1.Application of multi-omics and artificial intelligence in the prediction and diagnosis of liver metastases in colorectal cancer
Likun WANG ; Qi HAO ; Weihan JIN ; Shizheng DONG ; Xueliang WU ; Xiaofeng HU ; Liang WU ; Jing XUN ; Hongqing MA
The Journal of Practical Medicine 2025;41(7):1070-1078
Colorectal cancer stands as a leading cause of cancer-related morbidity and mortality globally,with liver metastases being a significant determinant of patient prognosis.Conventional diagnostic methods,includ-ing imaging studies and biomarker testing,frequently exhibit inadequate sensitivity and specificity,underscoring the necessity for more advanced technologies.Recent advancements in genomics,transcriptomics,proteomics,me-tabolomics,and epigenomics have revolutionized our understanding of the biological mechanisms driving colorectal cancer.These methodologies enable comprehensive analyses of genetic mutations,gene expression profiles,protein modifications,and metabolic reprogramming,all of which are pivotal to the metastatic process.This article high-lights the advanced capabilities of artificial intelligence(AI)technologies in processing complex multi-omics data,thereby enhancing diagnostic accuracy and supporting personalized treatment strategies.It also addresses the challenges AI encounters in multi-omics analyses,such as ensuring data quality,improving model interpretability,and facilitating clinical translation.Additionally,it explores the potential integration of emerging technologies like single-cell sequencing and spatial omics into large-scale,multicenter studies to further enhance the clinical utility of these tools.
2.Evaluation of the Degree of Fibrosis in Chronic Kidney Disease via Clinical Radiomics Nomogram Prediction Model
Xiaomin HU ; Weihan XIAO ; Xuebin LIU ; Chaoxue ZHANG ; Xiachuan QIN
Chinese Journal of Medical Imaging 2025;33(3):331-336
Purpose To explore the value of the clinical radiomics nomogram based on ultrasound in evaluating the degree of fibrosis in chronic kidney disease(CKD).Materials and Methods This retrospective study included 350 patients with CKD in Nanchong Central Hospital from January 2014 to July 2022 who underwent renal biopsy.The patients were categorized by the tubule atrophy with interstitial fibrosis(TA/IF)and divided into a training cohort(n=245)and test cohort(n=105).The patient demographics were evaluated to establish a clinical prediction model.The XGBoost machine learning model was constructed by extracting the radiomics features from the ultrasound images.The clinical radiomics nomogram prediction model was constructed by combining the radiomics score(Rad score)and important clinical features.The diagnostic performance of the three models was evaluated using receiver operating characteristic curve analysis.Results Among the 350 patients with CKD,226 had TA/IF 0 and 124 had TA/IF 1.Based on the clinical characteristics and Rad score,the clinical radiomics nomogram prediction model had the highest area under the curve in the training and testing cohorts,with the area under the curve of 0.938(95%CI 0.909-0.969)and 0.933(95%CI 0.891-0.980),respectively.Conclusion The ultrasound-based radiomics prediction model has potential value for the noninvasive diagnosis of TA/IF in CKD.Nomogram prediction models based on renal Rad scores and clinic may help clinicians to manage patients.
