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Programmed death protein 1 (PD-1) inhibitors have potent anti-tumor activities. However, they often result in immune-related adverse events (irAEs) of varying severity. Therefore, the factors affecting the incidence of irAEs warrant urgent investigation. This study aimed to identify specific and sensitive predictors of irAEs in a Chinese population. We conducted a genome-wide association study (GWAS) comprising 80 patients with malignant tumors to evaluate single-nucleotide polymorphism (SNP) loci associated with the incidence of irAEs. The SNP rs2157775 on the LOC339166 gene had the lowest P value but did not reach the significance threshold after Bonferroni correction. Therefore, potentially associated SNPs were further investigated through the mechanism-related PD-1 pathway using the ImmPort and PathCards Human Gene Databases. A binary logistic regression model revealed that CD3E (rs3782040) A/A was associated with a lower incidence of irAEs in patients with malignant tumors who received PD-1 inhibitors. In contrast, PTPN11 (rs143894582) C/CA was associated with a higher incidence of irAEs. These findings provide a basis for the verification and identification of new loci to provide insight into the etiology of irAEs.
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The role of gut microbiome in acute kidney injury (AKI) is increasing recognized. Caloric restriction (CR) has been shown to enhance the resistance to ischemia/reperfusion injury to the kidneys in rodents. Nonetheless, it is unknown whether intestinal microbiota mediated CR protection against ischemic/reperfusion-induced injury (IRI) in the kidneys. Herein, we showed that CR ameliorated IRI-elicited renal dysfunction, oxidative stress, apoptosis, and inflammation, along with enhanced intestinal barrier function. In addition, gut microbiota depletion blocked the favorable effects of CR in AKI mice. 16S rRNA and metabolomics analysis showed that CR enriched the gut commensal Parabacteroides goldsteinii (P. goldsteinii) and upregulated the level of serum metabolite dodecafluorpentan. Intestinal colonization of P. goldsteinii and oral administration of dodecafluorpentan showed the similar beneficial effects as CR in AKI mice. RNA sequencing and experimental data revealed that dodecafluorpentan protected against AKI-induced renal injury by antagonizing oxidative burst and NFκB-induced NLRP3 inflammasome activation. In addition, we screened and found that Hamaudol improved renal insufficiency by boosting the growth of P. goldsteinii. Our results shed light on the role of intestinal microbiota P. goldsteinii and serum metabolites dodecafluorpentan in CR benefits to AKI.
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Carbon ion beam irradiation (CIBI) is a highly efficient mutagenesis for generating mutations that can be used to expand germplasm resources and create superior new germplasm. The study investigated the effects of different doses of CIBI (50 Gy, 100 Gy, 150 Gy, 200 Gy and 300 Gy) on seed germination and seedling survival, seedling morphological and physiological traits of an elite centipedegrass cultivar Ganbei. The results showed that irradiation greater than 50 Gy cause inhibition of seed germination, and the semi-lethal dose (LD50) is around 90 Gy for CIBI treated seeds of Ganbei. A carbon ion beam-mutagenized centipedegrass population was generated from Ganbei, with irradiation dosages from 50 Gy to 200 Gy. More than ten types of phenotypic variations and novel mutants with heritable tendencies mainly including putative mutants of stolon number, length and diameter, of internode length, of leaf length and width, of leaf chlorophyll content, of stolon growth rate, of aboveground tissue dry weight, of sward height were identified. While the total sugar content of the plants from irradiated seeds showed no obvious change in all treatments as compared to the control, the crude protein content displayed significant reduction at a high-dose treatment of 200 Gy. Genetic polymorphism was detected in mutagenized centipedegrass population using SSR-PCR analysis, suggesting that CIBI caused alteration of larger fragments of the DNA sequence. As a result, a preliminary batch of mutants was screened in this study. In summary, carbon ion beam mutagenesis is an effective way for developing centipedegrass germplasm with wider variation, and treating seeds with CIBI at a dosage of ~100 Gy could be effective in centipedegrass mutation breeding.
