1.Efficacy and safety analysis of Wuling capsules combined with fluoxetine in the treatment of adolescents with first-episode moderate-to-severe depressive disorder accompanied by insomnia
Lian HE ; Yanping SHU ; Yuan YUN ; Yun MO ; Qian ZHANG
China Pharmacy 2026;37(4):456-461
OBJECTIVE To investigate the efficacy and safety of Wuling capsules combined with fluoxetine in the treatment of adolescents with first-episode moderate-to-severe depressive disorder accompanied by insomnia. METHODS The clinical data of 476 adolescents with first-episode moderate-to-severe depression accompanied by insomnia admitted to our hospital from June 2022 to May 2025, were retrospectively collected. According to the initial treatment regimen, patients were divided into a control group (241 cases, treated with fluoxetine alone) and an observation group (235 cases, treated with Wuling capsules combined with fluoxetine). The depression severity (Hamilton Depression Rating Scale-17 Item and the Self-Rating Depression Scale scores), sleep quality (Pittsburgh Sleep Quality Index score, sleep latency, wake after sleep onset, total sleep time, sleep efficiency), serum neuroendocrine indicator (cortisol) and inflammatory markers (C-reactive protein, interleukin-6) were compared between the two groups before treatment and at 4th and 8th weeks of treatment. The effective rate at 8th weeks and the occurrence of adverse drug reactions (ADRs) were also compared between the two groups. RESULTS Before treatment, there were no significant differences in depression severity, sleep quality, serum neuroendocrine indicator, and inflammatory markers between the two groups ( P >0.05). At 4th and 8th weeks, both groups showed significant improvement in these indicators compared to those before treatment, with the observation group demonstrating significantly greater improvement than the control group at the corresponding time points ( P <0.05). At 8th week, the eff ective rate of the observation group was 90.21%, significantly higher than 80.50% in the control group ( P <0.05). The incidence of nausea, headache, fatigue, dry mouth, and palpitations, as well as the total incidence of ADRs, did not differ significantly between the two groups ( P >0.05). CONCLUSIONS Wuling capsules combined with fluoxetine can significantly improve the effective rate in adolescents with first-episode moderate-to-severe depression accompanied by insomnia, accelerate the relief of depressive symptoms, improve sleep quality, and reduce serum neuroendocrine indicator and inflammatory markers, with a favorable safety profile.
2.Treatment Principles and Paradigm of Diabetic Microvascular Complications Responding Specifically to Traditional Chinese Medicine
Anzhu WANG ; Xing HANG ; Lili ZHANG ; Xiaorong ZHU ; Dantao PENG ; Ying FAN ; Min ZHANG ; Wenliang LYU ; Guoliang ZHANG ; Xiai WU ; Jia MI ; Jiaxing TIAN ; Wei ZHANG ; Han WANG ; Yuan XU ; .LI PINGPING ; Zhenyu WANG ; Ying ZHANG ; Dongmei SUN ; Yi HE ; Mei MO ; Xiaoxiao ZHANG ; Linhua ZHAO
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(5):272-279
To explore the advantages of traditional Chinese medicine (TCM) and integrative TCM-Western medicine approaches in the treatment of diabetic microvascular complications (DMC), refine key pathophysiological insights and treatment principles, and promote academic innovation and strategic research planning in the prevention and treatment of DMC. The 38th session of the Expert Salon on Diseases Responding Specifically to Traditional Chinese Medicine, hosted by the China Association of Chinese Medicine, was held in Beijing, 2024. Experts in TCM, Western medicine, and interdisciplinary fields convened to conduct a systematic discussion on the pathogenesis, diagnostic and treatment challenges, and mechanism research related to DMC, ultimately forming a consensus on key directions. Four major research recommendations were proposed. The first is addressing clinical bottlenecks in the prevention and control of DMC by optimizing TCM-based evidence evaluation systems. The second is refining TCM core pathogenesis across DMC stages and establishing corresponding "disease-pattern-time" framework. The third is innovating mechanism research strategies to facilitate a shift from holistic regulation to targeted intervention in TCM. The fourth is advancing interdisciplinary collaboration to enhance the role of TCM in new drug development, research prioritization, and guideline formulation. TCM and integrative approaches offer distinct advantages in managing DMC. With a focus on the diseases responding specifically to TCM, strengthening evidence-based support and mechanism interpretation and promoting the integration of clinical care and research innovation will provide strong momentum for the modernization of TCM and the advancement of national health strategies.
