Search Results (62,395)

Digital trade rules have proliferated rapidly, yet the literature still treats institutional environments and firm behavior in a comparative-static manner, overlooking the feedback loops and stock-like accumulation dynamics through which regulatory openness shapes firm capabilities over time. Drawing on general systems theory and system dynamics, this paper models the digital trade rule regime as an “institutional system” and the overseas subsidiary network of digital MNEs as an “enterprise system,” linked through three capability stocks (market, production, knowledge), cross-subsystem coupling, absorptive capacity modulation, and five internal feedback loops. We derive a reduced-form dynamic panel equation mapping structural parameters onto estimable coefficients, and test its static counterpart using data on 6850 subsidiaries of UNCTAD’s top 100 digital MNEs (2000–2024) matched with the TAPED database. Three findings emerge. First, institutional openness—measured by rule depth and breadth—exerts a positive causal effect on subsidiary ROA, surviving IV estimation and multiple robustness checks. Second, the effect transmits through market expansion, production efficiency, and knowledge accumulation channels, confirmed by Baron–Kenny mediation with Sobel tests. Third, the New Digital Economy (NDE) module displays point estimates 4–8 times larger than other modules, and joint Wald tests reject coefficient equality, providing qualified support for Meadows’ leverage-point hierarchy. Our contribution lies in bridging system dynamics modeling with econometric causal identification, and in unifying transaction cost theory, the OLI paradigm, and the knowledge-based view within a single open-system framework. Full article

Background/Objectives: Biosecurity and stamping out are key control measures against H5 high-pathogenicity avian influenza (HPAI) outbreaks. Vaccination in poultry is an additional tool to reduce disease risk and facilitate timely containment. This study aimed to establish a candidate vaccine strain against H5 HPAI in Asia and validate its protective efficacy. Methods: Based on genetic and antigenic analyses, a representative HPAI virus, A/duck/Vietnam/HU16-DD3/2023 (H5N1), collected in northern Vietnam, was selected to generate a candidate vaccine strain, rgPR8/VN23HA∆KRRK-NA (rgPR8/VN23; H5N1), using reverse genetics, followed by formulation of an inactivated oil-adjuvanted vaccine. Vaccine efficacy was evaluated by measuring humoral antibody responses after intramuscular vaccination and by assessing mortality and virus recovery following intranasal challenge with a clade 2.3.4.4b virus, A/Ezo red fox/Hokkaido/1/2022 (H5N1). Results were compared with those obtained using an antigenically homologous vaccine to the challenge strain and a Japanese stockpiled vaccine. Results: All vaccinated juvenile chickens developed sufficient immunity to survive the challenge at 21 days post-vaccination. The rgPR8/VN23 (H5N1) and homologous vaccines markedly reduced virus recovery, suggesting near-sterile protection, whereas low-titer viruses were transiently detected in chickens vaccinated with the stockpiled vaccine. The rgPR8/VN23 (H5N1) vaccine conferred clinical protection in juvenile chickens as early as 8 days post-vaccination. A single dose of the rgPR8/VN23 (H5N1) vaccine provided incomplete protection in laying hens, whereas a double-volume regimen improved protective efficacy. Conclusions: The rgPR8/VN23 (H5N1) vaccine conferred strong immunity to juvenile chickens; however, a refined vaccination strategy may be required to achieve complete protection in laying hens. Full article

Oral squamous cell carcinoma (OSCC) remains a major global health burden due to aggressive invasion, early metastasis, therapeutic resistance, and poor long-term survival. Beyond tumor-intrinsic genetic and epigenetic alterations, accumulating evidence highlights the critical role of the tumor microenvironment in shaping OSCC progression and clinical outcomes. Cancer-associated fibroblasts (CAFs) and immune cells orchestrate tumor initiation, immune evasion, and recurrence through extracellular matrix remodeling, cytokine signaling, angiogenesis, and metabolic and redox regulation. Key oncogenic pathways, including EGFR/PI3K/AKT/mTOR, TGF-β, Wnt, and Notch, integrate with non-coding RNA networks to reinforce stemness, epithelial–mesenchymal transition, and therapy resistance. Moreover, PD-1/PD-L1-mediated immune escape, CAF-driven biomechanical remodeling, and metabolic reprogramming such as aerobic glycolysis and lipid metabolism contribute to OSCC heterogeneity. This review synthesizes current insights into OSCC across genomic, epigenetic, metabolic, and microenvironmental dimensions, emphasizing CAF biology, immune landscape reprogramming, and non-coding RNA regulation. We further discuss emerging biomarkers, liquid biopsy approaches, and targeted therapeutic strategies, providing a system-level framework for biomarker-guided stratification and precision combination therapies in OSCC. Full article

