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Objective: Inflammation plays an important role in the transformation of pulmonary nodules (PNs) from benign to malignant. Prediction of benignancy and malignancy of PNs is still lacking efficacy methods. Although Mayo or Brock model have been widely applied in clinical practices, their application conditions are limited. This study aims to construct a diagnostic model of PNs by machine learning using inflammation-related biological markers (IRBMs). Methods: Inflammatory related genes (IRGs) were first extracted from GSE135304 chip data. Then, differentially expressed genes (DEGs) and infiltrating immune cells were screened between malignant pulmonary nodules (MN) and benign pulmonary nodule (BN). Correlation analysis was performed on DEGs and infiltrating immune cells. Molecular modules of IRGs were identified through Consistency cluster analysis. Subsequently, IRBMs in IRGs modules were filtered through Weighted gene co-expression network analysis (WGCNA). An optimal diagnostic model was established using machine learning methods. Finally, external dataset GSE108375 was used to verify this result. Results: 4 hub IRGs and 3 immune cells showed significantly difference between MN and BN, C1 and C2 module, namely PRTN3, ELANE, NFKB1 and CTLA4, T cells CD4 naïve, NK cells activated and Monocytes. IRBMs were screened from black module and yellowgreen module through WGCNA analysis. The Support vector machines (SVM) was identified as the optimal model with the Area Under Curve (AUC) was 0.753. A nomogram was established based on 5 hub IRBMs, namely HS.137078, KLC3, C13ORF15, STOM and KCTD13. Finally, external dataset GSE108375 verified this result, with the AUC was 0.718. Conclusion: SVM model established by 5 hub IRBMs was able to effectively identify MN or BN. Accumulating inflammation and immune dysfunction were important to the transformation from BN to MN.
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OBJECTIVE: To develop an investigation form for hemodialysis infection outbreak, and to identify sources of outbreak in early stage. METHODS: After an exhaustive literature review, we used the Delphi method to determine the indicators and relative risk scores of the assessment tools through two rounds of specialist consultation and overall consideration of the opinions and suggestions of 18 specialists. RESULTS: A total of 87 studies of hemodialysis infection outbreaks were eligible for inclusion. The mean authority coefficient (Cr) was 0.89. Kendall's W coefficient of the specialist consultation was 0.359 after two rounds of consultation (p <0.005), suggesting that the specialists had similar opinions. Based on 4 primary items and 13 secondary items of the source of hemodialysis infection outbreak, and tripartite distribution characteristics of infected patients, we constructed the investigation form. CONCLUSIONS: The investigation form can be used at the early stage of the cluster of cases, it's a prerequisite for taking effective control measures, avoiding hemodialysis infection outbreak occurrence. However, the effect of the investigation form needs to be further evaluated.
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Objective: Numerous studies have reported that metformin can reduce the risk of tumor development. However, some of the results of these studies are conflicting, necessitating a more reliable evaluation. Methods: We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) of tumors to explore the causal relationship between metformin and tumors. Two cohorts of patients taking metformin were obtained from the UK Biobank. Complete phenotype data of the tumors were obtained from FinnGen_R10. We elucidated the causal relationship using a two-sample Mendelian randomization (MR) analysis. More importantly, we conducted a meta-analysis to ensure relatively unbiased results. In the MR analysis, we used the inverse-variance weighted (IVW) method as the main outcome indicator. Subsequently, two cohorts were integrated for the meta-analysis. Finally, we investigated the mechanisms through mediational MR analysis. Results: MR analysis revealed that metformin might have a causal relationship with 13 tumor-associated phenotypes in the training cohort. Four phenotypes were validated in the testing cohort. In the training and testing cohorts, metformin exhibited a protective effect against brain meningiomas and malignant neoplasms of the breast (HER-positive), oral cavity, tonsils, and the base of the tongue. Intriguingly, after integrating the results of the two cohorts for the meta-analysis, 12 results were statistically significant. Mediational MR analysis suggested that the effects of metformin on brain meningiomas may be weakened by the presence of the family Oxalobacteraceae. Conclusion: Metformin exhibits potential preventive and therapeutic effects on four types of tumors: brain meningioma, malignant neoplasms of the breast (HER-positive), oral cavity and tonsils, and the base of the tongue. Large randomized controlled trials are required to confirm these findings.
