1.T-large granular lymphocytic leukemia presenting as aplastic anemia: a report of five cases and literature review.
Xiao Xia LI ; Jian Ping LI ; Xin ZHAO ; Yuan LI ; You Zhen XIONG ; Guang Xin PENG ; Lei YE ; Wen Rui YANG ; Kang ZHOU ; Hui Hui FAN ; Yang YANG ; Yang LI ; Lin SONG ; Li Ping JING ; Li ZHANG ; Feng Kui ZHANG
Chinese Journal of Hematology 2023;44(2):162-165
2.Incidence and prognosis of olfactory and gustatory dysfunctions related to infection of SARS-CoV-2 Omicron strain: a national multi-center survey of 35 566 population.
Meng Fan LIU ; Rui Xia MA ; Xian Bao CAO ; Hua ZHANG ; Shui Hong ZHOU ; Wei Hong JIANG ; Yan JIANG ; Jing Wu SUN ; Qin Tai YANG ; Xue Zhong LI ; Ya Nan SUN ; Li SHI ; Min WANG ; Xi Cheng SONG ; Fu Quan CHEN ; Xiao Shu ZHANG ; Hong Quan WEI ; Shao Qing YU ; Dong Dong ZHU ; Luo BA ; Zhi Wei CAO ; Xu Ping XIAO ; Xin WEI ; Zhi Hong LIN ; Feng Hong CHEN ; Chun Guang SHAN ; Guang Ke WANG ; Jing YE ; Shen Hong QU ; Chang Qing ZHAO ; Zhen Lin WANG ; Hua Bin LI ; Feng LIU ; Xiao Bo CUI ; Sheng Nan YE ; Zheng LIU ; Yu XU ; Xiao CAI ; Wei HANG ; Ru Xin ZHANG ; Yu Lin ZHAO ; Guo Dong YU ; Guang Gang SHI ; Mei Ping LU ; Yang SHEN ; Yu Tong ZHAO ; Jia Hong PEI ; Shao Bing XIE ; Long Gang YU ; Ye Hai LIU ; Shao wei GU ; Yu Cheng YANG ; Lei CHENG ; Jian Feng LIU
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2023;58(6):579-588
Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female
;
Humans
;
Adolescent
;
SARS-CoV-2
;
Smell
;
COVID-19/complications*
;
Cross-Sectional Studies
;
COVID-19 Vaccines
;
Incidence
;
Olfaction Disorders/etiology*
;
Taste Disorders/etiology*
;
Prognosis
3.Thoughts on path of R&D and registration of innovative traditional Chinese medicine with synchronous transformation of "series prescriptions".
Yan-Ling AI ; Jian-Yuan TANG ; Gang ZHOU ; Lei ZHANG ; Li-Ping QU ; Shi-Yao HUANG ; Zhong-Qi YANG ; Wei-An YUAN ; Yue-Hua ZHOU ; Ting WANG ; Jun-Ning ZHAO ; Xiao-Bo SUN ; Xiao-He XIAO ; Zi-Feng YANG ; Qing-Quan LIU ; Ming-Jun ZHU ; Xiang-Yang LENG ; Chun-Guang XIE ; Song-Yan CHAI
China Journal of Chinese Materia Medica 2022;47(4):1120-1125
Since the implementation of drug registration in China, the classification of Chinese medicine has greatly met the needs of public health and effectively guided the transformation, inheritance, and innovation of research achievements on traditional Chinese medicine(TCM). In the past 30 years, the development of new Chinese medicine has followed the registration transformation model of " one prescription for single drug". This model refers to the R&D and registration system of modern drugs, and approximates to the " law-abiding" medication method in TCM clinic, while it rarely reflects the sequential therapy of syndrome differentiation and comprehensive treatment with multiple measures. In 2017, Opinions on Deepening the Reform of Review and Approval System and Encouraging the Innovation of Drugs and Medical Devices released by the General Office of the CPC Central Committee and the General Office of the State Council pointed out that it is necessary to " establish and improve the registration and technical evaluation system in line with the characteristics of Chinese medicine, and handle the relationship between the traditional advantages of Chinese medicine and the requirements of modern drug research". Therefore, based on the development law and characteristics of TCM, clinical thinking should be highlighted in the current technical requirements and registration system of research and development of Chinese medicine. Based on the current situation of registration supervision of Chinese medicine and the modern drug research in China, the present study analyzed limitations and deficiency of " one prescription for single drug" in the research and development of Chinese medicine. Additionally, a new type of " series prescriptions" was proposed, which was consistent with clinical thinking and clinical reality. This study is expected to contribute to the independent innovation and high-quality development of the TCM industry.
