Exploring the Association between Low-dose Aspirin Intake and Hyperuricemia in Individuals over 40: A Cross-Sectional Study using NHANES Data (2011-2018).

BACKGROUND Long-term aspirin treatment was recommended for secondary prevention of cardiovascular and cerebrovascular disease. However, some studies reveal low-dose aspirin (LDA) can raise serum uric acid (SUA) levels. Thus, the purpose of this study was to analyze whether LDA intake is associated with hyperuricemia. MATERIAL AND METHODS Data was collected from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2018. All participants over 40 years old and who selected "preventive aspirin use" were included in the study. Logistic regression analyses were used to evaluate the relationship between LDA intake and hyperuricemia. The stratified analysis was based on race and estimated glomerular filtration rate (eGFR). RESULTS A total of 3540 participants were included in the study. Of them, 805 (22.7%) took LDA, and 190 (31.6%) had hyperuricemia. There was no significant association between hyperuricemia and LDA intake (OR=1.22, 95% CI: 0.97-1.54) after adjusting for confounding factors. However, further subgroup analysis by age showed a significant association between LDA intake and hyperuricemia (OR=3.44, 95% CI: 1.88-6.27) among those 40 to 50 years of age. After adjusting for confounding factors, the relationship was still significant (OR=2.28, 95% CI: 1.10-4.73); we also found that race (Hispanic American, OR=1.84, 95% CI: 1.11-3.06) and eGFR under 60 mL/min/1.73 m² (OR=1.94, 95% CI: 1.04-3.62) may play important roles in the development of hyperuricemia. CONCLUSIONS LDA does not increase the hyperuricemia risk in people over 40 years. However, those aged between 40 and 50 years, Hispanic American, and with impaired renal function should have careful evaluation during LDA treatment.

Advances and applications of fluids biomarkers in diagnosis and therapeutic targets of Alzheimer's disease.

AIMS: Alzheimer's disease (AD) is a neurodegenerative disease with challenging early diagnosis and effective treatments due to its complex pathogenesis. AD patients are often diagnosed after the appearance of the typical symptoms, thereby delaying the best opportunity for effective measures. Biomarkers could be the key to resolving the challenge. This review aims to provide an overview of application and potential value of AD biomarkers in fluids, including cerebrospinal fluid, blood, and saliva, in diagnosis and treatment. METHODS: A comprehensive search of the relevant literature was conducted to summarize potential biomarkers for AD in fluids. The paper further explored the biomarkers' utility in disease diagnosis and drug target development. RESULTS: Research on biomarkers mainly focused on amyloid-ß (Aß) plaques, Tau protein abnormal phosphorylation, axon damage, synaptic dysfunction, inflammation, and related hypotheses associated with AD mechanisms. Aß42 , total Tau (t-Tau), and phosphorylated Tau (p-Tau), have been endorsed for their diagnostic and predictive capability. However, other biomarkers remain controversial. Drugs targeting Aß have shown some efficacy and those that target BACE1 and Tau are still undergoing development. CONCLUSION: Fluid biomarkers hold considerable potential in the diagnosis and drug development of AD. However, improvements in sensitivity and specificity, and approaches for managing sample impurities, need to be addressed for better diagnosis.

