Search Results (4,639)

Background: Coronavirus disease 2019 (COVID-19) is frequently complicated by acute respiratory distress syndrome (ARDS), which is associated with high mortality. The lactate-to-albumin ratio (LAR) and C-reactive protein-to-albumin ratio (CAR) have been proposed as prognostic markers in critical illness, but their comparative performance in COVID-19–associated ARDS is not well established. Methods: We conducted a retrospective cohort study using the MIMIC-IV database, which contains data from Beth Israel Deaconess Medical Center, United States, including COVID-19 ICU admissions from 2020 to 2022. Adult COVID-19 patients with available PaO₂/FiO₂, lactate, albumin, and C-reactive protein measurements within the first 48 h of ICU admission were included. Receiver operating characteristic analysis, Kaplan–Meier survival analysis, and Cox proportional hazards regression were performed. Results: Of the 3620 patients screened, 66 met the inclusion criteria; 36 survived and 30 died. Non-survivors had significantly higher LAR and CAR values at ICU admission. In ROC analyses, LAR demonstrated moderate discrimination for 30-day mortality (AUC 0.706) and showed higher discriminatory performance than CAR in most subgroup analyses. Among ARDS patients, LAR showed moderate predictive ability (AUC 0.693), compared with CAR (AUC 0.655). In severe ARDS, both markers demonstrated improved discrimination (0.722 AUC for LAR and 0.797 for CAR). High LAR was associated with significantly higher 30-day mortality in all ARDS patients (60.5% vs. 24.0%; p = 0.0056) and severe ARDS patients (72.0% vs. 20.0%; p = 0.0022). Elevated CAR was also associated with increased mortality, particularly in severe ARDS (73.1% vs. 14.3%; p < 0.001). In multivariable Cox regression, LAR remained independently associated with 30-day mortality. Conclusions: LAR demonstrated independent prognostic value for 30-day mortality in critically ill COVID-19 patients with ARDS. CAR showed variable performance. These readily available biomarkers, particularly LAR, may aid early risk stratification although larger studies are needed to confirm these findings. Full article

Background/Objectives: Visual impairment is an underrecognized but functionally disabling complication of stroke that adversely affects rehabilitation potential, autonomy, and quality of life. Clinical, anatomical, and ophthalmologic determinants of post-stroke visual recovery remain incompletely defined, particularly in Eastern European tertiary stroke units where structured visual follow-up is not standardized. This study aimed to identify clinical, imaging, and ophthalmologic predictors of favorable visual recovery and to evaluate whether integrating these domains improves early prognostic stratification beyond standard neurological assessment. Methods: We conducted a retrospective single-center cohort study of 71 consecutive adult patients admitted with acute stroke and a documented visual complication between January 2022 and September 2025 at Pius Brinzeu Emergency County Hospital and Victor Babes University of Medicine and Pharmacy Timisoara. Favorable recovery was defined as ≥50% improvement in visual field index (VFI) at 6 months. Group comparisons used Student’s t-test, Mann–Whitney U test, chi-square test, and Fisher’s exact test. Multivariable logistic regression, Cox proportional hazards modeling, and unsupervised k-means clustering were performed. Results: Twenty-nine patients (40.8%) achieved favorable recovery, while 42 (59.2%) had persistent impairment. Responders were younger (62.8 ± 10.7 vs. 70.4 ± 10.8 years, p = 0.005) and had lower admission National Institutes of Health Stroke Scale (NIHSS) (6.4 ± 2.9 vs. 10.3 ± 4.4, p < 0.001), smaller lesion volumes (18.7 ± 11.4 vs. 33.2 ± 18.7 mL, p < 0.001), thicker peripapillary retinal nerve fiber layer (89.3 ± 7.6 vs. 78.2 ± 9.4 μm, p < 0.001), and earlier rehabilitation initiation (11.4 ± 5.3 vs. 21.7 ± 9.8 days, p < 0.001). NIHSS, time to rehabilitation, and optical coherence tomography (OCT) pRNFL thickness remained independent predictors. The full integrated model achieved an area under the receiver operating characteristic curve (AUC) of 0.87. Cluster analysis identified three distinct phenotypes with favorable recovery rates of 79.2%, 34.8%, and 8.3%. Conclusions: Combined clinical, neuroimaging, and ophthalmologic profiling—particularly OCT pRNFL—meaningfully refines early prediction of post-stroke visual recovery and supports phenotype-driven rehabilitation planning. Full article

