1.Ershen Zhenwu Decoction Treats Chronic Heart Failure by Regulating miR-423-5p/Smad7/TGF-β1/Smads Axis and Myocardial Fibrosis Indicators
Lan GE ; Zhenpeng ZHU ; Xinyue WANG ; Dan CHENG ; Yulong LIU ; Maomao ZHANG ; Xiaoyu CHENG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):157-165
ObjectiveTo investigate the clinical effect of Ershen Zhenwu Decoction on chronic heart failure (CHF) due to heart-kidney Yang deficiency and blood stasis and its regulatory effects on miR-423-5p/Smad7/transforming growth factor-β1 (TGF-β1)/Smads axis and myocardial fibrosis indicators. MethodsOne hundred and fourteen patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with mildly reduced ejection fraction (HFmrEF) were randomly allocated into a control group and an observation group. The control group was treated with dapagliflozin tablets, sacubitril-valsartan sodium tablets, metoprolol succinate, and spironolactone, and the observation group was treated with Ershen Zhenwu Decoction on the basis of the therapy in the control group. The course of treatment was 8 weeks in both groups. The 6-min walking distance, New York Heart Association (NYHA) heart function grade, Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, N-terminal pro-B-type natriuretic peptide (NT-proBNP), angiotensin Ⅱ (Ang Ⅱ), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVIDd), left ventricular end-systolic diameter (LVIDs), interventricular septum thickness at diastole (IVSd), left ventricular end-diastolic posterior wall thickness (LVPWd), left ventricular shortening fraction (FS), miR-423-5p, Smad7, Smad2, Smad3, Smad4, TGF-β1, Ang Ⅱ, type Ⅰ collagen (Col Ⅰ), type Ⅲ collagen (Col Ⅲ), mRNA levels of fibronectin (Fn) and α-smooth muscle actin (α-SMA) in the myocardial tissue were observed before and after treatment in both groups to evaluate the efficacy of cardiac function and drug safety. ResultsAfter treatment, both groups showed declined levels of NT-proBNP, Ang Ⅱ, miR-423-5p, Smad2, Smad3, Smad4, TGF-β1, Col Ⅰ, Col Ⅲ, and mRNA levels of Fn and α-SMA (P0.05), and the levels of the indicators above were lower in the observation group than in the control group (P0.05). After treatment, the Smad7 level increased obviously in both groups (P0.05) and was higher in the observation group than in the control group (P0.05). After treatment, both groups showed decreased MLHFQ scores and increased 6-min walking distance (P0.05), and the observation group had lower MLHFQ score and longer 6-min walking distance than the control group (P0.05). After treatment, the control group showed increased LVEF and FS (P0.05) and the observation group showcased decreased LVIDd and LVIDs and increased LVEF and FS (P0.05). Moreover, the observation group had lower LVIDd and LVIDs (P0.05) and higher LVEF and FS (P0.05) than the control group. The total response rate of cardiac function in the observation group was 90.38% (47/52), which was higher than that (70.59%, 36/51) in the control group (P0.05). No adverse reactions associated with Ershen Zhenwu Decoction were observed during the study period. ConclusionErshen Zhenwu Decoction can improve the cardiac function, exercise tolerance, and quality of life, regulate neuroendocrine factors, and slow down/reverse myocardial remodeling in the patients with HFrEF and HFmrEF (syndrome of heart-kidney Yang deficiency and blood stasis by regulating the miR-423-5p/Smad7/TGF-β1/Smads axis, inhibiting α-SMA and Fn expression, and alleviating myocardial fibrosis. It is worthy of further study.
