Search Results (42,453)

Background/Objectives: There is a need for prediction models which enable weighing benefits against risks of different treatment strategies for individual Hodgkin lymphoma (HL) patients. Therefore, we aimed to predict absolute risk of progression, first relapse or death (PRD) with and without incorporating HL treatment. Methods: The prognostic and treatment information of 2343 patients treated for classical HL at ages 15–60 years between 2008 and 2018 in the Netherlands was used to predict absolute risk of PRD up to 5 years after diagnosis using Cox proportional hazard models allowing for time-varying coefficients. Models were externally validated in 1675 patients treated for classical HL in Denmark between 2000 and 2018. Results: In early stages, gender, leukocyte, and lymphocyte counts were associated with risk of PRD. Additionally, receiving >4 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or ABVD plus radiotherapy predicted lower risk of relapse compared with receiving ≤4 cycles of ABVD. In advanced stages, age, albumin and leukocyte counts predicted PRD risk. Receiving (escalated) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) predicted lower PRD risk compared to ABVD. In Danish patients treated between 2008 and 2018, adding treatment information improved 5-year Inverse Probability of Censoring Weighted (IPCW) Area Under the Curve (AUC) values from 0.63 (95% Confidence Interval (CI): 0.55–0.72) to 0.71 (95% CI: 0.63–0.79) in early stages (p-value = 0.04) and from 0.59 (95% CI: 0.52–0.65) to 0.62 (95% CI: 0.55–0.68) in advanced stages (p-value = 0.33). Conclusions: We developed well calibrated models with reasonable discrimination, not only incorporating pre-treatment prognostic factors but also treatment effect enabling the prediction of absolute risk of first relapse/progression. Full article

The presence of various Ag species (Ag⁺ ions, Ag clusters, and Ag nanoparticles (NPs)) in Ag-zeolite nanocomposites strongly influences their catalytic, photocatalytic, and antibacterial properties. To tailor materials for specific applications, it is essential to employ strategies that control the redox processes between Ag⁺ and Ag⁰ and facilitate the formation of active Ag-containing composites. In this study, we present a comparative analysis of Ag-zeolite nanocomposites, focusing on their synthesis methods, structural characteristics, and antibacterial activity against Escherichia coli. Ag NPs were synthesized using three approaches: solid-state thermal reduction, chemical reduction in aqueous solutions with a mild reducing agent (sodium citrate, Na₃Cit), and chemical reduction with a strong reducing agent (sodium borohydride, NaBH₄). The resulting materials were characterized by X-ray diffraction (XRD), diffuse reflectance UV–Vis spectroscopy (DR UV–Vis), X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM), while antibacterial activity was assessed using biological assays. Microscopic and spectroscopic analyses confirmed the formation of Ag NPs and the co-existence of immobilized Ag⁺ ions within the zeolite framework. The specific influence of the treatment method of Ag⁺-zeolite on the presence of silver species in the nanocomposites and their role in antibacterial properties were evaluated. The highest antibacterial efficiency was observed in the nanocomposite produced by thermal treatment of Ag-exchanged zeolite. Thus, the crucial function of Ag⁺ ions in the mechanism of bacteria cell death was suggested. Full article

Ventricular arrhythmias such as ventricular fibrillation (VF) and ventricular tachycardia (VT) are among the leading causes of sudden cardiac death worldwide, making their timely and accurate detection a critical task in modern cardiology. This study presents an advanced framework for the automatic detection of critical cardiac arrhythmias—specifically ventricular fibrillation (VF) and ventricular tachycardia (VT)—by integrating deep learning techniques with neuro-fuzzy systems. Electrocardiogram (ECG) signals from the MIT-BIH and AHA databases were preprocessed through denoising, alignment, and segmentation. Convolutional neural networks (CNNs) were employed for deep feature extraction, and the resulting features were used as input for various fuzzy classifiers, including Fuzzy ARTMAP and the Adaptive Neuro-Fuzzy Inference System (ANFIS). Among these classifiers, ANFIS demonstrated the best overall performance. The combination of CNN-based feature extraction with ANFIS yielded the highest classification accuracy across multiple cardiac rhythm types. The classification performance metrics for each rhythm type were as follows: for Normal Sinus Rhythm, precision was 99.09%, sensitivity 98.70%, specificity 98.89%, and F1-score 98.89%. For VF, precision was 95.49%, sensitivity 96.69%, specificity 99.10%, and F1-score 96.09%. For VT, precision was 94.03%, sensitivity 94.26%, specificity 99.54%, and F1-score 94.14%. Finally, for Other Rhythms, precision was 97.74%, sensitivity 97.74%, specificity 99.40%, and F1-score 97.74%. These results demonstrate the strong generalization capability and precision of the proposed architecture, suggesting its potential applicability in real-time biomedical systems such as Automated External Defibrillators (AEDs), Implantable Cardioverter Defibrillators (ICDs), and advanced cardiac monitoring technologies. Full article

