Search Results (112)

Background/Objectives: There is high demand for Anshenbunao syrup (ABS) in Chinese medicine owing to its steady therapeutic efficacy for insomnia and neurasthenia. However, it contains a substantial proportion of Polygoni Multiflori Radix Praeparata (PMRP), which is associated with reported cases of drug-induced liver injury (DILI). Here, we aim to establish an integrated approach combining PK screening with a dual-model toxicity verification system to systematically identify liver injury components (from high to low concentrations and from direct to idiosyncratic hepatotoxicity) to accurately uncover diverse potential hepatotoxicity markers. Methods: A sensitive UPLC-MS/MS method was used to accurately quantify the components in plasma at the ng/mL level and conduct a pharmacokinetic analysis. Rat models were used to evaluate exposure levels of the eight active constituents and three major metabolites after a single oral gavage dose of 10 mL/kg ABS and identify the quality markers. The early-stage and high-throughput assessment of direct and idiosyncratic hepatotoxicity was conducted in vitro utilizing HepG2 cells. After the administration of the quality markers (0.01–80 μM), CCK-8 was used to detect cell viability on both normal and susceptible cells, and the latter was induced by lipopolysaccharide. Results: As a result, seven quality markers were screened based on their contents and exposure levels in rat plasma by UPLC–MS/MS, including emodin (EM), liquiritin (LI), 2,3,5,4′–Tetrahydroxystilbene–2–O–β–D–glucoside (TSG), icariin, emodin–8–O–β–D–glucoside, baohuoside I (BA), and 18β–glycyrrhetinic acid (GTA). Moreover, the half maximal inhibitory concentration values of both normal cells and the lipopolysaccharide-induced immune stress liver injury cells were fitted within the concentration range of 0.01–80 μM, based on which, EM, BA, and GTA were identified as the principal hepatotoxic constituents in ABS at elevated concentrations. This study is the first to demonstrate that TSG, EM, LI, and GTA exhibit synergistic cytotoxicity in LPS-sensitized hepatocytes at clinically relevant concentrations, whereas EM was also a direct hepatotoxic component. Given that TSG is one of the major ingredients in ABS, the underappreciated idiosyncratic hepatotoxicity could elevate the risk of adverse clinical outcomes. Conclusions: In conclusion, this study effectively identifies hepatotoxic constituents in ABS and evaluates their hazards under immune stress and toxicity profiles in clinical concentrations, which also provides a robust foundation for the awareness of PMRP-induced DILI due to ABS. Full article

This paper investigates the relationship between institutional ownership and firm-level idiosyncratic volatility across European equity markets, with a particular focus on the moderating role of dividend policy. Using a sample of STOXX Europe 600 constituents from 2005 to 2025, we estimate idiosyncratic volatility via the Fama-French three-factor model and employ fixed-effects regressions with clustered standard errors. Our empirical results reveal a positive and statistically significant association between institutional ownership and idiosyncratic volatility, suggesting a destabilizing rather than stabilizing role in European markets. This volatility-enhancing effect is significantly more pronounced among dividend-paying firms and is primarily driven by transient institutional investors with high portfolio turnover. Furthermore, we find that: (1) larger firm size (market capitalization) and higher leverage (debt-to-capital ratio) are positively associated with heightened volatility; (2) growth-oriented firms (high market-to-book ratios) exhibit increased volatility, particularly among non-dividend payers; and (3) higher profitability (ROE) and favorable analyst coverage (buy recommendations) act as stabilizers, reducing idiosyncratic risk. These findings persist in both contemporaneous and lagged specifications. This study contributes to the literature by identifying dividend policy as a key channel through which institutional trading behavior amplifies firm-specific risk, providing novel evidence on the asset class effect within major European benchmark indices. Full article

