Chasing Red Herrings: Palladium Metal Salt Impurities Feigning KRAS Activity in Biochemical Assays.

Identifying promising chemical starting points for small molecule inhibitors of active, GTP-loaded KRAS "on" remains of great importance to clinical oncology and represents a significant challenge in medicinal chemistry. Here, we describe broadly applicable learnings from a KRAS hit finding campaign: While we initially identified KRAS inhibitors in a biochemical high-throughput screen, we later discovered that compound potencies were all but assay artifacts linked to metal salts interfering with KRAS AlphaScreen assay technology. The source of the apparent biochemical KRAS inhibition was ultimately traced to unavoidable palladium impurities from chemical synthesis. This discovery led to the development of a Metal Ion Interference Set (MIIS) for up-front assay development and testing. Profiling of the MIIS across 74 assays revealed a reduced interference liability of label-free biophysical assays and, as a result, provided general estimates for luminescence- and fluorescence-based assay susceptibility to metal salt interference.

Mortality and neurodevelopmental outcomes at 2 years' corrected age of very preterm infants with necrotising enterocolitis or spontaneous intestinal perforation: The EPIPAGE-2 cohort study.

PURPOSE: The primary objective was to evaluate the impact of necrotising enterocolitis (NEC) and spontaneous intestinal perforation (SIP) on mortality and neurodevelopmental outcomes at 2 years' corrected age (CA) in infants born before 32 weeks' gestation (WG). METHODS: We studied neurodevelopment at 2 years' CA of infants with NEC or SIP who were born before 32 WG from the EPIPAGE-2 cohort study. The primary outcome was death or the presence of moderate-to-severe motor or sensory disability defined by moderate-to-severe cerebral palsy or hearing or visual disability. The secondary outcome was developmental delay defined by a score < 2 SDs below the mean for any of the five domains of the Ages and Stages Questionnaire. RESULTS: At 2 years' CA, 46% of infants with SIP, 34% of infants with NEC, and 14% of control infants died or had a moderate-to-severe sensorimotor disability (p < 0.01). This difference was mainly due to an increase in in-hospital mortality in the infants with SIP or NEC. Developmental delay at 2 years' CA was more frequent for infants with SIP than controls (70.8% vs 44.0%, p = 0.02) but was similar for infants with NEC and controls (49.3% vs 44.0%, p = 0.5). On multivariate analysis, the likelihood of developmental delay was associated with SIP (adjusted odds ratio = 3.0, 95% CI 1.0-9.1) but not NEC as compared with controls. CONCLUSION: NEC and SIP significantly increased the risk of death or sensorimotor disability at 2 years' CA. SIP was also associated with risk of developmental delay at 2 years' CA.

Complete biosynthesis of QS-21 in engineered yeast.

QS-21 is a potent vaccine adjuvant and remains the only saponin-based adjuvant that has been clinically approved for use in humans1,2. However, owing to the complex structure of QS-21, its availability is limited. Today, the supply depends on laborious extraction from the Chilean soapbark tree or on low-yielding total chemical synthesis3,4. Here we demonstrate the complete biosynthesis of QS-21 and its precursors, as well as structural derivatives, in engineered yeast strains. The successful biosynthesis in yeast requires fine-tuning of the host's native pathway fluxes, as well as the functional and balanced expression of 38 heterologous enzymes. The required biosynthetic pathway spans seven enzyme families-a terpene synthase, P450s, nucleotide sugar synthases, glycosyltransferases, a coenzyme A ligase, acyl transferases and polyketide synthases-from six organisms, and mimics in yeast the subcellular compartmentalization of plants from the endoplasmic reticulum membrane to the cytosol. Finally, by taking advantage of the promiscuity of certain pathway enzymes, we produced structural analogues of QS-21 using this biosynthetic platform. This microbial production scheme will allow for the future establishment of a structure-activity relationship, and will thus enable the rational design of potent vaccine adjuvants.

Doxapram for apnoea of prematurity and neurodevelopmental outcomes at age 5-6 years.

