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Glioblastomas represent the most aggressive and lethal form of primary brain cancer and continue to pose a major challenge to global health. MicroRNAs (miRNAs), as central regulators of gene expression, are intimately involved in the initiation, progression, and therapeutic resistance of numerous malignancies, including glioblastoma. Therefore, this class of non-coding RNAs are considered to be valuable candidates for innovative therapeutic strategies. However, despite many promising preclinical studies, miRNA-based therapies have yet to be translated into routine clinical practice. In the context of glioblastoma, one of the principal obstacles to the effective delivery of synthetic miRNA therapy is their limited ability to cross the blood–brain barrier (BBB). To address this challenge, a variety of locoregional delivery strategies have been developed in recent years. In this review, we provide a detailed discussion and a state-of-the-art overview of these local delivery methods in the context of glioblastoma treatment, with a specific emphasis on their application for delivering miRNA-based therapeutic oligonucleotides, formulated either with or without synthetic nanoparticles. Full article

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a critical pathogen associated with severe hospital infections and high antimicrobial resistance. Despite the global significance of A. baumannii, there are limited data from Costa Rica regarding the resistance rate and genomic characteristics of CRAB. Methods: This study aimed to provide initial and exploratory epidemiological data on infections caused by A. baumannii and CRAB isolated in Costa Rica and to gain insights on the genome of selected strains, focusing on their resistance determinants and phylogenetic relationships. Results: Based on data from five main hospitals in Costa Rica, resistance rate to carbapenems was estimated at 9.8% to imipenem and 6.1% to meropenem. From 190 carbapenem-resistant clinical isolates available in a local collection, seven A. baumannii strains were identified, all showing resistance to carbapenems and carrying the bla_NDM-1 gene. Whole-genome sequencing of two strains yielded two distinct MLST profiles (Pasteur scheme: ST-150 for strain IPAT15 and ST-250 for IPAT72), as well as variations in the number and identity of plasmids, genomic islands, and other elements of the mobilome. Both isolates carried ten antimicrobial resistance genes, which are predicted to be harbored in plasmids for IPAT15, unlike the chromosomal determinants in IPAT72. A pangenome analysis of 878 genomes from a public database identified over 51,000 genes, with only 1338 (2.6%) forming the core genome. Phylogenetic analysis and assignation of international clones (ICs) showed predominance of IC2. Isolates from Costa Rica clustered near IC9 and shared some resistance determinants, but they were not directly assigned to an IC. Conclusions: Overall, this study provides exploratory insights regarding the occurrence of CRAB in Costa Rica using epidemiological and genomic data, with profiles that are comparable to other regions in Latin America and diverse genomic resistance determinants. While this study does not show the whole landscape of CRAB in Costa Rica, these data constitute an initial approach for improving clinical management and public health responses to CRAB infections, to ultimately improve outcomes for patients affected by this pathogen. Full article

Background: Prostate cancer (PCa) arises from complex interactions among host genetics, androgen signaling, and microbial communities. Emerging genomic evidence supports the presence of microbial consortia within prostate tissue, suggesting that microbial genes, metabolites, and host–microbe interactions may contribute to chronic inflammation, oncogenic signaling, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies published between 2020 and 2025, complemented by selected mechanistic reports published in March 2026. Human studies and experimental research providing mechanistic insights into prostate models were prioritized. Due to the heterogeneous methodologies, evidence was synthesized qualitatively, with an emphasis on genomic and signaling perspectives. Results: Low-biomass microbial DNA is consistently detected in prostate tissue. Proteomic analyses of Corpora amylacea suggest a “fossil record” of past infections through sequestered microbial DNA and antimicrobial proteins, potentially priming tissue for long-term carcinogenic processes, although contamination remains a key limitation. Recurrent bacterial and viral signals, including Cutibacterium acnes, Escherichia coli, Pseudomonas, Acinetobacter, human papillomavirus, Epstein–Barr virus, and cytomegalovirus, appear to converge on a restricted set of tumor-relevant pathways, including TLR–NF-κB, MAPK, PI3K/AKT/mTOR, cGAS–STING, and p53/pRb disruption. These interactions may promote cytokine production, oxidative stress, DNA damage, epithelial–mesenchymal transition, extracellular matrix remodeling, immune evasion, and resistance to therapy. The gut–prostate axis further links intestinal dysbiosis and microbial metabolites with systemic IGF-1 signaling and castration resistance. Conclusions: Microbial genomic consortia in the prostate and gut may shape inflammatory, metabolic, and immune networks that influence PCa initiation and progression. However, most available data remain correlative and are limited by low-biomass sampling, contamination risk, and heterogeneous study designs. Future research should prioritize rigorous contamination control, longitudinal and prostate-specific mechanistic studies, and integrated multi-omic approaches to clarify causality and identify actionable microbial targets for prevention, diagnosis, and therapy. Full article