Intravenous thrombolysis with recombinant tissue-type plasminogen activator (tPA) remains a keystone of acute ischemic stroke treatment but in a subset of patients is complicated by angioedema, a potentially life-threatening adverse event largely mediated by bradykinin signaling. The unpredictable and idiosyncratic nature of this reaction has long suggested an underlying genetic contribution, yet its molecular architecture has remained poorly characterized. We hypothesized that alteplase-associated angioedema represents a multigenic susceptibility phenotype, arising from the convergence of rare genetic variants across multiple interacting physiological systems rather than from a single causal variant. To explore this hypothesis, we performed clinical exome sequencing in a cohort of 11 patients who developed angioedema following alteplase administration. Rather than identifying a shared pathogenic variant, we observed distinct yet convergent patterns of genetic vulnerability, allowing patients to be grouped according to dominant, but overlapping, biological axes. These included alterations affecting bradykinin regulation (e.g., ACE, SERPING1, XPNPEP2), endothelial structure and hemostasis (e.g., VWF, COL4A1), neurovascular and calcium signaling (e.g., SCN10A, RYR1), and vascular repair or remodeling pathways (e.g., PSEN2, BRCA2). Notably, many of the identified variants were classified as Variant of Uncertain Significance (VUS) or likely benign significance in isolation. However, when considered within an integrated, pathway-based framework, these variants can be interpreted as capable of contributing cumulatively to system level fragility, a phenomenon best described as “contextual pathogenicity”. Under the acute biochemical and proteolytic stress imposed by thrombolysis, this reduced physiological reserve may allow otherwise compensated vulnerabilities to become clinically manifest. Together, these findings support a model in which severe alteplase-associated angioedema appears as an emergent property of interacting genetic networks, rather than a monogenic disorder. This systems level perspective underscores the limitations of gene centric interpretation for adverse drug reactions and highlights the potential value of pathway informed, multi-genic approaches to risk stratification. Such frameworks may ultimately contribute to safer, more personalized thrombolytic decision, while providing a conceptual foundation for future functional and translational studies. Full article

In this study, we evaluated the returns and return volatility of a Brazilian stablecoin linked to fertilizers during periods preceding its discontinuation. In light of the safe haven literature, we also tested the correlation between this stablecoin and a traditional cryptocurrency, Bitcoin, and modeled its behavior during periods of Bitcoin’s extreme returns. In terms of methodology, we employ GARCH-family models (including DCC-GARCH) to analyze daily data from 1 December 2022 to 16 January 2025. We also employ an analysis using Large Language Models (LLMs), evaluating the stablecoin time series considering the period of its discontinuation. The results indicated that as the discontinuation date approached, the stablecoin exhibited statistically significant lower returns and higher volatility. While the DCC-GARCH indicated no correlation between the assets, we found that the stablecoin’s returns exhibited a negative relationship with Bitcoin’s extreme returns, challenging its potential efficacy as a safe haven. This article offers practical contributions for digital asset investors, indicating that even physically backed stablecoins, designed for stability, are subject to significant volatility, idiosyncratic risks, and potential discontinuation. Full article

Drug-induced liver injury (DILI) remains one of the most challenging adverse drug reactions in clinical practice, particularly in its idiosyncratic form, which is not dose-dependent and is largely driven by host-specific immune and genetic factors. Recent genomic studies have revealed strong associations between certain human leukocyte antigen (HLA) alleles and susceptibility to DILI, supporting an immunogenetic mechanism in which drug or metabolite–protein adducts act as neoantigens, triggering aberrant T-cell activation and hepatocellular injury. This review summarizes current evidence on the contribution of HLA polymorphisms to the pathogenesis of idiosyncratic DILI, highlighting allele-specific risk patterns, such as HLA-B*57:01 associated with flucloxacillin, HLA-DRB1*15:01–DQB1*06:02 in amoxicillin–clavulanate, and HLA-B*35:02 in minocycline-induced liver injury. Furthermore, ethnic variability and allele-haplotype interactions are discussed as potential modulators of susceptibility and clinical phenotype. By integrating genetic and immunological insights, the identification of HLA signatures offers promising tools for precision medicine, enabling earlier identification of at-risk individuals and improved prevention of severe hepatotoxic reactions. Full article

