Reported Xylazine Use Among Adults Aged ≥18 Years Evaluated for Substance Use Treatment - United States, July 2022-September 2023.

Xylazine has been increasingly detected in illegally manufactured fentanyl (IMF) products and overdose deaths in the United States; most xylazine-involved overdose deaths involve IMF. A convenience sample of U.S. adults aged ≥18 years was identified from those evaluated for substance use treatment during July 2022-September 2023. Data were collected using the Addiction Severity Index-Multimedia Version clinical assessment tool. Among 43,947 adults, 6,415 (14.6%) reported IMF or heroin as their primary lifetime substance-use problem; 5,344 (12.2%) reported recent (i.e., past-30-day) IMF or heroin use. Among adults reporting IMF or heroin as their primary lifetime substance-use problem, 817 (12.7%) reported ever using xylazine. Among adults reporting recent IMF or heroin use, 443 (8.3%) reported recent xylazine use. Among adults reporting IMF or heroin use recently or as their primary lifetime substance-use problem, those reporting xylazine use reported a median of two past nonfatal overdoses from any drug compared with a median of one overdose among those who did not report xylazine use; as well, higher percentages of persons who reported xylazine use reported other recent substance use and polysubstance use. Provision of nonjudgmental care and services, including naloxone, wound care, and linkage to and retention of persons in effective substance use treatment, might reduce harms including overdose among persons reporting xylazine use.

Directed-evolution mutations enhance DNA-binding affinity and protein stability of the adenine base editor ABE8e.

Adenine base editors (ABEs), consisting of CRISPR Cas nickase and deaminase, can chemically convert the A:T base pair to G:C. ABE8e, an evolved variant of the base editor ABE7.10, contains eight directed evolution mutations in its deaminase TadA8e that significantly increase its base editing activity. However, the functional implications of these mutations remain unclear. Here, we combined molecular dynamics (MD) simulations and experimental measurements to investigate the role of the directed-evolution mutations in the base editing catalysis. MD simulations showed that the DNA-binding affinity of TadA8e is higher than that of the original deaminase TadA7.10 in ABE7.10 and is mainly driven by electrostatic interactions. The directed-evolution mutations increase the positive charge density in the DNA-binding region, thereby enhancing the electrostatic attraction of TadA8e to DNA. We identified R111, N119 and N167 as the key mutations for the enhanced DNA binding and confirmed them by microscale thermophoresis (MST) and in vivo reversion mutation experiments. Unexpectedly, we also found that the directed mutations improved the thermal stability of TadA8e by ~ 12 °C (Tm, melting temperature) and that of ABE8e by ~ 9 °C, respectively. Our results demonstrate that the directed-evolution mutations improve the substrate-binding ability and protein stability of ABE8e, thus providing a rational basis for further editing optimisation of the system.

Coping with the concurrent heatwaves and ozone extremes in China under a warming climate.

Intensive human activity has brought about unprecedented climate and environmental crises, in which concurrent heatwaves and ozone extremes pose the most serious threats. However, a limited understanding of the comprehensive mechanism hinders our ability to mitigate such compound events, especially in densely populated regions like China. Here, based on field observations and climate-chemistry coupled modelling, we elucidate the linkage between human activities and the climate system in heat-related ozone pollution. In China, we have observed that both the frequency and intensity of heatwaves have almost tripled since the beginning of this century. Moreover, these heatwaves are becoming more common in urban clusters with serious ozone pollution. Persistent heatwaves during the extremely hot and dry summers of 2013 and 2022 accelerated photochemical ozone production by boosting anthropogenic and biogenic emissions, and aggravated ozone accumulation by suppressing dry deposition due to water-stressed vegetation, leading to a more than 30% increase in ozone pollution in China's urban areas. The sensitivity of ozone to heat is demonstrated to be substantially modulated by anthropogenic emissions, and China's clean air policy may have altered the relationship between ozone and temperature. Climate model projections further highlight that the high-emission climate-socioeconomic scenario tends to intensify the concurrent heat and ozone extremes in the next century. Our results underscore that the implementation of a strict emission strategy will significantly reduce the co-occurrence of heatwaves and ozone extremes, achieving climate and environmental co-benefits.

