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Majorbio Cloud (https://cloud.majorbio.com/) is a one-stop online analytic platform aiming at promoting the development of bioinformatics services, narrowing the gap between wet and dry experiments, and accelerating the discoveries for the life sciences community. In 2024, three single-omics workflows, two multiomics workflows, and extensions were newly released to facilitate omics data mining and interpretation.
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BACKGROUND: To evaluate the efficiency of artificial intelligence (AI)-assisted diagnosis system in the pulmonary nodule detection and diagnosis training of junior radiology residents and medical imaging students. METHODS: The participants were divided into three groups. Medical imaging students of Grade 2020 in the Jinzhou Medical University were randomly divided into Groups 1 and 2; Group 3 comprised junior radiology residents. Group 1 used the traditional case-based teaching mode; Groups 2 and 3 used the 'AI intelligent assisted diagnosis system' teaching mode. All participants performed localisation, grading and qualitative diagnosed of 1,057 lung nodules in 420 cases for seven rounds of testing after training. The sensitivity and number of false positive nodules in different densities (solid, pure ground glass, mixed ground glass and calcification), sizes (less than 5 mm, 5-10 mm and over 10 mm) and positions (subpleural, peripheral and central) of the pulmonary nodules in the three groups were detected. The pathological results and diagnostic opinions of radiologists formed the criteria. The detection rate, diagnostic compliance rate, false positive number/case, and kappa scores of the three groups were compared. RESULTS: There was no statistical difference in baseline test scores between Groups 1 and 2, and there were statistical differences with Group 3 (P = 0.036 and 0.011). The detection rate of solid, pure ground glass and calcified nodules; small-, medium-, and large-diameter nodules; and peripheral nodules were significantly different among the three groups (P<0.05). After seven rounds of training, the diagnostic compliance rate increased in all three groups, with the largest increase in Group 2. The average kappa score increased from 0.508 to 0.704. The average kappa score for Rounds 1-4 and 5-7 were 0.595 and 0.714, respectively. The average kappa scores of Groups 1,2 and 3 increased from 0.478 to 0.658, 0.417 to 0.757, and 0.638 to 0.791, respectively. CONCLUSION: The AI assisted diagnosis system is a valuable tool for training junior radiology residents and medical imaging students to perform pulmonary nodules detection and diagnosis.
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Inteligencia Artificial , Internado y Residencia , Radiología , Femenino , Humanos , Masculino , Competencia Clínica , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Radiología/educación , Nódulo Pulmonar Solitario/diagnóstico por imagen , Nódulo Pulmonar Solitario/diagnóstico , Estudiantes de MedicinaRESUMEN
BACKGROUND: Ribosome biogenesis is excessively activated in tumor cells, yet it is little known whether oncogenic transcription factors (TFs) are involved in the ribosomal RNA (rRNA) transactivation. METHODS: Nucleolar proteomics data and large-scale immunofluorescence were re-analyzed to jointly identify the proteins localized at nucleolus. RNA-Seq data of five prostate cancer (PCa) cohorts were combined and integrated with multi-dimensional data to define the upregulated nucleolar TFs in PCa tissues. Then, ChIP-Seq data of PCa cell lines and two PCa clinical cohorts were re-analyzed to reveal the TF binding patterns at ribosomal DNA (rDNA) repeats. The TF binding at rDNA was validated by ChIP-qPCR. The effect of the TF on rRNA transcription was determined by rDNA luciferase reporter, nascent RNA synthesis, and global protein translation assays. RESULTS: In this study, we reveal the role of oncogenic TF FOXA1 in regulating rRNA transcription within nucleolar organization regions. By analyzing human TFs in prostate cancer clinical datasets and nucleolar proteomics data, we identified that FOXA1 is partially localized in the nucleolus and correlated with global protein translation. Our extensive FOXA1 ChIP-Seq analysis provides robust evidence of FOXA1 binding across rDNA repeats in prostate cancer cell lines, primary tumors, and castration-resistant variants. Notably, FOXA1 occupancy at rDNA repeats correlates with histone modifications associated with active transcription, namely H3K27ac and H3K4me3. Reducing FOXA1 expression results in decreased transactivation at rDNA, subsequently diminishing global protein synthesis. CONCLUSIONS: Our results suggest FOXA1 regulates aberrant ribosome biogenesis downstream of oncogenic signaling in prostate cancer.
