1.In Vitro Anti-psoriatic Effect of Kangfuxin Liquid via Inhibiting Cell Proliferation and Migration Ability and Blocking JAK3/STAT3 Signaling Pathway
Shuai LI ; Xuan LIU ; Wenyan TANG ; Zhenqi WU ; Chunhui CHEN ; Dadan QIU ; Yi XU ; Chenggui ZHANG ; Jianquan ZHU ; Jiali ZHU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(10):123-133
ObjectiveThis paper aims to explore the in vitro anti-psoriasis activity and potential mechanism of Kangfuxin liquid (KFX liquid), providing experimental evidence for the anti-psoriasis effect of KFX liquid. MethodsFirstly, the uninduced human immortalized keratinocyte cells (HaCaT cells) were divided into seven groups, namely the control group and KFX liquid groups with different doses (5, 10, 20, 40, 80, 160 g·L-1). After being treated with different concentrations of KFX liquid, the effect of KFX liquid on the normal cell proliferation was detected by using the cell counting kit-8 (CCK-8) method. Secondly, the uninduced HaCaT cells were divided into six groups, namely the control group and recombinant human interleukin-7A (rh-IL-7A) groups with different doses (5, 10, 50, 100, 120 g·L-1). After being treated with different concentrations of recombinant human interleukin-17A (rh IL-17A) liquid, the effect of rh IL-17A on cell proliferation was detected. The optimal induction concentration was screened. Then, normal HaCaT cells were divided into a control group and KFX liquid groups with different doses (5, 10, 20, 40, 80, 160 g·L-1). Except for the control group, the other groups established psoriasis cell models with the optimal induction concentration of rh IL-17A. After being treated with different concentrations of KFX liquid, the effects of KFX liquid on the psoriasis-like HaCaT cell proliferation were investigated. Finally, the uninduced HaCaT cells were divided into six groups, namely the control group, rh IL-17A group, methotrexate (MTX) group, and KFX liquid groups with different doses (20, 40, 80 g·L-1). Except for the control group, the other groups used the optimal induction concentration of rh IL-17A to establish psoriasis cell models. After being treated with different drugs, the cell migration levels were detected through scratch assays, and real-time quantitative polymerase chain reaction (Real-time PCR) was used to detect the relative mRNA expression levels of Ki-67 antigen (Ki67), S100 calcium-binding protein A7 (S100A7), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9), thereby comprehensively evaluating the in vitro anti-psoriasis activity of KFX liquid. By detecting the relative mRNA expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine-20 (CXCL-20) inflammatory-related factors in psoriasis-like HaCaT cells and the protein expression levels of Janus kinase 3 (JAK3), phosphorylated Janus kinase 3 (p-JAK3), signal transducer and activator of transcription 3 (STAT3), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3), the mechanism was explored. ResultsCompared with that of control group, when treated with 80 g·L-1 KFX liquid for 72 h (P<0.05) and at different times with 160 g·L-1 KFX liquid, the HaCaT cell proliferation activity was significantly affected (P<0.01), while the other concentrations of KFX liquid had no significant differences in cell morphology and cell proliferation activity at different times, indicating that the KFX liquid is relatively safe for HaCaT cells and has no obvious toxic side effects. Compared with that of control group, when treated with different concentrations of rh IL-17A for 24 h, the HaCaT cell proliferation activity was significantly enhanced, and the cell activity was the strongest when the concentration was 100 μg·L-1 (P<0.05), with a density close to 100% and intact cell morphology, indicating that 100 μg·L-1 is the optimal concentration for inducing HaCaT cell proliferation. The results of the KFX liquid treatment on rh IL-17A-induced psoriasis-like cells show that the KFX liquid not only effectively inhibits the rh IL-17A-induced psoriasis-like HaCaT cell proliferation activity (P<0.01), but also significantly reduces the migration ability of rh IL-17A-induced psoriasis-like HaCaT cells (P<0.01), and the relative mRNA expression levels of Ki67, S100A7, S100A8, and S100A9 (P<0.01). Moreover, the KFX liquid can significantly reduce the relative mRNA expression levels of IL-1β, IL-6, and CXCL-20 in rh IL-17A-induced psoriasis-like cells (P<0.01), and significantly inhibit the phosphorylation levels of JAK3 and STAT3 proteins (P<0.05, P<0.01). ConclusionThe KFX liquid has no obvious toxicity to uninduced HaCaT cells. It can inhibit rh IL-17A-induced psoriasis-like HaCaT cell proliferation, reduce the cell migration ability, and has good in vitro anti-psoriasis activity. Its action mechanism may be related to downregulating the expression levels of inflammation-related cytokines in the JAK3/STAT3 signaling pathway and inhibiting the phosphorylation levels of JAK3 and STAT3 proteins.