Starting with screening strains to construct synthetic microbial communities (SynComs) for traditional food fermentation.

With the elucidation of community structures and assembly mechanisms in various fermented foods, core communities that significantly influence or guide fermentation have been pinpointed and used for exogenous restructuring into synthetic microbial communities (SynComs). These SynComs simulate ecological systems or function as adjuncts or substitutes in starters, and their efficacy has been widely verified. However, screening and assembly are still the main limiting factors for implementing theoretic SynComs, as desired strains cannot be effectively obtained and integrated. To expand strain screening methods suitable for SynComs in food fermentation, this review summarizes the recent research trends in using SynComs to study community evolution or interaction and improve the quality of food fermentation, as well as the specific process of constructing synthetic communities. The potential for novel screening modalities based on genes, enzymes and metabolites in food microbial screening is discussed, along with the emphasis on strategies to optimize assembly for facilitating the development of synthetic communities.

Realveolarization with inhalable mucus-penetrating lipid nanoparticles for the treatment of pulmonary fibrosis in mice.

The stemness loss-associated dysregeneration of impaired alveolar type 2 epithelial (AT2) cells abolishes the reversible therapy of idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 stemness for IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house-made ionizable lipids for high-efficiency pulmonary mucus penetration and codelivery of dual messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 and bone morphogenetic protein 4, respectively. After being inhaled in a bleomycin model, LNPs reverses the mitochondrial dysfunction through ameliorating nicotinamide adenine dinucleotide biosynthesis, which inhibits the accelerated senescence of AT2 cells. Concurrently, pathological epithelial remodeling and fibroblast activation induced by impaired AT2 cells are terminated, ultimately prompting alveolar regeneration. Our data demonstrated that the mRNA-LNP system exhibited high protein expression in lung epithelial cells, which markedly extricated the alveolar collapse and prolonged the survival of fibrosis mice, providing a clinically viable strategy against IPF.

Advances in precision gene editing for liver fibrosis: From technology to therapeutic applications.

This review presents a comprehensive exploration of gene editing technologies and their potential applications in the treatment of liver fibrosis, a condition often leading to serious complications such as liver cancer. Through an in-depth review of current literature and critical analysis, the study delves into the intricate signaling pathways underlying liver fibrosis development and examines the promising role of gene editing in alleviating this disease burden. Gene editing technologies offer precise, efficient, and reproducible tools for manipulating genetic material, holding significant promise for basic research and clinical practice. The manuscript highlights the challenges and potential risks associated with gene editing technology. By synthesizing existing knowledge and exploring future perspectives, this study aims to provide valuable insights into the potential of precision gene editing to combat liver fibrosis and its associated complications, ultimately contributing to advances in liver fibrosis research and therapy.

Hepatitis B-related hepatocellular carcinoma: classification and prognostic model based on programmed cell death genes.

