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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
Abstract   HTML PDF (1044KB) ( 37985 )  

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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Research progress on macrophage in radiation induced lung injury
LI Mengyao,LIU Pan,KE Yuehai,ZHANG Xue
J Zhejiang Univ (Med Sci)    2020, 49 (5): 623-628.   DOI: 10.3785/j.issn.1008-9292.2020.10.12
Abstract   HTML PDF (1055KB) ( 402 )  

Radiation-induced lung injury (RILI), including acute radiation pneumonitis and chronic radiation-induced pulmonary fibrosis (RIPF), is a side effect of radiotherapy for lung cancer and esophageal cancer. Pulmonary macrophages, as a kind of natural immune cells maintaining lung homeostasis, play a key role in the whole pathological process of RILI. In the early stage of RILI, classically activated M1 macrophages secrete proinflammatory cytokines to induce inflammation and produce massive reactive oxygen species (ROS) through ROS-induced cascade to further impair lung tissue. In the later stage of RILI, alternatively activated M2 macrophages secrete profibrotic cytokines to promote the development of RIPF. The roles of macrophage in the pathogenesis of RILI and the related potential clinical applications are summarized in this review.

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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
Abstract   HTML PDF (1114KB) ( 6381 )  

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
Abstract   HTML PDF (2555KB) ( 1907 )  

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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Mechanisms underlying remyelination with special focus on demyelination models of multiple sclerosis
ZHENG Shuangshuang,ZHAO Jingwei
J Zhejiang Univ (Med Sci)    2020, 49 (4): 524-530.   DOI: 10.3785/j.issn.1008-9292.2020.08.12
Abstract   HTML PDF (1071KB) ( 217 )  

Failure to remyelinate and rewrap the demyelinated axons has been revealed as the major hurdle for treatment of multiple sclerosis (MS), and the bottleneck is the inability of oligodendrocyte progenitor cell (OPC) to differentiate into mature oligodendrocyte. Remyelination is a spontaneous regenerative process, which includes activation, migration and differentiation of OPC, and is believed to protect the axon and further halt neurodegeneration. In recent years, studies have identified many potential drug targets for efficiently promoting OPC differentiation in in vivo demyelination models, such as metformin, clemostine, and drug targets as myelin transcription factor 1-like protein (Myt1L), N-methyl-D-aspartic acid (NMDA) receptor, connexin 43 (Cx43), G protein coupled receptor 17 (GPR17), κ opioid receptor (KOR), sterol 14α-demethylase (CYP51), Δ14-sterol reductase (TM7SF2), emopamil-binding protein (EBP). This review summarizes the recent progress on the mechanisms underlying the activation, migration and differentiation of OPC in remyelination with special focus on studies using demyelination models of MS, which may provide insights of further exploring new therapeutic strategies for MS.

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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
Abstract   HTML PDF (1077KB) ( 918 )  

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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Research progress on the biomedical application of microalgae
REN Chaojie,ZHONG Danni,ZHOU Min
J Zhejiang Univ (Med Sci)    2021, 50 (2): 261-266.   DOI: 10.3724/zdxbyxb-2021-0117
Abstract   HTML PDF (1977KB) ( 38 )  

Microalgae is an easy-to-obtain natural biological material with many varieties and abundant natural reserves. Microalgae are rich in natural fluorescein, which can be used as a contrast agent for fluorescence imaging and photoacoustic imaging for medical imaging. With its active surface, microalgae can effectively adsorb functional molecules, metal elements, etc., and have good application prospects in the field of drug delivery. Microalgae can generate oxygen through photosynthesis to increase local oxygen concentration, reverse local hypoxia to enhance the efficacy of hypoxic tumors and promote wound healing. In addition, microalgae have good biocompatibility, and different administration methods have no obvious toxicity. This paper reviews the research progress on the biomedical application of microalgae in bioimaging, drug delivery, hypoxic tumor treatment, wound healing.

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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
Abstract   HTML PDF (4462KB) ( 2180 )  

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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Research progress on biomarkers for endometriosis based on lipidomics
LIN Cuicui,CHEN Zhengyun,WANG Chunyan,XI Yongmei
J Zhejiang Univ (Med Sci)    2020, 49 (6): 779-784.   DOI: 10.3785/j.issn.1008-9292.2020.12.14
Abstract   HTML PDF (1022KB) ( 176 )  

The pathogenesis of endometriosis is not well understood at the moment, and the lack of effective biomarkers often leads to delayed diagnosis of the disease. Lipidomics provides a new approach for the diagnosis and prediction of endometriosis. Sphingomyelin, phosphatidylcholine and phosphatidylserine in peripheral blood, endometrial fluid, peritoneal fluid and follicular fluid have good diagnostic value for endometriosis and disease classification; the lipid metabolites in the eutopic endometrium tissue are expected to be biomarkers of early endometriosis; and the lipid metabolites in peripheral blood are also of great value for predicting endometriosis-related infertility. The development of lipidomics technique will further advance the progress on the pathogenesis, prediction, diagnosis and treatment of endometriosis.

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Diagnostic strategies for oral manifestations of infectious diseases
CHEN Qianming,LI Zaiye,ZENG Xin
J Zhejiang Univ (Med Sci)    2021, 50 (2): 141-147.   DOI: 10.3724/zdxbyxb-2021-0105
Abstract   HTML PDF (9639KB) ( 35 )  

Infectious diseases are caused by infection of organism with pathogenic agents, which may lead to epidemics. Many infectious diseases such as syphilis, diphtheria, measles, and acquired immunodeficiency syndrome have specific and non-specific manifestations in the oral cavity. However, the same disease may have different oral manifestations in different patients clinically. We can apply the strategy of “three unusuals and one change” in clinical reasoning for diagnosis of infectious diseases with oral manifestations. The so-called “three unusuals” refer to unusual age, unusual location and unusual effect, and “one change” means the change from rare to common. In this article, we will give a comprehensive introduction about the oral manifestations of common communicable diseases and their diagnostic strategies.

