1.Quantification of in vivo biomechanics and analysis of influencing factors in cervical spine fixed-point rotation manipulation
Jiyao LIANG ; Honghai ZHOU ; Guikang WEI ; Shaoting SU ; Longhao CHEN ; Xinyu HE ; Liangpu LIU
Chinese Journal of Tissue Engineering Research 2025;29(3):486-492
		                        		
		                        			
		                        			BACKGROUND:Fixed-point rotation manipulation of cervical spine is a mechanical operation with high technical requirements,but the biomechanics of fixed-point manipulation of cervical spine still lacks relevant quantitative data.Moreover,the research on the influencing factors of cervical fixed-point rotation manipulation includes many parameters and there are differences,so it is necessary to further analyze its influencing factors to improve its related data. OBJECTIVE:To quantify the biomechanical parameters of cervical spine fixed-point rotation manipulation,explore the correlation between different biomechanical parameters,and the influence of individual characteristics of the subjects on the biomechanical parameters of cervical spine fixed-point rotation manipulation. METHODS:Totally 35 cases of cervical spondylosis were Outpatients from Orthopedic Department of Renai Branch of the First Affiliated Hospital of Guangxi University of Chinese Medicine and selected as the subjects investigated.Wearable mechanical measuring gloves were used to collect biomechanical parameters of cervical spine fixed-point rotation manipulation,including:thumb preload,thumb maximum thrust,palm preload,palm wrench force,and palm wrench maximum force.Personal characteristic parameters were collected,including age,height,weight,and neck circumference.The key biomechanical parameters in the process of cervical spine fixed-point rotation manipulation were analyzed and different individual characteristics were quantified.The results of biomechanical parameters were analyzed using Spearman correlation analysis.The possible effects of different individual characteristic parameters on biomechanics were analyzed. RESULTS AND CONCLUSION:(1)Compared with bilateral mechanical parameters,there was no significant difference between left manipulation and right manipulation(P>0.05).(2)The average of thumb preload force was(7.21±1.19)N;the average of thumb maximum thrust was(28.40±4.48)N;the average of palm preload was(5.67±2.49)N;the average of palm wrench force was(10.90±5.11)N,and the average of palm wrench maximum force was(16.00±7.27)N.(3)There was a significant positive correlation between palm preload and palm wrench force(Rs=0.812,P<0.01).There was a significant positive correlation between palm preload and palm wrench maximum force(Rs=0.773,P<0.01).There was a significant positive correlation between palm wrench force and palm wrench maximum force(Rs=0.939,P<0.01).(4)The weight was positively correlated with thumb preload,palm preload,palm wrench force and palm wrench maximum force(P<0.05).(5)These findings confirm that there is a certain biomechanical standard value in the operation of cervical spine fixed-point rotation manipulation to treat cervical spondylosis.There is no significant difference between the left and right manipulations,which indicates that the manipulation has good consistency and repeatability.There is consistency and coordination among palm preload force,palm wrench force,and palm wrench maximum force.Their contributions to the therapeutic effect are similar.Body weight is an important factor affecting cervical spine fixed-point rotation manipulation.
		                        		
		                        		
		                        		
		                        	
2.Changes in lumbosacral sagittal plane parameters of L5/S1 disc herniation reabsorption
Xinyu HE ; Honghai ZHOU ; Hong JIANG ; Zhijia MA ; Shaoting SU ; Zehong LIN ; Junming TIAN ; Longhao CHEN ; Baijie LIU
Chinese Journal of Tissue Engineering Research 2024;28(9):1330-1335
		                        		
