1.Pharmacological Review, Challenges, and Future Prospects of Zhusha Anshenwan
Xiaosong HU ; Zhou LAN ; Ping WANG ; Li DING ; Chun GUI
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(9):329-335
Zhusha Anshenwan is a classical traditional Chinese medicine (TCM) formula originating from LI Dongyuan's Treatise on the Differentiation of Endogenous and Exogenous Injuries (Nei Wai Shang Bian Huo Lun) of the Jin-Yuan period. It is composed of five medicinal ingredients: Cinnabaris (Zhusha), Coptidis Rhizoma (Huanglian), Angelicae Sinensis Radix (Danggui), Rehmanniae Radix (Shengdihuang), and Glycyrrhizae Radix et Rhizoma (Gancao). Under the guidance of TCM theory, this formula is used to treat syndromes of disturbed spirit, including insomnia, palpitations, and anxiety, caused by hyperactivity of heart fire and deficiency of Yin-blood, and it also exerts auxiliary anticonvulsant effects in epilepsy and related conditions. However, the potential neurotoxicity, hepatotoxicity, and nephrotoxicity of its monarch drug, Cinnabaris (mainly composed of mercuric sulfide, HgS), together with the risk of in vivo accumulation, have rendered its clinical application controversial, and it has not yet been formally included in the Pharmacopoeia of the People's Republic of China. In addition, restrictions imposed by the Minamata Convention on Mercury have led to an increasing shortage of natural medicinal Cinnabaris resources, making the evaluation of the efficacy and safety of synthetic Cinnabaris particularly urgent. This contradiction highlights the complexity of safety evaluation for traditional medicines. Existing studies indicate that Zhusha Anshenwan exhibits definite pharmacological activities in calming the mind, improving sleep, and regulating emotional disorders. Moreover, other components of the formula may exert antagonistic effects on the toxicity of Cinnabaris, and reports of severe mercury poisoning caused by standardized clinical use of this prescription are extremely rare. Research suggests that other ingredients in the compound formula, such as Rehmanniae Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma, may effectively alleviate the hepatorenal toxicity of Cinnabaris through mechanisms including modulation of the gut microbiota, formation of mercury complexes, and direct protection of target organs. This article aims to systematically review the progress in pharmacodynamic research on Zhusha Anshenwan, to explore its mechanisms of action in depth, and to analyze the toxicokinetic characteristics and safety risks of Cinnabaris, as well as the scientific connotations of toxicity reduction and efficacy enhancement achieved through compound compatibility. In addition, it compares Zhusha Anshenwan with other commonly used sedative formulas, with the aim of providing a scientific basis and forward-looking perspectives for the safe and rational application and in-depth development of this classical prescription in a modern context, and of emphasizing the important value of holistic research on TCM compound formulas in addressing the challenges of single-component toxicity.
2.Comparison of Wild and Cultivated Gardeniae Fructus Based on Traditional Quality Evaluation
Yuanjun SHANG ; Bo GENG ; Xin CHEN ; Qi WANG ; Guohua ZHENG ; Chun LI ; Zhilai ZHAN ; Junjie HU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(5):225-234
ObjectiveBased on traditional quality evaluation of Gardeniae Fructus(GF) recorded in historical materia medica, this study systematically compared the quality differences between wild and cultivated GF from morphological characteristics, microscopic features, and contents of primary and secondary metabolites. MethodsVernier calipers and analytical balances were used to measure the length, diameter and individual fruit weight of wild and cultivated GF, and the aspect ratio was calculated. A colorimeter was used to determine the chromaticity value of wild and cultivated GF, and the paraffin sections of them were prepared by safranin-fast green staining and examined under an optical microscope to observe their microstructure. Subsequently, the contents of water-soluble and alcohol-soluble extracts of wild and cultivated GF were detected by hot immersion method under the general rule 2201 in volume Ⅳ of the 2020 edition of the Pharmacopoeia of the People's Republic of China, the starch content was measured by anthrone colorimetric method, the content of total polysaccharides was determined by phenol-sulfuric acid colorimetric method, the sucrose content was determined by high performance liquid chromatography coupled with evaporative light scattering detection(HPLC-ELSD), and the contents of representative components in them were measured by ultra-performance liquid