Medical Sciences doi: 10.3390/medsci14020249

Authors: Nicolas A. Sieben Sebastiaan Blank Alexis Tabah Kyle C. White Kevin B. Laupland Felicity Edwards Antony Attokaran Stephen Luke Aashish Kumar Stephen Whebell Dinesh Parmar James McCullough Peter Garrett Mahesh Ramanan

Introduction: Diabetic ketoacidosis (DKA) is a common complication of diabetes mellitus characterized by metabolic acidosis, ketogenesis, hypovolemia, hyperglycemia, and electrolyte depletion. During treatment of DKA with intravenous fluids and insulin, some electrolyte disturbances can worsen. Hypophosphatemia is one such electrolyte disturbance that has not been well characterized in patients with severe DKA requiring Intensive Care Unit (ICU) admissions. This study sought to evaluate the incidence, severity, associations, and outcomes of hypophosphatemia in DKA. Methods: This retrospective multicenter study was conducted across DKA admissions to Queensland ICUs from 2016 to 2021. Adult patients (>18 years) requiring ICU admission for management of DKA were included in this study. Patients with DKA were stratified by lowest recorded phosphate level as: normal ≥ 0.80 mmol/L, mild 0.50–0.79 mmol/L, moderate 0.30–0.49 mmol/L and severe < 0.3 mmol/L. Patient demographics, comorbidities, ICU-related supports, and medications (including fluid, insulin administration, phosphate, and other electrolyte replacement) were collected. Univariate analysis was performed between hypophosphatemia severity and normophosphatemia subgroups to determine risk factors, outcomes, replacement, and progression of hypophosphatemia in the ICU. Phosphate replacement and administered insulin was compared to nadir serum phosphate level. Multivariate analysis and linear regression were performed to identify risk factors for the development of hypophosphatemia. Results: A total of 842 admissions of 669 unique patients due to DKA were included; 436 of 842 (51.8%) admissions maintained normophosphatemia in the ICU, while 220 (26.1%, n = 220/842) had mild hypophosphatemia, 124 (14.7%, n = 124/842) had moderate hypophosphatemia and 62 (7.4%, n = 62/842) had severe hypophosphatemia. Patients with higher BMI, higher APACHE II/III score, cerebrovascular disease and all blood gas parameters (excluding PaO2) were found to have more severe hypophosphatemia. Lower serum phosphate was associated with greater replacement and greater insulin administration per kilogram body weight. ICU length of stay, hospital length of stay and mortality were not affected by degree of hypophosphatemia (p > 0.05). Linear regression revealed that standard base excess was strongly associated with the development of hypophosphatemia (β = 0.02, 95% CI 0.01–0.02, p < 0.001). Conclusions: Increasing severity of hypophosphatemia was associated with increasing severity of DKA. Increased ICU length of stay was related to increased severity of hypophosphatemia.

Medical Sciences doi: 10.3390/medsci14020248

Authors: Grigory Demyashkin Mikhail Parshenkov Sergey Zyryanov Alexander Yavorskiy Petr Shegai Andrey Kaprin

Artificial intelligence (AI) is becoming a central driver of change across the drug development lifecycle. However, its integration is evolving so rapidly that it remains essential to understand how these technologies are currently positioned within the field. Because reliable access to high-quality (effective and safe) drugs is essential to public health, the pharmaceutical product lifecycle (PPL) offers a coherent framework for evaluating how AI can enhance evidence and data creation across all stages. To understand where AI genuinely adds value, this review examines its contribution across the major stages of the PPL. Rather than treating drug discovery, nonclinical evaluation, clinical research, and post-marketing assessment as separate domains, we view them as a continuous chain of data, where digital technologies enhance different decision points in distinct ways. In early discovery, AI narrows the search space by integrating diverse datasets to prioritize candidates most likely to succeed. Nonclinical models increasingly rely on machine-learning systems designed to improve the human relevance of safety predictions. Within clinical trials, AI supports cohort formation, real-time monitoring, and new analytic strategies that supplement empirical evidence. Case studies from leading pharmaceutical companies illustrate that the most meaningful advances emerge when AI is embedded not as a standalone tool but as part of a broader data strategy that links information across stages. Taken together, current evidence suggests that AI is beginning to transform data generation and integration throughout the PPL. Given the accelerating pace of digital innovation, it is essential for the field to maintain continuous awareness of emerging methodologies and evolving regulatory frameworks to ensure that these technologies are implemented in a reliable, transparent, and scientifically grounded manner.

Medical Sciences doi: 10.3390/medsci14020247

Authors: Henry Sutanto Merlyna Savitri Een Hendarsih Ami Ashariati

Objective: Patient-reported outcomes (PROs) provide direct insight into symptom burden and functional status, yet their utility in early pharmacotherapy outcomes in breast cancer remains underexplored. This study investigated whether baseline PROs from the EORTC QLQ-C30 and BR23 questionnaires are associated with and demonstrate discriminative ability for short-term survival during the first pharmacotherapy cycle in breast cancer patients. Methods: We conducted a prospective cohort study at two secondary referral hospitals in Indonesia from January to October 2025. Women with breast cancer initiating systemic pharmacotherapy were enrolled and followed through completion of the first treatment cycle. The primary outcome was survival of the first cycle, defined as a combined endpoint of death or treatment discontinuation due to adverse effects. Baseline demographic, clinical, and tumor characteristics, along with PROs (EORTC QLQ-C30 and BR23), were compared between survivors (n = 99) and non-survivors (n = 7). Statistical comparisons used Mann–Whitney U tests for PROs. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the discriminative performance of PRO domains. Results: Non-survivors were more likely to present with metastatic disease (71.4% vs. 25.3%). Baseline PROs showed marked differences, with survivors reporting higher global health (83.3 vs. 41.7; p < 0.001) and better physical, role, emotional, and social functioning (all p < 0.05). Symptom burden—including pain, appetite loss, constipation, systemic side effects, arm symptoms, and financial difficulty—was higher among non-survivors (all p < 0.05). ROC analysis demonstrated strong discriminative performance for global health status (AUC 0.907; p < 0.001), emotional functioning (AUC 0.846; p = 0.002), and social functioning (AUC 0.843; p = 0.003), with moderate performance for physical functioning (AUC 0.737; p = 0.037). Symptom domains showed lower and inverse AUC values, reflecting scale directionality and limited discriminative capacity. Conclusions: Baseline PROs using EORTC QLQ-C30 and BR23 were strongly associated with early pharmacotherapy survival and demonstrated meaningful discriminative ability, particularly in global and functional domains. Integrating PRO assessments before treatment initiation may enhance early risk stratification, guide supportive care, and improve treatment continuity in breast cancer.

Medical Sciences doi: 10.3390/medsci14020246

Authors: Valeska Gatica-Rojas L. Eduardo Cofré Lizama

Background: Low-cost virtual reality exergames may help maintain and improve postural control in children with spastic hemiplegia cerebral palsy (CP). This study aimed to evaluate the comparative effectiveness of the same six-week, low-cost exergame programme delivered via telerehabilitation (TR) and face-to-face (FF) in CP children. Methods: In this randomised controlled trial, 15 CP patients completed 18 sessions over 6 weeks. The TR group received remotely delivered sessions, whereas the FF control group completed in-person sessions with a physiotherapist. Outcomes were assessed at baseline; weeks 2, 4, and 6; and follow-ups at weeks 8 and 10. Postural control (centre-of-pressure sway area; CoPsway) was measured during eyes open (EO), eyes closed (EC), voluntary mediolateral sway to a 30 bpm auditory cue (EO/EC), and during exergames targeting mediolateral (ML-WS) and anteroposterior (AP-WS) weight-shifting. Timed Up and Go (TUG) and Modified Modified Ashworth Scale (MMAS) were also assessed. Results: At week 6, both TR and FF significantly reduced CoPsway (TR: p = 0.001, EC; FF: p = 0.01, EO). TR also improved dynamic postural control (p < 0.05) and TUG scores (p = 0.03), with functional gains sustained until week 10. Between-group comparisons revealed that TR achieved significantly greater reductions in AP weight-shifting (SDML, p = 0.001; VML, p = 0.004) and TUG (p = 0.009) than FF, with these advantages persisting throughout follow-up as revealed by post hoc analysis. Conversely, only FF significantly reduced ankle muscle tone (MMAS, p = 0.05). TR demonstrated broader improvements in secondary CoP metrics and superior long-term retention of functional mobility gains. Conclusions: Both six-week exergame interventions led to improvements in postural control. This trial demonstrated that telerehabilitation is a viable, comparable alternative to face-to-face delivery. Long-term retention suggests both modalities are complementary, offering flexible solutions to enhance routine physiotherapy service pathways. These findings provide a basis for validating these models across larger clinical cohorts.

Medical Sciences doi: 10.3390/medsci14020245

Authors: Teddy Lazebnik Vered Aharonson

Chronic stress has been implicated in cancer occurrence, but a direct causal connection has not been consistently established. Machine learning and causal modeling offer opportunities to explore complex causal interactions between psychological chronic stress and cancer occurrences. We developed predictive models employing variables from stress indicators, cancer history, and demographic data from self-reported surveys to examine the direct association between chronic stress and cancer occurrence, as well as a hypothesized immune-suppression-mediated pathway. The models were corroborated by traditional statistical methods. Our findings indicated significant associations between stress frequency, stress level, perceived health impact, and cancer occurrence. Although stress alone showed limited predictive power, integrating socio-demographic and familial cancer history data significantly enhanced model accuracy. These results highlight the multidimensional nature of cancer risk, with stress emerging as a notable factor alongside genetic predisposition. These findings strengthen the case for addressing chronic stress as a modifiable cancer risk factor, supporting its integration into personalized prevention strategies and public health interventions to reduce cancer incidence.

Medical Sciences doi: 10.3390/medsci14020244

Authors: Vasileios Leivaditis Francesk Mulita Chrysa Andrikopoulou Ejona Shaska Elias Liolis Sofoklis Mitsos Konstantinos Grapatsas Periklis Tomos Nikolaos G. Baikoussis

Background: The increasing use of advanced cardiac surgical therapies, particularly left ventricular assist devices (LVADs), has improved survival in patients with end-stage heart failure. However, the psychological burden associated with these therapies—especially depression and suicidality—remains underrecognized. Objectives: This narrative review synthesizes current evidence on the prevalence, underlying mechanisms, risk factors, screening strategies, and management of depression and suicidality in patients undergoing LVAD implantation and other advanced cardiac surgical interventions. Methods: A structured literature search of PubMed, Embase, and Scopus was conducted for studies published between 2020 and 2025 addressing depression, suicidal ideation, suicide attempts, and psychological distress in LVAD and advanced cardiac therapy populations. Results: Depression affects approximately 20–42% of patients with advanced heart failure, including those supported with LVADs, while suicidal ideation is reported in up to 12% of LVAD recipients, with higher rates of suicide attempts compared to other chronic disease populations. Risk factors are multifactorial and can be categorized into patient-related, disease-related, device-related, and psychosocial domains. Proposed mechanisms include neurohormonal dysregulation, systemic inflammation, and psychological processes such as loss of autonomy and existential distress. Although validated screening tools and multidisciplinary management strategies are available, their implementation in routine clinical practice remains inconsistent. Conclusions: Depression and suicidality represent significant and complex challenges in patients undergoing advanced cardiac therapies, particularly LVAD support. Systematic mental health screening and integrated, multidisciplinary care models are essential to improve patient outcomes. Future research should focus on longitudinal assessment, standardized suicide risk monitoring, and the development of targeted, evidence-based interventions for this vulnerable population.

Medical Sciences doi: 10.3390/medsci14020243

Authors: Marius Ivănuță Abdallah Shurrab Dragoș Puia Ana-Maria Ivănuță Mihaela Corlade-Andrei Nicolae Stoican Cătălin Pricop

Background: Prostate-specific antigen (PSA) remains the primary biomarker for prostate cancer detection; however, its limited specificity leads to unnecessary biopsies. Systemic inflammatory indices derived from routine blood tests have been proposed as potential adjunctive diagnostic tools. This study aimed to evaluate the diagnostic performance of these indices in patients undergoing prostate biopsy for suspected prostate cancer. Methods: A retrospective observational study was conducted, including 307 patients who underwent transrectal ultrasound-guided prostate biopsy for elevated PSA between January 2021 and January 2023. Patients were classified as benign prostatic hyperplasia (BPH) or prostate cancer (PCa) based on histopathological findings. Inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), systemic immune–inflammation index (SII), Systemic Inflammation Response Index (SIRI), and aggregate index of systemic inflammation (AISI), were calculated. Logistic regression and receiver operating characteristic (ROC) analyses were performed to assess diagnostic performance. Results: PCa was diagnosed in 65.1% of patients. Several inflammatory indices were significantly higher in the PCa group. Among them, AISI showed diagnostic performance comparable to PSA. The integration of inflammatory indices into multivariable models improved predictive accuracy, with the combined model demonstrating the highest discriminative ability. In contrast, these markers showed limited capacity in distinguishing tumour aggressiveness. Conclusions: Systemic inflammatory indices are associated with prostate cancer presence and may enhance diagnostic performance when used alongside PSA. However, their role remains complementary, as they provide limited value in risk stratification and should not be considered standalone diagnostic tools.

Medical Sciences doi: 10.3390/medsci14020242

Authors: Nicoleta Zenovia Antone Flaviu Andreicovici Andrada Larisa Deac Roxana Pintican Maria Miclaus Adrian Pavel Trifa Andreea Catana Ovidiu Balacescu Cătălin Vlad Patriciu Achimas-Cadariu

Background/Objectives: Molecular tumor profiling has recently transformed oncologic care delivery, establishing precision medicine as an essential approach for defining cancer biology and revealing intratumoral heterogeneity. The growing accessibility of advanced nucleic acid sequencing technologies has created a demand for specialized expertise in interpreting comprehensive genomic profiling results. Academic institutions currently employ a strategy of conducting initial broad-spectrum genomic testing, followed by matching patients to investigational therapies targeting their specific genomic alterations. Consequently, molecular tumor boards (MTBs) have emerged predominantly within major cancer centers and academic medical institutions, providing the specialized knowledge necessary to translate precision oncology into routine clinical care. However, despite the substantial benefits of collaborative case review within tumor boards, clinicians frequently encounter multiple barriers to effective MTB implementation. Methods: this report examines these challenges performing an exploratory quantitative synthesis approach and explores implementation strategies and best practices derived from collective institutional experiences, with the goal of establishing a functional MTB at the local level and thereby expanding oncology patient access to cutting-edge therapeutic options.

Medical Sciences doi: 10.3390/medsci14020241

Authors: Joana Ferrer-Fàbrega Andrea Llaves-López Ramón Rull Ángeles García-Criado Pedro Ventura-Aguiar Rocío García-Pérez Martí Manyalich-Blasi Antonio J. Amor José Ríos Fritz Diekmann Josep Fuster Emma Folch-Puy

Background/Objectives: Ischemia–reperfusion injury (IRI) contributes to graft dysfunction in solid organ transplantation, with the pancreas vulnerable due to its fragile vasculature. Endothelial glycocalyx (eGCX) disruption is central to this process. This study prospectively examined perioperative endothelial injury in pancreas transplantation. Methods: Fifty-two recipients were included, of whom 47 underwent simultaneous pancreas-kidney (SPK) transplantation and 5 pancreas retransplantation. Biomarkers of eGCX degradation (syndecan-1, heparan sulfate (HS) and hyaluronan) and endothelial injury (soluble thrombomodulin, VEGF and soluble VEGFR1) were measured in plasma preoperatively, 10 min after pancreas reperfusion, 24 h later, and at discharge. Associations with donor type and early post-transplant outcomes were explored. Results: A marker endothelial injury was evident within 10 min of pancreas reperfusion, before kidney implantation, characterized by increased syndecan-1, HS, and sVEGFR1, together with decreased VEGF. Hyaluronan peaked at 24 h, consistent with a broader systemic endothelial response. Controlled donation after circulatory death donors showed higher syndecan-1 levels at 10 min PR and higher VEGF at 24 h. Seven recipients developed pancreas graft loss, which was linked to lower VEGF at 10 min post-reperfusion and lower hyaluronan levels both before surgery and at discharge. Kidney acute tubular necrosis was related with higher preoperative HS and elevated 24 h sVEGFR1. Among recipients with functioning grafts, preoperative endothelial biomarkers were linked to postoperative complications. Conclusions: Pancreas transplantation triggers early endothelial injury and glycocalyx shedding, particularly in a predominant SPK setting. Perioperative endothelial biomarkers may have a value for early risk stratification after transplantation.

Medical Sciences doi: 10.3390/medsci14020240

Authors: Alexandru Hristo Amarandei Stefana Avadanei-Luca Andra-Irina Bulgaru-Iliescu Dan Cristian Moraru Dragos Florin Gheuca Solovastru Mihai-Codrin Constantinescu Raluca Tatar Vladimir Poroch Laura Gheuca Solovastru Mihaela Pertea

Background/Objectives: Thermal injuries represent a significant global health burden, often complicated by hypertrophic scarring, chronic inflammation, and delayed re-epithelialization. While Mesenchymal Stem Cell (MSC) transplantation has shown promise, its clinical translation is hindered by risks of tumorigenicity and immunological concerns. This study evaluates the efficacy of cell-free Extracellular Vesicle (EV) therapy—derived from both mammalian MSCs and plant sources (PDNVs)—as standardized, off-the-shelf alternatives. This study synthesizes evidence focusing on re-epithelialization velocity, angiogenic activity, and anti-fibrotic outcomes, while assessing the impact of second-generation delivery scaffolds on therapeutic durability. Methods: Conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD420261305379), this review interrogated PubMed, Scopus, Embase, and Web of Science for studies published between 2015 and 2026. Eligible studies included in vivo animal models of thermal injury using purified vesicles from mammalian MSC sources or plant-derived nanovesicles compared with placebo, standard care, or untreated controls. Data were synthesized narratively; methodological quality was appraised using the SYRCLE risk of bias tool and compliance with MISEV guidelines. Results: Synthesis of 50 studies revealed that vesicle-based interventions consistently accelerate wound closure and improve histological healing. Mammalian ADSC-derived vesicles demonstrated superior anti-fibrotic effects via the miR-192-5p and miR-125b-5p axes, while hUC-MSC vesicles attenuated systemic inflammatory signaling via miR-181c. Plant-derived nanovesicles (PDNVs) showed potent antioxidant and re-epithelialization effects, with emerging potential as engineered genetic carriers. Crucially, advanced delivery systems, including bioactive hydrogels and microneedle patches, were repeatedly associated with improved local retention and more durable effects than bolus injections. Conclusions: Vesicle-based therapies show consistent pro-healing signals in preclinical models, suggesting source-dependent profiles: MSC-derived vesicles excel in immunomodulation and anti-fibrotic remodeling, while PDNVs provide a scalable, low-immunogenicity platform. As a cell-free strategy, these therapies circumvent the safety risks of live cell transplantation. This review identifies a critical shift toward second-generation delivery scaffolds to overcome the clearance crisis of topical applications, emphasizing the need for harmonized MISEV-aligned characterization in future clinical translation.

Medical Sciences doi: 10.3390/medsci14020239

Authors: Edi Rođak Robert Grgac Rok Kostanjšek Milorad Zjalić Nada Oršolić Nikola Bijelić

Background/Objectives: New approaches using plant-based extracts are increasingly investigated for osteoporosis treatment, including hop extract, which contains potent compounds that favorably affect bone quality. The objective of this research was to evaluate the early effect of alendronate, standardized hop extract and their combination on bone tissue quality, hematological and biochemical parameters, and markers of bone turnover in a rat model of osteoporosis. Methods: The study was performed on 6 month-old female Wistar rats. A sham operation was performed on 10 animals, and bilateral ovariectomy on 60 animals. Ovariectomized animals were divided into six groups, one untreated, and the others treated with a low dose of alendronate, high dose of alendronate, hop extract, or a combination of low/high dose of alendronate and hop extract. Bone quality was assessed using micro-CT imaging. Hematology and serum biochemistry were analyzed using standardized kits, and bone turnover markers were measured using Western blot. Results: Treatment with high-dose alendronate, hop extract, and a combination of low-dose alendronate and hop extract significantly improved bone quality in ovariectomized animals, but high-dose alendronate combined with hop extract had no favorable effect. Hematological and biochemical parameters were mostly unaffected and remained within the normal range. Changes in markers of bone turnover were modest. Conclusions: For the first time, combining alendronate with hop extract was analyzed. Short-term treatment with low-dose alendronate and hop extract produced effects comparable to high-dose alendronate or hop extract alone, without clinically relevant alterations in hematological or biochemical parameters. Standardized hop extract may represent a valuable adjunct in osteoporosis therapy.

Medical Sciences doi: 10.3390/medsci14020238

Authors: Lampros Vagiotas Asimina Fylaktou Ariadni Fouza Efstratios Kasimatis Georgios Tsoulfas Maria Daoudaki

Background: Post-transplant immune heterogeneity may influence kidney allograft outcomes, yet the clinical relevance of circulating T-cell phenotypes remains incompletely defined. We aimed to identify 12-month post-transplant data-driven T-cell clusters and examine their relation to graft-function patterns during the first post-transplant year. Methods: Peripheral blood T-cell subpopulations were analyzed in 112 kidney transplant recipients at 12 months post-transplantation using flow cytometry. Standardized subpopulation frequencies underwent unsupervised hierarchical clustering, with principal component analysis used for visualization. Longitudinal graft function trajectories (eGFR and serum creatinine at 1, 3, 6, and 12 months) were analyzed using generalized estimating equation models, including time-by-cluster interactions. Results: Three recipient clusters were identified: a CD8-skewed cytotoxic/senescent cluster, an innate-like cytotoxic cluster, and a CD4-dominant cluster. Cluster robustness was supported by complementary k-means analysis. Older recipient age and baseline cytomegalovirus seropositivity were associated with the CD8-skewed cluster. Recipients assigned to different T12 clusters showed differences in serum creatinine levels and graft function trajectories, although some associations were attenuated after additional adjustment for transplant-related factors. Conclusions: In this cohort, unsupervised clustering identified distinct post-transplant T-cell profiles associated with early graft function patterns. These findings are hypothesis-generating and require longitudinal and external validation.

Medical Sciences doi: 10.3390/medsci14020236

Authors: José Luis Socorro-Cumplido Blanca Roman-Viñas Miriam Almirall Judith Sánchez-Raya Josep Blanch-Rubió Maria José Castro Maria Giné-Garriga Patricia Launois Tamara Libertad Rodríguez Araya Anna Arias Gassol Raimon Milà Villarroel Joaquim Chaler

Background: Performance-based tests (PBTs) objectively assess functional capacity and are increasingly applied in fibromyalgia (FM) to complement patient-reported outcomes (PROMs). However, evidence regarding their reliability, especially considering patients’ socio-occupational status, is limited. This study aimed to determine test–retest reliability of a standardized PBT battery in women with FM and to examine the influence of employment status on measurement stability. Methods: A total of 119 women were assessed (89 with FM). The battery included the 6 min walk test (6MWT), handgrip strength test (HST), and 8 feet up and go test (8FUGT). Test–retest reliability was examined using the intraclass correlation coefficient (ICC), standard error of measurement (SEM), and smallest real difference (SRD). Analyses were conducted for the total FM group and socio-occupational subgroups (actively working, claiming disability, and permanent disability). Results: All PBTs demonstrated excellent test–retest reliability. Measurement stability was consistently higher in controls. Absolute reliability indices confirmed acceptable measurement stability. However, the claiming disability group showed markedly higher SEM% and SRD% for HST, suggesting reduced reproducibility. The 6MWT and 8FUGT maintained excellent reliability and stability across all groups. PROMs showed good-to-excellent reliability. Conclusions: PBTs showed excellent reliability in women with FM. However, reliability varied across socio-occupational groups, particularly for HST in patients claiming disability. PROMSs showed lower reliability than PBTs.

