RESUMO
BACKGROUND: No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. FINDINGS: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. INTERPRETATION: In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. FUNDING: Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.
Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/efeitos adversos , Alanina/uso terapêutico , Antivirais/efeitos adversos , Betacoronavirus , COVID-19 , China , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Resultados Negativos , Pandemias , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
BACKGROUND: This study was performed to explore the causal association between asthma and chronic obstructive pulmonary disease(COPD). METHODS: We obtained summary statistics for asthma from 408,442 Europeans in an open genome-wide association study (GWAS) from the UK Biobank to select strongly associated single nucleotide polymorphisms that could serve as instrumental variables for asthma (P < 5×10-8). Additional summary statistics for COPD were obtained from 193,638 individuals of European ancestry in the GWAS published by FinnGen. Univariable Mendelian randomization(UVMR) analysis was performed using inverse variance weighted (IVW) as the primary method of analysis. The reliability of the results was verified by multivariable MR(MVMR), reverse and replication MR analysis, and sensitivity analysis. RESULTS: In the UVMR analysis, asthma increased the risk of COPD, with an odds ratio (OR) of 1.27 (95% confidence interval (CI) = 1.16-1.39, P = 5.44×10-7). Estimates were consistent in MVMR analyses by the adjustments of smoking initiation, age of smoking initiation, cigarettes per day, PM 2.5, and the combination of the above factors. In the reverse MR analysis, there was no evidence of a causal effect of COPD on asthma risk(OR = 1.02, 95% CI = 0.97-1.07, P = 0.3643). In the replication MR analysis, asthma still increased the risk of COPD. Sensitivity analyses validated the robustness of the above associations. CONCLUSIONS: We found that genetically predicted asthma was positively associated with the risk of COPD. Additionally, there was no evidence that COPD increases the risk of asthma. Further clarification of this link and underlying mechanisms is needed to identify feasible measures to promote COPD prevention.
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Asma , Doença Pulmonar Obstrutiva Crônica , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Reprodutibilidade dos TestesRESUMO
Micro RNAs (MiRNAs) act as a key regulator participating in various biological process, and the roles of that play in chronic obstructive pulmonary disease (COPD) are discovered. However, recent pharmacological treatment for COPD focus on alleviating symptoms and reducing the risk events. The heterogeneous COPD causes variable responses to pharmacological interventions. COPD treatment has gradually developed into precision medicine, integrating clinical and biomarker information to optimize personalized therapy. Thus, targeting miRNAs represents a promising strategy for COPD individual therapy. Twelve COPD patients, 7 community-acquired pneumonia and 4 normal people were recruited. Total RNAs were collected from the bronch alveolar lavage cells and peripheral blood plasma of each participant. miRNAs were profiled by microarray and systematically compared between patients with different groups. Bioinformatic analysis identified pathways relevant to the pathogenesis of COPD. Next, the target pathway networks were mapped. Compared different groups, we obtain differential expression of miRNAs (Q value (Adjusted P value)â <â .05 and |log2FC| >2). Gene ontology enrichment analyses showed that differentially expressed miRNAs function as regulators in different modules of cellular component, molecular function and biological process. Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that signals, such as MAPK signaling pathway, Ras signaling pathway, FoxO signaling pathway and oxidative stress may participate in the pathogenesis of COPD. In the miRNAs target pathway networks, novel-hsa-miR26-3p or hsa-miR-3529-3p/CDC42/MAPK signaling pathway may play a role in regulating COPD. Our findings demonstrate critical roles of the miRNAs in COPD molecular pathology. The data support a plausible mechanism that miRNAs may be involved in the development of COPD by affecting the inflammatory and oxidative stress. Moreover, hsa-miR-4748/CDC42/MAPK signaling pathway may contribute to the pathogenesis of COPD, providing a potential novel therapeutic strategy in COPD.
