Search Results (3,370)

Osteoporosis (OP) is a common chronic disease that significantly increases the risk of bone fractures. Pharmacotherapy uses, among others, 17beta-estradiol (E2), which has been replaced in recent years by raloxifene hydrochloride (RLX). The need for long-term, high-dose therapy with these drugs is associated with serious adverse effects. The aim of this review is to analyze the current state of knowledge over the last 5 years (2020–2025) regarding the use of nanoparticles (NPs) in the delivery of E2 and RLX, with particular emphasis on their impact on bioavailability, pharmacokinetic profile, reduction in adverse effects, and improvement in the effectiveness of postmenopausal osteoporosis therapy. Preclinical studies show that combining E2 or RLX with various types of NPs reduces cytotoxicity, improves pharmacokinetic parameters, and enhances the therapeutic effects of drugs used in postmenopausal osteoporosis. These effects are mainly attributed to improved pharmacokinetics and controlled drug release, rather than confirmed active tissue targeting. However, these findings are based on preclinical models and require further validation in clinical studies. The analysis concludes that while NP systems significantly enhance the pharmacokinetic profile and safety of E2 and RLX in preclinical models, claims of true bone-specific targeting remain largely unsubstantiated, highlighting a key area for future research. Full article

Chronic kidney disease (CKD) and kidney failure significantly reduce patients’ quality of life and markedly increase cardiovascular risk and overall mortality. Disturbed metabolism of tryptophan (Trp) through kynurenine (KYN) pathways was implicated as an important factor in kidney damage and its complications. However, the expression of genes coding crucial enzymes of KYN pathway was not examined so far. The goal of the present study was to analyze the expression of Ido (indoleamine-2,3-dioxygenase), Kat1 (kynurenine aminotransferase 1), Kat2 (kynurenine aminotransferase 2), and Kmo (kynurenine-3-monooxygenase) genes in patients undergoing kidney failure with kidney replacement therapy (KFRT) treatment with either hemodiafiltration (HDF) or hemodialysis (HD) in relation to selected clinical and dialysis parameters. Our data imply that Ido, Kat1, and Kmo gene expression does not differ between KFRT patients with analyzed comorbidities, vascular access types, or diuresis occurrence. However, Ido and Kmo gene expression correlated with pre-dialysis concentration or reduction ratio (RR) of selected metabolites. Interestingly, patients treated with HDF manifested lower Kmo gene expression in comparison with patients treated by HD. Our study suggests that epigenetic factors do not exert noticeable impact on the KYN pathway enzymes expression in patients with KFRT. The advantageous effect of HDF vs. HD towards the KYN pathway genes expression has potential therapeutic implications, as it may reflect superiority of the former method in KFRT patients. Full article

Pancreatic β-cell replacement represents a promising therapeutic avenue for insulin-dependent diabetes, yet clinical translation has been limited by donor scarcity, immune rejection, and incomplete engraftment. Three-dimensional (3D) pancreatic organoids derived from human pluripotent stem cells (hPSCs) or primary tissue offer a scalable and physiologically relevant platform, recapitulating native islet architecture, paracrine interactions, and glucose-responsive insulin secretion. Recent advances in differentiation protocols, vascularization strategies, and immune-protective approaches—including encapsulation and hypoimmunogenic engineering—have enhanced β-cell maturation, survival, and functional performance in vitro and in vivo. Despite these developments, challenges remain in achieving fully mature β-cells, durable graft function, and scalable, reproducible production that is suitable for clinical use. This review highlights the promise of pancreatic organoid engineering, emphasizing strategies to optimize β-cell maturation, vascular integration, and immune protection, and outlines key future directions to advance organoid-based β-cell replacement toward safe, effective, and personalized diabetes therapies. Full article

