Adverse events of direct factor Xa inhibitors: a disproportionality analysis of the FAERS database.

OBJECTIVES: Direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, commonly used direct oral anticoagulant (DOAC), are widely used to prevent and treat stroke and venous thromboembolic events in patients with atrial fibrillation (AF). This study aimed to assess and compare reports of adverse events associated with rivaroxaban, apixaban, and edoxaban, including hemorrhagic and non-hemorrhagic events. METHODS: Reporting odds ratio (ROR), proportional reporting ratio (PRR), Medications and Health Care Products Regulatory Agency (MHRA), and the information component (IC) were used to perform a risk assessment of adverse event reports in the FDA Adverse Event Reporting System (FAERS) database for the years 2018-2022. RESULTS: Combined with disproportionality analysis in different backgrounds, the salient risks of the three-factor Xa inhibitors varied. Rivaroxaban had the most significant risk of hemorrhage, apixaban had a higher incidence and risk of death, cardiac and cerebral adverse events, and edoxaban showed a more prominent risk in the kidneys and urinary system. CONCLUSION: Hemorrhage is a common risk with factor Xa inhibitors, with rivaroxaban being the most significant. Apixaban and edoxaban also showed significant association with non-hemorrhagic adverse events, and increased attention to non-hemorrhagic adverse events is needed in clinical use.

Pathways and contributions of sulfate reducing-bacteria to arsenic cycling in landfills.

Sulfate-reducing bacteria (SRB) are generally found in sanitary landfills and play a role in sulfur (S) and metal/metalloid geochemical cycling. In this study, we investigated the influence of SRB on arsenic (As) metabolic pathways in refuse-derived cultures. The results indicated that SRB promote As(III) methylation and are beneficial for controlling As levels. Heterotrophic and autotrophic SRB showed significant differences during As cycling. In heterotrophic SRB cultures, the As methylation rate increased with As(III) concentration in the medium and reached a peak (85.1%) in cultures containing 25 mg L-1 As(III). Moreover, 4.0-12.6% of SO42- was reduced to S2-, which then reacted with As(III) to form realgar (AsS). In contrast, autotrophic SRB oxidized As(III) to less toxic As(V) under anaerobic conditions. Heterotrophic arsM-harboring SRB, such as Desulfosporosinus, Desulfocurvibacter, and Desulfotomaculum, express As-related genes and are considered key genera for As methylation in landfills. Thiobacillus are the main autotrophic SRB in landfills and can derive energy by oxidizing sulfur compounds and metal(loid)s. These results suggest that different types of SRB drive As methylation, redox reaction, and mineral formation in landfills. These study findings have implications for the management of As pollutants in landfills and other contaminated environments.

Association between methotrexate-induced Stevens-Johnson syndrome/toxic epidermal necrolysis and furosemide: a real-world disproportionality analysis.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and life-threatening skin adverse reactions that are usually induced by drugs. This study aimed to assess the association between methotrexate and SJS/TEN when combined with furosemide. RESEARCH DESIGN AND METHODS: Data on suspicious, interactions (PS, SS, I) from the FDA Adverse Event Reporting System database for 2016-2021 were analyzed using the reporting odds ratio (ROR), information component (IC), proportional reporting ratio (PRR) and the Medications and Health Care Products Regulatory Agency (MHRA). RESULTS: We identified 28 case reports of TEN associated with the combination of furosemide and methotrexate and 10 reports of SJS associated with furosemide and methotrexate. The association of methotrexate with SJS/TEN was more significant in the entire data set when combined with furosemide than when methotrexate was not combined with furosemide. The association of methotrexate with SJS/TEN remained significant when furosemide was combined with methotrexate in a tumor-based disease context. After sensitivity analysis of the entire dataset as well as all antineoplastic drug datasets, consistent results were observed for TEN. CONCLUSIONS: Our study confirmed a significant association between methotrexate and SJS/TEN when combined with furosemide, with an increased risk of SJS/TEN.

Compounding warning letters to 503A facilities between 2017 and 2021.

