1.Expert consensus on neoadjuvant PD-1 inhibitors for locally advanced oral squamous cell carcinoma (2026)
LI Jinsong ; LIAO Guiqing ; LI Longjiang ; ZHANG Chenping ; SHANG Chenping ; ZHANG Jie ; ZHONG Laiping ; LIU Bing ; CHEN Gang ; WEI Jianhua ; JI Tong ; LI Chunjie ; LIN Lisong ; REN Guoxin ; LI Yi ; SHANG Wei ; HAN Bing ; JIANG Canhua ; ZHANG Sheng ; SONG Ming ; LIU Xuekui ; WANG Anxun ; LIU Shuguang ; CHEN Zhanhong ; WANG Youyuan ; LIN Zhaoyu ; LI Haigang ; DUAN Xiaohui ; YE Ling ; ZHENG Jun ; WANG Jun ; LV Xiaozhi ; ZHU Lijun ; CAO Haotian
Journal of Prevention and Treatment for Stomatological Diseases 2026;34(2):105-118
Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.
2.Maternal depressive symptoms and adolescent suicidal ideation: the chain mediating roles of childhood trauma and ineffectiveness.
Ying-Yan ZHONG ; Yu-Ting LI ; Jian-Hua CHEN ; Ru-Meng CHEN ; En-Zhao CONG ; Yi-Feng XU
Chinese Journal of Contemporary Pediatrics 2025;27(11):1317-1325
OBJECTIVES:
To investigate the association between maternal depressive symptoms and adolescent suicidal ideation, and to examine the chain mediating roles of childhood trauma and ineffectiveness.
METHODS:
A cross-sectional online survey was administered by school psychologists to 4 157 mother-adolescent pairs from middle schools in Shanghai and Henan, China. Measures included the Center for Epidemiological Studies Depression Scale, the Childhood Trauma Questionnaire, and the Children's Depression Inventory. Using Bootstrap method to examine the chain mediating effect of childhood trauma and ineffectiveness on the relationship between maternal depression symptoms and adolescent suicidal ideation.
RESULTS:
The prevalence of maternal depressive symptoms was 17.68% (735/4 157); among adolescents, the prevalence of depressive symptoms was 15.49% (644/4 157), and suicidal ideation was 28.19% (1 172/4 157). Adolescent depressive symptoms and suicidal ideation were positively correlated with maternal depressive symptoms, childhood trauma, and ineffectiveness (all P<0.01). Childhood trauma significantly mediated the association between maternal and adolescent depressive symptoms (95%CI: 0.046 9-0.077 2). The chain mediation of childhood trauma and ineffectiveness in the association between maternal depressive symptoms and adolescent suicidal ideation was also significant (95%CI: 0.000 7-0.001 3).
CONCLUSIONS
Higher maternal depressive symptom levels are associated with a greater likelihood of adolescents' exposure to childhood trauma, which increases adolescents' ineffectiveness and, in turn, is associated with suicidal ideation. This chain effect has important implications for social interventions targeting adolescent depression.
Humans
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Suicidal Ideation
;
Adolescent
;
Female
;
Depression/etiology*
;
Cross-Sectional Studies
;
Mothers/psychology*
;
Male
;
Child
;
Adult
3.Expert consensus on orthodontic treatment of patients with periodontal disease.
Wenjie ZHONG ; Chenchen ZHOU ; Yuanyuan YIN ; Ge FENG ; Zhihe ZHAO ; Yaping PAN ; Yuxing BAI ; Zuolin JIN ; Yan XU ; Bing FANG ; Yi LIU ; Hong HE ; Faming CHEN ; Weiran LI ; Shaohua GE ; Ang LI ; Yi DING ; Lili CHEN ; Fuhua YAN ; Jinlin SONG
International Journal of Oral Science 2025;17(1):27-27
Patients with periodontal disease often require combined periodontal-orthodontic interventions to restore periodontal health, function, and aesthetics, ensuring both patient satisfaction and long-term stability. Managing these patients involving orthodontic tooth movement can be particularly challenging due to compromised periodontal soft and hard tissues, especially in severe cases. Therefore, close collaboration between orthodontists and periodontists for comprehensive diagnosis and sequential treatment, along with diligent patient compliance throughout the entire process, is crucial for achieving favorable treatment outcomes. Moreover, long-term orthodontic retention and periodontal follow-up are essential to sustain treatment success. This expert consensus, informed by the latest clinical research and practical experience, addresses clinical considerations for orthodontic treatment of periodontal patients, delineating indications, objectives, procedures, and principles with the aim of providing clear and practical guidance for clinical practitioners.