3.Different Effects of Fresh and Dried Dendrobium Huoshanense on Chronic Atrophic Gastritis
Mengqing HU ; Xinyu YANG ; Weihan GONG ; Huiqun XIE ; Lan HAN ; Daiyin PENG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(22):29-39
ObjectiveTo compare the protective effects of water extracts from fresh and dried Dendrobium huoshanense on gastric mucosa in chronic atrophic gastritis (CAG). MethodsMale SD rats (n=72) were randomly divided into 9 groups, with 8 rats in each group, which were normal group, model group, Yangwei Shu (4 g·kg-1) group, low-, medium-, and high-dose fresh D. huoshanense (3.5, 7, and 14 g·kg-1) groups, and low-, medium-, and high-dose dried D. huoshanense (0.7, 1.4, 2.8 g·kg-1) groups. The CAG rat model was successfully established by inducing with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and other factors for a total of 11 weeks. Then, the rats were intervened with fresh and dried D. huoshanense for 4 weeks. The serum and gastric tissues of the rats were collected. The changes in gastric juice secretion volume and gastric acid pH value in each group were observed. The gastric mucosal injury was observed by naked eyes and hematoxylin-eosin(HE) staining. The gastric mucus secretion level was determined by Alcian blue and periodic acid-Schiff staining(AB-PAS) staining. The expression levels of tight junction proteins Occludin and ZO-1 in gastric tissues were determined by immunofluorescence. The expression levels of serum pepsinogen Ⅰ (PG Ⅰ), pepsinogen Ⅱ (PG Ⅱ), gastrin 17 (G-17), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). The expression levels of aquaporin 1 (AQP1), aquaporin 3 (AQP3), and aquaporin 4 (AQP4) in gastric tissues were determined by Western blot. ResultsCompared with the normal group, the model group showed an obviously reduced gastric juice secretion volume (P0.05), significantly increased gastric acid pH value (P0.01), gastric mucosa with obvious atrophy, and a significantly reduced gastric mucus secretion volume (P0.01). The expression of Occludin and ZO-1 in the gastric mucosal barrier was significantly decreased (P0.01). The levels of PG Ⅰ and PG Ⅱ in the serum were obviously decreased (P0.05, P0.01), and the levels of G-17, IL-1β, IL-6, and TNF-α were significantly increased (P0.01). The expression level of AQP1 in the gastric tissue was significantly upregulated (P0.01), and the expression levels of AQP3 and AQP4 were significantly downregulated (P0.01). Compared with the model group, each drug administration group could improve the gastric mucosal atrophy of CAG model rats to varying degrees, obviously increase the gastric juice secretion volume of the model rats (P0.05, P0.01), significantly decrease the gastric acid pH value (P0.01), obviously increase the gastric mucus secretion volume (P0.05, P0.01), obviously decrease the expression levels of G-17, IL-6, IL-1β, and TNF-α (P0.05, P0.01), obviously increase the expression levels of Occludin, ZO-1, PG Ⅰ, and PG Ⅱ (P0.05, P0.01), obviously upregulate the expression levels of AQP3 and AQP4 (P0.05, P0.01), and obviously downregulate the expression level of AQP1 (P0.05, P0.01). ConclusionThe water extracts of fresh and dried D. huoshanense can exert therapeutic effects on CAG by improving gastric mucosal injury, reducing inflammation, and regulating water metabolism. Moreover, the dried D. huoshanense has a better effect.
4.Application of multi-omics and artificial intelligence in the prediction and diagnosis of liver metastases in colorectal cancer
Likun WANG ; Qi HAO ; Weihan JIN ; Shizheng DONG ; Xueliang WU ; Xiaofeng HU ; Liang WU ; Jing XUN ; Hongqing MA
The Journal of Practical Medicine 2025;41(7):1070-1078
Colorectal cancer stands as a leading cause of cancer-related morbidity and mortality globally,with liver metastases being a significant determinant of patient prognosis.Conventional diagnostic methods,includ-ing imaging studies and biomarker testing,frequently exhibit inadequate sensitivity and specificity,underscoring the necessity for more advanced technologies.Recent advancements in genomics,transcriptomics,proteomics,me-tabolomics,and epigenomics have revolutionized our understanding of the biological mechanisms driving colorectal cancer.These methodologies enable comprehensive analyses of genetic mutations,gene expression profiles,protein modifications,and metabolic reprogramming,all of which are pivotal to the metastatic process.This article high-lights the advanced capabilities of artificial intelligence(AI)technologies in processing complex multi-omics data,thereby enhancing diagnostic accuracy and supporting personalized treatment strategies.It also addresses the challenges AI encounters in multi-omics analyses,such as ensuring data quality,improving model interpretability,and facilitating clinical translation.Additionally,it explores the potential integration of emerging technologies like single-cell sequencing and spatial omics into large-scale,multicenter studies to further enhance the clinical utility of these tools.