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BACKGROUND: In the continuous endeavor to find safe and efficient treatments for Atopic Dermatitis (AD), there remains a considerable focus on dietary adjustments. Nevertheless, the limited availability of research and conflicting findings in the academic literature pose a hurdle in establishing conclusive recommendations. METHOD: Mendelian randomization (MR) was applied to the most comprehensive genome-wide association studies (GWAS) data on tea intake (447 485), green tea intake (n = 64 949), flavored milk intake (n = 64 941), never eat eggs, dairy, wheat, sugar: Wheat products(n = 461 046), never eat eggs, dairy, wheat, sugar: Sugar or foods/drinks containing sugar (n = 461 046), never eat eggs, dairy, wheat, sugar: I eat all of the above (n = 461 046) and atopic dermatitis (n = 218 467). We used the inverse-variance weighted method (IVW) as the primary method. RESULTS: The IVW analyses have demonstrated an increased tea intake was genetically associated with a reduced risk of AD (odds ratio [OR]: 0.646, 95% confidence interval [CI]: 0.430-0.968, p = 0.034). Furthermore, green tea intake was significantly negatively associated with AD (IVW OR: 0.986, 95% CI: 0.975-0.998; p = 0.024) in the IVW model. AD risk could be reduced by never eating wheat products (IVW OR: 8.243E-04, 95% CI: 7.223E-06-9.408E-02, p = 0.003). There was no association between never eating eggs, dairy, wheat, sugar: Sugar, or foods/drinks containing sugar, I eat all of the above and AD. CONCLUSIONS: Our MR study suggests a causal relationship between tea intake, green tea intake, and the avoidance of eating wheat products with atopic dermatitis. Our findings recommend that preventing and managing atopic dermatitis may be achieved by never eating wheat products while increasing tea and green tea intake.
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Dermatitis Atópica , Dieta , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Dermatitis Atópica/genética , Humanos , Dieta/efectos adversos , Té , Huevos , Leche , Triticum/genética , Productos Lácteos , Polimorfismo de Nucleótido SimpleRESUMEN
Photopyroptosis is an emerging research branch of photodynamic therapy (PDT), whereas there remains a lack of molecular structural principles to fabricate photosensitizers for triggering a highly efficient pyroptosis. Herein, a general and rational structural design principle to implement this hypothesis, is proposed. The principle relies on the clamping of cationic moieties (e.g., pyridinium, imidazolium) onto one photosensitive core to facilitate a considerable mitochondrial targeting (both of the inner and the outer membranes) of the molecules, thus maximizing the photogenerated reactive oxygen species (ROS) at the specific site to trigger the gasdermin E-mediated pyroptosis. Through this design, the pyroptotic trigger can be achieved in a minimum of 10 s of irradiation with a substantially low light dosage (0.4 J cmâ»2), compared to relevant work reported (up to 60 J cmâ»2). Moreover, immunotherapy with high tumor inhibition efficiency is realized by applying the synthetic molecules alone. This structural paradigm is valuable for deepening the understanding of PDT (especially the mitochondrial-targeted PDT) from the perspective of pyroptosis, toward the future development of the state-of-the-art form of PDT.
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Fotoquimioterapia , Fármacos Fotosensibilizantes , Piroptosis , Especies Reactivas de Oxígeno , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Piroptosis/efectos de los fármacos , Humanos , Especies Reactivas de Oxígeno/metabolismo , Animales , Ratones , Línea Celular Tumoral , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , LuzRESUMEN
CONTEXT: The Xihuang pill (XHP) is a traditional Chinese medicine formulation that has been historically used in the prevention and treatment of proliferative breast diseases. However, there is a lack of guidelines that offer recommendations for its clinical use. OBJECTIVE: The task force from the Chinese Guangdong Pharmaceutical Association aims to develop evidence-based guidelines for XHP to prevent and treat proliferative breast diseases. METHODS: We searched six Chinese and English electronic databases, including the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang Medical Database, PubMed, and Embase, up to November 1, 2022. Publications (case reports, clinical observation, clinical trials, reviews) on using XHP to treat proliferative breast diseases were manually searched. The search terms were Xihuang pill, hyperplasia of the mammary gland, breast lump, and mastalgia. The writing team developed recommendations based on the best available evidence. RESULTS: Treatment should be customized based on syndrome identification. We recommend using XHP for the prevention and treatment of breast hyperplasia disease when a patient presents the following syndromes: concurrent blood stasis syndrome, concurrent phlegm-stasis syndrome, and concurrent liver fire syndrome. Safety indicators, including blood analysis and liver and kidney function monitoring, should be performed regularly during treatment. CONCLUSIONS: Current clinical evidence suggests that XHP can be used as a standalone treatment or in conjunction with other medications to prevent and manage breast hyperplasia diseases. More randomized controlled studies are warranted to establish high-quality evidence of its use.
