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A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19
CHEN Jun,LIU Danping,LIU Li,LIU Ping,XU Qingnian,XIA Lu,LING Yun,HUANG Dan,SONG Shuli,ZHANG Dandan,QIAN Zhiping,LI Tao,SHEN Yinzhong,LU Hongzhou
J Zhejiang Univ (Med Sci)    2020, 49 (2): 215-219.   DOI: 10.3785/j.issn.1008-9292.2020.03.03
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Objective: To evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the treatment of patients with moderate coronavirus disease 2019 (COVID-19). Methods: We prospectively enrolled 30 treatment-naïve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Center. The patients were randomized 1:1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only. The primary endpoint was negative conversion rate of SARS-CoV-2 nucleic acid in respiratory pharyngeal swab on days 7 after randomization. This study has been approved by the Ethics Committee of Shanghai Public Health Clinical Center and registered online (NCT04261517). Results: One patient in HCQ group developed to severe during the treatment. On day 7, nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). The median duration from hospitalization to virus nucleic acid negative conservation was 4 (1, 9) days in HCQ group, which is comparable to that in the control group [2 (1, 4) days, Z=1.27, P>0.05]. The median time for body temperature normalization in HCQ group was 1 (0, 2) day after hospitalization, which was also comparable to that in the control group [1 (0, 3) day]. Radiological progression was shown on CT images in 5 cases (33.3%) of the HCQ group and 7 cases (46.7%) of the control group, and all patients showed improvement in follow-up examinations. Four cases (26.7%) of the HCQ group and 3 cases (20%) of the control group had transient diarrhea and abnormal liver function (P>0.05). Conclusions: The prognosis of COVID-19 moderate patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.

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Management of COVID-19: the Zhejiang experience
XU Kaijin,CAI Hongliu,SHEN Yihong,NI Qin,CHEN Yu,HU Shaohua,LI Jianping,WANG Huafen,YU Liang,HUANG He,QIU Yunqing,WEI Guoqing,FANG Qiang,ZHOU Jianying,SHENG Jifang,LIANG Tingbo,LI Lanjuan
J Zhejiang Univ (Med Sci)    2020, 49 (2): 147-157.   DOI: 10.3785/j.issn.1008-9292.2020.02.02
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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 Lactobacillus and Bifidobacterium, 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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Study on the epidemic development of COVID-19 in Hubei province by a modified SEIR model
CAO Shengli,FENG Peihua,SHI Pengpeng
J Zhejiang Univ (Med Sci)    2020, 49 (2): 178-184.   DOI: 10.3785/j.issn.1008-9292.2020.02.05
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Objective: To establish a SEIR epidemic dynamics model that can be used to evaluate the COVID-19 epidemic, and to predict and evaluate the COVID-19 epidemic in Hubei province using the proposed model. Methods: COVID-19 SEIR transmission dynamics model was established, which took transmission ability in latent period and tracking quarantine interventions into consideration. Based on the epidemic data of Hubei province from January 23, 2020 to February 24, 2020, the parameters of the newly established modified SEIR model were fitted. By using Euler integral algorithm to solve the modified SEIR dynamics model, the epidemic situation in Hubei province was analyzed, and the impact of prevention and control measures such as quarantine and centralized treatment on the epidemic development was discussed. Results: The theoretical estimation of the epidemic situation by the modified SEIR epidemic dynamics model is in good agreement with the actual situation in Hubei province. Theoretical analysis showed that prevention and control quarantine and medical follow-up quarantine played an important inhibitory effect on the outbreak of the epidemic.The centralized treatment played a key role in the rapid decline in the number of infected people. In addition, it is suggested that individuals should improve their prevention awareness and take strict self-protection measures to curb the increase in infected people. Conclusion: The modified SEIR model is reliable in the evaluation of COVID-19 epidemic in Hubei province, which provides a theoretical reference for the decision-making of epidemic interventions.

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Diagnosis and treatment recommendation for pediatric COVID-19 (the second edition)
CHEN Zhimin,FU Junfen,SHU Qiang,WANG Wei,CHEN Yinghu,HUA Chunzhen,LI Fubang,LIN Ru,TANG Lanfang,WANG Tianlin,WANG Yingshuo,XU Weize,YANG Zihao,YE Sheng,YUAN Tianming,ZHANG Chenmei,ZHANG Yuanyuan
J Zhejiang Univ (Med Sci)    2020, 49 (2): 139-146.   DOI: 10.3785/j.issn.1008-9292.2020.02.01
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The coronavirus disease 2019 (COVID-19) has caused a global pandemic. All people including children are generally susceptible to COVID-19, but the condition is relatively mild for children. The diagnosis of COVID-19 is largely based on the epidemiological evidence and clinical manifestations, and confirmed by positive detection of virus nucleic acid in respiratory samples. The main symptoms of COVID-19 in children are fever and cough; the total number of white blood cell count is usually normal or decreased; the chest imaging is characterized by interstitial pneumonia, which is similar to other respiratory virus infections and Mycoplasma pneumoniae infections. Early identification, early isolation, early diagnosis and early treatment are important for clinical management. The treatment of mild or moderate type of child COVID-19 is mainly symptomatic. For severe and critical ill cases, the oxygen therapy, antiviral drugs, antibacterial drugs, glucocorticoids, mechanical ventilation or even extracorporeal membrane oxygenation (ECMO) may be adopted, and the treatment plan should be adjusted timely through multi-disciplinary cooperation.

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Pharmaceutical care for severe and critically ill patients with COVID-19
JIANG Saiping,LI Lu,RU Renping,ZHANG Chunhong,RAO Yuefeng,LIN Bin,WANG Rongrong,CHEN Na,WANG Xiaojuan,CAI Hongliu,SHENG Jifang,ZHOU Jianying,LU Xiaoyang,QIU Yunqing
J Zhejiang Univ (Med Sci)    2020, 49 (2): 158-169.   DOI: 10.3785/j.issn.1008-9292.2020.03.01
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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 Diagnosis and treatment of novel coronavirus pneumonia (trial version 6), and Management of COVID-19: the Zhejiang experience, 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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Dynamic changes of chest CT imaging in patients with COVID-19
WANG Jincheng,LIU Jinpeng,WANG Yuanyuan,LIU Wei,CHEN Xiaoqun,SUN Chao,SHEN Xiaoyong,WANG Qidong,WU Yaping,LIANG Wenjie,RUAN Lingxiang
J Zhejiang Univ (Med Sci)    2020, 49 (2): 191-197.   DOI: 10.3785/j.issn.1008-9292.2020.02.03
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Objective: To analyze the dynamic changes of chest CT images of patients with coronavirus disease 2019 (COVID-19). Methods: Fifty-two cases of COVID-19 were admitted in the First Affiliated Hospital of Zhejiang University School of Medicine. The consecutive chest CT scans were followed up for all patients with an average of 4 scans performed per patient during the hospitalization. The shortest interval between each scan was 2 days and the longest was 7 days. The shape, number and distribution of lung shadows, as well as the characteristics of the lesions on the CT images were reviewed. Results: The obvious shadows infiltrating the lungs were shown on CT images in 50 cases, for other 2 cases there was no abnormal changes in the lungs during the first CT examination. Ground-glass opacities (GGO) were found in 48 cases (92.3%), and 19 cases (36.5%) had patchy consolidation and sub-consolidation, which were accompanied with air bronchi sign in 17 cases (32.7%). Forty one cases (78.8%) showed a thickened leaflet interval, 4 cases (7.6%) had a small number of fibrous stripes. During hospitalization, GGO lesions in COVID-19 patients gradually became rare, the fibrous strip shadows increased and it became the most common imaging manifestation. The lesions rapidly progressed in 39 cases (75.0%) within 6-9 days after admission. On days 10-14 of admission, the lesions distinctly resolved in 40 cases (76.9%). Conclusion: The chest CT images of patients with COVID-19 have certain characteristics with dynamic changes, which are of value for monitoring disease progress and clinical treatment.

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CT imaging features of patients with different clinical types of COVID-19
ZHONG Qi,LI Zhi,SHEN Xiaoyong,XU Kaijin,SHEN Yihong,FANG Qiang,CHEN Feng,LIANG Tingbo
J Zhejiang Univ (Med Sci)    2020, 49 (2): 198-202.   DOI: 10.3785/j.issn.1008-9292.2020.03.05
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Objective: To investigate the CT findings of patients with different clinical types of coronavirus disease 2019 (COVID-19). Methods: A total of 67 patients diagnosed as COVID-19 by nucleic acid testing were collected and divided into 4 groups according to the clinical stages based on Diagnosis and treatment of novel coronavirus pneumonia (trial version 6). The CT imaging characteristics were analyzed among patients with different clinical types. Results: Among 67 patients, 3(4.5%) were mild, 35 (52.2%) were moderate, 22 (32.8%) were severe, and 7(10.4%) were critical ill. No significant abnormality in chest CT imaging in mild patients. The 35 cases of moderate type included 3 (8.6%) single lesions, the 22 cases of severe cases included 1 (4.5%) single lesion and the rest cases were with multiple lesions. CT images of moderate patients were mainly manifested by solid plaque shadow and halo sign (18/35, 51.4%); while fibrous strip shadow with ground glass shadow was more frequent in severe cases (7/22, 31.8%). Consolidation shadow as the main lesion was observed in 7 cases, and all of them were severe or critical ill patients. Conclusion: CT images of patients with different clinical types of COVID-19 have characteristic manifestations, and solid shadow may predict severe and critical illness.