OBJECTIVE: To assess the long-term neurodevelopmental impact of doxapram for treating apnoea of prematurity. DESIGN: Secondary analysis of the French national cohort study EPIPAGE-2. Recruitment took place in 2011. A standardised neurodevelopmental assessment was performed at age 5-6 years. A 2:1 propensity score matching was used to control for the non-randomised assignment of doxapram treatment. SETTING: Population-based cohort study. PATIENTS: All children born before 32 weeks' gestation alive at age 5-6 years. INTERVENTIONS: Blind and standardised assessment by trained neuropsychologists and paediatricians at age 5-6 years. MAIN OUTCOME MEASURES: Neurodevelopmental outcomes at age 5-6 years assessed by trained paediatricians and neuropsychologists: cerebral palsy, developmental coordination disorders, IQ and behavioural difficulties. A composite criterion for overall neurodevelopmental disabilities was built. RESULTS: The population consisted of 2950 children; 275 (8.6%) received doxapram. Median (IQR) gestational age was 29.4 (27.6-30.9) weeks. At age 5-6 years, complete neurodevelopmental assessment was available for 60.3% (1780 of 2950) of children and partial assessment for 10.6% (314 of 2950). In the initial sample, children receiving doxapram had evidence of greater clinical severity than those not treated. Doxapram treatment was associated with overall neurodevelopmental disabilities of any severity (OR 1.43, 95% CI 1.07 to 1.92, p=0.02). Eight hundred and twenty-one children were included in the 2:1 matched sample. In this sample, perinatal characteristics of both groups were similar and doxapram treatment was not associated with overall neurodevelopmental disabilities (OR 1.09, 95% CI 0.76 to 1.57, p=0.63). CONCLUSIONS: In children born before 32 weeks' gestation, doxapram treatment for apnoea of prematurity was not associated with neurodevelopmental disabilities.

Clinical Chorioamnionitis and Neurodevelopment at 5 Years of Age in Children Born Preterm: The EPIPAGE-2 Cohort Study.

OBJECTIVE: To assess the association between clinical chorioamnionitis and neurodevelopmental disorders at 5 years of age in children born preterm. STUDY DESIGN: EPIPAGE 2 is a national, population-based cohort study of children born before 35 weeks of gestation in France in 2011. We included infants born alive between 240/7 and 346/7 weeks after preterm labor or preterm premature rupture of membranes. Clinical chorioamnionitis was defined as maternal fever before labor (>37.8°C) with ≥2 of the following criteria: maternal tachycardia, hyperleukocytosis, uterine contractions, purulent amniotic fluid, or fetal tachycardia. The primary outcome was a composite, including cerebral palsy, coordination disorders, cognitive disorders, sensory disorders, or behavioral disorders. We also analyzed each of these disorders separately as secondary outcomes. We performed a multivariable analysis using logistic regression models. We accounted for the nonindependence of twins and missing data by generalized estimating equation models and multiple imputations, respectively. RESULTS: Among 2927 children alive at 5 years of age, 124 (3%) were born in a context of clinical chorioamnionitis. Overall, 8.2% and 9.6% of children exposed and unexposed, respectively, to clinical chorioamnionitis had moderate-to-severe neurodevelopmental disorders. After multiple imputations and multivariable analysis, clinical chorioamnionitis was not associated with the occurrence of moderate-to-severe neurodevelopmental disorders (aOR, 0.9; 95% CI, 0.5-1.8). CONCLUSIONS: We did not find any association between clinical chorioamnionitis and neurodevelopmental disorders at 5 years of age in children born at <35 weeks of gestation after preterm labor or preterm premature rupture of membrane.

Complete biosynthesis of the potent vaccine adjuvant QS-21.

QS-21 is a potent vaccine adjuvant currently sourced by extraction from the Chilean soapbark tree. It is a key component of human vaccines for shingles, malaria, coronavirus disease 2019 and others under development. The structure of QS-21 consists of a glycosylated triterpene scaffold coupled to a complex glycosylated 18-carbon acyl chain that is critical for immunostimulant activity. We previously identified the early pathway steps needed to make the triterpene glycoside scaffold; however, the biosynthetic route to the acyl chain, which is needed for stimulation of T cell proliferation, was unknown. Here, we report the biogenic origin of the acyl chain, characterize the series of enzymes required for its synthesis and addition and reconstitute the entire 20-step pathway in tobacco, thereby demonstrating the production of QS-21 in a heterologous expression system. This advance opens up unprecedented opportunities for bioengineering of vaccine adjuvants, investigating structure-activity relationships and understanding the mechanisms by which these compounds promote the human immune response.

