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Improving the ease of operation and portability of hydrogen peroxide (H2O2) detection in daily production and life holds significant application value. However, it remains a challenge to achieve rapid colorimetric detection of H2O2 and color change quantification. In this study, we achieved rapid and visual detection of H2O2 by MoOx (2 ≤ x ≤ 3) nanoparticles with rich oxygen vacancies using machine vision. As the concentration of H2O2 increases, the detection system exhibited a visible multi-color change from blue to green and then yellow and the absorption peak near 680 nm measured by the UV-visible spectrophotometer gradually decreased. With excellent sensitivity, a wide linear range of 0.1-600 µmol/L, concentrations as low as 0.1 µmol/L can be detected with good selectivity towards H2O2. The sensing mechanism of detecting H2O2 by the change of oxygen vacancies in MoOx was revealed through characterization methods such as XPS, EPR, and DFT. In addition, the Hue, Saturation, Value (HSV) visual analysis system based on MoOx was constructed to assist in the rapid, portable, and sensitive monitoring of H2O2 in practical application scenarios. This work offers an easy-to operate, low cost, and convenience for achieving rapid colorimetric determination of H2O2 and has broad application prospects in daily life and industrial production.

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Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death worldwide and in Taiwan. It is highly prevalent and has a tremendous impact on global health. Therefore, the Taiwan Society of Cardiology developed these best-evidence preventive guidelines for decision-making in clinical practice involving aspects of primordial prevention including national policies, promotion of health education, primary prevention of clinical risk factors, and management and control of clinical risk factors. These guidelines cover the full spectrum of ASCVD, including chronic coronary syndrome, acute coronary syndrome, cerebrovascular disease, peripheral artery disease, and aortic aneurysm. In order to enhance medical education and health promotion not only for physicians but also for the general public, we propose a slogan (2H2L) for the primary prevention of ASCVD on the basis of the essential role of healthy dietary pattern and lifestyles: "Healthy Diet and Healthy Lifestyles to Help Your Life and Save Your Lives". We also propose an acronym of the modifiable risk factors/enhancers and relevant strategies to facilitate memory: " ABC2D2EFG-I'M2 ACE": Adiposity, Blood pressure, Cholesterol and Cigarette smoking, Diabetes mellitus and Dietary pattern, Exercise, Frailty, Gout/hyperuricemia, Inflammation/infection, Metabolic syndrome and Metabolic dysfunction-associated fatty liver disease, Atmosphere (environment), Chronic kidney disease, and Easy life (sleep well and no stress). Some imaging studies can be risk enhancers. Some risk factors/clinical conditions are deemed to be preventable, and healthy dietary pattern, physical activity, and body weight control remain the cornerstone of the preventive strategy.

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Background: By regulating the functions of multiple RNAs, 5-methylcytosine (m5C) RNA methylation, particularly mediated by NOP2, is involved in tumorigenesis and developments. However, the specific functions and potential mechanisms of m5C, especially involving NOP2, in clear-cell renal cell carcinoma (ccRCC), remain unclear. Methods: NOP2 expression in cell lines and patient tissues was detected using western blotting, quantitative real-time polymerase chain reaction (RT-qPCR), and immunohistochemistry. The biological effects of NOP2 on ccRCC cells were investigated through a series of in vitro and in vivo experiments. To explore the potential regulatory mechanisms by which NOP2 affects ccRCC progression, m5C bisulfite sequencing, RNA-sequencing, RNA immunoprecipitation and methylated RNA immunoprecipitation (RIP/MeRIP) RT-qPCR assay, luciferase reporter assay, RNA stability assay, and bioinformatic analysis were performed. Results: NOP2 expression was significantly upregulated in ccRCC tissues and was associated with poor prognosis. Moreover, loss-of-function and gain-of-function assays demonstrated that NOP2 altered ccRCC cell proliferation, migration, and invasion. Mechanistically, NOP2 stimulated m5C modification of apolipoprotein L1 (APOL1) mRNA, and m5C reader YBX1 stabilized APOL1 mRNA through recognizing and binding to m5C site in the 3'-untranslated regions. Silencing APOL1 expression inhibited ccRCC cell proliferation in vitro and tumor formation in vivo. Furthermore, NOP2/APOL1 affected ccRCC progression via the PI3K-Akt signaling pathway. Conclusion: NOP2 functions as an oncogene in ccRCC by promoting tumor progression through the m5C-dependent stabilization of APOL1, which in turn regulates the PI3K-Akt signaling pathway, suggesting a potential therapeutic target for ccRCC.

