Search Results (3,014)

Background: Cardiac involvement is common in Fabry disease (FD) and typically manifests with left ventricular hypertrophy (LVH). Patients with FD are frequently misdiagnosed, and this is mainly related to the lack of disease awareness among clinicians. The aim of this study was to determine whether providing a targeted educational intervention on FD may enhance FD diagnosis. Methods. This research was designed as a single-arm before-and-after intervention study and evaluated the impact of providing a specific training on FD to cardiologists from different Italian centers, without experience in rare diseases. In the 12-month period after the educational intervention, the rate of FD screening and diagnosis was assessed and compared with those conducted in the two years preceding the study initiation. Results: Fifteen cardiologists participated to this study, receiving a theoretical and practical training on FD. In the two previous two years, they conducted 12 FD screening (6/year), and they did not detect any cases of FD. After the training, they performed 45 FD screenings, with an eight-fold rise in the annual screening rate. The screened population (age: 61 ± 11 years, men: 82%) was mainly composed of patients with unexplained LVH (n = 43). There were four new FD diagnoses and, among of them, three had a late-onset GLA variant. After the cascade genetic screening, 11 affected relatives and 8 heterozygous carriers were also detected. Conclusions: A targeted educational intervention for cardiologists allowed the identification of four new families with FD. Enhancing FD awareness is helpful to reduce the diagnostic and therapeutic delay. Full article

The Generalized Hough Transform (GHT) is a powerful method for rigid shape detection under rotation, scaling, translation, and partial occlusion conditions, but its four-dimensional accumulator incurs prohibitive computational and memory demands that prevent real-time deployment. To address this, we propose a framework that compresses the 4-D search space into a concise 2-D voting scheme by combining two-level sparse point-pair screening with an accelerated lookup. In the offline stage, template edges are extracted using an adaptive Canny operator with Otsu-determined thresholds, and gradient-direction differences for all point pairs are quantized to retain only those in the dominant bin, yielding rotation- and scale-invariant descriptors that populate a compact 2-D reference table. During the online stage, an adaptive grid selects only the highest-gradient pixels per cell as a base points, while a precomputed gradient-direction bucket table enables constant-time retrieval of compatible subpoints. Each valid base–subpoint pair is mapped to indices in the lookup table, and “fuzzy” votes are cast over a 3 × 3 neighborhood in the 2-D accumulator, whose global peak determines the object center. Evaluation on 200 real industrial parts—augmented to 1000 samples with noise, blur, occlusion, and nonlinear illumination—demonstrates that our method maintains over 90% localization accuracy, matches the classical GHT, and achieves a ten-fold speedup, outperforming IGHT and LI-GHT variants by 2–3×, thereby delivering a robust, real-time solution for industrial rigid object localization. Full article

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that A190, a novel, potent, and selective PPARα agonist, effectively alleviates chemotherapy-induced peripheral neuropathy and CFA-induced inflammatory pain as a non-opioid therapeutic agent. However, A190 alone has solubility and permeability issues that limits its oral delivery. To overcome this challenge, in this study, four new-generation ester prodrugs of A190; A190-PD-9 (methyl ester), A190-PD-14 (ethyl ester), A190-PD-154 (isopropyl ester), and A190-PD-60 (cyclic carbonate) were synthesized and evaluated for their enzymatic bioconversion and chemical stability. The lead candidate, A190-PD-60, was further formulated as a microemulsion (A190-PD-60-ME) and optimized via Box–Behnken design. A190-PD-60-ME featured nano-sized droplets (~120 nm), low polydispersity (PDI < 0.3), and high drug loading (>90%) with significant improvement in artificial membrane permeability. Crucially, pharmacokinetic evaluation in rats demonstrated that A190-PD-60-ME reached a 16.6-fold higher Cmax (439 ng/mL) and a 5.9-fold increase in relative oral bioavailability compared with an A190-PD-60 dispersion. These findings support the combined prodrug-microemulsion approach as a promising strategy to overcome oral bioavailability challenges and advance PPARα-targeted therapies. Full article