China
;
Drugs, Chinese Herbal/therapeutic use*
;
Medicine, Chinese Traditional
;
Prescriptions
;
Public Health
4.Clinical effect of different maintenance doses of caffeine citrate in the treatment of preterm infants requiring assisted ventilation: a pilot multicenter study.
Yang YANG ; Ke-Yu LU ; Rui CHENG ; Qin ZHOU ; Guang-Dong FANG ; Hong LI ; Jie SHAO ; Huai-Yan WANG ; Zheng-Ying LI ; Song-Lin LIU ; Zhen-Guang LI ; Jin-Lan CAI ; Mei XUE ; Xiao-Qing CHEN ; Zhao-Jun PAN ; Yan GAO ; Li HUANG ; Hai-Ying LI ; Lei SONG ; San-Nan WANG ; Gui-Hua SHU ; Wei WU ; Meng-Zhu YU ; Zhun XU ; Hong-Xin LI ; Yan XU ; Zhi-Dan BAO ; Xin-Ping WU ; Li YE ; Xue-Ping DONG ; Qi-Gai YIN ; Xiao-Ping YIN ; Jin-Jun ZHOU
Chinese Journal of Contemporary Pediatrics 2022;24(3):240-248
OBJECTIVES:
To explore the optimal maintenance dose of caffeine citrate for preterm infants requiring assisted ventilation and caffeine citrate treatment.
METHODS:
A retrospective analysis was performed on the medical data of 566 preterm infants (gestational age ≤34 weeks) who were treated and required assisted ventilation and caffeine citrate treatment in the neonatal intensive care unit of 30 tertiary hospitals in Jiangsu Province of China between January 1 and December 31, 2019. The 405 preterm infants receiving high-dose (10 mg/kg per day) caffeine citrate after a loading dose of 20 mg/kg within 24 hours after birth were enrolled as the high-dose group. The 161 preterm infants receiving low-dose (5 mg/kg per day) caffeine citrate were enrolled as the low-dose group.
RESULTS:
Compared with the low-dose group, the high-dose group had significant reductions in the need for high-concentration oxygen during assisted ventilation (P=0.044), the duration of oxygen inhalation after weaning from noninvasive ventilation (P<0.01), total oxygen inhalation time during hospitalization (P<0.01), the proportion of preterm infants requiring noninvasive ventilation again (P<0.01), the rate of use of pulmonary surfactant and budesonide (P<0.05), and the incidence rates of apnea and bronchopulmonary dysplasia (P<0.01), but the high-dose group had a significantly increased incidence rate of feeding intolerance (P=0.032). There were no significant differences between the two groups in the body weight change, the incidence rates of retinopathy of prematurity, intraventricular hemorrhage or necrotizing enterocolitis, the mortality rate, and the duration of caffeine use (P>0.05).
CONCLUSIONS
This pilot multicenter study shows that the high maintenance dose (10 mg/kg per day) is generally beneficial to preterm infants in China and does not increase the incidence rate of common adverse reactions. For the risk of feeding intolerance, further research is needed to eliminate the interference of confounding factors as far as possible.
Caffeine/therapeutic use*
;
Citrates
;
Humans
;
Infant
;
Infant, Newborn
;
Infant, Premature
;
Respiration, Artificial
;
Retrospective Studies
5.Characteristics of bone marrow compensatory erythropoiesis in hereditary spherocytosis.
