Search Results (86)

In this study, the health impacts of improving access to treatment with axicabtagene ciloleucel (axi-cel) was assessed in patients with relapsed/refractory diffuse large B-cell lymphoma after ≥2 lines of therapy in Spain. A partitioned survival mixture cure model was used to estimate the lifetime accumulated life years gained (LYG) and quality-adjusted life years (QALYs) per patient treated with axi-cel versus chemotherapy. Efficacy data were extracted from the ZUMA-1 trial for axi-cel and from the SCHOLAR-1 study for chemotherapy. In the base case, the incremental outcomes of axi-cel versus chemotherapy were evaluated in a cohort of 187 patients treated with CAR T-cell therapies, as reported by the “Spanish National Health System Plan for Advanced Therapies”, and in the alternative scenario in the full eligible population based on epidemiological estimates (n = 490). Taking those currently treated with axi-cel, compared with chemotherapy, axi-cel provided an additional 1341 LYGs and 1053 QALYs. However, when all eligible patients (n = 490) were treated, axi-cel provided an additional 3515 LYs and 2759 QALYs. Therefore, if all eligible patients were treated with axi-cel rather than those currently treated as per the registry (n = 187), there would have been an additional 303 patients treated, resulting in an additional 2173 LYGs and 1706 QALYs in total. The lack of access in Spain has led to a loss of a substantial number of LYGs and QALYs, and efforts should be made to improve access for all eligible patients. Full article

Three new tridentate copper(II) N-heterocyclic carbene (NHC) complexes have been obtained and characterized with symmetrical C-4 substitutions on their pendent pyridine rings. Substitutions including methyl (Me), methoxy (OMe), and chloro (Cl) groups, which extend the library pincer Cu-NHC complexes under investigation, modify the impact of pyridinyl basicity on NCN pincer complexes. Both ligand precursors and copper(II) complexes are characterized using a range of techniques, including nuclear magnetic resonance (NMR) spectroscopy for ¹H, ¹³C, ³¹P, and ¹⁹F nuclei, electrospray ionization mass spectrometry (ESI-MS), X-ray crystallography, cyclic voltammetry, and UV-Vis spectroscopy. The pyridine substitutions lead to minimal changes to bond lengths and angles in the X-ray crystal structures of these related complexes; there is a pronounced impact on the electrochemical behavior of both the ligand precursors and copper complexes in the solution. The substitution in the pyridinyl units of these complexes show an impact on the catalytic reactivity of these complexes as applied to a model C–N bond-forming reaction (CEL cross-coupling) under well-established conditions; however, this observation does not correlate to the expected change in basicity in these ligands. Full article

Protective structures play a vital role in mitigating the risks associated with debris flows, yet assessing their performance poses crucial challenges for their real-world effectiveness. This study proposes a comprehensive procedure for evaluating the performance of protective structures exposed to impacts from media transported by large debris flow events. The method combines numerical modelling with site conditions for existing structures along the Hobart Rivulet in Tasmania, Australia. The Coupled Eulerian Lagrangian (CEL) model was validated by comparing simulation results with experimental data, demonstrating high agreement. Utilising three-dimensional modelling of debris flow–boulder interactions over the Hobart Rivulet terrain, boulder velocities were estimated for subsequent finite element analyses. Importantly, a model of interaction between boulders and I-beam posts was established, facilitating a comparative assessment of five distinct I-beam barrier systems defined as Type A to E, which are currently in use at the site. Simulation results reveal larger boulders display a slower increase in their velocities over the 3D terrain. Introducing a key metric, the failure ratio, enable a mechanism for comparative assessments of these barrier systems. Notably, the Type E barriers demonstrate superior performance due to fewer weak points within the structure. The combined CEL and FE assessments allow for multiple aspects of the interactions between debris flows, boulders, and structures to be considered, including structural failure and deformability, to enhance the understanding of debris flow risk mitigation in Tasmania. Full article