BACKGROUND: The growing population demand and the epidemic lead of coronavirus disease 2019 have highlighted the critical importance of patient access to compounded formulations, including for special purposes such as pediatrics, geriatrics, and other uses. However, there are many potential risks, including quality issues and 503A facilities have not received valid prescriptions for individually-identified patients for a portion of the drug products they produce. OBJECTIVE: The aim is to analyze the (503A facilities) warning letters and identify the problem of compounding medicines not meeting the United States Pharmacopoeia specifications. METHODS: Content analysis and descriptive statistics methods were used to analyze the violations of compounding warning letters from 2017 to 2021. The content of warning letter violations was analyzed in terms of both the compounding environment and 503A facilities that did not received valid prescriptions for individually-identified patients for a portion of the drug products they produced. RESULTS: A total of 113 compounding warning letters (503A facilities, N = 112) from 2017 to 2021 were analyzed in this study. The percentage of 503A facilities involved in sterile compounding environmental issues was 79.46%, with facility design and environmental controls (73/89, 82.02%), cleaning and disinfecting the compounding area (59/89, 66.29%), and personnel cleansing and garbing (44/89, 49.44%) being the top 3 issues. Seventy-two (72/112, 64.29%) 503A facilities that did not received valid prescriptions for individually-identified patients for a portion of the drug products they produced. Fifty-one (51/72, 70.83%) of these warning letters were related to sterile environment issues, and 28 warning letters identified specific drugs that did not qualify for Section 503A exemptions. CONCLUSION: The warning letter of compounding drugs issued by Food and Drug Administration can be used as a learning tool for compounders. Compounders can learn from the experience and lessons, improve compounding operations and reduce mistakes.

Arsenic methylation behavior and microbial regulation mechanisms in landfill leachate saturated zones.

Arsenic (As) is a potential contaminant in landfill. As methylation has been considered as a detoxification mechanism to address this problem. In this study, microcosm incubation was used to simulate leachate saturation zone (LSZ) and other landfill zones scenarios to explore the As methylation behavior. The As methylation rate of LSZ is 11.75%, which is slightly higher than that of other zone of landfill (10.87%). However, the difference was greatly increased by the addition of moderate content of As(III), with values of 29.25% in LSZ and 4.61% in other zones. The microbial community structure varied greatly between zones and a higher abundance of arsM was observed in the LSZ, which enhanced As methylation. Based on the annotated As functional genes from the KEGG database, the microbial As methylated pathway was summarized. Higher relative abundances of gst and arsC promoted the formation of more trivalent As substrates, stimulating the methylation behavior for As detoxification in the LSZ. According to microbial arsM contribution analysis, unclassified_p__Gemmatimonadetes, unclassified_p__Actinobacteria, unclassified_o_Hydrogenophilales, and Intrasporangium were the primary As methylation bacteria in the LSZ, while unclassified_f__Chitinophagaceae and unclassified_c_Gammaproteobacteria were the primary contributors in other landfill zones. These results highlight the specific As methylation process in the LSZ, and these insights could improve the control of As contamination in landfill sites.

Localized intensification of arsenic methylation within landfill leachate-saturated zone.

Leachate-saturated zone (LSZ) of landfills is a complicated biogeochemical hotspot due to the continuous input of electron donors and acceptors from the top refuse layer with leachate migration. In this study, the methylation behavior of the arsenic (As) was investigated. The results indicate that As-methylation processes are influenced by temperature fields in LSZ. The dimethylarsinic acid biotransformation capability can be enhanced with an increase in temperature. Microbial diversity, quantification of functional gene (arsM), and co-occurrence network analysis further characterized the drivers of As methylation in LSZ. As-biogeochemical cycle pathways, as well as As-functional gene distribution among different temperature fields, were modeled on the basis of KEGG annotation. Binning analysis was further employed to assemble As-methylated metagenomes, enabling the identification of novel species for As methylation in landfills. Then, 87 high-quality draft metagenome-assembled genomes (MAGs) were reconstructed from LSZ refuse samples; nearly 15 % (13 of 87) belonged to putative As-methylates functional MAGs. Combined with the model of the As-biogeochemical cycle, nine putative functional species could complete methylation processes alone. The findings of this study highlighted the temperature influence on the As-methylation behavior in LSZ and could facilitate the management of As contamination in landfills.

Microbes drive changes in arsenic species distribution during the landfill process.

