Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA)

Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/ behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = − 2.12, p = .055), GABA/Glx ratio (t(12) = − 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met ‘clinical responder’ criteria for behavioural outcome. Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network

Perinatal transport practices: a survey of inborn versus outborn very preterm infants admitted to European neonatal intensive care units

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Differences in rates and short-term outcome of live births before 32 weeks of gestation in Europe in 2003 : results from the MOSAIC Cohort

OBJECTIVES. Advances in perinatal medicine increased survival after very preterm birth in all countries, but comparative population-based data on these births are not readily available. This analysis contrasts the rates and short-term outcome of live births before 32 weeks of gestation in 10 European regions. METHODS. The Models of Organizing Access to Intensive Care for Very Preterm Births (MOSAIC) study collected prospective data on all very preterm births in 10 European regions covering 494463 total live births in 2003. The analysis sample was live births between 24 and 31 weeks of gestation without lethal congenital anomalies (N = 4908). Outcomes were rates of preterm birth, in-hospital mortality, intraventricular hemorrhage grades III and IV or cystic periventricular leukomalacia and bronchopulmonary dysplasia. Mortality and morbidity rates were standardized for gestational age and gender. RESULTS. Live births between 24 and 31 weeks of gestation were 9.9 per 1000 total live births with a range from 7.6 to 13.0 in the MOSAIC regions. Standardized mortality was doubled in high versus low mortality regions (18%–20% vs 7%–9%) and differed for infants ≤28 weeks of gestation as well as 28 to 31 weeks of gestation. Morbidity among survivors also varied (intraventricular hemorrhage/periventricular leukomalacia ranged from 2.6% to ≤10% and bronchopulmonary dysplasia from 10.5% to 21.5%) but differed from mortality rankings. A total of 85.2 very preterm infants per 10000 total live births were discharged from the hospital alive with a range from 64.1 to 117.1; the range was 10 to 31 per 10000 live births for infants discharged with a diagnosis of neurologic or respiratory morbidity. CONCLUSIONS. Very preterm mortality and morbidity differed between European regions, raising questions about variability in treatment provided to these infants. Comparative follow-up studies are necessary to evaluate the impact of these differences on rates of cerebral palsy and other disabilities associated with preterm birth

Rates of Bronchopulmonary Dysplasia in Very Preterm Neonates in Europe: Results from the MOSAIC Cohort.

Contains fulltext : 89512.pdf (publisher's version ) (Closed access

Rates of Bronchopulmonary Dysplasia in Very Preterm Neonates in Europe: Results from the MOSAIC Cohort.

Contains fulltext : 89512.pdf (publisher's version ) (Closed access

* Members of the MOSAIC Research group are listed in Appendix

Objective To describe obstetric intervention for extremely preterm births in ten European regions and assess its impact on mortality and short term morbidity. Design Prospective observational cohort study. Main outcome measures Use of antenatal corticosteroids, antenatal transfer and caesarean section by two-week gestational age groups as well as a composite score of these three interventions. Outcomes included stillbirth, in-hospital mortality and intraventricular haemorrhage (IVH) grades III and IV and/or periventricular leucomalacia (PVL) and bronchopulmonary dysplasia (BPD). Results There were large differences between regions in interventions for births at 22-23 and 24-25 weeks. Differences were most pronounced at 24-25 weeks; in some regions these babies received the same care as babies of 28-29 weeks, whereas elsewhere levels of intervention were distinctly lower. Before 26 weeks and especially at 24-25 weeks, there was an association between the composite intervention score and mortality. No association was observed at 26-27 weeks. For survivors at 24-25 weeks, the intervention score was associated with higher rates of BPD, but not with IVH or PVL. Conclusions There are large differences between European regions in obstetric practices at the lower limit of viability and these are related to outcome, especially at 24-25 weeks