1.Value of ultrasound artificial intelligence in assisting naval grassroots doctors for diagnosis of thyroid nodule
Zufeng CHEN ; Haibo JIANG ; Ruoyu SHEN ; Wei WANG ; Hai WANG ; Dahai TANG
Journal of Navy Medicine 2025;46(9):899-903
Objective To explore the value of ultrasound artificial intelligence(AI)in assisting naval grassroots doctors for the diagnosis of thyroid nodule in naval.Methods A total of 177 patients with thyroid nodules(200 thyroid nodules)who visited The First Affiliated Hospital of Naval Medical University from November 2020 to November 2023 were selected as research objects.The thyroid nodules were diagnosed by naval grassroots doctors,naval grassroots doctors assisted by AI,and senior doctors,respectively.Results The pathological results showed that there were 110 malignant nodules and 90 benign nodules.The diagnostic accuracy rate of AI-assisted group(85.0%)was similar to that of senior doctor group(87.0%),which were higher than that of naval grassroots doctor group(71.5%).Pathological results were taken as the gold standard,Kappa consistency test was carried out,and the area under the receiver operating characteristic(ROC)curve(AUC)was compared among groups.The diagnostic results of naval grassroots doctor group had a moderate consistency with pathological results(Kappa value was 0.424,P<0.001).The diagnostic results of AI group and senior doctor group had strong consistencies with pathological results(Kappa values were 0.693 and 0.735,respectively,both P<0.001).There was no significant difference in the AUC between AI group and senior doctor group(0.842 vs.0.864,P>0.05).However,there was a significant difference in the AUC between naval grassroots doctor group and AI group(0.712 vs.0.842,P<0.001).Conclusion AI can assist naval grassroots doctors in improving the diagnostic level of thyroid nodules.It has certain application prospects in naval forces.
2.Clinical advances of dual-pathway antithrombotic therapy in peripheral artery disease
Jiuyi SONG ; Nan SHEN ; Hai WANG ; Yinteng CHU ; Ruzhou CAO ; Qihong NI ; Yinan LI ; Lan ZHANG
Journal of Interventional Radiology 2025;34(11):1271-1274
Peripheral artery disease(PAD),commonly encountered in vascular surgery,predominantly affects the lower limbs and presents with ischemic symptoms resulting from atherosclerosis.It carries risks of adverse limb events and cardiovascular events.Antithrombotic therapy remains a cornerstone in the management of PAD.This article reviews the evidence and research progress regarding dual-pathway antithrombotic therapy for PAD.Multiple clinical trials have demonstrated that,compared to single antiplatelet therapy,dual-pathway antithrombotic therapy significantly reduces the risks of major adverse limb events and major adverse cardiovascular events without a significant increase in bleeding risk.For high-risk patients,such as those with advanced age,multivessel disease,comorbid coronary artery disease,or those undergoing endovascular revascularization,the benefits of dual-pathway antithrombotic therapy are particularly pronounced.Current clinical guidelines have incorporated dual-pathway antithrombotic therapy into their recommendations,standardized criteria for identifying the most appropriate patient populations remain lacking.Despite its advantages in reducing adverse events,its long-term safety profile and optimal target populations warrant further investigation.