Instruction: Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Programmed cell death (PCD) is a critical process in suppressing tumor growth, and alterations in PCD-related genes may contribute to the progression of HBV-HCC. This study aims to develop a prognostic model that incorporates genomic and clinical information based on PCD-related genes, providing novel insights into the molecular heterogeneity of HBV-HCC through bioinformatics analysis and experimental validation. Methods: In this study, we analyzed 139 HBV-HCC samples from The Cancer Genome Atlas (TCGA) and validated them with 30 samples from the Gene Expression Omnibus (GEO) database. Various bioinformatics tools, including differential expression analysis, gene set variation analysis, and machine learning algorithms were used for comprehensive analysis of RNA sequencing data from HBV-HCC patients. Furthermore, among the PCD-related genes, we ultimately chose DLAT for further research on tissue chips and patient cohorts. Besides, immunohistochemistry, qRT-PCR and Western blot analysis were conducted. Results: The cluster analysis identified three distinct subgroups of HBV-HCC patients. Among them, Cluster 2 demonstrated significant activation in DNA replication-related pathways and tumor-related processes. Analysis of copy number variations (CNVs) of PCD-related genes also revealed distinct patterns in the three subgroups, which may be associated with differences in pathway activation and survival outcomes. DLAT in tumor tissues of HBV-HCC patients is upregulated. Discussion: Based on the PCD-related genes, we developed a prognostic model that incorporates genomic and clinical information and provided novel insights into the molecular heterogeneity of HBV-HCC. In our study, we emphasized the significance of PCD-related genes, particularly DLAT, which was examined in vitro to explore its potential clinical implications.

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.

Spinosin ameliorates osteoarthritis through enhancing the Nrf2/HO-1 signaling pathway.

Osteoarthritis (OA) is a common degenerative joint disease in the elderly, while oxidative stress-induced chondrocyte degeneration plays a key role in the pathologic progression of OA. One possible reason is that the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), which acts as the intracellular defense factor against oxidative stress, is significantly inhibited in chondrocytes. Spinosin (SPI) is a potent Nrf2 agonist, but its effect on OA is still unknown. In this study, we found that SPI can alleviate tert-Butyl hydroperoxide (TBHP)-induced extracellular matrix degradation of chondrocytes. Additionally, SPI can effectively activate Nrf2, heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase 1 (NQO1) in chondrocytes under the TBHP environment. When Nrf2 was silenced by siRNA, the cartilage protective effect of SPI was also weakened. Finally, SPI showed good alleviative effects on OA in mice. Thus, SPI can ameliorate oxidative stress-induced chondrocyte dysfunction and exhibit a chondroprotective effect through activating the Nrf2/HO-1 pathway, which may provide a novel and promising option for the treatment of OA.

Development of a Human B7-H3-Specific Antibody with Activity against Colorectal Cancer Cells through a Synthetic Nanobody Library.

Nanobodies have emerged as promising tools in biomedicine due to their single-chain structure and inherent stability. They generally have convex paratopes, which potentially prefer different epitope sites in an antigen compared to traditional antibodies. In this study, a synthetic phage display nanobody library was constructed and used to identify nanobodies targeting a tumor-associated antigen, the human B7-H3 protein. Combining next-generation sequencing and single-clone validation, two nanobodies were identified to specifically bind B7-H3 with medium nanomolar affinities. Further characterization revealed that these two clones targeted a different epitope compared to known B7-H3-specific antibodies, which have been explored in clinical trials. Furthermore, one of the clones, dubbed as A6, exhibited potent antibody-dependent cell-mediated cytotoxicity (ADCC) against a colorectal cancer cell line with an EC50 of 0.67 nM, upon conversion to an Fc-enhanced IgG format. These findings underscore a cost-effective strategy that bypasses the lengthy immunization process, offering potential rapid access to nanobodies targeting unexplored antigenic sites.

Impact of Three Thiazolidinone Compounds with Piperine Skeletons on Trehalase Activity and Development of Spodoptera frugiperda Larvae.

Trehalases (TREs) are pivotal enzymes involved in insect development and reproduction, making them prime targets for pest control. We investigated the inhibitory effect of three thiazolidinones with piperine skeletons (6a, 7b, and 7e) on TRE activity and assessed their impact on the growth and development of the fall armyworm (FAW), Spodoptera frugiperda. The compounds were injected into FAW larvae, while the control group was treated with 2% DMSO solvent. All three compounds effectively inhibited TRE activity, resulting in a significant extension of the pupal development stage. Moreover, the treated larvae exhibited significantly decreased survival rates and a higher incidence of abnormal phenotypes related to growth and development compared to the control group. These results suggest that these TRE inhibitors affect the molting of larvae by regulating the chitin metabolism pathway, ultimately reducing their survival rates. Consequently, these compounds hold potential as environmentally friendly insecticides.