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Apolipoproteína L1 , Carcinoma de Células Renales , Neoplasias Renales , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero , Humanos , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias Renales/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/patología , Línea Celular Tumoral , Apolipoproteína L1/metabolismo , Apolipoproteína L1/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Ratones , 5-Metilcitosina/metabolismo , Animales , Proliferación Celular/genética , Ratones Desnudos , Masculino , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Transducción de Señal , Movimiento Celular/genética

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BACKGROUND: While the gradually aggravated motor and non-motor disorders of Parkinson's disease (PD) lead to progressive disability and frequent falling, skeletal muscle impairment may contribute to this condition. The leucine-rich repeat kinase2 (LRRK2) is a common disease-causing gene in PD. Little is known about its role in skeletal muscle impairment and its underlying mechanisms. METHODS: To investigate whether the mutation in LRRK2 causes skeletal muscle impairment, we used 3-month-old (3mo) and 14-month-old (14mo) LRRK2G2019S transgenic (TG) mice as a model of PD, compared with the age-matched littermate wild-type (WT) controls. We measured the muscle mass and strength, ultrastructure, inflammatory infiltration, mitochondrial morphology and dynamics dysfunction through behavioural analysis, electromyography (EMG), immunostaining, transmission electron microscopy (TEM) and other molecular biology techniques. RESULTS: The 3mo-TG mice display mild skeletal muscle impairment with spontaneous potentials in EMG (increased by 130%, p < 0.05), myofibre necrosis (p < 0.05) and myosin heavy chain-II changes (reduced by 19%, p < 0.01). The inflammatory cells and macrophage infiltration are significantly increased (CD8a+ and CD68+ cells up 1060% and 579%, respectively, both p < 0.0001) compared with the WT mice. All of the above pathogenic processes are aggravated by aging. The 14mo-TG mice EMG examinations show a reduced duration (by 31%, p < 0.01) and increased polyphasic waves of motor unit action potentials (by 28%, p < 0.05). The 14mo-TG mice present motor behavioural deficits (p < 0.05), muscle strength and mass reduction by 37% and 8% (p < 0.05 and p < 0.01, respectively). A remarkable increase in inflammatory infiltration is accompanied by pro-inflammatory cytokines in the skeletal muscles. TEM analysis shows muscle fibre regeneration with the reduced length of sarcomeres (by 6%;p < 0.05). The muscle regeneration is activated as Pax7+ cells increased by 106% (p < 0.0001), andmyoblast determination protein elevated by 71% (p < 0.01). We also document the morphological changes and dynamics dysfunction of mitochondria with the increase of mitofusin1 by 43% (p < 0.05) and voltage-dependent anion channel 1 by 115% (p < 0.001) in the skeletal muscles of 14mo-TG mice. CONCLUSIONS: Taken together, these findings may provide new insights into the clinical and pathogenic involvement of LRRK2G2019 mutation in muscles, suggesting that the diseases may affect not only midbrain dopaminergic neurons, but also other tissues, and it may help overall clinical management of this devastating disease.

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This paper proposes a novel multicomponent gas-sensing optical fiber probe system. It utilizes a precisely engineered Platinum-coated capillary fabricated via Atomic Layer Deposition (ALD) technology as the core for enhanced Raman spectroscopy, marking the first application of ALD in creating such a structure for gas Raman sensing. The noble metal capillary gas Raman probe demonstrates a low detection limit of 55 ppm for CO2 with a 30 s exposure time and good repeatability in multicomponent gas sensing. The capillary exhibits excellent stability, environmental resistance, and a large core diameter, enabling a rapid gas exchange rate and making it suitable for practical applications.

