1.Comparison of Wild and Cultivated Bupleurum scorzonerifolium Based on Traditional Quality Evaluation
Changsheng YUAN ; Feng ZHOU ; Xingyu LIU ; Yu SHI ; Yihan WANG ; Huaizhu LI ; Yongliang LI ; Shan GUAN ; Huaizhong GAO ; Yanmeng LIU ; Zhilai ZHAN
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(5):203-214
ObjectiveTo characterize the quality differences among different germplasm and introduced varieties of Bupleurum scorzonerifolium roots(BSR), and explore the underlying molecular mechanisms, providing a basis for high-quality production and quality control. MethodsWild BSR from Yulin(YLW) served as the quality reference, we conducted comparative analysis among YLW, locally domesticated wild germplasm in Yulin(YLC3), Daqing germplasm introduced and cultivated in Yulin(YLDQC3), and locally cultivated germplasm in Daqing(DQC3). A combination of traditional pharmacognostic methods and modern multi-omics analyses was employed, including macroscopic traits(appearance, odor), microscopic features(proportions of cork, phloem, xylem), cell wall component contents(hemicellulose, cellulose, lignin), carbohydrate contents(starch, water-soluble polysaccharides), marker compound contents(ethanol-soluble extracts, total saponins, liposoluble extracts, and saikosaponins A, B2, C, D), metabolomics, and transcriptomics, in order to systematically characterize quality differences and investigate molecular mechanisms among these samples. ResultsMacroscopically, Yulin-produced BSR(YLW, YLC3, YLDQC3) exhibited significantly greater weight, length, and upper and middle diameters than Daqing-produced BSR(DQC3). Odor-wise, YLW and YLC3 had a a fragrance taste, YLDQC3 had a rancid oil odor, and DQC3 had a sweet and fragrant taste. Microscopically, Yulin germplasm(YLW, YLC3) and Daqing germplasm(YLDQC3, DQC3) shared similar structural features, respectively. However, Yulin germplasm showed significantly higher proportions of cork and phloem, as well as stronger xylem vessel staining intensity compared to Daqing germplasm. Regarding various component contents, Yulin germplasm contained significantly higher levels of ethanol-soluble extracts, total saponins, and saikosaponins A, B2, C, D, while Daqing germplasm had significantly higher levels of hemicellulose, starch, and liposoluble extracts. After introduction to Yulin, the Daqing germplasm(YLDQC3) showed increased starch, water-soluble polysaccharides and liposoluble extracts contents, decreased cell wall component content, but no significant difference in other component contents. Metabolomics revealed that saponins and terpenes accumulated significantly in Yulin germplasm, while alcohols and aldehydes accumulated predominantly in Daqing germplasm. Transcriptomics indicated similar gene expression patterns within the same germplasm but specificity between different germplasms. Integrative metabolomic-transcriptomic analysis identified 145 potential key genes associated with the saikosaponin biosynthesis pathway, including one acetyl-coenzyme A(CoA) acetyltransferase gene(ACAT), one 3-hydroxy-3-methylglutaryl-coenzyme A synthase gene(HMGS), two hydroxymethylglutaryl-CoA(HMG-CoA) reductase genes(HMG), one phosphomevalonate kinase gene(PMK), one 1-deoxy-D-xylose-5-phosphate synthase gene(CLA), one hydroxymethylbuten-1-aldol synthase gene(HDR), two farnesyl pyrophosphate synthase genes(FPPS), one squalene synthase gene(SQS), one β-amyrin synthase gene(BAS), 102 cytochrome P450(CYP450) gene family members, and 32 uridine diphosphate-glucuronosyltransferase(UGT) gene family members. ConclusionAmong the three cultivated types, YLC3 most closely resembles YLW in appearance, microscopic features, contents of major bioactive constituents, metabolomic and transcriptomic profiles. Yulin germplasm exhibits superior saponin synthesis capability compared to Daqing germplasm, and Yulin region is more suitable for the growth of B. scorzonerifolium. Based on these findings, it is recommended that artificial cultivation in northern Shaanxi and similar regions utilize the local Yulin germplasm source cultivated for at least three years.