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Chinese medicine Buyang Huanwu decoction promotes neurogenesis and angiogenesis in ischemic stroke rats by upregulating miR-199a-5p expression
ZHUGE Lujie,FANG Yan,JIN Huaqian,LI Lin,YANG Yan,HU Xiaowei,CHU Lisheng
J Zhejiang Univ (Med Sci)    2020, 49 (6): 687-696.   DOI: 10.3785/j.issn.1008-9292.2020.12.03
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Objective: To investigate the mechanism of Chinese medicine Buyang Huanwu decoction (BYHWD) promoting neurogenesis and angiogenesis in ischemic stroke rats. Methods: Male SD rats were randomly divided into sham operation group, model group, BYHWD group, antagonist group and antagonist control group with 14 rats in each. Focal cerebral ischemia was induced by occlusion of the right middle cerebral artery for 90 min with intraluminal filament and reperfusion for 14 d in all groups except sham operation group. BYHWD (13 g/kg) was administrated by gastrogavage in BYHWD group, antagonist group and antagonist control group at 24 h after modeling respectively, and BrdU (50 mg/kg) was injected intraperitoneally in all groups once a day for 14 consecutive days. miR-199a-5p antagomir or NC (10 nmol) was injected into the lateral ventricle at d5 after ischemia in antagonist and antagonist control groups, respectively. The neurological deficits were evaluated by the modified neurological severity score (mNSS) and the corner test, and the infract volume was measured by toluidine blue staining. Neurogenesis and angiogenesis were detected by immunofluorescence double labeling method. The expression level of miR-199a-5p was tested by real-time RT-PCR, and the protein expressions of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) were determined by Western blotting. Results: BYHWD treatment significantly promoted the recovery of neurological function (P < 0.05 or P < 0.01), reduced the infarct volume (P < 0.05), increased the number of BrdU+/DCX+, BrdU+/NeuN+ and BrdU+/vWF+ cells (all P < 0.01), upregulated the expression of miR-199a-5p (P < 0.01), and increased the protein expression of VEGF and BDNF at d14 after cerebral ischemia (all P < 0.05). The above effects were reversed by intracerebroventricular injection of miR-199a-5p antagomir. Conclusion: Buyang Huanwu decoction promotes neurogenesis and angiogenesis in rats with cerebral ischemia, which may be related to increased protein expression of VEGF and BDNF through upregulating miR-199a-5p.

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Progress on structural biology of voltage-gated ion channels
SONG Fangjun,GUO Hongtao
J Zhejiang Univ (Med Sci)    2019, 48 (1): 25-33.   DOI: 10.3785/j.issn.1008-9292.2019.02.05
Abstract   HTML PDF (1097KB) ( 811 )  

Ion channels mediate ion transport across membranes, and play vital roles in processes of matter exchange, energy transfer and signal transduction in living organisms. Recently, structural studies of ion channels have greatly advanced our understanding of their ion selectivity and gating mechanisms. Structural studies of voltage-gated potassium channels elucidate the structural basis for potassium selectivity and voltage-gating mechanism; structural studies of voltage-gated sodium channels reveal their slow and fast inactivation mechanisms; and structural studies of transient receptor potential (TRP) channels provide complex and diverse structures of TRP channels, and their ligand gating mechanisms. In the article we summarize recent progress on ion channel structural biology, and outlook the prospect of ion channel structural biology in the future.

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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
Abstract   HTML PDF (1290KB) ( 658 )  

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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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
Abstract   HTML PDF (2588KB) ( 651 )  

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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Qualitative study on working experience of COVID-19 care nurses
WANG Jinying,HE Jiangjuan,ZHU Jianmei,QIU Jiangying,WANG Huafen,XU Hongzhen
J Zhejiang Univ (Med Sci)    2020, 49 (4): 480-486.   DOI: 10.3785/j.issn.1008-9292.2020.08.07
Abstract   HTML PDF (1077KB) ( 226 )  

Objective: To study the working experience of COVID-19 care nurses. Methods: Twenty two nurses taking care of COVID-19 patients were interviewed by means of descriptive phenomenology. All the data were transcribed and recorded, and then processed into WORD documents. The Colaizzi 7 footwork was used to classify, encode, establish nodes and extract themes based on Nvivo11.0 software. Results: Two main themes were extracted: one is the positive feelings of nurses, including the sense of professional mission and pride, the sense of achievement and happiness, the improvement of self-worth and ability, the powerful support system and the power of role models; the other is the negative experience of nurses, including the worry and anxiety at work, the lack of experience and trust, the difficulty of work, and the inconvenience of isolating life. Conclusions: While fully affirming the work value of nurses, it is necessary for the society, hospitals and patients to give extensive and continuous support, care and respect to nurses, so as to stimulate their working enthusiasm and sense of professional achievement. Hospital managers need to implement all kinds of security work, meet the safety needs of nurses, pay attention to the physical and mental health of nurses, strengthen the training of nursing talents for critical and severe diseases and infectious diseases, improve the allocation of human resources, and enhance the ability of material allocation and reserve for major health events, so as to make adequate preparations for coping with public health events in the future.

