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When searching over associations between congenital ear abnormalities, especially microtia and affiliated deformities like cleft lip or palate and congenital heart diseases, some clinical analysis and genetic theories are found. A 10-year-old boy sent to the plastic surgery hospital was puzzled by a congenital anterior auricular fistula with fluid trace for more than 9 years. The preoperative diagnoses were branchial cleft fistula and congenital left ear deformity with postoperation of TOF. By browsing over studies on genetic concerns and clinical performance, it may be attributed to a possible association between microtia, branchial cleft fistula, and tetralogy of Fallot, though whose fundamental mechanisms remain concerned.
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Região Branquial , Microtia Congênita , Tetralogia de Fallot , Humanos , Masculino , Tetralogia de Fallot/cirurgia , Região Branquial/anormalidades , Região Branquial/cirurgia , Criança , Microtia Congênita/cirurgia , Fístula/cirurgia , Fístula/congênito , Doenças Faríngeas , Anormalidades CraniofaciaisRESUMO
Due to rapid expansion in the global economy and industrialization, PM2.5 (particles smaller than 2.5 µm in aerodynamic diameter) pollution has become a key environmental issue. The public health and social development directly affected by high PM2.5 levels. In this paper, ambient PM2.5 concentrations along with meteorological data are forecasted using time series models, including random forest (RF), prophet forecasting model (PFM), and autoregressive integrated moving average (ARIMA) in Anhui province, China. The results indicate that the RF model outperformed the PFM and ARIMA in the prediction of PM2.5 concentrations, with cross-validation coefficients of determination R2, RMSE, and MAE values of 0.83, 10.39 µg/m3, and 6.83 µg/m3, respectively. PFM achieved the average results (R2 = 0.71, RMSE = 13.90 µg/m3, and MAE = 9.05 µg/m3), while the predicted results by ARIMA are comparatively poorer (R2 = 0.64, RMSE = 15.85 µg/m3, and MAE = 10.59 µg/m3) than RF and PFM. These findings reveal that the RF model is the most effective method for predicting PM2.5 and can be applied to other regions for new findings.
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Poluentes Atmosféricos , Poluição do Ar , Monitoramento Ambiental , Material Particulado , Material Particulado/análise , China , Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Poluição do Ar/estatística & dados numéricos , Previsões , Tamanho da Partícula , Modelos TeóricosRESUMO
BACKGROUND: Bone or brain metastases may develop in 20-40% of individuals with late-stage non-small-cell lung cancer (NSCLC), resulting in a median overall survival of only 4-6 months. However, the primary lung cancer tissue's distinctions between bone, brain and intrapulmonary metastases of NSCLC at the single-cell level have not been underexplored. METHODS: We conducted a comprehensive analysis of 14 tissue biopsy samples obtained from treatment-naïve advanced NSCLC patients with bone (n = 4), brain (n = 6) or intrapulmonary (n = 4) metastasis using single-cell sequencing originating from the lungs. Following quality control and the removal of doublets, a total of 80 084 cells were successfully captured. RESULTS: The most significant inter-group differences were observed in the fraction and function of fibroblasts. We identified three distinct cancer-associated fibroblast (CAF) subpopulations: myofibroblastic CAF (myCAF), inflammatory CAF (iCAF) and antigen-presenting CAF (apCAF). Notably, apCAF was prevalent in NSCLC with bone metastasis, while iCAF dominated in NSCLC with brain metastasis. Intercellular signalling network analysis revealed that apCAF may play a role in bone metastasis by activating signalling pathways associated with cancer stemness, such as SPP1-CD44 and SPP1-PTGER4. Conversely, iCAF was found to promote brain metastasis by activating invasion and metastasis-related molecules, such as MET hepatocyte growth factor. Furthermore, the interaction between CAFs and tumour cells influenced T-cell exhaustion and signalling pathways within the tumour microenvironment. CONCLUSIONS: This study unveils the direct interplay between tumour cells and CAFs in NSCLC with bone or brain metastasis and identifies potential therapeutic targets for inhibiting metastasis by disrupting these critical cell-cell interactions.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Encéfalo , Fibroblastos , Microambiente TumoralRESUMO
Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the cellular morphological data in Fig. 1C, the immunofluorescence data shown in Fig. 1E, and certain of the scratchwound assay data shown in Fig. 2A were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had already been published. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 18: 308314, 2018; DOI: 10.3892/mmr.2018.9005].