chromatography(UPLC). Finally, correlation analysis was conducted between quality traits and phenotypic traits, combined with multivariate statistical analysis methods such as principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA), key differential components between wild and cultivated GF were screened. ResultsIn terms of traits, the wild GF fruits were smaller, exhibiting reddish yellow or brownish red hues with significant variation between batches. While the cultivated GF fruits are larger, displaying deeper orange-red or brownish red. The diameter and individual fruit weight of cultivated GF were significantly greater than those of wild GF, while the blue-yellow value(b*) of wild GF was significantly higher than that of cultivated GF. In the microstructure, the mesocarp of wild GF contained numerous scattered calcium oxalate cluster crystals, while the endocarp contained stone cell class round, polygonal or tangential prolongation, undeveloped seeds were visible within the fruit. In contrast, the mesocarp of cultivated GF contained few calcium oxalate cluster crystals, or some batches exhibited extremely numerous cluster crystals. The stone cells in the endocarp were predominantly round-like, with the innermost layer arranged in a grid pattern. Seeds were basically mature, and only a few immature seeds existed in some batches. Regarding primary metabolite content, wild GF exhibited significantly higher total polysaccharide level than cultivated GF(P<0.01). In category-specific component content, wild GF exhibited significantly higher levels of total flavonoids and total polyphenols compared to cultivated GF(P<0.01). Analysis of 12 secondary metabolites revealed that wild GF exhibited significantly higher levels of Shanzhiside, deacetyl asperulosidic acid methyl ester, gardenoside and chlorogenic acid compared to cultivated GF(P<0.01). Conversely, the contents of genipin 1-gentiobioside, geniposide and genipin were significantly lower in wild GF(P<0.01). ConclusionThere are significant differences between wild and cultivated GF in terms of traits, microstructure, and contents of primary and secondary metabolites. At present, the quality evaluation system of cultivated GF remains incomplete, and this study provides a reference for guiding the production of high-quality GF medicinal materials.
3.Evaluate the anti-inflammatory activity of the magnolol ester derivative YW and investigate its mechanism of action on chondrocyte senescence
Haochen XU ; Jie PENG ; Pingting YANG ; Meihua ZHANG ; Weiwen HU ; Xulei WANG ; Wei WEI ; Chun WANG ; Shangxue YAN
Acta Universitatis Medicinalis Anhui 2026;61(5):845-854
ObjectiveTo evaluate the anti-inflammatory activity of the novel magnolol ester derivative YW and to investigate its effects on chondrocyte senescence and preliminary mechanisms. MethodsMagnolol and p-methylbenzoic acid were used as raw materials to synthesize the magnolol ester derivative YW (Molecular Formula: C26H24O3, Molecular Weight: 384.17, HPLC Purity >96%) via DCC/DMAP-catalyzed esterification. Cytotoxicity was assessed using the CCK-8 assay. A lipopolysaccharide (LPS)-induced RAW264.7 macrophage activation model and an interleukin-1β (IL-1β)-induced rat primary chondrocyte model were established. The release and mRNA expression of inflammatory factors including nitric oxide (NO), IL-1β, tumor necrosis factor-alpha (TNF-α), and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA), Griess reagent method, and quantitative real-time PCR (RT-qPCR). The expression of senescence markers such as inducible nitric oxide synthase (iNOS), pro-interleukin-1β (pro-IL-1β), lysine acetyltransferase 7 (KAT7), cyclin-dependent kinase inhibitor 1A (p21), and cyclin-dependent kinase inhibitor 2A (p16), as well as proteins related to chondrocyte extracellular matrix synthesis and catabolism, were analyzed by Western blot (WB). Molecular docking was performed using Discovery Studio 2019 to validate target binding. ResultsYW exhibited no significant cytotoxicity at concentrations ≤20 μmol/L. YW concentration-dependently inhibited LPS-induced macrophage inflammatory cytokine release, significantly downregulated iNOS, Pro-IL-1β protein, and inflammatory cytokine mRNA expression (P<0.01). YW stably bound to KAT7 protein (binding energy: -94.2 kcal/mol); YW downregulated KAT7 and aging marker protein expression in naturally aged and IL-1β-induced chondrocyte models (P<0.01); YW regulated chondrocyte matrix synthesis and catabolic protein expression in IL-1β-induced chondrocytes (P<0.01). ConclusionYW inhibits macrophage activation and inflammatory cytokine release while downregulating KAT7 and senescence marker protein expression in chondrocytes, thereby blocking chondrocyte senescence.