Cellular senescence represents a critical biological paradox in oncology. Although it evolved as a safety mechanism to halt tumorigenesis through stable cell cycle arrest, its persistence in tissues can alter the microenvironment, promoting tumor recurrence. In the context of glioblastoma (GBM), this phenomenon is critically important, as current standard therapies, such as radiotherapy and chemotherapy, inadvertently induce a state of senescence known as “therapy-induced senescence” (TIS). Senescent cells remain metabolically active and acquire a unique Senescence-Associated Secretory Phenotype (SASP), characterized by the release of pro-inflammatory cytokines, proteases, and growth factors. SASP reshapes the tumor microenvironment (TME) through paracrine signals, promoting immunosuppression, invasiveness, drug resistance and tumor recurrence. Different glial populations, including astrocytes, microglia, and oligodendrocyte precursor cells (OPCs), respond differently to senescence, specifically contributing to the creation of a permissive niche for tumor recurrence. To contrast the effects of this phenomenon, a promising therapeutic strategy has emerged, the “one-two punch,” which induces initial DNA damage followed by selective elimination of senescent cells with senolytic drugs. In this review, we analyze in detail the efficacy of targeted synthetic agents, such as the Bcl-2 family inhibitor Navitoclax, and natural bioactive compounds such as Quercetin and Fisetin. The analysis focuses on the molecular mechanisms through which these agents disrupt anti-apoptotic pathways (SCAPs) and inhibit the PI3K/AKT/mTOR axis, restoring sensitivity to apoptosis. We propose that the integration of senolytic adjuvants into standard clinical protocols may represent a crucial frontier for eliminating residual disease reservoirs and we also suggest the possibility of combining them with molecules with neuroprotective action to significantly improve the prognosis in GBM. Full article

Candida dubliniensis is an opportunistic yeast closely related to Candida albicans and an uncommon cause of central nervous system (CNS) infection. While isolates are often susceptible to azoles, reduced susceptibility or acquired resistance may occur, making species identification and antifungal susceptibility testing clinically relevant. We report a 3-year-old boy with Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (ALL) in hematologic remission who developed chronic meningitis during maintenance chemotherapy. The initial presentation was non-specific (marked somnolence without fever or meningeal signs) and lumbar puncture performed to exclude CNS relapse revealed neutrophil-predominant pleocytosis and elevated protein; the cerebrospinal fluid (CSF) culture grew C. dubliniensis. Treatment with intravenous liposomal amphotericin B followed by prolonged fluconazole led to clinical improvement and sterile CSF. Six months later, progressive gait disturbance, limb pain, and episodic severe headaches recurred; repeat CSF cultures again yielded C. dubliniensis, with a changed susceptibility profile. Spine MRI demonstrated leptomeningeal enhancement involving the cauda equina nerve roots. Intravenous voriconazole with therapeutic drug monitoring was initiated and combined with intrathecal liposomal amphotericin B (seven doses, dose-escalated up to 3 mg), which was well tolerated and associated with rapid neurologic improvement, CSF sterilization, and radiologic resolution. At 12 months of follow-up, the patient remained infection-free and in leukemia remission. This case highlights that C. dubliniensis chronic meningitis may present subtly yet progress, requiring repeated CSF cultures with susceptibility testing; intrathecal liposomal amphotericin B can be a safe and effective adjunct to systemic therapy in refractory or recurrent disease. Full article

