1.Expert Consensus on Clinical Application of Qinbaohong Zhike Oral Liquid in Treatment of Acute Bronchitis and Acute Attack of Chronic Bronchitis
Jian LIU ; Hongchun ZHANG ; Chengxiang WANG ; Hongsheng CUI ; Xia CUI ; Shunan ZHANG ; Daowen YANG ; Cuiling FENG ; Yubo GUO ; Zengtao SUN ; Huiyong ZHANG ; Guangxi LI ; Qing MIAO ; Sumei WANG ; Liqing SHI ; Hongjun YANG ; Ting LIU ; Fangbo ZHANG ; Sheng CHEN ; Wei CHEN ; Hai WANG ; Lin LIN ; Nini QU ; Lei WU ; Dengshan WU ; Yafeng LIU ; Wenyan ZHANG ; Yueying ZHANG ; Yongfen FAN
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(4):182-188
The Expert Consensus on Clinical Application of Qinbaohong Zhike Oral Liquid in Treatment of Acute Bronchitis and Acute Attack of Chronic Bronchitis (GS/CACM 337-2023) was released by the China Association of Chinese Medicine on December 13th, 2023. This expert consensus was developed by experts in methodology, pharmacy, and Chinese medicine in strict accordance with the development requirements of the China Association of Chinese Medicine (CACM) and based on the latest medical evidence and the clinical medication experience of well-known experts in the fields of respiratory medicine (pulmonary diseases) and pediatrics. This expert consensus defines the application of Qinbaohong Zhike oral liquid in the treatment of cough and excessive sputum caused by phlegm-heat obstructing lung, acute bronchitis, and acute attack of chronic bronchitis from the aspects of applicable populations, efficacy evaluation, usage, dosage, drug combination, and safety. It is expected to guide the rational drug use in medical and health institutions, give full play to the unique value of Qinbaohong Zhike oral liquid, and vigorously promote the inheritance and innovation of Chinese patent medicines.
2.Construction and Validation of a Large Language Model-Based Intelligent Pre-Consultation System for Traditional Chinese Medicine
Yiqing LIU ; Ying LI ; Hongjun YANG ; Linjing PENG ; Nanxing XIAN ; Kunning LI ; Qiwei SHI ; Hengyi TIAN ; Lifeng DONG ; Lin WANG ; Yuping ZHAO
Journal of Traditional Chinese Medicine 2025;66(9):895-900
ObjectiveTo construct a large language model (LLM)-based intelligent pre-consultation system for traditional Chinese medicine (TCM) to improve efficacy of clinical practice. MethodsA TCM large language model was fine-tuned using DeepSpeed ZeRO-3 distributed training strategy based on YAYI 2-30B. A weighted undirected graph network was designed and an agent-based syndrome differentiation model was established based on relationship data extracted from TCM literature and clinical records. An agent collaboration framework was developed to integrate the TCM LLM with the syndrome differentiation model. Model performance was comprehensively evaluated by Loss function, BLEU-4, and ROUGE-L metrics, through which training convergence, text generation quality, and language understanding capability were assessed. Professional knowledge test sets were developed to evaluate system proficiency in TCM physician licensure content, TCM pharmacist licensure content, TCM symptom terminology recognition, and meridian identification. Clinical tests were conducted to compare the system with attending physicians in terms of diagnostic accuracy, consultation rounds, and consultation duration. ResultsAfter 100 000 iterations, the training loss value was gradually stabilized at about 0.7±0.08, indicating that the TCM-LLM has been trained and has good generalization ability. The TCM-LLM scored 0.38 in BLEU-4 and 0.62 in ROUGE-L, suggesting that its natural language processing ability meets the standard. We obtained 2715 symptom terms, 505 relationships between diseases and syndromes, 1011 relationships between diseases and main symptoms, and 1 303 600 relationships among different symptoms, and constructed the Agent of syndrome differentiation model. The accuracy rates in the simulated tests for TCM practitioners, licensed pharmacists of Chinese materia medica, recognition of TCM symptom terminology, and meridian recognition were 94.09%, 78.00%, 87.50%, and 68.80%, respectively. In clinical tests, the syndrome differentiation accuracy of the system reached 88.33%, with fewer consultation rounds and shorter consultation time compared to the attending physicians (P<0.01), suggesting that the system has a certain pre- consultation ability. ConclusionThe LLM-based intelligent TCM pre-diagnosis system could simulate diagnostic thinking of TCM physicians to a certain extent. After understanding the patients' natural language, it collects all the patient's symptom through guided questioning, thereby enhancing the diagnostic and treatment efficiency of physicians as well as the consultation experience of the patients.