Xiao Xia LI ; Yuan LI ; Xin ZHAO ; Guang Xin PENG ; Jian Ping LI ; Lei YE ; Wen Rui YANG ; Kang ZHOU ; Hui Hui FAN ; Yang YANG ; You Zhen XIONG ; Yang LI ; Lin SONG ; Li Ping JING ; Li ZHANG ; Feng Kui ZHANG
Chinese Journal of Hematology 2022;43(2):115-119
Objective: To reveal the compensatory features of bone marrow (BM) erythropoiesis in hereditary spherocytosis (HS) and to explore the effect of diferent hemoglobin levels on this compensation. Methods: Clinical and laboratory data of patients with HS were collected, and the peripheral blood absolute reticulocytes counts value was taken as the surrogate parameter to evaluate the ability of erythropoiesis compensation. BM erythropoiesis compensation in HS with diferent degrees of anemia were evaluated. Results: ①Three hundred and two patients were enrolled, including 115 with compensated hemolytic disease, 74 with mild anemia, 90 with moderate anemia, and 23 with severe anemia. ②Hemoglobin (HGB) was negatively correlated with serum erythropoietin in the decompensated hemolytic anemia group (EPO; rs=-0.585, P<0.001) . ③The median absolute reticulocyte count (ARC) of HS patients was 0.34 (0.27, 0.44) ×10(12)/L, up to 4.25 times that of normal people. The maximum ARC was 0.81×10(12)/L, about 10 times that of normal people. The median ARC of patients with compensated hemolytic disease was 0.29 (0.22, 0.38) ×10(12)/L, up to 3.63 times that of normal people. The median ARC of patients with hemolytic anemia was 0.38 (0.30, 0.46) ×10(12)/L, which was significantly higher than the patients with compensated hemolytic disease, up to 4.75 times that of normal people (z=4.999, P=0.003) . ④ ARC was negatively correlated with HGB in the compensated hemolytic disease group (rs=-0.177, P=0.002) and positively correlated with HGB in the decompensated hemolytic anemia group (rs=0.191, P=0.009) . There was no significant difference in the ARC among patients with mild, moderate, and severe anemia (χ(2)=4.588, P=0.101) . ⑤The median immature reticulocyte production index of the mild, moderate, and severe anemia groups was 13.1% (9.1%, 18.4%) , 17.0% (13.4%, 20.8%) , and 17.8% (14.6%, 21.8%) , respectively; the mild anemia group had lower index values than the moderate and severe anemia groups (P(adj) values were both<0.05) , but there was no significant difference between the latter groups (P(adj)=1.000) . The median immature reticulocyte count of patients in the mild, moderate, and severe groups was 5.09 (2.60, 7.74) ×10(10)/L, 6.24 (4.34, 8.83) ×10(10)/L, and 7.00 (3.07, 8.22) ×10(10)/L, respectively; there was no significant difference among the groups (χ(2)=3.081, P=0.214) . Conclusion: HGB can be maintained at a normal level through bone marrow erythropoiesis, while red blood cells are reduced in HS. However, once anemia develops, the bone marrow exerts its maximum erythropoiesis capacity and does not increase, regardless of anemia aggravation or serum EPO increase.
Bone Marrow
;
Erythropoiesis
;
Humans
;
Reticulocyte Count
;
Reticulocytes
;
Spherocytosis, Hereditary
6.Pharmacokinetic study of anti-human T-cell porcine immunoglobulin combined with cyclosporine A immunosuppressive therapy in patients with severe aplastic anemia.
Li Ping JING ; Li ZHANG ; Kang ZHOU ; Guang Xin PENG ; Yang LI ; Hui Hui FAN ; Lei YE ; Yuan LI ; Jian Ping LI ; Lin SONG ; Wen Rui YANG ; Feng Kui ZHANG
Chinese Journal of Hematology 2022;43(4):300-304
Objective: To study the metabolic characteristics of anti-human T-cell porcine immunoglobulin (p-ATG) in patients with severe aplastic anemia (SAA) . Methods: For patients with SAA treated with p-ATG combined cyclosporine A (CsA) immunosuppressants between February 2017 and December 2017, the p-ATG dose was 20 mg·kg(-1)·d(-1) over 12 h of intravenous administration for 5 consecutive days. The blood concentration of p-ATG was detected by the three-antibody sandwich ELISA method, the pharmacokinetic analysis software was fitted, and the second-chamber model method was used to calculate the pharmacokinetic parameters and plot the pharmacokinetic curve. Adverse events were recorded and the hematologic reactions were determined at 6 months after treatment. Results: Sixteen patients with SAA treated with p-ATG were enrolled, including 8 females and 8 males, with a median age of 22 years (range, 12 to 49 years) and a median weight of 62.5 kg (range, 37.5 to 82.0 kg) . The pharmacokinetics of p-ATG could be evaluated in 14 cases. p-ATG is distributed in vivo as a two-chamber model, with an average drug concentration peak (T(max)) of (5.786±2.486) days, a peak concentration (C(max)) of (616±452) mg/L, and a half-life of (10.479±8.242) days. The area under the drug time curve (AUC) was (5.807±3.236) mg/L·d. Six months after treatment, 8 of 14 patients received a hematologic response; the AUC (0-t) of the effective group and ineffective groups was (7.50±3.26) mg/L·d vs (4.50±2.18) mg/L·d, and the C(max) was (627±476) mg/L vs (584±382) mg/L, respectively. Conclusion: The plasma concentration of p-ATG reached a peak after 5 days of continuous infusion, and then decreased slowly, with a half-life of 10.479 days, and the residual drug concentration was detected in the body 60 days after administration. A relationship between drug metabolism and efficacy and adverse reactions could not be determined.