The introduction of direct oral anticoagulants (DOACs), particularly factor Xa (FXa) inhibitors, has transformed the prevention and treatment of thromboembolic events. These agents have largely replaced vitamin K antagonists across most indications due to their predictable pharmacokinetics, reduced rates of intracranial bleeding, and overall ease of use. Nevertheless, a substantial residual bleeding risk remains, particularly gastrointestinal bleeding and clinically relevant non-major bleeding in elderly, frail, or polymedicated patients. Furthermore, the management of patients with severe renal dysfunction, active cancer, especially gastrointestinal or genitourinary malignancies and those requiring complex pharmacological regimens, continues to pose significant challenges. These limitations have intensified interest in targeting earlier steps of the coagulation cascade, specifically factor XI (FXI) and its activated form (FXIa). FXI occupies a unique mechanistic position: it contributes substantially to pathological thrombosis while playing only a limited role in physiological hemostasis. Genetic, observational, and mechanistic evidence consistently demonstrates that FXI deficiency confers protection against venous thromboembolism and cardiovascular events while causing minimal spontaneous bleeding. This biological paradigm has catalyzed the development of novel FXI/FXIa inhibitors, including small-molecule agents (asundexian, milvexian) and biological therapies (abelacimab). Clinical trials such as AXIOMATIC-TKR, PACIFIC-AF, and OCEANIC-AF, and ongoing programmes including ASTER and MAGNOLIA suggest that FXI inhibition may preserve antithrombotic efficacy while substantially reducing bleeding risk. This review summarizes the current landscape of oral FXa inhibitors, outlines the biological rationale for FXI/FXIa inhibition, and discusses the evolving clinical evidence supporting what may represent the next major advance in anticoagulant therapy. Full article

Neuromuscular diseases are biologically diverse, clinically heterogeneous, and often difficult to diagnose and treat, highlighting the need for computational tools that can help resolve overlapping phenotypes and support timely, mechanism-informed interventions. This narrative review synthesizes recent advances in artificial intelligence (AI) and machine learning applied to neuromuscular diseases across diagnosis, outcome modeling, biomarker development, and therapeutics. AI-based approaches may assist clinical and genetic diagnosis from phenotypic data; however, early phenotype-driven tools have seen limited clinician adoption due to modest accuracy, usability challenges, and poor workflow integration. Electrophysiological studies remain central to diagnosing neuromuscular diseases, and AI shows promise for accurate classification of electrophysiological signals. Predictive models for disease outcome and progression—particularly in amyotrophic lateral sclerosis—are under active investigation, but most remain at an early stage of development and are not yet ready for routine clinical use. Digital biomarkers derived from imaging, gait, voice, and wearable sensors are emerging, with MRI-based quantification of muscle fat replacement representing the most mature and widely accepted application to date. Efforts to apply AI to therapeutic discovery, including drug repurposing and optimization of gene-based therapies, are ongoing but have thus far yielded limited clinical translation. Persistent barriers to broader adoption include disease rarity, data scarcity, heterogeneous acquisition protocols, inconsistent terminology, limited external validation, insufficient model explainability, and lack of seamless integration into clinical workflows. Addressing these challenges is essential to moving AI tools from the laboratory into clinical practice. We conclude with a practical checklist of considerations intended to guide the development and adoption of AI tools in neuromuscular disease care. Full article

In Spain, Leishmania infantum causes both cutaneous (CL) and visceral leishmaniasis (VL). This study aimed to analyse trends in the clinical presentation, diagnosis, management, and epidemiology of leishmaniasis at Severo Ochoa University Hospital in Leganés, an endemic area in Southern Madrid affected by Europe’s largest outbreak (2009–2015). A retrospective study was conducted, including all confirmed cases from January 1992 to December 2024, using clinical records. Cases were stratified into pre-outbreak, outbreak, and post-outbreak periods. A total of 151 cases were identified, including 129 VL, 21 CL, and 1 simultaneous VL/CL. VL predominated among adults during the HIV epidemic, later shifting to elderly and non-HIV immunosuppressed patients, while paediatric cases remained stable. Diagnostic methods evolved from bone marrow microscopy, culture, and IFAT to molecular and chemiluminescence assays. VL treatment also evolved, with amphotericin B gradually replacing meglumine antimoniate as first-line VL treatment. Most patients required hospitalisation, with 8.5% mortality, mainly among immunocompromised or elderly individuals. A persistent concentration of cases near recently urbanised areas adjacent to the parks of Polvoranca and Bosquesur was observed. Despite advances in diagnosis and therapy, endemic transmission and underreporting continue, highlighting the need for ongoing surveillance and preventive measures. Hospital record review proved useful for monitoring compliance with mandatory VL notification, though its applicability to cutaneous cases remains limited. Full article