Composite materials, such as aluminum alloy FGMs, provide advantageous weight reduction properties compared to homogenous pure structures while still preserving sufficient stiffness for diverse applications. Despite various research on drilling simulation concepts and ideas for these materials, there still needs to be an agreement on the process modeling. Researchers have looked into a lot of different numerical methods, including Lagrangian, Eulerian, arbitrary Lagrangian–Eulerian (ALE), and coupled Eulerian–Lagrangian (CEL), to find solutions to problems like divergence issues and too much mesh distribution, which become more of a problem at higher speeds. This research provides a global analysis of bottom-up meshing for eleven 1 mm layers using ABAQUS^® software. It combines the internal surface contact approach with the Lagrangian domain’s kinematic framework. The model uses the Johnson–Cook constitutive equation to precisely predict cutting forces, stress, and strain distributions, optimizing cutting parameters to improve drilling performance. According to Taguchi analysis, the most favorable parameters for reducing cutting force and improving performance are a rotational speed of 700 rpm, a feed rate of 1 mm/s, and a depth of cut of 3 mm. The findings suggest that increasing the feed rate and depth of cut substantially affects the cutting force, while the rotational speed has a comparatively little effect. These ideal settings serve as a foundation for improving FGM drilling efficiency. Full article

Over the past few years, there has been an increased focus on offshore pipeline safety due to the development of offshore oil and gas resources. Both onshore and offshore pipelines may face significant geological hazards resulting from active faults. Pre-excavated soil can be used as backfill for trenches to prevent major pipeline deformations. Since these backfill materials have been heavily remolded, they are softer than the native soil. Therefore, the difference in shear strength between the backfill and native ground may have an effect on the interaction between the pipeline and the backfill. In this paper, the pipeline–backfill–trench interaction is investigated using a hybrid beam–spring model. The P-Y curves obtained from CEL analysis are incorporated into a 3D beam–spring model to analyze the pipeline’s response to lateral strike-slip faults. Additionally, the nonlinearity of pipeline materials is considered to study pipeline failure modes under strike-slip fault movements. A series of parametric studies were conducted to explore the effects of fault intersection angle, pipe diameter, buried depth of the pipe, and soil conditions on the failure modes of buckling pipelines. The developed method can be used to analyze and assess pipeline–backfill–trench interaction when subjected to strike-slip fault displacements. Full article

Multilayered flexible subsea pipelines may experience significant lateral movements due to manmade and environmental geohazards. These pipelines incorporate several structural and protective layers to resist different loads, and may require additional protection such as trenching, rock placement, or burial. In practice, simplifications are considered due to the complexities and uncertainties involved in the multi-layer pipe structure and the surrounding soil, compromising the pipe structure or the soil behavior. These simplifications are applied either on the pipe by assuming a rigid section or on the soil by representing it as elastic springs, which may result in inaccuracies. This study proposes a decoupled methodology combining the Coupled Eulerian–Lagrangian (CEL) model for soil displacement with a small-strain finite element analysis of the flexible pipe. This approach aims to accurately capture cross-sectional deformations and local stresses due to soil movement while maintaining reasonable computational effort. A parametric analysis was conducted to assess the impact of several variables on failure risk. The deformed cross-section was then used for a collapse analysis to determine critical loads at maximum operational depth. The study showed that modeling parameters such as soil strength and internal diameter might significantly influence pipe failure and the risk of collapse. Full article

Purpose: To estimate the cost-effectiveness of axi-cel vs. salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem-cell transplantation (HDT+ASCT) for responders to second-line treatment for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Methods: A partitioned survival mixture-cure model comprising three health states was used to estimate the costs, life years gained (LYG), and quality-adjusted life years (QALYs) accumulated over a lifetime horizon. Overall survival, event-free survival, and time to the next treatment with axi-cel and HDT+ASCT were derived from the ZUMA-7 study. The total costs (EUR, 2022) included drug acquisition and administration, ASCT, subsequent treatment, disease and adverse event management, and palliative care. The unitary costs were derived from local databases and the literature. A 3% discount rate was applied to the costs and outcomes. Results: Compared with HDT+ASCT, axi-cel provided higher LYG per patient (10.00 vs. 8.28 LYG/patient) and greater QALYs gained per patient (7.85 vs. 6.04 QALY/patient). The lifetime total costs were 343,581 EUR/patient with axi-cel vs. 257,994 EUR/patient with IQT+ASCT. The incremental cost-effectiveness ratio of axi-cel vs. HDT+ASCT was 49,627 EUR/LYG, and the incremental cost-utility ratio was 47,309 EUR/QALY. Sensitivity analyses confirmed the robustness of the model. Conclusion: Axi-cel is a potentially cost-effective alternative to HDT+ASCT for the treatment of R/R DLBCL in Spain. Full article