High Amino Acid Intake in Early Life Is Associated With Systolic but Not Diastolic Arterial Hypertension at 5 Years of Age in Children Born Very Preterm.

BACKGROUND: The life course of individuals born very premature is a topic of increasing concern. The association between high early amino acid intake and later high blood pressure (HBP) in preterm neonates is debated. METHODS AND RESULTS: In a national, prospective, population-based birth cohort, EPIPAGE-2 (Etude Epidémiologique sur Petits Ages Gestationnels), we assessed blood pressure at 5 years. Eligible infants were those born between 24 and 29 weeks of gestation. Infants were distributed in 2 groups of 717 infants matched on propensity score on whether or not they were exposed to high amino acid intake (>3.5 g/kg per day at day 7); 455 control term infants were also enrolled. A value ≥95th percentile of reference values for age and height defined systolic or diastolic HBP. Blood pressure at 5 years of age was assessed for 389 and 385 children in the exposed and nonexposed groups, respectively. Rates (in percent) of systolic and diastolic HBP were 18.0% (95% CI, 14.5%-22.2%), 13.3% (95% CI, 10.3%-17.0%), 8.5% (95% CI, 6.5%-11.1%), and 9.0% (95% CI, 6.6%-12.3%), 10.2% (95% CI, 7.5%-13.6%), and 5.4% (95% CI, 3.8%-7.6%) in exposed, nonexposed, and term-born groups, respectively. Exposure to high early amino acid intake and maximal serum creatinine (by 50 µmol/L) between day 3 and day 7 were 2 independent risk factors for systolic HBP (adjusted odds ratio [aOR], 1.60 [95% CI, 1.05-2.43] and aOR, 1.59 [95% CI, 1.12-2.26], respectively) but not for diastolic HBP (aOR, 0.84 [95% CI, 0.50-1.39] and aOR, 1.09 [95% CI, 0.71-1.67], respectively). After adjustment for 5-year weight Z score, the aOR between high early amino acid intake and systolic HBP was 1.50 [95% CI, 0.98-2.30]. CONCLUSIONS: These results suggest that mechanisms of childhood systolic HBP involve neonatal renal challenge by high amino acid intake or dysfunction.

SARS-CoV-2 seroprevalence in French 9-year-old children and their parents after the first lockdown in 2020.

Introduction: Children have been significantly less affected by COVID-19 than adults and presented with milder and less symptomatic forms of the disease. However, there has been suggestion that children older than 10 years and adolescents exhibits features closer to that of young adults. Most studies combine children in different age-groups and lack sufficient numbers to explore in detail age specificities. We report data on a population-based sample of 2,555 children at the pivotal age of 9 years. Methods: In April 2020, the participants in two French nationwide cohorts of children, Elfe and Epipage2, were invited to take part into an online survey about Covid related symptoms and family life during the lockdown. A second questionnaire was sent on May 5. This questionnaire also proposed to the child included in the cohort and to one of his/her parents to take part into a capillary blood collection for Covid serology. Families who agreed to the serological survey were sent kits for dried blood spots self-sampling (DBS) with instructions. Samples were processed with a commercial Elisa test (Euroimmun®, Lübeck, Germany) to detect anti-SARS-CoV-2 antibodies (IgG) directed against the S1 domain of the spike protein of the virus. Results: Children's acceptance rate for the serological survey was around 60%. 2,555 serological results were analyzed. The weighted prevalence of a positive Elisa Spike serology was 2.8% in 9 yr-old children (95% CI: 1.7%-4.0%). Positive serology was found in 8.6% (7.4%-9.7%) of parents who provided blood. There was a significant association (p < 0.001) between serology of the child and parent from the same household with an odds ratio of 13.8 (7.9-24.2). Discussion: We have shown that 9-yr old children had a lower susceptibility to SARS-Cov2 infection than adults with the initial Chinese strain, similar to younger children and estimated that around 3% of them have developed antibodies against SARS-Cov2 in France after the first wave of the Covid-19 epidemics.

Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study.