2.In Vitro Anti-psoriatic Effect of Kangfuxin Liquid via Inhibiting Cell Proliferation and Migration Ability and Blocking JAK3/STAT3 Signaling Pathway
Shuai LI ; Xuan LIU ; Wenyan TANG ; Zhenqi WU ; Chunhui CHEN ; Dadan QIU ; Yi XU ; Chenggui ZHANG ; Jianquan ZHU ; Jiali ZHU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(10):123-133
ObjectiveThis paper aims to explore the in vitro anti-psoriasis activity and potential mechanism of Kangfuxin liquid (KFX liquid), providing experimental evidence for the anti-psoriasis effect of KFX liquid. MethodsFirstly, the uninduced human immortalized keratinocyte cells (HaCaT cells) were divided into seven groups, namely the control group and KFX liquid groups with different doses (5, 10, 20, 40, 80, 160 g·L-1). After being treated with different concentrations of KFX liquid, the effect of KFX liquid on the normal cell proliferation was detected by using the cell counting kit-8 (CCK-8) method. Secondly, the uninduced HaCaT cells were divided into six groups, namely the control group and recombinant human interleukin-7A (rh-IL-7A) groups with different doses (5, 10, 50, 100, 120 g·L-1). After being treated with different concentrations of recombinant human interleukin-17A (rh IL-17A) liquid, the effect of rh IL-17A on cell proliferation was detected. The optimal induction concentration was screened. Then, normal HaCaT cells were divided into a control group and KFX liquid groups with different doses (5, 10, 20, 40, 80, 160 g·L-1). Except for the control group, the other groups established psoriasis cell models with the optimal induction concentration of rh IL-17A. After being treated with different concentrations of KFX liquid, the effects of KFX liquid on the psoriasis-like HaCaT cell proliferation were investigated. Finally, the uninduced HaCaT cells were divided into six groups, namely the control group, rh IL-17A group, methotrexate (MTX) group, and KFX liquid groups with different doses (20, 40, 80 g·L-1). Except for the control group, the other groups used the optimal induction concentration of rh IL-17A to establish psoriasis cell models. After being treated with different drugs, the cell migration levels were detected through scratch assays, and real-time quantitative polymerase chain reaction (Real-time PCR) was used to detect the relative mRNA expression levels of Ki-67 antigen (Ki67), S100 calcium-binding protein A7 (S100A7), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9), thereby comprehensively evaluating the in vitro anti-psoriasis activity of KFX liquid. By detecting the relative mRNA expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine-20 (CXCL-20) inflammatory-related factors in psoriasis-like HaCaT cells and the protein expression levels of Janus kinase 3 (JAK3), phosphorylated Janus kinase 3 (p-JAK3), signal transducer and activator of transcription 3 (STAT3), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3), the mechanism was explored. ResultsCompared with that of control group, when treated with 80 g·L-1 KFX liquid for 72 h (P<0.05) and at different times with 160 g·L-1 KFX liquid, the HaCaT cell proliferation activity was significantly affected (P<0.01), while the other concentrations of KFX liquid had no significant differences in cell morphology and cell proliferation activity at different times, indicating that the KFX liquid is relatively safe for HaCaT cells and has no obvious toxic side effects. Compared with that of control group, when treated with different concentrations of rh IL-17A for 24 h, the HaCaT cell proliferation activity was significantly enhanced, and the cell activity was the strongest when the concentration was 100 μg·L-1 (P<0.05), with a density close to 100% and intact cell morphology, indicating that 100 μg·L-1 is the optimal concentration for inducing HaCaT cell proliferation. The results of the KFX liquid treatment on rh IL-17A-induced psoriasis-like cells show that the KFX liquid not only effectively inhibits the rh IL-17A-induced psoriasis-like HaCaT cell proliferation activity (P<0.01), but also significantly reduces the migration ability of rh IL-17A-induced psoriasis-like HaCaT cells (P<0.01), and the relative mRNA expression levels of Ki67, S100A7, S100A8, and S100A9 (P<0.01). Moreover, the KFX liquid can significantly reduce the relative mRNA expression levels of IL-1β, IL-6, and CXCL-20 in rh IL-17A-induced psoriasis-like cells (P<0.01), and significantly inhibit the phosphorylation levels of JAK3 and STAT3 proteins (P<0.05, P<0.01). ConclusionThe KFX liquid has no obvious toxicity to uninduced HaCaT cells. It can inhibit rh IL-17A-induced psoriasis-like HaCaT cell proliferation, reduce the cell migration ability, and has good in vitro anti-psoriasis activity. Its action mechanism may be related to downregulating the expression levels of inflammation-related cytokines in the JAK3/STAT3 signaling pathway and inhibiting the phosphorylation levels of JAK3 and STAT3 proteins.
