Real-world safety profile of zanubrutinib: a disproportionality analysis based on the FAERS database.

OBJECTIVE: Zanubrutinib is a second-generation Bruton's tyrosine kinase inhibitor that has been approved for the treatment of several B cell malignancies. The aim of this study was to evaluate adverse events (AEs) associated with zanubrutinib based on the real-world data. DESIGN: A disproportionality analysis was performed to identify the potential zanubrutinib-related AEs. SETTING: The Food and Drug Administration AE Reporting System database from the fourth quarter of 2019 to the third quarter of 2023. MAIN OUTCOME MEASURES: The results of the disproportionality analyses were presented as reported ORs (RORs). When the lower limit of the 95% CI for the ROR is greater than 1 and the number of AE reports is≥3, it indicates that the preferred term (PT) may be a positive AE signal. RESULTS: A total of 846 AE reports with zanubrutinib as the primary suspect drug were obtained, with 2826 AEs. A total of 74 positive PT signals were detected across 18 system organ classes (SOCs). The most significant signal for SOC was 'blood and lymphatic system disorders' (ROR=2.8, 95% CI 2.3 to 3.3), while the most significant signal for PT was 'haemorrhage subcutaneous' (ROR=190.8, 95% CI 128.0 to 284.5). 13 unexpected off-label AEs were also observed, such as abnormal hair texture, skin discolouration, hypernatraemia, pericardial effusion and hypersomnia. The median time to onset of AEs associated with zanubrutinib was 51 days (IQR 13-192 days) and was consistent with the early failure model. In comparison with zanubrutinib monotherapy, the combination of zanubrutinib and rituximab therapy was linked to a higher risk of specific AEs, including myelosuppression, pneumonia, leucopenia, thrombocytopenia, abdominal pain, anaemia, pancytopenia and respiratory failure. Furthermore, the combination of zanubrutinib and chemotherapy increased the risk of several severe AEs, such as cardiac arrest, elevated blood lactate dehydrogenase levels and pancytopenia. CONCLUSIONS: The results of the analysis provided valuable insights into the safety profile of zanubrutinib-treated patients, which was helpful for clinical monitoring and identifying potential AEs related to zanubrutinib.

Reduced microRNA-744 expression in mast cell-derived exosomes triggers epithelial cell ferroptosis in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a critical disorder characterized by immune-related damage to epithelial cells; however, its underlying mechanism remains elusive. This study investigated the effects of alterations in microRNA (miRNA) expression in mast cell-derived exosomes on human bronchial epithelial (HBE) cells and ARDS development in cellular and mouse models challenged with lipopolysaccharide. Lipopolysaccharide-treated mast cell-derived exosomes reduced glutathione peroxidase 4 (GPX4) expression and increased long-chain acyl-CoA synthetase 4 (ACSL4), 15-lipoxygenase (ALOX15), and inflammatory mediator levels in HBE cells. miRNA sequencing revealed a reduction in mast cell-derived exosomal miR-744 levels, which was associated with the regulation of ACSL4, ALOX15, and GPX4 expression. This downregulation of exosomal miR-744 expression reduced miR-744 levels and promoted ferroptosis in HBE cells, whereas the experimental upregulation of miR-744 reversed these adverse effects. Down-regulation of miR-744 induced the expression of markers for ferroptosis and inflammation in HBE cells and promoted pulmonary ferroptosis, inflammation, and injury in LPS-stimulated mice. In vivo, treatment with ACSL4, ALOX15, and GPX4 inhibitors mitigated these effects, and experimental miR-744 expression rescued the lipopolysaccharide-induced changes in HBE cells and mouse lungs. Notably, miR-744 levels were reduced in the plasma and exosomes of patients with ARDS. We concluded that decreased mast cell-derived exosomal miR-744 levels trigger epithelial cell ferroptosis, promoting lung inflammation and damage in ARDS. This study provides new mechanistic insights into the development and sustained pulmonary damage associated with ARDS and highlights potential therapeutic strategies.

Minimum Local Anesthetic Dose of Ropivacaine in Cesarean Section for Real-Time Ultrasound-Guided Spinal Anesthesia Using 24-Gauge versus 26-Gauge Needles Based on Fluid Simulation Technology: A Randomized Controlled Trial.

