1.Clinical Efficacy of Tonifying Kidney and Replenishing Essence on Asthenospermia Patients with Syndrome of Kidney Essence Deficiency and Effect of This Method on Expression Levels of AMPK/mTORC1 Signaling Pathway-associated Proteins
Yuanjie FU ; Fuhao LI ; Chenghua PENG ; Dong XU ; Guoan YIN ; Xiaopeng HUANG ; Degui CHANG ; Liang DONG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(7):141-147
ObjectiveTo observe the clinical efficacy of tonifying kidney and replenishing essence on asthenozoospermia patients with the syndrome of kidney essence deficiency and the effects of this method on the adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. MethodsSeventy-two eligible asthenozoospermia patients with the syndrome of kidney essence deficiency treated in the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine from February 2023 to January 2024 were selected and randomly assigned into an observation group and a control group, with 36 patients in each group. The observation group received oral administration of Guilu Tianjing capsules, while the control group received oral administration of L-carnitine oral solution. The treatment course lasted for 4 weeks in both groups. The observed indicators included sperm progressive motility rate (PR), total sperm motility (PR+NP), percentage of normal mitochondrial membrane potential (MMP), and traditional Chinese medicine (TCM) symptom scores before and after treatment in both groups. A three-month follow-up was instituted to record the conception status of the patients’ spouses. Additionally, eight patients were randomly selected from the eligible patients in the observation group, and four healthy males with normal semen routine examination results were included as the control group for the determination of protein expression. Western blotting was conducted to assess the expression of AMPK, phosphorylated (p)-AMPK, regulatory-associated protein of mTOR (RAPTOR) and p-RAPTOR, and PTEN-induced putative kinase 1 (PINK1) in sperms from the observation group before and after treatment, as well as in the sperms of the control group. ResultsThe pregnancy rate of spouses in the observation group was 9.09% (3/33), which was higher than that (3.33%, 1/30) in the control group. The total response rate was 84.8% (28/33) in the observation group and 66.7% (20/30) in the control group, with no statistically significant difference. After treatment, both groups were improved considering PR, PR+NP, MMP, and TCM symptom scores (P<0.01). Moreover, the observation group exhibited more pronounced decreases in TCM symptom scores than the control group (P<0.05), while the changes in PR, PR+NP, and MMP showed no statistical significance between groups. Compared with the control group, the asthenozoospermia group exhibited upregulations in phosphorylation levels of AMPK and RAPTOR and protein level of PINK (P<0.01). The administration of Guilu Tianjing Capsules led to downregulations in the phosphorylation levels of AMPK and RAPTOR and protein level of PINK1 (P<0.01). However, the protein levels of AMPK and RAPTOR demonstrated no significant difference between before and after treatment. During the study period, neither group of patients exhibited any notable adverse reactions. ConclusionGuilu Tianjing capsules can enhance the sperm motility and percentage of normal mitochondrial membrane potential in asthenozoospermia patients with the syndrome of kidney essence deficiency by downregulating the AMPK/mTORC1 signaling pathway, lowering the protein level of PINK1, and inhibiting excessive activation of mitophagy.
