1.Development and validation of a diagnostic model based on machine learning algorithms for the development of interstitial lung diseases in patients with rheumatoid arthritis
Yancong NIE ; Yanqing JIN ; Meilin YIN ; Xiaoxia WANG ; Lixia QIU
Chinese Journal of Rheumatology 2024;28(3):167-175
		                        		
		                        			
		                        			Objective:Screening factors that might influence rheumatoid arthritis (RA) complicating interstitial lung diseases (ILD) by constructing and validating a model for early diagnostic.Methods:The study subjects were composed of 712 RA patients in the Department of Rheumatology and Immunology of the Second Hospital of Shanxi Medical University during December 2019 to October 2022. Fifty-two variables such as their demographic data, clinical symptoms, and laboratory indexes were collected. Patients were categorized into RA-only group and RA-ILD group with or without the occurrence of ILD disease. After data preprocessing, subjects were randomly assigned to the modeling and validation groups in a 7:3 ratio.Univariate analysis comparing baseline characteristics of the two groups of patients. Feature selection was performed using LASSO and SVM-RFE regression algorithms.Screening indicators were analyzed by logistic regression and the results were used to develop a nomograms model for the early diagnosis of RA complicating interstitial lung disease; and the modeling group was evaluated for its performance for internal assessment of the model and internal validation using data from the validation group.Results:A total of 712 subjects participated in the study, of which 498 in the modeling group and 214 in the validation group. Univariate analysis showed that the differences between the two groups were statistically significant ( P<0.05) in 18 characteristic indexes, including male, gender, age, smoking history, drinking history, number of swollen joints, number of painful joints, use of prednisone, WBC, ESR, CRP, IL-2, IL-10, IL-17, TNF-α, INF-γ, AFA family, APF, and serum albumin. The LASSO algorithm identified 13 risk variables for RA-ILD, the SVM-RFE algorithm identified 12 variables for RA-ILD, and the intersecting risk variables were male, age, history of alcohol consumption, number of painful joints, prednisone acetate, IL-2, AFA family, TNF-α, serum albumin, and IL-10. The results of multifactorial logistic regression analysis confirmed that the differences between males [ OR(95% CI)=3.61(2.11, 6.18)], gender, age [ OR(95% CI)=1.05(1.03, 1.08)], number of painful joints [ OR(95% CI)=1.03(1.01, 1.06)], IL-2 [ OR(95% CI)=0.91 (0.84, 0.99)], and TNF-α[ OR (95% CI)=1.06 (1.02, 1.10)] were statistically significant ( P<0.05) and were independently influences on ILD complicated by RA. The modeling and validation groups that were used to construct early diagnostic Nomograms had high calibration curve accuracies, and the model had a high diagnostic power, which was mainly demonstrated by the receiver operating characteristic (ROC) area under the curve (AUC) and decision curve analysis(DCA), the model modeling group had an AUC of 0.76 (95% CI=0.71, 0.81), with net benefit rates of 3%~82% and 93%~99%, whereas the model validation group had an AUC of 0.71 (95% CI=0.64, 0.79), with net benefit rates of 5%~11%, 14%~60% and 85%~89%. Conclusion:Male, gender, age, number of painful joints, IL-2, and TNF-α are independent factors for RA complicated with ILD, and the Nomogram model constructed has good performance in early diagnosis of the disease.
		                        		
		                        		
		                        		
		                        	
2.Effect of pressure support ventilation combined with low inspired oxygen concentration on atelectasis during general anesthetic emergence in elderly patients undergoing robotic-assisted radical prostatectomy
Yu HOU ; Zixuan WANG ; Lixia NIE ; Qilin YAO ; Shouyuan TIAN
Chinese Journal of Geriatrics 2023;42(12):1447-1452
		                        		
