In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGESNV uses deep learning and a ctDNA-specific feature space to increase SNV signal-to-noise enrichment in WGS by ~300× compared to previous WGS error suppression. MRD-EDGECNV also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1 Gb to 200 Mb, vastly expanding its applicability within solid tumors. We harness the improved performance to identify MRD following surgery in multiple cancer types, track changes in TF in response to neoadjuvant immunotherapy in lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal-to-noise enrichment in MRD-EDGESNV enables plasma-only (non-tumor-informed) disease monitoring in advanced melanoma and lung cancer, yielding clinically informative TF monitoring for patients on immune-checkpoint inhibition. Detection of circulating tumor DNA using MRD-EDGE, a machine-learning-guided single-nucleotide variant and copy-number variant detection platform for signal enrichment, enables monitoring of minimal residual disease and immunotherapy response in settings of low tumor burden.

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.

Abstract The goal of this research was to determine the effects of programmed work on the development of specific motor skills in young soccer players. The sample of subjects in this research were football players aged 11 and 12 and they were divided into two equal groups of 30 entities. All participants are involved in the regular training process in their football clubs. The research problem was to determine whether there are positive effects of programmed work on the development of specific motor skills. A total of 6 variables from the area of specific motor skills were used in the research. The experimental work program was carried out over a period of three months and included 38 training units. After initial testing and successfully implemented programmed work and final testing, a significant impact of programmed work on the development of specific motor skills was determined. Specific motor skills that were evaluated on 6 variables in the experimental group showed a significant difference on 4 variables. Keywords: specific motor abilities, work program, training effects, young soccer players

Mitochondria are the energy-producing organelles of mammalian cells with critical involvement in metabolism and signaling. Studying their regulation in pathological conditions may lead to the discovery of novel drugs to treat, for instance, cardiovascular or neurological diseases, which affect high-energy-consuming cells such as cardiomyocytes, hepatocytes, or neurons. Mitochondria possess both protein-coding and noncoding RNAs, such as microRNAs, long noncoding RNAs, circular RNAs, and piwi-interacting RNAs, encoded by the mitochondria or the nuclear genome. Mitochondrial RNAs are involved in anterograde-retrograde communication between the nucleus and mitochondria and play an important role in physiological and pathological conditions. Despite accumulating evidence on the presence and biogenesis of mitochondrial RNAs, their study continues to pose significant challenges. Currently, there are no standardized protocols and guidelines to conduct deep functional characterization and expression profiling of mitochondrial RNAs. To overcome major obstacles in this emerging field, the EU-CardioRNA and AtheroNET COST Action networks summarize currently available techniques and emphasize critical points that may constitute sources of variability and explain discrepancies between published results. Standardized methods and adherence to guidelines to quantify and study mitochondrial RNAs in normal and disease states will improve research outputs, their reproducibility, and translation potential to clinical application.

Aim To assess the association of single nucleotide polymorphisms (SNPs) in the ACE2 and TMPRSS2 genes with COVID-19 severity and key biomarkers. Methods The study involved 750 COVID-19 patients from Bosnia and Herzegovina, divided into three groups: mild, moderate, and severe cases. Genetic variations within the ACE2 (rs2285666) and TMPRSS2 (rs2070788) genes were examined with real-time polymerase chain reaction. Biochemical markers were determined with standard procedures. Results There was a significant difference in the rs2070788 genotype distribution between patients with mild and moderate symptoms, but not between other groups. For the rs2285666 polymorphism, no significant difference in genotype distribution was found. In patients with mild symptoms, carriers of the GG genotype of rs2070788 had significantly higher total bilirubin levels than carriers of the AA genotype. Similarly, carriers of the TT genotype of rs2285666 had significantly higher activated partial thromboplastin time and international normalized ratio, and lower lactate dehydrogenase levels compared with the CC genotype. Among patients with severe symptoms, carriers of the GG genotype showed significantly higher potassium levels than carriers of the AA genotype, while carriers of the TT genotype showed significantly higher erythrocyte count as well as hemoglobin and hematocrit levels compared with the CC genotype. Conclusion This study highlights the role of genetic factors, particularly SNPs in the ACE2 and TMPRSS2 genes, in determining COVID-19 severity, aiding patient risk assessment and prognosis.

Abstract The methodology for the evaluation of long-term exposure to the overhead line magnetic field is presented, in this paper. The developed methodology is based on the ambient temperature measurements and phase conductors’ height measurements to find a linear regression model to determine phase conductors’ height changes for different ambient temperatures. Based on the overhead transmission line geometry, and datasets about historical overhead line phase current intensity values and ambient temperatures long-term magnetic field exposure can be determined. For magnetic flux density determination, a method based on artificial neural networks is used. The methodology is applied to the case study of overhead line that connect substations Sarajevo 10 and Sarajevo 20. A period of one year is analyzed and magnetic flux density values are determined. The obtained results indicate that during the analyzed period for significant amounts of time magnetic flux density values surpass the recommended values for long-term exposure.

