1.Clinical comprehensive evaluation of 5 kinds of biologic targeted drugs in the treatment of severe eosinophilic asthma
Yufei LIAN ; Shujuan XIONG ; Hongtao LIU ; Haijing ZHAO ; Huizhen WU
China Pharmacy 2026;37(13):1755-1761
OBJECTIVE A clinical comprehensive evaluation of five biologic targeted drugs for the treatment of severe eosinophilic asthma (SEA) was conducted to provide objective evidence for the rational selection of these medications in medical institutions. METHODS Using the evaluation methods from the Chinese Medical Institution Drug Evaluation and Selection Rapid Guide ( Third Edition ), the effectiveness, safety, pharmaceutical characteristics, cost-effectiveness, and other attributes of five biologics targeting SEA (omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab) already marketed in China were quantitatively scored across five dimensions, and their recommendation levels were categorized based on the scores. RESULTS The comprehensive scoring results showed that mepolizumab scored 81.29, making it a highly recommended variety; benralizumab scored 78.05, dupilumab scored 77.84 and omalizumab scored 70.14,all of which are recommended varieties; tezepelumab scored 67.77, considered weakly recommended variety. CONCLUSIONS Mepolizumab shows excellent performance in eosinophil clearance, good accessibility, and is more cost-effective than the others, making it more selective in SEA treatment; omalizumab has more advantages in the treatment of SEA patients with elevated immunoglobulin E levels; dupilumab can be used as the preferred treatment for SEA patients with chronic obstructive pulmonary disease.
2.Clinical comprehensive evaluation of 5 kinds of biologic targeted drugs in the treatment of severe eosinophilic asthma
Yufei LIAN ; Shujuan XIONG ; Hongtao LIU ; Haijing ZHAO ; Huizhen WU
China Pharmacy 2026;37(13):1755-1761
OBJECTIVE A clinical comprehensive evaluation of five biologic targeted drugs for the treatment of severe eosinophilic asthma (SEA) was conducted to provide objective evidence for the rational selection of these medications in medical institutions. METHODS Using the evaluation methods from the Chinese Medical Institution Drug Evaluation and Selection Rapid Guide ( Third Edition ), the effectiveness, safety, pharmaceutical characteristics, cost-effectiveness, and other attributes of five biologics targeting SEA (omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab) already marketed in China were quantitatively scored across five dimensions, and their recommendation levels were categorized based on the scores. RESULTS The comprehensive scoring results showed that mepolizumab scored 81.29, making it a highly recommended variety; benralizumab scored 78.05, dupilumab scored 77.84 and omalizumab scored 70.14,all of which are recommended varieties; tezepelumab scored 67.77, considered weakly recommended variety. CONCLUSIONS Mepolizumab shows excellent performance in eosinophil clearance, good accessibility, and is more cost-effective than the others, making it more selective in SEA treatment; omalizumab has more advantages in the treatment of SEA patients with elevated immunoglobulin E levels; dupilumab can be used as the preferred treatment for SEA patients with chronic obstructive pulmonary disease.