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MicroRNAs , Doença Pulmonar Obstrutiva Crônica , Biomarcadores , Líquido da Lavagem Broncoalveolar , Humanos , MicroRNAs/metabolismo , Plasma/metabolismo , Doença Pulmonar Obstrutiva Crônica/genéticaRESUMO
OBJECTIVE: To investigate the characteristics and the risk factors of coronavirus disease 2019 (COVID-19) associated acute kidney injury (AKI). METHODS: A retrospective cohort study was performed to examine the basic data, clinical characteristics and prognosis of patients with COVID-19 in Zhongnan Hospital of Wuhan University and Wuhan Fourth Hospital from January 1st to February 1st in 2020. According to the diagnostic criteria of Kidney Disease: Improving Global Outcomes (KDIGO), patients with AKI were included in AKI group and those without AKI were included in non-AKI group. The differences of each index between the two groups were compared. The prognostic value of AKI for COVID-19 was analyzed by Kaplan-Meier survival curve and Cox regression. RESULTS: A total of 394 COVID-19 patients were included, with a total mortality of 5.6%; 37 (9.4%) of them developed AKI. The mortality of patients with COVID-19 associated AKI was 18.9%. There were significant differences in age, gender, smoking history, hypertension history, malignancy history, cardiovascular disease history and cerebrovascular disease history between the two groups. In addition to the difference of serum creatinine (SCr) and blood urea nitrogen (BUN), white blood cell count (WBC), neutrophil count (NEU), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), D-dimer, procalcitonin (PCT) and C-reaction protein (CRP) in AKI group were significantly higher than those in non-AKI group [WBC (×109/L): 5.75 (4.13, 7.83) vs. 4.52 (3.35, 5.90), NEU (×109/L): 4.55 (2.81, 6.11) vs. 3.06 (2.03, 4.50), AST (U/L): 40.0 (24.5, 69.5) vs. 30.0 (23.0, 42.5), LDH (µmol×s-1×L-1): 5.21 (3.68, 7.57) vs. 4.24 (3.05, 5.53), D-dimer (µg/L): 456 (266, 2 172) vs. 290 (152, 610), PCT (µg/L): 0.33 (0.03, 1.52) vs. 0.01 (0.01, 0.11), CRP (mg/L): 53.80 (26.00, 100.90) vs. 23.60 (9.25, 51.10), all P < 0.05], while lymphocyte count (LYM) and platelet count (PLT) were decreased [LYM (×109/L): 0.68 (0.47, 1.05) vs. 0.91 (0.63, 1.25), PLT (×109/L): 142.0 (118.0, 190.0) vs. 171.0 (130.0, 2 190.0), both P < 0.05]. The mortality of AKI group was significantly higher than that of non-AKI group [18.9% (7/37) vs. 4.2% (15/357), P < 0.01]. Kaplan-Meier survival curve showed that the 30-day cumulative survival of AKI group was lower than that of non-AKI group (log-rank: P = 0.003). Cox analysis also showed that AKI increased the odds of patients with COVID-19 mortality by 3.2-fold [hazard ratio (HR) = 3.208, 95% confidence interval (95%CI) was 1.076-9.566, P = 0.037]. CONCLUSIONS: The risk of AKI is higher in patients with COVID-19. Early intervention to prevent AKI in patients with COVID-19 is of great significance to improve the prognosis of patients.
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Injúria Renal Aguda , Betacoronavirus , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Injúria Renal Aguda/etiologia , COVID-19 , Humanos , Pandemias , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2RESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.
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Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Alanina/administração & dosagem , Alanina/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus/patogenicidade , COVID-19 , China , Ensaios Clínicos Fase III como Assunto , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Método Duplo-Cego , Estudos de Equivalência como Asunto , Feminino , Humanos , Infusões Intravenosas , Masculino , Estudos Multicêntricos como Assunto , Pandemias , Segurança do Paciente , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Medição de Risco , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Tratamento Farmacológico da COVID-19RESUMO
PURPOSE: Recent epidemiological evidence indicates an association between peritoneal dialysis (PD) patients and pulmonary hypertension (PH). However, the true prevalence of PH associated with PD has not been well described. So we conducted a meta-analysis to summarize the point prevalence of PH in adults with PD. METHODS: PubMed, EMBASE, the Cochrane Collaboration, and the reference lists of relevant articles were searched to identify eligible studies. We used a random-effect meta-analysis model to estimate the prevalence of PH. We also performed sensitivity analyses and assessments of publishing bias. RESULTS: Fourteen observational studies (n = 1483 participants) were included in this meta-analysis. The result of analysis in random-effect model showed that the pooled prevalence was 21% (95% CI 16-28), with significant heterogeneity between these studies (I2 = 84%, p < 0.01). Sensitivity analysis further demonstrated the results to be robust. Besides, the Egger's test (p = 0.287) showed no significant publication bias. CONCLUSIONS: PH is highly prevalent in patients with PD. Further studies are encouraged to definitively clarify the relationship between PH and PD.
