1.Two-dimensional black phosphorus materials for bone tissue engineering
Jiahan CHEN ; Chao FENG ; Xiaoxia HUANG ; Minghui NIU ; Xin WANG ; Yong TENG
Chinese Journal of Tissue Engineering Research 2025;29(10):2124-2131
BACKGROUND:Black phosphorus has a high degree of homology with human bone,so it has been extensively studied in the field of bone tissue engineering in recent years.Since 2014,two-dimensional black phosphorus materials have garned significant attention in the field of biomedicine due to their excellent exceptional physical,chemical,and biological properties. OBJECTIVE:To summarize the advancements made in black phosphorus-based nanomaterials for bone tissue engineering,focus on the synthesis methods,osteogenic characteristics,and applications in biomaterials pertaining to two-dimensional black phosphorus nanomaterials. METHODS:Chinese and English key words were"black phosphorus,bone tissue engineering,bone defect,bone regeneration,osteogenesis."Relevant articles in PubMed and CNKI databases from January 2014 to December 2023 were searched.After exclusion and screening,96 articles were analyzed. RESULTS AND CONCLUSION:Black phosphorus nanomaterials play an important role in bone tissue engineering due to their good biocompatibility,biodegradability,photothermal action,antibacterial ability,drug loading performance,and special osteogenic effect,and are ideal candidate materials for promoting bone regeneration.The preparation of black phosphorus nanomaterials is mainly a top-down top-layer stripping method.The main principle is to weaken the van der Waals force between the black phosphorus layers by physical or chemical means to obtain a single or less layer of phosphanse,that is,black phosphorus nanosheets or quantum dots.Black phosphate-based nanocomposites are mainly divided into hydrogels,3D printing scaffolds,composite scaffolds,electrospinning,bionic periosteum,microspheres,and bionic coatings.The research of nano-black phosphorus in bone tissue engineering is in its infancy,and still faces many challenges:the behavior of black phosphorus in vivo and the interaction mechanism with various biomolecules need to be further studied.The long-term potential toxicity of black phosphorus is unknown.The manufacturing process for black phosphorus is difficult to control.Therefore,how to develop uniform size,safe,reliable,and efficient nano black phosphorus and transform it into clinical application requires interdisciplinary research on modern biomedical technology,physicochemical technology,and precision manufacturing technology.
2.Association between dynamic indexes of maternal progesterone in the first trimester of pregnancy and fetal head circumference growth and development
Hui NIU ; Juan XIN ; Jinlu LIANG ; Jiayuan FENG ; Sijing ZHU ; Xiaoxue LI ; Yin YANG ; Liu FANG ; Mengfei SUN ; Ziyi CHEN ; Wenfang YANG
Journal of Xi'an Jiaotong University(Medical Sciences) 2025;46(5):871-879
Objective To explore the association between dynamic indexes of maternal progesterone in early pregnancy and the average level and growth rate of fetal head circumference(HC)in mid-and late pregnancy.Methods This study adopted a retrospective cohort design and included 255 singleton pregnant women in the maternal and infant cohort of The First Affiliated Hospital of Xi'an Jiaotong University from January 2015 to December 2024.The progesterone levels of their early venous blood were detected and divided into two groups of progesterone trajectories,namely,fluctuating type and increasing type,by morphology.The dynamic indicators of progesterone in early pregnancy were constructed:cumulative dynamic deviation index in the first trimester(CDDI-P1T),gestational age at progesterone peak(GA-PP),and maximal relative progesterone decline in the first trimester(MRD-P1T).The average head circumference level and linear growth rate of the fetuses in the middle and late pregnancy were calculated.Generalized linear regression(GLM)was used to analyze the linear association between progesterone dynamic indicators and head circumference development.The key gestational weeks of progesterone affecting fetal head development were explored by linear regression of gestational weeks.Ordinary least squares(OLS)regression and restricted cubic spline(RCS)plots were used to draw the nonlinear association between progesterone dynamic indicators and head circumference.Results Among the 255 pregnant women included,92.5%of the