PI3Kδ Mediates Fibrosis by Patient-Derived Vitreous.

The epithelial-mesenchymal transition (EMT) is a fundamental process in developing fibrotic diseases, including forming epiretinal membranes (ERMs). ERMs can result in irreversible vision loss. Previous research has demonstrated that vitreous (VIT) derived from patients with proliferative diabetic retinopathy can stimulate angiogenesis through the Axl/PI3K/Akt pathway. Building upon this knowledge, we aimed to explore the influence of VIT from patients with macular membranes in ARPE-19 cells. Our findings reveal that patient-derived VIT from individuals with macular membranes promotes EMT and phosphoinositide 3-kinase-delta (PI3Kδ) expression in ARPE-19 cells. To elucidate the function of PI3Kδ in the ERM, we conducted experiments involving the knockout of p110δ, a key subunit of PI3Kδ, and observed that its absence hinders EMT induced by patient-derived VIT. Moreover, p110δ depletion reduces cell proliferation and migration in ARPE-19 cells. Remarkably, these effects were further corroborated by applying the p110δ inhibitor idelalisib, which blocks fibrosis in the laser-induced fibrosis model. Collectively, our results propose that p110δ plays a critical role in the progression of ERMs. Consequently, targeting p110δ emerges as a promising therapeutic approach for mitigating fibrosis. These findings contribute to a better understanding of the underlying mechanisms involved in ERM formation and highlight the potential for p110δ-directed antifibrotic therapy in retinal diseases.

Impact of income-based public drug coverage deductibles on adherence to asthma medications.

BACKGROUND: Cost-related nonadherence to medications can be a barrier to asthma management. OBJECTIVE: To quantify the impact of public drug plan deductibles on adherence to asthma medications. METHODS: We used a quasi-experimental regression discontinuity analysis to determine whether thresholds in deductibles for public drug coverage, determined on the basis of annual household income, decreased medication use among lower-income children and adults with asthma in British Columbia from 2013 to 2018. Using dispensed medication records, we evaluated deductible thresholds at annual household incomes of $15,000 (a deductible increase from 0% to 2% of annual household income), and $30,000 (a deductible increase from 2% to 3% annual household income). We evaluated medication costs, use, the ratio of inhaled corticosteroids-containing controller medications to total medications, excessive use of short-acting ß-agonists, and the proportion of days covered by controller therapies. All costs are reported in 2020 Canadian dollars. RESULTS: Overall, 88,935 individuals contributed 443,847 person-years of follow-up (57% of female sex, mean age 31 years). Public drug subsidy decreased by -$41.74 (95% CI, -$28.34 to -$55.13) at the $15,000-deductible threshold, a 28% reduction, and patient costs increased by $48.45 (95% CI, $35.37-$61.53). The $30,000 deductible threshold did not affect public drug costs (P = .31), but patient costs increased by $27.65 (95% CI, $15.22-$40.09), which is an 11% increase. Asthma-related medication use, inhaled corticosteroids-to-total medication ratio, excessive use of short-acting ß-agonists, and proportion of days covered by controller therapies were not impacted by deductible thresholds. CONCLUSION: Income-based deductibles reduced public drug costs with no effect on asthma-related medication use, adherence to controller therapies, or excessive reliever therapy use in lower-income individuals with asthma.

How to handle a delayed or missed dose of edoxaban in patients with non-valvular atrial fibrillation? A model-informed remedial strategy.

AIMS: Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for the long-term prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOAC therapy has been unsatisfactory and decreases over time. Remedial strategies are currently used to address the non-adherence events. Current recommendations, however, are generic and not well supported by evidence. The aim of this study was to explore appropriate remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through Monte Carlo simulation. METHODS: Six regimens were compared with the current recommendations of the European Heart Rhythm Association (EHRA) guide based on total deviation time. Both edoxaban plasma concentration and intrinsic Factor Xa activity were considered. Monte Carlo simulations were performed using RxODE based on a published population pharmacokinetic/pharmacodynamic (PK/PD) model. RESULTS: The proposed remedial strategies were different than the EHRA recommendations and were related to the delay time. However, it was found that the missed dose can be administered immediately if the delay time is within 11 h. When the delay is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred. CONCLUSION: PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which can help maximise its therapeutic effect.

