Med. Sci., Volume 14, Issue 4 (August 2026) – 88 articles

Background: Atrial fibrillation (AF) is associated with atrial remodelling, hemodynamic stress, and complex cardiopulmonary interactions. While natriuretic peptides and echocardiographic abnormalities are established markers of AF-related substrate, the contribution of spirometry changes, as a landmark of pulmonary impairment, remains less clearly defined. This study evaluated whether AF is associated with an integrated cardiopulmonary profile characterized by altered spirometry, increased NT-proBNP, and conventional echocardiographic markers of left atrial structure and function. Methods: We performed a retrospective, single-center observational study based on an existing clinical database of adult patients referred for 24 h 12-lead Holter ECG monitoring because of palpitations and/or chest pain. None of the included patients had a previously documented diagnosis of atrial fibrillation before Holter monitoring. Because a single 24 h Holter recording cannot establish spontaneous termination or long-term temporal pattern with certainty, AF documented for the first time during this recording is referred to throughout as “newly detected AF” rather than “paroxysmal AF”. During Holter monitoring, no ECG changes suggestive of myocardial ischemia were detected. From 536 records of patients without previously known AF who underwent 24 h 12-lead Holter ECG monitoring for palpitations and/or chest pain, 164 patients were retained for the main comparison, including 48 with newly detected paroxysmal AF and 116 without AF. Demographic, biochemical, spirometric, and echocardiographic variables were analyzed. The main respiratory parameters were forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and peak expiratory flow (PEF). NT-proBNP was the primary biomarker, while conventional left atrial structural and functional variables were used for echocardiographic assessment. Results: NT-proBNP was markedly higher in the AF group (684.5 vs. 62.3 pg/mL, p = 0.001), even when accounting for confounders like age, CKD, or CPD, showing by far the largest between-group difference among the biomarkers assessed (formal discrimination statistics such as ROC/AUC were not computed). The exploratory inflammatory markers assessed (hs-CRP, neutrophil/lymphocyte ratio, homocysteine) showed only modest, non-significant differences. Conventional echocardiographic parameters did not differ significantly between groups. In the strict complete-case comparison, spirometric indices did not reach statistical significance; however, preliminary project-level analysis showed lower FVC, FEV1, and PEF in AF patients, but without supporting the COPD diagnosis, and exploratory correlations suggested a relationship between spirometric performance and left atrial function. Conclusions: In this cohort, AF was most strongly associated with NT-proBNP, while the respiratory signal was weaker but directionally consistent with a broader cardiopulmonary phenotype. These findings do not support spirometry or NT-proBNP as stand-alone diagnostic tools for AF. However, when interpreted alongside traditional AF risk factors and symptoms, elevated NT-proBNP with concordant spirometric impairment may represent a hypothesis-generating additive signal supporting longer or repeated rhythm monitoring beyond 24 h in selected patients with suspected AF; this additive value was not formally tested against clinical models alone and requires prospective confirmation. Full article

Background/Objectives: Type 2 diabetes (T2D) is a major risk factor for cardiovascular disease and chronic kidney disease (CKD), yet the extent of longitudinal CKD screening in routine clinical practice remains unclear. This study aimed to assess long-term cardiorenal outcomes and CKD screening practices in patients with T2D managed across primary care and endocrinology settings, evaluating the feasibility of risk stratification in real-world practice. Methods: We conducted a retrospective cohort study using anonymized data from the Telotrón database (2.2 million patients). Adults with T2D attended across primary and endocrinology care were followed from 1 January 2018 to 31 December 2022. Frequency of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) measurements, and cumulative proportion of kidney and cardiovascular events, hospitalizations, and mortality were assessed. Results: Among 13,600 individuals, 31.1% experienced a kidney event and 18.6% a cardiovascular event over 5 years. All-cause hospitalization occurred in 24.9% and 16.1% died. First occurrence of an abnormal eGFR or UACR measurement occurred in 37.0% of participants without baseline CKD, and 45.4% with baseline CKD showed progression. Annual monitoring was limited, with 39.1% and 16.6% undergoing at least one yearly assessment, and 2.9 and 1.5 mean number of measurements per patient for eGFR and UACR, respectively. Conclusions: Despite receiving endocrinology care, kidney disease progression and cardiovascular events remain a major concern in T2D, and yet suboptimal albuminuria and eGFR assessment limit early detection and risk stratification, thereby hindering risk-directed management. Full article

Background: Streptococcus suis serotype 2 is a major zoonotic pathogen responsible for severe systemic infections in pigs and humans, including septicemia, meningitis, and high mortality outcomes. Cefquinome, a fourth-generation β-lactam antibiotic widely used in veterinary medicine, is commonly applied for the treatment of S. suis infections. However, optimized dosing strategies remain insufficiently defined, particularly under conditions of varying bacterial burden, inoculum size, and reduced susceptibility or resistance phenotypes. These factors may significantly alter pharmacodynamic responses and compromise the predictive value of conventional MIC-based approaches. Objectives: This study aimed to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cefquinome against S. suis serotype 2 using an integrated ex vivo serum time-kill experiments and semi-mechanistic PK/PD modeling. A secondary objective was to evaluate optimized dosing regimens across different inoculum levels and susceptibility phenotypes, including a cefquinome-resistant mutant. Methods: Cefquinome pharmacokinetics following intramuscular administration at 2 and 4 mg/kg in piglets were described using a two-compartment model. Dose proportionality, exposure linearity, and clearance parameters were assessed. Ex vivo serum time-kill experiments were conducted using a parental strain and a cefquinome-resistant mutant (M1) under normal-inoculum (NI), high-inoculum (HI), and mutant/resistant (MS) conditions. A semi-mechanistic PK/PD model incorporating logistic bacterial growth, sigmoidal Emax killing, nutrient limitation, and a time-delay function was developed to describe dynamic bacterial responses. Model parameters (k₀, k_max, EC₅₀) were estimated using nonlinear least-squares regression (Scientist v2.0), and simulations were performed by integrating time-varying PK input functions. Results: Cefquinome demonstrated linear pharmacokinetics with dose-proportional increases in Cmax and AUC between 2 and 4 mg/kg, with comparable clearance across doses. Ex vivo studies revealed time-dependent antibacterial activity with a pronounced inoculum effect. Higher bacterial burdens significantly reduced bactericidal efficiency and promoted regrowth during declining drug exposure. No tested concentrations achieved ≥3-log₁₀ killing in HI or MS conditions, whereas the NI group achieved a maximal reduction of 3.5-log₁₀ CFU/mL. MIC values in serum and medium were consistent (0.03, 0.06, and 0.24 µg/mL for NI, HI, and MS, respectively), indicating minimal protein binding influence. The semi-mechanistic model accurately described observed bacterial dynamics (R² > 0.99; MSC > 1.5), capturing delayed drug effects, inoculum-dependent growth suppression, and regrowth phenomena. Growth rates were reduced under serum conditions, reflecting nutrient limitation. Importantly, inoculum size exerted a stronger impact on pharmacodynamic outcomes than resistance phenotype, as reflected by reductions in kmax and increases in EC₅₀ under HI conditions. Although %T>MIC exceeded conventional β-lactam targets (>40%) in most regimens, MIC-based indices poorly correlated with observed dynamic killing responses. Conclusions: Cefquinome exhibited time-dependent antibacterial activity against S. suis serotype 2, strongly modulated by inoculum size and reduced susceptibility. The developed semi-mechanistic PK/PD model provided robust prediction of bacterial time-kill behavior and outperformed MIC-based metrics in guiding dose optimization. Simulation results support 2 mg/kg every 24 h for normal infections and 2 mg/kg every 12 h for high-inoculum or less susceptible infections, emphasizing the value of model-informed dosing strategies for optimizing β-lactam therapy. Full article