Purpose: Previous research has demonstrated that real-time ultrasound-guided (UG) spinal anesthesia requires a higher minimum local anesthetic dose (MLAD) compared to traditional methods. However, the precise MLAD of ropivacaine for UG cesarean sections remains undetermined. In this study, we ascertained the MLAD of ropivacaine for cesarean section. We also investigated the mechanism underlying the diffusion of ropivacaine within the spinal canal using fluid simulation technology. Patients and Methods: We randomly placed 60 healthy parturients undergoing elective cesarean section with real-time UG spinal anesthesia into Groups I (26-gauge spinal needle) and II (24-gauge spinal needle). For the first parturient in both groups, 15 mg of ropivacaine was administered intrathecally. Based on the effective or ineffective response of the previous parturient, the dose for the subsequent parturient was increased or decreased by 1 mg. Spinal anesthesia characteristics and side effects were recorded. A computer-generated spinal canal model was developed. Leveraging fluid dynamics simulation technology, we documented the diffusion of ropivacaine in the spinal canal using 26-and 24-gauge spinal needles. Results: The MLADs in Groups I and II were 12.728 mg (12.339-13.130 mg) and 9.795 mg (9.491-10.110 mg), respectively. No significant difference was observed in the onset times and durations of sensory or motor blocks, incidence of complications, or neonatal Apgar scores between both groups. Fluid simulation modeling indicated that the 26-gauge spinal needle achieved a higher distribution level more quickly; however, its peak drug concentration was lower compared to the 24-gauge spinal needle. Conclusion: For cesarean section anesthetization, the required MLAD of ropivacaine when using a real-time UG 26-gauge spinal needle is significantly greater than that with a 24-gauge needle. The spinal needle diameter influences ropivacaine's MLAD by markedly affecting its diffusion rate within the spinal canal.

New training simulator for lumbar puncture base on magnetorheological.

In response to the difficulties in accurately reproducing the resistance drop generated by puncturing key tissue layers with a needle and the poor experience in existing simulators, based on the continuous controllability and rapid response of magnetorheological fluid under the influence of a magnetic field, this paper proposes a lumbar puncture training simulator(LPTS) that can accurately simulate the puncture feedback force within tissues such as the skin, subcutaneous fat, and supraspinous ligament throughout the entire process. By using a dual rod structure and reasonably arranging the damping channel gap, the influence of mechanical friction and zero-field damping force on the feedback force during tissue progression is minimized. This paper introduces the acquisition and modeling analysis of raw data, and based on this, the design, simulation, and mechanical testing of the simulator are carried out. Finally, a performance testing platform for the simulator is established to evaluate its tracking performance of the expected puncture strength and the reproducibility of the puncture sensation. The results show that the experimental puncture strength deviates from the expected puncture strength by 0.35 N to 0.61 N in the crucial steps of breaking through the supraspinous ligament, interspinous ligament, ligamentum flavum, and dura mater, with a relative error below 10 %.

Toward Model-Informed Precision Dosing for Remimazolam: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Remimazolam, widely used for procedural sedation and general anesthesia, is a new ultra short-acting benzodiazepine for intravenous sedation and anesthesia. We aim to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of remimazolam and its metabolite CNS 7054 in healthy Chinese volunteers using population analysis and suggest an optimal dosing regimen for sedation therapy. Data were collected from a single-center, placebo-controlled, randomized, and dose-escalation clinical pharmacology study. Forty-six healthy volunteers received a single infusion dose of remimazolam, while nine healthy subjects received a continuous infusion of remimazolam. A population PK/PD model was established and RxODE and Shiny in R were used to design the remimazolam dosing regimens. A three-compartment model best described the PK of remimazolam and a two-compartment model with one transit compartment was adopted for CNS 7054. The relationship between exposure and the bispectral index was best described using an effect compartment model with an inhibitory sigmoid model. Additionally, a web-based dashboard was developed to provide individualized dosing regimens, complemented by a graphical illustration of the PK/PD profiles of the proposed dosing regimen. The established population PK/PD model characterized the dose-exposure-response relationship of remimazolam well, which could be applied to optimize individual dosing regimens.

Drug-Induced Gynecomastia: Data Mining and Analysis of the FDA Adverse Event Reporting System Database.

