Dapsone is a sulfone used in treating inflammatory skin conditions. Despite its widespread dermatological use, the pharmacological actions of dapsone remain poorly understood. Here, we examined how different aspects of neutrophil functions are affected by dapsone. Peripheral blood neutrophils from healthy donors were stimulated with phorbol-12-myristate-13-acetate (PMA), N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), or calcium ionophore (CaI) or primed with cytokines prior to stimulation, in the presence of different concentrations of dapsone (from 10 to 50 µg/mL), followed by analyses of their survival, phenotype, and functional properties. We found that dapsone at the concentration of 50 μg/mL induced a significant neutrophil apoptotic rate during 6 h and 18 h, while other concentrations were well tolerated compared to control non-treated cells. However, dapsone significantly decreased the induced oxidative burst of neutrophils at all non-cytotoxic concentrations. Additionally, dapsone showed a dose-dependent suppression of NETosis in activated neutrophils. The production of IL-8 by dapsone-treated neutrophils was decreased under both stimulated (fMLP) and primed (TNF-α/fMLP) conditions. Moreover, dapsone inhibited the expression of CD11b/CD18, CD66, and CD89 and reversed or significantly mitigated the downregulation of CD16, CD32, CD181, CD88, and CD62L on neutrophils after priming and fMLP stimulation. In conclusion, our results indicate the complexity of dapsone actions on neutrophil functions, extending previous knowledge on the suppression of oxidative burst and IL-8 production upon neutrophils’ activation. Suppressed NETosis and modulation of marker expression associated with different neutrophil functions under inflammatory conditions are new findings, not recognized previously.

One of the complex decision-making problems, which requires consideration of several criteria, is the choice of a smartphone. This paper presents an approach that combines user review analysis with machine learning and multi-criteria decision making (MCDM) methods to identify and evaluate alternatives. Based on the processed reviews, the Random Forest algorithm was used to identify the criteria that most influence the selection of smartphones. The weights of the criteria were determined using the Defining Interrelationships Between Ranked criteria II (DIBR II) method, improved by the application of triangular fuzzy numbers for better processing of the subjective and imprecise nature of the data. For the final selection of the optimal alternative, the Weighted Aggregated Sum Product Assessment (WASPAS) method was applied in a fuzzy environment, which enables the combination of additive and multiplicative approaches in ranking. The methodological justification of the proposed approach was confirmed by a sensitivity analysis, through 15 scenarios of changes in the weight coefficients of the criteria, which showed that small oscillations in the weights do not significantly affect the final ranking, especially not in the first two positions. The validation was additionally supported by a comparative analysis with four other decision-making methods in a fuzzy environment, which confirmed the stability and consistency of the results. The proposed approach provides an empirically grounded and methodologically robust framework for solving decision-making problems under conditions of multi-criteria evaluation and uncertainty, and can be applied to a wide range of similar problems in different fields.

In recent decades, China has significantly increased its global economic presence, emerging as one of the leading powers in the international system, in alignment with its strategic plan through 2049. This presence includes a keen interest in Southeast Europe, with Serbia identified as a key strategic partner. China's approach to Serbia intersects with Russia's longstanding presence rooted in the historical and cultural ties with Serbia. This paper examines the strategic interests and goals of China and Russia in Serbia, exploring their respective methods and tools. It also delves into Serbia's foreign policy aspirations for sustainable security trying to balance the presence of superpowers within, and around its territory. The paper evaluates Serbia's try of strategic navigation of its geostrategic position between East and West, questioning if Serbia is actually naive or aware of its circumstances. The study elucidates on how China and Russia's strategic maneuvers in the region, often subconsciously, shape Serbia and its neighboring countries. Within this intricate landscape, the concept of “Strategic symmetry” emerges as a crucial element, highlighting the delicate balance of influence that both powers exert in Serbia while it strives to maintain its entry into the European Union.

Introduction. Colon cancer is one of the most common forms of cancer, affecting both sexes equally. The objective tumor response rate (ORR) is an important parameter that proves the effectiveness of treatment in oncology; one of the ways to evaluate ORR is the response evaluation criteria in solid tumors Response evaluation criteria in solid tumors (RECIST). The aim of the research is to determine and compare the impact of the objective response rate in patients with metastatic colorectal cancer and the impact on overall survival (OS) and progression-free survival (PFS). Methods. The work is based on a retrospective (2014-2020) clinical study, with follow-up of patients over a period of 5 years. The research included a total of n=101 patients diagnosed with colorectal cancer (stages II and III according to the American Joint Committee of Cancer -AJCC). Research included n=101 patients, 52% male, 48% female. The youngest patient is 18 years old, and the oldest patient is 80 years old. Results. The average age is 59.69 years. The obtained data show that the largest percentage of Colorectal Cancer-CRC patients are in the third age. Adenocarcinoma is the most common pathohistological verification of colon cancer (77.23%). Overall survival and progression-free time in relation to objective response to therapy (ORR) according to RECIST criteria did not show statistical significance. One patient had a complete response (CR) to therapy, six patients (5.94%) had a partial response (PR) to therapy. Stable disease (SD) was verified in 32.67%, and disease progression (PD) was confirmed in 60.39% of subjects. Conclusion. The extent of objective response to therapy has no influence on overall survival and survival without disease progression in patients with metastatic colorectal disease. Key words: colorectal, cancer, response evaluation criteria in solid tumors.

