BACKGROUND Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its impact on prognosis of young patients harboring BRCA pathogenic variant (PV). PATIENTS AND METHODS This international, multicenter, retrospective cohort study included young patients (≤40 years) diagnosed with invasive breast cancer and harboring germline PV in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest (disease-free survival [DFS], breast cancer specific survival [BCSS] and overall survival [OS]) were first investigated according to hormone receptors expression (positive vs. negative), and then according to breast cancer subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive breast cancer). RESULTS From 78 centers worldwide, 4,709 BRCA carriers were included, of whom 2,143 (45.5%) had hormone receptor-positive and 2,566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% vs. 9.6%, p<0.001), while the rate of second primary breast cancer was lower (9.1% vs. 14.7%, p<0.001) compared to patients with hormone receptor-negative disease. The 8-years DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive vs. negative disease changed over time for DFS, BCSS, and OS (p<0.05 for interactions of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-years DFS: 60.8% in luminal A-like vs. 63.5% in triple-negative vs. 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive vs. negative disease warrants consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

PURPOSE The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with various solid tumors with germline or somatic BRCA1/2 mutations treated with talazoparib are reported. METHODS Eligible patients had advanced solid tumors, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Patients with germline BRCA-mutated human epidermal growth factor receptor 2–negative locally advanced or metastatic breast cancer were not eligible for this study. Primary end point was disease control (DC) determined by investigator assessment of objective response (OR) or stable disease (SD) of at least 16 weeks duration (SD16+). The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = 0.82; α = .10). Secondary end points were OR, progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS Twenty-eight patients (20 cancer types) with BRCA1/2 mutations were enrolled from December 2019 to September 2021 and collapsed into a single histology pooled cohort for analysis. All patients were evaluable for efficacy. One complete response, nine partial response, and six SD16+ were observed for DC and OR rates of 57% (one-sided 90% CI, 43 to 100) and 36% (95% CI, 19 to 56), respectively. The null hypothesis of a 15% DC rate was rejected (P < .001). Patients with OR had the following tumor types: breast (2), nonmelanoma skin, mesothelioma, stomach, uterus, non–small cell lung cancer, ovary, hepatocellular carcinoma, and pancreas. Thirteen patients had at least one grade 3-5 adverse event (AE) or serious AE at least possibly related to talazoparib. All were consistent with the drug label except bilirubin increase and hyponatremia (both grade 3 AEs). CONCLUSION Talazoparib demonstrated antitumor activity in patients with advanced solid tumors and BRCA1/2 mutations, including cancer types for which poly ADP-ribose polymerase inhibitors are not yet US Food and Drug Administration–approved.

Wet synthesis approach afforded four new heteroleptic mononuclear neutral diamagnetic oxidovanadium(V) complexes, comprising salicylaldehyde-based 2-furoic acid hydrazones and a flavonol coligand of the general composition [VO(fla)(L-ONO)]. The complexes were comprehensively characterized, including chemical analysis, conductometry, infrared, electronic, and mass spectroscopy, as well as 1D 1H and proton-decoupled 13C(1H) NMR spectroscopy, alongside extensive 2D 1H1H COSY, 1H13C HMQC, and 1H13C HMBC NMR analyses. Additionally, the quantum chemical properties of the complexes were studied using Gaussian at the B3LYP, HF, and M062X levels on the 6-31++g(d,p) basis sets. The interaction of these hydrolytically inert vanadium complexes and the BSA was investigated through spectrofluorimetric titration, synchronous fluorimetry, and FRET analysis in a temperature-dependent manner, providing valuable thermodynamic insights into van der Waals interactions and hydrogen bonding. Molecular docking was conducted to gain further understanding of the specific binding sites of the complexes to BSA. Complex 2, featuring a 5-chloro-substituted salicylaldehyde component of the hydrazone, was extensively examined for its biological activity in vivo. The effects of complex administration on biochemical and hematological parameters were evaluated in both healthy and diabetic Wistar rats, revealing antihyperglycemic activity at millimolar concentration. Furthermore, histopathological analysis and bioaccumulation studies of the complex in the brain, kidneys, and livers of healthy and diabetic rats revealed the potential for further development of vanadium(V) hydrazone complexes as antidiabetic and insulin-mimetic agents.

Abstract This study investigates the benefits of international diversification in the stock markets of the 28 European countries (the EU and the UK) over two five-year periods: a stable period from 2014 to 2019 and a turbulent period from 2019 to 2024. The analysis draws on the Markowitz mean-variance, Sharpe reward-to-variability, and naive diversification models, based on which different investment strategies were developed and implemented. We find that actively managed portfolios perform significantly better than naively diversified portfolios. The analyzed markets exhibit positive short-term associations, with an average correlation coefficient of 0.29 in the first period and 0.46 in the second period. However, these markets do not show long-term cointegration. Recent crises have reduced diversification benefits, yet significant opportunities for diversification remain. Diversification benefits are almost halved in the second period: average single-market standard deviation can be reduced by 60.5% with investments in 20-indices portfolios in the stable period, and only by 33.7% with the same portfolio size in the turbulent period.