Background: Alcohol-related conditions may influence both injury patterns and in-hospital management in orthopaedic trauma. This study evaluated the clinical characteristics, injury mechanisms, treatment patterns, and hospital outcomes of adults with acute orthopaedic trauma and documented alcohol use, with particular attention to geriatric vulnerability and alcohol withdrawal. Methods: This retrospective single-centre cohort included adults admitted between January 2018 and December 2025 with acute musculoskeletal trauma and an alcohol-related diagnosis during the same hospitalisation. Patients were classified according to their predominant recorded alcohol-related presentation. Geriatric patients, defined as those aged 65 years or older, were compared with younger adults. Injury mechanisms, comorbidities, operative treatment, intensive care unit involvement, hospital length of stay, mortality, and recorded hospitalisation costs were analysed. Results: The final cohort comprised 294 patients, including 87 geriatric patients. Geriatric patients more frequently sustained same-level or low-energy falls than younger adults (46.0% versus 25.6%; Holm-adjusted p = 0.005) and had a higher prevalence of proximal femoral fractures (40.2% versus 21.7%; OR 2.42, 95% CI 1.41 to 4.16). Any recorded ICU involvement was more frequent among geriatric patients, although prolonged ICU stays of 24 h or longer did not differ significantly between age groups. Alcohol withdrawal was documented in 46 patients and was associated with longer hospitalisation and a longer admission-to-surgery interval. In-hospital mortality occurred in 5 of 46 patients with documented withdrawal (10.9%) and 5 of 248 without withdrawal (2.0%; unadjusted OR 5.93, 95% CI 1.64 to 21.37; p = 0.010). Conclusions: Orthopaedic trauma patients with documented alcohol use represent a clinically heterogeneous population. Geriatric patients showed greater vulnerability to low-energy trauma, proximal femoral fracture, comorbidity, and intensive care involvement, while alcohol withdrawal identified patients with a more complex hospital course. Early recognition of withdrawal risk and enhanced inpatient safety measures may improve orthopaedic care. These findings support careful assessment of alcohol-related risk, early recognition of withdrawal, and heightened inpatient safety precautions. Full article

Fever-range hyperthermia (38–41 °C) is a typical physiological response to infection, inflammation, and systemic stress. Although increased temperatures are known to affect blood rheology and erythrocyte activity, their comprehensive impact on red blood cell (RBC) structure, mechanics, and lifespan remains incompletely understood. This review summarizes current understanding of how moderate hyperthermia affects RBC membrane structure, internal behavior, mechanical properties, and clearance cues. Evidence shows that brief exposure to febrile temperatures primarily induces reversible biophysical modifications, including heightened membrane fluidity, increased membrane fluctuations, changes in hemoglobin–water interactions, and short-term improvements in deformability. These changes reflect adaptive adjustments within the membrane–cytosol–cytoskeleton system, potentially temporarily boosting microcirculatory flow. On the other hand, prolonged or repeated heat stress causes oxidative damage, hemoglobin auto-oxidation, accumulation of membrane-bound hemoglobin, band 3 clustering, cytoskeletal restructuring, calcium imbalance, and disruption of membrane lipid asymmetry. These effects weaken membrane stability and lead to vesiculation, shape changes, increased cell fragility, altered aggregation, enhanced adhesion, and activation of clearance mechanisms. A primary focus is the transition from reversible membrane softening to permanent structural damage over time. The research supports a model in which temperature affects RBC mechanics and related membrane, cytosolic, and signaling processes that influence RBC viability. We propose interpreting febrile hyperthermia as a dynamic factor that shifts RBCs from an adaptive phase to accelerated aging and removal during prolonged heat exposure. This perspective enhances our understanding of RBC behavior during fever and systemic inflammation and underscores the role of temperature in shaping erythrocyte function and lifespan. Full article

Background: Biological treatment of psoriasis has revolutionized the therapy of this disease, in most cases enabling complete remission of skin lesions. Methods: This study aimed to analyze real-world evidence from 165 patients (mean age 38.1 ± 5.66) treated with 11 biological drugs at our Dermatology Department. Results: Skin lesion severity, expressed by Psoriasis Area and Severity Index (PASI) and Body Surface Area (BSA), improved significantly throughout the treatment, along with the quality of life, expressed by Dermatology Life Quality Index (DLQI) (all p < 0.0001). We observed a statistically significantly higher reduction in skin lesion severity and life quality improvement with IL-23 and IL-17 inhibitors compared to TNFα inhibitors (both p < 0.0001). Secondary loss of response was observed in 26.7% of patients treated with anti-TNF agents, compared to 15.0% in the anti-IL-23 group and 8.3% in the anti-IL-17 group (χ² test, p = 0.0683). Patients who had been treated in the past with biologics had significantly higher PASI and BSA at week 16 of therapy compared to those who were bio-naïve. A positive correlation was demonstrated between PASI at 16 weeks and BMI (R = 0.15; p = 0.0396). There was no correlation between the duration of psoriasis, sex, or age of patients when introducing biologics and PASI at any of the timepoints (p > 0.05). The most frequent side effects were infections, occurring mainly in patients on anti-TNFα agents and bimekizumab. Conclusions: IL-17 and IL-23 inhibitors demonstrated superior efficacy compared to TNFα inhibitors, with higher rates of complete skin clearance and a lower tendency toward loss of response. The worst efficacy and the highest rate of loss of response were observed in case of adalimumab. These findings support the increasing role of IL-17 and IL-23 inhibitors as preferred therapeutic options in psoriasis. Previous biologic exposure and higher BMI seem to be associated with poorer therapeutic outcomes. Overall, biological treatment is an effective, rapid, and safe therapeutic option. Full article

Background/Objectives: Lifestyle interventions may alleviate treatment-related toxicity and improve patient-centered outcomes during radiotherapy (RT). This scoping review mapped randomized evidence on lifestyle interventions delivered during RT, summarized reported outcomes, and identified evidence gaps. Methods: PubMed and Web of Science were searched for randomized controlled trials (RCTs) published from April 2016 to April 2026. Eligible studies included adults who received exercise, nutritional, psychological, combined, or multimodal lifestyle interventions during their RT treatment. Study characteristics, intervention details, and outcomes were charted and narratively synthesized. Results: Twenty-three RCTs were included. Exercise interventions were evaluated in 12 studies, nutrition in five, psychological in one, combined exercise-and-nutrition in two, combined nutrition-and-psychological in two, and multimodal interventions comprising all three components in one study. Breast, head and neck, and prostate cancers were most frequently represented. QoL, fatigue, and functional capacity were the most commonly assessed outcomes. Exercise interventions were most consistently associated with improvements in fatigue and functional capacity, whereas effects on QoL were less consistent. Nutritional interventions showed favorable findings for nutritional status and treatment-related toxicity. Psychological, combined, and multimodal interventions showed favorable findings for selected QoL, fatigue, nutritional, and psychological outcomes. Key evidence gaps included heterogeneous intervention protocols and outcomes assessment, limited evidence for non-exercise interventions and underrepresentation of several cancer populations. Conclusions: Lifestyle interventions delivered during RT may improve selected patient-centered and treatment-related toxicity outcomes. Exercise comprised the largest body of evidence, whereas other intervention types were less frequently evaluated. Heterogeneity across studies limits conclusions regarding optimal approaches. Further RT-specific studies using standardized intervention programs and comparable outcome measures are required to inform supportive-care delivery. Full article

