The benefits and harms of corticosteroids for patients with severe coronavirus disease 2019 (COVID-19) remain unclear. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from December 31, 2019 to October 1, 2020 to identify randomized controlled trials (RCTs) that evaluated corticosteroids in severe COVID-19 patients. The primary outcome was all-cause mortality at the longest follow-up. Secondary outcomes included a composite disease progression (progression to intubation, ventilation, extracorporeal membrane oxygenation, ICU transfer, or death among those not ventilated at enrollment) and incidence of serious adverse events. A random-effects model was applied to calculate risk ratio (RR) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation approach to evaluate the certainty of the evidence. Seven RCTs involving 6250 patients were included, of which the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial comprised nearly 78% of all included subjects. Results showed that corticosteroids were associated with a decreased all-cause mortality (27.3 vs. 31.1%; RR: 0.85; 95% CI: 0.73–0.99; P = 0.04; low-certainty evidence). Trial sequential analysis suggested that more trials were still required to confirm the results. However, such survival benefit was absent if RECOVERY trial was excluded (RR: 0.83; 95% CI: 0.65–1.06; P = 0.13). Furthermore, corticosteroids decreased the occurrence of composite disease progression (30.6 vs. 33.3%; RR: 0.77; 95% CI: 0.64–0.92; P = 0.005), but not increased the incidence of serious adverse events (3.5 vs. 3.4%; RR: 1.16; 95% CI: 0.39–3.43; P = 0.79).

BackgroundTolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.MethodsThe microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests.ResultsWe found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.ConclusionsMetformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0754-9) contains supplementary material, which is available to authorized users.

Although circulating tumor cells (CTCs) have shown promise as potential biomarkers for diagnostic and prognostic assessment in gastric cancer (GC), determining the predictive and prognostic value of programmed death‐ligand 1 (PD‐L1)‐positive CTCs in patients with GC is a challenge. Here, we identified that the expression of total vimentin (VIM) protein was positively correlated with PD‐L1 and inhibited CD8+ T‐cell activation in patients with GC according to bioinformatics analysis. Notably, coexpression of PD‐L1 and cell‐surface VIM (CSV) was detected by immunofluorescence and immunohistochemistry assay in locally advanced GC tumor specimens and metastatic lymph nodes. Likewise, CSV expression level was significantly decreased after transiently knocking down PD‐L1 in GC cell lines. Based on our established CTC detection platform, CTCs were isolated from peripheral blood samples collected from 70 patients (38 resectable and 32 unresectable) with GC using magnetic positive selection and a CSV‐specific monoclonal antibody, 84‐1. CSV+PD‐L1+CTCs were observed in 50 of 70 (71%) GC patient samples, ranging from 0 to 261 mL−1. A higher number of CSV+PD‐L1+CTCs were significantly associated with a short survival duration and poor therapeutic response. This study demonstrated that detection of PD‐L1+CTCs using a CSV‐enrichment method has promising value as a clinically relevant prognostic marker for GC.