BACKGROUND: The administration of tocolytics after preterm prelabor rupture of membranes remains a controversial practice. In theory, reducing uterine contractility should delay delivery and allow for optimal antenatal management, thereby reducing the risks for prematurity and adverse consequences over the life course. However, tocolysis may be associated with neonatal death or long-term adverse neurodevelopmental outcomes, mainly related to prolonged fetal exposure to intrauterine infection or inflammation. In a previous study, we showed that tocolysis administration was not associated with short-term benefits. There are currently no data available to evaluate the impact of tocolysis on neurodevelopmental outcomes in school-aged children born prematurely in this clinical setting. OBJECTIVE: This study aimed to investigate whether tocolysis administered after preterm prelabor rupture of membranes is associated with neurodevelopmental outcomes at 5.5 years of age. STUDY DESIGN: We used data from a prospective, population-based cohort study of preterm births recruited in 2011 (referred to as the EPIPAGE-2 study) and for whom the results of a comprehensive medical and neurodevelopmental assessment of the infant at age 5.5 years were available. We included pregnant individuals with preterm prelabor rupture of membranes at 24 to 32 weeks' gestation in singleton pregnancies with a live fetus at the time of rupture, birth at 24 to 34 weeks' gestation, and participation of the infant in an assessment at 5.5 years of age. Exposure was the administration of any tocolytic treatment after preterm prelabor rupture of membranes. The main outcome was survival without moderate to severe neurodevelopmental disabilities at 5.5 years of age. Secondary outcomes included survival without any neurodevelopmental disabilities, cerebral palsy, full-scale intelligence quotient, developmental coordination disorders, and behavioral difficulties. A propensity-score analysis was used to minimize the indication bias in the estimation of the treatment effect on outcomes. RESULTS: Overall, 596 of 803 pregnant individuals (73.4%) received tocolytics after preterm prelabor rupture of membranes. At the 5.5-year follow-up, 82.7% and 82.5% of the children in the tocolysis and no tocolysis groups, respectively, were alive without moderate to severe neurodevelopmental disabilities; 52.7% and 51.1%, respectively, were alive without any neurodevelopmental disabilities. After applying multiple imputations and inverse probability of treatment weighting, we found no association between the exposure to tocolytics and survival without moderate to severe neurodevelopmental disabilities (odds ratio, 0.93; 95% confidence interval, 0.55-1.60), survival without any neurodevelopmental disabilities (odds ratio, 1.02; 95% confidence interval, 0.65-1.61), or any of the other outcomes. CONCLUSION: There was no difference in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolysis after preterm prelabor rupture of membranes. To date, the health benefits of tocolytics remain unproven, both in the short- and long-term.

Maternal health-related quality of life at 1 year after a preterm birth: role of socioeconomic status at birth.

BACKGROUND: Maternal problems in the postpartum period may lead to suboptimal long-term health for women and could affect mother-child attachment. Social disadvantage is a risk factor for preterm birth, which carries its own burden of health issues and stress. The main aim of this study was to investigate the role for social factors in mothers' physical and emotional health-related quality of life (HRQoL) at 1 year after a preterm birth. METHODS: EPIPAGE-2 is a French nationwide, prospective, population-based cohort of preterm children born before 35 weeks' gestation (N=3614 women). At birth, detailed data on the family's social status were collected. At 1 year after birth, mothers completed a mailed questionnaire to report information on their HRQoL, assessed by the Medical Outcomes Study 12-item Short Form. We used multivariate linear regression models to assess the association between social factors and maternal HRQoL. RESULTS: At 1 year after childbirth, the emotional HRQoL of mothers of preterm children was worse than their physical HRQoL, even in women without any previous signs of psychological distress at the infant's discharge from hospital. Baseline social characteristics were the most important factors influencing the physical component of HRQoL. None of the studied social factors had any clear association with the mental component of HRQoL. CONCLUSION: Our study underlines the importance of social disadvantage during pregnancy as risk factors for poor physical HRQoL at 1 year after a preterm birth.

Circumstances, causes and timing of death in extremely preterm infants admitted to NICU: The EPIPAGE-2 study.

