In response to the 2020 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) Feasibility Study was launched as an international collaboration hosted by CERN. This report describes the FCC integrated programme, which consists of two stages: an electron-positron collider (FCC-ee) in the first phase, serving as a high-luminosity Higgs, top, and electroweak factory; followed by a proton-proton collider (FCC-hh) at the energy frontier in the second phase. FCC-ee is designed to operate at four key centre-of-mass energies: the Z pole, the WW production threshold, the ZH production peak, and the top/anti-top production threshold - delivering the highest possible luminosities to four experiments. Over 15 years of operation, FCC-ee will produce more than 6 trillion Z bosons, 200 million WW pairs, nearly 3 million Higgs bosons, and 2 million top anti-top pairs. Precise energy calibration at the Z pole and WW threshold will be achieved through frequent resonant depolarisation of pilot bunches. The sequence of operation modes remains flexible. FCC-hh will operate at a centre-of-mass energy of approximately 85 TeV - nearly an order of magnitude higher than the LHC - and is designed to deliver 5 to 10 times the integrated luminosity of the HL-LHC. Its mass reach for direct discovery extends to several tens of TeV. In addition to proton-proton collisions, FCC-hh is capable of supporting ion-ion, ion-proton, and lepton-hadron collision modes. This second volume of the Feasibility Study Report presents the complete design of the FCC-ee collider, its operation and staging strategy, the full-energy booster and injector complex, required accelerator technologies, safety concepts, and technical infrastructure. It also includes the design of the FCC-hh hadron collider, development of high-field magnets, hadron injector options, and key technical systems for FCC-hh.

Volume 1 of the FCC Feasibility Report presents an overview of the physics case, experimental programme, and detector concepts for the Future Circular Collider (FCC). This volume outlines how FCC would address some of the most profound open questions in particle physics, from precision studies of the Higgs and EW bosons and of the top quark, to the exploration of physics beyond the Standard Model. The report reviews the experimental opportunities offered by the staged implementation of FCC, beginning with an electron-positron collider (FCC-ee), operating at several centre-of-mass energies, followed by a hadron collider (FCC-hh). Benchmark examples are given of the expected physics performance, in terms of precision and sensitivity to new phenomena, of each collider stage. Detector requirements and conceptual designs for FCC-ee experiments are discussed, as are the specific demands that the physics programme imposes on the accelerator in the domains of the calibration of the collision energy, and the interface region between the accelerator and the detector. The report also highlights advances in detector, software and computing technologies, as well as the theoretical tools /reconstruction techniques that will enable the precision measurements and discovery potential of the FCC experimental programme. This volume reflects the outcome of a global collaborative effort involving hundreds of scientists and institutions, aided by a dedicated community-building coordination, and provides a targeted assessment of the scientific opportunities and experimental foundations of the FCC programme.

Volume 3 of the FCC Feasibility Report presents studies related to civil engineering, the development of a project implementation scenario, and environmental and sustainability aspects. The report details the iterative improvements made to the civil engineering concepts since 2018, taking into account subsurface conditions, accelerator and experiment requirements, and territorial considerations. It outlines a technically feasible and economically viable civil engineering configuration that serves as the baseline for detailed subsurface investigations, construction design, cost estimation, and project implementation planning. Additionally, the report highlights ongoing subsurface investigations in key areas to support the development of an improved 3D subsurface model of the region. The report describes development of the project scenario based on the 'avoid-reduce-compensate' iterative optimisation approach. The reference scenario balances optimal physics performance with territorial compatibility, implementation risks, and costs. Environmental field investigations covering almost 600 hectares of terrain - including numerous urban, economic, social, and technical aspects - confirmed the project's technical feasibility and contributed to the preparation of essential input documents for the formal project authorisation phase. The summary also highlights the initiation of public dialogue as part of the authorisation process. The results of a comprehensive socio-economic impact assessment, which included significant environmental effects, are presented. Even under the most conservative and stringent conditions, a positive benefit-cost ratio for the FCC-ee is obtained. Finally, the report provides a concise summary of the studies conducted to document the current state of the environment.

