Digital twins (DTs) are increasingly used to monitor and secure Industrial Control Systems (ICS), yet detecting stealthy False Data Injection Attacks (FDIAs) that manipulate system states within normal physical bounds remains challenging. Deep learning anomaly detectors often over-generalize such subtle manipulations, while classical fault detection methods do not scale well in highly correlated multivariate systems. We propose a closed-loop Information-Theoretic Digital Twin (IT-DT) framework for real-time anomaly detection. N4SID identification is combined with steady-state Kalman filtering to quantify residual distribution shifts via closed-form KL divergence, capturing both mean deviations and malicious cross-covariance shifts. Evaluations on the SWaT and WADI datasets show that IT-DT achieves F1-scores of 0.832 and 0.615, respectively, with better precision than deep learning baselines such as TranAD. Computational profiling indicates that the analytical approach requires minimal memory and provides approximately a 600x inference speedup over transformer-based methods on CPU hardware. This makes the framework suitable for resource-constrained industrial edge controllers without GPU acceleration.

Diabetes mellitus is a growing global health challenge, and digital health technologies offer new opportunities to support self-management. Mobile applications can benefit both patients and healthcare professionals; however, awareness and integration of these tools into community pharmacy practice remain limited. As accessible frontline providers, pharmacists are well positioned to promote digital health, yet their readiness and engagement require further investigation. A cross-sectional survey was conducted among community pharmacists in Serbia using a structured questionnaire. Developed through a consensus-based process, the instrument assessed pharmacists’ awareness, attitudes, and experiences with digital health technologies, focusing on mobile applications for diabetes self-management. Only 15.8% of pharmacists were aware of such applications, and 2.4% reported receiving relevant training. Higher digital health technology literacy was associated with greater awareness, confidence, and preference for digital learning. Most participants supported expanding pharmacists’ roles in advising patients on digital tools and expressed interest in structured education and official guidance. These findings indicate limited awareness and training in mobile health applications among community pharmacists. Enhancing digital competencies through targeted education and structured guidance may facilitate greater integration of digital tools into routine pharmacy practice and strengthen pharmacists’ roles in chronic disease management.

OBJECTIVE This study aimed to investigate which of the two vitamin K antagonists, warfarin or acenocoumarol, provides more stable anticoagulation control in patients with mechanical heart valves and atrial fibrillation. PATIENTS AND METHODS This was a prospective, one-year clinical cohort study. In total, 73 outpatients with mechanical heart valves and atrial fibrillation who were already treated with warfarin or acenocoumarol were recruited from the Blood Transfusion Institute of the Federation of Bosnia and Herzegovina. The prothrombin time target values, expressed as the international normalized ratio (INR), were 2.0-3.0/4.0. Numerical data between the treatment groups were summarized descriptively. RESULTS Patients in the warfarin (N=35) and acenocoumarol (N=38) treatment groups were similar in terms of sex, age, body mass index, body surface area, and number of concomitant drugs known to interact with vitamin K antagonists. The number of INR measurements per patient, number of INR measurements within the therapeutic range per patient, mean time interval between successive INR measurements, and mean INR values across consecutive measurements were similar in both groups. However, compared to acenocoumarol, warfarin treatment seemed to be associated with more stable anticoagulation, i.e., with a higher mean time in the therapeutic range (TTR) (76.1±24.2 vs. 69.1±21.5%) and a smaller proportion of patients below all predefined TTR thresholds (<60%, <65%, and <70%). CONCLUSION Our unadjusted descriptive results suggested that warfarin, compared to acenocoumarol, may provide more stable and therefore safer anticoagulation control in patients with mechanical heart valves and atrial fibrillation. To confirm this, larger prospective clinical studies are needed in patients with mechanical heart valves with or without atrial fibrillation.

