1.Effects and mechanism of short-acting exenatide on improving diabetic cognitive dysfunction
Xin LING ; Deming WANG ; Qi LU ; Jinyue HUANG ; Xian ZHENG ; Xiaona ZHU
China Pharmacy 2026;37(5):589-594
OBJECTIVE To investigate the ameliorative effect and mechanism of short-acting exenatide on diabetic cognitive dysfunction. METHODS Spontaneously diabetic db / db mice were randomly divided into model group (normal saline) and exenatide group (50 μg/kg), with db / m mice as the normal control group (normal saline), with 8 mice in each group. Mice in each group were subcutaneously injected with corresponding drugs or normal saline twice daily for 8 consecutive weeks. Body weight and fasting blood glucose were measured at a fixed time every week. Cognitive function was evaluated by Morris water maze test. The levels of oxidative st ress indicators [malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) ] , cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) were detected in hippocampus tissue of mice. The hippocampal neuronal HT22 cells of mice were divided into control group (25 mmol/L glucose), high glucose group (125 mmol/L glucose), high glucose+exenatide group (125 mmol/L glucose+20 nmol/L exenatide), high glucose+exenatide+H89 (PKA inhibitor) group (125 mmol/L glucose+20 nmol/L exenatide+10 μmol/L H89), and high glucose+H89 group (125 mmol/L glucose+10 μmol/L H89). After 48 h of intervention with corresponding solutions/culture medium, the levels of oxidative stress indicators, cAMP and PKA, the activities of mitochondrial respiratory enzymes Ⅱ and Ⅳ, and the phosphorylation level of dynamin-related protein 1 (Drp1) were measured. RESULTS Animal experiments showed that compared with the normal control group, the model group exhibited significantly increased body weight, fasting blood glucose and MDA level in the hippocampus ( P <0.05), as well as significantly prolonged escape latency ( P <0.05); swimming speed significantly slowed down, the time spent in the target quadrant, the number of platform crossings, and the levels of SOD, GSH, cAMP and PKA in the hippocampus were significantly decreased ( P <0.05). Compared with model group, all the above indicators (except for swimming speed) in the exenatide group were significantly reversed ( P <0.05). Cell experiments showed that compared with high glucose group, the high glucose+exenatide group had significantly decreased MDA level ( P <0.05), and significantly increased levels of SOD, GSH, cAMP and PKA, the activities of mitochondrial respiratory enzymes Ⅱ and Ⅳ, and phosphorylation level of Drp1 ( P <0.05). Compared with high glucose+exenatide group, the above indicators in the high glucose+exenatide+H89 group were significantly reversed ( P <0.05). CONCLUSIONS Short-acting exenatide can activate the cAMP/PKA pathway, promote Drp1 phosphorylation, and increase the activities of mitochondrial respiratory enzymes, thereby maintaining mitochondrial stability, reducing oxidative stress injury, and ultimately improving diabetic cognitive dysfunction.
2.Association between random urine electrolytes and hypertension in children and adolescents
Chinese Journal of School Health 2026;47(3):314-318
Objective:
To systematically evaluate the association between random urinary electrolyte levels and hypertension among children and adolescents in Guizhou Province, so as to provide evidence for region specific dietary guidance and interventions.
Methods:
In 2023, a total of 2 480 children and adolescents aged 6 to 17 years were recruited from a nine-year coherent style school in Guizhou Province in a children health cohort, with follow ups conducted in 2024 and 2025. Random urine samples were collected to measure urinary sodium, potassium, calcium, and chloride, and the urinary sodium to potassium ratio (Na/K) was calculated. The diagnosis of hypertension was based on the criteria established by the Chinese Guidelines for Hypertension Prevention and Treatment (2024 revised edition) and relevant research. Linear mixed models and multinomial Logistic regression were used to assess the associations of urinary electrolytes with systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and the risk of hypertension.
