1.Association between visceral fat area measured with quantitative CT and fatty liver in normal weight population
Qi QIAO ; Yang ZHOU ; Yongbing SUN ; Xin QI ; Yawei DU ; Zhonglin LI ; Zhi ZOU ; Xiaoling WU ; Jing ZHOU ; Gong ZHANG ; Min QU ; Xiaolin ZHANG ; Yong WANG ; Shewei DOU ; Hongming LIU ; Fengshan YAN ; Jiadong ZHU ; Yongli LI
Chinese Journal of Health Management 2024;18(2):120-126
		                        		
		                        			
		                        			Objective:To analyze the association between visceral fat area (VFA) and fatty liver based on quantitative CT (QCT) in people receiving health examination with normal body mass index (BMI).Methods:A cross-sectional study. A total of 1 305 physical examiners who underwent chest CT and QCT examination in the Department of Health Management of Henan Provincial People′s Hospital from January to December 2021 were retrospectively selected as subjects. The physical components at the central level of the lumbar two cone were measured with QCT, including subcutaneous fat area (SFA), VFA and liver fat content (LFC). And the metabolic indexes, such as blood lipids and blood glucose, were collected. The t-test and χ2 test were used to analyze the correlation between the detection rate of fatty live and LFCr and age and gender. According to level of VFA (<100 cm 2, 100-150 cm 2 and≥150 cm 2), the subjects were divided into three groups, and one-way ANOVA and χ2 test were used in comparison between groups. Multiple linear regression was used to analyze the correlation between VFA and metabolic indexes and LFC. Results:Of the 1 305 subjects, there were 634 males and 671 females. The detection rate of fatty liver in normal BMI population was 65.67%, and it was 72.71% and 59.02% respectively in men and women ( χ2=27.12, P<0.001), and the detection rate of fatty liver and LFC increased with age (both P<0.05). With the increase of VFA, the age, BMI, SFA, LFC, total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), alanine aminotransferase (ALT), blood uric acid and prevalence of fatty liver increased (all P<0.05), and the low-density lipoprotein cholesterol (HDL-C) decreased ( P<0.001). Multiple linear regression analysis showed that after adjustment for age factors, regardless of male or female, LFC was independently positively related with VFA, BMI, and ALT (male β=0.206, 0.145, 0.174, female β=0.194, 0.150, 0.184; all P<0.05). FBG was positively correlated with male independently ( β=0.134; P<0.001). The indicators related to female independently were TC, TG, and blood uric acid ( β=-0.121, 0.145, 0.141, all P<0.05) Conclusion:In the population receiving health examination with normal BMI, the VFA measured by QCT technique is closely related to fatty liver.
		                        		
		                        		
		                        		
		                        	
2.Cost-effectiveness of pharmaceutical smoking cessation intervention in China primary cancer prevention
Peiyuan SUN ; Yuting XIE ; Ranran QIE ; Huang HUANG ; Zhuolun HU ; Mengyao WU ; Qi YAN ; Cairong ZHU ; Jufang SHI ; Kaiyong ZOU ; Yawei ZHANG
Chinese Journal of Oncology 2024;46(1):66-75
		                        		
		                        			
		                        			Objectives:To evaluate the cost-effectiveness of typical pharmaceutical smoking cessation intervention strategies in China in the context of primary cancer prevention.Methods:Markov cohort simulation models were established to simulate the burden of 12 smoking caused cancer, including lung cancer, oral cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, kidney cancer, bladder cancer, cervical cancer, and acute myeloid leukemia. Taking incremental cost effectiveness ratio (ICER) as the main indicator, the model sets one year as the cycling period for 50 periods and simulates the cohort of 10 000 thirty-five-year-old current smokers with various smoking cessation strategies. To ensure the robustness of conclusion, univariate sensitivity analysis, probability sensitivity analysis, and age-group sensitivity analysis were conducted.Results:The results showed that varenicline intervention was the most cost-effective intervention. Compared to the next most effective option, incremental cost of each additional quality-adjusted life year is 11 140.28 yuan, which is below the threshold of willingness to pay (1 year GDP per capita). The value of ICER increased as the increasing age group of adopting intervention, but neither exceeded the threshold of willingness to pay. One-way sensitivity analysis showed that the value of discount rate, the hazard ratio and cost of intervention strategy had a greater impact on the result of ICER.Conclusion:In China, the use of varenicline to quit smoking is highly cost effective in the context of cancer primary prevention, especially for younger smokers.
		                        		
