Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to treat type 2 diabetes. However, several studies have demonstrated its anti-inflammatory and immunomodulatory properties. The aim of this study was to investigate the effect of sitagliptin on the functional and phenotypic properties of human neutrophils under normal (NG, 5.5 mM)- and high (HG, 22 mM)-glucose conditions in vitro. Neutrophils were pretreated with varying concentrations of sitagliptin and stimulated with phorbol-12-myristate-13-acetate (PMA), N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), calcium ionophore (CaI), or opsonized zymosan (OpZym). Survival, phenotypic, and functional characteristics were then assessed. Our results showed that sitagliptin was non-cytotoxic to neutrophils even at very high concentrations. It decreased the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), generally following a stimulus- and concentration-dependent pattern. The effect was more pronounced under HG conditions. Furthermore, sitagliptin showed a significant ROS-scavenging effect in a cell-free system. It also rapidly altered the expression of surface markers in both resting and fMLP-stimulated neutrophils, typically upregulating CD10, CD16, CD62L, CD63, CD88, CD89, and PD-L1, and downregulating CD11b/CD18, CD66b, and CD182, a phenotype consistent with a dampened, less-primed activation state of these cells. In conclusion, sitagliptin exhibited marked antioxidative/ROS-scavenging activity in neutrophil cultures and induced a coordinated shift in neutrophil phenotype, accompanied by suppression of NETosis under both NG and HG conditions. Collectively, these data support the view that neutrophils may constitute an additional cellular target contributing to sitagliptin’s anti-inflammatory and immunomodulatory profile.

<p><strong>Introduction. </strong>The increasing use of digital devices among university students has raised concerns regarding its potential impact on physical and mental health. However, the independent contribution of different patterns of screen use remains insufficiently understood. This study aimed to examine screen use patterns among medical students and to assess their associations with selected health outcomes, with a particular focus on identifying independent predictors.<br /><strong>Methods. </strong>A cross-sectional study was conducted among 96 medical students aged 19&ndash;26 years. Data were collected using a self-administered questionnaire assessing daily screen time, timing of use, physical activity, and health-related outcomes. Multivariate binary logistic regression models were used to identify independent predictors of sleep disturbances, anxiety, and musculoskeletal pain.<br /><strong>Results.</strong> The median daily screen time was five hours. The most frequently reported health issues were eye strain (56.3%), musculoskeletal pain (53.1%), sleep disturbances (46.9%), and anxiety (40.6%). A weak but statistically significant positive correlation was observed between screen time and sleep disturbances (rs = 0.209, p = 0.044, N = 93 due to missing data for three participants). In multivariate analysis, late-night screen use was identified as an independent predictor of sleep disturbances (OR = 9.37, 95% CI: 1.96&ndash;44.75, p = 0.005), whereas total screen time was not significant after adjustment. No independent predictors were identified for anxiety or musculoskeletal pain.<br /><strong>Conclusion. </strong>The findings suggest that the impact of screen use on health outcomes is domain-specific. Behavioral patterns, particularly late-night use, appear to be more relevant than total screen time in relation to sleep disturbances. These results highlight the importance of a behavior-oriented approach to digital media use among students.</p>

<p><strong>Introduction. </strong>The development of information technologies in education has enabled the introduction of new teaching approaches, among which the Flipped classroom (FC) model has gained increasing attention. The FC model has emerged as a student-centered approach that promotes active learning in medical education. The&nbsp;<br />aim of this study was to examine students&rsquo; perceptions of the FC implementation in medical education.<br /><strong>Method.</strong> A cross-sectional study was conducted on a sample of 63 third-year medical students at the Faculty of Medicine in Foča. Data were collected through an anonymous online questionnaire distributed via the Moodle platform, consisting of six domains and a total of 31 statements.<br /><strong>Results. </strong>Students expressed generally positive attitudes toward the FC model: over 50% provided positive responses, about one-third were neutral. The highest average scores were related to learning independence&nbsp;<br />(x̄ = 3.84) and preparedness and motivation for classes (x̄ = 3.79). No statistically significant differences were&nbsp;<br />found between male and female students&rsquo; attitudes, while students with a higher-grade point average (&ge; 8.50) showed significantly more favorable attitudes in the domains of overall attitudes (p = 0.036) and communication (p = 0.013). Logistic regression analysis indicated that the communication domain was a significant predictor of belonging to the group with higher academic achievement (p = 0.020).<br /><strong>Conclusion.</strong> The results indicate that medical students perceive the FC positively and recognize its contribution&nbsp;<br />to better motivation, independence, and interactivity in the learning process. These findings may serve as a basis for further research on the impact of this model on academic outcomes and for a deeper understanding of students&rsquo; perceptions of modern learning approaches in medical education.</p>