Results:
At baseline, SBP, DBP, and MAP were 102.33 (94.33, 110.33), 61.33 (56.33, 67.00) and 75.22 (69.67, 81.33)mmHg among children and adolescents, respectively. After adjusting for potential confounders and two follow-ups, higher urinary Na/K ratio was positively associated with higher of SBP ( β=0.054, 95%CI =0.028- 0.081 ) and MAP ( β=0.038, 95%CI =0.010-0.066), as well as higher risks of hypertension ( OR=1.248, 95%CI =1.006-1.548) (all P <0.05). Higher of urinary chloride levels were positively associated with higher of SBP ( β=0.088, 95%CI = 0.009- 0.167), whereas higher of urinary potassium (SBP: β=-0.062, 95%CI =-0.096 to -0.028; MAP: β=-0.041, 95%CI = -0.078 to -0.005) and calcium levels (SBP: β=-0.036, 95%CI =-0.065 to -0.007) were negatively associated with blood pressure (all P < 0.05 ).
Conclusion
The urinary Na/K, as a comprehensive electrolyte marker, more stably reflects sodium load and excretory pressure in children and adolescents, and may serve as an early predictor of hypertension risk.
3.Influence of blood pressure variability and dyslipidemia on prognosis in young and middle-aged patients with ischemic stroke
Min LI ; Ping JU ; Ran GENG ; Xiaona ZHU ; Lingxin KONG
Journal of Public Health and Preventive Medicine 2026;37(2):166-169
Objective To understand the current status of blood pressure variability and dyslipidemia in young and middle-aged patients with ischemic stroke, and to explore their relationship with prognosis. Methods A total of 312 young and middle-aged patients with ischemic stroke who met the inclusion criteria in Beijing Pinggu District Hospital from January 2022 to January 2025 were selected. The prognosis status [modified Rankin scale (mRS)], blood pressure variability, and blood lipids [total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)] were analyzed. The correlation of blood pressure variability and blood lipids levels with prognosis was explored by logistic regression analysis. Results There were 206 patients with good prognosis and 106 patients with poor prognosis. The number of patients who received diversified health education in the good prognosis group was more than that in the poor prognosis group (P<0.05). The systolic blood pressure successive variation (SV) and average real variability (ARV), and diastolic blood pressure SV and ARV were lower in the good prognosis group than those in the poor prognosis group (P<0.05). Furthermore, compared with the poor prognosis group, the good prognosis group had lower levels of TC, TG and LDL-C, while the number of patients receiving diversified health education and the level of HDL-C were higher (P<0.05). After logistic regression analysis, it was found that the levels of TC, TG, LDL-C, systolic blood pressure SV and ARV, and diastolic blood pressure SV and ARV were risk factors for poor prognosis. Conversely, receiving diversified health education and HDL-C level were protective factors for poor prognosis (P<0.05). Conclusion High blood pressure fluctuation, dyslipidemia, and lack of health education will increase the risk of poor prognosis in young and middle-aged stroke patients.
4.Systematic review of renal metastases in differentiated thyroid cancer
Lu CHEN ; Shiguang CAO ; Yujun WANG ; Xiaona ZHU ; Fansheng MENG ; Zhanyu TIAN
Chinese Journal of Nuclear Medicine and Molecular Imaging 2025;45(8):503-507
Renal metastasis from differentiated thyroid cancer (DTC) is uncommon and is hard to be distinguished from primary renal cell carcinoma. There is no consensus on diagnosis and treatment, and decisions about surgery and 131I therapy doses usually depend on experience. To better understand clinical characteristics and current treatment status, this study systematically reviews existing studies, exploring epidemiological features, clinical symptoms, imaging findings (including lesions characteristics across various imaging modalities), therapeutic strategies, and prognosis of DTC renal metastases, providing evidence-based references for clinical practice.