3.Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione
Fu'an XIE ; Yujia NIU ; Xiaobing CHEN ; Xu KONG ; Guangting YAN ; Aobo ZHUANG ; Xi LI ; Lanlan LIAN ; Dongmei QIN ; Quan ZHANG ; Ruyi ZHANG ; Kunrong YANG ; Xiaogang XIA ; Kun CHEN ; Mengmeng XIAO ; Chunkang YANG ; Ting WU ; Ye SHEN ; Chundong YU ; Chenghua LUO ; Shu-Hai LIN ; Wengang LI
Journal of Pharmaceutical Analysis 2025;15(1):189-207
Ursodeoxycholic acid(UDCA)is a naturally occurring,low-toxicity,and hydrophilic bile acid(BA)in the human body that is converted by intestinal flora using primary BA.Solute carrier family 7 member 11(SLC7A11)functions to uptake extracellular cystine in exchange for glutamate,and is highly expressed in a variety of human cancers.Retroperitoneal liposarcoma(RLPS)refers to liposarcoma originating from the retroperitoneal area.Lipidomics analysis revealed that UDCA was one of the most significantly down-regulated metabolites in sera of RIPS patients compared with healthy subjects.The augmentation of UDCA concentration(≥25 μg/mL)demonstrated a suppressive effect on the proliferation of liposarcoma cells.[15N2]-cystine and[13Cs]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione(GSH)synthesis.Mechanistically,UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis,leading to reactive oxygen species(ROS)accumulation and mitochondrial oxidative damage.Furthermore,UDCA can promote the anti-cancer effects of ferroptosis inducers(Erastin,RSL3),the murine double minute 2(MDM2)inhibitors(Nutlin 3a,RG7112),cyclin dependent kinase 4(CDK4)inhibitor(Abemaciclib),and glutaminase inhibitor(CB839).Together,UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity,and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA.More importantly,in combination with other antitumor chemotherapy or physiotherapy treatments,UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.
4.Trends of Gastric Cancer Mortality and Age-Period-Cohort Among Residents in Wuxi City of Jiangsu Province from 2009 to 2023
Tianhong HAN ; Jia LIU ; Hai CHEN ; Qian SHEN ; Nanqian WANG ; Yun QIAN ; Lu WANG
China Cancer 2025;34(7):530-538
[Purpose]To analyze the trends of mortality and disease burden of gastric cancer among residents aged 30 and above from 2009 to 2023 in Wuxi City of Jiangsu Province and to estimate the age-period-cohort effect.[Methods]The gastric cancer mortality data from 2009 to 2023 were collected from Wuxi Death Registration System,and the crude mortality rate,age-standardized mortality rate,years of life lost(YLL)and YLL rate were calculated.The average annual percen-tage change(AAPC)was calculated with Joinpoint regression to analyze the trends of mortality and YLL rate of gastric cancer.The age-period-cohort model was used to analyze the effect of age,pe-riod and birth cohort on gastric cancer mortality.[Results]From 2009 to 2023,there were 32 348 gastric cancer deaths in Wuxi,the crude mortality rate was 44.24/105,and the age-standard mor-tality rate was 25.10/105,with a total YLL of 681 618.33 person-years.The crude mortality rate,age-standardized mortality rate and YLL rate showed decreasing trends,with AAPC of-1.77%(95%CI:-2.10%~-1.43%),-4.59%(95%CI:-4.97%~-4.20%)and-2.14%(95%CI:-2.56%~-1.74%),respectively.From 2009 to 2023,crude mortality rate,age-tandardized mortality rate,YLL in men were higher than those in women,and the decline rates of all indicators in women were faster than those in men.The age effect showed that the overall risk of gastric cancer death increased with age;the period effect showed a gradual decrease in the mortality risk and death burden of gastric cancer over time;the cohort effect showed that the later born cohort had a lower risk of death and death burden.[Conclusion]From 2009 to 2023,the disease burden of gastric cancer mortality in Wuxi showed a decreasing trend,with age and sex being the primary influencing factors.In the future,emphasis should be placed on gastric cancer screening and early intervention in middle-aged and elderly men.