3.From Cathartic Colon to Cathartic-dependent Constipation: Diagnostic-therapeutic Strategies from Integrative Medicine Perspective
Youcheng HE ; Fengru JIANG ; Yanru WANG ; Minghan HUANG ; Yue WU ; Chunyu ZHOU ; Lian MO ; Lifeng WEI ; Keyi PAN ; Shuyu CAI ; Jianye YUAN
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(11):162-172
Both cathartic colon (CC) and cathartic-dependent constipation (CDC) are caused by the abuse of stimulant laxatives, while their concepts are not completely the same.Starting from the disease name of CC, this article traced the origin and evolution of the concept of CC, summarizes and compared the similarities and differences between CC, CDC, and slow transit constipation (STC), and called for strict differentiation among the three.Furthermore, this article explored the specific contents of Western medicine clinical subtypes and traditional Chinese medicine (TCM) syndrome differentiation of CDC and delved into the TCM pathogenesis of CDC according to both literature and clinical practice.The relationship between clinical subtypes and TCM syndromes was established, and the syndrome characteristics of CDC of different clinical subtypes and TCM syndromes were summarized.The recommended prescriptions for corresponding syndromes were listed.A systematic CDC diagnosis and treatment approach of "clinical subtypes-syndrome differentiation-syndrome characteristics-recommended prescriptions" was thus formed.Additionally, the paper provides an overview of current research on CDC in both Western medicine and TCM contexts, identifies future research directions, and suggests research pathways for refining and advancing CDC studies.
4.Clinical Efficacy of Yiqi Yangyin Huoxue Prescription in Treatment of Cathartic Colon and Analysis of Influencing Factors of Disease Severity
Youcheng HE ; Jingyi SHAN ; Fengru JIANG ; Yue WU ; Chunyu ZHOU ; Lu HANG ; Yan ZHOU ; Lian MO ; Shuyu CAI ; Keyi PAN ; Lifeng WEI ; Jianye YUAN
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(11):173-184
ObjectiveTo observe the clinical efficacy of the Yiqi Yangyin Huoxue prescription (YYHP) in the treatment of cathartic colon (CC) and its effects on fecal short-chain fatty acids (SCFAs), and to explore the correlations among CC severity indicators and between these indicators and patient history. MethodsAccording to the inclusion and exclusion criteria, 98 patients meeting the diagnostic criteria of both traditional Chinese and Western medicine for CC with the syndrome of Qi-Yin deficiency complicated by blood stasis were randomly assigned to an observation group and a control group. The observation group received YYHP granules, while the control group received lactulose. Both medications were administered twice daily, one sachet each time, half an hour after breakfast and dinner, with a treatment course of 8 weeks. The primary constipation symptom score, Patient Assessment of Constipation Quality of Life (PAC-QOL) score, and TCM syndrome score were assessed before and after treatment and at the 8th week after the end of treatment. The overall clinical effective rate, as well as the efficacy attenuation index and degree, were evaluated. Fecal SCFA levels were measured using gas chromatography-mass spectrometry (GC-MS). Spearman correlation analysis was performed to explore the correlations among CC severity indicators and between these indicators and patient history. ResultsThe overall clinical effective rate in the observation group (95.83%) was higher than that in the control group (78.72%) (P<0.05). After treatment, the total scores for primary constipation symptoms, PAC-QOL, and TCM syndromes decreased in both groups (P<0.05), with more significant reductions in the observation group (P<0.05). The severity of all primary constipation symptoms was alleviated in both groups (P<0.05). In terms of "excessive straining and difficult defecation", "anal heaviness, incomplete evacuation, and bloating sensation", "abdominal distension", and "defecation frequency", the observation group showed better efficacy than the control group (P<0.05). Scores of the four PAC-QOL dimensions and the scores and severity of primary and secondary TCM symptoms were reduced in both groups (P<0.05), with more significant reductions in the observation group (P<0.05). After treatment, acetic acid, propionic acid, butyric acid, and total SCFAs in the observation group increased significantly (P<0.05). The efficacy attenuation index and degree in the observation group were lower than those in the control group (P<0.05). No severe adverse reactions occurred in either group, and there was no statistically significant difference in the incidence of adverse reactions between the two groups. Positive correlations of varying degrees were observed among the total scores of primary constipation symptoms, PAC-QOL, and TCM syndromes, as well as between these scores and the history of stimulant laxative use, disease duration, and age. ConclusionYYHP can effectively alleviate the primary constipation symptoms in CC patients, improve quality of life, and ameliorate TCM syndromes, with good safety. It also has the advantage of a lower rebound degree after drug withdrawal, and its mechanism may be related to increasing fecal SCFA levels. Long-term abuse of stimulant laxatives may aggravate the severity of CC and prolong the disease course.