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Factor Nuclear 3-alfa del Hepatocito , Neoplasias de la Próstata , ARN Ribosómico , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , ARN Ribosómico/biosíntesis , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-alfa del Hepatocito/genética , Línea Celular Tumoral , Transcripción Genética , Regulación Neoplásica de la Expresión Génica , Nucléolo Celular/metabolismoRESUMEN
This study focused on the association of LINC01270 and computed tomography (CT) signs with glioma development, to evaluate their potential in the early detection of glioma. Serum LINC01270 was evaluated in glioma patients and healthy individuals using PCR. The involvement of LINC01270 in glioma onset and development was evaluated by ROC and chisquare test. The association of LINC01270 with the CT signs and their combined effects in the diagnosis in glioma were also estimated. Serum LINC01270 was significantly elevated in glioma patients, which was closely associated with patients' advanced WHO grades and lower KPS. Both LINC01270 upregulation and CT findings showed significant potential in diagnosing glioma, and LINC01270 correlated significantly with the invasion risk and metastasis indicated on CT. The combination of LINC01270 expression and CT findings significantly improved the sensitivity and specificity of glioma diagnosis. Upregulated LINC01270 in glioma is associated with malignant and severe disease development and has significant diagnostic value. Combined detection of LINC01270 and CT findings could improve the diagnostic efficacy in glioma cases, thus optimizing clinical diagnosis.
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Glioma , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Glioma/diagnóstico por imagen , Glioma/genética , Tomografía Computarizada por Rayos X , Regulación hacia ArribaRESUMEN
Given the increasing use of bevacizumab in combinatorial drug therapy for a multitude of different cancer types, there is a need for therapeutic drug monitoring to analyze the possible correlation between drug trough concentration, and therapeutic effect and adverse reactions. An ultra-performance liquid chromatography tandem-mass spectrometry method was then developed and validated to determine bevacizumab levels in human plasma samples. Chromatographic separation was achieved on a Shimadzu InertSustainBio C18 HP column, whereas subsequent mass spectrometric analysis was performed using a Shimadzu 8050CL triple quadrupole mass spectrometer equipped with an electro-spray ionization source in the positive ion mode. In total, three multiple reaction monitoring transitions of each of the surrogate peptides were chosen with 'FTFSLDTSK' applied as the quantification peptide whereas 'VLIYFTSSLHSGVPSR' and 'STAYLQMNSLR' were designated as the verification peptides using the Skyline software. This analytical method was then fully validated, with specificity, linearity, lower limit of quantitation, accuracy, precision, stability, matrix effect and recovery calculated. The linearity of this method was developed to be within the concentration range 5-400 µg/ml for bevacizumab in human plasma. Subsequently, eight patients with non-small cell lung cancer (NSCLC) were recruited and injected with bevacizumab over three periods of treatment to analyze their steady-state trough concentration and differences. To conclude, the results of the present study suggest that bevacizumab can be monitored in a therapeutic setting in patients with NSCLC.
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In this paper, we explore a nonlinear interactive network system comprising nodalized flapping-wing micro air vehicles (FMAVs) to address the distributed H∞ state estimation problem associated with FMAVs. We enhance the model by introducing an information fusion function, leading to an information-fusionized estimator model. This model ensures both estimation accuracy and the completeness of FMAV topological information within a unified framework. To facilitate the analysis, each FMAV's received signal is individually sampled using independent and time-varying samplers. Transforming the received signals into equivalent bounded time-varying delays through the input delay method yields a more manageable and analyzable time-varying nonlinear network error system. Subsequently, we construct a Lyapunov-Krasovskii functional (LKF) and integrate it with the refined Wirtinger and relaxed integral inequalities to derive design conditions for the FMAVs' distributed H∞ state estimator, minimizing conservatism. Finally, we validate the effectiveness and superiority of the designed estimator through simulations.
