Belumosudil was approved by the Food and Drug Administration in the United States for the treatment of relapsed/refractory chronic graft-versus-host disease (cGVHD) based on a randomized phase 2 trial comparing 2 belumosudil doses. The efficacy and safety of belumosudil vs the best available therapy (BAT) has not been studied. Applying rigorous statistical methodology to real-world data, this study estimated the efficacy of belumosudil vs BAT in cGVHD patients whose disease failed to respond to 2 to 5 prior lines of therapy (LOTs). Retrospective data between March 2015 and 2024 were collected across 8 US sites for 196 patients, contributing 113 belumosudil and 245 BAT LOTs. The primary outcome was 6-month overall response rate (ORR), defined as the proportion of complete or partial responses based on 2014 National Institutes of Health consensus criteria, physician assessment, or corticosteroid dose taper of ≥50% without cGVHD progression. Death, relapse, and beginning a new LOT were considered a lack of response. Targeted maximum likelihood estimation (TMLE) was used to estimate the 6-month ORR following belumosudil vs BAT (38.7% vs 26.8%, respectively) or 44.2% improvement with belumosudil (1-sided 95% confidence interval [CI], [4.4 to ∞]; P = .031). TMLE was also used to estimate 1-year failure-free survival when treated with belumosudil (61.2%) or BAT (47.8%), a 13.5% difference (95% CI, 1.5-100; P = .032). Descriptive assessment of safety showed adverse events recorded in 27% of belumosudil and 36% of BAT LOTs. Findings demonstrated that belumosudil improved clinical outcomes compared to BAT in cGVHD patients with 2 to 5 prior LOTs, and safety was consistent with belumosudil's established profile.

ABSTRACT Reductive cross‐couplings have emerged as a powerful strategy for forging C–C bonds directly from electrophiles, circumventing the need for preformed organometallic reagents, yet they often suffer from limitations associated with heterogeneous reductants like Zn (e.g., poor reproducibility and scalability) or costly homogeneous alternatives such as TDAE. Inspired by prior explorations of hydrazide chemistry, we disclose arylhydrazines as inexpensive, readily available homogeneous sacrificial reductants that enable Ni‐catalyzed sp 2 ‐sp 3 cross‐coupling of aryl halides with secondary alkyl iodides under mild, operationally simple conditions using a Ni II precursor, bipyridine ligand, and hindered amine base. Optimization, substrate scope studies, and direct comparisons reveal superior yields and selectivity relative to Zn‐based methods, particularly for heterocyclic and electron‐rich partners, while calorimetry‐guided safety assessments and decagram‐scale demonstrations highlight enhanced thermal control, reproducibility, and practicality. Mechanistic investigations via UV–vis spectroscopy, 19 F NMR, and reaction calorimetry support a pathway involving hydrazine‐mediated Ni II reduction to initiate a Ni I /Ni III cycle, with benign byproducts (N 2 and arene), positioning arylhydrazines as versatile reagents for executing reductive coupling on scale.

Maritime safety is a key element of sustainable maritime transportation, particularly in strait regions with dense vessel traffic and dynamic environmental conditions that increase collision risk. Based on historical records, ship collisions can result in severe human casualties, environmental pollution, cargo and infrastructure damage, operational disruptions, and substantial economic losses; therefore, a reliable and integrated safety assessment is essential to support safe, efficient, and sustainable maritime transportation. This study proposes a novel safety index framework to assess the ship’s collision risk by integrating vessel characteristics, ship encounter conditions, operational time parameters, and oceanographic factors such as currents and waves. The analysis is based on questionnaire data, AIS records, and oceanographic information collected over a one-month period with a three-minute temporal resolution. Case studies are conducted in the Bali Strait and the Lombok Strait using grid-based spatial segmentation to represent spatial risk patterns. Two safety index models are developed. Model I emphasizes vessel, encounter, and temporal factors, while Model II extends the assessment by fully integrating oceanographic conditions. To improve interpretability and practical applicability, the calculated safety index is further transformed into a normalized safety index with values bounded between 0 and 1, allowing for explicit risk classification. A multivariate contribution analysis is applied to identify dominant risk factors. The results show that the maritime risk in both straits is mainly influenced by vessel traffic intensity, sailing hours, days of the week, and environmental conditions. High-risk zones in the Bali Strait are concentrated near Ketapang and Gilimanuk Ports, while elevated risks in the Lombok Strait are observed near Padangbai and Lembar Ports and along the ALKI II shipping route.