Landfills are considered an anthropogenic source of arsenic (As). The As species mediated by microbes in landfills vary significantly in toxicity. Based on random matrix theory, 16S rRNA genes were used to construct four microbial networks associated with different stages over 12 years of landfill ages. The results indicated that network size and microbial structure varied with landfill age. According to the network scores, about 208 taxa were identified as putative keystones for the whole landfill; the majority of them were Firmicutes, which accounted for 66.8% of all specialists. Random Forest analysis was performed to predict the keystone taxa most responsible for As species distribution under different landfill conditions; 17, 10 and 14 keystone taxa were identified as drivers affecting As species distribution at early, middle, and later landfill stages, respectively.

Mesenchymal stem cells therapy: A promising method for the treatment of uterine scars and premature ovarian failure.

Both intrauterine adhesions (IUA) and premature ovarian failure (POF) have plagued women all over the world for a long time. It is well known that all invasive operations involving the uterus can disrupt its structural and functional integrity to a varying degree, which inevitably lead to abnormal scar formation, such as IUA, also known as Asherman's syndrome with symptoms like hypomenorrhea or infertility. Another reproductive disorder that causes infertility is primary ovarian insufficiency (POI) or POF, which is a degenerative phenomenon in the ovary among women under the age of 40. In recent years, various types of stem cells, especially mesenchymal stem cells (MSCs) have been widely used in reproductive medicine due to their properties, such as immunoregulation, anti-inflammation, angiogenesis, anti-apoptosis, and trophicity. However, the extensive clinical application of cell therapy is impeded by their safety, cost, and manufacturing. In this review, we sought to summarize the recent advances in using different types of MSCs in treating uterine scars and POF. We also describe several biological pathways and molecules involved in animal studies and clinical application; extracellular vesicles secreted by MSCs may be a promising attractive tool to ensure the treatment of infertility by restoring normal reproductive function.

Drivers and ecological consequences of arsenite detoxification in aged semi-aerobic landfill.

Microbial populations responsible for arsenite [As(III)] detoxification were examined in aged refuse treated with 75 µM As(III) under semi-aerobic conditions. As(III) was rapidly oxidized to As(V) via microbial activity, and substantial As was fixed in the solid phase. The abundance of arsenite oxidase genes (aioA) was about four times higher in the moderate As(III) stressed treatment than in the untreated control. Network analysis of microbial community 16S rRNA genes based on MRT (random matrix theory) further illuminated details about microbe-microbe interactions, and showed six ecological clusters. A total of 166 "core" taxa were identified by within-module connectivity and among-module connectivity values. When compared with the control treatment without As(III), 12 putative keystone operational taxonomic units were positively correlated with As(III) oxidation, of which 10 of these were annotated to genera level. Eight genera were associated with As(III) detoxification: Pseudomonas, Paenalcaligenes, Proteiniphilum, Moheibacter, Mobilitalea, Anaerosporobacter, Syntrophomonas and Pusillimonas. Most of those putative keystone taxa were rare species in landfill, which suggests that low-abundance taxa might significantly contribute to As(III) oxidation.

MiR-141-3p downregulation promotes tube formation, migration, invasion and inhibits apoptosis in hypoxia-induced human umbilical vein endothelial cells by targeting Notch2.

Vascular endothelial cell damage is regarded as the carrier in the progression of the pathological changes of preeclampsia (PE) from the placenta to maternal organs. MicroRNA (miR)-141-3p was aberrantly expressed during PE pathogenesis. We investigated the role of miR-141-3p in regulating the biological behaviors of endothelial cells in PE. Human umbilical vein endothelial cells (HUVECs) were isolated from the human umbilical cords and cultured under hypoxia condition to establish PE models. The binding of miR-141-3p and Notch2 was confirmed by dual-luciferase reporter assay. HUVECs were transfected with miR-141-3p inhibitor and siRNA-Notch2. The viability, vascularization capability, migration, and invasion of HUVECs were evaluated by MTT, tube formation, and Transwell assays. Cell apoptosis was measured via flow cytometry. The expressions of miR-141-3p, Notch2, Bcl-2, Bax and cleaved caspase-3 were assessed by qRT-PCR or Western blot. MiR-141-3p expression was upregulated in the HUVECs isolated from PE tissues and hypoxia-induced HUVECs. Hypoxia treatment inhibited viability, tube formation, migration, and invasion, and promoted apoptosis in HUVECS, as well as increased Bax and cleaved caspase-3 expressions and decreased Bcl-2 expression. Downregulating miR-141-3p expression promoted viability, tube formation, migration and invasion, and inhibited apoptosis in HUVECs, counteracting the effect of hypoxia on HUVECs. MiR-141-3p directly targeted Notch2. Silencing Notch2 reversed the promoting effect of downregulated miR-141-3p expression on HUVECs. In conclusion, downregulating miR-141-3p expression during hypoxia promotes tube formation, migration, and invasion and inhibits apoptosis in HUVECs by targeting Notch2.

