Med. Sci., Volume 13, Issue 3 (September 2025) – 125 articles

Background: Heart rate (HR) and HR variability (HRV) are valid indices of psychophysical stress. Healthy individuals typically exhibit high vagal tone, as indicated by vagally mediated HRV (vmHRV) values. Despite current knowledge, HRV differences between anxious subjects and controls during a cognitive task have not yet been studied. Methods: Anxious people were compared to controls through the State–Trait Anxiety Inventory (STAI-Y), both considering State Anxiety (S-Anxiety) and Trait Anxiety (T-Anxiety) one at a time. Subsequently, a psychophysiological stress profile (PSP) was conducted to record HRV values (i.e., SDNN, RMSSD, and HF) at baseline and under induced stress with an electrocardiogram (ECG). During the stress test, the digit span forward task was conducted. Results: Significant differences were described by dividing the sample by S-Anxiety in the baseline values of log-HF (t = 2.68; p = 0.05; d = 0.85) and log-RMSSD (t = 2.34; p = 0.01; d = 0.74). Dividing the sample by T-Anxiety, significant differences were found in the reactivity (t = −2.26; p = 0.03; d = −0.70) and recovery (t = 2.11; p = 0.04; d = 0.66) log-HF values. Additionally, reactivity log-HF and recovery log-RMSSD values demonstrated significant discriminative power of 68% and 68%, respectively, in accurately identifying individuals with anxiety, as measured by T-Anxiety. Lastly, an association was found between the baseline HR value and the equivalent point of digit span forward in both the anxious (r = 0.59, p = 0.01) and control (r = −0.45, p = 0.05) groups. Conclusions: Although a high vmHRV is considered a protective factor against stress, our findings found that a reduced HRV modulation can distinguish a group of people with significant symptoms of anxiety and hinder cognitive efficiency. Full article

Left ventricular diastolic dysfunction (LVDD) is characterized by impaired ventricular relaxation and increased chamber stiffness during diastole, resulting in increased left ventricular filling pressures. It represents a highly prevalent yet frequently underdiagnosed cardiac condition with significant clinical implications, serving as a major contributor to heart failure with preserved ejection fraction (HFpEF), particularly among elderly individuals and those with hypertension, diabetes mellitus, obesity, or coronary artery disease. Multiple studies have identified the progression of LVDD as a marker of adverse prognosis, associated with increased morbidity and mortality, highlighting the importance of early recognition and targeted therapeutic strategies to improve diastolic function and clinical outcomes. This review summarizes the pathophysiology, current diagnostic strategies, and treatment options for LVDD, emphasizing its importance in clinical practice. Full article

Background: Juvenile fibromyalgia (JFM) is a chronic pain disorder characterised by widespread musculoskeletal pain, functional impairment, fatigue, and mood disturbances. Treatment remains challenging, considering the multifactorial nature of the condition and the limited high-quality evidence supporting pharmacological or non-pharmacological interventions. Objectives: This review aimed to critically appraise level I evidence from randomised controlled trials assessing the efficacy and safety of pharmacological and non-pharmacological treatments for adolescents with JFM. Methods: Seven published peer-reviewed clinical trials were examined, including studies investigating duloxetine, milnacipran, pregabalin, cognitive-behavioural therapy (CBT), and the integrated Fibromyalgia Integrative Training Teens (FIT) program, which combines CBT with neuromuscular training. Outcomes of interest included pain intensity, functional disability, depression symptoms, physical activity, and adverse events. Results: Pharmacological agents such as duloxetine, milnacipran, and pregabalin demonstrated modest improvements in pain, but failed to produce consistent benefits in function or mood, and were associated with a high incidence of adverse effects. CBT significantly improved functional disability and depression symptoms, yet it had a limited impact on pain reduction or objectively measured activity levels. The FIT Teens program showed superior outcomes in pain intensity and biomechanical function compared to CBT alone, suggesting a synergistic effect of combining psychological and physical reconditioning strategies. Conclusions: Current evidence supports the use of multimodal treatment approaches in JFM. Non-pharmacological interventions, particularly when integrated with structured exercise, offer meaningful benefits with minimal safety concerns. Larger, methodologically rigorous trials are needed to establish optimal treatment pathways and long-term outcomes for this complex and underserved paediatric population. Full article

Background/Objectives: This study aimed to profile the molecular variants of muscle-invasive bladder cancer (MIBC) based on immunohistochemical analysis and to make a correlation with morphological characteristics in a series of 100 consecutive patients. Methods: A retrospective single-center study was conducted on 100 consecutive cases of MIBC (2021–2024). A selected immunohistochemical (IHC) panel (including CK5/6, CK20, and p16) was applied in all cases to classify the tumors into known molecular variants (luminal papillary, luminal non-specified, luminal unstable, stroma-rich, basal/squamous, neuroendocrine-like). Results: Seven molecular subtypes are identified: basal (33%), luminal papillary (24%), luminal unstable (16%), luminal non-specified (10%), basoluminal (double-positive) (9%), neuroendocrine-like (double-negative with neuroendocrine morphology) (6%), and stroma-rich (2%). This distribution largely matches published data (Consensus Classification and The Cancer Genome Atlas (TCGA)), with minor differences (e.g., a lower share of the stroma-rich variant). A strong correlation is found between the histological subtypes of some tumors and their molecular variant (χ², p < 0.001): for example, all cases of urothelial carcinoma with squamous differentiation are basal, micropapillary tumors are entirely luminal, and small-cell carcinomas are neuroendocrine-like. Conclusions: The results demonstrate that the morphological subtype of urothelial carcinoma largely predetermines the molecular profile. Combining classic histopathology with IHC-based profiling allows for a more complete characterization of the tumor and aids prognosis and personalized treatment in MIBC. Full article