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Diagnostic efficacy of three test kits for SARS-CoV-2 nucleic acid detection
SHEN Lihua,HUANG Fei,CHEN Xiang,XIONG Zuan,YANG Xiaoyu,LI Hui,CHENG Feng,GUO Jian,GONG Guofu
J Zhejiang Univ (Med Sci)    2020, 49 (2): 185-190.   DOI: 10.3785/j.issn.1008-9292.2020.03.09
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Objective: To compare the diagnostic efficacy among three RT-PCR test kits for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid detection. Methods: The throat swab samples from 40 hospitalized patients clinically diagnosed as coronavirus disease 2019 (COVID-19) and 16 hospitalized non-COVID-19 patients were recruited. The SARS-CoV-2 nucleic acid was detected in throat swab samples with RT-PCR test kits from Sansure Biotech ("Sansure" for short), Jiangsu Bioperfectus Technologies ("Bioperfectus" for short) and BGI Genomics ("BGI" for short). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Kappa value were analyzed. The viral nucleic acid was extracted from the throat swab samples by one-step cleavage and magnetic bead methods, and the efficacy of two extraction methods was also compared. The results of magnetic bead method for nucleic acid extraction by two different extractors (Sansure Natch CS S12C Fully Automated Nucleic Acid Extraction System vs. Tianlong NP968-C Nucleic Acid Extractor) were also compared. Results: The sensitivity, specificity, PPV, NPV and kappa value were 95.00%, 87.50%, 95.00%, 87.50%and 0.825 for Sansure kit; 90.00%, 87.50%, 94.74%, 77.78%and 0.747 for the Bioperfectus kit, and 82.50%, 81.25%, 91.67%, 65.00%and 0.593 for the BGI kit, respectively. The positive, negative and total coincident rates and kappa value of viral nucleic acid detection results using the samples extracted by one-step cleavage and magnetic bead methods were 95.24%, 100.00%, 96.43%and 0.909, respectively, but the one-step cleavage method took only 25 min, while the magnetic bead method required 180 min. The positive, negative and total coincident rates and kappa value of viral nucleic acid detection results using the samples extracted by the two different nucleic acid extractors were 85.00%, 100.00%, 89.29% and 0.764, respectively. Conclusion: The detection efficacy for SARS-CoV-2 nucleic acid by the Sansure kit is relatively higher and the one-step cleavage method has advantages of convenient operation and less time consuming.

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Anesthesia management in cesarean section for patient with COVID-19: a case report
KANG Xianhui,ZHANG Rong,HE Huiliang,YAO Yongxing,ZHENG Yueying,WEN Xiaohong,ZHU Shengmei
J Zhejiang Univ (Med Sci)    2020, 49 (2): 249-252.   DOI: 10.3785/j.issn.1008-9292.2020.03.04
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Since the coronavirus disease 2019 (COVID-19) affects the cardio-pulmonary function of pregnant women, the anesthetic management and protection of medical staff in the cesarean section is significantly different from that in ordinary surgical operation. This paper reports a case of cesarean section for a woman with COVID-19, which was successfully performed in the First Affiliated Hospital of Zhejiang University School of Medicine on February 8, 2020. Anesthetic management, protection of medical staff and psychological intervention for the pregnant woman during the operation were discussed. Importance has been attached to the preoperative evaluation of pregnant women with COVID-19 and the implementation of anesthesia plan. For moderate patients, intraspinal anesthesia is preferred in cesarean section, and try to reduce its influence in respiration and circulation in both maternal and infant; general anesthesia with endotracheal intubation should be adopted for severe or critically ill patients. Ensure the safety of medical environment, and anesthetists should carry out level-Ⅲ standard protection. Special attention and support should be paid to maternal psychology: fully explanation before operation to reduce anxiety; relieve the discomfort during operation, so as to reduce tension; avoid the bad mood due to pain after operation.

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Principles and suggestions on biosafety protection of biological specimen preservation during prevalence of COVID-19
ZHANG Xiaoyan, SUN Wei, SHANG Shiqiang, MAO Jianhua, FU Junfen, SHU Qiang, JIANG Kewen
J Zhejiang Univ (Med Sci)    2020, 49 (2): 170-177.   DOI: 10.3785/j.issn.1008-9292.2020.02.04
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Coronavirus disease 2019 (COVID-19) is a grade B infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In pace with the spreading of the disease, biosafety risk of the biological specimen preservation in biobanks has been significantly increased and biosafety protection during biological specimen preservation become increasingly important. According to the related national rules and the corresponding guidelines of Chinese Medical Association, this paper introduced the etiology about SARS-CoV-2, epidemiology about COVID-19, and the biosafety protection principles of individuals and biological specimen storage places in the process of personal protection, protection of collection, transport, handling, preservation, detection, post-detection disposal and emergencies of biological specimen. Emphasized to carry out a strict biosafety-risk assessment on biological specimen basing on virus load information, infectivity, and sample type (possible contact transmission, aerosol transmission, and fecal oral transmission).

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Clinical observation of 6 severe COVID-19 patients treated with plasma exchange or tocilizumab
LUO Song,YANG Lijuan,WANG Chun,LIU Chuanmiao,LI Dianming
J Zhejiang Univ (Med Sci)    2020, 49 (2): 227-231.   DOI: 10.3785/j.issn.1008-9292.2020.03.06
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Objective: To observe the clinical effect of plasma exchange and tocilizumab in treatment of patients with severe coronavirus disease 2019 (COVID-19). Methods: Six patients with severe COVID-19 admitted in First Affiliated Hospital of Bengbu Medical College from January 25 to February 25, 2020. Three patients were treated with plasma exchange and three patients were treated with tocilizumab. The effect on excessive inflammatory reaction of plasma exchange and tocilizumab was observed. Results: The C-reactive protein (CRP) and IL-6 levels were significantly decreased and the lymphocyte and prothrombin time were improved in 3 patients after treatment with plasma exchange; while inflammation level was not significantly decreased, and lymphocyte and prothrombin time did not improve in 3 patients treated with tocilizumab. Conclusion: For severe COVID-19 patients with strong inflammatory reaction, plasma exchange may be preferred.

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Clinical analysis of suspected COVID-19 patients with anxiety and depression
LI Xin,DAI Tian,WANG Hong,SHI Junnian,YUAN Wei,LI Jing,CHEN Lijun,ZHANG Tianming,ZHANG Shanshan,KONG Yan,YUE Ning,SHI Hui,HE Yuping,HU Huifang,LIU Furong,YANG Caixia
J Zhejiang Univ (Med Sci)    2020, 49 (2): 203-208.   DOI: 10.3785/j.issn.1008-9292.2020.03.02
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Objective: To explore the risk factors of anxiety and depression in patients with suspected coronavirus disease 2019 (COVID-19) so as to achieve early intervention and better clinical prognosis. Methods: Seventy-six patients with suspected COVID-19 in fever isolation wards of Second Hospital of Lanzhou University were enrolled From January 31, 2020 to February 22, 2020. Their clinical baseline data were collected. The anxiety of patients was assessed by Hamilton Anxiety Scale, and the depression of patients was assessed by Hamilton Depression Scale. Multivariate Logistic regression analysis was performed to explore the risk factors of anxiety and depression in these patients. Results: Female patients are more likely to have anxiety (OR=3.206, 95%CI:1.073-9.583, P < 0.05) and depression (OR=9.111, 95%CI:2.143-38.729, P < 0.01) than male patients; patients with known contact history of epidemic area and personnel in epidemic area are more likely to have depression (OR=3.267, 95%CI:1.082-9.597, P < 0.05). Conclusion: During the isolation treatment of suspected COVID-19 patients, early psychological intervention should be carried out for the female patients with known contact history of epidemic area and personnel in epidemic area, and drug treatment should be given in advance if necessary.

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Follow-up testing of viral nucleic acid in discharged patients with moderate type of COVID-19
LI Youjiang,HU Yingying,ZHANG Xiaodong,YU Yuanyuan,LI Bin,WU Jianguo,WU Yingping,XIA Xiaoping,XU Jian
J Zhejiang Univ (Med Sci)    2020, 49 (2): 270-274.   DOI: 10.3785/j.issn.1008-9292.2020.03.11
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Objective: To investigate the clinical outcome of patients with moderate type of coronavirus disease 2019 (COVID-19) after discharge by retesting viral nucleic acid. Methods: Seven patients with moderate COVID-19 met the discharge criteria enacted by National Health Commission were quarantined in hospital for 7 days, then continuously quarantined at home for 4 weeks after discharged. During the quarantined period, the symptoms and signs were documented, and sputum or nasal swab and feces samples were collected to test SARS-CoV-2 nucleic acid by RT-PCR method. Results: There was no symptoms and signs during the quarantine period in all 7 patients. However, respiratory swabs from 3 patients were confirmed positive of SARS-CoV-2 nucleic acid at 5 to 7 days after they met the discharge criteria. Conclusion: There is a relatively high incidence of positive viral nucleic acid in patients met the discharge criteria, and it is suggested that patients met the current discharge criteria should be quarantined in hospital for another 7 days and the follow-up viral testing is necessary.

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Pregnant women complicated with COVID-19: a clinical analysis of 3 cases
CHEN Xu,LI Yang,WANG Jinxi,CAI Hongliu,CAO Hongcui,SHENG Jifang
J Zhejiang Univ (Med Sci)    2020, 49 (2): 240-244.   DOI: 10.3785/j.issn.1008-9292.2020.03.08
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Objective: To analyze the clinical characteristics and pregnancy outcomes of pregnant women complicated with coronavirus disease 2019 (COVID-19). Methods: The clinical data of 3 pregnant women with COVID-19 admitted to the First Affiliated Hospital of Zhejiang University School of Medicine from January 19 to February 10, 2020 were retrospectively analyzed. Results: There was one case in the first-trimester pregnancy (case 1), one in the second-trimester pregnancy (case 2) and one in third-trimester pregnancy (case 3). Cough, fever, fatigue, lung imaging changes were the main manifestations. The white cell count, lymphocyte percentage had no significantly changes in case 1 and case 3, while the levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IL-6 and IL-10 elevated. The lymphocyte count and lymphocyte percentage decreased and the inflammatory indicators significantly increased in case 2. All patients were treated with antiviral, antitussive, oxygen inhalation; case 3 received glucocorticoids, case 2 with severe illness received glucocorticoids and additionally gamma globulin. All three cases were cured and discharged. Case 1 with early pregnancy chose to terminate pregnancy after discharge; case 2 chose to continue pregnancy without obstetric complications; and case 3 had cesarean section delivery due to abnormal fetal heart monitoring. Conclusion: The report shows that COVID-19 in pregnancy women could be cured with active treatment, and the maternal and fetal outcomes can be satisfactory.

