Search Results (9,795)

Importance: Triple-negative breast cancer (TNBC) is characterized by high tumor mutation burden and frequent programmed cell death ligand 1 (PD-L1) expression, making immune checkpoint inhibitors (ICIs) a promising therapeutic approach. However, randomized trials of chemoimmunotherapy (Chemo-IO) in locally recurrent unresectable or metastatic TNBC have shown inconsistent results, necessitating a clearer understanding of efficacy and patient selection. Objective: The aim of this study was to evaluate the efficacy and safety of chemotherapy combined with immunotherapy vs. chemotherapy alone in patients with locally recurrent unresectable or metastatic triple-negative breast cancer and to identify beneficiary populations to guide optimal treatment selection. Data Sources: PubMed, Embase, and the Cochrane Library were searched from database inception through 23 August 2025. Study Selection: Randomized clinical trials (RCTs) comparing chemotherapy combined with ICIs vs. chemotherapy with placebo or control in patients with locally recurrent unresectable or metastatic TNBC were selected. Data Extraction and Synthesis: Two investigators independently performed data extraction and assessed risk of bias using the Cochrane Risk of Bias 2 tool (RoB 2). Heterogeneity was evaluated using the I² statistic. Data were synthesized using random-effects meta-analysis models to calculate hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for dichotomous outcomes according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Results: Seven RCTs comprising 3485 patients (2085 in the Chemo-IO group, 1400 in the control group) were included. The median age across trials ranged from 52 to 57 years. Chemo-IO significantly improved PFS (HR, 0.82 [95% CI, 0.76–0.89]; p < 0.01) and OS (HR = 0.88; 95% CI: 0.81–0.96; p = 0.004) in the intention-to-treat (ITT) population, with PFS benefit particularly evident in PD-L1-positive patients (HR = 0.68, 95% CI: 0.59–0.79). However, OS improvement in the PD-L1-positive subgroup was not statistically significant. CBR did not differ significantly in the intention-to-treat population (RR, 1.11 [95% CI, 0.99–1.25]; p =  0.08) but was higher in PD-L1-positive patients (RR, 1.15 [95% CI, 1.01–1.31]; p = 0.04). Safety analyses revealed no significant differences in overall AE (RR, 1.01 [95% CI, 0.99–1.02]; p = 0.35), TEAE (RR, 1.01 [95% CI, 0.99–1.03]; p = 0.19), or grade ≥ 3 TEAE (RR, 1.00; [95% CI, 0.93–1.07]; p =  0.98). However, serious AE (RR, 1.32 [95% CI, 1.11–1.57]; p = 0.001) and irAE (RR, 1.86 [95% CI, 1.41–2.45]; p <  0.01) were more frequent with Chemo-IO. Conclusions and Relevance: Chemotherapy combined with immunotherapy significantly improved PFS and OS in patients with locally recurrent unresectable or metastatic TNBC, without substantially increasing chemotherapy-related toxicities. However, the OS benefit in PD-L1-positive patients was not statistically significant, and the combined regimen was associated with higher rates of serious and immune-related adverse events. These findings support the use of Chemo-IO as a treatment option, highlighting the importance of PD-L1 status and careful monitoring of immune-mediated toxicities in clinical practice. Full article

