Search Results (8,437)

Background: Metastatic prostate cancers frequently harbour pathogenic aberrations in Homologous Recombination Repair (HRR) genes that confer sensitivity to PARP inhibitors (PARPi). Therefore, accurate identification of all eligible patients is needed. The development of a circulating tumour DNA (ctDNA) testing alternative is promising as genomic testing of archived tissue leads to a failure rate of up to 30–40% in prostate cancer. Methods: This was a bi-institutional retrospective cohort study of patients with metastatic prostate cancer treated at the Jewish General Hospital or the McGill University Health Center, Montreal, Canada, between 2021 and 2023. Molecular data and treatment information were abstracted from a chart review. Chi-square, Fisher’s exact test, and Mann–Whitney tests were used to assess differences between groups. Results: We identified 484 metastatic prostate cancer patients. Somatic and germline testing for HRR was performed in 55.4% (n = 268) and 20% (n = 97) patients, respectively. Somatic testing was performed on tissue (n = 192, 71.6%) or ctDNA from liquid biopsies (n = 18, 6.7%) or both (n = 58, 21.7%). Pathogenic somatic HRR alterations were detected in 48 patients (17.9%). BRCA2 was the most frequent (n = 17), followed by ATM (n = 11), then CHEK2 (n = 5). Amongst patients with germline testing, 13/97 (13.4%) had pathogenic alterations predicted to lead to deficient HRR, mostly BRCA2 (n = 9), and three had detectable BRCA2 in tissue. Dual testing modality (tissue+ctDNA) significantly enhanced the detection rate of HRR alterations 19/58 (32.7%) vs. 29/210 (13.8%) for single testing modality (tissue or ctDNA), p = 0.008. The rate of inconclusive results was significantly lower in dual testing modality 0/58 (0%) vs. 25/210 in single testing modality (11.9%), p = 0.003. Amongst the 14 patients who had discordant results between liquid and tissue tests, HRR abnormalities were more frequently identified in ctDNA (n = 11) vs. tissue (n = 3). Patients who had HRR deficiency detected only in ctDNA had older tissue samples (median 5.6 years) compared to those who had deficient HRR detected only in tissue (median 0.2 years; p = 0.14). Conclusions: These data highlight a potential role in implementing liquid biopsy—especially in patients who only have older archival tissue available or failed tissue testing—to improve the detection rate of deficient HRR. Our ongoing prospective study will further validate whether the addition of liquid biopsy can identify more patients who are eligible to receive precision therapies by increasing the rate of detection of HRR deficiency compared to routine tissue testing alone. Full article

Background/Objectives: The optimal duration of antibiotic therapy for bacterial prosthetic joint infections (PJI) remains a topic of considerable debate. Current recommendations are often based on limited evidence and expert consensus. Emerging data suggest that shorter antibiotic courses may be as effective as prolonged treatments in select cases. Shortening the duration of therapy offers several advantages, including a reduced risk of bacterial resistance, fewer adverse events, and cost savings. However, this approach must be carefully balanced with the individual patient’s risk of treatment failure. This narrative review aims to synthesize current evidence regarding the duration of antibiotic therapy in PJIs, according to surgical strategies—DAIR (debridement, antibiotics, and implant retention), one-stage exchange, two-stage exchange, and resection without reimplantation—and to identify parameters that may guide individualized and potentially shortened regimens. Methods: We conducted a comprehensive search of PubMed, Embase, and Cochrane Library databases through January 2025, including observational studies, randomized controlled trials, and international guidelines. Reference lists of key articles were also screened. Results: Studies on DAIR suggest that longer regimens (e.g., 8–12 weeks) are necessary, especially in staphylococcal infections, as confirmed by the DATIPO trial, which showed higher failure rates with 6 weeks compared to 12 weeks. Evidence on one-stage exchange is limited but increasingly suggests that 6 weeks may be sufficient in selected patients; however, no dedicated trial has confirmed this. In two-stage exchange, small retrospective series report successful outcomes with short antibiotic therapy combined with local antibiotics, but randomized trials show trends favoring longer regimens. For patients treated with permanent resection arthroplasty, arthrodesis, or amputation, antibiotic durations are highly variable, with few robust data. Across all strategies, most studies are limited by methodological weaknesses, including small sample sizes, retrospective design, lack of microbiological stratification, and heterogeneous outcome definitions. Conclusions: Despite growing interest in shortening antibiotic durations in PJIs, high-quality evidence remains limited. Until additional randomized trials are available—particularly in one- and two-stage exchange settings—12 weeks remains the safest reference duration for most patients, especially those with retained hardware. Future studies should incorporate stratification by infection type, causative organism, and host factors to define tailored and evidence-based antibiotic strategies. Full article