Humans
;
Consensus
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Orthodontics, Corrective/standards*
;
Periodontal Diseases/complications*
;
Tooth Movement Techniques/methods*
;
Practice Guidelines as Topic
4.Expert consensus on the diagnosis and treatment of cemental tear.
Ye LIANG ; Hongrui LIU ; Chengjia XIE ; Yang YU ; Jinlong SHAO ; Chunxu LV ; Wenyan KANG ; Fuhua YAN ; Yaping PAN ; Faming CHEN ; Yan XU ; Zuomin WANG ; Yao SUN ; Ang LI ; Lili CHEN ; Qingxian LUAN ; Chuanjiang ZHAO ; Zhengguo CAO ; Yi LIU ; Jiang SUN ; Zhongchen SONG ; Lei ZHAO ; Li LIN ; Peihui DING ; Weilian SUN ; Jun WANG ; Jiang LIN ; Guangxun ZHU ; Qi ZHANG ; Lijun LUO ; Jiayin DENG ; Yihuai PAN ; Jin ZHAO ; Aimei SONG ; Hongmei GUO ; Jin ZHANG ; Pingping CUI ; Song GE ; Rui ZHANG ; Xiuyun REN ; Shengbin HUANG ; Xi WEI ; Lihong QIU ; Jing DENG ; Keqing PAN ; Dandan MA ; Hongyu ZHAO ; Dong CHEN ; Liangjun ZHONG ; Gang DING ; Wu CHEN ; Quanchen XU ; Xiaoyu SUN ; Lingqian DU ; Ling LI ; Yijia WANG ; Xiaoyuan LI ; Qiang CHEN ; Hui WANG ; Zheng ZHANG ; Mengmeng LIU ; Chengfei ZHANG ; Xuedong ZHOU ; Shaohua GE
International Journal of Oral Science 2025;17(1):61-61
Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans
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Dental Cementum/injuries*
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Consensus
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Diagnosis, Differential
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Cone-Beam Computed Tomography
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Tooth Fractures/therapy*
5.Associations of Genetic Risk and Physical Activity with Incident Chronic Obstructive Pulmonary Disease: A Large Prospective Cohort Study.
Jin YANG ; Xiao Lin WANG ; Wen Fang ZHONG ; Jian GAO ; Huan CHEN ; Pei Liang CHEN ; Qing Mei HUANG ; Yi Xin ZHANG ; Fang Fei YOU ; Chuan LI ; Wei Qi SONG ; Dong SHEN ; Jiao Jiao REN ; Dan LIU ; Zhi Hao LI ; Chen MAO
Biomedical and Environmental Sciences 2025;38(10):1194-1204
OBJECTIVE:
To investigate the relationship between physical activity and genetic risk and their combined effects on the risk of developing chronic obstructive pulmonary disease.
METHODS:
This prospective cohort study included 318,085 biobank participants from the UK. Physical activity was assessed using the short form of the International Physical Activity Questionnaire. The participants were stratified into low-, intermediate-, and high-genetic-risk groups based on their polygenic risk scores. Multivariate Cox regression models and multiplicative interaction analyses were used.
RESULTS:
During a median follow-up period of 13 years, 9,209 participants were diagnosed with chronic obstructive pulmonary disease. For low genetic risk, compared to low physical activity, the hazard ratios ( HRs) for moderate and high physical activity were 0.853 (95% confidence interval [ CI]: 0.748-0.972) and 0.831 (95% CI: 0.727-0.950), respectively. For intermediate genetic risk, the HRs were 0.829 (95% CI: 0.758-0.905) and 0.835 (95% CI: 0.764-0.914), respectively. For participants with high genetic risk, the HRs were 0.809 (95% CI: 0.746-0.877) and 0.818 (95% CI: 0.754-0.888), respectively. A significant interaction was observed between genetic risk and physical activity.
CONCLUSION
Moderate or high levels of physical activity were associated with a lower risk of developing chronic obstructive pulmonary disease across all genetic risk groups, highlighting the need to tailor activity interventions for genetically susceptible individuals.