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Roles of multidisciplinary team in diagnosis and treatment of suspected cases of COVID-19
DING Shubo,YU Shi'an,CHEN Haijun,ZHANG Dehe,XU Yejin,ZHU Dan,CHENG Kun
J Zhejiang Univ (Med Sci)    2020, 49 (2): 209-214.   DOI: 10.3785/j.issn.1008-9292.2020.03.15
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Objective: To analyze the roles of multidisciplinary team (MDT) in the diagnosis and treatment of suspected cases of coronavirus disease 2019 (COVID-19). Methods: The clinical data of 48 patients with suspected COVID-19 admitted in Jinhua Municipal Central Hospital from January 21, 2020 to March 20, 2020 were retrospectively analyzed. Results: In the 48 suspected cases, 18 were diagnosed with COVID-19, and 30 were excluded. Each of the confirmed cases were discussed among MDT for 2 to 12 times with an average of (4.7±3.2) times; while for non-COVID-19 patients were discussed for 2 to 4 times with an average of (2.3±0.6) times. With the guidance of MDT, one COVID-19 patient was transferred to designated provincial hospital after effective treatment; one patient complicated with acute cholecystitis underwent gallbladder puncture and drainage; and COVID-19 was excluded in a highly suspected patient after alveolar lavage fluid examination. Except one transferred patient, all 17 confirmed COVID-19 patients were cured and discharged. There was no cross-infection occurred in suspected patients during the hospitalization. There were no deaths and no medical staff infections. Conclusion: The efficiency of diagnosis and treatment for suspected COVID-19 patients can be improved with MDT, particularly for complicated cases.

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Targeting Cullin-RING E3 ligases for anti-cancer therapy: efforts on drug discovery
YU Qing, XIONG Xiufang, SUN Yi
J Zhejiang Univ (Med Sci)    2020, 49 (1): 1-19.   DOI: 10.3785/j.issn.1008-9292.2020.02.21
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Cullin-RING E3 ligases (CRLs) are the major components of ubiquitin-proteasome system, responsible for ubiquitylation and subsequent degradation of thousands of cellular proteins. CRLs play vital roles in the regulation of multiple cellular processes, including cell cycle, cell apoptosis, DNA replication, signalling transduction among the others, and are frequently dysregulated in many human cancers. The discovery of specific neddylation inhibitors, represented by MLN4924, has validated CRLs as promising targets for anti-cancer therapies with a growing market. Recent studies have focused on the discovery of the CRLs inhibitors by a variety of approaches, including high through-put screen, virtual screen or structure-based drug design. The field is, however, still facing the major challenging, since CRLs are a large multi-unit protein family without typical active pockets to facilitate the drug design, and enzymatic activity is mainly dependent on undruggable protein-protein interactions and dynamic conformation changes. Up to now, most reported CRLs inhibitors are aiming at targeting the F-box family proteins (e.g., SKP2, β-TrCP and FBXW7), the substrate recognition subunit of SCF E3 ligases. Other studies reported few small molecule inhibitors targeting the UBE2M-DCN1 interaction, which specifically inhibits CRL3/CRL1 by blocking the cullin neddylation. On the other hand, several CRL activators have been reported, such as plant auxin and immunomodulatory imide drugs, thalidomide. Finally, proteolysis-targeting chimeras (PROTACs) has emerged as a new technology in the field of drug discovery, specifically targeting the undruggable protein-protein interaction. The technique connects the small molecule that selectively binds to a target protein to a CRL E3 via a chemical linker to trigger the degradation of target protein. The PROTAC has become a hotspot in the field of E3-ligase-based anti-cancer drug discovery.

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Dynamic inflammatory response in a critically ill COVID-19 patient treated with corticosteroids
ZHAGN Sheng,LI Danping,CHEN Huazhong,ZHENG Dan,ZHOU Yiping,CHEN Baoguo,SHI Weiwu,LIN Ronghai
J Zhejiang Univ (Med Sci)    2020, 49 (2): 220-226.   DOI: 10.3785/j.issn.1008-9292.2020.03.10
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Objective: To investigate the effect of corticosteroids therapy on the inflammatory response in a critically ill coronavirus disease 2019 (COVID-19) patient. Methods: A 55-year old female patient with critical ill COVID-19 was admitted in Taizhou Hospital on January 19, 2020. The patient was treated with methylprednisolone 80 mg on the 2nd day after admission. Thereafter, the dose was adjusted in a timely manner and the therapy lasted for 13 days. The peripheral lymphocyte subsets (CD3+T, CD4+ T, CD8+ T, NK cells, B cells), as well as serum levels of lymphocyte factors (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) were dynamically monitored. Results: On D1 of admission, the numbers of peripheral blood CD3+ T, CD4+ T, CD8+ T, and NK cells were significantly lower than the normal range. With the improvement of the disease, the numbers of CD3+ T, CD8+ T and CD4 + T cells gradually recovered and showed a linear growth trend (linear fitting equation: Y=18.59X+109.4, P < 0.05). On D2 of admission, the patient's IL-6 and IL-10 levels were significantly higher than normal values, IFN-γ was at a normal high value, and then rapidly decreased; IL-2, IL-4, and TNF-α were all in the normal range. On the D6 and D7, the IL-6 and IL-10 decreased to the normal range for the first time. On the D18, the sputum virus nucleic acid test was negative for the first time, and the fecal virus nucleic acid test was still positive; on the D20 the sputum and fecal virus nucleic acid test were both negative. On D34, the patient recovered and was discharged. At the discharge the muscle strength score of the patient was 44 and the daily life ability evaluation was 90. Conclusion: In the absence of effective antiviral drugs, early use of appropriate doses of corticosteroids in critically ill patient with COVID-19 can quickly alleviate inflammatory response and improve clinical symptoms, however, it may reduce the number of T cells, and to adjust the dose in time is necessary.

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Establishment of a rapid identification of adverse drug reaction program in R language implementation based on monitoring data
HONG Dongsheng,NI Jian,SHAN Wenya,LI Lu,HU Xi,YANG Hongyu,ZHAO Qingwei,ZHANG Xingguo
J Zhejiang Univ (Med Sci)    2020, 49 (2): 253-259.   DOI: 10.3785/j.issn.1008-9292.2020.03.07
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Objective: To establish a clinically applicable model of rapid identification of adverse drug reaction program (RiADP) for risk management and decision-making of clinical drug use. Methods: Based on the theory of disproportion analysis, frequency method and Bayes method, a clinically applicable RiADP model in R language background was established, and the parameters of the model were interpreted by MedDRA coding. Based on the actual monitoring data of FDA, the model was validated by the assessing hepatotoxicity of lopinavir/ritonavir (LPV/r). Results: The established RiADP model included four parameters: standard value of adverse drug reaction signal information, empirical Bayesian geometric mean value, ratio of reporting ratio and number of adverse drug reaction cases. Through the application of R language parameter package "phViD", the model parameters could be output quickly. After being encoded by MedDRA, it was converted into clinical terms to form a clinical interpretation report of adverse drug reactions. In addition, the evaluation results of LPV/r hepatotoxicity by the model were matched with the results reported in latest literature, which also proved the reliability of the model results. Conclusion: In this study, a rapid identification method of adverse reactions based on post marketing drug monitoring data was established in R language environment, which is capable of sending rapid warning of adverse reactions of target drugs in public health emergencies, and providing intuitive evidence for risk management and decision-making of clinical drugs.

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The role of ferroptosis in chronic diseases
CHEN Junyi,YANG Xiang,FANG Xuexian,WANG Fudi,MIN Junxia
J Zhejiang Univ (Med Sci)    2020, 49 (1): 44-57.   DOI: 10.3785/j.issn.1008-9292.2020.02.24
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Recently, ferroptosis, an iron-dependent novel type of cell death, has been characterized as an excessive accumulation of lipid peroxides and reactive oxygen species. Emerging studies demonstrate that ferroptosis not only plays an important role in the pathogenesis and progression of chronic diseases, but also functions differently in the different disease context. Notably, it is shown that activation of ferroptosis could potently inhibit tumor growth and increase sensitivity to chemotherapy and immunotherapy in various cancer settings. As a result, the development of more efficacious ferroptosis agonists remains the mainstay of ferroptosis-targeting strategy for cancer therapeutics. By contrast, in non-cancerous chronic diseases, including cardiovascular & cerebrovascular diseases and neurodegenerative diseases, ferroptosis functions as a risk factor to promote these diseases progression through triggering or accelerating tissue injury. As a matter of fact, blocking ferroptosis has been demonstrated to effectively prevent ischemia-reperfusion heart disease in preclinical animal models. Therefore, it is a promising field to develope potent ferroptosis inhibitors for preventing and treating cardiovascular & cerebrovascular diseases and neurodegenerative diseases. In this article, we summarize the most recent progress on ferroptosis in chronic diseases, and draw attention to the possible clinical impact of this recently emerged ferroptosis modalities.

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Replication and transmission mechanisms of highly pathogenic human coronavirus
HE Yeyan,ZHENG Chanying
J Zhejiang Univ (Med Sci)    2020, 49 (3): 324-339.   DOI: 10.3785/j.issn.1008-9292.2020.03.16
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The three known highly pathogenic human coronaviruses are severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human highly pathogenic coronaviruses are composed of non-structural proteins, structural proteins, accessory proteins and ribonucleic acid. Viral particles recognize host receptors via spike glycoprotein (S protein), enter host cells by membrane fusion, replicate in host cells through large replication-transcription complexes, and promote proliferation by interfering with and suppressing the host's immune response. Highly pathogenic human coronaviruses are hosted by humans and vertebrates. Viral particles are transmitted through droplets, contact and aerosols or likely through digestive tract, urine, eyes and other routes. This review discusses the mechanisms of replication and transmission of highly pathogenic human coronaviruses providing basis for future studies on interrupting the transmission and pathogenicity of these pathogenic viruses.