Background: Composite anthropometric and cardiometabolic indices have emerged as practical tools for identifying metabolic syndrome (MetS), but their comparative classification performance against ALAD-defined MetS has not been comprehensively evaluated in Panamanian adults. This study compared the classification performance of selected anthropometric, body composition, and cardiometabolic indices for identifying metabolic syndrome defined according to the Latin American Diabetes Association (Asociación Latinoamericana de Diabetes [ALAD]) criteria in non-diabetic Panamanian adults. Methods: This cross-sectional study included 262 adults without diabetes (110 men and 152 women). Clinical and laboratory measurements were used to calculate the body mass index (BMI), waist-to-height ratio (WHtR), visceral adiposity index (VAI), lipid accumulation product (LAP), triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C), atherogenic index of plasma (AIP), cardiometabolic index (CMI), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Classification performance was evaluated using receiver operating characteristic (ROC) curve analysis, optimal cut-off values, and DeLong’s test. Age-adjusted logistic regression assessed associations between each index and ALAD-defined MetS. Results: Composite indices integrating anthropometric and metabolic parameters showed high classification performance. CMI had the highest observed AUC in men (AUC = 0.933; 95% CI: 0.887–0.979), whereas LAP had the highest observed AUC in women (AUC = 0.854; 95% CI: 0.778–0.931). Conclusions: CMI and LAP showed high classification performance for identifying ALAD-defined MetS in Panamanian adults without diabetes, with the highest observed AUCs in men and women, respectively. These simple, inexpensive indices may have potential utility as screening tools for identifying ALAD-defined MetS in primary healthcare settings. The proposed cut-off values are exploratory and require external validation in independent Panamanian and Latin American populations before clinical implementation. Full article

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a relapsing course and a substantial multidimensional burden. Conventional clinical and patient-reported outcome measures mainly provide cross-sectional evaluations and may not fully capture the long-term impact of the disease. The concept of cumulative life course impairment (CLCI) has been proposed to describe the progressive and lifelong consequences of chronic dermatologic conditions. Methods: This narrative review is based on a non-systematic literature search conducted in PubMed/MEDLINE and Embase up to July 2026. Relevant studies addressing quality of life, mental health, comorbidities, and economic burden in AD were identified and narratively synthesized, with particular focus on evidence supporting the CLCI framework. Results: AD exerts a cumulative burden across multiple domains. Pruritus and sleep disturbance emerge as key drivers, contributing to a self-reinforcing cycle involving psychological distress and impaired daily functioning. Increased rates of anxiety and depression, along with social stigmatization, negatively affect interpersonal relationships, educational attainment, and work productivity. Comorbidities and the chronic relapsing nature of AD further amplify long-term impairment. Economic burden, including both direct and indirect costs, acts as both a consequence and a driver of cumulative disadvantage. Recurrent disease flares play a central role in sustaining and amplifying this trajectory over time. Conclusions: AD should be considered a life-course disease in which interacting biological, psychological, and social factors shape long-term outcomes. A CLCI-oriented approach may improve patient stratification and support earlier, multidisciplinary, and proactive management strategies aimed at reducing long-term burden and improving overall outcomes. Full article

Background: Optical coherence tomography angiography (OCTA) provides quantitative metrics of the retinal microvasculature, most prominently vessel density (VD), that are increasingly used as biomarkers in ocular, systemic, and cerebrovascular disease. Because OCTA relies on the detection of flow-related motion contrast, image quality has emerged as a pervasive determinant of these metrics, yet its effect has been reported in fragmentary and non-comparable ways across the literature. Methods: We identified OCTA studies indexed in PubMed that examined the relationship between image quality and quantitative OCTA parameters, and we summarised their methods and findings across the macular, foveal avascular zone, and peripapillary regions and across vascular layers. We integrated directly comparable per-unit scan-quality effects using random-effects meta-analysis and separately synthesized direct cross-sectional Pearson correlations between manufacturer-reported image quality and macular vessel-density outcomes from independent healthy cohorts. Results: Higher image quality was associated with higher measured vessel density in every contributing dataset. On the Optovue scan-quality (SQ, 0–10) scale, superficial macular VD increased by 3.46% (95% CI 1.85–5.07) per SQ unit in controlled signal-attenuation experiments and by covariate-adjusted observational estimates ranging from 0.90% to 2.16% per SQ unit; a combined order-of-magnitude estimate across both estimator types was 1.64% (95% CI 1.15–2.12). Peripapillary estimates were heterogeneous and derived from only two independent cohorts; they were therefore summarised descriptively rather than pooled. Across three independent externally authored healthy cohorts reporting direct cross-sectional Pearson correlations, higher image quality was strongly associated with higher macular vessel-density outcomes (random-effects pooled r = 0.64, 95% CI 0.50–0.75; I² = 49%). Conclusions: Image quality is an important, directional confounder of VD-based OCTA metrics whose magnitude can rival the biological or physiological signal of interest. Platform-appropriate standardisation, transparent reporting, and consideration of image quality in acquisition and analysis are therefore important for the valid interpretation of vessel-density measurements, particularly in functional and longitudinal studies. Full article

Background: Alcohol use disorder (AUD) is generally regarded as a relative contraindication to pancreas transplantation. Yet the effect of documented AUD before transplantation on long-term results after pancreas transplantation is still poorly understood. Therefore, we used a large real-world electronic health records database to compare the three-year outcomes among pancreas transplant recipients who had and who had not had documented AUD before transplantation. Methods: We carried out a retrospective cohort study involving propensity score matching using the TriNetX US Collaborative Network. Each adult patient who had a documented case of alcohol use disorder (ICD-10-CM codes F10.1/F10.2) before transplantation was paired one to one with a patient who did not have such a disorder, matching them on demographic characteristics, comorbidities, transplant-related factors, medications, body mass index, and glycated hemoglobin. The outcomes were evaluated from one day after transplantation up to three years later and comprised all-cause mortality, emergency visits, transplant complications, cachexia, severe protein–calorie malnutrition, pain, vitamin deficiencies, iron deficiency anaemia, diarrhea, and adult failure to thrive. Results: Out of 14,367 eligible recipients, propensity score matching resulted in 439 patients in each group. Pretransplant AUD was linked to a significantly higher rate of all-cause mortality (15.1% compared with 8.5%; risk ratio [RR] 1.78, 95% CI 1.22–2.60; hazard ratio [HR] 1.86, 95% CI 1.25–2.78; p = 0.002). Cachexia affected 5.2% rather than 2.5% (RR 2.09, 95% CI 1.03–4.24; HR 2.16, 95% CI 1.06–4.44; p = 0.036), while diarrhea occurred in 39.6% compared with 28.2% (RR 1.40, 95% CI 1.16–1.69; HR 1.54, 95% CI 1.22–1.94; p < 0.001). There were no significant differences in the case of emergency visits (49.0% versus 44.6%; p = 0.199), transplant complications (11.1% versus 14.4%; p = 0.163), severe protein–calorie malnutrition (12.1% versus 8.9%; p = 0.123), pain (59.0% versus 54.7%; p = 0.195), vitamin deficiencies (31.4% versus 29.4%; p = 0.509), iron deficiency anemia (21.2% versus 21.9%; p = 0.805), or adult failure to thrive (7.3% versus 4.3%; p = 0.061). Conclusions: The presence of a history of alcohol use disorder (AUD) before transplantation was found to be independently linked to a higher three-year mortality rate, as well as the occurrence of cachexia and diarrhea after pancreas transplantation, but it was not associated with an increased number of coded transplant complications or most of the other adverse outcomes following the procedure. These results indicate that pancreas transplant recipients with a history of AUD should have enhanced monitoring in the areas of nutrition, the gastrointestinal system, and addiction. Full article

