Search Results (10,721)

Environmental chemicals are rarely considered stressors in the way that psychological or physical stressors are. Yet many endocrine-disrupting chemicals (EDCs) interact with the body’s core stress response system. This review examines how EDCs alter hypothalamic–pituitary–adrenal (HPA) regulation and how biological sex influences those responses. Drawing on human epidemiological data and experimental models, we describe how EDC exposure affects cortisol dynamics, feedback sensitivity, and adrenal signaling, with a particular focus on sex-dependent outcomes. We propose the concept of endocrine noise to describe how low-dose, often mixed EDC exposures introduce persistent interference into hormone signaling without necessarily causing overt endocrine deficiency or excess. In this framework, EDCs act as chronic, low-grade stressors that reset the timing, feedback precision, and rhythmic organization of the HPA axis rather than as isolated reproductive toxicants. We argue that EDCs should be understood as chronic, context-dependent stress modifiers that reshape sex-specific “risk architectures” for affective, metabolic, and immune disorders. Recognizing sex-specific HPA architecture and endocrine noise has immediate implications for study design and regulation, including the need for sex-stratified analyses, circadian-sensitive sampling of cortisol, and risk assessments that consider how the same exposure can push female and male stress systems in divergent directions. Full article

This study investigates the effects of a novel marine byproduct oil extracted from the cephalopod Nototodarus sloani (Arrow squid) on human platelets and red blood cells (RBCs). The oil was produced using enzyme-assisted extraction under varying pH conditions without further refining. The level of oxidation of the different oils was determined. Hemocompatibility and oxidative effects were evaluated after 24 h of incubation at physiological and fever-like conditions. Hemolysis levels varied with extraction conditions and with the amount of oil in contact with the cells. Oils extracted using 0.5% Alcalase^® and 1% Protamex^{TM ®} at pH 5.9 demonstrated superior hemocompatibility. Intracellular reactive oxygen species (ROS) levels presented a dose-dependent increase, with higher levels observed in oils extracted at a higher pH. Although there was no direct correlation between hemolysis rate, ROS levels and oxidation, the less oxidized oils presented lower ROS formation and better hemocompatibility. Additionally, the oils exhibited a strong anticoagulant effect and low IC₅₀ values against TRAP-6-induced platelet aggregation. These findings highlight the potential of Nototodarus sloani as a source of bioactive compounds, providing initial evidence of potential cardiovascular benefits and resource valorization, underlining the importance of extraction conditions in determining the biological properties of marine byproduct oils. Full article

Venom-mediated systemic toxicity is not fully understood. This study explored the dose-dependent effects of Vespa mandarinia venom (VMV) on mice via integrated transcriptomic and metabolomic analyses. Subcutaneous VMV injection induced dose-dependent hypothermia: 80 μg caused severe transient hypothermia and partial mortality, while 40/60 μg led to reversible hypothermia within 24 h. Whole-blood sequencing identified 2400–3281 differentially expressed genes (DEGs) per group, including 1764 shared DEGs. Immune-related pathways were significantly activated, with hub genes validated by qRT-PCR. Serum metabolomics revealed alterations in organic acids, alkaloids, and other metabolites. Integrative transcriptome–metabolome analysis predicted the potential involvement of various pathways in VMV-induced toxicity, including ferroptosis (shared in low-dose VMV groups) and apoptosis. Cumulatively, this study confirms that VMV induces immunometabolic reprogramming, providing a molecular framework for understanding venom-induced systemic toxicity. Full article