Propranolol hydrochloride, a non-cardio-selective beta blocker, is used to treat several conditions in children, including hypertension, arrhythmias, hyperthyroidism, hemangiomas, etc. Commercial liquid formulations are available in Europe and the US, but they have disadvantages, such as limited stability, bitter taste, and the need for multiple daily doses due to the drug’s short half-life. Considering these limitations, controlled-release solid formulations, such as microparticles, may offer a better solution for pediatric administration. The main objective of this study was to formulate an encapsulation system for propranolol hydrochloride, based on sodium alginate and other polysaccharide polymers, to control and prolong its release. Microparticles were prepared using the ionotropic gelation method, which involves instilling a polymer solution into a solution of gelling ions via the extrusion technique. Physicochemical characterization was conducted by assessing the entrapment efficiency, drug loading, swelling index, microparticle size, rheological properties, and surface tension. In order to improve the characteristics of the tested microparticles, selected formulations were coated with chitosan. Further experimental work included differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) analysis, and SEM imaging. This in vitro release study showed that chitosan-coated microparticles demonstrate favorable properties, suggesting a novel approach to formulating pediatric dosage forms, although further optimization is necessary.

Background: During pregnancy, physiological changes can increase oxidative stress (OS) in both mothers and fetuses. The use of anesthesia for cesarean sections (CSs) could exacerbate this stress due to its impact on the ischemia-reperfusion effect. Our study aimed to explore the effects of target-controlled infusion of propofol on OS during CSs, and to compare these effects with those of spinal and thiopental-sevoflurane anesthesia. Methods: The study included ninety parturients undergoing elective CS, allocated into three groups: Group S (spinal) (n = 30), Group P (propofol) (n = 30), and Group TS (thiopental-sevoflurane) (n = 30). Venous blood samples were taken from mothers at three time points, before, during, and after surgery, and one sample was taken from the umbilical vein after delivery. Blood samples were analyzed with the thiobarbituric acid reactive substances (TBARS) assay and blood gas analysis. A statistical comparison between groups was obtained by one-way analysis of variance (ANOVA) and the Wilcoxon test where appropriate. Results: Levels of TBARS after the induction of anesthesia were lower in all groups compared to values preoperatively. In Group P, TBARS levels started to decrease in the first five minutes after the induction (1.90 ± 0.47; P < 0.001) and had significantly lower values compared to Group S (2.22 ± 0.21) and Group TS (2.40 ± 0.20). Two hours after surgery, TBARS values were the lowest in Group P (1.76 ± 0.15, P<0.001), compared to Group S (2.18 ± 0.24) and Group TS (2.41 ± 0.21). TBARS value in umbilical venous blood was significantly lower in Group P (1.56 ± 0.16, P < 0.001) compared to Group S (2.18 ± 0.17) and Group TS (2.09 ± 0.09). Umbilical cord venous blood gas values (pH, PCO2, HCO3, lactates, and base excess (BE)) were not different between the groups, except for PO2, which was significantly lower in Group S (20.5 ± 5.0; P < 0.001) compared to Group P (36.5 ± 19.2) and Group TS (33.5 ± 10.1). Conclusion: Target-controlled infusion of propofol anesthesia could be advantageous for parturients with compromised oxidative status, especially those undergoing emergency CSs when general anesthesia is required.

Abstract This paper investigates the strategic placement of capacitor banks in the distribution network of Gračanica, with a specific focus on the medium-voltage feeder Grades. The primary objective is to optimize voltage profiles, minimize power losses, and enhance the overall performance of the distribution network. The significance of this research lies in its thorough examination of optimal capacitor placement within the medium-voltage (MV) branch of distribution networks, specifically considering the intricate interplay between capacitor banks and MV branch components, underlining the necessity for informed decisions in the context of distributed generators (DG) integration to enhance overall network performance. The study further investigates the impact of integrating DGs on these objectives on capacitor placement in the MV feeder. Employing the DIgSILENT PowerFactory software tool for modelling the MV feeder and utilizing a genetic algorithm for capacitor placement optimization, the study underscores the robustness of this approach in handling various conditions and seeking optimal solutions. Simulation results demonstrate that strategically placing capacitor banks and integrating DGs can significantly improve the voltage profile and reduce power losses within the distribution system. The findings of this research support 2MVA of concentrated DGs at the middle of the line as the most efficient and most economically beneficial situation on the medium-voltage feeder Grades study case and contribute valuable insights, serving as a reference for future studies on optimal capacitor placement.

Abstract Voltage unbalance and voltage variations are common issues in low voltage distribution networks caused by unbalanced connection of single-phase loads and electric vehicles (EVs) among phases. Part of the real low voltage grid in Bosnia and Herzegovina, in the vicinity of the town of Tešanj, was analysed. The impact on single-phase consumer and single-phase EVs penetration was analysed. The grid was modelled using DIgSILENT PowerFactory software. Three cases of the distribution of consumers by phases were analysed. Each of the three cases is expanded with four scenarios depending on the penetration of EV into the grid. Results showed that none of the twelve scenarios remained within the permissible limits of −10% voltage variation limit of EN 50160 for phase A. Seven of the twelve scenarios exceeded voltage unbalance limits +2% according to EN 50160.

