1.Potential mechanisms by which exercise regulates iron metabolism in immune inflammatory diseases
Yaotian SUN ; Kai XU ; Peiyun WANG
Chinese Journal of Tissue Engineering Research 2026;30(6):1486-1498
BACKGROUND:Abnormal iron metabolism is closely related to immune inflammatory diseases.Exercise intervention is a potentially effective treatment that can reduce inflammation by regulating iron metabolism and improving immune response.However,how exercise regulates immune system function through iron metabolism still needs to be further explored.OBJECTIVE:To review and summarize the research progress of iron metabolism in immune inflammatory diseases,analyze the regulatory effect of exercise intervention on iron metabolism and the potential mechanism by which exercise regulates immune inflammatory diseases,thereby providing new ideas for the treatment of immune inflammatory diseases in the future.METHODS:The data sources included CNKI and PubMed databases.The retrieval time was from January 2010 to June 2024.The keywords were"iron metabolism,iron homeostasis,hepcidin,immune inflammation,rheumatoid arthritis(RA),inflammatory bowel disease(IBD),multiple sclerosis(MS),systemic lupus erythematosus(SLE),exercise"in Chinese and English,respectively.Finally,101 articles were included for review.RESULTS AND CONCLUSION:(1)Abnormal iron metabolism is closely related to the occurrence and development of a variety of immune inflammatory diseases,such as rheumatoid arthritis,systemic lupus erythematosus,and inflammatory bowel disease.Iron overload or iron deficiency can lead to dysfunction of the immune system,and thereby triggers or aggravates the inflammatory response.(2)Exercise intervention is an important means to regulate iron metabolism.Short-term aerobic exercise or strenuous exercise may lead to short-term iron metabolism disorders.Long-term aerobic exercise can promote the recovery of iron homeostasis.Regular aerobic exercise can reduce serum iron concentration,reduce iron storage in liver and muscle,and improve iron distribution in the body.Long-term exercise can help restore the balance of iron metabolism,thereby reducing the inflammatory response caused by iron metabolism disorders.Exercise types such as strength training and flexibility training also have a significant effect on iron metabolism.The effect of exercise on immune diseases has individual differences.Exercise intensity,duration,frequency and other factors may have different effects on iron metabolism.(3)In general,exercise intervention plays a role in the prevention and treatment of immune inflammatory diseases.However,there are still some limitations in the mechanism elucidation,long-term effects and individual differences in the existing studies.In the future,it is necessary to further explore the specific regulatory mechanism of exercise on iron metabolism and the individualized therapeutic effects of different types of exercise.
2.Potential mechanisms by which exercise regulates iron metabolism in immune inflammatory diseases
Yaotian SUN ; Kai XU ; Peiyun WANG
Chinese Journal of Tissue Engineering Research 2026;30(6):1486-1498
BACKGROUND:Abnormal iron metabolism is closely related to immune inflammatory diseases.Exercise intervention is a potentially effective treatment that can reduce inflammation by regulating iron metabolism and improving immune response.However,how exercise regulates immune system function through iron metabolism still needs to be further explored.OBJECTIVE:To review and summarize the research progress of iron metabolism in immune inflammatory diseases,analyze the regulatory effect of exercise intervention on iron metabolism and the potential mechanism by which exercise regulates immune inflammatory diseases,thereby providing new ideas for the treatment of immune inflammatory diseases in the future.METHODS:The data sources included CNKI and PubMed databases.The retrieval time was from January 2010 to June 2024.The keywords were"iron metabolism,iron homeostasis,hepcidin,immune inflammation,rheumatoid arthritis(RA),inflammatory bowel disease(IBD),multiple sclerosis(MS),systemic lupus erythematosus(SLE),exercise"in Chinese and English,respectively.Finally,101 articles were included for review.RESULTS AND CONCLUSION:(1)Abnormal iron metabolism is closely related to the occurrence and development of a variety of immune inflammatory diseases,such as rheumatoid arthritis,systemic lupus erythematosus,and inflammatory bowel disease.Iron overload or iron deficiency can lead to dysfunction of the immune system,and thereby triggers or aggravates the inflammatory response.(2)Exercise intervention is an important means to regulate iron metabolism.Short-term aerobic exercise or strenuous exercise may lead to short-term iron metabolism disorders.Long-term aerobic exercise can promote the recovery of iron homeostasis.Regular aerobic exercise can reduce serum iron concentration,reduce iron storage in liver and muscle,and improve iron distribution in the body.Long-term exercise can help restore the balance of iron metabolism,thereby reducing the inflammatory response caused by iron metabolism disorders.Exercise types such as strength training and flexibility training also have a significant effect on iron metabolism.The effect of exercise on immune diseases has individual differences.Exercise intensity,duration,frequency and other factors may have different effects on iron metabolism.(3)In general,exercise intervention plays a role in the prevention and treatment of immune inflammatory diseases.However,there are still some limitations in the mechanism elucidation,long-term effects and individual differences in the existing studies.In the future,it is necessary to further explore the specific regulatory mechanism of exercise on iron metabolism and the individualized therapeutic effects of different types of exercise.