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BACKGROUND: The visually assessed time difference between the mitral valve and tricuspid valve opening (VMT) score was correlated with the increase of left ventricular filling pressure (LVFP). HYPOTHESIS: We suspected that the VMT score might be a valuable prognostic biomarker for heart failure with mildly reduced ejection fraction (HFmrEF) patients. This study was to evaluate the predictive value of VMT score for 1-year all-cause and cardiovascular disease (CVD)-cause mortality in HFmrEF patients. METHODS: This cohort study enrolled 379 patients aged ≥18 years old with HFmrEF. Univariable and multivariable Cox regression analysis was employed to assess the association between VMT score and all-cause or CVD-cause mortality in HFmrEF patients. Hazards ratio (HR), and 95% confidence interval (CI) were effect sizes. Kaplan-Meier curves showed the survival probability of patients. The area under the curve (AUC) evaluated the prognostic value of the VMT score. RESULTS: The risk of all-cause mortality was increased in HFmrEF patients in the VMT score of 2 (HR = 2.80, 95%CI: 1.04-7.52) and 3 (HR = 4.29, 95%CI: 1.58-11.66). The VMT score of 3 was associated with an increased risk of 1-year CVD-cause mortality in patients with HFmrEF (HR = 7.63, 95%CI: 1.70-34.33). The AUC of VMT score for predicting 1-year all-cause mortality of HFmrEF patients was 0.724, and for predicting 1-year CVD-cause mortality of HFmrEF patients was 0.748. The survival probability of patients with the VMT score < 2 was higher than those with the VMT score of 2 and 3. CONCLUSION: The VMT score might be a reliable prognostic index for 1-year all-cause or CVD-cause mortality of HFmrEF patients.
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Doenças Cardiovasculares , Insuficiência Cardíaca , Humanos , Adolescente , Adulto , Valva Mitral/diagnóstico por imagem , Valva Tricúspide/diagnóstico por imagem , Estudos de Coortes , Prognóstico , Volume Sistólico , Insuficiência Cardíaca/diagnósticoRESUMO
An elderly female melanoma patient who experienced severe liver injury after treatment with pembrolizumab and axitinib,which improved with glucocorticoid therapy.Through medication analysis and adverse reaction scale evaluated,it was considered that severe liver injury was more closely related to the immune checkpoint inhibitor,pembrolizumab.After a comprehensive analysis of the relationship between liver injury and immunotherapy,as well as the benefits and risks of immunotherapy for patients,immunotherapy was rechallenged 40 days after discontinuation of pembrolizumab.Restarting treatment with pembrolizumab after immune-mediated hepatitis poses a risk of recurrence of hepatotoxicity.After reviewing related literature,it had been found that the incidence of severe hepatotoxicity caused by rechallenging treatment was low,and the overall safety was controllable.Pembrolizumab had brought therapeutic benefits to patients,with no further immune-mediated liver injury of 5 cycles medication.This case can provide a reference for rechallenging immunotherapy after immune-mediated hepatitis.