Proton therapy has emerged as a highly precise and tissue-sparing radiotherapy technique, capitalizing on the unique energy deposition pattern of protons characterized by the Bragg peak. Ensuring treatment accuracy relies on calibration phantoms, often composed of tissue-equivalent polymeric materials. This study investigates the dosimetric behavior of four commonly used polymers—Parylene, Epoxy, Lexan, and Mylar—by analyzing their linear energy transfer (LET) values and Bragg curve characteristics across various proton energies. Experimental LET data were collected and used to train and evaluate the predictive power for Bragg peak of multiple artificial intelligence models, including kNN, SVR, MLP, RF, LWRF, XGBoost, 1D-CNN, LSTM, and BiLSTM. These algorithms were optimized using 10-fold cross-validation and assessed through statistical error and performance metrics including MAE, RAE, RMSE, RRSE, CC, and R². Results demonstrate that certain AI models, particularly RF and LWRF, accurately (in terms of all evaluation metrics) predict Bragg peaks in Epoxy polymers, reducing the reliance on costly and time-consuming simulations. In terms of CC and R² metrics, the LWRF model demonstrated superior performance, achieving scores of 0.9969 and 0.9938, respectively. However, when evaluated against MAE, RMSE, RAE, and RRSE metrics, the RF model emerged as the top performer, yielding values of 12.3161, 15.8223, 10.3536, and 11.4389, in the same order. Additionally, the SVR model achieved the highest number of statistically significant differences when compared pairwise with the other eight models, showing significance against six of them. The findings support the use of AI as a robust tool for designing reliable calibration phantoms and optimizing proton therapy planning. This integrative approach enhances the synergy between materials science, medical physics, and data-driven modeling in advanced radiotherapy systems. Full article

Background/Objectives: Obstructive sleep apnea (OSA) is a highly prevalent disorder that significantly impacts quality of life and daily functioning. While continuous positive airway pressure (CPAP) therapy is effective, long-term adherence remains a challenge. This single-arm observational study aimed to evaluate clinical outcomes and adherence patterns during telemedicine-supported CPAP therapy and identify distinct phenotypic response clusters in Romanian patients with OSA. Methods: This prospective observational study included 86 adults diagnosed with OSA, treated with ResMed Auto CPAP devices at “Victor Babeș” University Hospital in Timișoara, Romania. All patients were remotely monitored via the AirView™ platform and received monthly telephone interventions to promote adherence when necessary. Clinical outcomes were assessed through objective telemonitoring data. K-means clustering and t-distributed stochastic neighbor embedding (t-SNE) were employed to explore phenotypic response patterns. Results: During telemedicine-supported CPAP therapy, significant clinical improvements were observed. The apnea–hypopnea index (AHI) decreased from 42.0 ± 21.1 to 1.9 ± 1.3 events/hour. CPAP adherence improved from 75.5% to 90.5% over six months. Average daily usage increased from 348.4 ± 85.8 to 384.2 ± 65.2 min. However, post hoc analysis revealed significant concerns about the validity of self-reported psychological improvements. Self-esteem changes showed negligible correlation with objective clinical measures (r < 0.2, all p > 0.1), with only 3.3% of variance being explained by measurable therapeutic factors (R² = 0.033). Clustering analysis identified four distinct adherence and outcome profiles, yet paradoxically, patients with lower adherence showed greater self-esteem improvements, contradicting therapeutic causation. Conclusions: Telemedicine-supported CPAP therapy with structured monthly interventions was associated with substantial clinical improvements, including excellent AHI reduction (22-fold) and high adherence rates (+15% after 6 months). Data-driven phenotyping successfully identified distinct patient response profiles, supporting personalized management approaches. However, the single-arm design prevents definitive attribution of improvements to telemonitoring versus natural adaptation or placebo effects. Self-reported psychological outcomes showed concerning patterns suggesting predominant placebo responses rather than therapeutic benefits. While the overall findings demonstrate the potential value of structured telemonitoring for objective CPAP outcomes, controlled trials are essential to establishing true therapeutic efficacy and distinguishing intervention effects from measurement bias. Full article