3.Clinical efficacy of robot versus video-assisted thoracoscopic surgery for the treatment of mediastinal tumor: A systematic review and meta-analysis
Wei CAO ; Haochi LI ; Kai YANG ; Qi WANG ; Zhuang ZUO ; unjiu GOU
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2026;33(05):799-806
Objective To systematically evaluate the therapeutic effects of video-assisted thoracoscopic surgery (VATS) and robot-assisted thoracic surgery (RATS) in treating mediastinal tumors. Methods A computer search was conducted on PubMed, Embase, Cochrane Library, Web of Science, Wanfang, CNKI, CBM, VIP databases for literature comparing the clinical efficacy of VATS and RATS in treating mediastinal tumors, with the search time from inception to March 31, 2024. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included cohort studies, and Review Manager 5.4 software was used to perform a meta-analysis. Results A total of 32 articles were included, with 7868 patients. The NOS scores of the included cohort studies were all≥7 points. Meta-analysis results showed that compared with the VATS group, the RATS group had less intraoperative blood loss [MD=−16.71, 95%CI (−23.88, −9.54), P<0.001], lower conversion rate to open thoracotomy [OR=0.41, 95%CI (0.26, 0.67), P=0.003], lower overall postoperative complication rate [OR=0.66, 95%CI (0.48, 0.92), P=0.01], shorter postoperative drainage time [MD=−0.64, 95%CI (−0.92, −0.36), P<0.001], and shorter postoperative hospital stay [MD=−1.03, 95%CI (−1.28, −0.78), P<0.001]. There was no statistical difference between the two groups in terms of tumor size [MD=−0.06, 95%CI (−0.31, 0.19), P=0.64] or operation time [MD=5.52, 95%CI (−2.35, 13.40), P=0.17]. The RATS group had higher hospitalization costs than the VATS group [MD=1.69, 95%CI (1.26, 2.13), P<0.001]. Conclusion In mediastinal tumors resection, RATS is superior to VATS in terms of intraoperative blood loss, conversion rate to open thoracotomy, overall postoperative complication rate, postoperative drainage time, and postoperative hospital stay, but it increases hospitalization costs.
4.Association between intergenerational parent-child separation and internalizing and externalizing behavioral problems among rural preschool children
ZHANG Anhui, MA Kai, WANG Yufen, WANG Lingling, SUN Ying
Chinese Journal of School Health 2026;47(5):680-684
Objective:
To explore the effects of intergenerational parent-child separation on internalizing and externalizing behavioral problems among rural preschoolers aged 3-6 years, so as to provide empirical evidence for formulating targeted intervention strategies and blocking the intergenerational transmission of parent-child separation.