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Objective:By detecting the level changes of CXC chemokine ligand 8(CXCL8)in acute myelogenous leukemia(AML)patients at different disease stages,to analyze its correlation with the clinical condition and prognosis of AML patients,and to explore the effect of CXCL8 in the bone marrow microenvironment on the occurrence and development of AML and the regulatory mech-anism of malignant biological behavior of AML cell lines,to provide novel reference for the basic research and clinical diagnosis and treatment of AML.Methods:Bone marrow specimens from AML patients at different disease stages were collected,and ELISA was used to detect the content of CXCL8;quantitative real-time PCR(qRT-PCR)was used to detect the expression of CXCL8-specific receptor CXCR1/2 in different AML cell lines.U937 cells were selected as the AML disease model,and different concentrations of exogenous rCXCL8 were intervened in U937 cells,and the morphological changes of the cells were observed under the microscope.BM-MSCs from newly diagnosed AML patients were co-cultured with U937 cells,and ELISA was used to detect the difference in the content of CXCL8 in the co-culture system;Annexin V/PI double staining flow cytometry was used to detect the effects of rCXCL8 and anti-CXCL8 on the apoptosis of U937 cells respectively,and Western blot was used to reveal the accompanying molecular protein mechanism.Results:The level of CXCL8 in newly diagnosed and relapsed AML patients was significantly higher than that in healthy people(P<0.05),the level of CXCL8 in relapsed stage of AML was significantly higher than that in other disease stages of AML(P<0.01),and the level of CXCL8 in AML patients with CR stage and no infection was significantly higher than that in healthy people(P>0.05).The content of CXCL8 in the co-culture system of BM-MSC and U937 cells and the level of CXCL8 mRNA in U937 cells in the co-culture system were significantly higher than those in the monoculture group without BM-MSC(P<0.05).Intervention of rCXCL8 in U937 cells could promote cell proliferation by up-regulating Bcl-2 expression and down-regulating Bax expression,and up-regulate the expression of CXCL8-specific receptors CXCR1/2.After antagonizing CXCL8(anti-CXCL8),it will induce U937 cell apoptosis by up-regulating of Bax expression and down-regulating of Bcl-2 expression while inhibiting the activation level of ERK1/2 signaling pathway.Conclusion:CXCL8 is closely related to the disease and prognosis of AML,and is an effective monitoring indicator for disease pro-gression and prognosis evaluation of AML patients.CXCL8 in the bone marrow microenvironment is an important chemokine for malig-nant proliferation and immune escape of leukemia cells.By antagonizing CXCL8,U937 cells can be induced to undergo apoptosis,whose mechanism may be related to the expression changes of Bcl-2 family proteins and the inhibition of ERK1/2 signaling pathway activation.
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Objective To evaluate the equity of health human resources allocation in traditional Chinese(TCM)hospitals from 2012 to 2021,and forecast the number of various health technicians,so as to provide theoretical basis for the reasonable allocation of health human resources of TCM health service.Methods The data of health personnel in TCM hospitals were collected,and Theil index and clustering degree were used to analyze the equity of health human resource allocation.The grey GM(1,1)model was used to predict the demand of health personnel in TCM hospitals.Results From 2012 to 2021,the health human resources of TCM hospitals in China showed an overall growth trend.According to the analysis of Theil index in each region,the contribution rate of Theil index showed that the difference between regions was the main factor causing the difference in personnel allocation.The concentration degree of TCM hospitals in terms of geographical allocation was eastern region,central region and western region,respectively.Conclusion The expansion of high-quality medical resources and the rational allocation of TCM resources should be promoted.Clear target responsibility,promote fine management,improve the fairness of medical personnel allocation;Based on traditional advantages,broaden training ideas,and effectively build a multi-dimensional training system for TCM talents.
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@#Introduction: University students’ perspectives on mental health issues remain scarce despite the growing prevalence of mental illness among this population. Therefore, this study aimed to explore university students’ perceptions and beliefs about mental health and mental illness. Methods: Virtual in-depth interviews were conducted from December 2021 to March 2022. All interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis. Results: Sixteen informants from a Malaysian university were interviewed. Four major themes emerged: (1) understanding of mental health and mental illness; (2) perceived causes of mental illness; (3) attitudes towards mental illness; (4) strategies to maintain good mental health. Most informants related mental health to an individual’s thoughts, emotions and behaviours, while a minority equated ‘mental health’ with ‘mental illness’. The majority of informants cited socio-environmental factors as the primary cause of mental illness. Unexpectedly, informants did not view religious factors as a cause of mental illness, although it was thought to be deeply rooted in the older generation. Nearly all informants expressed positive attitudes and willingness to help people with mental illness. However, some informants decided to cover up their mental health problems to avoid the likelihood of experiencing negative emotions. Most informants believed that living a fulfilling and balanced life, staying optimistic and being religious could help them to maintain good mental health. Conclusion: To mitigate the deterioration of students’ mental health, it is necessary to understand their perceptions and beliefs about mental health and mental illness as these may influence their help-seeking behaviours. The study findings showed that university students have a basic understanding of mental health and mental illness and most of them are supportive in handling people with mental illness.
