Background/Objectives: Chronic synovitis is a hallmark of osteoarthritis (OA) progression, driving cartilage degradation via inflammatory mediators. While the MAPK signaling pathway is implicated in OA pathogenesis its activation patterns in hip synovium remain poorly characterized, and regional differences within the synovial membrane have not been systematically examined. This research aims to determine the expression of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and the Epidermal Growth Factor Receptor (EGFR) in the MAPK signaling pathway in the synovial membrane of osteoarthritic hips. Methods: We compared synovial immunofluorescence expression of the aforementioned proteins in a control (CTRL) group of subjects with femoral neck fractures and a group with hip OA. Results: Higher ERK1/2 immunoexpression was detected in the intima compared with the subintima in the CTRL group (p < 0.05), and a similar distribution was observed in the OA group (p < 0.0001). The intima of the OA group exhibited a considerably greater area percentage of positive signal than the intima of the CTRL group (p < 0.01). In all groups examined, we observed that p38 MAPK expression was markedly more positive in the intima than in the subintima (p < 0.0001), but without statistically significant differences between groups. JNK and EGFR immunoexpression were higher in the intima than in the subintima across all analyzed groups, but the difference did not reach statistical significance (p > 0.05). No differences in the expression of these two markers were detected between the CTRL and OA groups (p > 0.05). Differential analysis of the GEO dataset revealed no significant differences in expression between the OA and CTRL groups in the expression of MAPK1, MAPK3, MAPK8, MAPK9, MAPK10, and MAPK11. EGFR was significantly elevated in OA compared to CTRLs in the differential analysis of the GEO dataset. Conclusions: This study provides the first comprehensive analysis of MAPK pathway activation in hip OA synovium, revealing ERK1/2 as a key player with region-specific upregulation in the synovial intima. Combined with elevated EGFR expression, these findings suggest potential therapeutic targets for hip OA synovitis. The discordance between protein and mRNA levels for ERK1/2 indicates post-transcriptional regulation, warranting further investigation into phosphorylation status and functional activation. Our results support the development of targeted interventions for hip OA, a condition with limited treatment options beyond joint replacement.

Background/Objectives: The meninges, the protective membranes covering the central nervous system, undergo complex developmental processes that are critical for CNS integrity and function. Connexin 37 (Cx37) and 40 (Cx40), members of the connexin family of gap junction proteins, have been implicated in various physiological and pathological processes. They play a critical role in cell–cell communication. The aim of our study was to investigate the expression of connexins Cx37, Cx40, and Panx1 in the meninges of both human and murine models (yotari and wild type) at the 6th week/E13.5 and 8th week/E15.5 of developmental stages. Methods: Human embryonic tissues (6th–8th week, n = 4 for the 6th week and n = 4 for the 8th week) and mouse embryos (yotari Dab1−/− and wild type, E13.5–E15.5) were collected and fixed in 4% paraformaldehyde. Paraffin sections were stained for Cx37, Cx40, and Panx1 using immunofluorescence. Images were analyzed in ImageJ, and statistical comparisons were performed using one-way ANOVA with Tukey’s post hoc test (p < 0.05). Results: Cx37 was consistently expressed across all developmental stages, with the highest threshold area percentage observed at E13.5 and E15.5 in murine leptomeninges, demonstrating statistically significant differences compared to controls (p < 0.05) and notably from corresponding human stages (p < 0.001). Strong Cx37 staining intensity at E13.5 was noted in both wild-type and yot mice, while human leptomeninges displayed mild staining at the 6th week of development. In contrast, both human and murine pachymeninges exhibited moderate Cx37 expression. Additionally, the expression of Cx37 in wild-type mice surpassed that of human samples at both E13.5 and E15.5 stages (p < 0.01 and p < 0.001, respectively). For the developing dura mater, Cx37 expression peaked at E15.5 in yot mice, significantly different from both wild-type and human dura mater (p < 0.01 and p < 0.05). Cx40 expression was highest in the leptomeninges at E15.5. Panx1 was similarly expressed across stages, with the highest threshold area percent observed in wild-type leptomeninges and pachymeninges at E15.5, showing significant differences compared to yot mice and human samples (p < 0.05). Both leptomeninges and pachymeninges exhibited mild Panx1 staining at E13.5, while stronger staining was observed at E15.5 in murine samples, contrasting with mild intensity in human counterparts. Conclusions: These findings highlight the implications of Dab1 deficiency for the expression of gap junction proteins during meninges development, implicating their importance in intercellular communication that is essential for normal meningeal and neurodevelopmental processes.

Spent coffee grounds (SCG) offer significant ecological and cosmetic potential. The conversion of SCG into safe and efficient cosmetic products promotes all aspects of sustainability and circular practices within the cosmetic industry.