Zonal ship central cooling systems, which are primarily implemented in naval platforms and advanced specialized vessels to ensure high survivability, exhibit complex fluid–thermal interactions and multi-level valve networks, challenging conventional resilience analysis, especially under large-scale fault scenarios and dynamic topology reconfiguration. This paper presents a physics-informed dynamic resilience assessment and reconfiguration optimization method tailored for such systems. To address the high-dimensional reconfiguration search space, a physics-informed pruning mechanism combining topological reachability filtering and nodal continuity-based feasible-flow verification is introduced, eliminating 42.6% of invalid topologies and reducing optimization time by approximately 38%. Additionally, a cumulative thermal severity (CTS) metric is developed to capture transient thermal shock risks, quantitatively assessing deviation from the 50 °C system safety boundary at the most critical node. Simulation results for a main seawater pump failure scenario demonstrate that the proposed reconfiguration strategy, which coordinates cross-zone tie valves and leverages healthy zones’ pressure margins, shortens recovery time by 47%, suppresses peak temperature from 51.5 °C to 50.2 °C, reduces maximum over-temperature from 1.5 °C to 0.2 °C, and decreases CTS from 8.5 °C·s to 0.1 °C·s (a 98.8% reduction). These findings demonstrate that physics-informed pruning substantially reduces the computational burden of high-dimensional reconfiguration, while the proposed CTS metric enables quantitative assessment of transient thermal-shock risk. Together, they offer robust methodological guidance for resilience-oriented decision support and fault-tolerant design in complex shipboard fluid–thermal systems. Full article

Stroke remains a major cause of morbidity and mortality worldwide. Although reperfusion therapies and secondary prevention have advanced, the global stroke burden continues to rise, driven by increasing rates of hypertension and diabetes mellitus. Type 2 diabetes (T2DM) increases the risk of acute ischemic stroke (AIS) through mechanisms involving chronic hyperglycemia, endothelial dysfunction, inflammation, and accelerated atherogenesis. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising agents for cardiovascular and cerebrovascular risk reduction in patients with T2DM. Beyond their glucose-lowering properties, GLP-1RAs improve blood pressure regulation and lipid metabolism, as mentioned in the 2025 AHA Journal guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults. Emerging preclinical and clinical evidence indicates that GLP-1RAs also provide direct neurovascular protection by stabilizing the blood–brain barrier, modulating neuroinflammation, and promoting neuronal survival. These mechanisms may reduce ischemic injury, improve recovery after stroke, and protect against cognitive decline. Major cardiovascular outcome trials have demonstrated significant reductions in major adverse cardiovascular events and, to a lesser degree, non-fatal stroke among patients receiving GLP-1RAs. This narrative review evaluates current evidence on the neurovascular, cardiometabolic, and anti-inflammatory actions of GLP-1RAs and their potential role in mitigating stroke risk and promoting cerebrovascular health. Additionally, it highlights gaps in the literature, explores clinical and guideline implications, and outlines future directions for integrating GLP-1RA therapy into comprehensive stroke prevention and recovery strategies. Full article

