1.Screening of biomarkers for fibromyalgia syndrome and analysis of immune infiltration
Yani LIU ; Jinghuan YANG ; Huihui LU ; Yufang YI ; Zhixiang LI ; Yangfu OU ; Jingli WU ; Bing WEI
Chinese Journal of Tissue Engineering Research 2025;29(5):1091-1100
		                        		
		                        			
		                        			BACKGROUND:Fibromyalgia syndrome,as a common rheumatic disease,is related to central sensitization and immune abnormalities.However,the specific mechanism has not been elucidated,and there is a lack of specific diagnostic markers.Exploring the possible pathogenesis of this disease has important clinical significance. OBJECTIVE:To screen the potential diagnostic marker genes of fibromyalgia syndrome and analyze the possible immune infiltration characteristics based on bioinformatics methods,such as weighted gene co-expression network analysis(WGCNA),and machine learning. METHODS:Gene expression profiles in peripheral serum of fibromyalgia syndrome patients and healthy controls were obtained from the gene expression omnibus(GEO)database.The differentially co-expressed genes were screened in the expression profile by differential analysis and WGCNA analysis.Least absolute shrinkage and selection operator(LASSO)and support vector machine-recursive feature elimination(SVM-RFE)machine learning algorithm were further used to identify hub biomarkers,and draw receiver operating characteristic curve(ROC)to evaluate the accuracy of diagnosing fibromyalgia syndrome.Finally,single sample gene set enrichment analysis(ssGSEA)and gene set enrichment analysis(GSEA)were used to evaluate the immune cell infiltration and pathway enrichment in patients with fibromyalgia syndrome. RESULTS AND CONCLUSION:Eight down-regulated differentially expressed genes(DEGs)were obtained after differential analysis of the GSE67311 dataset according to the conditions of log2|(FC)|>0 and P<0.05.After WGCNA analysis,497 genes were included in the module(MEdarkviolet)with the highest positive correlation(r=0.22,P=0.04),and 19 genes were included in the module(MEsalmon2)with the highest negative correlation(r=-0.41,P=6×10-5).After intersecting DEGs and the module genes of WGCNA,seven genes were obtained.Four genes were screened out by LASSO regression algorithm and five genes were screened out by SVM-RFE machine learning algorithm.After the intersection of the two,three core genes were identified,which were germinal center associated signaling and motility like,integrin beta-8,and carboxypeptidase A3.The areas under the ROC curve of the three core genes were 0.744,0.739,and 0.734,respectively,indicating that they have good diagnostic value and can be used as biomarkers for fibromyalgia syndrome.The results of immune infiltration analysis showed that memory B cells,CD56 bright NK cells,and mast cells were significantly down-regulated in patients with fibromyalgia syndrome compared with the control group(P<0.05),and were significantly positively correlated with the above three biomarkers(P<0.05).The enrichment analysis suggested that there were nine fibromyalgia syndrome enrichment pathways,mainly related to olfactory transduction pathway,neuroactive ligand-receptor interaction,and infection pathway.The above results showed that the occurrence and development of fibromyalgia syndrome are related to the involvement of multiple genes,abnormal immune regulation,and multiple pathways imbalance.However,the interactions between these genes and immune cells,as well as their relationships with various pathways need to be further investigated.
		                        		
		                        		
		                        		
		                        	
2.Inferring Mycobacterium Tuberculosis Drug Resistance and Transmission using Whole-genome Sequencing in a High TB-burden Setting in China
Feng Yu FAN ; Xin Dong LIU ; Wang Yi CHEN ; Chao Xi OU ; Zhi Qi MAO ; Ting Ting YANG ; Jiang Xi WANG ; Cong Wen HE ; Bing ZHAO ; Jiang Zhen LIU ; Maiweilanjiang ABULIMITI ; Maimaitiaili AIHEMUTI ; Qian GAO ; Lin Yan ZHAO
Biomedical and Environmental Sciences 2024;37(2):157-169
		                        		
