COVID-19 is caused by a novel coronavirus-severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which has being spreading around the world, posing a serious threat to human health and lives. Neutralizing antibodies and small molecule inhibitors for virus replication cycle are the main antiviral treatment for novel coronavirus recommended in China. To further promote the rational use of antiviral therapy in clinical practice, the National Center for Infectious Diseases (Beijing Ditan Hospital Capital Medical University and the First Affiliated Hospital, Zhejiang University School of Medicine) invited experts in fields of infectious diseases, respiratory and intensive care to develop an Expert Consensus on Antiviral Therapy of COVID-19 based on the Diagnosis and Treatment Guideline for COVID-19 ( trial version 10) and experiences in the diagnosis and treatment of COVID-19 in China. The consensus is concise, practical and highly operable, hopefully it would improve the understanding of antiviral therapy for clinicians and provide suggestions for standardized medication in treatment of COVID-19.

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34⁺ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34⁺ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.
Acrylamides/pharmacology* ; Animals ; Blood Platelets/drug effects* ; Cell Differentiation ; Megakaryocytes/drug effects* ; Mice ; Mice, Inbred C57BL ; Piperazines/pharmacology* ; Pyrimidines/pharmacology*

Objective:To discuss the essentials of anesthesia management and treatment strategies for emergency transcatheter aortic valve replacement (TAVR), and to provide standardized recommendations for the development of emergency TAVR technology in China.Methods:This study retrospectively analyzed the relevant data of patients undergoing emergency TAVR surgery in the Second Affiliated Hospital of Zhejiang University School of Medicine from March 2019 to February 2021, including baseline patient characteristics, perioperative echocardiography data, prognosis and 30-day follow-up. Post-operative data were compared with pre-operative data using paired-sample test.Results:Thirteen patients, aged (75.62±9.63) years, underwent emergency TAVR surgery, and 6 of them were male. Eleven patients were New York Heart Association class Ⅳ. The preoperative Society of Thoracic Surgeons score was (20.31±15.15)%. The trans-aortic valve differential pressure was significantly reduced after surgery [(68.92±30.66)mmHg vs. (2.70±2.36)mmHg, P<0.01]. Two patients died within 30 days after surgery, one patient developed a new third degree atrioventricular block, one patient had a stroke, and 4 patients developed pulmonary infection. Conclusions:Emergency TAVR surgery is a feasible and effective rescue strategy for patients with aortic stenosis in critical condition. The establishment of anesthesia standard operation procedure process for TAVR surgery helps ensure homogenized medical behavior and good teamwork.

Objective:To compare the efficacy of the combination of abidol, lopinavir/ritonavir plus recombinant interferon α-2b (rIFNα-2b) and the combination of lopinavir/ritonavir plus rIFNα-2b for patients with COVID-19 in Zhejiang province.Methods:A multicenter prospective study was carried out to compare the efficacy of triple combination antiviral therapy and dual combination antiviral therapy in 15 medical institutions of Zhejiang province during January 22 to February 16, 2020. All patients were treated with rIFNα-2b (5 million U, 2 times/d) aerosol inhalation, in addition 196 patients were treated with abidol (200 mg, 3 times/d) + lopinavir/ritonavir (2 tablets, 1 time/12 h) (triple combination group) and 41 patients were treated with lopinavir/ritonavir (2 tablets, 1 time/12 h) (dual combination group). The patients who received triple combination antiviral therapy were further divided into three subgroups: <48 h, 3-5 d and >5 d according the time from the symptom onset to medication starting. The therapeutic efficacy was compared between triple combination group and dual combination group, and compared among 3 subgroups of patients receiving triple combination antiviral therapy. SPSS 17.0 software was used to analyze the data.Results:The virus nucleic acid-negative conversion time in respiratory tract specimens was (12.2±4.7) d in the triple combination group, which was shorter than that in the dual combination group [(15.0±5.0) d] ( t=6.159, P<0.01). The length of hospital stay in the triple combination group [12.0 (9.0, 17.0) d] was also shorter than that in the dual combination group [15.0 (10.0, 18.0) d] ( H=2.073, P<0.05). Compared with the antiviral treatment which was started within after the symptom onset of in the triple combination group, the time from the symptom onset to the viral negative conversion was 13.0 (10.0, 17.0), 17.0 (13.0, 22.0) and 21.0 (18.0, 24.0) d in subgroups of 48 h, 3-5 d and >5 d, respectively ( Z=32.983, P<0.01), while the time from antiviral therapy to viral negative conversion was (11.8±3.9), (13.5±5.1) and (11.2±4.3) d, respectively( Z=6.722, P<0.05). Conclusions:The triple combination antiviral therapy of abidol, lopinavir/litonavir and rIFNα-2b shows shorter viral shedding time and shorter hospitalization time, compared with the dual combination antiviral therapy; and the earlier starting triple combination antiviral therapy will result in better antiviral efficacy.