4.Relationship between peer victimization and depressive symptoms among secondary vocational health school students: the chain mediating role of positive mental health and social media addiction
Houyi LI ; Chun XU ; Shasha HU ; Bo XIANG ; Kezhi LIU
Sichuan Mental Health 2025;38(2):159-165
BackgroundStudents in secondary vocational health school are at the age of puberty and prone to depressive symptoms. Peer victimization and social media addiction are found to be crucial in influencing the development of depression, and positive mental health has been proven to alleviate depressive symptoms, whereas there remains a striking lack of research on the mediating role of positive mental health and social media addiction in the relationship between peer victimization and depressive symptoms among secondary vocational health school students. ObjectiveTo explore the relationship between peer victimization and depressive symptoms and investigate the mediating role of positive mental health and social media addiction, so as to provide references for the prevention of depression among secondary vocational health school students. MethodsFrom October to December 2020, a cluster sampling framework was utilized to recruit 7 307 students from a secondary vocational health school in Luzhou City, Sichuan Province. Assessments were performed using Multidimensional Peer Victimization Scale (MPVS), Warwick-Edinburgh Mental Well-being Scale (WEMWBS), Bergen Social Media Addiction Scale (BSMAS) and Patient Health Questionnaire Depression Scale-9 item (PHQ-9). Spearman correlation analysis was calculated to determine correlations between scores of scales, Process 4.0 was employed to test the mediation effect, and the bias-corrected Bootstrap procedure was used to test the significance of the mediation effect. ResultsA total of 7 044 (96.40%) valid questionnaires were collected. And 4 391(62.34%)students were found to have depressive symptoms. Correlation analysis revealed that PHQ-9 score was positively correlated with BSMAS score and MPVS score (r=0.404, 0.506, P<0.01). WEMWBS score was negatively correlated with PHQ-9 score, BSMAS score and MPVS score (r=-0.587, -0.259, -0.358, P<0.01). BSMAS score was positively correlated with MPVS score (r=0.328, P<0.01). Positive mental health played a mediating role in the relationship between peer victimization and depressive symptoms, with an indirect effect value of 0.130 (95% CI: 0.119~0.141), accounting for 30.81% of the total effect. Social media addiction also mediated the relationship between peer victimization and depressive symptoms, with an indirect effect value of 0.052 (95% CI: 0.045~0.059), accounting for 12.34% of the total effect. Positive mental health and social media addiction exhibited a chained mediation effect on the relationship between peer victimization and depressive symptoms, with an indirect effect value of 0.012 (95% CI: 0.010~0.014) and accounting for 2.84% of the total effect. ConclusionPeer victimization can affect the presence of depressive symptoms among secondary vocational health school students both directly and indirectly through either separate or chained mediation of positive mental health and social media addiction.
5.Efficacy of ranibizumab combined with retinal laser photocoagulation in patients with macular edema secondary to BRVO
Fengyun HU ; Lian'e DING ; Fenfen CHEN ; Xiaoli CAO ; Hai CHU ; Kai MA ; Chun DENG
Journal of Navy Medicine 2025;46(8):816-820
Objective To explore the efficacy of ranibizumab combined with retinal laser photocoagulation in patients with macular edema secondary to branch retinal vein occlusion(BRVO)and its impact on best-corrected visual acuity(BCVA)and central macular thickness(CMT).Methods A prospective analysis was conducted on 70 patients with secondary macular edema caused by BRVO who were admitted to the 901th Hospital of Joint Logistics Support Force from March 2019 to March 2023.According to the random number table method,the patients were assigned into study group or control group,with 35 cases in each group.The control group was treated with ranibizumab,while the study group was treated with ranibizumab and retinal laser photocoagulation.The efficacy,BCVA,CMT,intraocular pressure,adverse reactions,and 36-item short form health survey(SF-36)score were compared between the two groups.Results There was a significant difference in the efficacy between the two groups(Z=2.272,P<0.05),and the total effective rate of the study group was higher than that of the control group(P<0.05).The results of repeated measure ANOVA showed that CMT and intraocular pressure decreased significantly,while BCVA increased significantly in both groups after 3 months,6 months,and 12 months of treatment(P<0.05);moreover,these parameters in the study group were superior to those in the control group(P<0.05).There were no significant differences in the incidence of cataracts,transient intraocular pressure elevation,subconjunctival hemorrhage,retinal detachment,or the total incidence of adverse reactions between the two groups(P>0.05).After 12 months of treatment,the total score of SF-36 increased in both groups(P<0.05),and the difference value of total score of SF-36 in the study group was superior to that in the control group(P<0.05).Conclusion The combination of ranibizumab and retinal laser photocoagulation can achieve a good therapeutic effect on macular edema caused by BRVO.It can effectively improve BCVA,CMT and intraocular pressure,reduce the risk of adverse reactions,and enhance the quality of life.