Mint (Mentha spp.) teas are widely consumed as functional herbal beverages and represent important dietary sources of bioactive volatile compounds. The present study comparatively evaluated the chemical composition and antimicrobial activity of essential oils (EOs) obtained from commercially available Mentha tea products purchased in Estonia, Lithuania, and Norway. In 10 EO samples studied, 85 compounds were identified by GC–MS. Carvone was the dominant constituent in the carvone chemotype (up to 58.1%), whereas menthol reached 30.7% in the menthol chemotype. Hierarchical clustering of CLR-transformed GC–MS data revealed three well-defined chemotypes among the analyzed Mentha EOs: carvone chemotype (three samples), menthol chemotype (five samples) and mixed, carvone-menthol chemotype (two samples). The antimicrobial activity of EOs was evaluated against 17 clinical antibiotic-sensitive and antibiotic-resistant microorganisms by the agar well diffusion method. The strongest antimicrobial activity was observed against resistant clinical Staphylococcus aureus strains, with MIC values as low as 0.10 mg/mL. EOs with a high carvone content consistently showed higher activity, especially against S. aureus, including resistant phenotypes. In contrast, menthol-chemotype EOs were associated with reduced antibacterial effectiveness. The obtained results demonstrate that the investigated commercial mint teas differ considerably in their phytochemical composition and biological properties, which may contribute to differences in their potential nutraceutical relevance as functional plant-derived beverages. Full article

Background: Pharmacist-led interventions in Gulf Cooperation Council (GCC) countries have been increasingly studied, yet their overall effectiveness across clinical and healthcare outcomes remains incompletely defined. To address this gap, a systematic review and meta-analysis of randomized controlled trials and quasi-experimental studies published between 2000 and 2025 was conducted, following PRISMA 2020 and Cochrane standards. Methods: Searches of PubMed/MEDLINE, Scopus, Web of Science, and CENTRAL identified 437 records, of which 20 studies met the inclusion criteria; 13 contributed meta-analyzable data as randomized controlled trials and seven as quasi-experimental studies. Results: Pooled random-effects estimates favored pharmacist-led care for HbA1c, fasting glucose, low-density lipoprotein cholesterol, diastolic blood pressure, and medication knowledge, although these estimates carried substantial, largely unexplained heterogeneity and were rated as low to very low certainty under GRADE. The effects on systolic blood pressure, total cholesterol, triglycerides, high-density lipoprotein cholesterol, unplanned healthcare use, and antimicrobial utilization were favorable but not statistically significant. Quasi-experimental studies consistently demonstrated reductions in mortality and readmissions, though hospital and ICU length of stay remained variable. Risk of bias was judged as some concerns for randomized trials and moderate to serious for quasi-experimental studies, with substantial heterogeneity observed across blood pressure and lipid outcomes. Conclusions: Overall, pharmacist-led interventions in GCC settings were associated with improvements in glycemic control and LDL cholesterol, with additional benefits in mortality and readmissions, although the certainty of evidence was low to very low, owing to substantial heterogeneity and the predominance of non-randomized designs for the inpatient outcomes. These findings underscore the need for standardized intervention models and outcome measures. Full article

Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger downstream of G protein-coupled receptors (GPCRs) and a central regulator of cellular signaling. Genetically encoded exchange proteins directly activated by cAMP (Epac)-based Förster resonance energy transfer (FRET) biosensors enable real-time monitoring of cAMP dynamics in living cells, but commonly used cyan/yellow FRET pairs require short-wavelength excitation, limiting compatibility with multiplex imaging and blue-light optogenetic tools such as bacterial photoactivated adenylyl cyclases (bPACs). Here, we engineered and systematically characterized four red-shifted Epac-based single-chain FRET cAMP sensors combining yellow or orange FRET donors with red fluorescent FRET acceptors. Using ratiometric live-cell imaging, we quantified stimulus-evoked FRET responses and identified Epac_red4 as the best-performing variant, showing an approximately 55% decrease in normalized FRET after forskolin stimulation. Epac_red4 also reliably detected G_i/o-mediated decreases in cAMP following μ-opioid receptor activation. Brief 405 nm light pulses induced graded and reversible cAMP elevations using the low dark-activity variant bPAC-F198Y. Furthermore, Epac_red4 enabled analysis of cAMP recovery kinetics during phosphodiesterase inhibition and multiplex imaging of cAMP and intracellular Ca²⁺ using Fura-2 with minimal spectral and pH-related interference under physiological imaging conditions. Together, Epac_red4 represents a robust red-shifted cAMP sensor for optogenetic and multiplex signaling studies. Full article

Osteoradionecrosis of the jaw (ORNJ) remains one of the most severe late complications of head and neck radiotherapy. Current evidence suggests that ORNJ is a progressive and biologically heterogeneous disorder driven by microvascular injury, chronic hypoxia, oxidative stress, fibro-atrophic remodeling, impaired bone turnover, immune dysregulation, and systemic susceptibility factors. Within this complex pathogenic network, heat shock protein 27 (HSP27) emerges as a biologically plausible but unexplored mediator. HSP27 regulates multiple stress-response pathways, including redox homeostasis, cytoskeletal stabilization, endothelial protection, apoptosis control, fibroblast activation, and osteoblast–osteoclast function, all of which overlap with key mechanisms implicated in ORNJ. However, no studies have directly investigated HSP27 expression, activation, or functional significance in irradiated mandibular tissues or ORNJ-specific cohorts. This review summarizes current knowledge of ORNJ pathobiology, examines potential mechanistic links with HSP27, and outlines future research priorities involving biomarker development, tissue-level characterization, preclinical modeling, and therapeutic targeting. Integrating HSP27 into ORNJ research may improve understanding of pathogenesis, risk stratification, and the development of novel preventive and therapeutic strategies. Full article

Metabolic dysfunction-associated steatohepatitis (MASH; formerly non-alcoholic steatohepatitis, NASH) is characterized by oxidative stress, inflammatory activation, hepatocellular injury, and progressive liver dysfunction. However, the global transcriptomic landscape underlying stress-induced hepatic injury remains incompletely understood. In this study, we employed a methionine–choline-deficient (MCD) diet-induced murine model to characterize the phenotypic and transcriptomic alterations associated with liver injury. Male C57BL/6J mice were fed either a control or MCD diet, and hepatotoxicity was assessed by survival analysis, body and liver weight measurements, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, histopathological examination, RNA sequencing, quantitative real-time PCR (qRT-PCR), and tumor necrosis factor-alpha (TNF-α) enzyme-linked immunosorbent assay (ELISA). MCD feeding markedly reduced survival and body weight while inducing hepatomegaly and significant elevations in serum ALT and AST, indicating severe hepatocellular injury. Histopathological analysis demonstrated hepatic steatosis, hepatocellular ballooning, and lobular inflammation without histological evidence of fibrosis. Transcriptomic profiling revealed extensive gene expression remodeling, characterized by activation of inflammatory pathways, enrichment of MAPK-related signaling, dysregulation of lipid metabolism, suppression of antioxidant defense systems, impairment of cytochrome P450-mediated detoxification, and upregulation of apoptosis-associated genes. qRT-PCR further validated the differential expression of representative genes involved in inflammatory signaling (Tlr4, Nfkb1, Nlrp3, and Casp1), MAPK signaling (Fos), xenobiotic metabolism (Cyp4f18), lipid metabolism (Apoa4 and Lpl), extracellular matrix remodeling (Mmp12), and oxidative stress responses (Sod1 and Gstp1). In addition, elevated serum TNF-α levels provided protein-level evidence supporting activation of the TLR4/NF-κB/TNF-α/NLRP3 inflammatory axis. Although fibrosis-associated transcriptional responses were detected, the absence of histological fibrosis suggests transcriptional priming of fibrogenic pathways rather than established fibrogenesis. Collectively, these findings provide a transcriptomic framework linking oxidative stress, impaired detoxification, inflammatory activation, and stress-responsive signaling to MCD-induced hepatic injury. The MCD model provides a valuable experimental platform for characterizing hepatic stress-response transcriptomes and for generating hypotheses that can subsequently be evaluated in environmentally relevant toxicological models. Nevertheless, caution should be exercised when extrapolating these findings to obesity-associated human MASLD, as the MCD model lacks key metabolic features of the human disease, including obesity and insulin resistance. Therefore, the present findings should be interpreted primarily as transcriptomic signatures of stress-induced hepatic injury rather than as a direct representation of the pathophysiological processes underlying human obesity-associated MASLD. Full article

