1.Guizhi Shaoyao Zhimutang and Active Components of Its Single Herbs in Treatment of Rheumatoid Arthritis: A Review
Jian LIU ; SHIPEIRU ; Shuang LI ; Jinzhao ZHAO ; Naijun CAO ; Mingxiu JIN ; Jing YU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(10):346-354
Rheumatoid arthritis (RA) is a common autoimmune disease characterised clinically by symmetrical joint pain, swelling, and stiffness. Long-term chronic synovial inflammation can lead to severe joint damage and even disability, thereby affecting quality of life for patients. Current clinical treatment of RA emphasises an integrated approach combining traditional Chinese and Western medicine, with traditional Chinese medicine offering certain advantages in reducing disease activity of RA, preventing relapses, and other aspects. Modern clinical evidence confirms that Guizhi Shaoyao Zhimutang (GSZT) is effective in improving symptoms such as immune metabolism, joint stiffness, and joint pain in RA patients. Pharmacological studies have revealed that GSZT primarily contains components such as cinnamaldehyde, total glucosides of paeony, total alkaloids of Aconiti Lateralis Radix Praeparata, glycyrrhetinic acid, zingiberone, isoimperatorin, ephedra polysaccharides, and cedrol. It improves RA symptoms via multiple mechanisms and targets, including enhancing immune responses, exerting anti-inflammatory and analgesic effects, regulating relevant signalling pathways, inhibiting cell apoptosis, and suppressing bone destruction. This paper reviewed the syndrome patterns and pharmacological basis of GSZT in the treatment of RA, as well as its clinical applications and related mechanisms, thereby providing a theoretical basis and reference for the further development and utilisation of GSZT in the treatment of RA.
2.Guizhi Shaoyao Zhimutang and Active Components of Its Single Herbs in Treatment of Rheumatoid Arthritis: A Review
Jian LIU ; SHIPEIRU ; Shuang LI ; Jinzhao ZHAO ; Naijun CAO ; Mingxiu JIN ; Jing YU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(10):346-354
Rheumatoid arthritis (RA) is a common autoimmune disease characterised clinically by symmetrical joint pain, swelling, and stiffness. Long-term chronic synovial inflammation can lead to severe joint damage and even disability, thereby affecting quality of life for patients. Current clinical treatment of RA emphasises an integrated approach combining traditional Chinese and Western medicine, with traditional Chinese medicine offering certain advantages in reducing disease activity of RA, preventing relapses, and other aspects. Modern clinical evidence confirms that Guizhi Shaoyao Zhimutang (GSZT) is effective in improving symptoms such as immune metabolism, joint stiffness, and joint pain in RA patients. Pharmacological studies have revealed that GSZT primarily contains components such as cinnamaldehyde, total glucosides of paeony, total alkaloids of Aconiti Lateralis Radix Praeparata, glycyrrhetinic acid, zingiberone, isoimperatorin, ephedra polysaccharides, and cedrol. It improves RA symptoms via multiple mechanisms and targets, including enhancing immune responses, exerting anti-inflammatory and analgesic effects, regulating relevant signalling pathways, inhibiting cell apoptosis, and suppressing bone destruction. This paper reviewed the syndrome patterns and pharmacological basis of GSZT in the treatment of RA, as well as its clinical applications and related mechanisms, thereby providing a theoretical basis and reference for the further development and utilisation of GSZT in the treatment of RA.
