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Against the backdrop of escalating environmental pollution and resource depletion induced by traditional agricultural industry development, the imperative for agricultural efficiency and ecologically friendly practices has become pivotal for global agricultural sustainability. In the digital era, rural digitalization has substantially amplified agricultural production efficiency while notably reducing environmental pollution. This study is based on panel data from 1602 counties in China spanning from 2011 to 2020, measuring the levels of rural digitalization and agricultural green total factor productivity (AGTFP) across these counties, empirically examining their dynamic correlation. The research findings reveal: (1) A significant enhancement of AGTFP with the elevation of rural digitalization; for every 1 % increase in rural digitalization, AGTFP increases by 1.78 %. Robustness checks, including instrumental variables and quasi-natural experiments, affirm the validity of these conclusions. Furthermore, by comparing regional differences in China, it can be observed that the impact of rural digitalization on AGTFP varies across different areas: in the eastern, central, and western regions, for every 1 % increase in rural digitalization, the AGTFP increases by 2.65 %, 1.53 %, and 0.82 %, respectively. (2) Rural digitalization fosters an increase in AGTFP by stimulating rural entrepreneurial activity, with the mediation effect of rural entrepreneurial activity accounting for 3.34 % of the total effect. (3) Utilizing a threshold model, observations indicate that when rural digitalization surpasses the first threshold of 0.3200, the AGTFP coefficient escalates from 0.0462 to 0.7519. However, when rural digitalization exceeds the second threshold of 0.7118, this coefficient declines to 0.2429, signifying a nonlinear trend in the marginal effect of rural digitalization on AGTFP-initial enhancement followed by attenuation. (4) In the spatial model analysis, the study confirms spatial spillover effects of rural digitalization on AGTFP, indicating variations in spatial effects among different matrices. However, the indirect effects of rural digitalization on AGTFP, mainly influenced by the neighboring counties' digitalization levels, contribute more significantly than the direct effects. Based on these conclusions, this paper proposes augmenting investments in rural digitalization, implementing diversified rural digitalization schemes, invigorating rural entrepreneurial activity, and harmonizing regional digital development as novel approaches to enhance AGTFP, thereby fostering rural economic development.
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Background: The effectiveness and safety of using Brucea javanica oil (BJO) in combination with Transarterial Chemoembolization (TACE) for liver cancer treatment are subjects of debate. This study aims to assess the comparative effectiveness and safety of BJO-assisted TACE versus TACE alone and quantifies the differences between these two treatment methods. Methods: A systematic search was conducted in multiple databases including PubMed, Cochrane, CNKI, and Wanfang, until 1 July 2023. Meta-analysis was conducted, and the results were presented as mean difference (MD), risk ratio (RR), and 95% confidence intervals (CI). Results: The search yielded 11 RCTs, with a combined sample size of 1054 patients. Meta-analysis revealed that BJO-assisted TACE exhibited superior outcomes compared to standalone TACE. Specific data revealed that BJO-assisted TACE improves clinical benefit rate by 22% [RR = 1.22, 95% CI (1.15, 1.30)], increases the number of people with improved quality of life by 32%, resulting in an average score improvement of 9.53 points [RR = 1.32, 95% CI (1.22, 1.43); MD = 9.53, 95% CI (6.95, 12.10)]. Furthermore, AFP improvement rate improved significantly by approximately 134% [RR = 2.34, 95% CI (1.58, 3.46)], accompanied by notable improvements in liver function indicators, with an average reduction of 27.19 U/L in AST [MD = -27.19, 95% CI (-40.36, -14.02)], 20.77 U/L in ALT [MD = -20.77, 95% CI (-39.46, -2.08)], 12.17 µmol/L in TBIL [MD = -12.17, 95% CI (-19.38, -4.97)], and a decrease of 43.72 pg/mL in VEGF [MD = -43.72, 95% CI (-63.29, -24.15)]. Most importantly, there was a 29% reduction in the occurrence of adverse reactions [RR = 0.71, 95% CI (0.60, 0.84)]. Conclusion: These findings indicate that BJO-assisted TACE may be considered as a potentially beneficial treatment option for liver cancer patients when compared to standalone TACE. It appears to contribute to improved treatment outcomes, enhanced quality of life, and potentially reduced adverse reactions, suggesting it warrants further investigation as a promising approach for liver cancer treatment. Systematic Review Registration: identifier CRD42023428948.