		                        			
		                        			BACKGROUND:Previous studies have shown the correlation between lumbosacral sagittal plane parameters and natural absorption of lumbar disc herniation.However,the lumbosacral sagittal plane parameters included lumbar lordosis angle,lumbosacral joint angle,sacral inclination angle and many other parameters.The effects of each parameter on the natural absorption of the herniated disc were different.In addition,there are few studies on the reabsorption of a specific segment of intervertebral disc herniation at present,and most of the measured data are obtained from digital radiography or CT,while the correlation between lumbosacral sagittal plane parameters measured from MRI and reabsorption after L5/S1 intervertebral disc herniation is rarely reported. OBJECTIVE:To study the corresponding changes of lumbar sagittal plane parameters after L5/S1 intervertebral disc herniation reabsorption and to screen out the lumbosacral sagittal plane parameters with the most significant changes during intervertebral disc reabsorption. METHODS:Totally 57 patients with lumbar disc herniation who had complete MRI image data were selected and met the diagnostic criteria for lumbar disc herniation and only received non-surgical treatment for reabsorption of L5/S1 protrusion segments.MRI measured the protrusion area of the maximum protrusion plane in the coronal plane,lumbosacral sagittal plane parameters[lumbar curvature index,lumbar lordosis(α),L5/S1 disc angle(β),intervertebral height measurement,lumbosacral joint angle,sacral platform angle,sacral inclination angle,and lower lumbar lordosis angle].Besides,lumbosacral sagittal plane parameters were ranked in the importance of variables by random forest model in R software,and then significant variables were fitted with multiple linear regression.The changes between parameters before and after treatment were analyzed and compared by paired sample t-test. RESULTS AND CONCLUSION:(1)A total of 57 patients with L5/S1 lumbar disc herniation were included in this study,and the symptoms and imaging features of the patients were significantly relieved to a large extent.(2)Before treatment,there were 4 cases of grade 1,29 cases of grade 2 and 24 cases of grade 3 according to the Classification of Michigan State University.After treatment,there were 48 cases of grade 1 and 9 cases of grade 2.(3)The random forest model suggested that intervertebral height,lumbar curve index,sacral inclination angle,and lower lumbar lordosis angle changed significantly in L5/S1 disc herniation reabsorption,and the order of their change significance was lumbar curve index>intervertebral space height>sacral inclination angle>lower lumbar lordosis angle.(4)Lumbar curve index,lumbar lordosis and sacral platform angle increased,with statistical significance(P<0.05).There were no significant differences in disc angle,intervertebral height,lower lumbar lordosis angle,sacral inclination angle or lumbosacral joint angle(P>0.05).(5)Lumbar curvature index was the most significant parameter of the lumbosacral sagittal plane in herniated disc reabsorption.In addition,lumbar curve index,sacral inclination angle,and lower lumbar lordosis angle are commonly used clinically to describe the change of lumbar curvature,suggesting that L5/S1 disc herniation reabsorption is correlated with the change of lumbar curvature.It is indicated that in the treatment of lumbar disc herniation,a clinical cure can be achieved by improving or restoring the disordered lumbar curvature.
		                        		
		                        		
		                        		
		                        	
3.Correlation between serum uric acid level and body composition, exercise capacity and cardiopulmonary function in medical examination population
Shan LIU ; Jia CUI ; Wei ZHAO ; Honghai HE ; Jie GE ; Xiaoyan HAO ; Tianyi QI ; Peng WANG
Chinese Journal of Health Management 2024;18(1):24-28
		                        		
		                        			
		                        			Objective:To investigate the correlation between blood uric acid level and body composition, exercise capacity, and cardiopulmonary function in medical examination population.Methods:In this cross-sectional study, 83 individuals who underwent physical examinations at Peking University Third Hospital from June 1, 2023, to October 1, 2023, and met the inclusion criteria were included. According to whether they had hyperuricemia (HUA), the participants were divided into HUA group (53 cases) and non-HUA group (30 cases). Body composition parameters, such as body mass index and visceral fat area, were measured with a body composition analyzer. Exercise capacity indicators, including grip strength, vertical jump, back strength, and sit-and-reach test, were measured using specific monitoring devices. Cardiopulmonary function was assessed using the stair index test. The clinical characteristics of the two groups were compared with t-tests or chi-square tests, and the correlation between uric acid levels and body composition, exercise capacity, and cardiopulmonary function was analyzed. Results:The HUA group had significantly higher skeletal muscle mass, body fat mass, body mass index, and visceral fat area when compared with the non-HUA group [(31.92±5.60) vs (26.11±6.19) kg, (23.66±9.33) vs (17.19±5.00) kg, (26.53±3.68) vs (23.27±3.59) kg/m2, 91.20 (74.25, 123.90) vs 68.25 (56.25, 90.48) cm 2, respectively] (all P<0.05). The grip strength, vertical jump, and back pull strength were all lower in the HUA group [32.70 (25.25, 40.30) vs 42.35 (35.95, 48.10) kg, 30.30 (24.10, 36.48) vs 40.55 (33.06, 45.10) kg, 24.20(20.60, 32.23) vs 29.90 (25.20, 35.50) cm, 65.60 (51.75, 78.00) vs 91.00 (67.25, 111.50) kg, respectivley] (all P<0.05). The increased step index was positively correlated with reduced risk of hyperuricemia ( OR=0.875, 95% CI: 0.793-0.966) ( P<0.05). Conclusions:Blood uric acid level is correlated with cardiopulmonary function in medical examination population. Individuals with better cardiopulmonary function have a lower risk of developing HUA. However, the relationship between blood uric acid level and body composition and exercise capacity is not clear.
		                        		