Hook defects are common in FSW butt–lap joints, resulting in a significant safety hazard for the parts that suffer cyclic load. In this study, a numerical simulation based on the Euler–Lagrange coupling method was conducted to investigate the formation process of hook defect during FSW of AA6005-T6 aluminum alloy. The simulation results were validated with experimental data, showing good agreement. The formation of the hook defect is caused by the threads on the probe promoting material flow in the thickness direction. In order to further study the effect of probe morphology on hook defects, three kinds of probe models with different morphology were established and numerically simulated by the CEL method. The simulation results show that all three kinds of probes can reduce the size of the hook. The welds obtained using the left–left probe (LLP) and the three-plane probe (TPP) both exhibit void defects, while the welds obtained by a right–left probe (RLP) have no internal void defects. The experimental results show the same characteristics as the simulation results, and the size of the hook defect is reduced to 58 μm. Full article

The growing increase in demand for water and the lack of balance between water supply and demand have led to conflicts among the downstream stakeholders of the international Hirmand River. This river is shared between Iran and Afghanistan and is located in the southeast of Iran, in the Sistan region. The Vardkhaneh is divided into two branches, Parian and Sistan, and it is the only main source of water in the Sistan region of Iran. The inner part of Hirmand catchment is considered bankrupt concerning its water resources, so there is a need to take the current status and resulting issues into account in order to resolve conflicts. In Hirmand catchment, four different games of bankruptcy theory, namely proportional (Pr), adjusted proportional (AP), constrained equal award (CEA), and constrained equal losses (CEL), were developed as optimization models based on genetic algorithms. For this purpose, the catchment was simulated with 26 scenarios using the WEAP 2022 version software for an average time period. The results of the bankruptcy game modeling showed that water could be effectively allocated to resolve conflicts among stakeholders. It is therefore recommended to use such a model to resolve fights and optimally allocate resources, even in bankrupt catchments. Full article

The dynamic response analysis of submerged floating tunnels (SFTs) under seismic action is a complex two-way fluid–structure coupling problem that requires expertise in structural dynamics, fluid mechanics, and advanced computational methods. The coupled Eulerian–Lagrangian (CEL) method is a promising method for solving fluid–structure interaction problems, but its application to SFTs is not well established. Therefore, it is crucial to verify the accuracy and reliability of the CEL method in fluid–structure coupling simulations. This study verified the applicability of the CEL method for simulating one-way and two-way fluid–structure coupling cylindrical flow problems, and then applied the CEL method for the analysis of a shaking table test of a model SFT. A comparison of results obtained with the CEL method with those obtained in a previous indoor model test of an SFT demonstrates the agreement between the results of the CEL method and the overall trend of the experimental results, indicating the reliability of the method for the seismic analysis of SFTs. Moreover, the analysis of the dynamic response characteristics of SFTs under seismic conditions provides data support and a technological means for the seismic design of SFTs. Full article