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Hyperuricemic nephropathy (HN) is renal injury caused by hyperuricemia (HUA). While sleeve gastrectomy (SG) has shown promise in improving renal injury in patients with obesity-related HN, the mechanisms are not fully understood. This study induced an obesity-combined HN model in male ob/ob mice and measured serum uric acid (SUA), creatinine, and other biochemical indicators 6 weeks post-surgery. Renal histological changes were evaluated through staining techniques, and the study also assessed renal adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation levels and urate transporter ABCG2 expression. In vitro experiments involved Nrf2 knockdown in AMPK-activated HK-2 cells and ChIP to confirm Nrf2 binding to the ABCG2 promoter. Results showed that SG reduced SUA levels, serum creatinine, and blood urea nitrogen, increased p-AMPK, p-Nrf2 protein, and ABCG2 expression, and alleviated renal fibrosis and inflammation. In vitro, Nrf2 knockdown down-regulated ABCG2 expression, and ChIP confirmed Nrf2's role in ABCG2 transcription. The study suggests that SG may improve renal injury in HN mice by modulating the AMPK/Nrf2 pathway and upregulating ABCG2 transcription.
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Proteínas Quinases Ativadas por AMP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Gastrectomia , Hiperuricemia , Fator 2 Relacionado a NF-E2 , Obesidade , Animais , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Hiperuricemia/metabolismo , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Obesidade/metabolismo , Obesidade/complicações , Obesidade/cirurgia , Gastrectomia/métodos , Transdução de Sinais , Nefropatias/metabolismo , Nefropatias/etiologia , Nefropatias/patologia , Modelos Animais de Doenças , Rim/metabolismo , Rim/patologia , Humanos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Ainuovirine, as a third-generation non-nucleoside reverse transcriptase inhibitor against HIV-1, is widely used in China. To evaluate its therapeutic efficacy and disadvantages, a comparative study based on Ainuovirine had been conducted. METHOD: We investigated 199 people living with HIV-1 who received Ainuovirine (ANV)/lamivudine/tenofovir and 202 people living with HIV-1 who received Efavirenz (EFV)/lamivudine/tenofovir. RESULTS: After 48 weeks of therapy, ANV and EFV showed similar viral inhibitory effects. However, in the ANV group, more participants had CD4/CD8 ratios restored to the normal range, lower levels of triglycerides and low-density lipoprotein, relatively normal liver alanine aminotransferase, and fewer adverse events. CONCLUSION: Therefore, due to its role in immune reconstitution, dyslipidemia, and safety, ANV may be a recommended option for people living with HIV-1.
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Background: The causality of autoimmune diseases with frailty has not been firmly established. We conducted this Mendelian randomization (MR) study to unveil the causal associations between autoimmune diseases with frailty. Methods: A MR analyses were performed to explore the relationships between autoimmune disease and frailty, using summary genome-wide association statistics. Results: Through a comprehensive and meticulous screening process, we incorporated 46, 7, 12, 20, 5, and 53 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for hypothyroidism, hyperthyroidism, rheumatoid arthritis (RA), type 1 diabetes (T1D), multiple sclerosis (MS), and overall autoimmune disease, respectively. Our analysis revealed that hypothyroidism (OR = 1.023, 95% CI: 1.008-1.038, p = 0.0015), hyperthyroidism (OR = 1.024, 95% CI: 1.004-1.045, p = 0.0163), RA (OR = 1.031, 95% CI: 1.011-1.052, p = 0.0017), T1D (OR = 1.011, 95% CI: 1.004-1.017, p = 0.0012), and overall autoimmune disease (OR = 1.044, 95% CI: 1.028-1.061, p = 5.32*10^-8) exhibited a positive causal effect on frailty. Conversely, there may be a negative causal association between MS (OR = 0.984, 95% CI: 0.977-0.992, p = 4.87*10^-5) and frailty. Cochran's Q test indicated heterogeneity among IVs derived from hypothyroidism, hyperthyroidism, T1D, and overall autoimmune diseases. The MR-Egger regression analyzes revealed an absence of horizontal pleiotropy in any of the conducted analyses. Conclusion: This study elucidates that hypothyroidism, hyperthyroidism, RA, T1D, and overall autoimmune disease were linked to an elevated risk of frailty. Conversely, MS appears to be associated with a potential decrease in the risk of frailty.