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Enfermedades de la Mama , Medicamentos Herbarios Chinos , Hiperplasia , Medicina Tradicional China , Humanos , Femenino , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/administración & dosificación , Enfermedades de la Mama/tratamiento farmacológico , Medicina Tradicional China/métodos , ChinaRESUMEN
Inspired by the sophisticated multicomponent and multistage assembly of proteins and their mixtures in living cells, this study rationally designs and fabricates photoresponsive colloidal tubes that can self-assemble and hybrid-assemble when mixed with colloidal spheres and rods. Time-resolved observation and computer simulation reveal that the assembly is driven by phoretic attraction originating from osmotic pressures. These pressures are induced by the chemical concentration gradients generated by the photochemical reaction caused by colloidal tubes in a H2O2 solution under ultraviolet (UV) irradiation. The assembled structure is dictated by the size and shape of the constituent colloids as well as the intensity of the UV irradiation. Additionally, the resulting assembly can undergo self-propelled motion originating from the broken symmetry of the surrounding concentration gradients. This motion can be steered by a magnetic field and used for microscale cargo delivery. The study demonstrates a facile synthesis method for colloidal tubes and highlights their unique potential for controlled, hierarchical self-assembly and hybrid-assembly.
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BACKGROUND: Reintroduction represents an effective strategy for the conservation of endangered wildlife, yet it might inadvertently impact the native ecosystems. This investigation assesses the impact of reintroducing endangered Przewalski's horses into the desert grassland ecosystem of the Kalamaili Nature Reserve (KNR), particularly its effect on the spatial distribution of ticks. In a 25 km2 core area of Przewalski's horse distribution, we set up 441 tick sampling sites across diverse habitats, including water sources, donkey trails, and grasslands, recording horse feces and characteristics to analyze the occurrence rate of ticks. Additionally, we gathered the data of 669 fresh feces of horses. To evaluate the spatial dynamics between these feces and ticks, we used methods such as Fixed Kernel Estimation (FKE), Moran's I spatial autocorrelation index, and Generalized Linear Models (GLM). RESULTS: The dominant species of ticks collected in the core area were adult Hyalomma asiaticum (91.36%). Their occurrence rate was higher near donkey trails (65.99%) and water sources (55.81%), particularly in areas with the fresh feces of Przewalski's horses. The ticks' three risk areas, as defined by FKE, showed significant overlap and positive correlation with the distribution of Przewalski's horses, with respective overlap rates being 90.25% in high risk, 33.79% in medium risk, and 23.09% in low risk areas. Moran's I analysis revealed a clustering trend of the fresh feces of Przewalski's horses in these areas. The GLM confirmed a positive correlation between the distribution of H. asiaticum and the presence of horse fresh feces, alongside a negative correlation with the proximity to water sources and donkey trails. CONCLUSIONS: This study reveals the strong spatial correlation between Przewalski's horses and H. asiaticum in desert grasslands, underlining the need to consider interspecific interactions in wildlife reintroductions. The findings are crucial for shaping effective strategies of wildlife conservation and maintaining ecological balance.
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Pradera , Animales , Caballos , Conservación de los Recursos Naturales/métodos , Análisis Espacial , Heces/parasitología , Heces/química , Clima Desértico , Ixodidae/fisiología , Especies en Peligro de ExtinciónRESUMEN
Background: Elderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats. Methods: Male wild-type Wistar rats aged 11-12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1ß, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence. Results: The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1ß (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1ß (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased. Conclusion: PA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.
