1.Construction and Application of "Source-Pivot-Convergence" Pattern Identification and Treatment Model for Malignant Tumors
Yuling JIANG ; Jiawei HE ; Yang ZHONG ; Chunxia HUANG ; Qiong MA ; Chuan ZHENG ; Xi FU ; Fengming YOU
Journal of Traditional Chinese Medicine 2026;67(9):956-960
Based on LI Gao's Academic Thought, focusing on the process of qi transformation and taking the regulation and restoration of metabolism and immunity as the entry point, a "source-pivot-convergence" diagnostic and therapeutic model for malignant tumors is constructed. In this model, spleen and stomach internal injury is the source of malignant tumor occurrence, while the disorder of ascending and descending is the pivot of the disease development, and the generation of yin fire is the convergence of malignant tumor progression. Based on this, the three major therapeutic methods of clearing the source, harmonizing the pivot, and resolving the convergence are established. To fortify spleen and boost qi, consolidate the root and clear the source, modified Buzhong Yiqi Decoction(补中益气汤)can be used. To raise the clear and direct the turbid downward, regulate qi and harmonize the pivot, modified Shengyang Yiwei Decoction (升阳益胃汤) is suggested. To restore balance and promote circulation, disperse accumulation and resolve convergence, modified Shengyang Sanhuo Decoction (升阳散火汤) is selected. In clinical practice, these formulas can be used in combination according to the complexity of the pathogenesis, and further adapted with prescriptions for promoting dispersion and penetrating pathogenic factors, resolving phlegm and promoting circulation, activating blood and eliminating concretions, which can provide a reference for the prevention and treatment of tumor diseases.
2.Construction and Application of "Source-Pivot-Convergence" Pattern Identification and Treatment Model for Malignant Tumors
Yuling JIANG ; Jiawei HE ; Yang ZHONG ; Chunxia HUANG ; Qiong MA ; Chuan ZHENG ; Xi FU ; Fengming YOU
Journal of Traditional Chinese Medicine 2026;67(9):956-960
Based on LI Gao's Academic Thought, focusing on the process of qi transformation and taking the regulation and restoration of metabolism and immunity as the entry point, a "source-pivot-convergence" diagnostic and therapeutic model for malignant tumors is constructed. In this model, spleen and stomach internal injury is the source of malignant tumor occurrence, while the disorder of ascending and descending is the pivot of the disease development, and the generation of yin fire is the convergence of malignant tumor progression. Based on this, the three major therapeutic methods of clearing the source, harmonizing the pivot, and resolving the convergence are established. To fortify spleen and boost qi, consolidate the root and clear the source, modified Buzhong Yiqi Decoction(补中益气汤)can be used. To raise the clear and direct the turbid downward, regulate qi and harmonize the pivot, modified Shengyang Yiwei Decoction (升阳益胃汤) is suggested. To restore balance and promote circulation, disperse accumulation and resolve convergence, modified Shengyang Sanhuo Decoction (升阳散火汤) is selected. In clinical practice, these formulas can be used in combination according to the complexity of the pathogenesis, and further adapted with prescriptions for promoting dispersion and penetrating pathogenic factors, resolving phlegm and promoting circulation, activating blood and eliminating concretions, which can provide a reference for the prevention and treatment of tumor diseases.
3.Association of personality and sleep quality with psychological distress of junior and senior high school stduents
Chinese Journal of School Health 2026;47(1):65-69
Objective:
To explore the effects of personality and sleep quality with psychological distress of junior and senior high school stduents, so as to provide a reference basis for precise interventions of junior and senior high school students mental health.
Methods:
In October 2023, a convenience sampling method was used to select 9 034 students aged 12-17 from Shiyan City as the study subjects. The Pittsburgh Sleep Quality Index (PSQI) and Kessler Psychological Distress Scale (K10) were used to collect information on sleep quality and psychological distress of junior and senior high school stduents. Between group comparison was conducted by using t-test and Chi-square test. Generalized linear models were employed to analyze the interaction and joint effects of personality and sleep quality on psychological distress.