Background/Objectives: The optimal management of anterior cruciate ligament (ACL) rupture remains debated, especially regarding long-term outcomes after early ACL reconstruction (ACLR) versus rehabilitation-first with optional delayed ACLR. The interpretation of randomized evidence is complicated by frequent treatment crossover. This review synthesized evidence from randomized controlled trial (RCT) cohorts comparing surgical versus rehabilitation-first management strategies across available follow-up durations. Methods: A structured review based on a systematic literature search and narrative synthesis was conducted, with study identification and reporting guided by PRISMA 2020. MEDLINE (via PubMed) and Google Scholar were searched in February 2026 for English-language human RCTs (2000–2026) comparing early ACLR plus rehabilitation with rehabilitation-first management allowing delayed ACLR for persistent instability. A linked-report PubMed search using the KANON trial registration number (ISRCTN84752559) was additionally performed to identify cohort-derived follow-up publications. Reports were grouped by underlying RCT cohort. Data were extracted on crossover, follow-up, and clinical outcomes. Risk of bias for primary RCT reports was assessed with Cochrane RoB 2. Results: Twenty-seven reports representing three RCT cohorts (KANON, COMPARE, ACL SNNAP) were included; six index reports were prioritized for synthesis. In acute ACL rupture (KANON, COMPARE), early ACLR did not show a consistent long-term superiority in patient-reported outcomes versus rehabilitation-first with optional delayed ACLR, although COMPARE reported a statistically significant 2-year subjective functional difference favoring early ACLR; early ACLR more consistently improved mechanical stability and reduced instability episodes. Crossover from rehabilitation to delayed ACLR was common. In non-acute ACL injury with persistent symptomatic instability (ACL SNNAP), surgery-first improved 18-month patient-reported outcomes. Meniscal procedure rates and osteoarthritis-related outcomes did not consistently favor early ACLR. Conclusions: In acute ACL rupture, rehabilitation-first with timely access to delayed ACLR appears to provide long-term patient-reported outcomes comparable to an early ACLR strategy in many patients, while early ACLR more consistently improves knee stability. In non-acute symptomatic ACL deficiency, a surgery-first strategy appears more effective in the mid-term. These randomized trials should be interpreted as comparisons of management strategies rather than of “pure” operative versus nonoperative treatment approaches. Full article

The CO₂ storage–regeneration (CO₂-SR) process represents a promising strategy for integrating CO₂ capture and catalytic conversion within a single cyclic operation using multifunctional catalysts. In this concept, CO₂ is first stored on basic sites and subsequently converted through methane activation, enabling the coupling of CO₂ capture and reforming reactions in a single reactor. In this work, a series of unsupported Ni–Ba catalysts were investigated as model multifunctional materials for the CO₂-SR process. Catalysts with different Ni/Ba ratios were prepared to analyze how the distribution of storage and catalytic sites influences the cyclic CO₂ capture–conversion behavior. In addition, Rh was introduced as a promoter either during synthesis by co-precipitation or ex situ by impregnation, allowing to evaluate the influence of Rh location and surface enrichment on the catalytic properties. Rh incorporation in the NiBa catalyst (Ni/Ba = 10/1 and Ni/Rh = 100/1) increased the specific surface area (BET area 64 m²·g⁻¹ vs. 55 m²·g⁻¹ for NiBa) and reduced the NiO crystallite size from 250.4 Å to 231.5 Å, indicating improved dispersion of the metallic phase. XPS analysis revealed the coexistence of Rh⁰ and Rh³⁺ species, suggesting that Rh acts as a redox mediator that facilitates hydrogen activation and promotes hydrogen spillover to neighboring Ni sites. Raman and CO₂-TPD results show that Ba-derived domains stabilize carbonate species responsible for CO₂ storage, while Rh enhances catalyst reducibility and modifies the kinetics of carbonate decomposition during the regeneration stage. Transient CO₂–CH₄ pulse experiments demonstrate that the CO₂-SR process proceeds through a dynamic surface cycle involving reversible carbonate formation on Ba-derived basic sites coupled with methane activation on Ni-containing interfacial sites. The results indicate that catalyst performance is governed by a hierarchical surface architecture composed of Ni–O–Ba interfacial domains, reversible Ba–O–Ba carbonate storage sites, and more stable Ba-rich domains. The distribution of these domains, controlled by the Ni/Ba ratio and the dispersion of the metallic phase, determines the reversibility of carbonate formation and the efficiency of the cyclic CO₂ storage–regeneration process. Full article