2.Efficacy and safety of immune checkpoint inhibitors combined with neoadjuvant chemotherapy in the treatment of early triple-negative breast cancer:a meta-analysis
Zhixuan YANG ; Shuo LI ; Peiyuan WANG ; Hongxin QIE ; Wenlin GONG ; Xiaonan GAO ; Jinglin GAO ; Mingxia WANG
China Pharmacy 2026;37(2):238-243
OBJECTIVE To evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with neoadjuvant chemotherapy in the treatment of early triple-negative breast cancer (TNBC). METHODS Randomized controlled trials (RCTs) comparing ICIs combined with neoadjuvant chemotherapy (experimental group) versus neoadjuvant chemotherapy alone (control group) were retrieved from PubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang Data, and VIP databases, as well as relevant studies published at oncology academic conferences. The search period was from database inception to June 30, 2025. After literature screening, data extraction, and quality assessment, a meta-analysis was performed by using RevMan 5.4 software. RESULTS A total of 6 RCTs involving 3 786 patients were finally included. The meta-analysis results showed that the experimental group had superior event-free survival [HR=0.73, 95%CI (0.62, 0.85), P<0.000 1], overall survival [HR=0.69, 95%CI (0.57, 0.84), P=0.000 3], and pathological complete response (pCR) [OR=1.57, 95%CI (1.37, 1.80), P<0.000 01] compared to the control group. The incidence of ≥grade 3 adverse event (AE), severe AE (SAE), and ≥ grade 3 immune-related adverse event (irAE) in the experimental group was significantly higher than that in the control group. There was no statistically significant difference between the two groups in the incidence of any AE or any irAE (P>0.05). Subgroup analysis revealed that, regardless of programmed cell death ligand 1 expression status (negative or positive),the pCR in the experimental group was significantly higher than that in the control group (P<0.05). Additionally, the pCR of the patients with positive lymph nodes in the experimental group was significantly higher to that in the ontrol group (P<0.05). There was no statistically significant difference in pCR between the two groups with negative lymph nodes (P=0.09). CONCLUSIONS ICIs combined with neoadjuvant chemotherapy can significantly improve event-free survival and overall survival in patients with TNBC, providing patients with long-term survival benefits. However, the risk of ≥ grade 3 AE, SAE and ≥ grade 3 irAE has increased.
3.POEMS syndrome with hepatosplenomegaly as the initial manifestation: A report of two cases
Ye ZHANG ; Wenqing WANG ; Jing LI ; Qianrong BAI ; Jiayu LI ; Yan CHENG ; Miaomiao FANG ; Nana GAO ; Changxing HUANG
Journal of Clinical Hepatology 2025;41(1):127-132
POEMS syndrome is a rare condition associated with plasma cell disorders, and it often involves multiple systems and has diverse clinical manifestations. This article reports two cases of POEMS syndrome with hepatosplenomegaly as the initial manifestation. During the course of the disease, the patients presented with lower limb weakness, hepatosplenomegaly, lymph node enlargement, ascites, hypothyroidism, positive M protein, and skin hyperpigmentation, and 18F-FDG PET-CT imaging revealed bone lesions mainly characterized by osteolytic changes and plasma cell tumors. There was an increase in the serum level of vascular endothelial growth factor. The patients were finally diagnosed with POEMS syndrome, and the symptoms were relieved after immunomodulatory treatment.