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Research progress on etiologic diagnosis of ocular viral diseases
DUAN Runping,XU Yesheng,ZHENG Libin,YAO Yufeng
J Zhejiang Univ (Med Sci)    2020, 49 (5): 644-650.   DOI: 10.3785/j.issn.1008-9292.2020.07.03
Abstract   HTML PDF (1073KB) ( 170 )  

A large number of viruses have been found to be associated with ocular diseases, including human adenovirus, human herpesvirus (HHV), human T lymphotropic virus type-1 (HTLV-1), and newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This group of diseases is prone to be misdiagnosed or missed diagnosis, resulting in serious tissue and visual damage. Etiological diagnosis is a powerful auxiliary mean to diagnose the ocular diseases associated with human adenovirus, herpes simplex virus 1 and varicella-zoster virus, and it provides the leading diagnosis evidence of infections with herpes simplex virus 2, Epstein-Barr virus, cytomegalovirus, HHV-6/7, HHV-8, HTLV-1 and SARS-CoV-2. Virus isolation, immunoassay and genetic diagnosis are usually used for etiologic diagnosis. For genetic diagnosis, the PCR technique is the most important approach because of its advantages of rapid detection, convenient operation, high sensitivity and high specificity.

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T lymphocyte subgroups and serum levels of trace elements in patients with diarrhea type of irritable bower syndrome
Journal of ZheJiang University(Medical Science)    2008, 37 (6): 634-637.   DOI: 10.3785/j.issn.1008-9292.2008.06.015
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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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Effect of glutamine metabolism on chemoresistance and its mechanism in tumors
HU Xinyang,JIN Hongchuan,ZHU Liyuan
J Zhejiang Univ (Med Sci)    2021, 50 (1): 32-40.   DOI: 10.3724/zdxbyxb-2021-0040
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The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required substances for glycolysis and oxidative phosphorylation and affects the homeostasis of carbohydrate,fat and protein metabolism to induce the chemoresistance of tumor cells. Combination of chemotherapeutic agents with inhibitors specific to different components of glutamine metabolic pathway has obtained favorable clinical results on various tumors. Glutamine metabolic pathway plays a role in drug resistance of tumor cells in various ways. Firstly,the dynamic change of glutamine transporters can directly affect intracellular glutamine content thereby causing drug resistance; secondly,tumor stromal cells including adipocyte,fibroblast and metabolite from tumor microenvironment would give rise to immune-mediated drug resistance; thirdly,the expression and activity of key enzymes in glutamine metabolism also has a critical role in drug resistance of tumors. This article reviews the effects of glutamine metabolic pathway in the development of tumor chemoresistance,in terms of transporters,tumor microenvironment and metabolic enzymes,to provide insight for improving the therapeutic efficacy for drug-resistant tumors.

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Clinical diagnosis of oral erosive and ulcerative diseases in children
LIU Chuanxia,CHEN Qianming
J Zhejiang Univ (Med Sci)    2021, 50 (2): 155-161.   DOI: 10.3724/zdxbyxb-2021-0122
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Mucosal disease is one of the most common oral cavity diseases in children, among which mucosal erosion and ulceration account for about 50%. Oral mucosal erosion and ulcer diseases in children are mostly acute with obvious pain, affecting speech, eating and swallowing. Some oral mucosal diseases are caused by infection and would result in epidemic among children. The onset age, sites, lesions size and quantity could vary, and some would have recurrence. The detailed medical history and comprehensive physical examination are necessary, some diseases can be diagnosed according to the medical history and clinical manifestations. If diagnosis can not be made, biopsy, blood test and immunofluorescence staining, immunohistochemistry, molecular biology detection, gene diagnosis, tuberculin test and other tests should be considered, and further investigation of systemic diseases should also be carried out if necessary. In some cases, multidisciplinary consultation should be sought. For those who still have no abnormal findings, therapeutic diagnosis can be tried out or secondary biopsy should be performed. In this article, the research progress of oral mucosal diseases in children is reviewed and our own clinical experiences of oral erosive and ulcerative diseases in children are summarized.

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Establishment of an intelligent cervical vertebrae maturity assessment system based on cone beam CT data
FENG Xiaoyan,LU Shijuan,LI Yiming,LIN Jun
J Zhejiang Univ (Med Sci)    2021, 50 (2): 187-194.   DOI: 10.3724/zdxbyxb-2021-0131
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Objective:To establish an intelligent cervical vertebra maturity assessment system, and to evaluate the reliability and clinical value of the system. Methods: Sixty children aged 8-16?years were recruited in the study. Lateral cephalometric radiograph and cone beam CT (CBCT) were taken at the same period. Based on the CBCT data, the system automatically extracted the patient’s facial area through Otsu’s method, intercepted the sagittal plane by three-dimensional least squares method, captured the second to fourth cervical vertebrae by superpixel segmentation. And then selected points were marked automatically through morphological algorithm and manual method. Consistency test was performed on the two sets of data to compare the reliability of automated cervical morphology capture. According to the parameters of morphological identification, positioning and staging algorithms were designed to form the intelligent cervical vertebra maturity assessment system. The cervical vertebra maturity was also judged manually on the lateral cephalometric radiograph. The weighted Kappa test and the Gamma correlation coefficient were subsequently applied to evaluate the consistency and correlation. Results: The results showed that the cervical vertebra features automatically captured based on CBCT data had a high accuracy on the overall morphological recognition. In the prediction of 8 inflection points out of 13 points, there was no significant difference between automatic and manual method on both X and Y axes (all P>0.05). The assessment results of the cervical vertebra maturity of the intelligent system had strong consistency and correlation with the manual recognition results (weighted Kappa value=0.877, Gamma value=0.991, bothP<0.05).Conclusion:The intelligent cervical vertebrae maturity assessment system based on CBCT data established in this study presents reliable outcome and high degree of automation, indicating that the system may be used clinically.

