Search Results (9,824)

Background: Sclerostin, an osteocyte-derived glycoprotein, plays a key role in bone metabolism by inhibiting the Wnt/β-catenin signaling pathway. While it is a recognized therapeutic target in osteoporosis, its relationship with sarcopenia remains unclear. This study aimed to investigate the associations between serum sclerostin levels, sarcopenia, and osteoporosis in older women. Methods: We conducted a cross-sectional study of 79 postmenopausal women aged ≥65 years. Sarcopenia was defined based on grip strength and appendicular skeletal muscle mass (ASM), osteoporosis was diagnosed according to femoral T-scores, and serum sclerostin levels were measured using ELISA. Associations with clinical variables and bone mineral density (BMD) were evaluated using correlation and logistic regression analyses. Results: Sclerostin levels were significantly higher in women with sarcopenia (p = 0.036) and exhibited a negative correlation with grip strength (r = −0.298, p = 0.008) but not with ASM. Positive correlations were found between sclerostin and multiple femoral BMD parameters. In a logistic regression analysis, sclerostin was modestly associated with sarcopenia (p = 0.045); however, no significant association was observed with osteoporosis (p = 0.257). Conclusions: Elevated sclerostin levels are associated with reduced muscle strength and sarcopenia in older women, independent of muscle mass, indicating that sclerostin may reflect a functional decline in musculoskeletal health. Muscle strength should therefore be considered when interpreting sclerostin’s clinical implications in aging populations. Full article

Stress granules (SGs) are dynamic, membraneless organelles that form in response to stress and play pivotal roles in translational control, RNA metabolism, and cell survival. In cancer, SGs are increasingly recognized as central mediators of therapy resistance, enabling malignant cells to evade apoptosis, reprogram metabolism, and modulate immune responses. Understanding the mechanistic and clinical insights into SG kinetics in healthy versus cancer cells holds significant potential for targeting them in precision oncology. This review integrates current knowledge on how chemotherapeutic agents, oncogenic signaling pathways, and tumor microenvironmental stressors promote SG formation, as well as evidence of altered SG kinetics across tumor types. We further highlight how the upregulation of SG components within the tumor microenvironment shapes cancer cell behavior and adaptability, and how crosstalk between SGs and other biomolecular condensates could contribute to resistance. Finally, we discuss emerging therapeutic strategies targeting SGs, including kinase inhibitors and modulators of SG dynamics, and propose that SGs represent tractable vulnerabilities in precision oncology. By bridging mechanistic insights with clinical implications, this review positions SGs as a promising frontier in overcoming cancer therapy resistance. Full article

Background: Leakage is a major concern for individuals living with a stoma and may negatively impact quality of life (QoL). A digital leakage notification system (DLNS) recently launched in the UK provides timely notifications to users via their smartphone when faeces is detected underneath the baseplate. This provides predictability and enables users to take proactive measures to help avoid leakages outside the baseplate. Methods: A single-arm, observational, longitudinal study of the DLNS, including its associated support service, has been initiated to follow 300 users for a year in the UK to evaluate long-term health benefits of the DLNS and its implications for healthcare resource utilisation in a real-world setting. The DLNS is prescribed by healthcare professionals (HCPs), and all users were invited to participate in the study. Study participants complete questionnaires capturing data on QoL (using the Ostomy Leak Impact tool), number of leakages outside the baseplate, utilisation of ostomy products, interactions with HCPs, and work productivity (using the Work Productivity and Activity Impairment questionnaire) at baseline and then every third month for one year. Data from the planned interim analysis of the first 100 participants who had been in the study for 6 months is presented. Results: Use of the DLNS for 6 months together with the associated support service was associated with a 51% reduction in leakage episodes outside the baseplate (p < 0.001) and great improvements in QoL (p < 0.001). Use of the DLNS reduced the number of unplanned baseplate changes due to worry about leakage by 47% (p < 0.001) and overall was associated with a reduction in the number of baseplates used by 14% (p = 0.002). Total time spent with HCPs related to stoma care was reduced by 65% after 6 months compared with baseline (p < 0.001). Work absenteeism and presenteeism improved significantly with the use of the DLNS. Conclusions: The interim results of this prospective, longitudinal study provided first insights into the long-term benefits of the DLNS in a real-world setting. ClinicalTrials.gov ID: NCT06554015. Full article