		                        			
		                        			Objective:To examine the impact of pressure support ventilation(PSV)in combination with low inspired oxygen concentration on atelectasis during the emergence from general anesthesia in elderly patients undergoing robotic-assisted radical prostatectomy.Methods:In this prospective randomized controlled study, a total of 144 elderly patients, aged 65-80 years(average age: 71.4±4.4 years), who were undergoing elective robotic-assisted radical prostatectomy under general anesthesia, were divided into 4 groups(n=36 each)using the random number table method.The groups were as follows: PSV+ 40% fraction of inspiration oxygen(FiO 2)(P40 group), PSV+ 80%FiO 2(P80 group), spontaneous breathing+ 40%FiO 2(S40 group), and spontaneous breathing+ 80%FiO 2(S80 group). These methods were used during the general anesthetic emergence, which refers to the period from the end of the operation to extubation.Atelectasis aeration loss score was measured using ultrasound, and the oxygenation index(OI)was calculated through arterial blood gas analysis.These measurements were recorded at different time points: at the end of surgery(T 1), after extubation(T 2), 30 minutes after entering the post anesthesia care unit(PACU)(T 3), and 48 hours after surgery(T 4). The number of hypoxemia cases(defined as saturation of pulse oxygen <92%)during emergence and within 30 minutes of entering the PACU, as well as the incidence of postoperative pulmonary complications(PPCs)at T 4, were also recorded. Results:A total of 137 patients completed the study.Compared with the P40 group, the patients in the P80 group had higher atelectasis aeration loss scores at T 2[6.0(3.0)scores vs.4.0(2.0)scores; Z=-3.733, P<0.001], the S40 group[8.0(3.0)scores vs.4.0(2.0)scores; Z=-4.868, P<0.001], and the S80 group[9.0(3.0)scores vs.4.0(2.0)scores; Z=-6.835, P<0.001]. At T 3, the S40 group[7.0(2.0)scores vs.5.0(2.0)scores; Z=-4.631, P<0.001]and the S80 group[9.0(2.5)scores vs.5.0(2.0)scores; Z=-6.590, P<0.001]also had higher atelectasis aeration loss scores.There was no significant difference in the incidence of hypoxemia between the four groups during the recovery period( χ2=0.405, P=0.939)and in PACU( χ2=4.048, P=0.256). The incidence of PPCs in the four groups at 48 hours after operation was 5.9%(2/34), 11.4%(4/35), 8.6%(3/35), and 6.1%(2/33)respectively( χ2=0.947, P=0.814). Conclusions:The combination of positive end-expiratory pressure support ventilation(PSV)and low inspired oxygen concentration can effectively decrease the occurrence of atelectasis in elderly patients undergoing robotic-assisted radical prostatectomy during the emergence phase.This approach also helps in reducing the incidence of hypoxemia in the post-anesthesia care unit(PACU)and improves the postoperative oxygenation index.
		                        		
		                        		
		                        		
		                        	
3.Effect of driving pressure-guided PEEP titration on lung injury in elderly patients undergoing robot-assisted radical prostatectomy
Jiayu ZHU ; Jing YAO ; Zixuan WANG ; Chao LI ; Xin YUAN ; Xin WANG ; Xuesen SU ; Wenjie ZHANG ; Lixia NIE ; Shouyuan TIAN
Chinese Journal of Anesthesiology 2022;42(1):39-43
		                        		
		                        			
		                        			Objective:To evaluate the effect of driving pressure (ΔP)-guided PEEP titration on lung injury in elderly patients undergoing robot-assisted radical prostatectomy (RARP).Methods:Forty-six American Society of Anesthesiologists physical status Ⅱ or Ⅲ patients, aged 65-80 yr, with body mass index of 19-28 kg/m 2, with Assess Respiratory Risk in Surgical Patients in Catalonia score assessed as medium to high risk, scheduled for elective RARP, were divided into control group (group C, n=23) and ΔP titration group (group D, n=23) using a random number table method.Volume-controlled mechanical ventilation was used after anesthesia induction and tracheal intubation.In group C, 5 cmH 2O was used to fix PEEP.In group D, the optimal PEEP was titrated after computer-controlled breathing and after establishing Trendelenburg position and pneumoperitoneum, the first titration started from 4 cmH 2O and increased by 1 cmH 2O every 4 min until ΔP reached the minimum value or PEEP increased to 12 cmH 2O, and the second titration was increased in increments as the method described above based on the optimal PEEP of the first titration.At 4 min after completion of the first PEEP titration (T 1, 4 min after mechanical ventilation with fixed PEEP in group C), 2 h after establishment of Trendelenburg position (T 2), 1 min after extubation (T 3) and 2 h after operation (T 4), serum concentrations of Clara cell protein (CC16), surfactant protein D (SP-D), soluble receptor for advanced glycation end-products (sRAGE) and soluble intercellular adhesion molecule-1 (sICAM-1). Pulmonary complications were assessed within 7 days after operation. Results:The serum concentrations of CC16, SP-D, sRAGE and sICAM-1 were significantly higher at T 2-4 than at T 1 in two groups ( P<0.05). Compared with group C, the serum concentrations of CC16, SP-D, sRAGE and sICAM-1 were significantly decreased at T 2-4 ( P<0.05), and no significant change was found in the incidence of pulmonary complications within 7 days after operation in group D ( P>0.05). Conclusions:ΔP-guided PEEP titration can reduce lung injury in elderly patients undergoing RARP.
		                        		
