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The blood-brain barrier is known to consist of a variety of cells and complex inter-cellular junctions that protect the vulnerable brain from neurotoxic compounds; however, it also complicates the pharmacological treatment of central nervous system disorders as most drugs are unable to penetrate the blood-brain barrier on the basis of their own structural properties. This dramatically diminished the therapeutic effect of the drug and compromised its biosafety. In response, a number of drugs are often delivered to brain lesions in invasive ways that bypass the obstruction of the blood-brain barrier, such as subdural administration, intrathecal administration, and convection-enhanced delivery. Nevertheless, these intrusive strategies introduce the risk of brain injury, limiting their clinical application. In recent years, the intensive development of nanomaterials science and the interdisciplinary convergence of medical engineering have brought light to the penetration of the blood-brain barrier for brain-targeted drugs. In this paper, we extensively discuss the limitations of the blood-brain barrier on drug delivery and non-invasive brain-targeted strategies such as nanomedicine and blood-brain barrier disruption. In the meantime, we analyze their strengths and limitations and provide outlooks on the further development of brain-targeted drug delivery systems.

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OBJECTIVES: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by a defect in the production, secretion or action of gonadotropin-releasing hormone. The absence of puberty and varying degrees of gonadotropic deficiency are common symptoms of this disorder. Heterogeneity exists in the clinical presentation of the different clinical subtypes and multiple genes have been implicated in CHH. A number of genetic defects have been identified as causes normosmic CHH, including mutations of GnRHR, GNRH1, KISS1R, KISS1, TACR3 and TAC3. Loss-of-function mutations in KISS1R gene are a rare cause of normosmic CHH. CASE PRESENTATION: We described an 11.5 years old Chinese patient who presented at birth with micropenis, microorchidia and bilateral cryptorchidism. Whole-exome sequencing was also performed and identified a homozygous mutation of KISS1R gene, c.1010_1028del (p.V337Afs*82). The variant was predicted as "deleterious" and classified as "likely pathogenic". This variant has never been reported in patients with CHH. Furthermore, we summarized the clinical presentations and analyzed the phenotype-genotype correlation between CHH and KISS1R mutations in previous reports. CONCLUSIONS: This study details the clinical phenotypes and hormone levels of the patient and expands the spectrum of mutations in the KISS1R gene associated with CHH.

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Background: Rosacea has a high incidence, significantly impacts quality of life, and lacks sufficient diagnostic techniques. This study aimed to investigate the feasibility of laser speckle contrast imaging (LSCI) for measuring facial blood perfusion in patients with rosacea and to identify differences in blood flow among various facial regions associated with different rosacea subtypes. Methods: From June to December 2023, 45 patients were recruited, with 9 excluded, leaving 36 subjects: 12 with erythematotelangiectatic rosacea (ETR), 12 with papulopustular rosacea (PPR), and 12 healthy controls. The Think View multispectral imaging analyzer assessed inflammation via gray reading values across the full face and five facial areas: forehead, nose, cheeks, and chin. LSCI measured and analyzed blood perfusion in the same areas. Plasma biomarkers interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) were tested in different groups. Results: Both ETR and PPR groups showed increased average blood perfusion and facial inflammation intensity by gray values compared to controls, with statistically significant differences. Average blood perfusion of ETR and PPR groups showed increased values in the forehead, cheeks, and nose, compared to controls, and the values in the cheeks were statistically different between ETR and PPR. The facial inflammation intensity of the ETR group showed increased values in the forehead and cheeks, and the PPR group showed increased gray values in the forehead, cheeks, nose, and chin compared to controls, and the values for the cheeks, nose, and chin were statistically significantly different between ETR and PPR. Plasma biomarkers IL-6, IL-1ß, and TNF-α were significantly elevated in both ETR and PPR groups compared to controls. Conclusion: LSCI is a valuable, non-invasive tool for assessing blood flow dynamics in rosacea, providing a data foundation for clinical research. Different rosacea subtypes exhibit distinct lesion distribution and blood flow patterns, and both ETR and PPR could affect all facial areas, particularly the cheeks in ETR and the forehead, nose, and chin in PPR.

