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.Association between sleep characteristics, physical activity patterns with depressive and anxiety symptoms in college students
Chinese Journal of School Health 2025;46(4):552-557
Objective:
To explore the relationship between sleep characteristics, physical activity patterns, with depressive and anxiety symptoms in college students, so as to provide reference for student mental health promotion.
Methods:
From September to November 2023, a convenience sampling method was used to select 7 954 college students aged 18-22 years from 9 universities in Shanghai, Hubei, and Jiangxi. Assessments were conducted using the International Physical Activity Questionnaire Short-Form (IPAQ-SF), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder Scale-7 (GAD-7), and Pittsburgh Sleep Quality Index (PSQI) to evaluate physical activity, depressive and anxiety symptoms, and sleep quality, respectively. Logistic regression analysis was employed to explore the impact of sleep characteristics and physical activity patterns on depressive and anxiety symptoms and their comorbidity among college students.
Results:
The detection rates for depressive symptoms, anxiety symptoms, and comorbid depression and anxiety symptoms were 25.67%, 35.39%, and 23.15%, respectively. Factors such as gender, grade, household registration, parental education level, annual family income, family structure, and dietary habits were all associated with the detection rates of depressive and anxiety symptoms and their comorbidity (χ2=4.41-118.39, P<0.05). Physical activity patterns, sleep duration, sleep quality, and sleepwake characteristics were also associated with the occurrence of depressive and anxiety symptoms and their comorbidity (χ2=9.66-627.70, P<0.05). Logistic regression analysis showed that college students who stayed up late and slept less than 7 had the highest risk of depressive and anxiety symptoms and their comorbidity (OR=1.93, 1.85, 1.88, P<0.05). Compared to regular physical activity patterns, insufficient physical activity patterns were associated with an increased risk of depressive and anxiety symptoms (all OR=1.18, P<0.05). Further stratified analysis results showed that the risk of depression, anxiety and their comorbidity increased in college students who stayed up late and slept less than 7 h, went to bed before midnight and slept less than 7 h, or went to bed before midnight and slept more than 7 h but did not have sufficient physical activity (P<0.05).
Conclusions
Sleep characteristics and physical activity patterns significantly affect depressive and anxiety symptoms in college students. Universities should strengthen sleep management and implement flexible physical activity interventions to help students establish healthy lifestyles.
3.Cost-effectiveness of angiographic quantitative flow ratio-guided coronary intervention: A multicenter, randomized, sham-controlled trial.
Yanyan ZHAO ; Changdong GUAN ; Yang WANG ; Zening JIN ; Bo YU ; Guosheng FU ; Yundai CHEN ; Lijun GUO ; Xinkai QU ; Yaojun ZHANG ; Kefei DOU ; Yongjian WU ; Weixian YANG ; Shengxian TU ; Javier ESCANED ; William F FEARON ; Shubin QIAO ; David J COHEN ; Harlan M KRUMHOLZ ; Bo XU ; Lei SONG
Chinese Medical Journal 2025;138(10):1186-1193
BACKGROUND:
The FAVOR (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease) III China trial demonstrated that percutaneous coronary intervention (PCI) lesion selection using quantitative flow ratio (QFR) measurement, a novel angiography-based approach for estimating fractional flow reserve, improved two-year clinical outcomes compared with standard angiography guidance. This study aimed to assess the cost-effectiveness of QFR-guided PCI from the perspective of the current Chinese healthcare system.
METHODS:
This study is a pre-specified analysis of the FAVOR III China trial, which included 3825 patients randomized between December 25, 2018, and January 19, 2020, from 26 centers in China. Patients with stable or unstable angina pectoris or those ≥72 hours post-myocardial infarction who had at least one lesion with a diameter stenosis between 50% and 90% in a coronary artery with a ≥2.5 mm reference vessel diameter by visual assessment were randomized to a QFR-guided strategy or an angiography-guided strategy with 1:1 ratio. During the two-year follow-up, data were collected on clinical outcomes, quality-adjusted life-years (QALYs), estimated costs of index procedure hospitalization, outpatient cardiovascular medication use, and rehospitalization due to major adverse cardiac and cerebrovascular events (MACCE). The primary analysis calculated the incremental cost-effectiveness ratio (ICER) as the cost per MACCE avoided. An ICER of ¥10,000/MACCE event avoided was considered economically attractive in China.