Autoclaved lightweight concrete (ALC) exhibits considerable potential as a wall material in prefabricated structures, but its high water absorption and limited mechanical properties limit its widespread application. Ultra-high-performance concrete (UHPC), which possesses superior mechanical strength and durability, presents a promising reinforcement strategy. This study proposes the development of a UHPC-ALC composite wall material to enhance structural performance. The effects of shrinkage-reducing agent (SRA) content and expansive agent (EA) dosage on UHPC properties were systematically investigated. Results indicate that increasing SRA content improves the fluidity of UHPC and significantly reduces early autogenous shrinkage while the optimal EA dosage enhances both its mechanical properties and volume stability. Furthermore, an interfacial agent was employed to enhance the bonding performance between UHPC and ALC resulting in an average bonding strength of 0.93 MPa which represents a 675% increase compared with the untreated group. Finite element simulations and mechanical tests revealed that the composite material demonstrates a compressive strength of 11.2 MPa and a flexural strength of 6.8 MPa which corresponds to increases of 111.3% and 325%, respectively, relative to monolithic ALC. The composite demonstrated ductile failure and the experimental damage modes were consistent with those of the simulation results. This study offers guidance for optimizing UHPC-based composite wall materials via the multi-scale regulation of shrinkage behavior, interfacial properties, and structural design. Full article

Background: Methicillin-resistant Staphylococcus aureus (MRSA) colonization is a risk factor for potential staphylococcal infection and outbreaks. Although it is recommended to obtain a swab culture to detect nasal colonization its necessity in low-prevalence countries is debated. The aim of this study was to determine the prevalence of MRSA nasal colonization, the rate of invasive infection development, and the risk factors for invasive infections in patients admitted to the intensive care unit. Materials and Methods: This retrospective study included patients who were followed up in one of the adult intensive care units at Kayseri City Training and Research Hospital between 1 January 2019 and 31 December 2024 (6 years) and from whom a culture was taken at the time of hospital admission to detect MRSA colonization in the nose. MRSA carriers were examined for the development of any invasive infection caused by MRSA within 28 days of their relevant admission. Results: Over a total period of six years, nasal swab samples were collected from 22,913 patients, and MRSA colonization was detected in 939 (4.0%). Of the patients with MRSA colonization, 32 (3.4%) were excluded from the analysis because they already had invasive MRSA infection. Additionally, 431 patients (45.8%) were excluded from the analysis because they were discharged or died within the first seven days of their admission. Consequently, invasive MRSA infection developed within 28 days in 29 of the 476 patients with MRSA colonization (6.0%). Patients who developed invasive infection had a higher rate of chronic renal failure (p < 0.001), hemodialysis (p < 0.001), central venous catheter (p = 0.028), staying in nursing home (p = 0.001), and a history of hospitalization within the last 90 days (p = 0.015). In the multivariable regression analysis, routine hemodialysis (OR: 5.216, p = 0.015), nursing home stay (OR: 3.668, p = 0.014), and a history of hospitalization within the last 90 days (OR: 2.458, p = 0.028) were found to be risk factors for developing invasive infection. The most common invasive infections were ventilator-associated pneumonia (n = 9), surgical site infection (n = 7), and catheter-related bloodstream infection (n = 6). All 29 strains were susceptible to vancomycin, linezolid, and daptomycin, while one strain was resistant to teicoplanin (3.5%). Conclusions: MRSA colonization has been detected in 4% of patients admitted to the intensive care unit. Screening should be performed because MRSA colonization may be a risk factor for invasive infections; however, screening all patients would be prohibitively expensive and labor-intensive. Instead, it may be more appropriate to identify risk factors and then screen select patients. Full article

