1.The value of preoperative LNLR combined with cM0(i+)staging in prognostic assessment and model construction for clear cell renal cell carcinoma
Yu QIAO ; Zhenlong WANG ; Haibin ZHOU ; Huayang ZHENG ; Zihao LI ; Yao DONG ; Geng TIAN ; Tie CHONG ; Yue CHONG
Journal of Modern Urology 2026;31(3):207-216
Objective To construct and evaluate a prognostic model for clear cell renal cell carcinoma(ccRCC)based on preoperative lipid ratios, cM0(i+)staging, and other clinical characteristics, so as to provide a precise tool for clinical prognosis assessment. Methods A retrospective analysis was conducted on the clinical data of 215 ccRCC patients treated in our hospital during May 2014 and May 2023. Lipid ratios were calculated using preoperative lipid data, and patients were divided into cM0(i+)stage or cM0 stage according to postoperative circulating tumor cells(CTCs)test results. The optimal lipid ratio and cutoff value were selected using receiver operating characteristic(ROC)curves and the X-tile method. Patients were subdivided into three groups based on the level of the low-density lipoprotein cholesterol to non-low-density lipoprotein cholesterol ratio(LNLR)and cM0(i+)staging:Group A [LNLR>1.68 and diagnosed with cM0(i+)], Group B [LNLR>1.68 or diagnosed with cM0(i+)], and Group C(LNLR ≤1.68 and diagnosed with cM0). Kaplan-Meier survival analysis was used to plot survival curves for patients in different groups. The log-rank test was employed to compare differences in recurrence-free survival(RFS)among the subgroups. Multivariate Cox regression analysis was conducted to identify the independent risk factors influencing RFS, and a nomogram prediction model was constructed based on these results. The predictive performance of the model was validated using ROC curves, calibration curves, and decision curves. Results ROC curves were plotted for lipid markers, and LNLR was identified as the most predictive for RFS. Its optimal cutoff point was 1. 68. Patients in Group A experienced a significantly shorter postoperative RFS. Multivariate Cox regression analysis identified preoperative LNLR, cM0(i+)staging, pathological grade, and stage as independent risk factors for RFS. A nomogram model was constructed based on these risk factors. The area under the ROC curve(AUC)for 1-, 3-, and 5-year RFS was 0.896(95% CI:0.8121-0.9627), 0.890(95%CI:0.7879-0.9641), and 0.870(95%CI:0.7697-0.9526), indicating good discriminatory ability and predictive performance. Calibration plots demonstrated good agreement between predicted and actual outcomes. Clinical decision curve analysis showed high clinical net benefit. Conclusion Preoperative LNLR level is an independent risk factor for RFS in ccRCC patients. The prognostic prediction model based on LNLR, cM0(i+)staging, patient pathological grade, and staging demonstrates good predictive performance for RFS and holds potential clinical application value.
2.Traditional Chinese Medicine Intervenes in Endoplasmic Reticulum Stress to Treat Diabetic Microvascular Complications:A Review
Zhenlong ZHOU ; Yu DUAN ; Yutian PANG ; Ying JIA ; Mingwei LI ; Hongyu SHA ; Haichun ZHOU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(20):293-305
Diabetic microvascular complications (DMC) are major chronic complications of diabetes,primarily including diabetic kidney disease (DKD),diabetic retinopathy (DR),diabetic cardiomyopathy (DCM),and diabetic peripheral neuropathy (DPN). These complications significantly impact patients' quality of life and prognosis. Modern medicine primarily focuses on symptomatic control in the treatment of DMC,with limited ability to reverse the disease progression. Endoplasmic reticulum stress (ERS),as a central event under hyperglycemic toxicity,is not only a key cause of pancreatic β-cell dysfunction (reduced insulin synthesis and secretion) but also a core driver of damage in various target organs of DMC. It activates three signaling pathways of the unfolded protein response (UPR)-inositol-requiring enzyme 1 (IRE1),activating transcription factor 6 (ATF6),and protein kinase R-like endoplasmic reticulum kinase (PERK),intertwining processes such as autophagy,apoptosis,oxidative stress,and calcium homeostasis imbalance. Traditional Chinese medicine (TCM) offers multi-target and multi-pathway therapeutic advantages and can curb the pathological progression of DMC by regulating ERS. This article systematically reviews the relationships of ERS with pancreatic β-cell function,insulin synthesis,and insulin secretion,and elucidates the core signaling pathways through which ERS mediates DMC. Furthermore,it categorizes and summarizes experimental evidence and mechanisms of single medicinal herbs and their extracts,TCM compound formulas,and modern TCM preparations in regulating ERS for the treatment of various DMC subtypes. Finally,this article proposes ERS as a molecular bridge for integrating traditional Chinese and Western medicine in DMC treatment. Future research should leverage emerging technologies such as network pharmacology,multi-omics analysis,and nano-formulations to establish a synergistic network combining modern hypoglycemic drugs and TCM regulation of ERS. This approach is expected to achieve dual efficacy,enhance drug targeting and bioavailability,deepen the understanding of scientific connotation of TCM,and pave new avenues for the prevention and treatment of DMC.