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Realtime spectroscopy access to ultrafast fiber lasers provides new opportunities for exploring complex soliton interaction dynamics. In this study, we employ a time-stretch technique that enables real-time access to both spectral and temporal dynamics, revealing rich nonlinear processes in asynchronous dual wavelength mode-locked pulses in an ultrafast fiber laser. Due to the different group velocities of the two wavelengths, the mode-locked solitons centered at different wavelengths periodically collide with each other. We recorded the entire process of soliton establishment, stabilization, and disappearance, shedding light on the mystery of stable transmission of dual-wavelength mode-locked pulses. These processes were observed for the first time in an ultrafast fiber laser, and the experimental evidence provides important insights into the understanding of nonlinear dynamics in fiber lasers, as well as the potential for improving laser performance for application in dual-comb spectroscopy.
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CRISPR/Cas9 is a promising RNA-guided genome editing technology, which consists of a Cas9 nuclease and a single-guide RNA (sgRNA). So far, a number of sgRNA prediction softwares have been developed. However, they were usually designed for protein-coding genes without considering that long non-coding RNA (lncRNA) genes may have different characteristics. In this study, we first evaluated the performances of a series of known sgRNA-designing tools in the context of both coding and non-coding datasets. Meanwhile, we analyzed the underpinnings of their varied performances on the sgRNA's specificity for lncRNA including nucleic acid sequence, genome location and editing mechanism preference. Furthermore, we introduce a support vector machine-based machine learning algorithm named CRISPRlnc, which aims to model both CRISPR knock-out (CRISPRko) and CRISPR inhibition (CRISPRi) mechanisms to predict the on-target activity of targets. CRISPRlnc combined the paired-sgRNA design and off-target analysis to achieve one-stop design of CRISPR/Cas9 sgRNAs for non-coding genes. Performance comparison on multiple datasets showed that CRISPRlnc was far superior to existing methods for both CRISPRko and CRISPRi mechanisms during the lncRNA-specific sgRNA design. To maximize the availability of CRISPRlnc, we developed a web server (http://predict.crisprlnc.cc) and made it available for download on GitHub.
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ARN Guía de Sistemas CRISPR-Cas , ARN Largo no Codificante , Sistemas CRISPR-Cas , ARN Largo no Codificante/genética , Edición Génica , Aprendizaje AutomáticoRESUMEN
Planktonic bacterial presence in many industrial and environmental applications and personal health-care products is generally countered using antimicrobials. However, antimicrobial chemicals present an environmental threat, while emerging resistance reduces their efficacy. Suspended bacteria have no defense against mechanical attack. Therefore, we synthesized silica hexapods on an α-Fe2O3 core that can be magnetically-rotated to inflict lethal cell-wall-damage to planktonic Gram-negative and Gram-positive bacteria. Hexapods possessed 600 nm long nano-spikes, composed of SiO2, as shown by FTIR and XPS. Fluorescence staining revealed cell wall damage caused by rotating hexapods. This damage was accompanied by DNA/protein release and bacterial death that increased with increasing rotational frequency up to 500 rpm. Lethal puncturing was more extensive on Gram-negative bacteria than on Gram-positive bacteria, which have a thicker peptidoglycan layer with a higher Young's modulus. Simulations confirmed that cell-wall-puncturing occurs at lower nano-spike penetration levels in the cell walls of Gram-negative bacteria. This approach offers a new way to kill bacteria in suspension, not based on antimicrobial chemicals.