		                        		
		                        		
		                        	
3.Correlation between body fat distribution measured by quantitative CT and body mass index in adults receiving physical examination
Yang ZHOU ; Yongbing SUN ; Qi QIAO ; Xin QI ; Yawei DU ; Zhonglin LI ; Zhi ZOU ; Xiaoling WU ; Jing ZHOU ; Min QU ; Xiaolin ZHANG ; Yong WANG ; Shewei DOU ; Hongming LIU ; Fengshan YAN ; Jiadong ZHU ; Yongli LI
Chinese Journal of Health Management 2024;18(5):354-360
		                        		
		                        			
		                        			Objective:To analyze the correlation between body fat distribution measured by quantitative CT (QCT) and body mass index in adults receiving physical examination.Methods:It was a cross-sectional study. From January to December 2021, 3 205 adults undergoing physical examination who met the inclusion criteria and underwent chest CT and QCT examination in the health management discipline of Henan Provincial People′s Hospital were selected as the research objects. The general data were collected; and the subcutaneous fat area, visceral fat area, total abdominal fat area, liver fat content, abdominal obesity and fatty liver detection rate were measured by QCT. According to body mass index, the subjects were divided into normal group (18.5-<24.0 kg/m 2, 1 343 cases), overweight group (24.0-<28.0 kg/m 2, 1 427 cases) and obesity group (≥28.0 kg/m 2, 435 cases). One-way analysis of variance and χ2 test were used to compare the differences of QCT indexes among the three groups. Pearson and Spearman correlation analysis were used to evaluate the correlation between QCT indexes and body mass index. Receiver operating characteristic (ROC) curve was drawn to analyze the diagnostic effect of QCT on obesity and fatty liver. Results:Subcutaneous fat area, visceral fat area, total abdominal fat area, liver fat content, abdominal obesity and fatty liver detection rate in obese group were all significantly higher than those in overweight group and normal group [males, (147.60±46.44) vs (104.33±27.68), (73.46±22.65) cm 2; (297.46±54.70) vs (229.40±53.12), (159.57±49.68) cm 2; (445.06±70.24) vs (333.73±62.91), (233.02±61.87) cm 2; 11.30% (7.90%, 15.55%) vs 8.75% (6.50%, 11.70%), 6.60% (4.80%, 8.70%); 100.0% vs 96.0%, 64.0%; 92.9% vs 86.7%, 73.3%; females, (213.96±48.61) vs (155.85±35.31), (107.24±31.01) cm 2; (185.41±43.88) vs (142.48±41.75), (96.56±36.50) cm 2; (399.37±68.07) vs (298.33±56.86), (203.80±57.53) cm 2; 9.80% (6.90%, 13.30%) vs 7.30% (5.05%, 9.80%), 5.40%(3.50%, 7.20%); 96.4% vs 74.8%, 28.9%; 87.3% vs 75.6%, 56.5%], and were all positively correlated with body mass index (males, r/ rs=0.709, 0.738, 0.831, 0.402, 0.464, 0.225; females, r/ rs=0.798, 0.695, 0.841, 0.416, 0.605, 0.276) (all P<0.001). In both male and female subjects, the detection rates of obesity based on QCT were significantly higher than those based on body mass index (male, 86.9% vs 16.6%; female, 49.3% vs 8.9%), and the detection rates of fatty liver based on QCT were significantly higher than those based on ultrasound (male, 83.6% vs 57.1%; female, 65.2% vs 27.6%) (all P<0.001). ROC curve showed that when the visceral fat area of 142 cm 2 was used as the cut-off value for the diagnosis of obesity in male subjects, the sensitivity and specificity was 100% and 15.8%, respectively; and when the cut-off value of liver fat content 5.0% was used to diagnose fatty liver, the sensitivity and specificity was 88.9% and 25.1%, respectively. When the visceral fat area of 115 cm 2 was set as the cut-off value for the diagnosis of obesity in female subjects, the sensitivity and specificity was 96.4% and 55.3%, respectively; when the liver fat content of 5.0% was set as the cut-off value for the diagnosis of fatty liver, the sensitivity and specificity was 83.7% and 43.2%, respectively. Conclusions:The indexes of abdominal fat and liver fat measured by QCT in adults receiving physical examination are all positively correlated with body mass index. The effect of QCT in the diagnosis of obesity and fatty liver are both better than body mass index and ultrasound.
		                        		