Dynamic Stomach Model-Capillary Electrophoresis-ICPMS for Evaluation of Release and Transformation Behaviors of Arsenic Species from Microplastics during Digestion.

Microplastics (MPs) can act as carriers of environmental arsenic species into the stomach with food and release arsenic species during digestion, which threatens human health. Herein, an integrated dynamic stomach model (DSM)-capillary electrophoresis-inductively coupled plasma mass spectrometry (CE-ICPMS) is developed for online monitoring of the release and transformation behaviors of arsenic species loaded on MPs (As-MPs) in the simulated human stomach. The 3D-printed DSM with a soft stomach chamber enables the behaviors of gastric peristalsis, gastric and salivary fluid addition, pH adjustment, and gastric emptying (GE) to be controlled by a self-written program after oral ingestion of food with As-MPs. The gastric extract during digestion is introduced into the spiral channel to remove the large particulate impurity and online filtered to obtain the clarified arsenic-containing solution for subsequent speciation analysis of arsenic by CE-ICPMS. The digestion conditions and pretreatment processes of DSM are tracked and validated, and the release rates of As-MPs digested by DSM are compared with those digested by the static stomach model and DSM without GE. The release rate of inorganic arsenic on MPs is higher than that of organic arsenic throughout the gastric digestion process, and 8% of As(V) is reduced to As(III). The detection limits for As(III), DMA, MMA, and As(V) are 0.5-0.9 µg L-1 using DSM-CE-ICPMS, along with precisions of ≤8%. This present method provides an integrated and convenient tool for evaluating the release and transformation of As-MPs during human gastric digestion and provides a reference for exploring the interactions between MPs and metals/metalloids in the human body.

Metabonomics analysis of the flavor characteristics of Wuyi Rock Tea (Rougui) with "rock flavor" and microbial contributions to the flavor.

Wuyi Rock Tea (WRT) has different characteristics of "rock flavor" due to different production areas. In this study, we investigated the flavor characteristics and key components of "rock flavor" and the influence of microorganisms on the substances by combining metabolomics and microbiomics with the Rougui WRTs from the Zhengyan, Banyan, and Waishan production areas. The results showed that Rougui has a strong floral and fruity aroma, which is mainly brought by hotrienol, and the sweet, smooth, and fresh taste is composed of epicatechin gallate, epigallocatechin, epigallocatechin gallate, caffeine, theanine, soluble sugar, and sweet and bitter amino acids. Bacteria Chryseobacterium, Pedobacter, Bosea, Agrobacterium, Stenotrophomonas, and Actinoplanes mainly influence the production of hotrienol, epicatechin gallate, and theanine. Fungi Pestalotiopsis, Fusarium, Elsinoe, Teichospora and Tetracladium mainly influence the production of non-volatile compounds. This study provides a reference for the biological formation mechanism of the characteristic aroma of WRT's "rock falvor".

Identification of diagnostic biomarkers and immune cell infiltration in coronary artery disease by machine learning, nomogram, and molecular docking.