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Effect of salpingectomy on ovarian function
Journal of ZheJiang University(Medical Science)    2006, 35 (5): 555-559.   DOI: 10.3785/j.issn.1008-9292.2006.05.017
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Clinical analysis of annular pancreas in neonates
WANG Linyan,XUE Jiajin,CHEN Yi,LYU Chengjie,HUANG Shoujiang,TOU Jinfa,GAO Zhigang,CHEN Qingjiang
J Zhejiang Univ (Med Sci)    2019, 48 (5): 481-486.   DOI: 10.3785/j.issn.1008-9292.2019.10.03
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Objective: To analyze clinical manifestations, diagnosis and treatment of annular pancreas in neonates. Methods: Clinical data of 114 neonates with annular pancreas admitted in the Children's Hospital of Zhejiang University from January 2009 to December 2018 were reviewed. The demographic parameters (gestational age, birth weight), clinical manifestations, onset time, results of antenatal examination, associated anomalies, radiological findings, operations, postoperative complications were analyzed. Results: One hundred and two cases were examined by abdominal echography, in which 68 cases showed duodenal obstruction, 4 cases showed annular pancreas. Plain abdomen X-ray examination performed in 113 cases before operation, 76 cases presented double-bubble sign, 12 cases presented single-bubble sign and 5 cases had high-position intestinal obstruction. Upper gastrointestinal radiography (UGI) was performed in 103 cases, which suggested duodenal obstruction in 102 cases. Operations were performed in all cases, of which 69 cases were operated under laparoscopy including 1 case converted to open laparotomy. The mean fasting time after surgery was (7.8±2.7) d, and the mean length of hospital stay was (16.9±10.1) d. Five patients had postoperative complications. The incidence of postoperative complications in antenatal abnormal group was lower than that in the antenatal non-abnormal group (P < 0.05); the average fasting time in laparoendscopic surgery group was shorter than that in traditional laparotomy group (P < 0.05). Conclusions: Neonates with recurrent vomiting early after birth should be highly suspected to have annular pancreas. The fetal chromosome examination should be performed with abnormal antenatal screening. Surgery is the only effective way to diagnose and treat annular pancreas, and laparoscopic surgery could be the first choice for experienced doctors.

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What is narrative medicine?
GUO Liping
J Zhejiang Univ (Med Sci)    2019, 48 (5): 467-473.   DOI: 10.3785/j.issn.1008-9292.2019.10.01
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Narrative medicine first entered China in 2011 and has developed rapidly since then. The patient-centered care, shared decision making and relational medicine in the medical sphere, together with patients narrating their illness and narratology contributed to the rise of narrative medicine. Through listening to patients' narratives, paying attention to their emotions, and representing their stories in various ways, clinicians can connect with patients and empathize with them. In this way, affiliation and mutual trust with patients can be established. Patients will feel good in the doctor-patient encounter because of such humane care, and clinicians may get satisfaction from their work. Narrative medicine courses characterized by close reading of literature and writing should be added to the curriculum of medical education as the major content of medical humanities, so as to train narrative competence for the future doctors.

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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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Astragaloside Ⅳ inhibits inflammation after cerebral ischemia in rats through promoting microglia/macrophage M2 polarization
ZHENG Xintian,GAN Haiyan,LI Lin,HU Xiaowei,FANG Yan,CHU Lisheng
J Zhejiang Univ (Med Sci)    2020, 49 (6): 679-686.   DOI: 10.3785/j.issn.1008-9292.2020.12.02
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Objective: To investigate the effects of astragaloside Ⅳ (AS-Ⅳ) on microglia/macrophage M1/M2 polarization and inflammatory response after cerebral ischemia in rats. Methods: Forty eight male SD rats were randomly divided into sham operation control group, model control group and AS-Ⅳ group with 16 rats in each. Focal cerebral ischemia model was induced by occlusion of the right middle cerebral artery (MCAO) using the intraluminal filament. After ischemia induced, the rats in AS-Ⅳ group were intraperitoneally injected with 40 mg/kg AS-Ⅳ once a day for 3 days. The neurological functions were evaluated by the modified neurological severity score (mNSS) and the corner test on d1 and d3 after modelling. The infarct volume was measured by 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining on d3 after ischemia. The expression of M1 microglia/macrophage markers CD86, inducible nitric oxide synthase (iNOS) and pro-inflammatory factors TNF-α, IL-1β, IL-6, M2 microglia/macrophages markers CD206, arginase-1 (Arg-1), chitinase-like protein (YM1/2) and anti-inflammatory factors interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) was detected by real-time RT-PCR. The expression of CD16/32/Iba1 and CD206/Iba1 was determined by double labeling immunefluorescence method in the peripheral area of cerebral ischemia. Results: Compared with model control group, AS-Ⅳ treatment improved neurological function recovery and reduced infarct volume after ischemia (P < 0.05 or P < 0.01). The qRT-PCR results showed that AS-Ⅳ treatment down-regulated the expression of CD86, iNOS, TNF-α, IL-1β, IL-6 mRNA (all P < 0.01), and up-regulated the expression of CD206, Arg-1, YM1/2, IL-10 and TGF-β mRNA (all P < 0.01). Furthermore, the results of immunefluorescence labeling showed that AS-Ⅳ treatment reduced the number of CD16/32+/Iba1+ cells (P < 0.05) and increased the number of CD206+/Iba1+ cells (P < 0.01) after cerebral ischemia. Conclusion: The findings suggest that AS-Ⅳ ameliorates brain injury after cerebral ischemia in rats, which may be related to inhibiting inflammation through promoting the polarization of the microglia/macrophage from M1 to M2 phenotype in the ischemic brain.