The discovery and development of new drugs is a lengthy, complex, and costly process, often requiring 10–20 years to progress from initial concept to market approval, with clinical trials representing the most resource-intensive stage. In recent years, Artificial Intelligence (AI) has emerged as a transformative technology capable of reshaping the entire pharmaceutical research and development (R&D) pipeline. The purpose of this narrative review is to examine the role of AI in drug discovery and development, highlighting its contributions, challenges, and future implications for pharmaceutical sciences and global public health. A comprehensive review of the scientific literature was conducted, focusing on published studies, reviews, and reports addressing the application of AI across the stages of drug discovery, preclinical development, clinical trials, and post-marketing surveillance. Key themes were identified, including AI-driven target identification, molecular screening, de novo drug design, predictive toxicity modelling, and clinical monitoring. The reviewed evidence indicates that AI has significantly accelerated drug discovery and development by reducing timeframes, costs, and failure rates. AI-based approaches have enhanced the efficiency of target identification, optimized lead compound selection, improved safety predictions, and supported adaptive clinical trial designs. Collectively, these advances position AI as a catalyst for innovation, particularly in promoting accessible, efficient, and sustainable healthcare solutions. However, substantial challenges remain, including reliance on high-quality and representative biomedical data, limited algorithmic transparency, high implementation costs, regulatory uncertainty, and ethical and legal concerns related to data privacy, bias, and equitable access. In conclusion, AI represents a paradigm shift in pharmaceutical research and drug development, offering unprecedented opportunities to improve efficiency and innovation. Addressing its technical, ethical, and regulatory limitations will be essential to fully realize its potential as a sustainable and globally impactful tool for therapeutic innovation. Full article

Each year, around 23 million miscarriages occur worldwide, which have a substantial emotional impact on parents, and impose significant societal costs. While medical care accounts for most expenses, work productivity loss contributes significantly. Addressing underlying causes of miscarriage could improve parents’ mental health and potentially their economic impact. In most countries, investigations into miscarriage causes are only recommended after recurrent cases, focusing mainly on maternal factors. Fetal and placental tissue are rarely examined, as current guidelines do not advise routine genetic analyses of pregnancy tissue, because the impact of further clinical decision making and individual prognosis is unclear. However, this leaves over 90% of all miscarriage cases unexplained and highlights the need for alternative methods. We therefore conducted a narrative review on genetic analysis, autopsy, and imaging of products of conception (POC). Karyotyping, QF-PCR, SNP array, and aCGH were reviewed in different research settings, with QF-PCR being the most cost-effective, while obtaining the highest technical success rate. Karyotyping, historically being considered the gold standard for POC examination, was the least promising. Post-mortem imaging techniques including post-mortem ultrasound (PMUS), ultra-high-field magnetic resonance imaging (UHF-MRI), and microfocus computed tomography (micro-CT) show promising diagnostic capabilities in miscarriages, with micro-CT achieving the highest cost-effective performance. In conclusion, current guidelines do not recommend diagnostic testing for most cases, leaving the majority unexplained. Although genetic and imaging techniques show promising diagnostic potential, they should not yet be implemented in routine clinical care and require thorough evaluation within research settings—assessing not only diagnostic and psychosocial outcomes but also economic implications. Full article

Chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) increasingly co-occur in low- and middle-income countries and aging populations. Prior pulmonary TB is a robust, smoking-independent determinant of COPD and is linked to persistent systemic inflammation, endothelial dysfunction, dyslipidemia, and hypercoagulability axes that also amplify cardiovascular disease (CVD) risk. We conducted a targeted narrative non-systematic review (2005–2025) of PubMed/MEDLINE, Embase, Scopus, and Web of Science, selecting studies for clinical relevance across epidemiology, clinical phenotypes, pathobiology, biomarkers, risk scores, sleep-disordered breathing, and management. No quantitative synthesis or formal risk-of-bias assessment was performed. Accordingly, findings should be interpreted as a qualitative synthesis rather than pooled estimates. Prior TB is associated with a distinctive COPD phenotype characterized by mixed obstructive–restrictive defects, reduced diffusing capacity (DLCO), radiographic sequelae, and higher exacerbation/hospitalization burden. Mechanistic insights: Convergent mechanisms chronic immune activation, endothelial injury, prothrombotic remodeling, molecular mimicry, and epigenetic reprogramming provide biologic plausibility for excess CVD, venous thromboembolism, and pulmonary hypertension. Multimarker panels spanning inflammation, endothelial injury, myocardial strain/fibrosis, and coagulation offer incremental prognostic value beyond clinical variables. While QRISK4 now includes COPD, it does not explicitly model prior TB or COPD-TB outcomes, but data specific to post-TB cohorts remain limited. Clinical implications: In resource-constrained settings, pragmatic screening, prioritized PAP access, guideline-concordant pharmacotherapy, and task-shifting are feasible adaptations. A history of TB is a clinically meaningful modifier of cardiopulmonary risk in COPD. An integrated, multimodal assessment history, targeted biomarkers, spirometry/lung volumes, DLCO, 6 min walk test, and focused imaging should guide individualized care while TB-aware prediction models and implementation studies are developed and validated in high-burden settings. Full article

Background/Objectives: Non-muscle invasive bladder cancer (NMIBC) management is increasingly complex due to conflicting guideline-based risk classifications, ongoing Bacillus Calmette–Guérin (BCG) shortages, and emerging alternative therapies. Computational Histology Artificial Intelligence (CHAI) tests are clinically available, providing insights from tumor specimens including predicting BCG responsiveness and individualized recurrence and progression risks, which may support precision medicine. This technology features biomarkers purpose-built for clinically unmet needs and has practical advantages including a fast turnaround time and no need for consumption of tissue or other specimens. We assessed the impact of such tests on physicians’ decision-making in routine, real-world NMIBC management. Methods: Physicians at six centers ordered CHAI tests (Vesta Bladder) at their discretion during routine NMIBC care. Tumor specimens were processed by a CLIA/CAP-accredited laboratory (Valar Labs, Houston, TX, USA) where H&E-stained slides were analyzed with the CHAI assay to extract histomorphic features of the tumor and microenvironment, which were algorithmically assessed to generate biomarker test results. For each case from 24 June 2024 to 18 July 2025, ordering physicians were surveyed to assess pre- and post-test management plans and post-test result usefulness. Results: Among 105 high-grade NMIBC cases with complete survey results available, primary management changed in 67% (70/105). Changes included modality shifts (n = 7; three to radical cystectomy with high prognostic risk scores; four avoiding cystectomy with low scores) and intravesical agent change (n = 63). Surveillance was intensified in 7%, predominantly among those with ≥90th percentile risk scores. The therapeutic agent changed in 80% (40/50) of predictive biomarker-present (indicative of poor response to BCG) tumors vs. 48% (23/48) of biomarker-absent tumors. Conclusions: In two thirds of cases, CHAI biomarker results influenced clinical decision-making during routine care. BCG predictive biomarker results frequently guided intravesical agent selection. These results have implications for optimizing clinical outcomes, especially in the setting of ongoing BCG shortages. Prognostic risk stratification results guided treatment escalation vs. de-escalation, including surveillance intensification and surgical vs. bladder-sparing decisions. CHAI biomarkers are currently utilized in routine clinical care and informing precision NMIBC management. Full article

Pseudomonas aeruginosa is a resilient Gram-negative pathogen frequently implicated in healthcare associated infections, particularly among immunocompromised individuals and those with chronic conditions such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), or cancer. It is well known for its high resistance to antibiotic treatment. This review briefly mentions P. aeruginosa’s resistance mechanisms, biofilm formation, and virulence factors, while primarily focusing on treatment challenges and recent advancements in therapeutic strategies aimed at overcoming resistance. Covered are novel non-antibiotic interventions such as quorum sensing inhibitors, quorum quenching agents, iron chelators, lectin and efflux pump inhibitors, as well as antimicrobial peptides and nanoparticles. Traditional medicine, phytochemicals, and probiotics are also evaluated. Additionally, this review explores the development of a viable vaccine, bacteriophage therapy, lactoferrin-hypothiocyanite combination, and topical use of electrochemical scaffolds. This review emphasizes the need for extensive safety studies and in vivo validation of these emerging non-antibiotic therapeutic strategies to determine their efficacy, pharmacological behavior, and clinical feasibility before they can be translated into practice. Many of these emerging treatments could play a vital role in future combination therapies by enhancing the efficacy of existing antibiotics and countering resistance and virulence mechanisms. Advancing these approaches from laboratory to clinical application remains a major challenge, making the development of approved therapies or vaccines a critical scientific and public health priority. Full article

