Publications by authors named "Yunqing Qiu"

61 Publications

Role and characteristics of hippocampal region microglial activation in poststroke depression.

J Affect Disord 2021 May 21;291:270-278. Epub 2021 May 21.

State Key Laboratory of Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address:

Aims: To study the role and characteristics of activated microglia in poststroke depression (PSD) .

Methods: Twenty-four male Wistar rats were randomly divided into three groups: the poststroke (PS) group, PSD group, and Sham group. Neurobehavioral testing was performed 24 h postoperation. The body weights of the rats were regularly recorded, and behavioral testing was regularly performed at 1, 2 and 3 weeks postmodeling. Immunofluorescent staining was used to detect the microglial marker OX42. Real-time PCR was used to analyze the relative gene expression of microglial activation markers (TNF-a, IL-10, IL-1, TGF-β, CD86, iNOS, CD206, IL-1β, and Arg1) .

Results: The relative gene expression of proinflammatory markers (IL-1, TNF-a, iNOS, and IL1β) and anti-inflammatory markers (CD206 and Arg1) significantly increased in the hippocampal region compared with that in the right cerebral and left cerebral hemispheres in the PSD group. The relative gene expression of proinflammatory markers (TNF-a, IL-1, iNOS, and CD86) in the hippocampal region was significantly increased in the PSD group compared with that in the Sham and PS groups. The anti-inflammatory markers (TGF-β and CD206) in the hippocampal region were significantly increased in the PSD group compared with that in the Sham group, and the M2 marker Arg1 was significantly increased in the PSD group compared with that in the PS group. Correlation analysis showed that IL-1 was strongly negatively correlated with PSD .

Conclusions: Most microglia in the hippocampal region of PSD had a proinflammatory status and an anti-inflammatory status. IL-1 showed a strong negative correlation with PSD.
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http://dx.doi.org/10.1016/j.jad.2021.05.022DOI Listing
May 2021

Opportunities and challenges of artificial intelligence in the medical field: current application, emerging problems, and problem-solving strategies.

J Int Med Res 2021 Mar;49(3):3000605211000157

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.

Recent advancements in the field of artificial intelligence have demonstrated success in a variety of clinical tasks secondary to the development and application of big data, supercomputing, sensor networks, brain science, and other technologies. However, no projects can yet be used on a large scale in real clinical practice because of the lack of standardized processes, lack of ethical and legal supervision, and other issues. We analyzed the existing problems in the field of artificial intelligence and herein propose possible solutions. We call for the establishment of a process framework to ensure the safety and orderly development of artificial intelligence in the medical industry. This will facilitate the design and implementation of artificial intelligence products, promote better management via regulatory authorities, and ensure that reliable and safe artificial intelligence products are selected for application.
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http://dx.doi.org/10.1177/03000605211000157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165857PMC
March 2021

Plasma metabolites, especially lipid metabolites, are altered in pregnant women with gestational diabetes mellitus.

Clin Chim Acta 2021 Jun 9;517:139-148. Epub 2021 Mar 9.

Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China. Electronic address:

Background And Aims: Gestational diabetes mellitus (GDM) is a pathological condition of glucose intolerance associated with adverse pregnancy outcomes and increased risk of developing maternal type 2 diabetes later in life. Metabolomics is finding increasing use in the study of GDM. To date, GDM-specific metabolomic changes have not been completely elucidated.

Materials And Methods: In this pilot study, metabolomics fingerprinting data, obtained by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS), of 54 healthy pregnant women and 49 patients with GDM at the second and third gestational trimesters were analyzed. Multilevel statistical methods were used to process complex metabolomic data from the retrospective cohorts.

Results: Using univariate analysis (p < 0.05), 41 metabolites were identified as having the most significant differences between these two groups. Lipid metabolites, particularly glycerophospholipids, were the most prevalent class of altered compounds. In addition, metabolites with previously unknown connection to GDM - such as monoacylglycerol, dihydrobiopterin, and 13S-hydroxyoctadecadienoic acid - were identified with strong discriminative power. The main metabolic pathways affected by GDM included glycerophospholipid metabolism, linoleic acid metabolism, and D-arginine and D-ornithine metabolism.

Conclusion: Our data provide a comprehensive overview of metabolite changes at different stages of pregnancy, which offers further insights into the pathogenesis of GDM.
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http://dx.doi.org/10.1016/j.cca.2021.02.023DOI Listing
June 2021

Inflammation and Antiviral Immune Response Associated With Severe Progression of COVID-19.

Front Immunol 2021 18;12:631226. Epub 2021 Feb 18.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Coronavirus disease-2019 (COVID-19) is a novel respiratory disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It remains poorly understood how the host immune system responds to the infection during disease progression. We applied microarray analysis of the whole genome transcriptome to peripheral blood mononuclear cells (PBMCs) taken from severe and mild COVID-19 patients as well as healthy controls. Functional enrichment analysis of genes associated with COVID-19 severity indicated that disease progression is featured by overactivation of myeloid cells and deficient T cell function. The upregulation of TLR6 and MMP9, which promote the neutrophils-mediated inflammatory response, and the downregulation of SKAP1 and LAG3, which regulate T cells function, were associated with disease severity. Importantly, the regulation of these four genes was absent in patients with influenza A (H1N1). And compared with stimulation with hemagglutinin (HA) of H1N1 virus, the regulation pattern of these genes was unique in PBMCs response to Spike protein of SARS-CoV-2 . Our data also suggested that severe SARS-CoV-2 infection largely silenced the response of type I interferons (IFNs) and altered the proportion of immune cells, providing a potential mechanism for the hypercytokinemia. This study indicates that SARS-CoV-2 infection impairs inflammatory and immune signatures in patients, especially those at severe stage. The potential mechanisms underpinning severe COVID-19 progression include overactive myeloid cells, impaired function of T cells, and inadequate induction of type I IFNs signaling.
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http://dx.doi.org/10.3389/fimmu.2021.631226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930228PMC
March 2021

Thyroid Function Abnormalities in COVID-19 Patients.

Front Endocrinol (Lausanne) 2020 19;11:623792. Epub 2021 Feb 19.

Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Purpose: The novel coronavirus COVID-19, has caused a worldwide pandemic, impairing several human organs and systems. Whether COVID-19 affects human thyroid function remains unknown.

