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.

PFAS are ubiquitous industrial chemicals with known adverse health effects, particularly on the liver. The liver, being a vital metabolic organ, is susceptible to PFAS-induced metabolic dysregulation, leading to conditions such as hepatotoxicity and metabolic disturbances. In this study, we investigated the phenotypic and metabolic responses of PFAS exposure using two hepatocyte models, HepG2 (male cell line) and HepaRG (female cell line), aiming to define phenotypic alterations, and metabolic disturbances at the metabolite and pathway levels. The PFAS mixture composition was selected based on epidemiological data, covering a broad concentration spectrum observed in diverse human populations. Phenotypic profiling by Cell Painting assay disclosed predominant effects of PFAS exposure on mitochondrial structure and function in both cell models as well as effects on F-actin, Golgi apparatus, and plasma membrane-associated measures. We employed comprehensive metabolic characterization using liquid chromatography combined with high-resolution mass spectrometry (LC-HRMS). We observed dose-dependent changes in the metabolic profiles, particularly in lipid, steroid, amino acid and sugar and carbohydrate metabolism in both cells as well as in cell media, with HepaRG cell line showing a stronger metabolic response. In cells, most of the bile acids, acylcarnitines and free fatty acids showed downregulation, while medium-chain fatty acids and carnosine were upregulated, while the cell media showed different response especially in relation to the bile acids in HepaRG cell media. Importantly, we observed also nonmonotonic response for several phenotypic features and metabolites. On the pathway level, PFAS exposure was also associated with pathways indicating oxidative stress and inflammatory responses. Taken together, our findings on PFAS-induced phenotypic and metabolic disruptions in hepatocytes shed light on potential mechanisms contributing to the broader comprehension of PFAS-related health risks.

Objectives: Lamivudin has been approved for the treatment of chronic hepatitis B but experience with lamivudin treatment for acute severe hepatitis B is still limited. Fulminant hepatitis develops in 1% of patients with acute hepatitis B. Severe acute hepatitis B in immunocompetent patients may progress to fulminant hepatitis and death. Aim: To evaluate the efficasy of lamivudine for the treatment of acute severe hepatitis B virus infection in imunocompetent adults in Clinic for infectious diseases Banja Luka. Patients and methods: In the period of 2006-2024 years, 12 immunocompetent patients (4 women, 8 men, age 24-77 years) with severe acute hepatitis B were treated with lamivudin. All 12 patients fulfil at least two of the criteria for severe acute hepatitis B infection: 1. hepatic encephalopathy; 2. total bilirubin 210 micromole per litre; and severe coagulopathy (international normalized ratio-INR was 4.5 ± 6.4 or prothrombin time-PT < 40%). All patients had evidence of severe hepatocyte lysis. Nine patients had rapid increase of total bilirubin and contemporary decrease of alanine aminotransferase level, which escalate risk of development of fulminant hepatitis B. All patients received lamivudin at a dose 100 mg per day. Results: Ten patients responded well to the treatment and their biochemical parameters improved rapidly. Within 1-6 months, the HBsAg was undetectable in 10 out of 12 investigated patients. Protective anti-HBs antibodies developed in 10 of them in 1-6 months. The corticosteroid therapy was short-term in 2 of 12 patients. Two patient developed fulminant hepatitis B and died after the lamivudine therapy was initiated. Lamivudine treatment was well tolerated in all patients. Conclusion: Lamivudin induces a prompt clinical, biochemical and serological response in immunocompetent patients with severe acute hepatitis B. Early treatment with lamivudine probably decreases the risk of progression to fulminant hepatitis in patients with severe acute hepatitis B.

Abstract Guidewire loss is a rare complication of central venous catheterization. A 65-year-old male was hospitalized in a high-dependency unit for exacerbation of chronic obstructive pulmonary disease, pneumonia, erythrocytosis, and clinical signs of heart failure. Upon admission, after an unsuccessful right jugular approach, a left jugular central venous catheter was placed. The next day, chest radiography revealed the catheter located in the left parasternal region, with suspected retention of the guidewire, visually confirmed by the presence of its proximal end inside the catheter. The left parasternal location of the catheter and the typical projection of the guidewire in the coronary sinus, later confirmed by echocardiography, raised suspicion of a persistent left superior vena cava (PLSVC). Agitated saline injected into the left antecubital vein confirmed bubble entry from the coronary sinus into the right atrium. After clamping the guidewire, the catheter was carefully retrieved along with the guidewire without any complications. This is the first reported case of guidewire retention in PLSVC and coronary sinus. It underscores the potential causes of guidewire loss and advocates preventive measures to avoid this potentially fatal complication.

