1.Huanglian Jiedutang Improves Cognitive Impairment after Schemic Stroke by Regulating Neuron via NF-κB Signaling Pathway
Mengying SUN ; Lizhen WANG ; Tong LI ; Leilei WANG ; Shiyan JIA ; Tingting WANG ; Yanwen YANG ; Kaiqiang SI ; Youxiang CUI ; Zhilong LIU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(11):68-76
ObjectiveTo investigate the effects of Huanglian Jiedutang (HLJDT) on cognitive function in mice with ischemic stroke (IS) and to elucidate whether its neuroprotective effects are mediated by inhibition of the nuclear factor-κB (NF-κB) signaling pathway and subsequent suppression of NF-κB-regulated neuronal apoptosis. MethodsAn IS model was established using middle cerebral artery occlusion (MCAO). Sixty C57BL/6J mice were randomly assigned to five groups (n =12 per group), i.e., sham operation, model, HLJDT low-dose (3.9 g·kg-1·d-1), HLJDT high-dose (7.8 g·kg-1·d-1), and Ginkgo biloba extract (GBE, 31.2 mg·kg-1·d-1). Post-operatively, neurological deficit scores (Longa score), cerebral infarct volume assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and brain water content were evaluated. Learning and memory were assessed using new object recognition (NOR) and fear conditioning (FC) tests. Hippocampal pathology was examined via hematoxylin and eosin (HE) staining. Immunofluorescence detected expression of glial fibrillary acidic protein (GFAP, astrocyte marker), cellular oncogene Fos (c-Fos, neuronal activation marker), and glutamate decarboxylase 65 (GAD65). Western blot measured nuclear factor-κB inhibitor protein α (IκBα), phosphorylated IκBα (p-IκBα), NF-κB p65, phosphorylated NF-κB p65 (p-NF-κB p65), ionic calcium binding adapter molecule 1 (Iba-1), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and apoptosis-related proteins, such as cleaved cysteinyl aspartate-specific protease 3 (Caspase-3), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax). Real-time quantitative PCR (Real-time PCR) was used to assess mRNA levels of Iba-1, TNF-α, IL-1β, NF-κB p65, cleaved Caspase-3, Bax, and Bcl-2. ResultsCompared with the sham group, the model group exhibited significantly increased neurological deficit scores, brain water content, and cerebral infarct volume (P<0.01). Hippocampal CA1 neurons were disorganized, showing nuclear pyknosis and karyolysis. NOR exploration time and FC freezing time were significantly reduced (P<0.01). GFAP and c-Fos expression were increased, while GAD65 expression was decreased (P<0.01). Cleaved Caspase-3 and Bax were upregulated, Bcl-2 was downregulated, and the Bax/Bcl-2 ratio was elevated (P<0.01). Expression levels of p-IκBα, p-NF-κB p65, IL-1β, TNF-α, and Iba-1 were significantly increased (P<0.01). Compared with the model group, HLJDT high-dose, low-dose, and GBE groups showed significant improvements in all parameters (P<0.01). Among them, the HLJDT high-dose group showed the most pronounced neuronal structural recovery and superior performance in NOR and FC tests (P<0.01). In this group, GFAP and c-Fos decreased, GAD65 increased (P<0.01), apoptosis-related protein expression was reversed, and NF-κB signaling and related inflammatory factor expression were suppressed (P<0.01). ConclusionHLJDT ameliorates cognitive dysfunction in mice after IS, potentially by inhibiting the NF-κB signaling pathway, thereby reducing neuroinflammation and hippocampal neuronal apoptosis.
