1.Characteristics of Traditional Chinese Medicine Syndromes and Their Correlation with Ocular Manifestations in Chronic Hepatitis B Complicated by Metabolic Dysfunction-associated Fatty Liver Disease
Jingdong CUI ; Dingqi LI ; Yichen PENG ; Xiaoxiao DENG ; Zhenglong ZHENG ; Zilin XIONG ; Haiyang HU ; Peijie WU ; Yuelian WANG ; Liang HUANG ; Quansheng FENG ; Baixue LI
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(14):144-154
ObjectiveThis paper aims to investigate the traditional Chinese medicine syndrome types in patients with chronic hepatitis B (CHB) complicated by metabolic dysfunction-associated fatty liver disease (MAFLD) and explore the correlations between these syndrome types and clinical indicators, as well as ocular manifestation characteristics, thereby providing a reference for syndrome differentiation and treatment strategies in traditional Chinese medicine. MethodsGeneral data, information from the four diagnostic methods of traditional Chinese medicine, clinical indicators, and ocular manifestation data were collected from 506 patients with CHB complicated by MAFLD enrolled at the Public Health Clinical Center of Chengdu between June 2024 and December 2024. Cluster analysis, principal component analysis, and complex network models were employed to identify the distribution patterns of traditional Chinese medicine syndromes. Correlations between different syndrome types and clinical indicators, as well as ocular manifestation characteristics, were further analyzed. ResultsThe predominant syndromes identified in patients with CHB complicated by MAFLD were dampness and heat accumulation (51.58%), liver depression with spleen deficiency (31.62%), blood stasis obstructing collaterals (8.89%), and Qi-Yin deficiency (7.91%). No statistically significant differences were found among the four syndrome types in routine blood tests and liver function indicators. However, patients with the dampness and heat accumulation type exhibited significantly higher levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), liver stiffness measurement (LSM), controlled attenuation parameter (CAP), and alpha-fetoprotein (AFP), along with lower levels of high-density lipoprotein cholesterol (HDL-C), compared with those with other syndrome types. Regarding ocular manifestations, the incidence of moon halo signs was significantly higher in patients with the blood stasis obstructing collaterals type than in those with other syndrome types. Additionally, the incidence in scleral zone 3 (corresponding to the large intestine) was higher in patients with the damp and heat accumulation type. ConclusionDampness and heat accumulation is the core syndrome type in patients with CHB complicated by MAFLD, commonly accompanied by spleen deficiency, liver depression, blood stasis, and Yin deficiency. A complex syndrome pattern characterized by a predominance of dampness and heat, along with a mixture of deficiency and excess, is formed. Different traditional Chinese medicine syndrome types are associated with distinct clinical indicators and ocular manifestation characteristics. Among them, patients with the dampness and heat accumulation type exhibit more pronounced metabolic disturbances and liver injury, whereas those with the blood stasis type show a higher incidence of moon halo signs. Abnormalities in scleral zone 3 are also more prevalent in patients with dampness and heat type.
