1.Impact of number of positive regional lymph nodes in N1 stage on the prognosis of patients with non-small cell lung cancer: A propensity score matching study
Dandan LIU ; Jiachen WANG ; Lidan CHANG ; Jia CHEN ; Ranran KONG ; Shiyuan LIU ; Minxia ZHU ; Jiantao JIANG ; Shaomin LI ; Zhengshui XU
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2026;33(01):63-71
Objective To explore the impact of number of positive regional lymph nodes (nPRLN) in N1 stage on the prognosis of non-small cell lung cancer (NSCLC) patients. Methods Patients with TxN1M0 stage NSCLC who underwent lobectomy and mediastinal lymph node dissection from 2010 to 2015 were screened from SEER database (17 Regs, 2022nov sub). The optimal cutoff value of nPRLN was determined using X-tile software, and patients were divided into 2 groups according to the cutoff value: a nPRLN≤optimal cutoff group and a nPRLN>optimal cutoff group. The influence of confounding factors was minimized by propensity score matching (PSM) at a ratio of 1 : 1. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate overall survival (OS) and lung cancer-specific survival (LCSS) of patients. Results A total of 1316 patients with TxN1M0 stage NSCLC were included, including 662 males and 654 females, with a median age of 67 (60, 73) years. The optimal cutoff value of nPRLN was 3, with 1165 patients in the nPRLN≤3 group and 151 patients in the nPRLN>3 group. After PSM, there were 138 patients in each group. Regardless of before or after PSM, OS and LCSS of patients in the nPRLN≤3 group were superior to those in the nPRLN>3 group (P<0.001). N1 stage nPRLN>3 was an independent prognostic risk factor for OS [HR=1.52, 95%CI (1.22, 1.89), P<0.001] and LCSS [HR=1.72, 95%CI (1.36, 2.18), P<0.001]. Conclusion N1 stage nPRLN>3 is an independent prognostic risk factor for NSCLC patients in TxN1M0 stage, which may provide new evidence for future revision of TNM staging N1 stage subclassification.
2.Mediating role of insulin resistance in the relationship between hypertension and NAFLD and construction of its risk prediction model.
Yaxuan HE ; Honghui HE ; Yu CAO ; Fang WANG
Journal of Central South University(Medical Sciences) 2025;50(7):1188-1201
OBJECTIVES:
Non-alcoholic fatty liver disease (NAFLD) and hypertension are common metabolic disorders, both closely associated with insulin resistance (IR), suggesting potential shared pathological mechanisms. This study aims to investigate the mediating role of IR in the relationship between hypertension and NAFLD, and to evaluate the applicability and modeling value of various IR surrogate indices in predicting NAFLD risk.
METHODS:
A total of 280 976 individuals who underwent health examinations at the Health Management Center of the Third Xiangya Hospital of Central South University between August 2017 and December 2021 were included. NAFLD was diagnosed based on abdominal ultrasound findings, and hypertension was defined according to the criteria of the Chinese Guidelines for the Management of Hypertension. Demographic information, anthropometric indices, and biochemical parameters were collected, and multiple IR surrogate indices were constructed, including the triglyceride-glucose index (TyG) and its derivatives, as well as the metabolic score for insulin resistance (METS-IR). Group comparisons were performed between hypertensive and non-hypertensive participants, as well as between NAFLD and non-NAFLD participants. Pearson correlation analysis was applied to assess the associations of metabolic parameters and IR indices with NAFLD. Furthermore, mediation models were constructed to explore the mediating role of IR in the "hypertension-NAFLD" relationship. Finally, parametric models and machine learning algorithms were compared to evaluate their predictive performance and value in assessing NAFLD risk in this population.
RESULTS:
The prevalence of NAFLD was significantly higher in hypertensive individuals than in non-hypertensive participants (63.61% vs 33.79%, P<0.001), accompanied by elevated IR levels and adverse metabolic features. Correlation analysis and variable importance rankings across multiple models consistently identified TyG-waist circumference (TyG-WC) and METS-IR as the IR indices most strongly associated with NAFLD. In mediation analysis, the TyG-WC pathway explained 32.03% of the total effect, and the METS-IR pathway explained 17.02%. Interaction analysis showed that hypertension status may attenuate the mediating effect of IR (all interaction estimates were negative). In prediction model comparisons, the simplified model incorporating sex, age, WC, TyG-WC, and METS-IR demonstrated good performance in the test set. Logistic regression and its regularized form (LASSO regression) achieved an accuracy of 0.83, receiver operating characteristic (ROC)-area under the curve (AUC) of 0.91, and a Brier score of 0.12, comparable to ensemble models (random forest and XGBoost), with consistently stable performance across different algorithms.