Sodium-glucose cotransporter-2 inhibitors and cardiovascular safety profile: a pharmacovigilance analysis of the US food and drug administration adverse event reporting system.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective in reducing the risk of heart failure (HF) in type 2 diabetic patients. We systematically examined the association between cardiac adverse events (CAEs) and SGLT2i. RESEARCH DESIGN AND METHODS: We analyzed CAEs in the FDA Adverse Event Reporting System between January 2013 and March 2021. The CAEs were classified into four major groups according to their preferred terms. Disproportionality and Bayesian analyses were performed to detect signals using reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM). Case seriousness was also described. RESULTS: There were 2,330 CAEs associated with SGLT2i, and 81 were used for HFs. The SGLT2i were not associated with over-reporting frequencies of CAE based on ROR (ROR = 0.97, 95% confidence interval [CI]: 0.93, 1.01), PRR (PRR = 0.97, 95% CI: 0.94, 1.01), Bayesian confidence propagation neural network (IC = -0.04, IC025: N.A.), and multi-item gamma Poisson shrinker (EBGM = 0.97, EBGM05:0.94), unless further restricted to myocardial infarction (ROR = 2.03, 95% CI = 1.89, 2.17). Additionally, SGLT2i-associated CAEs are associated with 11.33% fatality and 51.25% hospitalization. CONCLUSIONS: SGLT2i present a favorable cardiac safety profile; however, concerns should be raised regarding their potential association with specific events.

Pneumatosis intestinalis post steroid use in a patient with immune-related adverse events: Case report, literature review and FAERS analysis.

Introduction: The accurate diagnosis of pneumatosis intestinalis (PI) is increasing despite patients' limited identification of etiologic factors. Recently a patient with lung squamous carcinoma who developed pneumatosis intestinalis following methylprednisolone administration for immune-related adverse events was treated at our hospital. Subsequent a literature review and an analysis of the FDA Adverse Event Reporting System (FAERS) database enabled the identification of additional cases of pneumatosis intestinalis. Methods: A literature review of the MEDLINE/PubMed and Web of Science Core Collection databases using standard pneumatosis intestinalis search terms to identify published cases of immune checkpoint inhibitors (ICIs) or steroids causing pneumatosis intestinalis were performed. A separate retrospective pharmacovigilance study of FAERS enabled the extraction of unpublished cases of pneumatosis intestinalis between the first quarter of 2005 and the third quarter of 2022. Disproportionality and Bayesian analyses were performed to identify signal detection in reported odds ratios, proportional reporting ratios, information components, and empirical Bayesian geometric means. Results: Ten case reports of steroid-related pneumatosis intestinalis were retrieved from six published studies. The implicated drug therapies included pre-treatment with steroids before chemotherapy, combination therapy with cytotoxic agents and steroids, and monotherapy with steroids. In the FAERS pharmacovigilance study, 1,272 cases of immune checkpoint inhibitors or steroid-related pneumatosis intestinalis were incidentally reported. The signal detected in five kinds of immune checkpoint inhibitors and six kinds of steroids implied a positive correlation between the drugs and adverse events. Conclusion: Steroids might be the etiologic factors in the current case of pneumatosis intestinalis. Reports supporting the role of steroids in suspected cases of pneumatosis intestinalis can be found in literature databases and the FAERS database. Even so, as documented in FAERS, immune checkpoint inhibitors-induced pneumatosis intestinalis should not be excluded.

Glucagon-like peptide 1 receptor agonists and the potential risk of pancreatic carcinoma: a pharmacovigilance study using the FDA Adverse Event Reporting System and literature visualization analysis.