Objective: Comparing the benefit of Abidor, lopinavir/ritonavir and recombinant interferon α-2b triple combination antiviral therapy and lopinavir/ritonavir and interferon dual combination antiviral therapy to hospitalized novel coronavirus pneumonia 2019 in Zhejiang province. Methods: A multi-center prospective study was carried out to compare the effect of triple combination antiviral therapy with dual combination antiviral therapy in 15 medical institutions of Zhejiang Province. All patients were treated with recombinant interferon α-2b (5 million U, 2 times/d) aerosol inhalation. 196 patients were treated with abidol (200 mg, 3 times/d) + lopinavir / ritonavir (2 tablets, 1 time/12 h) as the triple combination antiviral treatment group. 41 patients were treated with lopinavir / ritonavir (2 tablets, 1 time/12 h) as the dual combination antiviral treatment group. The patients who received triple combination antiviral therapy were divided into three groups: within 48 hours, 3-5 days and > 5 days after the symptom onset. To explore the therapeutic effects of triple combination antiviral drugs and dual combination antiviral drugs, as well as triple combination antiviral drugs with different antiviral initiate time. SPSS17.0 software was used to analyze the data. Results: The time of virus nucleic acid turning negative was (12.2 ± 4.7) days in the triple combination antiviral drug group, which was shorter than that in the dual combination antiviral drug group [(15.0 ± 5.0) days] (t = 6.159, P < 0.01 ). The length of hospital stay [12 (9, 17) d] in the triple combination antiviral drug group was also shorter than that in the dual combination antiviral drug group [15 (10, 18) d] (H = 2.073, P < 0.05). Comparing the antiviral treatment which was started within 48 hours, 3-5 days and > 5 days after the symptom onset of triple combination antiviral drug group, the time from the symptom onset to the negative of viral shedding was 13 (10,16.8), 17 (13,22) and 21 (18-24) days respectively (Z = 32.983, P < 0.01), and the time from antiviral therapy to the negative of viral shedding was (11.8±3.9) , (13.5±5.1) and (11.2±4.3) d. The differences among the three groups were statistically significant (Z=32.983 and 6.722, P<0.01 or<0.05). Conclusions The triple combination antiviral therapy of Abidor, Lopinavir/Litonavir and recombinant interferon α-2b showed shorter viral shedding time and hospitalization time compared with the dual combination antiviral therapy. The earlier the time to initiate triple antiviral treatment, the shorter the time of virus shedding.

Objective: To evaluate the preliminary efficacy and safety of the 5-fluorouracil/leucovorin, irinotecan, and oxaliplatin (FOLF-OXIRI) and capecitabine, irinotecan, and oxaliplatin (CAPIRINOX) regimens as first-line therapy for unresectable advanced colorectal cancer. Methods: Between January 2013 and November 2018, 73 patients with metastatic colorectal cancer (mCRC) were analyzed. All patients received first-line chemotherapy. Of them, 45 patients were administered FOLFOXIRI, and the remaining 28 patients were ad-ministered CAPIRINOX. The clinical outcomes and safety profiles were evaluated according to the objective response rate (ORR), con-version resection rate, and adverse effects. Results: The ORR, median progression-free survival (mPFS), and R0 resection rate in the FOLFOXIRI group were not statistically different from those in the CAPIRINOX group (60% vs. 57.1%, 7.7 months vs. 9.6 months, 24.4% vs . 17.9% , respectively; P>0.05). No treatment-related deaths occurred. The major adverse events were leukopenia, neutropenia, fa-tigue, nausea, vomiting, diarrhea, alopecia, aspartate aminotransferase/alanine aminotransferase elevation, and neurotoxicity. The to-tal rate of grade 3/4 adverse events in the FOLFOXIRI group was 33.3% (15/45), while the total rate of grade 3/4 adverse events in the CAPIRINOX group was 46.4% (13/28). Toxicities between the two groups were not statistically significant (P=0.263). Conclusions: Both the FOLFOXIRI and CAPIRINOX regimens are effective as first-line treatment for metastatic colorectal cancer. The triple-agent chemo-therapy was associated with good efficacy and tolerable toxicity.

CRISPR-based genome editing has been widely implemented in various cell types. In-silico single guide RNA (sgRNA) design is a key step for successful gene editing using CRISPR system. Continuing efforts are made to refine in-silico sgRNA design with high on-target efficacy and reduced off-target effects. In this paper, we summarize the present sgRNA design tools, and show that efficient in-silico models can be built that integrate current heterogeneous genome-editing data to derive unbiased sgRNA design rules and identify key features for improving sgRNA design. Our review shows that systematic comparisons and evaluation of on-target and off-target effects of sgRNA will allow more precise genome editing and gene therapies using the CRISPR system.

OBJECTIVETo evaluate the feasibility of imatinib reintroduction in gastrointestinal stromal tumor(GIST) with high recurrence risk after imatinib adjuvant therapy failure.