Methods: Eighty-four hospitalized COVID-19 patients in the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China) were retrospectively enrolled in this study, among which 22 cases had complete records of thyroid hormones. In addition, 91 other patients with pneumonia and 807 healthy subjects were included as controls.

Results: We found that levels of total triiodothyronine (TT3) and thyroid stimulating hormone (TSH) were lower in COVID-19 patients than healthy group (p < 0.001). Besides, TSH level in COVID-19 patients was obviously lower than non-COVID-19 patients (p < 0.001). Within the group of COVID-19, 61.9% (52/84) patients presented with thyroid function abnormalities and the proportion of thyroid dysfunction was higher in severe cases than mild/moderate cases (74.6 vs. 23.8%, p < 0.001). Patients with thyroid dysfunction tended to have longer viral nucleic acid cleaning time (14.1 ± 9.4 vs. 10.6 ± 8.3 days, p = 0.088). To note, thyroid dysfunction was also associated with decreased lymphocytes (p < 0.001) and increased CRP (p = 0.002). The correlation between TT3 and TSH level seemed to be positive rather than negative in the early stage, and gradually turned to be negatively related over time.

Conclusion: Thyroid function abnormalities are common in COVID-19 patients, especially in severe cases. This might be partially explained by nonthyroidal illness syndrome.
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http://dx.doi.org/10.3389/fendo.2020.623792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933556PMC
March 2021

The miRNA: a small but powerful RNA for COVID-19.

Brief Bioinform 2021 03;22(2):1137-1149

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, the First Affiliated Hospital, Zhejiang University School of Medicine, China.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a severe and rapidly evolving epidemic. Now, although a few drugs and vaccines have been proved for its treatment and prevention, little systematic comments are made to explain its susceptibility to humans. A few scattered studies used bioinformatics methods to explore the role of microRNA (miRNA) in COVID-19 infection. Combining these timely reports and previous studies about virus and miRNA, we comb through the available clues and seemingly make the perspective reasonable that the COVID-19 cleverly exploits the interplay between the small miRNA and other biomolecules to avoid being effectively recognized and attacked from host immune protection as well to deactivate functional genes that are crucial for immune system. In detail, SARS-CoV-2 can be regarded as a sponge to adsorb host immune-related miRNA, which forces host fall into dysfunction status of immune system. Besides, SARS-CoV-2 encodes its own miRNAs, which can enter host cell and are not perceived by the host's immune system, subsequently targeting host function genes to cause illnesses. Therefore, this article presents a reasonable viewpoint that the miRNA-based interplays between the host and SARS-CoV-2 may be the primary cause that SARS-CoV-2 accesses and attacks the host cells.
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http://dx.doi.org/10.1093/bib/bbab062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989616PMC
March 2021

Molecular modeling evaluation of the binding effect of five protease inhibitors to COVID-19 main protease.

Chem Phys 2021 Feb 11;542:111080. Epub 2020 Dec 11.

Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.

Coronavirus disease 2019 (COVID-19) has caused more than 840,000 deaths as of 31 August 2020 in the whole world. The COVID-19 main protease (M) has been validated as an attractive target for drug design. In this work, the binding mechanisms of five protease inhibitors (e.g., danoprevir, darunavir, ASC09, lopinavir and ritonavir) to COVID-19 M were investigated. Based on the docking score, five protease inhibitors structures were selected for further evaluation. It is found that most of the selected drug molecules bind stably to the COVID-19 M from the molecular dynamics simulation. Moreover, the MM/PBSA free energy calculations suggest that lopinavir with positive charge might be most active against COVID-19 M.
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http://dx.doi.org/10.1016/j.chemphys.2020.111080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834164PMC
February 2021

Clinical efficacy of methylprednisolone and the combined use of lopinavir/ritonavir with arbidol in treatment of coronavirus disease 2019.

J Med Virol 2021 07 23;93(7):4446-4453. Epub 2021 Apr 23.

Department of Infectious Disease, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

This study aims to comparatively analyze the therapeutic efficacy upon multiple medication plans over lopinavir/ritonavir (LPV/r), arbidol (ARB), and methylprednisolone on patients with coronavirus disease 2019 (COVID-19). Totally, 75 COVID-19 patients admitted to The First Affiliated Hospital, Zhejiang University School of Medicine from January 22, 2020 to February 29, 2020 were recruited and grouped based on whether or not LPV/r and ARB were jointly used and whether or not methylprednisolone was used. Indexes including body temperature, time for nucleic acid negative conversion, hospital stays, and laboratory indexes were examined and compared. For all patients, there were no significant differences in the change of body temperature, the time for negative conversion, and hospital stays whether LPV/r and ARB were jointly used or not. While for severe and critically severe patients, methylprednisolone noticeably reduced the time for negative conversion. Meanwhile, the clinical efficacy was superior on patients receiving methylprednisolone within 3 days upon admission, and the duration of hospital stays was much shorter when methylprednisolone was given at a total dose of 0-400 mg than a higher dose of >400 mg if all patients received a similar dose per day. Nonetheless, no significant changes across hepatic, renal, and myocardial function indexes were observed. LPV/r combined with ARB produced no noticeably better effect on COVID-19 patients relative to the single-agent treatment. Additionally, methylprednisolone was efficient in severe and critically severe cases, and superior efficacy could be realized upon its early, appropriate, and short-term application.
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http://dx.doi.org/10.1002/jmv.26798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013375PMC
July 2021

The Artificial-Liver Blood-Purification System Can Effectively Improve Hypercytokinemia for COVID-19.

Front Immunol 2020 23;11:586073. Epub 2020 Dec 23.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Since the December 2019 outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, the infection has spread locally and globally resulting in a pandemic. As the numbers of confirmed diagnoses and deaths continue to rise, COVID-19 has become the focus of international public health. COVID-19 is highly contagious, and there is no effective treatment yet. New treatment strategies are urgently needed to improve the treatment success rate of severe and critically ill patients. Increasing evidence has shown that a cytokine storm plays an important role in the progression of COVID-19. The artificial-liver blood-purification system (ALS) is expected to improve the outcome of the cytokine storm. In the present study, the levels of cytokines were detected in 12 COVID-19 patients pre- and post-ALS with promising results. The present study shows promising evidence that ALS can block the cytokine storm, rapidly remove the inflammatory mediators, and hopefully, suppress the progression of the disease, thereby providing a new strategy for the clinical treatment of COVID-19.
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http://dx.doi.org/10.3389/fimmu.2020.586073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786016PMC
January 2021

Accuracy of circulating microRNAs in diagnosis of sepsis: a systematic review and meta-analysis.