		                        		
		                        		
		                        	
4.Quantitative CT study of fat distribution in normal weight population
Yang ZHOU ; Qi QIAO ; Yongbing SUN ; Xin QI ; Yawei DU ; Zhonglin LI ; Zhi ZOU ; Xiaoling WU ; Jing ZHOU ; Min QU ; Xiaolin ZHANG ; Yong WANG ; Shewei DOU ; Hongming LIU ; Fengshan YAN ; Gong ZHANG ; Jiadong ZHU ; Yongli LI
Chinese Journal of Health Management 2024;18(6):410-415
		                        		
		                        			
		                        			Objective:To analyze the distribution of body fat with quantitative computed tomography (QCT) in people with normal body mass index (BMI).Methods:A cross-sectional study was conducted in the physical examination population who underwent chest CT and QCT examination in the Department of Health Management, Henan Provincial People′s Hospital from January to December in 2021, and 1 395 physical examination subjects who met the inclusion criteria were selected as the research subjects. The subjects were divided into five groups according to their age. The general data of the subjects were collected. The total abdominal fat area (TFA), visceral fat area (VFA), subcutaneous fat area (SFA), total abdominal muscle area (TMA) and muscle fat content (MFC) in the subjects were measured by QCT. One-way analysis of variance, Welch test and Kruskal-Wallis test were used to compare the above QCT measurement indexes between the two genders among different age groups with normal BMI. Pearson correlation analysis was used to analyze the correlation between VFA and sarcopenia indexes. Multivariate linear regression was used to analyze the relationship between VFA and linear correlation variables in the related indicators of sarcopenia.Results:There were significant differences in TFA, VFA, TMA and SMI among different age groups in subjects with normal BMI (all P<0.05). Pearson correlation analysis showed that VFA was negatively correlated with TMA in some age groups (male: 18-39 years group: r=-0.351; 40-49 years group: r=-0.278; 60-69 years group: r=-0.245; female:40-49 years group: r=-0.251; 50-59 years group: r=-0.270;≥70 years group: r=-0.391; all P<0.01); it was negatively correlated with SMI (male: 18-39 years group: r=-0.352; 40-49 years group: r=-0.340; 50-59 years group: r=-0.266; 60-69 years group: r=-0.316; female: 40-49 years group: r=-0.240; 50-59 years group: r=-0.284; all P<0.001); it was positively correlated with MFC (male: 18-39 years group: r=0.342; 40-49 years group: r=0.291; female: 50-59 years group: r=0.133; 60-69 years group: r=0.284; all P<0.05). Multivariate linear regression analysis showed that VFA was independently and negatively correlated with SMI in both men and women after adjusting for age interference factors (male B=-1.881, t=-6.025, P<0.001; female B=-0.603, t=-2.887, P=0.004), and it was independently positively correlated with MFC (male B=1.230, t=4.271, P<0.001;female B=0.893, t=3.836, P<0.001). There was an independent negative correlation between VFA and TMA in male subjects ( B=0.263, t=2.478, P=0.013). Conclusions:VFA is correlated with TMA, SMI and MFC in people with normal BMI. Regardless of gender, SMI has a negative effect on VFA, and MFC has a positive effect on VFA.
		                        		