Results:
The generalized linear model analysis showed that the interaction between personality and sleep quality on psychological distress was statistically significant of junior and senior high school students(effect size=0.80, P <0.01). The general linear model analysis indicated that, after adjusting for variables such as age, gender, screen time, and daily sitting time with the extroverted and good sleep quality group as the reference, the introverted and poor sleep quality group had the largest mean difference in psychological distress scores (difference=0.51, P <0.05). When stratified by sleep quality, psychological distress scores were higher in the introverted and neutral personality groups with both poor and good sleep quality compared to the extroverted group (poor sleep quality: introverted difference=3.71, neutral difference=1.14; good sleep quality: introverted difference=2.23, neutral difference=0.57, all P < 0.05). When stratified by personality, psychological distress scores were higher in the poor sleep quality groups for introverted, neutral, and extroverted individuals compared to their good sleep quality counterparts (differences=8.66, 7.83, 7.34, all P < 0.05 ).
Conclusions
Personality and sleep quality have interactive and joint effects on psychological distress of junior and senior high school stduents. Personalized psychological interventions should be developed based on personality and sleep quality.
4.Pathogenesis Evolution of Atherosclerosis Induced by Novel Turbid-toxin Microplastics from Perspective of "Body Fluids and Blood Stasis Mixing"
He GUO ; Ying YANG ; Yi ZHENG ; Zhichao CHEN ; Huan ZHANG ; Ying ZHANG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(13):253-260
From the theoretical perspective of "body fluids and blood stasis mixing", environmental microplastics (MPs) are conceptualized as a "novel turbid-toxin". This study aims to elucidate the complete pathogenic pathway through which MPs act as a key driving force (the "crucible" of pathogenesis) in the initiation and progression of atherosclerosis (AS). By tracing the classical theories in the Chapter The Occurrence of All Diseases of Miraculous Pivot (Ling Shu), this paper clarifies the core connotations of "body fluids"-it not only refers to endogenous pathological fluids and lipid turbidity but also provides a theoretical basis for incorporating "exogenous turbid fluids", thereby laying a logical foundation for conceptualizing MPs as a "novel turbid-toxin". Meanwhile, the implications of "blood" (encompassing both blood quality abnormalities and blood stasis) and the dynamic process of "mixing" are elucidated. Drawing upon modern toxicological evidence, this paper demonstrates the high homology between MPs and "exogenous turbid-fluids" from three aspects: Morphology, toxicity, and invasion routes. The micro/nano-scale particle morphology of MPs enables mobility within the bloodstream. The multiple exposure pathways of MPs correspond to the traditional Chinese medicine understanding of pathogens invading through the mouth, nose, and skin. The characteristics of accumulating in vivo while inducing oxidative stress and inflammatory responses of MPs fully embody the pathogenic features-adhesion, binding, and vessel damage-of "turbid-toxin". On this basis, the dynamic pathogenesis of MP-induced AS is systematically interpreted. Initially, MPs with the "turbid-toxin" nature impair nutrient-defense harmony and cause endothelial dysfunction. Subsequently, as the core of "mixing", they interact with blood lipids and immune cells, generating heat and phlegm to form a major pathological hub of chronic inflammation. Ultimately, this process drives the coalescence of phlegm, stasis, and turbid-toxin into tangible plaques, evolving from stable lesions to vulnerable masses and accumulations. By integrating classical pathogenic model with contemporary environmental medicine, this study establishes an analytical framework that bridges macro-theory and micro-mechanisms for understanding the cardiovascular risks of MPs through an integrative Chinese-Western medicine lens.