Earth–rock dams provide cost-effective flood control and water storage through the utilization of locally available materials, making them essential infrastructure for regional safety, agricultural development, and sustainability. Electrical resistivity methods offer an efficient, non-destructive means to detect internal defects and potential hazards within dam bodies, thereby supporting dam safety assessment and service life extension. In this review, we focus on sand and clay, the most commonly used materials in earth–rock dams. We summarize the main methods and instruments for measuring soil resistivity and comparatively analyze the applicability and limitations of different approaches. Emphasis is placed on the key factors influencing soil resistivity, and recent progress in modeling the resistivity of soil materials is reviewed. The results show that soil resistivity parameters can effectively characterize physical and mechanical properties, structural features, and moisture migration behavior, providing an important basis for soil property evaluation. However, current studies are largely based on macroscopic experiments, with limited investigation of microscopic mechanisms and a lack of unified testing standards, leading to discrepancies between theoretical models and measured data. In this review, we aim to provide a theoretical reference for research and engineering applications of resistivity characteristics in earth–rock dam materials.

This study experimentally investigates the residual axial compression behavior of circular glass fiber-reinforced polymer (GFRP) tube-confined concrete short columns (CFGFT) after exposure to elevated temperatures. A total of 27 specimens were fabricated and tested under axial compression, with key parameters including GFRP tube wall thickness (5, 8, and 10 mm), exposure temperature (100, 150, 200, and 300 °C), and constant temperature duration (60 and 120 min). The results show that the load–displacement responses of CFGFT short columns after elevated temperature exposure exhibit distinct two-stage characteristics, culminating in brittle failure at the ultimate axial capacity. Wall thickness significantly influences the failure modes of the specimens, while elevated temperatures increase the occurrence of unfavorable failure modes. Temperature is identified as the primary factor governing the degradation of residual axial capacity and initial stiffness, with performance deterioration becoming more pronounced at temperatures exceeding 200 °C. In contrast, the effect of constant temperature duration within the range of 60–120 min is relatively limited. Based on the experimental results, a simplified binary quadratic regression model incorporating the coupled effects of temperature and wall thickness is proposed to predict the post-fire axial capacity reduction factor (Kr), with a coefficient of determination (R2) of 0.901. These findings provide experimental evidence and a practical predictive approach for the fire-resistant design and post-fire safety assessment of CFGFT members.

This study assesses the quality and safety of recycled plastic products from eight recycling industries in Kano, Nigeria. This study focuses on eight recycling companies in Kano: Danta Plastic Tudun Murtala, Camel Recycle, Solid Chemical Resources Ltd., I.Y. Factory, Dan-Barazana Recycling, Gidan Bello Recycling, A.I. Duma Global, and Dawakin Dakata Recycling Company. These industries operate within informal and semi-formal frameworks, Mechanical and chemical analyses were conducted on 160 samples, including buckets, chairs, pipes, and basins. Results revealed tensile strength reductions ranging from 15–30% compared to virgin plastics, with contamination levels averaging 7–10%. Companies such as Dawakin Dakata and I.Y. Factory demonstrated relatively lower contamination and smaller strength reductions, while A.I. Duma Global and Solid Chemical Resources exhibited higher contamination and greater mechanical losses. The findings highlight a clear correlation between contamination levels and tensile strength reduction, underscoring the importance of feedstock quality control. Recommendations include standardized testing protocols, shared laboratory facilities, and improved sorting and washing practices to enhance product safety and reliability in Kano’s recycling sector.