		                        			
		                        			Objective China is among the 30 countries with a high burden of tuberculosis(TB)worldwide,and TB remains a public health concern.Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China.However,molecular epidemiological studies of Kashgar are lacking. Methods A population-based retrospective study was conducted using whole-genome sequencing(WGS)to determine the characteristics of drug resistance and the transmission patterns. Results A total of 1,668 isolates collected in 2020 were classified into lineages 2(46.0%),3(27.5%),and 4(26.5%).The drug resistance rates revealed by WGS showed that the top three drugs in terms of the resistance rate were isoniazid(7.4%,124/1,668),streptomycin(6.0%,100/1,668),and rifampicin(3.3%,55/1,668).The rate of rifampicin resistance was 1.8%(23/1,290)in the new cases and 9.4%(32/340)in the previously treated cases.Known resistance mutations were detected more frequently in lineage 2 strains than in lineage 3 or 4 strains,respectively:18.6%vs.8.7 or 9%,P<0.001.The estimated proportion of recent transmissions was 25.9%(432/1,668).Multivariate logistic analyses indicated that sex,age,occupation,lineage,and drug resistance were the risk factors for recent transmission.Despite the low rate of drug resistance,drug-resistant strains had a higher risk of recent transmission than the susceptible strains(adjusted odds ratio,1.414;95%CI,1.023-1.954;P = 0.036).Among all patients with drug-resistant tuberculosis(DR-TB),78.4%(171/218)were attributed to the transmission of DR-TB strains. Conclusion Our results suggest that drug-resistant strains are more transmissible than susceptible strains and that transmission is the major driving force of the current DR-TB epidemic in Kashgar.
		                        		
		                        		
		                        		
		                        	
3.Analysis of the epidemic characteristics of reported pulmonary tuberculosis incidence in Kashgar Prefecture, Xinjiang Uygur Autonomous Region from 2015 to 2022 and establishment of SARIMA prediction
Chong TENG ; Fang XIE ; Bing ZHAO ; Lijie ZHANG ; Hui LI ; Yuanyuan SONG ; Yang ZHENG ; Yang ZHOU ; Jing WANG ; Fei HUANG ; Mingting CHEN ; Xichao OU
Chinese Journal of Preventive Medicine 2024;58(11):1665-1672
		                        		
		                        			
		                        			Objective:To analyze the epidemic characteristics of reported tuberculosis incidence in Kashgar from 2015 to 2022, and use the seasonal autoregressive integrated moving average (SARIMA) model to predict the incidence, providing references for the local control of pulmonary tuberculosis.Methods:The reported incidence data of tuberculosis in the Kashgar area of Xinjiang from January 2015 to August 2023 were collected through the"Infectious Disease Monitoring System", a subsystem of the "Chinese Disease Prevention and Control Information System". The epidemic characteristics of reported incidence in this area from 2015 to 2022 were analyzed. Two SARIMA models of monthly reported incidence number and rate were established. The prediction performance of the two models was evaluated using the reported incidence data of tuberculosis from January 2023 to August 2023. The χ2 test was used to analyze population characteristics, and the Cochran-Armitage trend test was used to analyze annual incidence. Results:From 2015 to 2022, 133 972 cases of pulmonary tuberculosis were reported in Kashgar, with a yearly reported incidence rate of 383.64/100 000, showing a rising trend ( TCA=77.03, P<0.001) and then a declining trend ( TCA=176.16, P<0.001). The proportion of pathogenic positive pulmonary tuberculosis had increased yearly ( TCA=132.66, P<0.001). The reported onset time was concentrated from January to June each year, with a peak in April. Yengisar County, Zepu County and Yopurga County had the highest reported incidence rate in Kashgar. The sex ratio of men to women was 1.03∶1, and the reported incidence rate of men was higher than that of women ( χ2=27.04, P<0.001). The reported incidence rate of the group aged 60 years and older was the highest. The patient′s occupation was mainly farmers (84.99%). The average relative errors of the SARIMA ( 1, 1, 2) ( 0, 1, 1) 12 model and SARIMA ( 0, 1, 1)( 0, 1, 1) 12 model in predicting the reported monthly incidence number and rate were 11.67% and -9.81%, respectively. Both models had good prediction accuracy (MAPE=33.55%, MAPE=38.22%). Conclusion:The average reported incidence rate of pulmonary tuberculosis in the Kashgar area shows a rising trend first and then a declining trend. The patients are mainly men and farmers, and attention should be paid to the prevention and control of tuberculosis among the elderly in winter and spring. The SARIMA ( 1, 1, 2) ( 0, 1, 1) 12 model and SARIMA ( 0, 1, 1)( 0, 1, 1) 12 model can fit the trend of reported tuberculosis incidence in the Kashgar area well and have good predictive performance.
		                        		
