Steady existence of Escherichia coli co-resistant to carbapenem and colistin in an animal breeding area even after the colistin forbidden.

Carbapenem- and colistin-resistant Escherichia coli (CCREC) cause high mortality rates and health costs, and have become serious health concerns. Total 1764 samples were collected from 60 animal farms in 2019 and 2021, including worker and animal faeces, wastewater, well water, air, vegetables, human hands, object surfaces, throat swabs, soil, and flies to investigate the prevalence and potential transmission pathways of CCREC. Eleven CCREC were detected: 9 (5 in 2019 and 4 in 2021) from 5 worker faeces, 3 animal faeces, 1 wastewater, and 2 from 1 flies sample. Chicken farms had the highest number of CCREC (n = 9). The detection rate was low (<1.1%) overall, and there was no significant difference in both years, indicating that CCREC existed stably after 4 years of colistin ban. The combinations of chromosomes and plasmids harbouring blaNDM and mcr-1.1 were divided into 4 patterns: IncX3 plasmid-blaNDM & chromosome-mcr.1.1 (n = 5); IncX3 plasmid-blaNDM & IncHI2 plasmid-mcr.1.1 (n = 3); IncFII plasmid-blaNDM & IncI2 plasmid-mcr.1.1 (n = 2); both chromosome (n = 1). The blaNDM located on plasmids was surrounded by similar genetic structures: Tn3-IS-blaNDM-bleMBL-TrpF-DsbD-IS. The genetic contexts of mcr-1.1 were highly similar, with 'ISApl1-mcr-1.1-PAP2' and 'mcr-1.1-PAP2'. All plasmids can be successfully transferred into E. coli J53, except for the IncHI2 plasmids with the transfer rate of 33.3%. The IncFII and IncI2 plasmids from same strain of flies could be co-transferred. The clonal spread of CCREC from humans to humans occurred on the same pig farm (P4) or different chicken farms (BC9 and LH7). This study suggested that flies, chromosomes, and plasmids jointly contribute to the steady existence of CCREC.

EjWRKY6 Is Involved in the ABA-Induced Carotenoid Biosynthesis in Loquat Fruit during Ripening.

The yellow-fleshed loquat is abundant in carotenoids, which determine the fruit's color, provide vitamin A, and offer anti-inflammatory and anti-cancer health benefits. In this research, the impact of abscisic acid (ABA), a plant hormone, on carotenoid metabolism and flesh pigmentation in ripening loquat fruits was determined. Results revealed that ABA treatment enhanced the overall content of carotenoids in loquat fruit, including major components like ß-cryptoxanthin, lutein, and ß-carotene, linked to the upregulation of most genes in the carotenoid biosynthesis pathway. Furthermore, a transcription factor, EjWRKY6, whose expression was induced by ABA, was identified and was thought to play a role in ABA-induced carotenoid acceleration. Transient overexpression of EjWRKY6 in Nicotiana benthamiana and stable genetic transformation in Nicotiana tabacum with EjWRKY6 indicated that both carotenoid production and genes related to carotenoid biosynthesis could be upregulated in transgenic plants. A dual-luciferase assay proposed a probable transcriptional control between EjWRKY6 and promoters of genes associated with carotenoid production. To sum up, pre-harvest ABA application could lead to carotenoid biosynthesis in loquat fruit through the EjWRKY6-induced carotenoid biosynthesis pathway.

Analysis of eplerenone in the FDA adverse event reporting system (FAERS) database: a focus on overall patient population and gender-specific subgroups.