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BACKGROUND: A major challenge in prevention and early treatment of acute kidney injury (AKI) is the lack of high-performance predictors in critically ill patients. Therefore, we innovatively constructed U-AKIpredTM for predicting AKI in critically ill patients within 12 h of panel measurement. METHODS: The prospective cohort study included 680 patients in the training set and 249 patients in the validation set. After performing inclusion and exclusion criteria, 417 patients were enrolled in the training set and 164 patients were enrolled in the validation set finally. AKI was diagnosed by Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: Twelve urinary kidney injury biomarkers (mALB, IgG, TRF, α1MG, NAG, NGAL, KIM-1, L-FABP, TIMP2, IGFBP7, CAF22 and IL-18) exhibited good predictive performance for AKI within 12 h in critically ill patients. U-AKIpredTM, combined with three crucial biomarkers (α1MG, L-FABP and IGFBP7) by multivariate logistic regression analysis, exhibited better predictive performance for AKI in critically ill patients within 12 h than the other twelve kidney injury biomarkers. The area under the curve (AUC) of the U-AKIpredTM, as a predictor of AKI within 12 h, was 0.802 (95% CI: 0.771-0.833, P < 0.001) in the training set and 0.844 (95% CI: 0.792-0.896, P < 0.001) in validation cohort. A nomogram based on the results of the training and validation sets of U-AKIpredTM was developed which showed optimal predictive performance for AKI. The fitting effect and prediction accuracy of U-AKIpredTM was evaluated by multiple statistical indicators. To provide a more flexible predictive tool, the dynamic nomogram (https://www.xsmartanalysis.com/model/U-AKIpredTM) was constructed using a web-calculator. Decision curve analysis (DCA) and a clinical impact curve were used to reveal that U-AKIpredTM with the three crucial biomarkers had a higher net benefit than these twelve kidney injury biomarkers respectively. The net reclassification index (NRI) and integrated discrimination index (IDI) were used to improve the significant risk reclassification of AKI compared with the 12 kidney injury biomarkers. The predictive efficiency of U-AKIpredTM was better than the NephroCheck® when testing for AKI and severe AKI. CONCLUSION: U-AKIpredTM is an excellent predictive model of AKI in critically ill patients within 12 h and would assist clinicians in identifying those at high risk of AKI.
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AIM: To evaluate the trending visual performance of different intraocular lenses (IOLs) over time after implantation. METHODS: Ninety-one patients received cataract surgery with implantations of monofocal (Mon) IOLs, segmental refractive (SegRef) IOLs, diffractive (Dif) IOLs, and extended-depth-of-focus (EDoF) IOLs were included. The aberrations and optical quality collected with iTrace and OQAS within postoperative 6mo were followed and compared. RESULTS: Most of the visual parameters improved over the postoperative 6mo. The postoperative visual acuity (POVA) of the Mon IOL, SegRef IOL, and EDoF IOL groups achieved relative stability in earlier states compared with the Dif IOL group. Nevertheless, the overall visual performance of the 3 IOLs continued to upturn in small extents within the postoperative 6mo. The optical quality initially improved in the EDoF IOL group, then in the Mon IOL, SegRef IOL, and Dif IOL groups. POVA and objective visual performance of the Mon IOL and EDoF IOL groups, as well as POVA and visual quality of the Dif IOL group, improved in the postoperative 1mo and stabilized. Within the postoperative 6mo, gradual improvements were observed in the visual acuity and objective visual performance of the SegRef IOL group, as well as in the postoperative optical quality of the Dif IOL group. CONCLUSION: The visual performance is different among eyes implanted with different IOLs. The findings of the current study provide a potential reference for ophthalmologists to choose suitable IOLs for cataract patients in a personalized solution.