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Face , Imagem de Contraste de Manchas a Laser , Rosácea , Humanos , Rosácea/diagnóstico , Rosácea/sangue , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Face/irrigação sanguínea , Fluxo Sanguíneo Regional , Biomarcadores/sangue

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Introduction. Cytotoxin-associated gene A (CagA) from Helicobacter pylori is highly related to chronic gastritis. Tyrosine phosphorylation of Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs from CagA determines the pathogenicity of H. pylori.Gap statement. The precise amino acid variations surrounding the EPIYA motifs and their correlation with clinical outcomes have been poorly explored.Aim. The purpose of this study was to examine the CagA 3' region polymorphism of H. pylori and its association with chronic gastritis in the Chinese population.Method. A total of 86 cagA-positive H. pylori strains were isolated from patients with chronic gastritis in two different hospitals in Beijing, PR China. Genomic DNA was extracted commercial kits, and the cagA 3' variable region of H. pylori was amplified by polymerase chain reaction (PCR). The PCR products were sequenced and analysed using the CLC Sequence Viewer, BioEdit, and WebLogo 3.Results. Two hundred and fifty-nine EPIYA motifs were identified from cagA-positive H. pylori strains. Notably, EPIYA-B exhibited a higher frequency of variation in comparison to EPIYA-A, EPIYA-C, and EPIYA-D. The prevalent sequences for East-Asian-type CagA were QVNK and TIDF, while KVNK and TIDD were most commonly observed for Western-type CagA. The CRPIA motifs of East-Asian-type CagA and Western-type CagA varied at positions 4, 6, 7, 8, and 10. CagA-ABD (73.2%) was the most prevalent type, followed by CagA-ABC (18.6%) and CagA-AB (3.4%). The ratio of CagA-ABD was observed to be higher in cases of chronic non-atrophic gastritis with erosive (NAGE) or chronic atrophic gastritis (AG) compared to chronic non-atrophic gastritis (NAG), and the difference was found to be statistically significant (χ2=59.000/64.000, P<0.001).Conclusions. The EPIYA segments of Western-type CagA and East-Asian-type CagA differ significantly and the presence of CagA-ABD may be associated with severe chronic gastritis from this study.

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Antígenos de Bactérias , Proteínas de Bactérias , Gastrite , Infecções por Helicobacter , Helicobacter pylori , Polimorfismo Genético , Humanos , Antígenos de Bactérias/genética , Helicobacter pylori/genética , Helicobacter pylori/isolamento & purificação , Helicobacter pylori/patogenicidade , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Gastrite/microbiologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/epidemiologia , Masculino , Feminino , China/epidemiologia , Doença Crônica , Pessoa de Meia-Idade , Adulto , Idoso , Povo Asiático/genética , Motivos de Aminoácidos , População do Leste Asiático

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Peroxymonosulfate (PMS) based on heterogeneous catalytic reaction was a promising advanced oxidation process (AOP) to remove refractory contaminants. However, the contaminant degradation efficiency was challenged by the limited number of catalytic active site and low capacity for durable electron transfer. In this study, cobalt-doped manganese-iron oxides (CoxMn1-xFe2O4) rich in oxygen vacancy (Ov) were synthesized using a microwaved hydrothermal method and applied to activate PMS for bisphenol A (BPA) degradation, which achieved the complete removal of BPA within 30 min. In all samples, Co0.5Mn0.5Fe2O4 exhibited good catalytic activity for PMS, which was approximately 21.10 times higher than that of MnFe2O4. The results of density functional theory calculations and in-situ characterization demonstrated that the enhanced performance was ascribed to the generation of Ov and the enrichment of active site, which significantly accelerated the cycling of redox pairs and improved the PMS adsorption, which was more favorable to the formation of active specie in the electron transport process. The oxidation process involved both free radical and non-radical mechanisms, with main reactive species of O2-, and 1O2 being responsible for BPA degradation. In addition, the effects of different aqueous matrices, the results of reusability experiments, and ecotoxicity assessment experiments demonstrated the viability of the Co0.5Mn0.5Fe2O4/PMS system for real sewage purification. This research revealed a structural regulation method to enhance the catalytic activity of the material and offered new perspectives on the engineering of rich Ov.