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Doenças Autoimunes , Fragilidade , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Doenças Autoimunes/genética , Doenças Autoimunes/epidemiologia , Fragilidade/genética , Fatores de Risco , Predisposição Genética para DoençaRESUMO
Soil health is integral to sustainable agroecosystem management. Current monitoring and assessment practices primarily focus on soil physicochemical properties, yet the perspective of multitrophic biodiversity remains underexplored. Here we used environmental DNA (eDNA) technology to monitor multitrophic biodiversity in four typical agroecosystems, and analyzed the species composition and diversity changes in fungi, bacteria and metazoan, and combined with the traditional physicochemical variables to establish a soil health assessment framework centered on biodiversity data. First, eDNA technology detected rich multitrophic biodiversity in four agroecosystems, including 100 phyla, 273 classes, 611 orders, 1026 families, 1668 genera and 1146 species with annotated classification, and the relative sequence abundance of dominant taxa fluctuates tens of times across agroecosystems. Second, significant differences in soil physicochemical variables such as organic matter (OM), total nitrogen (TN) and available phosphorus (AP) were observed among different agroecosystems, nutrients were higher in cropland and rice paddies, while heavy metals were higher in fish ponds and lotus ponds. Third, biodiversity metrics, including α and ß diversity, also showed significant changes across agroecosystems, the soil biota was generally more sensitive to nutrients (e.g., OM, TN or AP), while the fungal communities were mainly affected by heavy metals in October (e.g., Cu and Cr). Finally, we screened 48 sensitive organismal indicators and found significant positive consistency between the developed eDNA indices and the traditional soil quality index (SQI, reaching up to R2 = 0.58). In general, this study demonstrated the potential of eDNA technology in soil health assessment and underscored the importance of a multitrophic perspective for efficient monitoring and managing agroecosystems.
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Colistin is one of the last-resort antibiotics in treating infections caused by multidrug-resistant (MDR) pathogens. Unfortunately, the emergence of colistin-resistant gram-negative strains limit its clinical application. Here, we identify an FDA-approved drug, valnemulin (Val), exhibit a synergistic effect with colistin in eradicating both colistin-resistant and colistin-susceptible gram-negative pathogens both in vitro and in the mouse infection model. Furthermore, Val acts synergistically with colistin in eliminating intracellular bacteria in vitro. Functional studies and transcriptional analysis confirm that the combinational use of Val and colistin could cause membrane permeabilization, proton motive force dissipation, reduction in intracellular ATP level, and suppression in bacterial motility, which result in bacterial membrane disruption and finally cell death. Our findings reveal the potential of Val as a colistin adjuvant to combat MDR bacterial pathogens and treat recalcitrant infections.
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Antibacterianos , Colistina , Diterpenos , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , Colistina/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Camundongos , Diterpenos/farmacologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , HumanosRESUMO
As the types of fentanyl class substances continue to grow, a universal SERS sensor is essential for the application of discriminant detection of fentanyl substances. A new nanomaterial SERS sensor-Ag@Au NPs-paper was developed. The SERS sensitivity and stability of Ag@Au NPs-paper were investigated by using R6G molecule, and the results showed that Ag@Au NPs-paper has excellent performance. In combination with visual analysis and machine learning methods, Ag@Au NPs-paper has been successfully applied to the analysis of fentanyl class substances and the component identification of binary fentanyl mixtures, and thus it can be effectively used in food safety, environmental toxicants and other fields.