BACKGROUND: There are increasing data on the potential risk of pancreatic carcinoma associated with glucagon-like peptide 1 receptor agonists (GLP-1RAs). AIM: The study aimed to determine whether GLP-1RAs are associated with increased detection of pancreatic carcinoma based on the FDA Adverse Events Reporting System and clarify its potential mechanisms through keyword co-occurrence analysis from literature database. METHOD: Disproportionality and Bayesian analyses were used for signal detection using reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM). Mortality, life-threatening events, and hospitalizations were also investigated. VOSviewer was adopted to generate visual analysis of keyword hotspots. RESULTS: A total of 3073 pancreatic carcinoma cases were related to GLP-1RAs. Five GLP-1RAs were detected with signals for pancreatic carcinoma. Liraglutide had the strongest signal detection (ROR 54.45, 95% CI 51.21-57.90; PRR 52.52, 95% CI 49.49-55.73; IC 5.59; EBGM 48.30). The signals of exenatide (ROR 37.32, 95% CI 35.47-39.28; PRR 36.45, 95% CI 34.67-38.32; IC 5.00; EBGM 32.10) and lixisenatide (ROR 37.07, 95% CI 9.09-151.09; PRR 36.09; 95% CI 9.20-141.64; IC 5.17, EBGM 36.09) were stronger than those of semaglutide (ROR 7.43, 95% CI 5.22-10.57; PRR 7.39; 95% CI 5.20-10.50; IC 2.88, EBGM 7.38) and dulaglutide (ROR 6.47, 95% CI 5.56-7.54; PRR 6.45; 95% CI 5.54-7.51; IC 2.67, EBGM 6.38). The highest mortality rate occurred in exenatide (63.6%). Based on the bibliometric investigation, cAMP/protein-kinase, Ca2+ channel, endoplasmic-reticulum stress, and oxidative stress are potential pathogenesis of pancreatic carcinoma resulting from GLP-1RAs. CONCLUSION: Based on this pharmacovigilance study, GLP-1RAs, except albiglutide, are associated with pancreatic carcinoma.

Evidence-based guideline for the prevention and management of perioperative infection.

BACKGROUND: We have updated the guideline for preventing and managing perioperative infection in China, given the global issues with antimicrobial resistance and the need to optimize antimicrobial usage and improve hospital infection control levels. METHODS: We conducted a comprehensive evaluation of the evidence for prevention and management of perioperative infection, based on the concepts of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The strength of recommendations was graded and voted using the Delphi method and the nominal group technique. Revisions were made to the guidelines in response to feedback from the experts. RESULTS: There were 17 questions prepared, for which 37 recommendations were made. According to the GRADE system, we evaluated the body of evidence for each clinical question. Based on the meta-analysis results, recommendations were graded using the Delphi method to generate useful information. CONCLUSIONS: This guideline provides evidence to perioperative antimicrobial prophylaxis that increased the rational use of prophylactic antimicrobial use, with substantial improvement in the risk-benefit trade-off.

Drug-Induced Cardiotoxicity in Children During the Past 30 Years: A Bibliometric Study and Visualization Analysis.

BACKGROUND Drug-induced cardiotoxicity (DICT) is one of the most serious adverse drug reactions, which is an important safety issue in drug development and clinical practice. This study aimed to summarize the knowledge structure and to detect emerging trends, and provide ideas for future research on DICT in children using bibliometric methods. MATERIAL AND METHODS All publications on DICT in children were retrieved through the Web of Science Core Collection up to April 20, 2022. The document type was restricted to articles with the language set to English. CiteSpace and VOSviewer were used to conduct this bibliometric analysis. RESULTS A total of 298 articles were included, and the annual publications decreased since 2021. The United States was the leading country with the most publications (117), the highest centrality (0.39), and total citations (4055). The most influential institution was the University of British Columbia, while Carleton BC and Rassekh SR, both from Canada, were the most productive authors, but there was no leader in this field. The keywords with both high frequency and high centrality after excluding "cardiotoxicity" and "children" were acute lymphoblastic leukemia (Freq=43, Central=0.15), childhood cancer (Freq=42, Central=0.13), toxicity (Freq=33, Central=0.16), and breast cancer (Freq=29, Central=0.19). "Adriamycin cardiotoxicity" was the first burst keyword, while "childhood cancer", "oxidative stress", and "cardiac dysfunction" were emerging research hotspots. CONCLUSIONS Attention to DICT in children was insufficient. This study serves as a breakthrough point, providing a comprehensive overview of the knowledge structure, development landscape, and future opportunities in this field.

Hepatitis B virus reactivation associated with Janus kinase (JAK) inhibitors: a retrospective study of pharmacovigilance databases and review of the literature.