2.Action mechanisms and application pathways of biomaterials in promoting corneal alkali burn repair
Hui XIAO ; Dongyan LI ; Jing JI ; Lizhen WANG
Chinese Journal of Tissue Engineering Research 2025;29(10):2162-2170
BACKGROUND:Traditional treatments for corneal alkali burns are limited,especially in controlling inflammation,preventing neovascularization,and inhibiting corneal scarring.Natural,synthetic,or composite materials provide a wide range of treatment options.However,the mechanism by which biomaterials promote corneal alkali burn repair has not yet been systematically understood. OBJECTIVE:To summarize the current research on biomaterials in promoting corneal alkali burn repair in and outside China,and review the mechanism and application of biomaterials in repairing corneal alkali burn. METHODS:The first author searched"cornea,alkali burn,amniotic membrane,hyaluronic acid,collagen,chitosan,polymer materials"as Chinese keywords and"amniotic membrane,hyaluronic acid,collagen,chitosan,polymer,cornea,alkali burn"as English keywords in PubMed,Web of Science,CNKI,and WanFang databases.According to inclusion and exclusion criteria,76 eligible articles were finally included for review. RESULTS AND CONCLUSION:(1)In the field of corneal alkali burn repair,biomaterials such as amniotic membrane,hyaluronic acid,collagen,chitosan,and degradable polymer materials have been widely studied and applied.Each of these biomaterials has its own characteristics,advantages,and disadvantages,and stands out in different aspects.(2)First and foremost,amniotic membranes are considered one of the most promising biomaterials due to their abundance of bioactive factors.They are biocompatible and can regulate the corneal inflammatory response.However,there are issues with donor shortages and susceptibility to infectious diseases.(3)Hyaluronic acid has good moisturizing properties and biocompatibility,and is able to improve the survival rate of corneal cells and increase corneal transparency.(4)The good biocompatibility and scaffold structure of collagen enable the promotion of corneal cell adhesion and proliferation,as well as the reconstruction of corneal tissue structure.(5)Chitosan is recognized for its good biocompatibility and degradability,making it suitable as a carrier for drug delivery and cell transplantation.(6)Degradable polymer materials have good controllability over degradation and can provide a good support and delivery platform for the repair of corneal alkali burns,but further research is needed on their stability and biocompatibility.(7)Overall,there is currently no single biomaterial that can completely address the repair problem of corneal alkali burns,and each biomaterial has its own specific application scenarios and limitations.(8)Future research directions should focus on further improving the properties and structure of biomaterials,exploring more effective combination applications,and deeply understanding the interaction mechanism between biomaterials and corneal tissue,in order to enhance the therapeutic effect of corneal alkali burns and the quality of life of patients.
3.Levels of PCT,NLR,SAA and PLR of newborns with bloodstream infection and their values in early diagnosis
Weiwei XIE ; Jing LUO ; Yanfen YING ; Lizhen WANG
Chinese Journal of Nosocomiology 2025;35(12):1841-1845
OBJECTIVE To investigate the levels of procalcitonin(PCT),platelet-to-lymphocyte ratio(PLR),neu-trophil-to-lymphocyte ratio(NLR),white blood cell count(WBC)and serum amyloid A(SAA)in newborns with bloodstream infection,and their diagnostic value for early diagnosis of bloodstream infection in newborns.METHODS A total of 100 neonates with positive blood culture results from Jan.2021 to Jan.2024 at Taizhou Hos-pital of Zhejiang Province were selected.These cases were divided into three groups based on the type of pathogen:74 cases in the gram-negative bacterial group,19 cases in the gram-positive bacterial group,and 7 cases in the fungal group.Additionally,100 neonates with negative blood culture results during the same period were selected as the control group.By comparing the levels of PCT,PLR,NLR,WBC and SAA in the blood of newborns infec-ted with different pathogens,the diagnostic value of various indicators on the receiver operating characteristic(ROC)curve for diagnosis of bloodstream infection in newborns was evaluated.RESULTS Among 100 newborns with positive blood cultures,74 strains of gram-negative bacteria,19 strains of gram-positive bacteria,and 7 strains of fungi were identified.The levels of PCT,PLR,NLR,WBC and SAA in the gram-positive,gram-negative and fungal groups were all higher than those in the control group(P<0.05).The ROC curve re-sults showed that the diagnostic efficacy of the combination of PCT,PLR,NLR,WBC and SAA for gram-nega-tive and gram-positive bloodstream infections was superior to that of each individual indicator(P<0.05),with ar-ea under the curve(AUC)of 0.982 and 0.969,respectively.CONCLUSION PCT,PLR,NLR,WBC and SAA can serve as effective biomarkers for the early diagnosis of bloodstream infection in newborns,aiding in the rapid and accurate identification of the type of infection.