RESULTS:
At two years, the QFR-guided group demonstrated a reduced rate of MACCE compared to the angiography-guided group (10.8% vs . 14.7%, P <0.01). Total two-year costs were similar between the groups (¥50,803 ± 21,121 vs . ¥50,685 ± 23,495, P = 0.87). The ICER for the QFR-guided strategy was ¥3055 per MACCE avoided, and the probability of QFR being economically attractive was 64% at a willingness-to-pay threshold of ¥10,000/MACCE avoided. Sensitivity analysis showed that QFR-guided PCI would become cost-saving if the cost of QFR were below ¥3682 (current cost: ¥3800). Cost-utility analysis yielded an ICER of ¥56,163 per QALY gained, with a 53% probability of being cost-effective at a willingness-to-pay threshold of ¥85,000 per QALY gained.
CONCLUSION:
In patients undergoing PCI, a QFR-guided strategy appears economically attractive compared to angiographic guidance from the perspective of the Chinese healthcare system.
TRIAL REGISTRATION
ClinicalTrials.gov , NCT03656848.
Humans
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Cost-Benefit Analysis
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Percutaneous Coronary Intervention/methods*
;
Male
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Female
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Coronary Angiography/methods*
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Middle Aged
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Aged
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Coronary Artery Disease/surgery*
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Quality-Adjusted Life Years
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Fractional Flow Reserve, Myocardial/physiology*
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
;
Dental Cementum/injuries*
;
Consensus
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Diagnosis, Differential
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Cone-Beam Computed Tomography
;
Tooth Fractures/therapy*
5.The Role of APOE in Drug Resistance of Colon Cancer Based on Bioinformatics and Cell Experiments
Ruo SHU ; Huayou LUO ; Lijun SONG ; Yu GAO ; Yan HOU ; Xinfeng ZHANG ; Ying LI
Journal of Kunming Medical University 2025;46(9):15-22
Objective To evaluate the role and potential mechanism of apolipoprotein E(APOE)in drug resistance of colon cancer by bioinformatic tools and cellular experiments.Methods After downloading the microarray dataset GSE196900 from the GEO database,the online tool GEO2R was used to identify genes that were expressed differently in the drug-resistant and control groups.The differently expressed genes were then examined for Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment.The STRING database and Cytoscape software were used to build protein-protein interaction(PPI)networks and find hub genes.Hub genes'predictive significance in colon cancer was further assessed.Western blod and qRT-PCR were used to identify changes in APOE expression,whereas Transwell was used to identify changes in the colon cancer cells'capacity for invasion and migration.Results The analysis of GO and KEGG enrichment revealed that the differential genes derived from the GSE196900 dataset were primarily focused on receptor-ligand activity and cytokine-cytokine receptor interaction pathways.Using the CytoNCA plug-in in Cytoscape software,ten hub genes were obtained through PPI construction.Of these,the prognosis of the patients with colon cancer was negatively correlated with the expression of the APOE gene(P<0.05)and the overexpression of the APOE gene might significantly increase the migration and nvasivenessability of colon cancer cells(P<0.05).Conclusion The increased expression of APOE significantly promotes the migration and invasion ability of colon cancer cells,which may be one of the mechanisms by which APOE gene promotes tumor progression in the patients with colon cancer.
6.Effect of LncRNA OIP5-AS1 on Phenotypic Transformation of IOSE80 in Ovarian Epithelium
Linlin SONG ; Huanran MENG ; Lina ZHOU ; Rui LIU ; Lijun YIN
Chinese Journal of Modern Applied Pharmacy 2024;41(5):649-656
OBJECTIVE
To explore the phenotypic changes and possible mechanisms of lncRNA OIP5-AS1 on the proliferation, migration, apoptosis, invasion and cycle of ovarian epithelial cells IOSE80.
METHODS
The clinical data of patients were collected from TCGA database and GEO database. After R package analysis, the differential expression of OIP5-AS1 was visualized in the volcanic map. The correlation between survival rate and OIP5-AS1 was analyzed by Kaplan-Meier. The IOSE80 cell model of OIP5-AS1 over expression and silencing was constructed with lentivirus vector. The expression of OIP5-AS1 was verified by RT-qPCR. Cell proliferation was detected by CCK-8. Invasion was detected by Transwell. Cell migration was detected by scratch test. Cell cycle and apoptosis were detected by flow cytometry. Western blotting was used to detect the expression of E-cadherin and N-cadherin, as well as the expression of cyclin-dependent kinase(CDK) and cyclin-G-related kinase(GAK).
RESULTS
RT-qPCR results showed that IOSE80 cell lines over expressing and silencing OIP5-AS1 were successfully constructed. CCK-8 results showed that overexpressing OIP5-AS1 promoted the proliferation of IOSE80 cells. Scratch test results showed that overexpressing OIP5-AS1 promoted the migration of IOSE80 cells. Transwell results showed that overexpressing OIP5-AS1 would increase the invasiveness of IOSE80 cells. Flow cytometry results showed that overexpression of OIP5-AS1 weakened the apoptosis of IOSE80 cells and promoted the progress of cell cycle. Western blotting results showed that overexpression of OIP5-AS1 downregulated the expression of E-cadherin and upregulated the expression of N-cadherin, while overexpression of OIP5-AS1 increased the expression of CDK and GAK proteins.