Introduction: Polycystic ovary syndrome (PCOS) represents a state of androgen-driven metabolic dysregulation where visceral adiposity and inflammation critically define cardiometabolic risk. Visceral adiposity is not a bystander in PCOS; it is an active endocrine organ driving insulin resistance, low-grade inflammation, and androgen persistence. Interventions that reverse adipocyte hypertrophy and inflammatory signaling may therefore alter the metabolic trajectory of PCOS. Beyond its chronobiotic role, melatonin exerts profound metabolic actions via MT1/MT2 receptors in adipose tissue, modulating oxidative stress and inflammatory gene expression. Yet its direct impact on androgen-induced visceral adiposity remains unclear. Aim: The present study aimed to evaluate the effects of melatonin, metformin, and their combination on visceral fat accumulation in a testosterone-induced PCOS rat model. Material and methods: Thirty prepubertal female Wistar rats were randomized into five groups (n=6): control, PCOS (testosterone 20 mg/kg/day), PCOS+metformin (500 mg/kg/day), PCOS+melatonin (2 mg/kg/day), and PCOS+melatonin+metformin. Treatments lasted 36 days. Estrous cyclicity was monitored by daily vaginal cytology, and somatometric parameters were recorded weekly. On day 36, serum, ovaries, and visceral fat were collected for biochemical and histological analysis. Results: Vaginal smear changes and ovarian pathological alteration due to prolonged testosterone exposure confirmed the successful induction of the PCOS model. Measures of central adiposity, including abdominal circumference and the TC/AC ratio, were significantly higher in the PCOS model than in controls (p < 0.001). Abdominal circumference (AC) increase was greatest in the PCOS model (p < 0.001), while all treatment groups showed significant reductions, most notably in the melatonin + metformin group, followed by melatonin monotherapy and then metformin (all p < 0.001 vs. PCOS). Melatonin was more effective than metformin (p=0.029). AC/TC reduction was greatest in the combined treatment group (p < 0.05). Total weight gain among groups did not reach statistical significance. While total visceral fat weight did not differ among groups, histology revealed a marked reduction in adipocyte number in treated animals, most pronounced in the melatonin group (p < 0.033). Conclusion: Our findings identify melatonin as a metabolic modulator of androgen-driven adiposity, supporting its potential as an adjunctive therapy targeting visceral fat and inflammation in PCOS

Treatment of Clostridioides difficile infections in University Clinical Hospital Mostar from an economic perspective Clostridioides difficile is the most prominent pathogen directly tied to a healthcare system and proven to be one of the main causes of high economic impacts. It results in a frequent need for hospitalization, including the treatment of sepsis and post-acute care, and requires an extended number of days spent at the hospital. In addition to the costs of the medicine and laboratory analysis, extended hospitalization is the key component of the high healthcare expenses. The rational use of antibiotics, mandatory implementation of general hygiene measures, like washing hands, and disinfecting surfaces can significantly contribute towards hospital's overall expenses. This is particularly important for those in contact with an infected patient or with a patient suspected of having CDI. These basic measures establish security systems in the prevention of CDI. Proper managing and forecasting of the costs on the annual level for each individual healthcare institution is a necessary measure. Developing an accurate estimate of the funds needed for the treatment and prevention of CDI and its best Treatment of Clostridioides difficile infections in University Clinical Hospital Mostar from an economic perspective Clostridioides difficile is the most prominent pathogen directly tied to a healthcare system and proven to be one of the main causes of high economic impacts. It results in a frequent need for hospitalization, including the treatment of sepsis and post-acute care, and requires an extended number of days spent at the hospital. In addition to the costs of the medicine and laboratory analysis, extended hospitalization is the key component of the high healthcare expenses. The rational use of antibiotics, mandatory implementation of general hygiene measures, like washing hands, and disinfecting surfaces can significantly contribute towards hospital's overall expenses. This is particularly important for those in contact with an infected patient or with a patient suspected of having CDI. These basic measures establish security systems in the prevention of CDI. Proper managing and forecasting of the costs on the annual level for each individual healthcare institution is a necessary measure. Developing an accurate estimate of the funds needed for the treatment and prevention of CDI and its best

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Abstract Due to an ongoing energy crisis and fluctuating energy prices, the prerequisites for maintaining optimal indoor environmental quality (IEQ), a critical determinant of productivity, cognitive performance, and overall well-being, have been significantly disrupted. This study focuses on examining determinants of thermal comfort, a subjective evaluation of the thermal environment and a key component of IEQ. Through a survey of employees and users of public buildings in Bosnia and Herzegovina, the research employs a four-stage regression analysis to identify the main predictors of thermal comfort. Although 71.33% of respondents report satisfaction with the heating system, only 43.13% find the heating to be adequate, with the optimal perceived temperature averaging 21.66°C. The results show that key factors influencing thermal comfort include thermal sensation, thermal memory, gender, and respondent type (employee versus user). These seminal results could offer valuable productivity and financial implications for energy savings, especially for budgetary policymakers aiming to reduce energy consumption as well as for public sector management and public institutions seeking to improve well-being and productivity.