Purpose: Drug-induced gynecomastia significantly affects patient health and quality of life. This study aimed to perform an exploratory analysis of gynecomastia reports and the most commonly associated medications within the FAERS database. Patients and Methods: A comprehensive analysis of the FAERS from January 2004 to December 2023 was conducted. Disproportionality analysis and subsequent sensitivity analysis were performed to identify drugs potentially associated with gynecomastia, utilizing the reported odds ratio (ROR). Logistic regression analysis was employed to assess potential risk factors. The Weibull shape parameter (WSP) test was used to assess the time-to-onset characteristics of the top drugs associated with gynecomastia. Results: The study identified 30,265 cases of gynecomastia, primarily associated with nervous system drugs, accounting for 85.50% of cases. Notably, risperidone accounted for 80.81% of the total cases. Among the 165 agents with ≥ 5 cases of gynecomastia, the strongest signals were exhibited by risperidone (ROR 602.38, 95% CI 585.07-620.20), dutasteride (ROR 17.18, 95% CI 15.55-18.89), spironolactone (ROR 15.8, 95% CI 13.99-17.83), and paliperidone (ROR 7.16, 95% CI 6.55-7.84). In the sensitivity analysis of disproportionality, unexpected associations were observed, such as montelukast (n = 21, ROR 1.94, 95% CI 1.26-2.98). The logistic regression analysis indicated that the risk of risperidone-induced gynecomastia was significantly lower in adults compared to pediatric patients (OR 0.12, 95% CI 0.09-0.15) and in patients with higher body weight than in those with lower body weight (OR 5.24, 95% CI 3.62-7.76). The WSP test showed that gynecomastia induced by most of the top 10 common agents tends to occur in an early failure mode. Conclusion: The rankings and signal strengths of drugs associated with gynecomastia were extracted from the FAERS. The age distribution and time-to-onset distribution of the top 10 drugs linked to gynecomastia were investigated, which can facilitate accurate clinical recognition of drug-induced gynecomastia.

cost-effectiveness of aumolertinib as first-line treatment for EGFR-mutated advanced nonsmall-cell lung cancer.

Aim: To evaluate the cost-effectiveness of aumolertinib as the epidermal growth factor receptor-mutated advanced nonsmall-cell lung cancer first-line treatment from the Chinese healthcare system perspective.Methods: A Markov model was developed based on the AENEAS trial. Only direct medical costs were considered in the model. Utilities were obtained from published literature. Sensitivity and scenario analyses were performed to explore the robustness of the model.Results: Compared with gefitinib, aumolertinib yielded an additional 0.941 expected life-years and 0.692 quality-adjusted life-years (QALYs), with an incremental cost of $18,855.55 over a 20-year time horizon. The incremental cost-effectiveness ratios were $20,051.67/life-year and $27,272.29/QALY, that below the willing-to-pay threshold of $38,223.34/QALY.Conclusion: Aumolertinib was a cost-effective alternative first-line treatment for patients with epidermal growth factor receptor-positive advanced nonsmall-cell lung cancer in China.

What is this article about? This study assesses the costs and health outcomes associated with aumolertinib therapy for Chinese patients diagnosed with advanced or metastatic nonsmall cell lung cancer (NSCLC). Aumolertinib therapy is a specific type of medication used to treat a certain type of lung cancer called nonsmall cell lung cancer. It is a newer treatment that targets certain genetic changes in the cancer cells.How was this done? The costs and treatment benefits were estimated using data from the AENEAS trial, provincial medical cost lists and previously published studies. A Markov model was developed to simulate disease progression. Provincial Medical Cost Lists are official lists maintained by different provincial governments in China that specify the drugs and their prices that are covered by the public healthcare system. A Markov Model is a mathematical tool used to predict how a disease might progress over time. It is like a simulation where the possible outcomes of the disease are analyzed, helping to understand the likely course of the disease and how different treatments might affect it.What were the results? The cost of treatment with aumolertinib for Chinese patients with advanced or metastatic NSCLC was considered to be acceptable based on the benefits it provides.What do the study results mean? The results suggest that aumolertinib is a cost-effective treatment for patients with advanced or metastatic NSCLC in China.

Targeting mast cell activation alleviates anti-MHC I antibody and LPS-induced TRALI in mice by pharmacologically blocking the TLR3 and MAPK pathway.

Transfusion-related lung injury (TRALI) poses a significant risk following blood transfusion and remains the primary cause of transfusion-related morbidity and mortality, primarily driven by the activation of immune cells through anti-major histocompatibility complex class I (anti-MHC I) antibody. However, it remains to be defined how immune microenvironmental cue contributes to TRALI. Here, we uncover that activated mast cells within the immune microenvironment promote lung inflammation and injury in antibody-mediated TRALI, both in vitro and in vivo. This was demonstrated by co-culturing lipopolysaccharide (LPS)-pretreated mast cell line with anti-MHC I antibody and establishing a "two-hit" TRALI mouse model through intratracheal injection of LPS followed by tail-vein injection of anti-MHC I antibody. Importantly, mast cell-deficient KitW-sh/W-sh mice exhibited markedly reduced lung inflammation and injury responses in antibody-mediated TRALI compared with wild-type mice. Mechanistically, activation of toll-like receptor 3 (TLR3)/mitogen-activated protein kinase (MAPK) signaling pathway in mast cells contributes to the enhanced production of proinflammatory factors. These excessive proinflammatory factors produced by activated mast cells contribute to lung inflammation and injury in antibody-mediated TRALI. Pharmacologically targeting the TLR3/MAPK pathway to inhibit mast cell activation normalizes the proinflammatory microenvironment and alleviates lung inflammation and injury in the preclinical TRALI mouse model. Overall, we find that activation of mast cells via the TLR3/MAPK pathway contributes to lung inflammation and injury in antibody-mediated TRALI, providing novel insights into its underlying mechanisms. Furthermore, targeting activated mast cells and the associated pathway offers potential therapeutic strategies for antibody-mediated TRALI.

