Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87-1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%. CONCLUSIONS: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

Neurodevelopmental Outcomes of Preterm Infants With Retinopathy of Prematurity by Treatment.

OBJECTIVE: Among extremely preterm infants, we evaluated whether bevacizumab therapy compared with surgery for retinopathy of prematurity (ROP) is associated with adverse outcomes in early childhood. METHODS: This study was a retrospective analysis of prospectively collected data on preterm (22-26 + 6/7 weeks' gestational age) infants admitted to the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers who received bevacizumab or surgery exclusively for ROP. The primary outcome was death or severe neurodevelopmental impairment (NDI) at 18 to 26 months' corrected age (Bayley Scales of Infant and Toddler Development, Third Edition cognitive or motor composite score <70, Gross Motor Functional Classification Scale level ≥2, bilateral blindness or hearing impairment). RESULTS: The cohort (N = 405; 214 [53%] boys; median [interquartile range] gestational age: 24.6 [23.9-25.3] weeks) included 181 (45%) infants who received bevacizumab and 224 (55%) who underwent ROP surgery. Infants treated with bevacizumab had a lower median (interquartile range) birth weight (640 [541-709] vs 660 [572.5-750] g; P = .02) and longer durations of conventional ventilation (35 [21-58] vs 33 [18-49] days; P = .04) and supplemental oxygen (112 [94-120] vs 105 [84.5-120] days; P = .01). Death or severe NDI (adjusted odds ratio [aOR] 1.42; 95% confidence interval [CI] 0.94 to 2.14) and severe NDI (aOR 1.14; 95% CI 0.76 to 1.70) did not differ between groups. Odds of death (aOR 2.54 [95% CI 1.42 to 4.55]; P = .002), a cognitive score <85 (aOR 1.78 [95% CI 1.09 to 2.91]; P = .02), and a Gross Motor Functional Classification Scale level ≥2 (aOR 1.73 [95% CI 1.04 to 2.88]; P = .04) were significantly higher with bevacizumab therapy. CONCLUSIONS: In this multicenter cohort of preterm infants, ROP treatment modality was not associated with differences in death or NDI, but the bevacizumab group had higher mortality and poor cognitive outcomes in early childhood. These data reveal the need for a rigorous appraisal of ROP therapy.

Medical and developmental outcomes of bevacizumab versus laser for retinopathy of prematurity.

BACKGROUND: Infants with stage 3+ retinopathy of prematurity (ROP) in zone I or zone II posterior were randomized to initial treatment with bevacizumab or laser in a multicenter trial (BEAT-ROP). The purpose of this study was to assess the effects of bevacizumab on nonophthalmologic outcomes. METHODS: At one study site, inborn infants of <27 weeks' gestational age underwent medical and standardized neurologic and developmental assessments at 18-22 months' corrected age (age after expected date of full-term delivery). RESULTS: Of the 18 infants enrolled at our site, 16 (7 bevacizumab, 9 laser) were evaluated for medical and neurodevelopmental outcomes at 18-28 months' corrected age. For each of the groups, the medians and ranges of growth percentiles were low compared with norms for healthy infants. The ranges for Bayley III developmental scores were also low relative to expected norms for healthy infants. There were no significant differences between the bevacizumab and laser therapy groups in weight (median percentile: bevacizumab, 18; laser, 7), length, head circumference, cerebral palsy, or Bayley scores (median Cognitive Composite Score: bevacizumab, 85; laser, 65). There was a significant difference in length of hospital stay (median days, 98 vs 140 days) favoring the bevacizumab group. CONCLUSIONS: In this patient cohort 2-year follow-up evaluation of infants treated with bevacizumab versus laser therapy for retinopathy of prematurity showed no adverse effects on medical or neurodevelopmental outcomes.

Identifying novel transcription factors involved in the inflammatory response by using binding site motif scanning in genomic regions defined by histone acetylation.

The innate immune response to pathogenic challenge is a complex, multi-staged process involving thousands of genes. While numerous transcription factors that act as master regulators of this response have been identified, the temporal complexity of gene expression changes in response to pathogen-associated molecular pattern receptor stimulation strongly suggest that additional layers of regulation remain to be uncovered. The evolved pathogen response program in mammalian innate immune cells is understood to reflect a compromise between the probability of clearing the infection and the extent of tissue damage and inflammatory sequelae it causes. Because of that, a key challenge to delineating the regulators that control the temporal inflammatory response is that an innate immune regulator that may confer a selective advantage in the wild may be dispensable in the lab setting. In order to better understand the complete transcriptional response of primary macrophages to the bacterial endotoxin lipopolysaccharide (LPS), we designed a method that integrates temporally resolved gene expression and chromatin-accessibility measurements from mouse macrophages. By correlating changes in transcription factor binding site motif enrichment scores, calculated within regions of accessible chromatin, with the average temporal expression profile of a gene cluster, we screened for transcriptional factors that regulate the cluster. We have validated our predictions of LPS-stimulated transcriptional regulators using ChIP-seq data for three transcription factors with experimentally confirmed functions in innate immunity. In addition, we predict a role in the macrophage LPS response for several novel transcription factors that have not previously been implicated in immune responses. This method is applicable to any experimental situation where temporal gene expression and chromatin-accessibility data are available.