3.A study on the value of thromboelastography-guided antiplatelet therapy in preventing cerebral ischemic events after stent-assisted coil embolization of intracranial aneurysms
Yingqi WANG ; Xiaoming ZHOU ; Qi WU ; An ZHANG ; Hui DING ; Shujuan CHEN ; Jinlong DENG ; Xin ZHANG
Chinese Journal of Cerebrovascular Diseases 2025;22(6):395-402
Objective To investigate the value of adjusting antiplatelet treatment regimens guided by thromboelastography(TEG)in predicting cerebral ischemic events after stent-assisted embolization of intracranial aneurysms.Methods This study retrospectively and consecutively enrolled patients with intracranial aneurysms who underwent stent-assisted coil embolization admitted to the Department of Neurosurgery of the General Hospital of Eastern Theater Command,from March 2022 to May 2024.Baseline and clinical data of the patients,including gender,age,hypertension,diabetes,dyslipidemia,smoking history,drinking history,and intraoperative use of tirofiban were collected.Antiplatelet therapy(conventional dose aspirin[100 mg once daily]+clopidogrel[75 mg once daily])was initiated immediately after the diagnosis of intracranial aneurysm,and TEG was performed 3 days later.According to the platelet inhibition rate in TEG parameters(platelet inhibition rate induced by arachidonic acid[AA]pathway[AA inhibition rate]or adenosine diphosphate[ADP]pathway[ADP inhibition rate],AA inhibition rate ≥ 50%indicated aspirin effectiveness,AA inhibition rate<50%indicated aspirin resistance;ADP inhibition rate ≥ 30%indicated clopidogrel effectiveness,ADP inhibition rate<30%indicated clopidogrel resistance),the patients were divided into the control group(TEG test results met the criteria,i.e.,AA inhibition rate ≥ 50%and ADP inhibition rate ≥ 30%),the conventional dual antiplatelet therapy group(TEG test results did not meet the criteria but were not adjusted for antiplatelet therapy,i.e.,AA inhibition rate<50%and/or ADP inhibition rate<30%,but with complex aneurysm morphology[such as irregular shape,daughter sac formation]or high bleeding risk,continuing conventional dual antiplatelet therapy),and the intensified group(TEG test results did not meet the criteria and the antiplatelet therapy regimen was adjusted,i.e.,AA inhibition rate<50%and/or ADP inhibition rate<30%,adjusting the antiplatelet therapy regimen).All patients underwent stent-assisted coil embolization after TEG testing.From 0 to 3 months after the operation,all three groups maintained the above antiplatelet therapy.At 3 months after the operation,routine head MRI,CT and other examinations were performed.If no cerebral ischemic events occurred and the imaging results were satisfactory(good stent position,no aneurysm occlusion residual or slight residual at the neck[neck width of the aneurysm 2mm]),the treatment could be adjusted to single antiplatelet therapy(aspirin 100 mg once daily).If a patient experienced a cerebral ischemic event during the follow-up period,regardless of the stage after the operation,dual antiplatelet therapy(aspirin[100mg once daily]+clopidogrel[75 mg once daily])was immediately restarted or maintained and continued for at least 6 months.The primary endpoint was intraoperative and 6-months postoperative cerebral ischemic events(including DSA-confirmed intraoperative acute thrombosis and infarction foci confirmed by head CT or MRI).Baseline and clinical data of the three groups were compared.All patients were divided into groups with ischemic stroke event and without according to the primary endpoint,univariate Logistic regression analysis was then performed on both groups.Variables with P<0.1 in the univariate Logistic regression analysis were included in the multivariate Logistic regression analysis to explore the influencing factors of cerebral ischemic events after stent-assisted coil embolization for intracranial aneurysms.Results A total of 499 patients were included,including 178 males and 321 females,with a median age of 59(53,68)years.Among them,there were 341 patients in the control group,42 in the conventional dual antiplatelet therapy group,and 116 in the intensified group.There were 47 cases of cerebral ischemic events and 452 cases without cerebral ischemic events.There was a statistically significant difference in the intraoperative use rate of tirofiban across the control group,the conventional dual antiplatelet therapy group,and the intensified group(20.2%[69/341]vs.26.2%[11/42]vs.42.2%[49/116],P<0.01);no statistically significant differences were observed among the three groups in terms of age,gender composition,the proportion of patients with hypertension,diabetes,dyslipidemia,smoking history,drinking history,and the incidence of cerebral ischemic events(all P>0.05).The results of multivariate Logistic regression analysis showed that hypertension(OR,2.924,95%CI 1.416-6.037,P=0.004)and intraoperative use of tirofiban(OR,3.638,95%CI 1.892-6.996,P<0.01)were independent risk factors for intraoperative and 6-months postoperative cerebral ischemic events after stent-assisted coil embolization in patients with intracranial aneurysms.In comparison with the control group,the intensified group has reduced the risk of cerebral ischemic events(OR,0.238,95%CI 0.088-0.646,P=0.005),while there was no statistically significant difference between the conventional dual antiplatelet therapy group and the control group(OR,0.521,95%CI 0.149-1.826,P=0.308).Conclusions This study demonstrates that adjusting the antiplatelet therapy regimens in patients with intracranial aneurysms who did not meet the platelet inhibition rate based on TEG results can significantly reduce the risk of intraoperative and 6-months postoperative cerebral ischemic events.These finding may require validation through further,large-scaled,prospective studies.