AIM: To describe the circumstances, causes and timing of death in extremely preterm infants. METHODS: We included from the EPIPAGE-2 study infants born at 24-26 weeks in 2011 admitted to neonatal intensive care units (NICU). Vital status and circumstances of death were used to define three groups of infants: alive at discharge, death with or without withholding or withdrawing life-sustaining treatment (WWLST). The main cause of death was classified as respiratory disease, necrotizing enterocolitis, infection, central nervous system (CNS) injury, other or unknown. RESULTS: Among 768 infants admitted to NICU, 224 died among which 89 died without WWLST and 135 with WWLST. The main causes of death were respiratory disease (38%), CNS injury (30%) and infection (12%). Among the infants who died with WWLST, CNS injury was the main cause of death (47%), whereas respiratory disease (56%) and infection (20%) were the main causes in case of death without WWLST. Half (51%) of all deaths occurred within the first 7 days of life, and 35% occurred within 8 and 28 days. CONCLUSION: The death of extremely preterm infants in NICU is a complex phenomenon in which the circumstances and causes of death are intertwined.

Timing of antenatal corticosteroids and survival without neurologic disabilities at 5½ years in children born before 35 weeks of gestation.

BACKGROUND: The efficacy of antenatal corticosteroids for neonatal preterm complications wanes beyond 7 days after treatment. The neurodevelopmental effects of longer treatment-to-birth intervals have not been adequately evaluated. OBJECTIVE: This study aimed to assess the impact of antenatal corticosteroid timing on survival without moderate or severe neurologic disabilities at 5½ years. STUDY DESIGN: This was a secondary analysis of the EPIPAGE-2 study, a national population-based cohort (France) that recruited neonates in 2011 and followed them up at 5½ years (results first reported in 2021). Participants were children born alive between 24+0 and 34+6 weeks, with a complete corticosteroid course, delivery >48 hours after the first injection, and neither limitation of care decided before birth nor severe congenital malformation. The study included 2613 children, 2427 of whom were alive at 5½ years; 71.9% (1739/2427) had a neurologic assessment at this age; 1537 had a clinical examination (complete for 1532), and 202 were assessed with a postal questionnaire. Exposure was defined as the interval between the first injection of the last antenatal corticosteroid course and delivery in days, studied in 2 categories (days 3-7 and after day 7), in 4 categories (days 3-7, 8-14, 15-21, and after day 21), and continuously in days. The main outcome was survival at 5½ years without moderate/severe neurologic disabilities, defined as moderate/severe cerebral palsy, or unilateral or bilateral blindness or deafness, or Full-Scale Intelligence Quotient 2 standard deviations below the mean. A multivariate analysis with a generalized estimated equation logistic regression model assessed the statistical association between the main outcomes and the interval from the first corticosteroid injection of the last course to birth. Multivariate analyses were adjusted for potential confounders, defined with a directed acyclic graph: gestational age in days, number of corticosteroid courses, multiple pregnancy, and cause of prematurity in 5 categories. Because neurologic follow-up was complete in only 63.2% of cases (1532/2427), the analyses used imputed data. RESULTS: Among 2613 children, 186 died between birth and 5½ years. Overall survival was 96.6% (95% confidence interval, 95.9-97.0), and survival without moderate or severe neurologic disabilities was 86.0% (95% confidence interval, 84.7-87.0). Survival without moderate or severe neurologic disabilities was lower after day 7 (85.0%) than during the interval from day 3 to day 7 (87.0%) (adjusted odds ratio, 0.70; 95% confidence interval, 0.54-0.89). CONCLUSION: The association of a >7-day interval between antenatal corticosteroid administration and birth with a lower rate of survival without moderate or severe neurologic disabilities among children aged 5½ years emphasizes the importance of better targeting women at risk of preterm delivery to optimize the timing and thus benefits of treatment.

Neurodevelopment and healthcare utilisation at age 5-6 years in bronchopulmonary dysplasia: an EPIPAGE-2 cohort study.