3.TCM Guidelines for Diagnosis and Treatment of Chronic Cough in Children
Xi MING ; Liqun WU ; Ziwei WANG ; Bo WANG ; Jialin ZHENG ; Jingwei HUO ; Mei HAN ; Xiaochun FENG ; Baoqing ZHANG ; Xia ZHAO ; Mengqing WANG ; Zheng XUE ; Ke CHANG ; Youpeng WANG ; Yanhong QIN ; Bin YUAN ; Hua CHEN ; Lining WANG ; Xianqing REN ; Hua XU ; Liping SUN ; Zhenqi WU ; Yun ZHAO ; Xinmin LI ; Min LI ; Jian CHEN ; Junhong WANG ; Yonghong JIANG ; Yongbin YAN ; Hengmiao GAO ; Hongmin FU ; Yongkun HUANG ; Jinghui YANG ; Zhu CHEN ; Lei XIONG
Journal of Nanjing University of Traditional Chinese Medicine 2024;40(7):722-732
Following the principles of evidence-based medicine,in accordance with the structure and drafting rules of standardized documents,based on literature research,according to the characteristics of chronic cough in children and issues that need to form a consensus,the TCM Guidelines for Diagnosis and Treatment of Chronic Cough in Children was formulated based on the Delphi method,expert discussion meetings,and public solicitation of opinions.The guideline includes scope of application,terms and definitions,eti-ology and diagnosis,auxiliary examination,treatment,prevention and care.The aim is to clarify the optimal treatment plan of Chinese medicine in the diagnosis and treatment of this disease,and to provide guidance for improving the clinical diagnosis and treatment of chronic cough in children with Chinese medicine.
4.Incidence, prevalence, and causes of spinal injuries in China, 1990-2019: Findings from the Global Burden of Disease Study 2019
Chenjun LIU ; Tingling XU ; Weiwei XIA ; Shuai XU ; Zhenqi ZHU ; Maigeng ZHOU ; Haiying LIU
Chinese Medical Journal 2024;137(6):704-710
Background::Spinal injuries are an urgent public health priority; nevertheless, no China-wide studies of these injuries exist. This study measured the incidence, prevalence, causes, regional distribution, and annual trends of spinal injuries in China from 1990 to 2019.Methods::We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 to estimate the incidence and prevalence of spinal injuries in China. The data of 33 provincial-level administrative regions (excluding Taiwan, China) provided by the National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention (CDC) were use to systematically analyze the provincial etiology, geographical distribution, and annual trends of spinal injuries. The Bayesian meta-regression tool DisMod-MR 2.1 was used to ensure the consistency among incidence, prevalence, and mortality rates in each case.Results::From 1990 to 2019, the number of living patients with spinal injuries in China increased by 138.32%, from 2.14 million to 5.10 million, while the corresponding age-standardized prevalence increased from 0.20% (95% uncertainty interval [UI]: 0.18-0.21%) to 0.27% (95% UI: 0.26-0.29%). The incidence of spinal injuries in China increased by 89.91% (95% UI: 72.39-107.66%), and the prevalence increased by 98.20% (95% UI: 89.56-106.82%), both the most significant increases among the G20 countries; 71.00% of the increase could be explained by age-specific prevalence. In 2019, the incidence was 16.47 (95% UI: 12.08-22.00, per 100,000 population), and the prevalence was 358.30 (95% UI: 333.96-386.62, per 100,000 population). Based on the data of 33 provincial-level administrative regions provided by CDC, age-standardized incidence and prevalence were both highest in developed provinces in Eastern China. The primary causes were falls and road injuries; however, the prevalence and specific causes differed across provinces.Conclusions::In China, the overall disease burden of spinal injuries increased significantly during the past three decades but varied considerably according to geographical location. The primary causes were falls and road injuries; however, the prevalence and specific causes differed across provinces.