Background: Peritoneal dialysis (PD) effluent of kidney failure patients represents an accessible liquid biopsy of the peritoneal cavity, yet the mechanisms determining its molecular composition remain poorly understood. We applied an integrative multi-omics approach to characterize the composition, transport dynamics, and molecular origin of the PD effluentome. Methods: Cell-free effluent, effluent cells, and plasma were collected from stable PD patients during standardized peritoneal equilibration tests in a randomized clinical trial. Targeted metabolomics, proteomics, and transcriptomic profiling were integrated with a reference human plasma proteome to investigate temporal molecular changes, peritoneal transport characteristics, and protein origin. Results: A total of 207 metabolites and 2970 proteins were identified in PD effluent. Metabolites exhibited distinct class-specific transport kinetics, with rapid equilibration of amino acids and biogenic amines, whereas lipids remained markedly underrepresented despite prolonged dwell times, indicating that transport is governed by physicochemical properties beyond molecular size alone. The effluent proteome underwent concordant alteration, with dwell time-dependent enrichment of pathways related to extracellular matrix organization, angiogenesis, coagulation, and tissue repair. Integrative analysis of the effluent proteome, effluent-cell transcriptome, and human plasma proteome resolved distinct plasma-associated, effluent cell-associated, resident peritoneal tissue-associated, and mixed-origin protein populations. Conclusions: This study establishes the first systems-level approach describing the composition, transport dynamics, and molecular origin of the PD effluentome. By transforming PD effluent into a biologically interpretable molecular readout of peritoneal membrane biology, this work provides a reference for the mechanistic interpretation of effluent-derived biomarkers and supports future therapeutic monitoring and precision medicine in PD. Full article

Background: Physical activity is widely recommended for preserving musculoskeletal health and managing osteoarthritis-related pain, although its benefits are commonly framed in terms of muscle strengthening, weight control, and physical performance. This narrative review aimed to examine movement more broadly as a physiological regulator of synovial joint homeostasis, sensory calibration, and functional adaptation. Methods: A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science from database inception to 1 February 2026. Experimental studies, observational studies, clinical trials, systematic reviews, meta-analyses, and selected narrative reviews addressing movement-responsive joint biology or pain regulation were considered. Evidence was synthesized across four interrelated domains: mechanical, fluidic, immune-metabolic, and sensory regulation. Results: The narrative synthesis indicates that the concept of the synovial joint as a dynamic mechano-fluidic organ in which cartilage, synovium, synovial fluid, capsule, subchondral bone, periarticular tissues, and sensory pathways interact continuously. Repeated physiological movement may promote synovial fluid exchange, lubrication, cartilage nutrition, hyaluronic acid and lubricin function, matrix turnover, anti-inflammatory signaling, proprioceptive control, and exercise-induced hypoalgesia. In contrast, inactivity and unloading may impair fluid dynamics, promote muscle inhibition, stiffness, inflammatory persistence, sensory deconditioning, and loss of function. Excessive or poorly distributed loading may also disrupt homeostasis through matrix injury, inflammation, fatigue, and nociceptive sensitization. These findings informed the proposed adaptive loading window, a hypothesis-generating conceptual framework rather than a clinically validated threshold, describing the dynamic range of movement within which joint function and pain regulation may be supported without sustained tissue or symptom aggravation. Conclusions: Movement should be viewed not only as a therapeutic intervention, but also as a continuous regulator of joint biology and perception. Its clinical value may depend on identifying an individualized loading range that supports adaptation, function, and confidence in movement while avoiding both underloading and overload. Full article

Background and objectives: Melanoma survivors may develop additional primary malignancies, but data from Eastern European hospital cohorts are scarce. We aimed to estimate the observed incidence of second primary cancers (SPCs) within a Romanian referral-centre cohort, identify associated factors, and explore the association of SPC occurrence with overall survival. Methods: We conducted a retrospective, hospital-based cohort study of 394 patients with histopathologically confirmed cutaneous melanoma followed at two referral centres in Cluj-Napoca. Additional malignancies were counted as new primaries only when clinical and/or histopathological documentation distinguished them from recurrence or metastasis. Incidence density was expressed per 1000 person-years. Multivariable logistic regression assessed age, sex, residence, and Breslow thickness. Fixed-covariate Cox and Kaplan–Meier analyses were considered exploratory because of immortal-time and competing-risk limitations. Results: Over 1848 person-years, 79 patients (20.1%) developed at least one SPC (131 events; observed incidence 70.9/1000 person-years), most frequently cutaneous (53.6/1000 person-years). SPC occurrence increased with age (Cochran–Armitage Z = 5.63, p < 0.001); the Kaplan–Meier complement estimate reached 20.7% at five years. Age independently predicted SPC (OR 1.86 per decade, p < 0.001), whereas greater Breslow thickness was inversely associated (OR 0.86, p = 0.008). Actinic keratosis showed a strong unadjusted association (OR 6.64, p < 0.001) but was not included in the adjusted model. The fixed-status Cox model showed lower mortality among patients with an SPC (HR 0.36, p < 0.001), a finding vulnerable to detection and immortal-time bias. Conclusions: SPCs were frequent in this hospital cohort and predominantly cutaneous. Older age was an independent predictor, while actinic keratosis was a strong unadjusted marker. Prospective, population-based validation is needed before surveillance intensity is individualised. Full article

Background/Objectives: Adrenocortical carcinoma (ACC) is a rare malignancy in which overexpression of steroidogenic factor-1 (SF-1/NR5A1) and aberrant activation of canonical Wnt/β-catenin signaling are important oncogenic events. However, the extent to which these regulatory axes converge or interact at the transcriptional level remains unclear. We investigated their relationship using bulk transcriptomic and regulatory-network approaches. Methods: Regulatory network inference using RTN/ARACNe was applied to the TCGA-ACC cohort. NR5A1 and β-catenin-associated TCF/LEF regulon activities were evaluated in perturbation datasets and tested for associations with CpG island methylator phenotype (CIMP), overall survival, and gene-level interaction effects. Candidate modulators of NR5A1 activity were assessed using the MINDy algorithm. The effects of cBAF inhibition on NR5A1 regulon activity were also evaluated in H295R and CU-ACC1 cells. Results: NR5A1 knockdown repressed steroidogenic pathways, whereas β-catenin knockdown predominantly suppressed Wnt/β-catenin signaling. In TCGA-ACC, NR5A1 regulon activity was associated with CIMP-high status and overall survival. In contrast, β-catenin-related regulons were not significantly associated with CIMP-high status after adjustment for NR5A1 activity, and no significant multiplicative interaction effects were identified. Fewer than 3% of protein-coding genes showed improved fit in models including NR5A1 × TCF/LEF interaction terms, without enrichment for steroidogenic or Wnt/β-catenin-related pathways. CTNNB1 was identified as a statistically significant but low-ranking positive modulator of NR5A1 activity, whereas CTNNBIP1 was a top-decile negative modulator. cBAF inhibition was associated with NR5A1 regulon repression in both cell models. Conclusions: These findings indicate limited detectable global transcriptional convergence between NR5A1 and canonical β-catenin-related regulons in the evaluated bulk transcriptomic frameworks. Potential relationships between these pathways may depend on more localized, chromatin-dependent, protein-level, or context-specific regulatory mechanisms. NR5A1 regulon activity showed more consistent associations with CIMP-high status and clinical outcome than the β-catenin/TCF-LEF regulons in the evaluated TCGA-ACC models. The modulation patterns associated with CTNNB1 and CTNNBIP1, together with the repression of NR5A1 regulon activity following cBAF inhibition, raise the possibility that NR5A1 acts as a context-dependent regulatory node connecting oncogenic signaling and chromatin-remodeling mechanisms in ACC. These findings support further investigation into the role of chromatin-remodeling complexes in sustaining NR5A1-driven transcriptional programs in ACC. Full article

