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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.

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The two-way coupling mechanisms in particle-laden mixing layers are investigated, with and without particle settling, and with an emphasis on the resulting modifications to the fluid vorticity field. The governing equations are interpreted with respect to the production and cancellation of vorticity. These mechanisms are shown to be related to the misalignment of the concentration gradient and the slip velocity, as well as to the difference in fluid and particle vorticities. Preliminary insight into the physics is obtained from an analysis of the unidirectional base flow. For this model problem, the conditions are established under which the particle velocity remains a single-valued function of space for all times. The resulting simplified set of two-way-coupled equations governing the vorticity of the fluid and particulate phases, respectively, is solved numerically. The formation of a decaying travelling wave solution is demonstrated over a wide range of parameters. Interestingly, the downward propagation of the fluid vorticity field is not accomplished through convection, but rather by the production and loss of vorticity on opposite sides of the mixing layer. For moderate settling velocities, the simulation results reveal an optimal coupling mechanism between the fluid and particle vorticities at intermediate values of the mass loading parameter. For large settling velocities and intermediate mass loadings, more than one local maximum is seen to evolve in the vorticity field. A scaling law for the downward propagation rates of the vorticity fronts is derived.Two-dimensional particle-laden mixing layers are investigated by means of a mixed Lagrangian–Eulerian approach which is based on the vorticity variable. For uniformly seeded mixing layers, the simulations confirm some of the features observed by Druzhinin (1995b) for the model problem of a two-way-coupled particle-laden Stuart vortex, as well as by Dimas & Kiger (1998) in a linear stability analysis. For small values of the Stokes number, a mild destabilization of the mixing layer is observed. At moderate and large Stokes numbers, on the other hand, the transport of vorticity from the braids into the core of the evolving Kelvin–Helmholtz vortices is seen to be slowed by the two-way coupling effects. As a result, the particle ejection from the vortex cores is weakened. For constant mass loadings, the two-way coupling effects are strongest at intermediate Stokes number values. For moderately large Stokes numbers, the formation of two bands of high particle concentration is observed in the braids, which reflects the multi-valued nature of the particle velocity field. For mixing layers in which only one stream is seeded, the particle concentration gradient across the mixing layer leads to strong vorticity production and loss, which results in an effective net motion of the vortex in the flow direction of the seeded stream. Under particle settling, the vortex propagates downward as well. For the parameter range explored here, its settling velocity agrees well with the scaling law derived from the unidirectional flow analysis.