Background The concept of flipped classrooms (FCs) is gaining attention in medical education as it aligns with the digital age’s demand for more interactive and accessible learning experiences. By shifting the delivery of instructional content outside of the classroom, an FC allows students to engage with materials at their own pace, thereby maximizing in-class time for discussions, problem-solving, and other active learning activities. Objective This study aimed to conduct a comprehensive meta-analysis to appraise the comparative effectiveness of FC instruction in contrast to traditional pedagogical modalities, with a particular focus on postepidemic analyses within specific subfields of medical education. Methods The PubMed, Web of Science, and Scopus databases were systematically searched for studies comparing academic outcomes between the FC and traditional learning approaches in medical education. The primary outcome measures were knowledge assessment and students’ satisfaction. The standardized mean difference (SMD) was used as a measure of the overall effect, and subgroup analysis was performed according to the study design (randomized controlled trial [RCT] vs observational). The Cochran Q test and Baujat plots were used to estimate heterogeneity, coupled with I2. Highly influential studies were identified; sensitivity analyses and metaregression were performed. Results In total, 141 studies were included in the systematic review; 127 (90.1%) studies with 21,171 participants were included in the meta-analysis of students’ knowledge assessment, of which 37 (29.1%) were RCTs. FCs had significantly better outcomes than the traditional method in knowledge test scores in both observational studies and RCTs (SMD 0.90, 95% CI 0.59-1.20, P<.001 and SMD 0.93, 95% CI 0.65-1.22, P<.001, respectively). There was substantial heterogeneity among included studies (I2=95.2%, τ2=1.614; P<.001). The funnel plot showed high asymmetry with significant small study effects (P<.001). However, the effect estimate remained robust to the exclusion of highly influential studies in the sensitivity analysis. In total, 27 (21.3%) studies with a total of 5842 participants reported students’ satisfaction. Higher student satisfaction scores for FCs were demonstrated in contrast to control groups (SMD 0.82, 95% CI 0.45-1.19; P<.001). There was substantial heterogeneity among the included studies (I2=97.8%, τ2=0.913; P<.001) but no evidence for publication bias, and no studies were found to be influential. Conclusions The FC method is associated with better knowledge achievement and greater student satisfaction than the traditional approach in medical education, paving the way for its broader integration into medical school curricula. However, it is essential to consider various factors, such as the availability of resources, faculty readiness, and student preferences when implementing any new educational approach. This study holds promise for advancing medical education by exploring innovative teaching methodologies that leverage technology to enhance learning outcomes.

Abstract Objectives Epilepsy is a chronic neurological condition with complex etiopathogenesis, treated with antiepileptics. In addition to their ability to regulate the activation threshold of neurons, antiepileptics have demonstrated a potential in shaping inflammation and the immune response. The main objective of our study was to analyze the effects of valproate, carbamazepine, and lamotrigine (commonly used antiepileptics) on viability, lymphocyte proliferation, and cytokine production by human peripheral blood mononuclear cells (PBMCs). Methods PBMCs were treated with different concentrations of antiepileptics, with or without phytohemagglutinin (PHA). Cytotoxicity, assessed by viability and apoptosis/necrosis assay, was determined by flow cytometry using the Annexin V/Propidium iodide (PI) staining method. Proliferation was determined using the MTT assay, whereas cytokine levels were assessed by the ELISA assay. A selective peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist (SR-202) was used to evaluate the involvement of PPAR-γ. Results Nontoxic concentrations of valproate and carbamazepine reduced the levels of three major proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and impaired Th1 and Treg responses, without affecting the Th2 response. Lamotrigine did not exhibit immunomodulatory properties in this model. The effect of valproate on the production of proinflammatory and Th1 cytokines was significantly reversed by inhibiting PPAR-γ. In contrast, the blockade did not modify the effects of carbamazepine. Conclusion Our results demonstrated that valproate and carbamazepine, although similarly modulating the immune response in vitro, utilize different signaling mechanisms, in contrast to lamotrigine, which did not exhibit immunomodulatory effects.