Background/Objectives: Temporomandibular joint (TMJ) abnormalities are a common finding in the general adult population, but they have been rarely investigated in people receiving chronic dialysis. The TMJ is a unique synovial joint that can be altered by either inflammatory or degenerative processes, both of which are amenable to ultrasound (US) assessment. The aim of this study was to describe the pattern of TMJ involvement in a cohort of hemodialysis patients using TMJ ultrasound (TMJ US). Methods: This cross-sectional, single-center study evaluated the clinical utility of TMJ US to detect inflammatory and degenerative changes in patients undergoing chronic hemodialysis and was carried out between June and December 2025. Demographic data, dialysis vintage, the Controlling Nutritional Status (CONUT) score and the Charlson Comorbidity Index (CCI) were collected and related to TMJ US findings and to bone-metabolism biomarkers (calcium, phosphate, parathyroid hormone). Results: 100 hemodialysis patients were included (65 male, 65%; mean age 71.6 ± 13.1 years). Comorbidity and undernutrition were frequent findings (CCI ≥ 4 in 63%; CONUT ≥ 3 in 68%). TMJ US revealed that degenerative indicators were more common than inflammatory ones: calcifications (36%), condylar irregularities (33%) and enthesophytes (25%) were the most prevalent degenerative findings, whereas joint effusion (16%), synovial hypertrophy (15%) and cartilage changes (15%) were the leading inflammatory findings; a positive power Doppler signal was rare (1%). Cortical/condylar irregularity was significantly more prevalent in patients with a dialysis vintage of less than 30 months (43.8% vs. 23.1%, p = 0.034), who also had lower serum calcium levels. No other TMJ US finding showed a significant association with age, sex, comorbidity burden, nutritional status, or bone-metabolism parameters on univariate. Conclusions: TMJ US demonstrated a substantial burden of subclinical degenerative and, to a lesser extent, inflammatory TMJ findings in this cohort of hemodialysis patients; none of these abnormalities were spontaneously reported as symptomatic, and their prevalence was independent of age, dialysis vintage, comorbidity, nutritional status and classical bone-metabolism parameters. These findings cannot be directly attributed to the dialysis/uremic environment rather than to age-related degeneration; they support the concept that the TMJ warrants further investigation as a potentially under-recognized target within the broader systemic metabolic derangement of end-stage kidney disease, and suggest that TMJ US is a feasible, accessible technique for detecting subclinical TMJ involvement in this population, pending confirmation of clinical utility in controlled studies. Full article

Background/Objectives: High-grade pulmonary neuroendocrine carcinoma (HGNEC-L), including SCLC and LCNEC, is aggressive and usually treated according to SCLC paradigms. The clinical relevance of de novo actionable genomic alterations (AGA) remains incompletely defined. Methods: We performed a retrospective multicenter analysis of advanced HGNEC-L with de novo AGA, assessing rwORR, rwDCR, rwPFS, and OS. Findings were contextualized by a structured literature review and exploratory pooled reconstructed-IPD Cox analysis, with targeted therapy modeled as a source-stratified time-dependent covariate. Results: Ten patients from four tertiary centers were included. Most were women (90.0%) and never-smokers (70.0%); histology was LCNEC in 60.0% and SCLC/mixed SCLC in 40.0%. AGA included EGFR mutations (n = 6), EML4-ALK fusions (n = 2), KIF5B-RET fusion (n = 1), and KRAS p.G12C (n = 1). Targeted-containing regimens achieved rwORR 77.8%, rwDCR 88.9%, and median rwPFS 9.0 months (95% CI, 2.0–18.7), as opposed to 3.7 months for ICI-containing regimens and 2.6 months for chemotherapy alone. Median OS for the entire cohort was 17.2 months (95% CI, 4.8–36.3); overall survival did not differ significantly between patients with and without targeted-containing exposure (19.0 vs. 17.2 months; log-rank p = 0.50). In pooled reconstructed-IPD time-dependent Cox analysis (72 patients, 39 deaths), targeted therapy showed a favorable but non-significant OS association (HR, 0.89; 95% CI, 0.31–2.56; p = 0.831), maintained directionally in the age/sex-adjusted subset (HR, 0.54; 95% CI, 0.16–1.77; p = 0.306). Conclusions: De novo AGA-positive HGNEC-L represents a clinically relevant subgroup with potential sensitivity to genotype-matched targeted therapy, supporting comprehensive molecular profiling and early targeted therapy consideration. Full article

Background: Acute respiratory distress syndrome (ARDS) occurs in 20–40% of patients following esophagectomy and is associated with substantial postoperative morbidity and mortality. A major contributor to postoperative ARDS is pulmonary ischemia–reperfusion injury (IRI); however, the role of IRI in ARDS following esophagectomy is not adequately addressed in current experimental models. In this study, we established a large animal model of pulmonary IRI that reproduces key physiological, inflammatory, and histopathological features of pulmonary ischemia–reperfusion-induced acute lung injury relevant to postoperative ARDS after esophagectomy. Methods: Sequential pulmonary ischemia–reperfusion injury was induced in ten anesthetized Landrace pigs using unilateral hilar inflow occlusion. Right lung ischemia was achieved by clamping the hilar inflow for three hours, followed by reperfusion. Subsequently, the left lung underwent two hours of ischemia. Hemodynamic, respiratory, and inflammatory parameters were continuously monitored throughout the experiment. Blood samples were collected to assess leukocyte counts and circulating inflammatory cytokines, including tumor necrosis factor-α and interleukin-6. Lung tissue samples were obtained for histopathological evaluation. Results: ARDS-like lung injury was successfully induced in all animals, with PaO₂/FiO₂ ratios falling below 200 mmHg during the predefined reperfusion observation period. Lung compliance decreased by approximately 50% after ischemia and further declined following reperfusion. Progressive leukocyte elevation and elevated tumor necrosis factor-α and interleukin-6 levels were observed, indicating a systemic inflammatory response. Hallmark features of ARDS were histologically confirmed, including intra-alveolar hemorrhage, interstitial and perivascular edema, and neutrophil infiltration. Conclusions: This porcine model reproduces key physiological, inflammatory, and histopathological features consistent with pulmonary ischemia–reperfusion-induced ARDS-like lung injury. Although it does not reproduce the complete clinical syndrome of post-esophagectomy ARDS, it provides a clinically relevant translational platform for investigating pulmonary ischemia–reperfusion injury and evaluating potential preventive and therapeutic strategies. Full article

