Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity.

Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4 <sup>+</sup> T cell frequencies. These data suggest that the "Interferon paradox" previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity

Strength of fine-grained soils at the solid-fluid transition

Deepwater offshore oil and gas developments require an assessment to be made of the risk of infrastructure damage from submarine slides. The likelihood and magnitude of submarine slides, and the consequent impact loading on seabed infrastructure in the path of the debris from the slide, must be estimated. Export pipelines are especially vulnerable to impact from submarine slides, because of their length and the need to cross canyons and other seabed features that are potential paths for the flowing debris. Characterising the debris material represents a particular challenge, as the original soil, which is typically characterised using conventional geotechnical methods, evolves through remoulding and water entrainment into a viscous fluid. Because of this transition from soil to fluid, characterisation of the strength of flowing fine-grained sediment has been addressed separately within a soil mechanics framework and a fluid mechanics framework, resulting in two different approaches for expressing the strain-rate-dependent strength of debris flows, and the consequential impact loads on pipelines. In this paper we compare the two approaches, and show that the geotechnical characterisation of fine-grained sediments can be extended into the liquid range in a continuous fashion. This is supported by a series of undrained shear strength measurements on two different remoulded soils, from fall cone tests, vane shear (including viscometer) tests, T-bar and ball penetrometer tests. Analysis of the results shows that the variation in shear strength over the solid and liquid ranges can be described by a unique function of water content, for a given soil. Furthermore, the effects of rate of shearing are well captured by a dimensionless function of the normalised strain rate. The geotechnical approach also accounts for the observed strength reduction due to intense shearing.</p