Pulmonary adverse reaction caused by furazolidone: Two case reports and a literature review.

RATIONALE: As one of the drugs used to treat Helicobacter pylori, furazolidone has been reported to cause gastrointestinal reactions, allergies, dizziness, and more. However, its related drug-induced lung injury has been rarely reported. Furthermore, there have been no reports of the timing for initiating hormone therapy when a pulmonary adverse reaction occurs. PATIENT CONCERNS: We report 2 cases, both of them showed interlobular septal thickening and nodules on the chest computed tomography. One had more discomfort symptoms and had a higher eosinophil count than the normal range, while the other only had fever symptoms and had an eosinophil count within the normal range. DIAGNOSES: Pulmonary adverse reaction caused by furazolidone was diagnosed. INTERVENTIONS: Furazolidone was discontinued, and the person with increased eosinophils received hormone therapy, while the other person did not. OUTCOMES: After discontinuation of medication and treatment, the symptoms of the 2 patients gradually improved. LESSONS: This report suggests that furazolidone may cause pulmonary adverse reactions to raise clinical awareness, and for the first time indicates that hormone therapy is needed for patients whose eosinophils continue to increase after discontinuation.

Bioprinted, spatially defined breast tumor microenvironment models of intratumoral heterogeneity and drug resistance.

Cellular, extracellular matrix (ECM), and spatial heterogeneity of tumor microenvironments (TMEs) regulate disease progression and treatment efficacy. Developing in vitro models that recapitulate the TME promises to accelerate studies of tumor biology and identify new targets for therapy. Here, we used extrusion-based, multi-nozzle 3D bioprinting to spatially pattern triple-negative MDA-MB-231 breast cancer cells, endothelial cells (ECs), and human mammary cancer-associated fibroblasts (HMCAFs) with biomimetic ECM inks. Bioprinted models captured key features of the spatial architecture of human breast tumors, including varying-sized dense regions of cancer cells and surrounding microvessel-rich stroma. Angiogenesis and ECM stiffening occurred in the stromal area but not the cancer cell-rich (CCR) regions, mimicking pathological changes in patient samples. Transcriptomic analyses revealed upregulation of angiogenesis-related and ECM remodeling-related signatures in the stroma region and identified potential ligand-receptor (LR) mediators of these processes. Breast cancer cells in distinct parts of the bioprinted TME showed differing sensitivities to chemotherapy, highlighting environmentally mediated drug resistance. In summary, our 3D-bioprinted tumor model will act as a platform to discover integrated functions of the TME in cancer biology and therapy.

The addition of peripheral nerve blocks to routine spinal or general anesthesia was associated with decreased risks of major adverse events after total hip or knee arthroplasty: A retrospective, propensity score-matched cohort study.

Background: Although total joint arthroplasty is the most effective procedures for end-stage arthritis, the incidence of postoperative death and complications remains high. The association of additional peripheral nerve blocks (PNBs) to routine spinal or general anesthesia with major adverse events (including mortality and complication rates) in elective total hip arthroplasty (THA) or total knee arthroplasty (TKA) has been subject to inconclusive findings. Methods: This retrospective observational single institution study included all patients ≧ 18 years undergoing their first elective THA or TKA from January 1, 2012 to December 31, 2021. A 1:2 propensity score matching (PSM) was performed to account for the baseline differences between two groups that were accepted to PNB or not. Kaplan-Meier curves were employed to estimate the effects of PNB on mortality. The associations of PNB and the complications were assessed by logistic regression models. Results: We identified 1328 patients, among whom 197 had PNB and 1131 had not. The 90-day all-cause mortality was significantly reduced in patients with PNBs (0 % vs 2.79 %, P = 0.041) after THA or TKA, when compared to the non-PNB group. PNB was also associated with a lower risk of pulmonary complications (odds ratio [OR], 0.430; 95%confidence interval [CI],0.216-0.857) and deep vein thrombosis (OR, 0.103; 95%CI, 0.011-0.954). Interpretation: The results of this observational, propensity score-matched cohort study suggested a strong association between the addition of PNBs to routine spinal or general anesthesia and decreased risks of major adverse events.