Introduction. The aim of this article is to evaluate the efficacy and outcomes of FOLFIRINOX as a first-line treatment for initial metastatic pancreatic cancer patients at the Clinical Center University of Sarajevo. Methods. The research presents a retrospective analysis was conducted on 33 patients treated with FOLFIRINOX, between January 2021 and January 2023. Baseline characteristics, tumor markers (CEA, CA 19-9, CA 125), neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-platelet ratio (NPR) and initial metastatic site were evaluated using Cox regression analysis in order to identify predictive and prognostic factors for progression-free survival (PFS) and overall survival (OS). Results. The median age of patients was 64 (range 38-76). There were 18 males and 15 females. The median OS was 21.7 months (95% CI, 10.5-32.9) and the median PFS was 10.0 months (95% CI, 8.2-11.8). A statistically significant negative correlation was found between NLR and OS (r=-0.464, p=0.045). Patients with initial liver metastasis had a numerically worse median OS (16.3 months, 95% CI, 5.1-27.5), compared to those with non-liver metastasis (OS not reached, p=0.058). Tumor markers, NLR, NPR, and initial metastatic site were not independent predictors of PFS and OS. Conclusion. FOLFIRINOX demonstrates significant efficacy in treating metastatic pancreatic cancer in a real-world setting. Personalized approaches, including genetic profiling and microbiome analysis, along with AI integration, offer promising avenues to enhance treatment outcomes and quality of life for patients. Keywords: metastatic pancreatic cancer, enhanced outcomes, overall survival, progression-free survival.

Introduction. The coronavirus induced disease 2019 (COVID-19), caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2), which was identified in patients in China in 2019, was pronounced a pandemic in March 2020. It resulted in more than 7 million deaths worldwide. As hypercoagulation emerged as its key pathological hallmark, the objective of this study was to investigate if a polymorphism within the VKORC1 gene, which plays a role in the vitamin K-dependent blood coagulation pathway, contributed to the survival from thrombosis in individuals who developed some form of it during their COVID-19. Methods. This was an observational, case-control study. Characterization of the VKORC1 -1639G>A (rs9923231) polymorphism-associated genotypes was carried out in cases (N=16), volunteers who developed some form of thromboembolism during COVID-19, but who survived from it, and controls (N=32), volunteers who did not develop any form of thromboembolism during COVID-19, by using polymerase chain reaction restriction fragment length polymorphism method, followed by Sanger sequencing of the VKORC1 gene promoter-specific, polymerase chain reaction-amplified products. Results. Our preliminary data indicate that the variant or A allele, which is associated with intermediate or low blood coagulability, is more frequently present within the VKORC1 gene of individuals who developed some form of thromboembolism during their COVID-19, but who survived from it, than the wild-type or G allele, which is associated with standard or high blood coagulability. Conclusion. These results warrant further studies into the role of the VKORC1 promoter-associated polymorphism in the COVID-19-associated coagulopathy, as the specific VKORC1 genotypes could become genetic biomarkers for prediction of a thrombotic state during COVID-19, and possibly, other thrombosis-associated diseases and disorders. Keywords: COVID-19, Hypercoagulability, Thrombosis, Venous thromboembolism, Vitamin K epoxide reductase

Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the third leading cause of cancer-related deaths. It remains especially lethal among patients with cirrhosis and chronic liver diseases like hepatitis B and C, alcohol abuse and non-alcoholic fatty liver disease. A retrospective, multicenter study was conducted across five oncology centers in the Federation of Bosnia and Herzegovina, with the aim of gaining a better insight into the current state of healthcare for patients with HCC in this region. The study reveals several regional disparities in the etiology, treatment, and outcomes of HCC, but it also indicates that the diagnostic approach varies significantly from one city to another. One of the highlights of the study is the late-stage diagnosis of most patients, due to the limited healthcare access, diagnostic delays and, especially, lack of screening programs. Implementation of targeted screening methods, regular monitoring of high-risk patients and enhanced use of biomarkers could lead to a significant improvement in the diagnostic accuracy. The limited use of innovative treatments recommended by the global guidelines was also identified as an issue, which directly leads to limited surgical and other treatment options. This study signals the need for a standardized patient pathway in the Federation of Bosnia and Herzegovina, implementation of national registry and targeted HCC database, which could reduce mortality, improve overall care and patient outcomes. Keywords: hepatocellular carcinoma, healthcare, standardized patient pathway.