J Intensive Care 2020 Nov 2;8(1):84. Epub 2020 Nov 2.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Objectives: The aim of this study was to systematically assess the accuracy of circulating microRNAs (miRNAs) as a promising biomarker for sepsis via a meta-analysis.

Methods: PubMed, Cochrane Library, Embase, Web of Science, Scopus, and Ovid databases were searched up to April 3, 2020. The Quality in Prognostic Studies (QUADAS-2) tool was used to assess methodological quality. The pooled sensitivity (Sen), specificity (Spe), positive or negative likelihood ratios (PLR or NLR), diagnostic odds ratio (DOR), curve, and area under the curve (AUC) were calculated with 95% confidence interval (95% CI). The overall accuracy (OA) of miRNAs, procalcitonin (PCT), and C-reactive protein (CRP) was analyzed by the chi-square test.

Results: A total of 22 records were eligible for systematic review, including 2210 sepsis, 426 systemic inflammatory response syndrome (SIRS), and 1076 healthy controls (HC). The pooled Sen, Spe, and DOR of miRNAs were 0.80 (95% CI 0.75-0.83), 0.85 (95% CI 0.80-0.89), and 22 (15-32), respectively. The DOR of PCT and CRP were 17 (95% CI 4-68) and 7 (95% CI 1-48), respectively. The OA value of miRNAs (79.02%) and PCT (76.95%) were higher than CRP (61.22%) (P < 0.000). The subgroup analysis indicated that miRNAs in adults, serum type, downregulation of miRNA expression, criteria of Sepsis-3, internal reference of non-U6, and dysregulation expression of miR-223 had superior diagnostic accuracy. In addition, there was no significant publication bias among the included studies. Fagan's nomogram showed valuable clinical utility.

Conclusions: Our meta-analysis indicated that the level of circulating miRNAs, particularly the miR-223, could be used as an indicator for sepsis.
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http://dx.doi.org/10.1186/s40560-020-00497-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607638PMC
November 2020

Inhibiting RRM2 to enhance the anticancer activity of chemotherapy.

Biomed Pharmacother 2021 Jan 20;133:110996. Epub 2020 Nov 20.

State Key Laboratory for Diagnosis and Treatment of Infectious Disease, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China. Electronic address:

RRM2, the small subunit of ribonucleotide reductase, is identified as a tumor promotor and therapeutic target. It is common to see the overexpression of RRM2 in chemo-resistant cancer cells and patients. RRM2 mediates the resistance of many chemotherapeutic drugs and could become the predictor for chemosensitivity and prognosis. Therefore, inhibition of RRM2 may be an effective means to enhance the anticancer activity of chemotherapy. This review tries to discuss the mechanisms of RRM2 overexpression and the role of RRM2 in resistance to chemotherapy. Additionally, we compile the studies on small interfering RNA targets RRM2, RRM2 inhibitors, kinase inhibitors, and other ways that could overcome the resistance of chemotherapy or exert synergistic anticancer activity with chemotherapy through the expression inhibition or the enzyme inactivation of RRM2.
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http://dx.doi.org/10.1016/j.biopha.2020.110996DOI Listing
January 2021

Immune Checkpoint Inhibitors and Survival Outcomes in Brain Metastasis: A Time Series-Based Meta-Analysis.

Front Oncol 2020 20;10:564382. Epub 2020 Oct 20.

Research Center of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Immune checkpoint inhibitors (ICIs) have shown potential to improve the prognosis of patients with brain metastasis (BM) caused by advanced cancers. However, controversies still exist in regard to its survival benefits. In the present work, a time series-based meta-analysis based on the phase I/II/III trials and observational studies were performed to investigate the differences in mortality of ICI-treated BM patients. A number of public library databases, including MEDLINE, EMBASE, OVID, and COCHRANE, were systemically searched by March 2019. The quality of included studies was evaluated by the Newcastle-Ottawa Scale (NOS) scoring. Outcome measures here established were mortality and progression-free survival (PFS) at different follow-up endpoints. Survival rates and curve data were pooled for further analysis. To detect the data heterogeneity, subgroup analyses were conducted according to tumor and ICI types. Eighteen studies, 6 trials, and 12 controlled cohorts were assessed, involving a total of 1330 ICI-treated BM patients. The 6-month survival rate and PFS were 0.67 (95%CI: 0.59-0.74) and 0.36 (95%CI: 0.24-0.49), respectively. According to the tumor type (melanoma, NSCLC, and RCC), subgroup analyses indicated that melanoma presented the lowest survival rates among the three groups here selected. In regard to the type of ICIs, the anti-CTLA-4 combined with the anti-PD-1/PD-L1 showed the best survival outcome among these groups. The 12-month survival rate and PFS showed a consistent pattern of findings. In the long-term, the 24-month survival rate and PFS were 0.20 (95%CI: 0.12-0.31) and 0.18 (0.05-0.46) in BM patients. Hence, ICI therapy may be associated with an improved prognosis of BM patients. Nevertheless, current research presented a limited study design. Multicenter randomized trials may later assist in validating ICI-based therapies for a better outcome of BM patients.
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http://dx.doi.org/10.3389/fonc.2020.564382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606910PMC
October 2020

Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial.

Eur J Pharm Sci 2021 Feb 25;157:105631. Epub 2020 Oct 25.

State Key Laboratory for diagnosis and treatment of infectious diseases, Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address:

Background: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients.

Methods: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544).

Results: Baloxavir acid showed antiviral activity in vitro with the half-maximal effective concentration (EC) of 5.48 μM comparable to arbidol and lopinavir, but favipiravir didn't demonstrate significant antiviral activity up to 100 μM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir marboxil, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. One of the limitations of this study is the time from symptom onset to randomization, especially in the baloxavir marboxil and control groups, which is higher than the favipiravir group.