O-RAN (Open-Radio Access Network) offers a flexible, open architecture for next-generation wireless networks. Network slicing within O-RAN allows network operators to create customized virtual networks, each tailored to meet the specific needs of a particular application or service. Efficiently managing these slices is crucial for future 6G networks. O-RAN introduces specialized software applications called xApps that manage different network functions. In network slicing, an xApp can be responsible for managing a separate network slice. To optimize resource allocation across numerous network slices, these xApps must coordinate. Traditional methods where all xApps communicate freely can lead to excessive overhead, hindering network performance. In this paper, we address the issue of xApp conflict mitigation by proposing an innovative Zero-Touch Management (ZTM) solution for radio resource management in O-RAN. Our approach leverages Multi-Agent Reinforcement Learning (MARL) to enable xApps to learn and optimize resource allocation without the need for constant manual intervention. We introduce a Graph Convolutional Network (GCN)-based attention mechanism to streamline communication among xApps, reducing overhead and improving overall system efficiency. Our results compare traditional MARL, where all xApps communicate, against our MARL GCN-based attention method. The findings demonstrate the superiority of our approach, especially as the number of xApps increases, ultimately providing a scalable and efficient solution for optimal network slicing management in O-RAN.

This study aimed to examine the habits, attitudes, and consumption patterns of food supplements (FS) among gym users in Sarajevo, Bosnia and Herzegovina, with respect to gender, age, and training experience. Understanding these behaviors is essential given the rising global trend in FS use, often without professional guidance, which can have implications for individual health and public awareness. By investigating local patterns, this study seeks to provide valuable insights into the motivations and risks associated with supplement consumption, contributing to evidence-based recommendations and policy-making in the field of fitness and nutrition. Methods: Cross-sectional data were collected from various fitness centers using an online questionnaire composed of 21 questions divided into three segments. A total of 614 participants (mean ± SD: 32.77 ± 9.82 years), including both male (67.8%) and female (32.2%) gym users, took part in the study. Results: Participants predominantly belonged to the 36–45 age group, with 70.0% (p < 0.001) reporting more than one year of regular gym attendance, and 40.4% indicating regular FS consumption (p < 0.05). Supplements were mainly used to support faster recovery (29.1%, p < 0.05) and muscle growth (25%, p < 0.05). Magnesium was the most commonly used supplement, equally favored across genders and age groups. Creatine, fish oil capsules, and multivitamins were also frequently consumed (p < 0.05). Self-prescription emerged as the predominant method of FS use (40.3%, p < 0.05), followed by advice from gym coaches (21.8%), with only 5.6% of participants receiving guidance from a nutritionist. Conclusions: The findings highlight a societal trend toward self-directed FS use, often influenced by informal sources, underscoring the importance of further research and the development of targeted, evidence-based educational strategies. Males reported higher FS consumption, with younger users more focused on muscle gain and older individuals prioritizing health maintenance. The reliance on non-expert recommendations raises concerns about the safety and effectiveness of FS usage in the fitness community.

Introduction: Despite the presence of various constraints, Bosnia and Herzegovina has managed to establish healthcare services in the field of spinal surgery. Limiting factors associated with resource scarcity and a shortage of neurosurgeons may pose challenges, but they are not insurmountable in the context of spinal tumor surgery. This study aims to provide a comprehensive 10-year analysis of intradural spinal tumors in resource-constrained healthcare settings and assess surgical outcomes in these challenging environments. Methods: A retrospective study was conducted involving 39 patients with intradural spinal tumors in Zenica-Doboj Canton, Bosnia and Herzegovina, from 2011 to 2021. Patients underwent neurological examinations and spinal magnetic resonance imaging scans, followed by post-surgery assessments at 3 and 6 months using the McCormick scale. Results: Among the 39 patients, tumor distribution was as follows: meningioma (15, 38.5%), ependymoma (3, 7.7%), schwannoma (11, 28.2%), neurenteric cyst (1, 2.6%), primary melanoma (2, 5.1%), lipoma (1, 2.6%), and metastasis (6, 15.4%) (p < 0.001). A majority of patients reported localized and radicular pain (37, 94.9%, p < 0.001) and paresthesia (33, 84.6%, p < 0.001). Motor weakness was noted in 20 (51.3%) patients, while sphincteric dysfunction was reported by 17 (43.6%) patients. The average symptom duration was 397.9 ± 380.9 days, ranging from 14 to 1460 days (p < 0.001). Pneumonia and liquorrhea were reported by 1 (2.6%) patient each. Regarding mortality, 1 (2.6%) patient passed away within a 6-month follow-up period (p < 0.001), and 2 (5.1%) patients were diagnosed with primary malignant melanoma. Significant improvements in McCormick scores were observed between postoperative and 3-month assessments (p < 0.001) and between 3-month and 6-month assessments (p = 0.024). Conclusions: This study offers valuable insights into the management of intradural spinal tumors in resource-constrained healthcare settings. Timely diagnosis and surgical intervention are essential for achieving positive patient outcomes in these challenging environments.