Background: Azathioprine (AZA)-associated acute pancreatitis (AP) and gastrointestinal intolerance (GI-INT) are major causes of drug discontinuation in inflammatory bowel disease (IBD). This study compared HLA alleles, demographics, and clinical variables between AZA-AP and AZA-GI-INT. Methods: Data from five IBD centers included control (n = 88), AZA-AP (n = 44), and GI-INT (n = 44) groups. AP was defined by the Atlanta criteria, and GI-INT as acute dyspeptic symptoms related to AZA that resolved after withdrawal. Demographics, disease features, and HLA-DQA1/DRB1 alleles were assessed for associations. Results: Among 176 patients, female sex was more frequent in AZA-AP and GI-INT than controls (p = 0.018, p < 0.001). AZA-AP patients were older at diagnosis vs. controls (p = 0.016) but not vs. GI-INT (p = 0.15). Smoking and alcohol were more common in AZA-AP. The median onset of AP was four weeks, with 91% occurring within three months. GI-INT occurred rapidly, with a median of one day and a maximum of three days after the first dose. HLA-DQA1/DRB1 positivity was comparable in GI-INT and controls (9.2% vs. 14.8%, p = 0.42) but higher in AZA-AP (27.3% vs. 14.8%, p = 0.08). Regression identified female sex, smoking, alcohol, budesonide, and HLA-DQA1/DRB1 positivity (OR 3.01, 95% CI 1.004–9.058; p = 0.049) as independent risk factors for AZA-AP. Conclusions: AZA-AP, but not GI-INT, appears genetically influenced, with HLA-DQA1/DRB1 association extending across populations. In IBD, AZA-AP usually emerges within three months and is linked to female sex, smoking, alcohol, and budesonide. GI-INT typically develops within hours to three days of initiation. These findings support AZA-AP and GI-INT as distinct idiosyncratic entities shaped by genetic, metabolic, and sensitivity factors. Full article

The rapid integration of FinTech and sustainability-oriented sectors is reshaping financial risk dynamics, particularly in emerging markets such as China. This study investigates tail-dependent spillovers among ten Chinese FinTech and sustainability-linked sectors from 2015–2024 using a factor-purged Quantile Vector Autoregression (QVAR) with generalized forecast error variance decompositions. By isolating idiosyncratic shocks, the framework uncovers how risk creation, transmission, and absorption vary across market states. Results show that (i) FinTech acts as a net transmitter of shocks in adverse (lower-tail) states, amplifying downside risk to clean energy and green innovations; (ii) policy-intensive sectors (environmental and atmospheric governance) switch roles across quantiles, revealing asymmetric regulatory spillovers; and (iii) diversification benefits compress in the tails, with cross-sector linkages intensifying during crises. These findings highlight the importance of quantile-specific stress testing for regulators and the design of state-contingent hedging strategies for portfolio managers. Full article

Herb-induced liver injury (HILI) is an increasingly recognized cause of liver damage, associated with the widespread global use of herbal products. Despite its rising incidence, HILI remains underrecognized and underreported due to the absence of specific biomarkers, limited regulatory oversight, and the complexity of multi-ingredient formulations. Diagnostic efforts rely heavily on the Roussel Uclaf Causality Assessment Method (RUCAM), with clinical presentations often nonspecific and dominated by hepatocellular patterns of injury. Epidemiological data demonstrate regional variation, with notably higher case numbers in Asia and the Americas. Mechanistically, HILI may result from either intrinsic (predictable, dose-dependent) or idiosyncratic (unpredictable, immune-mediated) reactions. Genetic predispositions, including certain HLA alleles, have been identified as risk factors. Hepatotoxicity is often linked to specific phytochemicals such as pyrrolizidine alkaloids, catechins, anthraquinones, and diterpenoids, which may contribute to oxidative stress, mitochondrial damage, or immune activation. Additionally, product inconsistencies and contamination complicate risk assessment and safety evaluation. Current management focuses on immediate discontinuation of the suspected product and supportive care, though severe cases may require liver transplantation. Future directions include the development of specific diagnostic tools, implementation of globally harmonized regulatory standards, improved pharmacovigilance systems, and enhanced public and professional education. Addressing these priorities is crucial for reducing HILI-related morbidity while supporting the safe use of herbal therapies. Full article

Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in HER2-positive and HER2-low breast cancer. Its main safety concern is interstitial lung disease, while clinically relevant hepatotoxicity is rarely reported. In our case report we describe a 49-year-old woman with HER2-positive advanced breast cancer that developed persistent grade 3 transaminase elevations after 2 cycles of T-DXd, refractory to corticosteroid treatment and requiring treatment discontinuation. This case underlines the unpredictable and idiosyncratic nature of T-DXd associated hepatotoxicity and the importance of liver function monitoring. Clinicians should consider DILI in patients with unexplained liver enzyme elevations during therapy. Further studies are needed to clarify mechanisms and risk factors. Full article

The real estate industry, known for its complexity and exposure to systemic and idiosyncratic risks, requires increasingly sophisticated investment risk assessment tools. In this study, we present the Real Estate Construction Investment Risk (RECIR) model, a machine learning-based framework designed to quantify and manage multi-dimensional investment risks in construction projects. The model integrates diverse data sources, including macroeconomic indicators, property characteristics, market dynamics, and regulatory variables, to generate a composite risk metric called the total risk score. Unlike previous artificial intelligence (AI)-based approaches that primarily focus on forecasting prices, we incorporate regulatory compliance, forensic risk assessment, and explainable AI to provide a transparent and accountable decision support system. We train and validate the RECIR model using structured datasets such as the American Housing Survey and World Development Indicators, along with survey data from domain experts. The empirical results show the relatively high predictive accuracy of the RECIR model, particularly in highly volatile environments. Location score, legal context, and economic indicators are the dominant contributors to investment risk, which affirms the interpretability and strategic relevance of the model. By integrating AI with ethical oversight, we provide a scalable, governance-aware methodology for analyzing risks in the real estate sector. Full article

During the past two decades, researchers and professionals have increasingly explored the financial and macroeconomic implications of sustainable business practices, particularly through the lens of environmental, social, and governance (ESG) metrics. This review synthesizes evidence from financial economics and sectoral labor analysis to assess the impact of ESG performance and green employment on corporate financial performance (CFP) and broader economic growth. Using a discounted cash-flow framework and sectoral panel data from European economies (2008–2023), the findings reveal that robust ESG practices improve operating profits, reduce financial risk and support higher dividend distributions, while green jobs contribute significantly to Gross Value Added (GVA) and Gross Domestic Product (GDP), with each additional green job adding approximately EUR 101.920 to GVA and EUR 135.000 to GDP, in annual terms. Sectoral impacts are especially pronounced in construction, energy, and financial services, with annual contributions ranging from EUR 10.4 to EUR 11.1 million in GVA and EUR 13.7 to EUR 14.8 million in GDP. These results underscore the dual role of ESG as a financial indicator and strategic sustainability tool, advancing key United Nations Sustainable Development Goals (SDGs), including SDG 8 (Decent Work and Economic Growth), SDG 12 (Responsible Consumption and Production), SDG 13 (Climate Action), and SDG 17 (Partnerships for the Goals). The integration of green employment metrics into national productivity frameworks and corporate ESG strategies offers practical guidance to policymakers, investors, and cross-sector partners committed to sustainable development. Full article

This paper studies the joint distribution of the default and prepayment losses for a large portfolio of loans, based on a bottom-up approach. The repayment behaviors of loans in the portfolio are determined by both systematic and idiosyncratic risk factors and are conditionally independent given the systematic factors. The joint two-dimensional limit distributions of the portfolio default and prepayment losses are obtained, including the strong law of large numbers and the central limit theorem. A numerical study for the portfolio losses is performed for some simplified models. Finally, we conduct the empirical analysis on the residential mortgage-backed security (RMBS) based on Freddie Mac’s dataset. The empirical results reveal the impacts of different factors on the default and prepayment behaviors, and the distributions of the portfolio losses are simulated based on empirical estimation results to show its difference with the log-normal distributions. Full article