progesterone trajectories in early pregnancy were fluctuating,and 7.5%were increasing.The growth rates of the increasing progesterone trajectory group were higher in the second and third trimesters than in the fluctuating group,but the differences were not statistically significant(all P>0.05).GLM analysis showed that for every 1 unit increase in CDDI-P1T,the head circumference in the middle and late pregnancy increased significantly by 1.574 cm and 1.193 cm(Z=3.714,2.885,P<0.01).The delay of GA-PP was negatively correlated with the head circumference in the middle pregnancy(β=-0.190 cm,95%CI:-0.339--0.041,P=0.010)but positively correlated with the head circumference growth rate in the late pregnancy(β=0.022 cm/week,95%CI:0.003-0.041,P=0.025).A 10%decrease in the decline of CDDI-P1T increased the head circumference in the middle pregnancy by 0.200 cm(95%CI:0.016-0.384,P=0.033),and a 100%decrease in the decline increased the head circumference growth rate in the late pregnancy by 0.201 cm/week(95%CI:0.002-0.399,P=0.048).The analysis of the key time window showed that for every 20 nmol/L increase in progesterone during 9.5-13 weeks of pregnancy,the mid-term head circumference increased by 0.035-0.166 cm(Z=2.452-3.517,allP<0.05),and the late-term head circumference increased by 0.767 cm during 9-13 weeks of pregnancy(Z=2.452-3.517,all P<0.05).When progesterone increased during 9.5-10.5 weeks of pregnancy,the growth rate of mid-term head circumference increased by 0.013-0.023 cm/week(Z=2.074-2.243,all P<0.01).When progesterone increased during 8.5-10.5 weeks of pregnancy,the growth rate of late-term head circumference increased by 0.010-0.026 cm/week(Z=2.061-3.137,all P<0.05).Conclusion Progesterone dynamic index is a new sensitive tool for evaluating fetal head circumference development.There is a stage-specific window period for progesterone regulation.9.5-13 weeks of pregnancy is the critical period for progesterone to affect head circumference growth,and 9.5-10.5 weeks of pregnancy is the core window for regulating the growth rate of head circumference.Therefore,it is necessary to combine progesterone dynamic index and time window for individualized intervention to promote the transformation of prenatal care from pregnancy maintenance to eugenics intervention.
3.Association between intraoperative nasojejunal tube placement and delayed gastric emptying after laparoscopic pancreaticoduodenectomy
Meng LIU ; Heng WANG ; Xiaohan KONG ; Faji YANG ; Zheyu NIU ; Yijie HAO ; Xin WANG ; Huaqiang ZHU ; Hengjun GAO ; Jun LU ; Xu ZHOU
Chinese Journal of General Surgery 2025;34(9):1934-1945
Background and Aims:Laparoscopic pancreaticoduodenectomy(LPD)has become a preferred approach for periampullary tumors,yet delayed gastric emptying(DGE)remains a frequent complication that hampers postoperative recovery.The nasojejunal feeding tube(NJT)is commonly used for early enteral nutrition,but its impact on DGE is controversial.This study aimed to evaluate whether intraoperative NJT placement increases the risk of DGE after LPD and to assess its influence on postoperative recovery outcomes.Methods:A retrospective cohort of 319 patients who underwent LPD at Provincial Hospital Affiliated to Shandong First Medical University from April 2017 to November 2023 was analyzed.Patients were divided into two groups based on intraoperative NJT placement(NJT group,n=200;non-NJT group,n=119).The incidence of DGE and postoperative outcomes were compared.Multivariate logistic regression and propensity score matching(PSM)were performed to identify independent risk factors for DGE.Results:The incidence of grade B/C DGE was significantly higher in the NJT group than in the non-NJT group(36.5%vs.21.8%,P=0.006).NJT placement was associated with longer postoperative hospital stay and higher hospitalization costs(both P<0.05).Multivariate analysis revealed intraoperative NJT placement(OR=1.960,95%CI=1.142-3.363,P=0.015)and intraoperative blood loss>400 mL(OR=1.921,95%CI=1.155-3.194,P=0.012)as independent risk factors for DGE.These findings were consistent after PSM.Conclusions:Prophylactic intraoperative NJT placement confers no additional benefit for postoperative recovery after LPD and is associated with a higher risk of DGE,prolonged hospitalization,and increased medical costs.Routine NJT placement should therefore be avoided,and individualized strategies should be adopted to minimize postoperative complications and enhance recovery.