This study proposes a modelling framework for simulating cyclist–vehicle interactions at urban intersections characterised by geometric constraints and variable visibility conditions. A Digital Model (DM) of the intersection geometry was developed in SUMO, complemented by a custom behavioural model calibrated using experimental trajectory data to capture cyclists’ and drivers’ perception–reaction and braking behaviour. These two components were combined to simulate scenarios with varying visibility conditions and perception-triggered braking responses in severe conflict situations. Results show that reduced visibility significantly reduces temporal safety margins, with over 50% of all simulated interactions yielding differential time-to-arrival (TTA2) values below 2 s. Furthermore, obstructed conditions lead to higher- and more-dispersed relative crossing speeds (DV), typically increasing by 0.5–1.0 m/s compared to unobstructed conditions. Simulation data confirmed that clear visibility promotes anticipatory and adaptive user behaviour, whereas limited sightlines reduce braking availability and increase the likelihood and severity of conflicts, with distributions conditioned by the intersection’s geometry. The ability to generate detailed synthetic datasets of cyclist–vehicle interactions, often not obtainable through field observation, demonstrates the potential of the proposed framework for safety assessment. This approach supports the evaluation of mitigation strategies, including C-ITS-based solutions, and provides a basis for developing predictive AI models to enhance the safety of vulnerable road users.

Chronic kidney disease is a global health issue, and novel therapeutic alternatives to dialysis and kidney transplantation must be developed. Human-induced pluripotent stem cell-derived kidney organoids recapitulate developmental processes and mimic kidney-like structures in vitro and have thus attracted attention for treating chronic kidney disease. However, the limited vascularization and immaturity of human-induced pluripotent stem cell-derived kidney organoids remain major barriers to their clinical application. The latest technological advances and specific challenges in kidney organoid vascularization and maturation were thoroughly examined in this review. Diverse approaches were considered, including coculturing with endothelial cells, in vivo transplantation, applying biomaterials and microfluidic systems, controlling molecular signaling, and metabolic reprogramming. However, issues persist such as low reproducibility, lack of standardization, insufficient functional evaluations, and inadequate safety assessments. Future studies should focus on developing multifactorial and strategies for integrating multiple cell types, establishing maturation assessment criteria, and verifying the long-term functionality and safety of three-dimensional bioprinting technologies. Technologies for the vascularization and maturation of kidney organoids show promise as foundational methods for use innovative regenerative medicine and the development of drug discovery therapies.

AstaReal AB (“the applicant”) submitted a novel food (NF) application for the modification in condition of use of the NF Astaxanthin (ATX)-rich oleoresin from Haematococcus pluvialis algae to each nation of Great Britain in April 2024. The NF is produced from Haematococcus pluvialis algae and then dried and extracted into an oil containing ATX. The NF was authorised in the EU (and GB) in 2006 following an opinion through the substantial equivalence process of Regulation (EC) 258/97 to Haematococcus pluvialis biomass containing astaxanthin, which has been marketed in the EU since 1995. The NF is currently authorised for use as food supplements in the general population excluding infants, toddlers, children, and adolescents younger than 14 years. This application seeks to modify the specification of the oleoresin NF for ATX monoesters, ATX diesters, the 9-cis ATX stereoisomer, and the minimum protein content. The current maximum authorised level of the novel food is 40–80 mg/day of oleoresin, resulting in ≤ 8 mg astaxanthin per day, which will remain unchanged. In 2023, the European Food Safety Authority (EFSA) published a scientific opinion on the safety of the change to the conditions of use of the NF ingredient. The Food Standards Agency (FSA) and Food Standards Scotland (FSS) have reviewed the information available, including the EFSA opinion, and confirmed that the NF is safe under the proposed change to the conditions of use. The anticipated intake levels and use in food supplements were not considered to be nutritionally disadvantageous. This safety assessment represents the opinion of the FSA and FSS.