OBJECTIVE: We aimed to study neurodevelopmental outcomes and healthcare utilisation at age 5-6 years in very preterm children with bronchopulmonary dysplasia (BPD). DESIGN: Prospective and national population-based study. SETTING: All the neonatal units in 25 French regions (21 of the 22 metropolitan regions and 4 overseas regions). PATIENTS: Children born before 32 weeks' gestation in 2011. INTERVENTIONS: Blind, comprehensive and standardised assessment by trained neuropsychologists and paediatricians at age 5-6 years. MAIN OUTCOME MEASURES: Overall neurodevelopmental disabilities, behavioural difficulties, developmental coordination disorders, full-scale IQ, cerebral palsy, social interaction disorders, rehospitalisation in the previous 12 months and detailed developmental support. RESULTS: Of the 3186 children included, 413 (11.7%) had BPD. The median gestational age of children with BPD was 27 weeks (IQR 26.0-28.0) and without BPD was 30 weeks (28.0-31.0). At age 5-6 years, 3150 children were alive; 1914 (60.8%) had a complete assessment. BPD was strongly associated with mild, moderate and severe overall neurodevelopmental disabilities (OR 1.49, 95% CI 1.05 to 2.20; 2.20, 1.41 to 3.42 and 2.71, 1.67 to 4.40). BPD was associated with developmental coordination disorders, behavioural difficulties, lower IQ score as well as rehospitalisation in the last 12 months and developmental support. The association between BPD and cerebral palsy was statistically significant before adjustment but not in adjusted analyses. CONCLUSIONS: BPD was strongly and independently associated with many neurodevelopmental disabilities. Improving medical and neurodevelopmental management of BPD in very preterm children should be a priority to reduce its long-term consequences.

Parents' depression and anxiety associated with hyperactivity-inattention and emotional symptoms in children during school closure due to COVID-19 in France.

Several risk factors of children's mental health issues have been identified during the pandemic of COronaVIrus Disease first appeared in 2019 (COVID-19). This study aims to fill the knowledge gap regarding the association between parents' and children's mental health issues during the COVID-19 school closure in France. We conducted a cross-sectional analysis of data collected in the SAPRIS-ELFE study during the COVID-19 pandemic in France. Using multinomial logistic regressions, we estimated associations between parents' and children's mental health issues. Symptoms of anxiety were assessed by the General Anxiety Disorder-7 (GAD-7) and depression by the Patient Health Questionnaire-9 (PHQ-9) for the parents. Hyperactivity/inattention and emotional symptoms in children were assessed by the Strengths and Difficulties Questionnaire (SDQ). The sample included 3496 children aged 8 to 9 years, of whom 50.0% were girls. During the school closure, 7.1% of responding parents had moderate to severe levels of anxiety and 6.7% had moderate to severe levels of depression. A total of 11.8% of the children had an abnormal hyperactivity/inattention score and 6.6% had an abnormal emotional symptoms score. In multivariate regression models, parental moderate to severe level of anxiety and moderate to severe level of depression were associated with abnormal hyperactivity-inattention score (adjusted Odds Ratio (aOR) 3.31; 95% Confidence Interval (CI) 2.33-4.70 and aOR 4.65; 95% CI 3.27-6.59, respectively) and abnormal emotional symptoms score in children (aOR 3.58; 95% CI 2.33-5.49 and aOR 3.78; 95 CI 2.47-5.78 respectively). Children whose parents have symptoms of anxiety and/or depression have an increased likelihood of symptoms of hyperactivity/inattention and emotional symptoms during school closures in France due to COVID-19. Our findings suggest that public health initiatives should target parents and children to limit the impact of such crises on their mental health issues.

Elucidation of the pathway for biosynthesis of saponin adjuvants from the soapbark tree.

The Chilean soapbark tree (Quillaja saponaria) produces soap-like molecules called QS saponins that are important vaccine adjuvants. These highly valuable compounds are sourced by extraction from the bark, and their biosynthetic pathway is unknown. Here, we sequenced the Q. saponaria genome. Through genome mining and combinatorial expression in tobacco, we identified 16 pathway enzymes that together enable the production of advanced QS pathway intermediates that represent a bridgehead for adjuvant bioengineering. We further identified the enzymes needed to make QS-7, a saponin with excellent therapeutic properties and low toxicity that is present in low abundance in Q. saponaria bark extract. Our results enable the production of Q. saponaria vaccine adjuvants in tobacco and open the way for new routes to access and engineer natural and new-to-nature immunostimulants.

Intraventricular Hemorrhage in Very Preterm Children: Mortality and Neurodevelopment at Age 5.