CONCLUSION
LncRNA OIP5-AS1 further interferes with the regulation of IOSE80 cell cycle by up regulating the expression of CDK and GAK, and then indirectly regulates the malignant phenotype of ovarian epithelial cells.
7.Effects of evodiamine on inflammation and apoptosis of airway epithelial cells in asthma model rats and its mechanism
Jun LEI ; Lijun LU ; Lingyan LUO ; Song QIAO ; Yanan TONG ; Yang ZHENG ; Lei YAO
China Pharmacy 2024;35(11):1351-1356
OBJECTIVE To explore the effects and potential mechanism of evodiamine on inflammatory response and apoptosis of epithelial cells in asthma model rats. METHODS SD rats were separated into control group, model group, evodiamine low-dose group (10 mg/kg), evodiamine high-dose group (20 mg/kg), dexamethasone group (positive control, 0.5 mg/kg), epidermal growth factor (EGF) group [mitogen-activated protein kinase (MAPK) activator, 10 μg], evodiamine high-dose+EGF group (20 mg/kg evodiamine+10 μg EGF), with 10 rats in each group. Except for the control group, the other groups were sensitized by 3-point injection of 10% ovalbumin(OVA)-aluminium hydroxide mixture and stimulated by inhalation of 2%OVA nebulized liquid to establish an asthma model. The count of inflammatory cells (macrophages and lymphocytes) in bronchoalveolar lavage fluid (BALF) was detected in each group; pathological changes of lung tissue in rats were observed; the apoptosis of airway epithelial cells, the levels of serum inflammatory factors [tumor necrosis factor-α, interleukin-6 (IL-6) and IL-4], the expressions of pathway-related proteins p38 MAPK, phosphorylated p38 MAPK (p-p38 MAPK), signal transduction and transcription activating factor 1 (STAT1)] and apoptosis-related proteins [B cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax)] were all detected in lung tissue. RESULTS Compared with the control group, bronchial mucosal edema, thickening of alveolar septa and extensive infiltration of inflammatory cells were observed in the lung tissue of rats in the model group; the number of inflammatory cells, apoptosis rate of airway epithelial cells, the levels of inflammatory factors, p-38 MAPK/p-38 MAPK, and the protein expressions of Bax and STAT1 were increased significantly; the expressions of Bcl-2 protein and Bcl-2/Bax were reduced significantly (P<0.05). Compared with the model group, the pathological changes in lung tissues were alleviated to varying degrees in evodiamine low-dose and high-dose groups, and dexamethasone groups, and the above indicators were significantly reversed. However, the change trends of corresponding indicators in the EGF group were opposite to the above (P<0.05). EGF could significantly attenuate the effect of high-dose evodiamine on inflammatory response in asthmatic rats (P<0.05). CONCLUSIONS Evodiamine can relieve inflammatory reactions and inhibit the apoptosis of airway epithelial cells in asthmatic rats, the mechanism of which may be associated with inhibiting p38 MAPK/STAT1 signaling pathway.
8.Effects of evodiamine on inflammation and apoptosis of airway epithelial cells in asthma model rats and its mechanism
Jun LEI ; Lijun LU ; Lingyan LUO ; Song QIAO ; Yanan TONG ; Yang ZHENG ; Lei YAO
China Pharmacy 2024;35(11):1351-1356
OBJECTIVE To explore the effects and potential mechanism of evodiamine on inflammatory response and apoptosis of epithelial cells in asthma model rats. METHODS SD rats were separated into control group, model group, evodiamine low-dose group (10 mg/kg), evodiamine high-dose group (20 mg/kg), dexamethasone group (positive control, 0.5 mg/kg), epidermal growth factor (EGF) group [mitogen-activated protein kinase (MAPK) activator, 10 μg], evodiamine high-dose+EGF group (20 mg/kg evodiamine+10 μg EGF), with 10 rats in each group. Except for the control group, the other groups were sensitized by 3-point injection of 10% ovalbumin(OVA)-aluminium hydroxide mixture and stimulated by inhalation of 2%OVA nebulized liquid to establish an asthma model. The count of inflammatory cells (macrophages and lymphocytes) in bronchoalveolar lavage fluid (BALF) was detected in each group; pathological changes of lung tissue in rats were observed; the apoptosis of airway epithelial cells, the levels of serum inflammatory factors [tumor necrosis factor-α, interleukin-6 (IL-6) and IL-4], the expressions of pathway-related proteins p38 MAPK, phosphorylated p38 MAPK (p-p38 MAPK), signal transduction and transcription activating factor 1 (STAT1)] and apoptosis-related proteins [B cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax)] were all detected in lung tissue. RESULTS Compared with the control group, bronchial mucosal edema, thickening of alveolar septa and extensive infiltration of inflammatory cells were observed in the lung tissue of rats in the model group; the number of inflammatory cells, apoptosis rate of airway epithelial cells, the levels of inflammatory factors, p-38 MAPK/p-38 MAPK, and the protein expressions of Bax and STAT1 were increased significantly; the expressions of Bcl-2 protein and Bcl-2/Bax were reduced significantly (P<0.05). Compared with the model group, the pathological changes in lung tissues were alleviated to varying degrees in evodiamine low-dose and high-dose groups, and dexamethasone groups, and the above indicators were significantly reversed. However, the change trends of corresponding indicators in the EGF group were opposite to the above (P<0.05). EGF could significantly attenuate the effect of high-dose evodiamine on inflammatory response in asthmatic rats (P<0.05). CONCLUSIONS Evodiamine can relieve inflammatory reactions and inhibit the apoptosis of airway epithelial cells in asthmatic rats, the mechanism of which may be associated with inhibiting p38 MAPK/STAT1 signaling pathway.