Methylglyoxal (MGO) is a highly reactive α-dicarbonyl compound formed endogenously from 3-carbon glycolytic intermediates. Methylglyoxal accumulated in plasma and urine of hyperglycemic and diabetic individuals acts as a potent peptide glycation molecule, giving rise to advanced glycation end products (AGEs) like arginine-derived hydroimidazolone (MG-H1) and carboxyethyl-lysine (CEL). Methylglyoxal-derived AGEs exert their effects mostly via activation of RAGE, a cell surface receptor that initiates multiple intracellular signaling pathways, favoring a pro-oxidant environment through NADPH oxidase activation and generation of high levels of reactive oxygen species (ROS). Diabetic bladder dysfunction is a bothersome urological complication in patients with poorly controlled diabetes mellitus and may comprise overactive bladder, urge incontinence, poor emptying, dribbling, incomplete emptying of the bladder, and urinary retention. Preclinical models of type 1 and type 2 diabetes have further confirmed the relationship between diabetes and voiding dysfunction. Interestingly, healthy mice supplemented with MGO for prolonged periods exhibit in vivo and in vitro bladder dysfunction, which is accompanied by increased AGE formation and RAGE expression, as well as by ROS overproduction in bladder tissues. Drugs reported to scavenge MGO and to inactivate AGEs like metformin, polyphenols, and alagebrium (ALT-711) have shown favorable outcomes on bladder dysfunction in diabetic obese leptin-deficient and MGO-exposed mice. Therefore, MGO, AGEs, and RAGE levels may be critically involved in the pathogenesis of bladder dysfunction in diabetic individuals. However, there are no clinical trials designed to test drugs that selectively inhibit the MGO–AGEs–RAGE signaling, aiming to reduce the manifestations of diabetes-associated bladder dysfunction. This review summarizes the current literature on the role of MGO–AGEs–RAGE–ROS axis in diabetes-associated bladder dysfunction. Drugs that directly inactivate MGO and ameliorate bladder dysfunction are also reviewed here. Full article

In this study, sound insulation materials with a high sound absorption coefficient were prepared. In this paper, using cellulose (CEL) and graphene oxide (GO) as the main raw materials and epichlorohydrin as the cross-linker, the CEL-GO composite aerogels were prepared via lyophilisation. The structure, molecular bonding, and acoustic absorption mechanisms of the composite aerogel were characterised and analysed using SEM, FTIR, XRD, BET, and Raman. In addition, corresponding molecular structure models were constructed. The acoustic attenuation of the CEL-GO composite aerogel was measured using a standing wave tube acoustic attenuation tester. The results show that the chemical bond between the GO and CEL composite is established, and the addition of graphene makes the pores of the composite more advanced, which is more favorable for sound absorption, and the acoustic absorption coefficient can reach up to 0.87. Full article

Leptospirosis is a neglected zoonotic disease that commonly affects cattle, pigs, horses, and dogs in many countries. Infection in dogs is usually subclinical, but acute cases of leptospirosis may occur along with systemic failure, which may become fatal. After recovery from an acute infection, dogs may become asymptomatic carriers and shed pathogenic leptospires through urine for long periods of time. Here, a study of ten different cases of leptospirosis is presented, showing the relevance of dogs as asymptomatic carriers of pathogenic Leptospira. The diagnosis was confirmed via isolation and further serological and genetic identification. Four Leptospira isolates (LOCaS28, 31, 34, and 46) were obtained from the kidneys and urine samples of 58 dogs destined for destruction (6.89%) at a Canine Control Center in Mexico City. No spirochetes were observed in the urine samples of those Leptospira-positive dogs examined under dark-field microscopy, and no clinical signs of disease were observed either. Six additional isolates were obtained: two came from asymptomatic carrier dogs (CEL60 and UADY22); another isolate came from an asymptomatic dog that was a pack companion of a clinically ill dog with fatal leptospirosis (AGFA24); and finally, three isolates were taken from dogs that died of leptospirosis (LOCaS59, Citlalli, and Nayar1). Nine out of the ten isolates were identified as being from the serogroup Canicola via cross-absorption MAT using reference strains and specific antisera, and their identity was genetically confirmed as Canicola ST34 via multi-locus sequencing typing (MLST). In contrast, the isolate Nayar1 was identified as serovar Copenhageni ST2. Interestingly, the asymptomatic dogs from which Leptospira isolates were recovered consistently showed high antibody titers in the microscopic agglutination test (MAT), revealing values of at least 1:3200 against serogroup Canicola and lower titer values against other serogroups. Isolates showed different virulence levels in the hamster model. Taken as a whole, all these findings confirmed that dogs may act as asymptomatic carriers of pathogenic leptospires and possibly spread them out to the environment, thus representing an active public health risk. The results also showed that the Canicola ST34 clone is the most prevalent Leptospira serovar in dogs in Mexico, and finally that the old-fashioned MAT is a good alternative for the detection of presumptive Leptospira asymptomatic carrier dogs. Full article