5.Risk prediction models for pancreatic fistula in patients after pancreaticoduodenectomy: a systematic review
Shuting ZHU ; Lanping ZHENG ; Pin ZHANG ; Lihui LI ; Zhenqi LU
Chinese Journal of Hepatobiliary Surgery 2024;30(9):691-698
Objective:To evaluate the risk of bias and applicability of the risk prediction models for pancreatic fistula after pancreaticoduodenectomy (PD).Methods:The relevant studies were systematically searched from Chinese database (Chinese medical journals database, CNKI, Wanfang, Weipu, Sinomed) and English databases (PubMed, Embase, Web of Science, Cochrane Library, CINAHL Database) and the retrieval time limit was from the establishment of the database to December 31, 2023. Based on the risk of bias assessment tool of the predictive model study, the risk of bias and applicability of the model were evaluated, and the predictors with high repetition rate in the model were meta-analyzed by RevMan 5.4 software.Results:A total of 23 studies involving 30 models were included. The incidence of pancreatic fistula was 11.4%-41.7%. nineteen studies reported the discrimination index of model construction and/or validation, and the area under the curve (AUC) was 0.62-0.94. The other four studies reported the consistency index (c-index). The predictive performance of the 23 studies is good, but there is a high risk of bias. The main reasons are that the sample size is not saturated, the research object from the appropriate source is not selected, the continuous variables are not properly processed, and the predictive factors are screened by single factor analysis. Eight studies were rated as " high risk" for applicability due to inconsistencies between the included study subjects and outcome measures and the systematic review study questions. The meta-analysis results showed that the dilation of main pancreatic duct (>3 mm) ( OR=0.70, 95% CI: 0.65-0.76), soft pancreas texture ( OR=5.18, 95% CI: 3.90-6.88), and body mass index ≥25 kg/m 2 ( OR=1.12, 95% CI: 1.07-1.17) were effective predictors of postoperative pancreatic fistula (POPF). Conclusion:The existing predictive models for pancreatic fistula risk in patients undergoing PD both domestically and internationally have good predictive performance, but there is a certain risk of bias and some models have poor applicability. Predictors such as dilation of main pancreatic duct, soft pancreas texture, and body mass index≥25 kg/m 2 should be more emphasized in future predictive models.