2.Early PCSK9 Inhibitor Therapy Following Percutaneous Coronary Intervention (PERFECT): A Pilot Randomized Controlled Trial
Jiachun XIA ; Zhengguang XIAO ; Luyao WU ; Haiyang YU ; Yanan PANG ; Shan HU ; Lei HOU
Cardiology Discovery 2025;05(1):62-68
Objective::This study aimed to assess the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor treatment immediately after percutaneous coronary intervention (PCI) on the myocardial salvage index (MSI) in patients with anterior ST-segment elevation myocardial infarction (STEMI) 5-10 d after the procedure.Methods::The early PCSK9 inhibitor thERapy Following pErcutaneous Coronary inTervention (PERFECT) trial is a prospective randomized controlled trial. From January 2021 to December 2023, 32 patients with anterior STEMI from Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and Shanghai Tenth People’s Hospital were enrolled in the PERFECT trial. Patients were randomly assigned in a 1∶1 ratio to the PCSK9 inhibitor group ( n = 16) or the control group ( n = 16), and their baseline data were collected. Patients in the PCSK9 inhibitor group (ie, alirocumab group) received a subcutaneous injection of PCSK9 inhibitor (alirocumab, 75 mg) immediately after PCI based on conventional treatment. In the control group, patients received only conventional treatment. The primary endpoint was the MSI measured by cardiovascular magnetic resonance 5-10 d after PCI. The secondary endpoints included the left ventricular ejection fraction measured by cardiovascular magnetic resonance 5-10 d after PCI and the time to peak of creatine kinase isoenzyme-MB and high-sensitivity cardiac troponin T. Safety endpoints included any clinical adverse events that occurred during the 6-month follow-up period. Results::Baseline data during admission showed no intergroup significance. No significant difference in MSI (55.54% ± 14.80% vs. 44.72% ± 15.42%, P = 0.056) and left ventricular ejection fraction (51.24% ± 8.91% vs. 44.99% ± 8.84%, P = 0.060) was observed. Additional, there was no significant difference in the time to peak of creatine kinase isoenzyme-MB ((12.97 ± 5.67) h vs. (14.31 ± 7.04) h, P = 0.557) and high-sensitivity cardiac troponin T ((21.03 ± 12.46) h vs. (21.44 ± 9.99) h, P = 0.920) between the 2 groups. During the 6-month follow-up period, only 1 patient in the PCSK9 inhibitor group developed cerebral hemorrhage 6 months after PCI. Conclusions::Early treatment with alirocumab did not exhibit a significant increase in MSI at 5-10 d in patients with anterior STEMI. Larger trials are necessary to evaluate the impact of early administration of PCSK9 inhibitors after myocardial infarction.
3.Evaluation of Ice Hockey Helmet Protective Performance Grade Based on Entropy Weight Technique for Order Preference by Similarity to an Ideal Solution Combined with Rank Sum Ratio Method
Rui LIN ; Haiyang HU ; Xinglong ZHOU ; Ronghui WANG ; Xianglin WAN
Journal of Medical Biomechanics 2025;40(3):527-536
Objective The combined entropy weight technique for order preference by similarity to an ideal solution(TOPSIS)and rank sum ratio(RSR)methods were utilized to rate the protective performance of ice hockey helmets,and the effectiveness and influencing factors of the rating system,as well as the relationship between protective performance and purchase price were explored.Methods The linear acceleration data during impact drops of twenty-four ice hockey helmets were collected using a uniaxial accelerometer in a collision test machine after low and ambient temperature treatments.The protective performance of ice hockey helmets was rated using the STAR model combined with the entropy weight TOPSIS and RSR methods.One-way ANOVA or the Kruskal-Wallis H test was employed to assess the differences in protective performance among helmets across different grade groups.The correlation between different indicators was analyzed by Pearson's correlation coefficient.Results The comprehensive protective performance ratings of the CCM TACKS 310,IBX,BAUD,and WARRIORS COVERT RS PRO helmets were classified as poor,whereas the BAUER REAKT 150,HYPERLITE,and REAKT 200 helmets were rated as excellent.The remaining helmets were rated as moderate.There was a moderate to high positive correlation between the ambient temperature STAR(A)and Rowson's STAR values,the comprehensive Ti and low temperature Ti,the comprehensive T,and ambient temperature Ti(P<0.05).The comprehensive Ti satisfied the homogeneity of variance(P>0.05)and exhibited significant differences among groups(P<0.05).Significant differences were found in the low temperature indicators among different groups(P<0.05),and their weight coefficients ranked among the top three.The ambient temperature indicators were not affected by the protective performance grade(P>0.05).A weak positive correlation existed between the comprehensive Ti and purchase price(P<0.05).Conclusions According to the energy absorption test protocol,the combined entropy weight TOPSIS and RSR methods can efficiently rate the comprehensive protective performance of ice hockey helmets.The effectiveness of using low temperature indicators for the comprehensive evaluation and rating of ice hockey helmet protective performance is superior to that of ambient temperature indicators and purchase price.Consumers are advised not to use price as a criterion for evaluating the comprehensive protective performance of ice hockey helmets.