5.Oral Herombopag Olamine and subcutaneous recombinant human thrombopoietin after haploidentical hematopoietic stem cell transplantation
Dai KONG ; Xinkai WANG ; Wenhui ZHANG ; Xiaohang PEI ; Cheng LIAN ; Xiaona NIU ; Honggang GUO ; Junwei NIU ; Zunmin ZHU ; Zhongwen LIU
Chinese Journal of Tissue Engineering Research 2025;29(1):1-7
BACKGROUND:Allogeneic hematopoietic stem cell transplantation is an important treatment for malignant hematological diseases,and delayed postoperative platelet implantation is a common complication that seriously affects the quality of patient survival;however,there are no standard protocols to improve platelet implantation rates and prevent platelet implantation delays. OBJECTIVE:To compare the safety and efficacy of oral Herombopag Olamine versus subcutaneous recombinant human thrombopoietin for promoting platelet implantation in patients with malignant hematological diseases undergoing haploid hematopoietic stem cell transplantation. METHODS:Clinical data of 163 patients with malignant hematological diseases who underwent haploidentical hematopoietic stem cell transplantation from January 2016 to October 2022 were retrospectively analyzed.A total of 72 patients who started to subcutaneously inject recombinant human thrombopoietin at+2 days were categorized into the recombinant human thrombopoietin group;a total of 27 patients who started to orally take Herombopag Olamine at+2 days were categorized into the Herombopag Olamine group;and 64 patients who did not apply Herombopag Olamine or recombinant human thrombopoietin were categorized into the blank control group.The implantation status,incidence of acute graft-versus-host disease of degree II-IV within 100 days,1-year survival rate,1-year recurrence rate,and safety were analyzed in the three groups. RESULTS AND CONCLUSION:(1)The average follow-up time was 52(12-87)months.The implantation time of neutrophils in the blank control group,recombinant human thrombopoietin group,and Herombopag Olamine group was(12.95±3.88)days,(14.04±3.71)days,and(13.89±2.74)days,respectively,with no statistically significant difference(P=0.352);the implantation time of platelets was(15.16±6.27)days,(17.67±6.52)days,and(17.00±4.75)days,with no statistically significant difference(P=0.287).(2)The complete platelet implantation rate on day 60 was 64.06%,90.28%,and 92.59%,respectively,and the difference was statistically significant(P<0.001).The subgroup analysis showed that the difference between the blank control group and the recombinant human thrombopoietin group was statistically significant(P<0.001),and the difference between the blank control group and the Herombopag Olamine group was statistically significant(P=0.004).The difference was not statistically significant between the recombinant human thrombopoietin group and Herombopag Olamine group(P=0.535).(3)100-day II-IV degree acute graft-versus-host disease incidence in the blank control group,recombinant human thrombopoietin group,and Herombopag Olamine group were 25.00%,30.56%,and 25.93%,respectively,and the difference was not statistically significant(P=0.752).(4)The incidence of cytomegalovirus anemia,cytomegalovirus pneumonia,and hepatic function injury had no statistical difference among the three groups(P>0.05).(5)During the follow-up period,there was no thrombotic event in any of the three groups of patients.(6)The results showed that recombinant human thrombopoietin and Herombopag Olamine could improve the platelet implantation rate of malignant hematological disease patients after haploidentical hematopoietic stem cell transplantation,with comparable efficacy and good safety.
6.Effect of ropivacaine combined with dexmedetomidine in serratus anterior plane block on postoperative analgesia in patients undergoing breast cancer surgery
Lyudan HUANG ; Weijuan ZHU ; Jing HUANG ; Xiaona ZHU
Chongqing Medicine 2025;54(8):1854-1858
Objective To observe the effect of ropivacaine combined with dexmedetomidine in serratus anterior plane block on postoperative analgesia in patients undergoing breast cancer surgery.Methods Ninety patients scheduled for modified radical mastectomy in this hospital from May to October 2023 were divided in-to three groups by using random number table method:the R0.375 group,the DR0.375 group and the R0.500 group,with 30 cases in each group.All the three groups received serratus anterior plane block before surgery.The R0.375 group was injected with 20 mL of 0.375%ropivacaine,the DR0.375 group with 20 mL of a mix-ture of 0.375%ropivacaine and 1.0 μg/kg dexmedetomidine,and the R0.500 group with 20 mL of 0.500%ropivacaine.All patients received opioid-based patient-controlled intravenous analgesia pump after surgery.The numerical rating scale(NRS)was used to assess resting and movement pain at 1,2,6,12 and 24 hours postoperatively,and the pain-time area under the curve(AUC)was calculated.Postoperative opioid consump-tion,time of first analgesic drugs use were recoreded;sedation status at 1 hour postoperatively was evaluated by the American society of anesthesiologists(ASA)grading,quality of life at 24 hours postoperatively was as-sessed by the 15-item quality of recovery(QoR-15)scale,and postoperative adverse reactions were recorded.Results Compared with the R0.375 group,AUC of the resting pain-time and movement pain-time and the opioid consumption at 12 and 24 hours postoperatively of the DR0.375 group and the R0.500 groups were re-duced(P<0.05),while QoR-15 score after surgery was increased(P<0.05).The time of first analgesic drugs use in the R0.500 group was significantly longer than that in the R0.375 group(P<0.05).At one hour after surgery,all the three groups were evaluated as having mild to moderate sedation,with no statistical-ly significant differences among groups(P>0.05).There were also no statistically significant differences in the incidence of postoperative adverse reactions among the three groups(P>0.05).Conclusion Dexmedeto-midine can significantly improve the analgesic effect of low-concentration ropivacaine in serratus anterior plane block and reduce postoperative opioid consumption.
