Search Results (25,491)

Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), remains a leading cause of skin and soft tissue infections (SSTIs) worldwide. Patients with renal edema, including those with nephrotic syndrome and chronic kidney disease (CKD), and critical illness, are particularly susceptible because of barrier dysfunction, immune impairment, and altered antimicrobial pharmacokinetics. This narrative review examines the mechanisms linking renal edema to increased susceptibility to cutaneous S. aureus infection and discusses their diagnostic and therapeutic implications. Three interconnected pathophysiological pathways appear central to this susceptibility: disruption of the cutaneous barrier, nephrotic and uremic immune dysfunction, and impaired lymphatic immune surveillance. These abnormalities facilitate bacterial colonization, and invasion, while S. aureus further exploits the renal host through adhesins, toxins, biofilm formation, and immune-evasion mechanisms. The review also highlights the challenges of managing severe staphylococcal infections in patients with kidney disease and critical illness, where augmented renal clearance, expanded volume of distribution, extracorporeal renal support, and fluctuating renal function may substantially influence antimicrobial exposure. Current management requires early recognition, source control, individualized antimicrobial selection, renal-adapted dosing, therapeutic drug monitoring, and antimicrobial stewardship. Although emerging anti-virulence and immunomodulatory strategies show promise, most remain at the preclinical or early translational stage. Overall, renal edema should be regarded as a biologically active modifier of host–pathogen interactions that contributes to increased susceptibility to cutaneous S. aureus infection across the spectrum of kidney disease. Full article

Acute otitis media is an inflammatory disease affecting all compartments of the middle ear, characterized by localized pain, fever, hearing impairment, and, occasionally, purulent exudate. It represents a significant clinical concern in both pediatric and adult populations, with approximately 709 million cases reported annually worldwide, 51% of which occur in children. However, currently available topical otic formulations are limited by their inability to achieve predictable therapeutic concentrations at the site of inflammation, resulting in reduced efficacy. In addition, the selection of appropriate active pharmaceutical ingredients (APIs) for drug products remains challenging; as a result, existing therapies do not comprehensively address all stages of pathogenesis. This study aimed to analyze existing locally acting formulations for middle ear drug delivery, evaluate their advantages and limitations, and assess modern approaches to the development of novel drug delivery systems and API combinations. A critical review of 69 publications (2010–2026) was conducted, supplemented by a strengths and limitations analysis of dosage forms and an evaluation of APIs based on clinical data. The findings highlight a lack of targeted drug delivery systems, limited efficacy of existing API combinations against bacterial biofilms, and their risk of ototoxicity. Emerging innovative drug delivery approaches, including microemulsions, vesicular systems, stimuli-responsive systems, and hydrogels, have demonstrated promising results in preclinical studies; however, their efficacy and safety remain to be confirmed in clinical settings before their full therapeutic potential in otitis media treatment can be realized. Full article

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as one of the most significant global health crises in recent history. Coronaviruses are a diverse group of RNA viruses classified into alpha, beta, gamma, and delta genera, with SARS-CoV-2 belonging to the beta-coronavirus family. The virus exhibits high transmissibility and causes a wide spectrum of clinical manifestations ranging from mild respiratory symptoms to severe complications such as acute respiratory distress syndrome, multi-organ failure, and death, particularly among elderly and immunocompromised individuals. Structurally, SARS-CoV-2 possesses a large single-stranded RNA genome encoding major structural proteins, including spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins, which play critical roles in host-cell recognition and viral infection. Understanding the molecular mechanisms of virus–host interactions, especially protein–protein interactions (PPIs), is essential for uncovering viral pathogenesis and identifying potential therapeutic targets. Traditional experimental techniques for PPI detection, such as yeast two-hybrid and affinity purification methods, are often expensive, labor-intensive, and prone to inaccuracies. Consequently, computational approaches based on machine learning (ML) and deep learning (DL) have gained significant attention for efficient and scalable PPI prediction. These methods use diverse biological information, including protein sequences, structural features, genomic data, Gene Ontology annotations, and interaction networks, to model complex biological relationships. This survey reviews computational approaches to PPI prediction, highlighting ML- and DL-based techniques, methodological advances, performance evaluation practices, and limitations that affect benchmark comparability. It also discusses biological databases and data sources commonly used in PPI studies and explicitly considers how models trained in coronavirus-centered settings may generalize to other viral families with different mechanisms of host interaction. Full article