Anemia, Aplastic/drug therapy*
;
Animals
;
Antilymphocyte Serum/therapeutic use*
;
Cyclosporine/therapeutic use*
;
Female
;
Humans
;
Immunoglobulins/therapeutic use*
;
Immunosuppression Therapy
;
Immunosuppressive Agents/therapeutic use*
;
Male
;
Swine
;
T-Lymphocytes
;
Treatment Outcome
7.Research on medical radioisotope production technology by medium and high-energy cyclotron and solid target
Tianjue ZHANG ; Kai WEN ; Jingyuan LIU ; Li HUO ; Chengwei MA ; Junyi CHEN ; Jiantao BA ; Xianlu JIA ; Guofang SONG ; Haiqiong ZHANG ; Sumin WEI ; Lei WANG ; Suping ZHANG ; Shigang HOU ; He ZHANG ; Jingfeng WANG ; Lei CAO ; Guang YANG ; Zhibo LIU
Chinese Journal of Nuclear Medicine and Molecular Imaging 2022;42(6):340-346
In this paper, the domestic and international demand and development trend of clinical diagnostic radionuclides are analyzed, and the medium and high-energy cyclotrons, adequate and systematic facilities, and preparation techniques required for the production of medical radionuclides based on solid targets are introduced. This paper focuses on the research and development carried out by some important medical institutions and scientific research institutes in China over the years in the aspects of medium and high-energy cyclotrons, beam transmission lines, high-power irradiation target stations and new medical isotope production processes etc. It also looks forward to some new directions for the development of medical radionuclides in China during the 14th Five-Year Plan period.
8.Clinicopathological features of mature T/NK cell lymphoma with aberrant CD20 or CD79α expression.
Du Juan LI ; Hong KANG ; Lei ZHANG ; Zi Guang XU ; Xiao Yan WANG ; Li Fu WANG ; Xiao Xia SONG ; Ling Fei KONG
Chinese Journal of Pathology 2022;51(5):413-418
Objective: To investigate the clinicopathological characteristics and prognosis of mature T/NK cell lymphomas with aberrant CD20 or CD79α expression. Methods: A retrospective analysis of 641 cases of mature T/NK cell lymphoma diagnosed from January 2014 to December 2020 was performed, and 14 cases of CD20-positive and one case of CD79α-positive mature T/NK-cell lymphoma were identified. Histological examination, immunohistochemical characterization, in situ hybridization for Epstein-Barr virus encoded early RNA (EBER), and PCR testing for immunoglobulin and T cell receptor (TCR) gene rearrangements were performed. Clinicopathological characteristics of these lymphomas were analyzed. Results: There were 13 males and 2 females, with a median age of 56 years. There were 8 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 3 cases of extranodal NK/T-cell lymphoma, nasal type (ENKTCL), 2 cases of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) and 2 cases of angioimmunoblastic T-cell lymphoma (AITL). Twelve cases were stage Ⅲ or Ⅳ lymphomas. The prognosis was overall poor. The histology, immunophenotype and TCR gene rearrangement were not significantly different from the corresponding types of lymphoma. Ki-67 proliferation index was over 70% in all cases. The expression of CD20 or CD79α was weak and heterogeneous. All 15 case of Ig gene rearrangement were polyclonal. Conclusions: Mature T/NK cell lymphoma with abnormal expression of CD20 or CD79α is rare, commonly found in advanced stage, and associated with poor prognosis. The expression of CD20 or CD79α in these cases is weaker than the corresponding mature T/NK cell lymphomas, while its proliferation index is higher. Histomorphology, extensive immunoprofiling and molecular detection are required for accurate diagnosis.