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Background: Sepsis is a severe and potentially life-threatening condition characterized by a dysregulated host response and organ dysfunction. The causal relationship between intestinal microbiota and sepsis is unclear. Methods: A two-sample Mendelian randomization (MR) study was performed to proxy the causal association between gut microbiota and sepsis. The genome-wide association study (GWAS) data of sepsis and gut microbiome were collected from the Integrative Epidemiology Unit (IEU) OpenGWAS, with summary-level data obtained from the UK Biobank. Five traditional methods were used to estimate the potential causal relationships between gut microbiota and sepsis, including the inverse-variance weighted method, weighted median method, MR-Egger regression, simple mode, and weighted mode. Reverse MR analysis was performed on the bacteria that were found to be causally associated with sepsis in forward MR analysis. Cochran's Q statistic was used to quantify the heterogeneity of instrumental variables. Results: The inverse-variance weighted estimate suggested that class Lentisphaeria (odds ratio [OR]=0.86, 95% confidence interval [CI]: 0.78 to 0.94, P=0.0017, q=0.1596) and order Victivallales (OR=0.86, 95% CI: 0.78 to 0.94, P=0.0017, q=0.1596) have a protective effect on sepsis. The genus Eubacterium eligens group (OR=1.34, 95% CI: 1.11 to 1.63, P=0.0029, q=0.1881) was positively associated with the risk of sepsis. Sepsis may be a significant risk factor for genus Odoribacter (OR=1.18, 95% CI: 1.10 to 1.39, P=0.0415, q=0.9849) and Phascolarctobacterium (OR=1.21, 95% CI: 1.00 to 1.46, P=0.0471, q=0.9849), but this effect was not statistically significant after false discovery rate correction. There was a suggestive association between sepsis and Faecalibacterium (OR=0.85, 95% CI: 0.73 to 0.98, P=0.0278) and Ruminococcus 1 (OR=0.85, 95% CI: 0.73 to 1.00, P=0.0439), which were not significant after false discovery rate correction (q>0.2). Conclusions: This study found that class Lentisphaeria, order Victivallales, and genus Eubacterium eligens group may have a causal relationship with the risk of sepsis.
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Transarterial chemoembolization (TACE), the mainstay treatment of unresectable primary liver cancer that primarily employs nondegradable drug-loaded embolic agents to achieve synergistic vascular embolization and locoregional chemotherapy effects, suffers from an inferior drug burst behavior lacking long-term drug release controllability that severely limits the TACE efficacy. Here we developed gelatin-based drug-eluting microembolics grafted with nanosized poly(acrylic acid) serving as a biodegradable ion-exchange platform that leverages a counterion condensation effect to achieve high-efficiency electrostatic drug loading with electropositive drugs such as doxorubicin (i.e., drug loading capacity >34 mg/mL, encapsulation efficiency >98%, and loading time <10 min) and an enzymatic surface-erosion degradation pattern (â¼2 months) to offer sustained locoregional pharmacokinetics with long-lasting deep-tumor retention capability for TACE treatment. The microembolics demonstrated facile microcatheter deliverability in a healthy porcine liver embolization model, superior tumor-killing capacity in a rabbit VX2 liver cancer embolization model, and stabilized extravascular drug penetration depth (>3 mm for 3 months) in a rabbit ear embolization model. Importantly, the microembolics finally exhibited vessel remodeling-induced permanent embolization with minimal inflammation responses after complete degradation. Such a biodegradable ion-exchange drug carrier provides an effective and versatile strategy for enhancing long-term therapeutic responses of various local chemotherapy treatments.
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Quimioembolización Terapéutica , Doxorrubicina , Animales , Quimioembolización Terapéutica/métodos , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Conejos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Porcinos , Resinas Acrílicas/química , Polielectrolitos/química , Portadores de Fármacos/química , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/farmacocinética , Gelatina/química , Nanopartículas/química , Humanos , Liberación de Fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificaciónRESUMEN
Microsphere-based embolic agents have gained prominence in transarterial embolization (TAE) treatment, a critical minimally invasive therapy widely applied for a variety of diseases such as hypervascular tumors and acute bleeding. However, the development of microspheres with long-term, real-time, and repeated X-ray imaging as well as ultrasound imaging remains challenging. In this study, emulsion-based dual-modal imaging microbeads with a unique internal multi-interface structure is developed for TAE treatment. The embolic microbeads are fabricated from a solidified oil-in-water (O/W) emulsion composed of crosslinked CaAlg-based aqueous matrix and dispersed radiopaque iodinated oil (IO) droplets through a droplet-based microfluidic fabrication method. The CaAlg-IO microbeads exhibit superior X-ray imaging visibility due to the incorporation of exceptionally high iodine level up to 221 mgI mL-1, excellent ultrasound imaging capability attributed to the multi-interface structure of the O/W emulsion, great microcatheter deliverability thanks to their appropriate biomechanical properties and optimal microbead density, and extended drug release behavior owing to the biodegradation nature of the embolics. Such an embolic agent presents a promising emulsion-based platform to utilize multi-phased structures for improving endovascular embolization performance and assessment capabilities.