		                        		
		                        		
		                        	
5.METTL14 is a chromatin regulator independent of its RNA N6-methyladenosine methyltransferase activity.
Xiaoyang DOU ; Lulu HUANG ; Yu XIAO ; Chang LIU ; Yini LI ; Xinning ZHANG ; Lishan YU ; Ran ZHAO ; Lei YANG ; Chuan CHEN ; Xianbin YU ; Boyang GAO ; Meijie QI ; Yawei GAO ; Bin SHEN ; Shuying SUN ; Chuan HE ; Jun LIU
Protein & Cell 2023;14(9):683-697
		                        		
		                        			
		                        			METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.
		                        		
		                        		
		                        		
		                        			Animals
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		                        			Mice
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		                        			Methylation
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		                        			Chromatin
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		                        			Histones/metabolism*
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		                        			RNA, Messenger/genetics*
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		                        			Methyltransferases/metabolism*
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		                        			RNA/metabolism*
		                        			
		                        		
		                        	
6.Exercising to music combined with transcranial direct current stimulation improves the motor and cognitive functioning of persons with Parkinson′s disease
Shaopu WU ; Xue LI ; Yawei QI ; Heng WANG ; Jianjun MA
Chinese Journal of Physical Medicine and Rehabilitation 2023;45(8):678-682
		                        		
		                        			
		                        			Objective:To observe any effect of combining music exercise with transcranial direct current stimulation (tDCS) on the motor control, balance and cognition of persons with Parkinson′s disease (PD).Methods:A total of 120 PD patients were randomly divided into a control group, a music exercise group, a tDCS group and a combined group, each of 30. All received routine rehabilitation training, while the music exercise, tDCS and combined groups were additionally provided with music exercise therapy, tDCS treatment or both, respectively. Version three of the unified Parkinson′s disease scale (UPDRSIII), a 10m reentry movement test, the Berg balance scale (BBS), the Activity Balance Confidence scale (ABC) and Montreal cognitive assessments were applied before and after 4 weeks of the treatments.Results:After the treatment, the average UPDRSIII score and 10m reentry movement time of the music exercise group were significantly lower than in the control group, while the average BBS and ABC scores were significantly higher than the control group′s averages. The tDCS group′s average MoCA scores on all of the items and its total score were significantly higher than those of the music exercise and control groups. The average UPDRSIII score and 10m reentry movement time of the combined group were the lowest after the treatment, and that group′s average BBS, ABC, MoCA and total scores were the highest, significantly better than the other three groups.Conclusion:Combining music exercise training with tDCS can effectively improve the motor functioning, balance and cognition of persons with PD.
		                        		
		                        		
		                        		
		                        	
7.Clinical evaluation of direct drug sensitivity test for blood culture positive broths
Shuo YANG ; Qi WANG ; Hongfei LU ; Xiaojuan WANG ; Yawei ZHANG ; Shuguang LI ; Han MENG ; Feifei ZHANG ; Zhanwei WANG ; Hongbin CHEN ; Hui WANG
Chinese Journal of Laboratory Medicine 2023;46(6):582-588
		                        		