Pathological reduction in enzymatic activity of the tissue-non-specific alkaline phosphatase (TNSALP) is the molecular hallmark of hypophosphatasia (HPP), a group of rare inborn systemic diseases, mainly characterized by pathological affections of calcified tissue mineralization and the musculoskeletal system. The disease, in all clinical forms, is biochemically characterized by variable degrees of chronically reduced activity of circulating total alkaline phosphatase (ALP). Repeated detection of low values of ALP activity is mandatory to diagnose the presence of HPP, but, alone, it is not sufficient for the diagnosis of the disease. Detection of increased circulating levels of one of the main natural substrates of TNSALP, the pyridoxal 5′-phosphate (PLP), is needed to biochemically confirm the diagnosis of HPP. Urinary and/or blood levels of phosphoethanolamine (PEA) and inorganic pyrophosphate (PPi), two other natural substrates of TNSALP, can be elevated in a percentage of HPP patients. The contemporary biochemical evaluation of ALP activity and its target substrates is of great help in the diagnosis of HPP, and also for the monitoring of a patient’s response to enzymatic replacement therapy or other pharmacological treatments. Here, we describe and discuss possibilities and challenges of biochemical screenings for HPP, based also on the experience gained in our analysis laboratory. Full article

Endometrial cancer (EC) is the most common gynecological cancer in developed countries, with approximately 417,000 new cases reported worldwide in 2020. Its incidence has been rising for the past 30 years, primarily due to population aging, obesity, and type 2 diabetes; obesity accounts for almost half of cases due to excessive estrogen production. The classic division into types I and II was replaced in 2013 by the molecular TCGA classification, which distinguishes four subtypes: POLE-ultramutated (best prognosis), MSI-hypermutated, copy-number low, and copy-number high (worst prognosis). This classification (refined in ProMisE and TransPORTEC) enables precise treatment: immunotherapy (pembrolizumab, dostarlimab) works excellently in dMMR/MSI-H tumors, PI3K/AKT/mTOR inhibitors and trastuzumab deruxtecan in selected molecular subtypes, and hormone therapy in ER-positive tumors. ctDNA monitoring supports therapeutic decisions. Integrating the molecular profile with FIGO allows for truly personalized treatment, although MMRp/MSS tumors remain a challenge. The future lies in multi-omics, new biomarkers, and combination therapies. Full article

Acute respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality despite decades of progress in ventilatory support. Mechanical ventilation, while essential for oxygenation, may exacerbate lung injury through excessive mechanical power delivery, even when using lung-protective strategies. Extracorporeal carbon dioxide removal (ECCO₂R) was conceived to enable “ultra-protective” ventilation, allowing for further reductions in tidal volume and respiratory rate by selectively removing CO₂ at low extracorporeal blood flows, typically between 0.3 and 1.0 L/min. This physiological decoupling of ventilation and gas exchange aims to mitigate ventilator-induced lung injury (VILI) while maintaining adequate acid–base homeostasis. Although early physiological studies demonstrated feasibility, large, randomized trials have failed to show a survival benefit and have raised concerns about bleeding and technical complications. Recent evidence suggests that these neutral outcomes may stem from the biological and physiological heterogeneity of ARDS rather than from inefficacy of the intervention itself. Patients with high driving pressures, poor compliance, or hyperinflammatory phenotypes may derive greater benefit from ECCO₂R-mediated mechanical unloading. Ongoing technological improvements, including circuit miniaturization, enhanced biocompatibility, and integration with renal replacement therapy, have improved safety and feasibility, yet the procedure remains complex and resource-intensive. Future research should focus on phenotype-enriched trials and the integration of ECCO₂R into precision ventilation frameworks. Ultimately, ECCO₂R should be regarded not as a universal therapy for ARDS but as a targeted physiological tool for selected patients in experienced centers. Full article