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AIM: Non-invasive diagnostics for metabolic dysfunction-associated fatty liver disease (MAFLD) remain challenging. We aimed to identify novel key genes as non-invasive biomarkers for MAFLD, elucidate causal relationships between biomarkers and MAFLD and determine the role of immune cells as potential mediators. MATERIALS AND METHODS: Utilizing published transcriptome data of patients with biopsy-proven MAFLD, we applied linear models for microarray data, least absolute shrinkage and selector operation (LASSO) regressions and receiver operating characteristic (ROC) curve analyses to identify and validate biomarkers for MAFLD. Using the expression quantitative trait loci database and a cohort of 778 614 Europeans, we used Mendelian randomization to analyse the causal relationships between key biomarkers and MAFLD. Additionally, mediation analysis was performed to examine the involvement of 731 immunophenotypes in these relationships. RESULTS: We identified 31 differentially expressed genes, and LASSO regression showed three hub genes, IGFBP2, PEG10, and P4HA1, with area under the receiver operating characteristic (AUROC) curve of 0.807, 0.772 and 0.791, respectively, for identifying MAFLD. The model of these three genes had an AUROC of 0.959 and 0.800 in the development and validation data sets, respectively. This model was also validated using serum-based enzyme-linked immunosorbent assay data from MAFLD patients and control subjects (AUROC: 0.819, 95% confidence interval: 0.736-0.902). PEG10 was associated with an increased MAFLD risk (odds ratio = 1.106, p = 0.032) via inverse variance-weighted analysis, and about 30% of this risk was mediated by the percentage of CD11c + CD62L- monocytes. CONCLUSIONS: The MAFLD panels have good diagnostic accuracy, and the causal link between PEG10 and MAFLD was mediated by the percentage of CD11c + CD62L- monocytes.

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BACKGROUND: Calcium-dependent protein kinase (CDPK) plays a key role in cotton tolerance to abiotic stress. However, its role in cotton heat stress tolerance is not well understood. Here, we characterize the GhCDPK gene family and their expression profiles with the aim of identifying CDPK genes associated with heat stress tolerance. RESULTS: This study revealed 48 GhCDPK members in the cotton genome, distributed on 18 chromosomes. Tree phylogenetic analysis showed three main clustering groups of the GhCDPKs. Cis-elements revealed many abiotic stress and phytohormone pathways conserved promoter regions. Similarly, analysis of the transcription factor binding sites (TFBDS) in the GhCDPK genes showed many stress and hormone related sites. The expression analysis based on qRT-PCR showed that GhCDPK16 was highly responsive to high-temperature stress. Subsequent protein-protein interactions of GhCDPK16 revealed predictable interaction with ROS generating, calcium binding, and ABA signaling proteins. Overexpression of GhCDPK16 in cotton and Arabidopsis improved thermotolerance by lowering ROS compound buildup. Under heat stress, GhCDPK16 transgenic lines upregulated heat-inducible genes GhHSP70, GHSP17.3, and GhGR1, as demonstrated by qRT-PCR analysis. Contrarily, GhCDPK16 knockout lines in cotton exhibited an increase in ROS accumulation. Furthermore, antioxidant enzyme activity was dramatically boosted in the GhCDPK16-ox transgenic lines. CONCLUSIONS: The collective findings demonstrated that GhCDPK16 could be a viable gene to enhance thermotolerance in cotton and, therefore, a potential candidate gene for improving heat tolerance in cotton.