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In the general population, physical activity has been associated with a lower risk of several cancers; however, the evidence for ovarian cancer is not clear. It is suggested that early-life physical activity may differentially impact risk. Whether this is true among women at high risk due to a pathogenic variant (mutation) in the BRCA1 or BRCA2 genes has not been evaluated. Thus, we performed a matched case-control study to evaluate the association between adolescent and early-adulthood physical activity and ovarian cancer. BRCA mutation carriers who completed a research questionnaire on various exposures and incident disease and with data available on physical activity were eligible for inclusion. Self-reported activity at ages 12-13, 14-17, 18-22, 23-29, and 30-34 was used to calculate the average metabolic equivalent of task (MET)-hours/week for moderate, vigorous, and total physical activity during adolescence (ages 12-17) and early-adulthood (ages 18-34). Conditional logistic regression was used to estimate the OR and 95% confidence intervals (CI) of invasive ovarian cancer associated with physical activity. This study included 215 matched pairs (mean age = 57.3). There was no association between total physical activity during adolescence (ORhigh vs. low = 0.91; 95% CI: 0.61-1.36; Ptrend = 0.85), early-adulthood (ORhigh vs. low = 0.78; 95% CI: 0.51-1.20; Ptrend = 0.38) and overall (ORhigh vs. low = 0.81; 95% CI: 0.54-1.23; Ptrend = 0.56) and ovarian cancer. Findings were similar for moderate (Ptrend ≥ 0.25) and vigorous (Ptrend ≥ 0.57) activity. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, physical activity should continue to be encouraged to promote overall health. SIGNIFICANCE: In this matched case-control study, we observed no association between physical activity during adolescence or early-adulthood and subsequent risk of ovarian cancer. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, being active remains important to promote overall health and well-being.
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Neoplasias Ovarianas , Adolescente , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Estudos de Casos e Controles , Neoplasias Ovarianas/epidemiologia , Genes BRCA2 , Mutação , Exercício Físico , Proteína BRCA1/genética , Proteína BRCA2/genéticaRESUMO
PURPOSE: ASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study. METHODS: Adults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0-2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety. RESULTS: A total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53-0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1-12.5) and 13.9 months (95% CI 13.1-15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively. CONCLUSION: Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified. CLINICAL TRIAL NUMBER: NCT02474355.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , População do Leste Asiático , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
OBJECTIVE: To clarify the potential mechanism of Banxia Xiexin Decoction (BXD) on colorectal cancer (CRC) from the perspective of metabolomics. METHODS: Forty male C57BL/6 mice were randomly divided into normal control (NC), azoxymethane/dextran sulfate sodium (AOM/DSS) model, low-dose BXD (L-BXD), high-dose BXD (H-BXD) and mesalamine (MS) groups according to a random number table, 8 mice in each group. Colorectal cancer model was induced by AOM/DSS. BXD was administered daily at doses of 3.915 (L-BXD) and 15.66 g/kg (H-BXD) by gavage for consecutive 21 days, and 100 mg/kg MS was used as positive control. Following the entire modeling cycle, colon length of mice was measured and quantity of colorectal tumors were counted. The spleen and thymus index were determined by calculating the spleen/thymus weight to body weight. Inflammatory cytokine and changes of serum metabolites were analyzed by enzyme-linked immunosorbent assay kits and ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS), respectively. RESULTS: Notably, BXD supplementation protected against weight loss, mitigated tumor formation, and diminished histologic damage in mice treated with AOM/DSS (P<0.05 or P<0.01). Moreover, BXD suppressed expression of serum inflammatory enzymes, and improved the spleen and thymus index (P<0.05). Compared with the normal group, 102 kinds of differential metabolites were screened in the AOM/DSS group, including 48 potential biomarkers, involving 18 main metabolic pathways. Totally 18 potential biomarkers related to CRC were identified, and the anti-CRC mechanism of BXD was closely related to D-glutamine and D-glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arginine biosynthesis, nitrogen metabolism and so on. CONCLUSION: BXD exerts partial protective effects on AOM/DSS-induced CRC by reducing inflammation, protecting organism immunity ability, and regulating amino acid metabolism.