Anterior clinoidal meningioma (ACM) remains a challenging lesion to treat surgically due to its intricate neurovascular relationships with surrounding anatomy and often presents with ipsilateral visual loss. Anterior clinoidectomy (AC) by skilled skull base surgeons enables early optic nerve (ON) decompression, tumor devascularization, and radical tumor resection. The authors provide an update on ACM surgery, current views on the role of AC and its impact on outcomes in surgical treatment, as well as a new 2 stage 4 by 4 step concept of ON decompression involving AC. A systematic review of PubMed and meta-regression of surgically treated ACMs was performed. In total, 908 patients were analyzed; 415 (45.7%) underwent routine AC (performed in all cases) and 493 (54.3%) underwent selective AC (planned preoperatively). The routine AC cohort showed higher risk for new cranial-nerve (CN) deficits (12.5% vs. 3.0%; p < 0.001), vascular complications (6.7% vs. 3.3%; p = 0.02), and new focal neurological deficits (5.5% vs. 2.3%; p = 0.04). No differences were found in visual outcomes, gross-total resection, mortality, recurrence, or other major complications. Random-effects meta-regression of routine AC showed increased odds of new CN deficit (odds ratio [OR], 3.34; 95% confidence interval [95% CI], 1.51–7.38; p = 0.005; heterogeneity [I2] = 60.5%) and vascular complication (OR, 2.59; 95% CI, 1.05–6.38; p = 0.04; I2 = 47.8%), with moderate and substantial heterogeneity among routine AC studies, respectively. In experienced hands, AC remains an invaluable tool for ACM treatment as it offers more consistent tumor devascularization, prevention of tumor recurrence, optic nerve decompression, and increased working space, which facilitates optimal tumor resection and better long‐term control and functional outcome. We propose a new didactical structured concept of routine AC via 2-stage, 4 by 4 steps to improve the utility of AC and decrease associated operative risks compared to selective AC.

BACKGROUND Lower respiratory infections (LRIs) remain the world's leading infectious cause of death. This analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides global, regional, and national estimates of LRI incidence, mortality, and disability-adjusted life-years (DALYs), with attribution to 26 pathogens, including 11 newly modelled pathogens, across 204 countries and territories from 1990 to 2023. With new data and revised modelling techniques, these estimates serve as an update and expansion to GBD 2021. Through these estimates, we also aimed to assess progress towards the 2025 Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) target for pneumonia mortality in children younger than 5 years. METHODS Mortality from LRIs, defined as physician-diagnosed pneumonia or bronchiolitis, was estimated using the Cause of Death Ensemble model with data from vital registration, verbal autopsy, surveillance, and minimally invasive tissue sampling. The Bayesian meta-regression tool DisMod-MR 2.1 was used to model overall morbidity due to LRIs. DALYs were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs) for all locations, years, age groups, and sexes. We modelled pathogen-specific case-fatality ratios (CFRs) for each age group and location using splined binomial regression to create internally consistent estimates of incidence and mortality proportions attributable to viral, fungal, parasitic, and bacterial pathogens. Progress was assessed towards the GAPPD target of less than three deaths from pneumonia per 1000 livebirths, which is roughly equivalent to a mortality rate of less than 60 deaths per 100 000 children younger than 5 years. FINDINGS In 2023, LRIs were responsible for 2·50 million (95% uncertainty interval [UI] 2·24-2·81) deaths and 98·7 million (87·7-112) DALYs, with children younger than 5 years and adults aged 70 years and older carrying the highest burden. LRI mortality in children younger than 5 years fell by 33·4% (10·4-47·4) since 2010, with a global mortality rate of 94·8 (75·6-116·4) per 100 000 person-years in 2023. Among adults aged 70 years and older, the burden remained substantial with only marginal declines since 2010. A mortality rate of less than 60 deaths per 100 000 for children younger than 5 years was met by 129 of the 204 modelled countries in 2023. At a super-regional level, sub-Saharan Africa had an aggregate mortality rate in children younger than 5 years (hereafter referred to as under-5 mortality rate) furthest from the GAPPD target. Streptococcus pneumoniae continued to account for the largest number of LRI deaths globally (634 000 [95% UI 565 000-721 000] deaths or 25·3% [24·5-26·1] of all LRI deaths), followed by Staphylococcus aureus (271 000 [243 000-298 000] deaths or 10·9% [10·3-11·3]), and Klebsiella pneumoniae (228 000 [204 000-261 000] deaths or 9·1% [8·8-9·5]). Among pathogens newly modelled in this study, non-tuberculous mycobacteria (responsible for 177 000 [95% UI 155 000-201 000] deaths) and Aspergillus spp (responsible for 67 800 [59 900-75 900] deaths) emerged as important contributors. Altogether, the 11 newly modelled pathogens accounted for approximately 22% of LRI deaths. INTERPRETATION This comprehensive analysis underscores both the gains achieved through vaccination and the challenges that remain in controlling the LRI burden globally. Furthermore, it demonstrates persistent disparities in disease burden, with the highest mortality rates concentrated in countries in sub-Saharan Africa. Globally, as well as in these high-burden locations, the under-5 LRI mortality rate remains well above the GAPPD target. Progress towards this target requires equitable access to vaccines and preventive therapies-including newer interventions such as respiratory syncytial virus monoclonal antibodies-and health systems capable of early diagnosis and treatment. Expanding surveillance of emerging pathogens, strengthening adult immunisation programmes, and combating vaccine hesitancy are also crucial. As the global population ages, the dual challenge of sustaining gains in child survival while addressing the rising vulnerability in older adults will shape future pneumonia control strategies. FUNDING Gates Foundation.

