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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An efficient method for volumetric intensity modulated arc therapy (VMAT) planning was developed, where a single arc (360 degrees or less) is delivered under continuous variation of multileaf collimator (MLC) segments, dose rate, and gantry speed. Plans can be generated for any current linear accelerator that supports these degrees of freedom. MLC segments are derived from fluence maps at relatively coarsely sampled angular positions. The beam segments, dose rate, and gantry speed are then optimized using direct machine parameter optimization based on dose volume objectives and leaf motion constraints to minimize arc delivery time. The method can vary both dose rate and gantry speed or alternatively determine the optimal plan at constant dose rate and gantry speed. The method was used to retrospectively generate variable dose rate VMAT plans to ten patients (head and neck, prostate, brain, lung, and tonsil). In comparison to step-and-shoot intensity modulated radiation therapy, dosimetric plan quality was comparable or improved, estimated delivery times ranged from 70 to 160 s, and monitor units were consistently reduced in nine out of the ten cases by an average of approximately 6%. Optimization and final dose calculation took between 5 and 35 min depending on plan complexity.

Estrogen use was associated with enhanced recall of proper names. Previous failures to find differences associated with estrogen use may reflect the memory measures used or an increased inter-individual variability of the estrogen-taking group, as was observed in the present study. Interpretation of these results should be tempered by their retrospective nature.

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