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Regulación de la Expresión Génica de las Plantas , Gossypium , Respuesta al Choque Térmico , Proteínas de Plantas , Arabidopsis/genética , Arabidopsis/fisiología , Gossypium/genética , Gossypium/fisiología , Gossypium/metabolismo , Respuesta al Choque Térmico/genética , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genética , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Termotolerancia/genética

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The high tracking control precision and fast finite-time convergence for nonlinear systems is a significant challenge due to complex nonlinearity and unknown disturbances. To address this challenge, a dynamic surface intelligent robust control strategy with fixed-time sliding-mode observer (DSIRC-SMO) is proposed to improve the tracking control performance in a finite time. First, adaptive fuzzy neural network based on a predictor (P-AFNN) is designed to imitate the complex nonlinearity. In particular, the weight adaptive law is formulated by utilizing the prediction error information, which improves the accuracy of approximating the nonlinear system. Second, the fixed-time sliding-mode observer (SMO) is integrated into the dynamic surface control technique to deal with unknown disturbances and modeling errors in a fixed time. This integration allows for timely updates the dynamic surface using observation information, thereby enhancing the system's anti-interference capability. Then, the fixed-time convergence of SMO is proven. Third, the proposed DSIRC-SMO can be effectively implemented and the finite-time convergence of DSIRC-SMO is proven in detail based on the fixed-time convergence of SMO. Finally, numerical simulation and actual wastewater treatment processes simulation are conducted to validate the effectiveness of DSIRC-SMO.

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AIMS: While studies regarding the learning experiences of international nursing students are increasing, a summary of previous evidence about the challenges, support, and strategies to learning in those students was scarce. The current review was to examine the qualitative literature exploring challenges, support, and strategies for learning in nursing students who have English as an additional language. DESIGN: A meta-synthesis. METHODS: A search for relevant reports published between January 2000 and July 2023 was conducted across four electronic databases. Reports focusing on learning experiences among EAL nursing students were eligible for inclusion. Qualitative data were analyzed using the thematic analysis technique and all included reports were appraised by the CASP checklist. RESULTS: A total of 16 reports were included. The results exhibited that EAL nursing students faced multiple challenges like language barriers, balancing responsibilities, immigration issues, and more, but might benefit from a range of support systems and employ various strategies that enhance their skills and lead to academic success. CONCLUSIONS: This meta-synthesis on EAL nursing students highlighted their complex academic journey with unique barriers, support systems, and strategies employed to achieve success. The findings also underscored a need for tailored support and inclusive curricula to address their unique needs, fostering an equitable learning environment and enabling their full academic potential in this population.

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Traumatic brain injury (TBI) is a leading cause of disability and death. Thus, timely and effective secondary brain injury intervention is crucial, with potential to improve the prognosis of TBI. Oxidative stress contributes to post-traumatic secondary cognitive impairment, and the reduction of post-traumatic oxidative stress effectively enhances cognitive function. Phosphoglycerate-mutating enzyme 5 (PGAM5), a member of the phosphoglycerate transporter enzyme family, is upregulated in TBI and induces mitochondrial autophagy. This further exacerbates damage following TBI. The present study focused on the small molecule drug, LFHP-1c, which is a novel inhibitor of PGAM5. The present study used an in vivo mouse model incorporating a controlled cortical impact-induced TBI, to examine the impact of LFHP-1c on oxidative stress and cognitive function. The present study aimed to determine the impact of LFHP-1c on the PGAM5-Kelch-like ECH-associated protein 1 (KEAP1)- nuclear factor erythroid 2-related factor 2 (NRF2) ternary complex within the TBI context. Results of the present study indicated that LFHP-1c suppresses PGAM5 expression and inhibits the development of the PGAM5-KEAP1-NRF2 ternary complex, thereby promoting the release of NRF2 and KEAP1. This in turn promotes the entry of NRF2 into the nucleus following TBI, leading to increased expression of anti-oxidative stress downstream factors, such as heme oxygenase-1, glutathione peroxidase 1 and superoxide dismutase 1. In addition, LFHP-1c also released KEAP1, leading to mitochondrial Rho GTPase 2 degradation and reducing perinuclear aggregation of mitochondria in the cell, which reduced oxidative stress and ultimately improved cognitive function after TBI.