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OBJECTIVES: The Baveno VII consensus recommends endoscopic screening for varicose veins in cases of liver stiffness measurement (LSM) ≥ 20 kPa or platelet count ≤ 150 × 109/L. Whether this approach was appropriate for patients with primary biliary cholangitis (PBC) remains uncertain. This study expanded the observed risk factors by adding analysis of ultrasound images as a non-invasive tool to predict the risk of esophageal or fundic varices. METHODS: We enrolled 111 patients with PBC whose complete ultrasound images, measurement data, and LSM data were available. The value of the periportal hypoechoic band (PHB), splenic area, and LSM in determining the risk of varicose veins and variceal rupture was analyzed. A prospective cohort of 67 patients provided external validation. RESULTS: The area under the receiver operating characteristic curve (AUC) for predicting varicose veins using LSM > 12.1 kPa or splenic areas > 41.2 cm2 was 0.806 (95% confidence interval (CI): 0.720-0.875) and 0.852 (95% CI: 0.772-0.912), respectively. This finding could assist in avoiding endoscopic screening by 76.6% and 83.8%, respectively, with diagnostic accuracy surpassing that suggested by Baveno VII guidelines. The AUCs for predicting variceal rupture using splenic areas > 56.8 cm2 was 0.717 (95% CI: 0.623-0.798). The diagnostic accuracy of PHB for variceal rupture was higher than LSM and splenic areas (75.7% vs. 50.5% vs. 68.5%). CONCLUSION: We recommend LSM > 12.1 kPa as a cutoff value to predict the risk of varicosity presence in patients with PBC. Additionally, the splenic area demonstrated high accuracy and relevance for predicting varicose veins and variceal rupture, respectively. The method is simple and reproducible, allowing endoscopy to be safely avoided. CLINICAL RELEVANCE STATEMENT: The measurement of the splenic area and identification of the periportal hypoechoic band (PHB) on ultrasound demonstrated high accuracy and relevance for predicting the risk of esophageal or fundic varices presence and variceal rupture, respectively. KEY POINTS: Predicting varices in patients with primary biliary cholangitis (PBC) can reduce the morbidity and mortality of gastrointestinal hemorrhage. Transient elastography (TE) and ultrasound play an important role in predicting patients with PBC with varices. TE and ultrasound can predict varicose veins and variceal rupture. Liver stiffness measurement and splenic area measurements can allow endoscopy to be safely avoided.
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Clinical observational studies have suggested hyperlipidemia may disturb embryo implantation through endometrium; however, the mechanism has been unclear. With its profound implications for reproductive health, the present study aims to investigate whether hyperlipidemia affects endometrial epithelial cell tight junctions for implantation failures. By constructing hyperlipidemia mice model, the number and distribution of embryo implantation status were investigated after both natural mating and in vitro fertilization and embryo transfer (IVF-ET). Transmission electron microscopy (TEM) was used to compare the ultrastructure of tight junctions in endometrial endothelial cells. Western blot and immunofluorescence were used to explore the expression and localization of tight junction proteins, such as Claudin (CDLN)3, CLDN4, occludin (OCLN), and zonula occludens-1 (ZO1). For women with reproductive failure, mid-luteal phase endometrial tissues were collected, and gene expression of tight junction proteins was investigated using RNA sequencing and qRT-PCR. In hyperlipidemic mice, the number of embryo implantation sites significantly decreased with uneven distribution after natural mating and IVF-ET. Disrupted tight junctions were found, characterized by a decreased number of tight junctions by TEM, downregulated expressions of CDLN4, OCLN, and ZO1, and an increased expression of CLDN3 by western blot. In hyperlipidemic women with reproductive failure, the dysregulated expression of CLDN3 and CLDN4 was also present in the luteal phase endometrium. In this study, evaluation of both animal models and infertile women in vivo demonstrated that hyperlipidemia reduced female fertility, accompanied by disruption of tight junction structures and dysregulation of CLDN3 and CLDN4 expression in the endothelial cells of luteal phase endometrium.