3.Visualization Analysis of Research Hotspots and Trends in Field of Tumor Therapy Based on CiteSpace and VOSviewer
Yuhang FANG ; Chuchu ZHANG ; Bailu SUI ; Yan WANG ; Runxi WANG ; Yu CHEN ; Xinhe YUAN ; Hongjun YANG ; Ying ZHANG
Cancer Research on Prevention and Treatment 2025;52(4):297-304
Objective To explore the research hotspots and development trends in the field of cancer treatment in the past decade. Methods The CNKI and Web of Science Core Collection databases were searched for Chinese and English articles related to cancer treatment published over the last 10 years. Bibliometric research methods were employed, including keyword cluster analysis of published literature. Results A total of 45 455 Chinese articles and 866 958 English articles were retrieved. Combining the visualization analysis results and the current research dilemma of tumor treatment revealed that the current research hotspots of tumor treatment domestically and internationally can primarily focus on four key areas. In the realm of targeted therapy, efforts are directed towards the discovery of new drug targets, overcoming resistance to targeted therapy, and the development of monoclonal antibodies and antibody–drug conjugates. In the field of immunotherapy, the emphasis lies in enhancing the response rate to immune checkpoint inhibitors, determining the mechanisms behind resistance to immunotherapy, and improving the safety of treatment. The research in traditional Chinese medicine (TCM) covers evidence-based evaluation studies on TCM treatment, the identification of populations that can gain the most benefit from TCM, and strategies for improving the quality of life. In the area of novel drug development, cutting-edge technologies, such as organoid-based screening for anticancer drugs, synthetic biology, and artificial intelligence, are under investigation. Conclusion New targeted drugs, immune efficacy improvement, multidisciplinary integration, nano-delivery, and TCM innovation are the key research directions in the field of tumor therapy in the future.
4.Implementation Pathways for the Innovative Development of Traditional Chinese Medicine Master-Apprentice Education in the New Era
Chaoyi MAO ; Yilin YAN ; Zheji HAN ; Hongjun YANG
Journal of Traditional Chinese Medicine 2025;66(11):1186-1188
Master-apprentice education in traditional Chinese medicine (TCM) is an important approach for training TCM professionals. It compensates for the shortcomings of formal education, serves as a vivid practice of integrating Chinese traditional culture into TCM education, and is an effective pathway for cultivating high-level TCM talent. The implementation pathways for the innovative development of TCM master-apprentice education are as follows: fully utilizing the initiative of mentors and academic successors, innovating learning models that connect famous doctors and teachers, expanding master-apprentice model-based medical services to grassroots levels, integrating interdisciplinary, cross-border fields, and modern information technology with master-apprentice education, as well as promoting regular, systematic, and diversified theoretical learning. This approach aims to achieve innovative development of master-apprentice education in TCM under the background of the new era.