5.Prevention and Treatment Strategies for Chronic Atrophic Gastritis Based on Theory of Vigorous Fire Consuming Qi and ROS/NLRP3-mediated Inflammation-mitochondrial Damage Axis
Yu SHEN ; Shijin LIN ; Sihan LI ; Minghan HUANG ; Jingyao SHI ; Zeyu ZHENG ; Chunbo YANG ; Youcheng HE
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(19):287-295
Chronic atrophic gastritis (CAG), a premalignant gastric condition, represents a critical stage in inflammation-cancer transformation. In this pathological process, mitochondrial damage serves as a key mediator in the inflammation-driven transformation of normal gastric mucosal epithelial cells into gastric cancer cells, while the dysregulation of the reactive oxygen species (ROS)/NOD-like receptor protein 3 (NLRP3) axis plays a key role in perpetuating the vicious cycle of inflammation-mitochondrial damage. The classical theory of traditional Chinese medicine (TCM), vigorous fire consuming Qi, aptly encapsulates this pathological feature. The essence of this theory lies in the struggle between pathogenic and vital factors, wherein vigorous fire shares similarities with chronic inflammation and may be regarded as a driving force behind inflammation-cancer transformation. Qi reflects the mitochondrial function, and consuming Qi signifies structural and functional impairment of mitochondria. Thus, this theory accurately summarizes the pathological characteristics of inflammation-mitochondrial damage during CAG progression. Building upon this theoretical framework, the theory of vigorous fire consuming Qi provides a holistic understanding of CAG pathogenesis. Reviewing the clinical expertise of TCM master YANG Chunbo in treating spleen-stomach disorders, this paper further elucidates its therapeutic implications: modulating systemic inflammatory responses to restore gastric mucosal homeostasis and targeting mitochondrial damage as a pivotal intervention to delay CAG progression. Clinically, achieving dynamic equilibrium between fire and Qi is essential, mitigating excessive inflammation without compromising vital Qi, while reinforcing Qi without exacerbating pathological fire. This approach offers novel insights for developing preventive and therapeutic strategies against CAG.
6.The Establishment of a Virus-related Lymphoma Risk Warning System and Health Management Model Based on Traditional Chinese Medicine Conditions
Hanjing LI ; Shunan LI ; Zewei ZHUO ; Shunyong WANG ; Qiangqiang ZHENG ; Bingyu HUANG ; Yupeng YANG ; Chenxi QIU ; Ningning CHEN ; He WANG ; Tingbo LIU ; Haiying FU
Journal of Traditional Chinese Medicine 2025;66(4):335-339
Virus-related lymphoma exhibits a dual nature as both a hematologic malignancy and a viral infectious disease, making it more resistant to treatment and associated with poorer prognosis. This paper analyzes the understanding and therapeutic advantages of traditional Chinese medicine (TCM) in virus-related lymphoma. It proposes a TCM-based approach centered around syndrome differentiation, using standardized measurements of the overall TCM condition, multi-omics research of hematologic tumors, and artificial intelligence technologies to identify the "pre-condition" of virus-related lymphoma. A risk warning model will be established to early identify high-risk populations with viral infections that may develop into malignant lymphoma, thereby establishing a risk warning system for virus-related lymphoma. At the same time, a TCM health management approach will be applied to manage and regulate virus-related lymphoma, interrupting its progression and forming a human-centered, comprehensive, continuous health service model. Based on this, a standardized, integrated clinical prevention and treatment decision-making model for virus-related lymphoma, recognized by both Chinese and western medicine, will be established to provide TCM solutions for primary prevention of major malignant tumors.
7.Study on the distribution of traditional Chinese medicine syndromes and syndrome elements in lymphoma and the correlation between syndromes and Western medicine clinical indicators
Hanjing LI ; Shunan LI ; Zewei ZHUO ; Shunyong WANG ; Qiangqiang ZHENG ; Bingyu HUANG ; Yupeng YANG ; Chenxi QIU ; Ningning CHEN ; Yanyan QIU ; He WANG ; Tingbo LIU ; Haiying FU
Journal of Beijing University of Traditional Chinese Medicine 2025;48(1):127-137
Objective:
To investigate the distribution of traditional Chinese medicine (TCM) syndromes and syndrome elements in lymphoma, as well as the correlation between TCM syndromes and Western clinical indicators, in order to analyze associations between TCM syndromes and these indicators.
Methods:
From January 2023 to May 2024, 216 patients with lymphoma who met the inclusion criteria in the Department of Hematology, Third People′s Hospital Affiliated to Fujian University of Traditional Chinese Medicine were enrolled. Four diagnostic methods were applied to perform TCM syndrome differentiation and extract syndrome elements. The correlations between various syndromes and blood test indicators of lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), white blood cell (WBC), hemoglobin (Hb), platelet count (PLT), neutrophil (NEUT), immunohistochemical markers of B-cell lymphoma-6 (BCL6), B-cell lymphoma-2 (BCL2), proto-oncogene MYC, and Ki67 protein expression, Ann Arbor staging, international prognostic index (IPI) score, bone marrow infiltration, concurrent infections during chemotherapy, and post-chemotherapy bone marrow suppression rate were analyzed.