4.Research on the Factors Influencing the Evolution of COPD Qi Deficiency Syndrome Based on Nonlinear Mixed Effects Model
Weike LI ; Mingyang YI ; Yuanyuan NI ; Lizhen YAN ; Jianxin GUAN ; Shihao WANG ; Huijie WANG ; Jiansheng LI ; Zhiwan WANG
World Science and Technology-Modernization of Traditional Chinese Medicine 2025;27(8):2205-2214
Objective To provide methodological examples for related research,the influencing factors of the evolution of Qi deficiency syndrome in chronic obstructive pulmonary disease(COPD)based on a nonlinear mixed effects model was explored.Methods A research questionnaire on the influencing factors of the evolution of Qi deficiency syndrome in chronic obstructive pulmonary disease was developed,and clinical data of 650 COPD patients on the 1st and 14th day of acute exacerbation,the 1st and 28th day of risk window,the first day of stable period,and the 90th day were dynamically collected from 10 tertiary hospitals across the country.8 baseline data including gender and age were collected through the PROC NLMIXED process by SAS 9.4 software.Coronary heart disease,diabetes and hypertension accounted for the highest proportion.Nine concurrent syndromes including wind cold syndrome and phlegm heat syndrome were used as fixed effects,and individual level was used as random effects to gradually fit the model and screen the influencing factors of Qi deficiency syndrome in the entire process of disease occurrence and development.Results A total of 637 eligible cases were included,and clinical datas were dynamically collected on the 1st and 14th day of acute exacerbation,the 1st and 28th day of the risk window,the 1st and 90th day of the stable period.It was found that the number of acute exacerbations,alcohol consumption,concomitant hypertension,coronary heart disease,blood stasis syndrome,yin deficiency syndrome,yang deficiency syndrome,6-minute walking distance,and the modified Medical Research Council Dyspnea Questionnaire(mMRC)had an impact on the evolution of Qi deficiency syndrome in the previous year(P<0.05).Conclusion The use of a nonlinear mixed effects model revealed the relevant factors affecting the evolution of Qi deficiency syndrome from complex multi temporal dynamic data,providing methodological references for other related studies.
5.Development and application of a standardised nursing protocol for multidisciplinary team surgery assisted by da Vinci surgical system based on systems management theory
Liping WANG ; Mengting XIE ; Zifang LAI ; Liping XIAO ; Liping HE ; Lizhen LAI
Modern Clinical Nursing 2025;24(6):41-48
Objective To develop and evaluate a standardised nursing protocol for multidisciplinary team surgery assisted by a da Vinci surgical system based on systems management theory.Methods With the systems management theory,a nursing protocol was developed for multidisciplinary team surgery assisted by a da Vinci surgical system.Convenience sampling was employed to select 100 patients who received surgery assisted by a da Vinci surgical system between October 2022 and September 2023 at a Tire-ⅢA hospital in Longyan.The patients received the surgery between October 2022 and April 2023(n=50)were assigned to the control group,and those between May 2023 and September 2023(n=50)were assigned to the trial group.The patients in the control group received routine nursing care,while those in the trial group received a standardised nursing protocol for multidisciplinary team surgery assisted by a da Vinci surgical system based on systems management theory.Preoperative preparation time,setup time for surgery,surgical time,time of hospital stay,ICU admission rate,rate of surgical complication,and scores of satisfaction from medical staff and patients were compared between the two groups.Results Patients in trial group had a shorter time in preoperative preparation and setup than those in the control group(both P<0.001),However,there was no significant difference in surgical time(P>0.05).Patients in the trial group had shorter time of hospital stay,fewer ICU admission and a lower surgical complication rate(all P<0.05),and with higher satisfaction scores from patients,nurses and surgeons(all P<0.001).Conclusion The developed nursing protocol for the multidisciplinary team surgery assisted by a da Vinci surgical system is scientific.It improves surgical efficiency,patient safety and satisfaction among patients,surgeons and nurses.
