Search Results (8)

Introduction: Patients with malignant glioma are inherently at high risk of venous thromboembolism (VTE) and bleeding, and systemic therapy may further modify this vascular risk. This study used large spontaneous reporting databases to compare VTE, central nervous system (CNS) bleeding and gastrointestinal (GI) bleeding signals associated with four representative systemic therapies for glioma—temozolomide, bevacizumab and the nitrosourea alkylating agents lomustine and carmustine—and explore bevacizumab-based combination regimens. Methods: We conducted a retrospective pharmacovigilance study using the FAERS and the CVARD, identifying reports of patients with gliomas exposed to temozolomide, bevacizumab, lomustine or carmustine. VTE, CNS bleeding and GI bleeding were defined a priori, and disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals (CIs); a positive signal was defined as a ≥ 3 and a 95% CI lower bound > 1. In bevacizumab-exposed patients, we compared bevacizumab monotherapy with bevacizumab + temozolomide and bevacizumab + lomustine treatments and performed sensitivity analyses on a stricter glioma cohort. Results: Bevacizumab was the only drug that consistently showed positive signals for VTE and GI bleeding, whereas temozolomide showed no clear VTE signal, and nitrosourea agents yielded only sparse, unstable increases. Bevacizumab + temozolomide regimens had higher RORs for VTE and GI bleeding than bevacizumab alone, while bevacizumab + lomustine showed only modest VTE increases and no robust bleeding signals. Conclusions: In real-world pharmacovigilance data, bevacizumab-containing therapy, particularly when combined with temozolomide, carries the greatest disproportionate burden of VTE and GI bleeding among common systemic treatments for malignant glioma, whereas temozolomide alone appears largely neutral, and current evidence supporting nitrosourea-related signals remains inconclusive. Full article

This paper investigates the use of reinforcement learning (RL) algorithms to learn adaptive hedging strategies for derivatives under realistic market conditions, incorporating permanent market impact, execution slippage, and transaction costs. Market frictions arising from trading have been explored in the optimal trade execution literature; however, their influence on derivative hedging strategies remains comparatively understudied within RL contexts. Traditional hedging methods have typically assumed frictionless markets with only transaction costs. We illustrate that the dynamic decision problem posed by hedging with frictions can be modelled effectively with RL, demonstrating efficacy across various market frictions to minimize hedging losses. The results include a comparative analysis of the performance of three RL models across simulated price paths, demonstrating their varying effectiveness and adaptability in these friction-intensive environments. We find that RL agents, specifically TD3 and SAC, can outperform traditional delta hedging strategies in both simplistic and complex, illiquid environments highlighted by 2/3rd reductions in expected hedging losses and over 50% reductions in 5th percentile conditional value at risk (CVaR). These findings demonstrate that DRL agents can serve as a valuable risk management tool for financial institutions, especially given their adaptability to different market conditions and securities. Full article

A model is proposed to investigate the effects of power generation source diversification and CO₂ emission control in the presence of dispatchable fossil fuel sources and non-dispatchable carbon-free renewables. In a stochastic environment in which three random factors are considered, namely fossil fuels (gas and coal) and CO₂ prices, we discuss a planning methodology for power system portfolio selection that integrates the non-dispatchable renewables available in a given energy system and optimally combines cost, risk and CO₂ emissions. By combining the deep neural network probabilistic forecasting of fossil fuel path prices with a geometric Brownian motion model for describing the CO₂ price dynamics, we simulate a wide range of plausible market scenarios. Results show that under CO₂ price volatility, optimal portfolios shift toward cleaner energy sources, even in the absence of explicit emission targets, highlighting the implicit regulatory power of volatility. The results suggest that incorporating CO₂ price volatility through market mechanisms can serve as an effective policy tool for driving decarbonization. Our model offers a flexible and reproducible approach to support policy design in energy planning under uncertainty. Full article

Coxsackievirus-A6 (CV-A6) is responsible for more severe dermatological manifestations compared to other enteroviruses such as CV-A10, CV-A16, and EV-A71, causing HFMD in children and adults. Between 2005 and 2007, the recombinant subclade D3/RF-A started to expand globally, and a CV-A6 pandemic started. The study aimed to conduct whole-genome sequencing (WGS) of an isolated CV-A6 strain from currently circulating HFMD cases from India in 2022. Gene-specific RT-PCR and sequencing were used to perform molecular characterization of the isolated virus. Confirmation of these isolates was also performed by transmission electron microscopy and WGS. Among eleven positive clinical enterovirus specimens, eight CV-A6 strains were successfully isolated in the RD cell line. Isolates confirmed the presence of the CV-A6 strain based on VP1 and VP2 gene-specific RT-PCR. Sequences of isolates were clustered and identified as the novel CV-A6 strain of the D3/Y sub-genotype in India. The studies revealed that the D3/Y sub-genotype is being introduced into Indian circulation. The predicted putative functional loops found in VP1 of CV-A6 showed that the nucleotide sequences of the amino acid were a remarkably conserved loop prediction compatible with neutralizing linear epitopes. Therefore, this strain represents a potential candidate for vaccine development and antiviral studies. Full article