Conclusions: Our findings could not prove a benefit of addition of either baloxavir marboxil or favipiravir under the trial dosages to the existing standard treatment.
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http://dx.doi.org/10.1016/j.ejps.2020.105631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585719PMC
February 2021

[Construction of data remote monitoring and auditing system for clinical trials].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2020 Aug;49(4):531-536

Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.

Clinical trial management system is independently developed by our hospital, which basically realized the whole process management and data collection of clinical trials. Based on the platform, the functional architecture of data remote monitoring and auditing was established. By desensitizing and encrypting of data, the project and subject hologram were visualized to facilitate to review of data. The data remote monitoring and auditing cloud platform adopts the B/S architecture pattern. Users register to apply for an account through the cloud platform, and access to the account via HTTPS security protocol. The authorized users were able to view the relevant items online to ensure the secure data transmission and easy operating. The electronic management of data is the direction of future efforts. By compliance with laws and regulations, the remote monitoring/auditing can be realized, and the data security and personal privacy can be ensured with the application of information technology. In this paper, the feasibility of remote monitoring/auditing mode is explored, specific technical schemes and system functions are suggested, and the realization scenarios are conceived in case of major public health emergencies.
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http://dx.doi.org/10.3785/j.issn.1008-9292.2020.07.01DOI Listing
August 2020

In Vitro Antimicrobial Activity of Fosfomycin, Vancomycin and Daptomycin Alone, and in Combination, Against Linezolid-Resistant Enterococcus faecalis.

Infect Dis Ther 2020 Dec 22;9(4):927-934. Epub 2020 Sep 22.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Introduction: Enterococcus faecalis is a significant cause of nosocomial infections and is difficult to treat because of intrinsic and acquired resistance to many antibiotics. In addition, the emergence of linezolid-resistant E. faecalis (LZR-Efa) is reducing the choices available for anti-infective therapy. The aim of this study was to examine the in vitro antibacterial effects of fosfomycin (FM), vancomycin (VAN) and daptomycin (DAP), alone and in combination, against LZR-Efa.

Methods: Five LZR-Efa strains and E. faecalis ATCC 29212 were studied. The antibacterial effects of FM, and of FM, VAN and DAP, were assessed using the time-kill assay. Biofilm formation and elimination were evaluated by crystal violet staining.

Results: When used at concentrations greater than 0.5 × MIC, FM did not produce dose-dependent effects against LZR-Efa isolates. The use of DAP (47.1 mg/L) alone, and FM (83 mg/L) combined with DAP (20.6 mg/L), produced a persistent inhibitory effect against both planktonic LZR-Efa isolates and those forming biofilms. In addition, FM and VAN combined with glucose-6-phosphate produced visible eradication effects against biofilms grown for 24 h, while DAP alone or combined with FM resulted in the best eradication activity against biofilms grown for 72 h prior to exposure.

Conclusion: The use of FM combined with DAP provided the best potential therapeutic option for treating LZR-Efa infections out of those tested. In addition, the optimum treatment for biofilm elimination depended on the stage of biofilm formation.
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http://dx.doi.org/10.1007/s40121-020-00342-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680468PMC
December 2020

A Deep Learning System to Screen Novel Coronavirus Disease 2019 Pneumonia.

Engineering (Beijing) 2020 Oct 27;6(10):1122-1129. Epub 2020 Jun 27.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.

The real-time reverse transcription-polymerase chain reaction (RT-PCR) detection of viral RNA from sputum or nasopharyngeal swab had a relatively low positive rate in the early stage of coronavirus disease 2019 (COVID-19). Meanwhile, the manifestations of COVID-19 as seen through computed tomography (CT) imaging show individual characteristics that differ from those of other types of viral pneumonia such as influenza-A viral pneumonia (IAVP). This study aimed to establish an early screening model to distinguish COVID-19 from IAVP and healthy cases through pulmonary CT images using deep learning techniques. A total of 618 CT samples were collected: 219 samples from 110 patients with COVID-19 (mean age 50 years; 63 (57.3%) male patients); 224 samples from 224 patients with IAVP (mean age 61 years; 156 (69.6%) male patients); and 175 samples from 175 healthy cases (mean age 39 years; 97 (55.4%) male patients). All CT samples were contributed from three COVID-19-designated hospitals in Zhejiang Province, China. First, the candidate infection regions were segmented out from the pulmonary CT image set using a 3D deep learning model. These separated images were then categorized into the COVID-19, IAVP, and irrelevant to infection (ITI) groups, together with the corresponding confidence scores, using a location-attention classification model. Finally, the infection type and overall confidence score for each CT case were calculated using the Noisy-OR Bayesian function. The experimental result of the benchmark dataset showed that the overall accuracy rate was 86.7% in terms of all the CT cases taken together. The deep learning models established in this study were effective for the early screening of COVID-19 patients and were demonstrated to be a promising supplementary diagnostic method for frontline clinical doctors.
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http://dx.doi.org/10.1016/j.eng.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320702PMC
October 2020

Computational advances of tumor marker selection and sample classification in cancer proteomics.

Comput Struct Biotechnol J 2020 17;18:2012-2025. Epub 2020 Jul 17.

Department of Bioinformatics, Chongqing Medical University, Chongqing 400016, China.

Cancer proteomics has become a powerful technique for characterizing the protein markers driving transformation of malignancy, tracing proteome variation triggered by therapeutics, and discovering the novel targets and drugs for the treatment of oncologic diseases. To facilitate cancer diagnosis/prognosis and accelerate drug target discovery, a variety of methods for tumor marker identification and sample classification have been developed and successfully applied to cancer proteomic studies. This review article describes the most recent advances in those various approaches together with their current applications in cancer-related studies. Firstly, a number of popular feature selection methods are overviewed with objective evaluation on their advantages and disadvantages. Secondly, these methods are grouped into three major classes based on their underlying algorithms. Finally, a variety of sample separation algorithms are discussed. This review provides a comprehensive overview of the advances on tumor maker identification and patients/samples/tissues separations, which could be guidance to the researches in cancer proteomics.
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http://dx.doi.org/10.1016/j.csbj.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403885PMC
July 2020

Identification of osalmid metabolic profile and active metabolites with anti-tumor activity in human hepatocellular carcinoma cells.