4.Predictive value of serum AMH for micro-TESE outcomes in patients with non-mosaic Klinefelter syndrome
Hang XIN ; Jinhao LIU ; Wenbin NIU ; Shanjun DAI ; Yu LIU ; Yudong GUAN ; Ning XU ; Yihong GUO
Chinese Journal of Reproduction and Contraception 2025;45(4):372-379
Objective:To investigate the predictive value of anti-Müllerian hormone (AMH) on the outcome of microscopic testicular sperm extraction (micro-TESE) in patients with non-mosaic Klinefelter syndrome (KS) of the clinical data and to identify effective predictors for successful micro-TESE.Methods:A retrospective case-control study was conducted on the clinical data of 118 non-mosaic KS patients treated at the Center for Reproductive Medicine of the First Affiliated Hospital of Zhengzhou University between May 2018 and September 2023. Patients were divided into two groups based on whether sperm were successfully retrieved via micro-TESE: the sperm retrieved group ( n=45) and the no sperm retrieved group ( n=73). Differences between the two groups were compared, and multivariate logistic regression analysis was used to identify factors influencing sperm retrieval. Changes in testicular volume and sex hormone levels before and after surgery were also assessed. Results:The sperm retrieval rate was 38.1% (45/118). Patients in the sperm retrieved group were significantly younger [(26.93±3.80) years] than those in the no sperm retrieved group [(28.27±3.92) years, P=0.029], and the AMH level was significantly higher [0.44 (0.18, 1.13) μg/L] than that in the no sperm retrieved group [0.10 (0.03, 0.22) μg/L, P<0.001]. AMH was identified as an independent predictor of micro-TESE outcome in non-mosaic KS patients ( OR=7.867, 95% CI: 2.727-27.242, P=0.001). The area under the receiver operating characteristic curve was 0.802 (95% CI: 0.722-0.883), and the optimal reference threshold for AMH was ≥0.265 μg/L. Postoperatively, testosterone levels decreased significantly by a median of 0.27 μg/L ( P=0.019), while luteinizing hormone levels increased by a median of 2.08 U/L ( P=0.049), with a more significant decline in testosterone levels observed in the no sperm retrieved group by a median of 0.29 μg/L ( P=0.022). Conclusion:AMH can predict successful micro-TESE in non-mosaic KS patients, with higher AMH levels indicating a higher likelihood of success.
5.Analysis of Animal Models of Myasthenia Gravis Based on Its Clinical Characteristics in Chinese and Western Medicine
Yuhan CHEN ; Jinling CHEN ; Xin LI ; Yanhua OU ; Si WANG ; Jingyi CHEN ; Xingyi WANG ; Jiali YUAN ; Yuanyuan DUAN ; Zhongshan YANG ; Haitao NIU
Laboratory Animal and Comparative Medicine 2025;45(2):176-186
Myasthenia gravis(MG)is an autoimmune disease characterized primarily by skeletal muscle weakness and,in severe cases,respiratory involvement.Western medical treatment predominantly relies on immunosuppressants,but long-term administration often leads to notable side effects.In contrast,traditional Chinese medicine(TCM)offers the advantage of multi-target interventions.However,the pathogenesis of MG has not been fully elucidated,and the establishment of animal models that accurately reflect the clinical characteristics of both Chinese and Western medicine is essential for mechanism research and new drug development.This paper systematically reviews the etiology and pathogenesis,diagnostic criteria,and progress of animal model research for MG from both Chinese and Western medicine perspectives.In Western medicine,the pathogenesis of MG is closely related to genetic susceptibility,environmental factors,and autoantibody-mediated postsynaptic membrane damage.In TCM,MG is classified under the category of"flaccidity syndrome",attributed to congenital deficiencies and acquired malnourishment.Western diagnostic criteria involve a combination of clinical symptoms,fatigue testing,serum antibody assays,and electrophysiological evaluation.In contrast,TCM diagnosis emphasizes the integration of primary and secondary symptoms with tongue and pulse pattern differentiation.Currently available animal models mainly include experimental autoimmune myasthenia gravis(EAMG)and passive transfer myasthenia gravis(PTMG).The Toredo acetylcholine receptor(AChR)induced EAMG model aligns well with Western diagnostic criteria,but poorly matches secondary symptoms in TCM.The synthetic AChR peptide model is widely used,but shows low conformity with TCM syndromes.Models induced by muscle-specific tyrosine kinase(MuSK),low-density lipoprotein receptor-related protein 4(LRP4),and transgenic models demonstrate high innovation but exhibit low clinical conformity.Evaluation of these models requires integration of behavioral,electrophysiological,and immunological indicators.However,a systematic framework for modelling TCM syndromes is still lacking.Future research should integrate TCM-based etiological modelling methods with the Western pathological mechanisms to construct disease-syndrome combination models.Additionally,it is crucial to establish a TCM syndrome evaluation system based on"validation by prescription",as well as to improve the scientific rigor and practicality of animal models by the incorporation of emerging technologies.This review provides a theoretical foundation for optimizing MG animal model design,advancing the research on the combination of Chinese and Western medicine,and supporting efficacy assessment and mechanism exploration of Chinese herbal prescriptions.