Background and Objectives: Mitogen-activated protein kinases (p38, JNK, ERK1/2) regulate key cellular processes essential for kidney development. Disruptions in these signaling pathways can lead to congenital anomalies of the kidney and urinary tract (CAKUT), a major cause of pediatric kidney disease. This study investigates and compares the expression of these molecules in normal fetal kidneys and CAKUT-affected tissues. Materials and Methods: Forty-three human fetal kidney samples, including controls and specimens with horseshoe, hypoplastic, and dysplastic kidneys, were analyzed across developmental phases 2–4 using immunofluorescence. Quantitative image analysis and statistical comparisons were performed between developmental stages and phenotypes. Results: ERK1/2 expression increased during late development in control kidneys but was significantly reduced in hypoplastic kidneys. p38 showed phase-dependent alterations, with early upregulation in dysplastic kidneys and late elevation in horseshoe kidneys. JNK exhibited significant phase-dependent upregulation in horseshoe kidneys. P38 displayed dynamic expression associated with nephron maturation. Conclusions: MAPK pathways show distinct developmental and phenotype-specific expression patterns in human fetal kidneys. These differences reflect divergent pathogenic mechanisms in CAKUT and may support improved molecular characterization of congenital renal anomalies.

Background/Objectives: Congenital anomalies of the kidney and urinary tract (CAKUTs) represent the leading cause of pediatric chronic kidney disease, yet the molecular mechanisms underlying these malformations remain incompletely understood. While genetic studies have identified numerous CAKUT-associated genes, conventional knockout approaches often result in embryonic lethality or fail to reveal tissue-specific gene functions. This review aims to synthesize findings from conditional knockout mouse studies that have elucidated the spatiotemporal requirements of key signaling pathways during kidney development. Methods: We conducted a narrative synthesis of studies employing Cre-loxP conditional gene targeting in mouse models, identified through systematic searches of PubMed and cross-referencing of key primary research. Studies were selected based on their use of lineage-specific Cre drivers (Six2-Cre, Hoxb7-Cre, Foxd1-Cre) to investigate nephron progenitor maintenance, ureteric bud branching morphogenesis, and stromal–epithelial interactions. Results: Conditional knockout studies have redefined CAKUT pathogenesis as a disorder of dose-dependent signaling, temporal regulation, and inter-compartmental communication. WNT/β-catenin signaling operates in a biphasic, dose-dependent manner in nephron progenitors, with Six2-Cre-mediated β-catenin deletion causing premature progenitor depletion. BMP and FGF pathways demonstrate dose-dependent and context-specific functions in progenitor maintenance, while GDNF/RET signaling is essential for ureteric bud outgrowth and branching. Importantly, stromal-specific deletions have uncovered non-cell-autonomous mechanisms regulating nephron formation. Haploinsufficiency studies demonstrate that partial pathway disruption can reduce nephron endowment without overt CAKUT, predisposing to adult-onset hypertension and chronic kidney disease. Conclusions: Conditional gene targeting has mechanistically redefined CAKUT from a collection of structural malformations to a spectrum of disorders arising from quantitative perturbations in lineage-specific signaling networks. These findings establish that phenotypic severity is determined by the degree of pathway disruption, the developmental timing of insult, and the compartment affected, providing a framework for interpreting oligogenic interactions and variable penetrance in human CAKUTs.

Background/Objectives: Patients with local/locally advanced gastric cancer (GC) undergo gastrectomy/lymphadenectomy, but recurrences are common and the disease usually progresses to death. Tertiary lymphoid structures (TLS) of varying maturity can be observed in the immune microenvironment of the primary tumor. The aim of the study was to analyze the association of TLSs and their immune cellular composition with clinicopathological variables and overall survival (OS). Methods: In a cohort of 92 GC patients who underwent gastrectomy, the characteristics of tumor core TLSs were assessed and the density of cytotoxic CD8+ T cells and regulatory FOXP3+ T cells was analyzed. Results: Patients with TLS had a better OS than patients without TLS, 19.4 months vs. 9.2 months (p = 0.001). Immature TLSs were more frequently associated with lymphovascular invasion and regional lymph node metastasis (p = 0.014 and p = 0.034). Mature TLSs had a higher FOXP3+ T lymphocyte density and lower CD8+/FOXP3+ ratio than immature TLSs (p = 0.029 and p = 0.013), and patients had a longer OS than patients with immature TLSs, 34.55 months vs. 15.2 months (p = 0.033). In patients with TLS-positive GC, cases with FOXP3+ T cells had a shorter OS, 12.7 months vs. 47.5 months (p < 0.001). Conclusions: The presence of FOXP3+ cells in TLS is associated with significantly shorter OS of patients with local/locally advanced GC.