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Background: The clinical applications of endoscope-assisted transoral release for irreducible atlantoaxial dislocations are limited. This study aimed to investigate the clinical effect and prognostic factors of traditional and endoscope-assisted transoral release, as well as posterior reduction and fixation, in treating irreducible atlantoaxial dislocations. Materials and methods: We conducted a retrospective study on 59 patients with irreducible atlantoaxial dislocation who underwent either traditional or endoscope-assisted transoral release, posterior fixation, and fusion between January 2018 and January 2023. Various data, including surgical time, blood loss, drainage volume, oral intake, hospital stay, complications, and neurological status (assessed by the Japanese Orthopedic Association [JOA] score and Oswestry Disability Index [ODI]), were recorded. Imaging parameters such as the atlantodontoid interval (ADI), space available for the cord (SAC), and cervicomedullary angle (CMA) were analyzed and compared. In addition, the correlation between ODI, JOA and patient age, course of disease, preoperative ADI, SAC and CMA were analyzed. Results: No significant differences were observed in age, sex, BMI, preoperative ADI, preoperative SAC, or preoperative CMA. All patients achieved excellent reduction with no significant differences between the two groups. Patients in the endoscopic group experienced significantly reduced blood loss, earlier oral intake, and shorter hospital stays compared to those in the open group (P < 0.05). The ODI and JOA scores improved significantly in both groups at 1, 6, 12, 18, and 24 months postoperatively (P < 0.05). Postoperative ADI, SAC, and CMA values in both groups were significantly better than preoperative values (P < 0.001). The patient age, course of disease and the preoperative ADI were negatively correlated with the postoperative ODI and the JOA improvement ratio (P < 0.01), and the preoperative SAC and preoperative CMA had positive correlations with the postoperative ODI and the JOA improvement ratio (P < 0.01) at 6, 12 and 24 months postoperatively. Conclusion: Patient age, course of disease, preoperative ADI, SAC and CMA are correlated with the operative prognosis of irreducible atlantoaxial dislocation. The endoscope-assisted transoral approach, compared to the traditional transoral approach, is minimally invasive, resulting in less operative blood loss, earlier oral intake and a shorter length of hospital stay, which could be offered as an alternative for irreducible atlantoaxial dislocation.

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There are currently almost no ternary platinum-based nanosheets used for acidic oxygen reduction reactions (ORR) due to the difficulty in synthesizing ternary nanosheets with high Pt content. In this work, several ultrathin platinum-palladium-copper nanosheets (PtPdCu NSs) with a thickness of around 1.90 nm were prepared via a microwave heating-assisted method. Microwave heating allows a large number of Pt atoms to deposit into PdCu nanosheets, forming Pt-based ternary nanosheets with high Pt content. Among them, Pt38Pd50Cu12 NSs catalyst displays the highest mass activity (MA) measured in 0.1 M HClO4 of 0.932 A/mgPt+Pd which is 8.6 times of that Pt/C. Besides, Pt38Pd50Cu12 NSs catalyst also exhibits excellent stability with an extremely low MA attenuation after 80,000 cycles accelerated durability testing (ADT) tests. In the single cell tests, the Pt38Pd50Cu12 NSs catalyst manifests higher maximum power density of 796 mW cm-2 than Pt/C of 606 mW cm-2. Density functional theory (DFT) calculations indicate the weaker adsorption between Pt and O-species in Pt38Pd50Cu12 NSs leads to a significant enhancement of ORR activity. This study provides a new strategy to design and prepare ultrathin Pt-based trimetallic nanosheets as efficient and durable ORR catalysts.