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Photocaging is an emerging protocol for precisely manipulating spatial and temporal behaviors over biological activity. However, the red/near-infrared light-triggered photolysis process of current photocage is largely singlet oxygen (1O2)-dependent and lack of compatibility with other reactive oxygen species (ROS)-activated techniques, which has proven to be the major bottleneck in achieving efficient and precise treatment. Herein, we reported a lactosylated photocage BT-LRC by covalently incorporating camptothecin (CPT) into hybrid BODIPY-TPE fluorophore via the superoxide anion radical (O2-â¢)-cleavable thioketal bond for type I photodynamic therapy (PDT) and anticancer drug release. Amphiphilic BT-LRC could be self-assembled into aggregation-induced emission (AIE)-active nanoparticles (BT-LRCs) owing to the regulation of carbohydrate-carbohydrate interactions (CCIs) among neighboring lactose units in the nanoaggregates. BT-LRCs could simultaneously generate abundant O2-⢠through the aggregation modulated by lactose interactions, and DNA-damaging agent CPT was subsequently and effectively released. Notably, the type I PDT and CPT chemotherapy collaboratively amplified the therapeutic efficacy in HepG2 cells and tumor-bearing mice. Furthermore, the inherent AIE property of BT-LRCs endowed the photocaged prodrug with superior bioimaging capability, which provided a powerful tool for real-time tracking and finely tuning the PDT and photoactivated drug release behavior in tumor therapy.
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OBJECTIVE: To investigate whether the combination of chemotherapy with staged Chinese herbal medicine (CHM) therapy could enhance health-related quality of life (QoL) in non-small-cell lung cancer (NSCLC) patients and prolong the time before deterioration of lung cancer symptoms, in comparison to chemotherapy alone. METHODS: A prospective, double-blind, randomized, controlled trial was conducted from December 14, 2017 to August 28, 2020. A total of 180 patients with stage I B-IIIA NSCLC from 5 hospitals in Shanghai were randomly divided into chemotherapy combined with CHM (chemo+CHM) group (120 cases) or chemotherapy combined with placebo (chemo+placebo) group (60 cases) using stratified blocking randomization. The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life-Core 30 Scale (QLQ-C30) was used to evaluate the patient-reported outcomes (PROs) during postoperative adjuvant chemotherapy in patients with early-stage NSCLC. Adverse events (AEs) were assessed in the safety analysis. RESULTS: Out of the total 180 patients, 173 patients (116 in the chemo+CHM group and 57 in the chemo+placebo group) were included in the PRO analyses. The initial mean QLQ-C30 Global Health Status (GHS)/QoL scores at baseline were 57.16 ± 1.64 and 57.67 ± 2.25 for the two respective groups (P>0.05). Compared with baseline, the chemo+CHM group had an improvement in EORTC QLQ-C30 GHS/QoL score at week 18 [least squares mean (LSM) change 17.83, 95% confidence interval (CI) 14.29 to 21.38]. Conversely, the chemo+placebo group had a decrease in the score (LSM change -13.67, 95% CI -22.70 to -4.63). A significant between-group difference in the LSM GHS/QoL score was observed, amounting to 31.63 points (95% CI 25.61 to 37.64, P<0.001). The similar trends were observed in physical functioning, fatigue and appetite loss. At week 18, patients in the chemo+CHM group had a higher proportion of improvement or stabilization in GHS/QoL functional and symptom scores compared to chemo+placebo group (P<0.001). The median time to deterioration was longer in the chemo+CHM group for GHS/QoL score [hazard ratio (HR)=0.33, 95% CI 0.23 to 0.48, P<0.0010], physical functioning (HR=0.43, 95% CI 0.25 to 0.75, P=0.0005), fatigue (HR=0.47, 95% CI 0.30 to 0.72, P<0.0001) and appetite loss (HR=0.65, 95% CI 0.42 to 1.00, P=0.0215). The incidence of AEs was lower in the chemo+CHM group than in the chemo+placebo group (9.83% vs. 15.79%, P=0.52). CONCLUSION: The staged CHM therapy could help improve the PROs of postoperative patients with early-stage NSCLC during adjuvant chemotherapy, which is worthy of further clinical research. (Registry No. NCT03372694).