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Five coal samples were prepared by deashing Shengli lignite in distinct phases, which consisted of residual ash from spontaneous combustion. The effects of removal and introduction of inherent minerals on the water reabsorption performance of coal samples were systematically investigated in three aspects: pore structure, oxygen-containing functional groups, and lignite materials. Low-field nuclear magnetic resonance spectroscopy was employed to investigate the changes in the water molecular adsorption tendency of coal samples with the variation in the mineral content. The study elucidates that the hygroscopic performance of the coal samples is significantly reduced due to the massive removal of inherent minerals. However, the pore structure of the coal samples after HCl/HF washing becomes more developed, and the oxygen-containing functional groups on the surface are more exposed, leading to an increase in the equilibrium adsorbed moisture content (EMC) of the coal samples. The binding force between coal samples and water molecules is reduced by the removal of the inherent minerals, which weakens the interaction forces between lignite and water molecules. The oxygen-containing functional groups on the surface of lignite interact with the residual ash from spontaneous combustion to enhance the binding force between lignite and surface water molecules, thus leading to the improved tendency of lignite to adsorb water molecules. The formation of intermediate complexes between minerals and oxygen-containing functional groups, in particular, carboxyl functional groups, on the surface of lignite enhances the acting force of polar sites, which improves the interaction of lignite-water molecules.
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Objective:To investigate the status of disaster preparedness of pediatric nurses and its influencing factors, as well as the impact path of psychological capital and perceived organizational support on disaster preparedness.Methods:This was a cross-sectional study. A total of 361 pediatric nurses from Henan Provincial People ′s Hospital, the Third Affiliated Hospital of Zhengzhou University, Fuwai Central China Cardiovascular Hospital were sampled from August to October 2021. They were investigated by the general information questionnaire, psychological capital questionnaire, perceived organizational support questionnaire and disaster preparedness questionnaire. SPSS25.0 was used to analyze the questionnaire and scale data, and AMOS23.0 was used to construct a structural equation model about the disaster preparedness of pediatric nurses. Results:The scores of disaster preparedness from pediatric nurses was 4.65 ± 0.92. The level of disaster preparedness was significantly positively correlated with psychological capital and perceived organizational support ( r=0.690, 0.525, both P<0.05). Disaster training and emergency drill 2 dimensions of psychological capital questionnaire (hope, resilience), perceived organizational support were independent contributing factors ( P<0.05). Psychological capital had direct effect on disaster preparedness. And the direct effect was 0.77, the indirect effect was 0.11, the total effect was 0.88, and the direct effect of perceived organizational support on disaster preparedness was 0.21. Conclusions:The score of disaster preparedness of pediatric nurses was in the middle level. Hospital managers should strengthen the training of pediatric nurses in disaster knowledge, operational and simulation exercise, pay attention to the level of nurses' psychological capital and perceived organizational support, so as to provide reference for the follow-up clinical pediatric disaster nursing education and management.
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Objective:To summarize the management experience of helicopter medical transport in patients with critical heart disease, so as to provide reference for transport of patients with critical heart disease under the background of major natural disasters.Methods:The clinical and transport data of 36 critically ill cardiac patients in Fuwai Central China Cardiovascular Hospital from 16:30 on July 21 to 19:30 on July 22, 2021 due to historically rare heavy rainstorms were collected. All 36 critically ill cardiac patients were transported by helicopter. The safe transportation was implemented under the measures of quickly forming a transport leadership and coordination group, clarifying responsibilities and division of labor, doing a good job in the pretreatment of the patient's condition, pipeline assessment and mechanical circulation support (MCS) equipment, simulating and practicing the transfer process, improving the safety of the transfer implementation process, and effectively handing over with the target hospital. The gender, age, disease type, MCS, transport and outcome of patients were collected.Results:Thirty-six patients with cardiac critical illness were from adult extracardiac intensive care unit (ICU), adult cardiac care unit (CCU), children's CCU, comprehensive ICU and department of neurology. There were 24 males and 12 females; age (50.93±20.86) years old. There were 12 patients using respirator, 7 patients needing MCS, 2 of whom needed both extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pump (IABP), and 7 patients with post-cardiac surgery. The total distance of transportation of 36 patients was 1 638.4 km, the transit time was 10.5 hours, one way flight time of helicopter was about 8 minutes, and the average transport time per patient was about 17.5 minutes. The vital signs of 36 patients during transport were basically stable, without complications, and all of them reached the target hospital safely.Conclusion:Under the seamless connection of the rapid establishment of the transfer leadership coordination group, assessment of the patient's condition and pretreatment, the simulation of the transfer process, and the effective handover with the receiving hospital, the use of helicopter for medical transport for critically ill heart patients is feasible and safe, which can buy valuable time for saving patients' lives and further treatment.