6.Treatment of proximal malleolar fracture of distal tibia with retrograde intramedullary nail fixation
Mingming GAO ; Qingjun LIU ; Jianfei ZHU ; Pengwen SHI ; Chengshou LIN ; Shenggui XU ; Xuping LIN ; Jiayuan HONG ; Zhenqi DING
Chinese Journal of Orthopaedics 2024;44(19):1280-1287
Objective:To observe the clinical effect of retrograde distal tibial intramedullary nail fixation in the treatment of proximal ankle fracture of the distal tibia.Methods:A three-dimensional CT examination of 40 adult tibias was performed to measure anatomical indicators such as the posterior medial posterior torsion angle of the distal tibia, the height of torsion, and the height of the safety zone for nail placement. Based on the anatomy database of the human skeleton model, a retrograde distal tibial nail and its supporting instruments were developed in accordance with the anatomical characteristics of the distal tibia and the proximal ankle of Chinese people. From June 2019 to June 2023, a total of 25 patients with distal tibial proximal ankle fractures treated with retrograde intramedullary nail internal fixation in the 909th Hospital were retrospectively analyzed. There were 18 males and 7 females, aged 41.3±10.8 years (range, 22-65 years). The sample size was 1∶1 matched according to gender and age. Twenty-five patients with distal tibial proximal ankle fractures who underwent antegrade intramedullary nail fixation during the same period were matched, including 20 males and 5 females, aged 41.2±9.4 years (range 19-60 years). The reduction quality, postoperative Baird-Jackson score, American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot score, ankle range of motion and complications were observed.Results:All patients were successfully operated and followed up for 14.4±3.5 months (range, 12-24 months). The intraoperative blood loss and hospitalization time in retrograde intramedullary nail group were 33.12±7.38 ml and 10.32±1.75 d, less than 49.04±10.22 ml and 13.16±2.69 d in antegrade intramedullary nail group, and the difference was statistically significant ( P<0.05). The reduction quality was excellent in 23 cases and good in 2 cases in the retrograde intramedullary nail group, and was excellent in 17 cases and good in 8 cases in the anterograde intramedullary nail group. The proportion of excellent reduction quality in the retrograde intramedullary nail group was higher than that in the anterograde intramedullary nail group, and the difference was statistically significant (χ 2=4.500, P=0.034). The Baird-Jackson score and AOFAS ankle and hindfoot score in the retrograde intramedullary nail group were 85.6±2.5 and 85.8±3.3 at 3 months after operation, lower than those at 1 year after operation 95.3±3.1 and 95.8±3.6, and the difference was statistically significant ( P<0.05). The Baird-Jackson score and AOFAS ankle and hindfoot score of the antegrade intramedullary nail group were 85.1±3.3 and 86.1±2.5 at 3 months after operation, lower than 95.2±2.7 and 94.9±3.5 at 1 year after operation, and the difference was statistically significant ( P<0.05). There was no significant difference in Baird-Jackson score and AOFAS ankle and hindfoot score between the two groups at 3 months and 1 year after operation ( P>0.05). At the last follow-up, there was no ankle stiffness, neurovascular injury, deep vein thrombosis, infection or breakage of internal fixation in the two groups. Conclusion:The treatment of distal tibial proximal ankle fractures with retrograde intramedullary nail fixation has satisfactory reduction quality, good postoperative function recovery, and is helpful for early postoperative rehabilitation.
7. An analysis of symptom burden and its predictive factors in patients with prostate cancer
Xiaodan ZHU ; Zhenqi LU ; Xiaofeng GU
Chinese Journal of Practical Nursing 2019;35(15):1168-1172
Objective:
To assess the symptom burden and its predictive factors in patients with prostate cancer.
Methods:
A cross-sectional study of 370 men with prostate cancer were conducted in the department of urology, Fudan University Shanghai Cancer Center. The questionnaire included a general questionnaire, Expanded Prostate Cancer Index Composite 26-item version (EPIC-26) and Hospital Anxiety and Depression Scale (HADS).
Results:
The average score of EPIC-26 in patients with prostate cancer was 25.32±12.00. The sexual function (15.59±7.38) and endocrine disorder (4.09±3.70) scored higher in five domains. There were significant differences in symptom burden scores among different treatment methods (
8. Reliability and validity verification of the expanded prostate cancer index composite 26-item version in Chinese
Xiaodan ZHU ; Zhenqi LU ; Xiaofeng GU
Chinese Journal of Practical Nursing 2019;35(26):2035-2039
Objective:
To analyze the reliability and validity of the Expanded Prostate cancer Index Composite 26-item version (EPIC-26) in Chinese patients with prostate cancer.
Methods:
Totally 402 patients with prostate cancer at the Fudan University Shanghai Cancer Center were invited to fill in the Chinese version of EPIC-26. 402 samples were divided into two parts by random number table method. 201 samples were analyzed by exploratory factor analysis and another 201 samples were analyzed by confirmatory factor analysis.
