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Remdesivir (RDV) is used widely for COVID-19 patients despite varying results in recent clinical trials. Here, we show how serially passaging SARS-CoV-2 in vitro in the presence of RDV selected for drug-resistant viral populations. We determined that the E802D mutation in the RNA-dependent RNA polymerase was sufficient to confer decreased RDV sensitivity without affecting viral fitness. Analysis of more than 200,000 sequences of globally circulating SARS-CoV-2 variants show no evidence of widespread transmission of RDV-resistant mutants. Surprisingly, we also observed changes in the Spike (i.e., H69 E484, N501, H655) corresponding to mutations identified in emerging SARS-CoV-2 variants indicating that they can arise in vitro in the absence of immune selection. This study illustrates SARS-CoV-2 genome plasticity and offers new perspectives on surveillance of viral variants. One Sentence SummarySARS-CoV-2 drug resistance & genome plasticity
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There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. In the present study, we found that recombinant human interferon-alpha (IFNa) triggers intrinsic and extrinsic cellular antiviral responses, as well as reduces replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. Although IFNa alone was insufficient to completely abolish SARS-CoV-2 replication, combinations of IFNa with remdesivir or other antiviral agents (EIDD-2801, camostat, cycloheximide, or convalescent serum) showed strong synergy and effectively inhibited SARS-CoV-2 infection in human lung epithelial Calu-3 cells. Furthermore, we showed that the IFNa-remdesivir combination suppressed virus replication in human lung organoids, and that its single prophylactic dose attenuated SARS-CoV-2 infection in lungs of Syrian hamsters. Transcriptome and metabolomic analyses showed that the combination of IFNa-remdesivir suppressed virus-mediated changes in infected cells, although it affected the homeostasis of uninfected cells. We also demonstrated synergistic antiviral activity of IFNa2a-based combinations against other virus infections in vitro. Altogether, our results indicate that IFNa2a-based combination therapies can achieve higher efficacy while requiring lower dosage compared to monotherapies, making them attractive targets for further pre-clinical and clinical development.
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Objective To investigate the effect of low platelet (PLT) count on the early fatality rate of liver transplant recipients without intraoperative PLT transfusion. Methods Clinical data of 180 recipients undergoing orthotopic liver transplantation were retrospectively analyzed. The critical value of PLT count on postoperative 7 d to predict the early postoperative fatality rate was evaluated by the receiver operating characteristic(ROC) curve. All recipients were divided into the low PLT count group and control group according to the critical value. Relevant clinical data including perioperative PLT count, preoperative general conditions and intraoperative conditions of the recipients were included. The independent risk factors of the early fatality rate of liver transplant recipients were analyzed by Logistic regression analysis. The early prognosis of the recipients between two groups was observed and compared by the postoperative length of intensive care unit (ICU) stay, postoperative length of hospital stay, early allograft dysfunction and fatality rate on postoperative 30 d. Results The PLT count < 32×109/L on 7 d after liver transplantation was an independent risk factor of the fatality rate on postoperative 30 d (P < 0.05). The postoperative length of ICU stay of the recipients in the low PLT count group was 9 (5, 14) d, significantly longer than 5 (3, 6) d in the control group (P < 0.05). In the low PLT count group, the early allograft dysfunction rate was 55.0%, significantly higher than 20.6% in the control group (P < 0.05). In the low PLT count group, the fatality rate on postoperative 30 d was 40.0%, significantly higher than 2.5% in the control group (P < 0.05). The length of hospital stay did not significantly differ between two groups (P > 0.05). Conclusions The PLT count < 32×109/L on postoperative 7 d is an independent risk factor for the fatality rate on postoperative 30 d of liver transplant recipients. It can prompt the early allograft dysfunction and contribute to predict the early clinical prognosis of liver transplant recipients.