This study concentrated on the Qiantang River in Zhejiang Province, undertaking a comprehensive year-long investigation across 40 sites to quantify conventional pollutants, heavy metals, poly- and perfluoroalkyl substances (PFASs), neonicotinoid insecticides (NNIs), and organophosphate esters (OPEs), while also evaluating plankton diversity. A thorough water safety assessment was subsequently developed. The findings revealed significant pollution levels, with total nitrogen identified as the predominant conventional pollutant, alongside elevated concentrations of Fe and Mn in certain areas. The concentrations of ∑PFASs ranged from 31.2 to 1390ng/L, ∑NNIs from 10.6 to 115ng/L, and ∑OPEs from 1.15 to 35.9ng/L. The ecological risk assessment highlighted moderate to high risks associated with perfluorooctanoic acid, perfluorooctanesulfonic acid, and clothianidin, whereas other emerging pollutants were deemed to pose low risks. Zooplankton analysis identified 109 genera/species, exhibiting notable spatial variations, while the phytoplankton community demonstrated stability. The water safety assessment of the Qiantang River indicated a moderately healthy state with regional disparities: the upstream areas were classified as moderately healthy, the middle reaches as stable, and the downstream regions were under pressure from industrialization and urbanization.Biodiversity and water quality enhance water safety, but emerging pollutants have significant negative impacts and need better control.

Genomic safety assessment and metabolic modulation by Enterococcus faecium 140,623, a probiotic strain from lactasin tablets: implications for obesity management.

ABSTRACT To address the issue of determining and quantifying the safety level of vehicle following on icy and snow‐covered roads in cold regions, this study focuses on intelligent vehicles operating in such environments and aims to identify their safety states. Initially, key indicators for determining the safety state of intelligent vehicles are identified by analyzing the vehicle‐following operational conditions on icy and snow‐covered roads. Subsequently, a safety state identification model for intelligent vehicle operation in following scenarios on icy roads is constructed based on these indicators. Finally, a simulation scenario model is developed using the co‐simulation platform of CarSim and Simulink to perform simulation analysis and validation of the proposed safety state identification model. The results demonstrate that the constructed model integrates three key indicators: Time‐to‐Collision (TTC), Time‐to‐Stop (TTS), and Time Headway (TH). To unify the evaluation of different indicators, a dimensionless parameter termed the safety degree is introduced, which synthesizes the influence of TTC, TTS, and TH into a single criterion for distinguishing safe states from hazardous ones. The following safety degree of vehicles increases with the increase of TTC and TH and decreases with the increase of TTS. During vehicle‐following operations, the safety degree decreases from 1 to 0.3 when the leading vehicle decelerates, indicating a risky operational state, while it increases gradually when the leading vehicle accelerates. After 11 s, the leading vehicle's speed exceeds its initial value, and the safety degree of the following vehicle rises almost linearly, reflecting an improvement in the evaluated safety state. These results confirm that the proposed model satisfies the requirements for judging and predicting the operational safety state of intelligent vehicles in following scenarios on icy and snowy roads, and it provides theoretical support for the safety assessment of intelligent driving under complex low‐adhesion conditions.

Research on highly sensitive detection technology of nitrite based on a novel colorimetric fluorescent probe.

Bemiltenase alfa, a factor X (FX) activator derived from Daboia russelii siamensis venom, was developed as a hemostatic agent for hemophilia A and B with inhibitors (HAwI and HBwI). We conducted two consecutives multicenter, open-label clinical trials. The phase Ib/IIa study assessed the safety, hemostatic efficacy, and pharmacokinetics/pharmacodynamics characteristics of bemiltenase alfa at a dose of 0.1U/kg. The phase IIb study further evaluated the safety and efficacy at a dose of 0.1U/kg. Primary efficacy endpoints encompassed the effective hemostasis rate, safety assessment and anti-drug antibodies (ADAs) development. There were six participants enrolled in phase Ib study, 20 in phase IIa and 25 in phase IIb study. Patients received bemiltenase alfa for bleeding episodes in phase IIa and IIb studies. In phase IIa, the effective hemostasis rates were 94.1% (95% CI: 88.7-97.4). Phase IIb showed an 81.9% rate (95% CI: 71.0-92.9). Most adverse events were mild with grade one in severity, with no serious events. ADA was detected in five patients, but no impact on efficacy and safety was found. Pharmacokinetics findings showed repeated doses of bemiltenase alfa resulted in progressive drug concentration, as indicated by the accumulation ratio index. Pharmacodynamics results indicated a reduction in activated partial thromboplastin time and an increase in thrombin generation peak. Additionally, a mild decline in FX activity was observed post-administration. The study demonstrates FX activation as a novel hemostatic strategy, with snake venom-derived bemiltenase alfa showing promising safety and efficacy for treating bleeding episodes in HAwI and HBwI patients. (clinicaltrials.gov: NCT05027230, NCT06289166).