6.Comparison of the efficacy of remimazolam and propofol in the induction and maintenance of general anesthesia in elderly patients undergoing thoracoscopic lobectomy
Chun LIU ; Juan HU ; Yu HUANG ; Jinqiu YANG ; Junjie LI ; Ping YANG ; Pengfei PAN
China Pharmacy 2025;36(16):2040-2045
OBJECTIVE To compare the clinical efficacy and safety of remimazolam and propofol in general anesthesia induction and maintenance for elderly patients undergoing thoracoscopic lobectomy. METHODS A total of 86 elderly lung cancer patients who underwent thoracoscopic lobectomy at Chongqing University Three Gorges Hospital from February to July 2024 were selected and divided into the propofol group and the remimazolam group according to the randomized numerical table method, with 43 cases in each group. During anesthesia induction, patients in the propofol group and the remimazolam group were intravenously administered 2 mg/kg of Propofol medium- and long-chain fat emulsion injection or 0.25 mg/kg of Remimazolam tosilate for injection, respectively; during anesthesia maintenance, the two groups received intravenous infusion of 6-10 mg/(kg·h) of Propofol medium- and long- chain fat emulsion injection or 1-3 mg/(kg·h) of Remimazolam tosilate for injection, respectively. The anesthesia effects, anesthesia-related indicators, intraoperative opioid and muscle relaxant dosages, Ramsay sedation score, numerical rating scale (NRS) score, and hemodynamic parameters were compared between the two groups, and the occurrence of adverse drug reactions was recorded. RESULTS A total of 41 patients in the propofol group and 43 patients in the remimazolam group completed the trial. The proportion of patients with grade Ⅰ anesthesia effect in the remimazolam group was significantly higher than that in the propofol group, while the proportion of patients with grade Ⅱ anesthesia effect was significantly lower than that in the propofol group (P<0.05). In this group, the disappearance time of eyelash reflex, the time taken for the bispectral index to drop to 60, and the Ramsay sedation scores (2 and 6 hours after operation) were all significantly prolonged or increased, while the recovery time, NRS scores (2 and 6 hours after operation), and the incidence of intraoperative hypotension were all significantly shortened or reduced; moreover, the improvements of the above sedation/NRS scores exhibited a time-dependent pattern within 2 to 24 hours after operation (P<0.05). Compared with before anesthesia induction (T0), the heart rate [except at 2 min after medication (T1), 60 min after anesthesia (T4), and at the end of surgery (T5) in the remimazolam group] and mean arterial pressure [except at T1 in the remimazolam group] of patients in both groups significantly decreased at T1, 5 min after medication (T2), at the start of surgery (T3), T4, and T5 (P<0.05). Meanwhile, regional cerebral oxygen saturation significantly increased in both groups. Furthermore, the heart rate and mean arterial pressure of patients in the remimazolam group were significantly higher than those in the propofol group at T1, T2 and T4 (P<0.05). No statistically significant differences were observed between the two groups in terms of postanesthesia care unit stay time, dosage of opioids and muscle relaxants, regional cerebral oxygen saturation, or peripheral oxygen saturation at various time points (P>0.05). CONCLUSIONS Compared to propofol, remimazolam demonstrates superior anesthesia effects when used for the induction and maintenance of general anesthesia in elderly patients undergoing thoracoscopic lobectomy. It not only provides more stable intraoperative hemodynamics and shortens the postoperative recovery time but also effectively reduces the incidence of intraoperative hypotension.