5.Clinical Efficacy and Mechanism of Shengmai Jiuxin Decoction in Treating Chronic Heart Failure with Qi and Yin Deficiency, Yang Deficiency, and Blood Stasis
Yiming YAO ; Hongjun ZHU ; Yang ZHAO ; Man SHI ; Yujin GONG ; Yuan WANG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(17):151-158
ObjectiveTo investigate the clinical efficacy and potential mechanism of Shengmai Jiuxin decoction in the treatment of acute decompensated heart failure (ADHF) with the traditional Chinese medicine (TCM) pattern of Qi and Yin deficiency, Yang deficiency, and blood stasis. MethodsA total of 68 patients diagnosed with ADHF of Qi and Yin deficiency, Yang deficiency, and blood stasis type were randomly assigned to an observation group (34 cases) and a control group (34 cases). Both groups received conventional Western medical treatment, while the observation group was additionally administered Shengmai Jiuxin decoction. Parameters compared before and after treatment included: TCM syndrome score, TCM syndrome efficacy, New York Heart Association (NYHA) functional classification, left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), six-minute walk distance (6MWD), hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor A (VEGF-A), Caspase-3, and the number of rehospitalizations for heart failure within one month after discharge. ResultsThere were no significant differences in sex, age, vital signs, or underlying diseases between the two groups. Compared with baseline, both groups exhibited significant reductions in TCM syndrome scores, NT-proBNP, and HIF-1α levels (P<0.01), as well as significant increases in 6MWD, LVEF, VEGF-A, and Caspase-3 levels (P<0.05, P<0.01). After treatment, the observation group showed significantly greater reductions in TCM syndrome score, NT-proBNP, HIF-1α, and Caspase-3 levels compared with the control group (P<0.05) and significantly greater increases in 6MWD, TCM syndrome efficacy, and VEGF-A levels (P<0.05). No significant differences were observed between the groups in NYHA functional classification, LVEF, or the number of rehospitalizations for heart failure within one month after discharge. No drug-related adverse events were reported in either group during the treatment period. ConclusionShengmai Jiuxin decoction can improve cardiac function and clinical symptoms in patients with ADHF of Qi and Yin deficiency, Yang deficiency, and blood stasis type. Its mechanisms may be related to the regulation of the HIF-1 signaling pathway by modulating targets such as HIF-1α, VEGF-A, and Caspase-3.
6.Clinical Efficacy and Mechanism of Shengmai Jiuxin Decoction in Treating Chronic Heart Failure with Qi and Yin Deficiency, Yang Deficiency, and Blood Stasis
Yiming YAO ; Hongjun ZHU ; Yang ZHAO ; Man SHI ; Yujin GONG ; Yuan WANG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(17):151-158
ObjectiveTo investigate the clinical efficacy and potential mechanism of Shengmai Jiuxin decoction in the treatment of acute decompensated heart failure (ADHF) with the traditional Chinese medicine (TCM) pattern of Qi and Yin deficiency, Yang deficiency, and blood stasis. MethodsA total of 68 patients diagnosed with ADHF of Qi and Yin deficiency, Yang deficiency, and blood stasis type were randomly assigned to an observation group (34 cases) and a control group (34 cases). Both groups received conventional Western medical treatment, while the observation group was additionally administered Shengmai Jiuxin decoction. Parameters compared before and after treatment included: TCM syndrome score, TCM syndrome efficacy, New York Heart Association (NYHA) functional classification, left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), six-minute walk distance (6MWD), hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor A (VEGF-A), Caspase-3, and the number of rehospitalizations for heart failure within one month after discharge. ResultsThere were no significant differences in sex, age, vital signs, or underlying diseases between the two groups. Compared with baseline, both groups exhibited significant reductions in TCM syndrome scores, NT-proBNP, and HIF-1α levels (P<0.01), as well as significant increases in 6MWD, LVEF, VEGF-A, and Caspase-3 levels (P<0.05, P<0.01). After treatment, the observation group showed significantly greater reductions in TCM syndrome score, NT-proBNP, HIF-1α, and Caspase-3 levels compared with the control group (P<0.05) and significantly greater increases in 6MWD, TCM syndrome efficacy, and VEGF-A levels (P<0.05). No significant differences were observed between the groups in NYHA functional classification, LVEF, or the number of rehospitalizations for heart failure within one month after discharge. No drug-related adverse events were reported in either group during the treatment period. ConclusionShengmai Jiuxin decoction can improve cardiac function and clinical symptoms in patients with ADHF of Qi and Yin deficiency, Yang deficiency, and blood stasis type. Its mechanisms may be related to the regulation of the HIF-1 signaling pathway by modulating targets such as HIF-1α, VEGF-A, and Caspase-3.