Results:
Five TCM syndromes, ranked by frequency, were syndromes of yin deficiency with phlegm accumulation(41.67%), qi depression with phlegm obstruction(30.56%), cold-phlegm congelation and stagnation(12.96%), phlegm-blood stasis toxin(12.04%), and lingering pathogen due to deficient vital qi(2.77%). Yin deficiency(50.93%) and phlegm(45.37%) were the more prevalent syndrome elements. The TCM syndromes were correlated with β2-MG, PLT, MYC, BCL2/MYC, Ki67 protein expression, and bone marrow infiltration (P<0.05). No statistically significant differences were observed in Ann Arbor staging or IPI score across the syndromes. Compared to the syndrome of cold-phlegm congelation and stagnation, the syndrome of qi depression with phlegm obstruction exhibited higher levels of NEUT, MYC, BCL2/MYC, and Ki67 protein expression, as well as a higher rate of post-chemotherapy bone marrow suppression (P<0.05); the syndrome of phlegm-blood stasis toxin showed higher MYC and BCL2/MYC protein expression and a higher rate of post-chemotherapy bone marrow suppression rate (P<0.05); the syndrome of yin deficiency with phlegm accumulation demonstrated higher MYC and BCL2/MYC protein expression and bone marrow infiltration rates, whereas PLT level was lower (P<0.05); the syndrome of lingering pathogen due to deficient vital qi had higher MYC, BCL2/MYC, and Ki67 protein expression levels, as well as a higher rate of post-chemotherapy bone marrow suppression rate (P<0.05). Compared to the syndrome of qi depression with phlegm obstruction, the syndrome of phlegm-blood stasis toxin exhibited lower Ki67 protein expression (P<0.05); the syndrome of yin deficiency with phlegm accumulation had higher β2-MG level, bone marrow infiltration rate, and rate of concurrent infections during chemotherapy, whereas PLT and NEUT levels and the rate of post-chemotherapy bone marrow suppression rate were lower (P<0.05). Compared to the syndrome of phlegm-blood stasis toxin, the syndrome of yin deficiency with phlegm accumulation had higher β2-MG level, whereas NEUT and the rate of post-chemotherapy bone marrow suppression were lower(P<0.05); the syndrome of lingering pathogen due to deficient vital qi exhibited a higher Ki67 protein expression (P<0.05). Compared to the syndrome of yin deficiency with phlegm accumulation, the syndrome of lingering pathogen due to deficient vital qi also showed a higher Ki67 protein expression(P<0.05).
Conclusion
The syndrome of yin deficiency with phlegm accumulation is relatively common in lymphoma. There is a correlation between TCM syndromes and Western medicine clinical indicators. The presence of heat signs in the syndromes may indicate active disease and poor prognosis, while the presence of strong pathogenic factors and weak vital qi in the syndromes may indicate a severer chemotherapy-related bone marrow suppression.
8.Effect of ocular hypotensive agents on the intraocular metabolism of ranibizumab in rabbit
Tianyang ZHOU ; Jingjing YANG ; Xiang LI ; Huiyun XIA ; Jijun HE ; Zheng YUAN ; Junjie ZHANG
Chinese Journal of Experimental Ophthalmology 2025;43(5):438-442
Objective:To compare the effects of brinzolamide-timolol (B&T) eye drops and dipivefrine hydrochloride (DH) eye drops on the intraocular metabolism of ranibizumab after intravitreal injection in rabbit.Methods:Eighteen New Zealand white rabbits were randomly and equally divided into DH group, B&T group, and control group.The right eye was selected as the experimental eye.The B&T and DH groups received DH and B&T eye drops, respectively, twice daily, 30 μl each time.The control group did not receive any treatment.Intraocular pressure (IOP) was measured in both eyes before the first administration and 1 hour after the first administration on the second day.After IOP measurement, the experimental eye received an intravitreal injection of 0.25 mg ranibizumab (10 mg/ml).Aqueous humor samples were collected 1, 3, 7, 10, 14, 21 and 28 days after injection.Ranibizumab concentration in the aqueous humor was measured by ELISA kit.Pharmacokinetic