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α-Aminonitriles are not only broadly useful building blocks but also structural motifs in bioactive molecules. The Strecker reaction is one of the most widely used methods for α-aminonitrile synthesis. However, a severe drawback in Strecker reactions is the required use of a stoichiometric amount of toxic cyanation reagents. Thus, the development of a greener and widely applicable method for the synthesis of aminonitriles from readily available starting materials presents an important yet unmet challenge. We developed a general and new method for the synthesis of aminonitriles from readily available aminoacetonitrile. This method utilized off-the-shelf ammonium salts as catalysts, tolerated air and moisture, and avoided the use of cyanation reagents, which rendered it a greener alternative to the widely practiced Strecker reaction approach. We further illustrated that chiral ammonium-catalyzed asymmetric reactions of N-arylidene aminoacetonitriles could provide chiral α-tertiary and α-quaternary aminonitriles and α-aminonitriles bearing two continuous stereocenters.

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Objective: Readmission to the coronary care unit (CCU) has significant implications for patient outcomes and healthcare expenditure, emphasizing the urgency to accurately identify patients at high readmission risk. This study aims to construct and externally validate a predictive model for CCU readmission using machine learning (ML) algorithms across multiple hospitals. Methods: Patient information, including demographics, medical history, and laboratory test results were collected from electronic health record system and contributed to a total of 40 features. Five ML models: logistic regression, random forest, support vector machine, gradient boosting, and multilayer perceptron were employed to estimate the readmission risk. Results: The gradient boosting model was selected demonstrated superior performance with an area under the receiver operating characteristic curve (AUC) of 0.887 in the internal validation set. Further external validation in hold-out test set and three other medical centers upheld the model's robustness with consistent high AUCs, ranging from 0.852 to 0.879. Conclusion: The results endorse the integration of ML algorithms in healthcare to enhance patient risk stratification, potentially optimizing clinical interventions, and diminishing the burden of CCU readmissions.

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Channelrhodopsins are light-gated ion channels with a retinal chromophore found in microbes and are widely used in optogenetics, a field of neuroscience that utilizes light to regulate neuronal activity. GtACR1, an anion conducting channelrhodopsin derived from Guillardia theta, has attracted attention for its application as a neuronal silencer in optogenetics because of its high conductivity and selectivity. However, atomistic mechanisms of channel photoactivation and ion conduction have not yet been elucidated. In the present study, we investigated the molecular characteristics of GtACR1 and its photoactivation processes by molecular simulations. The QM/MM RWFE-SCF method which combines highly accurate quantum chemistry calculations with long-time molecular dynamics (MD) simulations were used to model protein structures of the wild-type and mutants with different protonation states of key groups and to calculate absorption energies for verification of the models. The QM/MM modeling together with MD simulations of free-energy calculations favors protonation of a key counterion carboxyl group of Asp234 with a strong binding of a chloride ion in the extracellular pocket in the dark state. A channel open state was also successfully modeled by the QM/MM RWFE-SCF free-energy optimizations, providing atomistic insights into the channel activation mechanism.

Asunto(s)

Simulación de Dinámica Molecular , Protones , Teoría Cuántica , Channelrhodopsins/química , Channelrhodopsins/metabolismo , Aniones/química , Aniones/metabolismo , Procesos Fotoquímicos

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Methamphetamine (METH) is a highly addictive psychostimulant that causes physical and psychological damage and immune system disorder, especially in the liver that contains a significant number of immune cells. Dopamine, a key neurotransmitter in METH addiction and immune regulation, plays a crucial role in this process. Here, we developed a chronic METH administration model and conducted single-cell RNA sequencing (scRNA-seq) to investigate the effect of METH on liver immune cells and involvement of dopamine receptor D1 (DRD1). Our findings reveal that chronic exposure to METH induces immune cell identity shifts from Ifitm3+Macrophage (Mac) and Ccl5+Mac to Cd14+Mac, and from Fyn+CD4+T effector (Teff), CD8+T, and natural killer T cells (NKT) to Fos+CD4+T and Rora+ group 2 innate lymphoid cells (ILC2), along with suppression of multiple functional immune pathways. DRD1 is implicated in regulating certain pathways and identity shifts among the hepatic immune cells. Our results provide valuable insights into development of targeted therapies to mitigate METH-induced immune impairment.