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Piercing-sucking pests are the most notorious group of pests for global agriculture. RNAi-mediated crop protection by foliar application is a promising approach in field trials. However, the effect of this approach on piercing-sucking pests is far from satisfactory due to the limited uptake and transport of double strand RNA (dsRNA) in plants. Therefore, there is an urgent need for more feasible and biocompatible dsRNA delivery approaches to better control piercing-sucking pests. Here, we report that foliar application of layered double hydroxide (LDH)-loaded dsRNA can effectively disrupt Panonychus citri at multiple developmental stages. MgAl-LDH-dsRNA targeting Chitinase (Chit) gene significantly promoted the RNAi efficiency and then increased the mortality of P. citri nymphs by enhancing dsRNA stability in gut, promoting the adhesion of dsRNA onto leaf surface, facilitating dsRNA internalization into leaf cells, and delivering dsRNA from the stem to the leaf via the vascular system of pomelo plants. Finally, this delivery pathway based on other metal elements such as iron (MgFe-LDH) was also found to significantly improve the protection against P. citri and the nymphs or larvae of Diaphorina citri and Aphis gossypii, two other important piercing-sucking hemipeteran pests, indicating the universality of nanoparticles LDH in promoting the RNAi efficiency and mortality of piercing-sucking pests. Collectively, this study provides insights into the synergistic mechanism for nano-dsRNA systemic translocation in plants, and proposes a potential eco-friendly control strategy for piercing-sucking pests.
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Hidróxidos , Interferência de RNA , RNA de Cadeia Dupla , Animais , Hidróxidos/química , Hidróxidos/farmacologia , Nanopartículas/química , Ninfa , Hemípteros , Folhas de Planta , Larva , Quitinases/metabolismo , Quitinases/genética , CitrusRESUMO
Flexible thermal-responsive encryption devices are widely employed in information encryption and anti-counterfeiting due to their cost-effectiveness and dynamic data encryption and decryption capabilities. However, most current devices are limited to a single layer of encryption, resulting in restricted decryption methods and storage capacity, as well as reliance on external heating. In this study, we integrate multiple layers of encryption within a single device and introduce self-heating thermochromic technology along with infrared thermal imaging encryption to establish a novel concept of a multilayer flexible encryption system. By combining infrared encryption and thermochromic encryption in three-dimensional space enhances the difficulty level for decryption while achieving high storage capacity for information. The internally integrated conductive heating layer within the multilayer structure facilitates rapid and adjustable heating for thermochromic patterns, eliminating the need for external heat sources. Furthermore, we employ a low-cost customizable multi-material integrated 3D printing process for manufacturing multilayer flexible encryption devices. This research presents an innovative solution for designing and fabricating high-density multilevel flexible encryption devices.
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Background: The widespread clinical use of lacosamide (LCM) has revealed significant individual differences in clinical response, with various reported influencing factors. However, it remains unclear how genetic factors related to the disposition and clinical response of LCM, as well as drug-drug interactions (DDIs), exert their influence on pediatric patients with epilepsy. Objectives: To evaluate the impact of genetic variations and DDIs on plasma LCM concentrations and clinical response. Design: Patients with epilepsy treated with LCM from June 2021 to March 2023 in the Children's Hospital of Nanjing Medical University were included in the analysis. Methods: The demographic information and laboratory examination data were obtained from the hospital information system. For the pharmacogenetic study, the left-over blood specimens, collected for routine plasma LCM concentration monitoring, were used to perform genotyping analysis for the selected 26 single nucleotide polymorphisms from 14 genes. The trough concentration/daily dose (C 0/D) ratio and efficacy outcomes were compared. Results: Patients achieved 90.1% and 68.9% responder rates in LCM mono- and add-on therapy, respectively. The genetic variant in the CYP2C19 *2 (rs4244285) was associated with a better responsive treatment outcome (odds ratio: 1.82; 95% confidence interval: 1.05-3.15; p = 0.031). In monotherapy, 36% of patients were CYP2C19 normal metabolizers (NMs), 49% were intermediate metabolizers (IMs), and 15% were poor metabolizers (PMs) carrying CYP2C19 *2 or *3. Of note, the C 0/D ratios of IMs and PMs were 9.1% and 39.6% higher than those of NMs, respectively. Similar results were in the add-on therapy group, and we also observed a substantial decrease in the C 0/D ratio when patients were concomitant with sodium channel blockers (SCBs). Conclusion: This study was the first to confirm that CYP2C19 *2 or *3 variants impact the disposition and treatment response of LCM in children with epilepsy. Moreover, concomitant with SCBs, particularly oxcarbazepine, also decreased plasma LCM concentration.