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Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), bypassing the requirement of type II fatty acid synthesis (FAS II), a druggable pathway. A growing body of bacterial AasS-type isoenzymes compromises the clinical efficacy of FAS II-directed antimicrobials, like cerulenin. Very recently, an acyl adenylate mimic, C10-AMS, was proposed as a lead compound against AasS activity. However, the underlying mechanism remains poorly understood. Here we present two high-resolution cryo-EM structures of AasS liganded with C10-AMS inhibitor (2.33 Å) and C10-AMP intermediate (2.19 Å) in addition to its apo form (2.53 Å). Apart from our measurements for C10-AMS' Ki value of around 0.6 µM, structural and functional analyses explained how this inhibitor interacts with AasS enzyme. Unlike an open state of AasS, ready for C10-AMP formation, a closed conformation is trapped by the C10-AMS inhibitor. Tight binding of C10-AMS blocks fatty acyl substrate entry, and therefore inhibits AasS action. Additionally, this intermediate analog C10-AMS appears to be a mixed-type AasS inhibitor. In summary, our results provide the proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.
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Ácidos Grasos , Vibrio , Ácidos Grasos/metabolismo , Ácidos Grasos/química , Vibrio/efectos de los fármacos , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Antibacterianos/farmacología , Microscopía por Crioelectrón , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/antagonistas & inhibidores , Acido Graso Sintasa Tipo II/metabolismo , Acido Graso Sintasa Tipo II/antagonistas & inhibidoresRESUMEN
Endocrine resistance poses a significant clinical challenge for patients with hormone receptor-positive and human epithelial growth factor receptor 2-negative (HR + HER2-) breast cancer. Dysregulation of estrogen receptor (ER) and ERBB signaling pathways is implicated in resistance development; however, the integration of these pathways remains unclear. While SMAD4 is known to play diverse roles in tumorigenesis, its involvement in endocrine resistance is poorly understood. Here, we investigate the role of SMAD4 in acquired endocrine resistance in HR + HER2- breast cancer. Genome-wide CRISPR screening identifies SMAD4 as a regulator of 4-hydroxytamoxifen (OHT) sensitivity in T47D cells. Clinical data analysis reveals downregulated SMAD4 expression in breast cancer tissues, correlating with poor prognosis. Following endocrine therapy, SMAD4 expression is further suppressed. Functional studies demonstrate that SMAD4 depletion induces endocrine resistance in vitro and in vivo by enhancing ER and ERBB signaling. Concomitant inhibition of ER and ERBB signaling leads to aberrant autophagy activation. Simultaneous inhibition of ER, ERBB, and autophagy pathways synergistically impacts SMAD4-depleted cells. Our findings unveil a mechanism whereby endocrine therapy-induced SMAD4 downregulation drives acquired resistance by integrating ER and ERBB signaling and suggest a rational treatment strategy for endocrine-resistant HR + HER2- breast cancer patients.
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Neoplasias de la Mama , Resistencia a Antineoplásicos , Receptor ErbB-2 , Receptores de Estrógenos , Transducción de Señal , Proteína Smad4 , Humanos , Proteína Smad4/metabolismo , Proteína Smad4/genética , Femenino , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Receptores de Estrógenos/metabolismo , Línea Celular Tumoral , Animales , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Tamoxifeno/análogos & derivados , Ratones , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Ratones Desnudos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Autofagia/efectos de los fármacos , Receptores ErbB/metabolismo , Receptores ErbB/genéticaRESUMEN
The emergence of nosocomial infections caused by hypervirulent and carbapenem-resistant K. pneumoniae (hv-CRKP) has become a significant public health challenge. The genetic traits of virulence and resistance plasmids in hv-CRKP have been extensively studied; however, research on the adaptive evolution strategies of clinical strains inside the host was scarce. This study aimed to understand the effects of antibiotic treatment on the phenotype and genotype characteristics of hv-CRKP. We investigated the evolution of hv-CRKP strains isolated from the same patient to elucidate the transition between hospital invasion and colonization. A comparative genomics analysis was performed to identify single nucleotide polymorphisms in the rmpA promoter. Subsequent validation through RNA-seq and gene deletion confirmed that distinct rmpA promoter sequences exert control over the mucoid phenotype. Additionally, biofilm experiments, cell adhesion assays, and animal infection models were conducted to illuminate the influence of rmpA promoter diversity on virulence changes. We demonstrated that the P12T and P11T promoters of rmpA possess strong activity, which leads to the evolution of CRKP into infectious and virulent strains. Meanwhile, the specific sequence of polyT motifs in the rmpA promoter led to a decrease in the lethality of hv-CRKP and enhanced cell adhesion and colonization. To summarize, the rmpA promoter of hv-CRKP is utilized to control capsule production, thereby modifying pathogenicity to better suit the host's ecological environment.IMPORTANCEThe prevalence of hospital-acquired illness caused by hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) is significant, leading to prolonged antibiotic treatment. However, there are few reports on the phenotypic changes of hv-CRKP in patients undergoing antibiotic treatment. We performed a comprehensive examination of the genetic evolutionary traits of hv-CRKP obtained from the same patient and observed variations in the promoter sequences of the virulence factor rmpA. The strong activity of the promoter sequences P11T and P12T enhances the consistent production of capsule polysaccharides, resulting in an invasive strain. Conversely, weak promoter activity of P9T and P10T is advantageous for exposing pili, hence improving bacterial cell attachment ability and facilitating bacterial colonization. This finding also explains the confusion of some clinical strains carrying wild-type rmpA but exhibiting a low mucoid phenotype. This adaptive alteration facilitates the dissemination of K. pneumoniae within the hospital setting.