CONCLUSIONS
IR plays a significant mediating role in the association between hypertension and NAFLD, with TyG-WC identified as a key indicator showing strong mechanistic relevance and predictive value. Risk prediction models based on IR surrogate indices demonstrate advantages in simplicity and interpretability, providing empirical support for the early screening and individualized prevention of NAFLD in the general population.
Humans
;
Non-alcoholic Fatty Liver Disease/complications*
;
Insulin Resistance
;
Hypertension/epidemiology*
;
Male
;
Female
;
Middle Aged
;
Risk Factors
;
Adult
;
Machine Learning
;
Triglycerides/blood*
3.Comprehensive Brain-wide Mapping of Afferent and Efferent Nuclei Associated with the Heart in the Mouse.
Haiying LIU ; Xin HUANG ; Ruixin XIA ; Xin ZHAO ; Zimeng LI ; Qian LIU ; Congye LI ; Honghui MAO ; Wenting WANG ; Shengxi WU
Neuroscience Bulletin 2025;41(10):1743-1760
Normal heart function depends on complex regulation by the brain, and abnormalities in the brain‒heart axis affect various diseases, such as myocardial infarction and anxiety disorders. However, systematic tracking of the brain regions associated with the input and output of the heart is lacking. In this study, we injected retrograde transsynaptic pseudorabies virus (PRV) and anterograde transsynaptic herpes simplex virus (HSV) into the left ventricular wall of mice to identify the whole-brain regions associated with the input to and output from the heart. We successfully detected PRV and HSV expression in at least 170 brain subregions in both male and female mice. Sex differences were discovered mainly in the hypothalamus and medulla, with male mice exhibiting greater correlation and hierarchical clustering than female mice, indicating reduced similarity and increased modularity of virus expression patterns in male mice. Further graph theory and multiple linear regression analysis of different injection timelines revealed that hub regions of PRV had highly similar clusters, with different brain levels, suggesting a top-down, hierarchically transmitted neural control pattern of the heart. Hub regions of HSV had scattered clusters, with brain regions gathered in the cortex and brainstem, suggesting a bottom-up, leapfrog, multipoint neural sensing pattern of the heart. Both patterns contain many hub brain regions that have been previously overlooked in brain‒heart axis studies. These results provide brain targets for future research and will lead to deeper insight into the brain mechanisms involved in specific heart conditions.
Animals
;
Male
;
Female
;
Heart/physiology*
;
Mice
;
Herpesvirus 1, Suid
;
Brain/physiology*
;
Mice, Inbred C57BL
;
Brain Mapping
;
Efferent Pathways/physiology*
;
Afferent Pathways/physiology*
;
Simplexvirus
;
Sex Characteristics
4.Retraction Note: Fluoxetine is Neuroprotective in Early Brain Injury via its Anti-inflammatory and Anti-apoptotic Effects in a Rat Experimental Subarachnoid Hemorrhage Model.
Hui-Min HU ; Bin LI ; Xiao-Dong WANG ; Yun-Shan GUO ; Hua HUI ; Hai-Ping ZHANG ; Biao WANG ; Da-Geng HUANG ; Ding-Jun HAO
Neuroscience Bulletin 2025;41(11):2106-2106
5.Analysis of labor function rehabilitation after total knee arthroplasty in patients with rheumatoid arthritis.
Tong KE ; Yang-Quan HAO ; Meng-Fei WANG ; Yu-Heng YAN ; Yuan-Zhen CAI ; Chao LU
China Journal of Orthopaedics and Traumatology 2025;38(6):594-600
OBJECTIVE:
To explore the functional rehabilitation of patients with rheumatoid arthritis (RA) after total knee arthroplasty (TKA).
