ObjectiveTo compare the effects of treatments for coronavirus disease 2019 (covid-19).DesignLiving systematic review and network meta-analysis.Data sourcesUS Centers for Disease Control and Prevention COVID-19 Research Articles Downloadable Database, which includes 25 electronic databases and six additional Chinese databases to 20 July 2020.Study selectionRandomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.MethodsAfter duplicate data abstraction, a bayesian random effects network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.Results23 randomised controlled trials were included in the analysis performed on 26 June 2020. The certainty of the evidence for most comparisons was very low because of risk of bias (lack of blinding) and serious imprecision. Glucocorticoids were the only intervention with evidence for a reduction in death compared with standard care (risk difference 37 fewer per 1000 patients, 95% credible interval 63 fewer to 11 fewer, moderate certainty) and mechanical ventilation (31 fewer per 1000 patients, 47 fewer to 9 fewer, moderate certainty). These estimates are based on direct evidence; network estimates for glucocorticoids compared with standard care were less precise because of network heterogeneity. Three drugs might reduce symptom duration compared with standard care: hydroxychloroquine (mean difference −4.5 days, low certainty), remdesivir (−2.6 days, moderate certainty), and lopinavir-ritonavir (−1.2 days, low certainty). Hydroxychloroquine might increase the risk of adverse events compared with the other interventions, and remdesivir probably does not substantially increase the risk of adverse effects leading to drug discontinuation. No other interventions included enough patients to meaningfully interpret adverse effects leading to drug discontinuation.ConclusionGlucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care. The effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.Systematic review registrationThis review was not registered. The protocol is included as a supplement.Readers’ noteThis article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

Multi-walled carbon nanotubes (MWCNTs) can be translocated into the targeted organs of organisms. We employed a model organism of the nematode Caenorhabditis elegans to investigate the role of a biological barrier at the primary targeted organs in regulating the translocation and toxicity formation of MWCNTs. A prolonged exposure to MWCNTs at predicted environmental relevant concentrations caused adverse effects associated with both the primary and secondary targeted organs on nematodes. The function of PEGylated modification in reducing MWCNTs toxicity might be mainly due to the suppression of their translocation into secondary targeted organs through the primary targeted organs. A biological barrier at the primary targeted organs contributed greatly to the control of MWCNTs translocation into secondary targeted organs, as indicated by functions of Mn-SODs required for prevention of oxidative stress in the primary targeted organs. Over-expression of Mn-SODs in primary targeted organs effectively suppressed the translocation and toxicity of MWCNTs. Our work highlights the crucial role of the biological barrier at the primary targeted organs in regulating the translocation and toxicity formation of MWCNTs. Our data also shed light on the future development of engineered nanomaterials (ENMs) with improved biocompatibility and design of prevention strategies against ENMs toxicity.

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Graphene oxide (GO) shows great promise as a nanomaterial for medical applications; however, the mechanism for its long-term adverse effects is still largely unclear. Here, we show that chronic GO exposure not only caused damage on the function of both primary and secondary targeted organs but also induced severe accumulation of pathogenic microbial food (OP50) in the intestine of Caenorhabditis elegans, a non-mammalian alternative toxicity assay system. GO accumulated in the intestine could be largely co-localized with OP50 and induced decreased immune response of animals. In contrast, feeding with UV-treated OP50 suppressed GO toxicity and accumulation in the intestine and maintained the relatively normal immune response of animals. The severe accumulation of OP50 in the intestine might be partially due to the damage by GO on the development and function of AVL and DVB neurons controlling defecation behavior. Reduction of chronic GO toxicity by PEG surface modification largely resulted from the inhibition of OP50 accumulation in the intestine and the maintenance of normal immune response. Our results highlight the key role of innate immunity in regulating in vivo chronic GO toxicity, which will be helpful for our understanding of the interactions between nanomaterials and biological systems during the long-term development of animals.

Graphene oxide (GO) can be potentially used in biomedical and nonbiomedical products. The in vivo studies have demonstrated that GO is predominantly deposited in the lung. In the present study, we employed SOLiD sequencing technique to investigate the molecular control of in vitro GO toxicity in GLC-82 pulmonary adenocarcinoma cells by microRNAs (miRNAs), a large class of short noncoding RNAs acting to post-transcriptionally inhibit gene expression. In GLC-82 cells, GO exposure at concentrations more than 50 mg/L resulted in severe reduction in cell viability, induction of lactate dehydrogenase leakage, reactive oxygen species production and apoptosis, and dysregulation of cell cycle. GO was localized in cytosol, mitochondria, endoplasmic reticulum, and nucleus of cells. Based on SOLiD sequencing, we identified 628 up-regulated and 25 down-regulated miRNAs in GO-exposed GLC-82 cells. Expression of some selected dysregulated miRNAs was concentration-dependent in GO-exposed GLC-82 cells. The dysregulated miRNAs and their predicted targeted genes were involved in many biological processes. By combining both information on targeted genes for dysregulated miRNAs and known signaling pathways for apoptosis control, we hypothesize that the dysregulated miRNAs could activate both a death receptor pathway by influencing functions of tumor necrosis factor α receptor and caspase-3 and a mitochondrial pathway by affecting functions of p53 and Bcl-2 in GO-exposed GLC-82 cells. Our results provide an important molecular basis at the miRNA level for explaining in vitro GO toxicity. Our data will be also useful for developing new strategies to reduce GO toxicity such as surface chemical modification.

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We employed an in vivo Caenorhabditis elegans assay system to perform SOLiD sequencing analysis to identify the possible microRNA (miRNA) targets of multi-walled carbon nanotubes (MWCNTs). Bioinformatics analysis on targeted genes for the identified dysregulated miRNAs in MWCNT exposed nematodes demonstrates their involvement in many aspects of biological processes. We used loss-of-function mutants for the identified dysregulated miRNAs to perform toxicity assessment by evaluating functions of primary and secondary targeted organs, and found the miRNA mutants with susceptible or resistant property towards MWCNT toxicity. Both the physiological state of the intestine and defecation behavior were involved in the control of the susceptible or resistant property occurrence for specific miRNA mutants towards MWCNT toxicity. This work provides the molecular basis at the miRNA level for future chemical design to reduce the nanotoxicity of MWCNTs and further elucidation of the related toxicological mechanism.