Retrotransposons exhibit increased activity in cancer cells. One possible approach to anticancer therapy is to use this activity to influence the energy balance in cells. Abnormal distribution of retrotransposons in the genome requires additional energy consumption, which can lead to a significant decrease in the total amount of free ATP molecules in the cell. A decrease in ATP levels below a certain threshold can in turn trigger a cell death program. To investigate the possibility of such a scenario, we developed a mathematical model of the cellular energy balance that describes the dynamics of energy consumption by the main cellular processes, including costs of retrotransposon activity. The model considers changes in the concentrations of ATP, active retrotransposons (LINE-1 and SINE) in the human genome, as well as mRNAs and proteins that are expression products of retrotransposon and constitutive genes. We estimated the parameter values in the model based on literature data and numerical optimization. We found a single stable stationary solution, characterized by low retrotransposon activity, and used it as the reference steady state for further analysis. Parametric sensitivity analysis revealed the parameters whose changes had the greatest impact on cellular ATP levels. The LINE-1 deactivation rate constant and the maximum LINE-1 transcription rate were the most sensitive among the transposon-related parameters. Perturbation of these parameters led to a decrease in the number of free ATP to 30% of the reference value and below. Transcription of retrotransposons under perturbed parameters became comparable to the translation of constitutive genes in terms of energy costs. The presented results indicate that cancer cell death can be initiated by increasing the load on the energy balance due to the activation of transposons. Full article

Doxorubicin (DOX) is an anthracycline chemotherapeutic agent that is clinically limited by doxorubicin-induced cardiotoxicity (DIC), with ferroptosis and apoptosis identified as key mechanisms. As an antioxidant enzyme, GPX4 undergoes ubiquitin-mediated degradation during myocardial ischemia–reperfusion injury; however, the role of its ubiquitination in DIC remains unclear. This study revealed that GPX4 undergoes ubiquitinated degradation during DIC, exacerbating ferroptosis and apoptosis in cardiomyocytes. NEDD4L was found to interact with GPX4, and its expression was upregulated in DOX-treated mouse myocardial tissues and cardiomyocytes. NEDD4L knockdown alleviated DIC, as well as ferroptosis and apoptosis in cardiomyocytes. Mechanistically, NEDD4L recognizes GPX4 through its WW domain and mediates K48-linked ubiquitination and degradation of GPX4 under DOX stimulation via its HECT domain. Knockdown of NEDD4L reduced DOX-induced GPX4 ubiquitination levels and subsequent degradation. Notably, while NEDD4L knockdown mitigated DOX-induced cell death, concurrent GPX4 knockdown attenuated this protective effect, indicating that GPX4 is a key downstream target of NEDD4L in regulating cardiomyocyte death. These findings identify NEDD4L as a potential therapeutic target for preventing and treating DIC. Full article