Background and Aims: Ornidazole, a nitroimidazole antibiotic, is widely used for protozoal and anaerobic infections and is generally considered safe. However, ornidazole-induced liver injury (OILI) is an underrecognized yet potentially severe adverse reaction. This multicenter study aims to characterize the clinical features, histopathology, and outcomes of OILI to improve the awareness and management of this rare entity worldwide. Methods: We conducted a retrospective analysis of 101 patients with OILI from eight tertiary centers between 2006 and 2023. Cases were included based on liver enzyme elevations temporally linked to ornidazole and the exclusion of other causes. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) score. Clinical data, laboratory parameters, autoantibody profiles, histology, treatments, and outcomes were evaluated. Results: OILI was classified as highly probable in 42.6% of cases (n = 43), probable in 51.5% of cases (n = 52), and possible in 5.9% (n = 6) of cases. The predominant pattern was acute hepatocellular injury (83.2%) (n = 84). Autoimmune-like hepatitis occurred in 5% of cases (n = 5), with ANA positivity in 16.8% of cases (n = 17). Corticosteroids were used in 24.8% of cases (n = 25) and were associated with higher ANA positivity and a 20% (n = 5) relapse rate post-discontinuation. Recovery was achieved in 87.7% of cases (n = 88), while 7.9% of cases (n = 8) required liver transplantation and 4% (n = 4) died. Conclusions: Ornidazole can cause serious idiosyncratic liver injury, including autoimmune phenotypes, and should be considered in the differential diagnosis of acute hepatitis. Given the notable risk of liver failure and death, early recognition, drug discontinuation, and close monitoring are essential. In select cases, corticosteroids and plasmapheresis may be beneficial, though the evidence remains limited. Full article

The link between ESG and financial performance is still under debate. In this study, we explore which aspects of ESG specifically drive market valuations through both systematic and idiosyncratic risk channels. We analyze the impact of the three core ESG pillars, 10 subcategories, and associated controversies on market valuations in the energy sector. This analysis reveals that the environmental factor has a stronger impact (regression coefficient = 0.05) than the governance factor (regression coefficient = 0.003), emphasizing the need to prioritize environmental performance in ESG strategies. The positive coefficients for environmental resource use (0.005) and innovation (0.008) indicate that investments in efficiency and clean technologies are beneficial, while the negative coefficient for emissions (−0.004) underscores the risks associated with poor emissions management. These findings suggest that environmental risks currently outweigh governance risks for the energy sector, reinforcing the importance of aligning governance practices with environmental goals. To maximize ESG effectiveness, energy firms should focus on measurable improvements in resource efficiency, innovation, and emissions reduction and transparently communicate this progress to stakeholders. The evidence suggests that energy firms approach the ESG landscape differently, with sustainability leaders benefiting from higher valuations, particularly when ESG efforts are aligned with core competencies. However, many energy companies under-invest in value-creating environmental initiatives, focusing instead on emission management, which erodes value. While they excel in emission control, they lag in innovation, missing opportunities to enhance valuations. This underscores the potential for ESG risk analysis to improve portfolio performance, as sustainability can both create value and mitigate risks by factoring into valuation equations as both risks and opportunities. This study uniquely contributes to the ESG–financial performance literature by disentangling the specific ESG dimensions that drive market valuations in the energy sector, revealing that value is created not through emission control but through strategic alignment with eco-innovation, governance, and social responsibility. Full article

Background: Cephalosporins are considered safe antibiotics. However, serious hematological abnormalities may occur, although rarely, after their therapeutic use. Case Presentation: We present a case of pancytopenia in a 72-year-old female patient treated with ceftriaxone for a urinary tract infection. After five days of therapy, pancytopenia was observed. Other causes were excluded through extensive diagnostic evaluation, including immunological tests, viral serologies, bone marrow aspiration, and peripheral blood smear. The patient’s clinical condition significantly improved following the discontinuation of ceftriaxone and the administration of granulocyte colony-stimulating factor (G-CSF). Bone marrow findings revealed hypocellularity without malignant infiltration, and peripheral smear showed no dysplasia, blasts, or hemolysis. Conclusions: This case demonstrates that ceftriaxone, although widely regarded as a safe antibiotic, can induce rare but serious hematologic complications such as pancytopenia. A high index of suspicion is required when patients on antibiotic therapy develop unexplained cytopenias. Detailed medication history, exclusion of other causes, and prompt discontinuation of the suspected drug are essential. The patient’s favorable outcome supports the likelihood of an idiosyncratic, immune-mediated mechanism. Future research should explore pharmacogenomic screening in patients at increased risk, particularly involving HLA variants. Full article