Background: Huntington’s disease (HD) causes progressive motor dysfunction, with chorea as its hallmark symptom. Vesicular monoamine transporter 2 (VMAT 2) inhibitors (tetrabenazine, deutetrabenazine, valbenazine) are established symptomatic therapies, while dopamine stabilizers (pridopidine, ordopidine) are emerging therapies, but their net benefit and safety remain uncertain. Methods: Seven databases were searched through May 2025 following PRISMA guidelines. Random effects meta-analyses calculated mean differences (MDs) for the Unified Huntington Disease Rating Scale total motor score (UHDRS TMS) and total maximal chorea score (TMC), plus risk ratios (RRs) for adverse events (AEs). Trial Sequential Analysis (TSA) applied a Lan DeMets O’Brien Fleming α spending function with 80% power. Results: Seven randomized trials (1431 participants) met inclusion criteria. VMAT 2 inhibitors significantly improved motor outcomes versus placebo (UHDRS TMS: MD −3.80, 95% CI −5.76 to −1.83; TMC: MD −3.05, 95% CI −3.84 to −2.26; both I² = 0%). Dopamine stabilizers produced no meaningful change (UHDRS TMS: MD −0.98, 95% CI −2.48 to 0.51; I² = 32%). Neither class increased total AEs (VMAT 2: RR 1.21, 95% CI 0.99 to 1.48; dopamine stabilizers: RR 1.05, 95% CI 0.92 to 1.20; both I² = 0%). TSA confirmed robust evidence for VMAT 2 benefits on TMC but indicated additional data are required to verify dopamine stabilizer effects on UHDRS TMS. Trial sequential analysis confirmed the reliability of VMAT2 for TMC; however, the sample size was insufficient to draw conclusions about the effects of dopamine stabilizers on UHDRS TMS or their safety outcomes, indicating that additional data are needed. Conclusions: VMAT-2 inhibitors may suggest potential improvements in motor symptoms in Huntington’s disease, while current evidence does not demonstrate a significant benefit of dopamine stabilizers. The safety profiles of both treatments appear generally comparable to placebo. Further rigorous and long-term studies are required to better establish their efficacy and safety. Full article

Background: Brain metastases (BMs) are a common and challenging complication of non-small cell lung cancer (NSCLC), historically associated with a poor prognosis. The development of targeted therapies, specifically tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene alterations, has significantly improved treatment outcomes. Methods: This article reports and evaluates the efficacy of different generations of TKIs for NSCLC with BMs. The primary endpoints assessed are intracranial objective response rates (IC-ORR), progression-free survival (PFS), and overall survival (OS). The analysis considers TKIs as monotherapy and in combination with radiotherapy. It also examines the impact of newer generation TKIs with enhanced blood–brain barrier (BBB) penetration on intracranial control. The report further discusses the integration of systemic therapy with local modalities like stereotactic radiosurgery (SRS) and the safety profiles of these agents, including central nervous system (CNS) and metabolic adverse events. Results: Newer generation TKIs demonstrate significantly enhanced BBB penetration, resulting in superior intracranial control compared to older generations. These agents show remarkable intracranial activity, contributing to improved IC-ORR, PFS, and OS. The optimal integration of systemic therapy with local modalities, such as SRS, is still under investigation. Treatment with these TKIs is associated with distinct safety profiles, including novel CNS and metabolic adverse events, which require careful management due to prolonged treatment durations. Conclusions: The management of CNS metastases in NSCLC is evolving towards more proactive and personalized therapeutic strategies. Newer generation TKIs have profoundly reshaped the treatment landscape by offering superior intracranial control. Further research is needed to determine the optimal integration of these systemic therapies with local modalities and to effectively manage the associated adverse events. Full article

Background: “Long COVID” refers to a condition in which individuals continue to experience persistent signs and symptoms even after recovering from the initial COVID-19 infection. Signs and symptoms that persist can affect multiple organs in the body. Vitamin D is an essential nutrient that plays a crucial role, particularly in the immune system, and may be linked to the development of long COVID. Objective: The study aimed to investigate the association between vitamin D levels and the prevalence of long COVID signs and symptoms in COVID-19 patients. Materials and Methods: The study enrolled 170 COVID-19 patients with mild signs and symptoms and confirmed COVID-Ag or RT-PCR tests. The subjects were aged 18–59 years. All patients had 25(OH)D levels measured within 60 days of COVID-19 diagnosis and had been followed for at least 3 months post-infection. Data collected included demographic characteristics, serum 25(OH)D levels, and self-reported long COVID signs and symptoms questionnaire responses. Results: The study results indicated a female-to-male ratio of 1.1:1 and a mean age of 45.87 ± 8.65 years; of these, 62.4% received three doses of the COVID-19 vaccine, and 64.7% developed long COVID. The most prevalent signs and symptoms were respiratory (55.3%), skin (50.6%), and general (39.4%). The median blood vitamin D level was 22.96 ng/mL, with 41.2% of subjects having insufficient levels, 30.6% having deficient levels, and 28.2% having sufficient levels. Patients with long COVID had significantly lower vitamin D levels compared with those without long COVID (21.52 ng/mL vs. 25.46 ng/mL; p < 0.05). Multivariable analysis found that vitamin D deficiency was significantly associated with overall long COVID signs and symptoms (Adj. OR, 5.80 [95% CI: 2.10, 16.13]). Additionally, vitamin D deficiency significantly increased the number of long COVID systemic signs and symptoms (Adj. IRR, 3.30 [2.12, 5.12]). Conclusion: Assessing and maintaining vitamin D levels, vitamin D supplementation, and sunlight exposure in COVID-19 patients can reduce the risk and severity of long-term COVID-19 signs and symptoms. Full article

Background: Allergic diseases in early childhood are influenced by genetic predisposition and modifiable early-life exposures, including epigenetic mechanisms. Understanding the interplay between environmental factors and allergy development in children with atopic heredity is critical for prevention strategies. Objective: To investigate the associations between selected early-life environmental exposures and the development of allergic conditions in children with a positive family history of atopy. Methods: A cross-sectional study was conducted among 120 children aged 2 years (±5 months) with atopic heredity, recruited at the Medical University of Varna, Bulgaria (2017–2020). Data on sociodemographic background, prenatal exposures, birth mode, feeding practices, pet contact, daycare attendance, and infectious burden were collected via structured questionnaires and medical records. Allergic outcomes (food allergy and atopic dermatitis) were physician-confirmed. Statistical analyses included t-tests and chi-square tests. Results: Food allergy was diagnosed in 23.3% and atopic dermatitis in 21.7% of participants. Formula feeding was significantly more common in children with food allergy (66.7% vs. 38.1%; p = 0.020). A lower maternal pregnancy experience score was significantly associated with both food allergy (p = 0.021) and overall allergic outcomes (p = 0.004). Indoor smoking was more common in households of non-allergic children (p = 0.034). Children with food allergy had significantly more rhinopharyngitis episodes (p = 0.014) and longer infection duration. Higher gastroenteritis frequency and hospitalization rates were also noted in food-allergic children. Conclusions: In children with atopic heredity, early formula feeding, prenatal maternal stress, and infection burden were associated with increased risk of allergic conditions. This study underscores the importance of early-life psychosocial and environmental influences, possibly mediated by epigenetic mechanisms, in the development of childhood allergies. These findings highlight novel targets for early prevention and warrant further longitudinal research. Full article