Introduction: Aeromonas infections are an emerging global public health challenge due to their complex pathogenicity and diverse virulence factors. These infections can lead to various conditions in humans, such as gastroenteritis, wound infections, and septicaemia. On February 12, 2024, an outbreak of Aeromonas hydrophila infection in Jinja and Luuka, Uganda, resulted in cases of abdominal pain, diarrhoea, vomiting, and death. This study described the epidemiology of the outbreak and the public health response. Methods: To investigate the outbreak and evaluate the epidemiology and public health response, a mixed-methods study was conducted using secondary data involving 185 individuals. Confirmed cases were identified through positive culture results from gastric aspirates or stool samples. Suspected and probable cases were defined by at least two symptoms, including abdominal pain, vomiting, and diarrhoea, history of exposure, and an epidemiological link to a confirmed case or outbreak cluster occurring between February 12 and 27, 2024. The study also included secondary laboratory investigations, food safety assessments, and an evaluation of timeliness using the 7-1-7 metric. Data analysis was performed using STATA-17. Results: Among 185 individuals investigated, 54.1% were female, the mean age was 23.9 ±18.7years, 103 Aeromonas hydrophila cases were identified, resulting in an attack rate of 55.7%(103/185), including one laboratory-confirmed case. Cases were younger than non-cases (22.1 vs. 26.3 years). The outbreak lasted five days (12–16 February 2024), peaked on 14 February, and had an incubation period of 33–38 hours, indicating a common-source exposure. Eight deaths occurred (case fatality rate: 7.8%). Geographical clustering of cases was observed, with high attack rates in Iziru (48%) and Bugomba (78%) parishes, respectively. Funeral food exposure showed an attributable risk of 9.3/100 and an attributable fraction of 15.7%. A. hydrophila was detected in gastric aspirate and water samples, implicating contaminated water and ill food handlers. Relapse occurred in 30.1% of cases. Conclusion: The outbreak of Aeromonas hydrophila was rapid, geographically clustered, and linked to contaminated water and ill food handlers, with funeral food exposure contributing to the outbreak. High attack, relapse, and fatality rates highlight the need for timely water safety interventions, improved food hygiene, and strengthened outbreak detection and response to prevent future occurrences.

Masonry retaining walls constitute an essential component of historic and urban infrastructure in seismic regions; however, their seismic performance remains insufficiently quantified due to material heterogeneity, limited tensile capacity, and complex soil–structure interaction. This study investigates the seismic response of historic stone masonry retaining walls using a finite element-based anisotropic macro-modeling approach. The analysis focuses on the perimeter retaining walls of Emirgan Grove in Istanbul, which represent culturally significant heritage structures constructed from natural limestone and cement–lime mortar. Material properties were defined based on experimental test results and representative values reported in the literature, while composite anisotropic behavior was incorporated into the numerical models. Static loads, earth pressures, and seismic actions were applied in accordance with the Turkish Building Earthquake Code (TBEC-2018) using the equivalent static earthquake load method. Representative wall segments with heights of 2.5 m, 3.5 m, 4.0 m, and 6.30 m were analyzed. The numerical results show that maximum compressive stresses reached approximately 0.48 MPa, remaining well below the allowable limit of 4.50 MPa, while maximum tensile stresses of about 0.28 MPa did not exceed the allowable tensile limit of 1.00 MPa. In contrast, shear stresses locally reached approximately 0.25 MPa, exceeding the allowable shear limit of 0.10 MPa, particularly along the soil–wall interface in taller walls. Sliding stability was satisfied in all cases, whereas overturning and shear behavior governed seismic vulnerability. These findings confirm that wall height is the primary parameter controlling seismic response and demonstrate the effectiveness of the proposed framework for preservation-oriented seismic safety assessment of historic masonry retaining walls.

