572 Background: Anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors and checkpoint inhibitors (CPI) a standard-of-care treatment for clear cell renal cell carcinoma (ccRCC). We investigated the biology underpinning benefit of anti-VEGFR TKI in the phase II A-PREDICT trial (NCT01693822), evaluating pre- and post-treatment, fresh multiregion tumour biopsies in patients with metastatic ccRCC treated with first-line axitinib. Methods: We analysed 123 tumour samples from 52 patients, 28 with paired pre/post-treatment samples. Post-treatment samples included week-9, nephrectomy, and on-progression timepoints. ‘Responders’ had progression-free survival (PFS) ≥6 months (n=35), ‘non-responders’ with PFS <6 months (n=17). We applied a custom Nanostring panel for gene expression analysis and multiplex immunofluorescence (mIF) for orthogonal validation. Wilcoxin test was used to analyze paired observations. Results: At baseline, angiogenesis scores were similar between responders and non-responders (p=0.22). Post-treatment, the angiogenesis, vascular sprouting, and endothelial cell proliferation signature scores were significantly decreased (p=0.023, 0.0034, & 0.0082, respectively) in all patients, suggesting suppression of angiogenesis and neovascularisation irrespective of clinical outcomes. mIF in 3 patients (with PFS of 3, 5.6, & 100 months) confirms widespread intratumoral vessel depletion. Immune deconvolution analysis shows total levels of T cells and CD8 + T cells were similar pre- and post-treatment, suggesting axitinib did not enhance immune cell trafficking. Rather, axitinib promoted increased levels of exhausted CD8 + T cells post-treatment (p=0.01). M2 tumour-associated macrophages increased post-treatment in responders (p=0.033) but not in non-responders (p=0.44). A minority of patients had durable (>2 years) responses to axitinib (n=7/65, 6 with tissue for analysis). In these patients, we found higher levels of pre-treatment intratumoral cytotoxic immune cells (p=0.041) and NK cells (p=0.015) compared to patients with primary resistant disease. Conclusions: Axitinib suppressed angiogenesis and neovascularisation leading to intratumoral vessel depletion, and therapy response associates with features of an immunosuppressive TME. Baseline endogenous immune priming appears critical for durable response to anti-VEGF therapy. These data are relevant to understanding the clinical efficacy of combined anti-VEGF and CPI regimens. Clinical trial information: NCT01693822 .

Thalassemia, a genetic condition characterized by defective hemoglobin synthesis, is often managed with transfusion therapy, which can lead to iron overload—a significant contributor to morbidity and mortality due to organ damage and pathogenic infections. Iron chelation therapy, the cornerstone of managing iron toxicity, may inadvertently influence the gut microbiome, a critical modulator of immunity and metabolism. This review provides new insights into the interplay between iron chelation therapy and gut microbiome dynamics in thalassemia patients. It synthesizes findings on how chelators such as deferoxamine, deferasirox, and deferiprone influence microbial composition, iron availability, and systemic inflammation. Emerging evidence highlights alterations in gut microbial diversity, with reduced beneficial taxa and increased pathogenic populations, driven by changes in luminal iron levels. This imbalance contributes to immune dysregulation, systemic inflammation, and susceptibility to infections. The review advocates for tailored treatment strategies that integrate microbiome-targeted interventions alongside traditional chelation therapy to improve patient outcomes. By combining genetic profiling, dietary adjustments, and microbiome modulation, this approach offers a promising avenue for personalized medicine in thalassemia care.

Ionization of atoms by a strong laser field can be described using the improved strong-field approximation. The corresponding transition amplitude of high-order above-threshold ionization is presented in the form of a two-dimensional integral over the electron ionization time t0 and the rescattering time t. This integral can be solved using the saddle-point (SP) method and the resulting T-matrix element is expressed as a sum (over the SP times t0 and t) of the partial transition amplitudes. We address the problem of finding the solutions of the system of SP equations for the times t0 and t. For a bichromatic linearly polarized laser field with the frequencies rω and sω (r and s are integers, s>r, and ω is the fundamental frequency) we found that there are 8s2 SP solutions per optical cycle. For one half of them the velocity of the electron emitted in the laser field polarization direction changes the sign at the rescattering time (we call such solutions backward-scattering solutions), while for the other half this velocity remains unchanged (these solutions we call forward-scattering SP solutions). For very short (or even negative) electron travel time we call these solutions backward-like and forward-like scattering SP solutions. For these solutions the imaginary parts of the times t0 and t become large so that the concept of real electron trajectories becomes questionable. Having such a classification, we found additional SP solutions even for the simplest case of a monochromatic linearly polarized laser field. For a bichromatic linearly polarized laser field with s=2 and equal component intensities we presented a detailed analysis of all 32 solutions per optical cycle, showing how the SP times t0 and t and the corresponding differential ionization rates depend on the photoelectron energy. We have also analyzed the case where the intensity of the second component decreases while the sum of the component intensities remains fixed. Published by the American Physical Society 2025