7.Exploration on the Mechanism of Huatan Quyu Decoction in Treating Vascular Dementia Based on Wnt/β-catenin Signaling Pathway
Wanyu ZHAO ; Yongjun FANG ; Yali HU ; Pengfang WEI ; Sen QIAO ; Jingyuan KONG ; Xiaona ZHU ; Hui LIU ; Yuqian TIAN ; Yongmei YAN
Chinese Journal of Information on Traditional Chinese Medicine 2025;32(5):98-105
Objective To investigate the effects and mechanisms of Huatan Quyu Decoction on learning and memory abilities in rats with vascular dementia(VD).Methods Totally 112 male SD rats were randomly selected with 16 rats as the sham-operation group,the remaining rats were used to prepare VD models by segmental ligation of the common carotid artery.The successfully modeled rats were randomly divided into model group,Huatan Quyu Decoction low-,medium-and high-dosage groups(6.1,12.1,24.2 g/kg),donepezil hydrochloride group(0.5 mg/kg)and combination group(Huatan Quyu Decoction 12.1 g/kg+donepezil hydrochloride 0.5 mg/kg),with 16 rats in each group.Each group was given the corresponding treatment measures for 4 weeks.The Morris water maze test was used to assess learning and memory abilities,neurological function was evaluated using Garcia score,HE staining was used to observe the morphology of the hippocampal tissue,ELISA was employed to detect the serum content of Aβ,immunohistochemistry was utilized to observe the β-catenin,LRP6 and GSK-3β protein expression in brain tissue.Results Compared with the sham-operation group,the escape latency of the model group rats was prolonged(P<0.01),the number of crossing platforms was reduced(P<0.01),and the neurological deficit score was decreased(P<0.01),the arrangement of hippocampal tissue cells was disorderly,and the tissue was severely damaged,the serum Aβ content increased(P<0.01),the expressions of β-catenin and LRP6 protein in brain tissue decreased,and the expression of GSK-3β protein increased(P<0.01).Compared with the model group,the escape latency of rats in each administration group was shortened,the number of crossing platforms increased,the neurological deficit score increased,the number of hippocampal cells was relatively more,the arrangement was more orderly,and the structure was relatively complete,the serum Aβ content decreased,the expressions of β-catenin and LRP6 proteins increased,and the expression of GSK-3β protein decreased.Among them,Huatan Quyu Decoction high-dosage group had a significantly better effect than Huatan Quyu Decoction low-and medium-dosage groups(P<0.01),and there was no statistical significance in various indicators compared with the donepezil hydrochloride group(P>0.05).Compared with the donepezil hydrochloride group,the combination group showed significant improvements in learning and memory abilities(P<0.01),the neurological deficit score significantly increased(P<0.01),the number of hippocampal cells significantly increased,arranged neatly,and structurally intact,the serum Aβ content significantly decreased(P<0.01),the expression of β-catenin and LRP6 proteins significantly increased,and the expression of GSK-3β protein significantly decreased(P<0.01).Conclusion Huatan Quyu Decoction can repair cognitive function in VD rats,improve learning and memory abilities,and alleviate VD symptoms by activating the Wnt/β-catenin signaling pathway to reduce serum Aβ content,decrease the apoptosis of nerve cells and alleviate the degree of pathological damage in hippocampal tissue.