Population aging has markedly increased the burden of cancer in older adults, in whom frailty, sarcopenia, and reduced physiological reserve limit tolerance to treatment and worsen clinical outcomes. Aging is accompanied by progressive functional decline and by biological processes such as cellular senescence, characterized by irreversible cell cycle arrest, chronic low-grade inflammation, and impaired immune surveillance. The accumulation of senescent cells and the persistence of a senescence-associated secretory phenotype contribute to tissue dysfunction and generate a microenvironment that favors tumor initiation and progression. Physical exercise has been associated with attenuation of inflammation, improvements in metabolic and immune function, and with lower levels of senescence-related biomarkers. Although aerobic exercise has been extensively studied in this setting, resistance training holds relevance for older adults due to its capacity to counteract sarcopenia, preserve muscle strength and power, and sustain functional independence. Structured and periodized approaches to resistance exercise may further enhance these benefits by delivering targeted stimuli aligned with age-related physiological deficits. Block strength training (BST), a periodized model that concentrates training adaptations into sequential phases of maximal strength, power, and muscular endurance, has demonstrated consistent improvements in functional performance and reductions in frailty risk in community-dwelling older adults. BST improves physical function. It may also influence biological processes related to aging and cancer; however, mechanistic evidence specific to BST remains to be established. We hypothesized that the exercise in block as a targeted, a structured and physiologically grounded resistance training intervention highlights the potential of BST to promote functional aging and healthy. In the case of cancer biology, and the environment near to tumour, the relationship between aging mechanisms in older adults and controlled exercise effects are currently in advance, but mechanistic trials are still lacking. Finally, we propose a novel training method, structured and personalized, that could impact different clinical outcomes in older patients with cancer. Full article

Remote ischemic conditioning (RIC) is an endogenous strategy that mitigates cerebral injury in preclinical stroke models. However, its bench-to-bedside translation is frequently hindered by complex patient environments that induce RIC resistance and limit its neuroprotective efficacy. To bridge this translational gap, this review systematically examines the extrinsic pathophysiological and pharmacological barriers to RIC. We categorize RIC resistance into three mechanism-driven phenotypes. Impaired signal initiation (Type I) is often linked to diabetic sensorimotor polyneuropathy and the reactive oxygen species-scavenging effects of propofol. Signal transmission blockade (Type II) is associated with specific P2Y12 inhibitors and smoking-induced endothelial dysfunction. Furthermore, effector desensitization (Type III) involves target-organ unresponsiveness exacerbated by aging, chronic hyperglycemia, and postmenopausal estrogen depletion. To address these barriers, potential phenotype-specific optimization strategies are discussed. Ultimately, transitioning from generalized empirical protocols to mechanism-based precision strategies may help bypass RIC resistance in clinical settings and enhance stroke cerebroprotection. Full article

A rock-socketed pile model load test was conducted for the renovation project of the dangerous old bridge at Shaoping Bridge. The experiment focused on the core parameter of the roughness factor (RF) of the pile body, revealing its influence on the bearing characteristics. The study delved into the load–displacement relationship, ultimate bearing capacity evolution, axial force transmission mechanism, average lateral resistance performance characteristics, and pile–soil relative displacement law of test piles in complex rock formations under different RF values. The research results indicated the following: The test pile exhibited typical brittle failure. At the moment of failure, the load at the pile head dropped abruptly, resulting in a steep drop in its load–displacement curve. Under ultimate load conditions, the average attenuation amplitudes of axial force in the four test piles decreased progressively in Rock Layer I, II, and III, measuring 26.96%, 14.86%, and 10.84%, respectively. The average side resistance distribution along the pile shaft showed a single-peak pattern, peaking in Rock Layer I. Increasing RF effectively enhanced the bearing capacity of test piles. However, a higher RF value does not necessarily yield better results, as it exhibits an inverted U-shaped relationship with bearing capacity. Under the specific conditions of this study, the highest bearing capacity among the tested RF values was observed at RF = 0.168; beyond this threshold, performance actually declined. The pile-top load was primarily shared by side resistance and end bearing resistance. Both components initially increased and then decreased with increasing RF, where the end bearing resistance accounted for 43.64~49.47% of the upper load. Full article