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Management of a colon cancer patient complicated with COVID-19
YE Ziqi,HONG Yun,WU Xiuhua,HONG Dongsheng,ZHANG Yanfang,DONG Xihao,RAO Yuefeng,LU Xiaoyang
J Zhejiang Univ (Med Sci)    2020, 49 (2): 245-248.   DOI: 10.3785/j.issn.1008-9292.2020.03.12
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Objective: To explore the feasibility of radical resection for cancer patients complicated with coronavirus disease 2019 (COVID-19). Methods: The management and clinical outcome of a sigmoid cancer patient with COVID-19 were analyzed. Results: The inflammation indicators and fever of this patient were effectively controlled and the lung lesions remained stable after active anti-viral treatment, then the radical colorectomy was performed after the viral negative conversion for twice. Conclusion: The case indicates that radical resection can be performed in SARS-CoV-2 patients with twice-negative SARS-CoV-2 nucleic acid testing results.

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Research progress on selective immunoproteasome inhibitors
KONG Limin,LU Jingyi,ZHU Huajian,ZHANG Jiankang
J Zhejiang Univ (Med Sci)    2019, 48 (6): 688-694.   DOI: 10.3785/j.issn.1008-9292.2019.12.15
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Immunoproteasome is associated with various diseases such as hematologic malignancies, inflammatory, autoimmune and central nervous system diseases, and over expression of immunoproteasome is observed in all of these diseases. Immunoproteasome inhibitors can reduce the expression of immunoproteasome by inhibiting the production of related cell-inducing factors and the activity of T lymphocyte for treating related diseases. In order to achieve good efficacy and reduce the toxic effects, key for development of selective immunoproteasome inhibitors is the high selectivity and potent activity of the three active subunits of the proteasome. This review summarizes the structure and functions of immunoproteasome and the associated diseases. Besides, structure, activity and status of selective immunoproteasome inhibitors are also been highlighted.

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Efficacy of letrozole in treatment of male adolescents with idiopathic short stature
LI Yanhong,DU Minlian,MA Huamei,CHEN Qiuli,CHEN Hongshan,ZHANG Jun
J Zhejiang Univ (Med Sci)    2020, 49 (3): 308-314.   DOI: 10.3785/j.issn.1008-9292.2020.04.05
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Objective: To evaluate the efficacy and safety of aromatase inhibitor letrozole in treatment of male adolescents with idiopathic short stature (ISS). Method: Seventy five boys with height less than 2 standard deviation (SD) below the mean who had entered puberty were enrolled in our study from 2004 to 2017, in the Pediatric Department of the First Affiliated Hospital, Sun Yat-Sen University. Among 75 patients, 28 in letrozole group received letrozole and spironolactone, 30 in gonadotrophin releasing hormone analogue (GnRHa) group received GnRHa injection and 17 had no intervention. Height velocity (HV), increment of bone age/chronological age (ΔBA/ΔCA), the final adult height (FAH) were compared among groups and the safety of letrozole treatment was evaluated. Results: HV maintained faster during letrozole treatment when compared with other groups. HV during GnRHa treatment showed slightly decline in the first 6 months, but decreased remarkably after 6 months, and was significantly lower than that in letrozole group (P < 0.05). The maturation of BA slowed down in both letrozole and GnRHa groups. But the ΔBA/ΔCA in letrozole group during the first and the second year of treatment were significantly higher (0.67±0.09, 0.50±0.15, respectively) when compared with GnRHa group (0.59±0.16, 0.44±0.13, respectively) (t=2.78 and 2.20, all P < 0.05). FAH in letrozole group and GnRHa group were (170±4) cm and (170±6)cm, there was no significant differences between the two groups (P>0.05), and both were higher than that in no intervention group (162±4 cm, P < 0.01). After 6 months of letrozole treatment, testicular volumes and serum testerone levels increased; 39.2% (11/28) boys had clinical manifestations of hyperandrogenemia, and 82.1% (23/28) boys had decreased serum high-density lipoprotein (HDL) levels. Serum levels of HDL and testerone returned normal and the hyperandrogenemia disappeared after the cessation of letrozole treatment. No significant changes in serum triglyceride, serum low-density lipoprotein (LDL), fating serum levels of insulin and glucose, HOMA-IR were observed. No abnormal liver function, myalgia, scoliosis or aggravations of scoliosis was found. Conclusions: Long term letrozole therapy during puberty in boys with ISS can delay bone maturation without significant decrease of linear growth, and thus can improve the final adult height. No severe adverse reactions were found.

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Clinical experience of high-flow nasal cannula oxygen therapy in severe COVID-19 patients
HE Guojun,HAN Yijiao,FANG Qiang,ZHOU Jianying,SHEN Jifang,LI Tong,PU Qibin,CHEN Aijun,QI Zhiyang,SUN Lijun,CAI Hongliu
J Zhejiang Univ (Med Sci)    2020, 49 (2): 232-239.   DOI: 10.3785/j.issn.1008-9292.2020.03.13
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Acute respiratory failure due to acute hypoxemia is the major manifestation in severe coronavirus disease 2019 (COVID-19). Rational and effective respiratory support is crucial in the management of COVID-19 patients. High-flow nasal cannula (HFNC) has been utilized widely due to its superiority over other non-invasive respiratory support techniques. To avoid HFNC failure and intubation delay, the key issues are proper patients, timely application and improving compliance. It should be noted that elder patients are vulnerable for failed HFNC. We applied HFNC for oxygen therapy in severe and critical ill COVID-19 patients and summarized the following experiences. Firstly, to select the proper size of nasal catheter, to locate it at suitable place, and to confirm the nose and the upper respiratory airway unobstructed. Secondly, an initial flow of 60 L/min and 37℃ should be given immediately for patients with obvious respiratory distress or weak cough ability; otherwise, low-level support should be given first and the level gradually increased. Thirdly, to avoid hypoxia or hypoxemia, the treatment goal of HFNC should be maintained the oxygen saturation (SpO2) above 95% for patients without chronic pulmonary disease. Finally, patients should wear a surgical mask during HFNC treatment to reduce the risk of virus transmission through droplets or aerosols.

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Aromatase inhibitors combined with growth hormone in treatment of adolescent boys with short stature
KONG Yuanmei,CHEN Hong,LIANG Li,ZHENG Maoni,FANG Yanlan,WANG Chunlin
J Zhejiang Univ (Med Sci)    2020, 49 (3): 283-290.   DOI: 10.3785/j.issn.1008-9292.2020.04.06
Abstract   HTML PDF (1058KB) ( 151 )  

Objective: To assess the efficacy and safety of aromatase inhibitors (AIs) combined growth hormone in treatment of adolescent boys with short stature. Methods: One hundred and fifty-one short stature pubertal boys with age of 10-14 years and bone age of 13-15 years, who were admitted to the Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, were included in this trial. According to their own or parents' intention, the children were divided into recombinant human growth hormone (rhGH)+AI group (n=108) and rhGH group (n=43). All children were injected subcutaneously with rhGH 0.15-0.2 IU·kg-1·d-1, and those in rhGH+AI group were additionally given 2.5 mg/d letrozole or 1 mg/d anastrozole, orally for 12 months or longer. The children were followed-up every 3 months. During the follow-up visit, the predicted adult height (PAH), sex hormone level, glucose and lipid metabolism, and other indicators were measured, and adverse reactions were monitored. Results: After intervention, there were significant differences in ΔBA(bone age)/ΔCA(chronological age), ΔHtSDSBA(height standard deviation score based on bone age)and ΔPAH between rhGH+AI group and the rhGH group(P < 0.05 or P < 0.01). During follow-up, 63.9%of the children in the rhGH+AI group had elevated uric acid and 51.9%had decreased high-density lipoprotein (HDL); 25.9%showed severe acne, excitement, hyperactivity and irritability, 11.1%had knee pain; 4.6%had fracture; 2.8%had mild renal dysfunction; 1.9%had inactivity, drowsiness, memory loss and performance decline; 1.9%showed mild abnormal liver function; 0.9%showed impaired fasting glucose; 0.9%showed granulocytopenia. In the rhGH group, 11.6%of the children presented with knee pain and 2.3%with impaired fasting glucose. Conclusions: AI combined with rhGH can delay the growth of BA and effectively improve the PAH of adolescent boys with larger bone age. However, the occurrence of adverse reactions of AI should be closely monitored during treatment.

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Reconsideration of the third-generation non-steroidal aromatase inhibitors in pediatrics
WANG Chunlin,LIANG Li
J Zhejiang Univ (Med Sci)    2020, 49 (3): 275-282.   DOI: 10.3785/j.issn.1008-9292.2020.04.01
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Aromatase is the rate-limiting enzyme in estrogen biosynthesis. The third generation aromatase inhibitors (AIs), represented by letrozoleand and anastrozole, can combine with aromatase, effectively reducing the estrogen level in the body. Because of its high efficiency, selectivity and reversibility, it has been used in the treatment of McCune-Albright syndrome, familial male-limited precocious puberty, gynecomastia, and adolescent boy with short stature. The good efficacy and safety of AIs have been observed. However, so far the drug instructions of AIs usually do not show indications for children; there are risks of adverse reactions involving liver and kidney function, lipid metabolism, hyperandrogenemia and bone metabolism; especially the long-term effects on reproductive system and bone metabolism are still not clear. Therefore, it is necessary to prescribe it carefully and follow up closely. It was not recommended that AIs be routinely used to improve adult height of adolescent boy with short stature. And more clinical evidences are needed for the safety and effectiveness of AIs prescribed in pediatrics.