Background: Tetralogy of Fallot is a congenital heart defect that requires early surgical correction. However, in developing countries, many patients undergo delayed treatment due to limited healthcare resources. This study aims to identify risk factors for postoperative complications in humanitarian patients undergoing late Tetralogy of Fallot repair, defined as surgery performed after 12 months of age. Methods: A retrospective analysis was conducted on 115 humanitarian paediatric patients with a median age of 1444 days (approximately 4 years) who underwent complete Tetralogy of Fallot correction. In this humanitarian programme, patients from developing nations underwent surgical repair at our tertiary referral centre in a high-resource country. Postoperative complications were monitored within the first 30 days after surgery. Two multivariable logistic regression models were used to analyse pre/perioperative (Model 1) and postoperative (Model 2) risk factors for complications. Results: Complications occurred in 24.3% of patients. No deaths were recorded. In Model 1, smaller pulmonary valve annulus (OR = 0.066; p < 0.01) and the use of right ventricle to pulmonary artery conduit (OR = 13.252; p < 0.01) were significantly associated with a higher risk of complications. In Model 2, prolonged invasive ventilation time (OR = 1.068; p < 0.01) and extended hospitalisation time (OR = 1.093; p = 0.04) were significantly associated with complications. Conclusions: Late surgical correction of Tetralogy of Fallot in humanitarian paediatric patients can be performed with low mortality but carries a significant risk of postoperative complications. The predictive models provide useful tools for proactive clinical monitoring, personalised management, and optimisation of hospital resources. Full article

Cardiovascular diseases, which are among the most common diseases of the population and among the leading causes of death, are a constant topic of many research centers. A deeper understanding of their pathogenesis may contribute to the development of innovative diagnostic and therapeutic techniques. Recently, the role of myokines—a group of cytokines secreted mainly by muscle cells—has been increasingly emphasized in the development of these diseases. Both their excess and deficiency can cause undesirable effects that are involved in the pathomechanism of these diseases. In this review, we focus on the latest studies on the role of myonectin, irisin, musclin, follistatin-like1 (FSTL1), dermcidin, apelin, and myostatin in the pathogenesis of coronary artery disease, heart attack, heart failure, and hypertension. In particular, we look at myostatin and irisin in the context of the development of heart failure and decreased levels of apelin with higher cardiovascular risk in a group of patients with rheumatoid arthritis. Full article

Background/objectives: Multiple systemic treatments are available for metastatic castration-resistant prostate cancer (mCRPC), with unclear safety profiles. This study seeks to describe the safety determined in randomized clinical trials of a systemic treatment for mCRPC and whether safety differs by age. Methods: We utilized individual patient data from industry-funded phase 2/3 trials in mCRPC on abiraterone acetate (AA). Vivli, a clinical trial repository site, was used. One investigator independently performed screening. Relative effects of treatment were assessed with frequencies and odds of serious adverse events (SAEs). The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. Subgroup analysis measured odds of SAEs as modified by age. Results: We identified 14 trials with 4296 patients. The median age of participants was 69 years. Nearly all participants experienced at least one adverse event (98.4% abiraterone, 97.3% standard of care [SOC]). More serious adverse events (grade 3 or 4) and deaths (grade 5) occurred in those receiving SOC (71.8%) compared to abiraterone (64.1%). The most frequent adverse event category was “Musculoskeletal and Connective Tissue Disorders”. The most frequent event types included anemia, back pain, hypertension, fatigue, hypokalemia, and bone pain. The odds of all events were lower in those receiving abiraterone compared to SOC. Odds of a serious musculoskeletal event were lower in older subjects by 22% (OR 0.78; 95% CI 0.63, 0.96). Conclusions: In this IPD meta-analysis, abiraterone acetate provides no greater risk of SAE in those receiving abiraterone than those receiving SOCs. Patients in the RCTs are younger and healthier than those in the general population; consequently, the results of RCTS might not be applied to the general population, especially those under-represented in the RCTs. There is a need to further evaluate abiraterone-related fractures and neuromuscular toxicities (NMTs) as key outcomes to gain insight into risk factors related to these adverse events. A real-world prospective study is warranted to examine the overall risks and benefits associated with treatment. Full article