Background: Coronary artery disease (CAD) is still a lethal disease worldwide. This study aims to identify clinically relevant diagnostic biomarker in CAD and explore the potential medications on CAD. Methods: GSE42148, GSE180081, and GSE12288 were downloaded as the training and validation cohorts to identify the candidate genes by constructing the weighted gene co-expression network analysis. Functional enrichment analysis was utilized to determine the functional roles of these genes. Machine learning algorithms determined the candidate biomarkers. Hub genes were then selected and validated by nomogram and the receiver operating curve. Using CIBERSORTx, the hub genes were further discovered in relation to immune cell infiltrability, and molecules associated with immune active families were analyzed by correlation analysis. Drug screening and molecular docking were used to determine medications that target the four genes. Results: There were 191 and 230 key genes respectively identified by the weighted gene co-expression network analysis in two modules. A total of 421 key genes found enriched pathways by functional enrichment analysis. Candidate immune-related genes were then screened and identified by the random forest model and the eXtreme Gradient Boosting algorithm. Finally, four hub genes, namely, CSF3R, EED, HSPA1B, and IL17RA, were obtained and used to establish the nomogram model. The receiver operating curve, the area under curve, and the calibration curve were all used to validate the accuracy and usefulness of the diagnostic model. Immune cell infiltrating was examined, and CAD patients were then divided into high- and low-expression groups for further gene set enrichment analysis. Through targeting the hub genes, we also found potential drugs for anti-CAD treatment by using the molecular docking method. Conclusions: CSF3R, EED, HSPA1B, and IL17RA are potential diagnostic biomarkers for CAD. CAD pathogenesis is greatly influenced by patterns of immune cell infiltration. Promising drugs offers new prospects for the development of CAD therapy.

Public Health Interventions and Overdose-Related Outcomes Among Persons With Opioid Use Disorder.

Importance: Given the high number of opioid overdose deaths in the US and the complex epidemiology of opioid use disorder (OUD), systems models can serve as a tool to identify opportunities for public health interventions. Objective: To estimate the projected 3-year association between public health interventions and opioid overdose-related outcomes among persons with OUD. Design, Setting, and Participants: This decision analytical model used a simulation model of the estimated US population aged 12 years and older with OUD that was developed and analyzed between January 2019 and December 2023. The model was parameterized and calibrated using 2019 to 2020 data and used to estimate the relative change in outcomes associated with simulated public health interventions implemented between 2021 and 2023. Main Outcomes and Measures: Projected OUD and medications for OUD (MOUD) prevalence in 2023 and number of nonfatal and fatal opioid-involved overdoses among persons with OUD between 2021 and 2023. Results: In a baseline scenario assuming parameters calibrated using 2019 to 2020 data remained constant, the model projected more than 16 million persons with OUD not receiving MOUD treatment and nearly 1.7 million persons receiving MOUD treatment in 2023. Additionally, the model projected over 5 million nonfatal and over 145 000 fatal opioid-involved overdoses among persons with OUD between 2021 and 2023. When simulating combinations of interventions that involved reducing overdose rates by 50%, the model projected decreases of up to 35.2% in nonfatal and 36.6% in fatal opioid-involved overdoses among persons with OUD. Interventions specific to persons with OUD not currently receiving MOUD treatment demonstrated the greatest reduction in numbers of nonfatal and fatal overdoses. Combinations of interventions that increased MOUD initiation and decreased OUD recurrence were projected to reduce OUD prevalence by up to 23.4%, increase MOUD prevalence by up to 137.1%, and reduce nonfatal and fatal opioid-involved overdoses among persons with OUD by 6.7% and 3.5%, respectively. Conclusions and Relevance: In this decision analytical model study of persons with OUD, findings suggested that expansion of evidence-based interventions that directly reduce the risk of overdose fatality among persons with OUD, such as through harm reduction efforts, could engender the highest reductions in fatal overdoses in the short-term. Interventions aimed at increasing MOUD initiation and retention of persons in treatment projected considerable improvement in MOUD and OUD prevalence but could require a longer time horizon for substantial reductions in opioid-involved overdoses.

Antibacterial activity of cinnamon essential oil and its main component of cinnamaldehyde and the underlying mechanism.