BACKGROUND: Recently, there have been clinical reports of hepatitis B virus reactivation (HBVr) related with Janus kinase (JAK) inhibitors. However, there were no studies to investigate the association between HBVr and different JAK inhibitors. RESEARCH DESIGN AND METHODS: This study was a retrospective review utilizing the FAERS pharmacovigilance database and a systematic literature search for all cases of HBVr reported with JAK inhibitors. Disproportionality analysis and Bayesian analysis were used in data detection to screen the suspected HBVr after the administration of different JAK inhibitors, based on the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database from Q4 2011 to Q1 2022. RESULTS: There were a total number of 2097 (0.02%) reports of HBVr in FAERS, of which 41 (1.96%) were associated with JAK inhibitors. Baricitinib appeared to have the strongest signal among four JAK inhibitors, based on the highest reporting odds ratio (ROR = 4.45, 95% confidence interval [CI] 1.67-11.89). Ruxolitinib also showed signals, whereas no signals were detected among Tofacitinib and Upadacitinib. CONCLUSION: While there may be an association between JAK inhibitors and HBVr, it appears to be a numerically uncommon occurrence. Further studies are needed to optimize the safety profiles of JAK inhibitors.

Trends in metabolic signaling pathways of tumor drug resistance: A scientometric analysis.

Background: Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. Since Warburg O first observed alterations in cancer metabolism in the 1950s, people gradually found tumor metabolism pathways play a fundamental role in regulating the response to chemotherapeutic drugs, and the attempts of targeting tumor energetics have shown promising preclinical outcomes in recent years. This study aimed to summarize the knowledge structure and identify emerging trends and potential hotspots in metabolic signaling pathways of tumor drug resistance research. Methods: Publications related to metabolic signaling pathways of tumor drug resistance published from 1992 to 2022 were retrieved from the Web of Science Core Collection database. The document type was set to articles or reviews with language restriction to English. Two different scientometric software including Citespace and VOS viewer were used to conduct this scientometric analysis. Results: A total of 2,537 publications including 1,704 articles and 833 reviews were retrieved in the final analysis. The USA made the most contributions to this field. The leading institution was the University of Texas MD Anderson Cancer Center. Avan A was the most productive author, and Hanahan D was the key researcher with the most co-citations, but there is no leader in this field yet. Cancers was the most influential academic journal, and Oncology was the most popular research field. Based on keywords occurrence analysis, these selected keywords could be roughly divided into five main topics: cluster 1 (study of cancer cell apoptosis pathway); cluster 2 (study of resistance mechanisms of different cancer types); cluster 3 (study of cancer stem cells); cluster 4 (study of tumor oxidative stress and inflammation signaling pathways); and cluster 5 (study of autophagy). The keywords burst detection identified several keywords as new research hotspots, including "tumor microenvironment," "invasion," and "target". Conclusion: Tumor metabolic reprogramming of drug resistance research is advancing rapidly. This study serves as a starting point, providing a thorough overview, the development landscape, and future opportunities in this field.

The potential roles of Nrf2/Keap1 signaling in anticancer drug interactions.

Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2), together with its suppressive binding partner Kelch-like ECH-associated protein 1 (Keap1), regulates cellular antioxidant response and drug metabolism. The roles of Nrf2/Keap1 signaling in the pathology of many diseases have been extensively investigated, and small molecules targeting Nrf2/Keap1 signaling have been developed to prevent or treat diseases such as multiple sclerosis, chronic kidney disease and cancer. Notably, Nrf2 plays dual roles in cancer development and treatment. Activation of Nrf2/Keap1 signaling in cancer cells has been reported to promote cancer progression and result in therapy resistance. Since cancer patients are often suffering comorbidities of other chronic diseases, anticancer drugs could be co-administrated with other drugs and herbs. Nrf2/Keap1 signaling modulators, especially activators, are common in drugs, herbs and dietary ingredients, even they are developed for other targets. Therefore, drug-drug or herb-drug interactions due to modulation of Nrf2/Keap1 signaling should be considered in cancer therapies. Here we briefly summarize basic biochemistry and physiology functions of Nrf2/Keap1 signaling, Nrf2/Keap1 signaling modulators that cancer patients could be exposed to, and anticancer drugs that are sensitive to Nrf2/Keap1 signaling, aiming to call attention to the potential drug-drug or herb-drug interactions between anticancer drugs and these Nrf2/Keap1 signaling modulators.