Introduction. Magnetic resonance imaging (MRI) is the preferred method for diagnosing the causes of lumboischialgia, as it offers the highest sensitivity and specificity compared to other imaging techniques. In clinical practice, there is often a notable discrepancy between patients’ clinical symptoms and the radiological findings. While there are various clinical tests for lumboischialgia, the Oswestry Disability Index (ODI) and the Visual Analogue Score (VAS) are the most commonly used and reliable. This article aims to explore the correlation between patients’ subjective pain experiences and their level of disability due to lumboischialgia and disc herniation as detected by MRI. Methods. In this prospective clinical study, a total of 100 patients of both genders, aged 18 to 65 years, were included. These patients were referred for magnetic resonance imaging of the lumbar spine due to complaints of lumboischialgia. MRI of the lumbar spine was performed, and the extent of degenerative changes was evaluated. Participants completed a questionnaire regarding their subjective pain experience and functional status, and the Oswestry Disability Index (ODI) and Visual Analogue Score (VAS) were calculated. Results. The statistical analysis revealed a significant correlation between the severity of disc herniation (classification) and the intensity of spinal pain (p = 0.010), as well as with the disability index (p = 0.003). Conclusion. A statistically significant relationship was confirmed between the levels of pain and disability and the degree of intervertebral disc herniation observed on MRI images of the lumbar spine. Keywords: lumbal disk herniation, lumboischialgia, pain.

Medical professionals have a responsibility to inform the public about contemporary research on alcohol consumption. Earlier health recommendations focused primarily on the link between alcohol and cardiovascular diseases. Over time, these guidelines have expanded to consider the broader impact of alcohol on all-cause morbidity and mortality. Unlike the tobacco industry, which remains profitable but faces strict regulations on marketing and lobbying, the alcohol industry benefits from fewer regulations. This allows alcohol manufacturers to freely promote their products and influence both federal and state policies. Clear emphasis on the importance of ceasing alcohol consumption is crucial, particularly in primary and secondary prevention efforts. Keywords: cardiovascular diseases, alcoholics, prevention.

Introduction. Morning stiffness (MS) is the hallmark of rheumatoid arthritis (RA) and it has important implications on daily life of the patients. There are conflicting reports of its association with disease activity. Methods. This observational study included 125 patients with seropositive RA from Health Care Center, Visoko. We obtained data on patient’s gender and age, duration of RA, pain in hands and feet, MS and its duration, hospital admission, blood pressure, laboratory values and treatment modalities. Results. MS lasted up to 30 minutes in 71 (56.8%) patients, 30 to 60 minutes in 40 (32%) patients, and more than 60 minutes in 14 (11.2%) patients. There was no difference in the duration of MS between genders. Patients with longer MS were younger and had a longer duration of illness. Patients with MS longer than 30 minutes had higher blood pressure and cholesterol levels. ESR in the second hour and CRP correlated with a duration of MS. Patients on methotrexate had a longer duration of MS. No significant differences in the duration of MS were observed for leflunomide, corticosteroids and supportive treatment modalities. Conclusion. Duration of MS correlates with RA disease activity and remains an important burden for patients. Usage of newer treatment options, such as biologic disease-modifying antirheumatic drugs (DMARDs), may be required. Keywords: biomarkers, disease activity, rheumatoid arthritis.

Introduction: Calciphylaxis (calcific uremic arteriolopathy), is a condition primarily observed in patients with end-stage renal disease (ESRD). Aim: To increase clinical awareness of calciphylaxis and to consider it a differential diagnosis in the presence of atypical skin nodules or ulcers occurring in patients with chronic kidney disease (CKD), especially in patients on hemodialysis and non-hemodialysis patients with the background of diabetes mellitus and secondary hyperparathyroidism. Case Report: We present the case of a 77-year-old woman with CKD and diabetes mellitus as well as severely painful, firm, indurated plaques on the lower extremities. The plaques progressed to involve larger areas with associated local ulceration and necrosis. Laboratory testing revealed hyperparathyroidism and incisional skin biopsy confirmed calciphylaxis. Conclusion: Each single CKD patient with diabetes mellitus and signs of secondary hyperparathyroidism with extremely painful ischemic cutaneous lesions or painful subcutaneous nodules without skin changes, although at times, pain may precede the development of the lesions, is a candidate for skin biopsy. Calciphylaxis is a rare but serious kidney complication. Keywords: calciphylaxis, chronic kidney disease, prognosis, treatment.

