BACKGROUND:Hypoxia is strongly associated with the development and progression of osteoarthritic chondrocyte injury,but the specific targets and regulatory mechanisms are unclear. OBJECTIVE:A machine learning approach was used to identify KDEL(Lys-Asp-Glu-Leu)receptor 3(KDELR3)as a characteristic gene for osteoarthritis hypoxia and immune infiltration analysis,to provide new ideas and methods for the treatment of osteoarthritis. METHODS:The osteoarthritis-related datasets were downloaded from the GEO database and the GSEA website to obtain hypoxia-related genes.The osteoarthritis datasets were batch-corrected and immune infiltration analyzed using R language,and osteoarthritis hypoxia genes were extracted for differential analysis.Differentially expressed genes were analyzed for GO function and KEGG signaling pathway.Weighted correlation network analysis(WGCNA)and machine learning were also used to screen osteoarthritis hypoxia signature genes,and in vitro cellular experiments were performed to validate expression and correlate immune infiltration analysis using the datasets and qPCR. RESULTS AND CONCLUSION:(1)8492 osteoarthritis genes were obtained by batch correction and principal component analysis,mainly strongly associated with immune cells such as Macrophages M2 and Mast cells resting;200 hypoxia genes were also obtained,resulting in 41 osteoarthritis hypoxia differentially expressed genes.(2)GO analysis involved mainly biological processes such as response to nutrient levels and glucocorticoids;cellular components such as lysosomal lumen and Golgi lumen;and molecular functions such as 14-3-3 protein binding and DNA-binding transcriptional activator activity.(3)KEGG analysis of osteoarthritis hypoxia differentially expressed genes was associated with signaling pathways such as PI3K-Akt,FoxO,and microRNAs in cancer.(4)The characteristic gene KDELR3 was obtained after using WGCNA analysis and machine learning screening.(5)The gene expression of KDELR3 was found to be higher in the test group than in the control group in the synovium(P=0.014)but lower in the meniscus(P=0.024)after validation by gene microarray.(6)In vitro chondrocyte assay showed that the expression of KDELR3 was higher in cartilage than in the control group(P=0.005),while KDELR3 was closely associated with Macrophages M0(P=0.014)and T cells follicular helper(P=0.014).Using a machine learning approach,we confirmed that KDELR3 can be used as a hypoxic signature gene for osteoarthritis and may intervene in osteoarthritis pathogenesis by improving hypoxia,expecting to provide a new direction for better treatment of osteoarthritis.

BACKGROUND:Ferroptosis is strongly associated with the occurrence and progression of osteoarthritis,but the specific characteristic genes and regulatory mechanisms are not known. OBJECTIVE:To identify osteoarthritis ferroptosis signature genes and immune infiltration analysis using the WGCNA and various machine learning methods. METHODS:The osteoarthritis dataset was downloaded from the GEO database and ferroptosis-related genes were obtained from the FerrDb website.R language was used to batch correct the osteoarthritis dataset,extract osteoarthritis ferroptosis genes and perform differential analysis,analyze differentially expressed genes for GO function and KEGG signaling pathway.WGCNA analysis and machine learning(random forest,LASSO regression,and SVM-RFE analysis)were also used to screen osteoarthritis ferroptosis signature genes.The in vitro cell experiments were performed to divide chondrocytes into normal and osteoarthritis model groups.The dataset and qPCR were used to verify expression and correlate immune infiltration analysis. RESULTS AND CONCLUSION:(1)12 548 osteoarthritis genes were obtained by batch correction and PCA analysis,while 484 ferroptosis genes were obtained,resulting in 24 differentially expressed genes of osteoarthritis ferroptosis.(2)GO analysis mainly involved biological processes such as response to oxidative stress and response to organophosphorus,cellular components such as apical and apical plasma membranes,and molecular functions such as heme binding and tetrapyrrole binding.(3)KEGG analysis exhibited that differentially expressed genes of osteoarthritis ferroptosis were related to signaling pathways such as the interleukin 17 signaling pathway and tumor necrosis factor signaling pathway.(4)After using WGCNA analysis and machine learning screening,we obtained the characteristic gene KLF2.After validation by gene microarray,we found that the gene expression of KLF2 was higher in the test group than in the control group in the meniscus(P=0.000 14).(5)In vitro chondrocyte assay showed that type Ⅱ collagen and KLF2 expression was lower in the osteoarthritis group than in the control group in chondrocytes(P<0.05),while in osteoarthritis ferroptosis,mast cells activated was closely correlated with dendritic cells(r=0.99);KLF2 was closely correlated with natural killer cells(r=-1,P=0.017)and T cells follicular helper(r=-1,P=0.017).(6)The findings indicate that using WGCNA analysis and machine learning methods confirmed that KLF2 can be a characteristic gene for osteoarthritis ferroptosis and may improve osteoarthritis ferroptosis by interfering with KLF2.