Rheumatoid arthritis (RA) may present with extra-articular pulmonary manifestations, including rheumatoid lung nodules. Leflunomide is an effective disease-modifying antirheumatic drug, but increasing case reports suggest an association with accelerated pulmonary nodulosis. We describe a 61-year-old woman with long-standing seropositive RA who developed left-sided lower chest pain, generalized weakness, fatigue, and loss of appetite after switching from methotrexate to leflunomide 20 mg/day. CT imaging demonstrated multiple bilateral cavitary nodules predominantly in the lower lobes. Extensive evaluation (bronchoscopy with microbiology, QuantiFERON-TB Gold, and malignancy assessment) was negative, and video-assisted thoracoscopic surgery lung biopsy showed necrotizing granulomatous inflammation consistent with rheumatoid nodules. The leflunomide dose was initially reduced and then discontinued, and methotrexate was reintroduced; at the four-month follow-up, the patient was clinically well without synovitis, and a CT eight months later showed near-complete regression of prior nodules, with residual left basal fibrotic changes containing calcifications and a remaining non-cavitary right lower-lobe nodule. Clinicians should consider leflunomide-associated pulmonary nodulosis in RA patients with new cavitary nodules after excluding infectious and malignant etiologies, and discontinuation of the drug may lead to radiologic improvement.

BACKGROUND Breast cancer is a leading cause of mortality and morbidity among females worldwide. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we provided an updated comprehensive assessment of the epidemiological trends, disease burden, and risk factors associated with breast cancer globally, regionally, and nationally from 1990 to 2023. METHODS Breast cancer incidence, mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) were estimated by age and sex for 204 countries and territories from 1990 to 2023. Mortality estimates were generated using GBD Cause of Death Ensemble models, leveraging data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Mortality-to-incidence ratios were calculated to derive both mortality and incidence estimates. Prevalence was calculated by combining incidence and modelled survival estimates. YLLs were established by multiplying age-specific deaths with the GBD standard life expectancy at the age of death. YLDs were estimated by applying disability weights to prevalence estimates. The sum of YLLs and YLDs equalled the number of DALYs. Breast cancer burden attributable to seven risk factors was examined through the comparative risk assessment framework. The GBD forecasting framework was used to forecast breast cancer incidence and mortality from 2024 to 2050. Age-standardised rates were calculated for each metric using the GBD 2023 world standard population. FINDINGS In 2023, there were an estimated 2·30 million (95% uncertainty interval [UI] 2·01 to 2·61) breast cancer incident cases, 764 000 deaths (672 000 to 854 000), and 24·1 million (21·3 to 27·5) DALYs among females globally. In the World Bank low-income group, where a low age-standardised incidence rate (ASIR) was estimated (44·2 per 100 000 person-years [31·2 to 58·4]), the age-standardised mortality rate (ASMR) was the highest (24·1 per 100 000 [16·8 to 31·9]). The highest ASIR was in the high-income group (75·7 per 100 000 [67·1 to 84·0]), and the lowest ASMR was in the upper-middle-income group (11·2 per 100 000 [10·2 to 12·3]). Between 1990 and 2023, the ASIR in the low-income group increased by 147·2% (38·1 to 271·7), compared with a 1·2% (-11·5 to 17·2) change in the high-income group. The ASMR decreased in the high-income group, changing by -29·9% (-33·6 to -25·9), but increased by 99·3% (12·5 to 202·9) in the low-income group. The increase in age-standardised DALY rates followed that of ASMRs. Risk factors such as dietary risks, tobacco use, and high fasting plasma glucose contributed to 28·3% (16·6 to 38·9) of breast cancer DALYs in 2023. The risk factors with a decrease in attributable DALYs between 1990 and 2023 were high alcohol use and tobacco. By 2050, the global incident cases of breast cancer among females were forecast to reach 3·56 million (2·29 to 4·83), with 1·37 million (0·841 to 2·02) deaths. INTERPRETATION The stable incidence and declining mortality rates of female breast cancer in high-income nations reflect success in screening, diagnosis, and treatment. In contrast, the concurrent rise in incidence and mortality in other regions signals health system deficits. Without effective interventions, many countries will fall short of the WHO Global Breast Cancer Initiative's ambitious target of achieving an annual reduction of 2·5% in age-standardised mortality rates by 2040. The mounting breast cancer burden, disproportionately affecting some of the world's most vulnerable populations, will further exacerbate health inequalities across the globe without decisive immediate action. FUNDING Gates Foundation, St Jude Children's Research Hospital.