		                        			
		                        			Objective:To evaluate the clinical performance of direct antimicrobial susceptibility test in blood culture-positive broth, and to provide a basis for optimizing the antibiotic use strategy in clinical bloodstream infection.Methods:A retrospective analysis was conducted on 780 blood culture-positive samples collected in Peking University People′s Hospital from May 2017 to December 2021. The direct antimicrobial susceptibility test was performed by disk diffusion method on blood culture-positive broth. The antimicrobial susceptibility breakpoints were in accordance with Clinical and Laboratory Standards Institute (CLSI) M100 S32 edition document.Results:In this study, a total of 331 strains of Gram-negative bacteria (139 strains of Escherichia coli, 79 strains of Klebsiella pneumoniae, 35 strains of Pseudomonas aeruginosa, 21 strains of Acinetobacter baumannii) and 396 strains of Gram-positive cocci (25 strains of Staphylococcus aureus, 316 strains of coagulase-negative staphylococci, 47 strains of Enterococcussp.) were collected, after excluding 53 cases with two or more isolates. Compared with the routine antimicrobial susceptibility test (AST), the rates of category agreement (CA), major error (ME), and very major error (VME) of Gram-negative bacteria were 86.0% (1368/1 591), 8.7% (139/1 591), and 0.5% (8/1 591), respectively. On the other hand, the CA%, ME%, and VME% of Gram-positive cocci were 89.2% (960/1 076), 7.5% (81/1 076), and 1% (11/1 076), respectively. Regarding the individual antimicrobial agents, the CA% of Escherichia coli was 16/17 for imipenem, 90.1% (109/121) for meropenem, and 70.8% (85/120) for cefepime. For Klebsiella pneumoniae, the CA% of was 10/13 for imipenem, 80.9% (55/68) for meropenem, and 80.3% (53/66) for cefepime. The CA% of meropenem in Pseudomonas aeruginosa and Acinetobacter baumannii were 96.0% (24/25) and 16/16. The CA% of linezolid and cefoxitin in Staphylococcus aureus were 100% (25/25) and 100% (24/24), respectively. The CA% of linezolid, cefoxitin and gentamicin in coagulase-negative staphylococci were 98.9% (269/272), 94.5% (277/293) and 71.6% (194/271) respectively. Finally, for Enterococcus sp., the CA% of vancomycin and ampicillin were 91.5% (43/47) and 94.7% (36/38), respectively. Conclusion:Compared with the conventional AST, the blood culture-positive broth direct AST exhibited high category agreement and low error rates for both Gram-negative bacteria and Gram-positive cocci, which can serve a rapid alternative for AST in cases of clinical bloodstream infection.
		                        		
		                        		
		                        		
		                        	
8.Effects of Danshen polyphenolate combined with edaravone on cognition,cerebral artery pulse index and serum visinin like protein-1 levels in patients with acute cerebral infarction
Saiqing QI ; Yawei ZHANG ; Junchao LI ; Zhiguo SHEN
Journal of Clinical Medicine in Practice 2023;27(22):114-117,122
		                        		
		                        			
		                        			Objective To investigate the effects of Danshen polyphenolate combined with edara-vone on cognitive function,cerebral artery pulse index(PIMCA)and serum trypanoprotein-like pro-tein-1(VILIP-1)levels in patients with acute cerebral infarction(ACI).Methods A total of 88 pa-tients with ACI were selected as study objects.The patients were divided into single drug group(n=44)and combination group(n=44)according to random number table method.The single drug group was treated with edaravone,and the combination group was treated with edaravone combined with salvianolic acid for injection.The efficacy,cognitive function,PIMCA and serum VILIP-1 levels of the two groups were observed and compared.Results The overall effective rate of treatment in the combi-nation group was higher than that of the single drug group(81.82%versus 54.55%,P<0.05).Af-ter treatment,the scores of Montreal Cognitive Assessment Scale(MoCA),Reactivity Exploration Scale(RSS)and Simple Mental State Assessment Scale(MMSE)in two groups were higher than be-fore treatment,and the combination group was higher than the single drug group(P<0.05).After treatment,the levels of PIMCA and serum VILIP-1 in two groups were lower than before treatment,and the combination group was lower than the single drug group(P<0.05).Conclusion Compared with edaravone alone,salvia miltiorrhiza polyphenolate injection combined with edaravone has a better therapeutic effect in ACI patients,which can effectively improve the patients'cognition,reduce PIMCA and serum VILIP-1 levels.
		                        		
		                        		
		                        		
		                        	
9.Effects of Danshen polyphenolate combined with edaravone on cognition,cerebral artery pulse index and serum visinin like protein-1 levels in patients with acute cerebral infarction
Saiqing QI ; Yawei ZHANG ; Junchao LI ; Zhiguo SHEN
Journal of Clinical Medicine in Practice 2023;27(22):114-117,122
		                        		