Purpose: The aim of this paper is to study the visual outcomes, changes in higher order aberration (HOA) and corneal densitometry after debridement and excimer laser phototherapeutic keratectomy (PTK) for the treatment of Salzmann nodular degeneration (SND). Methods: This monocentric study includes 69 eyes from 54 patients who underwent debridement and PTK for SND (mean follow-up time of 447.1 ± 597.7 days post-operatively). The following parameters were measured before and after PTK: best corrected visual acuity (BCVA) in logMAR, sphere, cylinder, calculated spherical equivalent (SPHQ), mean and maximum refractive power, astigmatism, HOA, corneal density and thickness. Patients were divided into two cohorts depending on additional visual acuity limitations (VAL). Results: Mean visual acuity improvement was 0.16 ± 0.21 logMAR (p < 0.001), independent of additional VAL, and was associated with normalization of the cornea (hyperopic reduction by 2.13 ± 2.60 dpt, p < 0.001), reductions in cylinder (1.49 ± 2.44 dpt, p < 0.001) and corneal astigmatism (3.01 ± 3.39 dpt, p < 0.001). HOA was reduced by 0.77 ± 1.11 µm (p < 0.001) and corneal density by 6.08 ± 16.45 gray scale units (GSUs) in the center (p = 0.019) and by 9.32 ± 12.08 GSUs in the mid-periphery (p < 0.001). Haze occurred in 26.1% of patients (15.9% mild; 10.1% moderate). Re-PTK was necessary in 5.8%. Conclusions: PTK is a low-complication method for visual improvement in patients with SND, regardless of additional VAL, and is associated with a normalization of corneal parameters. HOA, corneal density and K_max were reduced significantly and showed a correlation with visual acuity, implying that these objective parameters may have a good predictive value for visual acuity. Full article

Background: Emotional eating (EmE) is a maladaptive eating behavior that has been frequently observed among university students, possibly due to academic stress and lifestyle changes. However, its specific assessment in health science students has been poorly addressed, even though this population faces high levels of academic stress and emotional burden. Objective: This study explores the association between self-perceived health status, life satisfaction, and EmE among university students in the health field on the north coast of Peru. Methods: A cross-sectional study was conducted on a sample of 1213 students. Self-perceived health, life satisfaction, and EmE were assessed using validated instruments. In addition, sociodemographic data were considered as covariates and possible confounding factors. T-tests, chi-square tests, and Poisson regression with robust variance were applied. Results: EmE was more prevalent in women (78.0%) than in men (66.8%; p < 0.001). In addition, an inverse association was observed between self-perceived health and emotional eating: students with average self-perceived health (adjusted OR = 0.88; 95% CI: 0.83–0.94) and those with high self-perceived health (adjusted OR = 0.75; 95% CI: 0.69–0.81) showed a progressively lower prevalence of EmE compared to those with low self-perceived health. Similarly, high life satisfaction was associated with a lower prevalence of EmE (adjusted PR = 0.88; 95% CI: 0.80–0.96). Conclusions: Low self-perceived health and life dissatisfaction were significantly associated with a higher probability of EmE in medical and nursing students. These results highlight the need to strengthen university programs on mental health, emotional regulation, and subjective well-being promotion as strategies to prevent maladaptive eating behaviors in academic settings, considering gender. Full article

Background: Phosphaturic mesenchymal tumours secreting fibroblast growth factor 23 (hereinafter referred to as FGF23+ PMT) are rare neoplasms that can cause hypophosphataemic osteomalacia, owing to excessive FGF23 production. Mast cells (MCs) play a key role in tumour biology by modulating proliferative activity of atypical cells, resistance to innate and acquired immunity, angiogenesis, and metastatic behaviour. However, MCs associated with FGF23+ PMT have not previously been investigated. This study, to our knowledge, is the first to characterise features of the tumour microenvironment through spatial phenotyping of the immune and stromal landscape, together with histotopographic mapping of intercellular MC interactions with other subcellular populations in FGF23+ PMT. Methods: Histochemical staining (haematoxylin and eosin, toluidine blue, Giemsa solution, picro-Mallory protocol, silver impregnation), as well as monoplex and multiplex immunohistochemical staining with spatial phenotyping, were performed to detect atypical FGF23-secreting cells, immune cells (CD3, CD4, CD8, CD14, CD20, CD38, CD68, or CD163), stromal components (CD31, α-SMA, or vimentin), and specific MC proteases (tryptase, chymase, or carboxypeptidase A3). Bioinformatics analysis using artificial intelligence technologies was applied for spatial profiling of MC interactions with tumour, immunocompetent, and stromal cells in the tumour microenvironment. Results: Bioinformatic analysis of the entire tumour histological section, comprising over 70,000 cells stained using monoplex and multiplex immunohistochemical protocols, enabled identification of more than half of the cell population. The most abundant were CD14+ (30.7%), CD163+ (23.2%), and CD31+ (17.9%) cells. Tumour-associated MCs accounted for 0.7% of the total pool of immunopositive cells and included both mucosal and connective tissue subpopulations, predominantly of the tryptase + chymase-CPA3-specific protease phenotype. This pattern reflected combined multidirectional morphogenetic processes in the patient’s FGF23+ PMT. More than 50% of MCs were colocalized with neighbouring cells of the tumour microenvironment within 20 μm, most frequently with monocytes (CD14+CD68+), M2 macrophages (CD68+CD163+), and endothelial cells (CD31+). In contrast, colocalization with atypical FGF23-secreting cells was rare, indicating minimal direct effects on tumour cell activity. Interaction with T lymphocytes, including CD8+, was also infrequent, excluding their activation and the development of antitumour effects. Mapping of MC histotopography validated the hypothesis of their inductive role in monocyte differentiation into M2 macrophages and probable polarisation of macrophages from M1 into M2, thereby contributing to slow tumour growth. MCs were further involved in extracellular matrix remodelling and participated in the formation of pro-osteogenic niches within the FGF23+ PMT microenvironment, leading to pathological osteoid development. Conclusions: This study demonstrated active MC participation in the evolution of the FGF23+ PMT microenvironment. The findings may be applied in translational medicine to develop novel algorithms for personalised therapy in patients with FGF23-secreting tumours, offering an alternative when surgical removal of the tumour is not feasible. Full article