4.Mediating effect of intrinsic motivation of nurses between empowering leadership and job performance
Shujuan WEN ; Lili HOU ; Weihua WU ; Xiaomei JIANG ; Zhiwen ZHU ; Wenli ZHANG ; Lei YANG ; Siqi LI
Chinese Journal of Practical Nursing 2025;41(15):1168-1175
Objective:To explore the mediating effect of intrinsic motivation of nurses between empowering leadership and job performance, with the aim of providing a reference basis for managers to develop a scientific and effective intervention programme to improve nurses′ job performance.Methods:Convenience sampling method was used to select 1 213 clinical nurses from four tertiary general hospitals in Shandong Province, Henan Province, Yunnan Province, and Fujian Province from November to December 2023, and General Information Questionnaire, Empowering Leadership Scale, Intrinsic Motivation Scale, and Job Performance Scale were used to conduct a cross-sectional survey. AMOS26.0 software was used to test the mediating effect of intrinsic motivation of nurses between empowering leadership and job performance.Results:A total of 1 100 nurses completed the survey finally. Among them, there were 58 males and 1 042 females, 474 under 31 years old, 448 between 31-40 years old, and 178 over 40 years old.The total scores of the Empowering Leadership Scale, Intrinsic Motivation Scale, and Job Performance Scale were 49.44 ± 10.04, 82.35 ± 13.54 and 46.27 ± 6.20 in that order. Nurses' job performance were positive correlation with the empowered leadership and intrinsic motivation ( r=0.486, 0.703, both P<0.01), there was a positive correlation between nurse empowerment leadership and intrinsic motivation ( r=0.452, P<0.01). Nurses′ intrinsic motivation partially mediates the relationship between empowering leadership and job performance, accounting for 62.69% of the total effect. Conclusions:Intrinsic motivation of nurses is a mediating variable between empowered leadership and job performance. Nursing managers should focus on nurses' participation in autonomous decision-making to enhance nurses′ sense of competence and meaning at work, and mobilise their motivation to improve job performance.
5.A study on the value of thromboelastography-guided antiplatelet therapy in preventing cerebral ischemic events after stent-assisted coil embolization of intracranial aneurysms
Yingqi WANG ; Xiaoming ZHOU ; Qi WU ; An ZHANG ; Hui DING ; Shujuan CHEN ; Jinlong DENG ; Xin ZHANG
Chinese Journal of Cerebrovascular Diseases 2025;22(6):395-402
Objective To investigate the value of adjusting antiplatelet treatment regimens guided by thromboelastography(TEG)in predicting cerebral ischemic events after stent-assisted embolization of intracranial aneurysms.Methods This study retrospectively and consecutively enrolled patients with intracranial aneurysms who underwent stent-assisted coil embolization admitted to the Department of Neurosurgery of the General Hospital of Eastern Theater Command,from March 2022 to May 2024.Baseline and clinical data of the patients,including gender,age,hypertension,diabetes,dyslipidemia,smoking history,drinking history,and intraoperative use of tirofiban were collected.Antiplatelet therapy(conventional dose aspirin[100 mg once daily]+clopidogrel[75 mg once daily])was initiated immediately after the diagnosis of intracranial aneurysm,and TEG was performed 3 days later.According to the platelet inhibition rate in TEG parameters(platelet inhibition rate induced by arachidonic acid[AA]pathway[AA inhibition rate]or adenosine diphosphate[ADP]pathway[ADP inhibition rate],AA inhibition rate ≥ 50%indicated aspirin effectiveness,AA inhibition rate<50%indicated aspirin resistance;ADP inhibition rate ≥ 30%indicated clopidogrel effectiveness,ADP inhibition rate<30%indicated clopidogrel resistance),the patients were divided into the control group(TEG test results met the criteria,i.e.,AA inhibition rate ≥ 50%and ADP inhibition rate ≥ 30%),the conventional dual antiplatelet therapy group(TEG