Titanium alloys exhibit exceptional strength-to-density ratios, high hardness, and outstanding resistance to elevated temperatures, making them indispensable structural materials in aerospace engineering, marine construction, and biomedical applications. In aerospace systems specifically, fatigue failure represents the predominant failure mode for titanium alloy components. This review systematically examines prevalent surface treatment techniques for titanium alloys—including shot peening, ultrasonic rolling treatment, hot isostatic pressing (HIP), physical vapor deposition (PVD), micro-arc oxidation (MAO), and thermal spray processes—and critically evaluates their respective effects on fatigue performance. The underlying mechanisms of each technique are concisely outlined, with emphasis on stress state evolution, near-surface microstructural refinement, and interfacial integrity. Building upon the characteristic surface-dominated fatigue fracture behavior of titanium alloys, this work focuses on how coating composition, architecture (e.g., graded, multilayer, or nanocomposite designs), and interfacial bonding strength govern fatigue resistance. A unified analysis is presented on the distinct yet complementary roles of substrate deformation strengthening (e.g., residual compression, grain refinement) and coating-mediated protection (e.g., barrier function, crack deflection, stress redistribution) during fatigue crack initiation and propagation. Key determinants of fatigue performance, including residual stress distribution, coating/substrate adhesion, thermal mismatch, and environmental degradation susceptibility, are rigorously assessed. Finally, emerging research frontiers are identified, including intelligent process–structure–property mapping, in situ monitoring of fatigue damage at coated interfaces, and design of multifunctional gradient coatings that synergistically enhance strength, wear resistance, and fatigue endurance of titanium alloy components. Full article

High-speed railway corridors operating under dense traffic conditions often face capacity limitations and operational conflicts caused by minimum headway constraints and heterogeneous train services. Differences in running times and stopping patterns between fast and slow trains may lead to overtaking conflicts and inefficient infrastructure utilization. This study investigates a multi-objective timetable optimization problem for high-speed railways under minimum headway constraints. A timetable optimization framework is established for high-speed railways under dense heterogeneous operations. The core mathematical formulation explicitly models timetable variables and basic temporal bounds, including sectional running-time limits, dwell-time bounds, and operating time-window constraints. Additional engineering feasibility requirements, such as minimum headway, station-capacity restrictions, and in-station overtaking feasibility, are enforced through the BS-FGS feasibility-scheduling procedure and the repair-based constraint-handling mechanism in the improved MOPSO stage. A hierarchical solution framework is proposed in which a Binary Search–Feasibility-Guided Greedy Scheduling (BS-FGS) method first evaluates the maximum feasible train number and generates an initial feasible timetable, followed by an improved Multi-Objective Particle Swarm Optimization (MOPSO) algorithm to obtain Pareto-optimal solutions within the feasible region. A case study on the Shanghai–Hangzhou High-Speed Railway corridor shows that system utilization can reach approximately 0.93–0.94 when in-station overtaking is allowed. Robustness simulations further demonstrate that the optimized timetables maintain stable train intervals and exhibit strong disturbance resistance. These results indicate that the proposed framework provides effective support for capacity evaluation and timetable optimization in high-density high-speed railway operations. Full article

