Subjects
- Enterocolitis, Necrotizing etiology, Humans, Infant, Infant, Newborn, Infant, Premature, Bacterial Infections complications, Candidiasis complications, Enterocolitis, Necrotizing microbiology, Virus Diseases complications
- Abstract
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency among premature infants. Although a large body of research has focused on understanding its pathogenesis, the exact mechanism has not been elucidated. Of particular interest is the potential causative role of infectious culprits in the development of NEC. A variety of reports describe bacterial, viral, and fungal infections occurring in association with NEC; however, no single organism has emerged as being definitively involved in NEC pathogenesis. In this review, the authors summarize the literature on infectious causes of NEC., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
50. Maternal influences on fetal microbial colonization and immune development.
- Author
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Romano-Keeler J and Weitkamp JH
- Subjects
- Female, Humans, Immune System growth & development, Pregnancy, Fetus immunology, Fetus microbiology, Immune System embryology, Maternal-Fetal Exchange immunology, Microbiota immunology, Models, Immunological, Placenta microbiology
- Abstract
While critical for normal development, the exact timing of establishment of the intestinal microbiome is unknown. For example, although preterm labor and birth have been associated with bacterial colonization of the amniotic cavity and fetal membranes for many years, the prevailing dogma of a sterile intrauterine environment during normal term pregnancies has been challenged more recently. While found to be a key contributor of evolution in the animal kingdom, maternal transmission of commensal bacteria may also constitute a critical process during healthy pregnancies in humans with yet unclear developmental importance. Metagenomic sequencing has elucidated a rich placental microbiome in normal term pregnancies likely providing important metabolic and immune contributions to the growing fetus. Conversely, an altered microbial composition during pregnancy may produce aberrant metabolites impairing fetal brain development and life-long neurological outcomes. Here we review the current understanding of microbial colonization at the feto-maternal interface and explain how normal gut colonization drives a balanced neonatal mucosal immune system, while dysbiosis contributes to aberrant immune function early in life and beyond. We discuss how maternal genetics, diet, medications, and probiotics inform the fetal microbiome in preparation for perinatal and postnatal bacterial colonization.
- Published
- 2015
- Full Text
- View/download PDF
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