Objective:To retrieve, evaluate and summarize the best evidence of exercise reversal intervention in the elderly with cognitive frailty, and to provide evidence for guiding exercise in elderly patients.Methods:This study was a summary of evidence-based nursing evidence. Based on the PIPOST (P: Population; I: Intervention; P: Professional; O: Outcome; S: Setting; T: Type of evidence) mode, the evidence of exercise reversal intervention in the elderly with cognitive frailty in 25 relevant guideline network and association websites, Chinese and foreign language comprehensive databases such as PubMed, CINAHL, Web of Science, Embase, Chinese Biomedical Database, China National Knowledge Internet and others were searched, extracted and integrated. The retrieval time was from January 1, 2013 to February 14, 2022.Results:A total of 22 articles were included, including 3 guidelines, 2 expert consensuses, 1 clinical decision-making, 1 evidence summary, 9 Meta analysis, and 6 randomized controlled trials. Finally, 28 pieces of the best evidence including 7 dimensions were namely formulate principles,overall assessment, exercise mode, exercise intensity, exercise time and frequency, exercise management, health guidance.Conclusions:This study summarized the best evidence of exercise intervention in the elderly with cognitive frailty, which are systematic, comprehensive, rigorous, and reliable. It can provide references for healthcare administrators to dynamically evaluate patients′cognitive frailty status, formulate personalized exercise programs, and standardize exercise guidance for patients, so as to delay or even reverse cognitive frailty.

Objective:To evaluate the trend and hotspots of the research on cognitive frailty in China and abroad through literature visualization analysis.Methods:Literature related to cognitive frailty were retrieved from the databases of CNKI, Wanfang, VIP and Web of Science from January 1, 2013 to August 31, 2022 with"cognitive frailty""cognitive decline"and"cognitive impairment"as retrieval terms. Based on the visualization software CiteSpace and VOSviewer, the network map analysis was conducted on the number of publications, journal distribution, country distribution and cooperation, institution distribution and cooperation and research hotspots.Results:A total of 2 500 literatures were retrieved, including 151 in Chinese and 2 349 in English. The number of publications showed an increasing trend with time. Among Chinese journals, Chin J Mod Nurs published the most literature (10 articles), while BMC Geriatr published the most literature (105 articles) in English journals. The top 5 countries in the number of English literature published were the United States (608 articles), the United Kingdom (295 articles), Italy (271 articles), China (252 articles) and Canada (195 articles). The top 5 institutions in the number of Chinese literature published were Fudan University (12 articles), Capital Medical University (10 articles), Zhengzhou University (7 articles), Central South University (5 articles) and Huazhong University of Science and Technology (5 articles). The National Center For Geriatrics Gerontology in Japan published the most English articles (74 articles). A total of 22 Chinese keywords and 44 English keywords were included. The nodes of the network analysis diagram were closely connected and highly centralized. The Chinese and English keywords“cognitive frailty”“elderly”and“frailty”were all in the core position. The Chinese emergent words were“cognitive frailty”“heart failure”“chronic disease”and“risk prediction”. The English burst terms were“cognitive frailty”“questionnaire”“cohort study”“social isolation”and“prevention”. Conclusions:The research popularity in the field of cognitive frailty is increasing year by year, and the number of articles published in English is higher than those in Chinese. At present, the main research focus is cognitive frailty, the elderly and frailty with great differences between China and abroad.