Biomed Pharmacother 2020 Oct 4;130:110556. Epub 2020 Aug 4.

State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang 310000, People's Republic of China. Electronic address:

Backgrounds: Ribonucleotide reductase (RR) catalyzes the essential step in the formation of all four deoxynucleotides. Upregulated activity of RR plays an active role in tumor progression. As the regulatory subunit of RR, ribonucleotide reductase subunit M2 (RRM2) is regarded as one of the effective therapeutic targets for DNA replication-dependent diseases, such as cancers. Recent studies have revealed that osalmid significantly inhibits the activity of RRM2, but the metabolic profile of osalmid remains unknown.

Objective: The aim of this study was to clarify the metabolic profile including metabolites, isoenzymes and metabolic pathways of osalmid. The anti-human hepatocellular carcinoma activity and mechanism of metabolites were further investigated.

Materials And Methods: Ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) was used for identifying metabolites and for characterizing phase I and phase II metabolic pathways with recombinant enzymes or in human liver microsomes of osalmid. The eHiTS docking system was used for potential RRM2 inhibitor screening among metabolites. Cytotoxicity assays were performed for evaluating cell proliferation inhibitory activity of metabolites. Cell cycle assays and cell apoptosis assays were assessed by flow cytometry. Western blotting analysis of RRM2, cyclin D1, p21, p53, phosphorylated p53, Bcl-2 and Bax was performed to explore the anti-hepatocellular carcinoma mechanism of the active metabolites.

Results: Ten metabolites of osalmid were identified, and none of them have been reported previously. Hydroxylation, glucuronidation, sulfonation, acetylation and degradation were recognized as the main metabolic processes of osalmid. Isozymes of CYP1A2, CYP2C9, UGT1A1, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 were involved in phase I and phase II metabolism of osalmid. Metabolites M7, M8 and M10 showed higher binding affinities with the RRM2 active site than osalmid. Metabolite M7 exhibited potent inhibitory activity to hepatocellular carcinoma cell lines by both competitive inhibition and down-regulation of RRM2. Moreover, M7 significantly induced cell cycle arrest and apoptosis by activating p53-related pathways.

Conclusions: The metabolic profile of osalmid was identified. M7 significantly inhibited human hepatocellular carcinoma progression by inhibiting RRM2 activity. Furthermore, M7 induced cell cycle arrest and apoptosis by activating p53-related signaling pathways.
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http://dx.doi.org/10.1016/j.biopha.2020.110556DOI Listing
October 2020

Liver Injury in Critically Ill and Non-critically Ill COVID-19 Patients: A Multicenter, Retrospective, Observational Study.

Front Med (Lausanne) 2020 23;7:347. Epub 2020 Jun 23.

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Liver injury commonly occurs in patients with COVID-19. There is limited data describing the course of liver injury occurrence in patients with different disease severity, and the causes and risk factors are unknown. We aim to investigate the incidence, characteristics, risk factors, and clinical outcomes of liver injury in patients with COVID-19. This retrospective observational study was conducted in three hospitals (Zhejiang, China). From January 19, 2020 to February 20, 2020, patients confirmed with COVID-19 (≥18 years) and without liver injury were enrolled and divided into non-critically ill and critically ill groups. The incidence and characteristics of liver injury were compared between the two groups. Demographics, clinical characteristics, treatments, and treatment outcomes between patients with or without liver injury were compared within each group. The multivariable logistic regression model was used to explore the risk factors for liver injury. The mean age of 131 enrolled patients was 51.2 years (standard deviation : 16.1 years), and 70 (53.4%) patients were male. A total of 76 patients developed liver injury (mild, 40.5%; moderate, 15.3%; severe, 2.3%) with a median occurrence time of 10.0 days. Critically ill patients had higher and earlier occurrence (81.5 vs. 51.9%, 12.0 vs. 5.0 days; < 0.001), greater injury severity ( < 0.001), and slower recovery (50.0 vs. 61.1%) of liver function than non-critically ill patients. Multivariable regression showed that the number of concomitant medications (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.05-1.21) and the combination treatment of lopinavir/ritonavir and arbidol (OR: 3.58, 95% CI: 1.44-9.52) were risk factors for liver injury in non-critically ill patients. The metabolism of arbidol can be significantly inhibited by lopinavir/ritonavir ( < 0.005), which may be the underlying cause of drug-related liver injury. Liver injury was related to increased length of hospital stay (mean difference [MD]: 3.2, 95% CI: 1.3-5.2) and viral shedding duration (MD: 3.0, 95% CI: 1.0-4.9). Critically ill patients with COVID-19 suffered earlier occurrence, greater injury severity, and slower recovery from liver injury than non-critically ill patients. Drug factors were related to liver injury in non-critically ill patients. Liver injury was related to prolonged hospital stay and viral shedding duration in patients with COVID-19. World Health Organization International Clinical Trials Registry Platform, ChiCTR2000030593. Registered March 8, 2020.
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http://dx.doi.org/10.3389/fmed.2020.00347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324794PMC
June 2020

Critically ill patients with COVID-19 with ECMO and artificial liver plasma exchange: A retrospective study.

Medicine (Baltimore) 2020 Jun;99(26):e21012

Department of Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

COVID-19 is an emerging infectious disease capable of causing severe pneumonia. We aimed to characterize a group of critically ill patients in a single-center study.This was a retrospective case series of 23 patients with confirmed COVID-19-related critical illness in the intensive care unit (ICU) of a hospital in Hangzhou Zhejiang Province between January 22 and March 20, 2020.Of the 23 critically ill patients, the median age was 66 years (interquartile range [IQR] 59-80 years). The median time from disease onset to ICU admission was 10 days (IQR 6-11 days), to mechanical ventilation (MV) was 11 days (IQR 7.75-13 days), to artificial liver plasma exchange was 12 days (IQR 9.75-14.75 days), and to extracorporeal membrane oxygenation (ECMO) was 22 days (IQR 17.5-30 days). Nine patients required high flow oxygen. Fourteen patients received MV. Six required ECMO. Nine received artificial liver plasma exchange. Mortality was 0 at day 28.Mortality was 0 at day 28 in our single-center study. Extracorporeal membrane oxygenation reduced the requirements for ventilator support. Artificial liver plasma exchange significantly reduced inflammatory cytokine levels. These supportive therapies helped to extend the patients' survival times and increase the chance of follow-up treatments.
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http://dx.doi.org/10.1097/MD.0000000000021012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328989PMC
June 2020

Virus strain from a mild COVID-19 patient in Hangzhou represents a new trend in SARS-CoV-2 evolution potentially related to Furin cleavage site.