2.Clinical Efficacy of Tonifying Kidney and Replenishing Essence on Asthenospermia Patients with Syndrome of Kidney Essence Deficiency and Effect of This Method on Expression Levels of AMPK/mTORC1 Signaling Pathway-associated Proteins
Yuanjie FU ; Fuhao LI ; Chenghua PENG ; Dong XU ; Guoan YIN ; Xiaopeng HUANG ; Degui CHANG ; Liang DONG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(7):141-147
ObjectiveTo observe the clinical efficacy of tonifying kidney and replenishing essence on asthenozoospermia patients with the syndrome of kidney essence deficiency and the effects of this method on the adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. MethodsSeventy-two eligible asthenozoospermia patients with the syndrome of kidney essence deficiency treated in the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine from February 2023 to January 2024 were selected and randomly assigned into an observation group and a control group, with 36 patients in each group. The observation group received oral administration of Guilu Tianjing capsules, while the control group received oral administration of L-carnitine oral solution. The treatment course lasted for 4 weeks in both groups. The observed indicators included sperm progressive motility rate (PR), total sperm motility (PR+NP), percentage of normal mitochondrial membrane potential (MMP), and traditional Chinese medicine (TCM) symptom scores before and after treatment in both groups. A three-month follow-up was instituted to record the conception status of the patients’ spouses. Additionally, eight patients were randomly selected from the eligible patients in the observation group, and four healthy males with normal semen routine examination results were included as the control group for the determination of protein expression. Western blotting was conducted to assess the expression of AMPK, phosphorylated (p)-AMPK, regulatory-associated protein of mTOR (RAPTOR) and p-RAPTOR, and PTEN-induced putative kinase 1 (PINK1) in sperms from the observation group before and after treatment, as well as in the sperms of the control group. ResultsThe pregnancy rate of spouses in the observation group was 9.09% (3/33), which was higher than that (3.33%, 1/30) in the control group. The total response rate was 84.8% (28/33) in the observation group and 66.7% (20/30) in the control group, with no statistically significant difference. After treatment, both groups were improved considering PR, PR+NP, MMP, and TCM symptom scores (P<0.01). Moreover, the observation group exhibited more pronounced decreases in TCM symptom scores than the control group (P<0.05), while the changes in PR, PR+NP, and MMP showed no statistical significance between groups. Compared with the control group, the asthenozoospermia group exhibited upregulations in phosphorylation levels of AMPK and RAPTOR and protein level of PINK (P<0.01). The administration of Guilu Tianjing Capsules led to downregulations in the phosphorylation levels of AMPK and RAPTOR and protein level of PINK1 (P<0.01). However, the protein levels of AMPK and RAPTOR demonstrated no significant difference between before and after treatment. During the study period, neither group of patients exhibited any notable adverse reactions. ConclusionGuilu Tianjing capsules can enhance the sperm motility and percentage of normal mitochondrial membrane potential in asthenozoospermia patients with the syndrome of kidney essence deficiency by downregulating the AMPK/mTORC1 signaling pathway, lowering the protein level of PINK1, and inhibiting excessive activation of mitophagy.
3.Application of ADDIE Model in clinical teaching for nursing interns in spine surgery department
Bingdu TONG ; Yaping CHEN ; Fang LIU ; Yawen YE ; Wei WANG ; Hongyan LI ; Tao LIANG ; Xiaopeng HUO ; Donglei SHI
Chinese Journal of Modern Nursing 2024;30(32):4459-4464
Objective:To explore the effectiveness of applying the ADDIE (analysis, design, develop, implement, evaluate) Model in clinical teaching for nursing interns in spine surgery department.Methods:Using a convenience sampling method, 44 nursing interns in the Department of Orthopedics at Peking Union Medical College Hospital were selected as the control group from July 2021 to May 2022, and were taught using traditional methods. From July 2022 to May 2023, 45 nursing interns were selected as the observation group, and a teaching team was formed to design a training program based on the five stages of the ADDIE instructional design model. This program was tailored to improve the overall clinical competence of the spinal surgery nursing interns. After training, the teaching effects were evaluated based on knowledge test scores, skills test scores, overall clinical competence, and teaching satisfaction.Results:After the training, the skills test scores in specialized nursing for the observation group were (94.87±1.10) points, higher than the control group's (93.98±1.41) points, with a statistically significant difference ( P<0.01). The observation group also scored higher than the control group in clinical judgment, organizational effectiveness, overall performance, and total score in the Mini-Clinical Evaluation Exercise, with statistically significant differences ( P<0.01). Additionally, the observation group reported higher satisfaction with the teaching plan and methods compared to the control group ( P<0.05) . Conclusions:Clinical teaching for spinal surgery nursing interns based on the ADDIE instructional design model can improve their specialized practical skills and overall clinical competence. The interns also expressed a high level of acceptance for this teaching design model.