6.Predictive value of the triglyceride-glucose index combined with serological indicators for pancreatic fistula after pancreaticoduodenectomy
Jubao NIU ; Wenkai JIANG ; Cunbin LI ; Xin LI ; Hui ZHANG
Chinese Journal of General Surgery 2025;34(3):445-454
Background and Aims:Postoperative pancreatic fistula(POPF)is one of the most severe and common complications following pancreaticoduodenectomy(PD)and is a major cause of mortality after PD.Given the multiple risk factors associated with PD-POPF,developing an effective predictive model is of significant clinical importance.This study was conducted to explore the predictive performance of the triglyceride-glucose(TyG)index combined with serological indicators for POPF following PD.Methods:The preoperative general data,laboratory indicators within one week before surgery,and postoperative complication data of 291 patients who underwent PD at the Department of General Surgery,Second Hospital of Lanzhou University,from January 2019 to June 2024,were retrospectively collected.Patients were randomly divided into a modeling group(203 cases)and a validation group(88 cases)using a computer-generated random number method at a 7∶3 ratio.Univariate Logistic regression and multivariate binary Logistic regression(Back-Wald method)were performed on the modeling group data.Based on regression analysis results,a predictive model was constructed and visualized using a nomogram.The discriminative ability of the nomogram model was evaluated by the area under the receiver operating characteristic(ROC)curve(AUC).A calibration curve was used to assess the agreement between predicted and actual probabilities,and a decision curve analysis was conducted to evaluate the clinical application value of the model.Subgroup analysis was performed on potential factors influencing the outcome variables.Results:Among the 291 patients,70 developed POPF,with 49 cases in the modeling group and 21 in the validation group.There was no statistically significant difference between the two groups(all P>0.05).Univariate analysis in the modeling group identified body mass index(BMI),triglycerides,TyG index,albumin(ALB),platelet count(PLT),absolute lymphocyte count(LYM),and absolute neutrophil count(NEUT)as significant factors associated with POPF(all P<0.05).Multivariate analysis revealed that BMI,TyG index,ALB,PLT,LYM,and NEUT were independent influencing factors for POPF(all P<0.05).A PD-POPF risk prediction model and nomogram were constructed based on these results.The model achieved an AUC of 0.80(0.73-0.86),and when applied to the validation group,the ROC analysis yielded an AUC of 0.80(0.70-0.90).The calibration curves of both the modeling and validation groups closely aligned with the standard curve.Subgroup analysis indicated that tumor nature and tumor stage had minimal impact on PD-POPF risk factors,demonstrating good model stability.Conclusion:The TyG index,along with BMI,PLT,NEUT,ALB,and LYM,is closely associated with PD-POPF occurrence.The risk prediction model based on the TyG index and these influencing factors exhibits good predictive performance and holds significant clinical value for guiding early intervention.