		                        		
		                        		
		                        	
4.Determination of vanillin in lysine and vitamin B12 granules by HPLC
Haiyan TIAN ; Juan LIU ; Weibin LIU ; Honghai LIU
Drug Standards of China 2024;25(5):517-520
		                        		
		                        			
		                        			Objective:To establish an HPLC method to determine of vanillin in lysine and vitamin B12 granules.Methods:1.0 g of lysine and vitamin B12 granules was put into a 10mL graduated centrifuge tube,1 mL of water was added to dissolve,vortex for 1 min,and methanol was added to the scale and vortex for 1 min for extraction.The samples were separated on a C18 column(250 mm × 4.6 mm,5 μm)with a mobile phase of methanol and water(35∶65)at ta flow rate of 1.0 mL·min-1.The detection wavelength was 277 nm.Results:The limit of detection of vanillin was 0.2 μg·g-1,and the concentration was linear in the range of 1.962-49.04 μg·mL-1(r=0.999 9).The recoveries of vanillin at low,medium and high levels were 91.86%-101.61%with RSD of 2.9%(n=9).6 batches of samples were determined,and the results showed that the vanillin content in 4 batches of enterprise A was 55.18-79.55 μg·g-1,and no vanillin was detected in enterprise B and enterprise C.Conclusion:The method is simple and reliable,and can be used for the rapid determination of vanillin in lysine and vitamin B12 granules.
		                        		
		                        		
		                        		
		                        	
5.Causal association between inflammatory cytokines and fibromyalgia: a bidirectional Mendelian randomization analysis study
Jiyao LIANG ; Zehong LIN ; Yan LU ; Xinyu HE ; Liangpu LIU ; Jihu WEI ; Honghai ZHOU
Chinese Journal of Rheumatology 2024;28(7):478-483
		                        		
		                        			
		                        			Objective:To explore the causal association between inflammatory cytokines and fibromyalgia by Mendelian randomization analysis.Methods:By mining the GWAS Catalog database and FinnGen database, the exposure factor was set as inflammatory cytokines, and the outcome was fibromyalgia. The main analysis method adopted in this study is inverse variance weighted (IVW) method, with MR-Egger, Simple Mode method, weighted median (WM), and Weighted Mode as supplementary statistical methods for Mendelian randomization analysis. Subsequently, by swapping the exposure factors and outcomes, the directionality of the analysis was tested.Results:Among the 91 known inflammatory cytokines, a causal association was found between natural killer cell receptor 2B4 (CD244), monocyte chemotactic protein 2 (MCP-2), C-X-C chemokine 6 (CXCL6), interleukin 12β subunit (IL12B), and fibromyalgia. Among them, CD244, CXCL6, and IL12B were positively correlated with FM [CD244: OR(95% CI)=1.21(1.08, 1.35), P<0.001]. [MCP-2: OR(95% CI)=0.91(0.87, 0.96), P<0.001], [CXCL6: OR(95% CI)=1.15(1.06, 1.24), P<0.001], IL-12B [ OR(95% CI)=1.13(1.06, 1.20), P<0.001]. Sensitivity analysis did not find multiple effects, heterogeneity,or correlation. Conclusion:The increase in the levels of CD244, CXCL6, and IL-12B will increase the risk of FM, while the increase in the level of MCP-2 will reduce the risk of FM disease.
		                        		