Single-player role-playing games (RPGs) combine two promises that do not always align: delivering a compelling narrative experience (world, characters, choices, and consequences) while sustaining a demanding ludic trajectory in which players face obstacles, master systems, and progress over time. This Systematic Literature Review (SLR) synthesizes existing evidence on the evolution of narrative and challenge in single-player RPGs from a player-centered perspective, with particular attention paid to immersion, engagement, flow, and perceived agency. A multi-database search strategy was conducted across Google Scholar, Scopus, IEEE Xplore, and the ACM Digital Library using query strings targeting narrative/agency, challenge and dynamic difficulty adjustment (DDA), adaptive difficulty, and the historical evolution of RPG narrative design, following a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-reported selection flow and Rayyan-supported screening. From 423 identified records, duplicates and non-eligible records were removed through staged screening, yielding 43 reports sought for retrieval; because six were not accessible in full text at consolidation, the synthesis was conducted on 37 full-text articles. The findings indicate (i) a predominance of work on narrative and agency, where agency is framed as a design effect rather than merely the presence of explicit branching choices; (ii) a recent rise in challenge/adaptation research, frequently tied to flow, fairness, and differentiated player profiles; and (iii) the emergence of artificial intelligence (AI)-driven approaches, including non-player character (NPC) systems, combat AI, reinforcement learning, and large language model (LLM)-based narrative control, which amplify core design trade-offs between narrative coherence and perceived agency. Beyond synthesizing a dispersed body of literature, the review contributes an integrated player-centered analytical framework that brings together narrative, challenge, and player experience, while also highlighting the need for more consistent measurement practices, stronger comparative designs, and longer-term empirical work in single-player RPG research. Full article

Methicillin-resistant Staphylococcus aureus (MRSA) is a major clinical problem due to its resistance, virulence, and biofilm formation, which diminish antibiotic efficacy. This review explores natural products and antimicrobial nanoparticles (NPs) as alternative and combined strategies for controlling MRSA. Natural compounds, such as plant metabolites, essential oils, antimicrobial peptides, and fungal products, act by disrupting membranes, interfering with cellular processes, and limiting biofilm formation. Antimicrobial NPs, especially metal and metal oxide materials, act through membrane damage, oxidative stress, and metal ion release, enabling activity against resistant bacteria and improving biofilm penetration. Combining natural products with NPs increases stability, delivery, and local activity, enhances antibacterial effects, and reduces effective doses. Green synthesis enables direct integration of bioactive compounds, while nano-delivery platforms optimize solubility and controlled release. Nanotechnology-based applications such as wound dressings, nanocarriers, and multifunctional platforms support localized and sustained treatment and promote tissue repair. Despite these advances, clinical use is still constrained by safety concerns, variability in NP properties, and the lack of standardized evaluation and regulatory frameworks. Overall, combining natural products with antimicrobial NPs offers a practical strategy to augment MRSA treatment, but further progress depends on consistent design, robust safety evaluation, and clinical translation. Full article

Background: Ultrasonography (US) has emerged as a non-invasive method for anatomical and functional evaluation of upper airway structures in adult obstructive sleep apnea (OSA). However, its role in severity stratification, dynamic assessment, elastographic characterization, and therapeutic monitoring remain to be investigated. Background/Objectives: The goal herein is thus to systematically review and synthesize available evidence on US assessment in adults with OSA, including structural parameters, dynamic measurements, correlation with the apnea–hypopnea index (AHI), integration with artificial intelligence, and evaluation of myofunctional therapy outcomes. Methods: A PRISMA-compliant systematic review of 19 studies (2007–2025) was conducted, evaluating US in adult patients with polysomnography-diagnosed OSA. Observational, pilot, case–control, and exploratory studies were included. Risk of bias was assessed using the National Institutes of Health Quality Assessment Tool for observational studies. Due to methodological heterogeneity, a structured qualitative meta-analytic synthesis was performed. Results: The tongue base was the most frequently studied structure. Increased tongue thickness, area, and stiffness were consistently associated with higher AHI. Elastography revealed increased intrinsic rigidity in patients with OSA. Dynamic US correlated with drug-induced sleep endoscopy findings and hyoid displacement. Machine learning integration improved severity prediction. A single study evaluated anatomical changes following myofunctional therapy, representing a nascent research area. US may become a complementary, non-invasive tool for anatomical and functional assessment of upper airway structures in adult OSA. Conclusions: Further standardization of acquisition protocols and well-designed longitudinal studies are needed to clarify the clinical role of US in phenotyping and therapeutic monitoring. Full article