Abstract This paper presents a detailed model of low-frequency oscillations and their damping within the Electric Power System (EPS) of Bosnia and Herzegovina (B&H). The system is modeled using MATLAB software, analysing the steady state and dynamic responses. This research highlights the challenges and impacts of integrating renewable energy sources, such as wind farms, on grid stability and oscillation damping. The paper utilizes eigenvalue analysis to investigate the dynamic characteristics of the system, emphasizing the need for efficient damping strategies to maintain system stability. The methodology includes a comprehensive review of existing literature, the creation of a detailed EPS model of B&H, and the application of eigenvalue and oscillation amplitude analysis to determine damping ratios. The dynamic responses of hydro power plants, HPP Mostar and HPP Jablanica, to transient disturbances are analysed to validate the model and refine damping strategies. The results indicate that the B&H EPS is well-damped, with all eigenvalues possessing negative real parts, and demonstrate the system’s resilience to small disturbances. The results are compared with the technical report on the integration of the wind power plant WPP Podveležje. This comparative analysis shows consistent patterns between the modeled calculations and empirical data, confirming the robustness of the EPS model. This alignment underscores the effectiveness of current damping mechanisms and provides a foundational strategy for enhancing system stability with increasing renewable energy penetration. The findings highlight the importance of developing advanced control strategies to sustain system stability as the integration of variable renewable energy sources continues to grow.

Diabetes mellitus is a complex, multifactorial, progressive condition with a variety of approved therapeutic options. The purpose of this study was to offer an overview of the authorized antidiabetic medicines (excluding insulin) compared with marketed products in seven European countries. Data were obtained from primary sources, including the websites of national authorities and directly from specialists in the countries of interest. The range of marketed medicines compared with the authorized group was assessed in terms of active pharmaceutical ingredients (>60% in Bulgaria, France, Serbia), brand names (>70% in Bulgaria, the Czech Republic, Romania, Serbia, Spain), pharmaceutical forms (>60% in all countries), strengths (>60% in Bulgaria, the Czech Republic, Romania, Serbia, Spain), marketing authorization holder (≥50% in all countries) and the status of medicine. Spain was found to have the highest number of products based on most of these attributes. Over 90% of authorized medicines had a pharmacy price in Serbia. Regarding the newer class of GLP-1 receptor agonists, a retail price for all approved substances was available in Bulgaria, Romania, Serbia, and Spain. Only one brand name with one concentration was found available for some agents, being susceptible to drug shortages: glibenclamide (Romania, Serbia, Spain), glipizide (the Czech Republic, Poland, Romania, Spain), glisentide (Spain), acarbose (the Czech Republic), sitagliptin (Bulgaria, Poland), vildagliptin (the Czech Republic, Poland) and saxagliptin (the Czech Republic, France, Romania, Serbia). An overview of the national and international therapeutic options may allow competent authorities and health professionals to take rapid measures in case of supply problems or health crises.

Bioeconomy is becoming a more interesting field for investments in the Republic of Croatia, especially in its small regions and local administrative units. Vukovar-Srijem county is one such unit in eastern Croatia with noticeable potential for development in a circular, carbon-neutral, and sustainable bioeconomy. Due to the nature potential represented by one of the largest forest reservoirs in Europe-Spačva basin, forestry is one of the most important county branches. Aiming to provide more inputs on the wood biomass management, the study on the biomass flow of Vukovar -Srijem c ounty was conducted in 2020 by collecting data from local stakeholders and official reports. The study results have shown that Vukovar-Srijem county has the potential to increase the efficiency level of biomass use, but specific actions on the value-chain strengthening, finalisation of wood products, and innovative ecosystem establishment are still needed. The results highlight the predominant use of sawdust for heating purposes in the VSC region, suggesting potential for optimizing its utilization towards a circular, carbon-neutral, and sustainable bioeconomy, thus offering novel insights for future research and initiatives aiming to maximize economic and environmental benefits from wood biomass residues.

The tumor suppressor proteins are key transcription factors involved in the regulation of various cellular processes, such as apoptosis, DNA repair, cell cycle, senescence, and metabolism. The tumor suppressor protein p53 responds to different type of stress signaling, such as hypoxia, DNA damage, nutrient deprivation, oncogene activation, by activating or repressing the expression of different genes that target processes mentioned earlier. p53 has the ability to modulate the activity of many other proteins and signaling pathway through protein-protein interaction, post-translational modifications, or non-coding RNAs. In many cancers the p53 is found to be mutated or inactivated, resulting in the loss of its tumor suppressor function and acquisition of new oncogenic properties. The tumor suppressor protein p53 also plays a role in the development of other metabolic disorders such as diabetes, obesity, and fatty liver disease. In this review, we will summarize the current data and knowledge on the molecular mechanisms and the functions of p53 in different pathways and processes at the cellular level and discuss the its implications for human health and disease.