METHODS:
A retrospective analysis was conducted on 101 patients who needed TKA due to rheumatoid arthritis (RA) involving both knees from January 2017 to December 2020, including 16 males and 85 females, aged from 41 to 65 years old with an average of (58.13±5.53) years old;body mass index (BMI) ranged from 16.88 to 33.33 kg·m-2 with an average of (23.16±3.49) kg·m-2;63 patients with grade 1, 29 patients with grade 2, and 9 patients with grade 3 according to classification of American Society of Anesthesiologists (ASA). According to the latest follow-up results at 12 months after operation, 82 patients returned to work and 19 patients did not return to work. Visual analogue scale(VAS) was used to evaluate the degree of pain relief before operation and 12 months after operation, and work, osteoarthritis and joint replacement questionnaire (WORQ) was used to evaluate knee joint activity status of all patients before and after operation, and the working ability index was used to evaluate working ability of all patients before operation and 12 months after operation. For the 82 patients who returned to work, the labor time stopped before operation and within 12 months after operation was compared, and the changes in labor grades, types of work and labor hours of patients before and after operation were recorded. For the 19 patients who did not return to work, the specific reasons for their non-return to work was analyzed;the postoperative satisfaction of patients was evaluated by using Likert satisfaction scale. All patients were followed up for at least 12 months. VAS was decreased from (6.49±0.59) before operation to (1.10±0.43) at 12 months after operation (P<0.05);for WORQ questionnaire survey, scores of walking, sitting posture, standing and stair climbing were increased from (1.07±0.35), (1.05±0.29), (1.06±0.34) and (1.14±0.42) before operation to (3.00±0.00), (2.87±0.33), (2.95±0.21) and (2.95±0.21) after operation, respectively, had statistically significant (P<0.05);the labor work index of all patients increased from 1.11±0.46 before operation to 2.99±0.10 at 12 months after operation, and the difference was statistically significant (P<0.05). Among the 82 patients who returned to work after operation, regarding the time of stopping labor, 81 patients stopped working within 3 months before operation, 1 patient stopped working for 4 to 6 months after operation, and the number of patients who stopped working was 81, 1, and 0 respectively. Forty patients returned to work within 3 months after operation, 4 to 6 months after operation for 29 patients, and 12 months after operation for 13 patients. 95.1% (78/82) of patients engaged in light labor before operation, and 85.4% (70/82) of patients engaged in moderate labor after operation. At 12 months after operation, the types of jobs and working hours available to all patients increased compared with those before operation. Among 19 patients who did not return to work after TKA, 7 patients had poor control of rheumatoid arthritis, 5 patients still felt pain, swelling and numbness on knee joint, 2 patients had retired, and 5 patients had other reasons. Eighty-six patients (85%) expressed great satisfaction with the postoperative working ability, 8 patients (8%) expressed satisfaction with the postoperative working ability, 6 patients (6%) expressed acceptance of postoperative working ability, and 1 patient (1%) expressed dissatisfaction with postoperative working ability.
CONCLUSION
TKA is an effective treatment option for patients with RA. After undergoing TKA, patients could significantly improve pain and functional activities of knee joint, and effectively enhance the quality of life and working ability. For patients whose rehabilitation labor capacity is not fully met, postoperative management and personalized rehabilitation treatment need to be strengthened to achieve the best rehabilitation effect.
Humans
;
Female
;
Male
;
Arthroplasty, Replacement, Knee/rehabilitation*
;
Arthritis, Rheumatoid/physiopathology*
;
Middle Aged
;
Aged
;
Retrospective Studies
;
Adult
6.Visual analysis of dynamics and hotspots of biomechanics research on diabetic foot based on WoSCC.
Zhe WANG ; Wei-Dong LIU ; Jun LU ; Hong-Mou ZHAO ; Xue-Fei CAO ; Yun-Long ZHANG ; Xin CHANG ; Liang LIU
China Journal of Orthopaedics and Traumatology 2025;38(9):902-909
OBJECTIVE:
To explore the current research status and hotspots in the field of biomechanics of diabetic foot by bibliometric analysis methods.
METHODS:
Literatures related to biomechanics of diabetic foot published in the Web of Scienc Core Collection (WoSCC) from 1981 to 2024 were searched. CiteSpace software and R language bibliometrics plugin were used to conduct a visual analysis of annual publication volume of the literature, including publication volume of each country and region, the publication situation of authors and institutions, the citation situation of individual literature, and the co-occurrence network of keywords.