2.Analysis of Animal Models of Retinitis Pigmentosa Based on Diagnostic Features of Chinese and Western Medicine
Xiaoyu LI ; Lina LIANG ; Jiefeng CHEN ; Xiaoxiao ZHU ; Yina QI
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):198-203
Retinitis pigmentosa (RP) is the most common hereditary blinding eye disease in clinical practice, with the pathogenesis remaining unclear. Patients experience progressive apoptosis of retinal photoreceptor cells, accompanied by degeneration of retinal pigment epithelium (RPE) cells. Current Western medical treatments mainly focus on gene therapy and stem cell transplantation, showing limited efficacy. In contrast, clinical observations have confirmed the therapeutic effects of traditional Chinese medicine (TCM) treatments. Establishing an RP animal model that aligns with the diagnostic features of both TCM and Western medicine could help combine the strengths of both approaches, thereby broadening the treatment options for RP. This study categorizes and summarizes the existing RP animal models in terms of classification, types, inheritance patterns, and alignment with clinical manifestations. It is found that current RP models are primarily derived from natural animal models such as RD mice and RCS rats, transgenic animal models like RPE-65 knockout mice and rhodopsin gene knockout mice, and chemically induced models such as those created by monochromatic light exposure or N-ethyl-N-nitrosourea (ENU) administration. These three categories of models focus more on detecting RP-related histopathological, molecular biological, and cellular immunological indicators, but offer limited observation of the overall characteristics of the disease and lack insight into syndrome differentiation. Although RP is a congenital genetic disease, its progression is influenced by acquired factors such as environment, constitution, emotions, and care. Current models do not fully capture the characteristics of this disease. Therefore, establishing an RP animal model based on the diagnostic features of both TCM and Western medicine will have significant implications for future experimental and clinical research.
3.Ershen Zhenwu Decoction Treats Chronic Heart Failure by Regulating miR-423-5p/Smad7/TGF-β1/Smads Axis and Myocardial Fibrosis Indicators
Lan GE ; Zhenpeng ZHU ; Xinyue WANG ; Dan CHENG ; Yulong LIU ; Maomao ZHANG ; Xiaoyu CHENG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):157-165
ObjectiveTo investigate the clinical effect of Ershen Zhenwu Decoction on chronic heart failure (CHF) due to heart-kidney Yang deficiency and blood stasis and its regulatory effects on miR-423-5p/Smad7/transforming growth factor-β1 (TGF-β1)/Smads axis and myocardial fibrosis indicators. MethodsOne hundred and fourteen patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with mildly reduced ejection fraction (HFmrEF) were randomly allocated into a control group and an observation group. The control group was treated with dapagliflozin tablets, sacubitril-valsartan sodium tablets, metoprolol succinate, and spironolactone, and the observation group was treated with Ershen Zhenwu Decoction on the basis of the therapy in the control group. The course of treatment was 8 weeks in both groups. The 6-min walking distance, New York Heart Association (NYHA) heart function grade, Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, N-terminal pro-B-type natriuretic peptide (NT-proBNP), angiotensin Ⅱ (Ang Ⅱ), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVIDd), left ventricular end-systolic diameter (LVIDs), interventricular septum thickness at diastole (IVSd), left ventricular end-diastolic posterior wall thickness (LVPWd), left ventricular shortening fraction (FS), miR-423-5p, Smad7, Smad2, Smad3, Smad4, TGF-β1, Ang Ⅱ, type Ⅰ collagen (Col Ⅰ), type Ⅲ collagen (Col Ⅲ), mRNA levels of fibronectin (Fn) and α-smooth muscle actin (α-SMA) in the myocardial tissue were observed before and after treatment in both groups to evaluate the efficacy of cardiac function and drug safety. ResultsAfter treatment, both groups showed declined levels of NT-proBNP, Ang Ⅱ, miR-423-5p, Smad2, Smad3, Smad4, TGF-β1, Col Ⅰ, Col Ⅲ, and mRNA levels of Fn and α-SMA (P0.05), and the levels of the indicators above were lower in the observation group than in the control group (P0.05). After treatment, the Smad7 level increased obviously in both groups (P0.05) and was higher in the observation group than in the control group (P0.05). After treatment, both groups showed decreased MLHFQ scores and increased 6-min walking distance (P0.05), and the observation group had lower MLHFQ score and longer 6-min walking distance than the control group (P0.05). After treatment, the control group showed increased LVEF and FS (P0.05) and the observation group showcased decreased LVIDd and LVIDs and increased LVEF and FS (P0.05). Moreover, the observation group had lower LVIDd and LVIDs (P0.05) and higher LVEF and FS (P0.05) than the control group. The total response rate of cardiac function in the observation group was 90.38% (47/52), which was higher than that (70.59%, 36/51) in the control group (P0.05). No adverse reactions associated with Ershen Zhenwu Decoction were observed during the study period. ConclusionErshen Zhenwu Decoction can improve the cardiac function, exercise tolerance, and quality of life, regulate neuroendocrine factors, and slow down/reverse myocardial remodeling in the patients with HFrEF and HFmrEF (syndrome of heart-kidney Yang deficiency and blood stasis by regulating the miR-423-5p/Smad7/TGF-β1/Smads axis, inhibiting α-SMA and Fn expression, and alleviating myocardial fibrosis. It is worthy of further study.