OBJECTIVES: Major depressive disorder (MDD) patients with anhedonia tend to have a poor prognosis. The underlying imaging basis for anhedonia in MDD remains largely unknown. The relationship between nodal properties and anhedonia in MDD patients need to be further investigated. Herein, this study aims to explore differences of cerebral functional node characteristics in MDD patients with severe anhedonia (MDD-SA) and MDD patients with mild anhedonia (MDD-MA) before and after the antidepressant treatment. METHODS: Ninety participants with current MDD were recruited in this study. 24-Item Hamilton Depression Scale (HAMD-24) and Snaith-Hamilton Pleasure Scale (SHAPS) were used to assess the severity of depression and anhedonia at baseline and the end of 6-months treatment. The MDD patients who scored above the 25th percentile on the SHAPS were assigned to an MDD-SA group (n=19), while those who scored below the 25th percentile were assigned to an MDD-MA group (n=18). All patients in the 2 groups received antidepressant treatment. Functional magnetic resonance imaging (fMRI) images of all the patients were collected at baseline and the end of 6-months treatment. Graph theory was applied to analyze the patients' cerebral functional nodal characteristics, which were measured by efficiency (e_i) and degree (k_i). RESULTS: Repeated measures 2-factor ANCOVA showed significant main effects on group on the e_i and k_i values of left superior frontal gyrus (LSFG) (P=0.003 and P=0.008, respectively), and on the e_i and k_i values of left medial orbital-frontal gyrus (LMOFG) (P=0.004 and P=0.008, respectively). Compared with the MDD-MA group, the significantly higher e_i and k_i values of the LSFG (P=0.015 and P=0.021, respectively), and the significantly higher e_i and k_i values of the LMOFG (P=0.015 and P=0.037, respectively) were observed in the MDD-SA group at baseline. Meanwhile, higher SHAPS scores could result in higher e_i and k_i values of LSFG (P=0.019 and P=0.026, respectively), and higher e_i value of LMOFG (P=0.040) at baseline; higher SHAPS scores could result in higher e_i values of LSFG (P=0.049) at the end of 6-months treatment. The multiple linear regression analysis revealed that sex were negatively correlated with the e_i and k_i values of LSFG (r= -0.014, P=0.004; r=-1.153, P=0.001, respectively). The onset age of MDD was negatively correlated with the k_i value of LSFG (r=-0.420, P=0.034) at the end of 6-months treatment. We also found that SHAPS scores at baseline were positively correlated with the HAMD-24 scores (r=0.387, P=0.022) at the end of 6-months treatment. CONCLUSIONS There are obvious differences in nodal properties between the MDD-SA and the MDD-MA patients, such as the high e_i of LSFG in the MDD-SA patients, which may be associated with the severity of anhedonia. These nodal properties could be potential biomarkers for the prognosis of MDD. The increased e_i and k_i values in the LSFG of MDD-SA patients may underlie a compensatory mechanism or protective mechanism. The mechanism may be an important component of the pathological mechanism of MDD-SA. The poor prognosis in the MDD-SA patients suggests that anhedonia may predict a worse prognosis in MDD patients. Sex and onset age of MDD may affect the nodal properties of LSFG at baseline and the end of 6-months treatment.
Anhedonia ; Antidepressive Agents/therapeutic use* ; Depressive Disorder, Major/drug therapy* ; Humans ; Infant ; Infant, Newborn ; Magnetic Resonance Imaging ; Prefrontal Cortex

Objective:This study aimed to systematically evaluate the efficacy and safety of ivabradine in patients with dilated cardiomyopathy, and to provide evidence-based reference for clinical treatment.Methods:We searched PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wan Fang, VIP databases from inception to 1 September 2021 for randomized controlled trials (RCTs) that compared conventional therapies and ivabradine with conventional therapies in dilated cardiomyopathy patients. Studies meeting the inclusion criteria were included and analyzed. After data extraction and literature quality evaluation, we use the Review Manager 5.4 to perform the meta-analysis and publication bias test.Results:5 studies enrolling 494 patients were included. Compared with conventional therapies (control group), ivabradine and conventional therapies (observation group) significantly reduced resting heart rate [ MD=-7.58, 95% CI(-12.40, -2.76), Z=3.08, P=0.002], left ventricular end diastolic diameter (LVEDD) [ MD=-4.48, 95% CI(-7.33, -1.64), Z=3.09, P=0.002], left ventricular end systolic diameter (LVESD) [ MD=-4.94, 95% CI(-7.29, -2.59), Z=4.12, P<0.001], B-type natriuretic peptide (BNP) [ MD=-212.39, 95% CI(-230.55, -194.23), Z=22.92, P<0.001], New York Heart Association (NYHA) class [ MD=-0.36, 95% CI(-0.44, -0.27), Z=8.46, P<0.001] and Minnesota Questionnaire Score [ MD=-10.43, 95% CI(-15.72, -5.13), Z=3.86, P=0.001]. The left ventricular ejection fraction (LVEF) levels [ MD=1.31, 95% CI(0.64, 1.97), Z=3.85, P=0.001], 6-minute walk test level (6MWT) [ MD=54.83, 95% CI(40.58, 69.08), Z=7.54, P<0.001], systolic blood pressure [ MD=4.72, 95% CI(0.91, 8.54), Z=2.43, P=0.02], the incidence of visual symptoms (phosphene) [ OR=7.22, 95% CI(1.32, 45.00), P=0.02] and symptomatic bradycardia [ OR=8.90, 95% CI(1.21, 65.75), P=0.03] in the observation group were higher than those in the control group after treatment. In addition, there were no significant difference in the incidence of acute event between the two groups [ OR=0.72, 95% CI(0.12, 4.29), P=0.72]. Conclusions:Meta analysis showed that ivabradine combined β receptor blockers can effectively reduce resting heart rate and improve cardiac function in patients with dilated cardiomyopathy, but may increase the incidence of hallucinations and symptomatic bradycardia.