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The aim of the present study was to explore the molecular mechanisms by which miR-193b-3p-trans-fected bone marrow mesenchymal stem cells (BMSCs) transplantation improves neurological impairment after traumatic brain injury (TBI) through sphingosine-1-phosphate receptor 3 (S1PR3)-mediated regulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway at the cellular and animal levels. BMSCs were transfected with miR-193b-3p. A TBI cell model was established by oxygen-glucose deprivation (OGD)-induced HT22 cells, and a TBI animal model was established by controlled cortical impact (CCI). Cell apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL), and cell activity was detected by a cell counting kit 8 (CCK-8) assay. Western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of related proteins and genes. In this study, transfection of miR-193b-3p into BMSCs significantly enhanced BMSCs proliferation and differentiation. Transfection of miR-193b-3p reduced the levels of the interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-alpha (TNF-α) inflammatory factors in cells and mouse models, and it inhibited neuronal apoptosis, which alleviated OGD-induced HT22 cell damage and neural function damage in TBI mice. Downstream experiments showed that miR-193b-3p targeting negatively regulated the expression of S1PR3, promoted the activation of the PI3K/AKT/mTOR signaling pathway, and inhibited the levels of apoptosis and inflammatory factors, which subsequently improved OGD-induced neuronal cell damage and nerve function damage in TBI mice. However, S1PR3 overexpression or inhibition of the PI3K/AKT/mTOR signaling pathway using the IN-2 inhibitor weakened the protective effect of miR-193b-3p-transfected BMSCs on HT22 cells. Transplantation of miR-193b-3p-transfected BMSCs inhibits neurological injury and improves the progression of TBI in mice through S1PR3-mediated regulation of the PI3K/AKT/mTOR pathway.

Assuntos

Lesões Encefálicas Traumáticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , MicroRNAs , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptores de Esfingosina-1-Fosfato , Serina-Treonina Quinases TOR , Animais , Humanos , Masculino , Camundongos , Apoptose , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/terapia , Modelos Animais de Doenças , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Serina-Treonina Quinases TOR/metabolismo

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Avian astrovirus can infect a variety of poultry species and cause viral diarrhea, with a wide epidemic range strong pathogenicity and a high incidence. Among them, Duck astrovirus 3(DAstV-3), Duck astrovirus 4(DAstV-4), Goose astrovirus 1(GoAstV-1) and Goose astrovirus 2(GoAstV-2) are four types of astroviruses newly discovered in waterfowl in recent years. In order to realize the rapid detection of these four kinds of waterfowl stellate viruses, specific primers and probes were engineered to target a highly conserved region of ORF1b gene of DAstV-3, GoAstV-1 and GoAstV-2 and the ORF2 gene of DAstV-4, and a quadruple fluorescence quantitative RT-PCR method was developed. The results indicate that the method established in this study has good specificity and no cross reactivity with other pathogens. This method can detect viruses with a minimum concentration of 1 × 101 copies/µL for DAstV-4, GoAstV-1 and GoAstV-2, respectively, while the minimum concentration for DAstV-3 is 1 × 102 copies/µL. Compared with the routinely used RT-PCR method, the limit of detection by the multiplex RT-PCR lower. Both intra- and inter-assay variability tests revealed excellent reproducibility. This method was then used to analyze 269 field samples, and the results were verified by genome sequencing. In conclusion, this study presents a sensitive, accurate, and specific method for detecting DAstV-3, DAstV-4, GoAstV-1, and GoAstV-2 in a single reaction, enabling the monitoring and differential diagnosis of these four types of waterfowl astroviruses.

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Purpose: To evaluate the burden of type 2 diabetes (T2D) among adolescents (15-24 years old) from 1990 to 2019. Methods: The age-standardized incidence rate (ASIR) and disability-adjusted life years (DALYs) rate of adolescents were analyzed according to age, sex, geographical location, and sociodemographic index (SDI). The estimated annual percentage change (EAPC) was estimated to quantify the trends. Results: From 1990 to 2019, the ASIR (EAPC = 1.07) and age-standardized DALY rate (EAPC = 2.01) of T2D in adolescents showed an increasing trend. The ASIR was higher in males than in females. The burden was greater in the 20-24-year age group. Of the five SDI regions, the highest ASIR and age-standardized DALY rate were found in low-middle-SDI regions, while the greatest increase in these rates was observed in high-SDI regions (EAPC = 3.28 and 3.55, respectively). Of the 21 regions analyzed, the highest ASIR and age-standardized DALY rate were found in Oceania. Of the 204 countries analyzed, the Marshall Islands (651.16) and Kiribati (277.42) had the highest ASIR and DALYs, respectively. The regions with the greatest increase in the ASIR from 1990 to 2019 were Western Europe (EAPC = 4.15), high-income North America (EAPC = 4.72). Conclusions: The global burden of T2D in adolescents showed an overall upward trend from 1990 to 2019. It is necessary to strengthen prevention measures related to risk factors for T2D among young people, especially in areas with a low-to-medium SDI.