OBJECTIVES: The objectives were to describe mortality and causes of death in children with intraventricular hemorrhage (IVH) and to study neurodevelopmental outcomes. METHODS: The study was a secondary analysis of the French national prospective and population-based cohort EPIPAGE-2. Children were recruited in 2011. A standardized assessment was conducted at age 5. Children born before 32 weeks' gestation and admitted to a NICU were eligible. Exposure was IVH defined by the Papile classification. Main outcomes were mortality, causes of death, and neurodevelopmental outcomes at age 5. RESULTS: Among the 3468 children included, 578 (16.7%) had grade 1 IVH, 424 (12.2%) grade 2 IVH, and 114 (3.3%) grade 3 IVH; 144 (4.1%) had intraparenchymal hemorrhage (IPH). Mortality was 29.7% (36 of 114) for children with grade 3 IVH and 74.4% (109 of 144) for those with IPH; 67.6% (21 of 31) and 88.7% (86 of 97) of deaths, respectively, were because of withholding and withdrawing of life-sustaining treatment. As compared with no IVH, low-grade IVH was not associated with measured neurodevelopmental disabilities at age 5. High-grade IVH was associated with moderate and severe neurodevelopmental disabilities, reduced full-scale IQ, and cerebral palsy. CONCLUSIONS: Rates of neurodevelopmental disabilities at age 5 did not differ between children without IVH and those with low-grade IVH. For high-grade IVH, mortality rate was high, mostly because of withholding and withdrawal of life-sustaining treatment, and we found a strong association with overall neurodevelopmental disabilities in survivors.

Discovery of a Chemical Probe to Study Implications of BPTF Bromodomain Inhibition in Cellular and in†vivo Experiments.

The bromodomain and PHD-finger containing transcription factor (BPTF) is part of the nucleosome remodeling factor (NURF) complex and has been implicated in multiple cancer types. Here, we report the discovery of a potent and selective chemical probe targeting the bromodomain of BPTF with an attractive pharmacokinetic profile enabling cellular and in vivo experiments in mice. Microarray-based transcriptomics in presence of the probe in two lung cancer cell lines revealed only minor effects on the transcriptome. Profiling against a panel of cancer cell lines revealed that the antiproliferative effect does not correlate with BPTF dependency score in depletion screens. Both observations and the multi-domain architecture of BPTF suggest that depleting the protein by proteolysis targeting chimeras (PROTACs) could be a promising strategy to target cancer cell proliferation. We envision that the presented chemical probe and the related negative control will enable the research community to further explore scientific hypotheses with respect to BPTF bromodomain inhibition.

Early skin-to-skin contact and risk of late-onset-sepsis in very and extremely preterm infants.

BACKGROUND: To evaluate the association between exposure to early skin-to-skin contact (SSC) and incidence of late-onset sepsis (LOS) in extremely and very preterm infants. METHODS: Observational study using the national population-based EPIPAGE-2 cohort in 2011. A propensity score for SSC exposure was used to match infants with and without exposure to SSC before day 4 of life and binomial log regression used to estimate risk ratios and CIs in the matched cohort. The primary outcome was at least one episode of LOS during hospitalization. Secondary outcomes were the occurrence of any late-onset neonatal infection (LONI), LOS with Staphylococcus or Staphylococcus aureus, incidence of LOS and LONI per 1000 central venous catheter days. RESULTS: Among the 3422 included infants, 919 were exposed to early SSC. The risk ratio (RR) for LOS was 0.86 (95% CI, 0.67-1.10), for LONI was 1.00 (95% CI, 0.83-1.21), and for LOS with Coagulase-negative Staphylococcus or Staphylococcus aureus infection was 0.91 (95% CI, 0.68-1.21) and 0.77 (95% CI, 0.31-1.87). The incidence RR for LOS per-catheter day was 0.87 (95% CI, 0.64-1.18). CONCLUSION: Early SSC exposure was not associated with LOS or LONI risk. Thus, their prevention should not be a barrier to a wider use of SSC. IMPACT: Kangaroo Mother Care decreased neonatal infection rates in middle-income countries. Skin-to-skin contact is beneficial for vulnerable preterm infants but barriers exist to its implementation. In a large population-based study using a propensity score methods, we found that skin-to-skin contact before day 4 of life was not associated with a decreased risk of late-onset-sepsis in very and extremely preterm infants. Early skin-to-skin contact was not associated with an increased risk of any late-onset-neonatal-infection, in particular with staphylococcus. The fear of neonatal infection should not be a barrier to a wider use of early skin-to-skin contact in this population.