7.Efficacy of urapidil combined with nimodipine in treatment of elderly hypertensive intracerebral hemorrhage
Ping YAN ; Jinyu MA ; Chengwang HU ; Xin NIU ; Peng LIU
Chinese Journal of Geriatric Heart Brain and Vessel Diseases 2025;27(6):762-765
Objective To explore the effect of urapidil combined with nimodipine in the treatment of elderly hypertensive intracerebral hemorrhage(HICH).Methods A total of 128 elderly HICH patients admitted in our hospital from March 2022 to March 2024 were recruited and randomly di-vided into single group(64 cases)and combined group(64 cases).Both groups received routine treatment,and the single group was treated with urapidil while the combined group was given urapidil combined with nimodipine.Clinical efficacy,clinical indicators[cerebral hematoma vol-ume,intracranial pressure(ICP)],neurological function indicators[brain-derived neurotrophic factor(BDNF),neuron-specific enolase(NSE),nerve growth factor(NGF)],hemodynamic pa-rameters[perfusion index(PI),cerebrovascular reserve capacity(CVR),mean bilateral arterial flow velocity],and vascular endothelial function indicators[vascular endothelial growth factor(VEGF),endothelin-1(ET-1),angiopoietin-1(Ang-1)]were compared between the two groups.The incidence of adverse reactions was observed during treatment.Results The total effective rate was significantly higher in the combined group than the single group(89.06%vs 75.00%,P<0.05).After treatment,the ICP,hematoma volume,PI,and levels of NSE,VEGF,ET-1 and Ang-1 in both groups were significantly lower than those before treatment(P<0.05).These indi-cators in the combined group were significantly lower than those in the single group(P<0.05,P<0.01).The CVR,mean bilateral arterial flow velocity,and BDNF and NGF levels were notably increased in both groups after treatment,and the indicators were significantly higher in the com-bined group than the other group(P<0.05,P<0.01).There was no statistical difference in the incidence of adverse reactions between groups(P>0.05).Conclusion Urapidil combined with ni-modipine can shrink the volume of cerebral hematoma,reduce ICP,and improve neurological function,hemodynamics and vascular endothelial function in elderly HICH patients,and the treat-ment does not increase the incidence of adverse reactions.
8.Prevention and treatment of acute radiation-induced myocardial injury by the preparation of Abelmoschus manihot(L.)Medik(Jiahua Tablet)
Wenli YANG ; Tong BAO ; Xin LIN ; Ruge NIU ; Zhongchi XU ; Yunhe ZHAO
The Journal of Practical Medicine 2025;41(17):2631-2636
Objective To investigate the protective effects and potential mechanisms of the preparation of Abelmoschus manihot(L.)Medik(Jiahua Tablet)against acute radiation-induced myocardial injury,based on myo-cardial injury markers(sST2,cTnI)and oxidative stress damage-related indicators(SOD,MDA),and to provide new avenues for the prevention and treatment of radiation-induced heart disease(RIHD).Methods Sixty-nine patients with thoracic malignant tumor who received radiotherapy at the department of radiation oncology in Hospital Affiliated to Nanjing University of Chinese Medicine from December 2023 to November 2024 were enrolled in the study.Participants were randomly divided into control group(n=38)and observation group(n=31).The control group received standard radiotherapy in conjunction with conventional medications for RIHD,while the observation group was additionally administered Jiahua Tablet alongside the same regimen.Both groups took medications continuously for 1 month.Changes in serum levels of sST2,cTnI,SOD,and MDA were compared between the two groups 3 days prior to radiotherapy and 7 days after radiological therapy.Results On day 7 post-radiotherapy,the levels of sST2 and cTnI in the control group were highly elevated,showing statistically significant difference(P<0.01).In contrast,the levels of sST2 and cTnI in the observation group showed only mild elevation,and no statistically significant difference was observed(P>0.05).Between-group analysis demonstrated that post-treatment sST2 and cTnI levels in the observation group were substantially lower compared to those in the control group,indicating statistically significant difference(P<0.05).After treatment,SOD level in the control group was considerably lower compared to its pre-treatment level,and marked statistical significance was observed(P<0.01).SOD level in the observation group demonstrated a downward trend compared to baseline value,indicating no statistical significance(P>0.05).Between-group analysis demonstrated that post-treatment SOD level in the observation group was substantially elevated compared to that in the control group,indicating a highly significant disparity(P<0.05).After treatment,MDA level in the control group was considerably higher compared to its pre-treatment level,and a marked statistical significance was observed(P<0.05),whereas MDA level in the observation group showed only a mild increase compared to baseline value,with no statistically significant difference(P>0.05).Between-group analysis demonstrated that post-treatment MDA level in the observation group was substantially lower compared to that in the control group,demonstrating a remarkably statistically significant difference(P<0.01).Conclusion The preparation of Abelmoschus manihot(L.)Medik(Jiahua Tablet)effectively inhibits acute radiation-induced myocardial injury,with its potential mechanism closely linked to the suppression of oxidative stress responses.