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Carbapenémicos , Infecciones por Klebsiella , Klebsiella pneumoniae , Regiones Promotoras Genéticas , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/patogenicidad , Virulencia/genética , Humanos , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/tratamiento farmacológico , Regiones Promotoras Genéticas/genética , Carbapenémicos/farmacología , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Ratones , Enterobacteriaceae Resistentes a los Carbapenémicos/genética , Enterobacteriaceae Resistentes a los Carbapenémicos/patogenicidad , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Biopelículas/efectos de los fármacos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Polimorfismo de Nucleótido Simple , Infección Hospitalaria/microbiología , Infección Hospitalaria/tratamiento farmacológicoRESUMEN
BACKGROUND: Predicting whether Carbapenem-Resistant Gram-Negative Bacterial (CRGNB) cause bloodstream infection when giving advice may guide the use of antibiotics because it takes 2-5 days conventionally to return the results from doctor's order. METHODS: It is a regional multi-center retrospective study in which patients with suspected bloodstream infections were divided into a positive and negative culture group. According to the positive results, patients were divided into the CRGNB group and other groups. We used the machine learning algorithm to predict whether the blood culture was positive and whether the pathogen was CRGNB once giving the order of blood culture. RESULTS: There were 952 patients with positive blood cultures, 418 patients in the CRGNB group, 534 in the non-CRGNB group, and 1422 with negative blood cultures. Mechanical ventilation, invasive catheterization, and carbapenem use history were the main high-risk factors for CRGNB bloodstream infection. The random forest model has the best prediction ability, with AUROC being 0.86, followed by the XGBoost prediction model in bloodstream infection prediction. In the CRGNB prediction model analysis, the SVM and random forest model have higher area under the receiver operating characteristic curves, which are 0.88 and 0.87, respectively. CONCLUSIONS: The machine learning algorithm can accurately predict the occurrence of ICU-acquired bloodstream infection and identify whether CRGNB causes it once giving the order of blood culture.
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Bacteriemia , Carbapenémicos , Infecciones por Bacterias Gramnegativas , Unidades de Cuidados Intensivos , Aprendizaje Automático , Humanos , Carbapenémicos/farmacología , Masculino , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Anciano , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Bacteriemia/microbiología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/aislamiento & purificación , Adulto , Antibacterianos/farmacología , Farmacorresistencia BacterianaRESUMEN
Epidemiological studies have suggested that inhalation exposure to particulate matter (PM) air pollution, especially fine particles (i.e., PM2.5 (PM with an aerodynamic diameter of 2.5 microns or less)), is causally associated with cardiovascular health risks. To explore the toxicological mechanisms behind the observed adverse health effects, the hemolytic activity of PM2.5 samples collected during different pollution levels in Beijing was evaluated. The results demonstrated that the hemolysis of PM2.5 ranged from 1.98% to 7.75% and demonstrated a clear dose-response relationship. The exposure toxicity index (TI) is proposed to represent the toxicity potential of PM2.5, which is calculated by the hemolysis percentage of erythrocytes (red blood cells, RBC) multiplied by the mass concentration of PM2.5. In a pollution episode, as the mass concentration increases, TI first increases and then decreases, that is, TI (low pollution levels) < TI (heavy pollution levels) < TI (medium pollution levels). In order to verify the feasibility of the hemolysis method for PM toxicity detection, the hemolytic properties of PM2.5 were compared with the plasmid scission assay (PSA). The hemolysis results had a significant positive correlation with the DNA damage percentages, indicating that the hemolysis assay is feasible for the detection of PM2.5 toxicity, thus providing more corroborating information regarding the risk to human cardiovascular health.