7.Untargeted Metabolomics Reveals Mechanism of Modified Sinisan in Ameliorating Anxiety-like Behaviors Induced by Chronic Restraint Stress in Mice
Jie ZHAO ; Zhengyu FANG ; He XIAO ; Na GUO ; Hongwei WU ; Hongjun YANG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(21):70-79
ObjectiveTo elucidate the potential mechanism of modified Sinisan (MSNS) in alleviating anxiety-like behaviors induced by chronic restraint stress (CRS) in mice at the metabolic level based on serum untargeted metabolomics and identify key metabolites and metabolic pathways regulated by MSNS. MethodsSeventy-two male C57BL/6 mice were randomly assigned into six groups: control, model, high-dose (2.4 g·kg-1) MSNS, medium-dose (1.2 g·kg-1) MSNS, low-dose (0.6 g·kg-1) MSNS, and positive control (fluoxetine, 2.6 mg·kg-1). Except the control group, the other groups were subjected to CRS for the modeling of anxiety. Mice were administrated with corresponding agents by gavage 2 h before daily restraint for 14 days. Anxiety-like behaviors were evaluated by the open field test (OFT), elevated plus maze (EPM) test, and light/dark box (LDB) test. Serum levels of corticotropin-releasing hormone (CRH), adrenocorticotrophic hormone (ACTH), and corticosterone (CORT) were measured via ELISA to assess stress levels. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to detect 9 metabolites in the brain tissue and serum metabolites. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was adopted to identify differential metabolites (VIP>1.0, P<0.05). MetaboAnalyst 5.0 was used for metabolic pathway enrichment analysis of the differential metabolites. ResultsCompared with the control group, the model group showed reductions in the central activity time and central distance in the OFT (P<0.05), the proportions of open-arm residence time and open-arm residence times in the EPM test (P<0.01), and the proportions of open box activity time and open box activity distance in the LDB test (P<0.05), which were increased in the medium- and high-dose MSNS groups compared with the model group (P<0.05). Compared with the control group, the model group showed elevated levels of CRH, ACTH, and CORT in the serum (P<0.01), and the elevations were diminished in the medium- and high-dose MSNS groups (P<0.05). UPLC-MS results indicated that compared with the control group, the model group presented declined DA, GABA, 5-HIAA, 5-HT, and 5-HT/Trp levels (P<0.05, P<0.01) and raised Glu, NE, Kyn, and Kyn/Trp levels (P<0.05). Compared with the model group, high-dose MSNS increased the GABA, 5-HIAA, and 5-HT/Trp levels (P<0.05) and lowered the Glu and Kyn/Trp levels (P<0.05). Untargeted metabolomics identified that 16 CRS-induced metabolic disturbances were reversed by MSNS. KEGG pathway analysis indicated that MSNS primarily modulated eight core pathways including alanine/aspartate/glutamate metabolism, butyrate metabolism, arginine-proline metabolism, TCA cycle, unsaturated fatty acid biosynthesis, and tryptophan metabolism. The mechanisms involved multidimensional biological processes, including neurotransmitter homeostasis regulation, TCA cycle energy metabolism optimization, and inflammatory response suppression. ConclusionMSNS alleviates CRS-induced anxiety-like behaviors in mice by mitigating hypothalamic-pituitary-adrenal axis hyperactivity, improving hippocampal neurotransmitter and tryptophan metabolic pathways, and regulating alanine/aspartate/glutamate metabolism, butyrate metabolism, arginine-proline metabolism, and TCA cycle.