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Diabetes Mellitus Tipo 2 , Saúde Global , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Adolescente , Masculino , Feminino , Adulto Jovem , Incidência , Anos de Vida Ajustados por Deficiência/tendências , Efeitos Psicossociais da Doença , Carga Global da Doença/tendências

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INTRODUCTION: Depression is a major global health problem, with high prevalence rates of depressive symptoms observed among the elderly population in China, particularly exacerbating in rural areas. Due to a lack of professional mental health training and inadequate psychotherapy capacity within primary medical staff, rural elderly individuals grappling with depressive symptoms often encounter challenges in receiving timely diagnosis and treatment. In this landscape, the modified behavioural activation treatment (MBAT) emerges as a promising approach due to its practicality, ease of therapist training and application, patient acceptability, and broad applicability. However, existing evidence for MBAT mainly hails from developed countries, leaving a gap in its adaptation and implementation within rural China. This study aims to develop an MBAT training programme for primary medical staff to manage depressive symptoms among rural elderly and evaluate its effectiveness. METHODS AND ANALYSIS: A cluster randomised controlled trial will be conducted in 10 randomly selected township hospitals in Lengshuijiang and Lianyuan, Hunan Province. We aim to recruit 150 participants, with 5 township hospitals selected for each group, each consisting of 15 participants. The intervention group will implement the MBAT training programme, while the control group will receive usual care training programme. Depressive symptoms, psychosocial functioning, quality of life and satisfaction will be measured at baseline, immediately post-intervention, and at 3 and 6 months post-intervention. Effectiveness will be assessed using linear or generalised linear mixed models. ETHICS AND DISSEMINATION: This study has obtained approval from the Institutional Review Board of the Third Xiangya Hospital, Centre South University (No.: 2022-S261). Results will be disseminated through publication in international peer-reviewed journals and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300074544.

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Depressão , População Rural , Humanos , China , Depressão/terapia , Idoso , Ensaios Clínicos Controlados Aleatórios como Assunto , Feminino , Masculino , Qualidade de Vida , Pessoal de Saúde/educação , Pessoal de Saúde/psicologia , Terapia Comportamental/métodos , Atenção Primária à Saúde

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Catalytic mechanism-based, light-activated traps have recently been developed to identify the substrates of cysteine or serine hydrolases. These traps are hydrolase mutants whose catalytic cysteine or serine are replaced with genetically encoded 2,3-diaminopropionic acid (DAP). DAP-containing hydrolases specifically capture the transient thioester- or ester-linked acyl-enzyme intermediates resulting from the first step of the proteolytic reaction as their stable amide analogs. The trapped substrate fragments allow the downstream identification of hydrolase substrates by mass spectrometry and immunoblotting. In this protocol, we provide a detailed step-by-step guide for substrate capture and identification of the peptidase domain of the large tegument protein deneddylase (UL36USP) from human herpesvirus 1, both in mammalian cell lysate and live mammalian cells. Four procedures are included: Procedure 1, DAP-mediated substrate trapping in mammalian cell lysate (~8 d); Procedure 2, DAP-mediated substrate trapping in adherent mammalian cells (~6 d); Procedure 3, DAP-mediated substrate trapping in suspension mammalian cells (~5 d); and Procedure 4, substrate identification and validation (~12-13 d). Basic skills to perform protein expression in bacteria or mammalian cells, affinity enrichment and proteomic analysis are required to implement the protocol. This protocol will be a practical guide for identifying substrates of serine or cysteine hydrolases either in a complex mixture, where genetic manipulation is challenging, or in live cells such as bacteria, yeasts and mammalian cells.

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Optimizing the pore structure and its interaction with the electrolytes was vital for enhancing the performance of supercapacitors based on the electrical double layer mechanism. In this study, graded porous carbon material (STP) with outstanding properties was prepared by adjusting the activation temperature and KOH dosage in the microwave pyrolysis process of sargassum thunbergii. The results demonstrated that better electrochemical performance was obtained when 1 M NaNO3 was used as electrolyte and STP-800-3 was employed as electrode material, attributed to its excellent specific surface area (SSA) of 2011.8 m2 g-1, high micropore ratio, and the optimal matching degree between micropore size and electrolyte ion diameter. Moreover, the operating voltage window was expanded to 2.0 V in supercapacitors assembled with 6 M NaNO3 high-concentration electrolyte. Simultaneously, the symmetric supercapacitors exhibited a remarkable specific capacitance of 290.0 F g-1, a high energy density of 39.0 W h kg-1, and outstanding capacity retention at 70.9% after 10,000 charge/discharge cycles based on 6 M NaNO3 electrolyte. Consequently, the results provided valuable technical support and theoretical basis to foster progress of novel and high-performance supercapacitors.