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Aim To explore the effects of putative receptor protein related to ATI (APJ) homodimer on the behaviors-the proliferation, migration and tube formation of human umbilical vein endothelial cells (HU-VECs). Methods HUVECs at logarithmic growth stage were randomly divided into PBS, Apelin-13 + TM1 (APJ monomer group) and Apelin-13 + PBS group (APJ homodimer group). Western blot and Matrix-Assisted Laser Desorption/Ionization Time of Fligh Mass Spectrometry (MALDI-TOF MS) were used to detect the expression of APJ and APJ homodimer in HUVECs, respectively. Real-Time Cell Analyzers (RT-CA) was used to detect the concentration of the maximum effect of Apelin-13. Cell viability was detected by CCK-8. The cell migration ability was detected by scratch test, and the number of tubes formed on matri-gel that made artificial basement membrane was counted. Results Western blot and MALDI-TOF MS showed that APJ and APJ homodimer were expressed in HUVECs. The EC50 of Apelin-13 was 2.26 x 10
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The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.
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Animais , Camundongos , Antivirais/farmacologia , COVID-19 , Vírus da Hepatite B , Interferon Tipo I/metabolismo , SARS-CoV-2/efeitos dos fármacos , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/antagonistas & inibidoresRESUMO
AIM: To investigate the safety and efficacy of intense pulsed light in the treatment of severe chronic ocular graft-versus-host disease.METHODS: Prospective randomized controlled study. A total of 35 cases(35 eyes), who had a history of allogenic hematopoietic stem cell transplantation(allo-HSCT), admitted to the Affiliated Hospital of Xuzhou Medical University from January to September 2022 and were diagnosed by our hospital's hematology and ophthalmology departments with severe chronic ocular graft-versus-host disease(coGVHD)were selected. One eye was randomly selected for inclusion in the study if both eyes met the enrollment criteria, and the eye was selected if a single eye met the enrollment criteria. All patients were administrated with Dextran and Hypromellose eye drops 4 times a day and Cyclosporine eye drops twice a day. The experimental group was additionally treated with intense pulsed light, once every two weeks a week, for 4 times in total. The evaluation indicators were evaluated before treatment and 2wk, 1 and 2mo after treatment. The evaluation indicators include ocular surface disease index(OSDI)score, best corrected visual acuity(BCVA), intraocular pressure(IOP), tear meniscus height(TMH), non-invasive break-up time(NIBUT), conjunctival injection score(CIS), meibomian gland area proportion(MGAP), meibomian gland evaluation(MGE), cornea fluorescein staining(CFS), conjunctival lissamine green staining(CLGS), lid margin abnormality score(LMAS), and Schirmer's Ⅰ test(SⅠt).RESULTS: After treatment, OSDI score, TMH, NIBUT, BCVA, CFS, CLGS, and CIS improved in both groups compared with those before treatment(all P<0.05), with NIBUT, CFS and CLGS showing more significant improvements in the test group. In the control group, MGAP, MGE of the upper and lower eyelids and LMAS did not change significantly before and after treatment(P>0.05), while in the experimental group, MGAP of the lower eyelids, MGE of upper and lower eyelids and LMAS improved compared with those before treatment(P<0.05), except for MGAP of the upper eyelids, which did not differ from that before treatment(P>0.05). There was no difference in SⅠt and IOP between the two groups before and after treatment(P>0.05). Patients did not experience adverse reactions such as skin burns, redness and swelling in the treated area and eyelash loss during the follow-up period.CONCLUSION: Intense pulsed light is safe and effective in the treatment of severe coGVHD, which can significantly improve the symptoms and signs of patients and enhance the stability of tear film.