Medical Sciences doi: 10.3390/medsci14020237

Authors: Imran Sama-ae Mollaya Daloh Aman Tedasen Siriruk Changrob Monthon Lertcanawanichakul Pattamaporn Kwankaew Phenphitcha Issaro Natthanicha Maidam Nichakan Rattanapong Nurul Auma Mirfart Kaseng Malatee Tayeh

Background/Objectives: Kaposi’s sarcoma (KS) is an angioproliferative malignancy caused by Kaposi’s sarcoma-associated herpesvirus (KSHV), characterized by aberrant angiogenesis, chronic inflammation, and endothelial cell transformation. Given the multi-factorial nature of KS pathogenesis, strategies that simultaneously modulate multiple mo-lecular targets are considered more promising than single-target approaches. However, effective multi-target therapeutic agents for KS remain limited, prompting this study to employ an integrative in silico pipeline. Methods: An integrative in silico pipeline combining compound screening, target predic-tion, network pharmacology, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Ge-nomes (KEGG) enrichment, protein–protein interaction (PPI) analysis, molecular docking, and molecular dynamics (MD) simulations was employed. Streptomyces-derived metabolites were prioritized based on chemical diversity, annotation, and clinical prece-dent. Predicted targets were intersected with KS-associated genes, with hubs ranked by network topology. Docking and MD simulations evaluated binding affinity and stability. Results: Endostemonine I emerged as the top candidate, engaging nine of ten hub proteins, including EGFR, mTOR, PTGS2, SRC, PARP1, PPARγ, MAPK1, MAPK14, and ICAM1. Key nodes such as mTOR, PTGS2, PPARγ, and MAPK14 are central to KS-related an-gi-ogenesis, inflammation, and viral oncogenesis. GO and KEGG analyses revealed en-richment in kinase activity, cell adhesion, and PI3K–Akt/mTOR and MAPK signaling pathways. Docking indicated strong binding to mTOR, PTGS2, PARP1, PPARγ, and MAPK14, while MD simulations confirmed stable interactions for mTOR, PTGS2, PPARγ, and MAPK14. Conclusions: Collectively, these proteins represent high-confidence, druggable KS targets, with Endostemonine I as a promising multi-target scaffold. These findings highlight the therapeutic potential of Endostemonine I and warrant further validation through future in vitro and in vivo studies.

Medical Sciences doi: 10.3390/medsci14020235

Authors: Victor Esanu Horatiu Alexandru Colosi Stefan Agoston Elisa Marziali Radu Alexandru Ilies Lorena Maria Hantig Claudia Mihaela Paun Alexandra Ioana Stoia Alexia Onaciu Iulia Cezara Pop Cristina Maria Boznea Ana-Maria Vartolomei Farran Moustafa Clemens Dirven George Calin Dindelegan Victor Volovici

Background/Objectives: Objective end-product assessment of microsurgical anastomoses is intensive and partly subjective. Vision-capable large language models (LLMs) may enable standardized image-based scoring, but their agreement with expert assessment remains uncertain. Methods: We studied 200 end-to-end femoral artery anastomoses, performed on chicken legs by novice, intermediate, and experienced microsurgeons. Images were scored independently by two blinded expert panels; disagreements were adjudicated by a third senior reviewer to establish expert consensus. Two LLMs, ChatGPT 5.2 Thinking Extended and Gemini 3.1 Pro, were evaluated using the exact same prompt and rubric. Each image was analyzed three times per model. Final scores were aggregated by median for numeric items and majority vote for categorical items. The primary endpoint was exact-match agreement with expert consensus. Agreement within ±1 was also assessed for numeric items. Agreement was measured using simple percentage agreement, Light’s kappa, and Krippendorff’s alpha; Bland–Altman analysis was used for numeric count items. Results: LLM 1 achieved a higher overall exact-match agreement than LLM 2 (0.659 vs. 0.539). Both models performed better on categorical than numeric items (0.713 vs. 0.610 and 0.651 vs. 0.445, respectively). LLM 1 showed the greatest advantages for gaps, knots, oblique stitches, and wide bites. Krippendorff’s alpha was positive for most endpoints with LLM 1, whereas LLM 2 showed negative values throughout. Allowing a ±1 tolerance for numeric items greatly improved agreement, suggesting only minor counting discrepancies, from 0.610 to 0.900 for LLM 1 and from 0.445 to 0.826 for LLM 2. Conclusions: Under a constrained scoring workflow, LLMs partially approximated intraluminal microsurgical end-product scoring. LLM 1 outperformed LLM 2, but agreement remained insufficient to replace the expert assessment entirely. These models can be assistive tools within a human-in-the-loop framework.

Medical Sciences doi: 10.3390/medsci14020234

Authors: Alberto Ramírez Ramírez Gallegos Pedro Juan Tárraga López Mónica Silu Piña Dabreu Lluis Rodas Cañellas Ángel Arturo López-González José Ignacio Ramírez-Manent

Background: Body mass index (BMI) remains the standard tool for obesity screening; however, it does not account for body fat distribution or visceral adiposity, potentially leading to clinically relevant misclassification—particularly in young adults. Evidence on this issue in healthcare professionals is limited. Objective: To evaluate the extent of obesity misclassification when using BMI compared with alternative anthropometric and body composition indices, and to examine sex-specific associations between lifestyle factors and different adiposity phenotypes in young healthcare professionals. Methods: A large cross-sectional study was conducted in 12,874 medical residents, nursing residents, and age-matched controls (22–30 years). Obesity was defined using BMI (≥30 kg/m2), waist-to-height ratio (WtHR ≥ 0.5), Clínica Universidad de Navarra–Body Adiposity Estimator (CUN-BAE), body fat percentage, and bioimpedance-derived visceral fat. Multivariable logistic regression models adjusted for age, sex, professional group, smoking, physical activity, and Mediterranean diet adherence were fitted separately for each adiposity definition. Sex interaction terms were formally tested. Agreement between indices was assessed using Cohen’s kappa. Results: Obesity prevalence varied substantially according to the index applied and was consistently higher when central or visceral adiposity measures were used. Agreement between BMI and alternative indices was only fair to moderate, with the lowest concordance observed for visceral fat (κ = 0.29; 95% CI 0.26–0.32). Male sex was strongly associated with visceral fat-defined obesity (aOR 4.76; 95% CI 3.82–5.92), while effect sizes were attenuated for BMI-defined obesity (aOR 1.41; 95% CI 1.32–1.51). Significant sex interactions were detected for visceral adiposity, particularly for physical activity (p = 0.001) and smoking (p = 0.002), indicating differential lifestyle associations according to fat distribution phenotype. Conclusions: BMI substantially underestimates clinically relevant central and visceral adiposity in young healthcare professionals. Sex-specific differences were observed in the association between lifestyle behaviors and visceral fat. These findings highlight the limitations of relying exclusively on BMI for obesity screening. Incorporating waist-based or body composition-derived measures may improve early risk identification and support targeted preventive strategies.

Medical Sciences doi: 10.3390/medsci14020233

Authors: Abed Agbarya Kamel Mhameed Arina Soklakova Haitam Nasrallah Mahmoud Abu Amna Sabri El-Saied Mohammad Sheikh-Ahmad Walid Shalata

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality despite major advances in diagnostics and therapies. The prognosis remains poor, mostly due to late-stage presentation and molecular heterogeneity. Epidermal growth factor receptor (EGFR) mutations are common drivers of NSCLC. The development of EGFR tyrosine kinase inhibitors (TKIs) has significantly improved outcomes in patients with EGFR mutations. Variant allele frequency (VAF) is a quantitative genomic measure representing the proportion of sequencing reads harboring a given mutation. In NSCLC tissue, the EGFR mutation VAF reflects tumor clonality and intratumoral heterogeneity, and accumulating evidence suggests an association between EGFR VAF and response to EGFR-targeted TKIs. Methods: To address the limited synthesis of data on the relevance of EGFR mutation VAF in NSCLC, we conducted a narrative review of the literature using PubMed/MEDLINE and Embase databases and current clinical guidelines, synthesizing available evidence on EGFR VAF, including its biological, molecular, and therapeutic implications in EGFR-mutated disease. The review was structured in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) checklist. Results: EGFR VAF and on-treatment VAF dynamics are consistently associated with treatment response, progression-free survival, and overall survival in osimertinib-treated NSCLC. Baseline VAF enables risk stratification, early clearance kinetics predict durable benefit, and longitudinal VAF monitoring facilitates early detection of resistance. Importantly, the prognostic implications of VAF differ fundamentally between tissue-based and plasma-based measurements: high tissue VAF reflects clonal homogeneity and predicts favorable TKI response, whereas high plasma VAF indicates elevated tumor burden and is associated with inferior outcomes. In the second-line setting, the T790M/activating mutation ratio serves as a surrogate for resistance clonality and independently predicts osimertinib efficacy. Conclusions: EGFR VAF represents a promising dynamic molecular biomarker for treatment monitoring and precision decision-making in EGFR-mutated NSCLC.

Medical Sciences doi: 10.3390/medsci14020232

Authors: Federica Murgia Antonio Noto Marcello Giuseppe Tanca Carola Costanza Valeria Marletta Sara Carucci Antonella Gagliano Luigi Atzori

Background: Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) shares numerous clinical features with Tourette syndrome (TS), notably the presence of tics and frequent comorbidities such as obsessive-compulsive disorder, irritability, and ADHD-like behaviors, often indistinguishable, particularly in the early stages of the two syndromes. Also, pathogenic similarities between PANS and TS constitute a diagnostic challenge, highlighting the need for biomarkers elucidating the underpinnings of the two disorders. In this context, metabolomics has emerged as a powerful tool for identifying distinct biochemical patterns in various diseases. We previously compared PANS, autism patients, and controls, identifying specific metabolic patterns. However, no studies have directly compared the metabolomic profiles of Tourette syndrome and PANS patients. The present study aims to compare the serum metabolomic profiles of TS patients with those of PANS and healthy controls to advance the molecular understanding and clinical differentiation of these two pediatric neuropsychiatric disorders. Methods: Thirty-four PANS patients and twenty-three Tourette patients were matched with twenty-five healthy subjects (C), and their blood samples were analyzed with 1H NMR spectroscopy. Subsequently, data were analysed with multivariate and univariate statistical approaches. Results: Supervised models indicated that the metabolomic profile of TS patients was significantly different from that of controls (p = 0.02), with altered concentrations of glutamate, glycerol, glycine, lactate, and proline. No significant differences were found in the comparison between PANS and TS patients. Conclusions: These preliminary data suggest that Tourette and Pans also seem to share the metabolic profiles, while differences were found in TS patients compared to controls. On the other hand, the PANS phenotype comprises symptoms that largely overlap with those of all other NDDs, including TS, outlining a spectrum of disorders that share common pathogenetic pathways. Larger studies are needed to confirm these findings.

Medical Sciences doi: 10.3390/medsci14020231

Authors: Abdul Rehman Muhammad Awais Hafiza Noor Ul Ain Baloch Muhammad Omer Leghari Arfa Ahmad Hafiz Javed

Background/Objectives: Liquid biopsy (LB) is transforming cancer care by enabling minimally invasive tumor profiling. While current research and clinical pathways mostly focus on blood LB, sputum represents a non-invasive, readily available respiratory specimen that may offer unique advantages for lung cancer (LC) care. Despite its potential, the maturity, breadth, and clinical applicability of sputum-based LB remain elusive. Methods: We conducted a scoping review to systematically map the existing literature on sputum LB in LC. Electronic databases were searched for studies evaluating sputum-derived biomarkers—cytologic, genomic, epigenetic, transcriptomic, proteomic, metabolomic, metagenomic, and extracellular vesicle–derived products—across the LC care continuum. Study designs, technologies, clinical contexts, and reported outcomes were extracted and synthesized qualitatively. Results: The literature demonstrated substantial heterogeneity in sputum collection, processing, and analytical platforms. Early work focused on cytometry and genetic alterations, while recent studies increasingly explore DNA methylomics, microRNAs, extracellular vesicle-derived products, and multi-omics approaches. The evidence suggests potential utility of sputum biomarkers for early detection and risk stratification, particularly in high-risk populations, with emerging data supporting roles in molecular subtyping, response monitoring, prognostication, and surveillance. However, few studies report prospective validation, direct comparison with blood-based LB, or impact on actual patient outcomes. Conclusions: Sputum LB is a promising yet underdeveloped modality in LC care. This scoping review highlights technological innovations alongside significant methodological heterogeneity and translational gaps. Future research should focus on standardization, prospective validation, impact on patient outcomes, and integration with blood- and other body fluid–based LB, as well as imaging biomarkers. This will enable incorporation of sputum-based LB into actual clinical pathways of LC care.

Medical Sciences doi: 10.3390/medsci14020230

Authors: Yehan Xiao Yaru Zou Mingming Yang Jing Zhang Kyoko Ohno-Matsui Koju Kamoi

Background: Hematologic malignancies (HMs), including leukemia and lymphoma, are systemic diseases that may cause a wide range of ocular manifestations. Methods: We searched PubMed/MEDLINE (2015-2026) and identified articles with an emphasis on clinically relevant studies and recent developments. Results: Clinically, ocular involvement presents with diverse manifestations, including retinal hemorrhage, vitreoretinal lymphoma, choroidal infiltration, orbital masses, treatment-related ocular toxicities, graft-versus-host disease, and secondary infectious complications. These findings may mimic other ocular diseases and consequently lead to delayed diagnosis. In some cases, ocular manifestations may represent the initial presentation of hematologic malignancies or indicate disease recurrence. Diagnostic evaluation relies on comprehensive ophthalmic examination, imaging, and laboratory analysis. Management strategies include systemic treatment of the underlying malignancy, local ocular therapy, and targeted treatment of infectious or treatment-related complications. Conclusions: Ocular manifestations of hematologic malignancies have significant diagnostic and prognostic implications. Early recognition, multidisciplinary collaboration, and comprehensive ophthalmic assessment are essential for timely diagnosis and optimal management. Improved awareness of disease-related, treatment-related, and infection-related ocular manifestations may facilitate earlier intervention and contribute to better visual and systemic outcomes.

Medical Sciences doi: 10.3390/medsci14020229

Authors: Pirada Yincharoen Crystal Pravina Sharma Weeratian Tawanwongsri

Background: Radiologic–pathologic discordance remains an important concern owing to the absence of standardized guidelines. This systematic review aimed to summarize the prevalence of discordant benign outcomes, defined as suspicious imaging findings with benign biopsy histology insufficient to explain the imaging abnormality, and to quantify malignancy upgrades subsequent to additional tissue assessment. Methods: This review was conducted in accordance with PRISMA 2020 guidelines and was prospectively registered. Eligible studies reported primary patient-level or aggregated data on radiologic–pathologic correlations post-image-guided breast biopsy and provided extractable data on discordant benign prevalence and/or subsequent malignancy upgrades. Results: Twenty-three studies were included. Lesion-/biopsy-based cohorts focused on biopsied abnormalities for analysis. Twelve studies directly estimated discordant-benign prevalence, whereas 11 studies did not, as study designs were discrepant-only, lesion-defined, or excision-restricted. Unselected cohorts with a cohort-wide correlation reported 1.2–5.3% discordant benign prevalence for all biopsies. When restricted to excised lesions, the discordant benign ascertainment rate was 7.4%, representing an excision-ascertained subset rather than the cohort-wide prevalence. Using benign-biopsy denominators, the discordance rate was 1.5–19.2%. Malignancy upgrades among discordant benign lesions ranged from 0 to 100% in selected subsets; however, several clinically relevant cohorts reported representative rates of approximately 20–40%, with some high-risk cohorts exceeding 50%. Conclusions: Discordant benign biopsy results are rare in unselected biopsy populations but carry a clinically meaningful upgrade risk, which warrants structured radiologic–pathologic correlation and prompt diagnostic resolution through repeat sampling or excision. Improvements in comparability and management algorithms require standardized definitions, uniform denominators aligned with all biopsied lesions, and prospective multicenter designs.

Medical Sciences doi: 10.3390/medsci14020228

Authors: Celeste Patricia Gazcón-Rivas Iliannis Yisel Roa-Bruzón Luis Félix Duany-Almira Cesar Aly Valdéz-Gaxiola Sofia Dumois-Petersen Luis Eduardo Figuera-Villanueva Antonio Quintero-Ramos Carmen Magdalena Gurrola-Díaz Daniel Ortuño-Sahagun Yeminia Valle Oscar Arias-Carrión

Background: Early-onset Alzheimer’s disease (EOAD) caused by autosomal dominant mutations provides a deterministic framework for investigating genetic modifiers of neurodegeneration. Telomere biology has emerged as a central regulator of genomic stability, cellular ageing, and stress response integration, yet its role in EOAD, particularly in under-represented populations, remains poorly defined. Methods: We conducted a cross-sectional case–control study to evaluate the genetic distribution, disease association, and predicted regulatory consequences of common variants in the telomere maintenance genes TERT and TERC in individuals from Western Mexico. The EOAD group comprised genetically confirmed carriers of the PSEN1 p.Ala431Glu (A431E) founder mutation with clinical EOAD (n = 69), and controls were unrelated individuals without dementia (n = 179). Five common variants were analyzed: rs2242652, rs2853677, rs2736100, and rs10069690 (TERT), and rs12696304 (TERC). Results: Genotype distributions in controls conformed to the Hardy–Weinberg equilibrium. Single-variant analyses showed no significant allele-level associations. Most TERT variants did not show significant allele-level associations with EOAD. However, a preliminary genotype-level enrichment for the GC allele at rs12696304 (TERC) was observed among EOAD cases compared with controls; allele-level associations were not significant. Linkage disequilibrium analysis revealed low r2 values (<0.20), supporting variant independence. Population-level allele frequency comparisons revealed ancestry-dependent divergence across loci; in silico functional annotation localised all variants to non-coding regulatory regions. GTEx-based analyses indicated that rs12696304 acts as an eQTL for ACTRT3 in whole blood and pituitary, as well as for LRRC34 in the cerebellar hemisphere, suggesting a potential regulatory network within the TERC locus (3q26.2). Conclusions: Overall, common regulatory variants in TERT did not show strong independent effects on EOAD susceptibility in PSEN1 A431E carriers. However, the convergence of association patterns, functional annotation, and regulatory evidence provides hypothesis-generating support for the TERC locus (3q26.2), particularly rs12696304, as a candidate region for further investigation. Additional studies integrating telomere dynamics, functional validation, and multi-omics analyses are needed to clarify the role of telomere biology in the pathogenesis of autosomal dominant EOAD.

Medical Sciences doi: 10.3390/medsci14020227

Authors: Mesud Jamaković Armin Šljivo Azra Durak-Nalbantić Farid Ljuca Mugdim Bajrić Behija Hukeljić-Berberović

Background/Objectives: Elevated lipoprotein(a) [Lp(a)] is an independent causal risk factor for atherosclerotic cardiovascular disease and may contribute to increased coronary complexity and adverse outcomes after acute myocardial infarction (AMI). Data regarding its prognostic significance in Southeastern Europe remains limited. This study aimed to evaluate the association between elevated Lp(a) levels, coronary artery disease severity, and major adverse cardiovascular events (MACE) at 1 and 6 months after AMI. Methods: This prospective study included 150 consecutive patients with STEMI and NSTEMI enrolled between December 2024 and August 2025. MACE was defined as a composite of overall cardiac death, recurrent myocardial infarction, cerebrovascular insult, heart failure with reduced ejection fraction occurrence, and new revascularization, either PCI or CABG. Results: Patients with elevated Lp(a) had significantly greater coronary disease burden, reflected by higher mean SYNTAX scores (17.3 ± 7.0 vs. 13.8 ± 7.0; p = 0.011) and a greater proportion of intermediate- and high-risk SYNTAX classifications (p = 0.016). Although the number of diseased vessels did not differ significantly, three-vessel disease was more frequent in the elevated Lp(a) group. At 1-month follow-up, overall MACE incidence was numerically higher but not statistically significant between groups. At 6 months, heart failure with reduced ejection fraction was significantly increased in patients with elevated Lp(a) (27.7% vs. 12.2%; p = 0.027). Binary logistic regression demonstrated that elevated Lp(a) independently predicted 6-month MACE (OR 2.768, p = 0.011, 95% CI 1.262–6.072), but not 1-month outcomes. Conclusions: Elevated Lp(a) is associated with increased coronary artery disease severity and higher mid-term MACE risk after AMI.

Medical Sciences doi: 10.3390/medsci14020226

Authors: Lila Berle Yash Sodhi Poonam Mathur Nazary Nebeluk James B. Doub

Antibiotics primarily exert their effect on planktonic microbial states, limiting their ability to eradicate biofilms commonly seen in chronic infections. This is because the minimal inhibitory concentration of antibiotics needed to kill microbes in biofilms can be up to 1000 times greater than when microbes are in their planktonic state. Yet up to 70% of all chronic infections are associated with a biofilm component. Consequently, novel therapeutics are needed to aid in the treatment of chronic biofilm infections. One such approach is to repurpose drugs that have demonstrated safety for non-infectious clinical indications. The main advantage of this approach is that the agents have already been shown to be safe for human administration, which can expedite clinical trial development of agents for biofilm infections. Unfortunately, most clinicians are unaware of the antimicrobial properties of some commonly used drugs. Thus, the aim of this Perspective was to discuss the potential of four drugs that have theoretical promise as adjuvants in the treatment of chronic biofilm infections. This was accomplished by providing detailed discussion of each agent with respect to current clinical use, potential mechanisms of antimicrobial activity, and present data to support use as adjuvant biofilm agents.

Medical Sciences doi: 10.3390/medsci14020225

Authors: Angeliki Gerede Sofoklis Stavros Efthymios Oikonomou Anastasios Potiris Maria Danavasi Vasiliki Kourti Ismini Anagnostaki Ekaterini Domali Nikoletta Koutlaki Makarios Eleftheriadis

β-thalassemia minor, often referred to as the β-thalassemia trait, is among the most prevalent hemoglobinopathies globally, impacting around 80–90 million carriers, with a prevalence of up to 15% among Mediterranean, Middle Eastern, and Asian populations. Although traditionally regarded as clinically benign, pregnancy imposes hematologic and metabolic stressors that may unmask latent vulnerabilities. This review combines the latest data and findings about the pathophysiology of β-thalassemia minor during pregnancy, its short-term outcomes on the mother and fetus, and its long-term impact on the child, as well as management techniques. A narrative review of PubMed-indexed studies (2000–2025) was conducted, including cohort and case–control studies, systematic reviews, meta-analyses, and international guidelines. Outcomes were organized by theme, and quantitative findings (prevalence, relative risks, odds ratios) were combined when available. Anemia is a common health issue for mothers. Literature mentions that the pooled incidence is between 30% and 40% during the third trimester, with ~5%of carriers needing a blood transfusion (mainly in iron-deficient or baseline Hb 6–8 g/dL cases). Meta-analyses have shown elevated risks of pre-eclampsia (odds ratio (OR) ~ 1.4, 95% confidence interval (CI) 1.1–1.8) and postpartum hemorrhage (PPH); however, estimates differ by region. The odds of preterm delivery (OR ~ 1.4), small-for-gestational-age (SGA) (OR ~ 1.5), and low birth weight (LBW) are slightly increased for carriers, and neonatal intensive care unit (NICU) admission rates are also higher for carriers. However, the risk of stillbirth is not always increased. The usual approach is iron supplementation guided by ferritin levels to prevent overload, personalized transfusion thresholds, and regular folate support. There is not much evidence for long-term consequences for children of carrier mothers since no research has followed more than 200 children born to carrier mothers into adulthood. However, maternal anemia is linked to slower growth, neurodevelopmental issues, and a higher risk of cardiometabolic problems in larger groups of pregnant women. However, maternal anemia is associated with slower growth, neurodevelopment, and higher cardiometabolic risk in larger groups of pregnant women. β-thalassemia minor during pregnancy usually has a mild, though significant, impact. While most pregnancies proceed without complications, this condition is associated with a significantly higher prevalence of anemia and other adverse postnatal outcomes. Consequently, the implementation of risk-stratified monitoring, smart supplementation, and standardized management protocols is essential. Prospective registries, mechanistic placental research, and long-term offspring cohorts are necessary to better understand long-term trends.