Aims: To evaluate the impact of the COVID-19 pandemic on breast cancer presentation, surgical management, and lymph node involvement in a small, understudied population in Brčko District, Bosnia and Herzegovina. Methods: A retrospective cohort study conducted at the General Hospital of Brčko District, Bosnia and Herzegovina, from March 2018 to March 2022. We included 113 patients with histopathologically confirmed breast cancer. We divided the patients into two groups: the before-COVID group (65 patients, including one male) treated from March 2018 to March 2020, and the during-COVID group (47 patients) treated from March 2020 to March 2022. We analyzed patient data (age, gender, menopausal status) along with tumor and lymph node histopathological characteristics. Results: The number of surgeries performed decreased by 16.9% during the COVID period. Patients in the pre-COVID group mostly had grade II tumors, while those in the post-COVID group had predominantly grade III tumors. The average number of lymph nodes sampled was similar between groups (10.70 ± 4.12 before COVID vs. 10.39 ± 4.66 during COVID). Still, the average number of positive lymph nodes was higher in the COVID group (2.5±3.82) compared to the pre-COVID group (1.64±2.90). For patients without neoadjuvant therapy, the average time to surgery increased from 1.04 months (±0.66) before the COVID-19 pandemic to 2.59 months (±2.88) during the COVID-19 pandemic. For those receiving neoadjuvant therapy, time to surgery increased from 5.45 months (±2.97) to 7.29 months (±5.15). Conclusion: The COVID-19 pandemic led to delayed breast cancer management, higher tumor grade, and increased lymph node involvement in a small, resource-limited healthcare setting. Findings highlight the need for resilient oncology services in smaller districts during public health crises.

Cultural and event tourism plays a key role in the global tourism industry, contributing significantly to national, regional, and cross-border development strategies. It attracts visitors interested in cultural heritage, artistic events, and local traditions, supporting the preservation and promotion of local identity. Assessing cultural tourist flows become essential to understand their economic and social impact, and this article proposes an integrated methodology, combining quantitative and qualitative approaches, including data collection on cultural events, participant estimation, economic analysis, satisfaction assessment, data visualization, reporting, and continuous monitoring. The proposed model ensures a comprehensive evaluation of cultural tourist flows and supports the sustainable development of cultural tourism. Its relevance is both theoretical and applied: it offers a conceptual and analytical framework for studying this complex phenomenon, but also, it provides useful insights for decision-makers and stakeholders involved in tourism development, helping to design effective policies and strategies for promoting and managing cultural tourism. The novelty of the research lies in the proposal of a detailed and integrated methodology tailored to the specific challenges of evaluating cultural tourism, aiming to improve data accuracy, strategic planning, and long-term sustainability.

<p>The bird fauna of southern Bosnia and Herzegovina, extending to the tri-border area of Bosnia and Herzegovina, Montenegro, and Croatia, was studied. The habitats and migrations were analyzed over a five-year period with the aim of long-term monitoring and protection of species. The methods used for monitoring, marking, recording, and data processing included: the kilometer transect method, point census, free-route field surveys, and the &ldquo;playback&rdquo; method. Previous studies of bird fauna in this park were analyzed in order to synthesize results.The main results obtained from field research include a systematized list of bird species and maps indicating key nesting habitats. The results will contribute to stakeholders&rsquo; efforts to protect species and secure habitats in this area.</p>