Flexible Hydrazone-Linked Metal-Covalent Organic Frameworks with Copper Clusters for Efficient Electrocatalytic Oxygen Evolution Reaction.

Despite the challenges associated with the synthesis of flexible metal-covalent organic frameworks (MCOFs), these offer the unique advantage of maximizing the atomic utilization efficiency. However, the construction of flexible MCOFs with flexible building units or linkages has rarely been reported. In this study, novel flexible MCOFs are constructed using flexible building blocks and copper clusters with hydrazone linkages. The heterometallic frameworks (Cu, Co) are prepared through the hydrazone linkage coordination method and evaluated as catalysts for the oxygen evolution reaction (OER). Owing to the spatial separation and functional cooperation of the heterometallic MCOF catalysts, the as-synthesized MCOFs exhibited outstanding catalytic activities with an overpotential of 268.8 mV at 10 mA cm-2 for the OER in 1 M KOH, which is superior to those of the reported covalent organic frameworks (COFs)-based OER catalysts. Theoretical calculations further elucidated the synergistic effect of heterometallic active sites within the linkages and frameworks, contributing to the enhanced OER activity. This study thus introduces a novel approach to the fundamental design of flexible MCOF catalysts for the OER, emphasizing their enhanced atomic utilization efficiency.

Coenzyme A protects against ferroptosis via CoAlation of thioredoxin reductase 2.

The Cystine-xCT transporter-Glutathione (GSH)-GPX4 axis is the canonical pathway to protect against ferroptosis. While not required for ferroptosis-inducing compounds (FINs) targeting GPX4, FINs targeting the xCT transporter require mitochondria and its lipid peroxidation to trigger ferroptosis. However, the mechanism underlying the difference between these FINs is still unknown. Given that cysteine is also required for coenzyme A (CoA) biosynthesis, here we show that CoA supplementation specifically prevents ferroptosis induced by xCT inhibitors but not GPX4 inhibitors. We find that, auranofin, a thioredoxin reductase inhibitor, abolishes the protective effect of CoA. We also find that CoA availability determines the enzymatic activity of thioredoxin reductase, but not thioredoxin. Importantly, the mitochondrial thioredoxin system, but not the cytosolic thioredoxin system, determines CoA-mediated ferroptosis inhibition. Our data show that the CoA regulates the in vitro enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolishes its in vitro enzymatic activity and ability to protect cells from ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2, an effect that was rescued by CoA supplementation. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrate increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis leads to an oxidized thioredoxin system, mitochondrial lipid peroxidation, and loss in cell viability, which were all rescued by ferrostatin-1. These findings identify CoA-mediated post-translation modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.

The effect of remimazolam-based total intravenous anesthesia versus sevoflurane-based inhalation anesthesia on emergence delirium in children undergoing tonsillectomy and adenoidectomy: study protocol for a prospective randomized controlled trial.

Background: Remimazolam, a new ultrashort-acting benzodiazepine, is becoming increasingly applied in general anesthesia. This study is designed to investigate the effect of remimazolam-based total intravenous anesthesia and sevoflurane-based inhalation anesthesia on emergence delirium in pediatric tonsillectomy and adenoidectomy. Methods and analysis: This is a monocentric, prospective, randomized, double-blind clinical trial. A total of 90 pediatric patients will be randomized to receive remimazolam-based total intravenous anesthesia (remimazolam group, n = 45) or sevoflurane-based inhalation anesthesia (sevoflurane group, n = 45). The primary outcome will be the incidence of emergence delirium, which will be evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale. The secondary outcomes include the extubation time, recovery time, behavior change using the post-hospitalization behavior questionnaire for ambulatory surgery (PHBQ-AS), and adverse events. Ethics and dissemination: This study has been approved by the Institutional Review Board (IRB) of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (2023-K-262-02). Clinical trial registration: ClinicalTrials.gov, identifier NCT06214117.

Hsa-miR-134-5p predicts cardiovascular risk in circulating mononuclear cells and improves angiogenic action of senescent endothelial progenitor cells.