Halogenated boroxine K2[B3O3F4OH] (HB), an inorganic derivative of cyclic anhydride of boronic acid, is patented as a boron-containing compound with potential for the treatment of both benign and malignant skin changes. HB has effectively inhibited the growth of several carcinoma cell lines. Because of the growing interest in autophagy induction as a therapeutic approach in bladder carcinoma (BC), we aimed to assess the effects of HB on metabolic phenotype and autophagy levels in 5637 human bladder carcinoma cells (BC). Cytotoxicity was evaluated using the alamar blue assay, and the degree of autophagy was determined microscopically. Mitochondrial respiration and glycolysis were measured simultaneously. The relative expression of autophagy-related genes BECN1, P62, BCL-2, and DRAM1 was determined by real-time PCR. HB affected cell growth, while starvation significantly increased the level of autophagy in the positive control compared to the basal level of autophagy in the untreated negative control. In HB-treated cultures, the degree of autophagy was higher compared to the basal level, and metabolic phenotypes were altered; both glycolysis and oxidative phosphorylation (OXPHOS) were decreased by HB at 0.2 and 0.4 mg/mL. Gene expression was deregulated towards autophagy induction and expansion. In conclusion, HB disrupted the bioenergetic metabolism and reduced the intracellular survival potential of BC cells. Further molecular studies are needed to confirm these findings and investigate their applicative potential.

Introduction: Despite ongoing findings on the relationship between liver fibrosis in nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS), this association in diabetic patients remains unclear. Early diagnosis of liver fibrosis is important due to the easily available diagnostic tools, such as noninvasive indices that combine clinical and laboratory variables, and the possibility of preventing its complications in type 2 diabetes mellitus (T2DM) patients with MetS. Objective: This study examines the potential predictive values of non-invasive liver fibrosis indices for MetS in T2DM patients. Patients and methods: Over the course of a two-year prospective, observational, clinical study, 80 individuals with T2DM randomly selected from the Diabetes Counseling Centers of the Public Institution Health Center of Sarajevo Canton were divided into two groups: T2DM-MetS and T2DM-non-MetS, based on the development of MetS. The study included individuals with T2DM aged 30 to 60 who were clinically diagnosed without MetS, voluntarily agreed to participate, and provided complete data in the collection forms. Serum samples from the patients were assessed for levels of liver enzymes, platelet counts, total cholesterol, high-density lipoprotein cholesterol, fasting glucose, and triglycerides. Various equations were utilized to calculate liver fibrosis indices, including the Aspartate Aminotransferase to Platelet Ratio Index (APRI), Aspartate Aminotransferase to Gamma-Glutamyl Transferase to Platelet Ratio (AGPR), Aspartate Aminotransferase to Alanine Aminotransferase Ratio to Platelet Ratio Index (AARPRI), Fibrosis-4 (FIB-4) Index, Forns Index, and Gamma-Glutamyl Transpeptidase to Platelet Ratio (GPR). Receiver operating characteristic (ROC) analysis was utilized to determine the usefulness of noninvasive liver fibrosis indices for diagnosing MetS in individuals with T2DM. Logistic regression analysis was used to predict the onset of MetS in T2DM patients. Results: Significant differences in the values of APRI (p<0.001), AGPR (p<0.05), AARPRI (p<0.001), and the FIB-4 index (p=0.001) were observed in T2DM-MetS individuals compared to T2DM-non-MetS. According to ROC analysis, the area under the curve (AUC) was found to be highest for APRI (0.84), followed by FIB-4 (0.783) and AARPRI (0.747). Logistic regression analysis identified APRI as an independent positive predictor of MetS (OR 18.179, 95% CI 6.035-24.58, p=0.015). Conclusion: This research highlights the effectiveness of the APRI index as a reliable predictor of MetS development in individuals with T2DM.

Abstract In times when AI’s development and research is moving at an unprecedented speed, this paper explores its role in retail banking. The results presented are part of a wider research of market readiness and AI acceptance, especially in developing economies. The research was conducted in Bosnia and Herzegovina (B&H). The quantitative portion consisted of a survey completed by 671 respondents. This paper focuses on the influence of social factors (perceived humanness, perceived social interactivity, and perceived social presence) on the attitudes towards – and subsequently acceptance of - AI-based services. Chatbots, specifically ChatGPT-4, were the technology the research focused on. The results indicate that perceived humanness and perceived social interactivity have a positive effect on attitudes – and acceptance – of AI-based services. This research could not prove that there is a positive relationship between social presence and attitudes towards AI-based services. The positive relationship between attitude and acceptance was proven as well.