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Identification of dynamic co-expression networks in peripheral blood of rats after middle cerebral artery occlusion
PAN Zongfu,HU Xiaoping,ZHANG Yiwen,LI Li,HUANG Ping
J Zhejiang Univ (Med Sci)    2019, 48 (6): 587-593.   DOI: 10.3785/j.issn.1008-9292.2019.12.01
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Objective: To identify the time dependent profiles of gene expression and featured co-expression network modules in peripheral blood of rats after middle cerebral artery occlusion (MCAO). Methods: Microarray GSE119121 from GEO database was analyzed by R language to identify the significantly changed genes in peripheral blood at different time points (0, 1, 2, 3, 6 and 24 h) after MCAO. Gene expression patterns at different time courses were screened by STEM tools. Then, function annotation and pathway enrichment of differentially expressed genes (DEGs) were performed using the Gene Ontology (GO) database and the Kyoto Gene and Genomic Encyclopedia (KEGG) database. Depending on CEMiTool package, gene expression profile matrix was inputted into R to construct the co-expression networks and to analyze modules, and enrichment analysis was conducted to evaluate the correlation between the modules and different time points. Results: Comparing with gene at 0 h, the numbers of DEGs in peripheral blood at different time points after MCAO were 163 (1 h), 502 (2 h), 527 (3 h), 550 (6 h), and 75 (24 h), respectively. Moreover, a total of 38 gene expression patterns were enriched, and pattern 65 and pattern 34 were specifically up-regulated or down-regulated at 2-6 h. Hp, Nos2, P2ry10, and Klf12 were representative genes of these two models. The co-expression network module analysis showed that the gene status in the early acute phase (1-6 h) was positively correlated with the Module 2. Module 3 and Module 4 was positively correlated with phase phase 1-3 h and 2-6 h, respectively. Noteworthy, Module 6 gradually changed from positive correlation (0-2 h) to negative correlation (3-24 h) with the MCAO time course, and Module 6 was mainly related to viral response and innate immune response. The hub genes of Module 6 included Mx1, Mx2, and Rtp4. Conclusion: Our study has identified the featured genes and dynamic co-expression network modules in peripheral blood after acute ischemic stroke, which provides a potential basis for judging the onset time of ischemic stroke.

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Analysis of medication characteristics of traditional Chinese medicine in treating COVID-19 based on data mining
FAN Tiantian,CHEN Yongcan,BAI Yu,MA Fengqi,WANG Hengcang,YANG Yiping,CHEN Jinxu,LIN Yuqi
J Zhejiang Univ (Med Sci)    2020, 49 (2): 260-269.   DOI: 10.3785/j.issn.1008-9292.2020.03.14
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Objective: To analysis the medication characteristics of the prescriptions issued via open channel by the National and Provincial Health Committee and the State Administration of Traditional Chinese Medicine in treating coronavirus disease 2019 (COVID-19). Methods: We collected the data of traditional Chinese medicine related to treatment plans published by the National and Provincial Health Committee and the State Administration of Traditional Chinese Medicine from the start of COVID-19 outbreak to February 19, 2020. The frequency analysis, cluster analysis and association analysis were performed. Results: The study collected 4 national and 34 regional prevention and treatment plans, 578 items, 84 traditional Chinese formulations, 60 Chinese patent medicines, and 230 Chinese herbs. The high frequently used herbs were Liquorice, Scutellariabaicalensis, Semen armeniacaeamarae, and Gypsum. The commonly used traditional formulations included Maxing Shigan decoction, Yin Qiao powder, and Xuanbai Chengqi decoction. The Chinese patent drugs included Angong Niuhuang pill, Xuebijing injection, and Lianhua Qingwen capsule. The most common paired medications were Ephedra and Semen armeniacaeamarae, Fructusforsythiae and Liquorice. Two core combinations and one novel formula were discovered in the study. Conclusions: Yin Qiao powder and Huopo Xialing decoction are the basic formulations for Weifen syndrome of COVID-19. In addition, Maxing Shigan decoction, Liang Ge powder, Qingwen Baidu decoction and Da Yuan decoction are the basic formulations for Qifen syndrome of COVID-19. The main medication characteristics are clearing heat, entilating lung, removing toxicity and removing turbidity. It shows that removing toxicity and eliminating evil are the prescription thought in treating epidemic disease of traditional Chinese medicine.

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A case of Gilbert syndrome caused by UGT1A1 gene compound heterozygous mutations
OU Weijie,LIN Su,WU Yilong,ZHU Yueyong
J Zhejiang Univ (Med Sci)    2020, 49 (3): 406-409.   DOI: 10.3785/j.issn.1008-9292.2020.04.13
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A case of Gilbert syndrome (GS) with a heterozygous mutation in the UGT1A1 gene is reported. The patient had no symptoms except for recurrent sclera icterus since childhood. Laboratory examinations revealed an elevated unconjugated bilirubin. Biliary obstruction, hemolysis and other diseases that might cause jaundice were excluded. UGT1A1*28 and c.211G>A heterozygous mutations in UGT1A1 gene were found, which may be another type of mutation causing GS in Chinese population.

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Application of Logistic regression and decision tree analysis in prediction of acute myocardial infarction events
ZHANG Sheng,HU Zhenjie,YE Lu,ZHENG Yaru
J Zhejiang Univ (Med Sci)    2019, 48 (6): 594-602.   DOI: 10.3785/j.issn.1008-9292.2019.12.02
Abstract   HTML PDF (1713KB) ( 47 )  

Objective: To evaluate the application of decision tree method and Logistic regression in the prediction of acute myocardial infarction (AMI) events. Methods: The clinical data of 295 patients, who underwent coronary angiography due to angina or chest pain with unidentified causes in Zhejiang provincial People's Hospital during October 2018 and April 2019, were retrospectively analyzed. Fifty five patients were identified as AMI. Logistic regression and decision tree methods were performed to establish predictive models for the occurrence of AMI, respectively; and the models created by decision tree analysis were divided into Logistic regression-independent model (Tree 1) and Logistic regression-dependent model (Tree 2). The performance of Logistic regression and decision tree models were compared using the area under the receiver operating characteristic (ROC) curve. Results: Logistic regression analysis showed that history of coronary artery disease, multi-vessel coronary artery disease, statin use and apolipoprotein (ApoA1) level were independent influencing factors of AMI events (all P < 0.05). Logistic regression-independent decision tree model (Tree 1) showed that multi-vessel coronary artery disease was the root node, and history of coronary artery disease, ApoA1 level (the cutoff value:1.314 g/L) and anti-platelet drug use were descendant nodes. In Logistic regression-dependent decision tree model (Tree 2), multi-vessel coronary artery disease was still the root node, but only followed by two descendant nodes including history of coronary artery disease and ApoA1 level. The area under the curve (AUC) of ROC of Logistic regression model was 0.826, and AUCs of decision tree models were 0.765 and 0.726, respectively. AUC of Logistic regression model was significantly higher than that of Tree 2 (95% CI=0.041-0.145, Z=3.534, P < 0.001), but was not higher than that of Tree 1 (95% CI=-0.014-0.121, Z=-1.173, P>0.05). Conclusion: The predictive value for AMI event was comparable between Logistic regression-independent decision tree model and Logistic regression model, implying the data mining methods are feasible and effective in AMI prevention and control.

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Research progress on mechanism in adaptation of hemoglobin to plateau hypoxia
LI Xue,LI Wenbin,FENG Shilan,WANG Rong
J Zhejiang Univ (Med Sci)    2019, 48 (6): 674-681.   DOI: 10.3785/j.issn.1008-9292.2019.12.13
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Low oxygen partial pressure is the main cause of acute mountain sickness.Hemoglobin plays a crucial physiological role in the binding, utilization, transportation and release of oxygen in the body. To increase the capacity of oxygen binding of hemoglobin or the capacity of oxygen supply in tissues can help alleviate altitude sickness. However, increasing hemoglobin content has certain limitations. Using techniques from molecular biology, researchers are looking for endogenous or exogenous substances that can regulate the conformation of hemoglobin to increase oxygen uptake in the alveoli, or the availability of alveolar oxygen in the tissues. At present, the research on allosteric modulators to improve the affinity of hemoglobin has made some progress, and research on applying this mechanism to plateau hypoxia is also underway. This article reviews the relationship between hemoglobin and hypoxia, the structure of hemoglobin and the role of various allosteric modulators in hypoxia, which would provide information for finding new substances regulating the conformation of hemoglobin.

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Effects of resveratrol on aging of mesenchymal stem cells and its mechanism
ZHANG Dayong,LIN Jiuzhou,WANG Yayan,XU Shan,LUO Chengzhuan,CAI Jiaye,JIANG Xuefan,PAN Jianping
J Zhejiang Univ (Med Sci)    2019, 48 (6): 617-624.   DOI: 10.3785/j.issn.1008-9292.2019.12.05
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Objective: To investigate the effects of resveratrol (Res) on aging of marrow mesenchymal stem cells (MSCs), and to explore its mechanism. Methods: MSCs were isolated from young SD rats and cultured in vitro. The optimal D-gal concentration for induction of MSCs senescence was determined. Then MSCs were randomly divided into four groups, namely the control group, 10μmol/L, 50μmol/L and 100μmol/L Res groups. After the cells were treated with different concentration of Res for 48 h, the senescence-associated changes were examined with senescence-associated-β-galactosidase (SA-β-gal) staining; the expression of p53, p16 and γ-H2AX was evaluated by Western blot. The total active oxygen species (ROS) level was determined by flow cytometry with DCFH-DA staining. In order to assess the effect of Res on the mitochondrial function, MitoSox Red staining was used to detect mitochondrial ROS levels in each group, mitochondrial membrane potential was detected by JC-1 assay, mPTP method was used to detect mitochondrial membrane channel opening level, and Western blot was used to detect the expression level of cytoplasmic cytochrome C (Cyt-C). Results: D-gal 10 and 50 g/L significantly increased the number of SA-β-gal positive cells and the level of mitochondrial ROS (all P < 0.01). Therefore, 10 g/L D-gal was used to induce the senescence of MSCs in subsequent experiment. Compared with the control group, the number of SA-β-gal positive cells in Res groups significantly decreased (all P < 0.01), the expression of p53, p16 and γ-H2AX decreased, and the total and mitochondrial ROS level also decreased (all P < 0.01). Moreover, mitochondrial membrane potential, open level of mitochondrial membrane channels and the levels of cytoplasm Cyt-C in the Res treatment groups decreased compared with the control group (P < 0.05 or P < 0.01). Conclusion: Resveratrol can protect the mitochondrial function of MSCs, and effectively delay the MSC senescence.