Background: Plant essential oils have long been regarded as repositories of antimicrobial agents. In recent years, they have emerged as potential alternatives or supplements to antimicrobial drugs. Although literature reviews and previous studies have indicated that cinnamon essential oil (CIEO) and its major component, cinnamaldehyde (CID), possess potent antibacterial activities, their antibacterial mechanisms, especially the in vivo antibacterial mechanisms, remain elusive. Methods: In this study, we utilized the in vivo assessment system of Caenorhabditis elegans (C. elegans) to investigate the effects and mechanisms of high dose (100 mg/L) and low dose (10 mg/L) CIEO and CID in inhibiting Pseudomonas aeruginosa (P. aeruginosa). In addition, we also examined the in vitro antibacterial abilities of CIEO and CID against other common pathogens including P. aeruginosa and 4 other strains. Results: Our research revealed that both high (100 mg/L) and low doses (10 mg/L) of CIEO and CID treatment significantly alleviated the reduction in locomotion behavior, lifespan, and accumulation of P. aeruginosa in C. elegans infected with the bacteria. During P. aeruginosa infection, the transcriptional expression of antimicrobial peptide-related genes (lys-1 and lys-8) in C. elegans was upregulated with low-dose CIEO and CID treatment, while this trend was suppressed at high doses. Further investigation suggested that the PMK-1 mediated p38 signaling pathway may be involved in the regulation of CIEO and CID during nematode defense against P. aeruginosa infection. Furthermore, in vitro experimental results also revealed that CIEO and CID exhibit good antibacterial effects, which may be associated with their antioxidant properties. Conclusion: Our results indicated that low-dose CIEO and CID treatment could activate the p38 signaling pathway in C. elegans, thereby regulating antimicrobial peptides, and achieving antimicrobial effects. Meanwhile, high doses of CIEO and CID might directly participate in the internal antimicrobial processes of C. elegans. Our study provides research basis for the antibacterial properties of CIEO and CID both in vivo and in vitro.

Unveiling NUSAP1 as a common gene signature linking chronic HBV infection and HBV-related HCC.

BACKGROUND: Hepatitis B virus (HBV) is a significant contributor to the development of hepatocellular carcinoma (HCC). Chronic HBV infection (CHB) facilitates disease progression through various mechanisms. However, the specific factor responsible for the progression of HBV infection to HCC remains unresolved. This study aims to identify the hub gene linking CHB and HBV-related HCC through bioinformatic analysis and experimental verification. METHODS: Differentially expressed genes (DEGs) were identified in datasets encompassing CHB and HBV-HCC patients from the GEO database. Enriched pathways were derived from GO and KEGG analysis. Hub genes were screened by protein-protein interaction (PPI) analysis and different modules in Cytoscape software. The significance of the selected hub gene in prognosis was further assessed in validated datasets. The effects of hub genes on cell growth and apoptosis were further determined in functional experiments. RESULTS: The study revealed upregulation of NUSAP1 in CHBs and HBV-HCCs. High expression of NUSAP1 served as an independent predictor for poor prognosis of liver cancers. Functional experiments demonstrated that NUSAP1 promotes cell growth, influences cell cycle process, and protects cells from apoptosis in HepG2.2.15 cells. CONCLUSION: NUSAP1 serves as a poor prognostic indicator for liver cancers, and potentially plays a crucial role in HBV-HCC progression by promoting proliferation and inhibiting apoptosis.

Prediction of acute kidney injury after cardiac surgery with fibrinogen-to-albumin ratio: a prospective observational study.

Background: The occurrence of acute kidney injury (AKI) following cardiac surgery is common and linked to unfavorable consequences while identifying it in its early stages remains a challenge. The aim of this research was to examine whether the fibrinogen-to-albumin ratio (FAR), an innovative inflammation-related risk indicator, has the ability to predict the development of AKI in individuals after cardiac surgery. Methods: Patients who underwent cardiac surgery from February 2023 to March 2023 and were admitted to the Cardiac Surgery Intensive Care Unit of a tertiary teaching hospital were included in this prospective observational study. AKI was defined according to the KDIGO criteria. To assess the diagnostic value of the FAR in predicting AKI, calculations were performed for the area under the receiver operating characteristic curve (AUC), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results: Of the 260 enrolled patients, 85 developed AKI with an incidence of 32.7%. Based on the multivariate logistic analyses, FAR at admission [odds ratio (OR), 1.197; 95% confidence interval (CI), 1.064-1.347, p = 0.003] was an independent risk factor for AKI. The receiver operating characteristic (ROC) curve indicated that FAR on admission was a significant predictor of AKI [AUC, 0.685, 95% CI: 0.616-0.754]. Although the AUC-ROC of the prediction model was not substantially improved by adding FAR, continuous NRI and IDI were significantly improved. Conclusions: FAR is independently associated with the occurrence of AKI after cardiac surgery and can significantly improve AKI prediction over the clinical prediction model.

