Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404)

The Pediatric Oncology Group (POG) phase 3 trial 9404 was designed to determine the effectiveness of high-dose methotrexate (HDM) when added to multi-agent chemotherapy based on the Dana-Farber backbone. Children with T-cell acute lymphoblastic leukemia (T-ALL) or advanced lymphoblastic lymphoma (T-NHL) were randomized at diagnosis to receive/not receive HDM (5 g/m 2 as a 24-hour infusion) at weeks 4, 7, 10, and 13. Between 1996 and 2000, 436 patients were enrolled in the methotrexate randomization. Five-year and 10-year event-free survival (EFS) was 80.2% ± 2.8% and 78.1% ± 4.3% for HDM (n = 219) versus 73.6% ± 3.1% and 72.6% ± 5.0% for no HDM (n = 217; P = .17). For T-ALL, 5-year and 10-year EFS was significantly better with HDM (n = 148, 5 years: 79.5% ± 3.4%, 10 years: 77.3% ± 5.3%) versus no HDM (n = 151, 5 years: 67.5% ± 3.9%, 10 years: 66.0% ± 6.6%; P = .047). The difference in EFS between HDM and no HDM was not significant for T-NHL patients (n = 71, 5 years: 81.7% ± 4.9%, 10 years: 79.9% ± 7.5% vs n = 66, 5 years: 87.8% ± 4.2%, 10 years: 87.8% ± 6.4%; P = .38). The frequency of mucositis was significantly higher in patients treated with HDM ( P = .003). The results support adding HDM to the treatment of children with T-ALL, but not with NHL, despite the increased risk of mucositis

Maternal Black Race and Persistent Wheezing Illness in Former Extremely Low Gestational Age Newborns: Secondary Analysis of a Randomized Trial.

ObjectiveTo evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship.Study designWe assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis.ResultsOf 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively.ConclusionsAmong former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences.Trial registrationClinicalTrials.gov: NCT01022580

Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE).

BackgroundInitial 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.MethodsDose-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).ResultsTwenty-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.ConclusionsBudesonide/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

Early Cumulative Supplemental Oxygen Predicts Bronchopulmonary Dysplasia in High Risk Extremely Low Gestational Age Newborns.

ObjectiveTo assess the prognostic accuracy of early cumulative supplemental oxygen (CSO) exposure for prediction of bronchopulmonary dysplasia (BPD) or death, and to evaluate the independent association of CSO with BPD or death.Study designWe performed a secondary analysis of the Trial of Late Surfactant, which enrolled 511 infants born at ≤28 weeks gestational age who were mechanically ventilated at 7-14 days of life. Our primary outcome was BPD or death at 36 weeks postmenstrual age, as determined by a physiological oxygen/flow challenge. Average daily supplemental oxygen (fraction of inspired oxygen - 0.21) was calculated. CSO was calculated as the sum of the average daily supplemental oxygen over time periods of interest up to 28 days of age. Area under the receiver operating curve (AUROC) values were generated to evaluate the accuracy of CSO for prediction of BPD or death. The independent relationship between CSO and BPD or death was assessed in multivariate modeling, while adjusting for mean airway pressure.ResultsIn the study infants, mean gestational age at birth was 25.2 ± 1.2 weeks and mean birth weight was 700 ± 165 g. The AUROC value for CSO at 14 days was significantly better than that at earlier time points for outcome prediction (OR, 0.70; 95% CI, 0.65-0.74); it did not increase with the addition of later data. In multivariate modeling, a CSO increase of 1 at 14 days increased the odds of BPD or death (OR, 1.7; 95% CI, 1.3-2.2; P < .0001), which corresponds to a 7% higher daily supplemental oxygen value.ConclusionIn high-risk extremely low gestational age newborns, the predictive accuracy of CSO plateaus at 14 days. CSO is independently associated with BPD or death. This index may identify infants who could benefit from early intervention to prevent BPD

