1.Application of evidence-based medicine in standardized training of residents in hematology
Jia LIU ; Lidan ZHU ; Shichun GAO ; Huanfeng LIU ; Lu WANG ; Cheng ZHANG ; Li GAO ; Xi ZHANG ; Peiyan KONG ; Lei GAO
Chinese Journal of Medical Education Research 2024;23(4):560-563
Evidence-based medicine (EBM) is a science that uses the best available research data to make decisions, and the core is that clinical decision-making is supported by the best research evidence. Incorporating EBM into traditional standardized residency training in hematology can foster residents' professional theoretical knowledge and clinical skills, improve the quality of standardized training, and provide ideas and methods for standardized training of hematology residents, which is worthy of further research and exploration.
2.Comparing the effects of dual-task training and single-task training on walking, balance and cognitive functions in individuals with Parkinson’s disease: A systematic review
Xiaoying LIN ; Yanming ZHANG ; Xiaowei ZHANG ; Xi CHEN ; Jianhua LIU ; Lei YANG ; Pang Marco Yiu Chung
Chinese Medical Journal 2024;137(13):1535-1543
Background::This systematic review aimed to examine whether dual-task (DT) training was superior to single-task (ST) training in improving DT walking, balance and cognitive functions for individuals with Parkinson’s disease (PD).Methods::Literature search was performed in the following electronic databases: PubMed, the Cochrane Library, Web of Science, and Metstr covering inception to May 10, 2023. And in order to facilitate comparison across trials, we calculated the effect size (Hedges’ g) of gait, balance, cognitive, and other parameters under both ST and DT conditions, using the mean change score and standard deviation (SD) of change score of the experimental and control groups. Randomized controlled trials that examined the effects of DT motor and cognitive training in individuals with Parkinson’s disease were included for this systematic review.Results::A total of 214 participants recruited from six articles (actually five trials) were involved in this review. In terms of walking ability, only double support time and stride time variability showed significant between-group difference (Hedges’ g = 0.34, 0.18, respectively). Compared to ST training group, DT training group had a more improvement effect in laboratory balance measurement (Hedges’ g = 0.18, 1.25), but no significant improvement in clinical balance measurement. No significant between-group differences were observed, thus its training effect on cognitive function was inconclusive.Conclusions::The DT training failed to achieve promising results better than ST training in improving DT walking and balance functions for individuals with PD. Any firm conclusion cannot be drawn at present, due to the limited number of eligible publications. Larger sample size and high-quality studies are needed to investigate the effectiveness of DT training in individuals with PD.
3.Risk factors analysis of recurrent drug-eluting stent in-stent restenosis
Huan-Huan FENG ; Xiao-Hang YUAN ; Xin HU ; Yan HAN ; Xi ZHANG ; Hao-Yi YE ; Lei GAO
Chinese Journal of Interventional Cardiology 2024;32(9):489-495
Objective To evaluate the predictors of recurrent in-stent restenosis(R-ISR)occurrence in drug-eluting stents(DES).Methods A total of 201 patients with ISR who received percutaneous coronary intervention(PCI)surgery in the First Medical Center of the Chinese PLA General Hospital from January 2010 to August 2023 were selected as the study objects,and the patients were divided into R-ISR group and non-R-ISR group according to their post-discharge angiography review.The clinical baseline data and the features of interventional surgery during the first ISR-PCI were retrospectively analyzed.Results Among the 201 patients,168 were males and 33 were females,with an average age of(61.97±10.02)years.The median interval between initial and follow-up angiography was 1.5 years.Patients were divided into two groups based on their radiographic reviews:R-ISR group(98 patients and 104 ISR lesions)and non-R-ISR group(103 patients and 111 ISR lesions).Multivariate Logistic regression analysis showed that the incidence of R-ISR was correlated with Ostial disease(OR 2.987,95%CI 1.343-6.642,P=0.007),plain old balloon angioplasty(POBA)performed for ISR lesions(OR 3.081,95%CI 1.293-7.343,P=0.011)and the maximum diameter stenosis rate of ISR lesions before surgery(OR 1.016,95%CI 1.002-1.030,P=0.022).Conclusions In patients currently receiving interventional therapy for ISR,Ostial disease,POBA treatment for ISR disease,and maximum diameter stenosis rate of ISR disease were associated predictors of R-ISR development.