8.Untargeted Metabolomics Reveals Mechanism of Modified Sinisan in Ameliorating Anxiety-like Behaviors Induced by Chronic Restraint Stress in Mice
Jie ZHAO ; Zhengyu FANG ; He XIAO ; Na GUO ; Hongwei WU ; Hongjun YANG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(21):70-79
ObjectiveTo elucidate the potential mechanism of modified Sinisan (MSNS) in alleviating anxiety-like behaviors induced by chronic restraint stress (CRS) in mice at the metabolic level based on serum untargeted metabolomics and identify key metabolites and metabolic pathways regulated by MSNS. MethodsSeventy-two male C57BL/6 mice were randomly assigned into six groups: control, model, high-dose (2.4 g·kg-1) MSNS, medium-dose (1.2 g·kg-1) MSNS, low-dose (0.6 g·kg-1) MSNS, and positive control (fluoxetine, 2.6 mg·kg-1). Except the control group, the other groups were subjected to CRS for the modeling of anxiety. Mice were administrated with corresponding agents by gavage 2 h before daily restraint for 14 days. Anxiety-like behaviors were evaluated by the open field test (OFT), elevated plus maze (EPM) test, and light/dark box (LDB) test. Serum levels of corticotropin-releasing hormone (CRH), adrenocorticotrophic hormone (ACTH), and corticosterone (CORT) were measured via ELISA to assess stress levels. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to detect 9 metabolites in the brain tissue and serum metabolites. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was adopted to identify differential metabolites (VIP>1.0, P<0.05). MetaboAnalyst 5.0 was used for metabolic pathway enrichment analysis of the differential metabolites. ResultsCompared with the control group, the model group showed reductions in the central activity time and central distance in the OFT (P<0.05), the proportions of open-arm residence time and open-arm residence times in the EPM test (P<0.01), and the proportions of open box activity time and open box activity distance in the LDB test (P<0.05), which were increased in the medium- and high-dose MSNS groups compared with the model group (P<0.05). Compared with the control group, the model group showed elevated levels of CRH, ACTH, and CORT in the serum (P<0.01), and the elevations were diminished in the medium- and high-dose MSNS groups (P<0.05). UPLC-MS results indicated that compared with the control group, the model group presented declined DA, GABA, 5-HIAA, 5-HT, and 5-HT/Trp levels (P<0.05, P<0.01) and raised Glu, NE, Kyn, and Kyn/Trp levels (P<0.05). Compared with the model group, high-dose MSNS increased the GABA, 5-HIAA, and 5-HT/Trp levels (P<0.05) and lowered the Glu and Kyn/Trp levels (P<0.05). Untargeted metabolomics identified that 16 CRS-induced metabolic disturbances were reversed by MSNS. KEGG pathway analysis indicated that MSNS primarily modulated eight core pathways including alanine/aspartate/glutamate metabolism, butyrate metabolism, arginine-proline metabolism, TCA cycle, unsaturated fatty acid biosynthesis, and tryptophan metabolism. The mechanisms involved multidimensional biological processes, including neurotransmitter homeostasis regulation, TCA cycle energy metabolism optimization, and inflammatory response suppression. ConclusionMSNS alleviates CRS-induced anxiety-like behaviors in mice by mitigating hypothalamic-pituitary-adrenal axis hyperactivity, improving hippocampal neurotransmitter and tryptophan metabolic pathways, and regulating alanine/aspartate/glutamate metabolism, butyrate metabolism, arginine-proline metabolism, and TCA cycle.
9.ZHAO Hong's experience in treatment of gynecological diseases based on spleen-stomach theories.
Han TANG ; Hong ZHAO ; Yunhong YANG ; Hongjun KUANG
Chinese Acupuncture & Moxibustion 2025;45(11):1633-1638
The paper introduces Professor ZHAO Hong's clinical experience and the thinking of diagnosis and treatment for gynecological diseases based on spleen-stomach theories of TCM and explore the effects of the dysfunction of spleen and stomach on gynecological diseases. In clinical practice, Professor ZHAO proposes the "theory" for protecting the spleen and stomach, and in consideration of the other organs; focuses on the "principle" for strengthening the spleen, harmonizing the stomach, promoting qi circulation, removing stagnation and mutually-regulating the body, qi and mind; and adopts the "methods" of integrating acupuncture with medication and specially uses the warming and resolving techniques. She attaches importance to "acupoints" on the detection, and the selection of fewer but more effective ones; and delivers the "needling techniques" for releasing the stagnation and obstruction and inducing muscle jumping and sensation transmission. Professor ZHAO Hong integrates acupuncture with medication in views of spleen and stomach theories of TCM for ovarian insufficiency, polycystic ovary syndrome, endometriosis, thin endometrium and dysfunctional uterine bleeding, which provides the references for the treatment of gynecological diseases.