Introduction: Eplerenone is approved for the treatment of hypertension as well as symptomatic heart failure with reduced ejection fraction (HFrEF) following an acute myocardial infarction. However, the adverse events (AEs) have not been systematically analyzed. The aim of this study was to identify adverse drug reactions (ADRs) related to eplerenone using the FDA Adverse Event Reporting System (FAERS) database. By identifying previously unreported AEs, the study could potentially contribute to updating the drug's label. Methods: In order to find significant AEs, four algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN) and Empirical Bayesian Geometric Mean (EBGM), were used to analyze the signal strength of the ADRs connected to eplerenone that were gathered from the FAERS database over the previous 20 years. Results: From 2004Q1 to 2023Q4, a total of 20, 629, 811 reported cases were gathered from the FAERS database for this study. After processing the data and filtering, 1,874 case reports were analyzed. Of these cases, 1,070 AEs were identified, 128 of which were eplerenone-related ADRs. We investigated the occurrence of ADRs induced by eplerenone in 27 organ systems. Our study showed that the AEs listed in the medication's package insert correspond with those listed in the literature, including hyperkalemia and increased creatinine. Additionally, the prescription label for eplerenone does not include all system organ class (SOC) terms, like Vascular disorders, hepatobiliary Disorders, etc. Discussion: The study used multiple algorithms to quantify the signal strength and then identified any previously unrecognized ADRs, further studies are needed to confirm the association of ADRs with eplerenone. The findings of this study may provide important insights into the safety profile of eplerenone, ensure that healthcare providers have up-to-date information about their potential risks and help guide them in the correct use of the drug.

Non-alcoholic fatty liver disease and heart failure: A comprehensive bioinformatics and Mendelian randomization analysis.

AIMS: Heart failure (HF) and non-alcoholic fatty liver disease (NAFLD) are significant global health issues with a complex interrelationship. This study investigates their shared biomarkers and causal relationships using bioinformatics and Mendelian randomization (MR) approaches. METHODS: We analysed NAFLD and HF datasets from the Gene Expression Omnibus (GEO). The GSE126848 dataset included 57 liver biopsy samples [14 healthy individuals, 12 obese subjects, 15 NAFL patients and 16 non-alcoholic steatohepatitis (NASH) patients]. The GSE24807 dataset comprised 12 NASH samples and 5 healthy controls. The GSE57338 dataset included 313 cardiac muscle samples [177 HF patients (95 ischaemic heart disease patients and 82 idiopathic dilated cardiomyopathy patients) and 136 healthy controls]. The GSE84796 dataset consisted of 10 end-stage HF patients and 7 healthy hearts procured from organ donors. We identified differentially expressed genes (DEGs) and constructed a protein-protein interaction (PPI) network. Functional pathways were elucidated through enrichment analyses using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneMANIA annotation. Single nucleotide polymorphism (SNP) data for HF and NAFLD were sourced from genome-wide association studies (GWAS). The HF dataset included 486 160 samples (14 262 experimental and 471 898 control), and the NAFLD dataset comprised 377 988 samples (4761 experimental and 373 227 control). MR analysis investigates the causal interrelations. RESULTS: Our analysis revealed 4032 DEGs from GSE126848 and 286 DEGs from GSE57338. The top 10 hub genes (CD163, VSIG4, CXCL10, FCER1G, FPR1, C1QB, CCR1, C1orf162, MRC1 and CD38) were significantly enriched in immune response, calcium ion concentration regulation and positive regulation of monocyte chemotaxis. CIBERSORT analysis indicated associations between these hub genes and natural killer (NK) cells and macrophages. Transcription factor (TF) target prediction for CD38, CXCL10 and CCR1 highlighted related TFs. A two-sample MR analysis confirmed a bidirectional causal relationship between NAFLD and HF. The main method [inverse variance weighted (IVW)] demonstrated a significant positive causal relationship between NAFLD and HF [P = 0.037; odds ratio (OR) = 1.024; 95% confidence interval (CI): 1.001 to 1.048]. Similarly, HF was associated with an increase in the risk of NAFLD (P < 0.001; OR = 1.117; 95% CI: 1.053 to 1.185). CONCLUSIONS: Our findings reveal novel molecular signatures common to NAFLD and HF and confirm their bidirectional causality, highlighting the potential for targeted therapeutic interventions and prompting further investigation into their intricate relationship.

Nitrogen-Site Engineering in Covalent Organic Frameworks for H2O2 Photogeneration via Dual Channels of Indirect Two-Electron O2 Reduction.