3.Traditional Chinese Medicine Intervenes in Endoplasmic Reticulum Stress to Treat Diabetic Microvascular Complications:A Review
Zhenlong ZHOU ; Yu DUAN ; Yutian PANG ; Ying JIA ; Mingwei LI ; Hongyu SHA ; Haichun ZHOU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(20):293-305
Diabetic microvascular complications (DMC) are major chronic complications of diabetes,primarily including diabetic kidney disease (DKD),diabetic retinopathy (DR),diabetic cardiomyopathy (DCM),and diabetic peripheral neuropathy (DPN). These complications significantly impact patients' quality of life and prognosis. Modern medicine primarily focuses on symptomatic control in the treatment of DMC,with limited ability to reverse the disease progression. Endoplasmic reticulum stress (ERS),as a central event under hyperglycemic toxicity,is not only a key cause of pancreatic β-cell dysfunction (reduced insulin synthesis and secretion) but also a core driver of damage in various target organs of DMC. It activates three signaling pathways of the unfolded protein response (UPR)-inositol-requiring enzyme 1 (IRE1),activating transcription factor 6 (ATF6),and protein kinase R-like endoplasmic reticulum kinase (PERK),intertwining processes such as autophagy,apoptosis,oxidative stress,and calcium homeostasis imbalance. Traditional Chinese medicine (TCM) offers multi-target and multi-pathway therapeutic advantages and can curb the pathological progression of DMC by regulating ERS. This article systematically reviews the relationships of ERS with pancreatic β-cell function,insulin synthesis,and insulin secretion,and elucidates the core signaling pathways through which ERS mediates DMC. Furthermore,it categorizes and summarizes experimental evidence and mechanisms of single medicinal herbs and their extracts,TCM compound formulas,and modern TCM preparations in regulating ERS for the treatment of various DMC subtypes. Finally,this article proposes ERS as a molecular bridge for integrating traditional Chinese and Western medicine in DMC treatment. Future research should leverage emerging technologies such as network pharmacology,multi-omics analysis,and nano-formulations to establish a synergistic network combining modern hypoglycemic drugs and TCM regulation of ERS. This approach is expected to achieve dual efficacy,enhance drug targeting and bioavailability,deepen the understanding of scientific connotation of TCM,and pave new avenues for the prevention and treatment of DMC.
4.Ultrasound-Guided Microwave Ablation of Papillary Thyroid Cancer in the Context of Hashimoto Thyroiditis
Song LI ; Zhenlong ZHAO ; Ying WEI ; Lili PENG ; Yan LI ; Mingan YU
Chinese Journal of Medical Imaging 2025;33(6):627-630,632
Purpose To evaluate the safety and efficacy of microwave ablation(MWA)treatment for papillary thyroid cancer(PTC)in patients with Hashimoto thyroiditis(HT).Materials and Methods A retrospective analysis was conducted on clinical data from April 2020 to May 2022,involving 181 patients who underwent MWA at the China-Japan Friendship Hospital.All patients were divided into experimental group(n=89 cases)and control group(n=92 cases).The technical success rate,tumor volume reduction rate(VRR),disease progression and incidence of complications were compared between the two groups,respectively.Results Both groups achieved a technical success rate of 100%,with a median follow-up time of(16.90±11.43)months.At 3,6,12,and 18 months post-ablation,the VRR in the experimental group was significantly lower than that in the control group(3 months:-405.10(-778.57,-119.64)%vs.-190.00(-525.62,0)%;6 months:-50.00(-318.00,45.52)%vs.52.75(-93.33,97.13)%;12 months:83.33(17.70,100.00)%vs.100.00(64.88,100.00)%;18 months:100.00(96.05,100.00)%vs.100.00(100.00,100.00)%,Z=-2.77,-3.70,-2.41,-2.18,all P<0.05).At the end of follow-up,there was no significant difference in the disease progression rates and the incidence of hoarseness between the two groups(5.61%vs.4.34%,2.24%vs.4.34%,both P>0.05).Conclusion Patients with HT who received MWA treatment demonstrate safety and effectiveness,with no significant differences in postoperative disease progression rates compared to the controls.