9.Clinical guidelines for the treatment of ankylosing spondylitis combined with lower cervical fracture in adults (version 2024)
Qingde WANG ; Yuan HE ; Bohua CHEN ; Tongwei CHU ; Jinpeng DU ; Jian DONG ; Haoyu FENG ; Shunwu FAN ; Shiqing FENG ; Yanzheng GAO ; Zhong GUAN ; Hua GUO ; Yong HAI ; Lijun HE ; Dianming JIANG ; Jianyuan JIANG ; Bin LIN ; Bin LIU ; Baoge LIU ; Chunde LI ; Fang LI ; Feng LI ; Guohua LYU ; Li LI ; Qi LIAO ; Weishi LI ; Xiaoguang LIU ; Hongjian LIU ; Yong LIU ; Zhongjun LIU ; Shibao LU ; Yong QIU ; Limin RONG ; Yong SHEN ; Huiyong SHEN ; Jun SHU ; Yueming SONG ; Tiansheng SUN ; Yan WANG ; Zhe WANG ; Zheng WANG ; Hong XIA ; Guoyong YIN ; Jinglong YAN ; Wen YUAN ; Zhaoming YE ; Jie ZHAO ; Jianguo ZHANG ; Yue ZHU ; Yingjie ZHOU ; Zhongmin ZHANG ; Wei MEI ; Dingjun HAO ; Baorong HE
Chinese Journal of Trauma 2024;40(2):97-106
Ankylosing spondylitis (AS) combined with lower cervical fracture is often categorized into unstable fracture, with a high incidence of neurological injury and a high rate of disability and morbidity. As factors such as shoulder occlusion may affect the accuracy of X-ray imaging diagnosis, it is often easily misdiagnosed at the primary diagnosis. Non-operative treatment has complications such as bone nonunion and the possibility of secondary neurological damage, while the timing, access and choice of surgical treatment are still controversial. Currently, there are no clinical practice guidelines for the treatment of AS combined with lower cervical fracture with or without dislocation. To this end, the Spinal Trauma Group of Orthopedics Branch of Chinese Medical Doctor Association organized experts to formulate Clinical guidelines for the treatment of ankylosing spondylitis combined with lower cervical fracture in adults ( version 2024) in accordance with the principles of evidence-based medicine, scientificity and practicality, in which 11 recommendations were put forward in terms of the diagnosis, imaging evaluation, typing and treatment, etc, to provide guidance for the diagnosis and treatment of AS combined with lower cervical fracture.
10.Research progress in technologies for on-site monitoring and evaluation of fatigue during military operations
Mingxiao SONG ; Lijun FAN ; Xuewei CHEN ; Libin MA ; Jiangbei CAO ; Jing WANG
Military Medical Sciences 2024;48(2):143-147
The accumulation of fatigue during military operations may lead to decreased operational efficiency and non-combat attrition,which can impact combat effectiveness.On-site monitoring and evaluation of fatigue during military operations,as an important means to keep track of military operations and bring about quick changes in training,underlie the combat effectiveness of military personnel.Focusing on the on-site monitoring and evaluation methods of fatigue during military operations,this paper reviews the determinants of such fatigue as well as on-site monitoring and comprehensive evaluation methods so as to provide reference for accurate and efficient evaluation of fatigue during military operations and for early warning of such fatigue.


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