Coxsackievirus A10 (CV-A10) is a prevailing causative agent of hand–foot–mouth disease, necessitating the isolation and adaptation of appropriate strains in cells allowed for human vaccine development. In this study, amino acid sequences of CV-A10 strains with different cell tropism on RD and Vero cells were compared. Various amino acids on the structural and non-structural proteins related to cell tropism were identified. The reverse genetic systems of several CV-A10 strains with RD⁺/Vero⁻ and RD⁺/Vero⁺ cell tropism were developed, and a set of CV-A10 recombinants were produced. The binding, entry, uncoating, and proliferation steps in the life cycle of these viruses were evaluated. P1 replacement of CV-A10 strains with different cell tropism revealed the pivotal role of the structural proteins in cell tropism. Further, seven amino acid substitutions in VP2 and VP1 were introduced to further investigate their roles played in cell tropism. These mutations cooperated in the growth of CV-A10 in Vero cells. Particularly, the valine to isoleucine mutation at the position VP1-236 (V1236I) was found to significantly restrict viral uncoating in Vero cells. Co-immunoprecipitation assays showed that the release of viral RNA from the KREMEN1 receptor-binding virions was restricted in r0195-V1236I compared with the parental strain r0195 (a RD⁺/Vero⁺ strain). Overall, this study highlights the dominant effect of structural proteins in CV-A10 adaption in Vero cells and the importance of V1236 in viral uncoating, providing a foundation for the mechanism study of CV-A10 cell tropism, and facilitating the development of vaccine candidates. Full article

Coxsackievirus (CV)-A6 infections cause hand, foot, and mouth disease (HFMD) in children and adults. Despite the serious public health threat presented by CV-A6 infections, our understanding of the mechanisms by which new CV-A6 strains emerge remains limited. This study investigated the molecular epidemiological trends, evolutionary dynamics, and recombination characteristics of CV-A6-associated HFMD in Thailand between 2019 and 2022. In the HFMD patient samples collected during the 4-year study period, we identified enterovirus (EV) RNA in 368 samples (48.7%), of which CV-A6 (23.7%) was the predominant genotype, followed by CV-A4 (6%), EV-A71 (3.7%), and CV-A16 (3.4%). According to the partial viral protein (VP) 1 sequences, all these CV-A6 strains belonged to the D3 clade. Based on the viral-RNA-dependent RNA polymerase (RdRp) gene, four recombinant forms (RFs), RF-A (147, 84.5%), RF-N (11, 6.3%), RF-H (1, 0.6%), and newly RF-Y (15, 8.6%), were identified throughout the study period. Results from the similarity plot and bootscan analyses revealed that the 3D polymerase (3Dpol) region of the D3/RF-Y subclade consists of sequences highly similar to CV-A10. We envisage that the epidemiological and evolutionarily insights presented in this manuscript will contribute to the development of vaccines to prevent the spread of CV-A6 infection. Full article

Coxsackieviruses, a genus of enteroviruses in the small RNA virus family, cause fatal infectious diseases in humans. Thus far, there are no approved drugs to prevent these diseases. Human milk contains various biologically active components against pathogens. Currently, the potential activity of breast milk components against the coxsackievirus remains unclear. In our study, the inhibitory effect of 16 major human milk components was tested on coxsackievirus class A type 9 isolate (CV-A9), BUCT01; 2’-Fucosyllactose (2’-FL) was identified to be effective. Time-of-addition, attachment internalisation assays, and the addition of 2’-FL at different time points were applied to investigate its specific role in the viral life cycle. Molecular docking was used to predict 2’-FL’s specific cellular targets. The initial screening revealed a significant inhibitory effect (99.97%) against CV-A9 with 10 mg/mL 2’-FL, with no cytotoxicity observed. Compared with the control group, 2’-FL blocked virus entry (85%) as well as inhibited viral attachment (48.4%) and internalisation (51.3%), minimising its infection in rhabdomyosarcoma (RD) cells. The cell pre-incubation with 2’-FL exhibited significant inhibition (73.2–99.9%). Extended incubation between cells with 2’-FL reduced CV-A9 infection (93.9%), suggesting that 2’-FL predominantly targets cells to block infection. Molecular docking results revealed that 2’-FL interacted with the attachment receptor α_vβ₆ and the internalisation receptor FCGRT and β₂M with an affinity of −2.14, −1.87, and −5.43 kcal/mol, respectively. This study lays the foundation for using 2’-FL as a food additive against CV-A9 infections. Full article

Human enteroviruses and human parechoviruses are associated with a broad range of diseases and even severe and fatal conditions. For human cosaviruses, the etiological role is yet unknown. Little is known about the circulation of non-polio enteroviruses, human parechoviruses, and human cosaviruses in Nigeria. A total of 113 stool samples were collected from healthy individuals in Osun State between February 2016 and May 2017. RT-PCR assays targeting the 5′ non-coding region (5′ -NCR) were used to screen for human enteroviruses, human parechoviruses, and human cosaviruses. For human enteroviruses, species-specific RT-PCR assays targeting the VP1 regions were used for molecular typing. Inoculation was carried out on RD-A, CaCo-2, HEp-2C, and L20B cell lines to compare molecular and virological assays. Ten samples tested positive for enterovirus RNA with 11 strains detected, including CV-A13 (n = 3), E-18 (n = 2), CV-A20 (n = 1), CV-A24 (n = 1), EV-C99 (n = 1), and EV-C116 (n = 2). Three samples tested positive for human parechovirus RNA, and full genome sequencing on two samples allowed assignment to a new Parechovirus A type (HPeV-19). Thirty-three samples tested positive for cosavirus with assignment to species Cosavirus D and Cosavirus A based on the 5′-NCR region. Screening of stool samples collected from healthy individuals in Nigeria in 2016 and 2017 revealed a high diversity of circulating human enteroviruses, human parechoviruses, and human cosaviruses. Molecular assays for genotyping showed substantial benefits compared with those of cell-culture assays. Full article