4.Study on correlation between early immune cell dynamic changes and lung infection in acute respiratory distress syndrome caused by multiple injuries
Xiaoyang LEI ; Qing CHEN ; Shilai XU ; Xi ZHANG
Chinese Journal of Immunology 2024;40(6):1240-1247
Objective:To explore the correlation between the dynamic changes of early immune cells in acute respiratory dis-tress syndrome(ARDS)caused by multiple injuries and lung infection.Methods:Multiple injury patients with ARDS(235 cases)ad-mitted to the First Affiliated Hospital of Hunan University of Chinese Medicine from October 2017 to February 2023 were selected as the research subjects and included them in the training set;according to simple clinical pulmonary infection scores(sCPIS),they were divided into a pulmonary infection group(94 cases,>6 points)and an uninfected group(141 cases,≤6 points).Another multi-ple injury patients with ARDS(78 cases)were selected to be included in the validation set to verify the effectiveness of the prediction model.Dynamic detection of lymphocytes were used flow cytometry.Compared and analyzed the clinical data of two groups of patients.Constructed a joint model and used Cox regression to analyze the relationship.Multi factor Logistic regression analysis of risk factors,construction of a simple risk scoring model and evaluation.Results:As the patient progresses,CD4+and CD8+first decrease and then increased,and the lowest stage was 3~15 d after onset;CD19+was gradually increasing;CD16+gradually decreased and fluctuated within a certain range.The joint model showed that for every 1 piece/μl longitudinal decrease in CD4+,CD8+,CD19+,and CD16+,the risk of pulmonary infection increased by 5.6%,4.1%,3.4% and 1.3%,respectively(P<0.05).Injury severity score(ISS),chest inju-ry as the main factor,emergency surgery,acutephysiology and chronic health evaluation Ⅱ(APACHE Ⅱ),broncho-alveolar lavage fluid(BALF)sTREM-1 level,and CD4+,CD8+,and CD19+level on the 15th day after onset all were independent influencing factors for the occurrence of pulmonary infection(P<0.05).The score of the simple risk scoring model is 0~36.7 points,which could be divid-ed into three risk levels:low(<16 points),medium(16~22 points),and high risk(>22 points);there was no significant difference in the incidence of pulmonary infection between the two episodes of patients(P>0.05).The evaluation results showed that the predic-tive model has good discrimination.Conclusion:The fluctuation of immune cells will increase the risk of pulmonary infection in pa-tients with multiple injuries ARDS;Baseline CD4+,CD8+,and CD19+levels are independent influencing factors for the occurrence of pulmonary infection;controlling high-level immune cells and maintaining stability is crucial for improving prognosis.