Methods:
From March to June, 2024, ten kindergartens were selected from rural areas of Nanling County, Wuhu City, Anhui Province, and 2 279 preschool children aged 3- 6 years, along with their fathers, mothers and primary caregivers, were recruited for survey by cluster convenient sampling method. Children s fathers and mothers reported their own childhood parent-child separation information separately. Information on the children s history of psychological and behavioral problems was reported by the primary caregivers. Information of internalizing and externalizing behavioral problems in preschool children was reported with Strengths and Difficulties Questionnaire (SDQ).The Chi square test was used to compare the differences in the detection rates of psychological and behavioral problems among children with different intergenerational continuity of parent-child separation. Binary Logistic regression model was applied to analyze the association between intergenerational continuity of parent-child separation and internalizing and externalizing behavioral problems in preschool children.
Results:
The detection rate of internalizing behavioral problems was 27.5% and externalizing behavioral problems was 19.1% among rural preschool children. There were significant differences in internalization behavior, externalization behavior, hyperactivity impulse and peer communication problems among preschool children in different types of parent-child separation groups( χ 2=14.29, 8.80, 17.26, 13.84, all P <0.05). Binary Logistic regression analysis showed that after adjusting for covariates such as children s gender, birth weight, and delivery mode, compared with children without separation, intergenerational continuity of parent-child separation group( OR =1.95), only child separation( OR =1.74) were associated with significant higher risk of conduct problems(both P <0.05). Parent-child separation intergenerational continuation groups( OR =1.68), only child separation( OR = 1.47) were associated with significant higher risk of peer problems(both P <0.05). Both types of parent-child separation experiences significantly increased the risk of children s prosocial behavior problems,among them, the intergenerational continuation group was 1.99 times that of the control group ( OR =1.99), and the childhood only separation group was 2.09 times that of the control group ( OR =2.09)(both P <0.05). Compared with children whose parents and children had no experience of parent-child separation, children in the intergenerational continuation group of parent-child separation had increased risks of both internalizing and externalizing behavior problems ( OR =1.53, 1.65, both P <0.05).
Conclusion
All types of parent-child separation are associated with internalizing and externalizing behavioral problems among rural children aged 3 to 6 years.
5.Effect of Acupuncture at Neiguan (PC6) on Improving Autism by Promoting Myelination Through The METTL14/m⁶A/PTEN Axis Based on “Xuanfu-Suiqiao” Theory
Wei-Li DANG ; Lü-Yuan LIANG ; Yu-Xin LI ; Zhi-Yao LI ; Sai-Dan LIU ; Jia-Lei CAO ; Rong-Ze MA ; Yun-Kai WANG ; Xiao-Qing YANG ; Bing-Qi WEI ; Bing-Xiang MA
Progress in Biochemistry and Biophysics 2026;53(5):1165-1177
ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m6A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m6A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m6A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.
6.Effect of Acupuncture at Neiguan (PC6) on Improving Autism by Promoting Myelination Through The METTL14/m⁶A/PTEN Axis Based on “Xuanfu-Suiqiao” Theory
Wei-Li DANG ; Lü-Yuan LIANG ; Yu-Xin LI ; Zhi-Yao LI ; Sai-Dan LIU ; Jia-Lei CAO ; Rong-Ze MA ; Yun-Kai WANG ; Xiao-Qing YANG ; Bing-Qi WEI ; Bing-Xiang MA
Progress in Biochemistry and Biophysics 2026;53(5):1165-1177
ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m6A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m6A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m6A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.
