Summary SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2 1 , and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro , the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.

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Musculoskeletal infections (MSKI) remain the bane of orthopedic surgery, and result in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis, and treatment has remained largely unchanged over the last 50 years, a 2nd International Consensus Meeting on Musculoskeletal Infection (ICM 2018, https://icmphilly.com) was completed. Questions pertaining to all areas of MSKI were extensively researched to prepare recommendations, which were discussed and voted on by the delegates using the Delphi methodology. The questions, including the General Assembly (GA) results, have been published (GA questions). However, as critical outcomes include: (i) incidence and cost data that substantiate the problems, and (ii) establishment of research priorities; an ICM 2018 research workgroup (RW) was assembled to accomplish these tasks. Here, we present the result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, which range from 0.1% to 30%, and $17,000 to $150,000. The RW also identified the most important research questions. The Delphi methodology was utilized to initially derive four objective criteria to define a subset of the 164 GA questions that are high priority for future research. Thirty-eight questions (23% of all GA questions) achieved the requisite > 70% agreement vote, and are highlighted in this Consensus article within six thematic categories: acute versus chronic infection, host immunity, antibiotics, diagnosis, research caveats, and modifiable factors. Finally, the RW emphasizes that without appropriate funding to address these high priority research questions, a 3rd ICM on MSKI to address similar issues at greater cost is inevitable. ICM, International Consensus Meeting; MSKI, musculoskeletal infections; RW, research workgroup. * 2018 ICM RW consensus on the current and projected incidences of infection, and costs per patient, for all orthopedic subspecialties. These estimates, which were compiled from information were obtained from: (i) recent peer-reviewed publications, (ii) analysis of 2015 national administrative data using HCUPNet (https://hcupnet.ahrq.gov/#setup), and (iii) RW expertise. 998 SCHWARZ ET AL.

Biofilm-associated implant-related bone and joint infections are clinically important due to the extensive morbidity, cost of care and socioeconomic burden that they cause. Research in the field of biofilms has expanded in the past two decades, however, there is still an immense knowledge gap related to many clinical challenges of these biofilm-associated infections. This subject was assigned to the Biofilm Workgroup during the second International Consensus Meeting on Musculoskeletal Infection held in Philadelphia USA (ICM 2018) (https://icmphilly.com). The main objective of the Biofilm Workgroup was to prepare a consensus document based on a review of the literature, prepared responses, discussion, and vote on thirteen biofilm related questions. The Workgroup commenced discussing and refining responses prepared before the meeting on day one using Delphi methodology, followed by a tally of responses using an anonymized voting system on the second day of ICM 2018. The Working group derived consensus on information about biofilms deemed relevant to clinical practice, pertaining to: (1) surface modifications to prevent/inhibit biofilm formation; (2) therapies to prevent and treat biofilm infections; (3) polymicrobial biofilms; (4) diagnostics to detect active and dormant biofilm in patients; (5) methods to establish minimal biofilm eradication concentration for biofilm bacteria; and (6) novel anti-infectives that are effective against biofilm bacteria. It was also noted that biomedical research funding agencies and the pharmaceutical industry should recognize these areas as priorities. ß