Background: Parkinson’s disease (PD) exhibits remarkable clinical heterogeneity, with substantial variability in motor progression, cognitive decline, and the development of non-motor manifestations. Although the propagation of pathological alpha-synuclein is considered a central mechanism of PD pathogenesis, it does not fully explain why specific neuronal populations demonstrate differential susceptibility to degeneration. Emerging evidence suggests that selective neuronal vulnerability is determined by the interaction of multiple biological domains, including calcium homeostasis, mitochondrial bioenergetic capacity, lysosomal function, axonal architecture, synaptic resilience, and neuroinflammatory responses. Methods: A structured critical narrative review was performed using PubMed/MEDLINE, Scopus, and Web of Science databases from inception to March 2025. Only full-text articles published in English and peer-reviewed journals were included. Evidence from human post-mortem studies, genetic analyses, biomarker investigations, experimental models, induced pluripotent stem cell studies, and longitudinal clinical cohorts were systematically synthesised to identify the principal mechanisms underlying selective neuronal vulnerability and their potential translational application. To capture evidence published after this electronic cut-off, a supplementary manual review of reference lists of key systematic reviews and landmark publications was conducted up to the date of manuscript submission; references with 2025 or 2026 publication dates entered through this supplementary process. The supplementary manual review was conducted as a targeted scan of reference lists of key systematic reviews and high-impact publications identified during the primary search and did not constitute an independent updated systematic search. Results: Five interconnected biological domains emerged as key determinants of neuronal susceptibility in PD: calcium-mediated metabolic stress associated with autonomous pacemaker activity, mitochondrial dysfunction and energetic failure, impaired lysosomal degradation and proteostasis (particularly involving the GBA1–glucocerebrosidase pathway), vulnerability related to extensive axonal and synaptic architecture, and neuroinflammatory mechanisms involving microglial and astrocytic activation. Among these domains, the lysosomal pathway currently provides the strongest translational link between molecular mechanisms and measurable clinical outcomes. Based on this integrated framework, we propose the Parkinson’s Vulnerability Index (PVI), a hypothesis-generating multidimensional model combining genetic, enzymatic, alpha-synuclein seeding, cognitive, olfactory, and neuroimaging biomarkers to facilitate biological stratification and improve the design of mechanism-targeted clinical trials. Conclusions: Selective neuronal vulnerability provides a complementary framework to alpha-synuclein propagation models for understanding the heterogeneity of PD. The proposed PVI is not intended as a diagnostic or prognostic clinical instrument but as a research tool requiring prospective validation. Future precision medicine approaches in PD may benefit from integrating vulnerability-related biomarkers with existing biological staging systems to identify patients most likely to benefit from targeted disease-modifying therapies. Full article

Background: The early diagnosis of eye fundus pathologies is crucial, as they may go unnoticed until reaching advanced stages. To offer an improved screening methodology for this purpose, the effectiveness of a conditional variational autoencoder (CVAE) based on multispectral (MS) imaging and operating from the visible to the near-infrared range (416–1213 nm) has been assessed. Methods: A total of 2040 images from 102 patients (66 females, 36 males; aged 19–91 years) were acquired with an MS fundus camera to feed a fine-tuned CVAE for classifying eye fundus as healthy or diseased. The performance of the neural network was assessed for different image resolutions and spectral ranges. Results: The proposed deep generative model showed excellent results, reaching 100% of accuracy, sensitivity and specificity for the set of MS images from 416 nm to 955 nm at maximum resolution (1757 × 1757 pixels). Other instances with different image resolutions and spectral ranges led to good classifications (accuracy between 96% and 98%, sensitivity between 92% and 98%, and specificity between 97% and 100%). The CVAE exhibited robust performance with convergence of the accuracy and loss through the different epochs for training and validation in all instances. Conclusions: This study proves that a CVAE approach based on MS imaging is a highly effective tool for diagnosing eye fundus conditions and could potentially serve as a valuable clinical support tool for screening. The approach performs remarkably well when high spatial resolution MS images ranging from 416 nm to 955 nm are used. This underscores the importance of combining spatial and spectral information, particularly of wavelengths beyond the visible range. Full article

Background/Objectives: Peripheral arterial disease (PAD) and diabetes mellitus (DM) may produce different and overlapping plantar thermal patterns. This study descriptively characterized whole-foot temperature-distribution patterns in clinically defined healthy, PAD, DM, and combined PAD_DM cohorts. Methods: This single-center, exploratory, cross-sectional observational study included 73 participants: healthy controls (n = 21), isolated PAD (n = 13), isolated DM (n = 19), and combined PAD_DM (n = 20). Right- and left-foot temperature distributions were processed separately for each participant and interpreted as one paired bilateral thermal footprint using patient-level histograms, representative bilateral kernel density estimation (KDE) profiles, and a cohort-derived deterministic rule-based model. The model was developed from the present cohort and was not evaluated as an independent diagnostic classifier. Results: Among healthy controls, 11 of 21 participants (52.4%) were assigned to healthy and 8 of 21 (38.1%) to borderline healthy categories. In the DM cohort, 7 of 19 participants (36.8%) were assigned to DM, 3 of 19 (15.8%) to borderline healthy/suspected DM or controlled DM, 3 of 19 (15.8%) to DM suspected PAD, and 5 of 19 (26.3%) to PAD_DM. In the combined PAD_DM cohort, 15 of 20 participants (75.0%) were assigned to PAD_DM. The isolated PAD cohort was the most heterogeneous: 6 of 13 participants (46.2%) were assigned to PAD_DM, while none were assigned to the isolated PAD output. Conclusions: This exploratory, cross-sectional study demonstrated that whole-foot plantar temperature distributions can descriptively characterize differences among healthy individuals, patients with isolated DM, and those with combined PAD and DM. While healthy controls generally demonstrated symmetric thermal footprints, the DM cohort frequently exhibited globally elevated and compact temperature-distribution profiles, while mixed asymmetric patterns were common in participants with combined PAD and DM. In contrast, the isolated PAD cohort was characterized by pronounced thermal heterogeneity. Full article

Background: Chronic obstructive pulmonary disease (COPD) and acute myocardial infarction (AMI) frequently coexist and share several biological pathways and risk factors. Although COPD is associated with worse outcomes after AMI, the prognostic value of objective pulmonary function has not been well characterized. The aim of this study was to evaluate the association between airflow-obstruction severity and five-year all-cause mortality after AMI among patients with COPD. Methods: This single-center retrospective cohort study was restricted to adult post-AMI patients (2002–2017) with a background diagnosis of COPD and documented spirometry; therefore, the final cohort represents a selected subgroup of the source COPD-AMI population. Airflow obstruction was categorized according to forced expiratory volume in one second (FEV1) as Mild, Moderate, Severe, or Very Severe (according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD)). The outcome was all-cause mortality during up to five years of follow-up. Results: Among 1594 patients hospitalized with AMI and a COPD diagnosis, 169 patients with available spirometry were included in this selected analytical cohort (mean age 66.76 ± 9.86 years, 76.9% male). During follow-up, 65 patients died, corresponding to an overall five-year mortality rate of 38.5%. Mortality increased progressively across obstruction categories: 19.0%, 33.3%, 40.0%, and 70.8% in Mild, Moderate, Severe, and Very Severe, respectively (p for trend <0.001). In multivariable analysis, adjusted hazard ratios for mortality were: 2.49 (95% CI 0.86–7.24), 3.38 (95% CI 1.09–10.46), and 5.23 (95% CI 1.62–16.89) for Moderate, Severe, and Very Severe, compared with Mild obstruction. Conclusions: Among patients with COPD who survived hospitalization for AMI, more severe airflow obstruction was associated with substantially higher five-year all-cause mortality. These findings support the potential role of spirometry-based risk stratification and highlight the need for integrated cardiopulmonary follow-up after AMI. Full article