7.Long-term survival outcomes and prognostic factors following radical resection of pancreatic body and tail cancer:a retrospective analysis of 992 patients
Dong XU ; Yang WU ; Kai ZHANG ; Nan LYU ; Qianqian WANG ; Pengfei WU ; Jie YIN ; Baobao CAI ; Guodong SHI ; Jianzhen LIN ; Yazhou WANG ; Lingdi YIN ; Zipeng LU ; Min TU ; Jianmin CHEN ; Feng GUO ; Jishu WEI ; Junli WU ; Wentao GAO ; Cuncai DAI ; Yi MIAO ; Kuirong JIANG
Chinese Journal of Surgery 2026;64(1):46-54
Objective:To investigate the survival outcomes and prognostic factors in patients undergoing radical resection for pancreatic body and tail cancer.Methods:A retrospective case series study was conducted on 992 patients who underwent radical resection for pancreatic body and tail cancer at the Pancreatic Center of the First Affiliated Hospital of Nanjing Medical University from January 2016 to June 2024. In this study, 577 (58.2%) were male and 415 (41.8%) were female,with an age of (65±9) years (range: 26 to 86 years). Follow-up continued until June 2024. Survival rates were estimated using the Kaplan-Meier method,and prognostic factors were identified using univariate and multivariate Cox proportional hazards models.Results:Among 992 patients,open surgery was the predominant approach (89.1%, 884/992), and radical antegrade modular pancreatosplenectomy (RAMPS) was performed in 317 patients (32.0%). Combined organ resection,venous resection,and arterial resection were performed in 23.5%, 9.3%,and 11.2% of patients,respectively. The rates of R0, R1-1 mm, and R1-direct resections were 49.8% (494/992),41.5% (412/992), and 8.7% (86/992),respectively. Stage ⅡB was the most common TNM stage (32.2%,319/992). A total of 801 patients (80.8%) received adjuvant chemotherapy. The median follow-up period was 32.0(8.8) months(range:3.2 to 105.3 months),during which 508 patients (51.2%) died. The overall median survival (OS) was 26.4 months,with 1-,3-, and 5-year survival rates of 79.0%,40.0%, and 29.0%, respectively. In the recent five years (from 2020 to 2024), the median OS improved significantly to 34.1 months compared to 20.0 months from 2016 to 2019 ( P<0.01). Histological subtype analysis showed that the median OS time was 26.7 months for pancreatic ductal adenocarcinoma (PDAC, n=855),58.9 months for invasive intraductal papillary mucinous carcinoma (IPMC, n=32),and 15.7 months for adenosquamous carcinoma of pancreas (ASCP, n=73) ( P=0.001). Among PDAC patients, adjuvant chemotherapy significantly improved survival (29.1 months vs. 14.4 months, P<0.01);in IPMC patients, adjuvant chemotherapy also extended survival (65.7 months vs. 58.9 months, P=0.047). Although ASCP patients receiving chemotherapy had a longer median OS time than those without (18.8 months vs. 8.9 months),the difference was not statistically significant ( P=0.151). Multivariate Cox regression analysis in PDAC patients indicated that adjuvant chemotherapy, R0 resection, T stage,N stage,and tumor differentiation were independent prognostic factors ( P<0.01). The median OS time by TNM stage was:not reached for stage ⅠA, 51.6 months for ⅠB, 25.5 months for ⅡA, 23.7 months for ⅡB, 23.0 months for Ⅲ, and 14.4 months for Ⅳ. The median OS time for R0,R1-1 mm,and R1-direct resections was 34.1,24.7,and 15.7 months,respectively ( P<0.01). Conclusion:Adjuvant chemotherapy,R0 resection,tumor stage,and differentiation are independent prognostic factors for pancreatic body and tail cancer.