Bromodomain and extraterminal domain (BET) proteins act as epigenetic regulators of gene transcription. BET inhibitors have shown therapeutic potential in various models of heart failure; however, their efficacy in atrial fibrillation (AF) remains incompletely understood. This study investigated the effects of the BET inhibitor JQ1 in a mice model of AF. Wild-type male C57BL/6 mice were randomized into four groups: control, JQ1 alone (50 mg/kg, intraperitoneal), angiotensin II (AngII; 1 μg/kg/min), and AngII plus JQ1. After 2 weeks, electrophysiological studies revealed that JQ1 significantly reduced AngII-induced AF inducibility and duration. It also attenuated left atrial enlargement, diastolic dysfunction, and cardiac fibrosis. Molecular analyses indicated that JQ1 suppressed the AngII-induced upregulation of pro-fibrotic genes and restored Sirt1 expression. Moreover, JQ1 also inhibited AngII-enhanced oxidized CaMKII and phosphorylated RyR2 levels. In HL-1 atrial cardiomyocytes, JQ1 improved calcium handling abnormalities, shortened prolonged action potential duration (APD), and restored mitochondrial respiration and adenosine triphosphate (ATP) production, all of which had been impaired by AngII. These findings suggest that BET inhibition by JQ1 mitigates structural and electrical remodeling associated with AF by attenuating atrial fibrosis, and by restoring calcium homeostasis, mitochondrial function, and Sirt1 expression. JQ1 may represent a novel therapeutic strategy for the prevention and treatment of AF. Full article

Embryo implantation requires a finely tuned immune balance at the maternal–fetal interface. Interferon tau (IFN-τ), a key immunomodulator in ruminant implantation, may have therapeutic potential in human reproduction. This study investigated its effects on peripheral blood mononuclear cells (PBMCs) in vitro and the subsequent impact on endometrial immune composition following intrauterine administration of these cells. The work was conducted in two stages. First, in vitro assays were performed with PBMCs from 20 patients with recurrent implantation failure (RIF) cultured with or without IFN-τ for 24 h. Cytokines (IL-10, IL-4, TNF-α, IL-6) were measured by ELISA, and T cell subsets (Th, cytT, Th1, Th2, Th9, Tfh, Th17, Treg) were analyzed by flow cytometry. IFN-τ increased IL-4 and reduced TNF-α and IL-6, indicating a Th2 profile shift. T-cell analysis revealed fewer cytT, Th1, Th9, and Th17 cells, more Th2 cells, and improved Th/Tk, Th1/Th2, and Th17/Treg ratios after IFN-τ. A second clinical study included 55 RIF patients who received intrauterine IFN-τ-modulated PBMCs. Post-treatment endometrial biopsies revealed more helper T cells and macrophages, with higher Th/total T, Th/cytT, and Th/macrophage ratios, suggesting a tolerogenic environment. Overall, IFN-τ modulates PBMCs in vitro and promotes a favorable endometrial immune profile in vivo, highlighting its potential as an immunotherapy in assisted reproduction. Full article

Planetary gear trains offer numerous advantages over traditional gear systems, including high efficiency, the ability to handle large torque loads, and significant reductions in mass and size for the same torque capacity. However, their relatively complex design necessitates the use of optimization techniques to identify the most suitable configurations for specific applications. A key requirement for effective optimization is a mathematical model that accurately captures the essential operational characteristics of the system. Moreover, the optimization process must account for multiple, often conflicting, objectives. This paper focuses on the multicriteria optimization of a three-stage planetary gear train intended for use in a road vehicle winch. The development of the optimization model involves defining the objective functions, decision variables, and constraints. Optimization criteria were based on the following characteristics: overall volume, mass, transmission efficiency, and the production costs of the gear pairs. In addition to identifying the group of solutions that are Pareto optimal, the model employs the weighted coefficient method to select a single optimal solution from this set. The selected solution is then analyzed through simulation to assess potential gear failure scenarios. By combining optimization techniques with simulation and contact analysis, this study contributes to improving the reliability of planetary gear transmissions. Full article