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Research progress on Melkersson-Rosenthal syndrome
KUANG Wenjing,LUO Xiaobo,WANG Jiongke,ZENG Xin
J Zhejiang Univ (Med Sci)    2021, 50 (2): 148-154.   DOI: 10.3724/zdxbyxb-2021-0103
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Melkersson-Rosenthal syndrome (MRS) is a rare neuro-muco-cutaneous syndrome, which is characterized by recurrent orofacial swelling, recurrent facial paralysis and fissured tongue. It has a high prevalence in young adults. Up to now, the etiology of MRS is still not clear, it may related to infection, immune deficiency and hereditary factors. The pharmacological therapy and surgery are the main treatment. Corticosteroids seems to be the drug of choice for MRS patient, but the specific dosage and therapeutic effect have not yet been determined. Surgeries of lips provide excellent results in persistentlip edema MRS cases. This article reviews the research progress on MRS, focusing on its epidemiology, etiology, histopathological characteristics, clinical manifestations, classification, diagnostic criteria, differential diagnosis and treatment, to provide information for its early diagnosis and appropriate treatment.

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Research progress on transient receptor potential melastatin 2 channel in nervous system diseases
YING Yingchao,JIANG Peifang
J Zhejiang Univ (Med Sci)    2021, 50 (2): 267-276.   DOI: 10.3724/zdxbyxb-2021-0110
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Transient receptor potential M2 (TRPM2) ion channel is a non-selective cationic channel that can permeate calcium ions, and plays an important role in neuroinflammation, ischemic reperfusion brain injury, neurodegenerative disease, neuropathic pain, epilepsy and other neurological diseases. In ischemic reperfusion brain injury, TRPM2 mediates neuronal death by modulating the different subunits of glutamate N-methyl-D-aspartic acid receptor in response to calcium/zinc signal. In Alzheimer’s disease, TRPM2 is activated by reactive oxygen species generated by β-amyloid peptide to form a malignant positive feedback loop that induces neuronal death and is involved in the pathological process of glial cells by promoting inflammatory response and oxidative stress. In epilepsy, the TRPM2-knockout alleviates epilepsy induced neuronal degeneration by inhibiting autophagy and apoptosis related proteins. The roles of TRPM2 channel in the pathogenesis of various central nervous system diseases and its potential drug development and clinical application prospects are summarized in this review.

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ecent advances in metabolism-based drug-drug interactions
Journal of ZheJiang University(Medical Science)    2009, 38 (2): 215-224.   DOI: 10.3785/j.issn.1008-9292.2009.02.017
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Analysis of GFM1 gene mutations in a family with combined oxidative phosphorylation deficiency 1
SHEN Yaping,YAN Kai,DONG Minyue,YANG Rulai,HUANG Xinwen
J Zhejiang Univ (Med Sci)    2020, 49 (5): 574-580.   DOI: 10.3785/j.issn.1008-9292.2020.10.04
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Objective: To analyze the clinical phenotype and genetic characteristics of a family with combined oxidative phosphorylation deficiency 1 (COXPD-1). Methods: The whole exome sequencing was performed in parents of the proband; and the genetic defects were verified by Sanger sequencing technology in the dried blood spot of the proband, the amniotic fluid sample of the little brother of proband, and the peripheral blood of the parents. Results: Whole exome sequencing and Sanger validation showed compound heterozygous mutations of GFM1 gene c.688G>A(p.G230S) and c.1576C>T (p.R526X) in both the proband and her little brother, and the c.1576C>T of GFM1 variant was first reported. The two patients were died in early infancy, and presented with metabolic acidosis, high lactic acid, abnormal liver function, feeding difficulties, microcephaly, development retardation and epilepsy. Conclusion: GFM1 gene c.688G>A and c.1576C>T compound heterozygous mutations are the cause of this family of COXPD-1.

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Mechanism and intervention of mucosal immune regulation based on "lung and large intestine being interior-exteriorly related" theory of traditional Chinese medicine
LOU Zhaohuan,ZHAO Huajun,LYU Guiyuan
J Zhejiang Univ (Med Sci)    2020, 49 (6): 665-678.   DOI: 10.3785/j.issn.1008-9292.2020.12.01
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The "lung and large intestine being interior-exteriorly related" is one of the classical theories in traditional Chinese medicine, which indicates a close correlation between the lung and large intestine in physiology and pathology, and plays a pivotal role in guiding the treatment of the lung and bowel diseases. Modern medicine has revealed some connections between the lung and large intestine in tissue origin and mucosal immunity, and preliminarily illuminated the material basis and possible regulatory mechanism of the theory. Recently, this theory has been applied to guide the treatment of refractory lung and intestine diseases such as COVID-19 and ulcerative colitis and has obtained reliable efficacy. Existing research results show that the anatomical homogeneity of lung and large intestine promotes the correlation between lung-bowel mucosal immunity, and mucosal immunity and migration and homing of innate lymphocytes are one of the physiological and pathological mechanisms for lung and large intestine to share. Under the guidance of this theory, Chinese medicines with heat-clearing and detoxifying or tonic effects are commonly used in the treatment of the lung and intestinal diseases by regulating lung-bowel mucosal immunity and they can be candidate drugs to treat lung/intestinal diseases simultaneously. However, the existing studies on immune regulation are mainly focused on the expression levels of sIgA and cytokines, as well as the changes in the number of immune cells such as innate lymphocytes and B lymphocytes. While the following aspects need further investigation: the airway/intestinal mucous hypersecretion, the functional changes of pulmonary and intestinal mucosal barrier immune cells, the dynamic process of lung/intestinal mucosal immune interaction, the intervention effect of local pulmonary/intestinal microecology, the correlation and biological basis between the heat-clearing and detoxifying effect and the tonic effect, and its regulation of pulmonary/intestinal mucosal immunity. In this paper, we try to analyze the internal relationship between lung and intestine related diseases from the point of view of the common mucosal immune system of lung and intestine, and summarize the characteristics and rules of traditional Chinese medicine compound and its active ingredients, which have regulatory effect on lung and intestine mucosal immune system, so as to further explain the theoretical connotation of "lung and large intestine being interior-exteriorly related" and provide reference for the research and development of drugs for related diseases.