		                        		
		                        		
		                        	
6.Effect Evaluation of Responsible Segmental Decompression Combined with Orthopedic Fixation of Short-Segment Fusion Surgery for Treating Degenerative Lumbar Scoliosis
Hui ZENG ; Gangqiang WU ; Can HUANG ; Xiaojun HAN ; Bo LIU ; Cheng CHEN ; Long MA ; Bowen ZHANG ; Honghai WANG
Journal of Medical Biomechanics 2024;39(5):896-902
		                        		
		                        			
		                        			Objective To investigate the therapeutic effect of segmental decompression combined with corrective short-segment fusion surgery for the treatment of degenerative lumbar scoliosis.Methods In total,124 patients with degenerative lumbar scoliosis were selected and divided into short-and long-segment fusion groups using the random number table method,with 62 patients in each group.Posterior short-segment decompression,fixation,and fusion were performed in the short-segment fusion group;the fusion segment was the adjacent lumbar vertebra.Posterior long-segment decompression,fixation,and fusion were performed in the long-segment fusion group;the fusion segments included multiple adjacent lumbar vertebrae.At the 6th month after surgery,the coronal Cobb angle of lumbar convexity,sagittal Cobb angle of lumbar lordosis,intervertebral foramen height,intervertebral space height,intervertebral foramen area,spinal canal area,spinal canal diameter,Japanese Orthopedic Association(JOA)score,Oswestry Disability Index(ODI),degree of pain in the lower back and lower limbs,and postoperative complications were compared between the groups.Results The Cobb angle of the coronal lumbar scoliosis in the short-and long-segment fusion groups was significantly higher than that before surgery(P<0.05).At the 6th month after surgery,the intervertebral foramen height,intervertebral space height,intervertebral foramen area,spinal canal area,and spinal canal diameter in both groups increased,and those in the short-segment fusion group were higher than those in the long-segment fusion group(P<0.05);at the 6th month after the operation,the JOA scores of the short-segment and long-segment fusion groups were higher than those before surgery,and the JOA score of the short-segment fusion group was higher than that of the long-segment fusion group(P<0.05).The ODI score was lower than that before surgery in the short-and long-segment fusion groups,and the ODI score in the short-segment fusion group was lower than that in the long-segment fusion group(P<0.05).At the 6th month after surgery,the pain scores of the lower back and lower limbs in the short-and long-segment fusion groups were significantly higher than those before surgery(P<0.05).There were two cases of dural tears during decompression caused by lamina dura adhesion in the long-segment fusion group,and no serious complications were observed in the short-segment fusion group.Conclusions Both short-and long-segment decompression fixation fusion using a posterior approach can achieve good therapeutic effects for treating degenerative lumbar scoliosis.However,compared to the long-segment fusion group,the short-segment fusion group undergoing short-segment decompression fixation fusion through a posterior approach had a shorter surgical period,lower intraoperative blood loss,better recovery of lumbar function,and a lower risk of postoperative complications.
		                        		
		                        		
		                        		
		                        	
7.Laparoscopic or robotic serosa muscular layer circumferential incision combined with mucosal layer cutting and closure for gastrointestinal mesenchymal tumors at difficult sites of the stomach
Honghai GUO ; Yiyang HU ; Peigang YANG ; Yuan TIAN ; Dong WANG ; Zhidong ZHANG ; Xuefeng ZHAO ; Ping'an DING ; Yang LIU ; Yong LI ; Qun ZHAO
Chinese Journal of General Surgery 2022;37(11):817-820
		                        		
		                        			
		                        			Objective:To evaluate the use of serosa muscular layers circumferential incision combined with mucosal layer cutting and closure by laparoscopic or robotic surgery for gastrointestinal mesenchymal tumors at difficult sites of the stomach.Methods:From Jul 2019 to Apr 2021, 18 gastric mesenchymal tumor patients undergoing serosa muscular layers circumferential incision combined with mucosal layer cutting and closure by laparoscopic or robotic surgery at the Department of Surgery, the Fourth Hospital of Hebei Medical University were retrospectively analyzed.Results:All 18 patients had successful surgery, including 7 cases of robotic surgery, 11 cases of laparoscopic surgery, and there was no conversion to open surgery. Tumors were at the gastric in cardia, 8 cases at the gastric body and lesser curvature in 4 cases, and at the gastric antrum in 6 cases, respectively. Eleven cases were of endogenous and 7 cases were of dumbbell type. The average operation time was (99±29) min, the intraoperative blood loss was (10±5) ml, the first time taking food per mouth was (2.0±1.0) d, and the postoperative hospital stay was (4.9 ± 1.2) d. Pathology showed gastrointestinal stromal tumor in 11 cases, leiomyoma in 5 cases and schwannoma in 2 cases. All were with negative margins. The average tumor diameter was (4.7±1.4) cm. The median follow-up time was 16.5 months, and there was no sign of tumor recurrence or metastasis.Conclusion:The serosa muscular layers circumferential incision combined with mucosal layer cutting and closure technique in laparoscopic or robotic surgery is a safe and feasible procedure for treating gastrointestinal mesenchymal tumor at difficult sites of the stomach.
		                        		