The neurotoxic effects of pesticide residues on nontarget organisms, particularly pregnant women and fetuses, represent a critical concern in environmental and health research. In this study, dimethomorph (DMM) was detected in human cord blood in normal pregnancies at term (without maternal-fetal complications). And neurotoxicity of the fungicide DMM through integrated single-cell RNA sequencing (scRNA-seq) and metabolomic profiling in pregnant mice brain tissue. Our results demonstrate that DMM exposure induces significant alterations in both the proportions and functions of multiple neural cell populations, including microglia, oligodendrocytes, astrocytes, and endothelial cells, accompanied by metabolic reprogramming and blood-brain barrier (BBB) dysfunction. Single-cell analysis revealed cell subtype-specific transcriptional changes and aberrant activation of metabolic pathways (e.g., PI3K-AKT-mTOR signaling), while metabolomic profiling further identified substantial disturbances in amino acid, lipid, and energy metabolism. Furthermore, cell-cell communication analysis indicated enhanced pathological signaling network interactions under DMM exposure. These findings not only elucidate the mechanisms underlying DMM-induced neurotoxicity but also highlight the potential risks of pesticide exposure during pregnancy to maternal and fetal health, providing critical insights for pesticide safety assessment and the development of neuroprotective strategies.

Mechanistic insights and functional evaluation of an Artemisia annua essential oil nanoemulsion for antibacterial topical application against Staphylococcus aureus.

Introduction: Food additives are commonly used to improve the taste, color, shelf life and texture of products. Although most of them are approved for use after safety assessments, there are still concerns regarding their impact on health, including mental functioning. The aim of this study was to qualitatively analyze the presence of selected chemical substances in chosen food products and to discuss the hypothetical mechanisms of their effects on mental health. Material and methods: Fifteen food products were analyzed. The presence of chemical substances was determined using Fourier Transform Infrared Spectroscopy (FTIR), a technique that enables the identification of compounds based on their characteristic absorption spectra. Results: The analysis revealed the presence of typical technological additives as well as trace chemical compounds, some of which may theoretically influence mental health, for example by altering perception, modulating glycemia or affecting memory and mood. FTIR was used as a screening method, which does not allow for definitive or quantitative identification of trace, atypical or controversial compounds. The obtained spectra may reflect both actual components and signals originating from the matrix, packaging, or library matching. Reports concerning some potentially harmful substances do not confirm their actual presence and require verification using confirmatory analytical methods. Conclusions: The results should therefore be interpreted with caution and further research is necessary.

The Microreactor Applications Research Validation and Evaluation (MARVEL) microreactor utilizes natural circulation as a core cooling mechanism and liquid metal as a primary coolant. Moreover, the reactor core has a pitch-to-diameter ratio of 1.054, which is considered a tight lattice configuration. Numerous studies have widely reported that Reynolds-averaged Navier-Stokes (RANS) turbulence models inaccurately predict heat transfer in liquid metals and fail to capture flow pulsations that can occur within tight lattices, leading to further inaccuracies in simulation results. Therefore, evaluating the accuracy of RANS turbulence models in the thermal-hydraulic analysis of the MARVEL microreactor core is crucial for assessing reactor safety. In this study, a large eddy simulation (LES) of the MARVEL microreactor core subchannel was conducted and compared with a RANS simulation to evaluate the accuracies and conservatism of the RANS model. In comparison with the RANS model, LES captures flow pulsations in a tight lattice that enhance heat transfer, whereas the RANS model underpredicts heat transfer in liquid metal flow. As a result, the RANS model predicts a higher peak cladding temperature than LES. However, owing to the high thermal conductivity of the liquid metal, the discrepancy between the two approaches is limited. These results indicate that the steady-state RANS model is adequate for the thermal analysis of the liquid metal–cooled MARVEL microreactor core and can provide conservative, yet not excessively overpredicted, results for safety assessment.