Objective:To explore the value of intravoxel incoherent motion (IVIM) DWI in preoperative prediction of angiolymphatic invasion in esophageal squamous cell carcinoma (ESCC).Methods:From April 2016 to April 2019, 63 ESCC patients who planned to undergo resection of esophageal cancer were prospectively collected at Henan Cancer Hospital.According to the postoperative pathological results, 63 patients were divided into angiolymphatic invasion group (30 cases) and no angiolymphatic invasion group (33 cases). All patients underwent IVIM sequence and routine MRI examination before operation. The ADC, true diffusion coefficient (D), pseudodiffusion coefficient (D *) and pseudodiffusion fraction (f) were measured. The differences of parameter values between ESCC with and without angiolymphatic invasion were analyzed using Student′s t test or Wilcoxon rank sum test.The logistic regression was used to analyze the significance of various parameters. For the parameters with statistical significance, the ROC curves were performed to evaluatethe diagnostic performance of parameters for identifying angiolymphatic invasion.The Z test was used to compare the area under the ROC curves(AUC) of parameters. Results:The difference of ADC, D and f values between angiolymphatic invasion group and no angiolymphatic invasion group were statistically signi?cant ( t=4.476, 5.033 and 5.712 respectively, all P<0.001). The D * values showed no statistically signi?cant di?erence ( Z=0.184, P=0.854). The logistic regression analysis showed that D (OR=9.042) and f (OR=26.221) were in correlation with angiolymphatic invasion. The ROC analyses demonstrated that the AUCs of ADC, D and f values in predicting angiolymphatic invasion of ESCC were 0.787, 0.822 and 0.853, respectively. D combined with f had highest AUC (0.917) in predicting the angiolymphatic invasion of ESCC, sensitivity and specificity were 93.3% and 75.8%. D combined with f showed better diagnostic performance than the D and the f value, and the difference were statistically significant ( Z=2.403, 2.289, P=0.016, 0.022). Conclusions:IVIM can be used as an effective functional imaging modality for preoperative evaluation and prediction of the angiolymphatic invasion of ESCC. D value combined with f value can further improve prediction performance of angiolymphatic invasion.

Under the diagnosis-related groups(DRG) prospective payment system, innovative health technologies with high costs and risks may be limited to some extent. How to balance the increase of health care cost and the development of innovative health technology is a difficult problem to be solved in the current reform. By studying the relatively mature payment systems of innovative health technologies in the world, the authors found that countries generally adopted additional payment or compensation to encourage the development of new technologies. But at the same time, a relatively perfect health technology assessment and payment management mechanism had been established to ensure the standardized operation of payment plan. These international advanced experience and practice could provide references for China′s innovative health technology payment strategy under the DRG payment system. It is suggested to establish a scientific and reasonable assessment mechanism of innovative health technology, create a special access channel for innovative health technology with limited short-term evidence, and gradually form a long-term incentive mechanism of innovative health technology in DRG payment system.