Cadmium (Cd) is an environmental toxicant originating from both natural processes and human activities. Cd has been strongly associated with multiple diseases, including breast cancer (BC). Background/Objective: Environmental Cd exposure represents a significant contributor to BC onset and progression. Cd-induced breast carcinogenesis is driven by a constellation of molecular events, including DNA damage, oxidative stress (OS), and the dysregulation of key signaling pathways. These include the ERK/JNK/p38 MAPK cascade, the PI3K/AKT/mTOR axis, NF κB activation, and Wnt signaling, all of which collectively promote tumor initiation, survival, and metastasis. This review underscores the complex interplay between Cd exposure and its effects on cancer-triggering factors. Methods: The complexity of the mechanisms Cd-induced BC, underlying Cd-induced BC makes it challenging to treat, highlighting the need for novel therapeutic strategies that complement or enhance conventional chemotherapy. Therefore, this review was developed by reviewing the literature and presenting the different aspects of the challenge associated with Cd exposure and BC therapy. Results: Phytochemicals, especially phenolics, alkaloids, carotenoids, terpenoids, and related plant-derived compounds, have emerged as promising candidates for mitigating Cd-induced BC. Their antioxidants, anti-estrogenic, and anti-inflammatory properties position them as potential chemopreventive and therapeutic agents capable of counteracting Cd’s molecular toxicity. Conclusions: The review presents current evidence linking Cd exposure to BC development and highlights the protective potential of selected phytochemicals in preventing or attenuating Cd-induced BC. Understanding these interactions reinforces the importance of phytochemical-based interventions as a strategy to reduce Cd-related cancer risk and support breast health. Full article

Background/Objectives: The flavonoid quercetin (Q) has recently been suggested as a natural anti-aging and senolytic agent. However, its low stability and poor oral bioavailability may limit its efficacy. To address this, we investigated whether a lecithin-based formulation of Q, Quercefit™ (QF), enhances stress resistance and delays aging in vivo. Methods: The nematode Caenorhabditis elegans was used as an animal model to evaluate the effects of QF under physiological and stress conditions. Unformulated Q was administered as a control. Worm survival, healthspan, resistance to thermal and oxidative stress, and expression of stress- and longevity-related genes were assessed. All the experiments were conducted at least in triplicate, each including a minimum of 15 worms. The data were analyzed using Student’s t-test, one-way or two-way ANOVA, and Bonferroni’s post hoc test. Results: One hundred micromolar Q administered in QF was more effective than equimolar unformulated Q in increasing the worms’ ability to resist acute thermal stress at 35 °C (tested on 75 worms/group) and oxidative stress caused by 0.5 mM hydrogen peroxide (tested on 75 worms/group). In this last case, the protective effect of QF was similar to that of N-acetylcysteine and ascorbic acid. Under experimental conditions mimicking the long-term consequences of thermal stress, QF, like Q, increased the worms’ lifespan and healthspan by approximately 50%, counteracting the age-related decline associated with stress (120 worms/group). These benefits are supported by QF’s capacity to act as a reactive oxygen species scavenger; suppress heat-shock element gene transcription activated by thermal stress, such as hsp-16.2 and hsp-70, and stimulate the sod-3 and gst-4 genes that are involved in antioxidant and detoxification responses. Conclusions: These findings suggest that Q, when administered in the QF formulation, can act at the transcriptional level to protect against aging induced by stressful conditions. Full article

Background/Objectives: With increasing survival rates following oncologic mastectomies, loss of breast sensation can negatively impact a patient’s quality of life. Methods: PubMed, Embase, and Web of Science were searched in April 2025 for studies reporting sensory outcomes after neurotized breast reconstruction. Eligible studies included patients undergoing autologous or implant-based reconstruction with any neurotization technique. Forty studies were included, and outcomes involved objective sensory testing (e.g., Semmes-Weinstein monofilaments, pressure-specified sensory devices, and thermal thresholds) and patient-reported quality of life (e.g., BREAST-Q). Results: Neurotization consistently accelerated and improved recovery of tactile, thermal, and protective sensation compared with non-neurotized controls, particularly in DIEP and TRAM flaps. Direct coaptation was most frequently employed, while nerve allografts, conduits, and autologous grafts offered effective alternatives when direct repair was not feasible. Implant-based reconstructions using allografts also demonstrated significant improvements in the nipple–areola complex and breast skin sensation. Across studies, earlier and more uniform sensory return was reported, with improved sensation often associated with high patient satisfaction and quality of life. Conclusions: The preponderance of observational evidence suggests that nerve coaptation, whether by direct suture, conduit, allograft, or autograft, represents a promising adjunct to breast reconstruction in both autologous and implant-based reconstruction. However, many studies were retrospective in design, had small sample sizes, and lacked randomization. Full article