		                        		
		                        		
		                        	
4.Analysis of the epidemic characteristics of reported pulmonary tuberculosis incidence in Kashgar Prefecture, Xinjiang Uygur Autonomous Region from 2015 to 2022 and establishment of SARIMA prediction
Chong TENG ; Fang XIE ; Bing ZHAO ; Lijie ZHANG ; Hui LI ; Yuanyuan SONG ; Yang ZHENG ; Yang ZHOU ; Jing WANG ; Fei HUANG ; Mingting CHEN ; Xichao OU
Chinese Journal of Preventive Medicine 2024;58(11):1665-1672
		                        		
		                        			
		                        			Objective:To analyze the epidemic characteristics of reported tuberculosis incidence in Kashgar from 2015 to 2022, and use the seasonal autoregressive integrated moving average (SARIMA) model to predict the incidence, providing references for the local control of pulmonary tuberculosis.Methods:The reported incidence data of tuberculosis in the Kashgar area of Xinjiang from January 2015 to August 2023 were collected through the"Infectious Disease Monitoring System", a subsystem of the "Chinese Disease Prevention and Control Information System". The epidemic characteristics of reported incidence in this area from 2015 to 2022 were analyzed. Two SARIMA models of monthly reported incidence number and rate were established. The prediction performance of the two models was evaluated using the reported incidence data of tuberculosis from January 2023 to August 2023. The χ2 test was used to analyze population characteristics, and the Cochran-Armitage trend test was used to analyze annual incidence. Results:From 2015 to 2022, 133 972 cases of pulmonary tuberculosis were reported in Kashgar, with a yearly reported incidence rate of 383.64/100 000, showing a rising trend ( TCA=77.03, P<0.001) and then a declining trend ( TCA=176.16, P<0.001). The proportion of pathogenic positive pulmonary tuberculosis had increased yearly ( TCA=132.66, P<0.001). The reported onset time was concentrated from January to June each year, with a peak in April. Yengisar County, Zepu County and Yopurga County had the highest reported incidence rate in Kashgar. The sex ratio of men to women was 1.03∶1, and the reported incidence rate of men was higher than that of women ( χ2=27.04, P<0.001). The reported incidence rate of the group aged 60 years and older was the highest. The patient′s occupation was mainly farmers (84.99%). The average relative errors of the SARIMA ( 1, 1, 2) ( 0, 1, 1) 12 model and SARIMA ( 0, 1, 1)( 0, 1, 1) 12 model in predicting the reported monthly incidence number and rate were 11.67% and -9.81%, respectively. Both models had good prediction accuracy (MAPE=33.55%, MAPE=38.22%). Conclusion:The average reported incidence rate of pulmonary tuberculosis in the Kashgar area shows a rising trend first and then a declining trend. The patients are mainly men and farmers, and attention should be paid to the prevention and control of tuberculosis among the elderly in winter and spring. The SARIMA ( 1, 1, 2) ( 0, 1, 1) 12 model and SARIMA ( 0, 1, 1)( 0, 1, 1) 12 model can fit the trend of reported tuberculosis incidence in the Kashgar area well and have good predictive performance.
		                        		
		                        		
		                        		
		                        	
5.ChatGPT for shaping the future of dentistry: the potential of multi-modal large language model.
Hanyao HUANG ; Ou ZHENG ; Dongdong WANG ; Jiayi YIN ; Zijin WANG ; Shengxuan DING ; Heng YIN ; Chuan XU ; Renjie YANG ; Qian ZHENG ; Bing SHI
International Journal of Oral Science 2023;15(1):29-29
		                        		
		                        			
		                        			The ChatGPT, a lite and conversational variant of Generative Pretrained Transformer 4 (GPT-4) developed by OpenAI, is one of the milestone Large Language Models (LLMs) with billions of parameters. LLMs have stirred up much interest among researchers and practitioners in their impressive skills in natural language processing tasks, which profoundly impact various fields. This paper mainly discusses the future applications of LLMs in dentistry. We introduce two primary LLM deployment methods in dentistry, including automated dental diagnosis and cross-modal dental diagnosis, and examine their potential applications. Especially, equipped with a cross-modal encoder, a single LLM can manage multi-source data and conduct advanced natural language reasoning to perform complex clinical operations. We also present cases to demonstrate the potential of a fully automatic Multi-Modal LLM AI system for dentistry clinical application. While LLMs offer significant potential benefits, the challenges, such as data privacy, data quality, and model bias, need further study. Overall, LLMs have the potential to revolutionize dental diagnosis and treatment, which indicates a promising avenue for clinical application and research in dentistry.
		                        		