		                        			
		                        			Objective To investigate the effects of Danshen polyphenolate combined with edara-vone on cognitive function,cerebral artery pulse index(PIMCA)and serum trypanoprotein-like pro-tein-1(VILIP-1)levels in patients with acute cerebral infarction(ACI).Methods A total of 88 pa-tients with ACI were selected as study objects.The patients were divided into single drug group(n=44)and combination group(n=44)according to random number table method.The single drug group was treated with edaravone,and the combination group was treated with edaravone combined with salvianolic acid for injection.The efficacy,cognitive function,PIMCA and serum VILIP-1 levels of the two groups were observed and compared.Results The overall effective rate of treatment in the combi-nation group was higher than that of the single drug group(81.82%versus 54.55%,P<0.05).Af-ter treatment,the scores of Montreal Cognitive Assessment Scale(MoCA),Reactivity Exploration Scale(RSS)and Simple Mental State Assessment Scale(MMSE)in two groups were higher than be-fore treatment,and the combination group was higher than the single drug group(P<0.05).After treatment,the levels of PIMCA and serum VILIP-1 in two groups were lower than before treatment,and the combination group was lower than the single drug group(P<0.05).Conclusion Compared with edaravone alone,salvia miltiorrhiza polyphenolate injection combined with edaravone has a better therapeutic effect in ACI patients,which can effectively improve the patients'cognition,reduce PIMCA and serum VILIP-1 levels.
		                        		
		                        		
		                        		
		                        	
10.Association of urinary nickel levels with insulin resistance, islet function, and diabetes in adults aged 18 years and above in China
Yingli QU ; Zheng LI ; Saisai JI ; Qi SUN ; Yawei LI ; Jiayi CAI ; Zhuona ZHANG ; Haocan SONG ; Wenli ZHANG ; Feng ZHAO ; Ying ZHU ; Yuebin LYU ; Zhaojin CAO ; Xiaoming SHI
Chinese Journal of Epidemiology 2023;44(11):1717-1723
		                        		
		                        			
		                        			Objective:To investigate the effects of urinary nickel exposure on insulin resistance, islet function and diabetes risk in adults aged 18 years and above in China.Methods:Based on the China National Human Biomonitoring from 2017 to 2018, a total of 500 diabetes patients were randomly selected as the case group, and the matched euglycemic control were selected by 1∶1 matching ratio. The urinary and venous blood samples of the subjects were collected, and the urinary nickel levels and serum glucose metabolism indexes such as fasting blood glucose and fasting insulin were detected, and the insulin resistance index (HOMA-IR), β cell function index (HOMA-β), and adjusted HOMA-β were calculated by using homeostasis model assessment. A multivariate logistic regression model was used to analyze the association between urinary nickel level and diabetes risk. Multiple linear regression models were used to evaluate the association of urinary nickel level with HOMA-IR, HOMA-β and adjusted HOMA-β.Results:The sex ratio of controls and cases was 1∶1. The multivariate logistic regression model showed that after adjusting for factors such as education level, smoking status, alcohol consumption, rice and meat intakes, family history of diabetes, BMI, total cholesterol level, hypertension, and urinary creatinine, compared with T1 group, the ORs of diabetes risk in the T2 and T3 groups were 1.36 (95% CI: 0.98-1.89) and 1.60 (95% CI: 1.14-2.24), respectively. The multiple linear regression model showed a positive association between urinary nickel levels and the elevated HOMA-IR, the β value of HOMA-IR in the T3 group was 0.12 (95% CI: 0.01-0.25) compared with the T1 group and each one-unit increase in the log-transformed urinary nickel level (2.71 μg/L) was associated with a 0.06 elevation in HOMA-IR (95% CI: 0.02-0.10). Meanwhile, the urinary nickel levels were negative associated with the adjusted HOMA-β, the β value of adjusted HOMA-β in the T3 group were -0.26 compared with the T1 group (95% CI: -0.41- -0.11), and each one-unit increase in the log-transformed urinary nickel level (2.71 μg/L) was associated with a -0.09 decrease in adjusted HOMA-β(95% CI: -0.14- -0.04). Conclusion:Higher urinary nickel level is positively correlated with elevated insulin resistance and diabetes risk while negatively correlated with the function of pancreatic islet β cells in adults in China.
		                        		
		                        		
		                        		
		                        	
            
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