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Progress on epigenetic regulation of iron homeostasis
DUAN Lingyan,YIN Xiangju,MENG Hong'en,FANG Xuexian,MIN Junxia,WANG Fudi
J Zhejiang Univ (Med Sci)    2020, 49 (1): 58-70.   DOI: 10.3785/j.issn.1008-9292.2020.02.25
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Iron homeostasis plays an important role for the maintenance of human health. It is known that iron metabolism is tightly regulated by several key genes, including divalent metal transport-1(DMT1), transferrin receptor 1(TFR1), transferrin receptor 2(TFR2), ferroportin(FPN), hepcidin(HAMP), hemojuvelin(HJV) and Ferritin H. Recently, it is reported that DNA methylation, histone acetylation, and microRNA (miRNA) epigenetically regulated iron homeostasis. Among these epigenetic regulators, DNA hypermethylation of the promoter region of FPN, TFR2, HAMP, HJV and bone morphogenetic protein 6 (BMP6) genes result in inhibitory effect on the expression of these iron-related gene. In addition, histone deacetylase (HADC) suppresses HAMP gene expression. On the contrary, HADC inhibitor upregulates HAMP gene expression. Additional reports showed that miRNA can also modulate iron absorption, transport, storage and utilization via downregulation of DMT1, FPN, TFR1, TFR2, Ferritin H and other genes. It is noteworthy that some key epigenetic regulatory enzymes, such as DNA demethylase TET2 and histone lysine demethylase JmjC KDMs, require iron for the enzymatic activities. In this review, we summarize the recent progress of DNA methylation, histone acetylation and miRNA in regulating iron metabolism and also discuss the future research directions.

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Efficacy and safety of letrozole in treatment of male children with disorders of sex development
YU Bingqing,NIE Min,WU Xueyan,MAO Jiangfeng,WANG Xi,MA Wanlu,JI Wen,HUANG Qibin,ZHANG Rui
J Zhejiang Univ (Med Sci)    2020, 49 (3): 297-301.   DOI: 10.3785/j.issn.1008-9292.2020.04.02
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Objective: To investigate the efficacy and safety of aromatase inhibitor letrozole in treatment of male children with disorders of sex development (DSD). Methods: Clinical data of 12 male DSD children with a mean age of 14.6±2.5 years admitted to Peking Union Medical College Hospital from January 2014 to January 2016 were retrospectively analyzed. The patients were treated with letrozole (1.25-2.5 mg, once a day) for 3 months or longer, and followed up for 0.5-2.5 years. Clinical manifestation and laboratory test findings were documented, and the efficacy and safety were evaluated. Results: After half-year treatment, the blood luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone levels of patients increased (all P < 0.05), and estrogen levels decreased from baseline (P < 0.05). After 1 year of treatment, the blood testosterone level was significantly higher (P < 0.05); the LH and FSH levels tended to increase and the estrogen level tended to decrease, but there was no significant statistical difference (P>0.05). Semen was routinely detected in 8 patients, and sperms were detected in semen of 3 patients with hypospadias. There were no significant changes in biochemical results after treatment, and no significant adverse event was observed during the treatment. Conclusion: Letrozole can effectively increase testosterone levels in patients with disorders of sex development and promote spermatogenesis, it has no significant adverse effects in short-term administration.

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Emerging roles of Hippo signaling pathway in gastrointestinal cancers and its molecular mechanisms
HUANG Yaoping,YANG Feng,ZHOU Tianhua,XIE Shanshan
J Zhejiang Univ (Med Sci)    2020, 49 (1): 35-43.   DOI: 10.3785/j.issn.1008-9292.2020.02.23
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Hippo signaling pathway is highly conservative in evolution. MST1/2, LATS1/2, and the effector protein YAP/TAZ are the core members of this signaling pathway in mammalian cells. There have been many studies on YAP/TAZ and its downstream, however, the upstream regulatory factors of the Hippo signaling pathway remain unclear, and become one of the hot research directions of this pathway at present. In addition, Hippo signaling pathway can cross-talk with other signaling pathways such as Wnt and Notch signaling pathways, and plays an important role in controlling organ size, maintaining tissue homeostasis, and promoting tissue repair and regeneration. Abnormal Hippo signaling pathway may lead to the occurrence of a variety of tumors, especially gastrointestinal cancers such as liver cancer, colorectal cancer and gastric cancer. The abnormal expression of its members in gastrointestinal cancers is related to cancer cell proliferation, apoptosis, invasion and migration. Hippo signaling pathway is vital for liver repair and regeneration. Its inactivation will lead to the occurrence of primary liver cancer. The mechanism of YAP in liver cancer mainly depends on TEAD-mediated gene transcription. Hippo signaling pathway is also important for maintaining intestinal homeostasis, and its imbalance can lead to the occurrence and recurrence of colorectal cancer. In primary and metastatic gastric cancer, the expression of YAP/TAZ is significantly up-regulated, but the specific molecular mechanism is unclear. This article summarizes the recent progress on Hippo signaling pathway and its upstream regulatory factors, its roles in the development of gastrointestinal cancers and related molecular mechanisms; and also discusses the future research directions of Hippo signaling pathway.

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Progress on utilizing mesenchymal stem cells as cellular delivery system for targeting delivery of as drug/gene for anti-tumor therapy
LI Ai,ZHANG Tianyuan,GAO Jianqing
J Zhejiang Univ (Med Sci)    2020, 49 (1): 20-34.   DOI: 10.3785/j.issn.1008-9292.2020.02.22
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Mesenchymal stem cells (MSCs) have the inherent tumor-homing ability with the attraction of multiple chemokines released by tumor tissues or tumor microenvironments, which can be utilized as promising cellular carriers for targeted delivery of anti-tumor drugs and genes. In most circumstances, large amount of systemicly administrated MSCs will be firstly trapped by lungs, following with re-distribution and homing to tumor tissues after lung clearance. Several approaches like enhanced interactions between chemokines and receptors on MSCs or reducing the retention of MSCs by changes of administration methods are firstly reviewed for improving the homing of MSCs towards tumor tissues. Additionally, the potentials and gains of utilizing MSCs to carry several chemotherapeutics, such as doxorubicin, paclitaxel and gemcitabine are summarized, showing the advantages of overcoming the short half-life and poor tumor targeting of these chemotherapeutics. Moreover, the applications of MSCs to protect and deliver therapeutic genes to tumor sites for selectively tumor cells eliminating or promoting immune system are highlighted. In addition, the potentials of using MSCs for tumor-targeting delivery of diagnostic and therapeutic agents are addressed. We believed that the continuous improvement and optimization of this stem cells-based cellular delivery system will provide a novel delivery strategy and option for tumor treatment.

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Coagulation dysfunction in COVID-19
XU Yiming,LYU Dandan,YING Kejing
J Zhejiang Univ (Med Sci)    2020, 49 (3): 340-346.   DOI: 10.3785/j.issn.1008-9292.2020.05.02
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In addition to common clinical features, patients with coronavirus disease 2019 (COVID-19) have varying degree of coagulation dysfunction with the risk of thrombosis and/or bleeding. COVID-19 related coagulation dysfunction is a dynamic process, which may be accompanied by the formation of disseminated intravascular coagulation and is related to the severity of the disease. The imbalance of the body's immune and inflammatory response caused by coronavirus infection is an important cause of coagulation dysfunction. Dynamic monitoring as well as early prevention and treatment are of great significance for improving the prognosis of patients. This article reviews the research progress of COVID-19 related coagulation dysfunction, to provide reference for clinical research and management.

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Correlation between histone methylation level and pathological development of osteoarthritis
DU Xiaotian,OUYANG Hongwei
J Zhejiang Univ (Med Sci)    2019, 48 (6): 682-687.   DOI: 10.3785/j.issn.1008-9292.2019.12.14
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Osteoarthritis is the most common degenerative cartilage disease. A large number of studies have shown the close association between epigenetics and osteoarthritis. Histone methylation is a type of epigenetic modification, and the link between histone methylation and osteoarthritis has also been revealed. In this article, we summarize the correlation between methylation levels of different histones and osteoarthritis in an attempt to explore the changes and regulation mechanisms of histone methylation in osteoarthritis. It has been shown that there are possible relations between the methylation levels of different amino acids on histone H3 and the pathological development of osteoarthritis; specifically, the rise of methylation level at the lysine 4 would aggravate the pathological development of osteoarthritis, while the the pattern of lysine 9 and 27 would be the opposite. These results indicate the possible existence of a complex network of histone methylation modifications. And the specific regulation of histone methylation levels in different positions may delay or prevent the occurrence and development of osteoarthritis.

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Efficacy and safety of letrozole in treatment of McCune-Albright syndrome girls with peripheral precocious puberty
XU De,LU Wenli,WANG Xueqing,WANG Junqi,XIE Yiwen,DONG Zhiya,WANG Wei
J Zhejiang Univ (Med Sci)    2020, 49 (3): 291-296.   DOI: 10.3785/j.issn.1008-9292.2020.04.03
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Objective: To evaluate the efficacy and safety of the third-generation aromatase inhibitor letrozole in the treatment of McCune-Albright syndrome (MAS) girls with peripheral precocious puberty. Methods: Twenty-one MAS girls with peripheral precocious puberty treated in Pediatrics Department of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from March 2012 to June 2017 were enrolled in the study. Patients presented with repeated vaginal bleeding, premature breast enlargement, café-au-lait spots or dysplasia of bone fibers, and low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); and the congenital adrenal hyperplasia, estrogen-producing tumors, and exogenous estrogen intake were excluded. Letrozole were administrated at a dose of 0.5-2 mg·m-2·d-1 for 6 to 12 months. The patients were observed for changes in breast staging, vaginal bleeding, sex hormone levels, liver function and bone age changes, and changes in uterine and ovarian volume. Results: After treatment, bone age/chronological age (BA/CA)was decreased from 1.23±0.30 to 1.11±0.18 (P < 0.01); the predicted adult height (PAH) increased from (156.2±5.9)cm to (158.4±2.1)cm after treatment (P < 0.05); the vaginal bleeding was reduced and the estradiol level decreased, while the teststosterone level and the uterus showed no significant increase, and no adverse reactions such as ovarian torsion and abnormal liver function were observed. Conclusion: Precocious puberty is one of the most common endocrine manifestations in MAS. Our findings suggest that letrozole may be an effective and safe therapy to precocious puberty in girls with McCune-Albright Syndrome.