Growth trajectory during the first 1000 days and later overweight in very preterm infants.

OBJECTIVE: To identify the characteristics of early life growth associated with later overweight or obesity (OWO) in very preterm population. DESIGN: Length, weight and body mass index (BMI) were prospectively recorded from three prospective, population-based cohorts with 5 years (Loire Infant Follow-up Team (LIFT), EPIPAGE2 (Etude EPIdémiologique sur les Petits Ages GEstationnels 2)) and 15 years (EPIPAGEADO, Etude EPIdémiologique sur les Petits Ages GEstationnels-Adolescents) of follow-up. Missing data were imputed. SETTING: Regional (LIFT), national (EPIPAGE2) and multiregional (EPIPAGEADO) cohorts in France. PATIENTS: Eligible infants born before 33 weeks of gestation in 1997 (EPIPAGEADO), between 2003 and 2014 (LIFT), and in 2011 (EPIPAGE2). MAIN OUTCOME MEASURES: OWO was determined as BMI Z-score >85th percentile of the WHO reference curves at 5 years (LIFT, EPIPAGE2) and 15 years (EPIPAGEADO). RESULTS: In EPIPAGEADO, LIFT and EPIPAGE2, BMI Z-scores were known for 302 adolescents, 1016 children and 2022 children, respectively. In EPIPAGEADO, OWO was observed in 42 (13.9%, 95% CI 10.5 to 18.3) adolescents. In multivariable models, birthweight Z-score, increase in weight Z-score during neonatal hospital stay and increase in BMI between discharge and at 2 years of corrected age were positively associated with OWO at 15 years (adjusted OR (aOR)=3.65, 95% CI 1.36 to 9.76; aOR=3.82, 95% CI 1.42 to 10.3; and aOR=2.55, 95% CI 1.72 to 3.78, respectively, by Z-score), but change in length Z-score during neonatal hospital stay was negatively associated (aOR=0.41, 95% CI 0.21 to 0.78, p=0.007). These four associations with OWO assessed at 5 years were confirmed in the LIFT and EPIPAGE2 cohorts. CONCLUSIONS: Change in length Z-score during hospitalisation, a putative proxy of quality of neonatal growth, was negatively associated with risk of later OWO when change in BMI between discharge and at 2 years was included in the multivariable model.

Maternal pre-pregnancy obesity and offspring hyperactivity-inattention symptoms at 5 years in preterm and term children: a multi-cohort analysis.

The objective of this study was to determine the relationship between maternal pre-pregnancy body mass index (BMI) and child hyperactivity-inattention symptoms (HIS) at 5 years, including preterm and term-born children, and to determine whether this association varied with gestational age. Maternal pre-pregnancy BMI and offspring HIS were assessed in 10,898 participants born ≥ 33 weeks of gestation from the ELFE cohort and 2646 children born between 23 and 34 weeks from the EPIPAGE 2 cohort. Reported pre-pregnancy weight (kg) and measured height (m) were collected from mothers at inclusion and used to classify BMI (kg/m2). Child HIS were evaluated using the Strengths and Difficulties Questionnaire around 5 years of age. Logistic regression estimated odds ratios (OR) of a high HIS score (≥ 90th percentile) in the ELFE cohort and generalized estimated equations were used in EPIPAGE 2 to account for non-independence of multiple births. As a negative control, paternal BMI was also considered as an exposure of interest in sensitivity analyses. Maternal pre-pregnancy obesity and overweight were associated with child HIS at 5 years in ELFE (adjusted OR [aOR] for obesity 1.27 [1.06, 1.53]; overweight aOR 1.16 [1.00, 1.36]) and pre-pregnancy obesity was associated with high HIS scores in preterm infants of EPIPAGE 2 (aOR 1.48 [1.06, 2.08]). In ELFE, the magnitude of the association increased with decreasing gestational age (interaction p = 0.02). High maternal pre-pregnancy BMI is associated with greater likelihood of high HIS scores in both at-term and preterm children at 5 years of age.