4.Early PCSK9 Inhibitor Therapy Following Percutaneous Coronary Intervention (PERFECT): A Pilot Randomized Controlled Trial
Jiachun XIA ; Zhengguang XIAO ; Luyao WU ; Haiyang YU ; Yanan PANG ; Shan HU ; Lei HOU
Cardiology Discovery 2025;05(1):62-68
Objective::This study aimed to assess the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor treatment immediately after percutaneous coronary intervention (PCI) on the myocardial salvage index (MSI) in patients with anterior ST-segment elevation myocardial infarction (STEMI) 5-10 d after the procedure.Methods::The early PCSK9 inhibitor thERapy Following pErcutaneous Coronary inTervention (PERFECT) trial is a prospective randomized controlled trial. From January 2021 to December 2023, 32 patients with anterior STEMI from Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and Shanghai Tenth People’s Hospital were enrolled in the PERFECT trial. Patients were randomly assigned in a 1∶1 ratio to the PCSK9 inhibitor group ( n = 16) or the control group ( n = 16), and their baseline data were collected. Patients in the PCSK9 inhibitor group (ie, alirocumab group) received a subcutaneous injection of PCSK9 inhibitor (alirocumab, 75 mg) immediately after PCI based on conventional treatment. In the control group, patients received only conventional treatment. The primary endpoint was the MSI measured by cardiovascular magnetic resonance 5-10 d after PCI. The secondary endpoints included the left ventricular ejection fraction measured by cardiovascular magnetic resonance 5-10 d after PCI and the time to peak of creatine kinase isoenzyme-MB and high-sensitivity cardiac troponin T. Safety endpoints included any clinical adverse events that occurred during the 6-month follow-up period. Results::Baseline data during admission showed no intergroup significance. No significant difference in MSI (55.54% ± 14.80% vs. 44.72% ± 15.42%, P = 0.056) and left ventricular ejection fraction (51.24% ± 8.91% vs. 44.99% ± 8.84%, P = 0.060) was observed. Additional, there was no significant difference in the time to peak of creatine kinase isoenzyme-MB ((12.97 ± 5.67) h vs. (14.31 ± 7.04) h, P = 0.557) and high-sensitivity cardiac troponin T ((21.03 ± 12.46) h vs. (21.44 ± 9.99) h, P = 0.920) between the 2 groups. During the 6-month follow-up period, only 1 patient in the PCSK9 inhibitor group developed cerebral hemorrhage 6 months after PCI. Conclusions::Early treatment with alirocumab did not exhibit a significant increase in MSI at 5-10 d in patients with anterior STEMI. Larger trials are necessary to evaluate the impact of early administration of PCSK9 inhibitors after myocardial infarction.
5.Effect of self-made static progressive braces in the stepwise treatment of hand flexion dysfunction caused by scar contracture after burn injury
Haiyang ZHAO ; Qin ZHOU ; Jiaqi LIU ; Wanfu ZHANG ; Chan ZHU ; Jing XU ; Juntao HAN ; Dahai HU ; Hao GUAN
Chinese Journal of Burns 2025;41(2):155-162
Objective:To explore the effect of self-made static progressive braces in the stepwise treatment of hand flexion dysfunction caused by scar contracture after burn injury.Methods:This study was a retrospective observational study. From January 2022 to March 2024, the First Affiliated Hospital of Air Force Medical University admitted twenty-nine patients who met the inclusion criteria and used the self-made static progressive braces for stepwise treatment of hand flexion dysfunction caused by scar contracture, including 23 males and 6 females, aged 16 to 55 years. The depth of burn on the back of the hand was deep partial-thickness to full-thickness. The self-made static progressive brace referred to the self-made static progressive joint distractor and the self-made static progressive hand flexion distractor. The stepwise treatment was adopted. In the first stage, in-hospital treatment for 2 to 4 weeks was selected. The treatment contents included conventional rehabilitation training and training on the application of the self-made joint distractors. When the active flexion range of motion of the metacarpophalangeal joint was ≥60°, the second stage of treatment was carried out, that is, two weeks of home remote rehabilitation treatment. The treatment contents included individualized exercise training such as training with self-made static progressive joint distractors and training with self-made static progressive hand flexion distractors. Adverse events such as blister, brace compression, and tissue strain during the stepwise treatment were recorded. After the end of the stepwise treatment, the active flexion of the affected hand was observed. During follow-up, the total active range of motion of the affected hand was measured, and the extensibility of the scar and skin and soft tissue on the back of the affected hand and the patient's satisfaction with the therapeutic effect were evaluated. At the last follow-up, the function of the affected hand was evaluated according to the trial standards for evaluation of partial function of upper extremity by the Hand Surgery Society of Chinese Medical Association.Results:During the stepwise treatment, a small amount of blisters developed on the skin at the wrist joint in 2 patients, which was cured after symptomatic treatment; the other patients had no adverse events such as brace compression and tissue strain. After the end of the stepwise treatment, the active flexion function of the hand was better, and the fist could be basically clenched. After 1-3 months of follow-up, the total active range of motion of the affected hand was 200-245°; the scar on the back of the hand was soft and light-colored, and the skin and soft tissue was malleable. Twenty-two patients were very satisfied with the curative effect, 6 patients were satisfied, and 1 patient was dissatisfied. At the last follow-up, there were 20 cases with excellent hand function and 9 cases with good hand function.Conclusions:The stepwise treatment of hand flexion dysfunction caused by scar contracture after burn injury with self-made static progressive braces has a good effect and few complications. Moreover, the two self-made static progressive distractors are convenient in material acquisition, simple to make, cost-effective, and highly practical, which is worthy of clinical promotion.