Results:
The total Cronbach alpha coefficient of Chinese version EPIC-26 was 0.845, and the Cronbach
9. Analysis of reliability and validity of the Supportive Care Needs Questionnaire in Chinese patients with prostate cancer
Xiaodan ZHU ; Zhenqi LU ; Xiaofeng GU
Chinese Journal of Practical Nursing 2019;35(27):2097-2101
Objective:
To evaluate the reliability and validity of the Chinese version of the Supportive Care Needs Survey (SCNS-SF34) in patients with prostate cancer.
Methods:
The Chinese version of SCNS-SF34 was translated and revised. The exploratory factor analysis was used to assess the structural validity of the tool, and the Cronbach α coefficient was used to evaluate the reliability of the scale.
Results:
Two items of the Chinese version of SCNS-SF34 were deleted. Five factors were extracted by principal component analysis, including psychological, health systems and information, patient care and support, physical and daily living and sexuality needs. It was consistent with the structure of original scale. The cumulative variance contribution rate reached 70.500%. Except for item 17, the maximum load value was <0.4, and the other item load values were >0.4. The total Cronbach α coefficient of the questionnaire was 0.929, and the Cronbach α coefficient was 0.780-0.940.
Conclusions
The Chinese version of SCNS-SF34 has good psychometric properties and it can be used to assess the supportive care needs for patients with prostate cancer in China.
10.Decompression with fusion is not superior to decompression alone in lumbar short-segment stenosis based on randomized controlled trials: meta-analysis
Shuai XU ; Yan LIANG ; Zhenqi ZHU ; Kaifeng WANG ; Yalong QIAN ; Haiying LIU
Chinese Journal of Orthopaedics 2019;39(6):374-384
Objective A meta-analysis is to be performed to compare the entire efficacy on decompression (D) alone and decompression with fusion (F) for patients with 1-2 level lumbar stenosis (LSS) regardless of degenerative spandylolisthesis (DS) based on published RCTs.Methods The databases include Pubmed,Embase,Cochrane Library and Web of Science from January 1970 to March 2018 with a certain search strategy and inclusion criteria.Two reviewers assessed eligible trials,evaluated articles quality and extracted information independently and the information included basic characteristics of demographic information,primary and secondary measures,then data synthesis and meta-analysis was progressed as well as subgroup analysis by DS and follow-up time (36 months).Continuous variables were reported as weighted mean difference (WMD) and dichotomous variables were reported as odds ratios (ORs).Finally the strength of evidence and grade of recommendation was evaluated by the grades of recommendation,assessment,development and evaluation (GRADE) system for the overall outcome.Results A total of 9 RCTs with a low to moderate risk of bias met inclusion criteria with a total of 857 patients (367 were in D group and 490 were in F group) in 1-2 level operation and the average age,sex ratio and preoperative visual analogue scale (VAS) were of no significance.In primary measures,there were no statistical difference in VAS changes on back and leg pain between D and F group [MD=-0.03,95% CI (--0.38,0.76),Z=0.08,P=0.94;MD=0.1 1,95%CI (-1.08,1.30),Z=0.18,P=0.86,respectively];Patients' satisfaction was of no difference between the two groups (OR=0.74,P=0.48),together with the change of Oswestry disability index (ODI,P=0.29) and European quality of life-5 dimensions (EQ-SD,P=0.41).As to the secondary measures,there were no difference in the rate of complication (OR=0.75,P=0.50) and reoperation (OR=1.93,P=0.11) while a statistical significance of longer operation duration (P=0.000),more blood loss (P=0.004),longer hospital stays (P=0.000) but amazing lower rate of ASD (OR=2.35,P=0.02) in F group.The subgroup analysis on whether combined with DS showed that basically all of the compared measures were in consistency with the whole meta-analysis;As to the follow-up,there was a higher reoperation rate in middle-to-long term (> 36months) in D group while the other measures were in line with the overall meta-analysis and adjacent segment degeneration/disease (ASD) was the most seasons of reoperation yet no matter the follow-up time.According to the GRADE system,the grade of this meta-analysis is of "High" quality.Conclusion F group has no better clinical results than D alone in short-segment LSS,regardless of DS,and even further,no significant change with shot-term or middle-to-long term follow-up.F approach has a longer duration of operation,more hospital stays and more blood loss,even perhaps a lager cost.According to the GRADE,the grade of this meta-analysis is of "High" quality,the grade strength of recommendation was "Strong".

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