Medical Sciences doi: 10.3390/medsci14020224

Authors: Víctor Juan Vera-Ponce Jhosmer Ballena-Caicedo Holly Estrella Delgado-Toro Fiorella E. Zuzunaga-Montoya Julio César Bautista Zuta Rossmery Leonor Poemape Mestanza

Background/Objectives: Early diagnosis of hypertension (HTN) is critical, but most screening models do not simultaneously distinguish phenotypes based on systolic or diastolic patterns. We developed and temporally validated a multinomial model to predict normotension and three phenotypes of undiagnosed hypertension in Peru. Methods: We used ENDES 2017–2019 for development (final analytic n = 62,091) and ENDES 2021–2024 for temporal validation (final analytic n = 77,372), excluding 2020 due to COVID-19 disruptions. We included adults aged ≥18 years without self-reported HTN. The outcome was classified as normotension, isolated diastolic hypertension (IDH), isolated systolic hypertension (ISH), or systolic–diastolic hypertension (SDH). Eight nonlaboratory predictors were used: age, BMI, sex, residential altitude, smoking, alcohol consumption, vegetable intake, and fruit intake. Results: The model achieved an AUC of 0.789 (95% CI: 0.783–0.795) in training and 0.776 (95% CI: 0.770–0.781) in temporal validation. The prevalence of undiagnosed hypertension was 11.6% in the training set and 12.6% in the validation set. At a prespecified cutoff of 0.1004, sensitivity and specificity were 79.0% and 63.2% in training and 78.7% and 60.9% in validation, respectively (NPV 95.8% and 95.2%). Decision curve and clinical impact analyses suggested a positive net benefit and plausible referral volumes across a range of thresholds. Conclusions: This model could help prioritize confirmatory blood pressure measurements in resource-limited settings.

Medical Sciences doi: 10.3390/medsci14020223

Authors: Luis Andrés Vega-Quesada Zuilma Yurith Vásquez-Ortiz María Elena Soto-López Gerardo Marín Cristofer Zarate-Calderon

Background: Iron overload cardiomyopathy (IOC) is a major determinant of outcomes in hemochromatosis, and conventional echocardiography may miss early myocardial toxicity. Comparative data on primary (PH) versus secondary hemochromatosis (SH) using myocardial work (MW) indices are limited. Methods: We performed a retrospective cross-sectional study of 34 adults (16 PH and 18 SH patients) at a tertiary center. They all underwent echocardiography with speckle-tracking to obtain LV global longitudinal strain (GLS) and non-invasive MW indices from pressure-strain loops: global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). Echocardiographic phenotypes were classified as a Normal, Dilated, Restrictive, or right ventricular/pulmonary hypertension (RVPH) phenotype. Results: SH patients showed higher iron burden and neurohormonal activation than PH patients (maximum ferritin 2954 vs. 444 ng/mL; BNP 93 vs. 13.5 pg/mL; both p < 0.001) and accounted for all deaths (33% vs. 0%) despite similar 3D LVEFs and GLSs. PH patients predominantly exhibited Normal phenotypes (81%), whereas SH patients more often showed advanced phenotypes, mainly RVPH and Dilated. GWI correlated inversely with ferritin (ρ ≈ −0.40), particularly ferritin at echocardiography in SH patients, while PH patients showed no significant correlations. GWW was higher in Dilated/RVPH compared to Normal phenotypes, and in SH patients, higher maximum ferritin was associated with impaired right ventricular free-wall strain. Conclusions: PH and SH patients exhibit distinct IOC phenotypes, with SH patients showing more advanced remodeling and worse outcomes. In this exploratory analysis, MW indices showed modest associations with iron burden markers, suggesting they may provide complementary information beyond LVEF and GLS. These preliminary findings require validation in larger, prospective studies.

Medical Sciences doi: 10.3390/medsci14020222

Authors: Edson Fonseca Pinto Nailton José Brandão Albuquerque Filho Jéssica Costa Leite Tatianne Moura Estrela Gusmão Larissa Nayara de Souza Roque Ribeiro da Silva Júnior Maria Irany Knackfuss Grasiela Piuvezam

Introduction: Post-hospital rehabilitation is essential for survivors of severe COVID-19, as prolonged immobility and clinical severity often lead to muscle weakness, reduced cardiovascular capacity, and impaired respiratory function. Physical exercise during and after hospitalization may mitigate these effects and support functional recovery. This study aimed to evaluate the effectiveness of a physical exercise-based rehabilitation program in survivors of severe COVID-19. Methodology: A randomized clinical trial was conducted with 30 survivors allocated to two groups: multicomponent exercise (GEm) and multicomponent exercise combined with inspiratory muscle training (GEmTMI). The interventions were performed three times per week for 40–60 min. Quality of life, physical activity level, functional status, and physical capacity were assessed before and after six weeks. Results: Comparisons between GEm and GEmTMI showed significant differences in the 6 min walk test (6MWT) at baseline (p = 0.043) and in the Physical Activity Index (IPAQ) after the intervention (p = 0.002). When the total sample was analyzed, significant improvements were observed across all outcomes after rehabilitation, including quality of life (SF-36), functional capacity (PCFS), physical activity level (IPAQ), respiratory muscle strength, and additional functional tests. Notable improvements included SF-36 Physical Functioning (p = 0.006) and Social Functioning (p = 0.009), PCFS (p = 0.011), IPAQ (p = 0.012), and performance in the 6MWT, STS, STS-1min, TUG, handgrip strength, PEmax, and PImax (all p < 0.001). Discussion: Multicomponent physical rehabilitation, with or without inspiratory muscle training, produced significant gains in physical activity level, functional capacity, dynamic balance, neuromuscular fitness, respiratory muscle strength, and quality of life. These findings underscore the importance of structured post-ICU rehabilitation to support comprehensive physical and psychosocial recovery in survivors of severe COVID-19.

Medical Sciences doi: 10.3390/medsci14020221

Authors: Sílvia A. C. Duarte Rosário Pinto-Leite Felisbina L. Queiroga

Cancer is a major public health challenge worldwide, with increasing incidence and a growing economic and societal burden. Despite therapeutic advances, prevention remains the most effective strategy to reduce its impact. The One Health approach, which recognizes the interconnection between human, animal, and environmental health, provides a valuable framework to address cancer risk factors in a more integrated and sustainable way. This narrative review addresses cancer through a One Health lens. Human health aspects include the global burden, major lifestyle and infectious risk factors, and key prevention strategies. Environmental determinants of cancer are summarized with emphasis on climate change, air pollution, occupational exposures, microplastics, ultraviolet radiation, and nutrition/food safety. Animal health contributions include insights from comparative oncology, which offer translational opportunities for prevention, diagnosis, and treatment, and from microbiome research revealing promising biomarkers for early detection and treatment response. Integrating cancer prevention into the One Health framework is essential for addressing the complex interplay between environmental, animal, and human health. A multidisciplinary approach can enhance public health policies, promote sustainable prevention measures, and improve early detection and treatment strategies, ultimately reducing healthcare costs and advancing global health outcomes.

Medical Sciences doi: 10.3390/medsci14020220

Authors: Sorinel Lunca Gabriel Mihail Dimofte Ana Maria Musina Cristian Ene Roata Constantin Osman Wee Liam Ong Stefan Morarasu

Background: Low anterior resection syndrome (LARS) is a frequent survivorship problem after sphincter-preserving rectal cancer surgery. Pelvic radiotherapy (RT), often combined with chemotherapy, is frequently implicated in LARS development, but its apparent effect may be confounded by low tumor location and diversion. We evaluated whether RT (±chemotherapy) separates the risk of postoperative LARS severity—especially major LARS—beyond classical anatomic and pathway determinants. Methods: We conducted a single-centre observational cohort study of operated rectal cancer patients managed between 2013 and 2024, who completed the Romanian-validated LARS score by standardized telephone interview after restoration of bowel continuity (up to 18 months postoperatively). Outcomes were postoperative LARS score, LARS category, and major LARS. Comparisons were performed by RT status and by oncologic treatment pattern. Multivariable logistic regression assessed associations with major LARS, adjusting a priori for tumor location and diverting ileostomy; furthermore, extended sensitivity models incorporated technical/pathway variables. Discrimination was explored using 5-fold cross-validated ROC/AUC. Item-level LARS responses were analyzed to characterize symptom phenotype. Results: Overall, 182 patients were included (RT: 106; no RT: 76); 43.4% had LARS (minor 14.8%, major 28.6%). RT-treated patients had higher postoperative LARS scores (median 21 vs. 12; p = 0.002) and a higher prevalence of major LARS (35.8% vs. 18.4%; p = 0.012). Across treatment patterns, LARS severity was highest in RT + chemotherapy. Item-level analyses indicated that RT-associated differences were driven mainly by urgency and clustering domains. In adjusted models, RT was not independently associated with major LARS, whereas low tumor location and diverting ileostomy were strong predictors. Discrimination for major LARS was modest: AUC 0.561 for RT alone, 0.643 for location + ileostomy, and 0.654 for location + ileostomy + RT (5-fold cross-validation). Conclusions: RT is associated with worse unadjusted postoperative bowel dysfunction after rectal cancer surgery and is linked to urgency/clustering-dominant symptom patterns. However, in this cohort, the risk of major LARS was predominantly explained by tumor location and diversion rather than RT alone, supporting integrated risk stratification and early symptom-directed survivorship care.

Medical Sciences doi: 10.3390/medsci14020219

Authors: Dan Boitor Alexandru Farcasanu Simion Simon Daniel Muresan Ioana Cristina Rotar Mihai Surcel Mihaela Oancea

The visualization of embryonic and fetal brain development at mesoscopic resolution represents a critical frontier in developmental neuroscience. This review presents advances in high-field magnetic resonance imaging (HF-MRI) that achieve unprecedented spatial resolution in ex vivo human embryonic and fetal brain specimens. This mesoscopic imaging capability bridges the gap between conventional clinical MRI and histological microscopy, enabling three-dimensional visualization of transient developmental structures including cortical lamination, ganglionic eminences, and emerging white matter pathways. We review the technical foundations of HF-MRI, present methodological advances that enable mesoscopic resolution, demonstrate applications across gestation, and discuss validation through histological correlation. The integration of multimodal imaging approaches—including T1-weighted, T2-weighted, T2*-weighted, diffusion tensor imaging, and quantitative relaxometry—provides comprehensive characterization of tissue microstructure and connectivity during critical periods of neurodevelopment. These advances offer transformative potential for understanding normal brain development, identifying early markers of neurodevelopmental disorders, and establishing high-resolution atlases of human prenatal neuroanatomy.

Medical Sciences doi: 10.3390/medsci14020218

Authors: Alexandr Ceasovschih Nicholas G. Kounis Sura Markos Malik Ejubovic Maria Cherska Fotios Barkas Vladimir Ristovski Alexandru Corlateanu Pradeesh Sivapalan Stanislav Kotlyarov Victorita Sorodoc Laurentiu Sorodoc

Kounis syndrome (KS) describes the occurrence of acute coronary syndromes precipitated by allergic, hypersensitivity, or anaphylactic reactions and represents a unique intersection between immunologic activation and cardiovascular disease. The epidemiology of KS is likely underestimated due to diagnostic overlap with other cardiac and allergic conditions and limited awareness across medical specialties. This narrative review focuses on the distinctive features of KS in special populations, emphasizing how patients’ age, comorbidities, immune status, and vascular substrate modify presentation, diagnosis, and outcomes. In elderly patients, polypharmacy, increased plaque vulnerability, and endothelial dysfunction favor Type II and III KS. Pediatric cases, although rare, are predominantly Type I and strongly associated with food allergies, insect stings, vaccines, and antibiotics, with under-recognition driven by diagnostic bias and ethical concerns surrounding invasive testing. Patients with coronary stents, cardiac devices, chronic kidney disease, and those receiving dialysis exhibit heightened susceptibility due to chronic inflammation, foreign-body hypersensitivity, and prothrombotic states. Pregnancy and the peripartum period represent a unique immuno-hemodynamic milieu in which Th2 immune shift, increased coronary vasoreactivity, and obstetric triggers can compromise both maternal and fetal perfusion. Additional risk modulation is observed in atopic individuals, asthmatics, patients with autoimmune, inflammatory, oncologic, psychiatric, and neurodevelopmental conditions, as well as in COVID-19 and post-infectious states. We propose a host-modified framework for KS that complements traditional classification by integrating immune phenotype and vascular substrate, enabling improved risk stratification and personalized preventive strategies.

Medical Sciences doi: 10.3390/medsci14020217

Authors: Diego Santos García Ángela Solleiro Vidal Marta Blázquez Estrada Pablo Mir Nuria López Ariztegui Déborah Alonso Modino Inés Legarda Alejandro Peral Rocío García-Ramos Iria Cabo Pilar Sánchez Alonso Jorge Hernández-Vara Javier Ruíz Martínez María Álvarez Sauco Gustavo Fernández-Pajarín Lydia Vela Francisco Escamilla Sevilla Jesús Ramírez Sánchez-Ajofrin Débora M. Cerdán Santacruz Guillermo González Ortega DATs-PD GETM Spanish Registry Group DATs-PD GETM Spanish Registry Group

Background and Objective: Sex differences in the treatment of people with Parkinson’s disease (PwP) with a device-aided therapy (DAT) have been poorly investigated. Our aim was to analyze sex differences in the management and response to a DAT in PwP in daily clinical practice (DCP). Patients and Methods: Data collected in the DATs-PD GETM Spanish Registry until 30 October 2025 were used. This is a descriptive, observational, prospective, and multicenter clinical registry with progressive inclusion of PwP treated with a DAT in DCP conditions in more than 40 centers from Spain. Sex differences in the DAT received and changes in quality of life (QoL), motor symptoms (MS), non-motor symptoms (NMS), and autonomy for activities of daily living (AADL) after 6 months of treatment were analyzed. Results: A total of 618 PD patients (66.9 ± 9.5 years old; 57.6% men) were treated with a DAT. A significant difference was observed in the DAT type according to sex (p = 0.006), with 73.1% of PwP who were treated with deep brain stimulation being men. At the time of DAT indication, women were older, received a higher levodopa equivalent daily dose, and had a worse health-related QoL and AADL. OFF time decreased, whereas MS and NMS burden and health-related QoL improved at 6 months follow-up in both groups (men and women). AADL improved only in men during the OFF state. Conclusion: Sex differences were detected in the use of DATs in PwP. Improvement in OFF time, MS, NMS, and QoL was detected in both groups.

Medical Sciences doi: 10.3390/medsci14020216

Authors: Mustafa Al-Obaidi Andreas Winter Afsaneh Karimian-Tabrizi Thomas Walther Fabian Emrich

Background: Patients with coronary artery disease (CAD) and severely reduced left ventricular ejection fraction (LVEF) ≤ 30% represent a high-risk group for coronary artery bypass grafting (CABG). Outcomes are of significant concern; therefore, real-world outcome data and predictors of early mortality remain important for perioperative decision-making. Aim: This study aims to evaluate early and mid-term outcomes in patients with severe ischemic cardiomyopathy (LVEF ≤ 30%) undergoing isolated CABG and to identify independent predictors of in-hospital mortality. Methods: We conducted a retrospective single-centre cohort analysis including patients with preoperative LVEF ≤ 30% undergoing isolated CABG (2017–2021). Early outcomes included in-hospital and 30-day mortality. The mid-term outcome was all-cause mortality up to 36 months. Multivariable logistic regression was used to identify independent predictors of in-hospital mortality. A predefined subgroup comparison was performed for LVEF ≤ 20% versus LVEF 20–30%. Results: The study comprised 147 patients with LVEF ≤ 30% undergoing isolated CABG. Overall, in-hospital mortality was 21.1%, and 30-day mortality was 23.8%. Cumulative all-cause mortality was 31.3%, 37.4%, and 42.9% at 12, 24 and 36 months respectively. Patients with LVEF ≤ 20% showed significantly higher early mortality (in-hospital 37.2% vs. 14.4%; 30-day 41.9% vs. 16.3%) and 36-month mortality (58.1% vs. 36.5%) compared with those with LVEF at 20–30%. Independent predictors of in-hospital mortality included preoperative hemodynamic instability, elevated operative risk scores, emergency status, prolonged cardiopulmonary bypass time, and major postoperative complications (all p < 0.05). Conclusions: CABG in patients with LVEF ≤ 30% is associated with substantial early mortality, while mid-term survival remains acceptable. Severely reduced LVEF identifies a particularly high-risk subgroup requiring careful perioperative risk stratification.

Medical Sciences doi: 10.3390/medsci14020215

Authors: Hakan Taban Murat Ozdede Orkun Akman Sevgen Celik Onder Saadettin Kılıckap

Background: Sulfatase 2 (SULF2) is an extracellular enzyme involved in the modulation of multiple oncogenic signaling pathways and has been implicated in tumor progression across several malignancies. However, its prognostic significance in surgically resected non-small cell lung cancer (NSCLC) remains incompletely defined. Methods: SULF2 expression was evaluated by immunohistochemistry in tumor specimens from patients with stage I–III NSCLC who underwent curative-intent surgical resection between 2009 and 2016. Expression levels were quantified using an H-score-based system and categorized as low or high. Associations between SULF2 expression, clinicopathological characteristics, and survival outcomes, including overall survival (OS) and disease-free survival (DFS), were analyzed using Kaplan–Meier estimates and Cox proportional hazards models. Eighty-three patients were included, of whom 65 (78.3%) were male; 42.2% had stage I disease, 32.5% stage II, and 25.3% stage III. Results: SULF2 expression was detected in 94.0% of tumors, with 43 patients (51.8%) classified as high and 40 (48.2%) as low expression based on H-score. Overall survival and DFS did not differ significantly between SULF2-low and SULF2-high groups (log-rank p = 0.213 and p = 0.660, respectively). Median OS was 113.2 months (95% CI: 84.0–142.4) in the SULF2-low group and 54.9 months (95% CI: 39.4–186.9) in the SULF2-high group, while median DFS was 88.3 months (95% CI: 46.5–130.2) and 53.3 months, respectively, with numerically shorter survival in the SULF2-high group. Subgroup analyses stratified by pathological stage and histological subtype revealed no significant associations between SULF2 expression and survival outcomes. In multivariate analysis, SULF2 expression was not independently associated with either OS or DFS. Conclusions: SULF2 expression was highly prevalent in surgically resected NSCLC; although higher expression showed numerically poorer survival, this difference did not reach statistical significance.

Medical Sciences doi: 10.3390/medsci14020214

Authors: Itzel Elizabeth Garibay-Padilla Jorge Eduardo Hernandez-Del Río Dayana Estefania Orozco-Sepulveda Christian Gonzalez-Padilla Tomas Miranda-Aquino Vanessa Salas-Bonales Judith Carolina De Arcos-Jiménez Jaime Briseño-Ramírez

Background/Objectives: Infective endocarditis (IE) carries substantial mortality, particularly in middle-income settings where patient profiles and microbial ecology differ from those of cohorts used to derive international prognostic scores. Syndrome-specific, locally grounded decision aids for empirical therapy are also scarce. We aimed to identify predictors of in-hospital mortality, externally evaluate the RiskE and ICE scores, and construct a Bayesian weighted-incidence syndromic combination antibiogram (WISCA) for IE. Methods: We conducted a retrospective cohort study of consecutive adults with definite or possible IE admitted between January 2019 and January 2026. Candidate predictors were screened in two phases, and a clinically specified model was estimated with maximum-likelihood and Firth penalization, with 1000-replicate bootstrap optimism correction. Calibration was assessed with bootstrap calibration plots and the Hosmer–Lemeshow test. Discrimination was compared against RiskE and ICE using DeLong’s test and reclassification metrics. For empirical coverage, we built a WISCA using identified pathogens, reporting both non-Bayesian bootstrap estimates and Bayesian hierarchical partial-pooling estimates with species- and antibiotic-level random intercepts; analyses were also stratified by IE type. Results: In-hospital mortality was 22.9% in a young cohort (median 37 years) characterized by high hemodialysis prevalence (47.4%), substantial right-sided IE (46.4%), and Staphylococcus aureus predominance (32%) with no methicillin-resistant isolates. Vasopressor-requiring shock (Firth OR 9.23, 95% CI 2.40–40.61) and acute heart failure (OR 10.01, 95% CI 2.78–41.07) were the strongest predictors; the final model achieved an AUC of 0.922 (optimism-corrected 0.908), significantly outperforming RiskE (0.598) and ICE (0.632). The Bayesian WISCA identified multiple carbapenem-sparing and anti-MRSA–sparing regimens with adequate coverage (≥80%), particularly for community-acquired IE, supporting stewardship-oriented empirical selection. Coverage was consistently lower in healthcare-associated IE. Conclusions: A parsimonious three-variable model provided strong, locally valid mortality prediction in this hemodialysis-predominant, MRSA-free cohort, substantially outperforming European-derived scores. External validation in independent cohorts is required before clinical adoption. The Bayesian WISCA demonstrated that adequate empirical coverage is achievable without routine broad-spectrum agents, offering institution-specific guidance for stewardship-compatible regimen selection; multicenter validation is warranted.

Medical Sciences doi: 10.3390/medsci14020213

Authors: Akram M. Eraky Yasser Mokhtar Guy Grabau Adnan Khan Ashish Acharya Nichole Gadd Mark Jarosz Abhishek Premkumar

Calcium channel blockers (CCBs) are frequently used in the emergency department and intensive care unit for a wide range of critical conditions, including atrial fibrillation, hypertensive emergencies, acute pulmonary edema with sympathetic crashing, pulmonary hypertension, and vasospastic syndromes. However, their toxicity can lead to significant hemodynamic compromise, underscoring the importance of understanding their pharmacologic effects and safety profile. This review summarizes the current applications of CCBs in critically ill patients, evaluates their safety in congestive heart failure, and highlights emerging therapeutic roles and recent advances in the management of CCB toxicity.

Medical Sciences doi: 10.3390/medsci14020212

Authors: Mihai-Emilian Lapadat Oana Stanca Irina Nicoleta Triantafyllidis Anca Mariana Ciobanu Nicoleta Mariana Berbec Cristina Negotei Cristian Tudor Barta Ana Maria Bordea Madalina Marilena Oprea Andrei Colita

Background: Higher-risk myelodysplastic neoplasms (HR-MDS) are associated with poor survival and a substantial risk of leukemic transformation. Although azacitidine is a standard treatment in this setting, comparative real-world data remain limited. We evaluated the association between azacitidine exposure and clinical outcomes in patients with HR-MDS. Methods: We performed a retrospective single-center cohort study including 72 adults with HR-MDS, defined by the Revised International Prognostic Scoring System(IPSS-R) as High or Very High risk. Patients were categorized as azacitidine-treated (Aza, n = 44) or managed with best supportive care alone (No Aza, n = 28). Overall survival (OS) was defined from diagnosis to death from any cause. Progression-free survival (PFS) was defined as the time to acute myeloid leukemia transformation or death. Leukemic transformation (LT) was analyzed using Kaplan–Meier estimates and competing-risk cumulative incidence, with death without prior LT treated as a competing event. Univariable and multivariable Cox regression models were applied. Results: Azacitidine exposure was associated with longer OS compared with best supportive care, with a median OS of 13 vs.10 months and 24-month OS rates of 27% vs. 14% (p = 0.0239). PFS was also prolonged in the Aza group, with a median of 11 vs. 7 months (p = 0.0406). LT-related outcomes similarly favored azacitidine. In multivariable analyses, azacitidine remained independently associated with improved OS, PFS, and LT-related outcomes. IPSS-R Very High risk remained an adverse prognostic factor across endpoints, while a higher baseline bone marrow blast percentage independently predicted leukemic transformation. Conclusions: In this real-world HR-MDS cohort, azacitidine exposure was associated with improved survival outcomes and delayed leukemic transformation compared with best supportive care alone.