test results did not meet the criteria but were not adjusted for antiplatelet therapy,i.e.,AA inhibition rate<50%and/or ADP inhibition rate<30%,but with complex aneurysm morphology[such as irregular shape,daughter sac formation]or high bleeding risk,continuing conventional dual antiplatelet therapy),and the intensified group(TEG test results did not meet the criteria and the antiplatelet therapy regimen was adjusted,i.e.,AA inhibition rate<50%and/or ADP inhibition rate<30%,adjusting the antiplatelet therapy regimen).All patients underwent stent-assisted coil embolization after TEG testing.From 0 to 3 months after the operation,all three groups maintained the above antiplatelet therapy.At 3 months after the operation,routine head MRI,CT and other examinations were performed.If no cerebral ischemic events occurred and the imaging results were satisfactory(good stent position,no aneurysm occlusion residual or slight residual at the neck[neck width of the aneurysm 2mm]),the treatment could be adjusted to single antiplatelet therapy(aspirin 100 mg once daily).If a patient experienced a cerebral ischemic event during the follow-up period,regardless of the stage after the operation,dual antiplatelet therapy(aspirin[100mg once daily]+clopidogrel[75 mg once daily])was immediately restarted or maintained and continued for at least 6 months.The primary endpoint was intraoperative and 6-months postoperative cerebral ischemic events(including DSA-confirmed intraoperative acute thrombosis and infarction foci confirmed by head CT or MRI).Baseline and clinical data of the three groups were compared.All patients were divided into groups with ischemic stroke event and without according to the primary endpoint,univariate Logistic regression analysis was then performed on both groups.Variables with P<0.1 in the univariate Logistic regression analysis were included in the multivariate Logistic regression analysis to explore the influencing factors of cerebral ischemic events after stent-assisted coil embolization for intracranial aneurysms.Results A total of 499 patients were included,including 178 males and 321 females,with a median age of 59(53,68)years.Among them,there were 341 patients in the control group,42 in the conventional dual antiplatelet therapy group,and 116 in the intensified group.There were 47 cases of cerebral ischemic events and 452 cases without cerebral ischemic events.There was a statistically significant difference in the intraoperative use rate of tirofiban across the control group,the conventional dual antiplatelet therapy group,and the intensified group(20.2%[69/341]vs.26.2%[11/42]vs.42.2%[49/116],P<0.01);no statistically significant differences were observed among the three groups in terms of age,gender composition,the proportion of patients with hypertension,diabetes,dyslipidemia,smoking history,drinking history,and the incidence of cerebral ischemic events(all P>0.05).The results of multivariate Logistic regression analysis showed that hypertension(OR,2.924,95%CI 1.416-6.037,P=0.004)and intraoperative use of tirofiban(OR,3.638,95%CI 1.892-6.996,P<0.01)were independent risk factors for intraoperative and 6-months postoperative cerebral ischemic events after stent-assisted coil embolization in patients with intracranial aneurysms.In comparison with the control group,the intensified group has reduced the risk of cerebral ischemic events(OR,0.238,95%CI 0.088-0.646,P=0.005),while there was no statistically significant difference between the conventional dual antiplatelet therapy group and the control group(OR,0.521,95%CI 0.149-1.826,P=0.308).Conclusions This study demonstrates that adjusting the antiplatelet therapy regimens in patients with intracranial aneurysms who did not meet the platelet inhibition rate based on TEG results can significantly reduce the risk of intraoperative and 6-months postoperative cerebral ischemic events.These finding may require validation through further,large-scaled,prospective studies.