Humans
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Pulmonary Disease, Chronic Obstructive/epidemiology*
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Exercise
;
Male
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Female
;
Middle Aged
;
Prospective Studies
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Aged
;
Genetic Predisposition to Disease
;
Risk Factors
;
United Kingdom/epidemiology*
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Incidence
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Adult
6.Endoplasmic reticulum stressed HNSCC cell-derived exosomal miR-26a-5p promotes PD-L1 expression in mac-rophage through PTEN/AKT signaling pathway
Pengfei JIAO ; Zeyu WANG ; Heming WU ; Si-Yue YAO ; Huilin WANG ; Enhui YAO ; Yuyao ZHANG ; Yi YUAN ; Yi ZHONG
Journal of Prevention and Treatment for Stomatological Diseases 2024;32(1):12-21
Objective To investigate the impact of exosomal miRNAs derived from endoplasmic reticulum-stressed(ERS)head and neck squamous cell carcinoma(HNSCC)cells on macrophages.Methods This study was reviewed and approved by the Ethics Committee.The expression levels of ERS-associated proteins,including protein kinase R-like endoplasmic reticulum kinase(PERK)and glucose-regulated protein 78(GRP78),in HNSCC tissues and para-tumor tissues were detected by Western blot(WB)and quantitative real-time PCR(RT-qPCR).HN4 human laryngeal squamous cell carcinoma cells were treated with 500 U/mL interferon-γ(IFN-γ)for 48 h to induce ER stress,and exo-somes secreted by ER-stressed HN4 cells were collected and identified.The types of miRNAs in exosomes were identi-fied through bioinformatics analysis,and the target genes of miRNAs were predicted.Macrophages were transfected with miRNA,co cultured with collected exosomes,and the expression of PTEN in macrophages was knocked down.The downstream signaling pathway regulated by exosomal miRNAs was studied by WB and RT-qPCR.Results Compared with that in para-tumor tissues,the expression level of ER stress-associated proteins in HNSCC tissues was increased(P<0.05).RNA-seq analysis revealed that miR-26a-5p was highly upregulated in ER-stressed HN4 cell-derived exo-somes(P<0.05).PTEN is the target gene for miR-26a-5p.miR-26a-5p increased the expression level of PD-L1 in mac-rophages and downregulated the expression of PTEN(P<0.05).Macrophages co cultured with ERS extracellular vesi-cles showed an increase in miR-26a-5p and PD-L1 expression,a decrease in PTEN expression,and an increase in p-AKT expression(P<0.05).Knock down the expression of PTEN in macrophages and increase the expression of PD-L1(P<0.01).Conclusion ERS HNSCC cell-derived exosomal miR-26a-5p promotes the expression of PD-L1 in macro-phages through the PTEN/AKT signaling pathway.
7.Molecular epidemiological analysis of plague at the border area of Yunnan Province
Feng-Yi YANG ; Rong YANG ; Si-Ru LI ; Jin-Jiao KONG ; Hong-Li TAN ; Hai-Peng ZHANG ; Peng WANG ; You-Hong ZHONG ; Li-Yuan SHI ; Zhi-Zhong SONG
Chinese Journal of Zoonoses 2024;40(5):401-407
This study was aimed at exploring the epidemiological characteristics of plague,and the evolutionary relation-ships among the isolated plague strains in the Yunnan border area,to provide clues for further studying epidemic causes and ep-idemiological patterns.Plague epidemic data in the border area during the second epidemic period(1982-2007)were collected and analyzed with descriptive epidemiological methods.Whole genome sequences of 262 strains of Yersinia pestis in the border area were obtained for phylogenetic analysis.Plague outbreaks occurred in 17 counties(cities)among 25 border counties(cit-ies);a total of 552 epidemic foci and 123 human cases were identified.The 1.ORI2,1.ORI3,1.IN3,2.ANT and 2.MED geno-types were identified among Yersinia pestis isolated from the Yunnan border area,among which the 1.ORI2 population was dominant.A total of 258 strains of Yersinia pestis from the 1.OR12 population belonged to four subclusters.The Myanmar and Vietnam clade was embedded within the Yunnan clade in the overall phylogeny.The above results indicated that during the sec-ond period of the epidemic,the intensity of plague epidemics in Yunnan's border areas was high,showing a trend of devel-opment from west to south and east.Our findings indicated a risk of cross-border transmission of plague between Yunnan and neighboring countries;therefore,the surveillance,pre-vention,and control of plague in border areas should be strengthened.