5.Evaluation of the Degree of Fibrosis in Chronic Kidney Disease via Clinical Radiomics Nomogram Prediction Model
Xiaomin HU ; Weihan XIAO ; Xuebin LIU ; Chaoxue ZHANG ; Xiachuan QIN
Chinese Journal of Medical Imaging 2025;33(3):331-336
Purpose To explore the value of the clinical radiomics nomogram based on ultrasound in evaluating the degree of fibrosis in chronic kidney disease(CKD).Materials and Methods This retrospective study included 350 patients with CKD in Nanchong Central Hospital from January 2014 to July 2022 who underwent renal biopsy.The patients were categorized by the tubule atrophy with interstitial fibrosis(TA/IF)and divided into a training cohort(n=245)and test cohort(n=105).The patient demographics were evaluated to establish a clinical prediction model.The XGBoost machine learning model was constructed by extracting the radiomics features from the ultrasound images.The clinical radiomics nomogram prediction model was constructed by combining the radiomics score(Rad score)and important clinical features.The diagnostic performance of the three models was evaluated using receiver operating characteristic curve analysis.Results Among the 350 patients with CKD,226 had TA/IF 0 and 124 had TA/IF 1.Based on the clinical characteristics and Rad score,the clinical radiomics nomogram prediction model had the highest area under the curve in the training and testing cohorts,with the area under the curve of 0.938(95%CI 0.909-0.969)and 0.933(95%CI 0.891-0.980),respectively.Conclusion The ultrasound-based radiomics prediction model has potential value for the noninvasive diagnosis of TA/IF in CKD.Nomogram prediction models based on renal Rad scores and clinic may help clinicians to manage patients.
6.Safety of patients undergoing radical resection combined with paclitaxel-based hyperthermic intraperitoneal chemotherapy for locally advanced gastric cancer
Jiaxin MEI ; Linyong ZHAO ; Weihan ZHANG ; Kai LIU ; Xiaolong CHEN ; Kun YANG ; Jiankun HU
Chinese Journal of Gastrointestinal Surgery 2024;27(5):471-477
Objective:To analyze the safety of paclitaxel-based, hyperthermic, intraperitoneal perfusion chemotherapy (HIPEC) after radical resection of locally advanced gastric cancer.Methods:This was a retrospective cohort study of clinicopathological data of 467 patients with locally advanced gastric adenocarcinoma who had been admitted to the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University between July 2019 and April 2021. Among these patients, 151 had undergone radical resection combined with post-operative paclitaxel-based HIPEC (surgery+HIPEC group) and 316 radical resection alone (surgery group). The adverse perioperative events in study patients were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) published by the U.S. Department of Health and Human Services. Subgroup analysis was performed on patients in the surgery+HIPEC group according to the number of times HIPEC was administered and the incidence of adverse events was compared between subgroups using the χ 2 test. Independent risk factors for paclitaxel-based HIPEC-associated adverse events were identified by applying a logistic model. Results:In the surgery+HIPEC group, there were 113 (74.8%) male and 38 (25.2%) female patients of median age 64 (55, 68) years, 18 (11.9%), 79 (52.3%), and 54 (35.8%) of whom had undergone one, two, and three paclitaxel-based HIPEC treatments, respectively, after surgery. The median maximum tumor diameter was 5.0 (3.6, 6.5) cm. In the surgery group, there were 244 (77.2%) male and 72 (22.8%) female patients of median age 63 (54, 68) and the median maximum tumor diameter was 4.0 (3.0, 5.5) cm. In the surgery+HIPEC group, 112 patients (74.2%) had 198 Grade 2 or higher adverse perioperative events, postoperative hypoalbuminemia being the commonest (85 cases, 56.3%), followed by postoperative anemia (50 cases, 33.1%). Compared with the surgery group, the incidences of postoperative hypoalbuminemia (56.3% [85/151] vs. 37.7% [119/316], χ 2=14.420, P<0.001), anemia (33.1% [50/151] vs. 22.5% [71/316], χ 2=6.030, P=0.014), abdominal pain [7.3% [11/151] vs. 1.6% [5/316], χ 2=10.042, P=0.002) and abdominal distension (5.3% [8/151] vs. 1.3% [4/316], χ 2=5.123, P=0.024) were all significantly higher in the surgery+HIPEC group. Analysis of the three HIPEC subgroups revealed significant differences in the incidences of postoperative hypoalbuminemia (13/18 vs. 67.1% [53/79] vs. 35.2% [19/54], χ 2=12.955, P<0.001) and pulmonary infection (6/18 vs. 6.3% [5/79] vs. 1.9% [1/54], χ 2=13.232, P<0.001) between them. Univariate analysis identified body mass index, Borrmann's type and number of HIPEC treatments as associated with perioperative adverse events in the surgery+HIPEC group ( P<0.05). However, according to multifactorial logistic analysis, the above factors were not independent risk factors for perioperative adverse events in the surgery+HIPEC group ( P>0.05). Conclusions:Paclitaxel-based HIPEC after radical resection significantly increases the risk of postoperative hypoalbuminemia, anemia, abdominal pain, and abdominal distension in patients who have undergone excision of locally advanced gastric cancer. However, increasing the frequency of HIPEC treatments did not significantly increase the risk of paclitaxel-based HIPEC-related adverse events. Moreover, univariate and multivariate analysis did not identify any independent risk factors for paclitaxel HIPEC-related adverse events.