This paper proposes a formal framework for synthesizing multi-stage condition-based maintenance (CBM) decision logic for marine diesel monitoring systems. The design object is treated not as a single threshold or classifier output, but as an implementable decision logic with explicit stages of data-quality gating, thresholding, confirmation, fusion, and temporal filtering. Decision quality is evaluated using unconditional control-reliability indicators (CRIs) under a prescribed prior probability of rare abnormal events within a unified Monte Carlo verification protocol. Within a simplified Gaussian surrogate model, we compare baseline thresholding, repeated-measurement averaging, within-path confirmation, and measurement-level fusion. For the reported reference configuration, averaging five repeated measurements yields the largest reduction in the raw error criterion, “2 out of 3” confirmation provides a smaller but consistent improvement, and two-path multi-fidelity fusion is beneficial only after calibration toward the more informative path. The results show that, under rare abnormal events and limited measurement accuracy, decision quality is determined primarily by calibration of the multi-stage channel-level logic rather than by thresholding alone. Full article

The integration of photovoltaics, heat pumps, and energy storage systems is frequently assessed under the term “power grid integration”, yet studies operationalise grid interaction in different ways. This review addresses this inconsistency by synthesising and classifying assessment approaches according to the explicitness with which grid interactions are represented. A structured narrative review of peer-reviewed studies analysing coordinated photovoltaic–heat pump–storage operation was conducted. The literature is classified into three categories: A—grid-aware approaches that explicitly model distribution networks and evaluate compliance with voltage and loading constraints; B—interface-based approaches that represent the grid at the point of common coupling through aggregated import/export variables embedded as objectives or constraints; and C—grid-oriented approaches that evaluate grid-relevant indicators as proxies for grid stress without enforcing grid constraints. The synthesis shows that the categories align with distinct modelling perspectives, metrics, temporal resolutions, and control paradigms, reflecting different assessment questions rather than methodological quality. The proposed framework supports consistent interpretation and comparison of photovoltaic–heat pump–storage grid-integration studies within their respective modelling contexts. Full article

Sucrose synthase (SUS) is a key enzyme in plant carbon metabolism, catalyzing the reversible interconversion between sucrose + uridine diphosphate (UDP) and UDP-glucose (UDP-Glc) + fructose. It plays a central role in carbon flux allocation, cell wall and starch synthesis, as well as plant development and stress responses. SUS is encoded by a multigene family whose members exhibit significant functional diversification and expression specificity across species, tissues, and subcellular compartments. This review systematically summarizes the physiological functions of SUS in source–sink regulation, seed filling, and rapidly growing tissues; describes the organ-specific expression patterns and diverse subcellular localizations of different isoenzymes in Arabidopsis and major crops; and elucidates the phylogenetic pattern of the SUS gene family into three evolutionary clades—SUS I, SUS II, and SUS III—based on a comparative analysis of selected angiosperm species. Furthermore, it integrates the multi-level regulatory mechanisms of SUS, including transcriptional and post-transcriptional regulation, as well as the dynamic control of enzyme activity, stability, and subcellular localization through post-translational modifications such as phosphorylation and ubiquitination and protein interactions. Finally, this study identifies gaps in current research regarding ubiquitination mechanisms, metabolic network integration, and crop applications. It envisions SUS-centered molecular breeding strategies, informed by integrative regulatory genomics, multi-omics, and genome editing, to redirect crop carbon fluxes and thereby enhance yield, improve quality traits, and increase stress tolerance. Full article

Etruscan studies have reached great heights in the accumulation of cultural data. This is particularly true for landscape studies: the second half of the 20th century has been fruitful as it saw a growth in survey projects exploring ancient central Italian landscapes. Survey data indeed have a lot of potential for the study of urbanisation, facilitating the quantification of different patterns to draw comparisons of control strategies enacted by different power places. This paper is a synthesis of the analyses on rural settlement data between the 7th and the 5th centuries BCE, when urbanised institutions and lifestyles consolidated. Four case studies are selected and discussed, representing different types of territorial control: Tuscania, a mid-ranking centre tied to the city of Tarquinia; Chiusi and Cerveteri, both urban central places, with different developments and ways to administer territories; and finally, the palatial site of Murlo, in open conflict with urbanised realities. Site trends, proxies of population change and locational analysis, using GIS, reveal different rural infrastructures sustaining Etruscan central places. These centres adopted different strategies to control their lands and benefit from them. As part of the approach, I will show how structured Etruscan landscapes became, how they were exploited, who lived there, and how relationships with the central place were developed. Full article