		                        		
		                        		
		                        			Dentistry
		                        			;
		                        		
		                        			Artificial Intelligence
		                        			
		                        		
		                        	
6.Risk factors for metabolic bone disease of prematurity in very/extremely low birth weight infants: a multicenter investigation in China.
Xiao-Ri HE ; Can LIANG ; Yuan-Qiang YU ; Pei-Jia WU ; Xiang-Hong CHEN ; Yu-Jun CHEN ; Cui-Qing LIU ; Xiang-Dong OU-YANG ; Ruo-Bing SHAN ; Wei-Wei PAN ; Yan-Mei CHANG ; Dan WANG ; Xiao-Yun ZHONG ; Kai-Ju LUO ; Yong-Hui YANG ; Qing-Yi DONG ; Jin-Tao HU ; Ming-Feng HE ; Xiao-Mei TONG ; Ping-Yang CHEN
Chinese Journal of Contemporary Pediatrics 2021;23(6):555-562
		                        		
		                        			OBJECTIVE:
		                        			To investigate the incidence rate and risk factors for metabolic bone disease of prematurity (MBDP) in very low birth weight/extremely low birth weight (VLBW/ELBW) infants.
		                        		
		                        			METHODS:
		                        			The medical data of 61 786 neonates from multiple centers of China between September 1, 2013 and August 31, 2016 were retrospectively investigated, including 504 VLBW/ELBW preterm infants who met the inclusion criteria. Among the 504 infants, 108 infants diagnosed with MBDP were enrolled as the MBDP group and the remaining 396 infants were enrolled as the non-MBDP group. The two groups were compared in terms of general information of mothers and preterm infants, major diseases during hospitalization, nutritional support strategies, and other treatment conditions. The multivariate logistic regression analysis was used to investigate the risk factors for MBDP.
		                        		
		                        			RESULTS:
		                        			The incidence rate of MBDP was 19.4% (88/452) in VLBW preterm infants and 38.5% (20/52) in ELBW preterm infants. The incidence rate of MBDP was 21.7% in preterm infants with a gestational age of < 32 weeks and 45.5% in those with a gestational age of < 28 weeks. The univariate analysis showed that compared with the non-MBDP group, the MBDP group had significantly lower gestational age and birth weight, a significantly longer length of hospital stay, and a significantly higher incidence rate of extrauterine growth retardation (
		                        		
		                        			CONCLUSIONS
		                        			A lower gestational age, hypocalcemia, extrauterine growth retardation at discharge, and neonatal sepsis may be associated an increased risk of MBDP in VLBW/ELBW preterm infants. It is necessary to strengthen perinatal healthcare, avoid premature delivery, improve the awareness of the prevention and treatment of MBDP among neonatal pediatricians, and adopt positive and reasonable nutrition strategies and comprehensive management measures for preterm infants.
		                        		
		                        		
		                        		
		                        			Birth Weight
		                        			;
		                        		
		                        			Bone Diseases, Metabolic/etiology*
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		                        			China/epidemiology*
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		                        			Female
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Infant
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		                        			Infant, Extremely Low Birth Weight
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		                        			Infant, Newborn
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		                        			Infant, Premature
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		                        			Infant, Very Low Birth Weight
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		                        			Pregnancy
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		                        			Retrospective Studies
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		                        			Risk Factors
		                        			
		                        		
		                        	
7.Evaluation of the China Healthcare Improvement Initiative(2018-2020) in tertiary public hospitals in China: results of institutional survey
Jinhong ZHAO ; Linlin HU ; Bing QIN ; Yu′ou ZHANG ; Runnan YAN ; Linghe YANG ; Meicen LIU ; Yuanli LIU
Chinese Journal of Hospital Administration 2021;37(6):450-454
		                        		