4.Seasonal distribution characteristics, source analysis and health risk assessment of polycyclic aromatic hydrocarbons in PM2.5 in Lianyungang City in 2019-2023
Shengnan GAO ; Jinkun LI ; Li CHEN ; Zhengdong XYU ; Hongru ZHU ; Jian WANG ; Zhiyang YAO
Journal of Public Health and Preventive Medicine 2025;36(1):65-69
Objective To study the seasonal distribution characteristics of polycyclic aromatic hydrocarbons (PAHs) in PM2.5 in Lianyungang City, and analyze the sources of PAHs pollution, and to evaluate the health risks of PAHs in different seasons. Methods PM2.5 samples were collected regularly from January 2019 to December 2023, and 16 types of PAHs were determined by HPLC. Kruskal-Wallis H test was used to compare the concentrations of PM2.5 and PAHs in different years and seasons. The source of PAHs was analyzed by characteristic ratio and principal component analysis (PCA). Health risks were assessed using the BaP equivalent method and the incremental lifetime cancer risk (ILCR) model. Results The annual exceedance rates of PM2.5 and BaP in Lianyungang showed a decreasing trend from 2019 to 2023. PM2.5, total PAHs and PAHs monomers (except Ace, Flu and Acy) all showed significant seasonal differences, with the highest concentration in winter (P<0.001). The average proportion of 4-ring PAHs was the highest and the average proportion of 2-ring PAHs was the lowest. The proportion of 5-6 ring PAHs was relatively high in winter and spring. PM2.5and PAHs were negatively correlated with temperature, relative humidity and precipitation, and were positively correlated with atmospheric pressure. PM2.5 was negatively correlated with wind speed, while some PAHs monomers were positively correlated with wind speed. The characteristic ratio and PCA results showed that the main sources of PAHs in Lianyungang City were mixed sources of road dust and vehicle emissions, oil pollution sources and biomass combustion sources. The results of ILCR showed that the highest risk was found in adults, with males slightly higher than females. In Lianyungang, the maximum value of ILCR in winter was more than 10-6 in people over 9 years old. Conclusion The main sources of PAHs in PM2.5 in Lianyungang City are mixed sources of road dust and vehicle emissions, oil pollution sources, and biomass combustion sources. Under the current exposure level of PAHs in PM2.5, residents have a certain potential carcinogenic risk.
5.Clinical Observation of Guben Quyu Jiedu Prescription in Treating Nocturnal Hypoxemia of COPD Combined with OSAHS
Yi HE ; Ziyu LI ; Wenjiang ZHANG ; Jinzhu GAO ; Changzheng FAN ; Beibei WANG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(6):146-153
ObjectiveTo observe the clinical efficacy and safety of Guben Quyu Jiedu prescription in treating nocturnal hypoxemia of chronic obstructive pulmonary disease (COPD) combined with Obstructive sleep apnea hypopnea syndrome ( OSAHS ) (deficiency of lung, spleen and kidney with blood stasis and toxicity). MethodsThe paper used a forward-looking, random double-blind, placebo-controlled design method to select 96 patients with COPD combined with OSAHS, and their traditional Chinese medicines (TCM) syndrome differentiation was deficiency of lung, spleen and kidney with blood stasis and toxicity. These patients were randomly divided into the observation group and the control group, with 48 cases in each group. Based on conventional Western medicine treatment, the observation group was treated with Guben Quyu Jiedu prescription and the control group was treated with traditional Chinese medicine placebo. Both courses of treatment were 90 days. Then the paper compared the changes in minimum pulse oxygen saturation (SpO2) during the night, apnea index (AHI), OSAHS efficacy evaluation, TCM syndrome efficacy evaluation, and TCM symptom score before and after treatment between the two groups. ResultsThere were 5 withdrawals in the observation group and 8 withdrawals in the control group, so 43 cases in the observation group and 40 cases in the control group completed the trial. Compared with the condition before treatment, the minimum SpO2 during the night and AHI in the observation group were significantly improved at night (P<0.01) and were better than those in the control group (P<0.01). OSAHS efficacy in the observation group was better than in the control group (χ2=7.085, P<0.05). In terms of TCM syndrome efficacy, the total effective rate was 81.40% (35/43) in the observation group, significantly higher than that in the control group, which was 15.00% (6/40) (χ2=36.78, P<0.01). The TCM symptom scores of the two groups were improved compared with the condition before treatment, and the effect of the two groups was similar in the four main symptoms of snoring, choking, lethargy, and cough. However, the observation group was better than the control group in 10 details such as dizziness, headache, chest tightness, chest pain, wheezing, dry mouth, and thirst (P<0.05). ConclusionUsing Guben Quyu Jiedu prescription combined with conventional Western medicine can treat COPD combined with OSAHS hypoxemia at night (deficiency of lung, spleen and kidney with blood stasis and toxicity). In this way, the minimum pulse oxygen saturation (SpO2) of patients, the level of disease control, and the quality of life of patients can be improved, and the clinical symptoms can be relieved.