5.Stent-assisted coil embolization of an aneurysm associated with internal carotid artery fenestration malformation in the supraclinoid segment:a case report and literature review
Xinxin FAN ; Zhenbo LIU ; Jingwei LI ; Guilin LI ; Zhenlong JI
Chinese Journal of Cerebrovascular Diseases 2025;22(7):506-510
Supraclinoid internal carotid artery(ICA)fenestration is a rare vascular developmental variant,and this anomaly may be associated with aneurysm formation.Whether the fenestration is originated from the embryonic development of the ICA or the posterior communicating artery(PCoA)remains controversial.This article retrospectively analyzed the imaging data,diagnosis and treatment process of one patient with supraclinoid ICA fenestration combined with an aneurysm,and further literature review was conducted combining with the case study.The aim of this study was to analyze the etiology of supraclinoid ICA fenestration and its correlation with aneurysm formation,in order to improve clinicians' understanding of this rare anomaly and facilitate the formulation of appropriate treatment plans.
6.The value of coagulation function and inflammatory response biomarkers in predicting postoperative recurrence of non-muscle-invasive bladder cancer
Huafeng LI ; Zhenlong WANG ; Yao DONG ; Zihe PENG ; Haibin ZHOU
Chinese Journal of Postgraduates of Medicine 2025;48(1):60-66
Objective:To investigate the predictive value of preoperative coagulation function and inflammation response biomarkers for postoperative recurrence of non-muscle-invasive bladder cancer (NMIBC) patients.Methods:The clinical data of 390 NMIBC patients underwent surgical treatment from May 2014 to May 2021 in the Second Affiliated Hospital of Xi′an Jiaotong University were retrospectively analyzed. The baseline characteristics coagulation function, inflammation response indexes and tumor characteristics were recorded. The baseline characteristics included gender, age and smoking history; the coagulation function included prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) and D-dimer; the inflammation response indexes included neutrophil count, lymphocyte count, platelet count and monocyte count, and the systemic inflammatory response index (SIRI) and systemic immune-inflammation index (SII) were calculated; tumor characteristics included TNM stage, pathological grade, tumor length, tumor amount and postoperative instillation drugs. The patients were followed up until May 2022, with recurrence records and grouping. The "pROC" package was used to draw the receiver operating characteristic (ROC) curve, and calculate the optimal cutoff values of biomarkers. Multivariate Cox regression analysis was used to analyze the independent risk factors of recurrence in patients with NMIBC (variables were selected with P<0.1). The nomogram and its calibration curve were drawn by the "survival" and "rms" packages, and the area under the curve (AUC) was calculated with the "pROC" package for assessing the predictive ability of the model. The "caret" package was used for ten-fold cross-validation to evaluate the external applicability of the nomogram. Results:The ROC curve analysis result showed that the optimal cutoff values of PT, APTT, FIB, D-dimer, SIRI and SII were 11.95 s, 17.65 s, 0.233 mg/L, 565 ng/L, 0.62 and 291.5, respectively. The 390 patients with NMIBC were followed up 29 to 71 months, with a median follow-up time of 49 months. Among them, 113 patients experienced postoperative recurrence (recurrence group), and the recurrence rate was 29.0%; while 277 patients did not experience recurrence (non-recurrence group). The rate of FIB≥0.233 mg/L, D-dimmer ≥565 ng/L, SIRI≥0.62 and SII≥291.5, T 1 stage, high-grade tumor, tumor length ≥2.3 cm and multiple tumor in recurrence group were significantly higher than those in non-recurrence group: 90.3% (102/113) vs. 71.5% (198/277), 33.6% (38/113) vs. 23.5% (65/277), 74.3% (84/113) vs. 56.7% (157/277), 84.1% (95/113) vs. 60.6% (168/277), 77.9% (88/113) vs. 