Background: Endometrial cancer (EC) is the most common gynecological malignancy in Western countries. Although international guidelines recommend that patients with EC be treated at specialized oncology centers, many are still managed by general gynecologists. This study aimed to evaluate the influence of facility volume on treatment strategies and survival outcomes among EC patients. Methods: This is a retrospective multicenter study comparing 971 patients with EC treated at medium-volume centers (CVMs) (11–29 cases/year) with 1431 patients treated at high-volume centers (CVAs) (≥30 cases/year). Patient characteristics were recorded, including age, body mass index (BMI), American Society of Anesthesiologists (ASA) score, comorbidities, surgical approach, lymphadenectomy, total number of lymph nodes removed, number of positive lymph nodes, length of hospital stay, histological characteristics, ESMO-ESGO (European Society for Medical Oncology–European Society of Gynaecological Oncology) classification system, adjuvant treatment, recurrence, progression-free survival (PFS), and overall survival (OS). Postoperative fever, hemoglobin changes, and blood transfusions were also reported. Results: Compared with patients treated at the MVCs, patients treated at the HVCs were younger (mean age, 65 vs. 66.4 years, p = 0.03) and had a lower rate of comorbidities (41% vs. 55%, p < 0.001). Patients treated at HVCs were mostly in higher ESMO-ESGO recurrence risk classes (p < 0.001), were treated mostly laparoscopically (58% vs. 47%, p < 0.001) and had better staging (higher number of lymph nodes harvested (mean 19 vs. 11, p < 0.001) and more peritoneal biopsies performed (27% vs. 14%, p < 0.001). HVC patients had fewer complications and received less adjuvant therapy (40% vs. 50%, p < 0.001) but, when treated, received chemotherapy more frequently, showed mostly loco-regional recurrences (34% vs. 14%) and fewer extra-abdominal recurrences (34% vs. 54%). HVC patients had better PFS and OS. Center volume was found to be an independent factor influencing PFS in multivariate analysis. Conclusions: All EC patients should be centrally managed to receive superior treatment to improve postoperative recovery and oncological outcomes, particularly for patients with more-aggressive tumors. Full article

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, and its management is limited by heterogeneous risk profiles, suboptimal surveillance performance, diagnostic uncertainty in chronically diseased livers, and difficulty individualizing prognosis after treatment. The aim of this narrative review was to critically evaluate artificial intelligence (AI) applications across the HCC care continuum, with emphasis on their intended clinical role, reported performance, evidence maturity, and barriers to implementation. A major strength of this review is that it moves beyond a descriptive catalog of models by structuring the literature around clinically relevant decision points and by explicitly distinguishing emerging proof-of-concept tools from applications with stronger translational potential. Across risk stratification, surveillance, imaging-based diagnosis, pathology, treatment-response prediction, and prognostication, we found that AI consistently demonstrates promise, particularly for identifying patients at higher future HCC risk, improving lesion detection and characterization on ultrasound, CT, MRI, and contrast-enhanced ultrasound, assisting histopathologic classification, and predicting outcomes such as microvascular invasion, recurrence, survival, and response to locoregional therapies. However, we also found that the evidence base remains highly uneven: many diagnostic studies are retrospective and lesion-enriched rather than embedded in true surveillance populations, many prognostic models lack robust external validation and calibration assessment, and reference standards, imaging protocols, and dataset composition vary substantially across studies. These findings are clinically relevant because they highlight both where AI may offer near-term value and why most published systems are not yet ready for routine use. Overall, AI in HCC should be viewed as a rapidly evolving but still transitional field. Its future impact will depend not only on higher-performing algorithms but on clearly defined clinical use cases, multicenter and prospective validation, transparent reporting, workflow-aware evaluation, and implementation strategies that support safe, equitable, and scalable adoption. Full article