Prevention and management of bronchopulmonary dysplasia: Lessons learned from the neonatal research network.

Despite remarkable improvements in survival of extremely premature infants, the burden of BPD among survivors remains a frustrating problem for parents and caregivers. Advances, such as antenatal steroids and surfactant replacement, which have dramatically improved survival, have not reduced BPD among survivors. Other advances that have significantly improved the combined outcome of death or BPD, such as vitamin A and avoidance of mechanical ventilation, have had smaller magnitude effects on the outcome of BPD alone. Postnatal steroids have a clear beneficial effect on BPD, but the optimal preparation, dose, and timing for maximizing benefit and minimizing harm have yet to be determined. This persistent burden of BPD among the most immature survivors remains a challenge for the NRN and other researchers in neonatal medicine.

Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012.

IMPORTANCE: Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality. OBJECTIVE: To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers. DESIGN, SETTING, PARTICIPANTS: Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012. EXPOSURES: Extremely preterm birth. MAIN OUTCOMES AND MEASURES: Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex. RESULTS: Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P < .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P < .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P < .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P < .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P < .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P < .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation. CONCLUSIONS AND RELEVANCE: Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00063063.

Neurodevelopmental Outcomes of Extremely Preterm Infants Randomized to Stress Dose Hydrocortisone.

OBJECTIVE: To compare the effects of stress dose hydrocortisone therapy with placebo on survival without neurodevelopmental impairments in high-risk preterm infants. STUDY DESIGN: We recruited 64 extremely low birth weight (birth weight ≤1000 g) infants between the ages of 10 and 21 postnatal days who were ventilator-dependent and at high-risk for bronchopulmonary dysplasia. Infants were randomized to a tapering 7-day course of stress dose hydrocortisone or saline placebo. The primary outcome at follow-up was a composite of death, cognitive or language delay, cerebral palsy, severe hearing loss, or bilateral blindness at a corrected age of 18-22 months. Secondary outcomes included continued use of respiratory therapies and somatic growth. RESULTS: Fifty-seven infants had adequate data for the primary outcome. Of the 28 infants randomized to hydrocortisone, 19 (68%) died or survived with impairment compared with 22 of the 29 infants (76%) assigned to placebo (relative risk: 0.83; 95% CI, 0.61 to 1.14). The rates of death for those in the hydrocortisone and placebo groups were 31% and 41%, respectively (P = 0.42). Randomization to hydrocortisone also did not significantly affect the frequency of supplemental oxygen use, positive airway pressure support, or need for respiratory medications. CONCLUSIONS: In high-risk extremely low birth weight infants, stress dose hydrocortisone therapy after 10 days of age had no statistically significant effect on the incidence of death or neurodevelopmental impairment at 18-22 months. These results may inform the design and conduct of future clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00167544.

PaCO2 in surfactant, positive pressure, and oxygenation randomised trial (SUPPORT).

OBJECTIVE: To determine the association of arterial partial pressure of carbon dioxide PaCO2 with severe intraventricular haemorrhage (sIVH), bronchopulmonary dysplasia (BPD), and neurodevelopmental impairment (NDI) at 18-22 months in premature infants. DESIGN: Secondary exploratory data analysis of Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT). SETTING: Multiple referral neonatal intensive care units. PATIENTS: 1316 infants 24 0/7 to 27 6/7 weeks gestation randomised to different oxygenation (SpO2 target 85-89% vs 91-95%) and ventilation strategies. MAIN OUTCOME MEASURES: Blood gases from postnatal day 0 to day14 were analysed. Five PaCO2 variables were defined: minimum (Min), maximum (Max), SD, average (time-weighted), and a four level categorical variable (hypercapnic (highest quartile of Max PaCO2), hypocapnic (lowest quartile of Min PaCO2), fluctuators (hypercapnia and hypocapnia), and normocapnic (middle two quartiles of Max and Min PaCO2)). PaCO2 variables were compared for infants with and without sIVH, BPD and NDI (±death). Multivariable logistic regression models were developed for adjusted results. RESULTS: sIVH, BPD and NDI (±death) were associated with hypercapnic infants and fluctuators. Association of Max PaCO2 and outcomes persisted after adjustment (per 10 mm Hg increase: sIVH/death: OR 1.27 (1.13 to 1.41); BPD/death: OR 1.27 (1.12 to 1.44); NDI/death: OR 1.23 (1.10 to 1.38), death: OR 1.27 (1.12 to 1.44), all p<0.001). No interaction was found between PaCO2 category and SpO2 treatment group for sIVH/death, NDI/death or death. Max PaCO2 was positively correlated with maximum FiO2 (rs0.55, p<0.0001) and ventilator days (rs0.61, p<0.0001). CONCLUSIONS: Higher PaCO2 was an independent predictor of sIVH/death, BPD/death and NDI/death. Further trials are needed to evaluate optimal PaCO2 targets for high-risk infants.