Cross-reactivity among nonsteroidal anti-inflammatory drugs (NSAIDs) creates a significant clinical difficulty, especially in patients with NSAID hypersensitivity. These reactions are based on cyclooxygenase-1 (COX-1) inhibition and non-immunoglobulin E (IgE)-mediated reactions. COX-1 inhibition leads to dysregulation of arachidonic acid metabolism, with decreased prostaglandin synthesis and increased leukotriene production. Clinically, cross-intolerant reactions manifest in different phenotypes, including NSAID-exacerbated respiratory disease (NERD), NSAID-induced urticaria/angioedema (NIUA), and NSAID-exacerbated cutaneous disease (NECD). In contrast, true allergic reactions—such as single-NSAID-induced urticaria/angioedema and anaphylaxis (SNIUAA) and single-NSAID-induced delayed hypersensitivity reactions (SNIDHR)—are immunologically mediated and drug-specific. These phenotypes differ in underlying conditions, clinical manifestations, and patterns of NSAID tolerance. Paracetamol is generally considered a safer alternative due to its weak COX-1 inhibition; however, reactions may still occur, particularly at higher doses. Selective COX-2 inhibitors are usually better tolerated, however their safety should be confirmed, preferably through controlled drug provocation testing due to sporadic reactions in cross-intolerant patients. Understanding the distinction between pharmacologically mediated cross-intolerance and true allergic reactions is essential for accurate diagnosis, risk stratification, and therapeutic decision-making. This review summarizes current evidence on the mechanisms underlying NSAID hypersensitivity, analyzes the tolerability of paracetamol and alternative analgesics, and discusses practical management strategies to reduce the risk of adverse reactions. Full article

Background: Nutritional psychiatry increasingly links diet quality and specific bioactive nutrients to depression and anxiety outcomes. Mechanistic evidence implicates neuroimmune activation, inflammation, altered neurotransmitter synthesis, and microbiota-derived metabolites. Objective: The objective of this study is to synthesize evidence on omega-3 polyunsaturated fatty acids (n-3 PUFAs), the microbiota–gut–brain axis, and vitamins and minerals that influence neurotransmitter synthesis, inflammation, and brain function and to translate these findings into food-based strategies. Methods: This study consisted of a focused synthesis of randomized controlled trials (RCTs), meta-analyses, and systematic reviews indexed in PubMed, Scopus and Web of Science, selected for relevance to omega-3s, probiotics/prebiotics, dietary patterns, and micronutrients (folate/B-vitamins, vitamin D, magnesium, zinc, and vitamin C/copper pathways). Results: RCT and meta-analytic evidence suggest modest benefits of omega-3 supplementation for anxiety severity and depressive symptoms, with heterogeneity by dose, EPA: DHA composition, and baseline inflammatory status. The gut–brain axis literature supports bidirectional effects of stress and microbiota, and meta-analyses of probiotics/prebiotics show small improvements in depressive and anxiety symptoms, likely dependent on strain and host phenotype. Micronutrients serve as enzymatic cofactors for monoamine and GABA synthesis and modulate immune signaling; clinical effects are the most consistent when correcting insufficiency or in biomarker-defined subgroups. A whole-diet RCT demonstrates that structured dietary improvement can reduce depressive symptoms as adjunctive therapy. Conclusions: A food-first approach emphasizing Mediterranean-style dietary patterns, omega-3-rich seafood, a diverse array of fiber, and micronutrient density is the most defensible. Supplementation may be considered selectively, guided by clinical context and nutritional status. Full article

Iron-based nanoparticles, particularly iron oxide nanostructures (IONPs), have emerged as versatile and clinically relevant platforms for drug delivery and theranostic applications. Among these, superparamagnetic iron oxide nanoparticles (SPIONs), including magnetite (Fe₃O₄) and maghemite (γ-Fe₂O₃), are the most extensively investigated due to their biocompatibility, magnetic responsiveness, and established safety profiles. Their unique superparamagnetic behavior enables external magnetic-field-guided targeting, magnetic resonance imaging (MRI) contrast enhancement, and magnetically triggered hyperthermia, enabling simultaneous diagnosis and therapy. Surface functionalization with polymers, silica, lipids, peptides, and biomolecules further improves colloidal stability, circulation time, targeting specificity, and controlled drug release. Core–shell architectures and multifunctional hybrid systems have expanded the therapeutic scope of iron nanoparticles, integrating chemotherapy, gene delivery, photothermal therapy, and Fenton reaction–mediated catalytic therapy. Despite promising preclinical outcomes, challenges remain regarding long-term biosafety, oxidative stress induction, biodistribution, large-scale reproducibility, and regulatory translation. This review summarizes the physicochemical properties, synthesis strategies, surface-engineering approaches, drug-loading mechanisms, and biomedical applications of iron-based nanoparticles, highlighting recent advances in multifunctional and peptide-functionalized systems. Critical considerations for clinical translation and future perspectives in precision nanomedicine are also discussed. Full article