This research explores the role of microRNA in senescence of human endothelial progenitor cells (EPCs) induced by replication. Hsa-miR-134-5p was found up-regulated in senescent EPCs where overexpression improved angiogenic activity. Hsa-miR-134-5p, which targeted transforming growth factor ß-activated kinase 1-binding protein 1 (TAB1) gene, down-regulated TAB1 protein, and inhibited phosphorylation of p38 mitogen-activated protein kinase (p38) in hsa-miR-134-5p-overexpressed senescent EPCs. Treatment with siRNA specific to TAB1 (TAB1si) down-regulated TAB1 protein and subsequently inhibited p38 activation in senescent EPCs. Treatment with TAB1si and p38 inhibitor, respectively, showed angiogenic improvement. In parallel, transforming growth factor Beta 1 (TGF-ß1) was down-regulated in hsa-miR-134-5p-overexpressed senescent EPCs and addition of TGF-ß1 suppressed the angiogenic improvement. Analysis of peripheral blood mononuclear cells (PBMCs) disclosed expression levels of hsa-miR-134-5p altered in adult life, reaching a peak before 65 years, and then falling in advanced age. Calculation of the Framingham risk score showed the score inversely correlates with the hsa-miR-134-5p expression level. In summary, hsa-miR-134-5p is involved in the regulation of senescence-related change of angiogenic activity via TAB1-p38 signalling and via TGF-ß1 reduction. Hsa-miR-134-5p has a potential cellular rejuvenation effect in human senescent EPCs. Detection of human PBMC-derived hsa-miR-134-5p predicts cardiovascular risk.

High prevalence of exon-13 variants in USH2A-related retinal dystrophies in Taiwanese population.

BACKGROUND: Biallelic pathogenic variants in USH2A lead to Usher syndrome or non-syndromic retinitis pigmentosa, and shown to have geographical and ethnical distribution in previous studies. This study provided a deeper understanding of the detailed clinical features using multimodal imaging, genetic spectrum, and genotype-phenotype correlations of USH2A-related retinal dystrophies in Taiwan. RESULTS: In our cohort, the mean age at first visit was 47.66 ± 13.54 years, and the mean age at symptom onset, which was referred to the onset of nyctalopia and/or visual field constriction, was 31.21 ± 15.24 years. Among the variants identified, 23 (50%) were missense, 10 (22%) were splicing variants, 8 (17%) were nonsense, and 5 (11%) were frameshift mutations. The most predominant variant was c.2802T>G, which accounted for 21% of patients, and was located in exon 13. Patients with truncated alleles had significantly earlier symptom onset and seemly poorer disease progression regarding visual acuity, ellipsoid zone line length, and hypofluorescent lesions in the macula than those who had the complete gene. However, the clinical presentation revealed similar progression between patients with and without the c.2802T>G variant. During long-term follow-up, the patients had different ellipsoid zone line progression rates and were almost evenly distributed in the fast, moderate, and slow progression subgroups. Although a younger onset age and a smaller baseline intact macular area was observed in the fast progression subgroup, the results showed no significant difference. CONCLUSIONS: This is the first cohort study to provide detailed genetic and longitudinal clinical analyses of patients with USH2A-related retinal dystrophies in Taiwan. The mutated allele frequency in exon 13 was high in Taiwan due to the predominant c.2802T>G variant. Moreover, truncated variants greatly impacted disease progression and determined the length of therapeutic windows. These findings provide insight into the characteristics of candidates for future gene therapies.

LncRNA CRNDE promotes hepatoma cell proliferation by regulating the metabolic reprogramming of M2 macrophages via ERK pathway.