METHODSClinical and follow-up data of 24 recurrent GIST patients with high recurrence risk receiving imatinib standard dose reintroduction(400 mg/d or 600 mg/d) after stopping imatinib adjuvant treatment more than 3 months in Department of GI Oncology of Peking University Cancer Hospital from August 2005 to January 2016 were retrospectively analyzed. The objective response rate(ORR), relapse-free survival(RFS) of imatinib reintroduction were evaluated and the difference of efficacy in patients receiving different imatinib adjuvant therapy duration were compared.

RESULTSOf 24 patients, 21 were male and 3 were female. The median age was 53 years(39-72 years). Mutation detection of tumor tissues before imatinib therapy showed 20 patients had c-Kit exon 11 mutation,3 patients exon 9 mutation and 1 patient c-Kit/PDGFRA wild type mutation. The median recurrence time was 14 months in all the patients (95%CI:7.9-20.0) and in those patients receiving imatinib adjuvant therapy for 1 or 2 years (9 patients in each group, 95%CI:11.1-16.9 and 8.2-19.8 respectively). The median recurrence time of 3 patients receiving imatinib adjuvant therapy for 3 years was 24, 41 and 54 months respectively. Of 2 patients receiving imatinib adjuvant therapy for 5 years, the median recurrence time was 4 and 18 months. Only one patient received imatinib adjuvant therapy for 6 years, and the recurrence time was 6 months. Twenty patients with exon 11 mutation and 1 patient with wide type received imatinib treatment at a dose of 400 mg daily, and 3 patients with exon 9 mutation received the dosage of 600 mg per day. Among the patients receiving imatinib reintroduction, 11 patients(45.8%) got partial response(PR), 12 patients(50.0%) had stable disease and 1 patient had progression disease. The response rate in patients receiving imatinib adjuvant therapy for 1 year(6/9, 67%) was significantly higher than that in patients receiving adjuvant therapy for ≥2 years(3/15, 20%)(P=0.036). The median progression-free survival (PFS) of imatinib reintroduction was 31 months in all the patients(95%CI:23.6-38.4). The median PFS in patients receiving imatinib adjuvant therapy for 1 year(9 cases), 2 years (9 cases) and ≥3 years (6 cases) was 50 months(95%CI:27.3-72.7), 26 months(95%CI:10.7-41.3) and fall short of median PFS. No significant difference was observed among three groups(P=0.295).

CONCLUSIONSImatinib reintroduction is still effective to GIST after imatinib adjuvant therapy failure. The different imatinib adjuvant therapy duration can influence the benefit of imatinib reintroduction.

Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Benzamides ; Chemotherapy, Adjuvant ; Combined Modality Therapy ; Disease-Free Survival ; Exons ; Female ; Gastrointestinal Stromal Tumors ; drug therapy ; genetics ; Humans ; Imatinib Mesylate ; therapeutic use ; Male ; Middle Aged ; Mutation ; Neoplasm Recurrence, Local ; Piperazines ; Pyrimidines ; Retrospective Studies

OBJECTIVEThis study aims to do the following: construct a three-dimensional finite element model of an labial inverted impacted maxillary central incisor and its supporting tissues, analyze stress distribution in the periodontal tissue when various tractions are exerted, and provide references for treating impacted maxillary central incisor.

METHODSA three-dimensional finite element model oflabial inverted impacted maxillary central incisor and its periodontal tissues was established using Mimics 10.01 and Ansys 14.0 software based on original cone beam computed tomography (CBCT) data. Various traction values (20, 30, 40, 50, 60, and 70 g) were exerted on the incisal margin in the direction perpendicular to the impacted tooth. Different Von Mises stress values were determined.

RESULTSStress distribution on the periodontal ligament increased with traction size. When 30 g traction was exerted on the labial inverted impacted maxillary central incisor, the Von Mises stress was 24 919.0 Pa, which was within the range of the optimum force and close to its maximum value.

CONCLUSIONThe optimum traction for early orthodontic treatment of labial inverted impacted maxillary central incisor is nearly 30 g.

Finite Element Analysis ; Incisor ; Lip ; Maxilla ; Periodontal Ligament ; Tooth, Impacted

Objective This study aims to do the following: construct a three-dimensional finite element model of an labial inverted impacted maxillary central incisor and its supporting tissues, analyze stress distribution in the periodontal tissue when various tractions are exerted, and provide references for treating impacted maxillary central incisor. Methods A three-dimensional finite element model of labial inverted impacted maxillary central incisor and its periodontal tissues was established using Mimics 10.01 and Ansys 14.0 software based on original cone beam computed tomography (CBCT) data. Various traction values (20, 30, 40, 50, 60, and 70 g) were exerted on the incisal margin in the direction perpendicular to the impacted tooth. Different Von Mises stress values were determined. Results Stress distribution on the periodontal ligament increased with traction size. When 30 g traction was exerted on the labial inverted impacted maxillary central incisor, the Von Mises stress was 24 919.0 Pa, which was within the range of the optimum force and close to its maximum value. Conclusion The optimum traction for early orthodontic treatment of labial inverted impacted maxillary central incisor is nearly 30 g.