5.Mechanism of Yishen Qubi Tongluo Formula (益肾祛痹通络方) in the Treatment of Rheumatoid Arthritis:Based on Network Pharmacology,Molecular Docking and Experimental Verification
Liuping XU ; Canyu YANG ; Ying LU ; Lisha MO ; Qiang CHI ; Yuan XIA ; Shuijuan LIU ; Mingliang QIU
Journal of Traditional Chinese Medicine 2026;67(5):557-566
ObjectiveTo explore the mechanism of Yishen Qubi Tongluo Formula (益肾祛痹通络方, YQTF) in the treatment of rheumatoid arthritis(RA). MethodsNetwork pharmacology was employed to retrieve and screen the active components and potential targets of YQTF as well as RA-related targets using databases including TCMSP, BATMAN, ETCM and GEO. The intersection of targets related to active components and RA-related targets was identified, and a protein-protein interaction (PPI) network was constructed. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed, and a drug-active component-common target network of YQTF in the treatment of RA was established. The core components of YQTF were molecularly docked with key targets. Human rheumatoid arthritis synovial fibroblast cell line MH7A was divided into blank group, model group, methotrexate group and YQTF group. The blank group was cultured with 10% fetal bovine serum, while the other three groups were stimulated with 10 μg/L of recombinant human tumor necrosis factor-α (TNF-α) for 24 h to establish the RA cell model. On this basis, the methotrexate group was treated with methotrexate suspension at a concentration of 20 μmol/L, and the YQTF group was treated with 10% YQTF-medicated serum. After 48 h of intervention, the levels of TNF-α and interleukin-17A(IL-17A)contents in cell supernatants were detected by enzyme-linked immunosorbent assay (ELISA), and mRNA expressions of phosphatidylinositol 3-kinase(PI3K), protein kinase B(AKT) and mammalian target of rapamycin(mTOR) were detected by real-time quantitative polymerase chain reaction (RT-qPCR). ResultsNetwork pharmacological analysis identified 209 active components and 583 potential target genes of YQTF, as well as 818 RA-related targets. A total of 29 common targets were obtained from the intersection of drug-related targets and RA-related targets. Quercetin,β-sitosterol, kaempferol, stigmasterol and luteolin were the core active components of YQTF for the treatment of RA, while matrix metalloproteinase-9 (MMP9), prostaglandin-endoperoxide synthase 2 (PTGS2), Toll-like receptor 4 (TLR4), tumor protein p53 (TP53) and transcription factor AP-1 subunit JUN were the key targets. The GO and KEGG pathway enrichment analysis showed that the involved biological processes and pathways were mainly associated with antioxidant responses, PI3K-AKT signaling pathway and Toll-like receptor (TLR) signaling pathway. Molecular docking results showed that MMP9 and PTGS2 exhibited high binding affinities with quercetin, β-sitosterol, kaempferol, stigmasterol and luteolin; TLR4 exhibited high binding activities with β-sitosterol, stigmasterol and luteolin; and TP53 showed high binding affinity with luteolin. The results of cell experiments showed that compared with the control group, the contents of TNF-α and IL-17A as well as the mRNA expressions of AKT and mTOR in the model group significantly increased (P<0.05 or P<0.01). Compared with the model group, all the above indicators significantly decreased in the YQTF group, while the contents of TNF-α and the mRNA expression of AKT significantly decreased in the methotrexate group (P<0.05 or P<0.01). ConclusionThe mechanism of YQTF in the treatment of RA may be associated with reducing inflammatory cytokine secretion and inhibiting the activation of the PI3K-AKT-mTOR signaling pathway.
