Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age 65 36 weeks and a birth weight 65 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017

Measuring neutron yield and ρR anisotropies with activation foils at the National Ignition Facility

Neutron yields at the National Ignition Facility (NIF) are measured with a suite of diagnostics, including activation of ∼20–200 g samples of materials undergoing a variety of energy-dependent neutron reactions. Indium samples were mounted on the end of a Diagnostic Instrument Manipulator (DIM), 25–50 cm from the implosion, to measure 2.45 MeV D-D fusion neutron yield. The 336.2 keV gamma rays from the 4.5 hour isomer of 115mIn produced by (n,n′) reactions are counted in high-purity germanium detectors. For capsules producing D-T fusion reactions, zirconium and copper are activated via (n,2n) reactions at various locations around the target chamber and bay, measuring the 14 MeV neutron yield to accuracies on order of 7%. By mounting zirconium samples on ports at nine locations around the NIF chamber, anisotropies in the primary neutron emission due to fuel areal density asymmetries can be measured to a relative precision of 3%

Functional connectivity dynamics: modeling the switching behavior of the resting state

Functional connectivity (FC) sheds light on the interactions between different brain regions. Besides basic research, it is clinically relevant for applications in Alzheimer's disease, schizophrenia, presurgical planning, epilepsy, and traumatic brain injury. Simulations of whole-brain mean-field computational models with realistic connectivity determined by tractography studies enable us to reproduce with accuracy aspects of average FC in the resting state.Most computational studies, however, did not address the prominent non-stationarity in resting state FC, which may result in large intra- and inter-subject variability and thus preclude an accurate individual predictability. Herewe showthat this non-stationarity reveals a rich structure, characterized by rapid transitions switching between a few discrete FC states. We also show that computational models optimized to fit timeaveraged FC do not reproduce these spontaneous state transitions and, thus, are not qualitatively superior to simplified linear stochastic models, which account for the effects of structure alone. We then demonstrate that a slight enhancement of the non-linearity of the network nodes is sufficient to broaden the repertoire of possible network behaviors, leading to modes of fluctuations, reminiscent of some of themost frequently observed Resting State Networks. Because of the noise-driven exploration of this repertoire, the dynamics of FC qualitatively change now and display non-stationary switching similar to empirical resting state recordings (Functional Connectivity Dynamics (FCD)). Thus FCD bear promise to serve as a better biomarker of resting state neural activity and of its pathologic alterations.The research reported herein was supported by the Brain Network Recovery Group through the James S. McDonnell Foundation and funding from the European Union Seventh Framework Programme (FP7-ICT BrainScales and Human Brain Project (grant no. 60402)). DB was supported by the Marie Curie career development fellowship FP7-IEF 330792 (DynViB) and by the Federal Ministry of Education and Research (BMBF) Germany under grant number 01GQ1005B. We thank Patrick Hagmann and his group for providing the empirical data

Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease:Results from a European Collaboration

Objective: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). Study design: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. Results: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, β = −0.50). SES was independently associated with cognitive outcome (P &lt; .001, β = 0.26), and LOS with motor outcome (P &lt; .001, β = −0.35). Conclusion: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.</p