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Antiinfecciosos , Bacterias Gramnegativas , Antibacterianos/farmacología , Antibacterianos/metabolismo , Dióxido de Silicio/farmacología , Dióxido de Silicio/metabolismo , Bacterias Grampositivas/metabolismo , Plancton , Bacterias , Pared CelularRESUMEN
BACKGROUND: Herpes zoster (HZ) is a common medical condition accompanied by several distressing symptoms, including acute pain. Pien Tze Huang (PZH) is a well-known traditional Chinese medicine (TCM) with numerous pharmacological effects, including antiviral properties, neuroprotection, and immunity regulation. PURPOSE: To investigate the efficacy and safety of PZH capsules in patients with HZ. STUDY DESIGN: A multicenter, double-blinded, randomized, and placebo-controlled trial from 8 hospitals in 5 cities of China. METHODS: Eligible participants were randomly assigned to the PZH capsule and placebo group at a 1:1 ratio. Treatment was conducted for 14 days with a window period of no more than 2 days. For the first 7 days, participants received antiviral drugs combined with PZH capsules (0.6 g/time, 3 times a day) or placebos. For the remaining 7 days, they were only treated with PZH capsules (0.6 g/time, 3 times a day) or placebos. RESULTS: We included 222 patients in the full analysis set (FAS), and 187 patients in the per protocol set (PPS). The change of numeric rating scale pain scores from baseline to the seventh day (±1 day) after treatment in the PZH capsule group was statistically superior to the placebo group (FAS: 2.33 vs. 1.71, 97.5%CI: 0.03 â¼ 1.19; PPS: 2.29 vs. 1.51, 97.5%CI: 0.18 â¼ 1.38). In the PPS, there was a significant difference in the time (days) of pain relief between the placebo group and the PZH capsule group (Mean (SD): 5.71 (3.76) vs. 4.69 (3.57), p = 0.046). On the seventh day (±1 day) after treatment, the level of CD8+ cells in the PZH capsule group were higher than those of the placebo group (FAS: Mean (SD): 24.08 (6.81) vs. 21.93 (8.19), p = 0.007; PPS: Mean (SD): 24.26 (6.93) vs. 22.15 (8.51), p = 0.012). The level of cytotoxic lymphocyte cells found similar results on the seventh day (±1 day) (FAS: Mean (SD): 12.17 (4.65) vs. 10.55 (4.15), p = 0.018; PPS: Mean (SD): 12.25 (4.65) vs. 10.11 (3.93), p = 0.002). No serious adverse events were noted and PZH capsules were well tolerated. CONCLUSION: PZH capsules confer therapeutic effects on HZ with the TCM symptom of stagnated heat of liver channel by substantially reducing the pain intensity, shortening the time of pain relief as well as regulating the immune function. On the basis of the efficacy and safety profiles, PZH capsules may be a promising complementary therapy for the treatment of HZ.
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Medicamentos Herbarios Chinos , Herpes Zóster , Humanos , Medicamentos Herbarios Chinos/efectos adversos , Medicina Tradicional China , Herpes Zóster/tratamiento farmacológico , Dolor/tratamiento farmacológicoRESUMEN
In this study, amine vapor-sensitive films with ratiometric fluorescence attributes were developed. The pH-sensitive fluorescein 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) and its tetraphenylethylene derivative (TPB) were selected as ratiometric indicators and incorporated into a polyvinyl alcohol (PVA) matrix to produce HPTS/TPB-PVA films. The films responded well to amine vapors, and the interference of aromatic vapors did not substantially affect the fluorescence signals of the films. Under UV light at a wavelength of 365â¯nm, the fluorescence of the films changed from dark pink to light pink and finally to yellow when the freshness of the fish was visually checked during storage. In addition, the color difference values of the films showed a positive correlation with the total volatile basic nitrogen (TVB-N), ranging from 12.7 to 24.8â¯mg/100â¯g at 25⯰C and 8.4 to 25.6â¯mg/100â¯g at 4⯰C, respectively. This indicates that fluorescent films have good potential for quantifying fish freshness in the near future when connected to an automatic data processing system based on color differences.