Temperature and humidity are critical abiotic factors shaping the survival and adaptation of insect pests. However, the molecular mechanisms underlying high-temperature tolerance under contrasting humidity conditions remain poorly understood, particularly in globally invasive species such as the tomato pinworm, Tuta absoluta. Previous studies have examined individual stressors, leaving interactive thermo-hygrometric effects on gene expression and survival insufficiently resolved. Here, we assessed the contribution of cytochrome P450 genes to thermal adaptation under low- and high-humidity conditions using transcriptome profiling combined with nanocarrier-mediated RNA interference (RNAi). Third-instar larvae were exposed to high temperature under low humidity (HT-LH: 40 °C, 50% RH) or high humidity (HT-HH: 40 °C, 75% RH) for eight hours. Survival declined from 97.5% in the control to 74.16% under HT-LH and 68.33% under HT-HH conditions. Transcriptome analysis revealed extensive differential gene expression, with 464 genes upregulated and 565 downregulated in HT-LH, and 1145 upregulated and 1166 downregulated in HT-HH. Functional annotation highlighted pathways linked to metabolic regulation, proteostasis, and detoxification, including multiple cytochrome P450-associated processes. RT-qPCR confirmed the upregulation (3–5 fold) of four P450 genes (CYP6AB327, CYP6ABF1b, CYP6AE214, and CYP9A306c) under high temperature across both humidity regimes. RNAi-mediated silencing of these genes significantly reduced larval survival, demonstrating their functional role in thermal-hygrometric stress tolerance across. Cytochrome P450 genes underpin the adaptive capacity of the tomato pinworm to high-temperature stress across contrasting humidity conditions, highlighting RNAi-based disruption of P450 function as a promising avenue for sustainable pest management under climate change scenarios. Full article

Bronchoscopic cryotherapy is routinely used for endobronchial tumor debulking, but may also exert systemic immunologic effects that could interact with immune checkpoint blockade. We investigated peripheral blood T-cell dynamics following bronchoscopic cryotherapy and subsequent pembrolizumab-based first-line therapy in metastatic non-small-cell lung cancer (NSCLC). In this prospective, randomized, controlled single-center study, patients with metastatic NSCLC were randomized into treatment groups of bronchoscopic cryotherapy performed 7 (±1) days before standard-of-care pembrolizumab (with or without platinum-based chemotherapy) or to standard-of-care therapy alone. Peripheral blood mononuclear cells were analyzed by flow cytometry at baseline, week 3, and week 6. Radiologic response was assessed using RECIST 1.1. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan–Meier test and Cox regression. Flow cytometry was performed on 34 cryotherapy and 42 control patients. The cryotherapy group demonstrated a decrease in circulating CD4+ T cells (p = 0.002) and an increase in circulating CD8+ T cells (p = 0.013) by week 6. CD25+FOXP3+CD4+ Tregs decreased from baseline to week 3 (p = 0.024) and remained reduced through week 6. Overall response rate was higher in the cryotherapy group (41.2% vs. 16.7%; p = 0.022), while PFS and OS were numerically longer, although not statistically different (median PFS 9.5 vs. 5.3 months; median OS 17.6 vs. 14.8 months). The decrease in Tregs at week 3 was observed to predict better PFS. In patients with metastatic NSCLC receiving first-line pembrolizumab with or without chemotherapy, the addition of bronchoscopic cryotherapy was associated with a detectable peripheral immune remodeling and a higher objective response rate, whereas PFS and OS were numerically longer but not statistically different. Full article

Background/Objectives: Although triplet regimens have been shown to be effective and safe in pivotal studies involving frail patients with multiple myeloma (MM), their use in frail patients is often avoided in real-world settings. As MM treatment progresses and options increase, it is crucial to clarify the efficacy and safety of triplet regimens in clinical practice. Methods: Patients who received anti-CD38 antibody-containing triplet regimens at our hospital from 2017 to 2024 were divided into frail and non-frail groups based on the IMWG simplified frailty scale and retrospectively analyzed. Results: In the 150 patients included, the median age was 76 years for the frail group and 69 years for the non-frail group. Daratumumab-containing triplet regimens were given to 108 (82 frail) patients, and isatuximab-containing triplet regimens were given to 42 patients (18 frail). Progression-free survival and overall survival for the frail and non-frail groups were 15.4 vs. 11.4 months and 45.6 vs. 40.7 months, respectively; the overall response rate was 76% vs. 68%, with no significant differences. Prognoses by regimen were also not significantly different. There were no significant differences in any adverse events and grade 3–4 hematological and non-hematological adverse events between the two groups. This analysis showed that, in frail MM patients who were eligible to receive triplet regimens, anti-CD38 antibody-containing triplet regimens were as effective and safe as in non-frail patients. Conclusions: In conclusion, these regimens may be viable options for frail patients, provided that appropriate management, including withdrawal of therapeutic agents, dose reduction, and infection control, is rigorously performed, as for non-frail patients. Full article