6.Effect of auricular therapy on sleep improvement and the GABAergic system pathway in an insomnia rat model
Hao CHEN ; Xifen ZHANG ; Xuesong WANG ; Yuanbo GAO ; Xuxin LI ; Xihui ZHENG ; Yu WANG ; Xiaojun ZHENG ; Haiping LI ; Yanfen SHE
Journal of Beijing University of Traditional Chinese Medicine 2025;48(1):138-148
Objective:
To investigate the effect of auricular therapy on sleep improvement and the GABAergic system pathway in a rat model of insomnia and to explore its possible mechanism.
Methods:
According to the random number table, 60 male SD rats were randomly divided into blank control, model, auricular point sticking, auricular bloodletting, and auricular bloodletting combined with sticking groups, with 12 rats per group. Insomnia was induced by intraperitoneal injection of p-chlorophenylalanine. After establishing the insomnia model, 36 rats were treated once a day with auricular point sticking or bloodletting for 5 consecutive days. After the intervention, the general condition and body weight of rats were observed; the righting reflex test was used to detect the sleep latency and duration; HE staining was used to observe the morphology of hypothalamic neuron cells; and an enzyme-linked immunosorbent assay was used to detect the GABA and glutamate content in rat serum. Immunohistochemistry(IHC) and real-time fluorescence quantitative PCR were used to detect GABA ARα1 and GABA ARγ2 protein and mRNA expression in the hypothalamus of rats, and Western blotting(WB) was used to detect GABA ARα1, GABA ARγ2, GAD65/67, GAT-1, and GABA-T protein expression in the hypothalamus of rats.
Results:
Compared with the blank control group, the model group had a lower body weight, a significantly shorter sleep duration (P<0.05), severe damage to the morphological structure of hypothalamic neurons with disordered cell arrangement, larger intercellular gaps, enlarged cell bodies, and a vacuolated appearance. All the intervention groups had significantly higher body weight and longer sleep duration than the model group (P<0.05). Compared with the other intervention groups, the auricular point sticking group had a longer sleep duration (P<0.05), and the hypothalamic neuron cells in all intervention groups improved, with the auricular point sticking group showing more apparent improvement. The model group had a lower GABA and higher glutamate contents, and GABA ARα1, GABA ARγ2, and GAD65/67 protein expression in the hypothalamus were lower than in the blank control group. In contrast, GAT-1 and GABA-T protein expression was higher, and GABA ARα1 and GABA ARγ2 mRNA expression was lower (P<0.05). The serum GABA content in the auricular point sticking and auricular bloodletting groups was higher, and the serum glutamate content in the auricular point sticking and auricular bloodletting combined sticking groups was lower than in the model group. GABA ARα1 mRNA expression in the hypothalamus of each intervention group was significantly increased, and GABA ARγ2 mRNA expression in the hypothalamus of the auricular point sticking and auricular bloodletting combined sticking groups increased. GABA ARα1(IHC, WB), GABA ARγ2(WB), and GAD65/67 protein expression in the hypothalamus of the auricular point sticking group increased, whereas GAT-1 and GABA-T protein expression decreased. GABA ARα1 and GABA ARγ2 protein expression(IHC, WB) in the hypothalamus of the auricular bloodletting group increased, whereas GABA-T protein expression decreased. GABA ARγ1(IHC) and GABA ARγ2(WB) protein expression in the hypothalamus of the auricular bloodletting combined sticking group increased, whereas GAT-1 and GABA-T protein expression decreased (P<0.05). Compared with in the inventation groups, the serum GABA content in the auricular point sticking group increased, the serum glutamate content decreased, GABA ARα1 and GABA ARγ2 mRNA expression in the hypothalamus increased, and GABA ARα1(IHC), GAD65/67 protein expression increased. In contrast, GABA-T protein expression decreased (P<0.05), and GABA ARγ2 protein expression(IHC) in the hypothalamus of the auricular bloodletting group increased (P<0.05).
Conclusion
Auricular therapy, particularly auricular point sticking, may have modulated the GABAergic system pathway by upregulating hypothalamic GABA ARα1, GABA ARγ2, and GAD65/67 protein expression while downregulating GAT-1 and GABA-T protein expression to alleviate symptoms in an insomnia rat model.