Photocatalytic H2O2 production is a green and sustainable route, but far from meeting the increasing demands of industrialization due to the rapid recombination of the photogenerated charge carriers and the sluggish reaction kinetics. Effective strategies for precisely regulating the photogenerated carrier behavior and catalytic activity to construct high-performance photocatalysts are urgently needed. Herein, a nitrogen-site engineering strategy, implying elaborately tuning the species and densities of nitrogen atoms, is applied for H2O2 photogeneration performance regulation. Different nitrogen heterocycles, such as pyridine, pyrimidine, and triazine units, are polymerized with trithiophene units, and five covalent organic frameworks (COFs) with distinct nitrogen species and densities on the skeletons are obtained. Fascinatingly, they photocatalyzed H2O2 production via dominated two-electron O2 reduction processes, including O2-O2 •‒-H2O2 and O2-O2 •‒-O2 1-H2O2 dual pathways. Just in the air and pure water, the multicomponent TTA-TF-COF with the maximum nitrogen densities triazine nitrogen densities exhibited the highest H2O2 production rate of 3343 µmol g-1 h-1, higher than most of other reported COFs. The theoretical calculation revealed the higher activity is due to the easy formation of O2 •‒ and O2 1 in different catalytic process. This study gives a new insight into designing photocatalysis at atomic level.

Management of patient with Fusobacterim nucletum related pleural empyema: intrapleural antibiotic therapy can be considered for salvage therapy.

Pleural empyema can lead to significant morbidity and mortality despite chest drainage and antibiotic treatment, necessitating novel and minimally invasive interventions. Fusobacterium nucleatum is an obligate anaerobe found in the human oral and gut microbiota. Advances in sequencing and puncture techniques have made it common to detect anaerobic bacteria in empyema cases. In this report, we describe the case of a 65-year-old man with hypertension who presented with a left-sided encapsulated pleural effusion. Initial fluid analysis using metagenomic next-generation sequencing (mNGS) revealed the presence of Fusobacterium nucleatum and Aspergillus chevalieri. Unfortunately, the patient experienced worsening pleural effusion despite drainage and antimicrobial therapy. Ultimately, successful treatment was achieved through intrapleural metronidazole therapy in conjunction with systemic antibiotics. The present case showed that intrapleural antibiotic therapy is a promising measure for pleural empyema.

Melatonin extends shelf life in postharvest okra via delaying fruit softening and reducing weight loss.

BACKGROUND: Melatonin, a hormone present in animals and some plants, has garnered attention for its potential in preserving harvested produce. Softening due to changes in cell wall composition and wilting caused by weight loss are the major reasons for the loss of commercial value in postharvest okra. This study aimed to evaluate the impact of melatonin on the softening and weight loss of postharvest okra. RESULTS: The results revealed that the application of melatonin had a significant influence on the maintenance of fruit firmness by inhibiting the breakdown and dissolution of cell wall polysaccharides by suppressing the expression of specific genes responsible for cell wall degradation in okra. Conversely, melatonin treatment positively influenced the expression of genes involved in the synthesis of cell wall components. Furthermore, the treatment exhibited notable benefits in reducing weight loss in okra, which was accomplished by promoting the closure of stomata - the tiny pores on the surface of the fruit. CONCLUSION: Melatonin could serve as a novel approach to reduce water loss, delay fruit softening and extend the shelf life of okra. © 2024 Society of Chemical Industry.

Creating Asymmetric Fe-N3C-N Sites in Single-Atom Catalysts Boosts Catalytic Performance for Oxygen Reduction Reaction.