7.Safety of patients undergoing radical resection combined with paclitaxel-based hyperthermic intraperitoneal chemotherapy for locally advanced gastric cancer
Jiaxin MEI ; Linyong ZHAO ; Weihan ZHANG ; Kai LIU ; Xiaolong CHEN ; Kun YANG ; Jiankun HU
Chinese Journal of Gastrointestinal Surgery 2024;27(5):471-477
Objective:To analyze the safety of paclitaxel-based, hyperthermic, intraperitoneal perfusion chemotherapy (HIPEC) after radical resection of locally advanced gastric cancer.Methods:This was a retrospective cohort study of clinicopathological data of 467 patients with locally advanced gastric adenocarcinoma who had been admitted to the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University between July 2019 and April 2021. Among these patients, 151 had undergone radical resection combined with post-operative paclitaxel-based HIPEC (surgery+HIPEC group) and 316 radical resection alone (surgery group). The adverse perioperative events in study patients were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) published by the U.S. Department of Health and Human Services. Subgroup analysis was performed on patients in the surgery+HIPEC group according to the number of times HIPEC was administered and the incidence of adverse events was compared between subgroups using the χ 2 test. Independent risk factors for paclitaxel-based HIPEC-associated adverse events were identified by applying a logistic model. Results:In the surgery+HIPEC group, there were 113 (74.8%) male and 38 (25.2%) female patients of median age 64 (55, 68) years, 18 (11.9%), 79 (52.3%), and 54 (35.8%) of whom had undergone one, two, and three paclitaxel-based HIPEC treatments, respectively, after surgery. The median maximum tumor diameter was 5.0 (3.6, 6.5) cm. In the surgery group, there were 244 (77.2%) male and 72 (22.8%) female patients of median age 63 (54, 68) and the median maximum tumor diameter was 4.0 (3.0, 5.5) cm. In the surgery+HIPEC group, 112 patients (74.2%) had 198 Grade 2 or higher adverse perioperative events, postoperative hypoalbuminemia being the commonest (85 cases, 56.3%), followed by postoperative anemia (50 cases, 33.1%). Compared with the surgery group, the incidences of postoperative hypoalbuminemia (56.3% [85/151] vs. 37.7% [119/316], χ 2=14.420, P<0.001), anemia (33.1% [50/151] vs. 22.5% [71/316], χ 2=6.030, P=0.014), abdominal pain [7.3% [11/151] vs. 1.6% [5/316], χ 2=10.042, P=0.002) and abdominal distension (5.3% [8/151] vs. 1.3% [4/316], χ 2=5.123, P=0.024) were all significantly higher in the surgery+HIPEC group. Analysis of the three HIPEC subgroups revealed significant differences in the incidences of postoperative hypoalbuminemia (13/18 vs. 67.1% [53/79] vs. 35.2% [19/54], χ 2=12.955, P<0.001) and pulmonary infection (6/18 vs. 6.3% [5/79] vs. 1.9% [1/54], χ 2=13.232, P<0.001) between them. Univariate analysis identified body mass index, Borrmann's type and number of HIPEC treatments as associated with perioperative adverse events in the surgery+HIPEC group ( P<0.05). However, according to multifactorial logistic analysis, the above factors were not independent risk factors for perioperative adverse events in the surgery+HIPEC group ( P>0.05). Conclusions:Paclitaxel-based HIPEC after radical resection significantly increases the risk of postoperative hypoalbuminemia, anemia, abdominal pain, and abdominal distension in patients who have undergone excision of locally advanced gastric cancer. However, increasing the frequency of HIPEC treatments did not significantly increase the risk of paclitaxel-based HIPEC-related adverse events. Moreover, univariate and multivariate analysis did not identify any independent risk factors for paclitaxel HIPEC-related adverse events.