Emerg Microbes Infect 2020 Dec;9(1):1474-1488

Department of Neurosurgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.

The mutations in the SARS-CoV-2 virus genome during COVID-19 dissemination are unclear. In 788 COVID-19 patients from Zhejiang province, we observed decreased rate of severe/critical cases compared with patients in Wuhan. For mechanisms exploration, we isolated one strain of SARS-CoV-2 (ZJ01) from a mild COVID-19 patient. Thirty-five specific gene mutations were identified. Phylogenetic and relative synonymous codon usage analysis suggested that ZJ01 may be a potential evolutionary branch of SARS-CoV-2. We classified 54 global virus strains based on the base (C or T) at positions 8824 and 28247 while ZJ01 has T at both sites. The prediction of the Furin cleavage site (FCS) and sequence alignment indicated that the FCS may be an important site of coronavirus evolution. ZJ01 mutations identified near the FCS (F1-2) caused changes in the structure and electrostatic distribution of the S surface protein, further affecting the binding capacity of Furin. Single-cell sequencing and ACE2-Furin co-expression results confirmed that the Furin expression was especially higher in glands, liver, kidneys, and colon. The evolutionary pattern of SARS-CoV-2 towards FCS formation may result in its clinical symptom becoming closer to HKU-1 and OC43 caused mild flu-like symptoms, further showing its potential in differentiating into mild COVID-19 subtypes.
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http://dx.doi.org/10.1080/22221751.2020.1781551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473176PMC
December 2020

A COVID-19 Risk Assessment Decision Support System for General Practitioners: Design and Development Study.

J Med Internet Res 2020 06 29;22(6):e19786. Epub 2020 Jun 29.

Engineering Research Center of EMR and Intelligent Expert System, Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China.

Background: The coronavirus disease (COVID-19) has become an urgent and serious global public health crisis. Community engagement is the first line of defense in the fight against infectious diseases, and general practitioners (GPs) play an important role in it. GPs are facing unique challenges from disasters and pandemics in delivering health care. However, there is still no suitable mobile management system that can help GPs collect data, dynamically assess risks, and effectively triage or follow-up with patients with COVID-19.

Objective: The aim of this study is to design, develop, and deploy a mobile-based decision support system for COVID-19 (DDC19) to assist GPs in collecting data, assessing risk, triaging, managing, and following up with patients during the COVID-19 outbreak.

Methods: Based on the actual scenarios and the process of patients using health care, we analyzed the key issues that need to be solved and designed the main business flowchart of DDC19. We then constructed a COVID-19 dynamic risk stratification model with high recall and clinical interpretability, which was based on a multiclass logistic regression algorithm. Finally, through a 10-fold cross-validation to quantitatively evaluate the risk stratification ability of the model, a total of 2243 clinical data consisting of 36 dimension clinical features from fever clinics were used for training and evaluation of the model.

Results: DDC19 is composed of three parts: mobile terminal apps for the patient-end and GP-end, and the database system. All mobile terminal devices were wirelessly connected to the back end data center to implement request sending and data transmission. We used low risk, moderate risk, and high risk as labels, and adopted a 10-fold cross-validation method to evaluate and test the COVID-19 dynamic risk stratification model in different scenarios (different dimensions of personal clinical data accessible at an earlier stage). The data set dimensions were (2243, 15) when only using the data of patients' demographic information, clinical symptoms, and contact history; (2243, 35) when the results of blood tests were added; and (2243, 36) after obtaining the computed tomography imaging results of the patient. The average value of the three classification results of the macro-area under the curve were all above 0.71 in each scenario.

Conclusions: DCC19 is a mobile decision support system designed and developed to assist GPs in providing dynamic risk assessments for patients with suspected COVID-19 during the outbreak, and the model had a good ability to predict risk levels in any scenario it covered.
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http://dx.doi.org/10.2196/19786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332157PMC
June 2020

Decreased B Cells on Admission Associated With Prolonged Viral RNA Shedding From the Respiratory Tract in Coronavirus Disease 2019: A Case-Control Study.

J Infect Dis 2020 07;222(3):367-371

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.

The viral RNA shedding time (VST) for severe acute respiratory syndrome coronavirus 2 has not been well characterized. Clinical data were collected and compared between patients with short and long VSTs (in the lower and upper quartiles, respectively). The probability of recurrent positive reverse-transcription polymerase chain reaction results decreased sharply to 4.8% after 3 consecutive negative results. A series of ≥3 consecutive negative results was suitable as a criterion for the end of viral RNA shedding. The VST for shedding from the respiratory tract was significantly shorter in patients with normal B-cell counts on admission than in those with decreased B-cell counts (median [interquartile range], 11 [9-13] vs 16 [12-20] days, respectively; P = .001).
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http://dx.doi.org/10.1093/infdis/jiaa311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542891PMC
July 2020

[Pharmaceutical care for severe and critically ill patients with COVID-19].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2020 May;49(2):158-169

The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.

Severe and critically ill patients with coronavirus disease 2019 (COVID-19) were usually with underlying diseases, which led to the problems of complicated drug use, potential drug-drug interactions and medication errors in special patients. Based on ( 6), and -19: , we summarized the experience in the use of antiviral drugs, corticosteroids, vascular active drugs, antibacterial, probiotics, nutrition support schemes in severe and critically ill COVID-19 patients. It is also suggested to focus on medication management for evaluation of drug efficacy and duration of treatment, prevention and treatment of adverse drug reactions, identification of potential drug-drug interactions, individualized medication monitoring based on biosafety protection, and medication administration for special patients.
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http://dx.doi.org/10.3785/j.issn.1008-9292.2020.03.01DOI Listing
May 2020

[Management of COVID-19: the Zhejiang experience].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2020 May;49(2):147-157

The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.