6.Mediating effect of intrinsic motivation of nurses between empowering leadership and job performance
Shujuan WEN ; Lili HOU ; Weihua WU ; Xiaomei JIANG ; Zhiwen ZHU ; Wenli ZHANG ; Lei YANG ; Siqi LI
Chinese Journal of Practical Nursing 2025;41(15):1168-1175
Objective:To explore the mediating effect of intrinsic motivation of nurses between empowering leadership and job performance, with the aim of providing a reference basis for managers to develop a scientific and effective intervention programme to improve nurses′ job performance.Methods:Convenience sampling method was used to select 1 213 clinical nurses from four tertiary general hospitals in Shandong Province, Henan Province, Yunnan Province, and Fujian Province from November to December 2023, and General Information Questionnaire, Empowering Leadership Scale, Intrinsic Motivation Scale, and Job Performance Scale were used to conduct a cross-sectional survey. AMOS26.0 software was used to test the mediating effect of intrinsic motivation of nurses between empowering leadership and job performance.Results:A total of 1 100 nurses completed the survey finally. Among them, there were 58 males and 1 042 females, 474 under 31 years old, 448 between 31-40 years old, and 178 over 40 years old.The total scores of the Empowering Leadership Scale, Intrinsic Motivation Scale, and Job Performance Scale were 49.44 ± 10.04, 82.35 ± 13.54 and 46.27 ± 6.20 in that order. Nurses' job performance were positive correlation with the empowered leadership and intrinsic motivation ( r=0.486, 0.703, both P<0.01), there was a positive correlation between nurse empowerment leadership and intrinsic motivation ( r=0.452, P<0.01). Nurses′ intrinsic motivation partially mediates the relationship between empowering leadership and job performance, accounting for 62.69% of the total effect. Conclusions:Intrinsic motivation of nurses is a mediating variable between empowered leadership and job performance. Nursing managers should focus on nurses' participation in autonomous decision-making to enhance nurses′ sense of competence and meaning at work, and mobilise their motivation to improve job performance.
7.Long-term hypomethylating agents in patients with myelodysplastic syndromes: a multi-center retrospective study
Xiaozhen LIU ; Shujuan ZHOU ; Jian HUANG ; Caifang ZHAO ; Lingxu JIANG ; Yudi ZHANG ; Chen MEI ; Liya MA ; Xinping ZHOU ; Yanping SHAO ; Gongqiang WU ; Xibin XIAO ; Rongxin YAO ; Xiaohong DU ; Tonglin HU ; Shenxian QIAN ; Yuan LI ; Xuefen YAN ; Li HUANG ; Manling WANG ; Jiaping FU ; Lihong SHOU ; Wenhua JIANG ; Weimei JIN ; Linjie LI ; Jing LE ; Wenji LUO ; Yun ZHANG ; Xiujie ZHOU ; Hao ZHANG ; Xianghua LANG ; Mei ZHOU ; Jie JIN ; Huifang JIANG ; Jin ZHANG ; Guifang OUYANG ; Hongyan TONG
Chinese Journal of Hematology 2024;45(8):738-747
Objective:To evaluate the efficacy and safety of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS) .Methods:A total of 409 MDS patients from 45 hospitals in Zhejiang province who received at least four consecutive cycles of HMA monotherapy as initial therapy were enrolled to evaluate the efficacy and safety of HMA. Mann-Whitney U or Chi-square tests were used to compare the differences in the clinical data. Logistic regression and Cox regression were used to analyze the factors affecting efficacy and survival. Kaplan-Meier was used for survival analysis. Results:Patients received HMA treatment for a median of 6 cycles (range, 4-25 cycles) . The complete remission (CR) rate was 33.98% and the overall response rate (ORR) was 77.02%. Multivariate analysis revealed that complex karyotype ( P=0.02, OR=0.39, 95% CI 0.18-0.84) was an independent favorable factor for CR rate. TP53 mutation ( P=0.02, OR=0.22, 95% CI 0.06-0.77) was a predictive factor for a higher ORR. The median OS for the HMA-treated patients was 25.67 (95% CI 21.14-30.19) months. HMA response ( P=0.036, HR=0.47, 95% CI 0.23-0.95) was an independent favorable prognostic factor, whereas complex karyotype ( P=0.024, HR=2.14, 95% CI 1.10-4.15) , leukemia transformation ( P<0.001, HR=2.839, 95% CI 1.64-4.92) , and TP53 mutation ( P=0.012, HR=2.19, 95% CI 1.19-4.07) were independent adverse prognostic factors. There was no significant difference in efficacy and survival between the reduced and standard doses of HMA. The CR rate and ORR of MDS patients treated with decitabine and azacitidine were not significantly different. The median OS of patients treated with decitabine was longer compared with that of patients treated with azacitidine (29.53 months vs 20.17 months, P=0.007) . The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Conclusion:Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.