5.Efficacy and Prognosis of Chemotherapy Regimen Containing BTK Inhibitor in Treatment of Recurrent/Refractory Mantle Cell Lymphoma
Huan CHEN ; Xi-Yang LIU ; Yu CHANG ; Zi-Qi CHEN ; Wen-Qi LI ; Lei ZHANG
Journal of Experimental Hematology 2024;32(1):125-131
Objective:To investigate the efficacy and prognosis of chemotherapy regimen containing Bruton's tyrosine kinase(BTK)inhibitor in the treatment of relapsed/refractory mantle cell lymphoma(R/R MCL).Methods:The clinical data of 134 patients with R/R MCL were collected and analyzed retrospectively.The clinical characteristics of patients and effect of chemotherapy regimen on efficacy,overall survival(OS)and progression-free survival(PFS)were observed.Results:The median age of the patients was 58(56-61)years old,and male to female ratio was about 2.9∶1.Patients with Ann Arbor stage Ⅲ-Ⅳ accounted for 77.6%,extranodal involvement>2 for 43.3%,bone marrow involvement for 60.4%,gastrointestinal involvement for 24.6%,and hepatosplenomegaly for 38.1%.The median follow-up time was 30(2-103)months,overall response rate(ORR)was 41.8%,3-year PFS was not reached,and 3-year and 5-year OS rate was 62.7%and 53.8%,respectively.The ORR of BTK inhibitor group was 56.9%,which was higher than 32.5%of non-BTK inhibitor group(P=0.006).The difference was statistically significant in PFS between the two groups(P=0.002),but was not in OS(P>0.05).The difference was statistically significant in OS between classical and special morphology(P<0.001),but was not in PFS(P>0.05).Ki-67 was an influencing factor for OS and PFS.Multivariate analysis showed that Ki-67,B symptoms,MIPI score,and Ann Arbor stage were independent prognostic factors affecting patients'OS.The second-line treatment regimen was an independent prognostic factor affecting patients'PFS.Conclusions:The chemotherapy regimen containing BTK inhibitors can effectively improve the efficacy and prolong the PFS of R/R MCL patients.Ki-67,B symptoms,MIPI score,and Ann Arbor stage are independent prognostic factors for R/R MCL patients.
6.Characteristics of peripheral blood lymphocyte subsets in patients with relapsed neuromyelitis optica spectrum disorder during rituximab treatment
Yanning HUANG ; Lei WU ; Hui SUN ; Sai GAO ; Dehui HUANG ; Xi ZHANG
Chinese Journal of Neuromedicine 2024;23(4):372-378
Objective:To analyze the characteristics of peripheral blood lymphocyte subsets in patients with relapsed neuromyelitis optica spectrum disorder (NMOSD) during rituximab (RTX) treatment and to clarify the influence of these lymphocyte subsets in NMOSD relapse.Methods:The monitoring data of lymphocyte subsets (175 times) in 76 patients diagnosed as having aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive NMOSD during RTX treatment at Department of Neurology, General Hospital of Chinese People's Liberation Army from August 2018 to August 2023 were collected. A relapse group ( n=26) and a non-relapse group ( n=149) were divided based on states at data collection (relapse or not). Two-sample t-test or Mann-Whitney U test were used to compare the differences in RTX administration intervals and lymphocyte subsets between the 2 groups. Additionally, a point biserial correlation analysis was performed to investigate the correlations of lymphocyte subsets and RTX administration intervals with NMOSD relapse. Results:The relapse group had significantly longer RTX administration intervals (10.00 [6.73, 14.37] months vs. 7.27[6.30, 9.10] months), statistically lower percentage of CD3 -CD56 + natural killer lymphocytes (10.72% [7.06%, 15.34%) vs. 13.85% [9.42%, 20.13%]), and significantly higher CD19 + B lymphocytes (7.41% [1.18%, 15.70%] vs. 3.55% [0.38%, 8.74%]) than the non-relapse group ( P<0.05). Positive correlations were noted between RTX administration intervals and NMOSD relapse and between CD3 -D19 +B lymphocytes and NMOSD relapse ( r=0.363, P<0.001; r=0.218, P=0.004); negative correlation was noted between CD3 -CD56 + NK lymphocytes and NMOSD relapse ( r=-0.193, P=0.011). Conclusion:Extended RTX administration interval can increase NMOSD relapse; CD3 -CD56 + natural killer lymphocytes and CD19 +B lymphocytes may regulate the disease states of NMOSD patients.