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Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro-Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals.

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Proliferación Celular , Proteínas de Homeodominio , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Miocitos Cardíacos , Regeneración , Animales , Regeneración/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Proliferación Celular/efectos de los fármacos , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/metabolismo , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/genética , Neomicina/farmacología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Modelos Animales de Enfermedad , Aprobación de Drogas , Ratones , Función Ventricular Izquierda/efectos de los fármacos , United States Food and Drug Administration , Ratas , Estados Unidos , Cristalografía por Rayos X , Masculino , Ratones Endogámicos C57BL , Porcinos , Células Cultivadas , Transcripción Genética/efectos de los fármacos

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Introduction: The biomechanical indication for combining anterolateral structures reconstruction (ASLR) with ACL reconstruction (ACLR) to reduce pivot shift in the knee remains unclear. This study aims to investigate knee functionality after ACL rupture with different combinations of injuries, and to compare the effectiveness of ALSR with ACLR for treating these injuries. Methods: A validated finite element model of a human cadaveric knee was used to simulate pivot shift tests on the joint in different states, including 1) an intact knee; 2) after isolated ACL rupture; 3) after ACL rupture combined with different knee injuries or defect, including a posterior tibial slope (PTS) of 20°, an injury to the anterolateral structures (ALS) and an injury to the posterior meniscotibial ligament of the lateral meniscus (LP); 4) after treating the different injuries using isolated ACLR; v. after treating the different injuries using ACLR with ALSR. The knee kinematics, maximum von Mises stress (Max.S) on the tibial articular cartilage (TC) and force in the ACL graft were compared among the different simulation groups. Results and discussion: Comparing with isolated ACL rupture, combined injury to the ALS caused the largest knee laxity, when a combined PTS of 20° induced the largest Max.S on the TC. The joint stability and Max.S on the TC in the knee with an isolated ACL rupture or a combined rupture of ACL and LP were restored to the intact level after being treated with isolated ACLR. The knee biomechanics after a combined rupture of ACL and ALS were restored to the intact level only when being treated with a combination of ACLR and ALSR using a large graft diameter (6 mm) for ALSR. However, for the knee after ACL rupture combined with a PTS of 20°, the ATT and Max.S on the TC were still greater than the intact knee even after being treated with a combination of ACLR and ALSR. The finite element analysis showed that ACLR should include ALSR when treating ACL ruptures accompanied by ALS rupture. However, pivot shift in knees with a PTS of 20° was not eliminated even after a combined ACLR and ALSR.