8.Interpretation of the Guidelines for the Diagnosis and Treatment of Acute Pulmonary Embolism 2025
Peiran WANG ; Kai SUN ; Xiqi XU
Medical Journal of Peking Union Medical College Hospital 2026;17(1):140-147
With the advancement of more high-quality research, significant progress has been made in the diagnosis and treatment of acute pulmonary embolism. Based on the latest evidence in evidence-based medicine, the Chinese Society of Cardiology released the
9.A VBM study on gray matter structure alterations in patients with Alzheimer’s disease comorbid with apathy
Yi JI ; Xuerui PANG ; Chaoyi YANG ; Yulong DAI ; Shanshan ZHOU ; Xingqi WU ; Kai WANG
Acta Universitatis Medicinalis Anhui 2026;61(1):156-162
ObjectiveTo investigate the characteristics of gray matter structure and clinical symptoms in patients with Alzheimer's disease (AD) comorbid with apathy (AD-A). MethodsThe study included 30 patients with AD-A, 30 AD disease patients without apathy (AD without apathy, AD-NA), and 30 healthy controls (HCs) matched in gender, age, and years of education. All participants underwent a comprehensive neuropsychological assessment and magnetic resonance imaging (MRI) scans. Voxel-based morphometry (VBM) was used to analyze changes in gray matter volume among the three groups. Additionally, the correlation between the identified abnormal brain regions and apathy scale scores was analyzed. ResultsThere were no statistically significant differences among the three groups in terms of age, gender, years of education, or total intracranial volume. Compared with the HCs group, both the AD-A and AD-NA groups showed significantly lower scores in cognitive function (P<0.001). The AD-A group exhibited significantly higher apathy scale scores compared with the AD-NA group (P<0.001). Compared with the AD-NA group, the AD-A group showed reduced gray matter volume in the bilateral caudate nucleus, left orbitofrontal cortex, lingual gyrus, inferior frontal gyrus, superior frontal gyrus, entorhinal cortex, right middle frontal gyrus and posterior cingulate cortex (FWE-corrected, P<0.05 for all). Compared with the HCs group, the AD-A group exhibited reduced gray matter volume in the bilateral middle temporal gyrus, left fusiform gyrus, calcarine sulcus, postcentral gyrus, right inferior frontal gyrus and supramarginal gyrus (FWE-corrected, P<0.05 for all). Compared with the HCs group, the AD-NA group showed reduced gray matter volume in the left precuneus, inferior temporal gyrus, and right inferior temporal gyrus (FWE-corrected, P<0.05 for all). In the AD-A group, changes in the gray matter volume of the left caudate nucleus (r= -0.557, P=0.002) and right middle frontal gyrus (r=-0.620, P=0.001) were negatively correlated with the apathy evaluation scale (AES) scores. ConclusionPatients in the AD-A group exhibited significant atrophy in the frontal-temporal-basal ganglia circuit, and the degree of gray matter atrophy was correlated with the severity of apathy.
10.Mechanisms and Strategy of Traditional Chinese Medicine in Treatment of Ischemic Stroke: A Review
Maodi WENG ; Qiuyan CHEN ; Kai WANG ; Yun LUO ; Xiaobo SUN
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(1):310-316
Ischemic stroke (IS) represents a major global health challenge with complex pathological mechanisms. Although modern therapies such as intravenous thrombolysis and endovascular thrombectomy have advanced, their application remains constrained by narrow therapeutic time windows, hemorrhagic risks, and uneven distribution of medical resources. Traditional Chinese medicine (TCM) demonstrates unique value in the prevention and treatment of IS, owing to its multi-component, multi-target, and holistic regulatory characteristics. This review summarized the molecular mechanisms by which active ingredients and compound formulations of TCM exert therapeutic effects against IS through the regulation of inflammatory responses, oxidative stress, excitatory toxicity, apoptosis, and autophagy. Studies have indicated that components such as curcumin, baicalin, and astragaloside Ⅳ inhibit microglial activation and the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to attenuate neuroinflammation, activate the nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1) pathway to alleviate oxidative stress, modulate glutamate receptor function to counteract excitatory toxicity, and regulate the B-cell lymphoma 2(Bcl-2)/Bcl-2-associated X protein (Bax), cysteine aspartate-specific protease (Caspase), and phosphatidylinositol 3 kinases (PI3K)/protein kinase B (Akt) signaling pathways to suppress neuronal apoptosis. Recent research has further revealed that TCM can modulate ferroptosis by targeting key proteins glutathione peroxidase 4 (GPX4) and acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) to maintain iron homeostasis, intervene in the "microbiota-gut-brain axis" to ameliorate dysbiosis and reduce neuroinflammation, utilize exosomes for brain-targeted drug delivery, and influence neural repair processes through epigenetic regulation. Furthermore, the review discussed the integrated mechanisms of compound formulations, such as Buyang Huanwu Decoction, in improving cerebral microcirculation and promoting neurovascular remodeling via multi-component synergy. It also analyzed the strategy and advantages of integrating TCM with Western medicine for IS treatment, providing a novel theoretical foundation and research directions for future investigations and clinical translation of TCM in IS management.


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