8.The Impact of WeiDiao No.3 Formula on the Survival Outcomes of Patients with Advanced Non-Small Cell Lung Cancer of Lung-Spleen Qi Deficiency Type:A Retrospective Cohort Study
Liming ZHU ; Yuetong XIA ; Xiaona HUANG ; Jiayao XU ; Chunhui JIN
Journal of Nanjing University of Traditional Chinese Medicine 2025;41(12):1647-1656
OBJECTIVE To observe the effect of the Chinese herbal compound Weidiao No.3 Formula(WD-3)combined with immunotherapy and chemotherapy on survival outcomes in patients with advanced non-small cell lung cancer(NSCLC)with lung-spleen qi dificiency type.METHODS A total of 216 patients with stage Ⅲb-Ⅳ NSCLC without driver gene mutations and with lung-spleen qi vacuity pattern and admitted to the oncology departments of Wuxi Hospital of Traditional Chinese Medicine and Jiangnan Uni-versity Affiliated Hospital between January 1,2020,and March 1,2025,were enrolled.Based on whether they received WD-3 oral treatment(≥3 months),they were divided into a Chinese medicine exposure group(n=98;WD-3+immunotherapy combined with chemo-therapy)and a non-exposure group(n=118;immunotherapy combined with chemotherapy alone).Propensity score matching(PSM)was used to balance baseline characteristics.Overall survival(OS),progression-free survival(PFS),and baseline characteristics were com-pared between the two groups.Cox proportional hazards regression model was used to analyze the association between exposure and outcome,and sensitivity analysis was performed.RESULTS After PSM,there were no statistically significant differences in baseline characteristics between the two groups(P>0.05).After matching,the median OS(32.92 months)and median PFS(9.07 months)in the Chinese medicine exposure group were longer than those in the non-exposure group(23.24 months and 7.89 months,respectively),with statistically significant differences(P<0.05).Multivariate analysis was conducted,incorporating age,PD-L1 expression,KPS score,pathological type,and other factors as covariates to assess the independent association between WD3 exposure and OS and PFS outcomes.The results indicated that WD3 exposure was statistically significant in reducing the risk of death(OS outcome)and disease progression(PFS outcome).Specifically,for the OS outcome,the HR was 0.626,with a 95%CI of 0.438 to 0.894,and P=0.01;for the PFS outcome,the HR was 0.721,with a 95%CI of 0.535 to 0.972,and P=0.032.Sensitivity analysis showed robust results(E-value>2.1).CONCLUSION WD-3 combined with immunotherapy and chemotherapy may prolong OS and PFS and reduce mortality risk in patients with advanced NSCLC without driver gene mutations and with lung-spleen qi dificiency type,achieves adequate therapeutic effects.
9.Exploration on the Mechanism of Huatan Quyu Decoction in Treating Vascular Dementia Based on Wnt/β-catenin Signaling Pathway
Wanyu ZHAO ; Yongjun FANG ; Yali HU ; Pengfang WEI ; Sen QIAO ; Jingyuan KONG ; Xiaona ZHU ; Hui LIU ; Yuqian TIAN ; Yongmei YAN
Chinese Journal of Information on Traditional Chinese Medicine 2025;32(5):98-105
Objective To investigate the effects and mechanisms of Huatan Quyu Decoction on learning and memory abilities in rats with vascular dementia(VD).Methods Totally 112 male SD rats were randomly selected with 16 rats as the sham-operation group,the remaining rats were used to prepare VD models by segmental ligation of the common carotid artery.The successfully modeled rats were randomly divided into model group,Huatan Quyu Decoction low-,medium-and high-dosage groups(6.1,12.1,24.2 g/kg),donepezil hydrochloride group(0.5 mg/kg)and combination group(Huatan Quyu Decoction 12.1 g/kg+donepezil hydrochloride 0.5 mg/kg),with 16 rats in each group.Each group was given the corresponding treatment measures for 4 weeks.The Morris water maze test was used to assess learning and memory abilities,neurological function was evaluated using Garcia score,HE staining was used to observe the morphology of the hippocampal tissue,ELISA was employed to detect the serum content of Aβ,immunohistochemistry was utilized to observe the β-catenin,LRP6 and GSK-3β protein expression in brain tissue.Results Compared with the sham-operation group,the escape latency of the model group rats was prolonged(P<0.01),the number of crossing platforms was reduced(P<0.01),and the neurological deficit score was decreased(P<0.01),the arrangement of hippocampal tissue cells was disorderly,and the tissue was severely damaged,the serum