Nintedanib inhibits normal human vitreous-induced epithelial-mesenchymal transition in human retinal pigment epithelial cells.

PURPOSE: In this study, we aim to investigate the potential of nintedanib as a therapeutic approach to proliferative vitreoretinopathy (PVR), which is the leading cause of failure in retinal detachment repair. PVR is characterized by the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, and understanding the effects of nintedanib on EMT in the normal human vitreous (HV)-induced RPE cells is crucial. METHODS: Our research focuses on assessing the impact of nintedanib on HV-induced EMT in human retinal pigment epithelial (ARPE-19) cells in vitro. We employed various techniques, including quantitative real-time PCR (qPCR), western blot analysis, and immunofluorescence staining, to evaluate the mRNA and protein expression of EMT biomarkers in HV-induced ARPE-19 cells. Additionally, we measured the proliferation of RPE cells using cell counting, CCK-8, and Ki-67 assays. Migration was assessed through wound healing and transwell migration assays, while contraction was determined using a collagen gel contraction assay. Morphological changes were examined using phase-contrast microscopy. RESULTS: Our results demonstrate that nintedanib selectively attenuates the upregulation of mesenchymal markers in HV-induced ARPE-19 cells, at both the mRNA and protein levels. Furthermore, nintedanib effectively suppresses the HV-induced proliferation, migration, and contraction of ARPE-19 cells, while maintaining the cells' basal activity. These findings strongly suggest that nintedanib exhibits protective effects against EMT in ARPE-19 cells and could be a promising therapeutic option for PVR. CONCLUSIONS: By elucidating the anti-EMT effects of nintedanib in HV-induced RPE cells, our study highlights the potential of this oral triple tyrosine kinase inhibitor in the treatment of PVR. These findings contribute to the growing body of research aimed at developing novel strategies to prevent and manage PVR, ultimately improving the success rates of retinal detachment repair.

Duration of the influence of snowmelt on land surface temperature and humidity after snowmelt on the Mongolian Plateau.

The impact of snowmelt on surface hydrothermal conditions is a research hot spot given the background of global warming. However, existing remote sensing-based studies have mostly focused on demonstrating the impacts of snow and are based on large time scales. How to measure the duration of snowmelt impact on surface hydrothermal conditions more accurately is a problem that needs to be addressed. We used a method to quantify the impact duration of snowmelt based on the characteristics of the phase change in land surface temperature (LST) and land surface water index (LSWI) after melting. We analyzed the snow factors that have caused the difference in impact duration and the interaction on the impact duration. The results are described as follows: (1) The LST and LSWI changes after snow melting are characterized by distinct phases. (2) The duration of the snowmelt impact on LST ranged from 4.61 days in the south to 21.23 days in the north; the effect of snow on the LSWI ranged from 8.06 days in the south to 25.38 days in the north. (3) The two durations have a significant positive correlation with snow depth and snow melt date. The combination of several snow parameters and other meteorological factors has a significant interaction effect on the duration of snowmelt influence. In most combinations where there is no interaction, the duration is significantly affected only by snow elements. The interaction can change the direction and extent of the effect of a single snow or meteorological element on the duration of snow impact. This research can supplement the theoretical basis for solving ecological problems and production in the study area, such as spring drought, forage mowing, and cold protection of livestock.

Nintedanib prevents TGF-ß2-induced epithelial-mesenchymal transition in retinal pigment epithelial cells.

Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is a key fibrosis pathogenesis in proliferative vitreoretinopathy (PVR). However, few medicines can prevent proliferative membranes and cell proliferation in the clinic. Nintedanib, a tyrosine kinase inhibitor, has been shown to prevent fibrosis and be anti-inflammatory in multiple organ fibrosis. In our study, 0.1, 1, 10 µM nintedanib was added to 20 ng/mL transforming growth factor beta 2 (TGF-ß2)-induced EMT in ARPE-19 cells. Western blot and immunofluorescence assay showed that 1 µM nintedanib suppressed TGF-ß2-induced E-cadherin expression decreased and Fibronectin, N-cadherin, Vimentin, and α-SMA expression increased. Quantitative real-time PCR results showed that 1 µM nintedanib decreased TGF-ß2-induced increase in SNAI1, Vimentin, and Fibronectin expression and increased TGF-ß2-induced decrease in E-cadherin expression. In addition, the CCK-8 assay, wound healing assay, and collagen gel contraction assay also showed that 1 µM nintedanib ameliorated TGF-ß2-induced cell proliferation, migration, and contraction, respectively. These results suggested that nintedanib inhibits TGF-ß2-induced EMT in ARPE-19 cells, which may be a potential pharmacological treatment for PVR.

Diagnostic Value of DCE-MRI and Tofts Model in Children with Unilateral Hydronephrosis.

BACKGROUND: Hydronephrosis is a common condition, and the correct diagnosis of hydronephrosis is necessary to improve the early diagnosis rates of pediatric hydronephrosis. OBJECTIVE: The objective of this study is to explore and analyze the diagnostic value of dynamic contrast- enhanced magnetic resonance imaging (DCE-MRI) analyzed using the Tofts model in children with unilateral hydronephrosis. METHODS: We retrospectively selected data from 88 children with unilateral hydronephrosis treated in our hospital from September 2018 to October 2020. Routine and DCE-MR renal image indexes were collected and their pharmacokinetic variables were calculated based on the Tofts model to compare kinetic parameters of affected and normal kidney. We compared the renal parenchymal thickness and other renal function indexes in children with different degrees of hydronephrosis, and drew receiver operating characteristic (ROC) curves to evaluate the diagnostic value of this approach in children with hydronephrosis. RESULTS: The Ktrans, Kep, and Ve values in the diseased kidneys were lower than those in the normal ones (P<0.05). The thickness of the healthy renal parenchyma in children with severe hydronephrosis was higher than in children with moderate and mild hydronephrosis, but the renal parenchyma thickness and the thickness ratio of renal parenchyma on the affected side were lower than those in children with moderate and mild hydronephrosis (P<0.05). Sensitivity, specificity and accuracy of DCE-MRI and Tofts model in the diagnosis of hydronephrosis in children were higher than those of a single DCE-MRI (P<0.05). The area under the ROC curve for the DCE-MRI and Tofts model approach for the diagnosis of hydronephrosis in children was 0.789 (95% CI, 0.72-0.859), and the sensitivity and specificity were 86.36% and 71.59%, respectively. CONCLUSION: DCE-MRI and Tofts model can provide a clear picture of renal morphology, and renal function evaluation parameters. They have high sensitivity and specificity in the diagnosis of hydronephrosis in children.

Revealing composition and structure dependent deep-level defect in antimony trisulfide photovoltaics.

Antimony trisulfide (Sb2S3) is a kind of emerging light-harvesting material with excellent stability and abundant elemental storage. Due to the quasi-one-dimensional symmetry, theoretical investigations have pointed out that there exist complicated defect properties. However, there is no experimental verification on the defect property. Here, we conduct optical deep-level transient spectroscopy to investigate defect properties in Sb2S3 and show that there are maximum three kinds of deep-level defects observed, depending on the composition of Sb2S3. We also find that the Sb-interstitial (Sbi) defect does not show critical influence on the carrier lifetime, indicating the high tolerance of the one-dimensional crystal structure where the space of (Sb4S6)n ribbons is able to accommodate impurities to certain extent. This study provides basic understanding on the defect properties of quasi-one-dimensional materials and a guidance for the efficiency improvement of Sb2S3 solar cells.

Population pharmacokinetics of oxcarbazepine: a systematic review.