6.Gut microbiota modulates immune reconstitution in allogeneic hematopoietic stem cell transplantation
Haiyang LU ; Weili ZHAO ; Xiaoxia HU
The Journal of Practical Medicine 2025;41(5):628-633
As a symbiotic microbial community within the human body,the gut microbiota plays a crucial role in modulating various physiological processes,including metabolism,immunity,and endocrine function.During allogeneic hematopoietic stem cell transplantation(allo-HSCT),the hematopoietic and immune systems undergo significant changes,which are also influenced by the gut microbiota.Specifically,regarding hematopoietic function,the gut microbiota facilitates the multi-lineage differentiation of hematopoietic stem cells via NOD1-STATs and TLRs-MyD88 signaling pathways,and promotes rapid granulomonocytic lineage differentiation under infection stress.Consequently,early-stage primary graft dysfunction following transplantation may be associated with gut microbiota dysbiosis.In terms of immune function,the gut microbiota enhances the expression of antigen-presenting molecules on intestinal epithelial cells,thereby initiating acute graft-versus-host disease(aGVHD)in the gastrointestinal tract.Moreover,the gut microbiota regulates intestinal immune function through metabolites such as short-chain fatty acids,bile acids,and indole derivatives.Dysbiosis of the gut microbiota can lead to disrup-tion of the intestinal mucus barrier and immune barrier functions,further promoting the onset and progression of aGVHD in the gastrointestinal tract.Therefore,targeting the gut microbiota has emerged as an attractive therapeutic strategy and has been clinically applied.Notably,fecal microbiota transplantation combined with immunosuppressive therapy has shown significant efficacy in alleviating clinical severity and improving prognosis in steroid-refractory aGVHD,demonstrating high safety and manageable adverse reactions,representing a novel breakthrough in its treatment.
7.Flow Field Characteristics of Aortic Valve with Eccentric Lower Valve Placement:A PIV Experimental Study
Enhui HAN ; Qianwen HOU ; Yang XIAO ; Yana MENG ; Haiyang WEI ; Yu JIANG ; Jianjun HU ; Jianye ZHOU
Journal of Medical Biomechanics 2025;40(1):25-33
Objective To investigate the impact of eccentric placement for various types of artificial aortic valves on downstream flow dynamics.Methods A physiological pulsatile circulation simulation system was employed and particle image velocimetry(PIV)was utilized to analyze the downstream flow field variations for bioprosthetic and mechanical valves under two placement conditions:centralized placement(0 mm)and eccentric placement(1 mm).Hemodynamic parameters such as velocity,vorticity,and viscous shear stress were assessed to evaluate the flow field characteristics.Results By analyzing the flow field variations at four characteristic time points,namely,early systole,acceleration phase,peak systole,and deceleration phase,a significant difference in flow field distribution between bioprosthetic and mechanical valves was observed.The bioprosthetic valve exhibited a centrally symmetric jet with a higher flow velocity,whereas the mechanical valve displayed a three-jet structure with a lower central flow velocity.Under eccentric placement,the blood flow in the aortic sinus region was sluggish,with a reduction in average velocity,hindering the formation and maintenance of vortices.During the peak systolic phase,the maximum viscous shear stresses in the sinus region for the bioprosthetic and mechanical valves were 0.45 and 0.67 Pa,respectively,approaching the threshold for endothelial cell damage.Conclusions Eccentric placement of both mechanical and bioprosthetic valves resulted in reduced sinus blood flow velocity and diminished viscous shear stress,creating favorable conditions for thrombus formation.In clinical practice,careful attention should be given to the placement of valve replacement to prevent eccentric placement.