Suchverhalten, Reintegration und Prävention

This dissertation studies the search behavior and future labor market outcomes of the unemployed as well as ways to prevent unemployment. Chapter 2 is the first to empirically test the hypothesis that reservation wages of second generation migrants exceed those of first generation migrants, which may represent an explanation for the lack of migrants' intergenerational improvement. The empirical findings confirm this hypothesis. In as far as German language skills or self-evaluated returns to characteristics reflect a person's frames of reference, changing frames of reference are identified as a mechanism through which increasing reservation wages may arise. Chapter 3 extends the previous analysis by investigating the reemployment probabilities of natives and second generation migrants, particularly analyzing the economic preferences of these two groups, namely risk attitudes, time preferences, trust and reciprocity. Second generation migrants are found to have a higher willingness to take risks, and they are less likely to have a low amount of positive reciprocity when compared to natives. It is also found that more risk-loving individuals have a lower reemployment probability. However, the lower reemployment probability of second generation migrants cannot be explained by the difference in economic preferences. Chapter 4 also investigates reemployment probabilities, however, from a long-term perspective, namely one year after unemployment entry. In particular, this chapter investigates whether individual happiness is a predictor of future reemployment probabilities and wages. The results show that residual happiness has a statistically significant inverted U-shaped effect on the individual's reemployment probability and reentry wages. Further investigations offer three mechanisms, which appear to also be interrelated and have not previously been shown in this context: a) happiness matters mainly for future self-employment and less for standard employment; b) happiness matters only for male unemployed and not for females; and c) the concept of locus of control is able to explain part of the effect. The subsequent two chapters are complementary to the previous ones as they focus on processes that may improve the access to jobs or prevent unemployment in the first place. Chapter 5 focuses on discrimination at the hiring stage, and therefore on unequal opportunities in the access to jobs. Data from a randomized experiment on the introduction of anonymous job applications in the job market for Ph.D. economists show that female applicants have a higher probability of receiving an interview invitation than male applicants with standard applications, however this difference disappears with anonymous job applications. Moreover, evidence is found that recruiters tend to rely more strongly on the “traditional” quality signal of top journal publications when confronted with anonymous job applications. However, any structural differences that existed prior to the hiring process cannot be overcome with anonymous job applications. Accordingly, this shifts the focus to education, with Chapter 6 focusing on the German secondary education system and the persistent education gap between natives and migrants. This gap may be due to differences in the average socioeconomic background between native and migrant children, or to migrant- specific characteristics such as language skills or discrimination. Results indicate significant differences between migrant and native children in terms of household characteristics and parental background. These differences appear to be entirely responsible for differences in secondary school recommendations given by teachers, actual enrollment rates at different secondary school types, and differences in educational attainment at the age of 17. Comparable natives thus face similar difficulties to migrant children.Diese Dissertation untersucht das Suchverhalten und den Arbeitsmarkterfolg von Arbeitslosen in den Arbeitsmarkt sowie Möglichkeiten zur Prävention von Arbeitslosigkeit. Kapitel 2 untersucht zum ersten Mal die Hypothese steigender Reservationslöhne von einer Generation zur nächsten. Dies kann als mögliche Erklärung für die größtenteils ausbleibende wirtschaftliche Integration beider Generationen von Migranten dienen. Die empirischen Ergebnisse bestätigen die Hypothese steigender Reservationslöhne von einer Generation zur nächsten. Deutsche Sprachkenntnisse und die Selbsteinschätzung von Renditen individueller Charakteristika (u.a. Bildungsrenditen) dienen als Approximationen für die Vergleichsgruppe einer Person. Sofern diese Approximationen zutreffen, werden empirische Belege für die Hypothese der Veränderung der Vergleichsgruppe als Mechanismus steigender Reservationslöhne gefunden. Kapitel 3 erweitert die vorherige Analyse, indem Wiederbeschäftigungswahrscheinlichkeiten von arbeitslosen Einheimischen und Migranten der zweiten Generation im Zusammenhang mit ökonomischen Präferenzen untersucht werden. Unterschiede bei Risikoeinstellungen, Zeitpräferenzen, Vertrauen und Reziprozität können möglicherweise Teile der Diskrepanz der Wiederbeschäftigungsquoten zwischen Deutschen und Migranten der zweiten Generation erklären. Letztere weisen eine höhere Risikobereitschaft auf und die Wahrscheinlichkeit für eine geringe positive Reziprozität ist im Vergleich zu Deutschen niedriger. Diese Unterschiede können die niedrigere Beschäftigungswahrscheinlichkeit von Migranten der zweiten Generation jedoch nicht erklären. Kapitel 4 geht der Fragestellung nach, ob Lebenszufriedenheit einen Einfluss auf die Wiederbeschäftigungswahrscheinlichkeit zwölf Monate nach Eintritt in die Arbeitslosigkeit und auf zukünftige Löhne ausübt. Die Ergebnisse zeigen, dass Zufriedenheit einen inversen U-förmigen Effekt auf die Wiederbeschäftigungswahrscheinlichkeit und auf zukünftige Löhne hat. Weitere Untersuchungen führen in diesem Zusammenhang zu drei neuen Erkenntnissen: a) Lebenszufriedenheit hat hauptsächlich einen Einfluss auf die zukünftige Aufnahme von Selbstständigkeit; b) nur Männer erfahren Auswirkungen von Lebenszufriedenheit; und c) das Konzept des „locus of control“ (Kontrollüberzeugungen) kann Teile des Effektes erklären. Die folgenden zwei Kapitel ergänzen die vorherigen Kapitel durch den Fokus auf Prozesse, die Arbeitslosigkeit verhindern bzw. Beschäftigung fördern sollen. Können anonymisierte Bewerbungen, welche keine Angaben über die Identität des Bewerbenden wie z.B. das Geschlecht und die Herkunft enthalten, Diskriminierung im Bewerbungsprozess verringern? In Kapitel 5 werden hierzu Daten von einem randomisierten Experiment mit Bewerbenden auf eine Post-Doc Stelle an einem europäischen Wirtschaftsforschungsinstitut untersucht. Es zeigt sich, dass Frauen häufiger eingeladen werden, wenn ihre Bewerbungen auf herkömmliche Art betrachtet werden. Dieser Effekt verschwindet mit anonymisierten Bewerbungen. Außerdem scheinen mit anonymisierten Bewerbungen bestimmte Informationen – im konkreten Fall die Veröffentlichungen in renommierten Fachzeitschriften – ein größere Bedeutung zu erfahren. Existieren jedoch strukturelle Unterschiede zwischen gewissen Bewerbendengruppen, stoßen anonymisierte Bewerbungen an ihre Grenze. Ein zentraler Punkt ist hierbei die (Aus-)Bildung, welche in Kapitel 6 anhand des deutschen Schulsystems untersucht wird. Insbesondere werden die anhaltenden Unterschiede in Bezug auf den Besuch der weiterführenden Schulen zwischen Kindern mit und ohne Migrationshintergrund erforscht. Diese können zum einen durch Unterschiede im durchschnittlichen sozioökonomischen Hintergrund und zum anderen durch migrationsspezifische Merkmale entstehen. Die empirischen Ergebnisse zeigen, dass Unterschiede im durchschnittlichen Familienhintergrund zwischen deutschen Kindern und Kindern mit Migrationshintergrund die Unterschiede bei Empfehlungen für weiterführende Schulen, bei Einschulraten auf weiterführenden Schulen und beim Schulbesuch mit 17 Jahren vollständig erklären können. Diese Erkenntnisse deuten damit auf allgemeine Ungleichheiten und Hindernisse beim Übergang auf weiterführende Schulen im deutschen Schulsystem hin