Background and Objectives: Synthetic cannabinoids (SCs) are new psychoactive substances associated with acute intoxications. Experimental data obtained under controlled and comparable conditions remain limited for this category of compounds. This descriptive, hypothesis-generating screening study aimed to characterize the acute toxicity profile of three SCs, JWH-007, AM-694, and MAB-CHMINACA. Materials and Methods: Acute toxicity was evaluated in female Swiss Albino mice, in accordance with the OECD 423 guideline, following oral and intraperitoneal administration. Animals were monitored for 14 days for behavioral and clinical signs of toxicity. At the end, histopathological examination was performed to describe organ-level changes. Serum concentrations of the tested compounds were quantified by LC-ESI-MS/MS 24 h after intraperitoneal administration. Results: The three compounds were associated with distinct behavioral, clinical, and histopathological observations. JWH-007 was associated with transient behavioral depression and histopathological changes in peripheral organs. AM-694 was associated with histopathological changes in systemic organs and limited behavioral manifestations. MAB-CHMINACA was associated with acute behavioral toxicity and central nervous system lesions, including neuronal vacuolization, necrosis, oedema, and inflammatory changes. Conclusions: These preliminary findings describe compound-specific in vivo toxicity patterns and may inform the design of future confirmatory studies on SCs’ toxicity. The observed behavioral and histopathological changes should be interpreted as hypothesis-generating and require statistical validation before conclusions can be drawn regarding comparative toxicity, structural class effects, or predictive value for risk stratification. Full article

Background/Objectives: Ketamine use in emergency departments is expanding for the management of agitation, procedural sedation, and rapid sequence intubation. We aim to describe the indications and characteristics of ketamine administration in emergency department patients in Saudi Arabia through retrospective chart review. Methods: This was a single-center, retrospective chart review conducted at an academic medical center. The study population included patients who received intravenous (IV) or intramuscular (IM) ketamine in the emergency department between 1 January 2023, and 31 December 2024. Patients younger than 18 years of age or those who were pregnant were excluded. Results: A total of 192 patients were included. The median ketamine dose was 50 mg (a total range of 20–240 mg). Procedural sedation was the primary indication (79%), followed by pain management (12.5%), rapid sequence intubation (4.7%), and agitation (2.1%). Nearly all patients (99.5%) received ketamine intravenously, and 83.9% received it in conjunction with other medications. For procedural sedation, ketofol was the most common combination therapy, accounting for 83.6% of combination cases. No procedural failures, need for additional sedatives, or redosing within an hour were reported for procedural sedation. For pain management, ketamine was predominantly administered for musculoskeletal pain (50%) and was most often used as monotherapy (58.3%). Notably, no documented adverse effects were observed post ketamine administration across all indications. Conclusions: Among patients who received ketamine in emergency departments in Saudi Arabia, its administration was frequent, particularly for procedural sedation and acute pain management. In this study we found no adverse events or procedural failures were documented. Further research is warranted to validate these findings. Full article