Background: RNF114 gene encodes an E3 ubiquitin ligase involved in immune signaling and regulation of inflammation. Genetic variants, particularly nonsynonymous single-nucleotide polymorphisms (nsSNPs), may interfere with protein function and cause immune diseases such as psoriasis. Although significant, the structural and functional impact of RNF114 nsSNPs is not well understood. Methods: We used comprehensive bioinformatics analyses to predict the functional impact of RNF114 nsSNPs. Deleterious variants were predicted by SIFT, PolyPhen-2, PROVEAN, META-SNP, ESNP&GO, PANTHER, and Alpha-Missense. Protein stability was examined by I-Mutant2.0, and MUpro further contextualized variant effects. Structural modeling was performed by AlphaFold and visualized using UCSF ChimeraX 1.10.1. Additionally, we studied the Conservation using ConSurf and protein-protein interaction by STRING tools. Results: Among 252 available nsSNPs, three mutations—C49R (rs1600868749), R68C (rs745318334), and R68H (rs758000156)—were predicted to have a deleterious and destabilizing effects on the protein structure by all the tools. All three variants were located in extremely conserved residues and were predicted to significantly destabilize the protein structure. Structural modeling demonstrated disruptions in the RNF114 domain structure. STRING analysis revealed interactions of RNF114 with key immune regulators, and pathway enrichment pointed to roles in NF-κB signaling, ubiquitin-mediated proteolysis, and autoimmune disease pathways. Conclusions: In the current study, we predicted three novel, potentially pathogenic RNF114 variants with protein-destabilizing effect that could lead to immune dysregulation. Full article

Background and Objectives: Vitamin D deficiency affects bone health and immune function, especially in children. While universal screening is not cost-effective, targeted screening and supplementation strategies have proven effective. This study evaluates the effectiveness of Romania’s National Vitamin D Screening Programme in detecting vitamin D deficiency in paediatric patients, while also accounting for the impact of the COVID-19 pandemic. Materials and Methods: This retrospective observational study assessed the effectiveness of Romania’s National Vitamin D Screening Initiative in detecting vitamin D deficiency among children admitted to the Clinical Emergency Hospital for Children “Louis Țurcanu”, Timișoara, from January 2018 to December 2024. Serum 25-hydroxyvitamin D levels were analysed in 3596 tested patients out of 22,353 total admitted patients, to evaluate trends from before, during, and after the COVID-19 pandemic. Patients aged 0–18 with at least one admission were included, regardless of diagnosis. Patients in ICU, surgical departments, non-Romanian citizens, and those with life-threatening conditions were excluded. Logistic regression analysis was used to assess programme impact and risk factors for vitamin D insufficiency. Results: The study population had a mean age of 5.36 years, with 53.57% male patients. Patient admissions dropped significantly during pandemic years (mean of 2057 annually in 2020–2022 vs. 4045.5 in pre-/post-pandemic years). Vitamin D insufficiency (<20 ng/mL) peaked at 33.3% in 2020 and 32.5% in 2023, with lowest rates in 2019 (17.2%) and 2021 (16.5%). The National Screening Programme implementation resulted in 57.1% higher odds of vitamin D testing in 2023–2024 compared with 2018–2019 (adjusted OR = 1.571, 95% CI: 1.429–1.726, p < 0.001), with testing rates increasing from 12.6% to 17.5%. Age emerged as the strongest predictor of vitamin D insufficiency, with each additional year associated with 8–9% increased odds of deficiency. Conclusions: The National Vitamin D Screening Programme significantly enhanced detection of vitamin D insufficiency in paediatric populations, despite pandemic-related disruptions. An optimal testing rate of approximately 17% was identified for balancing detection efficiency with resource utilisation. These findings underscore the need for sustained risk-based screening programmes and public health education initiatives to address vitamin D insufficiency in children, particularly in developing countries with limited healthcare resources. Full article

Background: In exercise testing, the ventilatory threshold 1 (VT1) and ventilatory threshold 2 (VT2) are used in lifestyle-related diseases, cardiac rehabilitation, and athletic training. We investigated a VT2 measuring method using a pulse oximeter. Methods: Thirty-four adults (men: 15; women: 19) performed a bicycle ergometer Ramp Test. VT1 values were determined using expiratory gas data. The bifurcation of the curve obtained by designating the pulse rate (PR) as an independent variable and SpO₂/PR as a dependent variable was calculated using the residual sum of squares and defined as the SpO₂ threshold (ST) (SpO₂-Slope method). A second bifurcation with ST as the origin was further defined (ST2). ST2 validity was assessed by comparing and analyzing the differences and correlations with each VT2 obtained by expiratory gas analysis. Results: The correlation between ST2 determined by the SpO₂-Slope method using PR as an index and VT2 obtained from respiratory gas analysis was significant, showing a positive correlation (r = 0.74~0.92; p < 0.01), with most data points falling within the 1.96 ± SD in the Bland–Altman analysis. Conclusions: ST2 values derived from SpO₂ and pulse rate measurements by pulse oximeter may be a valuable VT2 measuring method. Full article