To better understand the genetic architecture and adaptability of native sheep, 22 breeds were genotyped using ovine50K SNP chips. Eleven additional populations from open-source repositories were included. Cross population Extended Haplotype Homozygosity (XP-EHH) and Relative Scaled Haplotype Homozygosity (Rsb) haplotype-based approaches were used to identify genetic variations influencing the adaptation of local sheep breeds to different climatic zones. The results indicate that all breeds exhibited high but declining genetic diversity levels, with a larger proportion of genetic variation explained by development history and refined by geographical origin, as shown by principal component analysis and Neighbor Net graphs. Admixture analysis revealed high admixture levels in European and North African breeds. Using XP-EHH and Rsb methods, 371 genes were putatively under selection, with only nine common among all population pairs, highlighting unique adaptability. Most identified genes, including Interleukin (IL) and cluster differentiation (CD) gene families underlie immune responses, emphasizing their role in resilience to climate change effects. These findings support that indigenous sheep breeds have retained significant genetic diversity, but improper genetic management may threaten it. Additionally, the research emphasizes that indigenous sheep breeds’ unique adaptability to specific climatic zones makes them valuable genetic assets for developing climate-resilient breeds.

Background and Objectives: Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, associated with increased morbidity and prolonged hospital stays. Oxidative stress has been implicated in POAF pathogenesis, with malondialdehyde (MDA), a marker of lipid peroxidation, proposed as a potential biomarker. However, conflicting evidence exists regarding its predictive value. This study aimed to assess the association between serum MDA levels and POAF incidence in patients undergoing cardiac surgery. Materials and Methods: This prospective observational study included 99 consecutive patients undergoing elective on-pump cardiac surgery. Patients with preoperative atrial fibrillation, chronic kidney disease requiring dialysis, or emergency surgery were excluded. Blood samples for MDA measurement were collected at six perioperative time points: preoperatively, intraoperatively after aortic clamp release, and at 8, 24, 48, and 72 h postoperatively. Patients were monitored for new-onset POAF during the first three postoperative days. Statistical analyses included independent samples t-tests, Mann–Whitney U-tests, and Fisher’s exact tests, with significance set at p < 0.05. Results: POAF occurred in 33 (33%) patients. Patients who developed POAF were significantly older (p = 0.017) and had higher EuroSCORE II values (p = 0.019). No significant differences were observed in serum MDA concentrations between POAF and non-POAF patients at any measured time point. The incidence of POAF was higher in patients undergoing valvular surgery (p = 0.014). Conclusions: Serum MDA levels were not associated with POAF development, suggesting that lipid peroxidation alone may not play a central role in POAF pathogenesis. These findings challenge the predictive value of MDA for POAF risk stratification. Future research should explore alternative oxidative stress markers and their potential therapeutic implications in POAF prevention.