The rational design of electrode materials with tailored composition and architecture is crucial for advancing high-capability electrochemical energy storage systems. This study reports that gadolinium-modified NiFe₂O₄ nanosheet electrodes were effectively synthesized on nickel foam via a hydrothermal approach followed by thermal treatment. A series of compositions (NiFe, NiFe–Gd1, NiFe–Gd2, and NiFe–Gd3) were prepared to systematically examine the effect of Gd incorporation on structural features and electrochemical properties. X-ray diffraction (XRD) analysis confirmed the formation of the cubic spinel NiFe₂O₄ phase without detectable secondary phases, indicating that the crystal structure remains intact after Gd introduction. X-ray photoelectron spectroscopy (XPS) further verified the presence of Ni²⁺, Fe³⁺, and Gd³⁺ species within the lattice environment. Morphological analysis using field-emission scanning electron microscopy (FESEM) revealed a nanosheet-based architecture, where the optimized NiFe–Gd2 electrode exhibited a porous and interconnected nanosheet framework with abundant exposed edges. This structural configuration improves electrolyte penetration and facilitates efficient ion transport during charge storage processes. Electrochemical measurements demonstrated that the NiFe–Gd2 electrode delivers an areal capacitance of 5235 mF cm⁻² at 10 mA cm⁻², along with improved reaction kinetics and low internal resistance. An asymmetric supercapacitor assembled using NiFe–Gd2 as the positive electrode and activated carbon as the negative electrode operated stably within a 0–1.5 V potential window, achieving an energy density of 0.136 mWh cm⁻² and a power density of 3.14 mW cm⁻², while retaining 86.55% of its initial capacitance after 7000 cycles. These results highlight the potential of rare-earth engineering as a viable strategy for designing advanced spinel ferrite electrodes and pave the way for the development of high-performance, durable, and scalable supercapacitor systems for practical energy storage applications. Full article

Background: Drug-resistant tuberculosis (DR-TB) remains a major public health challenge in South Africa, particularly in rural settings with high HIV co-infection rates. Understanding predictors of treatment response among people living with HIV is essential for improving clinical management and programmatic outcomes. This study aimed to identify socio-demographic and clinical predictors of treatment outcomes among HIV-positive individuals diagnosed with multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR-TB) in rural Eastern Cape Province, South Africa. Methods: A retrospective cohort study was conducted using routinely collected clinical records of DR-TB patients initiated on treatment between January 2020 and December 2024 at two public healthcare facilities. A total of 239 patients with complete treatment outcome data were included. Treatment outcomes were classified as favourable (cured or treatment completed) or unfavourable (death, treatment failure, or loss to follow-up). Descriptive statistics were used to summarise patient characteristics, while univariate and multivariable logistic regression analyses were performed to identify factors associated with treatment outcomes. Results: Most participants were aged ≤ 39 years (58%), male (60%), unemployed (90%), and without income (80%). MDR-TB accounted for 40% of cases, rifampicin-resistant-TB (RR-TB) for 53%, and XDR-TB for 7.1%. Multivariable analysis showed that XDR-TB was the strongest independent predictor of unfavourable treatment outcome (AOR = 0.18; 95% CI: 0.06–0.58; p = 0.004). Income status was also significantly associated with outcome, with participants reporting some incomes having lower odds of favourable outcomes (AOR = 0.46; 95% CI: 0.23–0.92; p = 0.036). The model demonstrated modest predictive performance (AUC = 0.67). Conclusions: These findings highlight the dominant influence of resistance phenotype, particularly XDR-TB, on treatment prognosis among HIV-positive DR-TB patients in rural Eastern Cape. Integrating early resistance profiling, intensified clinical management of XDR-TB, and socioeconomic support mechanisms may improve treatment outcomes in high-burden rural settings. Full article

Background/Objectives: Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA) are critical therapeutic options for multidrug-resistant Gram-negative infections; however, their comparative pharmacodynamics against carbapenem-resistant Pseudomonas aeruginosa (CRPA) remain incompletely defined. This study aimed to compare the bactericidal activity of C/T and CZA administered by intermittent infusion (II) or continuous infusion (CI) using a hollow fiber infection model (HFIM) against a clinical isolate of CRPA. Methods: Clinically relevant concentration–time profiles for C/T and CZA based on prescribing information were simulated in the HFIM. The standard P. aeruginosa strain ATCC 27853 and a GES-producing clinical CRPA isolate were utilized. The primary endpoint was bactericidal activity (≥3 log₁₀ CFU/mL reduction from baseline), while secondary endpoints included regrowth prevention and resistance development based on population analysis profiles (PAPs). Results: Against the standard strain, both agents achieved rapid killing without regrowth. However, for the GES-producing clinical isolate, C/T failed to achieve bactericidal activity. In contrast, CZA demonstrated sustained bacterial killing activity with the most pronounced early-phase bactericidal activity with CI of CZA (−4.25 log₁₀ CFU/mL at 24 h). The bactericidal activity was persistent over 7 days without bacterial regrowth after treatment discontinuation. Conversely, bacterial regrowth occurred with II of CZA after drug withdrawal. PAPs showed the lack of resistance development against CZA, whereas resistance to C/T developed within 48 h after initiating therapy. Conclusions: In this HFIM study, CI of CZA demonstrated the most sustained suppression of bacterial growth and prevented resistance emergence against the tested clinical isolate of CRPA producing GES β-lactamases. Future clinical studies are warranted to assess the effectiveness of the CI regimen. Full article