Background: Cognitive and neuropsychological effects of cancer and its treatments have gained increasing attention over the past decade, with growing evidence of persistent deficits across multiple cancer types. While numerous studies have examined these effects, the literature remains fragmented, and no comprehensive bibliometric synthesis has been conducted to map the field’s intellectual structure and emerging trends. Methods: A bibliometric and science mapping analysis was performed using the Scopus database to identify peer-reviewed articles published between 2015 and 2025 on neuropsychological or cognitive outcomes in adult cancer populations. Data from 179 eligible publications were analyzed with VOSviewer and Microsoft Power BI, applying performance metrics and network mapping techniques, including co-authorship, bibliographic coupling, co-citation, and keyword co-occurrence analyses. Results: Publication output increased steadily over the decade, with leading contributions from the Journal of Neuro-Oncology, Psycho-Oncology, and Brain Imaging and Behavior. Co-citation analysis identified three core intellectual pillars: (i) clinical characterization of cancer-related cognitive impairment, (ii) mechanistic and neuroimaging-based investigations, and (iii) neurosurgical and neuropathological research in brain tumors. Keyword mapping revealed emerging themes in sleep and circadian rhythm research, biological contributors to cognitive decline, and scalable rehabilitation strategies such as web-based cognitive training. Collaborative networks, while showing dense local clusters, remained moderately fragmented across disciplines. Conclusions: This review provides the first quantitative, decade-spanning map of cognitive oncology research, highlighting both consolidated knowledge areas and underexplored domains. Future efforts should prioritize methodological standardization, cross-disciplinary collaboration, and integration of cognitive endpoints into survivorship care, with the ultimate aim of improving functional outcomes and quality of life for cancer survivors. Full article

Adoptive cell therapies (ACTs) have revolutionized cancer treatment by harnessing the specificity and potency of T lymphocytes. Chimeric antigen receptor (CAR)-T cells have achieved landmark successes in B-cell malignancies and multiple myeloma. Tumor-infiltrating lymphocytes (TILs) and T-cell receptor (TCR)-engineered T cells offer complementary strategies to target solid tumors and intracellular antigens. Despite these advances, ACTs face challenges including cytokine release syndrome, neurotoxicity, on-target/off-tumor effects, manufacturing scalability, and immunosuppressive tumor microenvironments. Innovative strategies, such as dual-antigen targeting, localized delivery, checkpoint blockade combinations, gene-editing, and machine-learning-guided antigen discovery, are being used to mitigate toxicity, enhance efficacy, and streamline production. As CAR-T, TIL, and TCR modalities converge with advances in manufacturing and computational biology, the next generation of “living drugs” promises broader applicability across hematologic and solid tumors, improved safety profiles, and better treatment outcomes for patients. This review details the evolution of ACTs from first-generation CAR constructs to next-generation “armored” designs. It also focuses on the development and clinical deployment of TIL and TCR therapies. Furthermore, it synthesizes mechanisms, pivotal clinical trial outcomes, and ongoing challenges of ACTs. It also highlights strategies that will drive broader, safer, and more durable applications of these therapies across hematologic and solid tumors. Full article

Background: The shortage of donor kidneys has prompted interest in using organs from donors with severe acute kidney injury (AKI), but robust data on outcomes from donors with AKIN stage 3 remain limited. Methods: This single-centre, retrospective cohort study compared outcomes of kidney transplants from deceased donors with AKIN stage 3 AKI to matched non-AKI donors (n = 57 per group; matched by donor age ±5 years, year of transplant, and major cardiovascular risk factors). Primary outcomes were delayed graft function (DGF), death-censored graft survival, and patient survival. Secondary outcomes included renal function at follow-up. Results: DGF occurred in 54.4% (31/57) of AKIN 3 recipients vs. 33.3% (19/57) of non-AKI recipients (risk difference 21.1%, 95% CI 3.1–39.2; p = 0.037). Five-year death-censored graft survival was 94.7% vs. 96.4% (HR 1.28, 95% CI 0.25–6.52; p = 0.645). Five-year patient survival was 84.8% vs. 84.0% (HR 0.96, 95% CI 0.30–3.05; p = 0.979). Median follow-up was 32 months. Conclusions: In this preliminary, selected kidneys from AKIN stage 3 donors yielded similar medium-term graft and patient survival to non-AKI donors, despite higher DGF incidence. Findings should be interpreted cautiously and confirmed in adequately powered, multicentre studies with extended follow-up. Full article

Background: Ankylosing spondylitis (AS) is a chronic autoinflammatory rheumatic disease mainly affecting the sacroiliac joints and spine, causing altered bone remodeling. Pro-inflammatory cytokines such as TNF-α and IL-17 contribute to bone loss by modulating pathways including Wnt/β-catenin, which is inhibited by proteins like Dickkopf-1 (DKK-1) and sclerostin (SOST). Bone morphogenetic protein-6 (BMP-6) promotes osteoblast differentiation and bone formation. This study evaluated the association between serum levels of DKK-1, SOST, BMP-6, and bone mineral density (BMD) in AS patients treated with anti-TNF agents and conventional synthetic DMARDs (csDMARDs). Methods: A cross-sectional study included 76 AS patients diagnosed by modified New York criteria and 30 healthy donors matched by age and sex. BMD at the lumbar spine and hips was assessed by DXA in all participants. Disease activity (BASDAI) and functional index (BASFI) were measured in AS patients. Serum levels of DKK-1, SOST, BMP-6, TNF-α, and IL-17 were quantified by ELISA in both groups. AS patients were divided into two treatment groups: combined anti-TNFα and csDMARD therapy (n = 38), and only csDMARDs (n = 38). Results: Bone mineral density showed no significant statistical differences between the spine (p = 0.930) and hips (p = 0.876) in AS patients compared to healthy controls. The activity (BASDAI) and functionality (BASFI) scores were similar in both treatment groups (p = 0.161 and p = 0.271, respectively). No significant differences were found in serum levels of DKK-1 (p = 0.815), SOST (p = 0.771), BMP-6 (p = 0.451), or IL-17 (p = 0.335) between combined anti-TNFα and csDMARD therapy versus monotherapy with csDMARD. Conclusions: The combination of anti-TNF bDMARD therapy and csDMARD therapy is not significantly associated with serum levels of DKK-1, SOST, BMP-6, and BMD compared to those treated with csDMARD monotherapy in patients with AS. This study provides novel and clinically relevant evidence on how anti-TNF bDMARDs and csDMARDs differentially affect bone turnover biomarkers and bone health in patients with AS, contributing to a better understanding of therapeutic strategies and guiding future research and clinical decision-making. Full article