6.Study on the construction of a red blood cell rare blood type database and physical repository in the Guangzhou Region
Zhijian LIAO ; Shuangshuang JIA ; Yuan SHAO ; Boquan HUANG ; Chunyan MO ; Jizhi WEN ; Runqing ZHANG ; Xia RONG ; Hong LUO ; Huaqin LIANG ; Yanli JI
Chinese Journal of Blood Transfusion 2026;39(5):619-628
Objective: To conduct screening for rare blood types within important blood group systems for the Chinese population, such as Rh, Duffy, Kidd, P1Pk, Diego, and MNS, in the Guangzhou region, and to establish a corresponding rare blood type database and physical repository. Methods: The saline medium microplate method was used to screen blood donors with the ccDEE phenotype combined with either Jk(a-) or Jk(b-). The polybrene microplate method was employed to screen for donors with Fy(a-), s(-), Lu(b-), Di(b-), k(-), and p phenotypes. The urea lysis microplate method was applied to screen for the Jk(a-b-) phenotype. A high-resolution melting (HRM) curve method was established for screening some donors with the Di(b-) phenotype. Subsequently, expanded phenotyping of antigens in the Rh, Kidd, MNS, Duffy, P1Pk, Lewis, Kell, and Lutheran blood group systems was performed on identified rare blood type donors using monoclonal antibodies. The test results are entered into the Rare Blood Type Bank Management System of the Guangzhou Blood Center, enabling functions such as confirmation reminders and cryopreservation storage when the donor donates again. Red blood cells of rare blood types are processed into frozen red blood cells for long-term storage. Results: Among voluntary blood donors, 16 cases of the ccDEE combined with Jk(a-) phenotype were identified (0.221 7%, 16/7 216); 10 cases of the ccDEE combined with Jk(b-) phenotype (0.138 6%, 10/7 216); 78 cases of the Fy(a-) phenotype (0.169 5%, 78/46 012); 39 cases of the Lu(b-) phenotype (0.138 2%, 39/28 214); 31 cases of the s(-) phenotype (0.081 8%, 31/37 913); 22 cases of the Di(b-) phenotype (0.029 9%, 22/73 691); 30 cases of the Jk(a-b-) phenotype (0.010 1%, 30/298 250); and 1 case of the k(-) phenotype (0.001 3%, 1/77 382), which was further identified as KELnull phenotype (K0). No p phenotype donors were identified (0/88 528). A total of 228 units of frozen red blood cells were prepared. The screening results were compared and analyzed with rare blood type data from other regions. Conclusion: This study, through a combination of different screening methods, significantly improved the efficiency of rare blood type screening while remaining cost-effective. By conducting large-scale screening and performing data informatization processing, a database and physical repository of rare blood types in the Guangzhou region were successfully established. This provides a strong guarantee for the timely supply of blood to patients with difficult-to-match and rare blood types in the region, effectively enhances the level of transfusion safety in the region, and offers a practical paradigm for constructing a comprehensive blood transfusion support system.
7.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.