RESULTS:
Totally 996 literatures were included, and the number of published papers increased steadily. The United States (261 papers) and China (89 papers) were the top two countries in terms of the number of published papers. The mediating centrality of the United States was 0.94, and that of China was 0.01. Scholars such as Cavanagh and institutions like the Cleveland Clinic were at the core of research in this field. High-frequency keywords include plantar pressure (plantar pressure), diabetic foot (diabetic foot), ulceration (ulcer), etc. The research focuses on plantar pressure, ulcer formation and prevention, etc.
CONCLUSION
Biomechanical research on diabetic foot mainly focuses on the pressure distribution on the sole of the foot, callus formation, mechanical analysis of soft tissues on the sole of the foot, and the study of plantar decompression caused by Achilles tendon elongation. The research trend has gradually shifted from focusing on joint range of motion to gait and the design of braces and assistive devices, and has begun to pay attention to muscle strength, gait imbalance and proprioception abnormalities.
Humans
;
Diabetic Foot/physiopathology*
;
Biomechanical Phenomena
;
Bibliometrics
7.Progress in autophagy effect on the progression of SLE pathogenesis by regulating the immune system.
Tianzhen MA ; Honghui TANG ; Xuan CHEN ; Yuqing GUO ; Liping ZHANG ; Baiqing LI ; Jin XI ; Yuanyuan WANG
Chinese Journal of Cellular and Molecular Immunology 2025;41(7):649-654
Autophagy is a fundamental biological metabolic process involved in immune defense, material metabolism, and homeostasis and closely linked to immune regulation. Systemic lupus erythematosus (SLE) is a widespread connective tissue disorder primarily resulting from immune system imbalance. Due to the immune system's failure to recognize its own substances, it generates autoantibodies that can affect various tissues and organs, leading to diverse clinical manifestations. The pathogenesis and treatment of SLE are currently under extensive investigation. In normal metabolic processes, autophagy engages in both innate and adaptive immunity, regulates the immune response, and is crucial for maintaining normal immune function and the body's internal homeostasis. Research has indicated that SLE patients exhibit immune dysfunction and altered autophagy levels. Modulating autophagy expression can influence immune system functionality and alleviate SLE symptoms. Additionally, autophagy aids in the innate immune response and adaptive immunity by clearing metabolites and regulating the life cycle of immune cells. Studies suggest that drugs targeting autophagy can positively influence the progression of SLE. This article reviews advancements in research regarding the impact of autophagy on the pathogenesis of SLE through the regulation of immune system functions.
Lupus Erythematosus, Systemic/pathology*
;
Autophagy/immunology*
;
Humans
;
Animals
;
Immunity, Innate
;
Adaptive Immunity
;
Disease Progression
;
Immune System/immunology*
8.Effectiveness of triple osteotomy in correcting severe hallux valgus with the first metatarsal pronation deformity.
Yachang XING ; Xinwen WANG ; Yi LI ; Cheng LIU
Chinese Journal of Reparative and Reconstructive Surgery 2025;39(7):843-847
OBJECTIVE:
To explore the effectiveness of triple osteotomy in correcting severe hallux valgus with the first metatarsal pronation deformity.
METHODS:
A retrospective analysis was conducted on the clinical data of 29 patients (40 feet) with severe hallux valgus accompanied by the first metatarsal pronation deformity, who were admitted between January 2022 and December 2023 and met the selection criteria. There were 8 males (10 feet) and 21 females (30 feet), with an average age of 50.0 years (range, 44-62 years). The disease duration ranged from 5 to 9 years (mean, 6.5 years). All patients underwent triple osteotomy to correct the deformity. The American Orthopaedic Foot and Ankle Society (AOFAS) score and visual analogue scale (VAS) score were used to evaluate joint function and pain before and after operation. Based on pre- and post-operative X-ray films, hallux valgus angle (HVA), intermetatarsal angle (IMA), and distal metatarsal articular angle (DMAA) were measured to evaluate the correction of hallux valgus; the shape classification of the lateral edge of the first metatarsal and the pronation of first metatarsal angle (PFMA) were observed to assess the correction of the first metatarsal pronation deformity.