The removal of protein-bound uremic toxins (PBUTs) from the blood of kidney failure patients with conventional dialysis is limited. However, as their harmful effects and association with morbidity and mortality in dialysis patients are increasingly recognized, PBUTs have become important therapeutic targets. In this review, PBUT removal with current state-of-the-art dialysis technologies and future perspectives are discussed. Strategies to enhance PBUT clearance include methods that interfere with PBUT–albumin binding, such as chemical displacers, high ionic strength, pH changes, or electromagnetic fields, thereby increasing the free fraction available for dialysis. While these methods have shown promise in vitro, and some also in vivo, long-term safety data are lacking. PBUT removal can also be increased by adsorption, either directly via hemoperfusion, or indirectly, e.g., via sorbents incorporated in a mixed-matrix membrane or dissolved in the dialysate. In the kidney, PBUTs are secreted in the proximal tubules; hence, a cell-based bioartificial kidney (BAK) that secretes PBUTs is proposed as an add-on to current dialysis. Yet both PBUT adsorption strategies and, in particular, BAKs face considerable challenges in upscaling and mass production at acceptable costs. In conclusion, many novel technologies are under development, all requiring further (pre)clinical testing and upscaling before these strategies can be applied in the clinic. Full article

Background: Thrombocytopenia (platelet count < 100 × 10⁹/L) occurs in 20–40% of critically ill patients with sepsis and is associated with adverse outcomes. Most prior studies have treated thrombocytopenia as a static risk indicator rather than a dynamic process. We investigated whether platelet recovery within 7 days provides independent prognostic information in patients with sepsis. Methods: We performed a retrospective cohort study using the MIMIC-IV database. Among 22,513 adults with sepsis admitted to intensive care units, 5401 developed thrombocytopenia within 24 h of admission and had sufficient follow-up data. The primary exposure was sustained platelet recovery to ≥100 × 10⁹/L within 7 days. The primary outcomes were 28-day and in-hospital mortality. Propensity-score matching and overlap weighting were used to adjust for demographic characteristics, comorbid conditions, illness severity, and organ-support therapies. Results: Among 5401 septic ICU patients with thrombocytopenia, 3193 (59%) achieved platelet recovery within 7 days. A total of 2056 patients (38%) recovered by day 3, and 1137 (21%) recovered between days 4 and 7. After multivariable adjustment, platelet recovery was independently associated with markedly lower mortality (adjusted risk ratio, 0.56; 95% CI, 0.53–0.67 for in-hospital death; and 0.60; 95% CI, 0.53–0.67 for 28-day death) and more than a doubling of survival time (adjusted ratio, 2.08; 95% CI, 1.65–2.63). Early and intermediate recovery conferred similar benefits. Higher baseline platelet counts, antiplatelet therapy, and heparin use were associated with recovery, whereas cirrhosis, greater illness severity, and continuous renal replacement therapy were associated with non-recovery. Conclusions: In patients with sepsis and thrombocytopenia, platelet recovery within 7 days was a strong and independent predictor of survival. Exploratory timing-stratified analyses yielded similar associations across subgroups. These findings support platelet recovery as a useful prognostic marker reflecting broader physiologic stabilization in sepsis. Full article