7.Multicenter retrospect analysis of early clinical features and analysis of risk factors on prognosis of elderly patients with severe burns
Qimin MA ; Wenbin TANG ; Xiaojian LI ; Fei CHANG ; Xi YIN ; Zhaohong CHEN ; Guohua WU ; Chengde XIA ; Xiaoliang LI ; Deyun WANG ; Zhigang CHU ; Yi ZHANG ; Lei WANG ; Choulang WU ; Yalin TONG ; Pei CUI ; Guanghua GUO ; Zhihao ZHU ; Shengyu HUANG ; Liu CHANG ; Rui LIU ; Yongji LIU ; Yusong WANG ; Xiaobin LIU ; Tuo SHEN ; Feng ZHU
Chinese Journal of Burns 2024;40(3):249-257
Objective:To investigate the early clinical characteristics of elderly patients with severe burns and the risk factors on prognosis.Methods:This study was a retrospective case series study. Clinical data of 124 elderly patients with severe burns who met the inclusion criteria and were admitted to the 12 hospitals from January 2015 to December 2020 were collected, including 4 patients from the Fourth People's Hospital of Dalian, 5 patients from Fujian Medical University Union Hospital, 22 patients from Guangzhou Red Cross Hospital of Jinan University, 5 patients from Heilongjiang Provincial Hospital, 27 patients from the First Affiliated Hospital of Naval Medical University, 9 patients from the First Affiliated Hospital of Nanchang University, 10 patients from Affiliated Hospital of Nantong University, 9 patients from Tongren Hospital of Wuhan University & Wuhan Third Hospital, 12 patients from the 924 th Hospital of PLA, 6 patients from Zhangjiagang First People's Hospital, 4 patients from Taizhou Hospital of Zhejiang Province, and 11 patients from Zhengzhou First People's Hospital. The patients' overall clinical characteristics, such as gender, age, body mass index, total burn area, full-thickness burn area, inhalation injury, causative factors, whether combined with underlying medical diseases, and admission time after injury were recorded. According to the survival outcome within 28 days after injury, the patients were divided into survival group (89 cases) and death group (35 cases). The following data of patients were compared between the two groups, including the basic data and injuries (the same as the overall clinical characteristics ahead); the coagulation indexes within the first 24 hours of injury such as prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time, D-dimer, fibrinogen degradation product (FDP), international normalized ratio (INR), and fibrinogen; the blood routine indexes within the first 24 hours of injury such as white blood cell count, platelet count, neutrophil-to-lymphocyte ratio, monocyte count, red blood cell count, hemoglobin, and hematocrit; the organ function indexes within the first 24 hours of injury such as direct bilirubin, total bilirubin, urea, serum creatinine, aspartate aminotransferase, alanine aminotransferase, total protein, albumin, globulin, blood glucose, triglyceride, total cholesterol, alkaline phosphatase, creatine kinase, electrolyte indexes (potassium, sodium, chlorine, calcium, magnesium, and phosphorus in blood), uric acid, myoglobin, and brain natriuretic peptide; the infection and blood gas indexes within the first 24 hours of injury such as procalcitonin, C-reactive protein, pH value, oxygenation index, base excess, and lactate; treatment such as whether conducted with mechanical ventilation, whether conducted with continuous renal replacement therapy, whether conducted with anticoagulation therapy, whether applied with vasoactive drugs, and fluid resuscitation. The analysis was conducted to screen the independent risk factors for the mortality within 28 days after injury in elderly patients with severe burns. Results:Among 124 patients, there were 82 males and 42 females, aged 60-97 years, with body mass index of 23.44 (21.09, 25.95) kg/m 2, total burn area of 54.00% (42.00%, 75.00%) total body surface area (TBSA), and full-thickness burn area of 25.00% (10.00%, 40.00%) TBSA. The patients were mainly combined with moderate to severe inhalation injury and caused by flame burns. There were 43 cases with underlying medical diseases. The majority of patients were admitted to the hospital within 8 hours after injury. There were statistically significant differences between patients in the 2 groups in terms of age, total burn area, full-thickness burn area, and inhalation injury, and PT, APTT, D-dimer, FDP, INR, white blood cell count, platelet count, urea, serum creatinine, blood glucose, blood sodium, uric acid, myoglobin, and urine volume within the first 24 hours of injury (with Z values of 2.37, 5.49, 5.26, 5.97, 2.18, 1.95, 2.68, 2.68, 2.51, 2.82, 2.14, 3.40, 5.31, 3.41, 2.35, 3.81, 2.16, and -3.82, respectively, P<0.05); there were statistically significant differences between two groups of patients in whether conducted with mechanical ventilation and whether applied with vasoactive drugs (with χ2 values of 9.44 and 28.50, respectively, P<0.05). Age, total burn area, full-thickness burn area, serum creatinine within the first 24 hours of injury, and APTT within the first 24 hours of injury were the independent risk factors for the mortality within 28 days after injury in elderly patients with severe burns (with odds ratios of 1.17, 1.10, 1.10, 1.09, and 1.27, 95% confidence intervals of 1.03-1.40, 1.04-1.21, 1.05-1.19, 1.05-1.17, and 1.07-1.69, respectively, P<0.05). Conclusions:The elderly patients with severe burns had the injuries mainly from flame burns, often accompanied by moderate to severe inhalation injury and enhanced inflammatory response, elevated blood glucose levels, activated fibrinolysis, and impaired organ function in the early stage, which are associated with their prognosis. Age, total burn area, full-thickness burn area, and serum creatinine and APTT within the first 24 hours of injury are the independent risk factors for death within 28 days after injury in this population.