BACKGROUND As artificial intelligence within digital processes continues to advance and replace conventional manual workflows, it is crucial that digital data are consistent with analog data. The aim was to evaluate the validity and time efficiency of digital cast analysis on digital models in comparison with the manual, gold standard, cast analysis on plaster models. METHODS Cast analysis was performed on 30 patients in three various methods: manually measured variables on plaster models (MP), manually measured variables on digital three-dimensional models (MD), and automatically measured variables on digital three-dimensional models (AD) on digital models. Digital cast analysis was performed in CS Model+. Analyses included metrical and categorical variables and the required work time. Measurements in MD and AD were validated to MP. Validity of the metrical variables was analyzed with Bland-Altman, Dahlberg's formula, and paired sample t test. Categorical variables were validated by Cohen's Kappa. Work time was analyzed with Wilcoxon signed-rank test. RESULTS Metrical variables had measurement errors ranging 0.4 to 1.4 mm between MP-MD, and 0.6 to 3.2 mm between MP-AD. Observations of categorical variables had a moderate to strong (0.65 to 0.9) level of agreement between MP-MD, and a weak to moderate (0.4 to 0.68) level of agreement between MP-AD. Data for dental stage, vertical, and transversal relation was not provided in AD. Cast analysis was performed quicker digitally, P ≤ 0.05. CONCLUSIONS Digital cast analysis is consistent with manual cast analysis for metrical variables. Analyses of categorical variables show a weak level of agreement with automatic digital analysis, such as space conditions and midline assessments. Digital cast analysis optimizes time compared with manual cast analysis, with automatic analysis being the fastest.

Aim: To assess Red blood cell Distribution Width (RDW) and platelet indices values in patients with type 2 diabetes mellitus (T2DM) and to verify its association with kidney dysfunction (KD). Patients and Methods: A cross-sectional study included 149 T2DM subjects divided into two groups with (T2DM – KD; n=52) and without (T2DM-nKD; n=97) presence of kidney dysfunction and 30 healthy subjects. White Blood Cells (WBC) count, C-reactive protein (CRP), fibrinogen, RDW, platelet indices, urea, and creatinine, were measured in all participants. Kidney function was evaluated by the estimated glomerular filtration rate (eGFR) calculated using the simplified Modification of Diet in Renal Disease (MDRD) formula. Results: T2DM-KD subjects showed statistically significantly higher values of the parameters RDW (p<0.01), Mean Platelet Volume - MPV (p<0.01), Platelet Distribution Width-PDW (p<0.01), Platelecrit-PCT (p<0.01), and Platelet Mass Index-PMI (p<0.01) compared to T2DM-nKD subjects, and statistically significantly lower values of the WBC count in T2DM-KD subjects compared to subjects suffering from T2DM without kidney dysfunction (p<0.01). ROC curve analysis revealed that RDW (sensitivity of 80.8%, specificity of 78.3%), MPV (sensitivity of 75%, specificity of 78.4 %), and PDW (sensitivity of 80.8%, specificity of 83.5%) could be used as markers in distinguishing between T2DM subjects with and without kidney dysfunction. Conclusion: This study confirms the reliability of the RDW,MPV, and PDW as simple, low cost and useful markers in distinguishing between T2DM subjects with and without kidney dysfunction.

Abstract This paper presents an artificial neural network (ANN) based method for overhead lines magnetic flux density estimation. The considered method enables magnetic flux density estimation for arbitrary configurations and load conditions for single-circuit, multi-circuit, and also overhead lines that share a common corridor. The presented method is based on the ANN model that has been developed using the training dataset that is produced by a specifically designed algorithm. This paper aims to demonstrate a systematic and comprehensive ANN-based method for simple and effective overhead lines magnetic flux density estimation. The presented method is extensively validated by utilizing experimental field measurements as well as the most commonly used calculation method (Biot - Savart law based method). In order to facilitate extensive validation of the considered method, numerous magnetic flux density measurements are conducted in the vicinity of different overhead line configurations. The validation results demonstrate that the used method provides satisfactory results. Thus, it could be reliably used for new overhead lines’ design optimization, as well as for legally prescribed magnetic flux density level evaluation for existing overhead lines.

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.

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.

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.

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.