Background Healthy eating in preschools is a very important but challenging goal that can benefit from an adequate institutional and system approach. Five years ago, the Ministry of Education and Culture in the Republic of Srpska, Bosnia and Herzegovina, adopted a policy for healthy eating in preschools in the form of a rulebook and standards, whose use was not mandatory. The aim of this research was to determine the practices, perceptions, and experiences of preschool personnel related to the implementation of the abovementioned rulebook and standards. Methods We applied a qualitative research method and conducted six focus groups: three with teachers (n = 37) and three with managers in preschools (n = 19). The qualitative data were analyzed according to the Framework Method. Results We found that the practice of healthy eating in public preschool settings involves a certain number of facilitators and ongoing challenges. While there are no doubts that the existing rulebook and standards are facilitating efforts in establishing healthy eating in preschools, their implementation has not been an easy-going process, and they have encountered resistance that has appeared at several levels. The participants perceived cookers as resistant and “old-fashioned” in preparing meals, which was found to be a significant challenge that requires education training and ongoing supervision with support. Experiences with limited financial resources and rigid public procurement procedures make it difficult to obtain desired food items. All the participants agreed that long-term commitment is needed to achieve the full implementation of policy recommendations, together with tripartite and convergent education programs for personnel, parents, and children. Conclusion Promoting proper nutrition in preschools requires a holistic approach that addresses both feasibility and attitudes toward policies, continuous education for staff, creative strategies for implementing new eating habits, and overcoming financial challenges. Collaboration with parents and community stakeholders is crucial in creating a supportive environment for healthy eating habits in preschool settings. Supplementary Information The online version contains supplementary material available at 10.1186/s40795-025-01017-1.

The paper presents the most comprehensive and large-scale global study to date on how higher education students perceived the use of ChatGPT in early 2024. With a sample of 23,218 students from 109 countries and territories, the study reveals that students primarily used ChatGPT for brainstorming, summarizing texts, and finding research articles, with a few using it for professional and creative writing. They found it useful for simplifying complex information and summarizing content, but less reliable for providing information and supporting classroom learning, though some considered its information clearer than that from peers and teachers. Moreover, students agreed on the need for AI regulations at all levels due to concerns about ChatGPT promoting cheating, plagiarism, and social isolation. However, they believed ChatGPT could potentially enhance their access to knowledge and improve their learning experience, study efficiency, and chances of achieving good grades. While ChatGPT was perceived as effective in potentially improving AI literacy, digital communication, and content creation skills, it was less useful for interpersonal communication, decision-making, numeracy, native language proficiency, and the development of critical thinking skills. Students also felt that ChatGPT would boost demand for AI-related skills and facilitate remote work without significantly impacting unemployment. Emotionally, students mostly felt positive using ChatGPT, with curiosity and calmness being the most common emotions. Further examinations reveal variations in students’ perceptions across different socio-demographic and geographic factors, with key factors influencing students’ use of ChatGPT also being identified. Higher education institutions’ managers and teachers may benefit from these findings while formulating the curricula and instructions/regulations for ChatGPT use, as well as when designing the teaching methods and assessment tools. Moreover, policymakers may also consider the findings when formulating strategies for secondary and higher education system development, especially in light of changing labor market needs and related digital skills development.

Terrestrial laser scanners (TLS) are widely employed in structural health monitoring (SHM) of large objects due to their superior capabilities compared to traditional geodetic methods. TLS provides rapid and detailed data on the geometric properties of objects, enabling various types of analyses. In this study, TLS was utilized to examine the minaret of the Bjelave Mosque, located in Sarajevo, Bosnia and Herzegovina. The inclination of the minaret was assessed using principal component analysis (PCA) and linear regression (LR) applied to sampled data from four edges of the minaret’s body. The geodetically determined inclination values were used as input data for subsequent static and pushover analyses conducted in DIANA FEA, where the minaret was modeled. The analyses indicate that the inclination increases stress and strain, leading to larger cracks and reduced structural capacity, as demonstrated by the pushover analysis curves. This study highlights the combined impact of structural inclination, water infiltration, and settlement on the minaret’s integrity and proposes these findings as a basis for future maintenance and strengthening measures.