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Objective The aim of this study was to evaluate the clinical efficacy and hematologic toxicity of docetaxel in the treatment of metastatic breast cancer patients in different age groups. Methods The clinical data of three groups of single-agent do-cetaxel in the treatment of metastatic breast cancer patients were retrospectively analyzed. The clinical efficacy of docetaxel was ana-lyzed statistically. Results The objective response rate(ORR) and clinical beneficial rate( CBR) in the group of age < =45 year group were 30. 6% and 38. 7% ,and the ORR and CBR in the 46~59 age were 27. 5% and 35. 7% ,while ORR and CBR in the≥60 age group were 20. 0% and 27. 5% . The median progress free survival( PFS) in three groups was 6. 0(2. 9 ~9. 1) months,5. 0 (2. 9~7. 1)months and 4. 0(3. 3~4. 7) months,respectively. There was no statistical difference in three different age groups(P=0. 477,0. 492 and 0. 460,respectively). Cox regression analysis showed that the docetaxel rescue treatment of PFS had not associated with clinical stage,pathological type,ipsilateral axillary lymph node metastasis,disease free survival,unit dose of body surface area dose,number of rescue treatment lines,number of recurrence and metastasis,etc. in three different age groups of patients with meta-static breast cancer. Hematological toxicity was mainly manifested by a decrease in white blood cells and neutrophils,and docetaxel has less effect on hemoglobin and platelets. Conclusion The clinical efficacy and hematologic toxicity of docetaxel have a certain de-gree of correlation with ages. With the increase of age,the clinical curative effect is reduced and the blood toxicity is aggravated.
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Objective To compare the accuracy of lactate concentration and model for end-stage liver disease (MELD) to predict early mortality after liver transplantation, and to provide a convenient and timely predictive tool for clinical work. Methods A total of 121 patients who underwent Allograft liver transplantation in 2017 in our hospital, 92 males and 29 females, aged 25-78 years old, ASA physical status Ⅲ or Ⅳ, were selected to the retrospective study. Patients were divided into survival group and non-survival group, according whether survived within 30 days after the surgery. The preoperative and postoperative lactate concentrations were gotten and the preoperative and postoperative MELD scores were calculated. The preoperative lactate concentrations, postoperative lactate concentrations, preoperative MELD scores and postoperative MELD scores were compared between survival group and non-survival group, respectively. The predictive accuracy about early mortality (30 days) of lactate concentration and MELD score were compared at preoperation and postoperation through receiver operating characteristic, respectively. Results There were 109 patients (90.0％) survived and 12 patients (10.0％) non-survived within 30 days after the surgery. Compared with survival group, the preoperative lactate concentrations, postoperative lactate concentrations, preoperative MELD scores and postoperative MELD scores in the non-survival group were significantly increased (P ＜ 0.05). According to the ROC analysis, the area under the curve (AUC) of ROC of preoperative lactate concentration was 0.78 (95％ CI 0.62-0.93) with a cutoff value of 2.43 mmol/L, the AUC of preoperative MELD score was 0.70 (95％ CI 0.53-0.87) with a cutoff value of 24.50 scores. There was not statistically significant between the AUC of preoperative MELD score and lactate concentration. The AUC of postoperative lactate concentration was 0.85 (95％ CI 0.70-0.99) with a cutoff value of 9.57 mmol/L, the AUC of postoperative MELD score was 0.74 (95％ CI 0.61-0.88) with a cutoff value of 25.42 scores. The AUC of postoperative lactate concentration was statistically higher than that of MELD score (P ＜ 005). Conclusion The predictive capability of lactate concentration, especially that of postoperative lactate concentrations, was better than the predictive capability of MELD score.