Medical Sciences doi: 10.3390/medsci14020211

Authors: Maksymilian Niemczyk Justyna Fercho Szymon Goldszmyt Bogdan Jabłoński Oskar G. Chasles Jakub Soboń Marcin Birski Jacek Szypenbejl Maciej Mielczarek Marek Harat Mariusz Siemiński Jacek Furtak

Background: Intraventricular central nervous system (CNS) lymphoma is an atypical presentation of extranodal lymphoma, whether primary or secondary. The most commonly diagnosed subtype of lymphoma is diffuse large B-cell lymphoma (DLBCL). There is a documented relation of HIV, EBV and KSHV infections with lymphomagenesis. AIDS-related lymphomas (ARLs) are described as a defining illness of the acquired immunodeficiency syndrome (AIDS). This study presents a novel case and systematic review of clinical, radiographic and histopathological features of intraventricular lymphomas. Methods: We report on a 27-year-old woman with a left lateral ventricle DLBCL with surrounding edema treated with steroids. A systematic review of 147 additional cases (1977–2025) was conducted, analyzing patient demographics, tumor characteristics, clinical features, imaging, treatment, and outcomes. The tumor locations were divided into three groups depending on the extent of ventricular involvement. Descriptive statistics summarized findings. Findings: 147 cases (mean age, 54.2 years; range, 3–87; 63.3% male) were analyzed. Immunodeficiency in patients was unusual (6.1%). Fully intraventricular lesions were the most common presentation (52.4%), with systemic involvement solely in 10 cases (6.8%). The lesions were predominantly located in the lateral ventricles or fourth ventricles (46 times each), and bilateral involvement was noted 37 additional times. DLBCL was diagnosed in 101 cases (78.9%). Interpretation: Intraventricular involvement in central nervous system lymphoma poses a diagnostic and therapeutic challenge due to non-specific symptoms and atypical locations. Adding to the diagnostic difficulty of intraventricular masses in young patients, we wish to highlight that immunocompromised patients are a notably insignificant subgroup of patients in our study.

Medical Sciences doi: 10.3390/medsci14020210

Authors: Alejandro Martín-Arrabal Francisco M. Peinado Miguel A. Arrabal-Polo Antonio J. Gálvez-Muñoz Tomás Saz-Terrado María M. Olvera-García María S. Serrano-Atero Simón López-Soto Mariana F. Fernández

Introduction: Intraoperative hypotension (IOH) is a frequent manifestation of haemodynamic instability during general anaesthesia. Advances in arterial waveform analysis have led to two distinct monitoring strategies: flow-derived platforms and predictive algorithms designed to anticipate hypotension. However, prospective comparisons and their associations with IOH and postoperative outcomes remain limited. The objective was to compare predictive haemodynamic monitoring using the Hypotension Prediction Index (HPI) with flow-derived monitoring using the Vigileo/FloTrac system and to evaluate their associations with IOH and postoperative outcomes. Methods: In this single-center prospective observational study, 101 adults undergoing elective major abdominal surgery under general anaesthesia were monitored using either the HPI system (n = 49) or the Vigileo/FloTrac system (n = 52). Primary outcomes were cumulative duration and frequency of IOH (mean arterial pressure < 65 mmHg). Secondary outcomes included postoperative complications, organ injury biomarkers (troponin, creatinine, eGFR), and hospital length of stay. Multivariable regression models adjusted for predefined confounders were used to estimate associations. Results: Vigileo/FloTrac monitoring, compared with HPI, was independently associated with a greater cumulative duration of IOH (adjusted β = 1.66; 95% CI, 0.63–2.72) and a higher number of hypotensive episodes (adjusted β = 0.53; 95% CI, 0.10–0.95). Monitoring strategy was not associated with surgical site, respiratory, or neurological complications. However, Vigileo/FloTrac monitoring was associated with higher odds of vascular complications (adjusted OR = 4.36; 95% CI, 1.13–20.41). No significant associations were observed between monitoring strategy and postoperative organ injury biomarkers or length of hospital stay. Conclusions: Predictive haemodynamic monitoring using the HPI system was associated with lower IOH burden compared with the Vigileo/FloTrac system. However, these differences were not consistently accompanied by improvements in postoperative outcomes. Haemodynamic optimisation should be considered as one component within a broader, integrated perioperative management strategy. Further large-scale, multicenter prospective studies are warranted to clarify its impact on patient-centered outcomes.

Medical Sciences doi: 10.3390/medsci14020207

Authors: Vasileios Leivaditis Christodoulos Chatzigrigoriadis Efstratios Koletsis Virginia Mplani Periklis Dousdampanis Francesk Mulita Nicholas G. Kounis Stelios F. Assimakopoulos

Background: Kounis syndrome is an allergic acute coronary syndrome precipitated by coronary vasospasm, plaque destabilization, stent thrombosis, or bypass occlusion. Cardiac surgery represents a uniquely high-risk setting due to cardiopulmonary bypass–associated inflammation and exposure to multiple pharmaceutical agents. Importantly, Kounis syndrome remains underrecognized in this context, as classical signs of anaphylaxis may be masked under general anesthesia and cardiopulmonary bypass, while ischemic manifestations may be misattributed to other perioperative conditions. Methods: A narrative review of PubMed-indexed literature was conducted to synthesize current evidence on the pathophysiology, perioperative triggers, clinical presentation, diagnostic strategies, and management of Kounis syndrome in cardiac surgery, with emphasis on intraoperative recognition and surgical decision-making. Published cases were retrieved involving perioperative cardiac surgery patients with a definite diagnosis of Kounis syndrome. Additionally, cases presenting with severe perioperative anaphylaxis and life-threatening cardiovascular involvement (grade III with cardiovascular collapse and grade IV with cardiac arrest) were included as possible Kounis syndrome, reflecting real-world diagnostic uncertainty in the intraoperative setting. Results: The literature review identified five cases of definite Kounis syndrome and ten cases of possible Kounis syndrome, including three cases with cardiovascular collapse and seven cases with cardiac arrest. Recurrent episodes were reported in several patients, particularly due to re-exposure to the triggering agent. In the context of cardiac surgery, Kounis syndrome is most frequently triggered by chlorhexidine, protamine, antibiotic prophylaxis, and anesthetic agents. The clinical presentation is often subtle during cardiopulmonary bypass. Vasoplegia, pulmonary hypertension, ventricular dysfunction, new regional wall-motion abnormalities, and hyperdynamic ventricles on transesophageal echocardiography commonly precede overt electrocardiographic changes. Diagnosis is primarily clinical and relies on intraoperative ultrasound, hemodynamic monitoring, serum tryptase, serum troponin, and, when indicated, coronary angiography. A dual-pathway approach addressing both anaphylaxis and myocardial ischemia is essential; however, one component may predominate, particularly in perioperative patients with limited clinical information, potentially leading to misdiagnosis. A multidisciplinary approach is therefore required for rapid diagnosis and individualized management. In refractory cases, cardiopulmonary bypass or ventricular assist devices may provide lifesaving support. Conclusions: Kounis syndrome remains underrecognized in cardiac surgery but carries significant morbidity. Increased clinical awareness, multidisciplinary collaboration, structured diagnostic approaches, and preventive strategies are essential to improve outcomes and reduce the risk of recurrence during future procedures.

Medical Sciences doi: 10.3390/medsci14020209

Authors: Nora Goebel Micha Christ Nico Schmid Carmen Heidrich Joerg Latus Mark Dominik Alscher Bartosz Rylski Moritz Schanz

Background: Acute kidney injury following cardiac surgery is frequent and is associated with increased risks of morbidity and mortality. However, the incidence, severity, and impact of acute kidney injury after cardiac surgery are still underestimated. Therefore, we analyzed our large electronic database for the procedure-specific incidence, characterization, and outcomes of cardiac surgery-associated acute kidney injury (CSA-AKI). Methods: A total of 8564 patients who underwent cardiac surgery at our center between 2017 and 2024 were included. We used an algorithm-based data fusion technique to aggregate data from different electronic health record sources. Data were analyzed regarding acute kidney injury according to the full kidney disease: Improving Global Outcomes (KDIGO) criteria. Results: The patients’ median age was 68 [60; 75] years, and 75.2% were male. The overall incidence of CSA-AKI was 70.5% during the hospital stay, and its development was significantly associated with increased in-hospital mortality rates (5.9% vs. 0.9%, p < 0.001). In regression analysis, all AKI stages were independent predictors of mortality (stage 1: OR 2.92 [1.66–5.59], p < 0.001; stage 2: OR 2.74 [1.35–5.8], p = 0.007; stage 3: OR 4.16 [1.19–14.1], p = 0.02). The incidence and severity of procedure-specific AKI showed significant differences between the groups (p < 0.001). Conclusions: The occurrence of CSA-AKI is associated with a significantly increased risk of in-hospital mortality, irrespective of stage. Procedure-specific AKI rates differ significantly between types of surgeries. Therefore, consideration of procedure-related risks, as well as early detection, is crucial to improve outcomes after cardiac surgery.

Medical Sciences doi: 10.3390/medsci14020208

Authors: Narongkorn Saiphoklang Pitchayapa Ruchiwit Pasitpon Vatcharavongvan Kanyada Leelasittikul Apiwat Pugongchai Orapan Poachanukoon

Background: Industrial activities may contribute to airway diseases, particularly chronic obstructive pulmonary disease (COPD) and asthma, which are major respiratory health problems with geographically variable prevalence. The objective of this study was to assess the prevalence of COPD and asthma and to examine factors associated with impaired pulmonary function among workers and residents of the Navanakorn Industrial Zone, Thailand. Methods: A cross-sectional study was performed from September 2025 to January 2026 among adults aged ≥18 years who were employed in or residing within the Navanakorn Industrial Zone. Data collected included demographic characteristics, comorbidities, respiratory symptoms, chest radiographic findings, and spirometric parameters, including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and bronchodilator responsiveness (BDR). COPD was defined as the presence of respiratory symptoms in conjunction with at least one risk factor and a post-bronchodilator FEV1/FVC < 70%. Asthma was defined by the presence of respiratory symptoms with a positive BDR. Results: Among the 373 participants (65.4% female; mean age 55.0 ± 13.6 years), the prevalence of COPD and asthma was 4.3% and 5.4%, respectively. Abnormal chest radiographic findings were present in 8.6%, while abnormal pulmonary function was identified in 30.8%. Lung function abnormalities included airway obstruction (12.9%), restrictive patterns (9.7%), mixed defects (2.1%), and small airway disease (6.2%). A positive BDR was detected in 2.4% of participants. Multivariable logistic regression analysis demonstrated older age, male sex, a history of asthma, and the presence of chest tightness as independent predictors of abnormal lung function. Conclusions: COPD and asthma were prevalent among individuals working or living in the industrial zone, and abnormal pulmonary function—particularly obstructive defects—was common. Older age, male sex, a history of asthma, and respiratory symptoms were associated with a greater risk of lung function impairment, underscoring the importance of targeted surveillance and preventive strategies in industrial environments.

Medical Sciences doi: 10.3390/medsci14020206

Authors: María de Castro-García Sara Núñez-Palomares Juan Miguel Antón-Santos Alejandro Estrada-Santiago Yolanda Majo-Carbajo Pilar García de la Torre-Rivera Francisco Javier García-Sánchez Pilar Cubo-Romano

Background: Hypernatremia is an infrequent but clinically relevant electrolyte disorder in older adults and is associated with poor outcomes. Patients managed through Hospital-at-Home (HaH) programs, particularly those living in institutional settings, are especially vulnerable due to functional dependency and cognitive impairment. Evidence regarding the prevalence and prognostic impact of hypernatremia in HaH settings remains limited. Methods: We conducted a retrospective observational cohort study including all patients admitted to a Hospital-at-Home unit between 2019 and 2024. Patients were classified according to care setting as home-dwelling or institutionalized. Hypernatremia was defined as a serum sodium concentration >145 mmol/L. Sociodemographic, functional (Barthel Index), and cognitive (Global Deterioration Scale) variables were collected. Mortality during HaH admission and at 30, 60, and 90 days was analyzed, and survival was assessed using Kaplan–Meier methods. Results: A total of 4501 patients were included, of whom 2701 were treated at home and 1800 in institutional settings. Hypernatremia was significantly more prevalent among institutionalized patients than among home-dwelling patients (3.1% vs. 0.8%, p < 0.001). Institutionalized patients with hypernatremia showed greater functional dependency (Barthel Index 11 vs. 15, p = 0.041) and more advanced cognitive impairment (GDS 6 vs. 5.5, p = 0.033) compared with those without hypernatremia. Mortality among institutionalized patients with hypernatremia was high, reaching 32.9% during HaH admission, 61.2% at 30 days, 70.6% at 60 days, and approximately 79% at 90 days. Kaplan–Meier analysis demonstrated a rapid decline in survival during the first month following diagnosis. Conclusions: In Hospital-at-Home programs, hypernatremia is more prevalent among institutionalized older adults and is strongly associated with severe functional and cognitive impairment and very high short- and medium-term mortality. These findings suggest that hypernatremia should be considered a marker of advanced frailty rather than an isolated electrolyte disturbance.

Medical Sciences doi: 10.3390/medsci14020205

Authors: Enrico Altiero Giusto Vittorio Oteri Giorgio Guido Delia Anamaria Bogdan Jacopo Giuliani Carlotta Giorgi Paolo Pinton Francesco Fiorica

Introduction: Antipsychotic (AP) medications are widely prescribed beyond psychotic disorders, yet their long-term safety profile regarding breast cancer (BC) risk remains uncertain. Methods: We conducted a systematic review and meta-analysis of observational studies evaluating the association between AP exposure and incident BC. Eligible studies reported adjusted odds ratios (ORs) with 95% confidence intervals for any AP, prolactin-increasing antipsychotics (PIAPs), or prolactin-sparing antipsychotics (PSAPs). Study quality was assessed using the modified Newcastle-Ottawa Scale (mNOS), and certainty of evidence was graded with the GRADE framework. Random-effect models were used to pool effect estimates by exposure category, duration, and cumulative Defined Daily Dose (DDD). Results: Nine high-quality observational studies encompassing 108 effect estimates were included. Most studies achieved mNOS scores of 9, yet GRADE certainty ranged from very low to moderate, with the overall body of evidence graded as low certainty due primarily to residual confounding. Any AP exposure was associated with a modestly increased BC risk, particularly with long-term use: use for >5 years yielded pooled ORs around 1.5–1.6, while short-to-medium duration (1–5 years) showed smaller increases (pooled ORs in the range 1.2–1.3). For PIAPs, both longer duration (>5 years) and higher cumulative exposure (>1000–2000 DDDs) were consistently associated with ORs/HRs in the 1.3–1.6 range, suggesting a possible dose–response pattern. Histological analyses indicated stronger associations for ductal than lobular BC, and elevated risks were observed across age strata, including women aged <55 and ≥70 years. Discussion: This meta-analysis suggests that chronic exposure to prolactin-increasing antipsychotics is associated with a potentially clinically relevant increase in BC risk, whereas prolactin-sparing agents do not show a clear signal of harm. However, the certainty of this association is limited by inconsistently measured confounders and by the observational nature of the data. These findings support a cautious, individualized approach in which clinicians preferentially consider PSAPs when appropriate, discuss BC risk as part of shared decision-making, and integrate tailored screening strategies for women requiring long-term PIAP therapy. Further high-quality pharmacoepidemiologic studies with better confounder control and mechanistic integration are needed to refine risk estimates and inform preventive neuropsychopharmacology.

Medical Sciences doi: 10.3390/medsci14020204

Authors: Ivars Brecs Sandra Skuja Simons Svirskis Nityanand Jain Peteris Stradins

Background/Objectives: Ascending aortic aneurysm is a heterogeneous disease, with many cases of acute Stanford type A aortic dissection (ATAAD) presenting with aortic diameters below currently recommended surgical thresholds. Demographic factors such as age and sex, along with indexed aortic size groups, have been proposed to improve risk stratification. Methods: We included 65 adult patients who underwent surgical intervention for ATAAD. Morphometric measurements were obtained from computed tomography angiography (CTA) using centerline reconstruction. Maximum ascending aortic diameter and length were measured. Indexed parameters included the aortic size index (ASI), aortic height index (AHI), aortic length index (ALI) and cross-sectional aortic area indexed to height (CSA/H). Estimated pre-dissection dimensions were derived by reducing diameter by 18% and length by 2.7%. The cohort was stratified by age-, sex-, and ASI-defined groups. Results: Women were older than men (mean age 67 [SD 11] vs. 58 [SD 13] years, p = 0.01). Aortic diameter and length did not differ significantly by age or sex. At presentation, an ascending aortic diameter < 5.0 cm was observed in 37.1% of patients aged < 65 years and 26.7% of those aged ≥ 65 years. When stratified by sex, 25.0% of women and 35.6% of men presented with an ascending aortic diameter < 5.0 cm. Indexed parameters (ALI, AHI and ASI) were higher in older patients and women despite their smaller body size. In estimated pre-dissection analyses, less than 10% of the patients had diameters ≥ 5.5 cm, whereas most had estimated diameters < 5.0 cm. Conclusions: A substantial proportion of patients with ATAAD present with aortic dimensions below the current surgical thresholds. These findings underscore the limitations of diameter-based criteria and support the potential value of indexed geometric parameters in improving risk assessment in ATAAD patients.

Medical Sciences doi: 10.3390/medsci14020203

Authors: Maria Elena Flacco Flavia Minoia Gabriele Brunini Martina Rosticci Matteo Fiore Giancarlo Cicolini Cecilia Acuti Martellucci Claudio Borghi Lamberto Manzoli

The definition of hypertension and the values of systolic and diastolic blood pressure (BP) that should be considered as therapeutic targets have changed over time and vary across scientific societies, which may generate uncertainty in the decision-making process among clinicians and patients. We traced the evolution and described the differences in all the 32 Clinical Practice Guidelines for the management of hypertension released by the following national and international scientific societies: World Health Organization—WHO; International Society of Hypertension—ISH; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure—JNC; American Heart Association—AHA; American College of Cardiology—ACC; European Society of Cardiology—ESC; European Society of Hypertension—ESH; and UK National Institute for Health and Care Excellence—NICE. Throughout the decades, the BP values used for hypertension definition, treatment initiation, and targets to achieve started from SBP/DBP ≥ 160/95 mmHg, established at the end of the 70s, progressively decreased, and were differentiated by individual cardiovascular risk. In the last decade, a divergent approach emerged across scientific societies: while WHO/ISH and NICE recommended thresholds and targets for the general population at SBP/DBP < 140/90 mmHg, ESH/ESC and ACC/AHA guidelines further and markedly reduced both BP threshold values and therapeutic targets, recommending as ideal SBP/DBP values < 130/80 mmHg and encouraging an SBP < 120 mmHg. Discrepancies also emerged in the assessment of the quality of the evidence: although the methodological approaches largely improved over time and across all the institutions assessed, various degrees of incompleteness on the adopted scales were reported, and potentially conflicting situations emerged, particularly when weaker evidence was used to build strong recommendations. Although some degree of discrepancy among guidelines is expected, some of the differences are large and can lead to widely different approaches in the management of BP control. A standardization of the methodology and interpretation of the evidence supporting the guidelines may help to reduce the variability in order to provide the best possible guidance for clinical practice and patient health.

Medical Sciences doi: 10.3390/medsci14020202

Authors: Ferenc Sipos Györgyi Műzes

Trained immunity is a concept that is currently in development and refers to the long-term functional reprogramming of innate immune cells in response to microbial or inflammatory stimuli. This process serves a dual purpose in the gastrointestinal tract, contributing to chronic inflammatory conditions like inflammatory bowel disease and maintaining host defense. The production of pro-inflammatory mediators is augmented by epigenetic and metabolic changes that are induced by the persistent activation of innate immune cells, which is triggered by microbial components and damage-associated signals. Although this increased responsiveness may initially be protective, sustained activation leads to tissue damage, epithelial barrier dysfunction, and chronic inflammation. These mechanisms are significant contributors to colorectal carcinogenesis, particularly in colitis-associated cancer. Through the activation of oncogenic signaling pathways, the establishment of a pro-tumorigenic microenvironment, and an increase in oxidative stress, trained immunity also influences tumor development. Additionally, the systemic reprogramming of hematopoietic progenitor cells has the potential to exacerbate inflammation and facilitate the progression of tumors. The identification of epigenetic and metabolic biomarkers associated with trained immunity can lead to novel diagnostic opportunities. Targeting metabolic and epigenetic pathways, as well as regulating the intestinal microbiota, is a promising therapeutic approach that could enhance the effectiveness of treatments for colorectal cancer while minimizing adverse effects on the immune system. Nevertheless, it is necessary to maintain a delicate equilibrium to suppress pathological inflammation without compromising protective immune responses. In general, trained immunity may represent a potentially relevant mechanistic link between chronic inflammation and colorectal cancer; however, its role remains context-dependent and not yet fully defined.

Medical Sciences doi: 10.3390/medsci14020201

Authors: Iga Waluszewska Antoni Borowiec Alicja Paciorek Letycja Musz Wioletta Szczurek-Wasilewicz

Hormonal contraception is used by hundreds of millions of women worldwide and remains one of the most effective reversible methods of pregnancy prevention. Cardiovascular (CV) safety concerns, particularly venous thromboembolism (VTE), ischemic stroke, myocardial infarction, and blood pressure elevation, are important considerations when choosing forms of contraception. Estrogen-containing combined hormonal contraceptives (CHCs) increase the relative risk of VTE; however, among healthy young nonsmokers, absolute event rates remain low. Risk is strongly modified by estrogen dose, progestin type, route of administration, and individual factors such as age, smoking, migraine with aura, hypertension, obesity, inherited thrombophilia, the postpartum period, and concomitant prothrombotic medications. Progestin-only contraceptives and levonorgestrel-releasing intrauterine systems (LNG-IUSs) generally show a more favorable thrombotic profile and are preferred options for women with contraindications for estrogen. This review summarizes current evidence on the method-specific CV risks of hormonal contraception, highlights the mechanisms underlying these effects, and provides practical guidance for clinical decision-making.

Medical Sciences doi: 10.3390/medsci14020200

Authors: Humberto López Castillo Lorna E. Jenkins S. Víctor Israel Peñafiel Medina

Background. Cardiometabolic diseases (CMDs) have become a major health concern among adults living with HIV (ALWH) as antiretroviral therapy (ART) extends life expectancy. Metabolic syndrome (MetS)—a cluster of abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia, and hypoalphalipoproteinemia—is a key predictor of CMD risk. Despite high HIV prevalence in Panama, data on MetS among ALWH are scarce. Thus, the Colón C3 Study aimed to estimate the prevalence of MetS and its criteria in a large cohort of ALWH in Colón, Panama. Methods. Between April–December 2024, 659 ALWH aged ≥18 years were enrolled at the province’s sole ART Clinic (78.1% of active patients). Participants completed a computer-assisted survey on demographics and social determinants of health (SDoH), underwent anthropometry and body composition assessment, and provided ≥8 h fasting blood samples for glucose, lipid profiles, HbA1c, and high-sensitivity C-reactive protein (hsCRP). MetS was defined using NCEP-R ATP-III criteria, and analyses were stratified by sex. Results. Mean age was 43.9 (range 18–79) years; 55% were female, and 51% identified as Black/Afro-Caribbean. The overall prevalence of MetS was 38.6% (binomial 95% CI 34.5%, 42.9%), exceeding pooled estimates for ALWH in the Americas (30.4%). Among individual criteria, hypoalphalipoproteinemia (59.6%) and hypertension (52.6%) were most prevalent, followed by abdominal obesity (45.2%), hyperglycemia (33.5%), and hypertriglyceridemia (22.5%). Women exhibited significantly higher body fat mass and BMI than men. Mean hsCRP was 7.2 mg/L, indicating persistent inflammation despite virologic suppression. Socioeconomic vulnerabilities, food insecurity (30%), and housing instability (>40%) were common. Conclusions. Findings reveal a substantial cardiometabolic burden among ALWH in Colón and underscore the need for integrated HIV–CMD care models, earlier screening, and natal sex–responsive interventions. The results provide foundational evidence for improving long-term, equitable cardiometabolic outcomes in HIV care across Panama and the broader Latin American region.