Artificial intelligence (AI) is increasingly used to support tuberculosis (TB) screening and diagnosis, particularly through computer-aided detection (CAD) applied to chest radiography (CXR). However, the programmatic value of AI depends not only on diagnostic accuracy but also on implementation context, threshold calibration, and integration into diagnostic pathways. We conducted a narrative, state-of-the-art review of AI applications across the TB diagnosis pathway. Evidence was synthesized from World Health Organization policy documents, independent validation initiatives, and peer-reviewed studies published between 2010 and 2026, with a structured selection process aligned with PRISMA principles. CAD for CXR is the most mature AI application and is recommended by WHO for TB screening and triage among individuals aged ≥15 years in specific contexts. Across studies, CAD-CXR demonstrates sensitivity comparable to human readers, although performance varies by product, population, and imaging conditions, necessitating local threshold calibration. Evidence from implementation studies suggests improvements in screening efficiency and potential cost-effectiveness in high-burden settings. Other AI modalities, including computed tomography (CT)-based imaging analysis, point-of-care ultrasound interpretation, cough or stethoscope sound analysis, clinical risk models, and genomic resistance prediction show promising but heterogeneous results, with most requiring further independent validation and prospective evaluation. AI has the potential to strengthen TB screening and diagnostic pathways, but its impact depends on integration into health systems and evaluated using patient- and program-level outcomes rather than accuracy alone. A differentiated approach is needed, with responsible scale-up of policy-endorsed tools alongside rigorous evaluation of emerging technologies to support effective and equitable TB care. Full article

Introduction: Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor with potent activity against multidrug-resistant Gram-negative pathogens, notably Pseudomonas aeruginosa. Its use is vital in the management of severe infections in ICU patients, especially where resistance limits first-line antibiotic options. This study aimed to describe the clinical characteristics, infection profiles, antimicrobial therapies, and hospital outcomes of ICU patients in Brazil who were treated with ceftolozane/tazobactam. Methods: A multicenter retrospective analysis was conducted on ICU patients treated with ceftolozane/tazobactam across twelve private hospitals in Brazil admitted between July 2018 and February 2023. Data were extracted from electronic medical records, including demographics, comorbidities, infection characteristics, antimicrobial usage, and hospital outcomes. Additionally, microbiological data and treatment details were evaluated. Descriptive statistics were used for analysis. Results: The study included 104 patients, with a median age of 78 years (IQR 61, 87) and 43% of whom were female. Pneumonia (57%) and urinary tract infections (19%) were the primary indications for treatment. Mechanical ventilation was required in 62 patients (60%). Pathogens were isolated in 44 cases, with ESBL-producing Gram-negative bacteria (34%) and carbapenem-resistant strains (18%) being the most common. Empirical therapy was initiated in 57% of cases, with a median treatment duration of 10 days. Concomitant antibiotics were used in 64% of patients. Mechanically ventilated patients exhibited higher mortality (66% vs. 29%) and prolonged ICU stays (57 vs. 20 days) as compared to non-ventilated patients. Conclusions: Ceftolozane/tazobactam demonstrates efficacy and safety in managing multidrug-resistant Gram-negative infections in ICU settings. However, its empirical use, driven by high resistance rates, underscores the importance of microbiology-guided therapy. The observed high mortality and prolonged ICU stay highlight the critical need for optimized infection management strategies and continued antimicrobial stewardship in critically ill populations. Full article