BACKGROUND: LncRNA colorectal neoplasia differentially expressed (CRNDE) was found to be an important regulator in many cancers. This project focuses on the function of CRNDE on macrophage metabolic reprogramming and Hepatocellular carcinoma (HCC). METHOD: qRT-PCR and Immunofluorescence were used to analyze Arg-1, IL-10, CD163, CCL-18, CD206, and CRNDE expression in HCC tissues and macrophages. Western Blotting was used to analyze ERK and p-ERK expression. Edu assay, transwell assay and xenograft experiments were carried out to study cell viability, migrated and invasive capability. Immunohistochemical staining was used to evaluate Ki67 expression. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed for macrophages metabolites analysis. RESULTS: Arg-1, IL-10, CD163, CD206, and CRNDE were significantly up-regulated in HCC tissues, M2 macrophage and M0 macrophage with CRNDE overexpressed (OV-CRNDE-M0), which downregulated in M0 macrophage with CRNDE knockdown (sh-CRNDE-M0). The conditioned medium (CM) of M2 cells and OV-CRNDE-M0 cells promoted cell viability, invasion, and migration of HCC cells, the effect was reversed by sh-CRNDE-M0 cells CM. OV-CRNDE-M0 cells promoted tumor growth, Ki67 and CD206 expression in xenograft model. 61 metabolites were detected, of which 18 metabolites changed significantly in OV-CRNDE-M0 group compared to M0 group, with 9 upregulated and 9 downregulated. KEGG analysis showed the enrichment pathways were biosynthesis, glyoxylate and dicarboxylate metabolism. SMPDB analysis showed the enrichment pathways were hypoacetylaspartia, canavan disease, and aspartate metabolism. CONCLUSION: CRNDE regulated the metabolic reprogramming of M2 macrophage via ERK pathway, which thereby contributed to HCC proliferation, migration, and invasion.

A review on defect modulated electrocatalysts for the oxygen evolution reaction.

The oxygen evolution reaction (OER) is crucial for applications such as water splitting and rechargeable metal-air batteries. Recent research has focused on improving the activity and stability of OER electrocatalysts through various strategies including structural innovation, heteroatom doping, and conductivity enhancement. Among these, defect engineering has proved particularly effective, allowing precise modulation of the materials' electronic structure at the atomic level. This review addresses defect-rich materials that exhibit superior electrochemical properties for OER applications, with a particular focus on developments from the past five years. The discussion starts with an overview of the OER catalytic mechanism and then delves into the types of defects, synthesis methods, and their impact on electrochemical performance. This review concludes with insights into the rational design and synthesis of advanced electrocatalysts, aiming to improve efficiency and extend operational longevity. The objective is to highlight approaches for creating high-performance OER electrocatalysts that outperform noble-metal based systems in both activity and stability.

Rapid Glutathione Analysis with SERS Microneedles for Deep Glioblastoma Tissue Differentiation.

Rapid tissue differentiation at the molecular level is a prerequisite for precise surgical resection, which is of special value for the treatment of malignant tumors, such as glioblastoma (GBM). Herein, a SERS-active microneedle is prepared by modifying glutathione (GSH)-responsive molecules, 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), on the surface of Au@Ag substrates for the distinction of different GBM tissues. Since the Raman signals on the surface of the DTNB@Au@Ag microneedle can be collected by both portable and benchtop Raman spectrometers, the distribution of GSH in different tissues at centimeter scale can be displayed through Raman spectroscopy and Raman imaging, and the entire analysis process can be accomplished within 12 min. Accordingly, in vivo brain tissues of orthotopic GBM xenograft mice and ex vivo tissues of GBM patients are accurately differentiated with the microneedle, and the results are well consistent with tissue staining and postoperative pathological reports. In addition, the outline of tumor, peritumoral, and normal tissues can be indicated by the DTNB@Au@Ag microneedle for at least 56 days. Considering that the tumor tissues are quickly discriminated at the molecular level without the restriction of depth, the DTNB@Au@Ag microneedle is promising to be a powerful intraoperative diagnostic tool for surgery navigation.

ARID1A restrains EMT and stemness of ovarian cancer cells through the Hippo pathway.