Medical Sciences doi: 10.3390/medsci14020199

Authors: Dollapak Apipongrat Muhamad Rusdi Ahmad Rusmili Kornkanok Thapanasopon Khatsophon Poonaya Wittawat Chantkran Janeyuth Chaisakul

Background/Objectives: Pit vipers (subfamily Crotalinae) are responsible for a large proportion of snakebite envenoming cases in Southeast Asia. Envenomation by these snakes commonly causes hematotoxic effects, including platelet dysfunction and coagulation disturbances. Although antivenom remains the mainstay of treatment, species-specific antivenoms are not available for several regional pit viper species. This study evaluated the hematotoxic activities of selected Southeast Asian pit viper venoms and the cross-neutralizing capacity of commercially available antivenoms. Methods: Venoms from five medically important pit viper species—Calloselasma rhodostoma, Trimeresurus albolabris, T. hageni, T. purpureomaculatus, and Tropidolaemus wagleri—were tested. Washed platelets and platelet-poor plasma obtained from healthy individuals (n = 10) were used to assess venom-induced platelet aggregation and coagulation, respectively. The neutralizing effects of three antivenoms including hemato polyvalent antivenom (HPAV), T. albolabris antivenom (TAAV), and C. rhodostoma antivenom (CRAV)—were examined in vitro. Results: All tested venoms induced in vitro platelet aggregation (%Max > 50%) and promoted plasma coagulation. At the manufacturer-recommended concentration, TAAV significantly cross-neutralized the hematotoxic effects of T. purpureomaculatus and T. hageni venoms (p < 0.0001) but failed to neutralize coagulation induced by T. wagleri. CRAV showed no cross-neutralization against arboreal pit viper venoms. In contrast, HPAV strongly inhibited platelet aggregation and coagulation induced by all tested venoms (p < 0.0001). Conclusions: These findings highlight the limited cross-neutralization capacity of monovalent antivenoms against arboreal pit viper hematotoxicity. In contrast, HPAV demonstrated broad cross-neutralizing activity and may represent a practical therapeutic option for Southeast Asian pit viper envenoming when species-specific antivenoms are unavailable.

Medical Sciences doi: 10.3390/medsci14020198

Authors: Caterina Elisabetta Rizzo Roberto Venuto Maria Gabriella Caruso Cristina Genovese Pasqualina Laganà

Background: Air pollution, antimicrobial use, and population ageing are increasingly recognised as co-occurring pressures shaping population health. This study explores their ecological association with mortality patterns in the province of Messina (Southern Italy), within a One Health-informed framework. Methods: An ecological analysis was conducted using district-by-year data (2015–2024), integrating environmental monitoring (PM10, PM2.5, NO2, O3), outpatient antibiotic consumption, and cause-specific mortality rates. Multivariable regression models were used to assess associations between exposures and mortality outcomes. A post-2020 indicator was included to account for COVID-19-related disruption. Results: Marked geographic variability in pollutant concentrations was observed, with higher levels in urban-industrial districts. Infectious disease mortality increased from 13.8 to 44.6 per 100,000 inhabitants between the pre-pandemic and post-pandemic periods. In Poisson regression models, particulate matter showed a small and non-significant association with respiratory mortality (RR = 1.02, 95% CI: 0.89–1.18), while antibiotic consumption was not independently associated with mortality (RR = 0.99, 95% CI: 0.94–1.05). The post-2020 period was associated with higher mortality estimates (RR = 1.15, 95% CI: 0.72–1.83), although with wide confidence intervals. Conclusions: The findings suggest the co-occurrence of environmental, demographic, and pharmaceutical pressures within the same territories, rather than demonstrating formal synergistic interaction. The observed post-pandemic increase in mortality highlights the importance of accounting for COVID-19-related disruption. These results should be interpreted as exploratory, given the ecological design and limited sample size, but support the need for integrated surveillance approaches within a One Health perspective.

Medical Sciences doi: 10.3390/medsci14020197

Authors: Miguel A. Mejia Oscar J. Suarez Gilberto Perpiñan Leiner Barba Jimenez

Background: Metabolic syndrome (MetS) leads to alterations in cardiac autonomic control that can be detected from electrocardiogram (ECG)-derived markers, particularly when the cardiovascular system is challenged during an oral glucose tolerance test (OGTT). Methods: In this paper, we present an automated framework for MetS identification using RR intervals and heart rate variability (HRV) features extracted from 12-lead ECG recordings acquired during the five OGTT stages in 40 male participants (15 with MetS, 10 controls, and 15 endurance-trained marathon runners). RR intervals were first derived using a multilead Pan-Tompkins approach with fusion-based validation. From these RR series, HRV descriptors were computed from time-domain statistics (RR mean, SDNN, rMSSD, pNN50), spectral indices (VLF, LF, HF, LF/HF), and nonlinear measures (SD1, SD2, SampEn, DFA-α1). Conventional HRV analysis revealed pronounced physiological differences between groups: MetS subjects exhibited reduced parasympathetic activity, reflected by lower rMSSD and SD1, lower HF power, and higher LF/HF ratios, whereas marathoners showed greater vagal modulation, higher HF power, and increased signal complexity. Healthy controls showed an intermediate autonomic profile. Using RR sequences and HRV descriptors (256 samples per stage), we trained three multimodal classifiers: a CNN-MLP model with a softmax output, a CNN-MLP model with an SVM head, and a CNN + LSTM-MLP + SVM architecture. Results: All models achieved strong discriminative performance, with accuracies ranging from 0.92 to 0.95, F1-macro values from 0.92 to 0.95, and macro-AUC values from 0.96 to 0.97. The CNN-MLP model achieved the best overall performance, whereas the CNN + LSTM-MLP + SVM model showed strong class discrimination, particularly for endurance athletes, while maintaining competitive recall for MetS. Conclusions: These findings support the feasibility of ECG-based autonomic assessment as a complementary non-invasive approach for early metabolic risk detection in clinical and preventive cardiometabolic screening settings.

Medical Sciences doi: 10.3390/medsci14020196

Authors: Pareek Aayushi Hossam Gad Abdelhamed Elgazar Krzysztof Laudanski

Background: Surgical trauma disrupts hormone networks, but the duration required for these systems to recover remains unclear. We hypothesize that significant perioperative stress would trigger protracted abnormalities of the thyroid axis extending past 28 days. Methods: This retrospective exploratory study analyzed opportunistically obtained thyroid-related laboratory values (free T3 [FT3], free T4 [FT4], and thyroid-stimulating hormone [TSH]) and serum albumin from electronic medical records of patients undergoing CABG, AVR, or PCI between 2017 and 2022. Preprocedural baseline values were compared with post-procedural serum levels measured during the acute peri-procedural period (0–30 days), early recovery (31–90 days), intermediate recovery (91–180 days), late recovery (181–365 days), medium-term follow-up (1–2 years), and long-term follow-up (>2 years). Results: Free T3 demonstrated early suppression across all procedures, most pronounced in CABG during the acute peri-procedural period, with partial recovery at later timepoints. AVR showed moderate suppression at early and long-term follow-up, while PCI demonstrated minimal and inconsistent changes. Free T4 remained relatively stable across procedures, with limited significant post hoc differences after adjustment. TSH showed significant temporal variability in CABG and AVR but not in PCI. Serum albumin demonstrated marked early decline, most pronounced in CABG, with partial recovery over time, whereas AVR showed delayed long-term suppression. Data availability declined substantially at later timepoints across all biomarkers. Conclusions: In this retrospective exploratory analysis, CABG was associated with the most pronounced early perturbations in thyroid and albumin trajectories, while PCI and AVR demonstrated more heterogeneous temporal patterns. These findings are hypothesis-generating and should be interpreted cautiously given non-protocolized laboratory follow-up, substantial missingness, and potential selection bias.

Medical Sciences doi: 10.3390/medsci14020195

Authors: Antonio Luigi Manai Barbara Noli Aqsa Anjum Elias Manca Maria Antonietta Casu Marie-Christine Pardon Cristina Cocco

Background: In Parkinson’s disease (PD), changes in the brain begin before clinical symptoms. We have previously shown that VGF precursor levels were reduced in a presymptomatic PD animal model. Objectives: In the present study, we investigated whether two VGF precursor-derived products, namely NAPP-129 protein and TLQP-62 peptide, also exhibit alterations using the same PD animal model. Methods: Specifically, rats were unilaterally injected in the substantia nigra with a viral vector overexpressing green fluorescent protein (N = 12) or α-synuclein (N = 13), the latter resulting in mild dopaminergic alterations without overt motor deficits. Results: NAPP-129 and TLQP-62 were investigated in the substantia nigra, striatum, and plasma by Western blotting or immunoassays using specific antibodies against NAPP and TLQP sequences, alongside other NERP-1- and AQEE-related products. Plasma samples of a Huntington’s disease mouse model were also analyzed. We found reductions in NAPP-129 and TLQP-62 levels in the substantia nigra along with a decrease in NAPP- and TLQP-like plasma immunoreactivity in α-synuclein-overexpressed rats, while the striatum was not affected. NERP-1- and AQEE-related products were not altered. No changes were found in the Huntington’s disease model. Conclusions: These findings indicate that NAPP-129 and TLQP-62 may enhance the sensitivity and specificity of biomarker-based strategies for PD.

Medical Sciences doi: 10.3390/medsci14020194

Authors: Francesco Dondi Pietro Bellini Mattia Bertoli Gian Luca Viganò Roberto Rinaldi Luca Camoni Michela Cossandi Enrico Vizzardi Carlo Mario Lombardi Francesco Bertagna

Background: Evidence on the presence of an association between epicardial adipose tissue (EAT) and myocardial perfusion imaging (MPI) as assessed by positron emission tomography (PET) has been reported. This systematic review aimed to synthesize the existing literature investigating this topic. Methods: A comprehensive and systematic search of the PubMed/MEDLINE, Scopus, and Embase databases was performed to identify published studies investigating the association between EAT and myocardial perfusion assessed by PET imaging. Eligible studies included original research articles evaluating EAT and reporting PET MPI outcomes. Data regarding the study design, patient characteristics, imaging protocols, and main findings were extracted and qualitatively analyzed. Results: Ten studies were included in the final analysis. Overall, most studies demonstrated a significant association between increased EAT and impaired myocardial perfusion on PET imaging. In several studies, EAT remained an independent predictor of abnormal PET MPI after adjustment for traditional clinical risk factors. Nonetheless, important methodological differences among studies were observed, including heterogeneity in EAT measurement techniques, quantification methods, and PET tracers used for MPI evaluation, which limit the generalizability of these findings. Conclusions: This systematic review seems to suggest a potential association between increased EAT and impaired myocardial perfusion, as assessed by PET. However, significant methodological heterogeneity across the available studies—including differences in EAT quantification, PET protocols, and tracer selection—limits the strength of this conclusion. Standardized imaging protocols and larger, prospective, multicenter studies are required to validate this relationship, determine its incremental prognostic value, and evaluate its potential for integration into routine clinical risk stratification pathways.

Medical Sciences doi: 10.3390/medsci14020193

Authors: Ronen Brenner Hanna T. Frumin Edri Sabri El-Saied Ilia Berezhnov Anna Ievko Keren Rouvinov Sofiia Turaieva Amichay Meirovitz Tanzilya Tairov Shlomit Fenig Nashat Abu Yasin Alexander Yakobson Eyal Fenig Abed Agbarya Walid Shalata

Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, with prognosis influenced by tumor location and primary status. This study evaluated clinicopathological features and survival outcomes in patients with MCC from multiple centers in Israel. Methods: Data on demographics, tumor characteristics, lymph node (LN) involvement, treatment, and survival were collected. Patients were stratified by primary tumor status (known vs. unknown) and tumor location (sun-exposed vs. non-sun-exposed). Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier analysis, and multivariate analyses were performed. Results: The cohort included 80 patients diagnosed with stage 3 (with LN involvement) MCC, of whom 52 (65%) had primary MCC with lymph node involvement, and 28 patients (35%) with unknown primary MCC. The majority were male (81.3%), with a median age of 71.2 years (range, 37–92). The median DFS and OS for the entire cohort were 24 and 32 months, respectively. Patients with unknown primary tumors had longer DFS (34 vs. 18 months; p = 0.0503) and OS (43 vs. 28 months; p = 0.0362) compared with those with known primary MCC. Non-sun-exposed tumors were associated with longer median DFS (32 vs. 18.5 months; p = 0.0663) and OS (41 vs. 23 months; p = 0.0353). Five-year survival analysis showed improved outcomes in patients with unknown primary tumors (DFS 54% vs. 35%, p = 0.04; OS 57% vs. 42%, p = 0.03) and in non-sun-exposed tumors (DFS 51% vs. 33%, p = 0.05; OS 57% vs. 40%, p = 0.04). Conclusions: Unknown primary status and non-sun-exposed tumor location are potentially associated with improved long-term survival in patients with MCC. These findings highlight the prognostic importance of tumor origin and anatomical site in MCC management.

Medical Sciences doi: 10.3390/medsci14020192

Authors: Luis V. Bürck Rosa Berndt Clemens Gwinner Lorenz Pichler Moses Kamal Dieter El Kayali

Purpose: The posterior tibial plateau offset (PTPO) is a parameter of sagittal plane bony tibia morphology with high variability and clinical relevance, particularly in cases involving stemmed tibial implants, where posterior tibial cortex interference may occur. However, its change during total knee arthroplasty (TKA), and its relationship to tibial component positioning remain unknown. Methods: Pre- and postoperative sagittal radiographs of 98 patients undergoing primary, mechanically aligned TKA using a single implant system were retrospectively analyzed. PTPO was measured as the distance between the tibial anatomical axis and the center of the tibial plateau or tibial component. Tibial component placement (TCP) was assessed anteriorly and posteriorly and categorized as anatomical (0–1 mm), mild (1–3 mm), or moderate (>3 mm) underhang (TCU) or overhang (TCO). Pre- and postoperative changes in PTPO were analyzed, preoperative PTPO was compared across TCP categories. Correlations with absolute anterior and posterior deviation from anatomical component placements were calculated. Results: PTPO showed high preoperative variability (mean 6.89 ± 3.69 mm) and was significantly reduced after TKA (5.89 ± 3.44 mm; mean change −1.06 ± 3.44 mm; p < 0.001). Higher preoperative PTPO was associated with anterior (p = 0.01) and posterior TCU (p = 0.02). PTPO showed a moderate correlation with anterior (r = 0.53, p < 0.01) and a strong correlation with posterior implant deviation (r = 0.68, p < 0.01). Conclusions: PTPO shows high variability among patients undergoing TKA, is significantly altered through surgery and correlates with tibial component malposition, particularly TCU. Surgeons should consider PTPO during preoperative planning to optimize tibial component positioning and reduce the risk of implant-to-bone conflict, especially when using stemmed implants. In patients with a high preoperative PTPO, accuracy-enhancing techniques such as computer navigation or robotic assistance may be considered.

Medical Sciences doi: 10.3390/medsci14020191

Authors: Francesca K. Martino Marco Bogo Ludovica Brunetta Francesca Fioretti Leda Cattarin Lucia F Stefanelli Federico Nalesso

Background/Objectives: Asymptomatic hyperuricemia has been associated with increased cardiovascular risk; it is related to factors such as diet, genetic predisposition, and drug-related side effects. Impairment of uric acid control has been associated with the calcineurin inhibitors cyclosporin and tacrolimus, although available studies did not reach the same conclusions. Their widespread use in solid organ transplantation potentially exposes this population to higher cardiovascular risk. This systematic review aimed to assess their role in hyperuricemia risk compared with other immunosuppressive treatments and to clarify potential differences between cyclosporin and tacrolimus. Methods: The search was conducted in MEDLINE and Embase, limited to adult subjects, using the following terms: ((cyclosporin) OR (cyclosporine) OR (tacrolimus) OR (calcineurin inhibitor)) AND ((uric acid) OR (urate) OR (hyperuricemia)) AND ((transplant) OR (transplantation)). We assessed the quality of the studies according to the Critical Appraisal Skills Programme checklist. Results: After screening 639 manuscripts, we selected 36 studies that were relevant to our focus: 28 evaluated kidney transplant patients, while only eight focused on other solid organ transplants. Specifically, 20 studies compared calcineurin inhibitors with other immunosuppressants, while 15 assessed the impact of cyclosporin versus tacrolimus, and one study contributed to both scenarios. The prevalence of hyperuricemia ranged from 30 to 80% among patients receiving calcineurin inhibitors, with a slightly higher prevalence with cyclosporin than with tacrolimus (51–61% vs. 36–42%, respectively). The overall quality of the included studies was generally rated as low to moderate, with only ten studies focusing on uric acid control. Conclusions: Given the heterogeneity and overall quality of the available studies, no definitive conclusions can be drawn. In particular, the comparative effect of cyclosporin and tacrolimus remains uncertain because of conflicting findings across studies. Although calcineurin inhibitors may adversely affect uric acid control in transplant recipients, this association may be influenced by several confounding factors.

Medical Sciences doi: 10.3390/medsci14020190

Authors: Javier Muñiz-Sáenz-Diez Ana Ezponda Meylin Caballeros Ana de la Fuente Nahikari Salterain Gorka Bastarrika

Background/Objectives: Regadenoson is increasingly used as a vasodilator stress agent for perfusion cardiac magnetic resonance (CMR) imaging due to its favorable pharmacologic profile. However, its long-term prognostic value in patients with myocardial ischemia remains insufficiently established. Methods: We retrospectively analyzed all regadenoson stress-CMR studies performed at our institution between May 2017 and July 2020, including patients with follow-up longer than three months. Inducible ischemia and late gadolinium enhancement (LGE) were assessed using standardized criteria. The primary composite endpoint included cardiovascular death, non-fatal myocardial infarction, late coronary revascularization (≥3 months after CMR), or hospitalization for unstable angina. Event-free survival was analyzed with Kaplan–Meier curves, and prognostic factors were evaluated using a Fine–Gray competing-risks model. Results: Of 705 examinations, 698 were eligible, and 517 patients (78.5%) completed follow-up over a median of 1.93 years (IQR 1.37–2.79). Inducible ischemia was identified in 142 patients (27.5%). During follow-up, 38 composite events occurred. Event incidence was significantly higher in patients with ischemia (109.6 events/1000 person-years; 95% CI 75.7–158.7) than in those without (13.3 events/1000 person-years; 95% CI 7.2–24.7; RR 8.25; 95% CI 4.01–16.98; p < 0.001). In multivariable analysis, inducible ischemia independently predicted adverse outcomes (HR 4.50; 95% CI 1.86–10.9; p = 0.001), whereas LGE was not independently associated (HR 1.28; 95% CI 0.46–3.57; p = 0.63). Conclusions: Regadenoson stress-CMR provides robust medium-term risk stratification in patients with suspected or known coronary artery disease. Detection of inducible ischemia strongly predicts major cardiovascular events, underscoring its prognostic and clinical relevance.

Medical Sciences doi: 10.3390/medsci14020189

Authors: Rym Akrout Khouloud Ayed Hela Mrizak Ludovic Leloup Orace Mathieu Kenou Fidèle Fassinou Dhouha Bacha Rahma Boughriba Hanen Attia Hervé Kovacic Wassim Y. Almawi Asma Gati

Marine-derived natural products are increasingly recognized for their therapeutic potential in cancer and other chronic diseases. Despite significant advances, current cancer treatments remain challenged by toxicity, drug resistance, and limited survival benefits. Natural compounds offer promising alternatives due to their multi-target mechanisms and favorable safety profiles. Among them, Spirulina, a filamentous cyanobacterium, stands out for its rich composition and diverse biological activities. Its anticancer effects involve apoptosis induction via intrinsic and extrinsic pathways, cell cycle arrest at G1/S or G2/M phases, inhibition of angiogenesis through the VEGF/VEGFR2 axis, and suppression of epithelial–mesenchymal transition. These activities are mainly attributed to C-phycocyanin, allophycocyanin, phenolic compounds, and immunomodulatory polysaccharides. Spirulina also exhibits potent immunomodulatory effects by enhancing natural killer cell activity, promoting M1 macrophage polarization, and regulating Th1 and Th17 cytokine responses, highlighting its potential as both an immunotherapeutic and chemoprotective agent. Moreover, preclinical findings suggest it may reduce chemotherapy-associated side effects. However, translation into clinical therapy remains limited by low bioavailability, lack of standardized extracts, and scarce clinical evidence. This review summarizes current mechanistic and immunological insights and highlights the need for optimized formulations, defined dosing strategies, and well-designed clinical trials to validate Spirulina’s potential in cancer treatment.

Medical Sciences doi: 10.3390/medsci14020188

Authors: Constantin Aleodor Costin Adriana Grigoraș Cornelia Amalinei

Background: Malignant salivary gland tumors represent a highly diverse group of neoplasms, their heterogeneity likely arising due to variable origin in different tissue components. Emerging evidence suggests that SOX-2 and EZH-2 play critical roles in salivary gland carcinogenesis, being related to tumor cell stemness potential, along with accelerated tumor progression and unfavorable clinical outcomes. The aim of this study was to assess the association between SOX-2 and EZH-2 expression, survival parameters, and tumors’ pathological characteristics in a group of patients with primary epithelial malignant salivary gland tumors (MSGTs) and to evaluate their value as diagnostic and prognostic markers. Methods: Our study group comprised 104 patients with primary epithelial MSGTs diagnosed in “Sf. Spiridon” County Hospital, Iasi, over a period of fifteen years. Pathological parameters and survival evaluation, along with SOX-2 and EZH-2 immunohistochemistry assessment and scoring, were conducted, and the associations between different parameters were analyzed. Results: High SOX-2 immunoexpression was significantly associated with lymphatic invasion (LY) (p = 0.003), pT stage (p = 0.010), histological tumor type (p = 0.003), and tumor grading (p = 0.037), while high EZH-2 immunoexpression was significantly associated with perineural invasion (PnI) (p < 0.001), vascular invasion (p = 0.038), LY (p = 0.001), tumor grading (p = 0.002), and pathological extranodal extension (pENE) (p = 0.018). The tumors with high SOX-2 and EZH-2 expressions were associated with a reduced overall survival (OS) (p = 0.013 and p = 0.011). Cox regression analysis revealed that pT (HR = 1.826, p = 0.019), LY (HR = 0.318, p = 0.007), and tumor grade (HR = 0.505, p = 0.021) added to high SOX-2 and EZH-2 immunoexpression independently predicted a poor survival outcome (HR = 2.373, p = 0.016 and HR = 2.746, p = 0.015). Conclusions: Our findings suggest that SOX-2 and EZH-2 may serve as biomarkers of aggressive behavior and a poor prognosis in primary epithelial MSGTs, providing potential opportunities for precision-targeted therapies.

Medical Sciences doi: 10.3390/medsci14020187

Authors: Nermir Granov Farhad Bakhtiary Armin Šljivo Jude S. Sauer

Background/Objectives: Totally endoscopic mitral valve repair reduces surgical trauma and accelerates recovery but can be technically challenging, particularly for precise annuloplasty suturing. The VirtuoSEW® (LSI Solutions, Victor, NY 14564m, USA) automated annular suturing system was developed to standardize and simplify suture placement. This study was an early evaluation of this technology’s safety, efficacy, and feasibility in totally endoscopic microInvasive mitral valve repair (µMVr). Methods: We conducted a retrospective observational study of 20 patients with severe mitral valve disease of various etiologies. All patients underwent mitral valve repair using the VirtuoSEW® system for automated placement of annuloplasty sutures, combined with leaflet resection or chordal management as appropriate. Postoperative outcomes were assessed at one month using echocardiography and clinical evaluation. Perioperative and postoperative complications and early mortality were systematically recorded. Results: VirtuoSEW®-assisted mitral valve repair was safe and effective, achieving complete elimination of severe mitral regurgitation in all patients (N = 20, 100%). Annuloplasty rings included Physio-ring (N = 12, 60%), Memo 3D (N = 4, 20%), and Memo 4D (N = 4, 20%), combined with leaflet repair techniques: leaflet plication (N = 5, 25%), neochordae implantation (N = 7, 35%), sliding plasty (N = 2, 10%), commissural repair (N = 1, 5%), and hemibutterfly repair (N = 1, 5%). Concomitant procedures included: tricuspid valve repair (N = 1, 5%) and atrial septal defect closure (N = 1, 5%). Mitral annulus diameter decreased from 42.0 ± 5.3 mm to 34.2 ± 2.2 mm (p = 0.001). Mean total surgery, cardiopulmonary bypass, and aortic cross-clamp times were 170.3 ± 21.3, 143.4 ± 21.5, and 80.4 ± 7.9 min, respectively. ICU stay was 1.0 ± 0.2 days, with a hospital stay of 8.0 ± 1.9 days. No perioperative complications—including bleeding (N = 0, 0%), stroke (N = 0, 0%), infections (N = 0, 0%), or 30-day mortality (N = 0, 0%)—occurred. Conclusions: µMVR invasive mitral valve repair using the VirtuoSEW® system is safe, effective, and reproducible, as well as compatible with almost all repair techniques, providing complete restoration of valve competence with no early device-related complications. To our knowledge, this is the first clinical study reporting outcomes with this device, supporting its potential to streamline mitral repair and improve procedural efficiency.