		                        		
		                        		
		                        	
4.Effect of driving pressure-guided individualized PEEP titration on atelectasis in elderly patients undergoing robot-assisted radical prostatectomy
Zixuan WANG ; Jiayu ZHU ; Jing YAO ; Wenjie ZHANG ; Lixia NIE ; Xuesen SU ; Xin YUAN ; Chao LI ; Shufang LIU ; Shouyuan TIAN
Chinese Journal of Anesthesiology 2021;41(12):1446-1450
		                        		
		                        			
		                        			Objective:To evaluate the effect of driving pressure-guided individualized positive end-expiratory pressure (PEEP) titration on atelectasis in elderly patients undergoing robot-assisted radical prostatectomy.Methods:Fifty elderly patients, aged 65-80 yr, of American Society of Anesthesiologists physical status Ⅱ or Ⅲ, with body mass index of 19-28 kg/m 2, undergoing elective robot-assisted radical prostatectomy under general anesthesia, were divided into 2 groups ( n=25 each) according to the random number table method: traditional lung-protective ventilation group (group C) and driving pressure-guided individualized PEEP group (group D). The method for setting PEEP was as follows: PEEP 5 cmH 2O was used throughout operation in group C. In group D, the optimal PEEP was titrated after intubation and mechanical ventilation and Trendelenburg position-pneumoperitoneum construction, the initial value was the lowest PEEP allowed by the anesthesia machine, the PEEP was increased by 1 cmH 2O (PEEP≤12 cmH 2O) every 4 min, the plateau pressure and PEEP were simultaneously recorded to calculate the driving pressure, and the corresponding PEEP was considered as the optimal PEEP for the individual when the driving pressure reached the minimum.Ultrasound examination was performed after catheterization of radial artery (T 0), after anesthesia induction (T 1), 4 min after developing optimal PEEP ventilation (T 2, 4 min after developing ventilation in group C), after restoration of body position (T 3), before extubation (T 4), and at 2 h after admission to postanesthesia care unit (T 5). Atelectatic aeration loss scores were recorded at T 0, T 1, T 4 and T 5.Bilateral optic nerve sheath diameter was measured at T 0-4.Arterial blood gas analysis was performed at T 0, T 2, T 3 and T 5, PaO 2 and PaCO 2 were recorded, and oxygenation index was calculated.The postoperative pulmonary complications within 3 days after operation were recorded. Results:Compared with group C, atelectasis aeration loss scores at T 4, 5 and PaCO 2 at T 2, 3 were significantly decreased, and PaO 2 and oxygenation index were increased at T 2, 3, 5 in group D ( P<0.05). There were no significant differences in the bilateral optic nerve sheath diameter and incidence of postoperative pulmonary complications between the two groups ( P>0.05). Conclusion:Driving pressure-guided individualized PEEP can increase intraoperative oxygenation and decrease the development of atelectasis in elderly patients undergoing robot-assisted radical prostatectomy.
		                        		
		                        		
		                        		
		                        	
5.Effect of respiratory muscle exercise combined with lung protective ventilation strategy on atelectasis of elderly patients with robot-assisted radical prostatectomy
Xiaoli WU ; Lixia NIE ; Xuesen SU ; Shan HU ; Shouyuan TIAN
Chinese Journal of Geriatrics 2021;40(10):1304-1308
		                        		