Tuberculosis therapy is prolonged partly because dormant subpopulations of Mycobacterium tuberculosis show reduced susceptibility to first-line drugs. Therefore, agents active against both replicating and non-replicating mycobacteria remain important to explore. Here, we investigated secondary metabolites from the Indonesian marine-derived fungus Aspergillus ostianus for activity against Mycobacterium smegmatis, a BSL-1 mycobacterial model, under aerobic and hypoxia-induced non-replicating conditions, and examined the underlying mechanism. Bioassay-guided fractionation and spectroscopic analysis identified three hydroxamate pyrazinones: neohydroxyaspergillic acid (NHAA), hydroxyaspergillic acid (HAA), and neoaspergillic acid (NAA). The MIC values were 1.56 µg/mL for NHAA and 3.13 µg/mL for HAA and NAA under both aerobic and hypoxic atmospheres. Time-kill kinetics showed ≥3-log10 CFU reductions within 24–72 h at 4–8× MIC under aerobic conditions and within 48–96 h at 4–8× MIC under hypoxia, with no regrowth at the final sampling point. Scanning electron microscopy and release of UV-absorbing intracellular material at OD₂₆₀/OD₂₈₀ were consistent with envelope disruption in both atmospheres. Antimycobacterial activity was attenuated in a concentration-dependent manner by exogenous Fe³⁺ and was reversed at 100 µM FeCl₃, whereas isoniazid activity was unaffected, supporting iron-reversible and pyrazinone-specific killing. Together with the established Fe³⁺-binding hydroxamate pharmacophore shared by this compound class, these findings support iron sequestration as a plausible mechanism and identify fungal hydroxamate pyrazinones as scaffolds that retain bactericidal activity against hypoxia-adapted non-replicating mycobacteria, warranting further evaluation in M. tuberculosis models. Full article

Background/Objectives: Pharmacists play a key role in managing urinary tract infection (UTI) symptoms by providing medications, self-care advice, and over-the-counter treatments, while referring patients to a doctor when necessary. This study aimed to examine the practices of community pharmacists in managing UTI symptoms and to gain insight into their attitudes toward antibiotic use for this condition. Methods: A cross-sectional study was conducted among community pharmacists in Serbia using a previously validated online questionnaire, assessed for content and face validity and pilot-tested among pharmacists. Results: A total of 430 community pharmacists participated in the study. Patients more often consulted pharmacists before visiting a doctor than after (median 5 vs. 3 per week; p < 0.001). For uncomplicated UTIs, pharmacists primarily recommended increased fluid intake (92.8%), herbal teas (94.7%), and food supplements (85.6%), whereas for complicated UTIs, most referred patients to a doctor (95.4%). Attitudes, perceived competence, and support for over-the-counter antibiotic availability were significantly associated with gender, years of experience, and specialization. Pharmacists who agreed that antibiotics are the most effective treatment for uncomplicated urinary tract infections were more likely to refer patients to a doctor (p < 0.01). Conclusions: Pharmacists are frequently consulted for UTI management and emphasize non-antibiotic approaches for uncomplicated cases. Their attitudes influence counseling practices, highlighting the need for standardized UTI counseling services, antimicrobial stewardship education, and structured communication training to support appropriate antibiotic use. Full article

Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity. Emerging evidence suggests that epigenetic dysregulation, particularly altered DNA methylation, contributes to DOX-induced cardiac injury. Metformin has been reported to exert cardiometabolic and epigenetic regulatory effects. This study investigated genome-wide DNA methylation changes induced by chronic metformin exposure and their effects on doxorubicin sensitivity in H9c2 cardiomyoblast cells. Methods: Genome-wide DNA methylation changes induced by chronic metformin exposure were investigated in H9c2 cardiomyoblast cells using whole-genome bisulfite sequencing (WGBS). Cells were treated with metformin (0.7–2.8 mM) for four months prior to DOX exposure. Cellular sensitivity to DOX was evaluated using MTT-based dose–response analysis and IC₅₀ estimation. Results: DOX reduced cell viability (IC₅₀ = 0.164 µM). Chronic metformin pre-treatment produced a dose-dependent rightward shift in DOX dose–response curves, increasing IC₅₀ values to 0.21, 0.289, and 0.51 µM at 0.7, 1.4, and 2.8 mM metformin, respectively. WGBS revealed distinct separation between treatment groups in principal component analysis. Significant methylation changes (adjusted p-value < 0.05) were identified in genes related to oxidative stress, mitochondrial function, apoptosis, and chromatin regulation. Conclusions: Chronic metformin exposure induces dose-dependent genome-wide DNA methylation remodeling in cardiac cells and is associated with altered cellular sensitivity to doxorubicin. These findings suggest that metabolic modulation by metformin may influence epigenetic regulation and cellular stress responses relevant to chemotherapy-induced cardiotoxicity. Full article