Background/Objectives: Ivy leaf extract has been shown to alleviate bronchial infection symptoms through various mechanisms, including anti-inflammatory effects. However, its impact on adaptive immunity, particularly dendritic cell (DC)/T-cell interactions, remains unexplored. This study investigated the immunomodulatory potential of ivy leaf extract (EA 575®) using human monocyte-derived DCs (MoDCs). Methods: Immature MoDCs (imMoDCs) were differentiated with IL-4/GM-CSF and matured with LPS/IFN-γ (mMoDCs). MoDCs, treated with EA 575® during differentiation, were co-cultured with purified T cells. Results: EA 575® (non-cytotoxic up to 100 µg/mL) inhibited MoDC differentiation and maturation by reducing the expression of CD1a, CD83, CD40, CD86, HLA-DR, Dectin-1, CD206, CD209, HIF-1α, and proinflammatory cytokines (IL-12, IL-23, IL-27, IL-1β, IL-6, TNF-α). EA 575®-treated mMoDCs suppressed allogeneic T-cell proliferation and reduced Th1 (IFN-γ), Th17 (IL-17A, IL-22), Th9 (IL-9), Th21 (IL-21), TNF-α, and IL-6 responses. Effects were dose-dependent, with higher concentrations (100 µg/mL) showing stronger inhibition. At lower concentrations (20 µg/mL), EA 575® increased Th2 (IL-4, IL-5) and IL-10 responses, and the frequencies of CD4+ T cells with Treg properties, such as CD25hiFoxp3+, Tr1 (IL-10+Foxp3−), and IL-35+ Foxp3+ cells. Immunoregulatory mechanisms mediated by EA 575®-treated mMoDCs correlated with the upregulation of tolerogenic markers (PD-L1, ILT3, ILT4, IDO1) on mMoDCs and the increased frequency of exhausted CD4+ T cells (PD-1+CD69+) and cytotoxic T cells (Granzyme B+PD-1+). Conclusions: EA 575® induces tolerogenic DCs with significant anti-inflammatory and immunoregulatory properties, a previously undescribed phenomenon. Lower concentrations primarily enhance immunoregulatory responses, while higher concentrations exert more pronounced anti-inflammatory effects.

Biodentine, a tricalcium silicate cement, has emerged as a retrograde root-end filling material to promote periapical lesion (PL) healing after apicoectomy. However, its underlying mechanisms remain unclear. This study tested the hypothesis that Biodentine stimulates the osteogenic differentiation of mesenchymal stromal cells (MSCs) derived from PLs. The Biodentine extract (B-Ex) was prepared by incubating polymerized Biodentine in RPMI medium (0.2 g/mL) for three days at 37 °C. B-Ex, containing both released microparticles and soluble components, was incubated with PL-MSCs cultured in either a basal MSC medium or suboptimal osteogenic medium. Osteogenic differentiation was assessed by Alizarin Red staining and the expression of 20 osteoblastogenesis-related genes. Non-cytotoxic concentrations of B-Ex stimulated the proliferation of PL-MSCs and induced their osteogenic differentiation in a dose-dependent manner, with a significantly enhanced effect in suboptimal osteogenic medium. B-Ex upregulated most early and late osteoblastic genes. However, the differentiation process was prolonged, as indicated by the delayed expression of wingless-type MMTV integration site family member 2 (WNT2), bone gamma-carboxyglutamate protein (BGLAP), bone morphogenic protein-2 (BMP-2), growth hormone receptor (GHR), and FOS-like 2, AP-1 transcription factor subunit (FOSL2), compared with their expression under optimal osteogenic conditions. The stimulatory effect of B-Ex was primarily calcium dependent, as it was reduced by 85% when B-Ex was treated with the calcium-chelating agent EGTA. In conclusion, Biodentine promotes the osteogenic differentiation of PL-MSCs in a calcium-dependent manner, supporting its stimulatory role in periapical healing.