Multiscale representation of genomic signals.

Genomic information is encoded on a wide range of distance scales, ranging from tens of bases to megabases. We developed a multiscale framework to analyze and visualize the information content of genomic signals. Different types of signals, such as G+C content or DNA methylation, are characterized by distinct patterns of signal enrichment or depletion across scales spanning several orders of magnitude. These patterns are associated with a variety of genomic annotations. By integrating the information across all scales, we demonstrated improved prediction of gene expression from polymerase II chromatin immunoprecipitation sequencing (ChIP-seq) measurements, and we observed that gene expression differences in colorectal cancer are related to methylation patterns that extend beyond the single-gene scale. Our software is available at https://github.com/tknijnen/msr/.

Perinatal factors and regional brain volume abnormalities at term in a cohort of extremely low birth weight infants.

Our objective was to investigate diverse clinical antecedents of total and regional brain volume abnormalities and white matter hyperintensity volume on term MRI in extremely low birth weight (birth weight ≤1000 g) survivors. A consecutive cohort of extremely low birth weight infants who survived to 38 weeks postmenstrual age (n = 122) and a control group of 16 healthy term newborns underwent brain MRI at term-equivalent age. Brain volumes were measured using semi-automated and manual segmentation methods. Using multivariable linear regression, clinical antecedents were correlated with volumes of total brain tissue, white matter hyperintensities, and regional tissues/structures, adjusted for age at MRI, total cranial volume, and total tissue volume. Regional brain volumes were markedly reduced in extremely low birth weight infants as compared to term newborns (relative difference range: -11.0%, -35.9%). Significant adverse clinical associations for total brain tissue volume included: small for gestational age, seizures, caffeine therapy/apnea of prematurity, duration of parenteral nutrition, pulmonary hemorrhage, and white matter injury (p<0.01 for each; relative difference range: -1.4% to -15.0%). Surgery for retinopathy of prematurity and surgery for necrotizing enterocolitis or spontaneous intestinal perforation were significantly associated with increasing volume of white matter hyperintensities. Regional brain volumes are sensitive to multiple perinatal factors and neonatal morbidities or interventions. Brain growth measurements in extremely low birth weight infants can advance our understanding of perinatal brain injury and development.

Randomized trial of iron supplementation versus routine iron intake in VLBW infants.

OBJECTIVE: To determine if iron supplementation of 2 mg/kg per day, in addition to routine iron-fortified formula or mother's milk, increased the hematocrit (Hct) at 36 weeks' postmenstrual age (PMA). METHODS: : Infants with a birth weight <1500 g who reached 120 mL/kg per day of feedings before 32 weeks' PMA were randomly assigned to iron (multivitamin with iron) or control (multivitamin) from enrollment until 36 weeks' PMA (or discharge, if sooner). Investigators and caregivers were masked. Transfusion guidelines were used. The primary outcome was Hct at 36 weeks' PMA. A nonparametric rank sum analysis was performed so that infants who died before 36 weeks and infants who were transfused could be included in an intention-to-treat analysis. Infants were ranked by death (lowest rank) then by number of transfusions (next lowest ranks). For infants who survived and were not transfused, the 36-week PMA Hct was used for the rank. RESULTS: One hundred fifty infants were enrolled (76 iron, 74 controls). There were 2 deaths (1 in each group). One hundred other infants (47 iron, 53 controls) received transfusion(s). There was no significant difference in the primary outcome ranking (P = .59), in the number of transfusions per subject (P = .64), or in 36-week Hct (iron mean ± SD, 29.2% ± 4.0%; control, 28.3% ± 4.5%; mean difference and 95% confidence interval 0.9 [-0.5 to 2.3]; P = .21) or reticulocyte count among survivors. No short-term adverse effects of iron supplementation were observed. CONCLUSIONS: Among infants <1500 g birth weight, iron supplementation, in addition to routine iron intake, did not significantly increase the 36-week Hct or the decrease number of transfusions.