RESULTS:
A superficial infection occurred in 1 foot and the incison healed after dressing change; the remaining incisions healed by first intention. All patients were followed up 12-18 months (mean, 12.6 months). Three cases (4 feet) experienced limited movement of the metatarsophalangeal joint after operation, and the joint function recovered after strengthening functional exercises. During follow-up, no recurrence of deformity or secondary metatarsal pain occurred. Compared with preoperative scores, the AOFAS score increased and the VAS score decreased at last follow-up, and the differences were significant ( P<0.05). Radiographic examination showed that the osteotomy achieved bony healing, with the healing time of 2.5-6.2 months (mean, 4.1 months). The hallux valgus deformity was corrected, and the IMA, HVA, and DMAA were significantly smaller at last follow-up when compared with those before operation ( P<0.05). The first metatarsal pronation deformity was also corrected; there was no R-type (R-type for pronation deformity) on the lateral edge of the first metatarsal at last follow-up, and the PFMA decreased compared with preoperative levels ( P<0.05) and was corrected to the normal range.
CONCLUSION
Triple osteotomy can achieve good effectiveness for correcting severe hallux valgus with the first metatarsal pronation deformity. The functional training of the first metatarsophalangeal joint needs to be strengthened.
Humans
;
Hallux Valgus/diagnostic imaging*
;
Osteotomy/methods*
;
Female
;
Male
;
Middle Aged
;
Adult
;
Retrospective Studies
;
Metatarsal Bones/diagnostic imaging*
;
Treatment Outcome
;
Pronation
;
Radiography
9.Comparative study on effectiveness of the fourth-generation minimally invasive technique and Chevron osteotomy in treatment of hallux valgus.
Qiong WANG ; Junhu WANG ; Dongdong JI ; Tingting LIN ; Hongmou ZHAO
Chinese Journal of Reparative and Reconstructive Surgery 2025;39(10):1269-1275
OBJECTIVE:
To compare the efficacy of the fourth-generation minimally invasive technique-minimally invasive extra-articular metaphyseal distal transverse osteotomy (META) and Chevron osteotomy in treatment of hallux valgus.
METHODS:
A total of 80 patients with hallux valgus, who underwent single-foot surgery between July 2023 and January 2025 and met the inclusion criteria, were included in the study. Among them, 40 patients were treated with META and 40 with Chevron osteotomy. There was no significant difference in baseline data between the two groups ( P>0.05), including gender, age, height, weight, body mass index, disease duration, lesion site, hallux valgus deformity degree, as well as preoperative scores of each item (pain, function, alignment, total score) in the American Orthopaedic Foot and Ankle Society Hallux Metatarsophalangeal-Interphalangeal Joint Scale (AOFAS-Hallux-MTP-IP), scores of each item (pain, walking/standing, social interaction, total score) in the Manchester-Oxford Foot Questionnaire (MOXFQ), hallux valgus angle (HVA), intermetatarsal angle (IMA), distal metatarsal articular angle (DMAA), sesamoid position, and the 1st metatarsal head morphology. The postoperative AOFAS-Hallux-MTP-IP scores, MOXFQ scores, as well as HVA, IMA, DMAA, the 1st metatarsal head morphology, and sesamoid position measured based on weight-bearing foot X-ray films were compared between the two groups; the occurrence of postoperative complications was recorded.
RESULTS:
All patients in both groups were followed up 6-18 months, and there was no significant difference in the follow-up time between the two groups ( P>0.05). At last follow-up, the scores of all items in AOFAS-Hallux-MTP-IP in both groups were higher than those before operation, and the scores of all items in MOXFQ were lower than those before operation, with significant differences ( P<0.05); there was no significant difference in the change values of all items in MOXFQ between the two groups ( P>0.05). The change value in AOFAS function score in the META group was significantly higher than that in the Chevron osteotomy group ( P<0.05), while there was no significant difference in the change value of AOFAS pain score, alignment score, and total score between the two groups ( P>0.05). After operation, 1 case (2.5%) of superficial incision infection and 2 cases (5.0%) of numbness around the incision occurred in the Chevron osteotomy group, while only 2 cases (5.0%) of numbness around the incision occurred in the META group. Imaging reexamination showed that HVA, IMA, and DMAA in both groups were signifncatly smaller than those before operation ( P<0.05), and there was no significant difference in the change values of the above angles between the two groups ( P>0.05). The 1st metatarsal head morphology and sesamoid position in the META group were better than those in the Chevron osteotomy group after operation, with significant differences ( P<0.05).