The global cattle industry is experiencing significant growth, requiring advanced methods for monitoring animal health and welfare to ensure productivity and sustainability. Traditional manual monitoring techniques are labor-intensive and often impractical for large-scale operations. This review provides a comprehensive analysis of existing and emerging computer vision tools applied to the monitoring of cattle health and welfare. By systematically examining studies across major databases, this paper addresses six key research questions focusing on (1) the issues addressed by computer vision technologies, (2) data acquisition systems, (3) implemented techniques and algorithms, (4) performance outcomes, (5) challenges faced, and (6) potential applications for underexplored health and welfare aspects in cattle farming. The findings show that computer vision technologies have significantly progressed in areas such as body condition score detection, lameness detection, weight estimation, estrus detection, monitoring of feeding and drinking behavior, breathing detection, and recognition of general behaviors. Despite the progress, challenges such as variability in environmental conditions, the need for large annotated datasets, and the high cost of advanced imaging equipment persist. The review emphasizes future research opportunities to address these challenges by focusing on disease-specific monitoring. This review aims to provide veterinarians, farmers, and animal health professionals with greater insight into computer vision technologies and to promote their adoption by discussing their practical applications. Full article

Background: Natriuretic peptides, including B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), are established biomarkers of myocardial stress and circulatory overload. Although originally validated for diagnosis and exclusion of heart failure, their diagnostic and prognostic applications have expanded significantly in the context of critical illness. However, interpretation in critically ill patients is complicated by confounding factors such as systemic inflammation and renal dysfunction. Objective: This review synthesizes current evidence on the diagnostic, monitoring, and prognostic applications of natriuretic peptides in critically ill adults. It further outlines practical considerations, confounding variables, and emerging complementary biomarkers pertinent to clinical decision-making. Methods: A structured search of PubMed, Embase, and the Cochrane Library (January 2000 to October 2025) identified studies evaluating BNP, NT-proBNP, and atrial natriuretic peptide (ANP) in intensive care unit (ICU) patients. Eligible studies and review articles assessed diagnostic utility, volume status, hemodynamic monitoring, and prognostic performance. Narrative synthesis was employed using information obtained from eligible studies. Results: Twenty-four studies met the inclusion criteria. BNP and NT-proBNP facilitate differentiation between cardiogenic and noncardiogenic respiratory failure, identification of mixed shock states, and assessment of volume status when used in association with other modalities such as echocardiography and ultrasonography. Elevated natriuretic peptide concentrations consistently predict mortality, acute kidney injury, prolonged mechanical ventilation, and adverse outcomes in several disease states, including sepsis, acute respiratory distress syndrome [ARDS], postoperative cardiac dysfunction, and COVID-19-related critical illness. However, interpretation remains limited by confounders, including renal impairment, age, systemic inflammation, brain injury, mechanical ventilation, and right-ventricular strain/dysfunction. Conclusions: Natriuretic peptides serve as valuable adjuncts for diagnostic assessment, hemodynamic monitoring, and risk stratification in the ICU. When interpreted with attention to biological kinetics and clinical context, these biomarkers enhance multimodal monitoring and support individualized management. Future research should refine ICU-specific cutoffs and assess natriuretic peptide–guided therapeutic strategies in prospective multicenter trials. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease (CLD) globally and is closely linked to metabolic risk factors and systemic inflammation. Emerging evidence suggests that vitamin D deficiency may influence MASLD severity and outcomes, though limited real-world data often assess long-term clinical outcomes in MASLD patients stratified by vitamin D status. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network (2006–2025). Adult patients with MASLD were stratified into two cohorts based on serum 25-hydroxyvitamin D levels: normal (≥30 ng/mL) and deficient (<20 ng/mL). Patients with other CLD, malignancy, decompensated cirrhosis, and relevant confounding conditions were excluded. Primary outcomes included all-cause mortality, hospital readmissions, and ICU admissions at 1-year and 5-year follow-up. Results: After propensity score matching, 6959 patients were included in each cohort. Compared with patients with normal vitamin D levels, those with vitamin D deficiency had significantly higher rates of hospital readmissions, ICU admissions, and all-cause mortality at both 1-year and 5-year follow-up. A 1 year, readmissions occurred in 10% vs. 6%, ICU admissions 2.6% vs. 1.2%, and mortality 1.5% vs. 0.5% of patients (p = 0.01). Similar findings were observed at 5 years, with higher rates of readmissions 15% vs. 10%, ICU admissions 4.4% vs. 2.4% and mortality 3.2% vs. 1.3% in the vitamin D-deficient cohort (p = 0.01). Conclusions: Vitamin D deficiency was associated with significantly increased mortality, hospital readmissions, and ICU admissions among patients with MASLD. Our findings suggest that vitamin D status may represent a valuable prognostic indicator in this population. Although the observational nature of this study precluded establishing causality, our results support the consideration of routine assessment of vitamin D levels in patients with MASLD. Further prospective and mechanistic studies are needed to determine whether vitamin D supplementation can improve outcomes in this population. Full article