Background Community pharmacies must balance public health obligations with economic sustainability. However, integrated methods that jointly manage medical and non-medical inventory in community pharmacies in LMICs are limited. Objective To develop and apply a dual-matrix model separating medical from non-medical products into operational control categories and introducing a High–Medium–Low profitability (HML-P) classification. Methods We conducted a retrospective, descriptive analysis of all items handled in six community pharmacies in the Republic of Srpska, Bosnia and Herzegovina, during the analyzed 2022 year (12-month period) (n = 10,541). Medical products were classified by Always Better Control (ABC) by purchase value and Fast-/Slow-/Non-moving (FSN) by dispensing frequency (predefined thresholds: >4/day = F, 1–4 = S, <1 = N) to form an ABC–FSN matrix. Non-medical products were classified by ABC and a new HML-P scheme (expert-defined Pareto cut-offs: 70%/20%/10% of cumulative gross profit) to form an ABC–HML-P matrix. Each matrix was consolidated into three control categories: I (strict), II (moderate) and III (minimal). Results Non-medical products constituted 76.4% of all items. The ABC–FSN matrix identified Im = 149 medical products for strict control, while the non-medical ABC–HML-P matrix identified Inm = 580 items for strict control and a large segment for minimal oversight (IIInm = 6218). A pronounced Pareto pattern was observed (≈10% of items accounted for 70% of spend and 70% of gross profit), alongside low daily movement (only 3.2% dispensed ≥1/day). Conclusions The proposed dual-matrix model provides a practical decision-support tool for community pharmacies. It helps prioritize availability of patient-critical medical products while supporting economic sustainability.

This study explores the entrepreneurial intentions of university students from different educational, economic, and social backgrounds by comparing four European Union (EU) countries (Italy, Austria, Sweden, Greece) to an EU-candidate country (Bosnia and Herzegovina). Data were collected through surveys on a convenience sample of 301 students. The hierarchical regression and formal statistical hypothesis testing assess and compare the role of individual factors and contextual activating factors. In doing so, the paper adopts and adapts the EPIC tool, making it suitable for cross-country comparison. The results indicate a lack of significance of the risk-taking dimension, and a striking similarity in the influence of resources as a contextual activating factor, despite the differences of the investigated countries. In addition, the results indicate the individual mindset dimensions that significantly contribute to the entrepreneurial intentions of EU students (innovation-oriented, persistence, and peculiarity), and the different predictors for students from Bosnia and Herzegovina (innovation-oriented and action-oriented). The paper contributes to the stream of research on entrepreneurial intentions in higher education by assessing the individual and contextual factors within a fine-grained cross-cultural comparison. Insights for institutions and policymakers to enhance support and resources for aspiring entrepreneurs can ultimately be derived.