Background/Objectives: Evidence from transcriptomic and histopathologic studies has revealed that peri-implantitis lesions are characterized by deeper inflammatory infiltration, increased immune cell accumulation, and distinctive molecular signatures. This systematic review aimed to evaluate the diagnostic and pathophysiological potential of transcriptomic, metagenomic, and bioinformatic biomarkers in peri-implantitis by integrating findings from bioinformatics and machine learning-based studies. The dual objective was to identify biologically relevant markers and assess the accuracy of predictive models, addressing diagnostic gaps in peri-implant disease management. Methods: Eligible designs included cross-sectional, case–control, and cohort studies. Literature searches were conducted across PubMed, EMBASE, Scielo, and Scopus, with independent screening, data extraction, and quality assessment. Functional meta-synthesis was used to thematically organize biomarkers and pathways, while diagnostic meta-analysis pooled ROC-AUC values to assess model performance. Results: Eleven studies met the inclusion criteria. Functional synthesis revealed five recurring biomarker themes: innate and adaptive immune responses, immune cell infiltration, fibroblast activation, and ceRNA regulation. A meta-analysis of six studies reported a pooled AUC of 0.91 (95% CI: 0.88–0.93) with I² = 0%, indicating no heterogeneity, supporting the reliability of ML-based models in distinguishing peri-implantitis from healthy conditions. Sources of variation included differences in validation strategies and data preprocessing. Conclusions: Integrating transcriptomic, metagenomic, and bioinformatic biomarkers with machine learning may enable earlier and more accurate diagnosis of peri-implantitis. The identified biomarkers highlight molecular and microbial pathways linked to inflammation and tissue remodeling, underscoring their potential as diagnostic indicators and therapeutic targets with translational relevance. Full article

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent condition characterized by pelvic pain and urinary symptoms with multifactorial aetiology. Standard treatments, including alpha-blockers, often have limited long-term effectiveness. This study aimed to evaluate the efficacy and safety of a standardized pollen extract (Deprox^® 500), alone or in combination with alpha-blockers, in reducing CP/CPPS symptoms and the need for rescue medication. Methods: This prospective, multicentre study included 207 male patients with CP/CPPS treated at two Romanian urology centres between January 2023 and January 2025. Patients were divided into three groups: Group A—alpha-blocker monotherapy; Group B—standardized pollen extract monotherapy; and Group C—combination therapy with standardized pollen extract and alpha-blocker. Symptom severity and treatment response were evaluated using the validated English versions of the NIH Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score (IPSS), and International Index of Erectile Function-5 (IIEF-5), all of which were translated into Romanian for use in this study. Results: Groups B and C both demonstrated significantly greater reductions in pelvic pain and urinary symptoms compared to Group A (p = 0.01), with marked improvements in NIH-CPSI and IPSS. Conclusions: A standardized pollen extract used alone or in combination with an alpha-blocker significantly improved CP/CPPS symptoms and reduced the need for NSAID rescue medication. These findings support its potential as a safe and effective therapeutic option. Full article

Background: Mitral valve prolapse is a common valvular heart disorder, usually associated with a benign prognosis in the absence of significant mitral regurgitation. However, a subset of patients is at increased risk for complex ventricular arrhythmias and sudden cardiac death. Identifying these high-risk individuals remains a major clinical challenge. Case Summary: We present the case of a 71-year-old female patient with recurrent syncopal episodes, a strong family history of sudden cardiac death, and complex ventricular ectopy. Multimodality imaging revealed bileaflet mitral valve prolapse, severe mitral regurgitation, mitral annular disjunction, and the Pickelhaube sign, with no evidence of myocardial fibrosis on cardiac magnetic resonance imaging. The patient underwent minimally invasive mitral valve repair and received an implantable cardioverter-defibrillator for primary prevention of sudden cardiac death. Follow-up revealed significant reverse cardiac remodeling, marked reduction in arrhythmic burden, and restoration of mitral valve function. Family screening identified mitral annular disjunction in both of her daughters, who were asymptomatic and without arrhythmias. Discussion: Mitral annular disjunction has emerged as a potentially arrhythmogenic substrate, especially in patients with familial clustering, raising the possibility of a genetic predisposition. Risk stratification remains difficult, as no individual clinical, electrocardiographic, or imaging marker has demonstrated consistent predictive value. Surgical correction of mitral valve prolapse with associated mitral annular disjunction may lead to a reduction in arrhythmic risk and promote favorable structural remodeling. Conclusions: This case-based review emphasizes the importance of advanced imaging techniques in the identification and management of high-risk mitral valve prolapse phenotypes. Early surgical intervention and close arrhythmic surveillance may improve outcomes, although further research is necessary to define risk assessment tools and explore the genetic background of arrhythmogenic mitral valve disease. Full article