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Exploring early prevention and control of COVID-19 outbreak based on system dynamics model analysis
DONG Shi,CUI Zhiwei,PAN Xiaoxiong,WANG Jianwei,GAO Chao
J Zhejiang Univ (Med Sci)    2021, 50 (1): 41-51.   DOI: 10.3724/zdxbyxb-2021-0035
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Objective: To explore early prevention and control of coronavirus disease 2019 (COVID-19) outbreak based on system dynamics model analysis. Methods:The data of early outbreak of COVID-19 were collected from the World Health Organization,covering countries of the China,United States,United Kingdom,Australia,Serbia and Italy. The susceptible-exposed-infected-recovered (SEIR) model was generalized and then its parameters were optimized. According to the parameters in the basic infection number expression,the sensitivity in the system dynamics model was used to quantitatively analyze the influence of the protection rate,infection rate and average quarantine time on the early spread of the outbreak. Based on the analysis results,targeted prevention and control measures for the early outbreak of COVID-19 were proposed. Results:The generalized SEIR model had a good fit for the early prediction and evaluation of COVID-19 outbreaks in six countries. The spread of COVID-19 was mainly affected by the protection rate,infection rate and average quarantine time. The improvement of the protection rate in the first 10?days was the most important:the greater the protection rate,the fewer the number of confirmed cases. The infection rate in the first 5 days was the most critical:the smaller the infection rate,the fewer the number of confirmed cases. The average quarantine time in the first 5 days was very important:the shorter the average quarantine time,the fewer the number of confirmed cases. Through the comparison of key parameters of six countries,Australia and China had implemented strict epidemic prevention policies,which had resulted in good epidemic prevention effects. Conclusion:In the early stage of the outbreak,it is necessary to improve the protection rate,shorten the average quarantine time,and implement strict isolation policies to curb the spread of COVID-19.

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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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Prediction model of mid-term fatality risk after radical resection in patients with hepatocellular carcinoma based on ALBI-grade
WANG Xiaobo,ZHANG Zhaohui,WU Zhangqiang,SUN Yuezong,ZHANG Yili,GONG Ming,JI Feng
J Zhejiang Univ (Med Sci)    2020, 49 (3): 375-382.   DOI: 10.3785/j.issn.1008-9292.2020.06.04
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Objective: To establish a clinical prediction model of the mid-term fatality risk after radical resection in patients with primary hepatocellular carcinoma (HCC) based on the albumin-bilirubin (ALBI) grade and to assess its prediction value. Methods: Clinical data of 533 patients who received HCC radical resection in Jinhua Hospital of Zhejiang University, Jinhua People's Hospital, Jinhua Hospital of Traditional Chinese Medicine and Jinhua Guangfu Hospital from January 2010 to August 2016 were retrospectively reviewed. In the training group (n=407), Cox model was used to screen the clinical risk factors of postoperative death, and a predictive model based on ALBI grade was established and then examined in the validation group (n=126). The value of the prediction model was assessed by ROC curve and calibration curve; the prediction results of the model were visualized by the nomogram for the convenience of clinical use. Results: Cox model showed that ALT ≥ 80 U/L, tumor maximum diameter ≥ 5 cm, portal vein tumor thrombus and ALBI grade 2 were independent risk factors for the prognosis of patients with HCC radical resection. The prognosis index (PI) was 0.550×ALT+0.512×ALBI grade+0.872×maximum tumor diameter+1.377×portal vein tumor thrombus. The AUCs for predicting the risk of death in 12, 36 and 60 months were 0.872, 0.814 and 0.810, respectively (all P < 0.01), and the goodness of fit (r2) of the established model were 0.953, 0.976 and 0.994. AUC of the established model for predicting risk of death in 36 months after resection was 0.814, which was higher than those of ALBI (AUC=0.683), BCLC (AUC=0.713), CLIP (AUC=0.689), Child-Pugh (AUC=0.645), TNM (AUC=0.612) (P < 0.05 or P < 0.01). Conclusion: ALT ≥ 80 U/L, maximum tumor diameter ≥ 5 cm, portal vein tumor thrombus and ALBI grade 2 are independent risk factors of patients after HCC resection, and ALBI grade-based prediction model is satisfactory in prediction of mid-term death risk of the patients.

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Artificial intelligence technology in cardiac auscultation screening for congenital heart disease: present and future
XU Weize,YU Kai,XU Jiajun,YE Jingjing,LI Haomin,SHU Qiang
J Zhejiang Univ (Med Sci)    2020, 49 (5): 548-555.   DOI: 10.3785/j.issn.1008-9292.2020.10.01
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The electronic stethoscope combined with artificial intelligence (AI) technology has realized the digital acquisition of heart sounds and intelligent identification of congenital heart disease, which provides objective basis for heart sound auscultation and improves the accuracy of congenital heart disease diagnosis. At the present stage, the AI based cardiac auscultation technique mainly focuses on the research of AI algorithms, and the researchers have designed and summarized a variety of effective algorithms based on the characteristics of cardiac audio data, among which the mel-frequency cepstral coefficients (MFCC) is the most effective one, and widely used in the cardiac auscultation. However, the current cardiac sound analysis techniques are based on specific data sets, and have not been validated in clinic, so the performance of algorithms need to be further verified. The lack of heart sound data, especially the high-quality, standardized, publicly available heart sound database with disease labeling, further restricts the development of heart sound diagnostic analysis and its application in screening. Therefore, expert consensus is necessary in establishing an authoritative heart sound database and standardizing the heart sound auscultation screening process for congenital heart disease. This paper provides an overview of the research and application status of auscultation algorithm and hardware equipment based on AI in auscultation screening of congenital heart disease, and puts forward the problems to be solved in clinical application of AI auscultation screening technology.