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Neuroblastoma (NB) is a type of neuroectodermal tumor that originates from primitive sympathetic ganglion cells. Although many risk factors contributing to the occurrence of NB have been reported in recent years, the role of the gut microbiota in its development remains unclear. A bidirectional Mendelian randomization (MR) analysis was conducted to elucidate the causal relationship between the gut microbiota and NB. In the MR analysis, we employed the inverse-variance weighted (IVW) method as the primary criterion for assessing causality, while also utilizing three additional approaches, including MR-Egger, weighted median model, and weighted mode, for comprehensive evaluation. For gut microbiota that were causally associated with NB, a reverse MR was also used to assess the stability of this causal relationship. Finally, we also used external cohorts for validation and performed a meta-analysis of the results. The IVW results indicated a causal relationship between six gut microbiota and NB. Among the six gut microbiota, genus Lachnospiraceae [IVW odds ratio (OR): 2.66, 95% confidence interval (CI): 1.09-6.51, P value: 0.03] exhibited a detrimental effect against NB. On the other hand, the class Actinobacteria (IVW OR: 0.24, 95% CI: 0.07-0.77, P value: 0.02), the family Bifidobacteriaceae (IVW OR: 0.40, 95% CI: 0.17-0.96, P value: 0.04), the genus Desulfovibrio (IVW OR: 0.50, 95% CI: 0.25-0.97, P value: 0.04), the genus Bifidobacterium (IVW OR: 0.39, 95% CI: 0.16-0.92, P value: 0.03), and the genus Howardella (IVW OR: 0.55, 95% CI: 0.31-0.97, P value: 0.04) displayed a protective effect on NB. A reverse MR analysis did not reveal a causality between NB and the six gut microbiota. Meta-analysis showed that genus Bifidobacterium (meta OR: 0.41, 95% CI: 0.22-0.75, P < 0.01) and genus Lachnospiraceae (meta OR: 2.20, 95% CI: 1.01-4.79, P < 0.05) were still significant. IMPORTANCE: Bidirectional Mendelian randomization was used to explore the causality between gut microbiota and neuroblastoma (NB). The results showed that there is a causal relationship between the six gut microbiota and NB, of which two gut microbiota were further confirmed in the meta-analysis. This may provide a new perspective on the prevention and treatment of NB.
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Actinobacteria , Microbioma Gastrointestinal , Neuroblastoma , Humanos , Microbioma Gastrointestinal/genética , Análisis de la Aleatorización Mendeliana , Neuroblastoma/genética , Factores de Riesgo , Bifidobacterium/genética , Clostridiales , Estudio de Asociación del Genoma CompletoRESUMEN
Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model to simultaneously predict the pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis (LC) patients. Six prodrugs (enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. Parameters such as organ blood flows, plasma-binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate (GFR) and gastrointestinal transit rate were integrated into the simulation. The pharmacokinetic profiles of these drugs and their active metabolites were simulated for 1000 virtual individuals. The developed semi-PBPK model, after validation in healthy individuals, was extrapolated to LC patients. Most of the observations fell within the 5th and 95th percentiles of simulations from 1000 virtual patients. The estimated AUC and Cmax were within 0.5-2-fold of the observed values. The sensitivity analysis showed that the decreased plasma exposure of active metabolites due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model successfully predicted the pharmacokinetics of CES1 substrates and their metabolites in healthy individuals and LC patients, facilitating tailored dosing of CES1 substrates in LC patients.
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As a promising immune checkpoint of immunogenic cell death (ICD) and multifunctional calcium-binding molecular chaperone, calreticulin (CALR) has been attracting increasing attention. CALR mainly locates in cellular endoplasmic reticulum and significantly affects cell proliferation, invasion, induction of apoptosis, and angiogenesis in breast invasive carcinoma (BRCA). CALR overexpression might be correlated with a worse outcome. Nonetheless, it remains obscure how CALR correlates with immune infiltration and survival prognosis of BRCA. In this study, we investigated CALR expression utilizing RNAseq data from the cancer genome atlas (TCGA) and genotype-tissue expression (GTEx) database. The prognostic value of CALR was analyzed using clinical survival data. Enrichment analysis was conducted using the R package "clusterProfiler." We downloaded the immune cell infiltration score of TCGA samples from published articles and online databases and performed a correlation analysis between immune cell infiltration levels and CALR expression. We further assessed the association between CALR and immunomodulators. Moreover, we also evaluated the expression of CALR in 100 formalin-fixed and paraffin-embedded breast cancer and adjacent normal breast tissue specimens. Our results found that CALR was highly expressed in BRCA, and CALR expression levels differed in pathological stages, T stages, and N stages. Besides, these results suggested that CALR overexpression may have adverse effects on the progression-free interval (PFI) and disease-free interval (DFI), which may be related to tumor proliferation, invasion, and metastasis, leading to tumor deterioration. Meanwhile, immune cell infiltration analysis revealed a correlation between the expression of CALR and the number of neutrophils and dendritic cells, suggesting that CALR was highly correlated with many immunomodulators in BRCA. Our results provide potential biomarkers of CALR in BRCA. CALR may interact synergistically with other immunomodulators to regulate the immune microenvironment, which could be utilized to develop new immunotherapy drugs.