		                        		
		                        		
		                        	
8.Study on protective effects of Shiyifang medicinal wine on knee osteoarthritis in rabbits based on TLR 4/MyD88/ NF-кB signaling pathway
Wentao ZHANG ; Lingmei ZHOU ; Honghai HUANG ; Huihui BAO ; Dewen MAO ; Hui TIAN ; Shuling LIU
China Pharmacy 2022;33(18):2224-2229
		                        		
		                        			
		                        			OBJECTIVE To study the protective effect and mechanism of Shiyifang medicinal wine (SYF) on knee osteoarthritis(KOA)of rabbit induced by papain . METHODS Thirty-five rabbits were randomly divided into blank group ,model group,positive group (Diclofenac diethylamine emulsion 200 mg/kg),SYF high -dose group (386 mg/kg)and SYF low -dose group(97 mg/kg),with 7 rabbits in each group (all had 4 males and 3 females). Except for the blank group ,the other groups ’ rabbits were injected 0.5 mL papain mixture (containing 2% papain and 0.03 mol/L L -cysteine)into the right knee cavity on day 1, 4 and 7,to replicate KOA model . Blank group was given constant volume of normal saline . From the 15th day ,drugs were applied to right hind knee joints of rabbits in each group ,twice a day for 20 days. At the same time ,the diameter of right knee joints of rabbits was measured by vernier calipers at day 0,8,14 and 35 to calculate swelling degree . After the experiment ,the levels of IL-1β,TNF-α and PGE 2 in synovial tissue were determined by enzyme -linked immunosorbent assay . Hematoxylin-eosin(HE) staining was used to prepare the sections of synovial tissue ,and the pathological changes were observed . The relative mRNA expressions of TLR 4,MyD88 and NF - кB p 65 in the TLR 4/MyD88/NF- кB signaling pathway were detected by real -time quantitative polymerase chain reaction . The relative protein expressions of TLR 4,MyD88,NF-кB p 65 and p -NF-кB p 65 were detect by Western blot . RESULTS Compared with blank group,the degree of knee swelling could be increased in model group ,the pathological damage of synovial tissue was more serious ,and the levels of IL -1β,TNF-α and PGE 2 were increased significantly in synovial tissue (P<0.05). The relative expression levels of TLR 4,MyD88,NF-кB p 65 mRNAs and TLR 4,MyD88,p-NF-кB p 65 proteins were significantly increased(P<0.05). Compared with model group ,swelling degree of right hind knee and the pathological injury degree of synovial tissue were significantly improved in each treatment group ,while the levels of IL -1β,TNF-α and PGE 2 in synovial tissue were significantly decreased (P<0.05). The relative mRNA expressions of TLR 4,MyD88 and NF -кB p 65 and relative protein expressions of TLR 4,MyD88(except for SYF low -dose group )and p -NF-кB p 65 were all significantly decreased (P<0.05). CONCLUSIONS SYF shows protective effect on KOA induced by papain ,the mechanism of which is associated with decreasing the levels of IL -1β,TNF-α and PGE 2 and down -regulating TLR 4/MyD88/NF-кB signaling pathway .
		                        		