4.Chinese expert consensus on clinical treatment of adult patients with severe traumatic brain injury complicated by corona virus disease 2019 (version 2023)
Zeli ZHANG ; Shoujia SUN ; Yijun BAO ; Li BIE ; Yunxing CAO ; Yangong CHAO ; Juxiang CHEN ; Wenhua FANG ; Guang FENG ; Lei FENG ; Junfeng FENG ; Liang GAO ; Bingsha HAN ; Ping HAN ; Chenggong HU ; Jin HU ; Rong HU ; Wei HE ; Lijun HOU ; Xianjian HUANG ; Jiyao JIANG ; Rongcai JIANG ; Lihong LI ; Xiaopeng LI ; Jinfang LIU ; Jie LIU ; Shengqing LYU ; Binghui QIU ; Xizhou SUN ; Xiaochuan SUN ; Hengli TIAN ; Ye TIAN ; Ke WANG ; Ning WANG ; Xinjun WANG ; Donghai WANG ; Yuhai WANG ; Jianjun WANG ; Xingong WANG ; Junji WEI ; Feng XU ; Min XU ; Can YAN ; Wei YAN ; Xiaofeng YANG ; Chaohua YANG ; Rui ZHANG ; Yongming ZHANG ; Di ZHAO ; Jianxin ZHU ; Guoyi GAO ; Qibing HUANG
Chinese Journal of Trauma 2023;39(3):193-203
The condition of patients with severe traumatic brain injury (sTBI) complicated by corona virus 2019 disease (COVID-19) is complex. sTBI can significantly increase the probability of COVID-19 developing into severe or critical stage, while COVID-19 can also increase the surgical risk of sTBI and the severity of postoperative lung lesions. There are many contradictions in the treatment process, which brings difficulties to the clinical treatment of such patients. Up to now, there are few clinical studies and therapeutic norms relevant to sTBI complicated by COVID-19. In order to standardize the clinical treatment of such patients, Critical Care Medicine Branch of China International Exchange and Promotive Association for Medical and Healthcare and Editorial Board of Chinese Journal of Trauma organized relevant experts to formulate the Chinese expert consensus on clinical treatment of adult patients with severe traumatic brain injury complicated by corona virus infection 2019 ( version 2023) based on the joint prevention and control mechanism scheme of the State Council and domestic and foreign literatures on sTBI and COVID-19 in the past 3 years of the international epidemic. Fifteen recommendations focused on emergency treatment, emergency surgery and comprehensive management were put forward to provide a guidance for the diagnosis and treatment of sTBI complicated by COVID-19.
5.Relationship between red blood cell distribution width and short-term mortality of hip fractures in the elderly
Xiaofeng LIU ; Jinshan ZHANG ; Yongquan XU ; Liang LIN ; Zhenyu LIN ; Hongpeng ZHANG ; Xiaopeng HUANG ; Yangzhen FANG ; Yongqiang ZHENG
Chinese Journal of Geriatrics 2023;42(6):707-710
Objective:To study the relationship between red blood cell distribution width(RDW)and short-term mortality in elderly patients with hip fragility fractures.Methods:The clinical data and blood routine test at admission of 205 elderly patients with brittle hip fractures who were admitted to our hospital from 2020 to 2021 and were followed up for one year were retrospectively analyzed.The comorbid conditions, RDW and cumulative mortality at 6 months and 1 year after fractures were counted, and the relationship between RDW and short-term mortality were analyzed.Results:The 6-month(6.7% and 20.8%, χ2=8.591, P=0.003)and 1-year(6.7% and 26.7%, χ2=14.818, P<0.001)mortality of patients with ≤1 comorbidity were significantly lower than those of patients with ≥2 comorbidities.Moreover, the 6-month and 1-year mortality in patients with RDW>13.5% were significantly higher than those of patients with RDW ≤ 13.5%.The proportion of RDW>13.5 % in patients with at least two comorbidities was significantly higher than that in patients with ≤1 comorbidity.Taking RDW=13.6% as the cut-off value of 6-month and 1-year mortality, the sensitivity and specificity for predicting 6-month mortality were 71.4 % and 59.9 %, respectively, and the sensitivity and specificity for predicting 1-year mortality were 64.7 % and 59.6 %, respectively. Conclusions:Red cell distribution width is associated with short-term mortality, and higher RDW is associated with a higher risk of mortality among elderly patients with brittle hip fractures.