Medical Sciences doi: 10.3390/medsci14020186

Authors: Kit Neikirk Aliyah Allick Christopher J. Gamper Alicia D. Cannon Wilfreda Lindsey Bridget G. Gibbons Eboni I. Lance

Background: Sickle cell disease (SCD) is a hereditary disorder affecting red blood cells’ shape and functional capacity. Individuals with SCD report relatively high co-occurrence of neurodevelopmental disorders (NDDs). In addition, these children also have higher rates of enuresis (incontinence) and pica, disorders prevalent in children with developmental delays. Both enuresis and pica can have negative effects on mental health, but their pathophysiology, especially in SCD, remains unclear. Objectives: The objective of this study was to determine the rates of pica and enuresis in a pediatric SCD clinic to compare the co-occurrence of NDDs and enuresis/pica. Methods: To do so, we performed a cross-sectional explanatory retrospective chart review of 275 pediatric SCD patients. Results: Our SCD cohort had a 27% prevalence of enuresis, 9% prevalence of pica, and 24% prevalence of one or more NDDs. We noted significant inter-group overlap between pica/enuresis and other risk SCD severity factors. NDDs were approximately twice as frequent in SCD patients with pica or enuresis compared to those without. While pica was associated with HbSβ+, it was not linked to disease severity indicators. Enuresis was associated with hydroxyurea usage (66.7% vs. 42.6%, p = 0.001) and reticulocyte counts, indicative of higher disease severity. Conclusions: Clinically, these results are the first to show co-occurrence between pica, enuresis, and NDDs in SCD. We suggest that the occurrence of pica or enuresis may serve as an indicator for previously unknown NDD risk. Together, these results underscore the need for targeted screenings of pica and enuresis in SCD populations.

Medical Sciences doi: 10.3390/medsci14020185

Authors: Antonio Rizza Simona Sica Marco Ferraresi Giovanni Tinelli Yamume Tshomba Giovanni Rossi Giancarlo Trimarchi Ilenia Foffa Luca Bastiani Silvia Di Sibio Michele Murzi Cataldo Palmieri Nicola Tusini Carmelo Ricci Andrea Colli Antonio Lorido Francesco Talarico Mafalda Massara Chang Shu Sergio Berti SOCIAL Collaborative Study Group SOCIAL Collaborative Study Group

Objective: To evaluate early and mid-term outcomes of thoracic endovascular aortic repair (TEVAR) using the Castor single-branched aortic stent graft in a real-world multicenter Italian experience. Methods: This retrospective, nonrandomized, multicenter study included all consecutive patients treated with the Castor stent graft between January 2019 and April 2025 in eight Italian centers. The device was used in patients with thoracic aortic pathologies requiring TEVAR in proximal landing zones 1 or 2. Primary endpoints included technical success, intraoperative major adverse events (MAEs), and deployment accuracy. Secondary endpoints were aortic-related mortality, neurological complications, reinterventions, and endoleaks. Results: Fifty-one patients (mean age 68.8 ± 8 years, 75.5% male) were treated, primarily for type B aortic dissection (45.1%) and thoracic aortic aneurysm (27.5%). Proximal landing was in zone 2 in 92.1% and zone 1 in 7.8% of cases. The technical success rate was 94.1%, with three cases (5.8%) of intraoperative type Ia endoleak. No intraoperative deaths or major adverse events occurred. Two cases of minor embolic stroke (3.9%) were observed, both in zone 1 procedures involving left common carotid artery revascularization. At a median follow-up of 22.3 months (range 2–58), no additional endoleaks or neurological events were reported, with 100% branch patency rate. Conclusions: The Castor single-branched stent graft is a feasible option for TEVAR in zone 2, with high technical success and low rates of neurological complications. Accurate case selection and procedural planning are essential.

Medical Sciences doi: 10.3390/medsci14020184

Authors: Gennaro Boccia Luca Beratto Cantor Tarperi Alberto Rainoldi Chiara Calliera Daniele Ierace Maria Antonietta Satolli Simona Bo Paola Costelli

Background: Patients with pancreatic cancer (PC) commonly present with reduced aerobic fitness, sarcopenia, and malnutrition, which may increase perioperative risk and compromise access to chemotherapy treatments. Although exercise-based prehabilitation can improve physical fitness, its implementation is often limited by short diagnostic-to-surgery intervals and treatment-related toxicity. Methods: We conducted a pilot prospective pretest–posttest feasibility study in Torino, Italy. Patients with PC undergoing neoadjuvant chemotherapy prior to surgery were offered a 4-week, partially supervised, home-based bimodal exercise prehabilitation program (single-arm design) combining remotely monitored high-intensity interval training (HIIT) on a cycle ergometer with functional and resistance exercises. The primary outcome was adherence to prescribed exercise frequency, intensity, and duration, objectively assessed via remote monitoring. Secondary outcomes included cardiorespiratory fitness (CPET), muscle function, body composition, fatigue, quality of life, and circulating inflammatory markers. Results: From July 2022 to February 2024, 23 patients were screened; 15 were eligible and 10 enrolled. Four participants discontinued the intervention (two due to asthenia/fatigue, one due to chemotherapy-related adverse events, and one for organizational reasons), leaving six participants who completed the program. Among completers, fatigue and quality of life did not change meaningfully. Aerobic capacity and muscle function outcomes were generally stable, with few pre–post changes exceeding the minimum clinically important difference (MCID) thresholds used. Body composition markers and the assessed circulating cytokines/chemokines remained unchanged except for IL-6 levels, which decreased significantly (p < 0.05). Conclusions: A partially supervised, home-based HIIT-based prehabilitation program is feasible for a subset of PC patients undergoing neoadjuvant therapy, but a substantial attrition rate suggests the need for more flexible symptom-adapted prescriptions and enhanced supportive strategies.

Medical Sciences doi: 10.3390/medsci14020183

Authors: Carlos M. Ardila Eliana Pineda-Vélez Anny M. Vivares-Builes Alejandro I. Díaz-Laclaustra

Background/Objectives: Malignant salivary gland tumors (MSGTs) are rare, biologically heterogeneous neoplasms in which histopathologic diagnosis and classification are challenging and subject to interobserver variability. Artificial intelligence (AI) approaches using radiologic, histopathologic, and molecular data, including radiomics, deep learning, and biomarker-based models, have been proposed as adjunctive diagnostic tools. This systematic review aimed to identify and critically appraise AI/ML models across radiologic, histopathologic, and molecular domains for distinct diagnostic tasks in MSGTs, and to integrate their diagnostic roles through a functional meta-synthesis. Methods: We conducted a PRISMA 2020-compliant systematic review. Embase, PubMed/MEDLINE, and Scopus were searched from inception to February 2026. Eligible studies developed or validated AI/ML diagnostic or classification models in human salivary gland tumor cohorts and reported extractable performance metrics. Results: From 1265 records, eight studies (1922 participants) met the inclusion criteria, spanning CT/MRI radiomics or deep learning (n = 4), whole-slide histopathology deep learning (n = 3), and DNA methylation-based classification (n = 1). External validation was reported in two CT-based benign–malignant discrimination studies, with AUCs of 0.890 (95% CI 0.844–0.937) and 0.745 (95% CI 0.699–0.791). Heterogeneity in model construction, outcome definitions, and validation strategies precluded meta-analysis. Risk of bias was frequently high in QUADAS-2/PROBAST assessments, driven by retrospective sampling, limited blinding, and analysis-related concerns, while calibration and utility were rarely assessed. Conclusions: AI/ML models for MSGTs demonstrate promising diagnostic performance, particularly for preoperative benign–malignant discrimination, but the current evidence base is limited by heterogeneity, predominantly internal validation, and high risk of bias. The functional meta-synthesis identified three convergent diagnostic domains: malignancy discrimination, histopathologic subtype classification, and molecular/epigenetic taxonomy refinement.

Medical Sciences doi: 10.3390/medsci14020182

Authors: Jonah Schwarz Parwis Massoudy Marius Mihai Harpa Markus Czesla Christian Mogilansky Klara Brînzaniuc Emanuel-David Anitei Robert Balan

Background: Femoral cannulation is essential for minimally invasive mitral valve surgery (MIMVS). Our center transitioned from open femoral cut-down to ultrasound-guided percutaneous cannulation supported by smart venous cannulas, ThruPort arterial access, and the MANTA closure device. This study evaluates how this transition affects procedural efficiency, vascular safety, and postoperative outcomes. Methods: We retrospectively analyzed 575 consecutive MIMVS patients (2014–2025). Patients treated before 2021 formed the cut-down group, while those from 2021 onward underwent percutaneous cannulation. The outcomes included operative times, groin and lymphatic complications, MANTA performance, and 30-day mortality. Propensity score matching (PSM) was performed to adjust for baseline differences. Results: Of 575 patients, 393 (68.3%) underwent cut-down and 182 (31.7%) percutaneous access. Percutaneous access was associated with shorter cardiopulmonary bypass times (115 vs. 128 min, p < 0.0001), total operative times (210 vs. 242 min, p < 0.0001), ICU stays (2 vs. 3 days, p = 0.0267), and hospital stays (8 vs. 11 days, p < 0.0001). Lymph fistula occurred in 4.3% of cut-down cases and in 0% after the adoption of percutaneous access (p = 0.0004). Overall groin complication rates were comparable (2.8% vs. 4.9%, p = 0.51). MANTA closure had a 2.2% device-related complication rate (1.1% bleeding; 1.1% ischemia) with no documented long-term sequelae. Regarding 30-day mortality, this was 4.6% in the cut-down group and 1.6% in the percutaneous group (p = 0.096). In PSM (72 matched pairs), percutaneous access retained significantly shorter operative, bypass, and ICU times, with identical groin complication rates. Conclusions: Ultrasound-guided percutaneous femoral cannulation was associated with improved procedural efficiency and elimination of lymphatic morbidity, without increasing vascular risk or mortality. It represented a safe and effective standard strategy for contemporary MIMVS.

Medical Sciences doi: 10.3390/medsci14020180

Authors: Razvan George Bogdan Alina Helgiu Anca Maria Cimpean Mara Nicolau Rodica Elena Heredea Zorin Petrisor Crainiceanu

Background/Objectives: Radiotherapy following mastectomy induces persistent structural alterations in the chest wall, including fibrosis, extracellular matrix disorganization, and vascular changes that compromise reconstructive outcomes. Although autologous fat grafting is widely used to improve tissue quality in irradiated breasts, direct human histological evidence remains limited. The aim of this prospective pilot study was to evaluate intra-patient histological remodeling in irradiated postmastectomy breast tissue before and 4 months after autologous fat grafting using paired core needle biopsies. This study should be considered a hypothesis-generating histological pilot study. Methods: Five female patients with prior mastectomy and adjuvant radiotherapy underwent Tru-Cut core needle biopsy of irradiated chest wall tissue before lipofilling and at approximately four months (range between 3 and 12 months) post-procedure. Specimens were processed using formalin fixation, paraffin embedding, and hematoxylin and eosin staining. Histological assessment focused on collagen density, stromal organization, vascular structures, inflammatory infiltrate, and adipocyte integration. Comparative intra-patient analysis was performed descriptively. Results: Baseline biopsies demonstrated consistent post-radiation alterations, including collagen compaction, stromal disorganization, perivascular fibrosis, and variable inflammatory infiltrate. Post-lipofilling specimens showed heterogeneous remodeling characterized by focal collagen fiber insertion between adipocytes, areas of immature connective tissue formation, and variable preservation of adipose architecture. The extent and pattern of remodeling differed among patients. Inflammatory activity decreased or remained mild in most cases. Conclusions: Autologous fat grafting in irradiated postmastectomy tissue is associated with measurable histological remodeling. Structural adaptation appears heterogeneous and patient-specific, suggesting a dynamic multi-stage process rather than uniform regeneration. Further studies incorporating quantitative and molecular analyses are required to clarify the mechanisms underlying these changes.

Medical Sciences doi: 10.3390/medsci14020181

Authors: Emanuele Cerulli Irelli Adolfo Mazzeo Nicoletta Fallarino Francesca Caramia Gianmarco Tessari Enza Morgillo Carlo Di Bonaventura Rosaria Turchetta Giovanna Palumbo Maria Giulia Tullo Laura Mariani Marcella Nebbioso Patrizia Mancini Cecilia Guariglia Fiorina Giona

Background: Gaucher disease (GD) is a rare lysosomal storage disorder caused by mutations in the GBA1 gene. Traditionally, GD is classified into three subtypes based on the severity of neurological involvement; however, overlapping clinical features increasingly suggest a continuum of phenotypes rather than distinct categories. In this prospective observational cohort study, we conducted a multidisciplinary assessment of patients with GD to identify and monitor neurological, cognitive, auditory, and visual impairments. Materials and Methods: A comprehensive clinical and instrumental evaluation was performed at baseline and repeated at follow-up, with a median interval of 37 months (IQR 36–38). Neurological assessments included physical examination, clinical rating scales, video-EEG, and brain MRI. Cognitive status was assessed using a standardized battery of neuropsychological tests. Detailed audiological and ophthalmological evaluations were also conducted. Paired parametric or non-parametric tests were applied as appropriate, with Bonferroni correction for cognitive outcomes (p < 0.05). Results: Of the 22 patients assessed at baseline, 18 completed the follow-up evaluation. Neurological assessments showed a worsening of subtle parkinsonian signs, with significant increases in Movement Disorder Society–Unified Parkinson’s Disease Rating Scale Part III scores (p = 0.04) and non-motor symptom scores (p = 0.01). Two of the eighteen patients developed epilepsy during follow-up. A high prevalence of sleep disturbances was confirmed, with 27.8% exhibiting excessive daytime sleepiness and 16.7% reporting REM sleep behaviour disorder on standardized questionnaires. Compared with baseline, cognitive assessments revealed a higher proportion of patients with performance below normative population scores in at least one cognitive domain, particularly memory. Sensorineural hearing loss was confirmed in 11 of 15 patients (73.3%) who underwent audiological evaluation, with progressive worsening of audiometric thresholds observed in 7 of 11 (64%). Ophthalmological evaluations showed no changes in visual acuity or OCT findings; however, multifocal electroretinography abnormalities were detected in 12 of 13 patients. Conclusions: Through in-depth phenotyping, this study identifies measurable neurological, cognitive, and sensory progressive changes in patients with GD over time, supporting the value of tailored, multidisciplinary long-term care strategies to monitor and address emerging clinical needs in this rare disease.

Medical Sciences doi: 10.3390/medsci14020179

Authors: Carmen M. Galvez-Sánchez Julio A. Camacho-Ruiz Cristina González-Lara Rosa M. Limiñana-Gras

Background/Objectives: Alcohol Use Disorder (AUD) represents a significant global public health challenge that is associated with cognitive deficits, immune dysfunction, and increased susceptibility to different comorbidities. Recent evidence suggests that neuroimmune signalling, particularly microglial activation and cytokine-mediated pathways, plays a critical role in the development, persistence, and relapse vulnerability of AUD. This narrative review aims to synthesize current evidence on the role of cytokines and interleukins (ILs) in AUD, emphasizing their modulation during alcohol exposure, withdrawal, and abstinence. Methods: A comprehensive narrative review methodology was employed, including a search in PubMed, Scopus, and Web of Science using relevant keywords. Peer-reviewed studies published in English that examined cytokine and interleukin profiles in adults with AUD were included. The main findings were synthesized into thematic domains to identify recurring patterns, inconsistencies, and research gaps. Results: AUD is associated with significant alterations in cytokine profiles. Pro-inflammatory markers such as IL-1β, IL-6, tumour necrosis factor alpha (TNF-α), IL-8, and IL-18 are elevated during active alcohol use and early abstinence, while anti-inflammatory markers like IL-10 show fluctuations. These immune changes are linked to systemic inflammation, neurotoxicity, and AUD severity. Cytokine levels tend to normalize with sustained abstinence, although severe AUD may lead to prolonged immune dysregulation. Associations between inflammatory markers and psychiatric symptoms, including anxiety and depression, were also observed. Conclusions: Immune dysregulation plays a central role in AUD pathophysiology, with cytokines serving as potential biomarkers for disease progression and treatment response. Future research should focus on longitudinal studies, diverse patient populations, and mechanistic investigations to refine biomarker utility and develop targeted immunomodulatory therapies. Addressing inflammation and neuroplasticity may enhance clinical outcomes in AUD management.

Medical Sciences doi: 10.3390/medsci14020178

Authors: Hyun Sun Jung Geum Ok Baek Moon Gyeong Yoon Se Ha Jang Jae Youn Cheong Soon Sun Kim Jung Woo Eun

Background: Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality worldwide, yet reliable molecular biomarkers for early diagnosis and prognosis are limited. The cytochrome P450 (CYP) enzyme superfamily plays central roles in hepatic metabolism and tumor biology, but its global dysregulation in HCC has not been comprehensively defined. Methods: Here, we systematically analyzed 57 CYP genes across multi-cohort transcriptomic datasets (GepLiver, TCGA-LIHC, HCCDB2.0) to delineate their diagnostic, prognostic, and functional significance. Results: CYP2R1 emerged as a consistently upregulated and clinically relevant member, showing excellent diagnostic accuracy (AUC = 0.95, 95% CI: 0.94–0.98, p < 0.001) and strong overexpression validated across independent cohorts and spatial transcriptomics. Prognostic modeling identified CYP2C9 (favorable) and CYP26B1 (unfavorable) as independent survival markers. Functional enrichment analyses revealed that high CYP2R1 expression was associated with activation of DNA repair and replication pathways (NES = 1.31, adjusted p = 1.05 × 10−5) and with co-expression of core repair genes such as POLA2, LIG1, and PCNA. Moreover, CYP2R1 correlated with myeloid-derived suppressor cell infiltration, suggesting an immunosuppressive phenotype. Conclusions: These findings establish CYP2R1 as a novel metabolic and immunogenomic biomarker in HCC, linking hepatic metabolism, genomic maintenance, and tumor immune modulation.

Medical Sciences doi: 10.3390/medsci14020177

Authors: Tomasz Semań Sabina Krupa-Nurcek Mateusz Szczupak Jacek Kobak Amelia Dąbrowska Wioletta Mędrzycka-Dąbrowska Kazimierz Widenka

Introduction: Perioperative factors can significantly accelerate the development of sarcopenia in patients with aortic dissection, weakening their metabolic and functional reserves. Progressive sarcopenia after surgery is associated with a worse prognosis, increased mortality, and a higher risk of complications, which makes its early diagnosis and prevention key elements of care for this group of patients. Methods: The study included 116 patients hospitalized from April 2022 to May 2025 due to aortic dissection. Prospective studies were conducted using standardized tools as well as clinical data. The effect of blood transfusion, grip strength as measured with a hand dynamometer, and survival of patients after aortic dissection 3 months postoperatively were evaluated. Results: In the group of patients with a high risk of stroke, completely dependent and suffering from insomnia, transfusions were used significantly more often. SGA scores, CHA2DS2-VA score, and Barthel scale scores were dependent on the level of pain at discharge. Grip strength was significantly higher among patients who survived 3 months. The differences reached statistical significance on the second postoperative day. Conclusion: The results indicate that malnutrition is a key factor in the clinical condition of patients, increasing the risk of sarcopenia, stroke, and the severity of insomnia. At the same time, a higher degree of malnutrition is associated with reduced functional independence, which in turn affects the patient’s overall condition. The study found that malnutrition is a key factor in worsening the clinical condition of patients with aortic dissection, increasing the risk of sarcopenia, stroke and exacerbation of insomnia. The relationship between lower self-reliance and higher insomnia levels underscores the complex interplay among nutritional status, physical functioning, and sleep quality.

Medical Sciences doi: 10.3390/medsci14020176

Authors: Vasileios Leivaditis Anastasios Sepetis Francesk Mulita Athanasios Papatriantafyllou Sofoklis Mitsos Periklis Tomos Konstantinos Grapatsas Ejona Shaska Elias Liolis Efstratios Koletsis Nikolaos Baikoussis

Introduction: Delirium is one of the most common and serious neuropsychiatric complications following cardiac surgery. It is associated with increased mortality, prolonged intensive care unit (ICU) and hospital stay, long-term cognitive decline, and reduced quality of life. Aims and Objectives: The aim of this study is to synthesize current evidence on the epidemiology, psychiatric and psychosocial risk factors, biological mechanisms, perioperative modifiers, prevention strategies, and long-term outcomes of delirium after cardiac surgery, with particular emphasis on its role as a marker of brain vulnerability. Materials and Methods: A narrative literature review was conducted using articles published between 1990 and 2025, identified through the PubMed and ScienceDirect databases. The search strategy included the terms “delirium,” “cardiac surgery,” “psychiatric disorders,” and “cognitive impairment.” Results: Recent evidence suggests that approximately one quarter of patients undergoing cardiac surgery develop delirium, with hypoactive forms frequently remaining underrecognized in clinical practice. Pre-existing depression, cognitive impairment, substance use disorders, low educational level, frailty, and social isolation significantly increase the risk of postoperative delirium. Within a stress–diathesis framework, peripheral physiological insults may be reflected centrally as acute brain dysfunction in vulnerable individuals. Modifiable perioperative factors include sedative choice and depth, as well as sleep and circadian disruption. Multicomponent non-pharmacological interventions, early mobilization, structured psychiatric and cognitive screening, and dexmedetomidine-based sedation have demonstrated consistent efficacy in reducing the incidence and/or duration of delirium. Furthermore, delirium has been associated with persistent cognitive and psychiatric morbidity, functional decline, and increased long-term mortality. Conclusions: Delirium following cardiac surgery is a multifactorial syndrome with significant short- and long-term consequences. A comprehensive, multidisciplinary approach integrating biological, psychiatric, and perioperative perspectives is essential for effective risk stratification, prevention, and long-term follow-up.

Medical Sciences doi: 10.3390/medsci14020175

Authors: Virginia Zamponi Piero Paravani Rossella Mazzilli Flaminia Russo Marina Paola Gardiman Bruno Giometto Raffaele Iorio Alessandro Peri Marco Zoccarato Antongiulio Faggiano

Background: Paraneoplastic limbic encephalitis (PLE) with anti-Ma2 antibodies is a rare immune-mediated disorder associated with testicular cancer, particularly in young males. While neurological manifestations are well documented, hypothalamic–pituitary dysfunctions remain underreported. We present a case of anti-Ma2 PLE associated with testicular cancer together with a systematic review of PLE associated with testicular cancer, selectively restricted to anti-Ma2 positive cases and focusing on hypothalamic–endocrine involvement. Case presentation: We describe a 21-year-old male diagnosed with anti-Ma2 PLE and intratubular germ cell neoplasia of the right testis. He underwent orchifunicolectomy and immunosuppressive therapy with neurological improvement. Four years later, he developed new-onset temporal seizures, decreased libido, and a polyuria–polydipsia syndrome. Dynamic endocrine testing, including a water deprivation test and copeptin measurement, supported a diagnosis of partial central diabetes insipidus (CDI). Methods: A systematic literature review was performed in accordance with PRISMA guidelines. PubMed was searched using predefined keywords without time restriction. Studies reporting PLE associated with testicular tumors in humans with confirmed anti-Ma2 antibody positivity were included. Results: Eleven studies were included, reporting a total of 38 patients with anti-Ma2-associated PLE and testicular cancer. Hypothalamic or diencephalic involvement was described in 16 patients (42.0%), while endocrine manifestations were explicitly reported in four cases. Only two previous reports mentioned CDI, without detailed diagnostic evaluation. Conclusions: This study highlights the importance of recognizing hypothalamic-endocrine manifestations in PLE. In patients presenting with polydipsia and polyuria, CDI should be carefully differentiated from primary polydipsia using dynamic testing. Hypothalamic involvement may emerge years after tumor treatment, warranting long-term endocrine surveillance.