Background/Objectives: Mild traumatic brain injury (mTBI) is a leading cause of pediatric emergency department visits, particularly among children under three years old. Although computed tomography (CT) is the gold standard for diagnosing intracranial injuries, its use in young children poses radiation risks. Identifying reliable clinical indicators that justify CT imaging is essential for optimizing both patient safety and resource utilization. Objective: This study aimed to evaluate CT findings in children under three years of age with mTBI and no focal neurological deficits, as well as to identify clinical predictors associated with skull fractures and intracranial injuries. Methods: A retrospective analysis was conducted on 224 children under 36 months who presented with mTBI to a tertiary pediatric hospital from July 2019 to July 2024. Demographic data, injury mechanisms, clinical presentation and CT findings were evaluated. Univariate and multivariate regression analyses were performed to identify risk factors associated with skull fractures and intracranial injuries. Results: Falls accounted for 96.4% of injuries, with the majority occurring from heights of 0.5–1 m. The parietal region was the most frequently affected site (38%). Skull fractures were present in 46% of cases and were primarily linear (92.8%). Intracranial hematomas were identified in 13.8% of cases, while brain edema was observed in 7.6%. Significant predictors of skull fractures included age under 12 months (p < 0.001), falls from 0.5–1 m (p = 0.005), somnolence (p = 0.030), scalp swelling (p = 0.001) and indentation of the scalp (p = 0.016). Parietal bone involvement was the strongest predictor of both skull fractures (OR = 7.116, p < 0.001) and intracranial hematomas (OR = 4.993, p < 0.001). Conversely, frontal bone involvement was associated with a lower likelihood of fractures and hematomas. Conclusions: The findings highlight key clinical indicators that can guide decision-making for CT imaging in children with mTBI. Infants under 12 months, falls from moderate heights and parietal bone involvement significantly increase the risk of fractures and intracranial injuries. A more refined diagnostic approach could help reduce unnecessary CT scans while ensuring the timely identification of clinically significant injuries.

Because of the COVID-19 pandemic, people were recommended to implement new health behaviors into their daily routines to prevent the viral spread. The aim of this study was to investigate whether specific health behaviors, such as wearing face masks, taking immunity boosters and visiting risky places were associated with a higher level of stress due to COVID-19 in the general adult population. This cross-sectional study was conducted from September 1, 2020 to October 1, 2021 in eight randomly chosen cities of two Serbian speaking countries (Republic of Serbia and Republic of Srpska - Bosnia and Herzegovina). Participants filled a socio-epidemiologic questionnaire, COVID Stress Scales (CSS) and the Perceived Stress Scale (PSS). The study included 2,301 participants with an average age of 36.72 ± 13.82 years of whom 54.9% were female (p = 0.001). Most participants were healthy, highly educated, employed, married, non-smokers and consumed alcohol. The mean total CSS score was 32.7 ± 23.8 out of 144, suggesting a relatively low stress due to COVID-19. The mean PSS was 19.43 ± 5.05 out of 40 indicating slightly increased level of general stress. Participants who reported higher CSS scores were more likely to wear face masks, use immunity boosters, go to cafes and clubs, have chronic illnesses, have suspicious, but not proven contact with COVID-19 positive people, and use multiple sources of information about COVID-19. Few participants experienced high levels of stress due to COVID-19. People who used face masks, immunity boosters and visited risky places reported a higher level of stress during the pandemic.

Tungsten disulfide (WS2) nanoparticles have emerged in the biomedical field as potential theranostic agents due to their unique properties, including biocompatibility. However, their impact on the immune response remains unexplored. This study aimed to evaluate the effects of inorganic fullerene-like WS2 (IF-WS2) nanostructures on human peripheral blood mononuclear cells (PBMCs) in vitro. The study investigated several parameters to evaluate the effects of IF-WS2 nanoparticles. Cytotoxicity was assessed by measuring cell viability, apoptosis, and necrosis. Internalization of IF-WS2 by PBMCs was analyzed using morphological and flow cytometric techniques. Proliferation was studied in CellTrace Far Red-prestained total PBMCs stimulated with phytohemagglutinin (PHA) and in isolated T cell cultures stimulated with CD3/CD28-coated beads. Additionally, the production of cytokines and chemokines was measured in culture supernatants of total PBMCs and T cells. IF-WS2 nanoparticles were non-cytotoxic up to a concentration of 200 µg/mL. Concentrations ≥25 µg/mL inhibited PHA-stimulated PBMC proliferation but did not affect T cell proliferation. Morphological and flow cytometric analysis demonstrated dose- and time-dependent internalization of IF-WS2 by macrophages. Additionally, IF-WS2 significantly reduced the production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8, MCP-1, and GRO-α) in PHA-stimulated PBMCs. Th1, Th17, and Th21 cytokines were downregulated, while Th2, Th9, and T regulatory cytokines were upregulated. In conclusion, this study demonstrated for the first time that pristine IF-WS2 nanoparticles, at non-cytotoxic concentrations, exhibit notable anti-inflammatory and immunomodulatory properties on activated PBMCs in vitro.