6.A novel technique of pure transperitoneal laparoscopic nephroureterectomy at a single position for native upper tract urothelial carcinoma in ipsilateral renal transplant recipients
Xiaoyong YANG ; Zejia SUN ; Wei WANG ; Liang REN ; Hang LIU ; Wei WANG ; Xiaodong ZHANG ; Xiaopeng HU
Chinese Journal of Organ Transplantation 2023;44(6):354-359
Objective:To explore the techniques and outcomes of pure laparoscopic native nephroureterectomy (LNUT) with ipsilateral allograft at a single position for upper tract urothelial carcinoma (UTUC) in renal transplant (RT) recipients.Methods:Clinical data were retrospectively reviewed for 12 renal transplant children undergoing native UTUC with ipsilateral allograft from January 2016 to December 2021.There were 4 boys and 8 girls.Complete LNUT was performed with bladder cuff resection at a single position via a transperitoneal approach.The interval between UTUC and RT was 12-146 months.There were 6 pelvic UCs and 6 ureter UCs.Results:All laparoscopic procedures were successfully completed without any serious perioperative complication.Postoperative pathological examination confirmed the diagnosis of urothelial carcinoma.And all surgical margins were negative.One patient experienced an elevation of creatinine after one cycle chemotherapy and normalized after withdrawing chemotherapy.The median follow-up period was (4-65) month.Two cases of contralateral native transitional cell carcinoma had radical nephroureterectomy two years later and another two cases underwent transurethral resection of bladder tumor one year later.One case died from tumor metastasis.The remainders had no tumor recurrence or metastasis during follow-ups.Conclusions:Complete single-position LNUT for UTUC with ipsilateral allograft is a safe and effective mini-invasive technique.Effectively avoiding the injury of allograft, it also offers the advantages of standard operation, minimal trauma, simple handling and enhanced recovery after surgery (ERAS).
7.Influence of long-term use of entecavir on renal tubular function in patients with chronic hepatitis B
Yuanmei CHE ; Ai LI ; Liang WANG ; Lunli ZHANG ; Xiaopeng LI
Journal of Clinical Hepatology 2023;39(6):1313-1317
Objective To investigate the possible influence of long-term antiviral therapy with entecavir on renal function in patients with chronic hepatitis B (CHB) and the sensitive indicators for early identification of renal injury. Methods A cross-sectional real-world study was conducted for the clinical data of 125 CHB patients treated with entecavir for more than 1 year (treatment group) and 44 patients with chronic HBV infection who did not receive antiviral therapy (control group), including the changes in serum creatinine (SCr), estimated glomerular filtration rate (eGFR), and the levels of urinary α1 microglobulin (α1-MG), β2 microglobulin (β2-MG), and N-acetyl-β-D-glucosaminidase (NAG). The chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. The independent-samples t test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups. The Logistic regression analysis was used to investigate independent influencing factors for abnormal urinary α1-MG, β2-MG, and NAG in the treatment group. Results There were no significant differences in SCr and eGFR between the treatment group and the control group ( t =0.999 and -1.259, P > 0.05), and both indices were within the normal range in these two groups. The treatment group had significantly higher abnormal rates of urinary α1-MG and β2-MG than the control group (47.2%/42.4% vs 13.6%/13.6%, χ 2 =15.693 and 12.567, both P < 0.001), and compared with the control group, the treatment group had a significantly higher proportion of patients with α1-MG or β2-MG > 2×upper limit of normal (18.4%/21.6% vs 2.3%/4.5%, both P < 0.05); however, there were no significant differences between the treatment group and the control group in the abnormal rate of urinary NAG (8.0% vs 6.8%, P > 0.05) and the proportion of patients with urinary NAG > 2×upper limit of normal (8.8% vs 6.8%, P > 0.05). Compared with the control group, the treatment group had a significantly higher proportion of patients with abnormalities in two or more indicators for renal tubular injury (33.6% vs 11.4%, χ 2 =8.519, P < 0.05), while there was no significant difference between the two groups in the proportion of patients with abnormalities in one indicator (16.0% vs 11.4%, P > 0.05). Conclusion Long-term treatment of CHB with entecavir may be associated with the risk of renal tubular dysfunction, and abnormalities in more than two indicators for renal injury may help to identify renal tubular dysfunction in patients, so as to adjust related treatment in time.