9.Clinical features and pathogens for burn wound infections in a northwestern hospital from 2014 to 2023
Huixin ZHAN ; Xin XUE ; Xiaohong NIU ; Tao YANG ; Nan WANG ; Zejuan JIANG ; Yantan CHENG ; Yigang HE ; Zhongshu PU
Chinese Journal of Nosocomiology 2025;35(14):2126-2129
OBJECTIVE To investigate the epidemiological characteristics,clinical features and distribution of pathogens isolated from the burn wound patients with infections in a northwestern hospital from 2014 to 2023 so as to provide bases for prevention and treatment of burn wound infections in the northwestern region.METHODS The epidemiological characteristics,clinical features and distribution of pathogenic isolated from the burn wound patients with infections who were treated in the 940th Hospital of Joint Logistic Support Force from 2014 to 2023 were retrospectively analyzed.RESULTS A total of 2122 burn wound patients were enrolled in the study,397(18.71%)of whom had infections,including 306(14.42%)patients with community-acquired infections and 91(4.29%)patients with hospital-acquired infections.The proportion infections was higher among the patients aged no less than 60 years old(63/154)than among the patients aged less than 14 years old(231/983)and the pa-tients aged between 14 and 60 years old(103/985)(x2=108.840,P<0.001).The proportion of infections was higher among the patients with the burn wound depth no less than grade Ⅲ(146/458)than among the patients with the burn wound depth no less than grade Ⅱ(251/1664)(x2=66.600,P<0.001).The proportion infections was higher among the patients with burn wounds in limbs(370/1881)than among the patients with burn wounds in other sites(1153/1987)(x2=47.244,P<0.001).The isolation rates of methicillin-resistant Staphy-lococcus epidermidis and carbapenem-resistant Pseudomonas aeruginosa strains showed downward trends from 2014 to 2023,the isolation rates of carbapenem-resistant Klebsiella pneumoniae and the third generation cephalo-sporins-resistant Escherichia coli showed upward trends,however,there were no significant differences.CONCLUSIONS The patients with no less than 60 years of age,no lower than grade Ⅲ of burn wound depth and burn wounds in limbs are more likely to have burn wound infections.S.aureus is the predominant species of pathogens causing the infections.The isolation rates of carbapenem-resistant K.pneumoniae strains and the third generation cephalosporins-resistant E.coli strains show upward trends.It is necessary to take targeted prevention and treatment measures for the burn wound infections.
10.Effects of Different Anticipated Conditions on Biomechanical Characteristics of Lower Limbs in Individuals with Chronic Ankle Instability
Ling WANG ; Peng CHEN ; Huiwu ZUO ; Xinxin LIU ; Junjie NIU ; Kejun LI ; Xin LIU ; Haitao LIU ; Jinwu WANG
Journal of Medical Biomechanics 2025;40(4):980-987
Objective The differences in biomechanical characteristics of the lower limbs between individuals with chronic ankle instability(CAI)and healthy individuals during unanticipated and anticipated jumping were compared,in order to provide practical references and ideas for the prevention and treatment of recurrent ankle sprains.Methods Thirty subjects were recruited,including 15 patients with CAI and 15 healthy volunteers.All subjects completed unanticipated and anticipated jumping tests in a random order,with a 1-week interval between the two tests.Kinematic and kinetic data of lower limbs were collected synchronously using Vicon infrared high-speed motion capture system and Kistler three-dimensional force platform.Results At the moment of touchdown,knee flexion angle was significantly greater during unanticipated jumping than that during anticipated jumping(P=0.009),while ankle eversion angle was notably lower(P=0.043).During the early landing phase,unanticipated jumping showed significantly greater peak hip flexion and abduction angles,as well as knee flexion(P=0.038,P=0.036,P=0.04),while peak ankle dorsiflexion and eversion angles were significantly lower(P=0.001,P=0.01)compared to anticipated jumping.Additionally,peak hip abduction moment during unanticipated jumping was significantly higher in patients with CAI than that during anticipated jumping(P=0.028).Conclusions Unanticipated jumping reduced ankle dorsiflexion and eversion angles in individuals with CAI,putting the ankle in an open,sprain-prone position.Individuals with CAI compensated proximally by increasing hip flexion,abduction,knee flexion angles,and hip extension moment to stabilize the ankle.

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