Background/Objectives: Romania remains a tuberculosis (TB) hotspot in the European Union, yet host-derived factors of poor outcomes are poorly characterised. We quantified circulating pro-inflammatory cytokines and examined their interplay with behavioural risk factors, the nutritional status, and the clinical course in adults hospitalised with pulmonary TB. We analysed 80 adults with microbiologically confirmed pulmonary TB and 40 respiratory symptom controls; four TB patients (5%) died during hospitalisation, all within 10 days of admission. Methods: A retrospective analytical case–control study was conducted at the Constanța regional TB referral centre (October 2020—October 2023). Patients with smear- or culture-confirmed TB were frequency-matched by sex, 10-year age band, and BMI class to culture-negative respiratory controls at a 2:1 ratio. The patients’ serum interferon-γ (IFN-γ), interleukin-1α (IL-1α), interleukin-1β (IL-1β), and tumour-necrosis-factor-α (TNF-α) were quantified within 24 h of admission; the neutrophil/lymphocyte ratio (NLR) was extracted from full blood counts. Independent predictors of in-hospital mortality were identified by multivariable logistic regression; factors associated with the length of stay (LOS) were modelled with quasi-Poisson regression. Results: The median TNF-α (24.1 pg mL⁻¹ vs. 16.2 pg mL⁻¹; p = 0.009) and IL-1β (5.34 pg mL⁻¹ vs. 3.67 pg mL⁻¹; p = 0.008) were significantly higher in the TB cases than in controls. TNF-α was strongly correlated with IL-1β (ρ = 0.80; p < 0.001), while NLR showed weak concordance with multiplex cytokine patterns. Among the patients with TB, four early deaths (5%) exhibited a tripling of TNF-α (71.4 pg mL⁻¹) and a doubling of NLR (7.8) compared with the survivors. Each 10 pg mL⁻¹ rise in TNF-α independently increased the odds of in-hospital death by 1.8-fold (95% CI 1.1–3.0; p = 0.02). The LOS (median 29 days) was unrelated to the smoking, alcohol, or comorbidity load, but varied across BMI strata: underweight, 27 days; normal weight, 30 days; overweight, 23 days (Kruskal–Wallis p = 0.03). In a multivariable analysis, under-nutrition (BMI < 18.5 kg m⁻²) prolonged the LOS by 19% (IRR 1.19; 95% CI 1.05–1.34; p = 0.004) independently of the disease severity. Conclusions: A hyper-TNF-α/IL-1β systemic signature correlates with early mortality in Romanian pulmonary TB, while under-nutrition is the dominant modifiable determinant of prolonged hospitalisation. Admission algorithms that pair rapid TNF-α testing with systematic nutritional assessment could enable targeted host-directed therapy trials and optimise bed utilisation in high-burden settings. Full article

Viticis Fructus (VF), a fruit known for its unique flavor profile and various health benefits, demonstrates substantial quality variations depending on its area of production. Traditional methods of production area verification based on internal compound analysis are hampered by a number of technical limitations. This investigation systematically characterized the cuticular wax composition of VF sample from a diverse variety of production areas. Quantitative analyses were conducted to evaluate the spatial distribution patterns of the wax constituents. Significant regional variations were observed: Anhui sample exhibited the highest total wax content (21.39 μg/cm²), with n-alkanes dominating at 76.67%. High-latitude regions showed elevated triterpenoid acid levels, with maslinic acid (0.53 μg/cm²) and ursolic acid (0.34 μg/cm²) concentrations exceeding those of their low-latitude counterparts by four- and three-fold, respectively. Altitudinal influence manifested in long-chain alcohol accumulation, as triacontanol reached 0.87 μg/cm² in high-altitude sample. Five key biomarkers demonstrated direct quality correlations: eicosanoic acid, n-triacontane, dotriacontanol, β-amyrin, and α-amyrin. This study established three novel origin identification protocols: single-component quantification, multi-component wax profiling, and wax ratio analysis. This work not only reveals the latitudinal dependence of VF wax composition, but also provides a scientific framework for geographical authentication. Our findings advance wax-based quality evaluation methodologies for fruit products, offering practical solutions for production area verification challenges in food raw materials. Full article

Background: snoRNAs have traditionally been known for their role as guides in post-transcriptional rRNA modifications. Previously, our research group identified several RNAs that may bind to PIP2 with LIPRNA-seq. Among them, snR191 stood out due to its potential specific interaction with this lipid, distinguishing itself from other snoRNAs. However, a detailed study is needed to define the molecular interactions between RNA and lipids, which remain unknown but may serve as a mechanism for transport or liquid–liquid phase separation. This study aimed to determine the interaction between a snoRNA called snR191 and PIP2. Method: A novel methodology for RNA-PIP2 interaction was carried out. Total RNA from Saccharomyces cerevisiae was incubated with PIP2-bound nitrocellulose membranes and RT-PCR reactions. We performed the prediction of snR191-PIP2 interaction by molecular docking and in silico mutations of snoR191. Results: From LIPRNA-seq analysis, we identified that PIP2-bound RNAs were significantly enriched in diverse biological processes, including transmembrane transport and redox functions. Our RNA-PIP2 interaction approach was successful. We demonstrated that snR191 specifically interacts with PIP2 in vitro. The elimination of DNA ensured that the interaction assay was RNA-specific, strengthening the robustness of the experiment. PIP2 was docked to snR191 in a stem–loop–stem motif. Six hydrogen bonds across four nucleotides mediated the PIP2-snR191 interaction. Finally, mutations in snR191 affected the structural folding. Conclusions: In this study, we demonstrate the effectiveness of a new methodology for determining RNA–lipid interactions, providing strong evidence for the specific interaction between snR191 and PIP2. Integrating biochemical and computational approaches has allowed us to understand the binding of these biomolecules. Therefore, this work significantly broadens our understanding of snR191-PIP2 interactions and opens new perspectives for further research. Full article