Dynamic technological changes and the variability of market requirements pose significant challenges for modern manufacturing companies in the effective development and implementation of new technological solutions. The aim of the research was to develop an integrated approach covering all key stages of implementation—from formulating technological solutions, through selecting and evaluating variants, to preparing and managing production processes—under the conditions of a medium-sized manufacturing company specializing in the batch production of steel constructions. The analysis was based on an interdisciplinary approach, combining methods of creative design of new technological solutions, including Blue Ocean Strategy, value proposition design, and QFD methodology, with analytical approaches that include multi-criteria evaluation of solution variants, technical preparation of production, as well as the organization and management of production processes in modified organizational conditions. This approach enabled a comprehensive assessment of the developed solutions, taking into account both their operational potential and practical feasibility in realistic implementation conditions, through the use of case studies and simulations to validate the results. The results of the research indicate that integrating methods for creating new solutions with analytical assessment and simulation tools leads to a more precise and data-driven approach to process design, enabling better decision-making based on thorough analysis and predictive modeling. Furthermore, this approach allows for a significant reduction in the risk of implementation failure through early identification of potential problems. The conclusion of the study confirms that a comprehensive and interdisciplinary approach to the implementation of new technologies ensures better alignment with customer demands, reduces production downtime, and enhances product optimization and resource utilization, which are critical factors in building a sustainable competitive advantage for manufacturing companies. The proposed approach enables more deliberate design and organization of manufacturing processes, supporting their flexible adaptation to changing market and technological conditions. Full article

Staphylococcus aureus (S. aureus) is one of the most common hospital-acquired pathogens and poses a serious threat to patients with weakened immune systems. Transmission can occur through foodborne illness, skin infections, abscess formation, and bloodstream invasion. The most severe complication arises when S. aureus infects the heart, leading to valve damage and potentially progressing to heart failure. In addition, many strains have developed strong resistance to conventional antibiotic therapies, making treatment increasingly difficult. These challenges highlight the importance of early detection for effective prevention and management. This research focuses on the development of a polymer composite incorporating hydroxyproline for the preparation of molecularly imprinted polymers (MIPs) designed for the rapid detection of S. aureus. The sensing platform, based on electrochemical principles, enabled sensitive and efficient analysis of bacterial samples. The sensor exhibited a broad analytical range, detecting S. aureus from 1 to 10,000 CFU/mL, with a detection limit as low as 1.031 CFU/mL. Selectivity testing against Pseudomonas aeruginosa, Candida albicans, and Escherichia coli confirmed high specificity toward S. aureus. These findings highlight the potential of this MIP-based electrochemical sensor as a reliable tool for rapid bacterial detection in clinical and environmental settings. Full article

A modular, multi-functional (encompassing data acquisition, management, preprocessing, and transmission) sensing (MMFS) system based upon the Internet of Things (IoT) paradigm is discussed in this paper with the goal of continuous real-time, multi-sensor and multi-location monitoring of aircraft (including drones) structural performances during flight. According to industrial and system requirements, a microcontroller and four sensors (strain, acceleration, vibration, and temperature) were selected and integrated into the system. To enable the determination of potential in-flight failures and estimates of the remaining useful service life of the aircraft, resistance strain gauge networks, piezoelectric sensors for capturing structural vibrations and impact, accelerometers, and thermistors have been integrated into the MMFS system. Real flight tests with Evektor’s Cobra VUT100i and SportStar RTC aircraft have been undertaken to demonstrate the features of recorded data and provide requirements for the MMFS functional design. Real flight test data were analysed, indicating that a sampling rate of 1000 Hz is necessary to balance representation of relevant features within the data and potential loss of quality in fatigue life estimation. The design and evaluation of the performance of a prototype (evaluated via representative stress/strain experiments using an Instron Hydraulic 250 kN machine within laboratories) are detailed in this paper. Full article