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Expression of TLR4/MyD88/NF-κB pathway genes and its related inflammatory factors in secondary spinal cord injury
MI Shuang,WU Yanjun,HONG Zhenghua,WANG Zhangfu,FENG Xingbing,ZHENG Guangbin
J Zhejiang Univ (Med Sci)    2019, 48 (6): 609-616.   DOI: 10.3785/j.issn.1008-9292.2019.12.04
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Objective: To investigate the expression of Toll-like receptor 4 (TLR4)/myeloid differentiation factor (MyD88)/nuclear factor-κB (NF-κB) pathway genes and related inflammatory factors tumor necrosis factor-α (TNF-α), interleukin (IL)-12, IL-6 in patients with secondary spinal cord injury (SSCI) and the correlations with prognosis. Methods: The clinical data of 105 SSCI patients and 40 healthy subjects were reviewed. According to Frankel's classification of spinal cord injury, the patients were divided into complete injury group and incomplete injury group, and according to the improvement of Japanese Orthopedic Association (JOA) scores, the patients were divided into good prognosis group and poor prognosis group. The expression of TLR4, MyD88, NF-κB in peripheral blood mononuclear cells (PBMC) and serum TNF-α, IL-12, IL-6 levels were compared between SSCI patients and healthy controls, between patients with complete and incomplete injury, between patients with poor and good prognosis. Logistic regression analysis was used to analyze the risk factors leading to poor prognosis of SSCI, and Pearson's correlation analysis was used to analyze the correlation between JOA score and the above indicators. Results: The expressions of TLR4, MyD88, NF-κB in PBMC and serum TNF-α, IL-12, IL-6 levels in SSCI patients were significantly higher than those in healthy subjects (all P < 0.01), those in complete injury group were higher than those in incomplete injury group, and those in poor prognosis group were higher than those in good prognosis group (all P < 0.01). The proportions of patients with Frankel grade A, spinal cord edema or hemorrhage, spinal cord injury length longer than 4 cm in poor prognosis group was significantly higher than those in good prognosis group (all P < 0.01). Logistic regression analysis showed that Frankel grade, spinal cord edema or hemorrhage, length of spinal cord injury, relative expressions of TLR4, MyD88, NF-κB in PBMC, serum levels of TNF-α, IL-12 and IL-6 were risk factors for poor prognosis in SSCI patients (P < 0.05 or P < 0.01). Pearson's correlation analysis showed that JOA improvement rate was negatively correlated with the relative expressions of TLR4, MyD88, NF-κB mRNA in PBMC and serum TNF-α, IL-12, IL-6 levels (P < 0.05 or P < 0.01). Conclusion: The activation of TLR4/MyD88/NF-κB pathway and the up-regulation of the expression of related inflammatory factors TNF-α, IL-12 and IL-6 are involved in the progression of SSCI, which are closely related to the neuroinflammatory injury, and can be used as reference indexes for evaluating prognosis in SSCI patients.

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Effect of genipin pretreatment on type Ⅰ collagen mineralization
GU Tianyi,SHUAI Jing,CHEN Chaoqun,FENG Jianying
J Zhejiang Univ (Med Sci)    2019, 48 (6): 638-643.   DOI: 10.3785/j.issn.1008-9292.2019.12.08
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Objective: To investigate the effects of bio-crosslinker genipin pretreatment on type Ⅰ collagen mineralization. Methods: Type Ⅰ collagen gels were prepared and pretreated with 0.5wt%genipin (experimental group) and deionized water (control group) for 2 h, respectively. The pretreated products were subjected to Fourier transform infrared spectroscopy (FT-IR). Reconstituted collagen fibrils were pretreated with genipin or deionized water for 2 h and were mineralized for 4 h. The collagen density and mineralization degree were examined with transmission electron microscopy (TEM) and analyzed with ImageJ software. Then scanning electron microscopy (SEM) and TEM were used to observe the mineralization of cross-linked demineralized dentin collagen. Results: FT-IR spectrum showed that the genipin was crosslinked with collagen. TEM observation and ImageJ results showed that after 4 h mineralization, the mineralization effect of 0.5wt% genipin group was significantly better than that of the control group[(73.3±5.3)%vs.(7.4±3.5)%, P < 0.01]. TEM and SEM observation showed that the mineralization rate of type Ⅰ collagen and demineralized dentin pretreated with genipin were significantly faster than that of the control group. Conclusion: The study demonstrates that 0.5 wt% concentration of genipin can significantly promote the mineralization of type Ⅰ collagen.

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Chloroxoquinoline inhibits invasion in breast cancer via down-regulating Rho/Rho kinase signaling pathway
LIU Jingwen,YANG Xinglian,SHEN Kaili,ZENG Linghui,SUN Yan
J Zhejiang Univ (Med Sci)    2019, 48 (6): 631-637.   DOI: 10.3785/j.issn.1008-9292.2019.12.07
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Objective: To investigate the effect of chloroxoquinoline on cytoskeleton of breast cancer cells and its relation with Rho/Rho kinase signaling pathway. Methods: Breast cancer Bcap37 and MDA-MB-453 cells were treated with different concentrations of chloroxoquinoline. Wound healing and Transwell assay were conducted to detect cell migration and invasion, respectively. Rhodamine-phalloidin staining and immunofluorescent staining were used to observe the polymerization state of F-actin and the expression of α-Tublin in breast cancer cells, respectively. Western blot was used to detect the phosphorylation level of key protein in Rho/Rho kinase signaling pathway. Results: Compared with the control group, chloroxoquinoline treatment induced dose-dependent decrease in cell migration and invasion, and Bcap37 and MDA-MB-453 cells treated with chloroxoquinoline showed dose-dependent changes in cell morphology and decrease in cell body. The staining of F-actin and α-Tublin was irregular and clustered. Furthermore, treatment of chloroxoquinoline down-regulated the phosphorylation of the Rho/Rho kinase signaling proteins Cofilin, Limk and Rock2 (all P < 0.01). Conclusions: Chloroxoquinoline inhibits the cytoskeleton in breast cancer Bcap37 and MDA-MB-453 cells and inhibits cell migration. This effect may be associated with down-regulation of Rho/Rho kinase signaling pathway.

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Comparative analysis of structural characteristics and epitopes in S proteins between SARS-CoV-2 and SARS-CoV
LUN Yongzhi,LIU Ben,DONG Wen,SUN Jie,PAN Linghong
J Zhejiang Univ (Med Sci)    2020, 49 (3): 315-323.   DOI: 10.3785/j.issn.1008-9292.2020.05.01
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Objective: To provide data support for the study of pathogenic mechanism of SARS-CoV-2 at the molecular level, and provide suitable candidate targets for vaccine, antibody and drug research and development through comparative analysis for structural characteristics and epitopes of S protein of SARS-CoV-2 and SARS-CoV. Methods: Based on the reference sequences of S protein, physical and chemical properties, hydrophobicity, signal peptide, transmembrane region, domain, secondary structure, tertiary structure analysis and antigenic epitopes prediction were carried out. Meanwhile, the tissue expression, related pathways and reactome pathways of angiotensis Ⅰ converting enzyme 2 (ACE2) and C-type lectin domain family 4 member M (CLEC4M) receptors were analyzed. Results: The amino acid sequence of S protein of SARS-CoV-2 and SARS-CoV has a 75.80% consistency. The structural characteristics of the two coronaviruses are highly consistent, but the secondary structure and tertiary structure of SARS-CoV-2 is not as obvious as SARS-CoV. ACE2 and CLEC4M are expressed in alimentary system, heart, kidney, lung and placenta. The main related the pathways of renin-angiotensin system, protein digestion and absorption pathway, and the reactome pathways of metabolism of angiotensinogen to angiotensins, GPCR ligand binding, are related to typical symptoms of coronavirus disease 2019 induced by SARS-CoV-2. Three pairs of highly or completely homologous epitopes of S protein were obtained. The 600-605, 695-703 and 888-896 amino acid residues in SARS-CoV-2 were highly homologous with 586-591, 677-685 and 870-878 amino acid residues in SARS-CoV, respectively. Conclusions: The similarity of S protein of SARS-CoV-2 and SARS-CoV determines that they have similar infection patterns and clinical manifestations. The candidate epitopes with high reliability can provide reference for virus diagnosis and vaccine development.