6.Characteristics of cardiopulmonary exercise testing and analysis of risk factors for decreased aerobic capacity in children with non-acute bronchial asthma exacerbations
Pengli WANG ; Lizhen HUANG ; Wujun JIANG ; Wenjing GU ; Lina XU ; Pengyun LI ; Xuena XU ; Qianying YU ; Xiaoyan SHI ; Chuangli HAO
Chinese Journal of Applied Clinical Pediatrics 2025;40(8):595-602
Objective:To investigate the characteristics of cardiopulmonary exercise testing and risk factors for decreased aerobic capacity in children with non-acute asthma exacerbations, to assess their cardiopulmonary health and to provide a basis for improvement.Methods:A case-control study.Sixty-one children with non-acute asthma exacerbations treated at the Outpatient Department of Children′s Hospital of Soochow University from October 2022 to December 2023 and 22 control children during the same period were included.Binary Logistic regression was employed to assess risk factors for decreased aerobic capacity in children with asthma.Results:Among the included 61 children with non-acute asthma exacerbations, there were 33 cases in the chronic persistent phase (chronic persistent phase group) and 28 in the clinical remission phase(clinical remission group).There were 22 children in the control group.During the peak exercise phase of the cardiopulmonary exercise testing, the mean kilogram body weight oxygen uptake (VO 2/kg), the percentage of predicted kilogram body weight oxygen uptake, and metabolic equivalents (Met) in the chronic persistent phase group were lower than those in the control and clinical remission phase groups.The mean VO 2/kg recovery from the cardiopulmonary exercise testing in the first minute in the chronic persistent phase group was lower than that in the control and clinical remission phase groups.The median Met and ventilation per minute recovery in the chronic persistent phase group were lower than those in the control group.The median heart rate recovery in asthma children was lower than that in control children.The percentage of cardiopulmonary exercise testing abnormalities was higher in asthma children with symptoms after excise than that in asthma children without symptoms after excise.The percentage of decreased ventilation efficiency in asthma children with symptoms after excise was higher than that in asthma children without symptoms after excise.Multivariate regression analysis showed that a higher body mass index (BMI) ( OR=1.577, 95% CI: 1.113-2.235, P=0.010) and a higher peak respiratory reserve ( OR=1.103, 95% CI: 1.018-1.195, P=0.017) were risk factors of decreased aerobic capacity.The risk of decreased aerobic capacity in the chronic persistent phase was 7.949 times higher than that in the clinical remission phase ( OR=7.949, 95% CI: 1.290-48.996, P=0.025). Conclusions:The aerobic capacity is decreased and ventilatory recovery is slower in children with chronic persistent asthma than those in healthy children.The heart rate recovery in asthma children is slower than that in healthy children.A high BMI, a high peak respiratory reserve, and chronic persistence of asthma are independent risk factors for decreased aerobic capacity in children with non-acute asthma exacerbations.asthma.
7.Development and application of a standardised nursing protocol for multidisciplinary team surgery assisted by da Vinci surgical system based on systems management theory
Liping WANG ; Mengting XIE ; Zifang LAI ; Liping XIAO ; Liping HE ; Lizhen LAI
Modern Clinical Nursing 2025;24(6):41-48
Objective To develop and evaluate a standardised nursing protocol for multidisciplinary team surgery assisted by a da Vinci surgical system based on systems management theory.Methods With the systems management theory,a nursing protocol was developed for multidisciplinary team surgery assisted by a da Vinci surgical system.Convenience sampling was employed to select 100 patients who received surgery assisted by a da Vinci surgical system between October 2022 and September 2023 at a Tire-ⅢA hospital in Longyan.The patients received the surgery between October 2022 and April 2023(n=50)were assigned to the control group,and those between May 2023 and September 2023(n=50)were assigned to the trial group.The patients in the control group received routine nursing care,while those in the trial group received a standardised nursing protocol for multidisciplinary team surgery assisted by a da Vinci surgical system based on systems management theory.Preoperative preparation time,setup time for surgery,surgical time,time of hospital stay,ICU admission rate,rate of surgical complication,and scores of satisfaction from medical staff and patients were compared between the two groups.Results Patients in trial group had a shorter time in preoperative preparation and setup than those in the control group(both P<0.001),However,there was no significant difference in surgical time(P>0.05).Patients in the trial group had shorter time of hospital stay,fewer ICU admission and a lower surgical complication rate(all P<0.05),and with higher satisfaction scores from patients,nurses and surgeons(all P<0.001).Conclusion The developed nursing protocol for the multidisciplinary team surgery assisted by a da Vinci surgical system is scientific.It improves surgical efficiency,patient safety and satisfaction among patients,surgeons and nurses.