8.Comparison of long-term quality of life between Billroth-I and Roux-en-Y anastomosis after distal gastrectomy for gastric cancer: a randomized controlled trial.
Kun YANG ; Weihan ZHANG ; Zehua CHEN ; Xiaolong CHEN ; Kai LIU ; Linyong ZHAO ; Jiankun HU
Chinese Medical Journal 2023;136(9):1074-1081
BACKGROUND:
The results of studies comparing Billroth-I (B-I) with Roux-en-Y (R-Y) reconstruction on the quality of life (QoL) are still inconsistent. The aim of this trial was to compare the long-term QoL of B-I with R-Y anastomosis after curative distal gastrectomy for gastric cancer.
METHODS:
A total of 140 patients undergoing curative distal gastrectomy with D2 lymphadenectomy in West China Hospital, Sichuan University from May 2011 to May 2014 were randomly assigned to the B-I group ( N = 70) and R-Y group ( N = 70). The follow-up time points were 1, 3, 6, 9, 12, 24, 36, 48, and 60 months after the operation. The final follow-up time was May 2019. The clinicopathological features, operative safety, postoperative recovery, long-term survival as well as QoL were compared, among which QoL score was the primary outcome. An intention-to-treat analysis was applied.
RESULTS:
The baseline characteristics were comparable between the two groups. There were no statistically significant differences in terms of postoperative morbidity and mortality rates, and postoperative recovery between the two groups. Less estimated blood loss and shorter surgical duration were found in the B-I group. There were no statistically significant differences in 5-year overall survival (79% [55/70] of the B-I group vs. 80% [56/70] of the R-Y group, P = 0.966) and recurrence-free survival rates (79% [55/70] of the B-I group vs. 78% [55/70] of the R-Y group, P = 0.979) between the two groups. The scores of the global health status of the R-Y group were higher than those of the B-I group with statistically significant differences (postoperative 1 year: 85.4 ± 13.1 vs . 88.8 ± 16.1, P = 0.033; postoperative 3 year: 87.3 ± 15.2 vs . 92.8 ± 11.3, P = 0.028; postoperative 5 year: 90.9 ± 13.7 vs . 96.4 ± 5.6, P = 0.010), and the reflux (postoperative 3 year: 8.8 ± 12.9 vs . 2.8 ± 5.3, P = 0.001; postoperative 5 year: 5.1 ± 9.8 vs . 1.8 ± 4.7, P = 0.033) and epigastric pain (postoperative 1 year: 11.8 ± 12.7 vs. 6.1 ± 8.8, P = 0.008; postoperative 3 year: 9.4 ± 10.6 vs. 4.6 ± 7.9, P = 0.006; postoperative 5 year: 6.0 ± 8.9 vs . 2.7 ± 4.6, P = 0.022) were milder in the R-Y group than those of the B-I group at the postoperative 1, 3, and 5-year time points.
CONCLUSIONS:
Compared with B-I group, R-Y reconstruction was associated with better long-term QoL by reducing reflux and epigastric pain, without changing survival outcomes.
TRIAL REGISTRATION
ChiCTR.org.cn, ChiCTR-TRC-10001434.
Humans
;
Stomach Neoplasms/pathology*
;
Anastomosis, Roux-en-Y/methods*
;
Quality of Life
;
Treatment Outcome
;
Gastrectomy/methods*
;
Postoperative Complications
;
Gastroenterostomy/methods*
;
Pain
9.Prevention and treatment of anastomosis-related complications after gastric cancer surgery
Chinese Journal of Digestive Surgery 2020;19(9):946-950
Postoperative anastomosis-related complications are the common postoperative complications of gastric cancer. With the advancement of surgical technology and surgical instruments, the risk of postoperative anastomosis-related complications of gastric cancer has been greatly reduced. However, anastomotic stenosis, residual gastritis, anastomosis inflammation and reflux esophagitis seriously affect long-term quality of life in gastric cancer patients. Based on the incidence of short-term and long-term complications, the authors aim to conclude risks factors, preventive measures and means of treatment for postoperative anastomosis-related complications after gastric cancer surgery.