Abstract Basal cell carcinoma (BCC) is the most common type of skin cancer that usually appears in sun-exposed body regions such as the head, trunk, and extremities. There are four main clinicopathological subtypes of BCC: nodular, superficial, morpheaform, and fibroepithelial. BCC’s molecular basis includes inherited genetic susceptibility and somatic mutations, often induced by exposure to UV radiation. The aberrant activation of the hedgehog (Hh) signalling pathway, caused by mutations in the Hh components, plays a central role in the molecular pathogenesis of this carcinoma. This led to the development of Hh signalling pathway inhibitors as a new treatment option for patients with advanced disease. In this review, we summarise BCC’s clinical presentation and histopathology and present knowledge on the most studied Hh signalling inhibitors, vismodegib and sonidegib, and other inhibitors of this signalling, such as itraconazole, patidegib, taladegib, and arsenic trioxide, in the treatment of BCC. We also present the most common Hh signalling inhibitor adverse events and their management options, which could improve patients’ quality of life during treatment.

Background and Objectives: Carotid artery stenosis is a significant risk factor for ischemic stroke due to impaired cerebral blood flow (CBF). Even asymptomatic unilateral stenosis can induce subclinical cerebrovascular changes, potentially affecting both hemispheres through collateral circulation. This study aimed to systematically assess cerebral perfusion in asymptomatic individuals with unilateral carotid artery stenosis by comparing ipsilateral and contralateral hemispheres with healthy controls, challenging the assumption that the contralateral hemisphere remains unaffected. Materials and Methods: This cross-sectional study included 114 participants, comprising 54 asymptomatic individuals (mean age 65.5) with significant unilateral carotid stenosis and 60 age-matched controls (mean age 64.8). Cerebral perfusion was assessed using 1.5T Magnetic Resonance Imaging (MRI) with pseudo-continuous arterial spin labeling (pCASL). CBF was measured bilaterally in four predefined middle cerebral artery (MCA) regions: precentral gyrus, lentiform nucleus, insular cortex, and temporal cortex. Statistical analyses included multivariate analysis of variance (MANOVA), analysis of variance (ANOVA), paired t-tests, and discriminant analysis (DA). Results: Significant bilateral reductions in CBF were observed in individuals with carotid stenosis compared to controls (MANOVA and ANOVA, p < 0.001). The greatest perfusion deficit was in the ipsilateral insular cortex (49.88 ± 10.83 mL/100 g/min), followed by intermediate contralateral perfusion (51.49 ± 8.86 mL/100 g/min) and higher control values (58.78 ± 10.44 mL/100 g/min). DA indicated the insular cortex as the region with the highest discriminative contribution (64.7%). Conclusions: Unilateral carotid artery stenosis in asymptomatic individuals is associated with significant bilateral cerebral hypoperfusion, suggesting widespread hemodynamic effects. Pronounced perfusion deficits in the insular cortex underline its vulnerability. The observed contralateral perfusion reductions challenge the traditional use of the contralateral hemisphere as a reference standard, underscoring the need for comprehensive perfusion assessment in carotid artery disease.

Flow cytometry is a well-established method to analyze cell populations using antibody-based fluorescent detection of protein biomarkers. In this study, we demonstrate the ability to generate intact single cells and perform flow cytometry analysis with two types of formalin fixed tissue: FFPE curls and Representative Samples (RS). RS are homogenized, well-mixed tissue samples from formalin fixed tumors dissected from leftover surgical material. We demonstrate biomarker expression results which correlate with IHC scores. This new method for biomarker quantification may be considered alongside other methods (e.g. digital pathology). Intact single cells were dissociated from RS and FFPE curls using a non-enzymatic, mechanical dissociation method. Cells were stained in suspension for Cytokeratin 8&18 (CK8&18), Ki67, Her2, and DNA content was assessed via DAPI staining and analyzed by flow cytometry. Samples were analyzed on a BD FACSMelody or BD LSR II flow cytometer, and analysis was performed using FCS Express 7 software. Immunohistochemistry (IHC) was performed on the Benchmark ULTRA to compare Ki67 expression (n=78) and Her2 expression (n=16) to the flow analysis. Ki67 expression by IHC was assessed using the international Ki67 working group scoring methods to generate a positive percentage. Her2 expression by IHC was assessed by a pathologist and assigned a score ranging 0 to 3+. Formalin fixed tissue such as RS and FFPE curls can be mechanically dissociated into single cells with intact surface biomarkers. These single cells can be stained in suspension, analyzed via flow cytometry and generate correlating data with both weighted IHC-based scores and clinical IHC scores. The flow analysis of Her2 positive percentage correlates with the IHC scores showing an increasing trend and significant difference between scores for both FFPE and RS. Ki67 expression varied by tumor region using IHC analysis, however by flow cytometry showed a strong correlation with a weighted average across multiregional quantification of Ki67 expression. We demonstrate that millions of intact single cells can be generated from RS and FFPE curls for breast tissue, using non-enzymatic mechanical dissociation methods. Staining in suspension and flow cytometry analysis can be performed in a day for rapid biomarker quantification. Flow cytometry has the potential to analyze FFPE samples using workflows and technologies that have existed in the hematopathology space for decades. Samantha M. Hill, Hannah L. Veloz, Brian Hanley, Tracy Davis, Lisa L. Gallegos, Harold Sasano, Samra Turajlic, Nelson R. Alexander. Optimizing fixed flow cytometry for breast cancer biomarker expression in representative samples and FFPE curls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 670.