Genes encoding subunits of SWI/SNF (BAF) chromatin­remodeling complexes are recurrently mutated in a broad array of tumor types, and among the subunits, ARID1A is the most frequent target with mutations. In the present study, it was reported that ARID1A inhibits the epithelial­mesenchymal transition (EMT) and stemness of ovarian cancer cells, accompanied by reduced cell viability, migration and colony formation, suggesting that ARID1A acts as a tumor suppressor in ovarian cancer. Mechanistically, ARID1A exerts its inhibitory effects on ovarian cancer cells by activating the Hippo signaling pathway. Conversely, the overexpression of a gain­of­function transcriptional co­activator with PDZ­binding motif (TAZ) mutant (TAZ­Ser89) effectively reverses the effects induced by ARID1A. In addition, activation of Hippo signaling apparently upregulates ARID1A protein expression, whereas ectopic expression of TAZ­Ser89 results in the markedly decreased ARID1A levels, indicating a feedback of ARID1A­TAZ in regulating ovarian cancer cell EMT and stemness. Thus, the present study uncovered the role of ARID1A through the Hippo/TAZ pathway in modulating EMT and stemness of ovarian cancer cells, and providing with evidence that TAZ inhibitors could effectively prevent initiation and metastasis of ovarian cancer cases where ARID1A is lost or mutated.

Proactive consultation of laboratory medicine increased diagnostic rate of multiple myeloma: One single center's 12-year experience.

Multiple myeloma (MM) was one of the hardest cancers to diagnose because of numerous nonspecific symptoms, leading to diagnostic delay. Proactive consultation of laboratory medicine (PCLM) could help timely diagnosis of blood cancers, avoiding diagnostic delay. This study aimed to evaluate the effect of PCLM on diagnosis and outcomes in MM. This retrospective study was conducted in newly diagnosed MM patients from 2011 to 2022. Implementation of PCLM initiated in 2015 with a laboratory-oriented algorithm. The annual diagnostic rate, patient demographics, the time intervals from symptom onset to diagnosis and to treatment, and clinical outcomes were analyzed. A total of 134 patients were newly diagnosed during the study interval. The diagnostic rate increased from 4.65 ±â€…1.59 to 7.43 ±â€…1.52 per million patient-visits after implementation of PCLM. The median time interval from symptom onset to diagnosis was significantly shortened after implementation of PCLM (50 days with interquartile range [IQR]: 24-136 days vs 150 days with IQR: 41-385 days, P = .003). Besides, the 1-year survival was significantly higher in patients diagnosed as MM after implementation of PCLM (72.4% vs 51.7%, P = .035). Implementation of PCLM not only increased diagnostic rate of MM and improved outcomes, but also raise awareness for MM and promote multidisciplinary collaboration in healthcare.

Senescence induces miR-409 to down-regulate CCL5 and impairs angiogenesis in endothelial progenitor cells.

This study explores the impact of senescence on autocrine C-C motif chemokine ligand 5 (CCL5) in human endothelial progenitor cell (EPCs), addressing the poorly understood decline in number and function of EPCs during ageing. We examined the effects of replication-induced senescence on CCL5/CCL5 receptor (CCR5) signalling and angiogenic activity of EPCs in vitro and in vivo. We also explored microRNAs controlling CCL5 secretion in senescent EPCs, its impact on EPC angiogenic activity, and validated our findings in humans. CCL5 secretion and CCR5 levels in senescent EPCs were reduced, leading to attenuated angiogenic activity. CCL5 enhanced EPC proliferation via the CCR5/AKT/P70S6K axis and increased vascular endothelial growth factor (VEGF) secretion. Up-regulation of miR-409 in senescent EPCs resulted in decreased CCL5 secretion, inhibiting the angiogenic activity, though these negative effects were counteracted by the addition of CCL5 and VEGF. In a mouse hind limb ischemia model, CCL5 improved the angiogenic activity of senescent EPCs. Analysis involving 62 healthy donors revealed a negative association between CCL5 levels, age and Framingham Risk Score. These findings propose CCL5 as a potential biomarker for detection of EPC senescence and cardiovascular risk assessment, suggesting its therapeutic potential for age-related cardiovascular disorders.

Effects of disc overhang diameter on the uplift bearing capacity of new-type concrete expanded-plate pile groups.