Enzymatic nanomotors (EMNMs) represent an emerging class of intelligent nanosystems that exploit enzymatic biocatalysis to generate autonomous motion within biological environments, including complex cellular and tissue contexts within living organisms. Owing to their ability to utilize endogenous biofuels, high biocompatibility, and capacity for targeted propulsion, EMNMs have demonstrated considerable potential in diverse biomedical applications. These include targeted drug delivery, cancer therapy, diagnostics, and bioimaging, as well as the traversal of biological barriers. This review comprehensively discusses the mechanisms underlying enzyme-driven propulsion, nanomotor design strategies, and their current and prospective applications in medicine, while also addressing major challenges associated with enzymatic stability, biocompatibility, motion control, and clinical safety. Furthermore, future perspectives are highlighted, including enzyme cascade systems, intelligent nanomotor swarms, biodegradable materials, and strategies facilitating clinical translation. As a representative example of practical application, curcumin was employed as a model therapeutic agent due to its well-established anticancer, anti-inflammatory, and antioxidant properties, enabling evaluation of the nanomotors’ capability for controlled, pH-responsive release of therapeutic cargo. Nanophytomedicine enhances the therapeutic efficacy of phytochemicals by improving their stability, bioavailability, and targeted delivery through nanocarrier systems. The integration of phytotherapy with nanotechnology offers promising opportunities for the development of safer and more effective therapeutic strategies. Full article

Background: Intensive low-density lipoprotein cholesterol (LDL-C) reduction is essential for secondary prevention after acute coronary syndrome (ACS). Although randomized trials support the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, real-world evidence on long-term lipid control and the optimal timing of initiation remains limited. Objective: To evaluate lipid outcomes and atherosclerotic cardiovascular disease (ASCVD) events associated with evolocumab after ACS and to assess whether timing of initiation influences these outcomes in routine clinical practice. Methods: This multicenter, retrospective cohort study included adults who were initiated on evolocumab following ACS between 2017 and 2024. Lipid parameters were assessed at predefined follow-up time points (3 months, 6 months, 1 year, 2 years, and up to 3 years) using an available-case approach. Patients were categorized as early initiators (≤1 month) or late initiators (>1 month). Recurrent ASCVD events, hospitalization burden, and mortality were analyzed using multivariable regression. A propensity score-matched sensitivity analysis was also performed. Results: Among 525 included patients (mean age 53.1 ± 11.6 years; 80.2% male), baseline LDL-C was 3.68 ± 1.66 mmol/L. LDL-C decreased to approximately 1.8–2.0 mmol/L within 3 months, corresponding to an approximate 45–50% reduction from baseline, with consistent reductions observed across available follow-up time points. Recurrent ASCVD events occurred in 14.8% of patients, and in-hospital mortality was 2.3%. Although early initiators had higher baseline risk, adjusted analyses showed no statistically significant association between early initiation and recurrent ASCVD (adjusted OR 1.50; 95% CI 0.82–2.70; p = 0.17). Similarly, no statistically significant differences in lipid outcomes were observed between early and late initiation groups after adjustment. Findings were consistent in propensity score-matched analyses. Conclusions: In this real-world post-ACS cohort, evolocumab was associated with substantial and sustained LDL-C reduction across follow-up time points. No significant associations were observed between timing of initiation and lipid or ASCVD outcomes after adjustment. These findings should be interpreted cautiously, given the observational design, available-case analysis, and potential for residual confounding. Full article