Background/Objectives: Cancer ranks as the second most prevalent cause of death worldwide, according to the World Health Organization. Approximately one in six global deaths is attributed to cancer. Among females, breast cancer stands out as the most frequent type of tumor. Raloxifene (RLX), recognized as a selective estrogen receptor modulator, has been employed as a therapeutic option in treating breast cancer among postmenopausal women. The objective of this study was to investigate the anticancer potential of raloxifene-loaded hexosomes, nanoliposomes, and nanoniosomes to identify the most effective formulation. Methods: The particle size, zeta potential, entrapment efficiency, and structural elucidation of the various nanovesicle formulations was validated; Results: Each nanocarrier exhibited a negative surface charge, nanometric size, and a reasonable encapsulation efficiency. Cytotoxicity of the different raloxifene-loaded nanovesicles on MCF-7 breast cancer cell lines and MCF10 non tumorigenic cells revealed the substantial cytotoxic activity of the hexosomal nanocarrier compared to the other nanovesicles, exhibiting the lowest IC50 = 45.3 ± 1.10 µM. Conclusions: The RLX-loaded hexosomal formulation showed superior cytotoxic activity, indicating its potential as a highly effective therapeutic agent. To fully understand its capabilities and mechanisms, further in vitro characterization studies are necessary. Full article

The emergence of multi-drug-resistant bacteria (known as superbugs) represents one of the greatest challenges for human health and modern medicine. Due to their remarkable ability to rapidly develop resistance to currently used antibiotics, new molecular targets for bacteria and substances capable of effectively combating related infections are still being sought. Lasso (known also as lariat) peptides are an unusual subclass of ribosomally synthesized and post-translationally modified peptides (RiPPs) with a structurally constrained knotted fold resembling a lasso. They are synthesized by certain groups of microorganisms as a result of complex processes involving intricate structural changes leading to the formation of the lasso structure. Reproducing these processes using known peptide synthesis methods poses a major challenge for synthetic chemistry. Lasso peptides exhibit a range of bioactivities including antibacterial activity. Due to the lasso structure, the peptides are capable of binding to new molecular targets, including atypical sides of ribosomes, in relation to currently used antibiotics. Thus, creating new mechanisms that inhibit metabolic processes leading to the death of pathogenic bacteria. This feature makes lasso peptides a potential “last chance” weapon in the fight against emerging superbugs. Full article

Focal therapy for prostate cancer (PCa) provides approaches to treat PCa patients in a less invasive manner than traditional whole-gland surgical or radiation modalities. This manuscript provides a case series of high-intensity focused ultrasound (HIFU), cryoablation, and irreversible electroporation (IRE) for PCa at a single institution and cost analysis with a review of the literature. All patients who underwent HIFU, cryoablation, or IRE for localized PCa were retrospectively reviewed, excluding patients who received whole-gland therapy. Functional outcomes were erectile dysfunction and lower urinary tract symptoms. Cost data were collected. A total of 45 patients were included in the study with focal therapy ranging from 2023 to 2025 (4 HIFU, 20 cryoablation, 21 IRE). A total of 30 patients had focally treated lesions, and 15 patients had hemi-gland treatment. The mean preoperative PSA was 7.7 ng/mL. On the paired sample t-test, there was no significant difference between pre-focal and post-focal therapy PSA. Three patients experienced biochemical recurrence requiring prostate biopsy after focal treatment. Mean cost was USD 3804.50 and not significantly different by focal treatment. No metastatic events occurred nor deaths at a median follow-up of 6 months. Patients in this series had largely unaltered functional outcomes. Cost analysis in contemporary publications is lacking. Although follow-up was short, cancer control was adequate. Full article

Rift Valley Fever Virus (RVFV) is an arbovirus that predominantly affects sheep, goats, and cattle, causing epizootics in livestock and epidemics in humans. Infection in pregnant livestock leads to high abortion rates and neonatal mortality. In humans, RVFV usually causes a self-limiting febrile illness, but severe forms can develop, such as hepatitis, hemorrhage, encephalitis, and death. In addition, the association between RVFV infection during pregnancy and miscarriages or stillbirths has been documented. RVFV is transmitted by a range of mosquito species, and, due to the diffusion of these insects, the virus has spread in several world regions, making possible the risk of a public health emergency. Nevertheless, research remains limited and cellular pathology is still poorly characterized. This work aimed to fill some knowledge gaps on the comprehension of RVFV pathogenesis. For this purpose, transmission electron microscopy (TEM) was used to analyze cellular modifications associated with RVFV morphogenesis in four human cell lines (HuH-7, LAN-5, A549, and HTR-8/SVneo) derived from liver, brain, lung, and placenta. Our results showed that all four cell lines are permissive to RVFV infection and highlighted differences in the cytopathogenesis associated with the cell type. These findings could have important implications in understanding disease mechanisms and developing antiviral strategies. Full article