9.Research progress on traditional Chinese medicine in treating cardiotoxicity induced by anticancer drugs
Linling SU ; Xianxia YUAN ; Wenyu JIANG ; Ling MO ; Jiaxue WU ; Min WANG ; Dongling LIU ; Yang HAI
Journal of China Pharmaceutical University 2026;57(3):393-400
Cardiotoxicity induced by antineoplastic agents is an important factor affecting the prognosis of cancer patients. This article systematically summarizes the clinical manifestations of cardiotoxicity caused by chemotherapeutic drugs, molecular targeted cancer therapies, and immunotherapeutic drugs, and identifies the core injury mechanisms, including cardiomyocyte apoptosis, oxidative stress, and mitochondrial dysfunction. In Traditional Chinese Medicine (TCM) theory, anticancer drug-induced cardiotoxicity falls under the category of “heat toxins” characterized by dual deficiency of qi and blood, upward flaming of heart heat, stagnation of the heart vessels, and meridian obstruction induced by phlegm-dampness. Therefore, by reviewing the preventive and therapeutic effects and the underlying mechanisms of tonic medicines, interior heat-clearing medicines, blood-circulating and stasis-resolving medicines, phlegm-transforming, cough-suppressing and panting-relieving medicines, and interior-warming medicines, this paper concludes that TCM prevention and treatment of this condition adheres to the formulation principle of “reinforcing healthy qi, removing toxins, and resolving blood stasis”. Its mechanisms of action—including antioxidation effects, regulation of autophagic balance, antagonism of inflammatory responses, and improvement of microcirculation—are highly consistent with modern medical treatment strategies (e.g., dexrazoxane for inhibiting iron-dependent oxidative stress, statins for anti-inflammatory effects). This study provides theoretical support and practical guidance for the collaborative and precise prevention and treatment of anticancer drug-induced cardiotoxicity through the integration of traditional Chinese and Western medicine.
10.Systemic Lupus Erythematosus as a Dominant Disease in Traditional Chinese Medicine
Zihan WANG ; Yanyu CHEN ; Yong CUI ; Qingwen TAO ; Mei MO ; Ke XUE ; Xiaoxiao ZHANG ; Yuan XU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(13):263-269
Systemic lupus erythematosus (SLE), a refractory autoimmune disease, is among the dominant diseases where traditional Chinese medicine (TCM) shows advantages in the field of rheumatology and immunology. The China-Japan Friendship Hospital hosted the "46th Youth Salon on Dominant Diseases (Systemic Lupus Erythematosus)" organized by the China Association of Chinese Medicine, which led to a consensus on "the advantages, challenges, interdisciplinary approaches, and translational achievements of integrated TCM and Western medical approaches in the diagnosis and treatment of SLE." The diagnosis and treatment of SLE currently face several challenges, such as frequent misdiagnosis and missed diagnosis in the early stages, difficulty in achieving treatment targets, multiple side effects from pharmacotherapy, and the lack of management strategies for special populations, all of which hinder the fulfillment of the clinical needs of patients. Integrated TCM and Western medical approaches can improve clinical symptoms such as skin erythema, aversion to cold and cold limbs, fatigue, dry mouth, restlessness, and heat sensation in the palms and soles, thereby improving patients' quality of life. The approaches also help consolidate the efficacy of conventional Western medicine, slow disease progression, reduce relapse rates, address multi-organ involvement, and prevent or treat complications. Additionally, they enhance efficacy and reduce toxicity, prevent the side effects of Western medications, help reduce hormone use, and offer distinct advantages in the individualized intervention of special populations, contributing to the whole-process management of the disease. However, evidence-based medical support for this integrated approach remains limited, and the quality of available evidence is generally low. Common evaluation systems and modern research methodologies should be adopted to clarify the efficacy of TCM in SLE treatment. Efforts should be made to carry out high-quality evidence-based medical research, strengthen the development of fundamental and pharmacological research, and further explain the distinct advantages of TCM in the diagnosis and treatment of SLE. Future efforts should focus on advancing the integration of TCM and modern medicine, incorporating multi-omics technologies, individualized stratification, and other precision medicine concepts, in combination with artificial intelligence. Moreover, interdisciplinary collaboration should be promoted to utilize modern technology in exploring the essence of TCM theories and screening effective formulae, thereby comprehensively improving the diagnosis and treatment of SLE through integrated TCM and Western medical approaches.

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