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OBJECTIVES: To explore the relationship between cumulative ecological risk and individual risky behavior and multiple forms of aggregated behaviors among adolescents, and examine the gender differences. METHODS: A large-scale, nationally representative, and students-based investigation was conducted in rural and urban areas of eight provinces in China from October to December 2021. A total of 22 868 adolescents with an average age of 14.64 years completely standardized questionnaire in which the sociodemographic characteristics, socio-ecological risk factors and risky behaviors were used to analyze. RESULTS: Of included students, 48.4% encountered the high level of social-ecological risk. The prevalence of breakfast intake not daily, alcohol use (AU), smoking, physical inactivity, prolonged screen time (ST) on weekdays and weekends, suicidal ideation, suicidal plan, suicidal attempt, and non-suicidal self-injury (NSSI) was 41.0%, 11.9%, 3.4%, 61.9%, 15.1%, 51.1%, 27.7%, 13.9%, 6.5% and 27.0% respectively. 22.2% of participants engaged in high-risk behaviors. All were significantly influences of increased cumulative ecological risk on individual behavior and low-risk clustering behaviors separately. The odds ratio of breakfast intake not daily, AU, smoking, physical inactivity, prolonged ST in weekday and weekend, suicidal ideation, suicidal plan, suicidal attempt, and NSSI for the adjusted model in low versus high level of cumulative ecological risk was respectively significant in both boy and girls, and the ratio of odds ratios (ROR) was separately 0.95 (p = 0.228), 0.67 (p < 0.001), 0.44 (p < 0.001), 0.60 (p < 0.001), 0.78 (p = 0.001), 0.83 (p = 0.001), 0.80 (p = 0.001), 0.83 (p = 0.022), 0.71 (p = 0.005), 0.75 (p = 0.001). Girls encountering a high level of cumulative ecological risk were more likely to engage in multiple forms of clustering risky behaviors than boys (RORs: 0.77, p = 0.001). CONCLUSIONS: Research and effective inventions at the social-ecological environment, based on the view of cumulative risk, are needed to promote the healthy development of behaviors in adolescence, and pay more attention to decreasing the occurrence of risky behaviours in girls than boys.
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Conductas de Riesgo para la Salud , Conducta Autodestructiva , Masculino , Femenino , Humanos , Adolescente , Intento de Suicidio , Ideación Suicida , Conducta Autodestructiva/epidemiología , Factores de Riesgo , China/epidemiología , Encuestas y CuestionariosRESUMEN
This study proposed a scheme for improving people's health from the perspective of digital infrastructure construction. We used the China Family Panel Studies conducted between 2010 and 2020 and the digital infrastructure construction marked by the Broadband China policy between 2014 and 2016 as a quasi-natural experiment. We adopted the multi-time difference-in-differences method to identify the causal relationship between digital infrastructure and people's health. We found that digital infrastructure construction significantly improved people's health, and the effect was more prominent among young and middle-aged residents and those with less than a university education. Moreover, digital infrastructure construction improved the utilization of medical services, helped residents develop healthy lifestyles, and increased people's health investments. Additionally, digital infrastructure reduced health inequality among people and promoted health equity. The findings could guide future policies to improve people's health and well-being.
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Disparidades en el Estado de Salud , Salud Pública , Persona de Mediana Edad , Humanos , China , Salud Digital , PolíticasRESUMEN
As one of the most frequent intracranial tumors, glioma showed invasive development and poor prognosis. lncRNAs have been illustrated to serve as biomarkers in various cancers. Whether the long non-coding RNA Prader Willi/Angelman region RNA 6 (PWAR6) was involved in glioma development and the underlying mechanism was investigated. PWAR6 in glioma was evaluated by polymerase chain reaction and its clinical significance was assessed with a series of statistical analyses. The biological function of PWAR6 was investigated with the cell counting kit 8 and Transwell assay. The potential underlying mechanism was studied with the luciferase reporter assay. The significant downregulation of PWAR6 was observed in glioma, which showed a close relationship with the major clinicopathological features and poor prognosis of patients. PWAR6 restrained cell growth, migration and invasion of glioma, which was alleviated by the overexpression of microRNA-106a-5p (miR-106a-5p). PWAR6 functioned as a prognostic biomarker and tumor suppressor of glioma through regulating miR-106a-5p.
