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.

Shigellosis remains a significant global cause of infectious colitis, increasingly complicated by multidrug-resistant strains and the microbiota-disrupting effects of broad-spectrum antibiotics. Although conventional antimicrobial therapy can reduce symptom duration and bacterial shedding, it also contributes to gut dysbiosis, loss of colonization resistance, and further selection for antimicrobial resistance. These challenges have renewed interest in precision antimicrobial strategies, particularly bacteriophage therapy, which provides strain-level specificity and preserves the gut microbiota. This narrative review evaluates the biological rationale, preclinical and early clinical evidence, safety considerations, and translational challenges associated with bacteriophage therapy targeting Shigella spp. The historical development and mechanistic basis of phage therapy are summarized, with emphasis on the advantages of obligately lytic phages, receptor-specific targeting, self-amplification at infection sites, and activity against both planktonic and biofilm-associated bacteria. Recent microbiota research indicates that shigellosis is closely associated with early and persistent disruption of gut ecology, including depletion of short-chain fatty acids-producing taxa and reduced microbial resilience. Phage-based approaches may reduce pathogen burden while preserving beneficial microbial communities. Evidence from in vitro systems, animal models, human intestinal organoids, and a Phase 1 clinical trial demonstrates targeted efficacy and favorable safety profiles for Shigella-specific phages and phage cocktails. Major barriers to clinical adoption include immune interactions, phage resistance dynamics, genomic safety screening, regulatory classification, and the need for standardized susceptibility testing. Future directions emphasize the development of personalized phage therapy platforms that integrate rapid diagnostics, phage libraries, metagenomics, and artificial intelligence-assisted matching to enable scalable, precision treatment.

BACKGROUND Artificial intelligence (AI)-based algorithms are being implemented in breast screening to detect breast cancers on mammographic images. We aimed to apply an epidemiological approach to demonstrate how a cancer detection algorithm can be leveraged as an intermediate-term predictor of breast cancer (current and 4-year risk) to deliver greater risk-based personalisation in screening mammography. METHODS In this population cohort study, we used detection scores from an AI cancer detection algorithm (BRAIx AI Reader), which was calibrated using a training dataset of 397 648 women aged 40 years to 97 years from women who screened at BreastScreen Victoria, Australia between Jan 1, 2016, and Dec 31, 2017, to create a woman-specific mammography-based score for breast cancer risk, the BRAIx risk score. Subsequently, the BRAIx risk score was evaluated on an independent test dataset of women from BreastScreen Victoria, Australia, comprising a random population cohort of 96 348 women who screened from Jan 1, 2016, to Dec 31, 2017, aged 40 years to 74 years, and an independent, external dataset from woman screened at Karolinska University Hospital, Stockholm, Sweden. We applied logistic regression, using the BRAIx risk score to estimate risks of invasive breast cancers on the test dataset: (1) detected at cohort entry (n=525); and (2) for women given an all clear, diagnosed during the next 4 years either at future screens (n=790) or during intervals between screens (n=308). We also trained full multivariate risk models (logistic regression and elastic net) using the training dataset and evaluated their predictive performance on the test and external validation data, with assessment of familial aspects of the BRAIx risk score achieved with inference about causation from examining changes in regression coefficients in an innovative statistical analysis framework. FINDINGS In both Australian and Swedish test datasets, the BRAIx risk score predicted cancer detection at cohort entry and future cancer risk (all p<0·0001). The BRAIx risk score was the strongest tested explanatory factor for cancer detection at cohort entry (odds ratio 13·80 [95% CI 9·54-20·80] in Australian data; 8·89 [3·19-37·49] in Swedish data) and for intermediate-term cancer risk (2·29 [2·13-2.47] in Australian data; 2·15 [1·85-2·50] in Swedish data). We found that adding a thresholded binary version of the BRAIx risk score significantly improved model fit (p<2·2 × 10-16, Australian and Swedish data) and women with BRAIx risk scores of more than 2 were significantly at many-fold increased risk of intermediate-term cancer than women below that threshold (12·34 [7·33-20·91], Australia; 44·7 [11·9-184·9], Sweden; p<0·0001). For the top 2% of women given an all clear with the highest BRAIx risk score, the probability of a cancer diagnosis within 4 years was 9·7%. The BRAIx risk score explained 23% of why family history predicts 4-year risk (p<0·0001). After fitting the BRAIx risk score in a multivariate model, mammographic density was no longer significantly associated with breast cancer risk in the Australian test data (p>0·05) and became associated with lower risk for intermediate-term cancer in the external Swedish test dataset (0·83 [0·73-0·95]). INTERPRETATION The BRAIx risk score is a strong intermediate-term predictor of breast cancer (current to 4-year risk). Calibrating the score on a training dataset produces population-specific probabilities for calculating individual-specific risk scores for screening clients based on their mammogram images. These risk scores enable future development of personalised screening pathways to transform population breast cancer screening and save lives. Identification of women given an all clear but at very high risk, similar to those carrying BRCA1 and BRCA2 mutations, could reveal insights into both familial and non-familial causes of breast cancer. FUNDING Australian Government Medical Research Future Fund, the Ramaciotti Foundation, the National Breast Cancer Foundation, Cancer Australia, and the National Health and Medical Research Council.