8.Research on the Factors Influencing the Evolution of COPD Qi Deficiency Syndrome Based on Nonlinear Mixed Effects Model
Weike LI ; Mingyang YI ; Yuanyuan NI ; Lizhen YAN ; Jianxin GUAN ; Shihao WANG ; Huijie WANG ; Jiansheng LI ; Zhiwan WANG
World Science and Technology-Modernization of Traditional Chinese Medicine 2025;27(8):2205-2214
Objective To provide methodological examples for related research,the influencing factors of the evolution of Qi deficiency syndrome in chronic obstructive pulmonary disease(COPD)based on a nonlinear mixed effects model was explored.Methods A research questionnaire on the influencing factors of the evolution of Qi deficiency syndrome in chronic obstructive pulmonary disease was developed,and clinical data of 650 COPD patients on the 1st and 14th day of acute exacerbation,the 1st and 28th day of risk window,the first day of stable period,and the 90th day were dynamically collected from 10 tertiary hospitals across the country.8 baseline data including gender and age were collected through the PROC NLMIXED process by SAS 9.4 software.Coronary heart disease,diabetes and hypertension accounted for the highest proportion.Nine concurrent syndromes including wind cold syndrome and phlegm heat syndrome were used as fixed effects,and individual level was used as random effects to gradually fit the model and screen the influencing factors of Qi deficiency syndrome in the entire process of disease occurrence and development.Results A total of 637 eligible cases were included,and clinical datas were dynamically collected on the 1st and 14th day of acute exacerbation,the 1st and 28th day of the risk window,the 1st and 90th day of the stable period.It was found that the number of acute exacerbations,alcohol consumption,concomitant hypertension,coronary heart disease,blood stasis syndrome,yin deficiency syndrome,yang deficiency syndrome,6-minute walking distance,and the modified Medical Research Council Dyspnea Questionnaire(mMRC)had an impact on the evolution of Qi deficiency syndrome in the previous year(P<0.05).Conclusion The use of a nonlinear mixed effects model revealed the relevant factors affecting the evolution of Qi deficiency syndrome from complex multi temporal dynamic data,providing methodological references for other related studies.
9.Study on Graded Quantitative Diagnosis of Lung Qi Deficiency Syndrome in Chronic Obstructive Pulmonary Disease Based on Latent Class Analysis Combined with Hidden Structure Model
Weike LI ; Mingyang YI ; Yuanyuan NI ; Lizhen YAN ; Jianxin GUAN ; Shihao WANG ; Huijie WANG ; Zhiwan WANG
Journal of Traditional Chinese Medicine 2025;66(7):710-716
ObjectiveTo clarify the graded quantitative diagnostic characteristics of lung qi deficiency syndrome in chronic obstructive pulmonary disease (COPD) based on latent class analysis combined with a hidden structure model. MethodsClinical data, including the four diagnostic methods of traditional Chinese medicine (TCM), were collected from 745 COPD patients with lung qi deficiency syndrome. Latent class modeling was performed using R 4.1.2 software, and each patient was classified into one of three severity categories (mild, moderate, or severe) based on probabilistic parameterization, parameter estimation, and model fitting. A database was established for different severity levels of lung qi deficiency syndrome. Based on this, Lantern 5.0 software was used to construct hidden structure models for mild, moderate, and severe lung qi deficiency syndrome, and syndrome differentiation rules were developed through comprehensive clustering. ResultsA latent class model was constructed using 28 symptoms and signs with a frequency greater than 10%. Considering TCM theory and model simplicity, the optimal model was determined when the number of latent classes was three, categorizing lung qi deficiency syndrome into mild (298 cases), moderate (164 cases), and severe (283 cases). Hidden structure models were separately developed for each severity level, and syndrome differentiation rules were established. A comparison of common symptoms in the syndrome differentiation rules for mild and moderate lung qi deficiency syndrome showed no statistically significant differences in diagnostic values and weights (P>0.05), leading to their combined analysis and the development of a unified syndrome differentiation rule. Value and weight of quantitative diagnosis of mild-to-moderate lung qi deficiency syndrome were as followed: shortness of breath (diagnostic value 9.3, diagnostic weight 86.92%), dyspnea