The current epidemic situation of coronavirus disease 2019 (COVID-19) still remained severe. As the National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital of Zhejiang University School of Medicine is the primary medical care center for COVID-19 in Zhejiang province. Based on the present expert consensus carried out by National Health Commission and National Administration of Traditional Chinese Medicine, our team summarized and established an effective treatment strategy centered on "Four-Anti and Two-Balance" for clinical practice. The "Four-Anti and Two-Balance" strategy included antivirus, anti-shock, anti-hyoxemia, anti-secondary infection, and maintaining of water, electrolyte and acid base balance and microecological balance. Meanwhile, integrated multidisciplinary personalized treatment was recommended to improve therapeutic effect. The importance of early viralogical detection, dynamic monitoring of inflammatory indexes and chest radiograph was emphasized in clinical decision-making. Sputum was observed with the highest positive rate of RT-PCR results. Viral nucleic acids could be detected in 10%patients' blood samples at acute period and 50%of patients had positive RT-PCR results in their feces. We also isolated alive viral strains from feces, indicating potential infectiousness of feces.Dynamic cytokine detection was necessary to timely identifying cytokine storms and application of artificial liver blood purification system. The "Four-Anti and Two-Balance" strategy effectively increased cure rate and reduced mortality. Early antiviral treatment could alleviate disease severity and prevent illness progression, and we found lopinavir/ritonavir combined with abidol showed antiviral effects in COVID-19. Shock and hypoxemia were usually caused by cytokine storms. The artificial liver blood purification system could rapidly remove inflammatory mediators and block cytokine storm.Moreover, it also favored the balance of fluid, electrolyte and acid-base and thus improved treatment efficacy in critical illness. For cases of severe illness, early and also short period of moderate glucocorticoid was supported. Patients with oxygenation index below 200 mmHg should be transferred to intensive medical center. Conservative oxygen therapy was preferred and noninvasive ventilation was not recommended. Patients with mechanical ventilation should be strictly supervised with cluster ventilator-associated pneumonia prevention strategies. Antimicrobial prophylaxis was not recommended except for patients with long course of disease, repeated fever and elevated procalcitonin (PCT), meanwhile secondary fungal infection should be concerned.Some patients with COVID-19 showed intestinal microbial dysbiosis with decreased probiotics such as and , so nutritional and gastrointestinal function should be assessed for all patients.Nutritional support and application of prebiotics or probiotics were suggested to regulate the balance of intestinal microbiota and reduce the risk of secondary infection due to bacterial translocation. Anxiety and fear were common in patients with COVID-19. Therefore,we established dynamic assessment and warning for psychological crisis. We also integrated Chinese medicine in treatment to promote disease rehabilitation through classification methods of traditional Chinese medicine. We optimized nursing process for severe patients to promote their rehabilitation. It remained unclear about viral clearance pattern after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Therefore, two weeks' quarantine for discharged patients was required and a regular following up was also needed.The Zhejiang experience and suggestions have been implemented in our center and achieved good results. However, since COVID-19 was a newly emerging disease, more work was warranted to improve strategies of prevention, diagnosis and treatment for COVID-19.
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http://dx.doi.org/10.3785/j.issn.1008-9292.2020.02.02DOI Listing
May 2020

NOREVA: enhanced normalization and evaluation of time-course and multi-class metabolomic data.

Nucleic Acids Res 2020 07;48(W1):W436-W448

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Biological processes (like microbial growth & physiological response) are usually dynamic and require the monitoring of metabolic variation at different time-points. Moreover, there is clear shift from case-control (N=2) study to multi-class (N>2) problem in current metabolomics, which is crucial for revealing the mechanisms underlying certain physiological process, disease metastasis, etc. These time-course and multi-class metabolomics have attracted great attention, and data normalization is essential for removing unwanted biological/experimental variations in these studies. However, no tool (including NOREVA 1.0 focusing only on case-control studies) is available for effectively assessing the performance of normalization method on time-course/multi-class metabolomic data. Thus, NOREVA was updated to version 2.0 by (i) realizing normalization and evaluation of both time-course and multi-class metabolomic data, (ii) integrating 144 normalization methods of a recently proposed combination strategy and (iii) identifying the well-performing methods by comprehensively assessing the largest set of normalizations (168 in total, significantly larger than those 24 in NOREVA 1.0). The significance of this update was extensively validated by case studies on benchmark datasets. All in all, NOREVA 2.0 is distinguished for its capability in identifying well-performing normalization method(s) for time-course and multi-class metabolomics, which makes it an indispensable complement to other available tools. NOREVA can be accessed at https://idrblab.org/noreva/.
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http://dx.doi.org/10.1093/nar/gkaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319444PMC
July 2020

Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study.

BMJ 2020 04 21;369:m1443. Epub 2020 Apr 21.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Objective: To evaluate viral loads at different stages of disease progression in patients infected with the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first four months of the epidemic in Zhejiang province, China.

Design: Retrospective cohort study.

Setting: A designated hospital for patients with covid-19 in Zhejiang province, China.

Participants: 96 consecutively admitted patients with laboratory confirmed SARS-CoV-2 infection: 22 with mild disease and 74 with severe disease. Data were collected from 19 January 2020 to 20 March 2020.

Main Outcome Measures: Ribonucleic acid (RNA) viral load measured in respiratory, stool, serum, and urine samples. Cycle threshold values, a measure of nucleic acid concentration, were plotted onto the standard curve constructed on the basis of the standard product. Epidemiological, clinical, and laboratory characteristics and treatment and outcomes data were obtained through data collection forms from electronic medical records, and the relation between clinical data and disease severity was analysed.

Results: 3497 respiratory, stool, serum, and urine samples were collected from patients after admission and evaluated for SARS-CoV-2 RNA viral load. Infection was confirmed in all patients by testing sputum and saliva samples. RNA was detected in the stool of 55 (59%) patients and in the serum of 39 (41%) patients. The urine sample from one patient was positive for SARS-CoV-2. The median duration of virus in stool (22 days, interquartile range 17-31 days) was significantly longer than in respiratory (18 days, 13-29 days; P=0.02) and serum samples (16 days, 11-21 days; P<0.001). The median duration of virus in the respiratory samples of patients with severe disease (21 days, 14-30 days) was significantly longer than in patients with mild disease (14 days, 10-21 days; P=0.04). In the mild group, the viral loads peaked in respiratory samples in the second week from disease onset, whereas viral load continued to be high during the third week in the severe group. Virus duration was longer in patients older than 60 years and in male patients.