3.Effects of Modified Buyang Huanwu Tang on Mice with Cerebral Ischemia-reperfusion Injury by Regulating PINK1/Parkin Signaling Pathway-mediated Mitochondrial Autophagy
Li GUO ; Hengwen CHEN ; Cun ZHAN ; Zhenzhen YING ; Zuomin WU ; Shaoju JIN ; Shangmei CAO ; Shengming HUANG ; Jin WANG ; Xiaotao YU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(11):34-43
ObjectiveTo investigate the effects of modified Buyang Huanwu Tang on cerebral ischemia-reperfusion injury (CI/RI) in mice via the PTEN-induced putative kinase 1/E3 ubiquitin ligase (PINK1/Parkin) signaling pathway-mediated mitophagy, and to explore the underlying mechanism by which modified Buyang Huanwu Tang improves CI/RI. MethodsSeventy-two male C57BL/6J mice were randomly divided into six groups (n = 12 per group): Sham-operated group, middle cerebral artery occlusion/reperfusion (MCAO/R) model group, low-, medium-, and high-dose modified Buyang Huanwu Tang groups (8.84, 17.68, 35.36 g·kg-1·d-1), and an aspirin group (13.00 mg·kg-1·d-1). Neurological deficit scores were assessed using the Zea-Longa method. Cerebral infarct volume ratio was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Histopathological changes and neuronal injury in brain tissues were observed using hematoxylin-eosin (HE) staining and Nissl staining. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Mitochondrial ultrastructure in brain tissue was observed by transmission electron microscopy (TEM). Serum levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA and protein expression levels of PINK1, Parkin, microtubule-associated protein 1 light chain 3B (LC3B, LC3Ⅱ/Ⅰ), and p62 in brain tissues were detected by real-time quantitative reverse transcription PCR (Real-time PCR) and Western blot, respectively. ResultsCompared with the sham-operated group, the MCAO/R model group showed significantly increased neurological deficit scores and cerebral infarct volume ratios (P<0.01). Severe cortical injury on the infarct side was observed, characterized by decreased neuronal density, cytoplasmic vacuolation, nuclear pyknosis, a marked reduction in Nissl bodies, dissolution of Nissl bodies in the cytoplasm of some pyramidal neurons, and blurred cellular boundaries. The number of TUNEL-positive cells increased significantly (P<0.01). Mitochondria exhibited cristae membrane rupture and matrix vacuolation, with rupture of the outer mitochondrial membrane and formation of autophagosomes, the number of which increased significantly. Serum SOD activity decreased significantly (P<0.01), while MDA content increased significantly (P<0.01). In infarcted brain tissues of model mice, the relative mRNA expression and protein levels of PINK1, Parkin and LC3B were significantly increased (P<0.05, P<0.01), whereas p62 mRNA and protein expression were significantly decreased (P<0.05, P<0.01), showing statistical significance. Compared with the model group, all treatment groups showed significantly decreased neurological deficit scores and cerebral infarct volume ratios (P<0.01). Neuronal density increased significantly, cytoplasmic vacuolation was alleviated, nuclear morphology tended to be more regular and clearer, Nissl body density increased significantly with reduced dissolution and improved contour clarity. The mitochondrial cristae structure was partially restored, with some mitochondria showing autophagosome encapsulation, and the degree of mitochondrial damage was alleviated. Serum SOD activity increased significantly (P<0.01), while MDA content decreased significantly. The mRNA and protein expression levels of PINK1, Parkin, and LC3Ⅱ/Ⅰ were significantly increased (P<0.05, P<0.01), while p62 mRNA and protein expression in the low- and medium-dose modified Buyang Huanwu Tang groups were significantly decreased (P<0.05, P<0.01), showing statistical significance. ConclusionModified Buyang Huanwu Tang can upregulate the protein expression levels of PINK1, Parkin, and LC3Ⅱ/Ⅰ and downregulate p62 protein expression, suggesting that it may improve CI/RI by regulating the expression of proteins related to the PINK1/Parkin signaling pathway. Regulation of the mitophagy pathway may be one of the mechanisms by which modified Buyang Huanwu Tang alleviates CI/RI in mice.
4.Research progress on the correlation of dry eye with depression
Feng JIN ; Baoyue MI ; Jingqing MU ; Jingjing CAO ; Xia HUA
International Eye Science 2026;26(1):74-79
Dry eye disease is a chronic ocular surface disorder of multifactorial origin, characterized by a loss of tear film homeostasis and associated with a range of ocular discomfort symptoms. Growing evidence underscores a significant bidirectional relationship between dry eye and depression: individuals with dry eye disease exhibit a higher prevalence of depressive disorders, and conversely, those diagnosed with depression demonstrate an increased susceptibility to developing dry eye. This interplay is mediated through several pathophysiological pathways, such as chronic inflammation, cerebral functional alterations, gut microbiome dysregulation, and sleep disturbances, which may collectively sustain a vicious cycle. The use of antidepressant therapy introduces further complexity, exerting heterogeneous effects on dry eye—some agents may offer symptomatic relief, whereas others can aggravate ocular surface impairment. The mechanisms responsible for these differential outcomes remain incompletely elucidated and merit further investigation. This review systematically consolidates epidemiological data on the dry eye-depression link, examines potential shared pathological mechanisms, and evaluates current therapeutic options. We propose an integrated management approach that combines conventional dry eye treatments, such as traditional Chinese medicine, electroacupuncture, physical activity and antidepressants—a multimodal strategy that may yield synergistic benefits in alleviating both ocular and affective symptoms, thereby improving overall quality of life. Moving forward, research should focus on deciphering the underlying mechanistic pathways and facilitating the translation of these insights into clinical practice to inform targeted, combined treatment regimens for patients with dry eye and depression.