10.Effect of standardized surgical treatment and multidisciplinary treatment strategy on the prognosis of gastric cancer patients: report of a single-center cohort study
Weihan ZHANG ; Kun YANG ; Xinzu CHEN ; Kai LIU ; Xiaolong CHEN ; Linyong ZHAO ; Bo ZHANG ; Zhixin CHEN ; Jiaping CHEN ; Zongguang ZHOU ; Jiankun HU
Chinese Journal of Gastrointestinal Surgery 2020;23(4):396-404
Objective:To explore the effect of standardized surgical treatment and multidisciplinary treatment strategy on the treatment outcomes of gastric cancer patients.Methods:A single-center cohort study was carried out. Clinicopathological and long-term follow up data of primary gastric cancer patients were retrieved from the database of Surgical Gastric Cancer Patient Registry (SGCPR) in West China Hospital of Sichuan University. Finally, 4516 gastric cancer patients were included and were divided into three groups according to time periods (period 1 group: exploration stage of standardized surgical treatment, 2000 to 2006, 967 cases; period 2 group: application stage of standardized surgical treatment, 2007 to 2012, 1962 cases; period 3 group: optimization stage of standardized surgical treatment and application stage of multidisciplinary treatment strategy, 2013 to 2016, 1587 cases). Differences in clinical data, pathologic features, and prognosis were compared among 3 period groups. Follow-up information was updated to January 1, 2020. The overall follow-up rate was 88.9% (4016/4516) and median follow-up duration was 51.58 months. Survival curve was drawn by Kaplan-Meire method and compared with log-rank test. Univariate and multivariate analyses were performed by Cox proportional hazards model.Results:There were significant differences among period 1, period 2 and period 3 groups in the rates of D2/D2+ lymphadenectomy [14.4%(139/967) vs. 47.2%(927/1962) vs. 75.4%(1197/1587), χ 2=907.210, P<0.001], in the ratio of proximal gastrectomy [19.8%(191/967) vs. 16.6%(325/1962) vs. 8.2%(130/1587), χ 2=100.020, P<0.001], and in the median intraoperative blood loss (300 ml vs. 100 ml vs. 100 ml, H=1126.500, P<0.001). Besides, the increasing trend and significant difference were also observed in the median number of examined lymph nodes among period 1, period 2 and period 3 groups (14 vs. 26 vs. 30, H=987.100, P<0.001). Survival analysis showed that the 5-year overall survival rate was 55.3% in period 1, 55.2% in period 2 and 62.8% in period 3, and significant difference existed between period 3 and period 1 ( P=0.004). The Cox proportional hazards model analysis showed that treatment period (period 3, HR=0.820, 95%CI: 0.708 to 0.950, P=0.008), postoperative chemotherapy (HR=0.696, 95%CI: 0.631 to 0.768, P<0.001) and mid-low gastric cancer (HR=0.884, 95%CI: 0.804 to 0.973, P=0.011) were good prognostic factors. Whereas old age (≥65 years, HR=1.189, 95%CI: 1.084 to 1.303, P<0.001), palliative resection (R1/R2, HR=1.538,95%CI: 1.333 to 1.776, P<0.001), large tumor size (≥5 cm, HR=1.377, 95%CI: 1.239 to 1.529, P<0.001), macroscopic type III to IV (HR=1.165, 95%CI: 1.063 to 1.277, P<0.001) and TNM stage II to IV(II/I: HR=1.801,95% CI:1.500~2.162, P<0.001;III/I: HR=3.588, 95% CI: 3.028~4.251, P<0.001; IV/I: HR=6.114, 95% CI: 4.973~7.516, P<0.001) were independent prognostic risk factors. Conclusion:Through the implementation of standardized surgical treatment technology and multidisciplinary treatment model, the quality of surgery treatment and overall survival increase, and prognosis of gastric cancer patients has been improved.

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