The ZC4H2 gene is the site of congenital mutations linked to neurodevelopmental and musculoskeletal pathologies collectively termed ZARD (ZC4H2-Associated Rare Disorders). ZC4H2 consists of a coiled coil and a single novel zinc finger with four cysteines and two histidines, from which the protein obtains its name. Alpha Fold 3 confidently predicts a structure for the zinc finger but also for similarly sized random sequences, providing equivocal information on its folding status. We show using synthetic peptide fragments that the zinc finger of ZC4H2 is genuine and folds upon binding a zinc ion with picomolar affinity. NMR pH titration of histidines and UV–Vis of a cobalt complex of the peptide indicate its four cysteines coordinate zinc, while two histidines do not participate in binding. The experimental NMR structure of the zinc finger has a novel structural motif similar to RANBP2 zinc fingers, in which two orthogonal hairpins each contribute two cysteines to coordinate zinc. Most of the nine ZARD mutations that occur in the ZC4H2 zinc finger are likely to perturb this structure. While the ZC4H2 zinc finger shares the folding motif and cysteine-ligand spacing of the RANBP2 family, it is missing key substrate-binding residues. Unlike the NZF branch of the RANBP2 family, the ZC4H2 zinc finger does not bind ubiquitin. Since the ZC4H2 zinc finger occurs in a single copy, it is also unlikely to bind DNA. Based on sequence homology to the VAB-23 protein, the ZC4H2 zinc finger may bind RNA of a currently undetermined sequence or have alternative functions. Full article

In order to design new materials at atomic-length scales, there is a need to connect the fractal nature of fracture surfaces at the atomic scale using quantum mechanics modeling with that of the experimental data of fracture surfaces at macroscopic-length scales. We use a semi-empirical quantum mechanics simulation of fracture in amorphous silica to calculate a parameter identified as a critical characteristic length, $a_0$, which has been experimentally derived from the fractal nature of fracture for many materials that fail in a brittle matter. To our knowledge, there are no known simulation models other than our related research that use the fractal parameter $a_0$ to describe the fractal fracture of the fracture surface using quantum mechanical simulations. We provide evidence that $a_0$ can be calculated at both the atomic and macroscopic scale, making it a fundamental property of the structure and one of the elements of fractal fracture. We use a continuous random network model and reaction coordinate method to simulate fracture. We propose that fracture in amorphous silica occurs due to bond reconfiguration resulting in increased strain volume at the crack tip. We hypothesize two specific configurations leading to fracture from a four-fold ring reconfiguration to three-fold ring or (newly observed) five-fold ring configurations resulting in a change in volume. Finally, we define a reconfiguration fracture energy at the atomic level, which is approximately the value of the experimental fracture surface energy. Full article

Background: Hypoxic hepatitis contributes to the development and progression of multiple organ failure (MOF). We evaluated whether MOF is associated with 30-day mortality in patients with hypoxic hepatitis. Methods: This retrospective study included 1011 patients diagnosed with hypoxic hepatitis at two centers in South Korea between 2010 and 2021. Organ failure was defined as a sequential organ failure assessment score ≥ 3 for each individual organ system. Results: Circulatory failure was the most common organ failure (n = 521), followed by respiratory (n = 380), cerebral (n = 307), renal (n = 236), coagulation (n = 182), and hepatic failure (n = 73). The proportions of patients without organ failure, with single organ failure, and with MOF were 28.7%, 22.3%, and 49.1%, respectively, with corresponding 30-day mortality rates of 17.9%, 29.3%, and 70.0%. In the multivariate Cox regression model, the presence of MOF grade 1 (two organ failures), grade 2 (three organ failures), and grade 3 (≥four organ failures) increased the risk of 30-day mortality by approximately threefold, fourfold, and fivefold, respectively, compared to patients without MOF. Conclusions: MOF is frequently observed in patients with hypoxic hepatitis and is a strong independent predictor of short-term mortality. Full article