8.Effect and Molecular Mechanism of Paeonol on Renal Interstitial Fibrosis in Rats
Haiyang GAO ; Jincun ZHANG ; Xi CHEN ; Xiaohai GUAN ; Fenghong CAO ; Shaosan KANG ; Weixing GAO ; Lei WANG ; Anliang YAO ; Jian LIU ; Liguo ZHANG
Herald of Medicine 2024;43(7):1055-1060
Objective To study the effect and mechanism of paeonol(PAE)on renal interstitial fibrosis in rats.Methods The rats were randomly divided into sham operation(Sham)group,unilateral ureteral obstruction(UUO)group,PAE low dose(PAE-L)group,PAE medium dose(PAE-M)group,PAE high dose(PAE-H)group and irbesartan(IRB)group.Except for the Sham group,the UUO model was established in other groups.Each group was given a corresponding intervention for two weeks.Serum creatinine(Scr),blood urea nitrogen(BUN),serum 8-hydroxydeoxyguanosine(8-OHdG)levels,renal tissue superoxide dismutase(SOD),glutathione peroxidase(GPX)activities,α-smooth muscle actin(α-SMA),type Ⅰ collagen(Col-Ⅰ),fibronectin(FN),silent information regulator 1(SIRT1),nuclear factor E2-related factor 2(Nrf2)protein expression were detected;observe pathological changes of kidney tissue and calculate collagen volume fraction(CVF).Results Compared with the UUO group,the serum levels of Scr,BUN,and 8-OHdG in each dose group of PAE were decreased,the activities of SOD and GPX in kidney tissue were increased,the positive expressions of α-SMA,Col-Ⅰ and FN in kidney tissue were decreased,and the protein expressions of SIRT1 and Nrf2 were increased.Masson staining showed a decrease of CVF in renal tissue(all P<0.05),and HE staining showed a different degree of improvement in pathological changes such as inflammatory cell infiltration and tubular dilatation in renal tissue;PAE improves renal interstitial fibrosis in rats in a dose-dependent manner(P<0.05),and the effect of large dose PAE on renal interstitial fibrosis in rats was similar to that of IRB.Conclusion PAE can alleviate UUO-induced rat renal interstitial fibrosis and oxidative stress,and improve rat renal function.And this mechanism may be related to the activation of the SIRT1/Nrf2 signaling pathway.