The disc overhang diameter can significantly affect the uplift bearing capacity of new concrete expanded-plate pile groups, affecting their design and practical applications. Accordingly, this effect was investigated considering the failure laws of the soil surrounding various pile types and groups. Based on the uplift bearing capacities of single and double piles, a finite element simulation was adopted to establish models for the four-, six-, and nine-pile groups. The relationship between the disc overhang diameter and uplift-bearing capacity of each pile group was explored: as the disk overhang diameter increased, the uplift-bearing capacities of the pile groups increased; however, this relationship is nonlinear. The optimal disc overhang diameter was determined as 1.5-1.75 times the pile diameter. For a constant disc overhang diameter, corner piles have a greater uplift bearing capacity than side piles in the six-pile group, and a greater uplift bearing capacity than the side and center piles in the nine-pile group. Thus, the pile-group effect depends on the pile position. The uplift bearing capacity did not increase linearly with the number of piles, and the average uplift bearing capacity of a pile in a pile group was less than that of a single pile. Therefore, the uplift bearing capacity of the pile groups decreased as the number of piles increased. The reliability of the simulation was verified via visual testing of a small-scale half-cut pile model.

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Pleuromutilin Derivatives Containing Thiazole.

In this study, we designed and synthesized a series of pleuromutilin derivatives containing thiazole. The in vitro antimicrobial efficacy of these synthesized compounds was examined by using four strains. Compared with tiamulin (MIC = 0.25 µg/mL), compound 14 exhibited potency in inhibiting MRSA growth (MIC = 0.0625 µg/mL) in these derivatives. Meanwhile, the time-killing kinetics further demonstrated that compound 14 could efficiently inhibit the MRSA growth. After exposure at 4 × MIC, the postantibiotic effect (PAE) of compound 14 was 1.29 h. Additionally, in thigh-infected mice, compound 14 exhibited a more potent antibacterial efficacy (-1.78 ± 0.28 log10 CFU/g) in reducing MRSA load compared to tiamulin (-1.21 ± 0.23 log10 CFU/g). Moreover, the MTT assay on RAW 264.7 cells demonstrated that compound 14 (8 µg/mL) had no significant cytotoxicity. Docking studies indicated the strong affinity of compound 14 toward the 50S ribosomal subunit, with a binding free energy of -9.63 kcal/mol. Taken together, it could be deduced that compound 14 was a promising candidate for treating MRSA infections.

Senolytic effects of exercise in human muscles require acute inflammation.

Higher intensity exercise, despite causing more tissue damage, improved aging conditions. We previously observed decreased p16INK4a mRNA in human skeletal muscle after high-intensity interval exercise (HIIE), with no change following equivalent work in moderate-intensity continuous exercise. This raises the question of whether the observed senolytic effect of exercise is mediated by inflammation, an immune response induced by muscle damage. In this study, inflammation was blocked using a multiple dose of ibuprofen (total dose: 1200 mg), a commonly consumed nonsteroidal anti-inflammatory drug (NSAID), in a placebo-controlled, counterbalanced crossover trial. Twelve men aged 20-26 consumed ibuprofen or placebo before and after HIIE at 120% maximum aerobic power. Multiple muscle biopsies were taken for tissue analysis before and after HIIE. p16INK4a+ cells were located surrounding myofibers in muscle tissues. The maximum decrease in p16INK4a mRNA levels within muscle tissues occurred at 3 h post-exercise (-82%, p < 0.01), gradually recovering over the next 3-24 h. A concurrent reduction pattern in CD11b mRNA (-87%, p < 0.01) was also found within the same time frame. Ibuprofen treatment attenuated the post-exercise reduction in both p16INK4a mRNA and CD11b mRNA. The strong correlation (r = 0.88, p < 0.01) between p16INK4a mRNA and CD11b mRNA in muscle tissues suggests a connection between the markers of tissue aging and pro-inflammatory myeloid differentiation. In conclusion, our results suggest that the senolytic effect of high-intensity exercise on human skeletal muscle is mediated by acute inflammation.