5.Effects of Yunpi Tongchang Formula on intestinal mucosal barrier damage via TLR4/MyD88/NF-κB signaling pathway in rats with opioid-induced constipation of Spleen-Kidney Yang Deficiency Syndrome
Lu-mei ZHANG ; Zhi-ming ZHANG ; Zhong-yang SONG ; Xin WANG ; Qian XU ; Xia YANG ; Xin-yu LI ; Yan-yun SHEN ; Hai-hong ZHAO ; Zhi-gang WANG
Chinese Traditional Patent Medicine 2025;47(7):2205-2212
AIM To investigate the effects of Yunpi Tongchang Formula on intestinal mucosal barrier damage in rats with opioid-induced constipation(OIC)of Spleen-Kidney Yang Deficiency Syndrome.METHODS In contrast to the 10 rats of the blank group,the 50 rats of the modeling group were induced into models of OIC of Spleen-Kidney Yang Deficiency Pattern by 7 days consecutive administration of both subcutaneous loperamide injection and alternating gavage of activated carbon ice water and vinegar.Following successful modeling,rats were randomly allocated into the model group,the mosapride citrate tablet group(1.35 mg/kg),and the high-dose,medium-dose,and low-dose Yunpi Tongchang Formula groups(15.12,7.56,3.78 g/kg),with 8 mice in each group.Upon the completion of the 14 days treatment,the rats had their TCM Syndrome scores assessed;their fecal water content,initial black stool excretion time,and small intestine propulsion rate measured;their colon tissue morphology observed by HE staining;their serum levels of IL-6,TNF-α,and IL-1β detected by ELISA;their expressions of occludin and zonula occludens-1(ZO-1)in colon tissues detected by immunohistochemistry;their mRNA expressions of MyD88,TLR4 and NF-κB p65 in the colon tissues detected by RT-qPCR;and their protein expressions of MyD88,TLR4 and NF-κB p65 in the colon tissues detected by Western blot.RESULTS Compared to the blank group,the model group had higher TCM Syndrome scores(P<0.01);lower fecal water content and small intestine propulsion rate(P<0.05,P<0.01);longer initial black stool excretion time(P<0.01);more mucosal edema in colon tissue,obvious inflammatory infiltration,and glandular disorder;increased serum levels of IL-6,TNF-α and IL-1 β(P<0.05);decreased colon expressions of ZO-1 and occludin(P<0.01);and increased mRNA and protein expressions of TLR4,MyD88 and NF-κB p65(P<0.01).Compared to the model group,both the medium-dose Yunpi Tongchang Formula group and the mosapride citrate tablet group demonstrated effectively reduced TCM syndrome scores(P<0.01);increased fecal water content and small intestine propulsion rate(P<0.05,P<0.01);and shorter initial black stool excretion time(P<0.01);improved colon mucosal edema and inflammatory infiltration;decreased serum levels of IL-6,TNF-α and IL-1β(P<0.01);upregulated protein expressions of ZO-1 and occludin(P<0.01);and downregulated mRNA and protein expressions of TLR4,MyD88 and NF-κB p65(P<0.05,P<0.01).CONCLUSION Yunpi Tongchang Formula significantly ameliorates constipation symptoms in OIC rat models of Spleen-Kidney Yang Deficiency Syndrome because of its efficacy in attenuating intestinal inflammation and preserving the integrity of intestinal epithelial barrier structure,with its mechanistic action in downregulating TLR4/MyD88/NF-κB signaling pathway activation.
6.Antithrombotic effect in zebrafish of a fibrinolytic protein EPF3 from Dilong (Pheretima vulgaris Chen) and its transport mechanism in Caco-2 monolayer through cell bypass pathway.
Wan-Ling ZHONG ; Jian-Qiong YANG ; Hai LIU ; Ya-Li WU ; Hui-Juan SHEN ; Peng-Yue LI ; Shou-Ying DU
Journal of Integrative Medicine 2025;23(4):415-428
OBJECTIVE:
EPF3 is a fibrinolysin monomer isolated and purified from Pheretima vulgaris Chen, an earthworm used in traditional Chinese medicine as Dilong for treating blood stasis syndrome. Its composition, anticoagulant and fibrinolytic activities, and relevant mechanisms have been confirmed through in vitro experiments. However, whether it has antithrombotic effects in vivo and can be absorbed by the gastrointestinal tract is unknown. This study evaluates the antithrombotic effect in zebrafish and investigates the gastrointestinal stability and intestinal absorption mechanism of this protein in vitro.
METHODS:
The antithrombotic effect of EPF3 in vivo was verified using the zebrafish thrombus model induced by arachidonic acid and FeCl3. Then, the protein bands of EPF3 incubated with simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and homogenate of Caco-2 cells (HC2C) were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis to evaluate its gastrointestinal stability. Finally, the transport behavior and absorption mechanism of EPF3 were studied using Caco-2 cell monolayer.
