Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)

Public responses to CO2 storage sites: Lessons from five European cases

Studies of the factors involved in public perceptions of CO2 storage projects reveal a level of complexity and diversity that arguably confounds a comprehensive theoretical account. To some extent, a conceptual approach that simply organises the relevant social scientific knowledge thematically, rather than seeking an integrated explanation, is as useful as any single account that fails to do justice to the contingencies involved. This paper reviews and assembles such knowledge in terms of six themes and applies these themes to five European cases of carbon capture and storage (CCS) implementation. We identify the main factors involved in community responses to CCS as relating to: the characteristics of the project; the engagement process; risk perceptions; the actions of the stakeholders; the characteristics of the community, and the socio-political context

Characterization of an immune-evading doxycycline-inducible lentiviral vector for gene therapy in the spinal cord

Gene therapy is a powerful approach to promote spinal cord regeneration. For a clinical application it is important to restrict therapeutic gene expression to the appropriate time window to limit unwanted side effects. The doxycycline (dox)-inducible system is a widely used regulatable gene expression platform, however, this system depends on a bacterial-derived immunogenic transactivator. The foreign origin of this transactivator prevents reliable regulation of therapeutic gene expression and currently limits clinical translation. The glycine-alanine repeat (GAR) of Epstein-Barr virus nuclear antigen-1 protein inhibits its presentation to cytotoxic T cells, allowing virus-infected cells to evade the host immune system. We developed a chimeric transactivator (GARrtTA) and show that GARrtTA has an immune-evading advantage over "classical" rtTA in vivo. Direct comparison of lentiviral vectors expressing rtTA and GARrtTA in the rat spinal cord shows that the GARrtTA system is inducible for 6 doxycycline-cycles over a 47 week period, whereas with the rtTA-based system luciferase reporter expression declines during the 3rd cycle and is no longer re-inducible, indicating that GARrtTA provides an immune-advantage over rtTA. Immunohistochemistry revealed that GARrtTA expressing cells in the spinal cord appear healthier and survive better than rtTA expressing cells. Characterization of the immune response shows that expression of GARrtTA, in contrast to rtTA, does not recruit cytotoxic T-cells to the transduced spinal cord. This study demonstrates that fusion of the GAR domain to rtTA results in a functional doxycycline-inducible transactivator with a clear immune-advantage over the classical rtTA in vivo.Therapeutic cell differentiatio

Great tits Parus major and blue tits Cyanistes caeruleus as indicators of agri-environmental habitat quality

This study examined relationships between habitat and breeding success for two common bird species, the great tit Parus major and blue tit Cyanistes caeruleus. The aim was to determine the potential of these species to act as indicators of food resource availability for birds in managed semi-natural habitats on farmland and thus as a measure of the effectiveness of specific management practices under agri-environment schemes (AES). Breeding success was recorded for four years (2007–2010) using 90 nestboxes on arable farmland in central England. Habitat parameters were derived from high spatial resolution airborne Light Detection and Ranging (LiDAR) and hyperspectral data. Relationships of breeding variables with a range of habitat variables, many of which were influenced by AES management, were evident for both species, despite strong interannual variation in breeding parameters. Relationships were strongest for models using habitat variables within a 100 m radius of the nest, compared to values of 50 and 200 m. Both species showed significant, positive relationships with the area and proximity of tree canopy and, for great tits especially, with hedgerow height and volume. Therefore, tits may act as indicators of the quality of local habitat, particularly within-hedge trees and hedgerows, managed under agri-environmental provision, and provide insight into the spatial arrangement of AES options at the field scale