8.Efficiency and safety analysis of Plerixafor combined with granulocyte colony-stimulating factor on autologous hematopoietic stem cell mobilization in lymphoma.
Meng Meng JI ; Yi Ge SHEN ; Ji Chang GONG ; Wei TANG ; Xiao Qian XU ; Zhong ZHENG ; Si Yuan CHEN ; Yang HE ; Xin ZHENG ; Lin Di ZHAO ; Wei Lin ZHAO ; Wen WU
Chinese Journal of Hematology 2023;44(2):112-117
Objective: To evaluate the advantages and safety of Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) in autologous hematopoietic stem cell mobilization of lymphoma. Methods: Lymphoma patients who received autologous hematopoietic stem cell mobilization with Plerixafor in combination with G-CSF or G-CSF alone were obtained. The clinical data, the success rate of stem cell collection, hematopoietic reconstitution, and treatment-related adverse reactions between the two groups were evaluated retrospectively. Results: A total of 184 lymphoma patients were included in this analysis, including 115 cases of diffuse large B-cell lymphoma (62.5%) , 16 cases of classical Hodgkin's lymphoma (8.7%) , 11 cases of follicular non-Hodgkin's lymphoma (6.0%) , 10 cases of angioimmunoblastic T-cell lymphoma (5.4%) , 6 cases of mantle cell lymphoma (3.3%) , and 6 cases of anaplastic large cell lymphoma (3.3%) , 6 cases of NK/T-cell lymphoma (3.3%) , 4 cases of Burkitt's lymphoma (2.2%) , 8 cases of other types of B-cell lymphoma (4.3%) , and 2 cases of other types of T-cell lymphoma (1.1%) ; 31 patients had received radiotherapy (16.8%) . The patients in the two groups were recruited with Plerixafor in combination with G-CSF or G-CSF alone. The baseline clinical characteristics of the two groups were basically similar. The patients in the Plerixafor in combination with the G-CSF mobilization group were older, and the number of recurrences and third-line chemotherapy was higher. 100 patients were mobilized with G-CSF alone. The success rate of the collection was 74.0% for one day and 89.0% for two days. 84 patients in the group of Plerixafor combined with G-CSF were recruited successfully with 85.7% for one day and 97.6% for two days. The success rate of mobilization in the group of Plerixafor combined with G-CSF was substantially higher than that in the group of G-CSF alone (P=0.023) . The median number of CD34(+) cells obtained in the mobilization group of Plerixafor combined with G-CSF was 3.9×10(6)/kg. The median number of CD34(+) cells obtained in the G-CSF Mobilization group alone was 3.2×10(6)/kg. The number of CD34(+) cells collected by Plerixafor combined with G-CSF was considerably higher than that in G-CSF alone (P=0.001) . The prevalent adverse reactions in the group of Plerixafor combined with G-CSF were grade 1-2 gastrointestinal reactions (31.2%) and local skin redness (2.4%) . Conclusion: The success rate of autologous hematopoietic stem cell mobilization in lymphoma patients treated with Plerixafor combined with G-CSF is significantly high. The success rate of collection and the absolute count of CD34(+) stem cells were substantially higher than those in the group treated with G-CSF alone. Even in older patients, second-line collection, recurrence, or multiple chemotherapies, the combined mobilization method also has a high success rate of mobilization.
Humans
;
Granulocyte Colony-Stimulating Factor/therapeutic use*
;
Hematopoietic Stem Cell Mobilization/methods*
;
Hematopoietic Stem Cell Transplantation
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Heterocyclic Compounds/adverse effects*
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Lymphoma/drug therapy*
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Lymphoma, T-Cell/therapy*
;
Multiple Myeloma/drug therapy*
;
Retrospective Studies
;
Transplantation, Autologous
9.Trends of age of menarche among Chinese Han girls aged 9 to 18 years from 2010 to 2019.