4.Analysis of Animal Models of Retinitis Pigmentosa Based on Diagnostic Features of Chinese and Western Medicine
Xiaoyu LI ; Lina LIANG ; Jiefeng CHEN ; Xiaoxiao ZHU ; Yina QI
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(3):198-203
Retinitis pigmentosa (RP) is the most common hereditary blinding eye disease in clinical practice, with the pathogenesis remaining unclear. Patients experience progressive apoptosis of retinal photoreceptor cells, accompanied by degeneration of retinal pigment epithelium (RPE) cells. Current Western medical treatments mainly focus on gene therapy and stem cell transplantation, showing limited efficacy. In contrast, clinical observations have confirmed the therapeutic effects of traditional Chinese medicine (TCM) treatments. Establishing an RP animal model that aligns with the diagnostic features of both TCM and Western medicine could help combine the strengths of both approaches, thereby broadening the treatment options for RP. This study categorizes and summarizes the existing RP animal models in terms of classification, types, inheritance patterns, and alignment with clinical manifestations. It is found that current RP models are primarily derived from natural animal models such as RD mice and RCS rats, transgenic animal models like RPE-65 knockout mice and rhodopsin gene knockout mice, and chemically induced models such as those created by monochromatic light exposure or N-ethyl-N-nitrosourea (ENU) administration. These three categories of models focus more on detecting RP-related histopathological, molecular biological, and cellular immunological indicators, but offer limited observation of the overall characteristics of the disease and lack insight into syndrome differentiation. Although RP is a congenital genetic disease, its progression is influenced by acquired factors such as environment, constitution, emotions, and care. Current models do not fully capture the characteristics of this disease. Therefore, establishing an RP animal model based on the diagnostic features of both TCM and Western medicine will have significant implications for future experimental and clinical research.
5.The development process, research status, and prospect of physical ablation in the treatment of chronic obstructive pulmonary disease
Xiaoyu ZHOU ; Yirong AN ; Ran JU ; Haoze LENG ; Shiran TAO ; Jiawei TIAN ; Ming' ; e WU ; Haoyang ZHU ; Yi LÜ ; ; Nana ZHANG
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2026;33(04):646-651
Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory disease around the world, and pharmacotherapy is the foremost treatment method currently. In recent decades, with the rapid development of bronchoscopic interventional therapy, endoscopic physical ablation technology presents a therapeutic effect in treating COPD, with few treatment-related side effects, showing excellent application prospects in treating COPD. Since ablation techniques in this field are emerging technologies with low patient acceptance, they are not widely used in the clinical treatment of COPD. This article reviews the development process of physical ablation techniques. Moreover, their current application status and the prospects in the field of COPD treatment are also summarized and analyzed. We hope to promote the application of physical ablation in the clinical treatment of COPD and provide practical references and a theoretical basis for the clinical treatment of COPD.
6.LI Guolie's Experience in Treating Orthostatic Hypotension from the Perspective of "Raising the Clear and Directing the Turbid Downward"
Zhihui JIN ; Yanjie JIANG ; Wenshan LI ; Xiaoyu ZHU ; Yan LU ;
Journal of Traditional Chinese Medicine 2026;67(9):941-945
This paper summarizes professor LI Guolie's clinical experience in treating orthostatic hypotension (OH) based on the theory of "raising the clear and directing the turbid downward". It is considered that the core pathogenesis of OH lies in the body's transition from a supine to an upright position, during which dysfunction of the middle jiao (焦) transformation and transportation, along with impaired pivot function, hinders the ascending of clear yang and the descending of turbid yin. Treatment should follow the general principle of "ascending the clear and directing the turbid downward", placing emphasis on distinguishing the primary and secondary aspects. For cases where the clear yang fails to ascend, the self-formulated Li's Shengqing Jiangzhuo Decoction (李氏升清降浊汤)is used to supplement qi, raise the clear, and strengthen the middle jiao. For cases where the turbid yin fails to descend, the self-formulated Wuxiang Qingzhuo Beverage(五香清浊饮)with modifications is applied to resolve phlegm, eliminate stasis, harmonize the middle, and descend the turbid.