		                        			
		                        			Objective:To evaluate the implementation of the China Healthcare Improvement Initiative(CHII)from 2018 to 2020 in 143 tertiary public hospitals in China.Methods:In March 2019 and from January to March in 2021, 143 tertiary public hospitals in 31 provinces of China were investigated using the unified " medical institution questionnaire Ⅰ" and " medical institution Questionnaire Ⅱ" . The data were collected by means of hospital self-report and expert on-site scoring. Descriptive and inferential statistical analysis were used to analyze the data, and the data of two cross-sectional surveys were compared and analyzed.Results:The average score rate of implementing CHII in 143 sample hospitals in 2020 was 88.9%, which was higher than that in 2018(84.4%). The appointment diagnosis and treatment system, clinical pathway management system, day service, smart hospital and humanistic service were significantly improved. In 2020, the average score rate of logistics service, high quality nursing service and clinical pathway management system was higher than 95%, while the average score rate of day service, telemedicine system and medical social work system was lower than 85%. The total score rate of general hospitals was significantly higher than that of specialized hospitals( P<0.001). In 2020, the proportion of hospitals with full marks in 29 secondary indicators(74.4%)was more than 80%, reaching the standard level. Conclusions:The implementation level of CHII in tertiary public hospitals in China has been improved continuously and made significant progress, but some dimensions and indicators need to be further improved.
		                        		
		                        		
		                        		
		                        	
8.Application value of urinary IGFBP7 and TIMP-2 in acute kidney injury with decompensated hepatitis B virus-related liver cirrhosis
Huanqin HAN ; Jinjun OU ; Bing FENG ; Wei DENG ; Qiuyan JIANG ; Yang HUANG ; Qinfu ZHANG ; Weiqiang ZHENG
Chinese Journal of Hepatology 2020;28(9):760-765
		                        		
		                        			
		                        			Objective:To investigate the application value of new urinary biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue matrix metalloproteinase inhibitor-2 (TIMP-2) in acute kidney injury with decompensated hepatitis B virus-related liver cirrhosis.Methods:45 newly hospitalized cases with decompensated hepatitis B virus-related liver cirrhosis were selected. Among them, 19 cases were combined with AKI on admission (cirrhosis-AKI group), 26 cases without AKI (cirrhosis-non-AKI group), and 12 healthy cases (normal control group). First-morning urine samples were collected and IGFBP7 and TIMP-2 were detected by enzyme-linked immunosorbent assay (ELISA). Urinary IGFBP7 and serum creatinine (SCr) were dynamically monitored after hospitalization in cirrhosis-non-AKI group. Normally distributed measurement data were compared by t-test, and non-normally distributed measurement data were compared by rank sum test. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic accuracy of the indicators.Results:Urinary IGFBP7, IGFBP7 with TIMP-2 (IGFBP7×TIMP-2) in cirrhosis-AKI group ( n = 19) were equally higher than that of the cirrhosis-non-AKI group ( P < 0.05). Urinary IGFBP7, TIMP-2 and IGFBP7×TIMP-2 in cirrhosis-AKI group or cirrhosis-non-AKI group were significantly higher than those of the normal control group ( P < 0.01). The AUC of urinary IGFBP7 and urinary IGFBP7×TIMP-2 for diagnosis of AKI were 0.703 (95% CI 0.547-0.860) and 0.700 (95% CI 0.541-0.859), respectively. In the liver cirrhosis-non-AKI group ( n = 26), 5 cases of AKI were newly diagnosed according to the changes in SCr during hospitalization (progressive group). Urinary IGFBP7 was significantly increased 2 days before the diagnosis of AKI. The concentration of urinary IGFBP7 at admission in the progressive group ( n = 5) was higher than that of the non-progressive group ( n = 21) ( P < 0.05). Conclusion:Urinary IGFBP7 and TIMP-2 concentrations were significantly increased in patients with decompensated hepatitis B virus-related liver cirrhosis. When AKI occurred, urinary IGFBP7 and IGFBP7×TIMP-2 was further increased. Urinary IGFBP7 is valuable for early AKI diagnosis, and may play a role in predicting AKI occurrence.
		                        		