ccRCC is marked by niches of immune evasion in late-stage disease, that are associated with resistance to immune checkpoint inhibitors (CPI). Intratumoral microbes are emerging as key modulators of the tumor immune microenvironment and may therefore play a yet unrecognised role in ccRCC disease progression and therapy resistance, marking them as potential biomarkers, and novel therapeutic targets. We extracted bacterial reads from three cohorts of treatment-naïve primary tumors and one cohort of pre- and post-CPI treated tumors: Genomics England Renal (GEL) (636 patients, WGS), TRACERx Renal (154 patients, 629 samples, WGS); TCGA Renal (494 patients, RNA) & ADAPTeR (15 patients, 56 samples, RNA). Bespoke denoising, and decontamination were applied. Live presence of intratumoral bacteria was confirmed through culture and RNAscope. Genera associated with survival were identified using ElasticNet feature selection. We observed significant heterogeneity in bacterial abundance within and across tumors, driven by differences in Cutibacterium abundance. Cutibacterium makes up ∼90% of bacteria in each tumor sample and is enriched in tumors compared to adjacent normal tissue (p=7.1e-10). 9 of 11 colonies grown from two positive tumors were genotyped as Cutibacterium acnes, confirming its live presence and relative abundance in ccRCC tumors. Cutibacterium is higher in late-stage tumors (III&IV) than early-stage tumors (I&II)(p=7.8e-3). Its abundance also separates patients by progression free survival (PFS) and overall survival (OS) (p=9.9e-3, p=0.016) and is higher in CPI non-responders than responders (p=0.028). Association with survival is confirmed in the TCGA cohort independently of stage (PFS = 0.031, OS = 7.3e-4). While other genera associate with survival in either TRACERx or TCGA, only Cutibacterium is prognostic in both. Enrichment analyses of bulk RNA (TRACERx & TCGA), show upregulation of leukocyte taxis and innate immune response with Cutibacterium abundance. To further probe this interaction with the immune microenvironment we are performing single cell spatial transcriptomics, and in vitro co-cultures. Results of these ongoing experiments will be presented at the conference. Cutibacterium either creates or exploits a disease- and CPI-resistance-promoting environment in ccRCC tumors and can therefore act as a prognostic and predictive biomarker. The genus is known for causing chronic inflammation in sebaceous skin follicles, induces Nf-kB signalling, and M2-macrophage differentiation in vitro, and associates with myeloid response in ccRCC tumors. Together this supports a compelling hypothesis that Cutibacterium reduces survival in ccRCC by creating immunosuppressive niches, thereby fostering disease progression and CPI-resistance. Alice C. Martin, Anne-Laure Cattin, Irene Lobon, Zayd Tippu, Fiona Byrne, Charlotte Spencer, Clara Becker, Martha Zepeda Rivera, Krupa Thakkar, Hongui Cha, Angel Fernandez-Sanroman, Annika Fendler, Taja Barber, Leo Bickley, Daqi Deng, Scott Shepherd, Parise Lockwood, Maximiliano Gutierrez, Susan Bullman, Kevin Litchfield, Samra Turajlic. Intratumoral bacteria predict survival in clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2207.