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Footings of an existing building were removed under archaeological supervision, and excavation for new footings was monitored. An extension of one of the Iron Age ditches seen in the evaluation continued in the north of the site but a second to the south was not seen. Another ditch o a different alignment remains undated but does not appear to be related. No additional finds were recovered.

Objective: To estimate pairwise associations between administration of tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and non-invasive or mechanical ventilation, based on all available direct and indirect evidence. Methods: Eligible trials randomized hospitalized patients with COVID-19 that compared either interleukin-6 receptor antagonist with usual care or placebo in a recent prospective meta-analysis (27 trials, 10930 patients) or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomization. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomization were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence. Results: One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0.82 [0.71-0.95, P=0.008]] and sarilumab [0.80 [0.61-1.04, P=0.09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1.03 [95%CI 0.81-1.32, P=0.80]. The P value for the global test for inconsistency was 0.28. Conclusion: Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.

The goal of the Palaeoclimate Modelling Intercomparison Project (PMIP) is to understand the response of the climate system to changes in different climate forcings and to feedbacks. Through comparison with observations of the environmental impacts of these climate changes, or with climate reconstructions based on physical, chemical or biological records, PMIP also addresses the issue of how well state-of-the-art models simulate climate changes. Palaeoclimate states are radically different from those of the recent past documented by the instrumental record and thus provide an out-of-sample test of the models used for future climate projections and a way to assess whether they have the correct sensitivity to forcings and feedbacks. Five distinctly different periods have been selected as focus for the core palaeoclimate experiments that are designed to contribute to the objectives of the sixth phase of the Coupled Model Intercomparison Project (CMIP6). This manuscript describes the motivation for the choice of these periods and the design of the numerical experiments, with a focus upon their novel features compared to the experiments performed in previous phases of PMIP and CMIP as well as the benefits of common analyses of the models across multiple climate states. It also describes the information needed to document each experiment and the model outputs required for analysis and benchmarking.

IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. DATA EXTRACTION AND SYNTHESIS In this prospectivemeta-analysis, risk of biaswas assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I-2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. MAIN OUTCOMES AND MEASURES The primary outcome measurewas all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P =.003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P

Endosomal escape is a critical step in intracellular delivery of biomacromolecular drugs, but quantitative, high throughput study of endosomal vesicle disruption remains elusive. We designed two genetically encoded split luciferase “turn on” reporters that can be assayed rapidly in well plates on live cells using a luminometer. Both systems use non-luminescent N-terminal and C-terminal luciferase fragments which can reconstitute a functional luminescent enzyme when they are held in proximity by their fusion partners. The first system uses Gal8 and CALCOCO2 fused to these fragments, which interact following endosome disruption and facilitate complementation of the split luciferase fragments to produce significant luminescence when luciferin is added. The second system uses the N-terminal carbohydrate recognition domain of Gal8 (G8-NCRD) fused to both luciferase fragments. Following endosome disruption, G8-NCRD binds to exposed glycans inside endosomes, concentrating both fragments there to reconstitute active luciferase. Additionally, and in contrast to recently reported Gal8 intracellular tracking with fluorescent microscopy, these split luciferase-based assays enable simultaneous identification and downselection of cytotoxic test conditions because the luciferase reaction requires intracellular ATP. Further, we demonstrate that the lead luminescent cell line is more sensitive to detection of endosomal disruption at lower doses of an endosome disrupting drug carrier than the previously reported Gal8-YFP fluorescent system. These systems represent a first-in-class luminescent assay to detect endosome disruption in high throughput while excluding toxic formulations. Endosome disruption screening with these “turn on” systems has potential as a tool in the discovery and development of intracellular biologic drug delivery formulations.Graphical Abstract

The observation of the new footings revealed no deposits of archaeological interest.

Counselors’ decision-making processes have received little attention in the literature. The purpose of this study was to ascertain the ethical decision-making practices of counselors working in the field. The results of a phenomenological study indicate that linear models and an orientation to professional ethical guidelines learned in graduate training serve as a foundation, yet not a practical guide, in professional ethical decision making. The authors found that 4 themes guide counselors’ ethical decision making: personal values, clients’ best interest, transparency in decision making, and perceptions of formal training and practice. Implications for practice and counselor education are provided, with recommendations for future research.