7.Risk factors of blood transfusion in total knee revision in the United States
Xiaoyin LI ; Liangxiao BAO ; Hao XIE ; Qinfeng YANG ; Pengcheng GAO ; Jian WANG ; Zhanjun SHI
Chinese Journal of Blood Transfusion 2025;38(2):201-208
[Objective] To explore the incidence and risk factors of blood transfusion undergoing total knee revision (TKR) using a nationwide database. [Methods] A retrospective data analysis was conducted based on the Nationwide Inpatient Sample (NIS), enrolling patients who underwent TKR from 2015 to 2019 with complete information. Patients under 18 years old and those using anticoagulants, antiplatelets, antithrombotic and non-steroidal were excluded. The patients were divided into two groups based on whether they received blood transfusion or not. The demographic characteristics, length of stay (LOS), total charge of hospitalization, hospital characteristics, hospital mortality, comorbidities and perioperative complications by Wilcoxon rank test for continuous data and chi-square test for categorical data. Logistic regression was performed to identify risk factors of blood transfusion undergoing TKR. [Results] The NIS database included 63 359 patients who underwent TKR. Among them, 5 271 patients received blood transfusion, with an incidence of blood transfusion of 7.8%. There was a decrease in the incidence over the years from 2015 to 2019, dropping from 10.2% to 6.5%. TKR patients requiring transfusions had experienced longer LOS, incurred higher total medical expenses, utilized Medicare more frequently, and had increased in-hospital mortality rates (all P<0.001). Independent risk factors for blood transfusion included female gender, iron-deficiency anemia, rheumatoid disease, collagen vascular disease, chronic blood loss anemia, congestive heart failure, coagulopathy, diabetes with chronic complications, lymphoma, fluid and electrolyte disorders, peripheral vascular disorders, renal failure, valvular disease and weight loss (malnutrition). In addition, risk factors for transfusion in TKR surgery included sepsis, acute myocardial infarction, deep vein thrombosis, gastrointestinal bleeding, heart failure, pneumonia, urinary tract infection, acute renal failure, postoperative delirium, wound infection, lower limb nerve injury, hemorrhage, seroma, hematoma, wound rupture and non healing. [Conclusion] Our findings highlight the importance of recognizing the risk factors of blood transfusion in TKR and establishing corresponding clinical pathways and intervention measures to reduce the occurrence of adverse events.
8.Effects of loganin on inflammatory response and intestinal barrier damage in septic rats
Can WANG ; Yantao LI ; Zheng ZHOU ; Lupeng WANG ; Yuanyuan GAO ; Shaoxi FAN
China Pharmacy 2025;36(5):574-578
OBJECTIVE To investigate the effects of loganin on inflammatory response and intestinal barrier damage in septic rats by regulating the Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil forming protein kinase 1 (ROCK1) signaling pathway. METHODS A sepsis rat model was established by cecal ligation and puncture, and randomly divided into sepsis group, loganin low-dose group (50 mg/kg loganin, gavage), loganin high-dose group (200 mg/kg loganin, gavage), positive control group (0.2 mg/kg atorvastatin, intraperitoneal injection), and loganin high-dose + lysophosphatidic acid (LPA) group (200 mg/kg loganin gavage and intraperitoneal injection of 10 mg/kg RohA activator LPA). An additional sham surgery group was established. Each group consisted of 10 rats, and medications were administered once every 6 hours for 4 times. After 24 hours of the last intervention, the levels of serum inflammatory factors interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1β were detected. The pathological changes of ileal tissue were observed and Chiu’s intestinal mucosal injury score was also performed. The levels of intestinal function-lactate dehydrogenase (D-lactate), D-amino acid oxidase (DAO) and endotoxin, the percentages of zonula occludens-1 protein (ZO-1) and Occludin positive staining area, as well as protein expressions of RhoA, and ROCK1 were all detected. com RESULTS Compared with the sepsis group, the percentages of ZO-1 and Occludin positive areas increased significantly in loganin low-dose and high-dose groups; while the levels of IL-6, TNF-α, IL-1β, DAO, D-lactate and endotoxin, Chiu’s intestinal mucosal injury score as well as protein expressions of RhoA and ROCK1 decreased significantly (P<0.05); the destruction of rat ileal tissue was alleviated, and tissue edema and inflammatory infiltration were significantly reduced; moreover, the improvement effect in loganin high-dose group was superior to that in loganin low-dose group (P<0.05). Compared with loganin high-dose group, RhoA activator LPA reversed the trend of changes in the above indicators (P<0.05). CONCLUSIONS Loganin can alleviate inflammatory response and intestinal barrier damage in septic rats, the mechanism of which may be associated with inhibiting RhoA/ROCK1 signaling pathway.