Background: Although surfactant replacement therapy has been a cornerstone of respiratory distress syndrome (RDS) management for decades, traditional delivery via endotracheal intubation and mechanical ventilation is associated with procedure-related complications and increased risk of bronchopulmonary dysplasia (BPD). These concerns have driven the development of less invasive surfactant administration strategies. Objective: This review aims to summarize and evaluate the current literature on less invasive surfactant delivery techniques used in preterm infants with RDS, with a focus on their feasibility, efficacy, and short- and long-term neonatal outcomes. Methods: We reviewed the available literature evaluating less invasive surfactant administration methods, including InSurE, Less Invasive Surfactant Therapy/Minimally Invasive Surfactant Therapy (LISA/MIST), surfactant administration via laryngeal mask airway (SALSA/LMA), pharyngeal administration, and nebulized surfactant. We compared major outcomes, namely the need for mechanical ventilation, incidence of BPD, procedural complications and long-term neurodevelopmental outcomes. Results: Non-invasive surfactant administration techniques have been associated with reduced exposure to mechanical ventilation and lower rates of BPD compared with conventional approaches. Studies on LISA/MIST demonstrate the most consistent evidence in reducing the need for mechanical ventilation and BPD, while other techniques such as LMA-assisted delivery and nebulization show promise but remain limited by device constraints, gestational age applicability, and heterogeneous study designs. Long-term neurodevelopmental outcome data remain sparse across all techniques. Conclusions: Non-invasive surfactant administration represents an important advancement in the management of RDS. While several techniques offer potential advantages over traditional intubation-based delivery, further high-quality studies are required to optimize patient selection, standardize techniques, develop safe and effective delivery devices, and evaluate long-term neurodevelopmental outcomes. Full article

We aimed to highlight the roles of the pancreatic enzymes, with special reference to amylase, on glucose homeostasis in healthy pigs and in pigs with exocrine pancreatic insufficiency (EPI). Healthy pigs fed a high-fat diet (HFD) were subjected to mixed meal tolerance tests (MMTTs) and pancreatic enzyme treatments, and then blood glucose and insulin concentrations were determined. Following the development of surgically induced EPI, the same experiment was then repeated on the pigs. A significantly lower net postprandial glycemic response was observed in pigs with EPI compared to healthy pigs. Net postprandial glycemic response was not affected by enzyme supplementation during the MMTTs in healthy pigs, but it was affected by adaptation to macronutrient components of the MMTT test meal, both in healthy and EPI pigs. Net postprandial glycemic response and insulin release curves reached higher levels in Creon-treated EPI pigs compared to amylase-treated EPI pigs. In summary, glucose homeostasis mechanisms in EPI pigs were downregulated compared to healthy animals. Creon supplementation during EPI significantly increased postprandial glucose level, while amylase treatment had the opposite effect, which could be explained by its metabolic actions. Full article

African American (AA) women often experience earlier onset and more severe menopause symptoms, especially vasomotor symptoms (VMSs) like hot flashes, compared to other groups. However, limited research has examined the effectiveness and acceptability of menopause treatments in this population. This scoping review synthesized evidence on pharmacological (e.g., hormone replacement therapy [HRT], SSRIs, venlafaxine, nitroglycerin) and holistic (e.g., dietary changes, physical activity [PA], supplementation) approaches for managing menopause symptoms in AA women. Using Joanna Briggs Institute and PRISMA-ScR guidelines, a scoping review was conducted, guided by the PCC framework. Four databases (CINAHL, PsycInfo, PubMed, Scopus) were searched for English-language studies (2010–2025) involving AA women aged 40–65. Eligible studies included RCTs and observational designs with ≥10% AA participants. Data were charted and synthesized descriptively. Fourteen U.S.-based studies (11–53% AA representation) were included. Pharmacological treatments—especially HRT and SSRIs—were effective for VMSs and mood symptoms. Holistic approaches showed mixed outcomes; PA and magnesium offered modest benefit, while phytoestrogens sometimes worsened memory. Race-specific results were rarely reported. Effective pharmacological options exist, but evidence tailored to AA women is lacking. Future research must ensure greater AA representation and culturally responsive approaches to menopause care. Full article