7.Antibody threshold and demographic characteristics of low-titer group O whole blood donors in Jiangsu
Tao FENG ; Rui ZHU ; Wenjia HU ; Ling MA ; Hong LIN ; Xi YU ; Chun ZHOU ; Nizhen JIANG
Chinese Journal of Blood Transfusion 2025;38(9):1225-1229
Objective: To investigate the distribution of IgM anti-A/B titers among group O whole blood donors in Jiangsu, establish a low-titer threshold, and analyze the demographic characteristics of low-titer donors, so as to provide data for recruiting low-titer group O whole blood (LTOWB) donors. Methods: Plasma samples from 1 009 group O whole blood donors were tested for IgM anti-A and anti-B titers using the microplate technique. The distribution of antibody titers was analyzed to establish a low-titer threshold. The distribution trends of titers across different demographic groups were also analyzed. Results: The peak titer for anti-A, anti-B were 64 (31.5%), 4 (23.8%), respectively, The proportion of donors with both anti-A and anti-B titers below 64 was 97.3% (982/1 009). The mean anti-A titer was higher than anti-B titer. Anti-A titers were higher in female donors than in male donors (P<0.05). The anti-A titers differed significantly among different age groups (P<0.05). However, no significant difference in titers was observed based on the number of donations (P>0.05). Conclusion: A titer of 64 can be used as the reference threshold of LTOWB in Jiangsu. Male donors of appropriate age are more suitable than female donors for establishing an emergency panel of LTOWB mobile donors.
8.Therapeutic efficacy and its mechanism of methylprednisolone on smoke inhalation-induced acute lung injury in rats
Hu-Ming LI ; Xu-Xin CHEN ; Yong-Qun LI ; Chun-Yang ZHANG ; Yan ZHANG ; Wei CHEN ; Zhi-Hai HAN
Medical Journal of Chinese People's Liberation Army 2025;50(7):890-896
Objective To observe the therapeutic effects of different doses of methylprednisolone(MP)on smoke inhalation-induced acute lung injury(SI-ALI)in rats,and to explore the changes in the expression of aquaporins(AQPs)and the underlying mechanisms for alleviating lung injury.Methods A total of 86 healthy adult male Sprague-Dawley(SD)rats were randomly divided into five groups:control group(n=6),smoke inhalation injury(SI)group(n=20),low-dose MP group(LMP,SI+0.4 mg/kg MP,n=20),medium-dose MP group(MMP,SI+4 mg/kg MP,n=20),and high-dose MP group(HMP,SI+40 mg/kg MP,n=20).A model of smoke inhalation-induced lung injury was established.The survival status of the rats in each group was monitored.Lung tissues were collected 24 hours after injury to determine the wet-to-dry(W/D)ratio of the lung tissues,arterial oxygen partial pressure(PaO2),and the expression levels of inflammatory cytokines TNF-α and IL-6.The degree of lung injury was evaluated using HE staining,and the mRNA and protein expression levels of AQP1 and AQP5 in the lung tissues were detected.Results Compared with control group,the survival rate of the rats in SI group was significantly decreased(P<0.05);compared with SI group,the survival rates of the rats in MMP and HMP groups were significantly increased(P<0.05).Compared with control group,the PaO2 of the Rats in SI group was significantly decreased(P<0.05),and the wet-to-dry(W/D)ratio and lung injury scores were significantly increased(P<0.05).Compared with SI group,the PaO2 of the rats in LMP,MMP,and HMP groups(P<0.05)was significantly increased(P<0.05),and the lung W/D ratio and injury scores in MMP and HMP groups were significantly decreased(P<0.05).ELISA results showed that compared with control group,the serum concentrations of TNF-α and IL-6 in SI group were significantly increased(P<0.05);compared with SI group,the concentrations of TNF-α and IL-6 in MMP and HMP groups were significantly decreased(P<0.05).HE staining revealed that the alveolar structure of the rats in SI group was severely damaged;compared with SI group,the damage to the alveolar structure in MMP and HMP groups was alleviated.Real-time PCR and Western blotting analysis results showed that compared with control group,the mRNA and protein expression levels of AQP1 and AQP5 in lung tissues in SI group were significantly decreased(P<0.05);however,compared with SI group,these levels in LMP,MMP,and HMP groups were significantly increased(P<0.05).Conclusions Smoke inhalation can induce acute lung injury in rats and down-regulate the expression levels of AQP1 and AQP5 in the lung tissues.Methylprednisolone can alleviate pulmonary edema and tissue damage in rats caused by smoke inhalation,and induce the up-regulation of the expression of AQP1 and AQP5.