Pilot randomized trial of hydrocortisone in ventilator-dependent extremely preterm infants: effects on regional brain volumes.

OBJECTIVE: To test the hypothesis that high-risk ventilator-dependent extremely low birth weight (birth weight ≤1000 g) infants treated with 7 days of hydrocortisone will have larger total brain tissue volumes than placebo treated infants. STUDY DESIGN: A predetermined sample size of 64 extremely low birth weight infants, between 10-21 days old and ventilator-dependent with a respiratory index score ≥2, were randomized to systemic hydrocortisone (17 mg/kg cumulative dose) or saline placebo. Primary outcome was total brain tissue volume. Volumetric magnetic resonance imaging was performed at 38 weeks postmenstrual age; brain tissue regions were segmented and quantified automatically with a high degree of accuracy and 9 structures were segmented manually. All analyses of regional brain volumes were adjusted by postmenstrual age at magnetic resonance imaging scan. RESULTS: The study groups were similar at baseline and 8 infants died in each arm. Unadjusted total brain tissue volume (mean ± SD) in the hydrocortisone (N = 23) and placebo treated infants (N = 21) was 272 ± 40.3 cm(3) and 277.8 ± 59.1 cm(3), respectively (adjusted mean difference: 6.35 cm(3) (95% CI: (-20.8, 32.5); P = .64). Three of the 31 hydrocortisone treated infants and 5 of the 33 placebo treated infants survived without severe bronchopulmonary dysplasia (relative risk 0.62, 95% CI: 0.13, 2.66; P = .49). No significant differences were noted in prespecified secondary outcomes of regional structural volumes or days on respiratory support. No adverse effects of hydrocortisone were observed. CONCLUSIONS: Low dose hydrocortisone in high-risk ventilator-dependent infants after a week of age had no discernible effect on regional brain volumes or pulmonary outcomes prior to neonatal intensive care unit discharge.

Empiric antifungal therapy and outcomes in extremely low birth weight infants with invasive candidiasis.

OBJECTIVE: To assess the impact of empiric antifungal therapy for invasive candidiasis on subsequent outcomes in premature infants. STUDY DESIGN: This was a cohort study of infants with a birth weight ≤ 1000 g receiving care at Neonatal Research Network sites. All infants had at least one positive culture for Candida. Empiric antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of empiric antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI). RESULTS: A total of 136 infants developed invasive candidiasis. The incidence of death or NDI was lower in infants who received empiric antifungal therapy (19 of 38; 50%) compared with those who had not (55 of 86; 64%; OR, 0.27; 95% CI, 0.08-0.86). There was no significant difference between the groups for any single outcome or other combined outcomes. CONCLUSION: Empiric antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.

Leishmania promotes its own virulence by inducing expression of the host immune inhibitory ligand CD200.

Leishmania parasites infect macrophages, cells normally involved in innate defense against pathogens. Leishmania amazonensis and Leishmania major cause severe or mild disease, respectively, consistent with each parasite's ability to survive within activated macrophages. The mechanisms underlying increased virulence of L. amazonensis are mostly unknown. We show that L. amazonensis promotes its own survival by inducing expression of CD200, an immunoregulatory molecule that inhibits macrophage activation. L. amazonensis does not form typical nonhealing lesions in CD200(-/-) mice and cannot replicate in CD200(-/-) macrophages, an effect reversed by exogenous administration of soluble CD200-Fc. The less virulent L. major does not induce CD200 expression and forms small, self-healing lesions in both wild-type and CD200(-/-) mice. Notably, CD200-Fc injection transforms the course of L. major infection to one resembling L. amazonensis, with large, nonhealing lesions. CD200-dependent iNOS inhibition allows parasite growth in macrophages, identifying a mechanism for the increased virulence of L. amazonensis.

Systems analysis identifies an essential role for SHANK-associated RH domain-interacting protein (SHARPIN) in macrophage Toll-like receptor 2 (TLR2) responses.