INTRODUCTION: Oxcarbazepine is commonly used as first-line treatment for partial and generalized tonic-clonic seizures. Owing to the high pharmacokinetic variability, several population pharmacokinetic models have been developed for oxcarbazepine to explore potential covariates that affect its pharmacokinetic variation. AREAS COVERED: This review summarizes the published population pharmacokinetic studies of oxcarbazepine in children and adults available in PubMed and Embase databases. The quality of the retrieved studies was evaluated, and significant covariates that may have an impact on the dosage regimen of oxcarbazepine were explored. EXPERT OPINION: The pharmacokinetics of oxcarbazepine was founded to be affected by body weight and co-administration with enzyme inducers. Pediatric patients require a higher dose per kilogram than adults because children generally have a higher clearance than adults. Moreover, to maintain the target concentration, patients co-administrate with enzyme inducers need a higher dose than monotherapy due to higher clearance in those patients. Because limited information is available for exposure-response relationship, additional pharmacokinetic/pharmacodynamics investigations of oxcarbazepine need to be conducted to optimize the dosage regimen in clinical practice.

How to handle the delayed or missed dose of rivaroxaban in patients with non-valvular atrial fibrillation: model-informed remedial dosing.

BACKGROUND: Rivaroxaban is an oral anticoagulant widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are common. This study aimed to explore appropriate remedial dosing regimens for non-adherent rivaroxaban-treated patients. METHODS: Monte Carlo simulation based on a previously established rivaroxaban population pharmacokinetic/pharmacodynamic (PK/PD) model for patients with NVAF was employed to design remedial dosing regimens. The proposed regimens were compared with remedial strategies in the European Heart Rhythm Association (EHRA) guide by assessing deviation time in terms of drug concentration, factor Xa activity, and prothrombin time. RESULTS: The proposed remedial dosing regimens were dependent on delay duration. The missed dose should be taken immediately when the delay does not exceed 6 h; a half dose is advisable when the delay is between 6 and 20 h. A missed dose should be skipped if less than 4 h remains before the next dose. The proposed regimens resulted in shorter deviation time than that of the EHRA guide. CONCLUSION: PK/PD modeling and simulation provide valid evidence on the remedial dosing regimen of rivaroxaban, which could help to minimize the risk of bleeding and thromboembolism.

Sequential Coevaporation and Deposition of Antimony Selenosulfide Thin Film for Efficient Solar Cells.

Antimony selenosulfide (Sb2 (S,Se)3 ) is an emerging low-cost, nontoxic solar material with suitable bandgap and high absorption coefficient. Developing effective methods for fabricating high-quality films would benefit the device efficiency improvement and deepen the fundamental understanding on the optoelectronic properties. Herein, equipment is developed that allows online introduction of precursor vapor during the reaction process, enabling sequential coevaporation of Sb2 Se3 and S powders for the deposition of Sb2 (S,Se)3 thin films. With this unique ability, it is revealed that the deposition sequence manipulates both the interfacial properties and optoelectronic properties of the absorber film. A power conversion efficiency of 8.0% is achieved, which is the largest value in vapor-deposition-derived Sb2 (S,Se)3 solar cells. The research demonstrates that multi-source sequential coevaporation is an efficient technique to fabricate high-efficiency Sb2 (S,Se)3 solar cells.

Bioactivity and pharmacokinetics of two human serum albumin-thymosin alpha1-fusion proteins, rHSA-Talpha1 and rHSA-L-Talpha1, expressed in recombinant Pichia pastoris.