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OBJECTIVE: Oxidative stress plays a pivotal role in neurodegenerative diseases. Astaxanthin (AST) can play a neuroprotective role owing to its long-chain conjugated unsaturated double bond, which imparts potent antioxidant, anti-neuroinflammatory, and anti-apoptotic properties. However, the biological mechanisms underlying these effects remain unknown. Therefore, this study aimed to investigate and validate the protective effect of AST on neuronal senescence and apoptosis caused by oxidative stress induced by Aß25-35 peptide, with the goal of preventing the onset of cognitive dysfunction. METHODS: Alzheimer's disease models comprising ICR mice and PC12 cells were established using Aß25-35. The Morris water maze test was used to assess mouse behavior. Nissl staining revealed morphological changes in the mouse hippocampal neurons. To elucidate the mechanism of action of AST, ICR mice and PC12 cells were treated with the silent information regulator 1 (SIRT1) inhibitor nicotinamide (NAM). Additionally, immunofluorescence, western blotting, and reverse transcription polymerase chain reaction were used to evaluate changes in the expression of Bcl-2 and Bax in the mouse hippocampus, and SIRT1/PGC-1α signaling pathway proteins were detected. Moreover, the oxidative stress markers in ICR mice and PC12 cells were evaluated. Further, CCK-8 assays, Annexin V/PI double staining, and ß-galactosidase activity assays were performed in PC12 cells to evaluate the anti-senescence and apoptotic effects of AST. RESULTS: In vivo experiments showed that Aß25-35 impaired cognitive function, promoted morphological changes in hippocampal neurons, decreased Bcl-2 expression, increased Bax expression, decreased superoxide dismutase and GSH-px levels, and increased reactive oxygen species and malondialdehyde levels. Conversely, AST alleviated the impact of Aß25-35 in mice, with reversed outcomes. NAM administration reduced SIRT1 and PGC-1α expression in the hippocampus. This decrease was accompanied by cognitive dysfunction and hippocampal neuron atrophy, which were also evident in the mice. Additionally, in vitro experiments showed that Aß25-35 could promote oxidative stress and induce the senescence and apoptosis of PC12 cells. Nonetheless, AST treatment counteracted this effect by inhibiting oxidative stress and altering the state of PC12 cells. Notably, the Aß + NAM group exhibited the most significant rates of senescence and apoptosis in PC12 cells following NAM treatment. CONCLUSION: AST can improve cellular senescence and apoptosis mediated by oxidative stress via the SIRT1/PGC-1α signaling pathway and plays a vital role in inhibiting neuronal senescence and apoptosis and enhancing cognitive ability.
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BACKGROUND AND AIMS: A few researches have reported the exposure-efficacy/toxicity relationships of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). On account of the large interpatient pharmacokinetic variability, therapeutic drug monitoring (TDM) seems promising for optimizing dosage regimen and improving treatment efficacy and safety. Therefore, a rapid and convenient ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of icotinib, osimertinib, gefitinib and O-demesthyl gefitinib in human plasma for TDM. MATERIALS AND METHODS: Icotinib-D4 and osimertinib-13CD3 were used as the internal standards (ISs). The samples were prepared by protein precipitation using acetonitrile. Chromatographic separation was achieved on a 40 â Shimadzu Shim-pack Scepter C18-120 column (2.1 ×50 mm, 3.0 µm, Japan) by a Shimadzu 30 A solvent management system. Detection was carried out using a Shimadzu LC-MS 8050CL triple quadrupole mass spectrometer coupled with an electrospray ionization source in positive mode. RESULTS: This analytical method was fully validated with selectivity, carry-over, linearity, lower limit of quantification, accuracy (from 92.68% to 106.62%) and precision (intra- and inter-day coefficients of variation ranged from 0.92% to 9.85%), matrix effect, extraction recovery, stability and dilution integrity. The calibration curves were developed to be within the concentration ranges of 200-4000 ng/mL for icotinib, 50-1000 ng/mL for osimertinib, gefitinib and O-desmethyl gefitinib in human plasma which meet the needs of routine TDM. CONCLUSIONS: The proposed method was used in 100 patients with non-small cell lung cancer for monitoring plasma concentration of the mentioned EGFR-TKIs. The trough concentrations of ICO were distributed between 226.42 ng/mL and 3853.36 ng/mL, peak concentrations were between 609.20 ng/mL and 2191.54 ng/mL. The trough concentrations of OSI were distributed between 110.48 ng/mL and 1183.13 ng/mL. The trough concentrations of GEF were distributed between 117.71 ng/mL and 582.74 ng/mL, while DeGEF was distributed from 76.21 ng/mL to 1939.83 ng/mL with two less than 20 ng/mL. The results of therapeutic drug monitoring aimed to investigate exposure-efficacy/toxicity relationship and improve the efficacy and safety of targeted therapies.