Design, synthesis, biological evaluation of novel piperidine-based derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a crucial member of DNA repair enzymes responsible for repairing DNA single-strand breaks. Developing PARP inhibitors based on synthetic lethality strategies is an effective approach for treating breast cancer and other diseases. In this study, a series of novel piperidine-based benzamide derivatives were designed and synthesized using structure-based drug design principles. The anticancer activities of these compounds were evaluated against five human cancer cell lines (MDA-MB-436, CAPAN-1, SW-620, HepG2, SKOV3, and PC3) and the preliminary structure-activity relationships were delineated. Among the compounds, 6a and 15d demonstrated potent antiproliferative effects against MDA-MB-436 cells with IC50 values of 8.56 ± 1.07 µM and 6.99 ± 2.62 µM, respectively. Furthermore, both compounds exhibited excellent inhibitory activity against PARP-1, with IC50 values of 8.33 nM and 12.02 nM, respectively. Mechanistic investigations revealed that 6a and 15d effectively inhibited colony formation and cell migration of HCT116 cells. Moreover, they induced apoptosis by upregulating the expression of Bax and cleaved Caspase-3, while downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. Based on its impressive pharmacodynamic data in vitro, we conducted a study to evaluate the efficacy of 15d in a xenograft tumor model in mice when used in combination with cytotoxic agents. Collectively, these findings suggest that 15d could be promising drug candidates worthy of further investigation.

Two-Dimensional Electron-Hole Plasma in Colloidal Quantum Shells Enables Integrated Lasing Continuously Tunable in the Red Spectrum.

Combining integrated optical platforms with solution-processable materials offers a clear path toward miniaturized and robust light sources, including lasers. A limiting aspect for red-emitting materials remains the drop in efficiency at high excitation density due to non-radiative quenching pathways, such as Auger recombination. Next to this, lasers based on such materials remain ill characterized, leaving questions about their ultimate performance. Here, we show that colloidal quantum shells (QSs) offer a viable solution for a processable material platform to circumvent these issues. We first show that optical gain in QSs is mediated by a 2D plasma state of unbound electron-hole pairs, opposed to bound excitons, which gives rise to broad-band and sizable gain across the full red spectrum with record gain lifetimes and a low threshold. Moreover, at high excitation density, the emission efficiency of the plasma state does not quench, a feat we can attribute to an increased radiative recombination rate. Finally, QSs are integrated on a silicon nitride platform, enabling high spectral contrast, surface emitting, and TE-polarized lasers with ultranarrow beam divergence across the entire red spectrum from a small surface area. Our results indicate QS materials are an excellent materials platform to realize highly performant and compact on-chip light sources.

Ion solvation free energy calculations based on first-principles molecular dynamics thermodynamic integration.

Numerous electrochemistry reactions require the precise calculation of the ion solvation energy. Despite the significant progress in the first-principles calculations for crystals and defect formation energies for solids, the liquid system free energy calculations still face many challenges. Ion solvation free energies can be calculated via different semiempirical ways, e.g., using implicit solvent models or cluster of explicit molecule models; however, systematically improving these models is difficult due to their lack of a solid theoretical base. A theoretically sound approach for calculating the free energy is to use thermodynamic integration. Nevertheless, owing to the difficulties of self-consistent convergence in first-principles calculations for unphysical atomic configurations, the computational alchemy approach has not been widely used for first-principles calculations. This study proposes a general approach to use first-principles computational alchemy for calculating the ion solvation energy. This approach is also applicable for other small molecules. The calculated ion solvation free energies for Li+, Na+, K+, Be2+, Mg2+, and Ca2+ are close to the experimental results, and the standard deviation due to molecular dynamics fluctuations is within 0.06 eV.

Development and Validation of a Risk Prediction Model for Female Stress Urinary Incontinence in Rural Fujian, China.