on exertion (8.2, 76.64%), low voice and reluctance to speak (6.7, 62.62%), poor appetite (4.0, 37.38%), loose stools (4.0, 37.38%), weak cough sound (2.9, 27.10%), wheezing (2.3, 21.50%), fatigue (1.8, 16.82%), spontaneous sweating (1.7, 15.89%), susceptibility to colds (1.6, 14.95%), swollen tongue (1.4, 13.08%), teeth marks on the tongue edge (1.2, 11.21%), deep pulse (1.6, 14.95%), with a diagnostic threshold of 10.3. Value and weight of quantitative diagnosis of severe lung qi deficiency syndrome were as followed: weak cough sound (15.1, 61.13%), soreness and weakness of the waist and knees (12.6, 51.01%), shortness of breath (11.1, 44.94%), low voice and reluctance to speak (8.3, 33.60%), frequent nocturia (6.1, 24.70%), spontaneous sweating (3.7, 14.98%), susceptibility to colds (3.5, 14.17%), teeth marks on the tongue edge (7.8, 31.58%), pale tongue body (1.9, 7.69%), white tongue coating (5.5, 22.27%), thin pulse (1.5, 6.07%), with a diagnostic threshold of 23.7. ConclusionThe combination of latent class analysis and a hideen structure model effectively clarified the graded quantitative diagnostic characteristics of lung qi deficiency syndrome, providing a reference for the quantitative diagnosis of other fundamental syndromes in TCM.
10.Characteristics of cardiopulmonary exercise testing and analysis of risk factors for decreased aerobic capacity in children with non-acute bronchial asthma exacerbations
Pengli WANG ; Lizhen HUANG ; Wujun JIANG ; Wenjing GU ; Lina XU ; Pengyun LI ; Xuena XU ; Qianying YU ; Xiaoyan SHI ; Chuangli HAO
Chinese Journal of Applied Clinical Pediatrics 2025;40(8):595-602
Objective:To investigate the characteristics of cardiopulmonary exercise testing and risk factors for decreased aerobic capacity in children with non-acute asthma exacerbations, to assess their cardiopulmonary health and to provide a basis for improvement.Methods:A case-control study.Sixty-one children with non-acute asthma exacerbations treated at the Outpatient Department of Children′s Hospital of Soochow University from October 2022 to December 2023 and 22 control children during the same period were included.Binary Logistic regression was employed to assess risk factors for decreased aerobic capacity in children with asthma.Results:Among the included 61 children with non-acute asthma exacerbations, there were 33 cases in the chronic persistent phase (chronic persistent phase group) and 28 in the clinical remission phase(clinical remission group).There were 22 children in the control group.During the peak exercise phase of the cardiopulmonary exercise testing, the mean kilogram body weight oxygen uptake (VO 2/kg), the percentage of predicted kilogram body weight oxygen uptake, and metabolic equivalents (Met) in the chronic persistent phase group were lower than those in the control and clinical remission phase groups.The mean VO 2/kg recovery from the cardiopulmonary exercise testing in the first minute in the chronic persistent phase group was lower than that in the control and clinical remission phase groups.The median Met and ventilation per minute recovery in the chronic persistent phase group were lower than those in the control group.The median heart rate recovery in asthma children was lower than that in control children.The percentage of cardiopulmonary exercise testing abnormalities was higher in asthma children with symptoms after excise than that in asthma children without symptoms after excise.The percentage of decreased ventilation efficiency in asthma children with symptoms after excise was higher than that in asthma children without symptoms after excise.Multivariate regression analysis showed that a higher body mass index (BMI) ( OR=1.577, 95% CI: 1.113-2.235, P=0.010) and a higher peak respiratory reserve ( OR=1.103, 95% CI: 1.018-1.195, P=0.017) were risk factors of decreased aerobic capacity.The risk of decreased aerobic capacity in the chronic persistent phase was 7.949 times higher than that in the clinical remission phase ( OR=7.949, 95% CI: 1.290-48.996, P=0.025). Conclusions:The aerobic capacity is decreased and ventilatory recovery is slower in children with chronic persistent asthma than those in healthy children.The heart rate recovery in asthma children is slower than that in healthy children.A high BMI, a high peak respiratory reserve, and chronic persistence of asthma are independent risk factors for decreased aerobic capacity in children with non-acute asthma exacerbations.asthma.

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