Individualized music induces theta-gamma phase-amplitude coupling in patients with disorders of consciousness.

Objective: This study aimed to determine whether patients with disorders of consciousness (DoC) could experience neural entrainment to individualized music, which explored the cross-modal influences of music on patients with DoC through phase-amplitude coupling (PAC). Furthermore, the study assessed the efficacy of individualized music or preferred music (PM) versus relaxing music (RM) in impacting patient outcomes, and examined the role of cross-modal influences in determining these outcomes. Methods: Thirty-two patients with DoC [17 with vegetative state/unresponsive wakefulness syndrome (VS/UWS) and 15 with minimally conscious state (MCS)], alongside 16 healthy controls (HCs), were recruited for this study. Neural activities in the frontal-parietal network were recorded using scalp electroencephalography (EEG) during baseline (BL), RM and PM. Cerebral-acoustic coherence (CACoh) was explored to investigate participants' abilitiy to track music, meanwhile, the phase-amplitude coupling (PAC) was utilized to evaluate the cross-modal influences of music. Three months post-intervention, the outcomes of patients with DoC were followed up using the Coma Recovery Scale-Revised (CRS-R). Results: HCs and patients with MCS showed higher CACoh compared to VS/UWS patients within musical pulse frequency (p = 0.016, p = 0.045; p < 0.001, p = 0.048, for RM and PM, respectively, following Bonferroni correction). Only theta-gamma PAC demonstrated a significant interaction effect between groups and music conditions (F (2,44) = 2.685, p = 0.036). For HCs, the theta-gamma PAC in the frontal-parietal network was stronger in the PM condition compared to the RM (p = 0.016) and BL condition (p < 0.001). For patients with MCS, the theta-gamma PAC was stronger in the PM than in the BL (p = 0.040), while no difference was observed among the three music conditions in patients with VS/UWS. Additionally, we found that MCS patients who showed improved outcomes after 3 months exhibited evident neural responses to preferred music (p = 0.019). Furthermore, the ratio of theta-gamma coupling changes in PM relative to BL could predict clinical outcomes in MCS patients (r = 0.992, p < 0.001). Conclusion: Individualized music may serve as a potential therapeutic method for patients with DoC through cross-modal influences, which rely on enhanced theta-gamma PAC within the consciousness-related network.

Exploring the effect of part differences on metabolite molecule changes in refrigerated pork: Identifying key metabolite compounds and their conversion pathways.

Effect of part differences on metabolite molecule alterations in refrigerated pork was investigated. A metabolomics methodology combined with chemometric analysis was successfully established to identify key compounds and their conversion pathways, including precursors and volatile metabolites, in the Longissimus lumborum as well as the breast and flank stored for 11 days. In total, 12 discriminative precursors were identified using the Short Time-series Expression Miner. In tandem with Random Forest and ANOVA analyses, nine volatile metabolites were identified as key compounds that could be attributed to differences in pork sections. Bidirectional orthogonal partial least squares analysis revealed a potential correlation between these key metabolites and discriminative precursors. Metabolic pathway enrichment analysis demonstrated that the primary metabolic process affected by variations in pork sections is linoleic acid metabolism, which participates in the metabolism of cysteine and glutamic acid to produce methoxy-phenyl-oxime. This study provides valuable insights into the identification of differential metabolites.

In-depth metaproteomics analysis reveals the protein profile and metabolism characteristics in pork during refrigerated storage.

Alterations in microbiotas and endogenous enzymes have been implicated in meat deterioration. However, the factors that mediate the interactions between meat quality and microbiome profile were inadequately investigated. In this study, we collected pork samples throughout the refrigeration period and employed metaproteomics to characterize both the pork and microbial proteins. Our findings demonstrated that pork proteins associated with the catabolic process are upregulated during storage compared to the initial stage. Pseudomonas, Clostridium, Goodfellowiella, and Gonapodya contribute to the spoilage process. Notably, we observed an elevated abundance of microbial proteins related to glycolytic enzymes in refrigerated pork, identifying numerous proteins linked to biogenic amine production, thus highlighting their essential role in microbial decay. Further, we reveal that many of these microbial proteins from Pseudomonas are ribosomal proteins, promoting enzyme synthesis by enhancing transcription and translation. This study provides intrinsic insights into the underlying mechanisms by which microorganisms contribute to meat spoilage.