parameters including time to peak concentration ( tmax), peak concentration ( Cmax), elimination half-life ( t1/2) and area under the concentration-time curve (AUC) of ranibizumab were calculated.This experiment was approved by the Ethics Committee of Henan Eye Hospital (No.HNEECA-2023-03). Results:The tmax of ranibizumab in the aqueous humor was 1 day in all three groups.The Cmax values in the control, B&T and DH groups were (8.122±2.445), (13.079±3.140) and (8.299±0.899)μg/ml, respectively.Except for day 3 in the control group, the ranibizumab concentrations in aqueous humor of the B&T group were higher than that of the DH group and the control group at all time points after injection, with statistically significant significances (all P<0.05).The t1/2 of ranibizumab in aqueous humor in the control group, B&T group, and DH group were (2.90±0.29), (3.36±0.35) and (2.80±0.29) days, respectively, and the AUC0-t values were (52.697±10.178), (80.244±11.249) and (51.985±8.734)μg/ml·d, respectively.The t1/2 and AUC0-t of ranibizumab in aqueous humor of the B&T group were significantly higher than those of the DH group and the control group, and the differences were statistically significant (all P<0.05).The mean bioavailability in the B&T group was increased by 52.3% compared to the control group. Conclusions:B&T eye drops prolong the half-life and enhance the intraocular bioavailability of ranibizumab after intravitreal injection in rabbits, whereas DH has no significant effect on its intraocular metabolism.
9.Analysis of echinococcosis in the population and canine Echinococcus infection in Yushu City, Qinghai Province in 2023
Xiaojin MO ; Chunhua GONG ; Wentao GUO ; Gengcheng HE ; Bin JIANG ; Qiufeng LAN ; Xiao MA ; Yufang LIU ; Guirong ZHENG ; Tian TIAN ; Shijie YANG ; Shusheng WU ; Ting ZHANG ; Xiaonong ZHOU
Chinese Journal of Endemiology 2025;44(8):668-673
Objective:To study echinococcosis in the population and canine Echinococcus infection in Yushu City, Qinghai Province, and to explore the current epidemic situation and main transmission species of Echinococcus. Methods:In June 2023, a multi-stage sampling method was used to select 2 villages each in Shanglaxiu Township and Longbao Town, Yushu City, Qinghai Province. Each village included at least 100 permanent residents who had lived locally for at least 1 year and were 2 years old or older as the survey subjects. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum antibodies against Echinococcus larvae in the population, and B-mode ultrasound was used for abdominal organ scanning. Meanwhile, on the main roads of Shanglaxiu Township and Longbao Town, canine feces were collected in designated areas at intervals. ELISA was used to detect the antigen of canine fecal Echinococcus, and PCR was used to detect the types of parasites ( Echinococcus multilocularis, Echinococcus granulosus and Echinococcus shiquicus). Results:A total of 511 residents were investigated in Yushu City, and the positive rate of serum Echinococcus larvae antibodies in the population was 26.22% (134/511), and the detection rate of echinococcosis B-mode ultrasound was 1.37% (7/511). Among them, the detection rates of B-mode ultrasound for cystic echinococcosis (CE) and alveolar echinococcosis (AE) were 1.17% (6/511) and 0.20% (1/511), respectively. The positive rate of Echinococcus antigen in 543 canine feces detected by ELISA was 12.89% (70/543). PCR was used to test 497 canine feces, and the detection rate of Echinococcus was 3.02% (15/497). Among them, the detection rate of Echinococcus multilocularis was higher than that of Echinococcus granulosus [2.82% (14/497) vs 0.20% (1/497)], and the difference was statistically significant (χ 2 = 11.44, P < 0.001). No Echinococcus shiquicus was detected. Conclusions:The positive rates of Echinococcus larvae antibodies in the population and canine Echinococcus antigen in Yushu City, Qinghai Province are both relatively high. There is a mixed epidemic of CE and AE, with Echinococcus multilocularis being the main species.