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The recycling of organic solvents is a widely discussed topic. The waste organic solvents from thin-film-transistor liquid-crystal display (TFT-LCD) production is characterized by large quantities, multiple types, and complex compositions. Thus, the unified and compatible component analysis method is important for studying the recovery of waste organic solvents. In our work, based on the study of existing analytical methods, we designed a compatible method for the analysis of moisture using Karl Fischer analysis, for the analysis of organic compounds using gas chromatography, and for the analysis of the photoresist and other solids by evaporation. These were specific methods for analyzing the components of near-total formulation thin-film-transistor liquid-crystal display waste organic solvent. The organic matter content was analyzed via gas chromatography with a CP-Sil8CB column and flame ionization detector. The initial temperature of the column was 90 °C and the holding time was 1 min. The heating rate was 30 °C/min. The temperature was raised to 270 °C for 7 min. The internal standard method and the external standard method were used to determine the content of the main components of organic compounds. The relative standard deviation of the analytical results was 1.14~2.93%, 1.21~4.74% and 0.61%, respectively. The analytical results had good accuracy, but the external standard method was better; the recoveries were 99.76~107.60%, 95.86~107.70%, and 95.23~96.88%, respectively. Based on the composition analysis, the composition rule of the waste organic solvent was summarized. Through the exploration of the effect of the waste solvent, the common characteristics of the waste solvent were obtained. This study provides a good strategy and an optimized method for improving the efficiency of organic solvent recovery.
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Objectives: Teicoplanin has been extensively used in the treatment for infections caused by gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). However, current teicoplanin treatment is challenging due to relatively low and variable concentrations under standard dosage regimens. This study aimed to investigate the population pharmacokinetics (PPK) characteristics of teicoplanin in adult sepsis patients and provide recommendations for optimal teicoplanin dosing regimens. Methods: A total of 249 serum concentration samples from 59 septic patients were prospectively collected in the intensive care unit (ICU). Teicoplanin concentrations were detected, and patients' clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modeling approach. Monte Carlo simulations were performed to evaluate currently recommended dosing and other dosage regimens. The optimal dosing regimens were defined and compared by different pharmacokinetic/pharmacodynamic parameters, including trough concentration (Cmin), the ratio of 24-h area under the concentration-time curve to the minimum inhibitory concentration (AUC0-24/MIC), as well as the probability of target attainment (PTA) and the cumulative fraction of response (CFR) against MRSA. Results: A two-compartment model adequately described the data. The final model parameter estimates for clearance, central compartment volume of distribution, intercompartmental clearance and peripheral compartment volume were 1.03 L/h, 20.1 L, 3.12 L/h and 101 L, respectively. Glomerular filtration rate (GFR) was the only covariate that significantly affected teicoplanin clearance. Model-based simulations revealed that 3 or 5 loading doses of 12/15 mg/kg every 12 h followed by a maintenance dose of 12/15 mg/kg every 24 h-72 h for patients with different renal functions were required to achieve a target Cmin of 15 mg/L and a target AUC0-24/MIC of 610. For MRSA infections, PTAs and CFRs were not satisfactory for simulated regimens. Prolonging the dosing interval may be easier to achieve the target AUC0-24/MIC than reducing the unit dose for renal insufficient patients. Conclusion: A PPK model for teicoplanin in adult septic patients was successfully developed. Model-based simulations revealed that current standard doses may result in undertherapeutic Cmin and AUC, and a single dose of at least 12 mg/kg may be needed. AUC0-24/MIC should be preferred as the PK/PD indicator of teicoplanin, if AUC estimation is unavailable, in addition to routine detection of teicoplanin Cmin on Day 4, follow-up therapeutic drug monitoring at steady-state is recommended.