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Objective@#To observe the distribution of occupational activity disorders of extremely severe mass burn patients in recovery period after injury.@*Methods@#From December 2014 to December 2015, 65 extremely severe burn patients conforming to the inclusion criteria involved in August 2 Kunshan factory aluminum dust explosion accident were admitted to Kunshan Rehabilitation Hospital. They received comprehensive rehabilitation treatment after burns, including wearing pressure clothes, ultrasound treatment, semiconductor laser and red light irradiation, motor function training, and so on. Over 2 years after injury, a cross-sectional survey was conducted on the patients′ occupational activity disorders. Modified Barthel index (MBI) was used to assess the degree of activities of daily living (ADL) disorder of patients and to grade the independent level of completing each item of MBI, and then the independent level of patients completing self-care MBI items (bathing, dressing, grooming, eating, going to the toilet, urine control, and stool control) was compared with that of mobility items (going up and down stairs, bed and chair transfer, and walking). The Canadian Occupational Performance Measure (COPM) was used to assess the distribution of occupational activity disorders of patients. The distribution of the five most serious occupational activity disorders was counted, then the frequency and probability of which with frequency greater than or equal to 16 times were calculated. Data were processed with Pearson Chi-square test.@*Results@#Over 2 years after injury, the MBI score of patients was (76±22) points, and the ADL of 83.08% (54/65) patients reached completely self-care or light ADL disorder level. The MBI items arranged according to the completing independent level of patients from high to low were urine control/stool control, walking, bed and chair transfer, going up and down stairs, going to the toilet, eating, grooming, dressing, and bathing. The independent level of patients completing self-care MBI items was lower than that of mobility items (χ2=62.298, P<0.001). Over 2 years after injury, the five most serious occupational activity disorders in COPM dimension were mainly concentrated in the self-care dimension, accounting for 55.38% (180/325), followed by 22.46% (73/325) of production activities and 22.15% (72/325) of recreational activities, and the centrally distributed item was the personal self-care item under self-care dimension, accounting for 42.46% (138/325). Over 2 years after injury, the five most serious occupational activity disorders with frequency greater than or equal to 16 times were dressing and undressing, bathing, perineal cleaning, wearing pressure clothes, caring for children, visiting relatives and friends, 31, 25, 16, 17, 18, and 22 times respectively, with a probability of 47.69%, 38.46%, 24.62%, 26.15%, 27.69%, and 33.85% respectively.@*Conclusions@#Over 2 years after injury, most of the patients with extremely severe burns caused by the aluminum dust explosion were completely or basically self-care in their daily life. The disorder of self-care ADL was more serious than that of mobility, and the disorder of individual self-care activity was still the most serious occupational activity disorder of patients in this stage.@*Clinical trial registration@#Chinese clinical trial registry, ChiCTR-OOC-16009188.
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Objective To understand the health literacy status,influencing factors and demand carrying out the health education based on the mobile terminal among college students to provide a new idea for formulating and implementing the health literacy promotion plan for university students.Methods The multi-stage stratified cluster random sampling method was adopted to extract 1 949 students from partial universities in Nanjing City and conduct the investigation by adopting the Rapid Estimate System of Health Literacy and Health Education Demand Based on the Mobile Terminal Questionnaire of College Students.The influence factors were analyzed by using the univariate analysis and ordinal multi-classification Logistic regression analy sis.Results The university students with high,marginal and low health literacy level accounted for 31.3％,48.9％ and 19.8％ respectively.The proportions of the students with high health literacy in the four dimensions,including health knowledge,health behaviors,health skill and health status,were 57.9％,18.3％,61.0％ and 44.5％ respectively.The ordinal multi-classification Logistic regression analysis showed that the major influence factors affecting the health literacy of university students were gender,education background of mothers,majors,grades,electively taking the health education course.81.2 ％ of university students wanted to or urgently wanted to understand the health literacy knowledge.The main route getting the health literacy knowledge by the university students was network(83.8％).91.8％ of students were willing to learn the health literacy knowledge through mobile terminal.87.1％ of students believed that the WeChat was suitable to learn the health knowledge,81.3％ of students hoped to use the WeChat platform for learning the health knowledge,73.8％ of students hoped the Wechat to push the health knowledge with the modes of words combined with images and video.It was recommended that the health knowledge pushing for 1-3 times per week was suitable.Conclusion The health literacy of university students is at the marginal level.The health behaviors literacy is most lacking and the demand for the health education based on the mobile terminal is stronger.The health literacy intervention of university students should sufficiently apply the new media platform superiority and the emphasis should be placed on the populations of males,low education background mothers,non-medicine major,low grade and without electively taking the health education course.