Zinc oxide (ZnO) is currently one of the most significant wide-bandgap semiconductor materials, attracting extensive research across diverse fields including materials science, chemistry, physics, medicine, electronics, and power engineering. Its exceptional properties, such as high optical transparency, high electron mobility, chemical stability, and compatibility with low-cost fabrication techniques, have established ZnO as a versatile material with immense application potential. A critical application for ZnO is its role as a transparent conducting oxide (TCO) in modern optoelectronic and photovoltaic devices, as well as in sensors, transparent electronics, and spintronics. To meet the requirements of these advanced applications, precise control over the structural, optical, and electrical properties of ZnO thin films is essential. This is effectively achieved through the selection of specific synthesis methods and intentional modification techniques, such as doping. This review provides a comprehensive overview of the synthesis and modification of ZnO thin films, with a particular focus on how various dopants influence their fundamental characteristics. The work discusses a range of deposition techniques, including physical vapor deposition (PVD), chemical vapor deposition (CVD), atomic layer deposition (ALD), sol–gel methods, spray pyrolysis, and other solution-based approaches. The novelty of this review lies in its comparative analysis of different doping strategies combined with various thin-film deposition techniques, highlighting how specific synthesis routes influence dopant incorporation and ultimately determine functional properties. Furthermore, recent advances in tailoring ZnO thin films are summarized, alongside the identification of key challenges and future research directions. Ultimately, this work aims to provide researchers with a systematic perspective on the synthesis–structure–property relationships in doped ZnO thin films to support the development of optimized materials for next-generation electronic and optoelectronic devices. This review, thus, serves as a comprehensive reference for researchers and engineers seeking to optimize the functionality of ZnO-based thin films for emerging technological applications. Full article

Background: The global aging population faces an increasing prevalence of type 2 diabetes mellitus (T2DM), often complicated by frailty, cognitive decline, and impaired manual dexterity. These factors make glucose self-monitoring particularly challenging. Minimally invasive glucose monitoring methods, particularly continuous glucose monitoring (CGM) as well as emerging non-invasive glucose monitoring technologies offer potential solutions, but remain insufficiently evaluated in older adults. Objective: To systematically review and synthesize available evidence on the advantages of continuous glucose monitoring (CGM) and non-invasive glucose monitoring methods in older adults aged ≥65 years, focusing on clinical efficacy, usability, adherence, and existing knowledge gaps. Methods: A systematic literature search was conducted across PubMed, Scopus, and Web of Science, including studies from 2020 to 2025. Eligible studies included participants aged ≥65 years and evaluated the clinical performance of CGM or other minimally invasive or non-invasive glucose monitoring technologies. The PRISMA framework guided screening and selection. Risk of bias was assessed using RoB 2 and ROBINS-I tools. Due to substantial heterogeneity among study designs and reported outcomes, a narrative synthesis approach was adopted. Results: A total of 426 records were identified, of which 13 met the predefined eligibility criteria after full-text screening. After risk of bias assessment, one study was excluded, resulting in 12 studies included in the final synthesis. No eligible studies evaluating completely non-invasive glucose monitoring technologies were identified, highlighting a significant research gap in this area specifically for older adults. CGM was associated with improved glycemic control, reduced hypoglycemia, and increased time in range among older adults. Usability was generally high, particularly with newer, user-friendly devices. Conclusions: CGM is associated with improved glycemic outcomes and favorable usability in adults aged ≥65 years. However, a significant gap exists in research on non-invasive glucose monitoring technologies in this population. Future studies should address the accuracy, feasibility, and usability of non-invasive glucose monitoring devices, while accounting for the physiological and behavioral complexities associated with aging. Full article