8.The influence of pulmonary artery diameter on the image quality of dual-layer spectral detector CT pulmonary angiography with low contrast agent dosage
Xiaoxue LIANG ; Jianbo GAO ; Rui LI ; Xiaopeng WANG ; Lei SU
Chinese Journal of Radiological Medicine and Protection 2023;43(10):812-819
Objective:Evaluate the image quality of dual-layer spectral detector CT pulmonary angiography with low-dose contrast agents, and explore the influence of pulmonary artery diameter on the image quality.Methods:A total of 91 spectral CT pulmonary angiography from March 2022 to August 2022 were retrospectively analyzed. The cases were divided into Group 1 ( n=34, main pulmonary artery diameter ≥ 30 mm) and Group 2 ( n=57, main pulmonary artery diameter<30 mm). The dosage of contrast agent was 30 ml. The CT attenuation values(CT values), standard deviation(SD), signal-to-noise ratio(SNR), and contrast-to-noise ratio(CNR) values of pulmonary artery from the main trunk to the subsegmental pulmonary artery between two groups were compared. The CT dose index volume(CTDI vol) and dose-length production (DLP) were recorded. Two readers evaluated the image quality using three-point method. The inter-reader agreement was performed by Kappa test. Results:The CT values of the pulmonary trunk and left pulmonary artery between two groups was not significantly different ( P>0.05). The CT values of the left upper lobe artery, segmental artery, and subsegmental artery in Group 1 were lower than those in Group 2 ( t=-2.13, -2.17, Z=-2.33, P<0.05). The SD values of pulmonary trunk and segmental artery in Group 1 were higher than those in Group 2 ( t=2.27, Z=-2.23, P<0.05). The SD values of left pulmonary artery, left upper lobe artery, and subsegmental artery between two groups were not significantly different ( P>0.05). The SNR and CNR values of main pulmonary trunk, left pulmonary artery, left superior lobar artery, and segmental artery in Group 2 were higher than those in Group 1 ( Z=-2.45, -2.57, -2.09, -3.58, P<0.05; Z =-2.33, -2.42, -2.07, -3.45, P<0.05), while these values of the subsegmental artery between two groups were not significantly different ( P>0.05). The two readers had good consistency in evaluating image quality (Kappa value>0.75, P<0.05). Conclusions:Spectral CT pulmonary angiography with 30 ml contrast agent would generate good quality images. However, the distal pulmonary artery would be poorly revealed when the diameter of main pulmonary artery more than 30 mm, especially in patients with suspected pulmonary hypertension.
9.Clinicopathological characteristics and prognosis of subsequent upper tract urothelial carcinoma in non-muscle invasive bladder cancer patients after renal transplantation
Hao ZHANG ; Yue XU ; Bohan FAN ; Liang REN ; Wei WANG ; Xiaopeng HU ; Wei WANG
Chinese Journal of Urology 2022;43(12):893-897
Objective:We aim to investigate the clinical characteristics and prognosis of upper tract urothelial carcinoma (UTUC) in patients with non-muscle invasive bladder cancer (NMIBC) after renal transplantation.Methods:We retrospectively analyzed the clinical and follow-up information of 13 kidney recipients with NMIBC admitted to our hospital from January 2014 to June 2022 who subsequently underwent complete transperitoneal laparoscopic nephroureterectomy. There were 8 males and 5 females, aged (56.1±11.5), 3 cases with history of smoking and 10 cases without history of smoking, 4 cases with history of Aristolochic acids and 9 cases with no history of Aristolochic acids. Six and seven cases were treated with transurethral resection of bladder tumor for hematuria and bladder tumors detected by ultrasound or imaging respectively. Single and multiple bladder tumors were 9 and 4 cases; bladder tumor size ≤ 3 cm, >3 cm were 9 and 4 cases respectively; low-and high-grade bladder tumors were 3 and 10 cases separately, with; T a and T 1 of 3 and 10 cases respectively; recurrent bladder cancer and non-recurrent bladder cancer were 5 and 8 cases respectively. Follow-up after transurethral resection of bladder tumor showed that 6 cases with imaging evidence of UTUC for 6-52 months after transurethral resection of bladder tumor were treated with ipsilateral laparoscopic nephroureterectomy, including 2 cases of hydronephrosis, 1 