		                        			
		                        			Objective:To evaluate the effect of preoperative respiratory muscle exercise combined with intraoperative lung protective ventilation strategy on atelectasis in elderly patients undergoing robot-assisted radical prostatectomy.Methods:In the prospective study, a total of 45 patients aged 65-80 years undergoing scheduled robot-assisted radical prostatectomy in First Hospital of Shanxi Medical University from August 2020 to November 2020 were divided into three groups( N=15, each): respiratory muscle exercise combined with lung protective ventilation strategy group(combined group), lung protective ventilation strategy group(pulmonary protective group)and conventional ventilation strategy(control group). Heart rate, systolic blood pressure, diastolic pressure, and pulse oxygen saturation as well as blood gas analysis of arterial blood and the calculated oxygenation index were measured and recorded immediately after establishing invasive artery monitoring in operating room, 10 min after endotracheal intubation, 1 h after the flexitic position, 30 min after tracheal extubation, 24 h after operation in all three groups of patients.The lung compliance values, peak airway pressure, and end-tidal carbon dioxide were recorded at 10 minutes after tracheal intubation, 30 minutes after tracheal extubation, 1 hour after succession position.A single-slice chest CT scan was performed at 1 h after surgery while satisfying the anesthesia recovery steward score ≥ 5.And the percentage of atelectasis area was calculated. Results:The American Society of Anesthesiologisits(ASA)classification of patients was 11/4, 12/3, and 11/4 in the combination group, lung protection group and control group respectively, and the difference was not statistically significant( χ2=0.127, P>0.05). Oxygenation index(mmHg)(1 mmHg=0.133 kPa)at 24 h after surgery was significantly higher in the combined group(351.1±11.2)than in lung protection group(337.0±13.4)( t=3.287, P<0.05). Atelectasis area(Median, Interquartile range)assessed by CT imaging at 30 min after tracheal extubation was 1.92(0.77)% in the combination group, 2.09(1.13)% in lung protection group, and 3.01(1.01)% in control group, with statistically significant difference( χ2 values, 26.036, 12.313, both P<0.05). Atelectasis area at 30 minutes after tracheal extubation was statistically significant smaller in the combination group than in lung protection group( χ2=6.240, P<0.05). Conclusions:Preoperative respiratory muscle exercise combined with intraoperative lung protective ventilation strategy can achieve the better effect of lung protection, reduce the degree of perioperative atelectasis in elderly patients, and improve oxygenation function.
		                        		
		                        		
		                        		
		                        	
6.Effects of driving pressure-guided individualized positive end-expiratory pressure on intraoperative pulmonary function in elderly patients undergoing robot-assisted laparoscopic radical prostatectomy
Yujie MENG ; Lixia NIE ; Zhiping CAO ; Zhelu FAN ; Rui ZHANG ; Xuesen SU ; Xin YUAN ; Shouyuan TIAN
Chinese Journal of Geriatrics 2020;39(8):931-935
		                        		
		                        			
		                        			Objective:To investigate the effects of driving pressure(DP)-guided individualized positive end-expiratory pressure(PEEP)on intraoperative pulmonary function in elderly patients undergoing robot-assisted laparoscopic radical prostatectomy.Methods:This was a retrospective case-control study.A total of 40 elderly patients undergone robot-assisted radical resection of prostate cancer were enrolled and divided into the control group and the DP-guided group(n=20, each group)based on the random number table method.Data on the peak inspiratory pressure(PIP)at time points including 4 min after the first PEEP set(T1), 4 min, 1 hour, 2 hours(T2-4)after the second PEEP set, and 1 min after closing abdomen(T5), lung compliance(Crs), PEEP and the partial pressure of carbon dioxide in end expiratory gas(PetCO 2)were recorded and compared between the two groups.Blood gas analysis was conducted, and the oxygenation index(OI), alveolar-arterial oxygen tension difference(A-aDO 2)and the dead space volume/tidal volume(Vd/Vt)were calculated. Results:Compared with the control group, Crs, OI and PaO 2 were increased and DP, Vd/Vt, A-aDO 2 and PaCO 2 were decreased in the DP-guided group at each time point( P<0.05). PIP showed no significant difference between the two groups at each time point( P>0.05). Compared with T1, PIP and DP were increased and Crs was decreased( P<0.05)in both groups at T2-T4( P<0.05). At T5, PIP was increased in both groups( P<0.05), Crs was decreased and DP was increased in the control group( P<0.05), while Crs and DP had no significant difference in the DP group at T1( P>0.05). OI and PaO 2 showed no significant difference between the two groups at T2-T5( P>0.05). Vd/Vt and PaCO 2 were increased in both groups at T3-T5( P<0.05). Compared with T1 levels, A-aDO 2 was increased in the control group at T3-T5( P<0.05)and in the DP group at T4( P<0.05). Conclusions:DP-guided individualized PEEP can reduce the occurrence of intraoperative atelectasis, improve intraoperative respiratory mechanical state and gas exchange, reduce the risk of potential ventilator-related lung injury and has good lung-protective effects of PEEP in elderly patients undergoing robot-assisted laparoscopic prostatectomy.
		                        		