Physical literacy (PL) is considered an important determinant of physical activity level (PAL), but studies have rarely examined the associations between PL and PAL in preadolescents. This study aimed to evaluate associatios between PL, PAL and sedentary behavior (SB) in preadolescents from southeastern Europe. The participants were 9- to 11-year-old children from Croatia and Bosnia and Herzegovina (n=333, 52% girls) who were tested for PL, PAL and SB. The PLAYself questionnaire was used for the evaluation of PL, while PAL was estimated by data provided throughout the Physical Activity Questionnaire for Children (PAQ-C). Pearson’s correlations and multiple regressions were calculated to identify the associations between study variables. The results revealed a significant correlation between PL and PAL in the total sample (16% of the common variance) among boys (10% of the common variance) and girls (25% of the common variance), which was additionally confirmed by multiple regression calculated between the PL subdomains and PAL (R2=0.23, 0.15, and 0.31 for total sample, boys and girls, respectively). The SB was not significantly correlated with PL (<2% of the common variance; p>0.05) or with PAL (<1% of the common variance; p>0.05). The results indicated a stronger association between PL and PAL in girls than in boys, indicating the possible influence of the types of physically demanding activities children are involved in on the studied associations. To explore causality more specifically, intervention studies are warranted.

Abstract The preschool years are characterized by additional physical development changes, enhanced motor abilities, and strengthened movement apparatus in the kid. The feet undergo morpho-functional changes at that period, particularly between the ages of 3 and 6, which result in the development of their longitudinal and transverse arches. The aim of this study was to evaluate the actual causes of foot deformity and its degree of severity in preschool-aged children, as well as the distinction in deformity representation between the sexes. The "Institution for preschool education" kindergarten "Aladin" in Tuzla is the focus of this study, which involves 74 children of both sexes, ages 3-6, were measured in 2023. Foot deformities are equally present in girls and boys. Deformities in boys are particularly pronounced: pedes recti 21 (56.8%), pedes planovalgi 6 (16.2%), while in girls: pedes recti 20 (54.1%), pedes excavati 8 (21.6%). With the Chi-square test, we determined the statistical significance of the presence of foot deformities between the sexes. By looking at the size of the chi-square (Pearson Chi-Square) 5.964a and Asymp. Sig. (2-sided) .544 tells us that there is no statistically significant difference in the representation of foot deformities between the sexes and that these deformities are equally represented. Because foot deviations can lead to problems kindergarten kids' foot arches need to be continuously monitored. This allows for timely intervention and the adoption of suitable treatment procedures to avoid the development of deformities. Keywords: children, preschool strature, foot, deformity, gender.

Abstract OBJECTIVES To overcome some of the challenges of endoscopic minimally invasive valve surgery, an automated annular suturing device has been used in aortic and mitral valve replacement surgeries. The current study investigates early clinical outcomes of patients who received aortic or mitral valve replacement with the help of the RAM® device as first experiences in minimally invasive valve surgery. METHODS Between September 2020 and June 2023, 66 consecutive patients (mean age 61.8 ± 11 years) underwent endoscopic minimally invasive aortic or mitral valve replacement through right anterior mini-thoracotomy at 2 cardiac surgery referral centres in Germany. The RAM® device was used in all Patients. 3.5 and 5.0 sizes were used in 16.7% and 83.3% of patients, respectively. Aortic, mitral and double valve surgery was performed in 81.8%, 15.2% and 1.5% of patients, respectively. Clinical data were prospectively entered into our institutional database. RESULTS Cardiopulmonary bypass time and cross-clamping time were 97.9 ± 20.9 and 66 ± 15.7 min, respectively. Intensive care unit and hospital stays were 1 [1–2] and 9 [7–13] days, respectively. No paravalvular leak and no other intraoperative complications occurred. 30-day and in-hospital mortality were zero. Conversion to sternotomy occurred in 1 (1.5%) patient due to bleeding. CONCLUSIONS The usage of the RAM® device is a safe, feasible and effective approach to the endoscopic implantation of aortic or mitral valves and yield excellent early outcomes. Larger size studies are needed to evaluate the efficacy and safety of RAM® device.

ABSTRACT Population genetic studies have shown that the Bosnian-Herzegovinian (B&H) population is a part of the European gene pool, but there has been limited information on the genetic structure of ancient B&H populations. This study aimed to determine the frequency and distribution of mitochondrial DNA (mtDNA) haplogroups for a medieval Bosnian population. Thirty-four samples, excavated from medieval necropolises located within the borders of medieval Bosnia, were analyzed. Sequencing of the mtDNA hypervariable segment 1 (HVS1) region and RFLP analysis were performed for haplogroup determination. All 32 samples were identified as haplogroup H, with subhaplogroups H2a and H5 in 30 and 2 samples, respectively. The frequency of the H haplogroup was significantly different between the studied samples and previous studies of contemporary B&H populations, where the H haplogroup frequency was approximately half that of the ancient population studied here. A significant difference in H haplogroup frequency compared with other medieval populations outside of Bosnia was also observed: the ancient B&H population is most similar to ancient Italians. These results provide insight into the mitochondrial landscape of populations that inhabited the territory of present-day Bosnia and Herzegovina in the Middle Ages. Our study reveals that inhabitants of medieval Bosnia carried genetic lineages that exist today in B&H populations, suggesting continuity of mtDNA haplogroups over a long period of time, regardless of various historical demographic events that shaped the genetic structure of the modern B&H population.