Background/Objective: Advances in intensive care medicine have substantially improved the survival of critically ill patients; however, they have also revealed the growing burden of neurological complications that affect both short-term outcomes and long-term functioning. Neurological complications in the intensive care unit (ICU) include a wide spectrum of disorders, ranging from acute brain dysfunction such as delirium, coma, and encephalopathy to persistent cognitive impairment after discharge, which represents a key component of Post-Intensive Care Syndrome (PICS). Delirium affects approximately one-third of ICU patients and is independently associated with increased mortality, prolonged hospitalization, and worse long-term neurocognitive outcomes. Due to the limited effectiveness of pharmacological therapies, current clinical approaches emphasize prevention, early diagnosis, and non-pharmacological strategies in line with PADIS guidelines. This narrative review aims to provide a clinically relevant synthesis of neurological complications in adult ICU patients, conceptualized as a continuum from acute brain dysfunction to long-term cognitive impairment. Methods: A narrative review of the literature was conducted, focusing on studies addressing epidemiology, pathophysiology, risk factors, diagnostic strategies, and prevention of neurological complications in critically ill adults. Attention was given to delirium, ICU-acquired cognitive impairment, and their association with PICS, as well as to current guideline-based and non-pharmacological interventions. Results: Available evidence indicates that neurological complications in the ICU are multifactorial and result from the interaction between patient vulnerability, severity of illness, systemic inflammation, sedative exposure, and environmental factors. Delirium remains the most common manifestation of acute brain dysfunction and is strongly associated with adverse outcomes. Increasing evidence supports the effectiveness of structured screening, early mobilization, sleep optimization, and multidisciplinary care bundles in reducing delirium incidence and duration. Moreover, growing attention is directed toward post-ICU follow-up and rehabilitation to reduce long-term cognitive decline. Conclusions: Neurological complications should be considered a central component of critical illness and a continuum extending beyond ICU discharge. Early identification of high-risk patients, implementation of preventive strategies, and integration of acute and post-ICU care are essential to improve survival and long-term cognitive outcomes. Further research should focus on personalized preventive and neuroprotective approaches in critically ill patients. Full article

Background/Objectives: Primary amoebic meningoencephalitis (PAM) is a rare, fulminant, and often fatal central nervous system infection caused by the opportunistic free-living amoeba Naegleria fowleri. Although Naegleria species are widely present in freshwater and soil worldwide, human disease is associated specifically with pathogenic N. fowleri rather than the many nonpathogenic environmental species, and virulence may vary across N. fowleri isolates. This systematic review aimed to synthesize contemporary global data from 2000 to 2024 to identify recent trends in epidemiology, clinical presentation, diagnosis, treatment, and outcomes. Methods: A systematic literature search was conducted across PubMed, Scopus, and the Cochrane Library, identifying 58 eligible publications encompassing 66 individual cases. Results: Most reports originated from the United States, India, and China. The median patient age was 14 years, with 78% of cases occurring in males. Annual case reports increased from one per year (2000–2005) to over four per year (2020–2024), reflecting either a true rise in incidence or improved detection. Common presenting symptoms included fever, headache, and altered mental status. Diagnosis was confirmed via polymerase chain reaction (PCR) testing or post-mortem biopsy in nearly one-third of cases. Treatment regimens varied, with amphotericin B and miltefosine being the most frequently used agents. Overall mortality was 83%, with survival strongly associated with early initiation of combination therapy. Pediatric patients had a higher survival rate (22%) compared to adults (7.1%). Conclusions: The findings highlight the need for heightened clinical awareness, especially in the context of climate-driven ecological changes that may expand N. fowleri’s geographic range. This review underscores critical gaps in surveillance and diagnostics and emphasizes the importance of a One Health approach to addressing emerging threats like PAM. Further research into novel therapeutics, rapid diagnostics, and global case reporting systems is urgently needed. Full article