Background/Objectives: Exercise capacity and patient prognosis are heavily influenced by comorbidities. However, the specific impact of individual comorbid conditions on objective measures of exercise performance remains insufficiently characterized. The study aimed to identify predictors of reduced physical capacity in patients qualified for cardiac rehabilitation. Methods: A single-center retrospective analysis was conducted on 518 patients qualified for cardiac rehabilitation. After excluding 51 post-cardiac surgery patients, cardiopulmonary exercise testing data from 425 patients (316 men, median age 63 years) were analyzed. Comorbidities data, peak oxygen uptake (peak VO₂), and the ventilation-to-carbon dioxide output slope (VE/VCO₂ slope) were evaluated. Results: A significantly reduced exercise capacity (peak VO₂ < 70% of the predicted value) was observed in 29.4% of patients, while an increased VE/VCO₂ slope (≥36) was noted in 20.8% of patients. Univariate logistic regression identified sex, heart failure, valvular disease, peripheral artery disease, diabetes mellitus (T2DM), chronic kidney disease (CKD), Charlson Comorbidity Index (CCI), left ventricular ejection fraction <50%, diastolic dysfunction, and anemia as predictors of both reduced peak VO₂ and a steeper VE/VCO₂ slope. Multivariate regression analysis further identified T2DM and CKD as independent predictors of reduced peak VO₂, while sex, CKD, and CCI were independent predictors of a steeper VE/VCO₂ slope. Conclusions: Among patients qualified for cardiac rehabilitation, patient’s sex, T2DM, CKD, and the CCI emerged as key predictors of reduced exercise capacity. Reduced peak VO₂ was more commonly observed in men, while women more frequently exhibited a steeper VE/VCO₂ slope, indicating potential sex-related physiological mechanisms influencing exercise performance. Full article

Reinforcement corrosion significantly reduces the load-bearing capacity, ductility, and energy dissipation of reinforced concrete (RC) structures, thereby increasing their seismic failure risk. To enhance the seismic performance of in-service RC structures, this study employs an FRP mesh–engineered cementitious composite (ECC) retrofitting method and develops a multi-objective optimization decision-making framework. A finite element model incorporating reinforcing steel corrosion, concrete deterioration, and bond–slip effects is first established and validated against experimental results. Based on this model, a six-story RC frame is selected as a case study, and eight alternative FRP mesh–ECC retrofitting schemes are designed. Five core indicators are quantified, namely annual collapse probability, expected annual loss, capital expenditure, carbon emissions, and downtime. The results indicate that FRP mesh–ECC retrofitting can significantly improve the seismic performance of corroded RC structures. The overall uniform retrofitting scheme (SCS-2) achieves the most significant improvements in seismic safety and economic performance, but they are associated with highest capital expenditure and carbon emission. Story-differentiated schemes (SCS-3 to SCS-6) provide a trade-off between performance enhancement and cost–emission control. While partial component-focused schemes (SCS-7 and SCS-8) cut cost and carbon but do not lower seismic downtime. Furthermore, the improved fuzzy-TOPSIS method with interval weights and Monte Carlo simulation indicates that the balanced scheme SCS-1 delivers the most robust performance across five dimensions, with a best probability close to 90%. The results confirm the potential of FRP mesh–ECC retrofitting at both component and structural levels and provide a practical reference for selecting seismic retrofitting strategies for existing RC structures. Full article