CYP2C19 genotype and sodium channel blockers in lacosamide-treated children with epilepsy: two major determinants of plasma lacosamide concentration or treatment efficacy This study examined the impact of genetic factors and drug combinations on the effectiveness and plasma concentrations of lacosamide, an antiseizure medication, in patients under 18. Analyzing blood samples from 316 patients at the Children's Hospital of Nanjing Medical University, researchers discovered that genetic variations in the CYP2C19 (i.e. *2 and *3), along with metabolic capacity, and co-medication with sodium channel blockers, all influence plasma lacosamide concentration. Understanding these genetic influences could inform personalized dosing strategies, improving the medication's management for pediatric epilepsy patients.
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Objective: Copy number changes at Chromosomal 16p13.11 have been implicated in a variety of human diseases including congenital cardiac abnormalities. The clinical correlation of copy number variants (CNVs) in this region with developmental abnormalities remains controversial as most of the patients inherit the duplication from an unaffected parent. Methods: We performed CNV analysis on 164 patients with defective left-right (LR) patterning based on whole genome-exome sequencing (WG-ES) followed by multiplex ligation-dependent probe amplification (MLPA) validation. Most cases were accompanied with complex congenital heart disease (CHD). Results: CNVs at 16p13.11 were identified in a total of 21 cases, accounting for 12.80% (21/164) evaluated cases. We observed a marked overrepresentation of chromosome 16p13.11 duplications in cases when compared with healthy controls according to literature reports (15/164, 9.14% versus 0.09% in controls). Notably, in two independent family trios, de novo 16p13.11 micro-duplications were identified in two patients with laterality defects and CHD. Moreover, 16p13.11 micro-duplication was segregated with the disease in a family trio containing 2 affected individuals. Notably, five coding genes, NOMO1, PKD1P3, NPIPA1, PDXDC1, and NTAN1, were potentially affected by micro-CNV at 16p13.11 in these patients. Conclusion: Our study provides new family-trio based evidences to support 16p13.11 micro-duplications predispose individuals to defective cardiac left-right patterning and laterality disorder.
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BACKGROUND: The burden of common urologic diseases, including benign prostatic hyperplasia (BPH), urinary tract infections (UTI), urolithiasis, bladder cancer, kidney cancer, and prostate cancer, varies both geographically and within specific regions. It is essential to conduct a comprehensive and precise assessment of the global burden of urologic diseases. METHODS: We obtained data on incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) for the aforementioned urologic diseases by age, sex, location, and year from the Global Burden of Disease (GBD) 2021. We analyzed the burden associated with urologic diseases based on socio-demographic index (SDI) and attributable risk factors. The trends in burden over time were assessed using estimated annual percentage changes (EAPC) along with a 95% confidence interval (CI). RESULTS: In 2021, BPH and UTI were the leading causes of age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR), with rates of 5531.88 and 2782.59 per 100,000 persons, respectively. Prostate cancer was the leading cause of both age-standardized mortality rate (ASMR) and age-standardized DALYs rate (ASDR), with rates of 12.63 and 217.83 per 100,000 persons, respectively. From 1990 to 2021, there was an upward trend in ASIR, ASPR, ASMR, and ASDR for UTI, while urolithiasis showed a downward trend. The middle and low-middle SDI quintile levels exhibited higher incidence, prevalence, mortality, and DALYs related to UTI, urolithiasis, and BPH, while the high and high-middle SDI quintile levels showed higher rates for the three cancers. The burden of these six urologic diseases displayed diverse age and sex distribution patterns. In 2021, a high body mass index (BMI) contributed to 20.07% of kidney cancer deaths worldwide, while smoking accounted for 26.48% of bladder cancer deaths and 3.00% of prostate cancer deaths. CONCLUSIONS: The global burden of 6 urologic diseases presents a significant public health challenge. Urgent international collaboration is essential to advance the improvement of urologic disease management, encompassing the development of effective diagnostic screening tools and the implementation of high-quality prevention and treatment strategies.