Cannabis sativa L. is an economically significant multi-use crop valued for fiber, seed, and phytochemical production. Compared with other crops, advancement in Cannabis sativa has been slow due to regulatory constraints and genetic resource limitations. Recent advances in technology have transformed the research landscape, supporting a deeper understanding of the genetic architecture underlying key agronomic traits. This review summarizes current progress in Cannabis sativa genetics and genomics, mainly focusing on structural genome organization, including chromosome-level assemblies and emerging pangenomic resources that capture species-wide diversity. We explore the molecular basis of key agronomic traits, including sex determination, cannabinoid biosynthesis, fiber quality, seed composition, disease resistance, and abiotic stress tolerance, highlighting their complex regulatory networks. Functional genomics tools including virus-induced gene silencing, transient expression systems, and CRISPR/Cas9 genome editing are reviewed as approaches enabling direct gene functional validation. We further review integration of these resources with molecular breeding strategies, including marker-assisted and genomic selection, to accelerate elite genotype development. Finally, we address persistent challenges such as genomic complexity, reference bias, and phenotyping limitations while outlining future research directions. Together, these advances position C. sativa as a compelling system for both fundamental plant biology and applied crop improvement. Full article

Extreme temperatures are an emerging public health concern due to their significant impact on humans, yet the evidence remains limited in tropical countries. This study examined the non-linear relationship between ambient temperature and non-accidental and cause-specific mortality in two northern parts of Peninsular Malaysia, from 2011 to 2019. Daily mortality and meteorological data were analyzed using a quasi-Poisson Generalized Linear Model with a Distributed Lag-Non-Linear model to estimate the relationship between temperature and mortality. A U-shaped and J-shaped relationship was observed for the cumulative effects of 21-day lag periods for Kedah and Penang, respectively. The minimum mortality temperature (MMT) at 27.4 °C in Kedah and 28.2 °C in Penang was observed. Extremely high temperatures were associated with an increased non-accidental mortality, with a 16% increase at cumulative lag days 0–3 in Kedah and a 21% increase at cumulative lag days 0–7 in Penang. Vulnerable groups included individuals with respiratory diseases, the elderly, both genders and those residing in both urban and rural areas. These findings highlight the acute impact of heat on mortality in Malaysia and underscore the need for targeted public health interventions. Strengthening heat-health warning systems, improving healthcare preparedness, and prioritizing vulnerable populations are essential to mitigate the health impacts of rising temperatures in tropical regions. Full article

Background/Objectives: Elevated lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor associated with atherosclerotic cardiovascular disease and calcific aortic valve disease. Historically, therapeutic options for reducing Lp(a) have been limited. This study aimed to characterize the clinical development landscape of emerging Lp(a)-targeted therapies, evaluate endpoint assessment strategies, and summarize available efficacy evidence from investigational agents. Methods: A qualitative clinical trial landscape review was conducted using ClinicalTrials.gov. Interventional Phase I–III studies evaluating therapies specifically targeting Lp(a) were identified through a structured registry search performed on 5 November 2025. Eligible studies were screened according to predefined inclusion and exclusion criteria. Extracted data included trial characteristics, therapeutic class, endpoint methodologies, and published efficacy outcomes. Data were synthesized narratively. Results: Twenty clinical trials met the eligibility criteria. Three therapeutic classes were identified: antisense oligonucleotides (ASOs), small interfering RNA (siRNA)-based therapies, and small-molecule inhibitors. Pelacarsen represented the sole ASO program, whereas siRNA-based therapies constituted the largest therapeutic category. Five studies were designed as cardiovascular outcomes trials. Percent change from baseline in circulating Lp(a) concentration was the most frequently used efficacy endpoint. Published data demonstrated substantial reductions in Lp(a) concentrations across all major therapeutic platforms. Available non-head-to-head published evidence showed substantial Lp(a) reductions across several investigational agents, including siRNA-based therapies, pelacarsen, and muvalaplin, although differences between studies preclude direct comparison between therapeutic platforms. Conclusions: The Lp(a) therapeutic landscape has rapidly evolved, with RNA-based therapies demonstrating unprecedented reductions in circulating Lp(a) concentrations. Ongoing cardiovascular outcomes trials will determine whether these reductions translate into meaningful cardiovascular benefits, establish Lp(a) as a therapeutic target in cardiovascular prevention and clarify the long-term safety and risk–benefit profile of Lp(a)-targeted therapies. Full article