RESULTS:
EPF3 could significantly enhance the returned blood volume and blood flow velocity in zebrafish with platelet aggregation thrombus induced by arachidonic acid. It could also prolong the formation time of tail artery thrombus and increase the blood flow velocity in zebrafish with vessel injury thrombus induced by FeCl3. EPF3 was stable in SIF and HC2C and unstable in SGF. The permeability of EPF3 in Caco-2 monolayer was time-dependent and concentration-dependent. The efflux ratio was less than 1.2 during transport, and the transport behavior was not affected by inhibitors. EPF3 could reversibly reduce the expression of tight junction-related proteins, including zonula occludens-1, occludin, and claudin-1 in Caco-2 cells.
CONCLUSION
EPF3 could play a thrombolytic and antithrombotic role in zebrafish. It could be transported and absorbed into the intestine through cellular bypass pathway by opening the intestinal epithelium tight junction. This study provides a scientific explanation for the antithrombotic effect of earthworm and provides a basis for the feasibility of subsequent development of EPF3 as an antithrombotic enteric-soluble preparation. Please cite this article as: Zhong WL, Yang JQ, Liu H, Wu YL, Shen HJ, Li PY, Du SY. Antithrombotic effect in zebrafish of a fibrinolytic protein EPF3 from Dilong (Pheretima vulgaris Chen) and its transport mechanism in Caco-2 monolayer through cell bypass pathway. J Integr Med. 2025; 23(4): 415-428.
Animals
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Zebrafish
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Humans
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Caco-2 Cells
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Fibrinolytic Agents/pharmacology*
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Thrombosis/drug therapy*
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Intestinal Absorption
7.International clinical practice guideline on the use of traditional Chinese medicine for functional dyspepsia (2025).
Sheng-Sheng ZHANG ; Lu-Qing ZHAO ; Xiao-Hua HOU ; Zhao-Xiang BIAN ; Jian-Hua ZHENG ; Hai-He TIAN ; Guan-Hu YANG ; Won-Sook HONG ; Yu-Ying HE ; Li LIU ; Hong SHEN ; Yan-Ping LI ; Sheng XIE ; Jin SHU ; Bin-Fang ZENG ; Jun-Xiang LI ; Zhen LIU ; Zheng-Hua XIAO ; Jing-Dong XIAO ; Pei-Yong ZHENG ; Shao-Gang HUANG ; Sheng-Liang CHEN ; Gui-Jun FEI
Journal of Integrative Medicine 2025;23(5):502-518
Functional dyspepsia (FD), characterized by persistent or recurrent dyspeptic symptoms without identifiable organic, systemic or metabolic causes, is an increasingly recognized global health issue. The objective of this guideline is to equip clinicians and nursing professionals with evidence-based strategies for the management and treatment of adult patients with FD using traditional Chinese medicine (TCM). The Guideline Development Group consulted existing TCM consensus documents on FD and convened a panel of 35 clinicians to generate initial clinical queries. To address these queries, a systematic literature search was conducted across PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Database, China Biology Medicine (SinoMed) Database, Wanfang Database, Traditional Medicine Research Data Expanded (TMRDE), and the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS). The evidence from the literature was critically appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The strength of the recommendations was ascertained through a consensus-building process involving TCM and allopathic medicine experts, methodologists, pharmacologists, nursing specialists, and health economists, leveraging their collective expertise and empirical knowledge. The guideline comprises a total of 43 evidence-informed recommendations that span a range of clinical aspects, including the pathogenesis according to TCM, diagnostic approaches, therapeutic interventions, efficacy assessments, and prognostic considerations. Please cite this article as: Zhang SS, Zhao LQ, Hou XH, Bian ZX, Zheng JH, Tian HH, Yang GH, Hong WS, He YY, Liu L, Shen H, Li YP, Xie S, Shu J, Zeng BF, Li JX, Liu Z, Xiao ZH, Xiao JD, Zheng PY, Huang SG, Chen SL, Fei GJ. International clinical practice guideline on the use of traditional Chinese medicine for functional dyspepsia (2025). J Integr Med. 2025; 23(5):502-518.
