Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T-cells and B-lineage cells. Proteomic comparison of liver tissue from cases and healthy controls, identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and in severe cases HHV-6B, may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

The Surface Array planned for IceCube-Gen2

IceCube-Gen2, the extension of the IceCube Neutrino Observatory, will feature three main components: an optical array in the deep ice, a large-scale radio array in the shallow ice and firn, and a surface detector above the optical array. Thus, IceCube-Gen2 will not only be an excellent detector for PeV neutrinos, but also constitutes a unique setup for the measurement of cosmic-ray air showers, where the electromagnetic component and low-energy muons are measured at the surface and high-energy muons are measured in the ice. As for ongoing enhancement of IceCube’s current surface array, IceTop, we foresee a combination of elevated scintillation and radio detectors for the Gen2 surface array, aiming at high measurement accuracy for air showers. The science goals are manifold: The in-situ measurement of the cosmic-ray flux and mass composition, as well as more thorough tests of hadronic interaction models, will improve the understanding of muons and atmospheric neutrinos detected in the ice, in particular, regarding prompt muons. Moreover, the surface array provides a cosmic-ray veto for the in-ice detector and contributes to the calibration of the optical and radio arrays. Last but not least, the surface array will make major contributions to cosmic-ray science in the energy range of the transition from Galactic to extragalactic sources. The increased sensitivities for photons and for cosmic-ray anisotropies at multi-PeV energies provide a chance to solve the puzzle of the origin of the most energetic Galactic cosmic rays and will serve IceCube’s multimessenger mission

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children