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.

OBJECTIVES The objective of the present study was to explore whether gender differences exist in waist-to-height ratio (WtHR) values and to assess the correlation between WtHR and other obesity indicators after categorising older adults of Bosnian descent based on the presence or absence of abdominal obesity. METHODS The study included 151 inhabitants of the Geriatric Centre in Sarajevo, Bosnia and Herzegovina, aged 65 years and older (66 males and 85 females). Anthropometric indices and blood pressure values were measured by standard methods. WtHR was calculated using the following formula: waist circumference (WC) (cm)/height (cm). Differences between compared groups were analysed using the Student's t-test, Mann-Whitney U test or chi-square test. Correlations were assessed by Spearman's or Pearson's test. RESULTS Females had significantly higher WtHR values compared to males. Significant positive correlation was determined between WtHR and body mass index (BMI), WC, hip circumference (HC), neck circumference (NC), mid-upper arm circumference (MUAC), calf circumference (CC), and the weight-adjusted waist index (WWI) in both male and female elderly individuals. In elderly participants with abdominal obesity, there was a statistically significant positive correlation between WtHR and all of the tested anthropometric indices. Amongst elderly participants without abdominal obesity, a statistically significant positive correlation was observed between WtHR and BMI, WC, MUAC, and the WWI. However, no statistically significant correlations were observed between WtHR and HC, NC or CC in elderly participants without abdominal obesity. CONCLUSIONS The results of this study imply that WtHR is a valid parameter for assessing abdominal obesity in elderly individuals. The observed WtHR values indicate that women are at greater health risk than men. Given the high prevalence of sarcopenic obesity in older adults and the demonstrated limitations of BMI, we propose that WtHR should be incorporated into routine clinical practice for obesity assessment in this age group.

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.

In the rapidly evolving landscape of software engineering, the demand for robust and secure systems has become increasingly critical. This is especially true for self-adaptive systems due to their complexity and the dynamic environments in which they operate. To address this issue, we designed and developed the SAFT-GT toolchain that tackles the multifaceted challenges associated with ensuring both safety and security. This paper provides a comprehensive description of the toolchain's architecture and functionalities, including the Attack-Fault Trees generation and model combination approaches. We emphasize the toolchain's ability to integrate seamlessly with existing systems, allowing for enhanced safety and security analyses without requiring extensive modifications and domain knowledge. Our proposed approach can address evolving security threats, including both known vulnerabilities and emerging attack vectors that could compromise the system. As a use case for the toolchain, we integrate it into the feedback loop of self-adaptive systems. Finally, to validate the practical applicability of the toolchain, we conducted an extensive user study involving domain experts, whose insights and feedback underscore the toolchain's relevance and usability in real-world scenarios. Our findings demonstrate the toolchain's effectiveness in real-world applications while highlighting areas for future improvements. The toolchain and associated resources are available in an open-source repository to promote reproducibility and encourage further research in this field.

Background: African swine fever virus (ASFV) causes a fatal hemorrhagic disease in domestic pigs and wild boars. While live attenuated vaccines (LAVs) provide protection, their use raises safety concerns. Therefore, the aim of the present study was to identify viral B-cell antigens associated with protection and to test their potential using highly immunogenic vaccine delivery platforms. Methods: We employed a microarray of 169 ASFV proteins expressed in a cell-free prokaryotic system to identify immunodominant antigens using sera from immune pigs. Six structural proteins were selected and formulated into AP205 virus-like particles (VLPs). Additionally, replication-defective vesicular stomatitis virus (VSV)-based vaccine candidates expressing glycosylated CD2v and EP153R proteins were generated. Three groups of specific pathogen-free pigs were immunized with either VLP- or VSV-based vaccines and challenged with the virulent ASFV Georgia 2007 strain. Control groups included pigs immunized with the attenuated ASFV Estonia 2014 strain and a naïve group. Results: Most vaccine candidates induced detectable antibody responses against target ASFV proteins. However, neither VLP- nor VSV-based vaccines provided protection, as clinical scores, hematology, cytokine responses, and viremia levels were similar to those in the negative control group. In contrast, only the ASFV Estonia 2014 strain elicited a robust T-cell response and protective immunity. Conclusions: These findings highlight the challenges in identifying protective B-cell antigens of ASFV and emphasize the pivotal role of cellular immunity in mediating protection.