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Summary: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells, with increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL-6 may be preferable to IL-1 or TNF-α. We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease.

Background: There is little current consensus regarding the route or duration of antibiotic treatment for acute osteomyelitis (OM) and septic arthritis (SA) in children. Objective: To assess the overall feasibility and inform the design of a future randomised controlled trial (RCT) to reduce the duration of intravenous (i.v.) antibiotic use in paediatric OM and SA. Design: (1) A prospective service evaluation (cohort study) to determine the current disease spectrum and UK clinical practice in paediatric OM/SA; (2) a prospective cohort substudy to assess the use of targeted polymerase chain reaction (PCR) in diagnosing paediatric OM/SA; (3) a qualitative study to explore families’ views and experiences of OM/SA; and (4) the development of a core outcome set via a systematic review of literature, Delphi clinician survey and stakeholder consensus meeting. Setting: Forty-four UK secondary and tertiary UK centres (service evaluation). Participants: Children with OM/SA. Interventions: PCR diagnostics were compared with culture as standard of care. Semistructured interviews were used in the qualitative study. Results: Data were obtained on 313 cases of OM/SA, of which 218 (61.2%) were defined as simple disease and 95 (26.7%) were defined as complex disease. The epidemiology of paediatric OM/SA in this study was consistent with existing European data. Children who met oral switch criteria less than 7 days from starting i.v. antibiotics were less likely to experience treatment failure (9.6%) than children who met oral switch criteria after 7 days of i.v. therapy (16.1% when switch was between 1 and 2 weeks; 18.2% when switch was > 2 weeks). In 24 out of 32 simple cases (75%) and 8 out of 12 complex cases (67%) in which the targeted PCR was used, a pathogen was detected. The qualitative study demonstrated the importance to parents and children of consideration of short- and long-term outcomes meaningful to families themselves. The consensus meeting agreed on the following outcomes: rehospitalisation or recurrence of symptoms while on oral antibiotics, recurrence of infection, disability at follow-up, symptom free at 1 year, limb shortening or deformity, chronic OM or arthritis, amputation or fasciotomy, death, need for paediatric intensive care, and line infection. Oral switch criteria were identified, including resolution of fever for ≥ 48 hours, tolerating oral food and medicines, and pain improvement. Limitations: Data were collected in a 6-month period, which might not have been representative, and follow-up data for long-term complications are limited. Conclusions: A future RCT would need to recruit from all tertiary and most secondary UK hospitals. Clinicians have implemented early oral switch for selected patients with simple disease without formal clinical trial evidence of safety. However, the current criteria by which decisions to make the oral switch are made are not clearly established or evidence based. Future work: A RCT in simple OM and SA comparing shorter- or longer-course i.v. therapy is feasible in children randomised after oral switch criteria are met after 7 days of i.v. therapy, excluding children meeting oral switch criteria in the first week of i.v. therapy. This study design meets clinician preferences and addresses parental concerns not to randomise prior to oral switch criteria being met. Funding: The National Institute for Health Research Health Technology Assessment programme.

Virtual screening of large chemical libraries is essential to support computer-aided drug development, providing a rapid and low-cost approach for further experimental validation. However, existing computational packages are often for specialised users or platform limited. Previously, we developed VSpipe, an open-source semi-automated pipeline for structure-based virtual screening. We have now improved and expanded the initial command-line version into an interactive graphical user interface: VSpipe-GUI, a cross-platform open-source Python toolkit functional in various operating systems (e.g., Linux distributions, Windows, and Mac OS X). The new implementation is more user-friendly and accessible, and considerably faster than the previous version when AutoDock Vina is used for docking. Importantly, we have introduced a new compound selection module (i.e., spatial filtering) that allows filtering of docked compounds based on specified features at the target binding site. We have tested the new VSpipe-GUI on the Hepatitis C Virus NS3 (HCV NS3) protease as the target protein. The pocket-based and interaction-based modes of the spatial filtering module showed efficient and specific selection of ligands from the virtual screening that interact with the HCV NS3 catalytic serine 139.