Systems Medicine aims to understand the dynamics of physiological systems and the differences between healthy and disease states, to then bring the latter back to health. To this aim, it is critical to identify the states that allow modifying the phenotype of a model system and are robust to perturbations. Indeed, for these changes to be sustained in time, the system’s robustness shall be investigated through various analyses and their emerging results. Lie symmetry analysis—a study of fixed variable relations in a differential equations model—uncovers the model’s hidden robustness through its conservation laws. The emerging conservation laws can then be used as a series of robust invariant characteristics of the system under a specific type of perturbations. Although it holds much predictive potential for robustness investigations, the application of Lie symmetry-based conservation law analysis to physiological systems is currently unexplored. Here, we propose a novel application of Lie symmetry-based conservation law analysis to identify the conservation laws—and their existence conditions—influencing the dynamics of a system towards robust remission or relapse. This methodology is used to analyse a minimal model of rheumatoid arthritis with the aim to: (i) investigate the existence and extent of robust disease characteristics as conservation laws of the model, (ii) clinically interpret their biological viability, and (iii) inform model plausibility, testing, and selection. This novel application of the Lie symmetry analysis can retrieve the robust characteristics of physiological conditions, thus providing a new analytical contribution to the Systems Medicine field. Full article

Snakebite envenoming is a neglected tropical disease causing approximately 81,410–137,880 deaths globally each year and four-fold more disabilities than mortality rate. Despite the availability of antivenoms for treatment, several in vitro and in vivo preclinical studies have shown that their efficacy is limited by many factors including regional venom variation and poor neutralization of major venom toxins. To address these limitations, the potential of alternatives including aptamers, recombinant monoclonal antibodies, camelid antibodies, small molecule inhibitors, and natural product-based inhibitors targeting key venom proteins have been explored. Among these, small molecule inhibitors targeting key enzymatic snake venom proteins are emerging as adjuvants to antivenom treatment. Most of these small molecules are repurposed drugs with established safety, oral bioavailability, and lower cost compared to antivenoms. In this regard, this review tries to compile available information regarding the use of small molecule inhibitors to counteract envenomation with special emphasis on three major enzymatic snake venom protein families: phospholipase A₂, snake venom metalloproteinases, and snake venom serine proteases. In vitro studies have shown that these small molecule inhibitors used either alone or in combination with antivenom can potentially reduce the adverse effects of venom-induced coagulopathy, neurotoxicity, tissue damage, and inflammation. However, critical gaps remain including limited human clinical trial data, uncertain efficacy across diverse venoms, and undefined dosing strategies. Overall, small molecules represent a mechanistically targeted and clinically promising adjunct to antivenom therapy, warranting further validation through randomized trials, pharmacokinetic studies, and development of field-applicable treatment protocols. Full article

The diagnostic evaluation of interstitial lung diseases (ILDs) remains challenging when clinical assessment and imaging findings are inconclusive. Although surgical lung biopsy has traditionally represented the diagnostic gold standard, its invasiveness and perioperative risks limit its applicability, particularly in patients with advanced disease or impaired respiratory reserve. This review aims to examine the evolving roles of transbronchial lung cryobiopsy (TBLC) and awake video-assisted thoracoscopic surgery (Awake VATS) within contemporary diagnostic pathways for ILD. A narrative review of the current literature was performed, focusing on studies evaluating the diagnostic performance, safety profiles, clinical indications, and complementary integration of TBLC and Awake VATS in patients with suspected ILD. Evidence from multidisciplinary ILD referral centers and recent guideline recommendations was critically analyzed. TBLC has progressively emerged as an appropriate first-line histological procedure in many ILD centers, providing a pooled diagnostic yield of approximately 80% with an acceptable safety profile. Awake VATS has refined the surgical approach by preserving spontaneous ventilation while maintaining high diagnostic accuracy. Current evidence suggests that these techniques should be considered complementary rather than competitive. A TBLC-first strategy, followed by selective surgical escalation when endoscopic sampling is non-diagnostic or insufficient, appears to achieve diagnostic accuracy comparable to upfront surgical biopsy while reducing complications, length of hospital stay, and overall patient burden. The choice between Awake VATS and conventional surgical biopsy should be individualized according to patient characteristics, institutional expertise, and available resources. TBLC and Awake VATS represent complementary tools within a multidisciplinary, personalized, and risk-adapted diagnostic framework for ILD. Their integrated use enables optimization of diagnostic accuracy while minimizing procedural invasiveness and improving patient safety, supporting a stratified approach to histological assessment in contemporary clinical practice. Full article