Humans
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Female
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Acupuncture Therapy
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Spleen/physiopathology*
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Genital Diseases, Female/physiopathology*
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Stomach/physiopathology*
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Medicine, Chinese Traditional
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Acupuncture Points
10.Super-thin free anterolateral thigh flap harvested at the junction plane of superficial and deep fat of superficial fascia to repair soft tissue defect of foot
Tao GUO ; Hongjun LIU ; Qiaochu ZHANG ; Yang WANG ; Peng JIN ; Wenzhong ZHANG ; Tao XU ; Chaoqun YUAN ; Jiaxiang GU
Chinese Journal of Plastic Surgery 2024;40(9):954-962
Objective:To investigate the clinical effect of super-thin free anterolateral thigh (ALT) flap at the junction plane of superficial and deep fat of superficial fascia to repair the soft tissue defects of the foot.Methods:The clinical data of patients with foot soft tissue defects admitted to Northern Jiangsu People’s Hospital Affiliated to Yangzhou University from June 2017 to December 2022 were retrospectively analyzed. During the operation, the super-thin free ALT flap on the affected side was harvested at the junction of superficial and deep fat of superficial fascia to repair the foot wound. The donor site wound was sutured directly or repaired with full-thickness skin graft. The flap survival and complications were observed after the operation, and the operation effect was evaluated from the following five aspects. (1) The Maryland foot function score was used to evaluate the recovery of foot function. The full score was 100 points, of which 90-100 points were excellent, 75-89 points were good, 50-74 points were fair, and < 50 points were poor. (2) The Vancouver scar scale (VSS) was used to evaluate the scar condition of the foot. The total score was 0-15 points. The higher the score, the more serious the scar. (3) The cold intolerance symptom severity (CISS) scale was used to evaluate the cold tolerance of the affected foot. The total score was 4-100 points. The higher the score, the more serious the symptoms. (4) Measuring static two-point discrimination to evaluate foot sensation, the smaller the measured value, the better the sensory recovery. (5) The satisfaction of patients with foot appearance was investigated, which was divided into five grades: very satisfied, satisfied, general, dissatisfied and very dissatisfied. Descriptive analysis of the data was performed using SPSS 26.0 software.Results:A total of 13 patients with foot soft tissue defects were enrolled, including 8 males and 5 females. The mean age was 54.7 years (range, 39-70 years). There were 10 cases of left foot and 3 cases of right foot. The wound area after thorough debridement ranged from 5.5 cm ×5.0 cm to 22.0 cm ×18.0 cm. The operation time was (145.1 ± 30.6) min. The area of the flap was 6.0 cm×5.5 cm to 23.5 cm×19.0 cm, and the thickness was (5.2 ± 1.1) mm (range, 3.0- 6.5 mm). The wound at the donor site was sutured directly in 9 cases, and coverd with the abdominal full-thickness skin graft in 4 cases. After the operation, 1 patient had partial epidermal necrosis at the distal end of the flap, 1 patient had venous crisis.The flaps survived after symptomatic treatment. The remaining 11 flaps survived smoothly. The patients were followed up for 12 to 20 months, with an average of 16 months. The foot flaps were soft and free of damage, and no secondary fat reduction or plastic surgery was required. There were no complications such as wound dehiscence, skin graft necrosis, muscle hernia, and quadriceps weakness in 13 cases of donor site except for hypoesthesia caused by scar hyperplasia in 4 cases with skin graft. At the last follow-up, the Maryland foot function score was (87.4±7.3) points, of which 7 cases were excellent, 4 cases were good, and 2 cases were fair. The excellent and good rate was 11/13. The foot scar was not obvious, the VSS score was (3.2±1.2) points. The foot was more tolerant to cold and the sensory recovery was better, the CISS score was (37.5±7.1) points and the static two-point discrimination was (13.9±1.0) mm. One month after the operation, the results of patients’ satisfaction with foot appearance were as follows: 11 cases were very satisfied and 2 cases were satisfied.Conclusion:The super-thin free ALT flap is obtained at the junction plane of superficial and deep fat of superficial fascia to repair the soft tissue defect of the foot, which can optimize the operation time. The appearance and function of the foot recover well after the operation, avoiding the secondary shaping operation, reducing the damage to the donor site, and the patients are satisfied.

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