Fine tuning of the metal site coordination environment of a single-atom catalyst (SAC) to boost its catalytic activity for oxygen reduction reaction (ORR) is of significance but challenging. Herein, we report a new SAC bearing Fe-N3C-N sites with asymmetric in-plane coordinated Fe-N3C and axial coordinated N atom for ORR, which was obtained by pyrolysis of an iron isoporphyrin on polyvinylimidazole (PVI) coated carbon black. The C@PVI-(NCTPP)Fe-800 catalyst exhibited significantly improved ORR activity (E1/2 = 0.89 V vs RHE) than the counterpart SAC with Fe-N4-N sites in 0.1 M KOH. Significantly, the Zn-air batteries equipped with the C@PVI-(NCTPP)Fe-800 catalyst demonstrated an open-circuit voltage (OCV) of 1.45 V and a peak power density (Pmax) of 130 mW/cm2, outperforming the commercial Pt/C catalyst (OCV = 1.42 V; Pmax = 119 mW/cm2). The density functional theory (DFT) calculations revealed that the d-band center of the asymmetric Fe-N3C-N structure shifted upward, which enhances its electron-donating ability, favors O2 adsorption, and supports O-O bond activation, thus leading to significantly promoted catalytic activity. This research presents an intriguing strategy for the designing of the active site architecture in metal SACs with a structure-function controlled approach, significantly enhancing their catalytic efficiency for the ORR and offering promising prospects in energy-conversion technologies.

IDO1 Inhibitor RY103 Suppresses Trp-GCN2-Mediated Angiogenesis and Counters Immunosuppression in Glioblastoma.

Glioma is characterized by strong immunosuppression and excessive angiogenesis. Based on existing reports, it can be speculated that the resistance to anti-angiogenic drug vascular endothelial growth factor A (VEGFA) antibody correlates to the induction of novel immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1), while IDO1 has also been suggested to be related to tumor angiogenesis. Herein, we aim to clarify the potential role of IDO1 in glioma angiogenesis and the mechanism behind it. Bioinformatic analyses showed that the expressions of IDO1 and angiogenesis markers VEGFA and CD34 were positively correlated and increased with pathological grade in glioma. IDO1-overexpression-derived-tryptophan depletion activated the general control nonderepressible 2 (GCN2) pathway and upregulated VEGFA in glioma cells. The tube formation ability of angiogenesis model cells could be inhibited by IDO1 inhibitors and influenced by the activity and expression of IDO1 in condition medium. A significant increase in serum VEGFA concentration and tumor CD34 expression was observed in IDO1-overexpressing GL261 subcutaneous glioma-bearing mice. IDO1 inhibitor RY103 showed positive anti-tumor efficacy, including the anti-angiogenesis effect and upregulation of natural killer cells in GL261 glioma-bearing mice. As expected, the combination of RY103 and anti-angiogenesis agent sunitinib was proved to be a better therapeutic strategy than either monotherapy.

Synergistic Linker and Linkage of Covalent Organic Frameworks for Enhancing Gold Capture.

The tunable pore walls and skeletons render covalent organic frameworks (COFs) as promising absorbents for gold (Au) ion. However, most of these COFs suffered from low surface areas hindering binding sites exposed and weak binding interaction resulting in sluggish kinetic performance. In this study, COFs have been constructed with synergistic linker and linkage for high-efficiency Au capture. The designed COFs (PYTA-PZDH-COF and PYTA-BPDH-COF) with pyrazine or bipyridine as linkers showed high surface areas of 1692 and 2076 m2 g‒1, providing high exposed surface areas for Au capture. In addition, the Lewis basic nitrogen atoms from the linkers and linkages are easily hydronium, which enabled to fast trap Au via coulomb force. The PYTA-PZDH-COF and PYTA-BPDH-COF showed maximum Au capture capacities of 2314 and 1810 mg g-1, higher than other reported COFs. More importantly, PYTA-PZDH-COF are capable of rapid adsorption kinetics with achieving 95% of maximum binding capacity in 10 min. The theoretical calculation revealed that the nitrogen atoms in linkers and linkages from both COFs are simultaneously hydronium, and then the protonated PYTA-PZDH-COF are more easily binding the AuCl4 ‒, further accelerating the binding process. This study gives the a new insight to design COFs for ion capture.

Global burden of myocarditis in youth and middle age (1990-2019): A systematic analysis of the disease burden and thirty-year forecast.