		                        		
		                        		
		                        	
9.Diabetes Medication Use in Association with Survival among Patients of Breast, Colorectal, Lung, or Gastric Cancer
Michelle L BAGLIA ; Yong CUI ; Tao ZHENG ; Gong YANG ; Honglan LI ; Mingrong YOU ; Liling XU ; Harvey MURFF ; Yu Tang GAO ; Wei ZHENG ; Yong Bing XIANG ; Xiao Ou SHU
Cancer Research and Treatment 2019;51(2):538-546
		                        		
		                        			
		                        			PURPOSE: Studies suggest that regular use of metformin may decrease cancer mortality. We investigated the association between diabetes medication use and cancer survival. MATERIALS AND METHODS: The current study includes 633 breast, 890 colorectal, 824 lung, and 543 gastric cancer cases identified from participants of two population-based cohort studies in Shanghai. Information on diabetes medication use was obtained by linking to electronic medical records. The associations between diabetes medication use (metformin, sulfonylureas, and insulin) and overall and cancer-specific survival were evaluated using time-dependent Cox proportional hazards models. RESULTS: After adjustment for clinical characteristics and treatment factors, use of metformin was associated with better overall survival among colorectal cancer patients (hazards ratio [HR], 0.55; 95% confidence interval [CI], 0.34 to 0.88) and for all four types of cancer combined (HR, 0.75; 95% CI, 0.57 to 0.98). Ever use of insulin was associated with worse survival for all cancer types combined (HR, 1.89; 95% CI, 1.57 to 2.29) and for the four cancer types individually. Similar associations were seen for diabetic patients. Sulfonylureas use was associated with worse overall survival for breast or gastric cancer (HR, 2.87; 95% CI, 1.22 to 6.80 and HR, 2.05; 95% CI, 1.09 to 3.84, respectively) among diabetic patients. Similar association patterns were observed between diabetes medication use and cancer-specific survival. CONCLUSION: Metformin was associated with improved survival among colorectal cancer cases, while insulin use was associated with worse survival among patients of four major cancers. Further investigation on the topic is needed given the potential translational impact of these findings.
		                        		
		                        		
		                        		
		                        			Breast
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		                        			Cohort Studies
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		                        			Colorectal Neoplasms
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		                        			Electronic Health Records
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		                        			Humans
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		                        			Insulin
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		                        			Lung
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		                        			Metformin
		                        			;
		                        		
		                        			Mortality
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		                        			Proportional Hazards Models
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		                        			Stomach Neoplasms
		                        			
		                        		
		                        	
10.The Short-Term Effect of Paris polyphylla Smith var. Yunnanensis Powder Combined with Anti-tuberculosis Drugs in the Treatment of Superficial Lymph Node Tuberculosis
Jiang-Chun ZHU ; Yi FU ; Le ZHANG ; Yang-Bing OU
Journal of Kunming Medical University 2018;39(1):81-84
		                        		
		                        			
		                        			Objective To observe the short-term effect of Paris polyphylla Smith var. yunnanensis powder combined with anti-tuberculosis drugs in the observation of superficial lymph node tuberculosis. Methods A total of 170 patients were randomly divided into two groups: 80 in the control group and 90 in the observation group. The observation group consisted of nodular type, infiltrating type and abscess type, each of which had 30 cases. The control group were treated with Isoniazid, Rifampicin, Pyrazinamide and Ethambutol. Besides the four medications, the observation group were treated with external application of Paris polyphylla Smith var. yunnanensis. Results The response rate was 30.00%in the control group and 64.44%in the observation group. The response rate in the observation group was higher than that in the control group, with a statistically significant difference ( <0.01). In the observation group, the response rates of abscess, infiltration and nodule were 76.67%, 73.33%and 43.33%, respectively.By the comparative analysis, the response rate of infiltration was higher than that of nodule ( <0.05), with a significant difference; the response rate of abscess was also higher than that of nodule ( <0.05), with a significant difference. There was no significant difference between the response rates of abscess and infiltration ( >0.5) .Conclusions The external application of Paris polyphylla Smith var. yunnanensis powder combined with anti-tuberculosis drugs is curative in the observation of superficial lymph node tuberculosis, especially in the types ofinfiltrating and abscess.
		                        		
		                        		
		                        		
		                        	
            
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