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AIM: To detect the expression of interleukin(IL)-36(α, β, γ)in tears of patients undergoing allogeneic hematopoietic stem cell transplantation(allo-HSCT), investigate its correlation with ocular surface microenvironment, and further analyze the relationship between its expression and ocular graft-versus-host disease(oGVHD).METHODS: Prospective study. A total of 35 patients(70 eyes)underwent allo-HSCT in the hematology department of our hospital in January 2020 were selected, and 35 healthy volunteers(70 eyes)with appropriate age and gender were selected as normal control group. The patients in the allo-HSCT group were followed up 3 times after operation once every 3mo. The subjects with postoperative ocular symptoms were divided into oGVHD and Non-oGVHD group.Ocular surface disease index(OSDI)questionnaire, Schirmer test, tear break-up time(TBUT), corneal fluorescein staining(FL), and conjunctival impression cytology(CIC)was conducted in three groups. Furthermore, the expression levels of IL-36(α,β,γ)in tears were detected by ELISA.RESULTS: In the normal control group, IL-36(α, β, γ)expression levels were 74.32±5.27, 70.02±8.43, 97.41±8.66 pg/mL, respectively; in the allo-HSCT group, IL-36(α, β, γ)baseline expression levels were 77.27±7.03, 74.53±7.53, 100.77±9.74 pg/mL, with no statistically significant differences between the two groups(t=1.648, 1.954, 1.262, all P>0.05). There were no significant differences in IL-36α, IL-36β and IL-36γ in Non-oGVHD group at different time points(P>0.05), while there were significant differences in IL-36α, IL-36β and IL-36γ in oGVHD group at different time points(P<0.05). Compared with Non-oGVHD group, the levels of IL-36α and IL-36β at different time points were significantly increased in oGVHD group(all P<0.05).IL-36(α, β, γ)of oGVHD group was positively correlated with OSDI score, FL and CIC, while it was negatively correlated with TBUT and Schirmer test(all P<0.05).CONCLUSION: Evaluation of levels of tear IL-36(α, β, γ)can be of significance in diagnosing oGVHD after allo-HSCT. IL-36(α, β, γ)is highly expressed in the tears of oGVHD patients before the onset of ocular symptoms, and it is correlated with the ocular surface parameters.
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AIM: To study the effects of long-term use of clozapine on tear film stability and ocular surface tissue structure.METHODS: Case-control study was conducted on 45 patients(group 1)who were diagnosed with schizophrenia and treated with clozapine for 3.45±0.72a between March 2021 and December 2021. Another 45 healthy subjects(group 2)served as controls, whose demographic characteristics were similar to those of group 1. Patients' dry eye symptoms were investigated using OSDI questionnaire, tear secretion was detected by the Schirmer I test, ocular surface damage was assessed by the ocular surface staining score, and comprehensive ophthalmic examination was performed on all patients through LipiView ocular surface interferometer, ocular surface integrated analyzer, corneal confocal microscope and slit lamp photographic system.RESULTS: Slit-lamp photography showed diffuse grayish-white spot-like opacification in the corneal stroma of group 1, accompanied by brown star-like opacification in the center of the anterior capsule of the lens. OSDI scores were 38.00(31.50, 48.50)and 15.00(9.00, 19.50)in the two groups respectively. Schirmer test showed that the group 1 was 5.27±2.18mm/5min, while group 2 was 15.62±3.05mm/5min. Corneal fluorescein staining score: 4.00(2.50, 5.00)for group 1 and 1.00(0.00, 1.50)for group 2. The lissamine green staining score for the conjunctiva was 9.00(6.50, 10.00)and 3.00(2.00, 3.50)for the two groups, respectively. LipiView detected lipid layer thickness(LLT), suggesting that the results of group 1 and group 2 were similar, respectively 75.91±15.51 and 77.24±12.11nm; and the results were similar for the lid gland deficiency score, with 1.37±0.26 and 1.29±0.31 points, respectively. The mean tear meniscus height in group 1 was 0.13±0.06mm, which was lower than 0.23±0.04mm of group 2. Non-invasive breakup time(NIBUT)was 6.04±2.62 and 11.4±2.74s in group 1 and group 2 respectively. OSDI score, Schirmer Ⅰ test, ocular surface staining score, tear meniscus height and NIBUT were significantly different between the two groups(P<0.05). Confocal corneal microscopy suggested decreased corneal nerve fiber density with stromal layer inflammatory cell infiltration and pigmentation in group 1.CONCLUSION: The antipsychotic drug clozapine can induce dry eye with a range of ocular surface injuries such as corneal pigmentation, and patients who taking such drugs should be routinely examined by an ophthalmologist.