BACKGROUND: Myocarditis is increasingly recognized as a critical health issue, particularly among youth and middle-aged populations. This study aims to analyze the global burden and trends of myocarditis in these age groups to emphasize the need for region-specific prevention and treatment strategies. METHODS: Using data from the Global Burden of Disease (GBD) study (1990-2019), we evaluated the age-standardized rates (ASR) of myocarditis in individuals aged 10 to 54 years. We calculated average annual percentage changes (AAPC) and estimated annual percentage changes (EAPC). Additionally, we examined the correlation between myocarditis incidence and the Human Development Index (HDI) and Socio-demographic Index (SDI). Age and sex trends in myocarditis were analyzed, and Bayesian age-period-cohort (BAPC) models were used to forecast prevalence trends up to 2050. RESULTS: The High-income Asia Pacific region had the highest ASR of myocarditis, while North Africa and the Middle East had the lowest. North Africa and the Middle East also experienced the fastest average annual growth in ASR, whereas High-income North America saw the most significant decline. Correlational analysis showed that countries with a high SDI exhibited higher myocarditis ASR. The burden of myocarditis was greater among males than females, with this disparity increasing with age. Projections indicate a stable trend in the incidence of myocarditis among the youth and middle-aged population up to 2050, although the total number of cases is expected to rise. CONCLUSION: Our study reveals a significant upward trend in myocarditis among youth and middle-aged populations, highlighting the urgency for early monitoring and preventative strategies.

In Situ Construction of Highly Dispersed Pd on Cobalt Nanoparticle on Hollow Functional Cubic Graphene by Double Framework for ORR.

Developing advanced functional carbon materials is essential for electrocatalysis, caused by their vast merits for boosting many key energy conversion reactions. Herein, the covalent organic frameworks (COFs) is utilized on metal-organic frameworks (MOFs) as the template, under the controllable metal atoms thermal migration process successfully in situ constructs Pd-Co alloy nanoparticles on hollow cubic graphene. The electrocatalytic oxygen reduction reaction (ORR) evaluation showed excellent performances with a half-wave potential of 0.866 V, and a limited current density of 4.975 mA cm-2, that superior to the commercial Pt/C and Co nanoparticles. The contrast experiments and X-ray absorption spectrum demonstrated the aggregated electrons at highly dispersed Pd atoms on Co nanoparticle that promoted the main activities. This work not only enlightens the novel carbon materials designing strategies but also suggests heterogeneous electrocatalysis.

In vitro cytocompatibility of triclosan coated Polyglactin910 sutures.

Bioabsorbable sutures can improve the medical functions of existing non-absorbable sutures, and may produce new medical effects, and are expected to become a new generation of medical degradable materials. In this study, the cytocompatibility of triclosan coated polyglactin910 sutures (CTS-PLGA910) was analyzed and different concentrations of sutures were prepared. The effects of sutures on the cytotoxicity and cell proliferation of HUVEC were studied by CCK-8 assay. The hemolysis, total antioxidant capacity (T-AOC) activity and nitric oxide (NO) content were investigated to improve the blood compatibility of sutures. The results showed that the hemolysis rate of CTS-PLGA910 was less than 5%. After treatment on HUVEC cells for 48 and 72 h, there was no significant change in NO content in CTS-PLGA910 groups compared with the control group, while T-AOC activity and antioxidant capacity were significantly increased in medium and high dose groups. In summary, the blood compatibility and cell compatibility were significantly improved, which provided a basis for the clinical application of sutures in the future.

Association between blood inflammatory indices and heart failure: a cross-sectional study of NHANES 2009-2018.