Background/Objectives: Chronic inflammation in the tumor microenvironment (TME) promotes immune evasion and metastasis in breast cancer, where the IL-23/IL-17 axis is a key mediator. We investigated the expression of IL-23 in breast cancer and identified a small natural molecule therapeutically targeting this axis. Methods: IL-23 expression and its clinicopathological significance were assessed in a Moroccan breast cancer cohort and the METABRIC dataset. A High-throughput virtual screening of Allium sativum L. compounds was conducted to target the IL-23/IL-17 axis. In vitro, the selected candidate, IL-23RI, was evaluated for its effects on IL-17A and IFNγ production in human PBMCs using flow cytometry, as well as on the migration of MCF-7 and MDA-MB-231 breast cancer cells using wound-healing assays. Results: IL-23 was found to be overexpressed in aggressive breast cancer subtypes and correlated with unfavorable clinicopathological features and a poor prognosis. Elevated IL-23 expression was associated with an immunosuppressive TME, characterized by increased inhibitory immune checkpoints and immunosuppressive chemokines. In silico, IL-23RI demonstrates a high binding affinity for the IL-23 receptor, with a docking score of −7.482 kcal/mol and a binding free energy of −48.80 kcal/mol, stabilized by five hydrogen bonds. In vitro, IL-23RI selectively suppressed IL-17A production by CD4⁺ T cells without affecting IFNγ secretion by both CD4⁺ and CD8⁺ T cells. Furthermore, IL-23RI significantly inhibited the migration of MCF-7 and MDA-MB-231 breast cancer cells. Conclusions: These findings establish the IL-23/IL-17 axis as a critical therapeutic target and present IL-23RI as a promising dual-function agent for breast cancer treatment, concurrently modulating immunity and inhibiting tumor cell migration. Full article

Background: Lipoprotein(a) [Lp(a)] has emerged as a key mediator of calcific aortic valve disease and is strongly linked to the development and progression of aortic stenosis (AS). Whether elevated Lp(a) influences disease severity, long-term prognosis, or both in patients undergoing transcatheter aortic valve implantation (TAVI) remains uncertain. Methods: This multicenter study included 213 patients with severe symptomatic AS undergoing TAVI between 2016 and 2018. Pre-procedural Lp(a) concentrations were measured using a standardized immunoturbidimetric assay. Associations with long-term all-cause mortality were evaluated using Kaplan–Meier analyses and Cox proportional hazards models. The relationship between Lp(a) and AS severity was assessed using correlation analyses, multivariable linear regression models, and restricted cubic spline analyses. Anatomical and hemodynamic measures included aortic valve calcium score (AVCS), peak aortic jet velocity (AV Vmax), and transvalvular pressure gradients. Results: During a median follow-up of 7.58 years (IQR 4.33–8.66 years), Lp(a) was not associated with all-cause mortality, irrespective of whether it was analyzed as a continuous variable, according to established clinical thresholds, or across quartiles. In contrast, higher Lp(a) concentrations were associated with greater valvular calcification and more severe hemodynamic obstruction. These associations remained significant after adjustment for age, sex, diabetes mellitus, and renal function. Restricted cubic spline analyses suggested predominantly linear associations without evidence of significant non-linearity. Conclusions: Elevated Lp(a) concentrations were associated with greater anatomical and hemodynamic severity of AS but not with long-term mortality after TAVI. These findings suggest that elevated Lp(a) is associated with greater anatomical and hemodynamic severity of calcific aortic valve disease but was not linked to long-term mortality after TAVI. Full article

Background/Objectives: Sleep disturbances are common but frequently underrecognized in multiple sclerosis (MS), independently predicting reduced quality of life and worsening fatigue, cognitive impairment, and depression. While pain, nocturia, fatigue, and mood symptoms are established contributors, cardiometabolic, and inflammatory factors remain largely unexplored despite their known links to poor sleep in other populations. This study used interpretable machine learning to determine the relative contribution of disease-related, cardiometabolic, and inflammatory parameters to sleep quality, assessed by the PSQI, in patients with MS. Methods: This cross-sectional, observational, single-center cohort study enrolled adult patients with MS. Sleep quality (PSQI), daytime sleepiness (ESS), and restless legs syndrome severity (IRLS) were assessed alongside clinical, anthropometric, hemodynamic, and laboratory parameters, including inflammatory and metabolic indices. Three regression models, Support Vector Regression (SVR), Random Forest, and XGBoost, were trained on 28 predictors to predict PSQI global scores and evaluated on an internal test set, with feature contributions examined using SHAP analysis. Results: A total of 173 patients with MS were included (mean age 39.66 ± 11.86 years, 69.9% female, 90.2% RRMS), with 48.0% classified as poor sleepers (PSQI > 5) and a mean PSQI score of 6.06 ± 3.47. XGBoost achieved the best predictive performance (test R² = 0.451). SHAP analysis identified IRLS severity as the strongest predictor of PSQI across all three models, followed by EDSS score and depression in the Random Forest and XGBoost models, while daytime sleepiness (ESS) ranked consistently among the top predictors. Cardiometabolic and inflammatory parameters contributed inconsistently, with several showing effects opposite to physiological expectation. Conclusions: Sleep impairment in MS was most strongly associated with restless legs syndrome severity and neurological disability, with depression also contributing in the two best-performing models. Disease-related and symptomatic factors outweighed cardiometabolic and inflammatory contributions. These findings support the value of interpretable machine learning for identifying clinically relevant correlates of sleep quality in MS, though the exploratory design and modest sample size warrant confirmation in larger, independent cohorts. Full article

Background/Objectives: Gestational diabetes mellitus (GDM) is a metabolic disorder associated with an amplified risk of unfavorable pregnancy outcomes. This study aimed to compare clinical characteristics and pregnancy outcomes among GDM patients belonging to different ethnic groups. Patients and Methods: This retrospective analysis included n = 466 women with GDM (n = 167 Asian; n = 299 European). The impact of ethnicity on pregnancy outcomes was evaluated using multivariable logistic regression models, adjusting for confounding factors. Results: Asians were younger than Europeans (p < 0.001) and more frequently multiparous (p = 0.003). Fasting glucose at OGTT was higher in Asians, as well as HbA1c values at the end of pregnancy (p = 0.010 and p = 0.001, respectively). Asian ethnicity was associated with an increased likelihood of insulin therapy (OR = 3.36 [1.72–6.58] 95% CI, p < 0.001), in the adjusted model. The gestational week of delivery was lower in Asians compared to Europeans (p = 0.007). The Asian group had a higher occurrence of cesarean section (p = 0.048) and emergency cesarean section (p = 0.006) compared to the European group. Delivery complications were more frequent in the Asian cohort, adjusting for confounders (OR = 2.19 [1.11–4.32] 95% CI, p = 0.023). Newborns of the Asian group were more frequently small for gestational age (SGA) in adjusted models (OR = 2.36 [1.08–5.15] 95% CI, p = 0.031). Conclusions: Worse GDM outcomes were observed in the Asian cohort compared to the European cohort. Identifying risk factors for GDM-related complications is crucial for developing tailored interventions and reducing the overall disease burden. Full article