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Relationship of group B streptococcus colonization in late pregnancy with perinatal outcomes
YANG Lindong,BAO Fang,WU Yuanzhe,SUN Lizhou
J Zhejiang Univ (Med Sci)    2020, 49 (3): 389-396.   DOI: 10.3785/j.issn.1008-9292.2020.04.12
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Objective: To investigate the relationship of group B streptococcus (GBS) colonization in late pregnancy with perinatal outcome. Methods: Pregnant women who underwent antenatal check-up at General Hospital of PLA Eastern Theater Command and the First Affiliated Hospital of Nanjing Medical University from January 2016 to December 2018 were enrolled in the study. The vaginal and rectal swab samples were collected for GBS culture at 35-37 weeks of pregnancy. The perinatal outcomes of positive and negative GBS groups were compared. The GBS-positive group samples were tested for antibiotic susceptibility. In GBS positive group the maternal and child perinatal outcomes were compared between pregnant women with antibiotics treatment and those without antibiotics. Results: A total of 13 000 pregnant women were enrolled, and the overall colonization rate of GBS was 3.65%(475/13 000). The colonization rate of GBS in the vagina was 2.33%(303/13 000), and the colonization rate in the rectum was 1.75%(227/13 000). Through the collection and detection of rectal specimens, the positive rate of GBS increased by 56.77%(172/303). The monthly colonization rate of GBS showed significant fluctuations with the highest in March and October (all P < 0.05). The sensitivity of 475 GBS-positive specimens to ceftriaxone, vancomycin and linezolid were 100%, and the sensitivity to ampicillin and penicillin were 97.26%and 93.47%, respectively. The resistance rates of the strains to levofloxacin, clindamycin, erythromycin and tetracycline were 30.11%, 48.00%, 52.21%and 88.63%. The incidence of premature rupture of membranes, postpartum hemorrhage, puerperal infection, neonatal pneumonia and sepsis in GBS positive group were significantly higher than those in GBS negative group (all P < 0.01). In pregnant women with positive GBS, the incidence of puerperal infection, neonatal infection and admission to the NICU in the antibiotic group were significantly lower than those in the non-antibiotic group (P < 0.05 or P < 0.01). Conclusions: The total colonization rate of GBS is low. The detection of GBS can be significantly improved by supplementing rectal examination. Ceftriaxone, ampicillin and penicillin are currently the drugs of choice for the prevention and treatment of GBS-related diseases. GBS infection can increase the incidence of maternal and child complications. The use of antibiotics during labor can improve the outcome of mothers and infants.

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Research progress on neutrophil extracellular traps in tumor
XU Yiming,YING Kejing
J Zhejiang Univ (Med Sci)    2020, 49 (1): 107-112.   DOI: 10.3785/j.issn.1008-9292.2020.02.11
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Neutrophil extracellular traps(NET)is neutrophil-derived extracellular fiber web-like structure, composed of DNA scaffold studded with various active proteins. In addition to its bactericidal effect, NET is closely related to various diseases including immune disease, thrombosis and tumor. Recently, lots of researches have shown that NET is highly expressed in a variety of tumors, tumor cells and microenvironment can promote NET formation, whereas NET participates in tumor progression as well, and is closely related to tumor proliferation, metastasis and thrombosis, which provides new clinical thinking in tumor diagnosis as well as treatment indeed. This review will focus on the research progress of NET and tumor, meanwhile make a prospect for its clinical application value.

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Research progress on the effects of plateau hypoxia on blood-brain barrier structure and drug permeability
DING Yidan,LI Wenbin,WANG Rong,ZHANG Jianchun
J Zhejiang Univ (Med Sci)    2019, 48 (6): 668-673.   DOI: 10.3785/j.issn.1008-9292.2019.12.12
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Drugs for the treatment of central nervous system diseases need to enter the brain tissue through the blood-brain barrier to function. In high altitude hypoxic environment, there are changes in tight junction proteins of blood-brain barrier tissue structure, transporters in astrocytes and endothelial cells and ATP in endothelial cells; at the same time the permeability of the blood-brain barrier is increased. These changes are an important reference for rational drug use in patients with central nervous system disease in the plateau region. This article reviews the research progress on the effects of plateau hypoxia on the structure of the blood-brain barrier and related drug permeability.

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Correlation of cardiovascular risk factors with brain iron deposition: A magnetic resonance imaging study
HU Linlin,ZHANG Ruiting,WANG Shuyue,HONG Hui,HUANG Peiyu,ZHANG Minming
J Zhejiang Univ (Med Sci)    2019, 48 (6): 644-650.   DOI: 10.3785/j.issn.1008-9292.2019.12.09
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Objective: To study the correlation of common cardiovascular risk factors with brain iron deposition. Methods: Eighty-four elderly subjects without neurological diseases or brain trauma were included in the study. The cardiovascular risk factors were comprehensively assessed. MRI examination was performed to obtain high-resolution T1-weighted images and enhanced susceptibility weighted angiography (ESWAN) images, and R2* figure was obtained by post-processing the ESWAN sequence. High definition T1 images were segmented using computer segmentation technique. After registration to the ESWAN image, R2* values of each region of interest were extracted. Multiple linear regression analysis was used to analyze the relationship of R2* values in each area of interest with gender, age and vascular risk factors. Results: Smoking was associated with increased R2* values in the hippocampus, white matter and cortex (β=0.244, 0.317, 0.277, P < 0.05 or P < 0.01). Hypertension was correlated with the increase of R2* in the putamen (β=0.241, P=0.027). Hyperglycemia was associated with the increase of R2* in the thalamus (β=0.234, P < 0.05). In the thalamus, the R2* value of males was higher than that of females (β=0.320, P < 0.05). Age was correlated with the R2* values of thalamus, caudate nucleus, pallidus, white matter and cortex (β=-0.218、-0.254、0.216、-0.280 and -0.238, P < 0.05 or P < 0.01). Conclusion: Common cardiovascular risk factors may lead to iron deposition in the brain, and the deposition patterns vary with the gender, age and different risk factors.

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Poly adenosine diphosphate-ribosylation and neurodegenerative diseases
WANG Yi,LU Yunbi
J Zhejiang Univ (Med Sci)    2020, 49 (1): 100-106.   DOI: 10.3785/j.issn.1008-9292.2020.02.10
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The morbidity of neurodegenerative diseases are increased in recent years, however, the treatment is limited. Poly ADP-ribosylation (PARylation) is a post-translational modification of protein that catalyzed by poly(ADP-ribose) polymerase (PARP). Studies have shown that PARylation is involved in many neurodegenerative diseases such as stroke, Parkinson's diseases, Alzheimer's disease, amyotrophic lateral sclerosis and so on, by affecting intracellular translocation of protein molecules, protein aggregation, protein activity, and cell death. PARP inhibitors have showed neuroprotective efficacy for neurodegenerative diseases in pre-clinical studies and phase Ⅰ clinical trials. To find new PARP inhibitors with more specific effects and specific pharmacokinetic characteristics will be the new direction for the treatment of neurodegenerative diseases. This paper reviews the recent progress on PARylation in neurodegenerative diseases.

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Efficacy of letrozole in treatment of children with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency
WANG Qian,ZHANG Shule,MA Xue,LI Guimei,WANG Zengmin,WANG Fengxue
J Zhejiang Univ (Med Sci)    2020, 49 (3): 302-307.   DOI: 10.3785/j.issn.1008-9292.2020.04.04
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Objective: To assess the efficacy of letrozole in treatment of children with congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency (21-OHD). Methods: Twenty eight children, including 19 boys and 9 girls aged 4-10y, with CAH due to 21-OHD were enrolled in the study. At the first six months of study, all children received conventional treatment with hydrocortisone or fludrocortisone, then letrozole was added to original regimen. The height velocity (HV), difference between bone age and chronological age (BA-CA), height standard diviation score based on bone age (HtSDSBA), predicted adult height (PAH), Tanner phase, sex hormone, and possible adverse reaction were evaluated and compared between those before and after letrozole treatment. Results: After 6 months of letrozole treatment, there was significant deceleration of HV, but it would recover soon. There was significant increase of HtSDSBA after 12 months of letrozole treatment (P < 0.05 or P < 0.01), and significant changes in BA-CA after 18 months of letrozole treatment (P < 0.05). PAH of female children was significantly increased during letrozole treatment (P < 0.05), whereas PAH of male children was significantly increased 18 months after letrozole treatment (P < 0.05). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were significantly increased, but did not meet the diagnostic criteria of central precocious puberty. Estradiol was significantly decreased (P < 0.01), but no changes in testosterone level was observed. During 24 months letrozole treatment, no hirsutism, severe acne, headache, bone pain, obesity, hypertension, rash and other adverse reactions were observed. Conclusions: Letrozole can delay bone maturation and improve PAH, which can be used with conventional treatment for children with CAH due to 21-OHD, especially for those with high BA and low PAH.

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Synthesis and cell biological properties of polyaspartic acid drug/gene vector
SHEN Jie,WANG Qiwen,GAO Dongruo,LYU Yuanyuan,TANG Guping
J Zhejiang Univ (Med Sci)    2019, 48 (6): 657-667.   DOI: 10.3785/j.issn.1008-9292.2019.12.11
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Objective: Taking polysuccinimide as the main chain, amine side chain and alkyl side chain were grafted to prepare the drug/gene co-delivery vector. The property of the polymers with various side links were investigated to select an optimal vector. Methods: Poly-D, L-polysuccinimide was synthesized by polymerization reaction of D, L-aspartic acid as monomer. Therefore, N, N-dimethylenedipropyl-triamine and 3, 3'-diaminodipropylamine were grafted with dodecylamine/adecylamine/octadecylamine at different proportions by ring-opening reaction to obtain amphiphilic PEECs. The structure of the material was confirmed by 1H NMR; the particle size and surface potential of the micelles were measured by dynamic light scattering; the critical micelle concentration (CMC) was determined by pyrene fluorescent probe; the RNA blocking ability was characterized by agarose gel electrophoresis; the release behavior of the PEECs was examined and the cytotoxicity, cellular uptake and gene silencing efficiency of the PEECs were studied at the cellular level. Results: A series of PEECs with different grafting rates was successfully synthesized. The particle sizes and surface potential of the PEEC derived micelles were between 250 nm and 350 nm and 27 mV and 45 mV, respectively, with a small CMC value. The RNA binding ratio of PEECs was at a mass ratio of about 0.8:1. MTT assay demonstrated that PEEC micelles had certain cytotoxicity. PEECs had excellent micelle formation, drug-loading and gene binding abilities, particularly, PEEC16-2 showed high gene silencing efficiency at the cellular level. Conclusion: PEECs are able to co-delivery drug and gene, and PEEC16-2 micelles have the best ability of drug encapsulation and gene delivery.

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