BACKGROUND: Inflammation plays a pivotal role in the pathogenesis of heart failure (HF). This study was aimed to the potential association between complete blood cell count (CBC)-derived inflammatory biomarkers and HF. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2009-2018 were utilised. We evaluated the associations between HF and five systemic inflammation markers derived from CBC: systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR). Demographic characteristics, physical examinations, and laboratory data were systematically collected for comparative analysis between HF and non-HF individuals. Fitted smoothing curves and threshold effect analysis delineated the relationship. In addition, Spearman correlation and subgroup analyses were further conducted. RESULTS: A total of 26,021 participants were categorised into HF (n = 858) and non-HF (n = 25,163) groups. After adjusting for confounding variables, SIRI, NLR, and MLR had significant positive correlations with the risk of HF. Participants in the highest quarter groups of SIRI, NLR, and MLR showed a increased risk of developing HF compared to those in the lowest quarter group. Furthermore, subgroup and sensitivity analyses indicated that SIRI, NLR, and MLR had a stronger correlation to HF (all p < 0.05). Smoothing curve fitting highlighted a nonlinear relationship between CBC-derived inflammatory biomarkers and HF. CONCLUSIONS: Our results illustrated a significant association between elevated levels of SIRI, NLR, and MLR and an increased risk of HF. SIRI, NLR, and MLR could potentially serve as systemic inflammation hazard markers for HF.

High Prevalence and Risk Factors Associated with Vitamin D Deficiency Among Chinese Hospital Staff: A Cross-Sectional Study.

Purpose: To determine the current status of vitamin D status and the associated factors for its deficiency among Chinese hospital staff. Methods: The physical examination data of 2509 hospital staff members was analyzed alongside that of 1507 patients who visited the hospital during the corresponding period of the examination. Serum concentration of 25-hydroxyvitamin D (25(OH)D) were measured in the participants. The hospital staff also completed surveys about general information, laboratory examination, and occupational characteristics. Results: The median vitamin D status (serum 25(OH)D concentration) of the participants was 9.0 ng/mL, ranging from 6.5 to 44.7 ng/mL, and the prevalence of deficiency (<12.3 ng/mL) was 81.47% (2044/2509). The multivariable logistic regression revealed that nurses (OR = 1.54, 95% CI 1.09-2.19, p = 0.015), BMI below 18 (OR = 2.39, 95% CI 1.02-5.58, p = 0.045) associated with higher prevalence of vitamin D deficiency. In the contrast, age above 30 (OR = 0.69, 95% CI 0.53-0.91, p = 0.009) and a high level of uric acid (OR = 0.56, 95% CI 0.41-0.78, p = 0.001) associated with lower prevalence of vitamin D deficiency. The prevalence of vitamin D deficiency was higher among the hospital staff (81.47%) compared to the patients who visited the hospital during the same time period (65.69%). A substantial disparity was observed in the propensity score matching dataset (69.14% vs 79.94%, p < 0.001). Conclusion: Hospital staff are a high-risk group for vitamin D deficiency. Paying attention to vitamin D status and supplementation of this vitamin are pertinent aspects of hospital staff health care. Outdoor activities, vitamin D supplementation, and foods rich in vitamin D should be advocated.

Tryptophan deficiency induced by indoleamine 2,3-dioxygenase 1 results in glucose transporter 1-dependent promotion of aerobic glycolysis in pancreatic cancer.

Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme in the catabolism of the essential amino acid tryptophan (Trp) through kynurenine pathway, induces immune tolerance and is considered as a critical immune checkpoint, but its impacts as a metabolism enzyme on glucose and lipid metabolism are overlooked. We aim to clarify the potential role of IDO1 in aerobic glycolysis in pancreatic cancer (PC). Analysis of database revealed the positive correlation in PC between the expressions of IDO1 and genes encoding important glycolytic enzyme hexokinase 2 (HK2), pyruvate kinase (PK), lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1). It was found that IDO1 could modulate glycolysis and glucose uptake in PC cells, Trp deficiency caused by IDO1 overexpression enhanced glucose uptake by stimulating GLUT1 translocation to the plasma membrane of PC cells. Besides, Trp deficiency caused by IDO1 overexpression suppressed the apoptosis of PC cells via promoting glycolysis, which reveals the presence of IDO1-glycolysis-apoptosis axis in PC. IDO1 inhibitors could inhibit glycolysis, promote apoptosis, and exhibit robust therapeutic efficacy when combined with GLUT1 inhibitor in PC mice. Our study reveals the function of IDO1 in the glucose metabolism of PC and provides new insights into the therapeutic strategy for PC.