Psoriasis is a chronic immune-mediated inflammatory disease in which cytokine-driven epidermal activation is accompanied by extensive remodeling of the extracellular matrix, basement membrane, and cutaneous microvasculature. Matrix metalloproteinase-9 (MMP-9; gelatinase B) may provide an important link between these structural alterations and several key features of psoriatic inflammation, including neutrophil activation, endothelial dysfunction, vascular hyperpermeability, and leukocyte recruitment. This review critically examines the biological and clinical relevance of MMP-9 across the spectrum of psoriatic disease. Particular focus is given to the cellular sources and regulation of MMP-9, its expression in lesional and non-lesional skin, and its interactions with the IL-23/Th17, IL-17, TNF-α, IL-36, MAPK, and NF-κB signaling pathways. Experimental studies support a functional neutrophil–MMP-9–endothelium axis in which MMP-9 can promote endothelial activation, vasodilation, vascular hyperpermeability, and leukocyte transmigration. However, this mechanistic evidence derives predominantly from experimental systems, whereas human studies mainly demonstrate associations between psoriasis and increased tissue or circulating MMP-9. The interpretation of circulating MMP-9 is further complicated by sample type, enzymatic activation state, assay heterogeneity, treatment exposure, and inflammatory and cardiometabolic confounders. Overall, MMP-9 represents a biologically possible contributor to psoriatic tissue remodeling and vascular inflammation, but its causal importance in human psoriasis remains insufficiently established. Future studies should determine whether MMP-9 can contribute to validated phenotype-specific multimarker models. At present, its clinical utility as either a biomarker or therapeutic target remains exploratory. Full article

Background/Objectives: In-hospital cardiac arrest (IHCA) remains associated with poor survival, while the contribution of arrest etiology and early physiological markers to outcome remains incompletely defined. We examined associations between clinical, neurological, metabolic, and etiological factors and sustained return of spontaneous circulation (ROSC) lasting >20 min, 28-day survival, and 60-day mortality. Methods: This retrospective single-center cohort included 134 adults with confirmed IHCA requiring cardiopulmonary resuscitation at a tertiary university hospital with advanced transplant care between 2011 and 2015. Sustained ROSC and 28-day survival were analyzed using parsimonious Firth penalized logistic regression models, and 60-day mortality using Cox proportional hazards regression. Selected neurological and biomarker analyses were considered exploratory. Results: Sustained ROSC was achieved in 91 patients (67.9%), 33 (24.6%) survived to day 28, and 30 (22.4%) survived to day 60. Initial non-shockable rhythm was associated with lower odds of sustained ROSC (aOR 0.26, 95% CI 0.09–0.69) and 28-day survival (aOR 0.27, 95% CI 0.10–0.68), and with higher 60-day mortality (aHR 1.96, 95% CI 1.25–3.08). The presence of a potentially reversible cause was associated with more favorable outcomes, whereas active hematologic malignancy was associated with higher 60-day mortality (aHR 1.89, 95% CI 1.15–3.10). Exploratory analyses also showed associations of initially dilated pupils with lower 28-day survival and higher lactate with 60-day mortality. Among patients who survived beyond 24 h, higher BNP was associated with subsequent mortality. Conclusions: Non-shockable rhythm and the presence of a potentially reversible cause were consistently associated with outcomes following IHCA, while active hematologic malignancy was associated with poorer longer-term survival. Exploratory findings from lactate, initial pupillary assessment, and BNP may provide complementary prognostic information, although the BNP analysis was limited to patients who survived beyond 24 h. These findings require confirmation in contemporary multicenter cohorts and do not establish validated clinical prediction tools. Full article

Background/Objectives: Breast cancer is the most frequent malignant neoplasm in women and presents marked biological heterogeneity. The androgen receptor (AR) has emerged as a biomarker with important prognostic and therapeutic implications, its effect varying according to the molecular subtype. The objective of this study was to analyze AR expression in breast carcinoma samples and its relationship with the different molecular subtypes and clinicopathological variables. Methods: An observational, descriptive, cross-sectional, and prospective study was conducted based on the immunohistochemical analysis of 215 formalin-fixed, paraffin-embedded breast carcinoma samples. AR expression was digitally evaluated as the percentage of positive tumor cells after incubation with an anti-AR monoclonal antibody. Results: A high frequency of AR expression was demonstrated in the cohort, with a median of 53.3%. There were statistically significant differences between molecular subtypes (p < 0.001), detecting greater expression in luminal tumors and markedly low levels in triple-negative breast cancer (TNBC) (median 0.41%). A significant negative correlation was evidenced between AR expression and the Ki-67 proliferation index (ρ = −0.272; p < 0.001), both in the overall sample and in the TNBC subgroup. Conclusions: The androgen receptor is associated with specific molecular subtypes and lower tumor proliferation, suggesting a less aggressive phenotype and supporting its role as a biological biomarker and potential therapeutic target in the management of breast cancer. Full article

Background: Large loop excision of the transformation zone (LLETZ) is an established surgical procedure for cervical intraepithelial neoplasia; however, secondary postoperative bleeding may lead to unplanned outpatient visits, hospitalization, or surgical intervention. This study aimed to evaluate the incidence and risk factors of postoperative bleeding after LLETZ. Methods: We conducted a retrospective single-center cohort study comprising 1493 patients who underwent LLETZ for the treatment of cervical dysplasia between January 2008 and May 2023 at the Medical University of Vienna. Postoperative bleeding was defined as an unscheduled outpatient presentation for bleeding from the operative site within eight weeks after LLETZ requiring additional treatment. Clinical, surgical and histopathological parameters were analyzed. Univariable logistic regression was performed to identify factors associated with postoperative bleeding, with additional stratified analyses according to the use of intraoperative cervical infiltration. Results: Postoperative bleeding occurred in 56 patients (3.8%). The median time to bleeding was 13.5 days (IQR 9.0–17.0). Among patients with postoperative bleeding, 20 (35.7%) required hospitalization, 10 (50.0%) underwent operative intervention, and 2 (10.0%) required blood transfusion. In logistic regression, increasing cone length was associated with higher odds of postoperative bleeding (OR 1.83 per cm, 95% CI 1.06–3.18, p = 0.031). Anticoagulation and/or antiplatelet therapy was also associated with an increased bleeding risk (OR 3.61, 95% CI 1.46–8.96, p = 0.006). Higher BMI was associated with lower odds of postoperative bleeding (BMI per +5 kg/m²: OR 0.62, 95% CI 0.43–0.90, p = 0.011). Conclusions: LLETZ is associated with a low risk of clinically relevant postoperative bleeding, with an unplanned outpatient re-presentation rate of 3.8% and a re-operation rate of 0.7%. Increased cone length and anticoagulation and/or antiplatelet therapy were associated with higher bleeding rates. Larger prospective studies are needed to validate these findings and improve individualized perioperative risk assessment. Full article