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OBJECTIVE: To investigate the changes and clinical significance of NOD like receptor protein 3 (NLRP3) inflammasomes and related factors in patients with spinal fractures complicated with acute spinal cord injury (SCI). METHODS: Eighty-six spinal fracture patients complicated with acute SCI admitted to hospital from June 2019 to March 2022 were selected as SCI group, There were 48 males and 38 females, with an average age of (43.48±6.58) years old. And 100 healthy volunteers who underwent physical examination during the same time were selected as control group, including 56 males patients and 44 females patients, with an average age of (45.13±6.43) years old. Peripheral blood mononuclear cell (PBMC) were collected, and the mRNA expressions of NLRP3 and Caspase-1 were detected. Serum was collected and the levels of interleukin (IL)- 1ß, IL-18 were detected. According to Frankel's grade, the SCI group was divided into complete injury patients and incomplete injury patients, and according to the Japanese Orthopedic Society (JOA) grade, the SCI group was divided into good prognosis group and poor prognosis group. The difference of NLRP3, Caspase-1, IL-1ß, IL-18 among groups were compared, the influencing factors for poor prognosis in SCI patients was analyzed by Logistic regression. RESULTS: The mRNA expression levels of NLRP3 (1.41±0.33) and Caspase-1 (1.44±0.35) in PBMC and the levels of IL-1ß(45.34±13.22) pg·ml-1, IL-18(40.95±8.77) pg·ml-1 in serum of SCI group were higher than those of the control group[(1.00±0.19), (1.00±0.16), (16.58±4.24) pg·ml-1, (12.57±3.68) pg·ml-1] (P<0.05). The mRNA expression levels of NLRP3(1.63±0.34) and Caspase-1 (1.67±0.27) in PBMC and the levels of IL-1ß(51.09±11.10) pg·ml-1, IL-18 (47.65±7.93) pg·ml-1 in serum of patients with complete injury in the SCI group were higher than those of patients with incomplete injury [(1.31±0.27), (1.34±0.33), (42.85±13.36) pg·ml-1, (38.05±7.48) pg·ml-1](P<0.05). The mRNA expression levels of NLRP3 (1.66±0.31) and Caspase-1 (1.72±0.31)in PBMC and the levels of IL-1ß(51.21±11.31) pg·ml-1, IL-18 (45.70±7.25) pg·ml-1 in serum, the proportion of complete injury(21 patients), and the proportion of spinal cord edema or bleeding of patients(15 patients) with poor prognosis in the SCI group were higher than those of patients with good prognosis[(1.28±0.26), (1.37±0.36), (42.79±13.25) pg·ml-1、(38.90±8.63) pg·ml-1, 5、20 cases](P<0.05). Complete injury and the mRNA expression of NLRP3 in PBMC were the influencing factors for poor prognosis in the SCI group (P<0.05). CONCLUSION: The activation of NLRP3 inflammasomes in patients with spinal fractures complicated with acute SCI is associated with worsening injury and poor prognosis, and NLRP3 expression can serve as a marker for evaluating prognosis.

Asunto(s)

Caspasa 1 , Inflamasomas , Interleucina-18 , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR , Traumatismos de la Médula Espinal , Fracturas de la Columna Vertebral , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Masculino , Femenino , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/sangre , Adulto , Persona de Mediana Edad , Interleucina-18/sangre , Interleucina-1beta/sangre , Interleucina-1beta/genética , Caspasa 1/sangre , Fracturas de la Columna Vertebral/sangre , Fracturas de la Columna Vertebral/complicaciones , Leucocitos Mononucleares/metabolismo , Pronóstico , Relevancia Clínica

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BACKGROUND AND OBJECTIVE: Endometriosis and adenomyosis are two common diseases that impair women's health, and dienogest is one of the pharmacologic treatments which is the first-line therapeutic option for patients with pelvic pain and individuals who have no desire for immediate pregnancy. The goal of this study was to summarize the current evidence of adverse events associated with dienogest as well as the prevalence of these adverse events during treatment with dienogest. METHODS: Several databases (PubMed, Embase, Cochrane Central and Clinicaltrials.gov, etc.) and the US FDA Adverse Event Reporting System (FAERS) Public Dashboard were searched on May 31, 2023, using the topic words alongside free words of dienogest and "adverse reaction". Studies were incorporated into this research if they reported or assessed safety issues or adverse reactions of dienogest during the period of endometriosis treatment or adenomyosis therapy. The extracted information comprised trial design, dienogest and control group demographics, as well as reported side effects. RESULTS: This systematic review comprehended 39 publications in total. The mean age of patients in the included studies was 34.43 years. The follow-up duration varied from 3 to 60 months. Most adverse reactions were common and not serious, and the most common adverse reactions during dienogest medication were abnormal uterine bleeding (55%, 95% CI 37-73%), amenorrhea (17%, 95% CI 2-42%) and swelling (13%, 95% CI 3-28%). Uncommon adverse reactions included dysmenorrhea (0.2%, n = 1), dyspepsia (0.4%, n = 1), and (lower) abdominal pain (1%, 95% CI 0-3%), urticaria (1%, 95% CI 0-3%) and peritonitis (1%, n = 1). Serious adverse reactions including decreased lumbar spine Bone Mineral Density (BMD), depression, peritonitis and so on have been reported. Heterogeneity assessment revealed that patient number and study design are influencing factors to adverse reaction prevalence. Moreover, abdominal pain, diarrhea, nausea and vomiting, back pain and anemia are side effects reported both in the FAERS database and in the systematic review. CONCLUSIONS: Dienogest's most frequent side effects were not severe. Dienogest is generally safe for treating endometriosis and adenomyosis. Nevertheless, people should be aware of serious adverse reactions, such as decreased lumbar spine BMD and hemorrhagic shock.