The emergence of multidrug-resistant pathogens has driven the development of novel antimicrobial peptides (AMPs) as therapeutic alternatives. Lactolisterin LBU (LBU) is a bacteriocin with promising activity against Gram-positive bacteria, including Staphylococcus aureus. In this study, we designed and evaluated a panel of amino acid variants of LBU to investigate domain–activity relationships and improve activity. Peptides were commercially synthesized, and their effect was evaluated for minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), hemolytic activity, cytotoxicity, in vivo toxicity, and virulence modulation. AlphaFold3 structural prediction of LBU revealed a four-helix topology with amphipathic and hydrophobic segments. Helical wheel projections identified helices I and IV as amphipathic, suggesting their potential involvement in membrane interaction and activity. Glycine-to-alanine substitutions at helix I markedly increased antimicrobial activity but altered toxicity profiles. In contrast, changes at helix junctions and kinks reduced antimicrobial activity. We also showed differential regulation of virulence genes upon sub-MIC treatment. Overall, rational substitution enabled identification of residues critical for activity and toxicity, providing insights into therapeutic tuning of lactolisterin-based peptides. Full article

Background: Scrub typhus (ST) is caused by Orientia tsutsugamushi (OT) infection, which is transmitted to humans through the bites of infected chiggers. The clinical presentations range from mild to life-threatening multi-organ dysfunction. This report describes a cluster of ST cases involving five oil palm estate workers in Pekan district, Pahang, Malaysia. Methods: The clinical history, laboratory, and entomological investigation were conducted on the patients, including the index case and four suspected cases in the cluster. Polymerase chain reaction (PCR) tests for OT and genotyping were performed on the patients’ blood and urine samples. Serological testing by indirect immunoperoxidase (IIP) test against Rickettsial diseases was also conducted. Principal Findings: Patients presented with fever, myalgia, headache, rash, cough, and eschar. The index case developed severe ST complicated by acute kidney injury (AKI) and respiratory distress, requiring intubation and ventilation at the intensive care unit of a tertiary hospital. ST was confirmed through PCR analysis of a urine sample, showcasing a novel diagnostic approach. The other four cases were confirmed by a four-fold rise in immunoglobulin G (IgG) antibody titers. Conclusions: oil palm estate workers are at high risk for chigger exposure in Malaysia. Awareness among clinicians and the public of ST is crucial for effective prevention, accurate diagnosis, and optimal management. Full article

Solid fuels are still widely used in household heating in Europe and North America. Emissions from boilers are released in proximity to people. Therefore, there is a need to minimise the toxicity of emissions affecting human health to the greatest extent possible. This study compares the genotoxic potential of the emissions of four boilers of modern and old design (automatic, gasification, down-draft, over-fire) operating at reduced output to simulate the real-life combustion fed by various fossil and renewable solid fuels (hard coal, brown coal, brown coal briquettes, wood pellets, wet and dry spruce). Organic emissions were tested for genotoxic potential by analysing bulky DNA adducts and 8-oxo-dG adduct induction. There was no consistent genotoxic pattern among the fuels used within the boilers. Genotoxicity was strongly correlated with polycyclic aromatic hydrocarbon (PAH) content, and even stronger correlation was observed with particulate matter (PM). In all measured variables (PM, PAHs, genotoxicity), the technology of the boilers was a more important factor in determining the genotoxic potential than the fuels burned. The highest levels of both bulky and 8-oxo-dG DNA adducts were induced by organics originating from the over-fire boiler, while the automatic boiler exhibited genotoxic potential that was ~1000- and 100-fold lower, respectively. Full article

Background: Gastrointestinal (GI) cancer patients face a four-fold higher suicide risk than the general US population. This study explores psychosocial aspects of GI cancer patient experiences, assessing suicidal ideation and behavior, mental distress during treatment phases, and psychosocial factors on mental health. Methods: A two-phase mixed-methods approach involved a web-based survey and follow-up interviews. Quantitative data analysis validated mental health and suicidal ideation constructs, and correlation analyses were performed. The patient journey was charted from diagnosis to treatment. Results: Two hundred and two individuals participated, with 76 from the rural Appalachian region and 78 undergoing treatments. Quantitative analysis showed a higher prevalence of passive suicidal ideation than active planning. The post-treatment recovery period was the most emotionally challenging. Qualitative data emphasized emotional support and vulnerability to isolation. Care quality concerns included individualized treatment plans and better communication. Patients also needed clear, comprehensive information about treatment and side effects. The in-depth interview with four GI cancer patients revealed a healthcare system prioritizing expedient treatment over comprehensive care, lacking formal psychological support. AI emerged as a promising avenue for enhancing patient understanding and treatment options. Conclusions: Our research advocates for a patient-centric model of care, enhanced by technology and empathetic communication. Full article