This study employs a finite element approach to investigate wellbore stability in interbedded weak formations, such as unconsolidated layers, with a focus on the failure-tendency method, which is derived according to the principle of Mohr–Coulomb theory. The numerical model is successfully verified through analytical solutions for stress distributions around a borehole. Through finite element modeling, the method captures critical shear failure thresholds, exemplifying how variations in horizontal stress anisotropy, orientation of interbedded weak layers, and mechanical properties of layered geological formations impact wellbore stability in stratified formations. Results indicate that the potential unstable regions, aligned in the direction of minimum principal stress, and the range of unstable regions gradually enlarge as the internal cohesive strength decreases. By modeling heterogeneous rock sequences with explicit representation of interbedded weak layers and stress anisotropy, the analysis reveals that interbedded weak layers are prone to shear-driven borehole breakouts due to stress redistribution and relatively lower internal cohesive strength. As compressive stresses concentrate at interfaces between stiff and compliant layers, breakouts are induced at those weak layers along the interfaces; this type of failure is also manifested through a field borehole breakout observation. Simulation results reveal the significant influences of the mechanical properties of layered formations and in situ stress on the distribution of instability regions around a borehole. The study underscores the necessity of layer-specific geomechanical models to predict shear failure in complex layered geological formations and offers insights for optimizing drilling parameters to enhance wellbore stability in anisotropic, stratified subsurface environments. Full article

(1) Background: To report two cases of severe tick-borne encephalitis (TBE) in elderly patients presenting with a previously undescribed subarachnoid T2/FLAIR hyperintensity on repeated MRI examinations, which may serve as an early imaging biomarker of disease severity. (2) Methods: Two unvaccinated 82-year-old patients (one male and one female) presented with acute encephalitis and required intensive care. Serial brain MRI, EEG, CSF analysis, and neurophysiological assessments were performed. (3) Results: Both patients showed rapid progressive neurological deterioration in the context of TBE, confirmed by elevated serum and CSF IgM and IgG titers. Early follow-up MRI revealed striking sulcal hyperintensities on T2/FLAIR sequences, interpreted as protein-rich subarachnoid inflammatory changes. These changes paralleled clinical worsening and resolved on follow-up imaging. The male patient developed meningoencephalomyeloradiculitis, remained comatose, and died from respiratory failure (the brain and spinal cord were examined postmortem). The female patient had meningoencephaloradiculitis with severe dysphagia and was discharged with a modified Rankin Scale score of four. Both patients demonstrated epileptiform EEG activity. The CSF analysis revealed markedly elevated total protein, lactate, tau protein, and CXCL13, as evidence of blood–brain barrier disruption and inflammatory neurodegeneration. (4) Conclusions: We describe acute subarachnoid T2/FLAIR hyperintensity in TBE as an imaging feature that may correlate with severe systemic inflammation and a poor prognosis. This radiological finding could serve as a potential early prognostic marker in TBE. Full article

Sepsis remains one of the major challenges in modern intensive care, characterized by high mortality and complex metabolic and immunological disturbances. Given the limited effectiveness of current therapeutic strategies, increasing attention has been directed toward supportive interventions aimed at restoring metabolic homeostasis. Particular interest has been focused on selected vitamins that exhibit pleiotropic biological effects. Thus, we summarized the current evidence on the role of selected vitamins (C, D, B1, B9, B12) in the treatment and supportive management of sepsis, highlighting their mechanisms of action, potential clinical benefits, and limitations derived from available studies. A comprehensive analysis of the literature was performed, including clinical trials and meta-analyses evaluating the efficacy of vitamin supplementation in sepsis, with particular emphasis on combined interventions and randomized controlled trials in severe sepsis and septic shock. Vitamin D might demonstrate the greatest therapeutic potential, particularly in patients with severe sepsis and respiratory failure, with benefits associated with achieving appropriate therapeutic concentrations. Thiamine (vitamin B1) appears to provide potential advantages primarily in deficient patients, improving mitochondrial function and reducing the risk of renal failure. Evidence regarding folic acid (vitamin B9) and cobalamin (vitamin B12) remains inconclusive, as both deficiency and elevated serum levels have been linked to adverse outcomes. Vitamin C, despite its well-documented antioxidant and microcirculatory effects, has not yet shown consistent evidence of mortality reduction. In conclusion, current evidence suggests that vitamin supplementation might represent an adjunct to standard sepsis therapy, particularly within a personalized approach that considers nutritional status and metabolic phenotype. The development of standardized dosing protocols and well-designed clinical trials is essential to determine the efficacy and safety of phenotype-driven individualized approaches in sepsis management. Full article