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Objectives: Opioid nonadherence represents a significant barrier to cancer pain treatment efficacy. However, there is currently no effective prediction method for opioid adherence in patients with cancer pain. We aimed to develop and validate a machine learning (ML) model and evaluate its feasibility to predict opioid nonadherence in patients with cancer pain. Methods: This was a secondary analysis from a cross-sectional study that included 1195 patients from March 1, 2018, to October 31, 2019. Five ML algorithms, such as logistic regression (LR), random forest, eXtreme Gradient Boosting, multilayer perceptron, and support vector machine, were used to predict opioid nonadherence in patients with cancer pain using 43 demographic and clinical factors as predictors. The predictive effects of the models were compared by the area under the receiver operating characteristic curve (AUC_ROC), accuracy, precision, sensitivity, specificity, and F1 scores. The value of the best model for clinical application was assessed using decision curve analysis (DCA). Results: The best model obtained in this study, the LR model, had an AUC_ROC of 0.82, accuracy of 0.82, and specificity of 0.71. The DCA showed that clinical interventions for patients at high risk of opioid nonadherence based on the LR model can benefit patients. The strongest predictors for adherence were, in order of importance, beliefs about medicines questionnaire (BMQ)-harm, time since the start of opioid, and BMQ-necessity. Discussion. ML algorithms can be used as an effective means of predicting adherence to opioids in patients with cancer pain, which allows for proactive clinical intervention to optimize cancer pain management. This trial is registered with ChiCTR2000033576.

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Analgésicos Opioides , Dor do Câncer , Aprendizado de Máquina , Adesão à Medicação , Humanos , Feminino , Masculino , Dor do Câncer/tratamento farmacológico , Pessoa de Meia-Idade , Analgésicos Opioides/uso terapêutico , Estudos Transversais , Adesão à Medicação/estatística & dados numéricos , Idoso , Adulto , Algoritmos

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Background: Sepsis-associated acute lung injury (ALI) and acute kidney injury (AKI) are common complications that significantly impact patient prognosis. Danlou tablet (DLT) is a traditional herbal preparation with anti-inflammatory and antioxidant properties. However, its therapeutic potential in sepsis remains unknown. Methods: The impact of DLT on ALI and AKI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of DLT on macrophages were observed through LPS-stimulated RAW264.7 cell line. Inflammatory cytokines, oxidative stress indicators, HE, PAS, and DHE staining, lung wet-to-dry weight ratio, and serum creatinine and urea nitrogen levels were used to assess tissue injury. Network pharmacology, molecular docking, and molecular dynamics simulations were used to explore the potential regulatory mechanisms of DLT in sepsis. Western blot and immunohistochemical staining were used to validate the expression of mechanism-related proteins. Results: DLT inhibited the inflammatory response and oxidative stress, improved structural and functional abnormalities in lung and kidney tissues in CLP mice, and alleviated pro-inflammatory responses of LPS-stimulated macrophages. PARP1 and HMGB1 were identified as key regulatory targets. The results of in vitro and in vivo experiments suggest that DLT can effectively inhibit PARP1/HMGB1 and improve sepsis-associated ALI and AKI. Conclusion: The present study demonstrated that DLT suppressed pro-inflammatory responses of macrophage and alleviated ALI and AKI in the CLP mice by inhibiting the transition activation of PARP1/HMGB1. These findings partially elucidate the mechanism of DLT in sepsis-associated ALI and AKI and further clarify the active components of DLT, thereby providing a scientific theoretical basis for treating sepsis with DLT.