It has been postulated that advanced glycation end products (AGEs) and their soluble receptor (sRAGE) may play a relevant role as inducers in the chronic inflammatory pathway in various conditions, among them, in immune-mediated diseases such as systemic lupus erythematosus (SLE). However, previous studies show conflicting results about their association with SLE characteristics and their usefulness as disease biomarkers. We aimed to study the association of specific serum AGEs (pentosidine, Nξ-(carboxymethyl)lysine (CML), Nξ-(carboxyethyl)lysine (CEL)), sRAGE levels and AGEs (specific serum AGEs and skin AGEs) to sRAGE ratios with various disease parameters, in order to clarify their potential as new biomarkers in SLE and to study their relationship with cardiovascular disease (CVD). To this aim, serum pentosidine, CML, CEL and sRAGE were measured via ELISA, and skin AGEs levels were measured by skin autofluorescence. Correlations of pentosidine levels with demographic and clinical data, indexes of activity, accrual damage and patient-reported outcomes were analyzed through multiple linear regression models, while correlations of the rest of the AGEs, sRAGE and AGE to sRAGE ratios (non-normal) were analyzed using both an OLS regression model and a GML. All of the analyses were adjusted for confounders. A total of 119 SLE patients were recruited. Serum AGEs and sRAGEs were significantly associated with SLE activity indexes and/or demographic or disease characteristics: pentosidine with pulmonary manifestations; CML with anti-dsDNA antibodies, IL-6, disease duration and non-Caucasian ethnicities; CEL with anti-dsDNA antibodies, IL-6 and accumulated number of manifestations; and sRAGE with male gender, photosensitivity and being on specific immunosuppressants. These results suggest that the AGE–sRAGE axis may serve as a novel biomarker for managing and prognosticating this disease. Its correlation with certain antibodies, demographics and disease presentations may indicate a distinct clinical phenotype associated with varying levels of AGEs and/or sRAGE. The significance of specific AGE/sRAGE ratios, introduced in this study for the first time, warrants additional investigation in forthcoming research. Our study did not confirm the link between serum AGEs and CVD, which merits further exploration through studies designed for this specific purpose. Full article

As a typical climacteric fruit, tomato (Solanum lycopersicum) is widely used for studying the ripening process. The negative regulation of tomato fruits by transcription factor SlNAC1 has been reported, but its regulatory network was unclear. In the present study, we screened a transcription factor, SlERF109-like, and found it had a stronger relationship with SlNAC1 at the early stage of tomato fruit development through the use of transcriptome data, RT-qPCR, and correlation analysis. We inferred that SlERF109-like could interact with SlNAC1 to become a regulatory complex that co-regulates the tomato fruit ripening process. Results of transient silencing (VIGS) and transient overexpression showed that SlERF109-like and SlNAC1 could regulate chlorophyll degradation-related genes (NYC1, PAO, PPH, SGR1), carotenoids accumulation-related genes (PSY1, PDS, ZDS), ETH-related genes (ACO1, E4, E8), and cell wall metabolism-related genes expression levels (CEL2, EXP, PG, TBG4, XTH5) to inhibit tomato fruit ripening. A dual-luciferase reporter and yeast one-hybrid (Y1H) showed that SlNAC1 could bind to the SlACO1 promoter, but SlERF109-like could not. Furthermore, SlERF109-like could interact with SlNAC1 to increase the transcription for ACO1 by a yeast two-hybrid (Y2H) assay, a luciferase complementation assay, and a dual-luciferase reporter. A correlation analysis showed that SlERF109-like and SlNAC1 were positively correlated with chlorophyll contents, and negatively correlated with carotenoid content and ripening-related genes. Thus, we provide a model in which SlERF109-like could interact with SlNAC1 to become a regulatory complex that negatively regulates the tomato ripening process by inhibiting SlACO1 expression. Our study provided a new regulatory network of tomato fruit ripening and effectively reduced the waste of resources. Full article