8.The role of YAP1 in regulating mitochondrial function and ATP release in bladder dysfunction induced by partial bladder outlet obstruction
Yongxiang SHAO ; Meng CHENG ; Mengyuan LIU ; Lingchen KONG ; Conglei HU ; Zilong LIANG ; Haofeng PANG ; Haiyang DU ; Zudu FAN ; Liping YAO ; Qian ZHANG ; Fei LIU
Chinese Journal of Urology 2025;46(2):134-140
Objective:To investigate the role of mechanosensor Yes-associated protein 1 (YAP1) in urothelial cells in inducing bladder dysfunction in a partial bladder outlet obstruction (pBOO) model.Methods:Ten female C57BL/6 mice were included in this study and randomly divided into pBOO and sham groups based on body weight using a stratified pairing method, with 5 mice in each group. The pBOO group underwent proximal urethral ligation surgery, while the sham group underwent a sham operation. Two weeks after surgery, the urinary pattern was analyzed using the urine spot test. The significant increase in urine spot numbers indicated the successful establishment of the pBOO model. The mice were then sacrificed, and bladder tissues were weighed and stained with hematoxylin and eosin (HE) to observe morphological changes. The bladder urothelial layer was further isolated, and total cell proteins were extracted to detect the expression levels of YAP1 protein using Western blotting. Mouse immortalized bladder urothelial cells were divided into three experimental groups: the negative control (NC) group, which was treated with YAP1-NC lentivirus; the overexpression (OE) group, which was treated with YAP1-OE lentivirus to induce YAP1 protein overexpression; and the verteporfin treatment (VP) group, which was treated with verteporfin on the basis of the OE group. Real-time quantitative PCR and Western blotting were used to verify the transcription and expression levels of YAP1 protein, the co-transcriptional activator TEAD4 protein, and the phosphorylated protein DRP1-616 (at serine 616) of dynamin-related protein 1 (DRP1). An ATP detection kit was used to measure the ATP release concentration in the NC, OE, and VP groups. The interaction between YAP1 and TEAD4 was investigated using co-immunoprecipitation, and the expression of the mitochondrial marker translocase of the outer mitochondrial membrane 20 (Tom20) was observed using immunofluorescence staining.Results:The results of the urine spot test showed that the number of urine spots on the filter paper in the pBOO group was higher than that in the sham group within 6 hours [(283.0±9.1) spots vs. (3.7±0.3) spots, P<0.01], and the urine spots were scattered. The bladder wet weight in the pBOO group was significantly higher than that in the sham group [(105.70±6.84) mg vs. (22.33±1.20) mg, P<0.01]. Histological observations revealed reduced bladder mucosal folds and increased detrusor muscle thickness in the pBOO group. The expression of YAP1 protein in the bladder urothelial cells of the pBOO group was significantly upregulated compared to the sham group [(1.26±0.08) vs. (0.50±0.04), P<0.01]. In vitro experiments showed that compared to the NC group, the OE group had significantly increased expression of DRP1-616 [(0.94±0.05) vs. (0.33±0.01), P<0.01] and higher ATP release concentration [(24.45±0.16) μmol/mg vs. (19.67±0.42) μmol/mg, P<0.01]. In contrast, the VP group had significantly decreased expression of DRP1-616 [(0.29±0.04) vs. (0.94±0.05), P<0.01] and lower ATP release concentration [(10.55±0.01) μmol/mg vs. (24.45±0.16) μmol/mg, P<0.01] compared to the OE group. Co-immunoprecipitation experiments using YAP1 and TEAD4 antibodies showed that YAP1 and TEAD4 proteins could interact and form a transcriptional complex to regulate ATP release. Immunofluorescence staining revealed increased expression of Tom20 in the OE group compared to the NC group [(104.20±3.28) vs. (74.51±3.87), P<0.01]. Conclusions:In the pBOO-induced bladder dysfunction model, YAP1 is highly expressed in urothelial cells. YAP1 forms a transcriptional complex with TEAD4 to regulate ATP release by promoting mitochondrial fission via DRP1-616 expression, which is a key mechanism underlying pBOO-induced bladder dysfunction.