Ning MA ; Di SHI ; Shan CAI ; Jia Jia DANG ; Pan Liang ZHONG ; Yun Fei LIU ; Jing LI ; Yan Hui DONG ; Pei Jin HU ; Bin DONG ; Tian Jiao CHEN ; Yi SONG ; Jun MA
Chinese Journal of Preventive Medicine 2023;57():36-41
Objective: To analyze the trends of the age of menarche among Chinese Han girls aged 9 to 18 years from 2010 to 2019. Methods: Data were extracted from the Chinese National Surveys on Students' Constitution and Health in 2010, 2014 and 2019. A total of 253 037 Han girls aged 9 to 18 years with complete data on menarche were selected in this study. They were asked one-on-one about their menstrual status, age and residence information. The median age of menarche was estimated by probability regression. U tests were used to compare the difference in median age at menarche in different years. Results: The median age at menarche (95%CI) among Chinese Han girls was 12.47 (12.09-12.83) years in 2010, 12.17 (11.95-12.38) years in 2014 and 12.05 (10.82-13.08) years in 2019, respectively. Compared with that in 2010, the median age at menarche in 2019 decreased by 0.42 years (U=-77.27, P<0.001). The annual average changes were-0.076 years from 2010 to 2014 (U=-57.19, P<0.001) and-0.023 years from 2014 to 2019 (U=-21.41, P<0.001), respectively. The average annual changes in urban areas in the periods of 2010 to 2014 and 2014 to 2019 were-0.071 years and 0.006 years, respectively, while those in rural areas were-0.082 years and-0.053 years, respectively. The average annual changes in the regions of north, northeast, east, south central, southwest and northwest were-0.064, -0.099, -0.091, -0.080, -0.096 and-0.041 years in the period of 2010 to 2014 and 0.001, -0.040, -0.002, -0.005, -0.043 and-0.081 years in the period of 2014 to 2019. Conclusion: The age of menarche among Chinese Han girls aged 9 to 18 years shows an advanced trend from 2010 to 2019, and the trends in urban and rural areas and different regions have different characteristics.
10.Prevalence trend of malnutrition among Chinese Han children and adolescents aged 7-18 years from 2010 to 2019.
Jie Yu LIU ; Pan Liang ZHONG ; Ning MA ; Di SHI ; Li CHEN ; Yan Hui DONG ; Bin DONG ; Tian Jiao CHEN ; Jing LI ; Yi SONG ; Jun MA ; Pei Jin HU
Chinese Journal of Preventive Medicine 2023;57():27-35
Objective: To analyze the prevalence trend of malnutrition among Chinese Han children and adolescents aged 7-18 years from 2010 to 2019. Methods: Based on the data from the Chinese National Surveys on Students' Constitution and Health in 2010, 2014 and 2019, about 215 102, 214 268 and 212 713 Han students aged 7-18 years were included in this study. According to the National Screening Standard for Malnutrition of School-age Children and Adolescents, the detection rate of malnutrition among Chinese Han children and adolescents aged 7-18 was calculated, and the prevalence trend of malnutrition from 2010 to 2019 was analyzed. Results: In 2019, the detection rate of malnutrition among Chinese Han students aged 7-18 years was 8.64% (18 381/212 713), of which the rate of growth retardation, moderate-to-severe wasting and mild wasting was 0.50% (1 062/212 713), 3.25% (6 914/212 713) and 4.89% (10 405/212 713), respectively. In 2019, the detection rate of malnutrition in these boys was higher than that of girls (9.97% vs. 7.31%), and the detection rate in rural areas was higher than that in cities (9.30% vs. 7.98%). The detection rates were 9.74% (5 252/53 916), 8.17% (4 408/53 937), 7.29% (3 885/53 310), and 9.38% (4 836/51 550) in 7-9, 10-12, 13-15, and 16-18 years groups, and 8.14% (6 563/80 618), 7.61% (4 237/55 694) and 9.92% (7 581/76 401) in the eastern, central, and western regions. Malnutrition among students in China was mainly caused by mild wasting, and the detection rate of growth retardation accounted for only 5.78% (1 062/18 381). Malnutrition was mostly concentrated in the southwest region, and the rate was relatively low in eastern provinces. In three surveys from 2010 to 2019, the detection rate of malnutrition among Han students aged 7-18 in China decreased gradually, and the differences were statistically significant (P<0.05). Among them, the detection rates in western rural areas decreased significantly, as well as the gap between urban and rural areas. Compared with that in 2014, the detection rate of malnutrition in Shandong, Hunan, Qinghai and Hainan provinces in 2019 decreased significantly (P<0.05). Conclusion: In 2019, the malnutrition of Chinese children and adolescents aged 7-18 years is dominated by wasting malnutrition. The detection rate shows a downward trend from 2010 to 2019, with regional differences.


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