Dyspepsia/drug therapy*
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Humans
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Medicine, Chinese Traditional/methods*
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Practice Guidelines as Topic
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Drugs, Chinese Herbal/therapeutic use*
8.Clinical guideline for diagnosis and treatment of nonunion of osteoporotic vertebral fractures (version 2025)
Haipeng SI ; Le LI ; Junjie NIU ; Wencan ZHANG ; Fuxin WEI ; Jinqiu YUAN ; Qiang YANG ; Hongli WANG ; Guangchao WANG ; Shihong CHEN ; Yunzhen CHEN ; Xiaoguang CHENG ; Jianwen DONG ; Shiqing FENG ; Rui GU ; Yong HAI ; Tianyong HOU ; Bo HUANG ; Xiaobing JIANG ; Lei ZANG ; Chunhai LI ; Nianhu LI ; Hua LIN ; Hongjian LIU ; Peng LIU ; Xinyu LIU ; Sheng LU ; Shibao LU ; Chunshan LUO ; Lvy CHAOLIANG ; Lvy WEIJIA ; Xuexiao MA ; Wei MEI ; Chunyang MENG ; Cailiang SHEN ; Chunli SONG ; Ruoxian SONG ; Jiacan SU ; Honglin TENG ; Hui SHENG ; Beiyu WANG ; Bingwu WANG ; Liang WANG ; Xiangyang WANG ; Nan WU ; Guohua XU ; Yayi XIA ; Jin XU ; Youjia XU ; Jianzhong XU ; Cao YANG ; Maowei YANG ; Zibin YANG ; Xiaojian YE ; Hailong YU ; Xijie YU ; Hua YUE ; Zhili ZENG ; Xinli ZHAN ; Hui ZHANG ; Peixun ZHANG ; Wei ZHANG ; Zhenlin ZHANG ; Jianguo ZHANG ; Tengyue ZHU ; Qiang LIU ; Huilin YANG
Chinese Journal of Trauma 2025;41(10):932-945
Nonunion of osteoporotic vertebral fractures (OVF), predominantly affecting the elderly, can lead to intractable pain, vertebral collapse, progressive kyphotic deformity, and neurological impairment, significantly compromising patients′ quality of life. There exists considerable debate on diagnosis and management of OVF, encompassing key issues such as clinical diagnosis and staging criteria for nonunion, surgical indications and procedure selection, and postoperative rehabilitation planning. Currently, there lacks standardized clinical guideline and expert consensus on the diagnosis and management of OVF nonunion in China. To address this gap, Minimally Invasive Surgery Group of Chinese Orthopedic Association, Osteoporosis Committee of Chinese Association of Orthopedic Surgeons, Prevention and Rehabilitation Committee for Osteoporosis of Chinese Association of Rehabilitation Medicine and Minimally Invasive Orthopedic Surgery Branch of China Association for Geriatric Care jointly organized domestic experts in spinal surgery, endocrinology, and rehabilitation to formulate the Clinical guideline for the diagnosis and treatment for nonunion of osteoporotic vertebral fractures ( version 2025), based on existing literature and clinical experience and adhering to principles of scientific rigor and practicality. The guideline provided 13 evidence-based recommendations encompassing diagnosis and treatment of OVF nonunion, aiming to standardize its clinical management.
9.The efficacy of ultrasound-guided genicular nerve block in treating knee osteoarthritis
Fanxiang FENG ; Hai SHEN ; You LI ; Kai REN ; Fulong LIU ; Yicheng XIAO ; Weixia ZHAO ; Xin ZHANG
Chinese Journal of Physical Medicine and Rehabilitation 2025;47(9):834-840
Objective:To document the effectiveness of ultrasound-guided genicular nerve block (GNB) in treating knee osteoarthritis (KOA).Methods:A total of 92 KOA patients were randomly divided into an observation group and a control group with 46 in each. Those in both groups were treated conventionally, including with non-steroidal anti-inflammatory drugs, acupuncture, ultrasound, laser irradiation and manipulation therapy. The observation group additionally underwent ultrasound-guided genicular nerve block treatment, once a week for 2 weeks. Pain scoring on a visual analog scale (VAS), the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and a 6-minute walk test (6MWT) were used to evaluate everyone before and after the treatment, and then 8 weeks later.Results:In the observation group the average VAS rating [(3.54±2.00) at week 2 and (4.13±2.04) at week 8] and the average WOMAC subscale and total scores [(36.91±16.91) at week 8] had improved significantly right after the experiment and 8 weeks later. But in the control group this was true only right after the treatment. The observation group also demonstrated superior improvements in 6MWT distance at week 2 [(434.22±125.19)m] and week 8 [(446.35±126.45)m] compared to both its own baseline and the control group.Conclusions:Ultrasound-guided genicular nerve block is a rapid, precise, effective, and long-lasting intervention for alleviating pain, improving knee function and enhancing walking endurance in KOA patients.