		                        		
		                        		
		                        	
7.Effect of ketamine anesthesia on proteome in hippocampus of aged rats
Shouyuan TIAN ; Wenjie ZHANG ; Lixia NIE ; Lili WANG ; Zhijia GUO ; Xiang YU ; Zhelu FAN ; Dingrui CAO
Chinese Journal of Anesthesiology 2019;39(10):1194-1198
		                        		
		                        			
		                        			Objective To evaluate the effects of ketamine anesthesia on proteome in hippocampus in aged rats.Methods Thirty healthy male Wistar rats,aged 20 months,weighing 560-610 g,were di-vided into 2 groups(n=15 each)using a random number table method: control group(group C)and ket-amine group(group K).In group K,ketamine 80 mg/kg was intraperitoneally injected,additional 1/2 ini-tial dose was given when the righting reflex was recovered,and anesthesia was maintained for 3 h.Morris water maze test was performed starting from 1st day after the end of anesthesia.Five rats were selected at days 1 and 7 after the end of anesthesia and sacrificed,and hippocampal tissues were obtained to extract proteins.Proteins extracted from rat hippocampi were identified by 2-dimensional electrophoresis(2-DE).The differentially expressed proteins were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF-MS)and biological information system.Results Compared with group C,the escape latency and total swimming distance to find the submerged platform in Morris water maze at the 1st day after anesthesia were significantly prolonged in group K(P<0.05 or 0.01).The MAL-DI-TOF-MS analysis showed that there were 21 differentially expressed proteins at 1st day after ketamine an-esthesia,of which 6 proteins(involving maintenance of intracellular protein homeostasis,energy metabo-lism,etc.)presented with up-regulated expression and 15 proteins(involving synaptic vesicle transport ef-ficiency,synaptic structural and functional plasticity,maintenance of intracellular protein homeostasis,NMDA-mediated Ca2+signal transport,energy metabolism,etc.)presented with down-regulated expres-sion.There were 8 differentially expressed proteins at 7th day,including 3 proteins with up-regulated ex-pression and 5 proteins with down-regulated expression(P<0.05).Conclusion Ketamine anesthesia can induce 21 differentially expressed proteins in hippocampi of aged rats,involving synaptic vesicle transport efficiency,synaptic structural and functional plasticity,intracellular protein homeostasis,NMDA-mediated Ca2+signal transport,energy metabolism,and etc.which may be involved in the mechanism of ketamine-induced temporary cognitive dysfunction.
		                        		
		                        		
		                        		
		                        	
8. Effect of ketamine anesthesia on proteome in hippocampus of aged rats
Shouyuan TIAN ; Wenjie ZHANG ; Lixia NIE ; Lili WANG ; Zhijia GUO ; Xiang YU ; Zhelu FAN ; Dingrui CAO
Chinese Journal of Anesthesiology 2019;39(10):1194-1198
		                        		
		                        			 Objective:
		                        			To evaluate the effects of ketamine anesthesia on proteome in hippocampus in aged rats.
		                        		
		                        			Methods:
		                        			Thirty healthy male Wistar rats, aged 20 months, weighing 560-610 g, were divided into 2 groups (
		                        		
		                        	
9.Effect of Cdyn-guided PEEP titration on pulmonary function of elderly patients undergoing robotic-assisted radical prostatectomy
Rui ZHANG ; Shouyuan TIAN ; Lixia NIE ; Xin WANG ; Xuesen SU ; Xin YUAN
Chinese Journal of Anesthesiology 2019;39(2):150-153
		                        		