Conclusion: The duration of SARS-CoV-2 is significantly longer in stool samples than in respiratory and serum samples, highlighting the need to strengthen the management of stool samples in the prevention and control of the epidemic, and the virus persists longer with higher load and peaks later in the respiratory tissue of patients with severe disease.
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http://dx.doi.org/10.1136/bmj.m1443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190077PMC
April 2020

The mechanistic, diagnostic and therapeutic novel nucleic acids for hepatocellular carcinoma emerging in past score years.

Brief Bioinform 2021 Mar;22(2):1860-1883

State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital in Zhejiang University, China.

Despite The Central Dogma states the destiny of gene as 'DNA makes RNA and RNA makes protein', the nucleic acids not only store and transmit genetic information but also, surprisingly, join in intracellular vital movement as a regulator of gene expression. Bioinformatics has contributed to knowledge for a series of emerging novel nucleic acids molecules. For typical cases, microRNA (miRNA), long noncoding RNA (lncRNA) and circular RNA (circRNA) exert crucial role in regulating vital biological processes, especially in malignant diseases. Due to extraordinarily heterogeneity among all malignancies, hepatocellular carcinoma (HCC) has emerged enormous limitation in diagnosis and therapy. Mechanistic, diagnostic and therapeutic nucleic acids for HCC emerging in past score years have been systematically reviewed. Particularly, we have organized recent advances on nucleic acids of HCC into three facets: (i) summarizing diverse nucleic acids and their modification (miRNA, lncRNA, circRNA, circulating tumor DNA and DNA methylation) acting as potential biomarkers in HCC diagnosis; (ii) concluding different patterns of three key noncoding RNAs (miRNA, lncRNA and circRNA) in gene regulation and (iii) outlining the progress of these novel nucleic acids for HCC diagnosis and therapy in clinical trials, and discuss their possibility for clinical applications. All in all, this review takes a detailed look at the advances of novel nucleic acids from potential of biomarkers and elaboration of mechanism to early clinical application in past 20 years.
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http://dx.doi.org/10.1093/bib/bbaa023DOI Listing
March 2021

Analysis of Epidemiological and Clinical Features in Older Patients With Coronavirus Disease 2019 (COVID-19) Outside Wuhan.

Clin Infect Dis 2020 07;71(15):740-747

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Background: The outbreak of coronavirus disease 2019 (COVID-19) has become a large threat to public health in China, with high contagious capacity and varied mortality. This study aimed to investigate the epidemiological and clinical characteristics of older patients with COVID-19 outside Wuhan.

Methods: A retrospective study was performed, with collecting data from medical records of confirmed COVID-19 patients in Zhejiang province from 17 January to 12 February 2020. Epidemiological, clinical, and treatment data were analyzed between older (≥ 60 years) and younger (< 60 years) patients.

Results: A total of 788 patients with confirmed COVID-19 were selected; 136 were older patients with corresponding mean age of 68.28 ± 7.31 years. There was a significantly higher frequency of women in older patient group compared with younger patients (57.35% vs 46.47%, P = .021). The presence of coexisting medical conditions was significantly higher in older patients compared with younger patients (55.15% vs 21.93%, P < .001), including the rate of hypertension, diabetes, heart disease, and chronic obstructive pulmonary disease. Significantly higher rates of severe clinical type (older vs younger groups: 16.18% vs 5.98%, P < .001), critical clinical type (8.82% vs 0.77%, P < .001), shortness of breath (12.50% vs 3.07%, P < .001), and temperature of > 39.0°C (13.97% vs 7.21%, P = .010) were observed in older patients compared with younger patients. Finally, higher rates of intensive care unit admission (9.56% vs 1.38%, P < .001) and methylprednisolone application (28.68% vs 9.36%, P < .001) were also identified in older patients compared with younger ones.

Conclusions: The specific epidemiological and clinical features of older COVID-19 patients included significantly higher female sex, body temperature, comorbidities, and rate of severe and critical type disease.
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http://dx.doi.org/10.1093/cid/ciaa242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184356PMC
July 2020

A novel multitarget kinase inhibitor BZG with potent anticancer activity in vitro and vivo enhances efficacy of sorafenib through PI3K pathways in hepatocellular carcinoma cells.

Biomed Pharmacother 2020 May 25;125:110033. Epub 2020 Feb 25.

State Key Laboratory for Diagnosis and Treatment of Infectious Disease, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang, 310000, PR China. Electronic address:

Objectives: BZG as a novel multitarget kinase inhibitor, has been proved to inhibit the proliferation of hepatocellular carcinoma (HCC) previously. In this study, we aimed at investigating the underlying mechanisms of BZG with and without sorafenib and evaluating their anti-tumor effects as well as whether BZG could inhibit the activation of phosphoinositide 3-kinase (PI3K)/AKT signaling which is associated with acquired resistance to sorafenib.

Methods: We evaluated the proliferation of HCC cells by CCK-8 assay and colony formation assay. Cell apoptosis was assessed by Hoechst 33342 staining assay and flow cytometry. Western blot was used to detect the critical enzymes in the PI3K pathways and the expression of p-ERK after BZG alone and combined with sorafenib treatments. Huh-7 hepatocellular carcinoma xenograft model was used to evaluate the anti-carcinoma effects of BZG alone and in combination in vivo. HE staining and TUNEL assay tested the necrosis of tumor tissue and apoptosis of tumor cells.

Results: BZG could inhibit the proliferation of HCC cells in a dose-dependent manner. The combination of BZG and sorafenib produced synergistic effects. PI3K and p-ERK pathway were involved in the anti-tumor functions of BZG alone and when combined with sorafenib. In addition, the combination treatment was seen to be more effective in inhibiting the expression of p-AKT, p-ERK and p-mTOR. Furthermore, Tumor necrosis and cell apoptosis were also observed in Huh-7 hepatocellular carcinoma xenograft models.

Conclusions: BZG is an attractive agent for treating HCC. The effects of BZG and sorafenib's co-treatment on HCC are more effective than BZG or sorafenib alone.
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http://dx.doi.org/10.1016/j.biopha.2020.110033DOI Listing
May 2020