Thymosin-alpha1 (Talpha1) is indicated for the treatment of certain viral infections, including hepatitis B and C, and cancers, such as melanoma. In this paper, the fusion genes encoding human serum albumin (HSA) and Talpha1 with (rHSA-L-Talpha1) and without a linker peptide (rHSA-Talpha1) were constructed and overexpressed in P. pastoris. Through the process of ion interaction chromatography (Q-Sepharose F.F), hydrophobic interaction chromatography (Phenyl Sepharose HP) and affinity chromatography (Blue Sepharose F.F), the purity of fusion proteins was greater than 97%. In contrast to the reactivity of normal spleen cells to Con A, the data of in vitro murine spleen lymphocytes proliferation experiment suggested that spleen cells achieved a higher degree of T cell maturation after rHSA-L-Talpha1, rHSA-Talpha1 and Talpha1 treatments, respectively. Moreover, rHSA-L-Talpha1, rHSA-Talpha1 and Talpha1 can also antagonize dexamethasone-induced apoptosis of thymocyte sub-populations. In hydrocortisone-induced immunosuppression mice (in vivo experiments), after subcutaneous injections with two fusion proteins and Talpha1 for seven consecutive days, the net increment of body weight, the spleen index and the thymus index were significantly improved. Simultaneously, the increase in SOD level and the decrease in MDA level in plasma were observed. The pharmacokinetic data of rHSA-L-Talpha1 and rHSA-Talpha1 administered in rats showed an improved pharmacokinetic profile with a conspicuous prolonged half life. The analysis of bioactivity and pharmacokinetics suggested that fusion proteins rHSA-L-Talpha1 and rHSA-Talpha1 were new drug candidates.

Analysis on Entrepreneurship Psychology of Preschool Education Students With Entrepreneurial Intention.

To diversify the creative thinking of preschool education students and improve their ability to innovate and start a business, a survey of preschool education students under entrepreneurial psychology theory was conducted in this research. Based on the theoretical foundation of entrepreneurial psychology, this article analyzed the entrepreneurial psychological quality and psychological education of college students. By investigating preschool education students in a certain college in Sichuan as the research object, the author explored the current entrepreneurial intentions of college students and their entrepreneurial psychological problems. In response to the current entrepreneurial situation of college graduates, relevant countermeasures were proposed from the perspective of the school to support their entrepreneurial psychology. Among the 205 preschool education college students, the students were more willing to give full play to their professional expertise in terms of employment intentions. At the same time, there were still situations in which students were dissatisfied with the prospects of preschool education career development and wanted to achieve the value of life through other approaches. Most students in preschool education had a wait-and-see attitude toward entrepreneurship. Only 35% of students had a clear intention to start a business and made their plans for entrepreneurship. More than 90% of students held that they had developed inadequate entrepreneurial ability, and 80% of students believed that they lacked the required professional knowledge. These two factors constitute the main reasons for students' negative attitudes toward entrepreneurship. Nevertheless, colleges may stimulate the potential of students' self-development through the improvement of entrepreneurial psychological education courses, the construction of psychological consultation institutions on campus, and the establishment of interactive platforms for entrepreneurship. In this way, students' entrepreneurial psychology can be cultivated in an all-round way. Therefore, to deal with the weak overall entrepreneurial consciousness of college students, the colleges should cultivate entrepreneurial innovative talents by strengthening the psychological education of entrepreneurship for students, and help college students achieve entrepreneurial success.

Aqueous solution processed MoS3 as an eco-friendly hole-transport layer for all-inorganic Sb2Se3 solar cells.

Here we report a solution processed environmentally friendly MoS3 hole-transport material for Sb2Se3 solar cells, where MoS3 exhibits a matched energy level relative to Sb2Se3. In the synthesis, H2S produced by the thermal decomposition of (NH4)2MoS4 is found to efficiently eliminate the antimony oxide impurity formed on the Sb2Se3 surface. Finally, the all-inorganic Sb2Se3 solar cell delivers an efficiency of 6.86% with excellent stability.

Composition engineering of Sb2S3 film enabling high performance solar cells.

Sb2S3 is a kind of stable light absorption materials with suitable band gap, promising for practical applications. Here we demonstrate that the engineering on the composition ratio enables significant improvement in the device performance. We found that the co-evaporation of sulfur or antimony with Sb2S3 is able to generate sulfur- or antimony-rich Sb2S3. This composition does not generate essential influence on the crystal structure, optical band and film formability, while the carrier concentration and transport dynamics are considerably changed. The device investigations show that sulfur-rich Sb2S3 film is favorable for efficient energy conversion, while antimony-rich Sb2S3 leads to greatly decreased device performance. With optimizations on the sulfur-rich Sb2S3 films, the final power conversion efficiency reaches 5.8%, which is the highest efficiency in thermal evaporation derived Sb2S3 solar cells.