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Application of medical magnifying loupes in diagnosis of oral mucosal diseases
ZHANG Yuting,YUAN Peiyang,JIANG Han,QIU Xuemei,WANG Jiongke,LUO Xiaobo,DAN Hongxia,ZHOU Yu,ZENG Xin,JIANG Lu,CHEN Qianming
J Zhejiang Univ (Med Sci)    2021, 50 (2): 205-211.   DOI: 10.3724/zdxbyxb-2021-0132
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Objective: To evaluate the application of medical magnifying loupes in diagnosis of oral mucosal diseases. Methods: Twenty-four patients with plaque-type oral lichen planus or homogeneous oral leukoplakia were inspected by naked eyes or assistance with magnifying loupes. Histopathological results were used as the gold standard to evaluate the sensitivity, specificity and accuracy of the two methods in clinical diagnosis. Questionnaires were used to evaluate the subjective effect of magnifying loupes on the diagnosis efficiency of oral mucosal diseases and to explore the most suitable parameters for application. Results:The sensitivity, specificity and accuracy of medical magnifying loupes for the identification of plaque-type oral lichen planus and homogeneous oral leukoplakia were 94.74%, 100.00% and 95.83%, respectively, which were significantly higher than those of naked eye inspection (89.47%, 80.00% and 87.50%). The effective rate of magnifying loupes assisted diagnosis was 91.76% according to physicians’ subjective evaluation. The most suitable parameters were 3.5 times magnification and 400?mm working distance. Conclusion: The medical magnifying loupes can effectively improve the efficiency of the inspection and diagnosis of oral mucosal diseases, and have the characteristics of convenience and real-time. The recommended clinical parameters are 3.5 times magnification and 400?mm working distance.

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Journal of ZheJiang University(Medical Science)    1992, 21 (6): 283-286.   DOI: 10.3785/j.issn.1008-9292.1992.06.019
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Application of mechanosensitive channels in sonogenetics
HONG Feifan,LI Yuezhou
J Zhejiang Univ (Med Sci)    2019, 48 (1): 34-38.   DOI: 10.3785/j.issn.1008-9292.2019.02.06
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As a non-invasive approach, sonogenetics is applied to control neuronal activity. The mechanosensitive channel(MSC), which has low threshold of responding to ultrasound, may be the alternative solution. Sonogenetics is the technique that activates the MSC expressed in targeted neurons by low intensity ultrasound, thus achieve the neuromodulation. In this review, we introduce the mechanosensitive channel of large conductance, transient receptor potential, channels of the two-pore-domain potassium family, Piezo and the recent progress on their application in sonogenetics.

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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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Impact of public health emergency on public psychology: analysis of mental health assistance hotlines during COVID-19 in Zhejiang province
WANG Weidan,XU Fangzhong,XU Songquan,ZHANG Jianmin,ZHANG Ning
J Zhejiang Univ (Med Sci)    2020, 49 (4): 409-418.   DOI: 10.3785/j.issn.1008-9292.2020.08.05
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Objective: To analyze the usage of mental health assistance hotline during COVID-19 in Zhejiang province from January 25th to February 29th 2020, and summarize the characteristics of the demand for mental health services and the dynamic changes of public mental health status during COVID-19 pandemic. Methods: Both quantitative and qualitative methods were used. The calls related to pandemic were divided into four categories: medical, psychological, information and the others. The secondary categories of psychological calls were determined by text analysis. The number of calls were calculated weekly and the number of various types of calls over time were analyzed. We used stratified random sampling method to extract 600 cases of all kinds of calls related to pandemic and conducted a semantic analysis, through marking new, similar combination to form a feature set, then summed up the call content characteristics of each stage. Two hundred callers were followed up to understand how they felt about the call process in four aspects: the waiting time, call duration, the degree of problem-solving and the way to end the call. Results: In a total of 13 746 calls, 8978 were related to pandemic, among which 12.59%(1130/8978) were about medical issues, 26.50%(2379/8978) were about mental health, 27.18%(2440/8978) were about information regarding the pandemic and 33.74%(3029/8978) were about other pandemic related issues. Pandemic situation, relevant policy release, frequency of advertising campaigns were predictors of the number of calls per day during the pandemic (P < 0.05 or P < 0.01). The number of calls differed by gender and identities of callers (both P < 0.05). Finally 181 callers accepted telephone follow-up. Among them, 51.38%(93/181) of the callers thought that the waiting time was too long, 33.15%(60/181) of the callers thought that the call time was insufficient, 80.66%(146/181) of callers believed that the hotline could partially or completely resolve their concerns, and 39.23%(71/181) of the callers said the operator proposed to end the call. Conclusions: The changes of the number and content of the mental health assistance hotline calls reflected that the public mental health status experienced four stages during the pandemic: confusion, panic, boredom, and adjustment. The specialized mental health assistance hotlines should be further strengthened, and the efficiency should be improved. Mental health interventions should be tailored and adopted according to the characteristics of the public mental health status at different stages of the pandemic.