Distinct expression profiles of peptides in placentae from preeclampsia and normal pregnancies.

This study sought to identify potential bioactive peptides from the placenta that are involved in preeclampsia (PE) to obtain information about the prediction, diagnosis and treatment of PE. The liquid chromatography/mass spectrometry was used to perform a comparative analysis of placental peptides in normal and PE pregnancies. Gene ontology (GO), pathway analysis and ingenuity pathway analysis (IPA) were used to evaluate the underlying biological function of the differential peptides based on their protein precursors. Transwell assays and qPCR were used to study the effect of the identified bioactive peptides on the function of HTR-8/SVneo cells. A total of 392 upregulated peptides and 420 downregulated peptides were identified (absolute fold change ≥ 2 and adjusted P value < 0.05). The GO analysis, pathway analysis, and IPA revealed that these differentially expressed peptides play a role in PE. In addition, the up-regulated peptide "DQSATALHFLGRVANPLSTA" derived from Angiotensinogen exhibited effect on the invasiveness of HTR-8/SVneo cells. The current preliminary research not only provides a new research direction for studying the pathogenesis of PE, but also brings new insights for the prediction, diagnosis and treatment of PE.

Analysis of factors related to preterm birth: a retrospective study at Nanjing Maternity and Child Health Care Hospital in China.

Preterm birth is the most important cause of neonatal mortality and morbidity worldwide. The aim of this study was to identify factors associated with preterm birth and examine the heterogeneity and interactions between these factors.We collected data from 1607 pregnant women treated at Nanjing Maternity and Child Health Care Hospital in China. The women included in the study were divided into the full-term group and the preterm-birth group. We used t-tests to compare the characteristics of age and body mass index, Chi-square tests for the other variables, and we used the Wald test to calculate the interaction between factors that may affect preterm birth. The heterogeneity test was used to study the relationship between subgroups. Multivariable logistic regression analysis was used to explore the associations between risk factors and preterm birth, which included all risk factors. All tests were 2-tailed, P < 0.05 was considered significant, and 95% confidence intervals were estimated for percentages.There was no statistical difference in basic characteristics such as age between the full-term and preterm groups. We found 6 independent risk factors that were associated with preterm birth (P < .05): preeclampsia (PE), intrahepatic cholestasis, premature rupture of the membranes (PROM), placenta previa, chorioamnionitis, and scarred uterus. Five combinations of these factors were statistically significant (P < .05) in terms of heterogeneity: PE and PROM; placenta previa and polyhydramnios; chorioamnionitis and PE; PROM and maternal body mass index; and PROM and gestational diabetes mellitus. Ultimately, the 2 subgroups that showed interactions were PE and PROM and chorioamnionitis and PE.The interaction between different factors over the course of preterm birth cannot be ignored. When independent risk factors are combined with other diseases, such as PE combined with PROM or chorioamnionitis in this study, it may more likely result in preterm birth. Thus, this situation deserves particular clinical attention.

Overexpression of Long Noncoding RNA Uc.187 Induces Preeclampsia-Like Symptoms in Pregnancy Rats.