7.LI Guolie's Experience in Treating Orthostatic Hypotension from the Perspective of "Raising the Clear and Directing the Turbid Downward"
Zhihui JIN ; Yanjie JIANG ; Wenshan LI ; Xiaoyu ZHU ; Yan LU ;
Journal of Traditional Chinese Medicine 2026;67(9):941-945
This paper summarizes professor LI Guolie's clinical experience in treating orthostatic hypotension (OH) based on the theory of "raising the clear and directing the turbid downward". It is considered that the core pathogenesis of OH lies in the body's transition from a supine to an upright position, during which dysfunction of the middle jiao (焦) transformation and transportation, along with impaired pivot function, hinders the ascending of clear yang and the descending of turbid yin. Treatment should follow the general principle of "ascending the clear and directing the turbid downward", placing emphasis on distinguishing the primary and secondary aspects. For cases where the clear yang fails to ascend, the self-formulated Li's Shengqing Jiangzhuo Decoction (李氏升清降浊汤)is used to supplement qi, raise the clear, and strengthen the middle jiao. For cases where the turbid yin fails to descend, the self-formulated Wuxiang Qingzhuo Beverage(五香清浊饮)with modifications is applied to resolve phlegm, eliminate stasis, harmonize the middle, and descend the turbid.
8.Role of IL-17A in acute inhalational pneumonia caused by highly virulent and multidrug-resistant Staphylococcus aureus
Qi KUANG ; Xiaoyu ZHU ; Lu LI ; Xueyan WANG ; Peijie YAN ; Lili ZHANG ; Meng LÜ ; Lingfei HU ; Dongsheng ZHOU ; Wenhui YANG
Acta Universitatis Medicinalis Anhui 2026;61(4):599-605
ObjectiveTo investigate the role of interleukin (IL)-17A in acute inhalational pneumonia induced by the highly drug-resistant and hypervirulent Staphylococcus aureus strain USA300-R in mice. MethodsAn acute inhalational pneumonia model was established in mice using an aerosolized pulmonary delivery technique. RNA sequencing (RNA-seq) and enzyme-linked immunosorbent assay (ELISA) were employed to examine the expression dynamics of Il17a mRNA and IL-17A protein, respectively, in the lungs of infected mice. Il17a knockout (Il17a-/-) mice were generated using CRISPR/Cas9 gene editing technology. The survival rate, body weight, bacterial load in lung tissue, and histopathological changes were compared between Il17a-/- and wild-type (WT) mice following inhalational infection with USA300-R. Results12 hours after USA300-R infection, compared to pre-infection, the expression level of Il17a mRNA in lung tissue and the level of IL-17A protein in bronchoalveolar lavage fluid (BALF) increased by approximately 50-fold (P<0.01) and 6-fold (P<0.001), respectively. Compared to WT mice, Il17a-/- mice exhibited approximately 10-fold higher bacterial loads in lung tissue at both 12 and 24 hours post-infection (P<0.001, P<0.05). However, they showed significantly attenuated lung histopathological injury, reduced alveolar wall thickening, markedly decreased neutrophil infiltration, and an approximately 50% improvement in survival rate (P<0.05). ConclusionIn acute Staphylococcus aureus USA300-R inhalational pneumonia, IL-17A contributes to bacterial clearance by recruiting neutrophils; however, excessive neutrophil infiltration exacerbates pulmonary inflammation and injury, reduces survival rates, and represents a potential therapeutic target.