9.Research progress on exercise pre-rehabilitation in patients undergoing elective cardiac surgery
Ping ZHANG ; Anni HU ; Chun LIU ; Di WANG ; Hong HUANG ; Xiaoli XIE ; Yuexiu HU ; Qing ZHOU ; Yunyan SU
Journal of Clinical Medicine in Practice 2025;29(19):131-135
Cardiac surgery patients often present with multiple comorbidities,the risk of periop-erative complications and the complexity of postoperative rehabilitation have significantly increased,posing higher demands on comprehensive perioperative management.Preoperative exercise pre-reha-bilitation,as a multidisciplinary collaborative intervention strategy,has been demonstrated to signifi-cantly improve the clinical prognosis of patients undergoing elective cardiac surgery by enhancing their cardiopulmonary function,muscle strength,and overall physiological functional reserve,thereby in-creasing the body's tolerance to surgical stress.Although phase-specific research achievements have been made domestically and internationally in the field of exercise pre-rehabilitation,its standardized implementation and clinical translation on a global scale still face numerous obstacles,necessitating systematic review and in-depth exploration.Therefore,this study aimed to conduct a systematic re-view of the intervention protocols,clinical efficacy,safety,and feasibility of preoperative exercise pre-rehabilitation in patients undergoing elective cardiac surgery,with the goal of providing theoretical evidence and practical references for optimizing perioperative management pathways and promoting the implementation of enhanced recovery after surgery concepts.
10.Construction of an evaluation indicator system based on Delphi method and analytic hierarchy process for accessories of patient monitor
Donglin XING ; Wei LI ; Chun PAN ; Yu WAN ; Ke XIA ; Zhenyan LU ; Yu DENG ; Hu ZHANG ; Tengfei WANG ; Gang LI
China Medical Equipment 2025;22(8):22-28
Objective:To construct an evaluation indicator system for accessories of patient monitor,so as to provide a basis for clinical management,equipment procurement,and technical improvement for accessories of medical monitor.Methods:The initial selection indicators of corresponding accessories of three types of monitoring of medical monitors,including electrocardiogram(ECG),blood oxygen saturation(SpO2)and non-invasive blood pressure(NIBP),were determined through literature research,expert consultation,and actual investigation.The Delphi method was adopted to conduct two rounds of questionnaire consultation for experts from clinical medicine,biomedical engineering and other fields in medical institutions included Sichuan Provincial People's Hospital,The Affiliated Hospital of Southwest Medical University and Medical Institute of Chengdu Institute of Metrology Verification and Testing.The evaluation indicators were screened and optimized,and the Analytic Hierarchy Process(AHP)was used to calculate the weights of each indicator.The consistency test was conducted to verify the rationality of the evaluation indicator system.Results:The evaluation indicator system for accessories of medical monitor included three first-level indicators:clinical value,cost value,and management value.The number of second-level indicators about ECG,SpO2 and NIBP of evaluation indicator system were respectively 10,9 and 8,and the number of third-level indicators of that were respectively 20,19,and 14.In the first-level indicators,the clinical value had the highest weight,with 72.49%for ECG,70.88%for SpO2 and 70.32%for NIBP.In the second-level indicators,the accuracy(28.70%for ECG,38.13%for SpO2 and 43.03%for NIBP)and safety(27.47%for ECG,26.48%for SpO2 and 23.06%for NIBP)were the core indicators.The weights of cost value and management value were between 14.62%and 17.41%,and between 12.27%and 12.89%,respectively.Conclusion:The evaluation indicator system for accessories of medical monitor integrates multi-dimensional expert opinions and quantitative analysis,highlights the priority principle for clinical performance.It can provide theoretical support for optimizing selection about accessory for medical institutions,and improving quality of monitoring,and promoting standardized management in the industry.

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