8.Efficacy of Fuyang Tongluo therapy combined with conventional western medicine in elderly patients with coronary heart disease and heart failure
Songbo CHAI ; Yakang DU ; Shujuan ZHANG ; Jiangbo WU ; Xiaofei WANG
Journal of China Medical University 2024;53(6):531-535
Objective To explore the therapeutic efficacy of the Fuyang Tongluo therapy combined with conventional western medicine in elderly patients with heart failure due to coronary heart disease.Methods In this single-blind randomized controlled trial,96 elderly patients with coronary heart disease and heart failure were randomly divided into three groups,each consisting of 32 individuals.Control group A was treated with conventional western medicine(atorvastatin combined with metoprolol),control group B with Fuyang Tongluo therapy,and the observation group with Fuyang Tongluo therapy and conventional western medicine.The three groups were compared in terms of therapeutic efficacy and traditional Chinese medicine symptom points as well as blood interleukin(IL)-23 and IL-17 levels,left ventricular end-systolic diameter(LVESD),left ventricular end-diastolic diameter(LVEDD),and left ventricular ejection fraction(LVEF)values before and after treatment.Results The total clinical efficacy rate in the observation group was 93.75%,which was significantly higher than those in control groups A(68.75%)and B(65.63%)(P<0.05).After 4 and 8 weeks of treatment,the primary and minor symptom scores,total symptom scores,LVESD,LVEDD,and IL-23 and IL-17 levels in the observation group were significantly lower than those in control groups A and B(P<0.05).Conclusion The combination of the Fuyang Tongluo therapy with conventional western medicine exhibited good therapeutic efficacy in elderly patients with coronary heart disease and heart failure.These effects were achieved by inhibiting excessive expression of the inflammatory axis factors IL-23 and IL-17 and promoting the recovery of cardiac function.
9.Research on the application of non-contact physiological and psychological detection in the analysis of long-term simulated weightlessness effects
Shuai DING ; Zi XU ; Qian RONG ; Shujuan LIU ; Zihao LIU ; Yuan WU ; Yao YU ; Zhili LI ; Cheng SONG ; Lina QU ; Hao WANG ; Yinghui LI
Space Medicine & Medical Engineering 2024;35(2):78-83,98
Objective Explore a non-contact physiological and psychological detection model based on facial video in simulations of weightlessness effects,research new methods for non-contact heart rate and negative mood state detection in long-term simulations of weightlessness effect analysis.Methods Construct a non-contact physiological and psychological data collection system for fusion analysis of visible light and thermal infrared videos.Collect physiological and psychological data of volunteers in the"Earth Star-Ⅱ"90-day head-down bed rest experiment.A non-contact heart rate detection model based on GCN facial multi-region feature fusion and a non-contact negative mood state detection model considering data reliability were constructed,and the effectiveness of the models were validated with finger clip heart rate and POMS-SF scale as labels.Results The experimental results show that the average difference in the Bland-Altman plot of the non-contact heart rate detection model is-1.26 bpm,and 96.3%of value error detection data falls within the 95%confidence interval,indicating a high consistency between the model detected heart rate and the finger clip heart rate.The non-contact negative mood state detection model achieves an accuracy of>0.85 for detecting tension,depression,anger,and fatigue.Features such as heart rate,AU06,eye gaze,and head pose were observed to be important to mood state detection.Conclusion Non-contact physiological and psychological detection methods not only can be utilized for long-term physiological analysis in simulations of weightlessness effects,but also provide a novel technical approach for on-orbit astronauts health assurance during long-term space flight in the future.
10.Discussion on the revision of the general chapter for lotions in the Chinese Pharmacopoeia 2020 Volume Ⅳ
Jiana OU ; Shujuan LI ; Mei YANG ; Liangyong WU ; Weiling LI ; Wenxue ZENG ; Jinqian WANG ; Yuesheng WANG
Drug Standards of China 2024;25(5):443-445
Objective:To analyze the general chapter for lotions 0127 of the Chinese Pharmacopoeia 2020 Vol-ume Ⅳ,and discuss how to improve the general technical requirements of lotions 0127 in the Chinese Pharma-copoeia.Methods:By comparing the general chapter for lotions in domestic and international pharmacopoe-ias,the definition,classification,process,storage and corresponding inspection requirements were analyzed.Results and Conclusions:The general chapter for lotions 0127 of the Chinese Pharmacopoeia should be revised,including improvement of the definition,increasement of forms of preparations,and expansion of included varieties,so as to promote scientific regulation for drugs and exhibit a guiding role of the Chinese pharmacopoeia in drug control.

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