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AIM: The guideline is meant to standardize the principles, procedures, and methods for developing therapeutic drug monitoring (TDM) guidelines and promoting open, transparent, scientific, and credible TDM guidelines. METHODS: Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society established guideline working groups, declared and managed conflicts of interest. The guideline working groups used the Delphi method to formulate the purpose and scope of the guidelines and questions in the PICO format, searched and synthesized evidence, and integrated with the current situation in China and TDM characteristics to preliminarily develop recommendations for the guideline for TDM guideline development in China. Through internal discussions of the guideline working groups and external peer review, the content was improved, and we eventually formulated a guideline suitable for guiding TDM-related guidelines. RESULTS: The guideline provides suggestions for problems to be identified and solved in the planning, development, publishing, and updating stages of TDM guidelines, including forming guideline working groups, planning guidelines, declaration and management of interests, formulating questions and selecting outcomes, preparing the planning proposal, evidence retrieval and synthesis, evidence assessment, developing recommendations, drafting guidelines, external review guidelines, publishing and disseminating guidelines, postevaluation of guidelines, and updating guidelines. CONCLUSIONS: This guideline can provide methodological guidance and reference for the development of TDM guidelines.
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Monitoreo de Drogas , China , Monitoreo de Drogas/métodosRESUMEN
Ribosomal deoxyribonucleic acid (DNA) (rDNA) repeats are tandemly located on five acrocentric chromosomes with up to hundreds of copies in the human genome. DNA methylation, the most well-studied epigenetic mechanism, has been characterized for most genomic regions across various biological contexts. However, rDNA methylation patterns remain largely unexplored due to the repetitive structure. In this study, we designed a specific mapping strategy to investigate rDNA methylation patterns at each CpG site across various physiological and pathological processes. We found that CpG sites on rDNA could be categorized into two types. One is within or adjacent to transcribed regions; the other is distal to transcribed regions. The former shows highly variable methylation levels across samples, while the latter shows stable high methylation levels in normal tissues but severe hypomethylation in tumors. We further showed that rDNA methylation profiles in plasma cell-free DNA could be used as a biomarker for cancer detection. It shows good performances on public datasets, including colorectal cancer [area under the curve (AUC) = 0.85], lung cancer (AUC = 0.84), hepatocellular carcinoma (AUC = 0.91) and in-house generated hepatocellular carcinoma dataset (AUC = 0.96) even at low genome coverage (<1×). Taken together, these findings broaden our understanding of rDNA regulation and suggest the potential utility of rDNA methylation features as disease biomarkers.
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Carcinoma Hepatocelular , Ácidos Nucleicos Libres de Células , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Ácidos Nucleicos Libres de Células/genética , Islas de CpG , Metilación de ADN , ADN Ribosómico/genética , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Regiones Promotoras GenéticasRESUMEN
WHAT IS KNOWN AND OBJECTIVE: The presence of extracorporeal membrane oxygenation (ECMO) is suggested to further exacerbate the pharmacokinetics (PK) alterations that occur during critical illness. The objectives of this study were to determine the population PK model of polymyxin B in critically ill patients with or without ECMO support investigated the influence of ECMO on PK variability and to identify an optimal dosing strategy. METHODS: Forty-four critically ill patients were enrolled, including eight patients with ECMO support. Eight serial serum samples were collected from each patient at steady state. The population PK was determined using NONMEM and Monte Carlo simulation was performed to evaluate the exposures of different dosing regimens. RESULTS: The PK analyses included 342 steady-state concentrations and a two-compartment model was optimal for polymyxin B PK data modelling. In the final model, creatinine clearance (CLCR ) was the significant covariate on CL (typical value 1.27 L/h; between-subject variability 15.1%) and ECMO did not show a significant impact on the polymyxin B PK. Additionally, we found that the PK parameter estimates of patients with and without ECMO support were mostly similar. Based on Monte Carlo simulations, the dose escalation of polymyxin B in patients with increased CLCR improved the probability of achieving required exposure. For patients with CLCR ≤ 120 ml/min, a dosage regimen of 100 mg every 12 h may represent the optimal regimen at an MIC of 1 mg/L. WHAT IS NEW AND CONCLUSION: The impact of ECMO on the polymyxin B PK is likely to be minimal. Our study showed a potential relationship between CLCR and polymyxin B CL, and the dose of polymyxin B should be adjusted in patients with increased CLCR .