		                        		
		                        		
		                        	
9.Influence of different injection time of carbon nanoparticle tracer on the acquisition of lymph nodes in adenocarcinoma of esophagogastric junction treated by neoadjuvant chemoradio-therapy combined with surgical resection: a prospective study
Peigang YANG ; Yuan TIAN ; Honghai GUO ; Bibo TAN ; Ping′an DING ; Yang LIU ; Zhidong ZHANG ; Yong LI ; Qun ZHAO
Chinese Journal of Digestive Surgery 2022;21(3):385-390
		                        		
		                        			
		                        			Objective:To investigate the influence of different injection time of carbon nanoparticle tracer on the acquisition of lymph nodes in adenocarcinoma of esophagogastric junc-tion (AEG) treated by neoadjuvant chemoradiotherapy (nCRT) combined with surgical resection.Methods:The prospective randomized controlled study was conducted. The clinicopathological data of 120 AEG patients who were treated by nCRT combined with surgical resection in the Fourth Hospital of Hebei Medical University from March 2020 to March 2021 were selected. Based on random number table, patients were allocated into two groups. Patients undergoing endoscopic injection of carbon nanoparticle tracer 24 hours before nCRT were allocated into the experiment group, and patients undergoing endoscopic injection of carbon nanoparticle tracer 24 hours before surgical resection were allocated into the control group. All patients received the same plan of nCRT combined with D 2 radical gastrectomy. Observation indicators: (1) grouping situations of the enrolled patients; (2) surgical and postoperative pathological situations; (3) postoperative complications and treatment. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was analyzed using the independent sample t test. Measurement date with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was analyzed using the chi-square test. Comparison of ordinal data was analyzed using the non-parameter rank sum test. Results:(1) Grouping situations of the enrolled patients. A total of 120 patients were selected for eligibility. There were 85 males and 35 females, aged (60±9)years. There were 60 patients in the experiment group and 60 patients in the control group, respectively. (2) Surgical and postoperative pathological situations. Patients in the two groups underwent D 2 radical gastrectomy successfully, with R 0 resection. The number of lymph nodes harvest, the number of lymph nodes stained, the number of metastatic lymph nodes stained, the number of micro lymph nodes, the number of inferior mediastinal lymph nodes, the number of inferior mediastinal lymph nodes stained, cases in postoperative pathological stage N0, stage N1, stage N2, stage N3a were 40.6±13.9,20.1±7.7, 1.0(0,3.0), 8.1±2.8, 3.7±1.3, 2.0(1.0,2.0), 18, 13, 23, 6 in patients of the experiment group, respectively. The above indicators were 30.4±8.3, 12.7±3.5, 0(0,1.0), 6.2±2.0, 2.4±1.2, 1.0(0,1.0), 23, 21, 15, 1 in patients of the control group, respectively. There were significant differences in the above indicators between the two groups ( t=-5.01, 6.85, Z=-3.78, t=-4.04, -5.57, Z=-5.48, -2.12, P<0.05). (3) Postoperative complications and treatment. There were 5 cases of the experiment group and 7 cases of the control group with postoperative complications, showing no significant difference between the two groups ( χ2=0.37, P>0.05). The patients with postoperative complications were improved after symptomatic treatment. Conclusion:Compared with injection of carbon nanoparticle tracer 24 hours before surgical resection, injection of carbon nanoparticle tracer 24 hours before nCRT can improve the acquisition of lymph nodes in AEG treated by nCRT combined with surgical resection.
		                        		
		                        		
		                        		
		                        	
10.Clinicopathological Characteristics and Prognosis of Borrmann Type Ⅳ Gastric Cancer
Pingan DING ; Peigang YANG ; Yuan TIAN ; Yecheng LIN ; Honghai GUO ; Yang LIU ; Zhidong ZHANG ; Dong WANG ; Yong LI ; Qun ZHAO
Cancer Research on Prevention and Treatment 2021;48(3):261-267
		                        		
		                        			
		                        			Objective To investigate the clinicopathological characteristics and prognosis of patients with Borrmann type Ⅳ gastric cancer. Methods A cohort retrospective analysis of 2386 patients with gastric cancer who underwent radical surgery was used to screen out Borrmann type Ⅳ patients, and analyze their clinical features and prognostic factors. Results Among 2386 patients with gastric cancer, 363 cases (15.21%) were Borrmann type Ⅳ. Compared with non-Borrmann type Ⅳ gastric cancer patients, Borrmann type Ⅳ patients had higher rates of simultaneous liver metastasis, metachronous liver metastasis, lymph node metastasis and vascular infiltration. Moreover, the age of onset tended to be younger and the pathological type tended to be poorly differentiated-undifferentiated (all 
		                        		
		                        	
            
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