BACKGROUND: As a serious pregnancy-specific condition, preeclampsia (PE) is a serious pregnancy-specific condition characterized by insufficient trophoblastic invasion and shallow placental implantation. Long noncoding RNA uc.187, which is transcribed from an ultra-conserved region is highly expressed in the placental tissue of patients with PE, is associated with abnormal trophoblast invasion. Therefore, we aimed to further characterize the relationship between uc.187 and PE through in vitro experimental studies to find new targets to treat PE. METHODS: In this study, we constructed PE rat models induced by lipopolysaccharide, experimented with overexpressing uc.187 and performed experiments using HTR-8/SVneo cells. RESULTS: We found uc.187 was elevated in the placenta of PE rats. By injecting pregnant rats with a lentivirus containing the lncRNA uc.187, we successfully triggered maternal hypertension along with a series of symptoms similar to PE in humans. In vitro experiments demonstrated that high levels of uc.187 lead to decreased trophoblast invasion. In addition, our results revealed that uc.187 had high expression in PE and fetal growth restricted cells, but low expression in placental site trophoblastic tumors compared with the control groups. Results of western blot and cell immunofluorescence indicated that the aberrant biological behavior of HTR-8/SVneo cells were related to the distribution of ß-catenin in the cytoplasm and nucleus. CONCLUSIONS: Taken together, our study revealed that uc.187 was negatively correlated to trophoblastic cell invasion, and overexpression of uc.187 could induce PE-like symptoms in a pregnant rat model by affecting the distribution of ß-catenin in the cytoplasm and nucleus.

Peptidome analysis of amniotic fluid from pregnancies with preeclampsia.

Preeclampsia (PE), a life­threatening, complicated pregnancy­associated disease, has recently become a research focus in obstetrics. However, the peptidome of the amniotic fluid in PE patients has rarely been investigated. The present study used peptidomic profiling to perform a comparative analysis of human amniotic fluid between normal and PE pregnancies. Centrifugal ultrafiltration and liquid chromatography­tandem mass spectrometry (LC­MS/MS) was combined with isotopomeric dimethyl labels to gain a deeper understanding of the role of proteins and the peptidome in the onset of PE. Following ultrafiltration and LC­MS/MS, 352 peptides were identified. Of these, 23 peptides were observed to be significantly differentially expressed (6 downregulated and 17 upregulated; P<0.05). Using Gene Ontology and Blastp analyses, the functions and biological activities of these 23 peptides were identified and revealed to include autophagy, signal transduction, receptor activity, enzymatic activity and nucleic acid binding. In addition, a bibliographic search revealed that some of the identified peptides, including Titin, are crucial to the pathogenesis underlying PE. The present study identified 23 peptides expressed at significantly different levels in the amniotic fluid of PE and normal pregnancies. A comprehensive peptidome analysis is more efficient than a simple biomarker analysis at revealing deficiencies and improving the detection rate in diseases. These analyses therefore provide a substantial advantage in applications aimed at the discovery of disease­specific biomarkers.

Potential Significance of Circular RNA in Human Placental Tissue for Patients with Preeclampsia.

AIMS: This study aimed to identify the different expression of circular RNAs (circRNAs) in the placental tissues of pregnant women with preeclampsia (PE) and to provide a new avenue of research regarding the pathological mechanisms of PE. METHODS: In this study, we collected 40 placental tissues from PE patients and 35 placental tissues from gestational age-matched patients who gave premature birth. Arraystar circRNA Microarray Technology (KANGCHEN, Shanghai, China) was used to analyze the differential expression of circRNAs. According to the basic content of circRNAs in the two groups and their fold changes and due to the practicability of the designed divergent primers of each candidate circRNA, we selected three up-regulated circRNAs, hsa_circRNA_100782, hsa_circRNA_102682 and hsa_circRNA_104820, to validate the data. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was utilized to estimate the Ct values in both groups. We further evaluated the differences with a paired t-test and a receiver operating characteristic (ROC) curve. RESULTS: Many circRNAs were found to be differentially expressed in PE placental tissues versus their controls; of these, 143 circRNAs were up-regulated and 158 were down-regulated. The expression levels of hsa_circRNA_100782 (p < 0.05), hsa_circRNA_102682 (p < 0.05), and hsa_circRNA_104820 (p < 0.0001) were validated as significantly up-regulated in the experimental group compared with the controls. Finally, we performed a literature comparison to forecast the possible mechanisms of circRNA function during PE. CONCLUSION: circRNA expression significantly differed in placental PE tissues compared with controls. According to the circRNA microarray results and the existing papers, circRNAs may contribute to the pathogenesis of PE by acting as miRNA sponges; this possibility requires additional investigation in future studies.