38.6% (107/277), 25.7% (29/113) vs. 8.3% (23/277), 49.6% (56/113) vs. 32.1% (89/277) and 41.6% (47/113) vs. 19.9% (55/277), and there were statistical differences ( P<0.01 or <0.05); there were no statistical differences in gender ratio, age, smoking history, PT, APTT and postoperative instillation drugs between the two groups ( P>0.05). Multivariate Cox regression analysis result showed that FIB≥0.233 mg/L, SII≥291.5, T 1 stage, high pathological grade, tumor length≥2.3 cm and multiple tumor were independent risk factors of postoperative recurrence in patients with NMIBC ( HR = 2.186, 1.627, 3.182, 1.675, 1.775 and 2.052; 95% CI 1.149 to 4.159, 0.913 to 2.902, 1.988 to 5.095, 1.067 to 2.630, 1.208 to 2.608 and 1.388 to 3.033; P<0.1). A nomogram model was constructed to predict postoperative 1-, 3- and 5-year non-recurrence based on FIB, SII, T stage, tumor length, pathological grade and tumor amount. The calibration curve analysis result showed that the nomogram model predicted good consistency between the postoperative 1-, 3-, 5-year non-recurrence rates and the actual incidence rate in patients with NMIBC. ROC curve analysis result showed that the AUC of the nomogram model for predicting postoperative 1-, 3- and 5-year non-recurrence in patients with NMIBC were 0.746, 0.789 and 0.835 (95% CI 0.695 to 0.832, 0.703 to 0.875 and 0.756 to 0.915). The ten-fold cross-validation result showed that the nomogram model had good external applicability for predicting postoperative 1-, 3- and 5-year non-recurrence in patients with NMIBC, with AUC of 0.754, 0.781 and 0.832 (95% CI 0.689 to 0.817, 0.724 to 0.832 and 0.778 to 0.879). Conclusions:The nomogram model based on FIB, SII, T stage, tumor length, pathological grade and tumor amount can accurately predict the postoperative 1-, 3- and 5-year recurrence risks in patients with NMIBC. The model helps clinical doctors early identify high-risk recurrent NMIBC patients, and provides reference for the development of individualized treatment plans.
7.The value of coagulation function and inflammatory response biomarkers in predicting postoperative recurrence of non-muscle-invasive bladder cancer
Huafeng LI ; Zhenlong WANG ; Yao DONG ; Zihe PENG ; Haibin ZHOU
Chinese Journal of Postgraduates of Medicine 2025;48(1):60-66
Objective:To investigate the predictive value of preoperative coagulation function and inflammation response biomarkers for postoperative recurrence of non-muscle-invasive bladder cancer (NMIBC) patients.Methods:The clinical data of 390 NMIBC patients underwent surgical treatment from May 2014 to May 2021 in the Second Affiliated Hospital of Xi′an Jiaotong University were retrospectively analyzed. The baseline characteristics coagulation function, inflammation response indexes and tumor characteristics were recorded. The baseline characteristics included gender, age and smoking history; the coagulation function included prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) and D-dimer; the inflammation response indexes included neutrophil count, lymphocyte count, platelet count and monocyte count, and the systemic inflammatory response index (SIRI) and systemic immune-inflammation index (SII) were calculated; tumor characteristics included TNM stage, pathological grade, tumor length, tumor amount and postoperative instillation drugs. The patients were followed up until May 2022, with recurrence records and grouping. The "pROC" package was used to draw the receiver operating characteristic (ROC) curve, and calculate the optimal cutoff values of biomarkers. Multivariate Cox regression analysis was used to analyze the independent risk factors of recurrence in patients with NMIBC (variables were selected with P<0.1). The nomogram and its calibration curve were drawn by the "survival" and "rms" packages, and the area under the curve (AUC) was calculated with the "pROC" package for assessing the predictive ability of the model. The "caret" package was used for ten-fold cross-validation to evaluate the external