9.Gut microbiota modulates immune reconstitution in allogeneic hematopoietic stem cell transplantation
Haiyang LU ; Weili ZHAO ; Xiaoxia HU
The Journal of Practical Medicine 2025;41(5):628-633
As a symbiotic microbial community within the human body,the gut microbiota plays a crucial role in modulating various physiological processes,including metabolism,immunity,and endocrine function.During allogeneic hematopoietic stem cell transplantation(allo-HSCT),the hematopoietic and immune systems undergo significant changes,which are also influenced by the gut microbiota.Specifically,regarding hematopoietic function,the gut microbiota facilitates the multi-lineage differentiation of hematopoietic stem cells via NOD1-STATs and TLRs-MyD88 signaling pathways,and promotes rapid granulomonocytic lineage differentiation under infection stress.Consequently,early-stage primary graft dysfunction following transplantation may be associated with gut microbiota dysbiosis.In terms of immune function,the gut microbiota enhances the expression of antigen-presenting molecules on intestinal epithelial cells,thereby initiating acute graft-versus-host disease(aGVHD)in the gastrointestinal tract.Moreover,the gut microbiota regulates intestinal immune function through metabolites such as short-chain fatty acids,bile acids,and indole derivatives.Dysbiosis of the gut microbiota can lead to disrup-tion of the intestinal mucus barrier and immune barrier functions,further promoting the onset and progression of aGVHD in the gastrointestinal tract.Therefore,targeting the gut microbiota has emerged as an attractive therapeutic strategy and has been clinically applied.Notably,fecal microbiota transplantation combined with immunosuppressive therapy has shown significant efficacy in alleviating clinical severity and improving prognosis in steroid-refractory aGVHD,demonstrating high safety and manageable adverse reactions,representing a novel breakthrough in its treatment.
10.Flow Field Characteristics of Aortic Valve with Eccentric Lower Valve Placement:A PIV Experimental Study
Enhui HAN ; Qianwen HOU ; Yang XIAO ; Yana MENG ; Haiyang WEI ; Yu JIANG ; Jianjun HU ; Jianye ZHOU
Journal of Medical Biomechanics 2025;40(1):25-33
Objective To investigate the impact of eccentric placement for various types of artificial aortic valves on downstream flow dynamics.Methods A physiological pulsatile circulation simulation system was employed and particle image velocimetry(PIV)was utilized to analyze the downstream flow field variations for bioprosthetic and mechanical valves under two placement conditions:centralized placement(0 mm)and eccentric placement(1 mm).Hemodynamic parameters such as velocity,vorticity,and viscous shear stress were assessed to evaluate the flow field characteristics.Results By analyzing the flow field variations at four characteristic time points,namely,early systole,acceleration phase,peak systole,and deceleration phase,a significant difference in flow field distribution between bioprosthetic and mechanical valves was observed.The bioprosthetic valve exhibited a centrally symmetric jet with a higher flow velocity,whereas the mechanical valve displayed a three-jet structure with a lower central flow velocity.Under eccentric placement,the blood flow in the aortic sinus region was sluggish,with a reduction in average velocity,hindering the formation and maintenance of vortices.During the peak systolic phase,the maximum viscous shear stresses in the sinus region for the bioprosthetic and mechanical valves were 0.45 and 0.67 Pa,respectively,approaching the threshold for endothelial cell damage.Conclusions Eccentric placement of both mechanical and bioprosthetic valves resulted in reduced sinus blood flow velocity and diminished viscous shear stress,creating favorable conditions for thrombus formation.In clinical practice,careful attention should be given to the placement of valve replacement to prevent eccentric placement.

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