9.A multicenter study of neonatal stroke in Shenzhen,China
Li-Xiu SHI ; Jin-Xing FENG ; Yan-Fang WEI ; Xin-Ru LU ; Yu-Xi ZHANG ; Lin-Ying YANG ; Sheng-Nan HE ; Pei-Juan CHEN ; Jing HAN ; Cheng CHEN ; Hui-Ying TU ; Zhang-Bin YU ; Jin-Jie HUANG ; Shu-Juan ZENG ; Wan-Ling CHEN ; Ying LIU ; Yan-Ping GUO ; Jiao-Yu MAO ; Xiao-Dong LI ; Qian-Shen ZHANG ; Zhi-Li XIE ; Mei-Ying HUANG ; Kun-Shan YAN ; Er-Ya YING ; Jun CHEN ; Yan-Rong WANG ; Ya-Ping LIU ; Bo SONG ; Hua-Yan LIU ; Xiao-Dong XIAO ; Hong TANG ; Yu-Na WANG ; Yin-Sha CAI ; Qi LONG ; Han-Qiang XU ; Hui-Zhan WANG ; Qian SUN ; Fang HAN ; Rui-Biao ZHANG ; Chuan-Zhong YANG ; Lei DOU ; Hui-Ju SHI ; Rui WANG ; Ping JIANG ; Shenzhen Neonatal Data Network
Chinese Journal of Contemporary Pediatrics 2024;26(5):450-455
Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75%(27/36);boys accounted for 64%(23/36).Among the 36 neonates,31(86%)had disease onset within 3 days after birth,and 19(53%)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61%)had left cerebral infarction and 13(36%)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75%)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72%)and seizures in 10 neonates(34%).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33%,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44%(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.
10.Clinical Application of Microwave Ablation in Potentially Resectable Colorectal Cancer With Simultaneously Multiple Liver Metastases
Lei HAN ; Xueliang WU ; Fei GUO ; Yuning XI ; Xiaoyan CHANG ; Chunze ZHANG ; Jianfeng ZHANG ; Pengcheng MA
Acta Academiae Medicinae Sinicae 2024;46(2):161-168
Objective To analyze the clinical efficacy of microwave ablation in the colorectal cancer with simultaneously multiple liver metastases that was initially evaluated as potentially resectable.Methods The patients with potentially resectable colorectal cancer with simultaneous multiple liver metastases treated in the De-partment of General Surgery of the First Affiliated Hospital of Hebei North University,the Center of Minimally Invasive Therapy in Oncology of Traditional Chinese and Western Medicine in Dongzhimen Hospital of Beijing U-niversity of Chinese Medicine,and the Second Department of General Surgery in the Fourth Hospital of Hebei Medical University from October 1,2018 to October 1,2020 were selected in this study.The general data,pathological features,treatment methods,and clinical efficacy of the patients were collected.According to the treatment methods,the patients were assigned into a surgical resection group(conversion therapy + laparoscopic primary resection +hepatectomy)and a microwave ablation group(conversion therapy +laparoscopic primary re-section +microwave ablation).The surgical indicators(operation duration,time to first postoperative anal ex-haust,hospital stay,etc.)and postoperative complications(anastomotic stenosis,anastomotic hemorrhage,incision infection,etc.)were compared between the two groups.The survival period was followed up,including the overall survival period and disease-free survival period,and the survival curves were drawn to analyze the clinical efficacy of the two treatment regimens.Results A total of 198 patients with potentially resectable color-ectal cancer with simultaneous multiple liver metastases were included in this study.Sixty-six patients were cured by neoadjuvant chemotherapy(FOLFOX or FOLFIRI),including 30 patients in the surgical resection group and 36 patients in the microwave ablation group(with 57 tumors ablated).After the first ablation,54(94.74%)tumors achieved complete ablation,and all of them reached no evidence of disease status after re-ablation.The microwave ablation group had shorter operation duration,less intraoperative blood loss,shorter time to first post-operative anal exhaust,shorter time of taking a liquid diet,shorter hospital stay,and lower hospitalization cost than the surgical resection group(all P<0.001).In addition,the microwave ablation group had lower visual analogue scale score(P<0.001)than the surgical resection group.The incidences of complications such as inci-sion infection(P =0.740),anastomotic fistula(P =1.000),and anastomotic stenosis(P =1.000),the over-all survival period(P =0.191),and the disease-free survival period(P =0.934)showed no significant differ-ences between the two groups.Conclusions For patients with colorectal cancer with simultaneous multiple liver metastases initially assessed as potentially resectable,laparoscopic primary resection +surgical resection/microwave ablation after conversion therapy was safe,effective,and had similar survival outcomes.Microwave ablation outper-formed surgical resection in postoperative recovery,economy,and tolerability,being worthy of clinical promotion.

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