applicability of the nomogram. Results:The ROC curve analysis result showed that the optimal cutoff values of PT, APTT, FIB, D-dimer, SIRI and SII were 11.95 s, 17.65 s, 0.233 mg/L, 565 ng/L, 0.62 and 291.5, respectively. The 390 patients with NMIBC were followed up 29 to 71 months, with a median follow-up time of 49 months. Among them, 113 patients experienced postoperative recurrence (recurrence group), and the recurrence rate was 29.0%; while 277 patients did not experience recurrence (non-recurrence group). The rate of FIB≥0.233 mg/L, D-dimmer ≥565 ng/L, SIRI≥0.62 and SII≥291.5, T 1 stage, high-grade tumor, tumor length ≥2.3 cm and multiple tumor in recurrence group were significantly higher than those in non-recurrence group: 90.3% (102/113) vs. 71.5% (198/277), 33.6% (38/113) vs. 23.5% (65/277), 74.3% (84/113) vs. 56.7% (157/277), 84.1% (95/113) vs. 60.6% (168/277), 77.9% (88/113) vs. 38.6% (107/277), 25.7% (29/113) vs. 8.3% (23/277), 49.6% (56/113) vs. 32.1% (89/277) and 41.6% (47/113) vs. 19.9% (55/277), and there were statistical differences ( P<0.01 or <0.05); there were no statistical differences in gender ratio, age, smoking history, PT, APTT and postoperative instillation drugs between the two groups ( P>0.05). Multivariate Cox regression analysis result showed that FIB≥0.233 mg/L, SII≥291.5, T 1 stage, high pathological grade, tumor length≥2.3 cm and multiple tumor were independent risk factors of postoperative recurrence in patients with NMIBC ( HR = 2.186, 1.627, 3.182, 1.675, 1.775 and 2.052; 95% CI 1.149 to 4.159, 0.913 to 2.902, 1.988 to 5.095, 1.067 to 2.630, 1.208 to 2.608 and 1.388 to 3.033; P<0.1). A nomogram model was constructed to predict postoperative 1-, 3- and 5-year non-recurrence based on FIB, SII, T stage, tumor length, pathological grade and tumor amount. The calibration curve analysis result showed that the nomogram model predicted good consistency between the postoperative 1-, 3-, 5-year non-recurrence rates and the actual incidence rate in patients with NMIBC. ROC curve analysis result showed that the AUC of the nomogram model for predicting postoperative 1-, 3- and 5-year non-recurrence in patients with NMIBC were 0.746, 0.789 and 0.835 (95% CI 0.695 to 0.832, 0.703 to 0.875 and 0.756 to 0.915). The ten-fold cross-validation result showed that the nomogram model had good external applicability for predicting postoperative 1-, 3- and 5-year non-recurrence in patients with NMIBC, with AUC of 0.754, 0.781 and 0.832 (95% CI 0.689 to 0.817, 0.724 to 0.832 and 0.778 to 0.879). Conclusions:The nomogram model based on FIB, SII, T stage, tumor length, pathological grade and tumor amount can accurately predict the postoperative 1-, 3- and 5-year recurrence risks in patients with NMIBC. The model helps clinical doctors early identify high-risk recurrent NMIBC patients, and provides reference for the development of individualized treatment plans.
8.Stent-assisted coil embolization of an aneurysm associated with internal carotid artery fenestration malformation in the supraclinoid segment:a case report and literature review
Xinxin FAN ; Zhenbo LIU ; Jingwei LI ; Guilin LI ; Zhenlong JI
Chinese Journal of Cerebrovascular Diseases 2025;22(7):506-510
Supraclinoid internal carotid artery(ICA)fenestration is a rare vascular developmental variant,and this anomaly may be associated with aneurysm formation.Whether the fenestration is originated from the embryonic development of the ICA or the posterior communicating artery(PCoA)remains controversial.This article retrospectively analyzed the imaging data,diagnosis and treatment process of one patient with supraclinoid ICA fenestration combined with an aneurysm,and further literature review was conducted combining with the case study.The aim of this study was to analyze the etiology of supraclinoid ICA fenestration and its correlation with aneurysm formation,in order to improve clinicians' understanding of this rare anomaly and facilitate the formulation of appropriate treatment plans.