10.Assessment of the relationship between spatial navigation impairment and dynamic functional connectivity in individuals with subjective cognitive decline across different traditional Chinese medicine constitutions
Weiping LI ; Shuying LI ; Xuefeng MA ; Hai LU ; Qian CHEN ; Peihua SHEN ; Jiaming LU ; Xin ZHANG ; Bing ZHANG
Chinese Journal of Internal Medicine 2025;64(12):1226-1234
Objective:To investigate the relationship between alterations in dynamic functional connectivity (dFC) and spatial navigation abilities in individuals with subjective cognitive decline (SCD) across different Traditional Chinese Medicine (TCM) constitutions.Methods:Seventy-five participants with SCD, comprising 34 individuals with balanced constitutions and 41 individuals with biased constitutions, were recruited from the Affiliated Drum Tower Hospital of Nanjing University Medical School between August 2022 and January 2025. The participants underwent TCM constitution assessment, spatial navigation ability testing, and neuropsychological scale evaluation. Additionally, each participant was assessed using 3.0 T resting-state functional magnetic resonance imaging (rs-fMRI) and high-resolution T1-weighted imaging scans. Based on prior research, 20 spatial navigation-related regions of interest (ROIs) were defined. Afterwards, rs-fMRI time series were segmented using a sliding time window approach before calculating the dFC within the spatial navigation brain network.Results:Compared to the balanced constitution group, the biased constitution SCD group showed significantly lower scores on the Mini-Mental State Examination (MMSE) ( z=-3.05, P=0.002) and the Auditory Verbal Learning Test (AVLT) measures: immediate recall ( z=-2.12, P=0.035), short-delay recall ( z=-2.22, P=0.026), long-delay recall ( z=-2.88, P=0.004), cued recall ( z=-2.91, P=0.004), and recognition ( z=-2.20, P=0.028). They also exhibited significantly higher average error distances in ego-allocentric navigation ( z=-2.28, P=0.023), egocentric navigation ( z=-2.31, P=0.021), and delayed navigation ( z=-2.02, P=0.043). Participants with SCD who had a biased constitution also demonstrated significantly reduced dFC between the left parahippocampal gyrus (PHG) and left prefrontal cortex (PFC) ( t=2.43), right precuneus and right retrosplenial cortex (RSC) ( t=2.96), and left inferior parietal lobule (IPL) and left hippocampus ( t=2.42) (all P<0.05, Bonferroni-corrected). Conversely, the dFC was significantly increased between the right PHG and left PFC ( t=-2.29, P<0.05, Bonferroni-corrected). Significant correlations were also found in participants with SCD who had biased constitutions: the dFC between the left PHG and left PFC positively correlated with the egocentric navigation average total error ( r=0.34, P=0.030) and negatively correlated with the visuospatial memory cognitive domain ( r=-0.35, P=0.026); the dFC between the left IPL and left hippocampus negatively correlated with the egocentric navigation average total error ( r=-0.32, P=0.043); and the dFC between the right PHG and left PFC positively correlated with the delayed navigation average total error ( r=0.33, P=0.037). The area under the ROC curve for the combined differences in cognitive assessments, spatial navigation behavior, and navigation-related brain network dFC was 0.966 in predicting biased constitution versus balanced constitution in participants with SCD. Conclusions:Individuals with SCD and biased constitutions demonstrated poorer spatial navigation ability, possibly due to altered dFC within the spatial navigation brain network. Furthermore, the integrated model based on spatial navigation behaviors and dFC exhibited a high predictive value in distinguishing between individuals with SCD who had balanced and biased constitutions.

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