Calcium ions (Ca²⁺) serve as universal second messengers regulating endocrine, neuronal, and metabolic processes. In children and adolescents, tight calcium signaling control is crucial for growth, hormone homeostasis, neuromuscular function, and neurodevelopment. Disruptions in Ca²⁺-dependent pathways—whether genetic, metabolic, or acquired—underlie a spectrum of pediatric endocrine diseases often presenting with neurological manifestations This review summarizes calcium’s roles in hormone secretion, parathyroid and vitamin D metabolism, and neuronal excitability, and discusses monogenic and metabolic disorders affecting calcium sensing and signaling, including CASR, GNA11, AP2S1, STIM1, and ORAI1 mutations. Diagnostic challenges, therapeutic strategies, and future directions for precision medicine in pediatric neuroendocrinology are highlighted, emphasizing early recognition and improved clinical outcomes. Full article

Monogenic diabetes (MD) is a rare and heterogeneous group of disorders caused by genetic variants in genes involved in glucose metabolism. Among many MD genes, the insulin gene (INS) deserves special attention, as its variants are responsible for both permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM), as well as a form of MODY (maturity-onset diabetes of the young)—INS-MODY. The aim of the study was to perform a clinical and molecular analysis of patients focused on the evaluation of INS gene variants identified during molecular testing in patients referred with suspected MD, and to assess the prediction of their impact on protein structure using in silico methods. Between 2017 and 2024, 1043 unrelated probands were tested using targeted next-generation sequencing (tNGS) panels. Three pathogenic or likely pathogenic variants in the INS gene were identified in three unrelated families, indicating that this gene accounts for 0.38% of MD cases. This allowed for the diagnosis of PNDM in two patients with diabetes diagnosed within the first four months of life and INS-MODY in a patient with diabetes since the age of 16. Moreover, in the patient with PNDM and the INS:c.T104C variant, additional disorders were identified in the form of intrauterine growth restriction (IUGR) and neurological disorders. Importantly, two of the identified genetic variants, c.C103G and c.G3C, have not previously been described in the literature. Furthermore, in silico analysis of the variants at the protein level, i.e., investigation of mutations at the 35th residue, indicated that symptom severity correlates with the extent of structural changes in insulin. The results obtained broaden the spectrum of causative variants of the INS gene, but also emphasize the clinical significance of these variants in patients with various forms of diabetes, pointing to the key role of comprehensive genetic testing in enabling accurate diagnosis and targeted treatment of patients. Full article

Suicide in children and young adults is a leading cause of premature mortality, and there is a need to develop a more profound understanding of the factors that contribute to these deaths. This study is part of the nationwide Retrospective Investigation of Health Care Utilization in Individuals who died by Suicide in Sweden 2015, conducted at Lund University, Sweden. The aim was to examine symptoms and diagnoses in children and young adults who died by suicide, as documented in their medical records at their last visits for primary care, somatic specialist care, or psychiatric care 24 months prior to suicide, and to apply contemporary psychological research in youth suicidality to the findings to formulate clinical implications. The proportions of symptoms and diagnoses in children (0–17 years), young adults (18–24 years), males, and females are described. The main symptoms noted in the cohort were depressive symptoms (28%), anxiety symptoms (26%), and pain (25%). The diagnoses predominately covered mental and behavioural disorders, and the most frequent of the mental and behavioural diagnoses were neurotic, stress-related, and somatoform disorders (32%) and mood (affective) disorders (29%). The diagnoses and symptoms were not sufficient to uncover suicidality in children and young adults. The clinical implications for alternative assessments and preventive interventions are discussed. Full article