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Causes and management of respiratory complication after liver transplantation
Journal of ZheJiang University(Medical Science)    2004, 33 (2): 170-173.   DOI: 10.3785/j.issn.1008-9292.2004.02.018
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Ultrasound diagnosis of left inferior vena cava and double inferior vena cava in fetus
ZHANG Ziwei,WANG Junmei
J Zhejiang Univ (Med Sci)    2019, 48 (4): 446-452.   DOI: 10.3785/j.issn.1008-9292.2019.08.16
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Objective: To evaluate the application of ultrasonography in prenatal diagnosis of left inferior vena cava and double inferior vena cava in fetus. Methods: The clinical data and ultrasonographic findings of the fetuses with left inferior vena cava (18 cases) or double inferior vena cava (16 cases) were retrospectively analyzed. Results: The ultrasonographic images of left inferior vena cava showed that in the transverse view of the fetal upper abdomen the inferior vena cava and abdominal aorta were in the normal position; below the level of the hilum, the inferior vena cava was located behind the left side of the abdominal aorta; at the level of the hilum, it crossed the front of the abdominal aorta and run diagonally to the upper right, forming the right inferior vena cava and finally entered into the right atrium. The ultrasonographic images of double inferior vena cava showed that in the transverse view of the fetal lower abdomen, in front of spine there were three transections of blood vessels; in coronal plane of abdomen, the veins run on both sides of the abdominal aorta and entered to the iliac vein of the same side. In 34 cases of abnormal inferior vena cava, there were 17 cases complicated with other system abnormalities, including 13 cases of cardiac anomalies. Conclusions: The left inferior vena cava and double inferior vena cava have characteristic imaging findings, and prenatal diagnosis can be made with ultrasonography. This type of congenital deformity is frequently complicated with other system abnormalities, which should be excluded in fetus, especially for heart system.

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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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Effects of antihyperglycemics on endothelial progenitor cells
HAN Xue,JIANG Guojun,SHI Qiaojuan
J Zhejiang Univ (Med Sci)    2020, 49 (5): 629-636.   DOI: 10.3785/j.issn.1008-9292.2020.10.13
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Endothelial progenitor cells (EPCs) play an important role in diabetic vascular complications. A large number of studies have revealed that some clinical antihyperglycemics can improve the complications of diabetes by regulating the function of EPCs. Metformin can improve EPCs function in diabetic patients by regulating oxidative stress level or downstream signaling pathway of adenosine monophosphate activated protein kinase; Pioglitazone can delay the aging of EPCs by regulating telomerase activity; acarbose, sitagliptin and insulin can promote the proliferation, migration and adhesion of EPCs. In addition to lowering blood glucose, the effects of antihyperglycemics on EPCs may also be one of the mechanisms to improve the complications of diabetes. This article reviews the research progress on the regulation of EPC proliferation and function by antihyperglycemics.

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Current status and prospects of tumor immunotherapy
Journal of ZheJiang University(Medical Science)    2010, 39 (4): 339-344.   DOI: 10.3785/j.issn.1008-9292.2010.04.001
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Relationship between temperament, parenting style and resilience of children aged 3-5 years
NIU Yubai,ZHANG Lingyan,HAO Zesheng,JI Yuzhu
J Zhejiang Univ (Med Sci)    2019, 48 (1): 75-82.   DOI: 10.3785/j.issn.1008-9292.2019.02.12
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Objective

To investigate the developmental characteristics of resilience in children aged 3-5, and to explore the relationship between temperament, parenting style and resilience.

Methods

A total of 570 preschoolers aged 3-5 years in Hangzhou participated in this study. The children’s teachers completed the assessment of the resilience scale of DECA-P2 (Devereux Early Childhood Assessment for Preschoolers Second Edition); the children’s parents completed assessment of temperament questionnaire CBQ (Children’s Behavior Questionnaire) and parenting style questionnaire PSDQ (Parenting Styles and Dimensions Questionnaire).

Results

Totally 432 valid questionnaires were retrieved with a recovery rate of 75.79%. The levels of initiative and self-regulation of 5-y children were higher than those of children aged 3 or 4 (all P<0.01); the level of attachment/relationship of 5-y children was higher than that of children aged 4 (P<0.01); the levels of initiative and self-regulation of girls were higher than those of boys (P<0.05 or P<0.01). The negative affect dimension of temperament was negatively correlated with resilience (all P<0.05), while the effortful control and authoritative parenting styles were positively correlated with resilience (all P<0.05). The negative affect and effortful control were able to partially predict resilience of children through authoritative parenting style (mediating effect were -0.0143 and 0.0363).

Conclusion

Preschoolers aged 3-5 years with different age and gender show differences in resilience, and parenting styles may play a mediating effect between temperament and resilience.

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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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Consensus on diagnosis and treatment of ornithine trans-carbamylase deficiency
Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health
J Zhejiang Univ (Med Sci)    2020, 49 (5): 539-547.   DOI: 10.3785/j.issn.1008-9292.2020.04.11
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Ornithine transcarbamylase deficiency(OTCD)is a most common ornithine cycle (urea cycle) disorder. It is a X-link inherited disorder caused by OTC gene mutation that in turn leads to reduction or loss of OTC enzyme activity. Its onset time is related to the lack of enzyme activity. Patients with neonatal onset usually have complete absence of OTC enzyme activity, which is mainly associated with male semi-zygotic mutations; and the disease progresses rapidly with high mortality rates. Patients with late onset vary in onset age and clinical manifestations, and the course of disease can be progressive or intermittent. The acute attack mainly manifests neuropsychiatric symptoms accompanied by digestive symptoms like liver function damage or even acute liver failure. Elevated blood ammonia is the main biochemical indicator of OTCD patients. Increased glutamine, decreased citrulline in blood, and increased orotic acid in urine are typical clinical manifestations for OTCD patients. Genetic testing of OTC gene is important for OTCD diagnosis. The goal of treatment is to minimize the neurological damage caused by hyperammonemia while ensuring the nutritional needs for patient development. For patients with poor response to medication and diet, liver transplantation is recommended under the condition of stable metabolic state and absence of severe neurological damage. During long-term treatment, physical growth indicators, nutrition status, liver function, blood ammonia and amino acids should be regularly monitored. This consensus aims to standardize the diagnosis and treatment of OTCD, improve the prognosis, reduce the mortality and disability of patients.

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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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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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