Identification of common mechanisms and biomarkers of atrial fibrillation and heart failure based on machine learning.

AIMS: Atrial fibrillation (AF) is the most common arrhythmia. Heart failure (HF) is a disease caused by heart dysfunction. The prevalence of AF and HF were progressively increasing over time. The co-existence of AF and HF presents a significant therapeutic challenge. In order to provide new ideas for the diagnosis of AF and HF, it is necessary to carry out biomarker related studies. METHODS AND RESULTS: The training set and validation set data of AF and HF patient samples were downloaded from the GEO database, 'limma' was used to compare the differences in gene expression levels between the disease group and the normal group to screen for differentially expressed genes (DEGs). Weighted correlation network analysis (WGCNA) identified the modules with the highest positive correlation with AF and HF. Functional enrichment and PPI network construction of key genes were carried out. Biomarkers were screened by machine learning. The infiltration of immune cells in AF and HF groups was evaluated by R-packet 'CIBERSORT'. The miRNA network was constructed and potential therapeutic agents for biomarker genes were predicted through the drugbank database. Through WGCNA analysis, it was found that the modules most positively correlated with AF and HF were MEturquoise (r = 0.21, P value = 0.09) and MEbrown (r = 0.62, P value = 8e-12), respectively. We screened 25 genes that were highly correlated with both AF and HF. Lasso regression analysis results showed 7 and 20 core genes in AF and HF groups, respectively. The top 20 important genes in AF and HF groups were obtained as core genes by RF model analysis. Four biomarkers were obtained after the intersection of core genes in four groups, namely, GLUL, NCF2, S100A12, and SRGN. The diagnostic efficacy of four genes in AF validation sets was good (AUC: GLUL 0.76, NCF2 0.64, S100A12 0.68, and SRGN 0.76), as well as in the HF validation set (AUC: GLUL 0.76, NCF2 0.84, S100A12 0.92, and SRGN 0.68). The highest correlation with neutrophils was observed for GLUL, NCF2, and S100A12, while SRGN exhibited the strongest correlation with T cells CD4 memory resting in the AF group. GLUL, NCF2, S100A12, and SRGN were most associated with neutrophils in the HF group. A total of 101 miRNAs were predicted by four genes, and GLUL, NCF2, and S100A12 predicted a total of 10 potential therapeutic agents. CONCLUSIONS: We identified four biological markers that are highly correlated with AF and HF, namely, GLUL, NCF2, S100A12, and SRGN. Our findings provide theoretical basis for the clinical diagnosis and treatment of AF and HF.

Analysis of Inclisiran in the US FDA Adverse Event Reporting System (FAERS): a focus on overall patient population and sex-specific subgroups.

BACKGROUND: Our study aimed to identify inclisiran-related adverse events(AEs) for primary hypercholesterolemia and arteriosclerotic cardiovascular disease(ASCVD) from the US FDA Adverse Event Reporting System (FAERS) database, analyzing its links to AEs in the overall patient population and sex-specific subgroups to improve medication safety. METHODS: We analyzed inclisiran-related AEs signals by using statistical methods like Reporting Odds Ratio (ROR), Proportional Reporting Ratios (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma-Poisson Shrinker (MGPS). RESULTS: Analyzing 2,400 AE reports with inclisiran as the primary suspected drug in the FAERS database, we identified 70 AE signals over 13 organ systems using the above four methods. Notable findings were strong signals for systemic diseases and various reactions at the site of administration (ROR 1.49, 95% CI 1.41-1.57), and various musculoskeletal and connective tissue diseases (ROR 4.07, 95% CI 3.83-4.03) in overall and gender-specific populations. Myalgia, a new ADE signal not in the drug insert, was a top signal by intensity and frequency (ROR 14.76, 95% CI 12.84-16.98). CONCLUSION: Our study revealed the strongest AE signals associated with inclisiran in both the overall population and gender subgroups, highlighting potential risks in clinical medication use and guiding balanced clinical decision-making.