5.Nomogram clinical prediction model for severe perioperative complications of hepatic resection for hepatolithiasis based on the albumin-bilirubin score
Ming CAO ; Haoran SUN ; Zhangliu JIN ; Bin ZHANG ; Lei WANG
Acta Universitatis Medicinalis Anhui 2026;61(3):569-575
ObjectiveTo develop and validate a nomogram based on the albumin-bilirubin (ALBI) score for predicting the risk of severe perioperative complications in patients undergoing hepatectomy for hepatolithiasis. MethodsA retrospective analysis was conducted on the clinical data of 163 hepatolithiasis patients who underwent hepatectomy. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for severe perioperative complications. A nomogram prediction model was constructed and its performance was evaluated. ResultsAmong the 163 patients, 66 and 97 were classified into the low-grade and high-grade ALBI groups, respectively. Significant intergroup differences were observed in gender, total bilirubin, albumin levels, and the incidence of severe complications (P0.05). Severe complications occurred in 40 patients. Independent risk factors included age 60 years (OR=5.49, P0.001), high-grade ALBI (OR=8.30, P0.001), history of biliary surgery (OR=2.60, P=0.035), hepatectomy (segmentectomy)≥3 (OR=2.75, P=0.028), and open surgical approach (OR=4.00, P=0.009). A nomogram for predicting severe perioperative complications was successfully established. Internal validation showed that the model had an area under the ROC curve (AUC) of 0.865, which outperformed traditional single predictors. The calibration curve closely aligned with the ideal curve, with a mean absolute error (MAE) of 0.027. Decision curve analysis (DCA) demonstrated a net clinical benefit when the threshold probability exceeded 10%, superior to that of traditional predictors. ConclusionThe ALBI score-based nomogram is successfully developed and validated to predict the risk of severe perioperative complications in hepatolithiasis patients undergoing hepatectomy. The model demonstrated favorable predictive performance and high clinical utility, serving as an effective tool for both preoperative risk assessment and postoperative risk stratification.
6.Analysis of risk factors for allogeneic blood transfusion and construction of a prediction model in patients with ovarian cancer undergoing cytoreductive surgery
Jia CAO ; Wenyan CHEN ; Panpan MA ; Jin ZHAO ; Hongyue TANG ; Jianhui LIU ; Ruili GENG
Chinese Journal of Blood Transfusion 2026;39(8):1026-1032
Objective: To explore the independent risk factors of allogeneic blood transfusion during perioperative period of cytoreductive surgery in patients with ovarian cancer, and to construct a predictive model to facilitate clinical risk assessment and optimize perioperative blood management. Methods: Clinical data of 156 patients who underwent cytoreductive surgery for ovarian cancer in our hospital from January 2020 to December 2025 were retrospectively collected. The patients were divided into transfusion group (n=51) and non-transfusion group (n=105) according to whether they received allogeneic blood transfusion during perioperative period. The 1∶1 propensity score matching (PSM) was used to correct the confounding factors. Independent sample t test or Mann-Whitney U test was used for measurement data, and chisquare test was used for enumeration data. Variables with P<0.05 in univariate analysis were included in binary logistic regression for multivariate analysis to determine independent risk factors. A nomogram model for perioperative allogeneic blood transfusion risk prediction was constructed based on independent risk factors. Bootstrap method (100 samples) was used for internal calibration verification. ROC curve was used to evaluate the discrimination efficiency, and decision curve analysis (DCA) was used to evaluate the clinical net benefit of the model. Results: After propensity matching, the baseline data of the two groups were balanced and comparable. Multivariate logistic regression analysis showed that preoperative prothrombin time (PT) (OR=2.666, 95%CI 1.249~5.693, P=0.011), preoperative hemoglobin (Hb) (OR=0.953, 95%CI 0.923~0.984, P=0.003), intraoperative blood loss (OR=1.004, 95%CI 1.001-1.006, P=0.004), preoperative anemia grade (OR=3.052, 95%CI 1.007-9.252, P=0.049) were independent influencing factors of perioperative allogeneic blood transfusion. The nomogram model based on the above four factors was significant (LR χ