Antigens, CD20
;
Epstein-Barr Virus Infections/complications*
;
Female
;
Herpesvirus 4, Human/genetics*
;
Humans
;
Killer Cells, Natural/pathology*
;
Lymphoma, T-Cell, Peripheral/pathology*
;
Male
;
Middle Aged
;
Receptors, Antigen, T-Cell
;
Retrospective Studies
9. The Application of the Mosoteach-based Mobile Interactive Teaching Modein Literature Reading and Discussion of the Molecular Biology Course
Fu-Rong GAO ; Xiu-Juan SHI ; Wen-Xia JIANG ; Jiao LI ; Jie XU ; Song JIA ; Lei XU ; Si-Guang LI ; Li-Xia LYU ; Guo-Tong XU
Chinese Journal of Biochemistry and Molecular Biology 2022;38(2):204-210
Graduate education emphasizes the development of students’ scientific research andinnovation abilities. Literature reading and discussion (LRD) plays an active role in the development ofinnovative thinking and critical thinking for graduate students. However, in traditional, large molecularbiology classes, the effective implementation of large-scale, collective LRD presents a great challenge. Mosoteach is a cloud-based free app designed specifically for education with powerful human-computerinteraction and human-human interaction functions. In the present study, LRD was introduced into amolecular biology course for graduate students and was conducted via the Mosoteach app. The onlinediscussion board in the Mosoteach cloud class was restricted to enrolled students and was designated theprivate online discussion board (PODB). The PODB built a sense of community for students and was aneffective approach for organizing and facilitating discussion in large classes. Small-group learning in LRDwas helpful to understand the literature and foster collaboration and discussion. Overall, we demonstratedthat Mosoteach-based LRD was helpful in improving student learning outcomes. The relationship betweenstudent learning style and engagement, satisfaction and academic performance in cloud classes meritsfurther investigation.
10.National incidence of joint dislocation in China: a retrospective survey of 512,187 individuals
Hongzhi LV ; Wei CHEN ; Zhiyong HOU ; Siming JIA ; Yanbin ZHU ; Bo LIU ; Xiao CHEN ; Guang YANG ; Lei LIU ; Tao ZHANG ; Haili WANG ; Bing YIN ; Song LIU ; Jialiang GUO ; Xiaolin ZHANG ; Yichong LI ; Yingze ZHANG
Chinese Medical Journal 2022;135(14):1742-1749
Background::Joint dislocations significantly impact public health. However, a comprehensive study on the incidence, distribution, and risk factors for joint dislocations in China is lacking. We conducted the China National Joint Dislocation Study, which is a part of the China National Fracture Study conducted to obtain the national incidence and risk factors for traumatic fractures, and to investigate the incidence and risk factors for joint dislocations.Methods::For this national retrospective epidemiological study, 512,187 participants were recruited using stratified random sampling and probability-proportional-to-size method from January 19 to May 16, 2015. Participants who sustained joint dislocations of the trunk, arms, or legs (skull, sternum, and ribs being excluded) in 2014 were personally interviewed to obtain data on age, educational background, ethnic origin, occupation, geographic region, and urbanization degree. The joint-dislocation incidence was calculated based on age, sex, body site, and demographic factors. The risk factors for different groups were examined using multiple logistic regression.Results::One hundred and nineteen participants sustained 121 joint dislocations in 2014. The population-weighted incidence rate of joint dislocations of the trunk, arms, or legs was 0.22 (95% confidence interval [CI]: 0.16, 0.27) per 1000 population in 2014 (men, 0.27 [0.20, 0.34]; women, 0.16 [0.10, 0.23]). For all ages, previous dislocation history (male: OR 42.33, 95% confidence interval [CI]: 12.03–148.90; female: OR 54.43, 95% CI: 17.37–170.50) and alcohol consumption (male: OR 3.50, 95% CI: 1.49–8.22; female: OR 2.65, 95% CI: 1.08–6.50) were risk factors for joint dislocation. Sleeping less than 7 h/day was a risk factor for men. Compared with children, women aged ≥15 years (female 15–64 years: OR 0.16, 95% CI: 0.04–0.61; female ≥65 years: OR 0.06, 95% CI: 0.01–0.41) were less likely to sustain joint dislocations. Women with more than three children were at higher dislocation risk than women without children (OR 6.92, 95% CI: 1.18–40.78).Conclusions::The up-to-date data on joint dislocation incidence, distribution, and risk factors can be used as a reference for national healthcare, prevention, and management in China. Specific strategies for decreasing alcohol consumption and encouraging adequate sleeping hours should be developed to prevent or reduce dislocation incidents.Trial Registration::Chinese Clinical Trial Registry, ChiCTR-EPR-15005878.

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