CONCLUSION
Both META and Chevron osteotomy can correct hallux valgus deformity, improve foot function, and relieve pain, but META has more advantages in correcting metatarsal rotation and reducing dislocated sesamoids.
Humans
;
Hallux Valgus/diagnostic imaging*
;
Osteotomy/methods*
;
Minimally Invasive Surgical Procedures/methods*
;
Male
;
Female
;
Middle Aged
;
Treatment Outcome
;
Adult
;
Metatarsophalangeal Joint/surgery*
;
Aged
;
Retrospective Studies
10.The renoprotective effect of Salvia miltiorrhiza injection on HBOC-CHP01 resuscitated haemorrhagic shock rats
Shasha HAO ; Xintong XIE ; Shen LI ; Honghui ZHANG ; Hong WANG ; Chengmin YANG ; Wentao ZHOU ; Jiaxin LIU
Chinese Journal of Blood Transfusion 2025;38(2):172-180
[Objective] To investigate the protective effect of Salvia miltiorrhiza injection (SMI) on the kidneys of HBOC-CHP01 resuscitated haemorrhagic shock rats. [Methods] A 50% haemorrhagic shock rat model was established, with 12 rats divided into two groups: SMI + HBOC-CHP01 group and HBOC-CHP01 group, with 6 rats in each group. The rats in the SMI+ HBOC-CHP01 group were given an equal volume of HBOC-CHP01 for resuscitation after haemorrhagic shock, and an 8 mL/kg dose of SMI. Rats in the HBOC-CHP01 group were resuscitated by administering an equilibrium blood loss volume of HBOC-CHP01 and given an 8 mL/kg dose of 0.9% NaCl solution. Blood was taken from rats at five points: before bloodletting (baseline), during haemorrhagic shock (HS), immediately after resuscitation (RS0h), 1 h after resuscitation (RS1h), and 24 h after resuscitation (RS24h). A blood gas analyser was used to detect the lactate level (Lac), glucose content (Glu), residual base (BEecf), pH, bicarbonate (HCO3-), high iron haemoglobin (MetHb). White blood cells (WBC), platelets (PLT), haemoglobin content (Hb), carboxyhaemoglobin (COHb) were detected using a quintuple classification. Blood creatinine (SCr), uric acid (UA), kidney-related indexes were detected using biochemistry instrument. Kidney tissues of the rats were taken after 24 h of resuscitation and after execution, and the inflammation of kidneys of the rats of the two groups was analyzed using HE staining. Fluorescence staining was used to detect the level of ROS in the kidneys of rats in both groups. [Results] At RS 0h, the Beecf, Glu and Lac levels of rats in the SMI+HBOC-CHP01 group were significantly lower than those of rats in the HBOC-CHP01 group, and the pH level of rats in the SMI+HBOC-CHP01 group was significantly higher than that of rats in the HBOC-CHP01 group, and the Glu levels of rats in the SMI+HBOC-CHP01 group were significantly lower than those of rats in the HBOC-CHP01 group at RS 1h. At RS 0h, the WBC, PLT and COHb contents of rats in the SMI+HBOC-CHP01 group were all significantly higher than those of rats in the HBOC-CHP01 group, and at RS 1h, the WBC content of rats in the SMI+HBOC-CHP01 group was significantly higher than that of rats in the HBOC-CHP01 group; at RS 1h, the UA content of rats in the SMI+HBOC-CHP01 group was significantly lower than that of rats in the HBOC-CHP01 group; at RS 24h, the SCr content of rats in the SMI+HBOC-CHP01 group was significantly lower than that of rats in the HBOC-CHP01 group; at RS 24h, the inflammation level of kidney tissues of rats in the SMI+HBOC-CHP01 group was significantly lower than that of rats in the HBOC -CHP01 group rats, and the ROS and MPO levels in the kidney tissues of rats in the SMI+HBOC-CHP01 group were significantly lower than those of rats in the HBOC-CHP01 group. [Conclusion] The combination of Salvia miltiorrhiza injection during the resuscitation of rats with severe haemorrhagic shock by HBOC-CHP01 can alleviate renal injury by reducing inflammatory response and oxidative stress.

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