=58.617, P<0.001), and the internal calibration curve showed that the predicted probability of the model was in good agreement with the actual probability (mean absolute error=0.042). The area under the ROC curve (AUC) was 0.890, indicating good discrimination efficiency. DCA showed that the clinical net benefit of the model was better than that of the unified transfusion/non-transfusion strategy in the 0-0.45 risk threshold range. Conclusion: Intraoperative blood loss, preoperative PT, preoperative Hb and preoperative anemia grade are independent risk factors for perioperative allogeneic blood transfusion in patients undergoing cytoreductive surgery for ovarian cancer. The nomogram model based on the above factors has good predictive efficacy and clinical hierarchical decision-making value, which can provide reference for clinical implementation of individualized blood management for high-risk patients and reduction of unnecessary blood transfusion rate.
7.An exploratory study on the effect of ultrasonic waves against Aedes albopictus larvae
Shuqing JIN ; Xinyi CAI ; Heyi WEN ; Jian FAN ; Hui CAO ; Tianyu SHA ; Hongxia LIU ; Yuan FANG ; Qiang GAO
Shanghai Journal of Preventive Medicine 2026;38(7):550-555
ObjectiveTo evaluate the larvicidal effect of ultrasonic waves against Aedes albopictus larvae at various exposure parameters (distance and time), and to preliminarily investigate the effects of different containers (water volume and depth) and ultrasonic devices on the larvicidal efficacy, so as to provide experimental evidence for the application of ultrasound-based mosquito control technology. MethodsUnder controlled laboratory conditions, two commercially available ultrasonic devices [40 kHz/300 W and (50±5) kHz/70 W] were used to systematically examine the effects of exposure distance (20, 40, 60, 80, and 100 cm), exposure duration (1, 3, 6, 15 and 60 min), larval instar(Ⅰ‒Ⅱ and Ⅲ‒Ⅳ), and container type on the immediate mortality of Aedes albopictus larvae collected from urban areas of Shanghai. Statistical analysis of the mortality rates of larvae among different experimental groups was performed using the chi-square test. ResultsUltrasonic exposure exerted a detectable larvicidal effect against Aedes albopictus larvae of all instars. For early-instar larvae, exposure time significantly affected mortality at all tested distances (20, 40, 60, 80 and 100 cm), with χ² values ranging from 25.57 to 32.74 ( all P<0.001). No significant distance effect was observed in the first and second instar larvae after short-term exposure (1 and 3 min; P>0.05). However, a distance-dependent effect emerged from 6 min onward (P<0.05). During short-term exposure (1 min and 3 min) at close range (20 cm and 40 cm), the immediate mortality of the third and fourth instar larvae was higher than that of the first and second instar larvae. Conversely, during prolonged exposure (15 min and 60 min), the first and second instar larvae exhibited significantly higher mortality than that of the third and fourth instar larvae. These results indicated that larval mortality was jointly influenced by exposure duration and distance. Preliminary experiments indicated that larvicidal efficacy in shallow water was lower than that in deep water. No significant difference in larvicidal effect was observed between the two ultrasonic devices with different frequencies and power outputs. ConclusionUnder laboratory conditions, ultrasound can effectively kill Aedes albopictus larvae, and the larvicidal effect is jointly influenced by larval instar, exposure distance, and aquatic environment. Compact ultrasonic devices show potential for field application in biological mosquito control.