Medical Sciences doi: 10.3390/medsci14020174

Authors: Elaine Dinardi Barioni Kaan Orhan Ana Cristina Borges-Oliveira Sérgio Lúcio Pereira de Castro Lopes Andre Luiz Ferreira Costa

Radiogenomics examines associations between imaging phenotypes and underlying biological characteristics across cancer types. This structured narrative review focuses on oropharyngeal squamous cell carcinoma (OPSCC) and evaluates how genomic programs characteristic of HPV-positive and HPV-negative tumors have been investigated across computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) as variations in heterogeneity, diffusion patterns, perfusion and metabolic activity. A structured literature search was conducted in PubMed/MEDLINE, Scopus and Web of Science to identify studies on radiomics and radiogenomics in OPSCC and related head and neck cancers. After screening and eligibility assessment, 81 studies were included in the narrative synthesis. The reviewed literature indicates that imaging-derived features have been associated with HPV status, hypoxia-related signatures, extranodal extension and treatment outcomes. However, the current evidence base remains heterogeneous and is largely composed of retrospective, single-institution studies with relatively small cohorts. Methodological challenges, including variability in imaging acquisition, segmentation and feature harmonization, limit reproducibility and generalizability. Although cone-beam computed tomography (CBCT) is not used for primary OPSCC staging and no CBCT-based radiogenomic studies in OPSCC have been reported, existing radiomics research in dentomaxillofacial imaging suggests its potential as a hypothesis-generating modality for future investigation. Overall, current evidence supports the biological plausibility of radiogenomic imaging signatures in OPSCC, while emphasizing the need for larger multicenter datasets, standardized imaging protocols and prospective validation before clinical implementation.

Medical Sciences doi: 10.3390/medsci14020173

Authors: Zenon Pogorelić Mateo Kraljević Ivan Lovrinčević Ivan Maleš

Background: Surgical site infection (SSI) remains the most frequent postoperative complication after pediatric laparoscopic appendectomy. Evidence is scarce regarding whether the specimen extraction port site represents a modifiable risk factor. This study evaluated the association between 10 mm trocar placement for appendix extraction and postoperative outcomes in children undergoing laparoscopic appendectomy. Methods: A retrospective single-center cohort study was conducted including children aged 0–17 years who underwent laparoscopic appendectomy between January 2012 and January 2026 with ≥30-day follow-up. Patients were grouped by placement site of the 10 mm trocar: supraumbilical versus left lower quadrant (LLQ). The primary outcome was postoperative wound infection. Secondary outcomes included overall complications, intra-abdominal abscess, postoperative ileus, stump dehiscence, operative time, length of stay, readmission, reoperation, and conversion to laparotomy. Subgroup analyses assessed the impact of endoscopic retrieval-bag use within each trocar-position group. Results: Baseline demographic, clinical, laboratory, and histopathological characteristics were comparable between the two 10 mm trocar placement sites. Overall, postoperative complications were higher with supraumbilical placement than with LLQ placement (6.9% vs. 2.9%, p < 0.001). SSI was more frequent with supraumbilical placement (3.7% vs. 0.3%, p < 0.001). Multivariable analysis confirmed trocar position as an independent predictor of SSI, with LLQ placement associated with a lower risk (OR 0.52, 95% CI 0.30–0.88, p = 0.015). Operative time was shorter with LLQ placement (median 32 vs. 36 min, p < 0.001). No significant differences were observed between placement sites in intra-abdominal abscess, postoperative ileus, readmission, reoperation, conversion to laparotomy, or length of hospital stay. Retrieval-bag use was not associated with differences in complication rates within either trocar placement site. Conclusions: LLQ 10 mm trocar placement site was associated with substantially lower SSI rates and shorter operative time compared with supraumbilical extraction, without increasing other postoperative complications. Extraction port selection may represent a simple technical measure to improve outcomes in pediatric laparoscopic appendectomy without requiring additional resources.

Medical Sciences doi: 10.3390/medsci14020172

Authors: Giovanni Baronchelli Francesco Berinato Maddalena Toffali Giacomo Urbinati Stefano Forlivesi Mario Sebastiani Chiara Tolassi Irene Girotto Giorgio Busto Enrico Fainardi Ilaria Casetta Michele Laudisi Andrea Zini Andrea Pilotto Andrea Morotti Alessandro Padovani

Background: The triglyceride glucose index (TyG-i), a biomarker of insulin resistance, has been associated with adverse vascular outcomes and risk stratification in several cardiovascular and cerebrovascular phenotypes. However, data on TyG-i as a prognostic marker in spontaneous intracerebral hemorrhage (ICH) remain limited. Objective: To explore the association between TyG-i and 90-day functional outcome in patients with ICH. Methods: A retrospective analysis of adult patients admitted for non-traumatic small vessel disease-related ICH at three Italian neurological institutions was conducted. TyG-i was calculated on admission as Ln[(fast triglycerides (mg/dL) × fast glucose (mg/dL))]/2. Functional outcome was measured with the modified Rankin Scale (mRS) at 90 days from the index event. TyG-i was analyzed as a continuous variable and categorized in quintiles (Q1 to Q5). Predictors of poor outcome (mRS 4–6) were investigated with multivariable logistic regression. Results: A total of 463 patients were included, of whom 197 (42.5%) had poor outcome at 90 days. TyG-i analyzed as a continuous variable was not associated with unfavorable prognosis. TyG-i analyzed as a categorical variable stratified by quintiles showed a non-linear U-shaped relationship with functional outcome; patients in Q4 had the lowest risk of poor outcome (Q1 reference, OR 0.44, 95% CI 0.22–0.87, p = 0.019). Discussion: We found a potential non-linear relationship between TyG-i and ICH outcome, with higher odds of good prognosis in patients with intermediate values. Conclusions: TyG-i may represent a promising, low-cost and widely available biomarker that might improve prognostication in clinical practice, but further studies are needed.

Medical Sciences doi: 10.3390/medsci14020171

Authors: Kalliopi Mavrea Katerina Katsibardi Kleoniki Roka Roser Pons Vasiliki Efthymiou Alexandros-Stamatios Antoniou Antonios I. Christou Christina Kanaka-Gantenbein George P. Chrousos Antonis Kattamis Flora Bacopoulou

Background/Objectives: To study the hypothesis that cognitive functions and learning skills are impaired in child/adolescent childhood cancer survivors (CCS). Secondary outcomes included psychosocial parameters and quality of life. Methods: This case–control study was conducted over four years (2017–2021) at the largest pediatric Aghia Sophia Children’s Hospital, in Greece. Eligible participants were children and adolescents in Greece. For CCS, ≥1 year should have elapsed from completion of cancer treatment. Assessments of neurocognitive function, learning and psychosocial skills and health-related quality of life (HRQoL) were performed with validated instruments (WISC-III, LAMDA software, Achenbach CBCL/6-18 and YSR, KIDSCREEN-52, respectively). Results: In total, 219 participants (47.49% males, mean age ± SD 11.72 ± 2.32 years), 70 CCS and 149 controls (matched for age, sex, family income), were included. Cases were CCS of acute lymphoblastic leukemia (n = 25)/brain tumors (n = 19)/lymphoma (n = 17)/nephroblastoma (n = 5)/Ewing sarcoma (n = 3)/rhabdomyosarcoma (n = 1). CCS had worse scores in full-scale Intelligence Quotient (FSIQ) (p = 0.004), verbal IQ (VIQ) (p = 0.005) and all its subscales, performance IQ (PIQ) (p = 0.021), and almost all learning parameters than controls. Attention, working memory, writing/visual–motor coordination, processing accuracy/speed, language acquisition/expression, all psychosocial scales, and HRQoL domains of mood and emotions, were negatively affected in CCS. Female CCS demonstrated lower FSIQ (p = 0.019) and VIQ (p = 0.014) than control females, whereas male CCS retained their total IQ unaffected. Among CCS, those with non-central nervous system (CNS) tumors, higher parental educational level or higher family income had significantly higher IQ than those with CNS tumors, lower parental educational level or lower family income, respectively. Conclusions: CCS in Greece carry a significant burden of cognitive and psychological morbidity. Cognitive/educational and psychosocial support to CCS is imperative.

Medical Sciences doi: 10.3390/medsci14020170

Authors: Radu-Alexandru Iacobescu Vasile Lucian Boiculese Gianina Dodi Tiberiu Lunguleac Cristina Grigorescu Sabina Antoniu

Background: Frailty has been linked with systemic inflammation in elderly oncology patients. In this paper, we report the results of an analysis evaluating the association between blood cell biomarkers of inflammation and frailty in patients with operable non-small-cell lung cancer (NSCLC). Methods: A retrospective analysis was performed on patients undergoing surgery for NSCLC between March 2022 and March 2023. Frailty was assessed using the modified Frailty Index-5 (mFI-5) and 11 (mFI-11). Inflammation was evaluated using the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune–inflammation index (SII), and systemic immune–inflammation response index (SIRI), all calculated from preoperative assessments. Results: In this sample of surgical NSCLC patients (n = 106), frailty prevalence was 29.2% with mFI-11 and 17% with mFI-5. The log of the neutrophil-to-lymphocyte ratio (logNLR) emerged as the most significant predictor of frailty (OR of 3.13, 95% CI: 1.12–9.09, p = 0.03 for mFI-11 and 3.82, 95% CI: 1.28–11.11, p = 0.02 for FI-5). The platelet-to-lymphocyte ratio (PLR) was predictive only in the model assessing mFI-5. Furthermore, both the NLR and PLR showed an inverse linear correlation with frailty severity, a finding that remained consistent regardless of age, gender, disease stage, nutrition status, or comorbidity burden. Conclusions: Frail patients with operable NSCLC exhibit distinct inflammatory response patterns compared with those observed in non-frail lung cancer patients. Using these biomarkers could help identify patients suitable for preoperative interventions that could improve their postoperative course. However, further studies are needed to explore these preliminary findings prospectively and to understand the causal relationship between the observed association with frailty status and severity.

Medical Sciences doi: 10.3390/medsci14020169

Authors: Hacer Akbas Cakmak Ahmet Bulent Yazici Derya Guzel Erdogan Yavuz Selim Ogur Esra Yazici

Background: This study aimed to investigate the relationship between serum neuroactive steroids (NAS) and oxytocin and craving and psychosocial functioning in men diagnosed with methamphetamine use disorder (MUD). Methods: In this observational cross-sectional study, 40 men with MUD (PG) and 41 non-substance-use-disorder controls (CG) completed measures of emotion dysregulation (DERS-16), attachment (ECR-R), aggression (BPAQ), and suicidal ideation (BSS). PG additionally completed the Substance Craving Scale (SCS) and Addiction Profile Index (API). Serum allopregnanolone (ALLO), DHEAS, testosterone, 17β-estradiol (E2), and oxytocin were assayed. Results: The results indicated that the PG exhibited significantly higher scores than the CG across all psychological measures. Robust adjusted group effects were observed for DERS-16 (Model 1: F = 35.507, p < 0.001; Model 2: F = 18.225, p < 0.001) and trait anger (Model 1: F = 41.104, p < 0.001; Model 2: F = 16.732, p < 0.001). Notably, serum levels of ALLO, DHEAS, testosterone, E2, and oxytocin did not differ significantly between groups. However, hormonal measures were strongly intercorrelated within both groups (r ≈ 0.877–0.936, all p < 0.001). In the PG, craving demonstrated positive correlations with DHEAS (r = 0.384, p = 0.014), testosterone (r = 0.415, p = 0.008), E2 (r = 0.360, p = 0.023), and oxytocin (r = 0.350, p = 0.027). A multivariable model analyzing craving was statistically significant (R2 = 0.350; F(3,36) = 6.474, p = 0.001), with composite hormonal factor (B = 2.390, p = 0.016) serving as an independent predictor, while API Excluding Craving(API-EC) (p = 0.094) and DERS-16 did not emerge as a significant factor (p = 0.056). In hormone-specific models controlling for API-EC and DERS-16, DHEAS (p = 0.012), testosterone (p = 0.007), oxytocin (p = 0.023), and E2 (p = 0.023) retained significance after false discovery rate (FDR) correction; ALLO did not (p = 0.055). Conclusions: Despite the absence of significant differences in peripheral NAS and oxytocin levels between groups, men with MUD exhibited pronounced psychosocial impairments. The craving experienced during inpatient treatment was primarily elucidated by an integrated endocrine profile. These findings underscore the necessity for larger longitudinal studies incorporating repeated hormonal assessments to further explore these relationships.

Medical Sciences doi: 10.3390/medsci14020167

Authors: Victoria Mutruc Mara Sânziana Sângeap Cristina Bologa Victorița Sorodoc Ovidiu Rusalim Petriș Oana Sîrbu Bianca Codrina Morărașu Luiza Elena Corneanu Elisabeta Jaba Laurențiu Șorodoc Cătălina Lionte

Background/Objectives: There are significant gaps in knowledge regarding the heterogeneity of heart failure (HF) phenotypes, particularly among patients with preserved left ventricular ejection fraction (HFpEF). Our aim was to identify phenotypes within the hospitalized North-Eastern Romanian HFpEF cohort and their impact on short-term outcomes. Methods and Results: We derived a cluster model from 924 patients with HFpEF hospitalized over an 18-month interval in the Internal Medicine II Department of the “Sf. Spiridon” Emergency Clinical County Hospital in Iași, Romania. The median age of the patients was 74 years [range 30–101], 59.8% were women, and the most frequent comorbidities were arterial hypertension (93.2%), valvular heart disease (68.7%), atherosclerotic cardiovascular disease (ASCVD, 64.6%) and atrial fibrillation (43%). Statistical analysis identified five distinct phenotypes: cluster 1 (21.6% of patients) consisted of normal-weight patients with valvular disease predominance; cluster 2 (18.2%) described a severe cardiometabolic phenotype; cluster 3 (19.6%) defined a young, hypertensive, and atherosclerotic phenotype; cluster 4 (21.26%) described a hypertensive–atrial fibrillation phenotype; and cluster 5 (18.9%) included elderly, hypertensive non-diabetic patients with severe vascular burden (ASCVD 100%). Conclusions: This study defines five distinct phenotypes within the HFpEF population in our region which differ in terms of clinical characteristics and heart failure pharmacological therapy. These results confirm the significant heterogeneity of HFpEF. The identified phenotypes were not associated with significant differences in composite short-term outcomes, including in-hospital mortality and 30-day rehospitalization for heart failure.

Medical Sciences doi: 10.3390/medsci14020168

Authors: Camila Vantini Capasso Palamim Fernando Augusto Lima Marson

Background/Objectives: Positive end-expiratory pressure (PEEP) is a standardized component of the invasive mechanical ventilation (IMV) settings to improve oxygenation; however, its physiological effects in patients with no documented prior lung disease remain poorly defined. This study evaluated the impact of moderate PEEP variations on macrohemodynamic parameters, gas exchange, and driving pressure (ΔP). Methods: This single-arm, non-randomized, crossover study included adult intensive care unit (ICU) patients with no documented prior lung disease during the early phase of IMV. Sequential PEEP levels of 6, 8, and 10 cmH2O were applied for 30 min each within the first 24 h of ICU admission, while all other ventilatory parameters were kept constant. Arterial blood gases [partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), and arterial oxygen saturation (SaO2)], oxygenation index [PaO2/fraction of inspired oxygen (FiO2)], systolic, diastolic, and mean arterial pressures, ΔP, and static compliance (Cstat) were measured. Friedman and Mann–Whitney U tests were used, with adjustment for multiple comparisons. Results: A total of 150 patients were enrolled (64.7% male). The observed mortality rate was 53.3%; however, mortality was not defined as a primary or secondary outcome, and was used only as a grouping variable for comparative analyses. Intraindividual comparison across PEEP levels of 6, 8, and 10 cmH2O showed small but significant reductions in systolic and mean arterial pressure at higher PEEP (p-value < 0.05), with Bonferroni-adjusted significance for PEEP 6 vs. 10. No significant differences were observed in oxygenation (SaO2, PaO2, and PaO2/FiO2), PaCO2, ΔP, or Cstat. These results suggest that moderate PEEP changes produced limited macrohemodynamic effects without relevant impact on gas exchange or respiratory mechanics. Overall, no clinically relevant or statistically significant differences were observed in gas exchange, macrohemodynamic parameters, ΔP, or Cstat across PEEP levels when mortality was used as the grouping variable. Among survivors, higher PEEP was associated with modest reductions in systolic and mean arterial pressures and higher PaCO2 values; however, these findings did not translate into consistent physiological benefits. Conclusions: In mechanically ventilated patients with no documented prior lung disease, PEEP may exert divergent effects on macrohemodynamics, gas exchange, and ΔP, supporting a cautious and individualized approach to PEEP selection in this population.

Medical Sciences doi: 10.3390/medsci14020166

Authors: Diana Nikolova Zdravko Kamenov Julieta Hristova Antoaneta Trifonova Gateva

Background: Chronic low-grade inflammation plays a central role in the pathogenesis of type 2 diabetes (T2DM) and its complications. Neopterin, a marker of macrophage activation and Th1-mediated immune response, has been associated with cardiovascular disease and metabolic disorders. However, its relationship with diabetic autonomic neuropathy remains insufficiently investigated. Methods: We conducted a cross-sectional study including 129 participants (93 with T2DM and 36 with obesity without carbohydrate disturbances). Clinical, anthropometric, and biochemical assessments were performed. Cardiovascular autonomic neuropathy was evaluated using Ewing cardiovascular reflex tests and sudomotor dysfunction scoring. Neopterin concentrations were measured in serum. Correlation, ROC, and logistic regression analyses were performed. Results: Neopterin levels were not significantly different between T2DM and obesity groups. No differences were observed in patients with versus without peripheral neuropathy, nephropathy, or retinopathy. However, neopterin levels were significantly higher in individuals with cardiovascular autonomic neuropathy (p = 0.013). Neopterin correlated with cardiovascular autonomic neuropathy score, sudomotor dysfunction, fasting glucose, fasting insulin, and HOMA-IR. It showed a moderate negative monotonic correlation with eGFR (Spearman’s rho = −0.41, p< 0.001). In multivariable logistic regression adjusted for age, HbA1c, BMI, eGFR, and diabetes duration, each 1-SD increase in neopterin was associated with 2.67-fold higher odds of cardiovascular autonomic neuropathy (95% CI 1.21–5.89; p = 0.015). Conclusions: Circulating neopterin is independently associated with cardiovascular autonomic neuropathy in T2DM but not with classical microvascular complications. These findings suggest a potential role of immune-mediated mechanisms in the pathogenesis of diabetic cardiovascular autonomic neuropathy.

Medical Sciences doi: 10.3390/medsci14020165

Authors: Polyana Evangelista Lima Anthony Rodrigues de Vasconcelos Arthur Gabriel de Amorim Pulça Maria Luiza de Menezes Barros Tibério José Lopes de Alencar Dario Celestino Sobral Filho Paula Andreatta Maduro Paulo Adriano Schwingel

Background/Objectives: Heart failure (HF) increases the risk of cognitive impairment (CI). Consequently, early detection and prevention of HF progression may reduce the impact of cognitive decline. The employment of novel echocardiographic imaging techniques, such as myocardial function assessment via speckle tracking strain, allows for the detection of subclinical myocardial dysfunction. The objective of this study is to identify whether speckle tracking strain has the capacity to demonstrate early cardiac alterations in patients with CI. Methods: Following a systematic review across five databases, three studies utilizing left ventricular global longitudinal strain (GLS) and seven studies utilizing left atrial global strain (LAS) were included. Results: In the assessment of myocardial strain, the sample totaled 20,614 individuals, with a mean and median age of 70 years and a predominance of females (55.3%). Left atrial global strain was the myocardial deformation marker that most frequently demonstrated an association with cognitive impairment in the listed studies. Speckle tracking GLS also demonstrated differences between groups. Only one study found no association between sensitive measures of left ventricular and left atrial function and the presence of CI. Conclusions: In conclusion, the results of this systematic review suggest that GLS and LAS are early markers of cognitive impairment.

Medical Sciences doi: 10.3390/medsci14020164

Authors: Caius-Glad Streian Vlad-Alexandru Meche Horea Bogdan Feier Dragos Cozma Ciprian Nicușor Dima Constantin Tudor Luca Sergiu-Ciprian Matei

Introduction: Artificial intelligence (AI) and robot-assisted platforms are increasingly influencing cardiothoracic surgery. AI enhances risk prediction, imaging interpretation, and early complication detection, while robotics improves visualization, dexterity, and minimally invasive access. This systematic review evaluates the current evidence supporting these technologies and their implications for clinical practice. Methods: A systematic literature search was conducted across PubMed, Embase, Scopus, Web of Science, and Google Scholar (January 2000–May 2025) following PRISMA 2020 guidelines. After screening and eligibility assessment, 67 studies met predefined inclusion criteria and were incorporated into the qualitative synthesis. Additional high-impact reviews and consensus documents were consulted for contextual interpretation. Results: Machine learning models demonstrated modest but consistent improvements in predictive performance compared with EuroSCORE II and STS scores, particularly in high-risk cohorts. Robot-assisted mitral and coronary procedures showed reduced postoperative pain, blood loss, ICU stay, and recovery time in experienced centers, though early learning phases were associated with longer operative, cross-clamp, and bypass times. AI-enabled intraoperative tools, such as video analysis, workflow recognition, and real-time anatomical segmentation, emerged as promising adjuncts for surgical precision. Structured robotic training programs, especially simulation-based and dual-console pathways, accelerated proficiency acquisition. Conclusions: AI and robotic systems act as augmentative technologies that enhance rather than replace the surgeon’s role. Their safe and effective adoption requires standardized training, transparent AI decision pathways, and clear ethical and medico-legal governance.

Medical Sciences doi: 10.3390/medsci14020163

Authors: Minela Bećirović Emir Bećirović Emir Begagić Kenana Ljuca Amir Bećirović Denis Mršić Nadina Ljuca Mugdim Bajrić Farid Ljuca

Background/Objectives: Cardiorenal syndrome type 2 (CRS-2) is characterized by progressive renal dysfunction caused by chronic heart failure (HF) and is associated with increased morbidity and mortality. However, the prognostic value of renal biomarkers in patients with CRS-2 hospitalized for decompensated HF remains unclear. Methods: This prospective observational cohort study included 200 consecutive patients hospitalized for decompensated HF in the Intensive Care Unit of the Clinic for Internal Medicine at the University Clinical Centre Tuzla between April and October 2025. CRS-2 was defined as chronic HF with chronic kidney disease persisting for ≥3 months before admission according to KDIGO criteria. Patients were followed for three months. The primary composite outcome was all-cause mortality or initiation of renal replacement therapy. Results: CRS-2 was identified in 130 patients (65.0%) and was associated with higher in-hospital mortality (32.3% vs. 11.4%, p = 0.002) and three-month mortality (44.6% vs. 21.4%, p = 0.002). Within the CRS-2 subgroup, patients who experienced the primary composite outcome had higher admission levels of cystatin C and urinary albumin-to-creatinine ratio (UACR) and lower estimated glomerular filtration rate (eGFR). ROC analysis demonstrated moderate discriminative ability of cystatin C (AUC 0.739) and UACR (AUC 0.733). In Cox regression analysis, cystatin C (HR 1.534, 95% CI 1.263–1.863, p < 0.001) and UACR (HR 1.003, 95% CI 1.001–1.006, p = 0.001) were significantly associated with the primary composite outcome. Conclusions: Renal dysfunction markers, particularly cystatin C and albuminuria, are associated with early adverse outcomes in CRS-2 patients hospitalized for decompensated HF. Routine assessment of these biomarkers may provide additional prognostic information and support risk assessment in this high-risk population.