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BACKGROUND: The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated. METHODS: Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and functional experiments. RESULTS: Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10. CONCLUSIONS: The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.
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Caveolina 3 , Cardiomiopatías Diabéticas , Complejo I de Transporte de Electrón , Mitocondrias , Miocitos Cardíacos , Animales , Masculino , Ratones , Apoptosis , Caveolina 3/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Complejo I de Transporte de Electrón/metabolismo , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaRESUMEN
BACKGROUND: Predicting the successful weaning of acute kidney injury (AKI) patients from renal replacement therapy (RRT) has emerged as a research focus, and we successfully built predictive models for RRT withdrawal in patients with severe AKI by machine learning. METHODS: This retrospective single-center study utilized data from our general intensive care unit (ICU) Database, focusing on patients diagnosed with severe AKI who underwent RRT. We evaluated RRT weaning success based on patients being free of RRT in the subsequent week and their overall survival. Multiple logistic regression (MLR) and machine learning algorithms were adopted to construct the prediction models. RESULTS: A total of 976 patients were included, with 349 patients successfully weaned off RRT. Longer RRT duration (7.0 vs. 9.6 d, p = 0.002, OR = 0.94), higher serum cystatin C levels (1.2 vs. 3.2 mg/L, p < 0.001, OR = 0.46), and the presence of septic shock (28.1% vs. 41.5%, p < 0.001, OR = 0.63) were associated with reduced likelihood of RRT weaning. Conversely, a positive furosemide stress test (FST) (60.2% vs. 40.7%, p < 0.001, OR = 2.75) and higher total urine volume 3 d before RRT withdrawal (755 vs. 125 mL/d, p < 0.001, OR = 2.12) were associated with an increased likelihood of successful weaning from RRT. Next, we demonstrated that machine learning models, especially Random Forest and XGBoost, achieving an AUROC of 0.95. The XGBoost model exhibited superior accuracy, yielding an AUROC of 0.849. CONCLUSION: High-risk factors for unsuccessful RRT weaning in severe AKI patients include prolonged RRT duration. Machine learning prediction models, when compared to models based on multivariate logistic regression using these indicators, offer distinct advantages in predictive accuracy.
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Lesión Renal Aguda , Enfermedad Crítica , Humanos , Enfermedad Crítica/terapia , Estudios Retrospectivos , Destete , Terapia de Reemplazo Renal , Lesión Renal Aguda/terapia , Aprendizaje AutomáticoRESUMEN
Background: Fallopian tubal tuberculosis (FTTB), which typically presents with non-specific clinical symptoms and mimics ovarian malignancies clinically and radiologically, often affects young reproductive females and can lead to infertility if not promptly managed. Early diagnosis by imaging modalities is crucial for initiating timely anti-tuberculosis (anti-TB) treatment. Currently, comprehensive radiological descriptions of this relatively rare disease are limited. We aimed to comprehensively investigate the computed tomography (CT) and magnetic resonance imaging (MRI) characteristics of FTTB in patients from the Kashi area, which has the highest incidence of TB in China, to extend radiologists' understanding of this disease. Methods: We conducted a retrospective cross-sectional study of 26 patients diagnosed with FTTB at the First People's Hospital of Kashi Area. All the patients underwent abdominal and pelvic contrast-enhanced CT examinations and/or pelvic contrast-enhanced MRI from January 2017 to June 2022. The imaging findings were evaluated in consensus by two experienced radiologists specialized in abdominal and pelvic imaging. The evaluated sites included the fallopian tubes, ovaries, peritoneum, mesentery, retroperitoneal nodes, and parailiac nodes. The patient characteristics are reported using descriptive statistics. The patient imaging results are presented as percentages. The normally distributed continuous variables are reported as the mean ± standard deviation (SD), and otherwise as the median with the interquartile range (IQR). Results: The median age of the patients was 27 years (IQR: 25-34 years). Bilateral involvement of the fallopian tubes was observed in all patients. The tubal wall appeared coarse with tiny intraductal nodules in 96% (25 of 26) of the patients. The mean CT value of the tubal contents was 34 Hounsfield units (HUs; SD: 3.3 HUs). Ascites was present in 92% (24 of 26) of the patients, with 20 patients showing encapsulated effusion. Among these patients, 20 exhibited the highest CT values of ascites (>20 HUs). Linear enhancement of the parietal peritoneum was observed in 88% (23 of 26) of the patients, of whom 22 had peritoneal nodules measuring a median diameter of 0.4 cm (IQR: 0.3-0.6 cm). Eight patients had retroperitoneal and parailiac nodal enlargement, of whom two showed nodal necrosis, and none displayed nodal calcification. Conclusions: FTTB is consistently accompanied by tuberculous peritonitis. FTTB typically presents with tubal dilation, and coarseness and nodules in the lumen, as well as intraductal caseous material and calcification. Tuberculous peritonitis exhibits high-density ascites, peritoneal adhesion, linear enhancement of the parietal peritoneum, and tiny peritoneal nodules. The co-occurrence of these features strongly suggests a diagnosis of FTTB.