According to the World Health Organization, cardiovascular diseases, including cardiac arrhythmias, are the leading cause of death worldwide due to their silent, asymptomatic nature. To address this problem, early and accurate diagnosis is crucial. Although this task is typically performed by a cardiologist, diagnosing arrhythmias can be imprecise due to the subjectivity of reading and interpreting electrocardiograms (ECGs), and electrocardiograms are often subject to noise and interference. Deep learning-based approaches present methods for automatically detecting arrhythmias and are positioned as an alternative to support cardiologists’ diagnoses. However, these methods are trained and tested only on open datasets of electrocardiograms from Holter devices, whose results aim to improve the accuracy of the state of the art, neglecting the efficiency of the model and its application in a practical clinical context. In this work, we propose an efficient model based on a 1D CNN architecture to detect arrhythmias from smartwatch ECGs, for subsequent deployment in a practical scenario for the monitoring and early detection of arrhythmias. Two datasets were used: UMass Medical School Simband for a binary arrhythmia detection model to evaluate its efficiency and effectiveness, and the MIT-BIH arrhythmia database to validate the multiclass model and compare it with state-of-the-art models. The results of the binary model achieved an accuracy of 64.81%, a sensitivity of 89.47%, and a specificity of 6.25%, demonstrating the model’s reliability, especially in specificity. Furthermore, the computational complexity was 1.2 million parameters and 68.48 MFlops, demonstrating the efficiency of the model. Finally, the results of the multiclass model achieved an accuracy of 99.57%, a sensitivity of 99.57%, and a specificity of 99.47%, making it one of the best state-of-the-art proposals and also reconfirming the reliability of the model. Full article

Lifetime reproductive output (LRO), also called lifetime reproductive success (LRS) is often described by its mean (total fertility rate or net reproductive rate), but it is in fact highly variable among individuals and often positively skewed. Several approaches exist to calculating the variance and skewness of LRO. These studies have noted that a major factor contributing to skewness is the fraction of the population that dies before reaching a reproductive age or stage. The existence of that fraction means that LRO has a zero-inflated distribution. This paper shows how to calculate that fraction and to fit a zero-inflated Poisson or zero-inflated negative binomial distribution to the LRO. We present a series of applications to populations before and after demographic transitions, to populations with particularly high probabilities of death before reproduction, and a couple of large mammal populations for good measure. The zero-inflated distribution also provides extinction probabilities from a Galton-Watson branching process. We compare the zero-inflated analysis with a recently developed analysis using convolution methods that provides exact distributions of LRO. The agreement is strikingly good. Full article

Flooding can cause root hypoxia and can lead to significant agricultural losses. Therefore, understanding plant adaptations to flooding, including root aerenchyma development, is one important avenue for insuring future global food security. We investigated cell wall modifications during root aerenchyma formation in response to the prolonged 0–48 h flooding of Phaseolus coccineus, Pisum sativum, and Cicer arietinum seedlings. Using transmission electron microscopy, toluidine blue O (TBO) staining, and immunolabeling with antibodies targeting de-methyl-esterified homogalacturonan (DMEH), partially DMEH, and methyl-esterified homogalacturonan (MEH), we examined changes in cell wall composition. Transmission electron microscopy and TBO staining revealed degradation of cell walls and middle lamella, with accumulation of DMEH near flooding-induced aerenchyma cavities. Immunolabeling indicated increased DMEH epitope availability in flooded roots, suggesting a role in cell wall remodeling. Enzyme pretreatments, used to “unmask” homogalacturonan by removing cellulose and hemicellulose, revealed that specific forms of homogalacturonan, particularly DMEH complexed with calcium and MEH, are masked by these cell wall components. The study highlights the complex interplay of pectin, cellulose, and hemicellulose in cell wall degradation during aerenchyma development, providing insights into legume flooding stress responses. Full article