Aims: Surgery remains the only definitive treatment option for abdominal aortic aneurysms (AAA), as no conclusive evidence supports drug effectiveness in preventing AAA growth. Although type 2 diabetes (T2D) is an important cardiovascular risk factor, patients with T2D show reduced AAA presence and growth, associated with metformin use. We aimed to investigate the potential benefits of metformin on AAA using proteomics and in vitro experiments. Methods: Proteomics analysis using tandem mass spectrometry was performed on aortic smooth muscle cells (SMCs) from non-pathological controls (C-SMC, n = 8), non-diabetic (ND, n = 19) and diabetic (D, n = 5) AAA patients. Key findings were subsequently validated in aortic tissue using mass spectrometry-based proteomics. SMCs were cultured with/without metformin and analyzed. Results: Comparison of the proteome of SMCs from ND-AAA patients with controls revealed a reduction in proteins associated with metabolic processes and mitochondrial function. Cytoskeletal and extracellular matrix (ECM) proteins were elevated in ND-AAA-SMCs versus C-SMCs, with a similar cluster of mechanosensitive proteins being increased in ND-AAA-SMCs versus D-AAA-SMCs. D-AAA-SMCs showed an improved metabolic and antioxidant profile, enriched in pentose phosphate pathway proteins responsible for NAD(P)H generation (G6PD, PGD) and NAD(P)H-dependent antioxidants (NQO1, CBR1, AKR1C1, AKR1B1, GSTM1), all regulated by NRF2, an antioxidant transcription factor. Over half of the proteins identified in the protein–protein interaction network, constructed from proteins with higher expression in D-AAA SMCs versus ND-AAA SMCs, were verified in D-AAA aortic tissue. In vitro, metformin causes a shift from aerobic to anaerobic metabolism, increased AMPK activation and elevated mitochondrial biogenesis, indicated by increased PGC-1α expression. Metformin increased the gene expression of PGD, CBR1 and the protein expression of NQO1, with enhanced translocation of pNRF2 to the nucleus, due to reduced KEAP1 as negative regulator of NRF2. Consequently, metformin enhanced the gene expression of well-known antioxidant regulators SOD2 and CAT. Conclusions: This study identified significant differences in the proteome of SMCs derived from controls, ND-AAA and D-AAA patients. It highlights distinct pathways in relation to mechanosensing, metabolism and redox balance as therapeutic targets of metformin that may underlie its inhibition of AAA progression. Full article

Background/Objectives: Renal failure (RF) and systolic heart failure (sHF) are very often associated with each other, and their synergistic influence can affect the prognosis of acute pulmonary embolism (aPE) patients. The aim of this study is to evaluate the associations between RF, sHF, and in-hospital mortality in patients with normotensive aPE. Methods: We analyzed data from the Regional PE Registry (REPER), and 1968 patients with CT pulmonary angiography-confirmed aPE who had a systolic blood pressure of 100 mmHg and higher, and for whom creatinine blood levels and left ventricular ejection fraction (LVEF) were measured at admission to hospital were enrolled. The patients were divided into four groups: the first group comprised patients without renal and systolic heart failure, the second those with RF (creatinine clearance less than 60 mL/min), the third those with sHF (LVEF less than 50%), and the fourth those with both RF and sHF. The primary endpoint of this study was in-hospital all-cause mortality. Results: There are significant differences between in-hospital mortality among the groups: 38/1247 (3.0%) vs. 63/514 (12.9%) vs. 10/99 (10.1%) vs. 20/108 (18.5%) (p < 0.001). In the multivariable regression model adjusted for age, right ventricular dysfunction, and troponin levels, the presence of renal failure, sHF, and both were independently associated with in-hospital all-cause mortality with ORs of 3.59 (95%CI 2.04–6.30, p < 0.001) vs. 3.97 (1.71–9.25, p = 0.001) vs. 6.39 (3.15–12.99, p < 0.001), respectively. Conclusions: The association of renal failure and systolic heart failure has a deleterious prognosis in patients with normotensive aPE. Full article

This review explores the impact of maternal obesity on pregnancy outcomes, emphasizing its significant global health challenge and profound implications for both mothers and infants. It influences the timing and mode of childbirth, elevating the risk of conditions like hypertensive disorders, cesarean delivery, and gestational diabetes mellitus. The review focuses on analyzing how maternal obesity affects postpartum recovery, birth timing, and delivery methods. Relevant studies were identified using PubMed and Scopus. Findings indicate that obese pregnant women are at higher risk for medically indicated preterm birth, scheduled and emergency cesarean sections, and labor induction. Postpartum recovery is often prolonged due to breastfeeding challenges, infection risks, and delayed wound healing. Additionally, maternal obesity increases the likelihood of fetal complications such as macrosomia and long-term metabolic disorders. These results highlight the importance of personalized treatments and early weight control to improve the health of both mother and baby. A comprehensive approach integrating clinical care, public health initiatives, and policy measures is essential to reduce pregnancy complications associated with obesity. Full article

Background: Preoperative stress is a multifactorial phenomenon shaped by physiological, psychological, and social influences, with a substantial impact on postoperative recovery. This study aimed to quantify preoperative stress levels, identify associated factors, and rank their predictive importance. Methods: A prospective study was conducted on 197 patients scheduled for general surgery, orthopedics, neurosurgery, or otorhinolaryngology procedures between December 2024 and June 2025 at Suceava County Emergency Clinical Hospital. Stress levels were assessed using the Brief Measure of Emotional Preoperative Stress (B-MEPS), translated and culturally adapted into Romanian. Statistical analyses included nonparametric tests, generalized linear modeling, and Random Forest regression. Results: The mean B-MEPS score was 21.42 ± 6.04 (range: 11–34), indicating a moderate level of preoperative stress. Higher stress scores were significantly associated with female sex (p < 0.001), lower educational attainment (p = 0.003), divorced marital status (p = 0.007), a history of cancer (p = 0.002), and the type of surgical intervention (p = 0.003). Random Forest analysis identified the type of surgery, educational level, and sex as the strongest predictors. Conclusions: Preoperative stress is chiefly influenced by the type of surgical procedure, educational level, and sex, with potential synergistic effects among these factors. Early identification of high-risk patients enables targeted, personalized interventions to mitigate anxiety and improve perioperative outcomes. Further research should include formal validation of the Romanian version of B-MEPS and the integration of additional psychosocial variables. Full article

Obesity-induced insulin resistance and type 2 diabetes mellitus (T2DM) represent complex systemic disorders marked by chronic inflammation, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. These pathophysiological processes disrupt insulin signaling and β-cell function, leading to impaired glucose homeostasis across multiple organs. Conventional therapies often target isolated pathways, overlooking the intricate molecular crosstalk and organelle-level disturbances driving disease progression. Citrus-derived polyphenols—including hesperidin, naringenin, nobiletin, and tangeretin—have emerged as promising agents capable of orchestrating a multi-targeted “metabolic reprogramming.” These compounds modulate key signaling pathways, including AMPK, PI3K/Akt, NF-κB, and Nrf2, thereby enhancing insulin sensitivity, reducing pro-inflammatory cytokine expression, and restoring redox balance. Furthermore, they improve mitochondrial biogenesis, stabilize membrane potential, and alleviate ER stress by modulating the unfolded protein response (UPR), thus supporting cellular energy homeostasis and protein folding capacity. Evidence from preclinical studies and select clinical trials suggests that citrus polyphenols can significantly improve glycemic control, reduce oxidative and inflammatory markers, and preserve β-cell function. Their pleiotropic actions across molecular and organ-level targets position them as integrative metabolic modulators. This review presents a systems-level synthesis of how citrus polyphenols rewire metabolic signaling networks and organelle resilience, offering a holistic therapeutic strategy to mitigate the root causes of obesity-induced insulin resistance. Full article