10.Clinical value of evaluation of anatomical position of inferior mesenteric artery and vein as well as left colic artery in laparoscopic radical resection of colorectal
Bo ZHANG ; Tao WU ; Shuai ZHOU ; Ling DANG ; Jiaxing HE ; Ying YANG ; Zhuo HAN ; Longlong ZHENG ; Nan WANG
Chinese Journal of Digestive Surgery 2025;24(6):754-761
Objective:To investigate the clinical value of laparoscopic evaluation of anato-mical position of inferior mesenteric artery (IMA), inferior mesenteric vein (IMV) and left colic artery (LCA).Methods:The prospective one-arm study was conducted. The clinical data of 229 pati-ents who underwent laparoscopic left hemicolectomy for left colon or laparoscopic radical resection of rectal cancer in The Second Affiliated Hospital of Air Force Medical University from December 2022 to December 2023 were selected. The distance between the origin point of IMA and the origin point of the first branch (L1) as well as the distance from the origin point of LCA root to the junction of LCA and IMV (L2) were measured during the operation. IMA classification, the location relation-ship of LCA and IMV junction were recorded. Observation indicators: (1) situations of enrolled patients; (2) difference analysis between L1, L2 and clinical features; (3) distribution characteristics of the location relationship between LCA and IMV in different types of IMA. Mann-Whitney U test was used for comparison of measurement data with skewed distribution between groups, Kruskal-Wallis H test was used for comparison between multiple groups, and Dunn-Bonferroni test was used for pairwise comparison. Comparison of count data between groups was performed by chi-square test. Pearson or Spearman correlation analysis was conducted for correlation of continuous variables. Results:(1) Situations of enrolled patients. A total of 229 eligible patients were screened out, including 146 males and 83 females, aged 64(range, 55-71)years. The height of 229 patients was 168(range, 160-172)cm, the weight was 65.0(55.5,71.5)kg, the body surface area was (1.68±0.17)m 2, the tumor maximum diameter was 3.0(2.5,4.0)cm. The total number of lymph nodes dissected was 19(17,21), and the number of No.253 lymph node dissected was 4(3,5). The L1 was 3.50(1.20,8.00)cm, and the L2 was 2.20(0.50,7.30)cm. There were 58, 31, 32, 71, 22, 90, 26 and 212 patients with smoking, alcohol drinking, diabetes, hypertension, coronary heart disease, neoadjuvant chemo-therapy, neoadjuvant radiotherapy and preservation of the LCA, respectively. Among 229 patients, cases with BMI <18.5 kg/m 2, 18.5-23.9 kg/m 2 and >23.9 kg/m 2 were 11, 133 and 85, respectively. There were 153 cases in pathological stage Ⅰ-Ⅱ and 76 cases in stage Ⅲ. There were 168 cases of Dixon operation, 6 cases of Miles operation and 55 cases of sigmoid colon resection. There were 135 cases of IMA type 1, 44 cases of IMA type 2, 23 cases of IMA type 3, 2 cases of IMA type 4, and 25 cases of IMA type unable to judge. (2) Difference analysis between L1, L2 and clinical features.Correlation analysis showed negative correlation between the height, body surface area and L1 ( r=-0.17, -0.15, P<0.05). The L1 was 3.20(2.68,4.00)cm for male patients and 3.60(3.00,4.20)cm for female patients, respectively, showing a significant difference between the two groups ( Z=-2.37, P<0.05). The L1 of patients with IMA type 1, 2, and 3 was 3.20(2.80,4.00)cm, 3.85(3.00,4.48)cm, and 3.20(2.50,4.30)cm, respectively, showing a significant difference among them ( H=7.54, P<0.05). Further pairwise com-parison showed that there was a significant difference in L1 between patients with IMA type 2 and those with IMA type 1 ( P<0.05). The L2 of smokers and non-smokers were 2.50(1.95,3.20)cm and 2.20(1.60,2.80)cm, respectively, showing a significant difference between the two groups ( Z=-2.24, P<0.05). (3)Distribution characteristics of the location relationship between LCA and IMV in different types of IMA. There was no significant difference in LCA distribution between the anterior and posterior positions of IMV among the three IMA types (type 1, 2, 3) ( χ2=1.63, P>0.05). Conclusions:Patients with greater height have larger body surface area and shorter L1. L1 is significantly longer in female patients than in male patients. L1 is significantly longer in patients with IMA type 2 than in those with type 1. L2 is significantly longer in smokers than in non-smokers. There was no significant difference in the distribution location between LCA and IMV among patients of IMA type 1, 2 and 3.


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