(1) Background: Reactive oxygen species (ROS) act as physiological signaling mediators but contribute to oxidative damage, cellular dysfunction, and age-related disease when redox homeostasis fails. Forkhead box O4 (FOXO4) has emerged as a redox-sensitive regulator linking stress adaptation, antioxidant defense, and cellular senescence. This structured narrative review critically evaluates which redox- and aging-related conclusions are supported directly for FOXO4 and which remain inferred from other FOXO isoforms. (2) Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched from inception to May 2026; Google Scholar was used only for supplementary citation tracking and did not contribute a separate platform-level count. Of 420 records, 300 remained after deduplication, 110 full texts were assessed, and 89 publications were retained. FOXO4-related evidence was classified as directly FOXO4-specific (n = 18), FOXO-family/conserved (n = 24), or extrapolated predominantly from FOXO1/FOXO3/DAF-16 (n = 20); 27 contextual publications on redox biology, senescence, disease, and NRF2 were tracked separately. (3) Results: The strongest FOXO4-specific evidence supports three mechanistic axes: cysteine-dependent redox sensing, stress-regulated nuclear trafficking and coactivator engagement through transportin-1 and p300/CBP, and FOXO4–p53-mediated survival of senescent cells. By contrast, direct FOXO4 regulation of commonly cited antioxidant targets, including SOD2, catalase, sestrins, and GADD45, remains insufficiently demonstrated and is inferred mainly from FOXO3 or broader FOXO-family studies. FOXO4-DRI has shown senolytic activity in preclinical models, including vascular endothelium, but has not been clinically validated. (4) Conclusions: FOXO4 is a redox-responsive transcriptional regulator with well-supported roles in cysteine-based signaling and senescent-cell survival, whereas its target-gene-level antioxidant program remains incompletely resolved. Clinical translation of FOXO4–p53 disruption requires isoform- and tissue-specific validation, pharmacokinetic and delivery studies, long-term toxicology, and explicit assessment of p53-dependent tumor surveillance. Full article

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection remain a world health problem leading to fibrosis and cirrhosis. Liver damage is primarily mediated by the innate and adaptive immune responses since HBV and HCV are not directly cytotoxic. Kupffer cells and liver-recruited macrophages are heavily implicated in both viral elimination and progression of the disease. HBV and HCV proteins polarize macrophages into either an M1 pro-inflammatory phenotype, promoting hepatocyte damage or into an M2 immunosuppressive phenotype, leading to viral persistence and fibrogenesis via cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). In this review a brief overview of the heterogeneity of liver macrophages in health and during chronic viral infection is presented. Recognition of viruses by macrophages and the modulation of macrophages by viral proteins in the pathogenesis of liver inflammation and injury are discussed in detail. Most importantly, the mechanisms that HBV and HCV are using to manipulate macrophages and escape elimination are also presented. The role of macrophages in the evolution of acute-on-chronic liver failure is analyzed. Finally, a concise presentation of the emerging, but not yet clinically used, therapeutic strategies targeting macrophages to control chronic HBV infection and restore the dysregulated immune response is discussed. In conclusion, this integrated review of liver macrophage implication summarizes the pathophysiology and pathogenesis of HBV and HCV including acute-on-chronic- liver failure and viral cirrhosis. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and significant neuropathological changes. Early and accurate diagnosis remains a major challenge, highlighting the need for reliable, minimally invasive biomarkers. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising candidates. Their expression is altered in the brains of AD patients, reflecting disease-specific pathological processes, and they are detectable in peripheral biofluids. However, discrepancies in miRNA profiles between the brain and the circulation, and between patient populations remain a significant limitation, raising questions about their origin, transport across the blood–brain barrier, and their reliability in reflecting central nervous system pathology. This review provides a comprehensive overview of current research comparing miRNA expression profiles in brain tissue and blood in AD, with a focus on their biological relevance, mechanisms of release and transport, and diagnostic potential. We also discuss the challenges associated with cross-tissue variability, methodological inconsistencies, and the need for standardized approaches. Finally, we highlight future directions, including multi-tissue analyses and integration with other noninvasive modalities, to improve the clinical utility of miRNA-based biomarkers in AD. Full article