Objective:To evaluate the positive rate of the bronchodilation test (BDT) in asthmatic children with normal forced expiratory volume in 1 second (FEV 1), forced vital capacity (FVC) and FEV 1/FVC, so as to improve the recognition of the importance of the BDT test in asthmatic children with normal FEV 1, FVC and FEV 1/FVC. Methods:Children aged 5-14 who were diagnosed with asthma in the outpatient clinic of Shandong Provincial Hospital Affiliated to Shandong University from September 2018 to August 2019 and willing to receive pulmonary function and BDT examinations were enrolled.Data of pulmonary function of children with normal FEV 1, FVC and FEV 1/FVC were collected to analyze the rate of positive BDT results and the status of small airway function. Results:A total of 1 631 asthmatic children with normal FEV 1, FVC and FEV 1/FVC were enrolled in this study, including 1 414 children with normal pulmonary function and 217 children with small airway dysfunction.Fifteen minutes after the bronchodilator was inhaled, 127 children (87 males and 40 females) showed positive BDT results, accounting for 7.8%.Among these children, 62 cases (28.6%) with co-existing small airway dysfunction showed positive BDT results.The improvement rate of FEV 1 was 8.0% to 11.9% in 132 cases (8.1%). The FEV 1 before bronchodilator inhalation accounted for (98.5±10.3)% of the predicted value.Fifteen minutes after terbutaline sulfate inhalation, the improvement rate was 13.5% (12.5%, 16.2%). The improvement rates of forced expiratory flow at 50% of FVC exhaled (FEF 50, r=-0.339, P<0.01), forced expiratory flow at 75% of forced vital capacity exhaled (FEF 75, r=-0.400, P<0.01), maximum mid-expiratory flow(MMEF, r=-0.375, P<0.01) were negatively correlated with their baseline values.The improvement rate of FEV 1 was not associated with its baseline value ( r=-0.128, P=0.153), but negatively correlated with the baseline value of MMEF ( r=-0.231, P<0.01). Conclusions:BDT results are positive in some asthmatic children with normal FEV 1, FVC and FEV 1/FVC.It is recommended that BDT testing should be conducted as much as possible in the diagnosis and follow-up of children with typical or atypical asthma.In this way, the diagnosis can be confirmed and the current optimal results can be obtained.Meanwhile, small airway function testing is helpful for comprehensive assessment of asthma and its control level.

Objective:To analyze the risk factors of central venous catheter-related thrombosis (CRT) in critically ill patients and develop the model of a nomogram.Methods:A prospective investigation study was conducted on 385 critically ill patients who received central venous catheters during hospitalization in Hengshui People's Hospital from May 2018 to March 2021. Color Doppler ultrasonography was performed daily after catheterization. Patients were divided into thrombosis group and non-thrombosis group according to whether CRT was formed. The patient's gender, age, body mass index (BMI), acute physiology and chronic health evaluationⅡ(APACHEⅡ) score, complications, existing tumor, D-dimer level on the 3rd day after catheterization, maximum velocity of right internal jugular vein on the 3rd day after catheterization, mechanical ventilation time, and catheter indwelling time were recorded, and the differences of above indexes between the two groups were compared. Multivariate Logistic regression was performed on the influencing factors with statistical differences between the two groups to establish the nomogram prediction. The receiver operator characteristic curve (ROC curve) and calibration curve were used to evaluate the predictive power of the model.Results:The incidence of central venous CRT in critically ill patients was 16.1% (62/385). Compared with non-thrombosis patients, the thrombosis group patients had higher APACHEⅡscore, the proportion of existing tumor, and D-dimer level on the 3rd day after catheterization [APACHEⅡscore: 17 (15, 19) vs. 15 (12, 18), the proportion of existing tumor: 51.6% (32/62) vs. 35.3% (114/323), D-dimer (mg/L): 0.84 (0.64, 0.94) vs. 0.57 (0.44, 0.76), all P < 0.05], the maximum flow rate of right internal jugular vein was slower on the 3rd day after catheterization [cm/s: 14 (13, 15) vs. 16 (14, 18), P < 0.05]. Univariate analysis showed that high APACHEⅡscore, critical patients with existing tumor, high D-dimer level on the 3rd day after catheterization, and slow maximum flow rate of right internal jugular vein on the 3rd day after catheterization were more likely to develop central venous CRT. Further multivariate Logistic regression analysis showed that high APACHEⅡscore, existing tumor, high D-dimer level on the 3rd day after catheterization and slow maximum flow rate of right internal jugular vein on the 3rd day after catheterization were independent risk factors for central venous CRT in critical patients [odds ratio ( OR) and 95% confidence interval (95% CI) were 0.876 (0.801-0.957), 0.482 (0.259-0.895), 0.039 (0.011-0.139), 1.401 (1.218-1.611), and P values were 0.003, 0.021, < 0.001, < 0.001, respectively]. According to the results of multivariate analysis, the prediction model of the nomogram was constructed. The area under ROC curve (AUC) was 0.820, 95% CI was 0.767-0.872, P < 0.001. The calibration curve showed that the prediction probability of central venous CRT nomogram model in critically ill patients had good consistency with the actual occurrence probability. Conclusions:Existing tumor, high APACHEⅡscore, elevated D-dimer on the 3rd day after catheterization, and decreased maximum velocity of right internal jugular vein on the 3rd day after catheterization are independent risk factors for central venous CRT in critical patients. The prediction model based on the proposed model has good clinical efficacy.