		                        			
		                        			Objective To evaluate the effect of dynamic lung compliance (Cdyn)-guided positive end-expiratory pressure (PEEP) titration on the pulmonary function of elderly patients undergoing roboticassisted radical prostatectomy.Methods Forty patients,aged 65-80 yr,with body mass index of 19-28 kg/m2,of American Society of Anesthesiologists physical status Ⅱ or Ⅲ,scheduled for elective robotic-assisted laparoscopic radical prostatectomy,were divided into 2 groups (n=20 each) using a random number table method:control group (group C) and PEEP group (group P).After anesthesia induction and endotracheal intubation,all the patients were mechanically ventilated in pressure-controlled ventilation-volume guaranteed mode,with tidal volume 6-8 ml/kg,respiratory rate 12 breaths/min,fraction of inspired oxygen 50%,and inspiratory/expiratory ratio 1 ∶ 2.Respiratory rate was adjusted after onset of pneumoperitoneum to maintain the end-tidal pressure of carbon dioxide at 30-45 mmHg.Immediately after intubation and immediately after establishing pneumoperitoneum-Trendelenburg position,patients received PEEP titration from the lowest PEEP available in the anesthesia machine,with an increment of 2 cmH2O every 4 min until the maximal Cdyn was achieved in group P.Patients in group C received no PEEP during procedure.At 4 min after completion of the first PEEP titration,4 min and 1 and 2 h after completion of the second PEEP titration,and 1 min after closure of abdominal cavity in group P and at 4 min after the end of intubation,4 min and 1 and 2 h after establishing pneumoperitoneum-Trendelenburg position in group C,blood samples from the radical artery were obtained for blood gas analysis,peak airway pressure was recorded,and oxygenation index,driving pressure,alveolar-arterial oxygen difference,and ratio of physical dead space to tidal volume were calculated.Results Compared with group C,the oxygenation index and partial pressure of arterial oxygen were significantly increased,and driving pressure and alveolar-arterial oxygen difference were decreased at each time point (P<0.05),and no significant change was found in peak airway pressure,ratio of physical dead space to tidal volume or partial pressure of arterial carbon dioxide in group P (P>0.05).Conclusion Cdyn-guided PEEP titration can improve pulmonary function of elderly patients undergoing robotic-assisted radical prostatectomy.
		                        		
		                        		
		                        		
		                        	
10.Effect of dynamic lung compliance-guided PEEP titration on lung injury in elderly patients undergo-ing robot-assisted radical prostatectomy
Xin YUAN ; Shouyuan TIAN ; Xin WANG ; Lixia NIE ; Xuesen SU ; Rui ZHANG ; Chao LI ; Shu-Fang LIU
Chinese Journal of Anesthesiology 2019;39(3):264-267
		                        		
		                        			
		                        			Objective To evaluate the effect of dynamic lung compliance ( Cydn)-guided positive end-expiratory pressure (PEEP) titration on lung injury in the patients undergoing robot-assisted radical prostatectomy. Methods Forty American Society of Anesthesiologists physical status Ⅱ or Ⅲ patients, aged 65-80 yr, with body mass index of 19-28 kg∕m2 , scheduled for elective robot-assisted radical prosta-tectomy under general anesthesia, were divided into 2 groups ( n=20 each) using a random number table method: control group (group C) and PEEP group (group P). Mechanical ventilation was performed ac-cording to preset parameters after tracheal intubation in group C, and PEEP was set by a double titration method after tracheal intubation and after pneumoperitoneum in group P. At 4 min after intubation (T1), 4 min, 1 h and 2 h after establishing pneumoperitoneum-Trendelenburg position ( T2-4 ) , and 1 and 30 min after extubation ( T5,6 ) in group C or at 4 min after completing the first PEEP titration ( T1 ) , 4 min, 1 h and 2 h after completing the second PEEP titration (T2-4) and T5,6 in group P, blood samples were collect-ed from the radial artery for determination of club cell protein 16, surfactant protein-D, tumor necrosis fac-tor-alpha and interleukin-6 concentrations in serum ( by enzyme-linked immunosorbent assay) . Results Compared with group C, the serum concentrations of club cell protein 16 at T2-6 and surfactant protein-D, tumor necrosis factor-alpha and interleukin-6 at T3-6 were significantly decreased in group P (P<0. 05). Conclusion Cydn-guided PEEP titration can reduce the lung injury in patients undergoing robot-assisted radical prostatectomy.
		                        		
		                        		
		                        		
		                        	
            
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