Purpose: With China's rapidly aging population and the rising proportion of obese people, an increase in the number of women suffering from urinary incontinence (UI) is to be expected. In order to identify high-risk groups before leakage occurs, we aimed to develop and validate a model to predict the risk of stress UI (SUI) in rural women. Patients and methods: This study included women aged 20-70 years in rural Fujian who participated in an epidemiologic survey of female UI conducted between June and October 2022. Subsequently the data was randomly divided into training and validation sets in a ratio of 7:3. Univariate and multivariate logistic regression analyses were used to identify independent risk factors as well as to further construct a nomogram for risk prediction. Finally, concordance index (C-index), calibration curve and decision curve analysis were applied to evaluate the performance of the predictive models. Results: A total of 5290 rural females were enrolled, of whom 771 (14.6%) had SUI. Age, body mass index (BMI), postmenopausal status, number of vaginal deliveries, vaginal delivery of large infant, constipation and family history of pelvic organ prolapse (POP) and SUI were included in the nomogram. C-index of this prediction model for the training and validation sets was 0.835 (95% confidence interval [CI] = 0.818-0.851) and 0.829 (95% CI = 0.796-0.858), respectively, and the calibration curves and decision analysis curves for both the training and validation sets showed that the model was well-calibrated and had a positive net benefit. Conclusion: This model accurately estimated the SUI risk of rural women in Fujian, which may serve as an effective primary screening tool for the early identification of SUI risk and provide a basis for further implementation of individualized early intervention. Moreover, the model is concise and intuitive, which makes it more operational for rural women with scarce medical resources.

Genetics in neovascular age-related macular degeneration susceptibility and treatment response to anti-VEGF intravitreal injection: A case series study.

BACKGROUND: To identify genotypes associated with neovascular age-related macular degeneration (nAMD) and investigate the associations between genotype variations and anti-vascular endothelial growth factor (VEGF) treatment response. METHODS: This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti-VEGF treatment in National Taiwan University Hospital with at least one-year follow-up between 2012 and 2020. A genome-wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed. RESULTS: In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2-DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049). CONCLUSIONS: Among the 16 SNPs found in the GWAS, four loci-CFH, ARMS2/HTRA1, and two novel loci-were correlated with the susceptibility of nAMD and anatomical/functional responses after anti-VEGF treatment.

Fecal Carriage of Multidrug-Resistant Organisms Increases the Risk of Hepatic Encephalopathy in Cirrhotic Patients: Insights from Gut Microbiota and Metabolite Features.

Background: Impact of fecal colonization by multidrug-resistant organisms (MDROs) on changes in gut microbiota and associated metabolites, as well as its role in cirrhosis-associated outcomes, has not been thoroughly investigated. Methods: Eighty-eight cirrhotic patients and 22 healthy volunteers were prospectively enrolled with analysis conducted on plasma metabolites, fecal MDROs, and microbiota. Patients were followed for a minimum of one year. Predictive factors for cirrhosis-associated outcomes were identified using Cox proportional hazards regression models, and risk factors for fecal MDRO carriage were assessed using logistic regression model. Correlations between microbiota and metabolic profiles were evaluated through Spearman's rank test. Results: Twenty-nine (33%) cirrhotic patients exhibited MDRO carriage, with a notably higher rate of hepatic encephalopathy (HE) in MDRO carriers (20.7% vs. 3.2%, p = 0.008). Cox regression analysis identified higher serum lipopolysaccharide levels and fecal MDRO carriage as predictors for HE development. Logistic regression analysis showed that MDRO carriage is an independent risk factor for developing HE. Microbiota analysis showed a significant dissimilarity of fecal microbiota between cirrhotic patients with and without MDRO carriage (p = 0.033). Thirty-two metabolites exhibiting significantly different expression levels among healthy controls, cirrhotic patients with and without MDRO carriage were identified. Six of the metabolites showed correlation with specific bacterial taxa expression in MDRO carriers, with isoaustin showing significantly higher levels in MDRO carriers experiencing HE compared to those who did not. Conclusion: Fecal MDRO carriage is associated with altered gut microbiota, metabolite modulation, and an elevated risk of HE occurrence within a year.