Precise control of the innate immune response is essential to ensure host defense against infection while avoiding inflammatory disease. Systems-level analyses of Toll-like receptor (TLR)-stimulated macrophages suggested that SHANK-associated RH domain-interacting protein (SHARPIN) might play a role in the TLR pathway. This hypothesis was supported by the observation that macrophages derived from chronic proliferative dermatitis mutation (cpdm) mice, which harbor a spontaneous null mutation in the Sharpin gene, exhibited impaired IL-12 production in response to TLR activation. Systems biology approaches were used to define the SHARPIN-regulated networks. Promoter analysis identified NF-κB and AP-1 as candidate transcription factors downstream of SHARPIN, and network analysis suggested selective attenuation of these pathways. We found that the effects of SHARPIN deficiency on the TLR2-induced transcriptome were strikingly correlated with the effects of the recently described hypomorphic L153P/panr2 point mutation in Ikbkg [NF-κB Essential Modulator (NEMO)], suggesting that SHARPIN and NEMO interact. We confirmed this interaction by co-immunoprecipitation analysis and furthermore found it to be abrogated by panr2. NEMO-dependent signaling was affected by SHARPIN deficiency in a manner similar to the panr2 mutation, including impaired p105 and ERK phosphorylation and p65 nuclear localization. Interestingly, SHARPIN deficiency had no effect on IκBα degradation and on p38 and JNK phosphorylation. Taken together, these results demonstrate that SHARPIN is an essential adaptor downstream of the branch point defined by the panr2 mutation in NEMO.

Prediction of bronchopulmonary dysplasia by postnatal age in extremely premature infants.

RATIONALE: Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment. OBJECTIVES: To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death. METHODS: We assessed infants of 23-30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000-2004. MEASUREMENTS AND MAIN RESULTS: Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and Fi(O(2)), and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org. CONCLUSIONS: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.

A new method to orient 3-dimensional computed tomography models to the natural head position: a clinical feasibility study.

PURPOSE: The purpose of this study was to evaluate the clinical feasibility of a new method to orient 3-dimensional (3D) computed tomography models to the natural head position (NHP). This method uses a small and inexpensive digital orientation device to record NHP in 3 dimensions. This device consists of a digital orientation sensor attached to the patient via a facebow and an individualized bite jig. The study was designed to answer 2 questions: 1) whether the weight of the new device can negatively influence the NHP and 2) whether the new method is as accurate as the gold standard. PATIENTS AND METHODS: Fifteen patients with craniomaxillofacial deformities were included in the study. Each patient's NHP is recorded 3 times. The first NHP was recorded with a laser scanning method without the presence of the digital orientation device. The second NHP was recorded with the digital orientation device. Simultaneously, the third NHP was also recorded with the laser scanning method. Each recorded NHP measurement was then transferred to the patient's 3D computed tomography facial model, resulting in 3 different orientations for each patient: the orientation generated via the laser scanning method without the presence of the digital orientation sensor and facebow (orientation 1), the orientation generated by use of the laser scanning method with the presence of the digital orientation sensor and facebow (orientation 2), and the orientation generated with the digital orientation device (orientation 3). Comparisons are then made between orientations 1 and 2 and between orientations 2 and 3, respectively. Statistical analyses are performed. RESULTS: The results show that in each pair, the difference (Δ) between the 2 measurements is not statistically significantly different from 0°. In addition, in the first pair, the Bland-Altman lower and upper limits of the Δ between the 2 measurements are within 1.5° in pitch and within a subdegree in roll and yaw. In the second pair, the limits of the Δ in all 3 dimensions are within 0.5°. CONCLUSION: Our technique can accurately record NHP in 3 dimensions and precisely transfer it to a 3D model. In addition, the extra weight of the digital orientation sensor and facebow has minimal influence on the self-balanced NHP establishment.

Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity is a leading cause of childhood blindness worldwide. Peripheral retinal ablation with conventional (confluent) laser therapy is destructive, causes complications, and does not prevent all vision loss, especially in cases of retinopathy of prematurity affecting zone I of the eye. Case series in which patients were treated with vascular endothelial growth factor inhibitors suggest that these agents may be useful in treating retinopathy of prematurity. METHODS: We conducted a prospective, controlled, randomized, stratified, multicenter trial to assess intravitreal bevacizumab monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of prematurity. Infants were randomly assigned to receive intravitreal bevacizumab (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of retinopathy of prematurity in one or both eyes requiring retreatment before 54 weeks' postmenstrual age. RESULTS: We enrolled 150 infants (total sample of 300 eyes); 143 infants survived to 54 weeks' postmenstrual age, and the 7 infants who died were not included in the primary-outcome analyses. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (6 of 140 eyes [4%]) and 19 infants in the laser-therapy group (32 of 146 eyes [22%], P=0.002). A significant treatment effect was found for zone I retinopathy of prematurity (P=0.003) but not for zone II disease (P=0.27). CONCLUSIONS: Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina. This trial was too small to assess safety. (Funded by Research to Prevent Blindness and others; ClinicalTrials.gov number, NCT00622726.).