8.TIMP1 Participates in VEGFA-associated Endothelial Cell Activation and Aberrant Angiogenesis in Ulcerative Colitis
Zhi-Yu JIN ; Yi-Wei JIANG ; Zhen CAO
Progress in Biochemistry and Biophysics 2026;53(10):2665-2680
ObjectiveAbnormal intestinal angiogenesis and dysregulation of the mucosal immune microenvironment are important mechanisms underlying the occurrence and progression of ulcerative colitis (UC). This study aimed to identify biomarkers associated with angiogenesis in UC through integrated bioinformatics analysis and to validate their expression patterns and effects on vascular endothelial cell function through in vivo and in vitro experiments. MethodsSix UC-related datasets were retrieved from the GEO database. GSE48959, GSE59071, and GSE73661 were batch-corrected using the ComBat algorithm and used as the discovery cohort, while GSE47908, GSE92415, and GSE206285 were used as independent external validation cohorts. Differentially expressed genes were identified using the limma package, and a weighted gene co-expression network was constructed using WGCNA. The DEGs, WGCNA core module genes, and angiogenesis-related genes were intersected to obtain candidate genes. Multiple machine learning methods were further integrated to screen candidate features, followed by DNN and SHAP-based analysis of candidate gene feature contributions. PPI network topology analysis was further performed to identify hub genes, and the CIBERSORT algorithm was used to evaluate candidate genes and immune infiltration features. In addition, a DSS-induced mouse model of colitis and a TNF-α-stimulated HUVECs inflammatory model were established for experimental validation, combined with hematoxylin and eosin staining, immunofluorescence staining, Western blotting, wound healing assays, Transwell invasion assays, and Matrigel tube formation assays. ResultsA total of 481 upregulated and 285 downregulated genes were identified in the discovery cohort, and these genes were mainly enriched in pathways related to leukocyte migration and the complement and coagulation cascades. WGCNA identified the yellow module as the module most strongly associated with UC. The intersection of DEGs, WGCNA core module genes, and angiogenesis-related genes yielded 26 candidate genes. Four machine learning algorithms further identified C2, TIMP1, and TGM2 as common candidate features, while DNN-SHAP analysis and PPI network topology analysis further highlighted TIMP1 as a key hub gene. After multi-step screening, TIMP1 was ultimately identified as a key candidate gene. Validation across multiple datasets showed that TIMP1 was significantly upregulated in UC tissues and exhibited favorable discriminatory performance (all AUCs>0.85). In the DNN model, TIMP1 showed a relatively high feature contribution, supporting its potential relevance to UC classification. CIBERSORT analysis indicated that TIMP1 expression was positively correlated with neutrophils and resting NK cells, but negatively correlated with regulatory T cells and CD8⁺ T cells. In vivo and in vitro experiments further confirmed that TIMP1 expression was markedly increased under inflammatory conditions. In DSS-induced colitis mice, increased CD31-positive vascular signals were accompanied by elevated TIMP1 expression and reduced VE-cadherin expression. Moreover, TIMP1 knockdown significantly inhibited endothelial cell migration, invasion, and tube formation, accompanied by decreased expression of VEGFA, VEGFR-2, and VEGFR-3. ConclusionTIMP1 may participate in UC-associated abnormal angiogenesis and changes in vascular endothelial cell function under inflammatory conditions, highlighting its potential as a biomarker and a candidate for further therapeutic investigation.