case of renal pelvis mass, and 3 cases of ureteral mass, and 7 cases without imaging evidence of UTUC were performed with bilaterally prophylactic laparoscopic nephroureterectomy. The Kaplan-Meier curve and log-rank test were used for survival analysis to evaluate the prognostic effect of UTUC in kidney recipients with NMIBC. Results:Six of 13 patients named UTUC group were diagnosed with UTUC and 7 of 13 patients named no-UTUC group were not detected with UTUC. There was no statistical difference between these two groups in terms of clinical characteristics, including age( P=0.10), sex( P=0.10), smoking( P=0.19), history of Aristolochic acids( P=0.99), number( P=0.56), grade( P=0.19), stage ( P=0.19)and recurrence of bladder tumor number( P=0.10), and radiological findings of UTUC ( P=0.29). However, patients with larger-sized bladder tumors (larger than 3cm) had a higher rate of UTUC compared to patients with equal or smaller than 3 cm ( P=0.29). In addition, two patients with negative radiological findings developed UTUC following the detection of a large bladder tumor size (larger than 3 cm). The median survival of overall survival time and cancer specific survival time after laparoscopic nephroureterectomy were 42(17, 65) months. Two patients died from any cause during follow-up in patients with UTUC, whereas no significant difference between UTUC group and non-UTUC group in overall survival time and cancer specific survival time, as evaluated by the Kaplan-Meier curves and log-rank tests. ( P=0.29). Conclusions:After kidney transplantation, the diameter of the bladder tumor in NMIBC patients with UTUC was significantly larger than that in patients without UTUC, and no significant difference was observed in the remaining clinical features. Considering the non-functioning kidney after kidney transplantation, prophylactic laparoscopic nephroureterectomy can be considered for NMIBC patients with bladder tumor size >3 cm. Survival analysis showed no significant difference between UTUC group and non-UTUC group.
10.Application of fluorescent targeted retroperitoneal lymph node dissection in the treatment of lymph node recurrence after radical prostatectomy
Yu WANG ; Weicong LIANG ; Zhuolun SUN ; Jinming DI ; Xiaopeng LIU ; Tengcheng LI ; Ke LI ; Xingqiao WEN ; Xin GAO
Chinese Journal of Urology 2021;42(9):666-669
Objective:To explore the efficacy of fluorescent retroperitoneal lymph node dissection in the comprehensive treatment of lymph node recurrence after radical prostatectomy (RP).Methods:From January 2017 to December 2020, 25 patients with lymph node recurrence diagnosed by 68Ga-PSMA PET/CT after RP in our hospital were enrolled in this study. The patients were 67 (59-77) years old. The median PSA was 7.7 (0.5-12.6) ng/ml at lymph node recurrence, and was treated with androgen deprivation therapy (ADT), suggesting hormone-sensitive prostate cancer. Before recurrence, 4 cases were in T 2 stage, 17 cases in T 3, 4 cases in T 4, 10 cases in N 0, and 15 cases in N 1stage, 25 cases in M 0stage. 2 cases diagnosed as ISUP grade group <3, 9 cases in group 4, and 14 cases in group 5. The median time from radical resection to recurrence was 43 (27-56) months. All 25 cases were diagnosed as lymph node recurrence by 68Ga-PSMA PET/CT examination. Fluorescence retroperitoneal lymph node dissection was performed. Pelvic lymph nodes were detected in the dark field under the fluorescence mode, and positive lymph nodes were found. The white light mode was switched, and the lymph nodes were cleaned, and recorded. For metastatic lymph nodes indicated by preoperative PSMA PET/CT, routine dissection was performed regardless of whether the lymph nodes were fluorescently positive or not. The only routine examination was performed if there were no lymph nodes with fluorescently positive staining in other sites. Perioperative data, biochemical recurrence (BCR) rate, radiological recurrence (RAR) rate, and follow-up data were collected and analyzed. Results:25 patients were pathologically diagnosed with lymph node metastasis. The median lymph node dissection time was 21(15-28) min, estimated blood loss was 30(20-50) ml, hospital days was 4(3-5)d without any severe complications (

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