9.Availability and use of child safety seats among children aged 0-3 years
CHEN Bo ; WANG Xihui ; QIU Fengqian ; YU Yan ; GAO Shuna ; HE Lihua ; LI Weiyi ; JI Yunfang ; CHEN Weihua
Journal of Preventive Medicine 2025;37(1):21-25
Objective:
To investigate the availability and use of child safety seats among children aged 0-3 years, so as to provide the basis for improving riding safety for children.
Methods:
Parents of children aged 0-3 years in Huangpu District, Shanghai Municipality, were recruited using the stratified multistage random sampling method from May to July 2024. Demographic information, family travel patterns, the use of child safety seat and related health beliefs were collected using questionnaire surveys. Factors affecting the use of child safety seats were identified using a multivariable logistic regression model.
Results:
Totally 514 valid questionnaires were recovered, with an effective rate of 96.98%. The respondents included 122 fathers (23.74%) and 392 mothers (76.26%), with a median age of 34.00 (interquartile range, 5.00) years. There were 446 families equipping with child safety seats, accounting for 86.77%; and 169 families using child safety seats, accounting for 32.88%. Multivariable logistic regression analysis showed that the parents who had children aged >1-2 years (OR=0.597, 95%CI: 0.366-0.973), travelled 2-4 times per month (OR=0.359, 95%CI: 0.213-0.607) or once per month or less (OR=0.384, 95%CI: 0.202-0.729), and scored high in perceived barrier (OR=0.634, 95%CI: 0.486-0.827) were less likely to use child safety seats; the parents who had children with local household registration (OR=2.506, 95%CI: 1.356-4.633), travelled 5-<10 km (OR=1.887, 95%CI: 1.148-3.101) or ≥10 km (OR=2.319, 95%CI: 1.355-3.967), always wore seat belts (OR=2.342, 95%CI: 1.212-4.524), scored high in perceived susceptibility (OR=1.392, 95%CI: 1.091-1.778) and self-efficacy (OR=1.413, 95%CI: 1.156-1.727) were more likely to use child safety seats.
Conclusions
Equipping family cars with child safety seats and using them can prevent and reduce traffic injuries among children aged 0-3 years. It is recommended to strengthen publicity to promote the use of child safety seats.
10.Analysis on the use of medicines in treatment of benign prostatic hyperplasia in sample hospitals under the national volume-based procurement policy
Rui LI ; Qianqian ZHANG ; Ruidong WANG ; Xiaofeng GAO
Journal of Pharmaceutical Practice and Service 2025;43(1):41-46
Objective To explore the impact of national volume-based procurement policies on the use of medicines in treatment of benign prostatic hyperplasia (BPH) and provide data support for the rational clinical use of medicines in BPH treatment. Methods Data on the use of BPH treatment medications from 2019 to 2023 were extracted from the Chinese Medicine Economic Information Network (CMEI), covering 892 hospitals (including 645 tertiary hospitals and 247 secondary hospitals). The changes in various indicators, including the consumption sum, Defined daily doses (DDDs), Defined daily dose cost (DDDc), and the ranking ratio (B/A) of these drugs were analyzed and compared. Results From 2019 to 2023, due to the influence of relevant policies, the overall consumption sums of medicines used in the sample hospitals in BPH treatment showed a trend of decreasing first and then rising steadily. The DDDs showed an overall upward trend, while the DDDc demonstrated a gradual decline. Tamsulosin and finasteride consistently ranked first and second in DDDs. The B/A value for tamsulosin was significantly higher than that of other BPH treatment medications. Conclusion The implementation of national centralized drug volume-based procurement policies and other policies from 2019 to 2023 had effectively reduced the economic burden of patients with benign prostatic hyperplasia. Tamsulosin and finasteride, which had the highest B/A in the two categories of α-blockers and 5α-reductase inhibitors, dominated the market for BPH treatment. The clinical use of BPH treatment medications was relatively rational.


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