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BACKGROUND: The proinflammatory response induced by macrophages plays a crucial role in the development of sepsis and the resulting multiorgan dysfunction. Identifying new regulatory targets for macrophage homeostasis and devising effective treatment strategies remains a significant challenge in contemporary research. PURPOSE: This study aims to identify new regulatory targets for macrophage homeostasis and develop effective strategies for treating sepsis. STUDY DESIGN AND METHODS: Macrophage infiltration in septic patients and in lungs, kidneys, and brains of caecum ligation and puncture (CLP)-induced septic mice was observed using CIBERSORT and immunofluorescence (IF). Upon integrating the MSigDB database and GSE65682 dataset, differently expressed macrophage-associated genes (DEMAGs) were identified. Critical DEMAGs were confirmed through machine learning. The protein level of the critical DEMAG was detected in PBMCs of septic patients, RAW264.7 cells, and mice lungs, kidneys, and brains using ELISA, western blot, immunohistochemistry, and IF. siRNA was applied to investigate the effect of the critical DEMAG in RAW264.7 cells. A natural product library was screened to find a compound targeting the critical DEMAG protein. The binding of compounds and proteins was analyzed through molecular docking, molecular dynamics simulations, CETSA, and MST analysis. The therapeutic efficacy of the compounds against sepsis was then evaluated through in vitro and in vivo experiments. RESULTS: Macrophage infiltration was inversely correlated with survival in septic patients. The critical differentially expressed molecule RasGRP1 was frequently observed in the PBMCs of septic patients, LPS-induced RAW264.7 cells, and the lungs, kidneys, and brains of septic mice. Silencing RasGRP1 alleviated proinflammatory response and oxidative stress in LPS-treated RAW264.7 cells. Catechin Hydrate (CH) was identified as an inhibitor of RasGRP1, capable of maintaining macrophage homeostasis and mitigating lung, kidney, and brain damage during sepsis. CONCLUSION: This study demonstrates that RasGRP1, a novel activator of macrophage proinflammatory responses, plays a crucial role in the excessive inflammation and oxidative stress associated with sepsis. CH shows potential for treating sepsis by inhibiting RasGRP1.

Assuntos

Catequina , Fatores de Troca do Nucleotídeo Guanina , Macrófagos , Sepse , Animais , Sepse/tratamento farmacológico , Camundongos , Humanos , Células RAW 264.7 , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Catequina/farmacologia , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Simulação de Acoplamento Molecular , Rim/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos

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BACKGROUND: Lysimachia christinae Hance (LCH) is a traditional medicine used to treat gallstone disease and cholecystitis. Despite its known anti-inflammatory and choleretic effects, its quality has not been extensively evaluated. OBJECTIVE: In this study, we aimed to establish a reliable quality evaluation method for LCH via fingerprint, spectrum-effect relationship, and quantitative analyses of multicomponents by a single marker (QAMS). METHODS: First, the fingerprints and anti-inflammatory and choleretic activities of 14 LCH batches were determined. Then, the gray relation analysis method was used to analyze the peak areas of the fingerprint profile and pharmacodynamic data. Subsequently, the characteristic peaks were tentatively identified using high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Finally, rutin was selected as the internal reference material, and QAMS was used to analyze the LCH components. RESULTS: Pharmacodynamic experiments confirmed that LCH exerted anti-inflammatory and choleretic effects. Moreover, 15 flavonoids related to the anti-inflammatory and choleretic effects of LCH were identified. Notably, relative error percentage between the QAMS and external standard method was less than 5%. CONCLUSION: This study successfully established a comprehensive evaluation method for the qualitative and quantitative analyses of LCH.

Assuntos

Lysimachia , Animais , Masculino , Ratos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/análise , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/análise , Lysimachia/química , Controle de Qualidade , Feminino , Camundongos