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Infant-type hemispheric glioma (IHG) is a rare pediatric brain tumor with variable response to chemotherapy and radiotherapy. Molecular insights into IHG can be useful in identifying potentially active targeted therapy. A male fetus was found to have congenital hydrocephalus at the gestational age of 37 weeks. Fetal MRI showed a 2.6 × 2.0-cm tumor located at the frontal horn of the left lateral ventricle, involving the left basal nuclei and thalamus. Tumor biopsy at the age of 2 days revealed an IHG consisting of spindle tumor cells with strong expression of GFAP and ALK. Targeted RNA sequencing detected a novel fusion gene of SOX5::ALK. After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 3 months of treatment, reduction of tumor size was observed. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.
Asunto(s)
Aminopiridinas , Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Glioma , Lactamas , Neoplasias Pulmonares , Pirazoles , Lactante , Niño , Masculino , Humanos , Recién Nacido , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quinasa de Linfoma Anaplásico/genética , Lactamas Macrocíclicas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/terapia , Glioma/tratamiento farmacológico , Factores de Transcripción SOXDRESUMEN
Background: Drug-drug interactions (DDIs) are a major but preventable cause of adverse drug reactions. There is insufficient information regarding DDIs in lung transplant recipients. Objective: This study aimed to determine the prevalence of potential DDIs (pDDIs) in intensive care unit (ICU) lung transplant recipients, identify the real DDIs and the most frequently implicated medications in this vulnerable population, and determine the risk factors associated with pDDIs. Methods: This retrospective cross-sectional study included lung transplant recipients from January 2018 to December 2021. Pertinent information was retrieved from medical records. All prescribed medications were screened for pDDIs using the Lexicomp® drug interaction software. According to this interaction software, pDDIs were classified as C, D, or X (C = monitor therapy, D = consider therapy modification, X = avoid combination). The Drug Interaction Probability Scale was used to determine the causation of DDIs. All statistical analysis was performed in SPSS version 26.0. Results: 114 patients were qualified for pDDI analysis, and total pDDIs were 4051. The most common type of pDDIs was category C (3323; 82.0%), followed by D (653; 16.1%) and X (75; 1.9%). Voriconazole and posaconazole were the antifungal medicine with the most genuine DDIs. Mean tacrolimus concentration/dose (Tac C/D) before or after co-therapy was considerably lower than the Tac C/D during voriconazole or posaconazole co-therapy (p < 0.001, p = 0.027). Real DDIs caused adverse drug events (ADEs) in 20 patients. Multivariable logistic regression analyses found the number of drugs per patient (OR, 1.095; 95% CI, 1.048-1.145; p < 0.001) and the Acute Physiology and Chronic Health Evaluation II (APACHE â ¡) score (OR, 1.097; 95% CI, 1.021-1.179; p = 0.012) as independent risk factors predicting category X pDDIs. Conclusion: This study revealed a high incidence of both potential and real DDIs in ICU lung transplant recipients. Immunosuppressive drugs administered with azole had a high risk of causing clinically significant interactions. The number of co-administered drugs and APACHE â ¡ score were associated with an increased risk of category × drug interactions. Close monitoring of clinical and laboratory parameters is essential for ensuring successful lung transplantation and preventing adverse drug events associated with DDIs.