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Hipertensão Pulmonar , Falência Renal Crônica/terapia , Diálise Peritoneal , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/epidemiologia , Diálise Peritoneal/efeitos adversos , Diálise Peritoneal/métodos , Diálise Peritoneal/estatística & dados numéricos , PrevalênciaRESUMO
Heat shock proteins (Hsps) have been reported to protect cells, tissues, and organisms against damage from a wide variety of stressful stimuli. Whether they protect against deoxyribonucleic acid (DNA) damage in individuals exposed to environmental stresses and chemical carcinogens is unknown. In the study, we investigated the association between Hsp70 levels (the most abundant mammalian Hsp) and genotoxic damage in lymphocytes of workers exposed to coke-oven emission using Western dot blot and 2 DNA damage assays, the comet assay and the micronucleus test. The data show that there is a significant increase in Hsp70 levels, DNA damage score, and micronucleus rates in lymphocytes of workers exposed to coke-oven emission as compared with the control subjects. Furthermore, there was a significant negative correlation of Hsp70 levels with DNA damage scores in the comet assay (r = -0.663, P < 0.01) and with micronucleus rates (r = -0.461, P < 0.01) in the exposed group. In the control group, there was also a light negative correlation between Hsp70 with DNA damage and micronuclei rate (r = -0.236 and r = 0.242, respectively), but it did not reach a statistically significant level (P > 0.05). Our results show that individuals who had high Hsp70 levels generally showed lower genotoxic damage than others. These results suggest a role of Hsp70 in the protection of DNA from genotoxic damage induced by coke-oven emission.
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Poluentes Ocupacionais do Ar/toxicidade , Coque/toxicidade , Dano ao DNA/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Mutagênicos/toxicidade , Adulto , Ensaio Cometa , Dano ao DNA/genética , Exposição Ambiental , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/genética , Micronúcleos com Defeito Cromossômico/patologia , Testes para Micronúcleos , Fatores de Risco , Fumar , Estatística como AssuntoRESUMO
OBJECTIVE: To explore the biomarkers of early diagnosis in patients with polycyclic aromatic hydrocarbons (PAHs)-related lung cancer for the application to detection of occupational lung cancer or related lung cancer. METHODS: Western dot blotting was used to explore the expression of ras, p53 and heat stress protein 70 (HSP70) in 29 patients with PAHs-related lung cancer (LC), and 28 patients with non-cancerous pulmonary disease, and 30 healthy controls. RESULTS: The positive detection rates of P21, P53, and HSP70 in LC group (58.62%, 34.48%, 41.38% respectively) were higher than those in non-cancerous pulmonary disease group (14.29%, 7.14%, 10.71% respectively, P < 0.01). The sensitivity of P21, P53 and HSP70 were 58.62%, 34.48% and 41.38% respectively, negative predictive value (NPV) were 68.42%, 78.05% and 63.04% respectively. The co-detection of the three proteins mentioned above produced a sensitivity of 82.76% with a NPV of 78.26% (P < 0.05). Of 18 cases of LC with negative cytology, 13 (72.22%) were found HSP21, P53 or HSP70 positive. CONCLUSIONS: Co-detection of the P21, P53, and HSP70 may be used as the screening marker for diagnosis of PAHs-related lung cancer, and may supplement the diagnostic value of conventional cytology.