Postnatal weight gain in preterm infants with severe bronchopulmonary dysplasia

OBJECTIVES: To characterize postnatal growth failure (PGF), defined as weight < 10th percentile for postmenstrual age (PMA) in preterm (≤27 weeks’ gestation) infants with severe bronchopulmonary dysplasia (sBPD) at specified time points during hospitalization, and to compare these in subgroups of infants who died/underwent tracheostomy and others. STUDY DESIGN: Retrospective review of data from the multicenter Children’s Hospital Neonatal Database (CHND). RESULTS: Our cohort (n = 375) had a mean ± standard deviation gestation of 25 ± 1.2 weeks and birth weight of 744 ± 196 g. At birth, 20% of infants were small for gestational age (SGA); age at referral to the CHND neonatal intensive care unit (NICU) was 46 ± 50 days. PGF rates at admission and at 36, 40, 44, and 48 weeks’ PMA were 33, 53, 67, 66, and 79% of infants, respectively. Tube feedings were administered to > 70% and parenteral nutrition to a third of infants between 36 and 44 weeks’ PMA. At discharge, 34% of infants required tube feedings and 50% had PGF. A significantly greater (38 versus 17%) proportion of infants who died/underwent tracheostomy (n = 69) were SGA, compared with those who did not (n = 306; p < 0.01). CONCLUSIONS: Infants with sBPD commonly had progressive PGF during their NICU hospitalization. Fetal growth restriction may be a marker of adverse outcomes in this population