9.Prognostic value of peripheral blood NLR and TrxR expression in ovarian cancer patients receiving immunotherapy
Qiumei JIN ; Xiaoli CAO ; Yifeng GU ; Xiaoxia ZHANG ; Yujie LI
International Journal of Laboratory Medicine 2025;46(6):714-718
Objective To investigate the prognostic value of peripheral blood neutrophil-lymphocyte ratio(NLR)and thioredoxin reductase(TrxR)in patients with ovarian cancer receiving immunotherapy.Methods A total of 109 patients with advanced ovarian cancer treated in the Tumor Hospital Affiliated to Nantong University from January 2021 to December 2021 were selected as the research objects.The levels of NLR and TrxR in peripheral blood before immunotherapy were detected,and the evaluation value of NLR and TrxR on short-term efficacy,progression-free survival(PFS)and overall survival(OS)in ovarian cancer pa-tients receiving immunotherapy was explored.Results The optimal cut-off values of TrxR and NLR were 4.97 U/mL and 2.49%,respectively.According to the optimal cut-off value of TrxR and NLR,the patients were divided into the high level of TrxR group(69 cases,≥4.97 U/mL)and the low level of TrxR group(40 cases,<4.97 U/mL),the high level of NLR group(72 cases,≥2.49%)and the low level of NLR group(37 cases,<2.49%).The objective response rate(ORR)of the high level of NLR group was lower than that of the low level NLR group(P<0.05),and the disease progression rate(DPR)was higher than that of the low NLR group(P<0.05).The high level of TrxR group had a significantly lower ORR and a significantly higher DPR than the low level of TrxR group(P<0.05).The median PFS and OS of the high level of NLR group were 15.0 months and 16.0 months,respectively.The median PFS and OS of the low level of NLR group were 19.0 months and 21.0 months,respectively.The median PFS and OS of the high level of TrxR group were 15.0 months and 17.0 months,respectively.The median PFS was 18.0 months and the median OS was 21.0 months in the low level of TrxR group.NLR and TrxR were the influencing factors of PFS and OS in pa-tients with ovarian cancer immunotherapy(P<0.05).Conclusion The levels of NLR and TrxR in peripheral blood can be used as important prognostic indicators for advanced ovarian cancer patients receiving immuno-therapy.The lower the levels of NLR and TrxR,the better the prognosis of ovarian cancer patients.
10.Value of peripheral blood T-lymphocyte subsets and mitochondrial damage indexes in assessing pregnancy outcome in patients with diminished ovarian reserve
Wenhong CAO ; Lingzhen BU ; Yu JIN ; Fang SUN
International Journal of Laboratory Medicine 2025;46(8):931-936
Objective To investigate the value of peripheral blood T-lymphocyte subsets and mitochondrial damage index(MDI)in evaluating the pregnancy outcome of patients with diminished ovarian reserve(DOR).Methods A total of 230 DOR patients admitted to the hospital from August 2020 to August 2023 were selected as DOR group,230 healthy women with normal ovarian reserve function were selected as control group,and all subjects were tested for peripheral blood T-lymphocyte subsets and MDI.DOR patients were di-vided into clinical pregnancy group(n=86)and non-clinical pregnancy group(m=144)according to clinical pregnancy.The influencing factors of pregnancy outcomes of DOR patients were analyzed by multivariate Lo-gistic regression model,and the predictive value of peripheral blood T-lymphocyte subsets and MDI for poor pregnancy outcomes of DOR patients was analyzed by receiver operating characteristic(ROC)curve.Results Com-pared with control group,CD3+,CD4+and CD4+/CD8+in DOR group were decreased(P<0.05),and CD8+,positive rate of helper T cell(Th)-MDI and positive rate of suppressor T cell(Ts)-MDI were increased(P<0.05).The clinical pregnancy rate of 230 DOR patients was 37.39%(86/230).Compared with clinical pregnancy group,CD4+in non-clinical pregnancy group was decreased(P<0.05),and CD8+,CD4+/CD8+and the positive rates of Th-MDI and Ts-MDI were increased(P<0.05).There was no significant difference in CD3+between two groups(P>0.05).The levels of anti-Müllerian hormone(AMH)and estradiol(E2)in non-clinical pregnancy group were lower than those in clinical pregnancy group(P<0.05).Th-MDI positive and Ts-MDI positive were independent risk factors for poor pregnancy outcomes in DOR patients(P<0.05),and high levels of CD4+/CD8+,AMH and E2 were protective factors for poor pregnancy outcomes in DOR patients(P<0.05).The area under the curve of AMH,E2,CD4+/CD8+,Th-MDI,Ts-MDI alone and com-bined in predicting poor pregnancy outcome in DOR patients were 0.735,0.784,0.767,0.691,0.703,0.882,respectively,and the predictive efficacy of combined application was significantly higher than that of each sin-gle application(P<0.05).Conclusion DOR patients have immune dysfunction and oxidative activation,low CD4+/CD8+,Th-MDI positive and Ts-MDI positive are risk factors for poor pregnancy outcomes in DOR pa-tients,and the detection of the three has a high predictive effect on poor pregnancy outcomes in DOR patients.

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