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Enfermedad Crítica , Oxigenación por Membrana Extracorpórea , Antibacterianos , Creatinina , Humanos , Pruebas de Sensibilidad Microbiana , Polimixina BRESUMEN
MOTIVATION: Intermediately methylated regions occupy a significant fraction of the human genome and are closely associated with epigenetic regulations or cell-type deconvolution of bulk data. However, these regions show distinct methylation patterns, corresponding to different biological mechanisms. Although there have been some metrics developed for investigating these regions, the high noise sensitivity limits the utility for distinguishing distinct methylation patterns. RESULTS: We proposed a method named MeConcord to measure local methylation concordance across reads and CpG sites, respectively. MeConcord showed the most stable performance in distinguishing distinct methylation patterns ('identical', 'uniform' and 'disordered') compared with other metrics. Applying MeConcord to the whole genome data across 25 cell lines or primary cells or tissues, we found that distinct methylation patterns were associated with different genomic characteristics, such as CTCF binding or imprinted genes. Further, we showed the differences of CpG island hypermethylation patterns between senescence and tumorigenesis by using MeConcord. MeConcord is a powerful method to study local read-level methylation patterns for both the whole genome and specific regions of interest. AVAILABILITY AND IMPLEMENTATION: MeConcord is available at https://github.com/WangLabTHU/MeConcord. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Metilación de ADN , Genoma Humano , Línea Celular , Islas de CpG , Genómica , HumanosRESUMEN
Background: Radiomics is characterized by high-throughput extraction of texture features from medical images and the mining of information that can potentially be used to define neuroimaging markers in many neurological or psychiatric diseases. However, there have been few studies concerning MRI radiomics in post-traumatic stress disorder (PTSD). The study's aims were to appraise changes in microstructure of the medial prefrontal cortex (mPFC) in a PTSD animal model, specifically single-prolonged stress (SPS) rats, by using MRI texture analysis. The feasibility of using a radiomics approach to classify PTSD rats was examined. Methods: Morris water maze and elevated plus maze were used to assess behavioral changes in the rats. Two hundred and sixty two texture features were extracted from each region of interest in T2-weighted images. Stepwise discriminant analysis (SDA) and LASSO regression were used to perform feature selection and radiomics signature building to identify mPFC radiomics signatures consisting of optimal features, respectively. Receiver operating characteristic curve plots were used to evaluate the classification performance. Immunofluorescence techniques were used to examine the expression of glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) in the mPFC. Nuclear pycnosis was detected using 4',6-diamidino-2-phenylindole (DAPI) staining. Results: Behavioral results indicated decreased learning and spatial memory performance and increased anxiety-like behavior after SPS stimulation. SDA analysis showed that the general non-cross-validated and cross-validated discrimination accuracies were 86.5% and 80.4%. After LASSO dimensionality reduction, 10 classification models were established. For classifying PTSD rats between the control and each SPS group, these models achieved AUCs of 0.944, 0.950, 0.959, and 0.936. Among four SPS groups, the AUCs were 0.927, 0.943, 0.967, 0.916, 0.932, and 0.893, respectively. The number of GFAP-positive cells and intensity of GFAP-IR within the mPFC increased 1 day after SPS treatment, and then decreased. The intensity of NeuN-IR and number of NeuN-positive cells significantly decreased from 1 to 14 days after SPS stimulation. The brightness levels of DAPI-stained nuclei increased in SPS groups. Conclusion: Non-invasive MRI radiomics features present an efficient and sensitive way to detect microstructural changes in the mPFC after SPS stimulation, and they could potentially serve as a novel neuroimaging marker in PTSD diagnosis.
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For decades, coaxial printing has been widely applied in 3D tissue engineering scaffold fabrication. However, there are few reports regarding polymeric materials application in shell production due to fabrication constraints. In this study, a combination of cryogenic printing and coaxial printing aims to approach the challenge. Polycaprolactone (PCL) and sodium alginate (SA) were selected as the representative shell and core materials to test the feasibility of the coaxial cryogenic printing by optimizing key parameters, including working temperature, air pressure, PCL, and SA concentration. According to the optical and SEM images, the SA core contracts a string inside the PCL shell, illustrating the shell/core structure of the 3D coaxial PCL/SA scaffolds. Besides, the shell/core 3D scaffold possesses a 38.39 MPa Young's modulus in mechanical tests; the PCL shell could retain at least 8 h in 5 mol/L HCl solution, leading to a fabricated drug-loaded PCL/SA shell/core "responsive" to acidic pH. In summary, coaxial cryogenic printing was developed to fabricate 3D scaffolds with a PCL/SA shell/core scaffold, broadening the material range of coaxial printing and providing promising applications in drug release.