RESUMO

Background: Acute myocardial infarction (AMI) is a common cardiovascular disease in clinic. Currently, there is no specific treatment for AMI. Carbon dots (CDs) have been reported to show excellent biological activities, which hold promise for the development of novel nanomedicines for the treatment of cardiovascular diseases. Methods: In this study, we firstly prepared CDs from the natural herb Curcumae Radix Carbonisata (CRC-CDs) by a green, simple calcination method. The aim of this study is to investigate the cardioprotective effect and mechanism of CRC-CDs on isoproterenol (ISO) -induced myocardial infarction (MI) in rats. Results: The results showed that pretreatment with CRC-CDs significantly reduced serum levels of cardiac enzymes (CK-MB, LDH, AST) and lipids (TC, TG, LDL) and reduced st-segment elevation and myocardial infarct size on the ECG in AMI rats. Importantly, cardiac ejection fraction (EF) and shortening fraction (FS) were markedly elevated, as was ATPase activity. In addition, CRC-CDs could significantly increase the levels of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and reduce the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in myocardial tissue, thereby exerting cardioprotective effect by enhancing the antioxidant capacity of myocardial tissue. Moreover, the TUNEL staining image showed that positive apoptotic cells were markedly declined after CRC-CDs treatment, which indicate that CRC-CDs could inhibit cardiomyocyte apoptosis. Importantly, The protective effect of CRC-CDs on H2O2 -pretreated H9c2 cells was also verified in vitro. Conclusion: Taken together, CRC-CDs has the potential for clinical application as an anti-myocardial ischemia drug candidate, which not only provides evidence for further broadening the biological application of cardiovascular diseases, but also offers potential hope for the application of nanomedicine to treat intractable diseases.

Assuntos

Infarto do Miocárdio , Isquemia Miocárdica , Animais , Ratos , Peróxido de Hidrogênio , Infarto do Miocárdio/tratamento farmacológico , Miocárdio , Carbono

RESUMO

AIM: We aimed to assess the global implications of low physical activity (LPA) on type 2 diabetes mellitus (T2DM) by utilizing data from the Global Burden of Disease (GBD) 2019. METHODS: The analysis was conducted by examining the age-standardized disability-adjusted life years (DALYs) rates over a 30-year period. To assess the trends, we utilized estimated annual percentage changes (EAPCs). RESULTS: The study revealed a notable increase in the burden of DALYs attributable to T2DM resulting from LPA, with an EAPC of 0.84 (95% confidence interval 0.78-0.89). Among the regions examined, Oceania showed the highest burden, whereas Eastern Europe exhibited the lowest burden. Specifically, within the Central Asia region, a considerable increase in T2DM-LPA DALYs was observed, with an EAPC of 3.18 (95% confidence interval 3.01-3.36). The burden associated with T2DM-LPA DALYs was found to be similar between genders and increased across all age groups, peaking in the 80-84 years. Furthermore, there was a clear association between the socio-demographic index (SDI) and the age-standardized DALYs rate. Regions categorized as low-middle and middle SDI experienced a substantial rise in burden. CONCLUSION: This study highlights a substantial increase in the T2DM-LPA DALYs in low-middle and middle SDI regions, as well as among individuals aged 80-84 years. These findings emphasize the importance of implementing comprehensive global health interventions that promote physical activity, particularly targeting high-risk populations and regions.

Assuntos

Diabetes Mellitus Tipo 2 , Exercício Físico , Carga Global da Doença , Saúde Global , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Adulto , Anos de Vida Ajustados por Deficiência , Comportamento Sedentário , Adulto Jovem , Oceania/epidemiologia

RESUMO

Optimizing the electrode/electrolyte interface structure is the key to realizing high-voltage Li-metal batteries (LMBs). Herein, a functional electrolyte is introduced to synergetically regulate the interface layer structures on the high-voltage cathode and the Li-metal anode. Saccharin sodium (NaSH) as a multifunctional electrolyte additive is employed in fluorinated solvent-based electrolyte (FBE) for robust interphase layer construction. On the one hand, combining the results of ex-situ techniques and in-situ electrochemical dissipative quartz crystal microbalance (EQCM-D) technique, it can be seen that the solid electrolyte interface (SEI) layer constructed by NaSH-coupled fluoroethylene carbonate (FEC) on Li-metal anode significantly inhibits the growth of lithium dendrites and improves the cyclic stability of the anode. On the other hand, the experimental results also confirm that the cathode-electrolyte interface (CEI) layer induced by NaSH-coupled FEC effectively protects the active materials of LiCoO2 and improves their structural stability under high-voltage cycling, thus avoiding the material rupture. Moreover, theoretical calculation results show that the addition of NaSH alters the desolvation behavior of Li+ and enhances the transport kinetics of Li+ at the electrode/electrolyte interface. In this contribution, the LiCoO2ǁLi full cell containing FBE+NaSH results in a high capacity retention of 80% after 530 cycles with a coulombic efficiency of 99.8%.