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Objective:Positive effects of bioactive glass (BG) on proliferation,mineralization,and differentiation of human dental pulp cells (hDPCs) was already verified in various former studies.The Arg-Gly-Asp-Ser sequence (RGDS) was confirmed of affecting cell adhesion.Before further investigation,the objective of this study is to investigate whether RGDS can affect the effects of BG on the adhesion,proliferation and mineralization of hDPCs.Methods: hDPCs were harvested from third molars of 18-25-year-old individuals after informed consent.Enzyme digestion technique was used.The 4th to 6th ge-neration of hDPCs were used for all experiments.The cells of the experimental groups were cultured in Dulbecco minimum essential medium (DMEM) containing ionic dissolution products of BG and RGDS of seve-ral concentrations (12.5 mg/L,25.0 mg/L,50.0 mg/L,100.0 mg/L,200.0 mg/L).DMEM containing ionic dissolution products of BG without RGDS was used for cell culture as control group.Cell adhesion was tested 4 h after cell seeding by MTT assay.Cell proliferation was examined at 1,3,5,7,and 9 d after cell seeding by MTT assay.Cell mineralization was investigated on days 14 and 28 by alizarin red staining.After being stained and dried,mineralized nodules were dissolved by cetylpyridinium chloride (CPC) for semi-quantitative test.Results were statistically analyzed by one way ANOVA,SPSS (version 19.0) and P<0.05 was considered to be significant.Results: Cell adhesion in BG group showed no difference from that in DMEM group.Compared with BG group,hDPCs in BG+RGDS groups suggested weaker cell adhesion.When the concentration of RGDS increased,the adhered cell number decreased.hDPCs cultured with BG and RGDS showed lower proliferation activity in the early stage,while no significant difference was observed after 3 d.BG group promoted the mineralization of hDPCs compared with positive control group,negative control group and RGDS group.No significant difference was observed between BG+RGDS group and BG group or between RGDS group and positive control group.Conclusion: BG promotes proliferation and mineralization without affecting cell adhesion of hDPCs.Unbounded RGDS inhibits cell adhesion,but has no influence on the positive effects of BG on the proliferation and mineralization of hDPCs.
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Objective:To investigate the proliferation,odontogenic differentiation and mineralization of human dental pulp cells (HDPCs) on bioactive glass(BG) and extracted dentin proteins(EDP).Me-thods: Primary HDPCs were isolated from third molars by enzyme digestion and were cultured in Dulbecco's minimum essential medium (DMEM).Then the 4th generation of HDPCs was cultured with DMEM,which contained BG-EDP,BG,and EDP,respectively.Meanwhile HDPCs were cultured in DMEM as control group.Proliferation of HDPCs was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide(MTT) colorimetric assay.Odontogenic differentiation was determined by alkaline phosphatase (ALP) activity assay and real-time PCR.Mineralization was investigated by Alizarin red staining and cetylpyridinium chloride (CPC) assay.Results: The proliferation of HDPCs was increased significantly in BG-EDP group on 3,7,and 9 d(optical density value:1.36±0.06,2.52±0.20,2.72±0.29) compared with BG(optical density value: 1.20±0.26,2.33±0.26,2.50±0.30),EDP(optical density value: 1.13±0.15,2.10±0.13,2.38±0.22) and control group(optical density va-lue: 0.84±0.17,1.84±0.18,1.95±0.19),P0.05).After 14 days,ALP activity of BG-EDP group (56.67±1.83) was significantly upregulated compared with EDP group (41.98±9.71) and control group (30.82±6.70),P0.05;DSPP gene expression was upregulated significantly in BG-EDP group (5.79±1.94) compared with the other groups (P0.05).The alizarin red staining showed more mineral nodules in BG-EDP group,the cetylpyridinium chloride semi-quantification presented higher calcification in BG-EDP group (0.27±0.01) compared with the other groups (P<0.05).Conclusion: Compared with either BG or EDP,BG-EDP significantly promotes the proliferation,odontogenic differentiation and mineralization of HDPCs.
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Acute leukemia is the most common hematological malignancies.Based on the development of chemotherapy drugs and the improvement of chemotherapy regimens,the remission rate after induction chemotherapy increases obviously.But leukemia patients can not live for a long time mainly because of the ease relapse,so how to extend remission after treatment become the key to solve the problem.People are paying more and more attention on the cellular immunotherapy since it playes major roles in eradicating minimal residual disease of leukemia,reducing leukemia relapse and improving leukemia patients overall survival.This article reviews the application advances in research on this subject.