p53/E2F7 axis promotes temozolomide chemoresistance in glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer, and chemoresistance poses a significant challenge to the survival and prognosis of GBM. Although numerous regulatory mechanisms that contribute to chemoresistance have been identified, many questions remain unanswered. This study aims to identify the mechanism of temozolomide (TMZ) resistance in GBM. METHODS: Bioinformatics and antibody-based protein detection were used to examine the expression of E2F7 in gliomas and its correlation with prognosis. Additionally, IC50, cell viability, colony formation, apoptosis, doxorubicin (Dox) uptake, and intracranial transplantation were used to confirm the role of E2F7 in TMZ resistance, using our established TMZ-resistance (TMZ-R) model. Western blot and ChIP experiments provided confirmation of p53-driven regulation of E2F7. RESULTS: Elevated levels of E2F7 were detected in GBM tissue and were correlated with a poor prognosis for patients. E2F7 was found to be upregulated in TMZ-R tumors, and its high levels were linked to increased chemotherapy resistance by limiting drug uptake and decreasing DNA damage. The expression of E2F7 was also found to be regulated by the activation of p53. CONCLUSIONS: The high expression of E2F7, regulated by activated p53, confers chemoresistance to GBM cells by inhibiting drug uptake and DNA damage. These findings highlight the significant connection between sustained p53 activation and GBM chemoresistance, offering the potential for new strategies to overcome this resistance.

Barriers to retention in medications for opioid use disorder treatment in real-world practice.

BACKGROUND: Medications for Opioid Use Disorder (MOUD) are an effective method to treat persons with opioid use disorder (OUD). Longer treatment times are associated with better health outcomes, yet treatment retention rates remain low. This study aimed to assess patient characteristics and experiences associated with retention in treatment. METHODS: Data were from an observational cohort study of OUD treatments. Among persons receiving buprenorphine or methadone, log-binomial regression models assessed the relationship between patient characteristics and experiences and three retention outcomes: retention in any OUD treatment, retention in the index treatment (OUD treatment being administered at the time when patients were screened for study eligibility), and 6-month retention in the index treatment. RESULTS: Individuals being treated with methadone at the start of the study compared to those treated with buprenorphine were more likely to remain in their same index treatment at the 18-month follow-up (aPR = 1.35; 95 % CI = 1.11-1.65), and to have remained on their index treatment for 6-months or longer (aPR = 1.22; 95 % CI = 1.14-1.32), but were not significantly more likely to remain in any OUD treatment overall. Individuals residing five miles or less from treatment were more likely to have been retained in any OUD treatment (aPR = 1.06; 95 % CI = 1.00-1.12), to remain in their index treatment at the 18-month follow-up (aPR = 1.21; 95 % CI = 1.08-1.36), and to have remained in their index treatment for 6 months or more (aPR = 1.08; 95 % CI = 1.02-1.13). Individuals without health insurance were less likely to be retained in any OUD treatment (aPR = 0.86; 95 % CI = 0.78-0.95). CONCLUSION: The prevalence of retention in any OUD treatment was higher for individuals residing five miles or less from treatment. These findings expand on previous studies that have shown distance to and location of treatment sites can impact treatment access and retention. Lack of health insurance was also associated with lower retention in any OUD treatment in this study. Given the high burden associated with overdose deaths, it is important to understand and address barriers to retention in treatment.