Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.[Background] Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants.[Methods] Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures.[Results] Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities.[Conclusion] This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu (2022-500385-99-00).EU-SolidAct is part of the European pandemic preparedness network EU RESPONSE, funded by the EU Horizon 2020 Research and Innovation programme, under grant number 101015736. EU-SolidAct has also received funding from CAPNET (France) and Klinbeforsk (Norway).Peer reviewe

Effects of bubble coalescence on pool boiling heat transfer and critical heat flux - a parametric study based on artificial cavity geometry and surface wettability

Controlling the onset of boiling is highly desirable for enhancing boiling heat transfer. In this study, a systematic set of pool boiling experiments on surfaces with artificial cavities were performed to investigate the effect of surface morphology on bubble coalescence and resultant boiling heat transfer performance. Circular cavities with various diameters and pitch sizes were fabricated on silicon surfaces. The effect of surface wettability on the performance of the structured surfaces were examined with the use of 50 nm thick Teflon film. Using a high speed camera to examine the bubble dynamics, the results reveal that there exists a critical hole pitch size/hole diameter ratio (ND = 10), below which horizontal bubble coalescence occurs at the lower wall superheats. Furthermore, the visual results indicated that surface wettability alters the critical heat flux (CHF) mechanism. In contrast to the hydrophobic surfaces, hydrodynamic instability is the main reason for CHF occurrence on the hydrophilic surfaces. The results indicate that although increasing the hole diameter enhances the CHF for all the fabricated samples, the effect of pitch size depends on the surface wettability with the CHF increasing with pitch size on the hydrophobic surface and decreasing with pitch size on the hydrophilic surface. A maximum heat transfer coefficient enhancement of 100% was achieved on the hydrophilic structured surface relative to the hydrophobic structured surface. The maximum CHF increase was 100% on the hydrophilic surface and 48% on the hydrophobic surface. (C) 2019 Elsevier Ltd. All rights reserved

Pool boiling heat transfer of ferrofluids on structured hydrophilic and hydrophobic surfaces: the effect of magnetic field

The combined effect of external magnetic field and surface modification on boiling heat transfer of ferrofluids was investigated in this study. Experiments were performed on suspensions of Fe3O4 nanoparticles (volume fraction of 0.025% vf%) with and without presence of magnetic field on structured (surfaces with artificial cavities) hydrophilic and hydrophobic surfaces. Surface related effects such as the hole diameter, pitch size and surface wettability on boiling heat transfer were revealed using the high speed camera system. According to the obtained results, application of magnetic field enhanced boiling heat transfer. The effect of magnetic field was more pronounced on surfaces with larger pitch sizes. Magnetic field promoted bubble nucleation on the superheated surfaces by generating an additional force via Fe3O4 nanoparticles, resulting in enhanced bubblebubble interactions and coalescence. Furthermore, the surfaces with the larger cavity diameter performed better in terms of heat transfer. Scanning Electron Microscopy (SEM) images showed that as the cavity diameter decreased, deposited nanoparticles tended to completely fill the cavities on hydrophilic surfaces and thus deteriorate boiling heat transfer. On hydrophobic surfaces, deposition of nanoparticles led to a biphilic surface, thereby enhancing boiling heat transfer. As the cavity size increased, smaller portion of the cavities was filled with nanoparticles, and nucleation could still occur from the nucleation sites

HRs for the T-cell parameters in relation to early acute allograft rejection (multivariate analysis).

<p>HRs for the T-cell parameters in relation to early acute allograft rejection (multivariate analysis).</p

Patient characteristics.

<p>Data are presented as medians (interquartile range).</p

Hazard ratios for the clinical characteristics in relation to early acute allograft rejection (univariate analysis).

<p>Hazard ratios for the clinical characteristics in relation to early acute allograft rejection (univariate analysis).</p