Acetylsalicylic acid is the most common antithrombotic drug, which started its pharmacological journey as a non-steroidal, anti-inflammatory drug. When used as a low-dose drug (of 75-100mg) once per day, it irreversibly inhibits prostaglandin H synthase, commonly termed cyclooxygenase 1 or COX-1 enzyme, which is acetylsalicylic acid's molecular drug target in human platelets. This mechanism of action ensures that the inhibition of the pro-aggregatory prostanoid - thromboxane A2 synthesis is achieved permanently in platelets throughout their lifespan, which is responsible for acetylsalicylic acid's antithrombotic effect. In this literature review, we provide an overview of acetylsalicylic acid's development through history, the current understanding of the molecular mechanism of its action, as well as the resulting side effects impacting different tissues due to its control of the arachidonic acid metabolism and prostanoid synthesis in them. In an effort to begin a dialogue regarding the evidence in favor of unresponsiveness to acetylsalicylic acid's therapeutic effect in specific patients, we describe already identified molecular mechanisms of resistance to acetylsalicylic acid and list the existing biomarkers which are able to quantifiably measure the achieved degree of acetylsalicylic acid's clinical efficacy. Furthermore, we look to the future by encouraging a personalized approach to acetylsalicylic acid's use in order to maximize its therapeutic effect and its safety. Moreover, we mention the ongoing clinical trials evaluating the role of acetylsalicylic acid in prevention of colorectal and other cancers. Keywords: Acetylsalicylic Acid, Aspirin, Cyclooxygenase Inhibitors, Prostaglandin Endoperoxide Synthase Inhibitors, Platelet Aggregation Inhibitors, Antithrombotic Agents

Introduction: Physiotherapy, a non-invasive method of conservative treatment, that includes manual therapy, exercises and physical procedures, is used in the treatment of temporomandibular dysfunction and polyarticular laxity. It has been proven that physiotherapy focused on temporomandibular dysfunction is an essential element of treatment that leads to a reduction in pain, an improvement in temporomandibular joint (TMJ) function, and an improvement in quality of life. Physiotherapy treatment aims to alleviate the symptoms and try to restore the normal function of the masticatory system, for which various techniques can be used. The aim of the study was to determine the type, intensity, and frequency of TMJ dysfunction pain before and after physiotherapy. Methods: The study was conducted in a private practice in Munich, Germany. All subjects who met the criteria for inclusion in the study completed a standardized questionnaire on TMJ dysfunction (TMJ disorder [TMJ/TMD] Questionnaire). The questionnaire was used to obtain data on the type and location of pain, duration of pain, and other symptoms related to the TMJ. The anamnestic data of the respondents who came to the doctor’s office with the symptoms mentioned were examined, and the orthodontic or dental findings were analyzed.Results: The analysis showed that before treatment some of the joints were affected in 28 subjects, while after treatment the joints were affected in 19 subjects. After treatment a significant decrease in affected TMJ was observed (χ2 = 9.516, p = 0.008). Ear pain occurred in 17 (54.84%) subjects before treatment, and in 5 (16.13%) after treatment. A significant reduction was observed at the p = 0.003 level. Pain around the eyes occurred in 9 (29.03%) of the respondents before treatment, and after treatment in 2 (6.45%) of the respondents. Facial pain was reported in 16.13% of the anamnestic data before the treatment, and it was not reported in any of the respondents after treatment. There was also a significant reduction in the occurrence of tinnitus (p = 0.004). The occurrence of headaches also decreased after treatment (p < 0.001). Ear pressure was present before treatment in 45.16% of cases, and after treatment in 22.58% of cases, so there was no significant decrease. Conclusion: Physiotherapy for people with TMJ dysfunction contributed significantly in reducing pain and alleviating other TMD symptoms.

This study examines the impact of media convergences on the evolution of role-playing games (RPGs) from the early 1970s to the present day. The analytical focus of this research is directed at the dynamics between player community participation and the process of commodification within this genre. In this context, specific phases in the development of RPGs are highlighted, including tabletop role-playing games (TRPGs), classic computer role-playing games (CRPGs), massively multiplayer online role-playing games (MMORPGs), live-action role-playing (LARP), and actual play (AP). This study highlights the similarities and differences between these forms, their mutual convergence, and their convergence with other analog and digital media (such as books, comics, television, film, and podcasts). Special attention is given to the phenomenon of prosumerism within the RPG subculture; that is, the specific interaction between the content offered by the entertainment industry and the efforts of RPG communities to maintain the participative and creative aspects of the genre. This research is based on a diachronic comparison of specific phases in the development of the RPG genre, as well as a secondary analysis of the dominant media content on current trends in the RPG subculture.