Medical Sciences doi: 10.3390/medsci14020162

Authors: Roland Fejes Tamás Jámbor Andrea Szabó Szabolcs Péter Tallósy

Background: Hyperuricemia frequently coexists with type 2 diabetes mellitus (T2DM), contributing to a heterogeneous patient population. While previous analyses compared the overall longitudinal effects of allopurinol and SGLT2 inhibitors in this cohort, it remains unclear whether baseline metabolic heterogeneity modifies treatment response. This study aimed to determine whether data-driven metabolic clustering identifies phenotypic subgroups with prognostic or predictive relevance in hyperuricemic T2DM. Methods: In a retrospective cohort of 224 patients with T2DM and hyperuricemia, model-based clustering was applied to age, diabetes duration, body mass index (BMI), serum uric acid (sUA), HbA1c, eGFR, and sex. A sensitivity analysis excluded outliers, yielding 207 patients. Longitudinal trajectories of eGFR and sUA were assessed using linear mixed-effects models and individual slopes. Effect modification by cluster was tested via three-way interactions and analysis of covariance. Results: Clustering identified two groups with weak separation: an adipose–metabolic cluster (n = 116; exclusively male, BMI 33.1 ± 5.7 kg/m2, sUA 478 ± 62 µmol/L) and a lean–metabolic cluster (n = 91; exclusively female, BMI 31.3 ± 6.0 kg/m2, sUA 426 ± 67 µmol/L). Treatment-agnostic analyses showed no differences in eGFR and sUA slopes or in all-cause mortality across clusters. In both clusters, SGLT2 inhibitors yielded significantly more favourable eGFR slopes than allopurinol, while sUA reductions were comparable across treatments. No significant three-way interactions were detected. Conclusions: In this cohort, although baseline metabolic characteristics differ among patients, using the selected baseline variables, no clinically actionable treatment-relevant phenotypes were identified.

Medical Sciences doi: 10.3390/medsci14020161

Authors: Alexandru-Florinel Oancea Mathilde Leonard Paula Cristina Morariu Maria Godun Alexandru Jigoranu Ionela-Larisa Miftode Radu Stefan Miftode Aurelia Mihaela Nica Alexandra Rotaru Paul Simion Ana Maria Buburuz Diana-Elena Floria Raluca Mitea Cristina Gena Dascalu Elena Cojocaru Antoniu Octavian Petriș Irina-Iuliana Costache-Enache Mariana Floria

Atrial fibrillation (AF) frequently coexists with chronic coronary syndrome (CCS), reflecting shared cardiovascular risk factors and structural remodeling pathways. Identifying CCS patients at increased likelihood of AF remains clinically relevant, particularly when arrhythmia is silent or paroxysmal. Background: We hypothesized that established clinical and angiographic risk scores used in CCS may capture cumulative cardiovascular burden and could therefore assist in AF risk stratification. The biomarker-based ABC-stroke score was incorporated as a biological reference framework reflecting myocardial stress and injury. Methods: This prospective, single-center proof-of-concept study included 131 consecutive patients undergoing invasive coronary angiography for suspected myocardial ischemia. Patients were classified according to rhythm status, irrespective of AF subtype. Coronary artery disease severity was quantified using the Gensini and SYNTAX (PCI and CABG) scores. Global cardiovascular risk was assessed using Framingham, ASCVD, SCORE2, and SCORE2-OP. Correlation analyses, ROC curves, and multivariable logistic regression were performed to evaluate associations between risk scores, coronary complexity, and AF. Results: Clinical and angiographic risk scores differed significantly according to rhythm status and AF phenotype. Patients with AF exhibited higher global cardiovascular risk and greater coronary anatomical complexity compared with those in sinus rhythm. SYNTAX PCI and SYNTAX CABG demonstrated moderate discriminative performance for AF detection (AUC 0.745 and 0.760, respectively), with SYNTAX CABG remaining independently associated with AF in multivariable analysis. Significant correlations were observed between traditional cardiovascular risk scores and SYNTAX-derived measures of coronary complexity, whereas correlations with the Gensini score were weaker. The ABC-stroke reference model showed a strong discriminative signal, consistent with its biological proximity to AF-related myocardial stress. Conclusions: Established clinical and angiographic risk scores used in CCS are associated with the presence and phenotype of AF. These findings suggest that routinely available coronary risk assessment tools may serve as practical instruments for identifying CCS patients at increased likelihood of AF, potentially facilitating targeted rhythm screening and earlier risk stratification.

Medical Sciences doi: 10.3390/medsci14020160

Authors: Raluca-Elena Alexa Raluca Ecaterina Haliga Bianca Codrina Morărașu Alexandr Ceasovschih Oana Sîrbu Andreea Asaftei Victorița Șorodoc Laurențiu Șorodoc

Background: Obesity is commonly seen as a condition of overnutrition; however, it is paradoxically associated with micronutrient deficiencies. These deficiencies are clinically relevant and may contribute to the progression of obesity-related comorbidities through interconnected pathways, including chronic low-grade inflammation, oxidative stress, gut dysbiosis, and impaired nutrient absorption. Objectives: This narrative review aims to summarize current evidence regarding the prevalence, underlying mechanisms, and clinical consequences of micronutrient deficiencies in individuals with obesity, with particular emphasis on their metabolic implications and potential therapeutic strategies. Results: Among individuals with obesity, iron, zinc, magnesium, calcium, vitamin D, vitamin B12, and folate are the most frequently reported deficiencies. These deficiencies arise from multiple mechanisms, including poor diet quality, increased metabolic demands, and compromised gastrointestinal absorption. In addition, obesity-related alterations in pharmacokinetics may further interfere with micronutrient distribution and bioavailability. Together, these mechanisms may lead to various clinical outcomes, such as anemia, immune, metabolic, and cardiovascular dysfunctions, along with cognitive impairment. Although several studies suggest that correcting these deficiencies may improve clinical outcomes, findings remain inconsistent, highlighting the complex and multifactorial pathophysiology underlying micronutrient imbalance in obesity. Conclusions: Micronutrient deficiencies represent frequently overlooked contributors to metabolic dysregulation in obesity. Their identification and correction should be considered a central part of the obesity management strategy. A personalized supplementation approach, based on clinical, biological, and pathophysiological characteristics, may provide a complementary support for weight-management treatments.

Medical Sciences doi: 10.3390/medsci14010159

Authors: Alessandra Scampoli Tomaso Caporossi

This review critically synthesizes current evidence regarding the natural history, advanced diagnostic imaging, and therapeutic interventions for acquired retinoschisis and retinoschisis-associated retinal detachment. A systematic search of PubMed and Embase databases was conducted for literature published up to 2026, focusing on comparative outcomes of scleral buckling versus pars plana vitrectomy and novel imaging modalities. The advent of ultra-widefield optical coherence tomography has shifted the diagnostic paradigm, enabling the precise identification of outer layer breaks as the primary biomarkers for progression. While observation is mandated for asymptomatic, non-progressive cases, the choice between buckling and vitrectomy for active detachments is often driven by surgeon preference rather than anatomical necessity. We propose an updated decision-making algorithm that integrates lens status, break localization, and vitreous findings to guide the surgical approach. Moving beyond a “one-size-fits-all” strategy, this review advocates for a personalized management plan that balances anatomical success with long-term quality of life.

Medical Sciences doi: 10.3390/medsci14010158

Authors: Madeline Günther Dimitrij Zilakov Ardawan J. Rastan Sebastian Vogt

Background/Objectives: This retrospective exploratory study aimed to characterize sex-specific patterns of coronary artery disease (CAD) and valvular heart disease (VHD) in a cardiac surgical cohort. In clinical routine, men appear to be more commonly affected by obstructive CAD, whereas women more frequently present valvular heart disease requiring surgical intervention. It remains unclear whether these sex-specific patterns are related to ABO blood groups and selected clinical parameters. Methods: Here, we retrospectively analyzed 983 patients admitted between 2020 and 2024 to a single cardiac centre with CAD and/or VHD requiring valve replacement. Patients were stratified by sex and disease entity (CAD only, CAD + VHD, isolated VHD). ABO and Rhesus factor distributions, cardiovascular risk factors, body mass index (BMI), and renal function (estimated glomerular filtration rate, eGFR) were assessed. Group comparisons were performed using Chi-square and Welch’s t-tests. Associations were evaluated using multivariable logistic and linear regression models adjusted for age, BMI, diabetes mellitus, hypertension, smoking, and eGFR. Results: Men were predominantly represented in the CAD-only group, whereas women more frequently underwent valve replacement, either isolated or combined with CAD (p < 0.001). When comparing the overall study cohort, blood group O was less prevalent in women than in men (p = 0.031), whereas blood group A was more frequent among female patients, although this difference did not reach statistical significance. Moreover, patients with valve disease demonstrated lower eGFR compared with those without valve involvement (men: −6.3 mL/min/1.73 m2, p = 0.0036; women: −10.4 mL/min/1.73 m2, p = 0.0019). This effect remained independently associated with reduced eGFR, with women slightly more affected. Conclusions: Gender- specific diseases should be included as secondary diagnoses when considering cardiac surgery. Nephrological complications in the postoperative period can be an important factor in assessing the benefits of surgery. Blood group O was more common in male Patients, suggesting that cardiovascular diseases also exhibit blood group dependence.

Medical Sciences doi: 10.3390/medsci14010157

Authors: Stefana Avadanei-Luca Dan-Cristian Moraru Andra-Irina Bulgaru-Iliescu Raluca Tatar Iulia Nacea Alexandru Hristo Amarandei Mihai-Codrin Constantinescu Mihaela Pertea

Background: NexoBrid® (NXB; MediWound Ltd., Yavne, Israel) (anacaulase-bcdb) is a bromelain-based enzymatic debriding agent approved for eschar removal in burn care. Despite widespread clinical use, histological evidence of tissue-level changes after enzymatic debridement remains limited. This systematic review aimed to evaluate preclinical and clinical studies describing histological findings following bromelain-based enzymatic debridement of thermal burns. Methods: Following PRISMA 2020 guidelines, we performed parallel systematic searches of preclinical (animal) and clinical (human) studies across PubMed, Embase, CENTRAL, Web of Science, and Scopus. Included studies reported thermal burns treated with bromelain-based enzymatic debridement and tissue biopsies with histological analysis. Quality was assessed using the SYRCLE Risk of Bias Tool (preclinical) and JBI Critical Appraisal Checklists (clinical). Results: Six preclinical studies (five porcine, one rat) met inclusion criteria. Findings included: selective eschar removal with dermal preservation; protection of the zone of stasis (67% partial- vs. 100% full-thickness necrosis; p = 0.05); viable dermal thickness of 1.1 ± 0.7 mm; and accelerated re-epithelialization (7.4 ± 0.8 vs. 9.1 ± 2.1 days; p < 0.05). Only two clinical studies (n = 9 patients) met the inclusion criteria: one case series (n = 8) and one case report. Clinical findings showed upper dermal homogenisation with preserved deep dermis, vascular congestion correlating with pinpoint bleeding, and pseudoeschar formation via transepidermal elimination. Conclusions: Preclinical evidence supports selective enzymatic debridement with dermal preservation. However, clinical histological data are limited to nine patients after over 13 years of use. This highlights a critical translational gap and underscores the need for prospective clinical histological studies.

Medical Sciences doi: 10.3390/medsci14010156

Authors: Kannan Sridharan Gowri Sivaramakrishnan

Background: Warfarin pharmacogenomics is critical due to its narrow therapeutic index and significant interpatient variability. While machine learning (ML) can predict anticoagulation control status (ACS), its “black-box” nature limits clinical translatability. Explainable Artificial Intelligence (XAI) addresses this by providing interpretable insights. This study applied ML and XAI to a warfarin pharmacogenomic dataset to predict poor ACS and explain model decisions. Methods: A post hoc analysis was conducted on a cross-sectional dataset of 232 patients receiving warfarin for ≥6 months. Data included age, gender, interacting drugs, SAMe-TT2R2 score, and genotypes for CYP2C9, VKORC1, and CYP4F2. Poor ACS was defined as time in therapeutic range (TTR) < 70%. The dataset was split into training (70%) and testing (30%) cohorts. Three models, Random Forest, XGBoost, and Logistic Regression, were developed and evaluated using AUC-ROC, sensitivity, and specificity. XAI techniques, including permutation importance and SHapley Additive exPlanations (SHAP), were employed for global and local interpretability. Results: Of 232 patients, 141 (60.8%) had poor ACS. XGBoost and Random Forest demonstrated comparable predictive accuracy (AUC-ROC: 0.67), outperforming Logistic Regression. Sensitivity was 0.83 and 0.79 for XGBoost and Random Forest, respectively. However, specificity was modest for both ensemble methods (Random Forest: 0.48; XGBoost: 0.41) and extremely low for Logistic Regression (0.04), indicating poor discrimination, particularly for identifying patients with adequate anticoagulation control. Globally, important predictors included the age, SAMe-TT2R2 score, CYP2C9 (*2/*2), female gender, and VKORC1 (C/T). XAI revealed predictions were primarily driven by VKORC1, CYP4F2, SAMe-TT2R2 scores, and drug interactions. Concordance between XAI predictions and actual ACS was 78% for adequate and 88.6% for poor ACS. SHAP analysis showed VKORC1 provided a stable risk signal (mean absolute SHAP: 1.44 ± 0.49 in concordant cases), while CYP2C9 was a high-variance, high-impact driver of discordance (mean SHAP: 3.44 ± 3.79 in discordant cases). Conclusions: ML models, particularly ensemble methods, show modest ability to predict poor warfarin control with limited ability to correctly identify patients with adequate control from our dataset. XAI transforms these models into interpretable tools, with SHAP analysis attributing predictions to specific genetic and clinical features. While predictive accuracy remains modest, this approach enhances transparency and provides a foundation for generating hypotheses that may ultimately support clinical decision-making in pharmacogenomic-guided warfarin therapy.

Medical Sciences doi: 10.3390/medsci14010155

Authors: Michał Wasiak Mateusz Sypniewski Paula Dobosz Maria Stępień Anna Michalska-Foryszewska Patryk Rzońca Zbigniew J. Król

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and has a substantial genetic component. Genome-wide association studies (GWASs) have identified more than 100 susceptibility loci; however, replication across populations remains variable, suggesting potential population-specific differences in the genetic determinants of AF. To date, no whole-genome sequencing (WGS)-based study has evaluated AF susceptibility in a Polish population. Methods: We performed WGS (mean coverage 35×) in 233 unrelated individuals recruited within the Thousand Polish Genomes Project, including 56 patients with non-valvular AF and 177 controls without AF. After quality control and linkage disequilibrium pruning within a cardiovascular gene panel, 19,395 variants were analyzed. Association testing was performed using logistic regression adjusted for age and sex, applying both false discovery rate and Bonferroni correction thresholds. Results: No variants reached statistical significance for association with AF after correction for multiple evaluation. Previously reported susceptibility loci were not replicated in this cohort. Age was strongly associated with AF risk, whereas sex showed no significant effect. Given the relatively modest sample size, the study was primarily powered to detect variants with moderate or large effect sizes; smaller genetic effects reported in large GWASs may remain undetected. Conclusions: This pilot WGS-based study provides an initial exploration of AF-associated genetic variation in a Polish population. The absence of significant associations likely reflects the importance of further investigation in larger and well-characterized Central–Eastern European cohorts before genetic risk stratification approaches can be broadly applied across populations.

Medical Sciences doi: 10.3390/medsci14010154

Authors: Jessy Korina Peña-Esparragoza Alina Chávez-Guillén Paloma Ramos-López Oscar Rueda-Elías Susana López-Ongil Matilde Alique Rafael Ramírez-Chamond Julia Carracedo Diego Rodríguez-Puyol Patricia Martínez-Miguel

Background/Objectives: Higher iron doses are used in the anemia treatment of hemodialysis patients, which allows for lower doses of erythropoiesis-stimulating agents; however, there are concerns regarding the risk of iron toxicity. This study aimed to evaluate the potential toxicity of iron deposition in prevalent hemodialysis patients on iron therapy and its relationship with parameters used to assess iron status, plasma protein oxidation, and cellular iron toxicity. Methods: Magnetic resonance imaging was performed in 56 patients to assess hepatic iron deposition, which was related to clinical and analytical parameters. In patients included in the first and fourth quartiles, according to hepatic iron deposition, plasma protein oxidative stress was quantified, as were iron and cytokine levels in peripheral blood mononuclear cells (PBMCs). Results: Patients with higher hepatic iron deposition had a longer time on hemodialysis (42.0 ± 43.0 vs. 4.9 ± 3.4 months, p < 0.001) and higher ferritin levels (1200 ± 516 vs. 429 ± 278 ng/mL, p < 0.001) than those with lower hepatic iron deposition, without differences in transferrin saturation or hepatic enzyme serum concentration. No differences were found in plasma protein oxidation, iron content, or cytokine mRNA content in PBMCs, except for a decrease in IL-6 levels in patients with higher hepatic iron deposition. Conclusions: Patients with longer hemodialysis times had higher iron stores, suggesting that iron treatment over time increases hepatic iron deposition. No parameters supporting increased toxicity in patients with higher hepatic iron deposition were observed.

Medical Sciences doi: 10.3390/medsci14010153

Authors: Kannan Sridharan Gowri Sivaramakrishnan

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2i) are widely used in older adults for diabetes, heart failure, and kidney disease. This is the first network meta-analysis focusing on the effects of SGLT2i in older adults. Methods: Databases were searched for randomized clinical trials comparing SGLT2i against non-SGLT2i controls or other SGLT2i in relevant populations. Key safety outcomes included acute renal failure (ARF), genital infections, volume depletion, mortality, and serious adverse events (SAEs). Pooled odds ratios (OR) with 95% confidence intervals (CI) were generated using random-effects models for direct and mixed treatment comparisons. Results: From 97 included trials in the meta-analysis, SGLT2i versus non-SGLT2i were associated with reduced risks of ARF (OR 0.86, 95% CI 0.79–0.94), mortality (OR 0.84, 0.75–0.93), and SAEs (OR 0.84, 0.78–0.89), but increased risks of genital infections (OR 3.32, 2.68–4.12) and volume depletion (OR 1.18, 1.09–1.27). The risk of genital infections was observed more frequently with higher doses (high-dose OR 4.73 vs. low-dose OR 2.90) and escalated sharply with age (≥75 years OR 9.29, 3.13–27.6). The mortality benefit was strongest in adults ≥75 years (OR 0.58, 0.38–0.88). Intra-class analysis revealed distinct safety profiles; for instance, empagliflozin reduced the ARF risk, while sotagliflozin increased the volume depletion risk. Bootstrap and trial sequential analyses confirmed the results’ robustness. Grading of Recommendations Assessment, Development, and Evaluation assessment indicated moderate certainty of evidence. Conclusions: In older adults, SGLT2i maintain a favorable benefit–risk profile, with significant reductions in mortality and SAEs, though risks of genital infections and volume depletion require vigilance. The risk of genital infections exhibits a strong dose–response relationship and increases markedly in the oldest adults, while the mortality benefit appears to be most pronounced in those aged 75 years and older. This study provides actionable insights for personalized therapy in geriatric care.

Medical Sciences doi: 10.3390/medsci14010152

Authors: Carlo Dani Camilla Fazi Francesca Cialdai Chiara Risaliti Lorenzo Notari Monica Monici

Background: The multifactorial pathogenesis of bronchopulmonary dysplasia (BPD) includes prematurity, inflammation, and oxidative stress. Photobiomodulation therapy (PBMT) using near-infrared (NIR) laser sources was found to have anti-inflammatory effects in several respiratory disorders. Our aim was to evaluate whether PBMT could reduce inflammation in an in vitro model of BPD. Materials and Methods: Precision-cut lung slices (PCLSs) from premature rabbits were exposed to lipopolysaccharide (LPS) and treated with three PBMT protocols (A, B, and C) differing for the treatment parameter such as fluence (energy delivered per unit area, laser A: 7.09, laser B: 7.41, laser C: 7.01 J/cm2) and exposure time (25, 20, 12 s, respectively). The expression level of TNFα and IL-6 was measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) after 2 or 6 h from PBMT. Results: PBMT protocols A and B reduced IL-6 and TNFα mRNA at both timepoints, although the effect was less pronounced after 6 h than after 2 h. Furthermore, protocol A, which involved intermediate fluence and longer laser exposure, was more effective than protocol B. Conclusions: PBMT with NIR laser sources has an effective anti-inflammatory effect in an in vitro model of BPD, such as PCLSs from premature rabbits pretreated with LPS. These encouraging results support the planning of further studies in animal models of BPD and help identify the most effective PBMT protocol to use.

Medical Sciences doi: 10.3390/medsci14010151

Authors: Pietro Pozzessere Mattia Di Lauro Francesco Incantalupo Alessandro Cinquantasei Stefano Palazzo Mario Erminio Lepera Antonella Pistone Sandra De Matteis Marco Matteo Ciccone Vincenzo Brescia Roberto Lovero Marcello Albanesi Angela Pia Cazzolla

Background and Aim: The correct identification of patients presenting with chest pain and the stratification of their risk for major adverse cardiovascular events (MACE) is essential. The aim of this study was to evaluate subjects who came to the ED for chest pain through the chest pain score, the HEART score and the TIMI risk score in order to assess their validity and prognostic accuracy and to compare their performance. Methods: Patients included in the study met the following criteria: age ≥18 years, reported atraumatic chest pain, and consent to participate in the clinical study. Subsequently, the final scores were calculated based on the information collected and a follow-up was performed to assess the occurrence of adverse cardiovascular events (MACEs) at 30 days. The MACEs considered were a composite endpoint of STEMI or NSTEMI myocardial infarction, positive coronary angiography for critical lesions, percutaneous coronary angioplasty, coronary artery bypass grafting, and death. Results: A total of 102 patients were included in the study sample, divided into 76 patients who did not develop MACEs and 26 patients who experienced MACEs. The AUC values of the ROC curves of the chest pain score, HEART score and TIMI risk score were 0.8312, 0.9757 and 0.9378 respectively. Conclusions: All three scores examined were considered excellent tools to predict the onset of MACEs in patients with chest pain at different points of clinical management, although the HEART score outperformed both the chest pain score and the TIMI risk score in terms of prognostic accuracy.

Medical Sciences doi: 10.3390/medsci14010150

Authors: Evgenia Konstantinou Efrossyni Lyraraki Michalis Mazonakis

Objectives: To evaluate the effectiveness of different optimization parameters on radiotherapy plan quality for seventeen head and neck cancer patients. Methods: Volumetric Modulated Arc Therapy with Simultaneous Integrated Boost (VMAT-SIB) plans, involving up to three tumors, were generated. For each participant, a reference plan (Plan_Ref) was created using dual-arc with 180 control points, 20° gantry-angle increment and 1 cm minimum segment width. Modified plans were developed with dose constraints and optimization settings constant by changing to single-arc, 150 and 200 control points, 0.5 cm minimum segment width, and 30° and 40° gantry-angle increments. These plans were referred to as Plan_Arc1, Plan_CP150, Plan_CP200, Plan_SW0.5, Plan_Inc30, and Plan_Inc40, respectively. D95% of planning target volumes (PTVs), homogeneity index (HI), monitor units (MUs), maximum dose (Dmax) of spinal cord, mandible, and brainstem were recorded. Statistical and Bland–Altman analysis was performed comparing the modified plans to Plan_Ref. Results: Average D95% values for PTV1, PTV2, and PTV3 ranged from 93.13 to 98.82%. Plan_SW0.5 provided superior target coverage and homogeneity with higher MUs than Plan_Ref. Plan_Arc1 significantly reduced PTV coverage and dose homogeneity, while increasing MUs compared with Plan_Ref (p < 0.05). The average Dmax as derived from all planning approaches was up to 43.86 Gy, 65.86 Gy, and 48.85 Gy for spinal cord, mandible and brainstem, respectively. For spinal cord, Plan_Ref led to significantly lower doses compared to Plan_Arc1 and Plan_Inc30, while the brainstem recorded statistically higher Dmax doses than Plan_Arc1. Significantly higher Dmax was observed for the mandible using Plan_SW0.5 (p < 0.05). However, for Dmax, the comparison plans showed good agreement with Plan_Ref based on Bland–Altman analysis. Conclusions: The VMAT plan quality is strongly affected by the minimum segment width whereas no differences were observed with the modification of the number of control points.