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Teorema de Bayes , Endometriosis , Nandrolona , Humanos , Nandrolona/análogos & derivados , Nandrolona/efectos adversos , Nandrolona/uso terapéutico , Femenino , Endometriosis/tratamiento farmacológico , Adenomiosis/tratamiento farmacológico , Antagonistas de Hormonas/efectos adversos , Antagonistas de Hormonas/uso terapéutico

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Motivation: Large datasets containing multiple clinical and omics measurements for each subject motivate the development of new statistical methods to integrate these data to advance scientific discovery. Model: We propose bootstrap evaluation of association matrices (BEAM), which integrates multiple omics profiles with multiple clinical endpoints. BEAM associates a set omic features with clinical endpoints via regression models and then uses bootstrap resampling to determine statistical significance of the set. Unlike existing methods, BEAM uniquely accommodates an arbitrary number of omic profiles and endpoints. Results: In simulations, BEAM performed similarly to the theoretically best simple test and outperformed other integrated analysis methods. In an example pediatric leukemia application, BEAM identified several genes with biological relevance established by a CRISPR assay that had been missed by univariate screens and other integrated analysis methods. Thus, BEAM is a powerful, flexible, and robust tool to identify genes for further laboratory and/or clinical research evaluation. Availability: Source code, documentation, and a vignette for BEAM are available on GitHub at: https://github.com/annaSeffernick/BEAMR. The R package is available from CRAN at: https://cran.r-project.org/package=BEAMR. Contact: Stanley.Pounds@stjude.org. Supplementary Information: Supplementary data are available at the journal's website.

RESUMEN

Background: In individuals receiving treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), those exhibiting positive PD-L1 expression might experience reduced progression-free survival (PFS). However, the effects on overall survival (OS) and the determination of efficacious treatment approaches are still not well-defined. Methods: In our retrospective study, we examined data from 193 NSCLC patients with advanced EGFR mutations who received first-line TKI treatments, treated at two centers of Shaw Hospital in Zhejiang, China. This analysis covered a period from 1 January 2016 to 30 April 2023. Results: Patients with PD-L1 positivity exhibited a markedly shorter average PFS (9.5 months versus 17.8 months, P < 0.001) and OS (44.4 months versus 65.7 months, P = 0.016) relative to those without PD-L1 expression. This difference in both PFS and OS remained statistically significant even after adjusting for multiple factors (P < 0.001 for PFS and P = 0.028 for OS). In the PD-L1-positive cohort, introducing combination antiangiogenic significantly extended both PFS (from 9.1 to 25.7 months, P = 0.026) and OS (from 42 to 53.5 months, P = 0.03). Post-first-line TKI therapy, 39.3% of PD-L1-positive patients and 54.5% of PD-L1-negative patients developed the T790M mutation (P = 0.212), with no notable difference in PFS from second-line TKI treatments between the groups. Additionally, subsequent combination therapy with immunotherapy markedly prolonged OS in the PD-L1-positive group. However, for PD-L1-negative patients, neither combination antiangiogenic therapy nor later-line immunotherapy demonstrated significant benefits in PFS or OS. Conclusion: For PD-L1-positive patients, combined antiangiogenic treatments and immunotherapy can significantly improve survival outcomes. In contrast, PD-L1-negative patients show less benefit from these therapies, highlighting the greater efficacy of these treatments in PD-L1-positive individuals.