9.Pathological changes and macrophage polarization in the liver and spleen of mice infected with Angiostrongylus cantonensis
Xiaoyu QIN ; Yuchun CAI ; Yang HONG ; Fanna WEI ; Yahong HU ; Yumeng CAI ; Yuan HU ; Ting ZHANG ; Xiaojin MO ; Bin XU ; Yan LU ; Jiahui SUN ; Yan ZHOU ; Zelin ZHU ; Muxin CHEN
Chinese Journal of Schistosomiasis Control 2026;38(2):169-183
Objective To investigate the temporal changes in pathological damage and macrophage polarization in liver and spleen tissues of mice infected with Angiostrongylus cantonensis, and to preliminarily unravel the peripheral immune responses during the early stage of A. cantonensis infection. Methods Forty female BALB/c mice at ages of 6 to 8 weeks were randomly divided into four groups, including the control group and 7-, 14-, and 21-day infection groups, with 10 mice in each group. Each mouse in the infection groups was inoculated with 30 third-stage (L3) larvae of A. cantonensis by oral gavage, and five mice were randomly selected from each infection group on days 7, 14, and 21 post-infection, while mice in the control group were given the same volume of physiological saline and five mice were randomly selected from the control group on the day of oral gavage. Mouse liver and spleen tissues were sampled. The histopathological changes of mouse liver and spleen tissues were observed using hematoxylin and eosin (HE) staining, and the percentage of positive staining area and the co-localization positive rates of the macrophage surface antigens F4/80, CD86, and CD206 were quantified in mouse liver and spleen tissues using immunohistochemical and immunofluorescence staining. In addition, five mice were collected from each infection group on days 7, 14, and 21 post-infection, and five mice were collected from the control group on the day of oral gavage. Mouse liver and spleen tissues were sampled for detection of macrophage markers CD86 and CD206 and macrophage phenotyping using flow cytometry, and the expression of M1 macrophage markers, including inducible nitric oxide synthase (Nos2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and M2 markers, including arginase 1 (Arg1), mannose receptor C-type 1 (Mrc1) and chitinase-like protein 3 (Chil3) was quantified in mouse liver and spleen tissues using real-time quantitative PCR (RT-qPCR) assay. Results Proliferative lesions of the hepatocyte were observed in mouse liver tissues and the follicular structures of the mouse spleen white pulp were disrupted 21 days post-infection with A. cantonensis. Immunohistochemical staining showed that there were significant differences in the percentages of F4/80, CD86 and CD206 positive staining areas in the liver and spleen tissues among the four groups of mice (F = 242.40, 197.14, 183.19, 157.65, 242.35 and 146.24; all P values < 0.001), and the percentages of positive staining in the liver and spleen tissues of mice in the 14-day infection group [(4.45 ± 0.51)%, (3.74 ± 0.67)%, (8.32 ± 0.72)%, (16.56 ± 1.14)%, (11.62 ± 0.52)%, and (8.29 ± 0.72)%, respectively] and the 21-day infection group [(3.70 ± 0.11)%, (3.22 ± 0.43)%, (11.53 ± 1.03)%, (12.59 ± 1.05)%, (9.02 ± 0.83)%, and (11.67 ± 1.10)%, respectively] were higher than in the control group [(0.35 ± 0.16)%, (0.40 ± 0.02)%, (0.93 ± 0.05)%, (2.78 ± 0.26)%, (2.33 ± 0.20)%, and (1.85 ± 0.20)%, respectively] (all P values < 0.05). Immunofluorescence staining showed significant differences in the positive rates of F4/80 co-localization with CD86 and CD206 in mouse liver and spleen tissues among the four groups (F = 24.42, 25.28, 54.51 and 130.55; all P values < 0.001). Flow cytometry detected significant differences in the proportions of CD86+ and CD206+ macrophages in mouse liver and spleen tissues among the four groups (F = 67.98, 18.41, 29.77, 172.80; all P values < 0.001), and the proportions of CD206+ macrophages in the liver and spleen of the 21-day infection group were significantly higher than those in the control group [(9.25 ± 2.55)% vs (3.83 ± 0.72)%, and (4.22 ± 0.56)% vs (0.47 ± 0.18)%, respectively] (both P values < 0.05). In addition, RT-qPCR assay quantified significant differences in the relative mRNA expression of M1 macrophage markers (IL-1β, TNF-α and Nos2) and M2 macrophage markers (Arg1, Chil3 and Mrc1) in mouse liver and spleen tissues among the four groups (F = 41.30, 31.82, 199.33, 19.96, 62.01, 119.76, 23.67, 95.90, 72.27, 82.59, 123.41 and 29.75; all P values < 0.05). Conclusions A. cantonensis infection may cause progressive pathological damage in mouse liver and spleen tissues, accompanied by dynamic temporal changes in macrophage polarization. M1 macrophage polarization predominates at the early stage of A. cantonensis infection and shifts towards M2 polarization at the later stages, suggesting that M2 polarization may participate in immune regulation at late stages of A. cantonensis infection by suppressing excessive inflammatory responses and promoting tissue repair.