Aβ content increased(P<0.01),the expressions of β-catenin and LRP6 protein in brain tissue decreased,and the expression of GSK-3β protein increased(P<0.01).Compared with the model group,the escape latency of rats in each administration group was shortened,the number of crossing platforms increased,the neurological deficit score increased,the number of hippocampal cells was relatively more,the arrangement was more orderly,and the structure was relatively complete,the serum Aβ content decreased,the expressions of β-catenin and LRP6 proteins increased,and the expression of GSK-3β protein decreased.Among them,Huatan Quyu Decoction high-dosage group had a significantly better effect than Huatan Quyu Decoction low-and medium-dosage groups(P<0.01),and there was no statistical significance in various indicators compared with the donepezil hydrochloride group(P>0.05).Compared with the donepezil hydrochloride group,the combination group showed significant improvements in learning and memory abilities(P<0.01),the neurological deficit score significantly increased(P<0.01),the number of hippocampal cells significantly increased,arranged neatly,and structurally intact,the serum Aβ content significantly decreased(P<0.01),the expression of β-catenin and LRP6 proteins significantly increased,and the expression of GSK-3β protein significantly decreased(P<0.01).Conclusion Huatan Quyu Decoction can repair cognitive function in VD rats,improve learning and memory abilities,and alleviate VD symptoms by activating the Wnt/β-catenin signaling pathway to reduce serum Aβ content,decrease the apoptosis of nerve cells and alleviate the degree of pathological damage in hippocampal tissue.
10.The Impact of WeiDiao No.3 Formula on the Survival Outcomes of Patients with Advanced Non-Small Cell Lung Cancer of Lung-Spleen Qi Deficiency Type:A Retrospective Cohort Study
Liming ZHU ; Yuetong XIA ; Xiaona HUANG ; Jiayao XU ; Chunhui JIN
Journal of Nanjing University of Traditional Chinese Medicine 2025;41(12):1647-1656
OBJECTIVE To observe the effect of the Chinese herbal compound Weidiao No.3 Formula(WD-3)combined with immunotherapy and chemotherapy on survival outcomes in patients with advanced non-small cell lung cancer(NSCLC)with lung-spleen qi dificiency type.METHODS A total of 216 patients with stage Ⅲb-Ⅳ NSCLC without driver gene mutations and with lung-spleen qi vacuity pattern and admitted to the oncology departments of Wuxi Hospital of Traditional Chinese Medicine and Jiangnan Uni-versity Affiliated Hospital between January 1,2020,and March 1,2025,were enrolled.Based on whether they received WD-3 oral treatment(≥3 months),they were divided into a Chinese medicine exposure group(n=98;WD-3+immunotherapy combined with chemo-therapy)and a non-exposure group(n=118;immunotherapy combined with chemotherapy alone).Propensity score matching(PSM)was used to balance baseline characteristics.Overall survival(OS),progression-free survival(PFS),and baseline characteristics were com-pared between the two groups.Cox proportional hazards regression model was used to analyze the association between exposure and outcome,and sensitivity analysis was performed.RESULTS After PSM,there were no statistically significant differences in baseline characteristics between the two groups(P>0.05).After matching,the median OS(32.92 months)and median PFS(9.07 months)in the Chinese medicine exposure group were longer than those in the non-exposure group(23.24 months and 7.89 months,respectively),with statistically significant differences(P<0.05).Multivariate analysis was conducted,incorporating age,PD-L1 expression,KPS score,pathological type,and other factors as covariates to assess the independent association between WD3 exposure and OS and PFS outcomes.The results indicated that WD3 exposure was statistically significant in reducing the risk of death(OS outcome)and disease progression(PFS outcome).Specifically,for the OS outcome,the HR was 0.626,with a 95%CI of 0.438 to 0.894,and P=0.01;for the PFS outcome,the HR was 0.721,with a 95%CI of 0.535 to 0.972,and P=0.032.Sensitivity analysis showed robust results(E-value>2.1).CONCLUSION WD-3 combined with immunotherapy and chemotherapy may prolong OS and PFS and reduce mortality risk in patients with advanced NSCLC without driver gene mutations and with lung-spleen qi dificiency type,achieves adequate therapeutic effects.


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