9.Ultrasound-Guided Microwave Ablation of Papillary Thyroid Cancer in the Context of Hashimoto Thyroiditis
Song LI ; Zhenlong ZHAO ; Ying WEI ; Lili PENG ; Yan LI ; Mingan YU
Chinese Journal of Medical Imaging 2025;33(6):627-630,632
Purpose To evaluate the safety and efficacy of microwave ablation(MWA)treatment for papillary thyroid cancer(PTC)in patients with Hashimoto thyroiditis(HT).Materials and Methods A retrospective analysis was conducted on clinical data from April 2020 to May 2022,involving 181 patients who underwent MWA at the China-Japan Friendship Hospital.All patients were divided into experimental group(n=89 cases)and control group(n=92 cases).The technical success rate,tumor volume reduction rate(VRR),disease progression and incidence of complications were compared between the two groups,respectively.Results Both groups achieved a technical success rate of 100%,with a median follow-up time of(16.90±11.43)months.At 3,6,12,and 18 months post-ablation,the VRR in the experimental group was significantly lower than that in the control group(3 months:-405.10(-778.57,-119.64)%vs.-190.00(-525.62,0)%;6 months:-50.00(-318.00,45.52)%vs.52.75(-93.33,97.13)%;12 months:83.33(17.70,100.00)%vs.100.00(64.88,100.00)%;18 months:100.00(96.05,100.00)%vs.100.00(100.00,100.00)%,Z=-2.77,-3.70,-2.41,-2.18,all P<0.05).At the end of follow-up,there was no significant difference in the disease progression rates and the incidence of hoarseness between the two groups(5.61%vs.4.34%,2.24%vs.4.34%,both P>0.05).Conclusion Patients with HT who received MWA treatment demonstrate safety and effectiveness,with no significant differences in postoperative disease progression rates compared to the controls.
10.Establishment of a prediction model for postoperative progression-free survival in patients with renal cell carcinoma
Huafeng LI ; Zhenlong WANG ; Hongyi ZHANG ; Zihe PENG ; Chenyue WANG ; Yao DONG ; Haibin ZHOU
Journal of Modern Urology 2024;29(10):892-897
[Objective] To analyze factors influencing the postoperative progression-free survival (PFS) in patients with renal cell carcinoma (RCC), construct a nomogram model for predicting PFS, and compare it with other predictive models. [Methods] A retrospective analysis was conducted on the general and clinical data of 263 RCC patients who underwent surgery at the Department of Urology, the Second Affiliated Hospital of Xi'an Jiaotong University, during Apr.2014 and Nov.2021.Patients were divided into the progression group (n=34) and non-progression group (n=229). The data of the two groups were analyzed to identify prognostic variables associated with PFS, and a nomogram model was constructed.The performance of this model was compared with that of the University of California, Los Angeles Integrated Staging System (UISS) score, tumor staging, tumor size, tumor pathological grade, and tumor necrosis scoring system (SSIGN score), and Leibovich score by plotting receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC). Calibration curve of the nomogram was used to validate the model's performance, and K-fold cross-validation was employed to assess its external validity. [Results] Multivariate Cox regression analysis revealed that age (HR=2.255, 95%CI: 1.032-4.926), T stage (HR=5.766, 95%CI: 2.351-14.142), pathological grade (HR=3.100, 95%CI: 1.445-6.651), and pathological necrosis (HR=2.656, 95%CI: 1.253-5.629) were independent risk factors of PFS (P<0.05). The nomogram model based on these four independent variables had AUCs (95%CI) of 0.750 (0.630-0.870), 0.803 (0.705-0.902), and 0.847 (0.757-0.937) for 1, 3, and 5 years, respectively, which were higher than those of UISS score, SSIGN score, and Leibovich score.The calibration curve of the nomogram showed good consistency between predicted and actual probabilities.In K-fold cross-validation, the average AUCs of the nomogram at 1, 3, and 5 years were 0.761, 0.808, and 0.842, indicating good external validity of the nomogram. [Conclusion] The nomogram based on age, T stage, pathological grade and pathological necrosis can accurately predict the risk of postoperative PFS in RCC patients at 1, 3, and 5 years, which can aid clinicians in the early identification of high-risk progression.

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