Global publication trends and hotspots of molecular biomarkers in DILI from 1991 to 2020: A 30-year bibliometric analysis.

Drug-induced liver injury (DILI) is one of the common adverse drug reactions and the leading cause of drug development attritions, black box warnings, and post-marketing withdrawals. Current biomarkers are suboptimal in detecting DILI and predicting its outcome. This study aimed to quantitatively and qualitatively investigate the research trends on DILI biomarkers using bibliometric analysis. All relevant publications were extracted from the Web of Science database. An online analysis platform of literature metrology, bibliographic item co-occurrence matrix builder, and CiteSpace software were used to analyze the publication trends. CitNetExplorer was used to construct direct citation networks and VOSviewer was used to analyze the keywords and research hotspots. We found a total of 485 publications related to DILI biomarkers published from 1991 to 2020. Toxicological Sciences had been the most popular journal in this field over the past 30 years. The USA maintained a top position worldwide and provided a pivotal influence, followed by China. Among all the institutions, the University of Liverpool was regarded as a leader for research collaboration. Moreover, Professors Paul B. Watkins and Tsuyoshi Yokoi made great achievements in topic area. We analyzed the citation networks and keywords, therefore identified five and six research hotspot clusters, respectively. We considered the publication information regarding different countries/regions, organizations, authors, journals, et al. by summarizing the literature on DILI biomarkers over the past 30 years. Notably, the subject of DILI biomarkers is an active area of research. In addition, the investigation and discovery of novel promising biomarkers such as microRNAs, keratin18, and bile acids will be future developing hotspots.

Predicting 1-Hour Thrombolysis Effect of r-tPA in Patients With Acute Ischemic Stroke Using Machine Learning Algorithm.

Background: Thrombolysis with r-tPA is recommended for patients after acute ischemic stroke (AIS) within 4.5 h of symptom onset. However, only a few patients benefit from this therapeutic regimen. Thus, we aimed to develop an interpretable machine learning (ML)-based model to predict the thrombolysis effect of r-tPA at the super-early stage. Methods: A total of 353 patients with AIS were divided into training and test data sets. We then used six ML algorithms and a recursive feature elimination (RFE) method to explore the relationship among the clinical variables along with the NIH stroke scale score 1 h after thrombolysis treatment. Shapley additive explanations and local interpretable model-agnostic explanation algorithms were applied to interpret the ML models and determine the importance of the selected features. Results: Altogether, 353 patients with an average age of 63.0 (56.0-71.0) years were enrolled in the study. Of these patients, 156 showed a favorable thrombolysis effect and 197 showed an unfavorable effect. A total of 14 variables were enrolled in the modeling, and 6 ML algorithms were used to predict the thrombolysis effect. After RFE screening, seven variables under the gradient boosting decision tree (GBDT) model (area under the curve = 0.81, specificity = 0.61, sensitivity = 0.9, and F1 score = 0.79) demonstrated the best performance. Of the seven variables, activated partial thromboplastin clotting time (time), B-type natriuretic peptide, and fibrin degradation products were the three most important clinical characteristics that might influence r-tPA efficiency. Conclusion: This study demonstrated that the GBDT model with the seven variables could better predict the early thrombolysis effect of r-tPA.

Fucoxanthin Elicits Epigenetic Modifications, Nrf2 Activation and Blocking Transformation in Mouse Skin JB6 P+ Cells.