10.Rules of moxibustion for low back pain by ZHOU Meisheng based on data mining and knowledge graph technology.
Chi WANG ; Caifeng ZHU ; Jiayu ZHANG ; Bingyuan ZHOU ; Xiaoyu CHEN ; Le CHENG ; Miaomiao XIE ; Xuechun DING
Chinese Acupuncture & Moxibustion 2025;45(6):823-833
OBJECTIVE:
To analyze the rules of moxibustion for low back pain by ZHOU Meisheng by using data mining and knowledge graph technology.
METHODS:
Taking the medical cases of moxibustion for low back pain from ZHOU Meisheng's legacy manuscripts and existing works as the research objects, information on disease types, symptoms, tongue manifestations, pulse conditions, syndrome patterns, moxibustion methods and acupoints were collected. Frequency statistics and community analysis were conducted by the ancient and modern medical record cloud platform V 2.3.7, cluster analysis of high-frequency acupoints was performed by SPSS26.0, association rule analysis of high-frequency acupoints was performed by SPSS Modeler 18.0, and the generated linked data were imported into Cytoscape 3.9.1 for complex network analysis. Knowledge graph of moxibustion for low back pain by ZHOU Meisheng was constructed based on the results of data mining. The data storage and display of knowledge graph were realized through the Neo4j 3.5.25 graph database, and the Cypher query language was used for knowledge graph retrieval and discovery.
RESULTS:
A total of 219 medical cases were collected, involving 14 disease types, 85 related clinical symptoms, 5 related TCM syndrome types, and 6 moxibustion methods. The acupoints were mostly attributed to the governor vessel, the bladder meridian of foot-taiyang, non-meridian and non-acupoint areas. The core prescription of acupoints derived from complex network analysis included tender points, Shenshu (BL23), Jinsuo (GV8), Yinjiao (CV7), Yaoyangguan (GV3), Yanglingquan (GB34), which were largely coincides with high-frequency acupoints. Cluster analysis obtained 4 cluster combinations. Community analysis yielded 6 communities, each corresponding to different acupoints.The constructed knowledge graph contained 187 nodes and 696 relationships, by retrieving clinical elements related to low back pain, the disease-moxibustion association graph, disease-acupoint association graph, accompanying symptom-acupoint association graph and syndrome type-matching point association graph were obtained.
CONCLUSION
When treating low back pain with moxibustion, ZHOU Meisheng adopts the principle of promoting circulation, distinguishing diseases to determine the treatment, selecting acupoints according to the diseases, and matching points according to the symptoms.And taking tender points, Shenshu (BL23), Jinsuo (GV8), Yinjiao (CV7), Yaoyangguan (GV3), Yanglingquan (GB34) as core acupoints, combined with tenderness point selection, acupoint selection based on meridian and zangfu syndrome differentiation, "sunshine area" acupoint selection, yin-yang acupoint matching. Additionally, he skillfully employs special points, such as Zhongzhu (KI15) and ear tips, pays attention to the reform of moxibustion tools, and innovates the moxibustion techniques, using distinctive moxibustion tools and methods to treat low back pain.
Moxibustion/methods*
;
Humans
;
Data Mining
;
Low Back Pain/history*
;
Acupuncture Points
;
History, Ancient
;
Female
;
China
;
Male
;
Adult
;
Middle Aged

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