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Calreticulina , Carcinoma , Humanos , Pronóstico , Calreticulina/genética , Microambiente Tumoral , Biomarcadores , Factores InmunológicosRESUMEN
BACKGROUND: Burns represent important global health problems. Whereas many studies are limited by the difficulties in estimating the burden of burns and instead focus on the causes of burns, such as fire, heat, and hot substances. Therefore, a complete assessment of the burden of all injuries leading to burns is essential to developing reasonable global intervention strategies. METHODS: Data on three classes of burns, including "< 20 % total burned surface area without lower airway burns" (Moderate injury), "> =20 % total burned surface area or > = 10 % burned surface area if head/neck or hands/wrist involved w/o lower airway burns" (Major injury), "Lower airway burns" (Inhalation injury) were collected from the Global Burden of Disease 2019 database. Age-standardized incidence rates (ASR-I) and Years Lived with Disability (ASR-YLDs) for burns has been standardized by removing the influence of population size and age structure. They were extracted and stratified by cause, year, sex, age, socio-demographic index, country, and territory. RESULTS: In terms of ASR-I and ASR-YLDs, burns showed a significant decrease from 1990 to 2019, especially for moderate and major injury. In 2019, the burden of moderate injury was positively correlated with socio-demographic index while major injury was negatively correlated (P < 0.05). We found no correlation between socio-demographic index and the burden for inhalation injury (P > 0.05). Fire, heat, and hot substances were the most important cause of burns except for inhalation injury. The most common association with inhalation injury was falls, which were also a major cause of moderate and major injury. CONCLUSIONS: The Global Burden of Disease 2019 database data can be used to guide the allocation of resources to reduce ASR-I and ASR-YLDs of different burn classes.
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Quemaduras , Personas con Discapacidad , Humanos , Quemaduras/epidemiología , Desarrollo Económico , Incidencia , Clase Social , Salud GlobalRESUMEN
BACKGROUND: To develop an investigation form for postoperative infection outbreak (PIO), and to identify sources of the outbreak in the early stage. METHODS: After an exhaustive literature review, we used the Delphi method to determine the indicators and relative risk scores of the assessment tools through 2 rounds of specialist consultation and overall consideration of the opinions and suggestions of 20 specialists. RESULTS: A total of 203 studies of PIO were eligible for inclusion. The mean authority coefficient (Cr) was 0.87. Kendall's W coefficient of the specialist consultation was 0.704 after 2 rounds of consultation (P < .005), suggesting that the specialists had similar opinions. Based on 4 primary items and 19 secondary items of the source of PIO, and tripartite distribution characteristics of infected patients, we constructed the PIO investigation form. CONCLUSIONS: The PIO investigation form can be used in the investigation of the early-stage cluster of cases, it's a prerequisite for taking effective control measures, avoiding PIO occurrence. However, the effect of the investigation form needs to be further evaluated.
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The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug-induced TdP risks, a model of cardiac ionic current suppression in human ventricular myocytes (ToR-ORd model), combined with the maximum effective free therapeutic plasma concentration or the maximum effective free therapeutic myocyte concentration was often used, with the latter proved to be more relevant and more accurate. We aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model, incorporated with a human cardiomyocyte pharmacodynamic (PD) model, to provide a comprehensive assessment of drug-induced TdP risks in normal and specific scenarios. Quinidine served as an example to validate the PBPK-PD model via predicting plasma quinidine concentrations and quinidine-induced changes in QT interval (ΔQTc). The predicted plasma quinidine concentrations and ΔQTc values following oral administration or intravenous administration of quinidine were comparable to clinic observations. Visual predictive checks showed that most of the observed plasma concentrations and ΔQTc values fell within the 5th and 95th percentiles of simulations. The validated PBPK-PD model was further applied to assess the TdP risks using frequencies of early afterdepolarization and long-QT syndrome occurrence in 4 scenarios, such as therapeutic dose, supra-therapeutic dose, alkalosis, and hyperkalemia in 200 human subjects. In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions, such as hypokalemia and alkalosis.