Nuclear factor erythroid-2-related factor-2 (Nrf2 or NFE2L2) is a master regulator of the anti-oxidative stress response, which is involved in the defense against many oxidative stress/inflammation-mediated diseases, including anticancer effects elicited by an increasing number of natural products. Our previous studies showed that the epigenetic modification of the Nrf2 gene plays a key role in restoring the expression of Nrf2. In this study, we aimed to investigate the epigenetic regulation of Nrf2 by astaxanthin (AST) and fucoxanthin (FX), carotenoids which are abundant in microalgae and seaweeds, in mouse skin epidermal JB6 P+ cells. FX induced the anti-oxidant response element (ARE)-luciferase and upregulated the mRNA and protein levels of Nrf2 and Nrf2 downstream genes in HepG2-C8 cells overexpressing the ARE-luciferase reporter. Both FX and AST decreased colony formation in 12-Otetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 P+ cells. FX decreased the methylation of the Nrf2 promoter region in the JB6 P+ cells by the bisulfite conversion and pyrosequencing. Both FX and AST significantly reduced DNA methyltransferase (DNMT) activity but did not affect histone deacetylase (HDAC) activity in JB6 P+ cells. In summary, our results show that FX activates the Nrf2 signaling pathway, induces the epigenetic demethylation of CpG sites in Nrf2 and blocks the TPA-induced transformation of JB6 P+ cells, indicating the potential health-promoting effects of FX in skin cancer prevention.

Dibenzoylmethane Protects Against CCl4-Induced Acute Liver Injury by Activating Nrf2 via JNK, AMPK, and Calcium Signaling.

Oxidative stress is an important pathogenic factor in various hepatic diseases. Nuclear factor-erythroid 2-related factor-2 (Nrf2), which coordinates the expression of an array of antioxidant and detoxifying genes, has been proposed as a potential target for prevention and treatment of liver disease. Dibenzoylmethane (DBM) is a minor ingredient in licorice that activates Nrf2 and prevents various cancers and oxidative damage. In the present study, the mechanisms by which DBM activates Nrf2 signaling were delineated, and its protective effect against carbon tetrachloride (CCl4)-induced liver injury was examined. DBM potently induced the expression of HO-1 in cells and in the livers of mice, but this induction was diminished in Nrf2-deficient mice and cells. Overexpression of Nrf2 enhanced DBM-induced HO-1 expression, while overexpression of a dominant-negative fragment of Nrf2 inhibited this induction. DBM treatment resulted in dissociation from Keap1 and nuclear translocation of Nrf2. Moreover, DBM activated Akt/protein kinase B, mitogen-activated protein kinases, and AMP-activated protein kinase and increased intracellular calcium levels. Inhibition of JNK, AMPK, or intracellular calcium signaling significantly suppressed the induction of HO-1 expression by DBM. Finally, DBM treatment significantly inhibited CCl4-induced acute liver injury in wild-type but not in Nrf2-deficient mice. Taken together, our results revealed the mechanisms by which DBM activates Nrf2 and induces HO-1 expression, and provide molecular basis for the design and development of DBM and its derivatives for prevention or treatment of liver diseases by targeting Nrf2.

Biotransformation of 20(R)-panaxadiol by the fungus Rhizopus chinensis.

Microbial transformation of 20(R)-panaxadiol by the fungus Rhizopus chinensis CICC 3043 yielded seven metabolites. Their structures were elucidated on the basis of extensive spectroscopic analyses. R. chinensis could catalyze hydroxylation and further dehydrogenation at C-24 of 20(R)-panaxadiol, as well as hydroxylation at C-7, C-15, C-16, and C-29. Three of these compounds at 10µM could moderately inhibit growth of HepG2 human hepatocellular carcinoma cells with an inhibition rate of about 40%. Three compounds (also at 10µM) showed approximately 30% inhibition on NF-κB transcriptional activity in SW480 human colon carcinoma cells stably transfected with NF-κB luciferase reporter and induced by LPS.