Background: Total arterial revascularization (TAR) may improve outcomes in patients with ischemic cardiomyopathy and heart failure with reduced ejection fraction (HFrEF). Methods: We retrospectively screened 574 adults with HFrEF (LVEF < 40%) undergoing isolated CABG across four German centers (2017–2023). After 1:1 propensity score matching, 240 patients were analyzed (120 TAR vs. 120 NTAR). The primary endpoint was in-hospital MACCE (death, MI, stroke). Key secondary endpoints included ICU/hospital length-of-stay, ventilation time, delirium, transfusion requirements, and acute kidney injury. Results: MACCE occurred in 4.1% (TAR) vs. 14.2% (NTAR) (p = 0.007). TAR was associated with shorter ICU stay (median 44.5 h vs. 90 h, p < 0.001), shorter hospital stay (10 d vs. 12 d, p = 0.002), reduced ventilation time (8 h vs. 12 h, p < 0.001), lower delirium (5.0% vs. 14.2%, p = 0.016), and fewer RBC transfusions intra-operatively (0.13 ± 0.45 vs. 0.31 ± 0.58 units, p = 0.028) and during the entire stay (0.70 ± 1.33 vs. 1.77 ± 2.91 units, p < 0.001). Conclusions: In this multicenter propensity-matched cohort, TAR was associated with lower in-hospital MACCE and more favorable perioperative outcomes compared with NTAR. Prospective studies are warranted to confirm causality and long-term benefits. Full article

Introduction: Metabolic dysfunction associated steatotic liver disease (MASLD), previously termed as nonalcoholic fatty liver disease (NAFLD), is a growing global health concern, particularly in South Asia. While PNPLA3 is a well-recognized genetic contributor to MASLD, the role of other metabolic genes, such as ABCC8, remains unexplored in South Asian populations. In this study, we aim to investigate the genetic association and potential synergy between PNPLA3 (rs738409) and ABCC8 (rs146378237) variants in MASLD pathogenesis in a Pakistani cohort. Methods: A two-phased case–control study was conducted. Whole Exome Sequencing (WES) was performed on 6 MASLD cases and 6 healthy controls to identify relevant variants, followed by validation via Sanger sequencing in an extended MASLD cohort (n = 52). Variant frequencies were compared with 96 ethnically matched controls from the 1000 Genomes Project. Furthermore, the association of the variants with clinical, biochemical, and fibrotic parameters was assessed. Results: The PNPLA3 rs738409 G allele (MAF = 0.47) and ABCC8 rs146378237 T allele (MAF = 0.36) were significantly enriched in MASLD cases and strongly associated with cirrhosis. The TT genotype of ABCC8 was also linked to T2DM and low HDL levels. Importantly, eight MASLD patients harbored both GG (PNPLA3) and TT (ABCC8) genotype, and all were known cases of diabetes, suggesting a synergistic genetic interaction. Conclusions: This is the first report of ABCC8 rs146378237 in a South Asian MASLD cohort, revealing population-specific risk and a gene–gene interaction that may inform targeted screening and personalized management of MASLD in high-risk diabetic individuals. Full article

Background: Urgent care clinics (UCCs) embedded within primary healthcare settings play a vital role in managing acute, non-life-threatening conditions in children. However, limited data exist on medication prescribing patterns in such settings in the Kingdom of Saudi Arabia (KSA), particularly regarding antibiotic use. This study aimed to describe the epidemiology of pediatric urgent care visits and identify factors associated with prescribing within a model primary healthcare (PHC) center. Methods: A retrospective chart review was conducted for all urgent care visits made by pediatric patients (<14 years) at a model PHC center in the KSA for all visits in 2024. Sociodemographic variables, visit timing, diagnosis, and prescription data were extracted from electronic health records. Multivariable logistic regression was used to analyze predictors of medication prescribing. Results: Of the 1016 pediatric urgent care visits, 62.5% resulted in medication prescriptions, and 23.62% of those visits included at least one antibiotic, primarily penicillins (71.33%). Cephalosporins and tetracyclines were not prescribed. Prescriptions were 67% more likely among adolescents and 70% less likely among infants when compared to school-aged children (95% CI = 1.04–2.67 and 95% CI = 0.15–0.61, respectively). Respiratory and ENT-related diagnoses accounted for most prescriptions. No significant sex-based differences in prescribing were observed. Conclusions: The epidemiological patterns observed indicate that respiratory and ENT conditions, as well as seasonal peaks in autumn and winter, are the main drivers of prescribing in pediatric urgent care. These findings have implications for strengthening disease surveillance, anticipating service demand, guiding preventive interventions such as vaccination and health education, and supporting evidence-based planning of primary care resources. Full article

Diagnosis of clinical obesity has been highlighted by the recent publication from a Commission Report in The Lancet, suggesting the addition of a new diagnostic category, “Preclinical Obesity,” to the already existing ones. Diagnostic criteria for obesity began in the first half of the 20th century, when life insurance companies provided information tables of ideal body weight levels and/or desirable body weight levels based on actuarial associations with mortality. This was replaced by the body mass index or BMI in the third quarter of the 20th century. This tool documented the epidemic of obesity in the US in the last three decades of the 20th century. The recognition of the importance of fat distribution, pioneered by the work of Jean Vague in France, provided a new understanding of obesity. The limitations of BMI and the availability of effective new treatments have heightened the need for new diagnostic guidelines. Obesity represents an increase in body fat and an alteration in its distribution and function. But at the same time, obesity is a stigmatized word and a pejorative term. This communication discusses ways to better diagnose the increase in body fat and its abnormal distribution. We ask whether there is an alternative word to replace obesity and suggest that adiposity or healthy weight could be options. Full article