Invertebrates are increasingly consumed and kept as pets, research models, and in zoological exhibits, creating a growing need to better understand their clinical management and welfare. However, the knowledge regarding nociception, pain perception, and euthanasia in invertebrates remains limited, and standardized protocols are largely absent. Current guidelines are incomplete, often anecdotal, and omit several major invertebrate phyla. To address this gap, we conducted a narrative review of the literature, aiming to critically evaluate existing euthanasia methods, associated welfare implications, and opportunities for refinement. The amount of peer-reviewed species-specific literature is limited and scattered. In addition, most described methods are insufficiently studied and/or do not align with our definition of euthanasia. Based on the available literature, and to provide practical guidance despite these limitations, we propose a two-step approach to invertebrate euthanasia. The first step consists of inducing anesthesia to achieve loss of responsiveness, followed by a second step; a terminal procedure involving physical or chemical destruction of the brain or major ganglia. Our review focuses on the application of this two-step approach. The effectiveness and humaneness of euthanasia techniques vary considerably across taxa and life stages. Substantial further research is required to validate and optimize humane end-of-life procedures for diverse invertebrate species. Full article

This paper aims to examine the current landscape of novel biomarkers in diabetes mellitus (DM), with particular emphasis on emerging candidates, and their roles in early diagnosis, monitoring disease progression, risk stratification, and managing complications. Given the global prevalence of DM and its complex pathophysiology, identifying reliable biomarkers is critical for optimizing prevention strategies and personalized treatment approaches. This review highlights the shift from traditional glycemic markers, which remain clinically useful but limited, to a broader array of novel biomarkers that more accurately reflect the complex pathophysiology of DM. In addition to conventional measures, inflammatory and oxidative stress mediators, along with genetic and epigenetic regulators, provide added predictive value for disease susceptibility, progression, and complications. Recent research has identified emerging biomarkers, such as adiponectin, adropin, netrin-1, α-hydroxybutyrate, fetuin-A, lipo-protein(a), and lysophosphatidylcholine, which detect early metabolic imbalances and reveal mechanistic links to insulin resistance, β-cell dysfunction, and vascular injury. Their integration into multimarker panels holds particular promise for precision medicine, supporting tailored prevention, targeted therapy, and improved outcomes for individuals with prediabetes and DM. Full article

Background/Objectives: Intense physical activity can cause gastrointestinal symptoms, negatively impacting athletic performance. A low-FODMAP diet has the potential to reduce these symptoms and is increasingly being considered by physically active individuals. The aim of this review is to present the current knowledge on the importance of FODMAPs in sports nutrition. Methods: A narrative review was conducted in PubMed, Web of Science, ScienceDirect, and Google Scholar, covering publications published up to October 2025. Original studies, reviews, and meta-analyses addressing the relationship between FODMAP intake and gastrointestinal symptoms during physical activity were included. Selected articles were assessed for specific criteria, and the results were grouped thematically to present the current state of knowledge. Results: FODMAP consumption increases the risk of intestinal symptoms. Short-term FODMAP restriction, especially before and during exercise, reduced the severity of symptoms in most of the analyzed studies. Data on the long-term effects of a low FODMAP diet on the health, nutrition, and gut microbiota of athletes remain limited. Conclusions: A strategy of short-term FODMAP restriction in athletes’ diets shows potential for reducing gastrointestinal symptoms. An optimal approach requires individualization. Further research is needed to monitor potential side effects and long-term outcomes. Full article

Arginine is a semi-essential amino acid for adults, which serves as a central hub synthesizing various metabolites. Arginine plays a critical role in carcinogensis. As a polar amino acid, the uptake and the transportation of arginine across cell membrane systems rely on transporter proteins. Arginine transporters remain critically important, particularly as potential biomarkers and therapeutic targets in cancer. Based on the subcellular localization, arginine transporters could be divided into two types: cell membrane arginine transporters and intracellular membrane arginine transporters. This review aims to investigate the latest advancements of arginine transporter proteins in cancer, focusing on their cellular localization, structural characteristics, and mechanism, with the goal of promoting the design and development of targeted anticancer therapeutics against these transporters. Full article