Background/Objectives: Heart failure (HF) is associated with substantial morbidity, impaired quality of life (QOL), and reduced functional capacity. In selected patients with symptomatic HF despite Optimal Medical Therapy (OMT), Cardiac Contractility Modulation (CCM) may be a therapeutic option. Identifying patients most likely to benefit from CCM remains an unmet need. The Predict-CCM study aims to evaluate long-term clinical and objective outcomes after CCM therapy and to assess the predictive value of pre-implant low-dose dobutamine stress echocardiography (LDDSE). Methods and Results: Predict-CCM is an independent, non-profit, multicenter, observational cohort study conducted in Italy, with both retrospective and prospective enrollment. The primary endpoint is the proportion of subjects with a clinical response to CCM at 12 months, defined as a ≥1-class reduction in NYHA class. Secondary clinical endpoints include reductions in HF-related hospitalizations, changes in QOL assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and changes in NT-proBNP levels from baseline to follow-up. Outcomes will be evaluated in the overall cohort and in two subcohorts stratified by pre-implant LDDSE response: (1) reduction in left ventricular end systolic volume (LVESV) ≥ 15% (DeltaLVESV ≥ 15%); and (2) reduction in LVESV < 15% (DeltaLVESV < 15%). Assuming a 70% clinical response rate at 12 months, the estimated sample size is 120 patients. The study was approved by the Ethics Committee in March 2025. Enrollment will continue for 2 years, with a 12-month follow-up period after implant for each subject. Conclusions: This study may provide new criteria for patient selection and outcome assessment in CCM therapy. Left ventricular contractile reserve assessed by stress echocardiography may be a promising predictor of response. Full article

Introduction: Placental malaria increases the risk of adverse birth outcomes. Current preventive measures are undermined by poor coverage, growing resistance to chemo-preventive and therapeutic drugs, and vector eliminating insecticides. Candidate placental malaria (PM) vaccines (PAMVAC and PRIMVAC) have shown safety and immunogenicity in Phase I trials, but empirical evidence on their potential population-level value is lacking. This study modelled the expected cost-effectiveness of a PM vaccine administered before pregnancy. Methods: A decision-analytic model compared two strategies from the provider’s perspective: vaccinating women of childbearing age versus no vaccination. The model incorporated gravidity-specific risks of PM, neonatal mortality and the malaria attributable fractions from the literature. Since the efficacy of a PM vaccine for malaria prevention is unknown, we assumed a 40% efficacy and varied this estimate widely in sensitivity analyses. Primary outcomes were incremental cost-effectiveness ratios (ICERs) per perinatal disability adjusted life years (DALYs) averted. Baseline, best-case, and worst-case scenarios were analysed. One-way and probabilistic sensitivity analyses were used to assess parameter uncertainty. Cost-effectiveness was defined as an ICER below half of sub- Saharan Africa’s 2025 GDP per capita ($1556). Results: The vaccine was most cost-effective among primigravidae. Under baseline assumptions (40% efficacy; 30% uptake; $5 dose price), the ICER was $321 per perinatal DALY averted for primigravidae versus $4444 for multigravidae. Best-case assumptions further improved cost-effectiveness ($225 vs. $3148). Sensitivity analyses showed robust cost-effectiveness for primigravidae across all plausible parameter ranges, while ICERs in multigravidae were highly sensitive to programme costs and vaccine efficacy. Cost-effectiveness acceptability curves demonstrated that vaccination becomes favourable for primigravidae at relatively low willingness-to-pay thresholds. Conclusions: A placental malaria vaccine delivered before pregnancy has high potential to be cost-effective in endemic areas when targeted to protect primigravidae. These findings support prioritised deployment strategies and highlight the value of early economic modelling to inform vaccine development and policy planning. Full article

This narrative review examines the clinical application of tiletamine–zolazepam (TZ) in exotic pet and wildlife anesthesia, addressing the complexities inherent in managing a broad taxonomic spectrum with diverse physiological profiles and temperaments. As a fixed-dose combination, TZ is a cornerstone of multimodal protocols designed to achieve balanced anesthesia. Its lyophilized formulation permits reconstitution with various sedative solutions, facilitating low-volume administration, a critical requirement for the immobilization of wildlife and small exotic patients. Given the significant variability in species-specific responses and environmental influences, selecting and adapting appropriate TZ-based protocols remain a challenge for practitioners. By synthesizing heterogeneous data into expert-validated guidance, this review provides specialized and general veterinarians with practical considerations for the judicious use of TZ. Emphasis is placed on integrating TZ within multimodal protocols to mitigate arousal risks, ensure consistent immobilization, and facilitate rapid recovery. This approach seeks to optimize anesthetic outcomes and promote animal welfare across these physiologically diverse populations. Full article

Overexpression of protein arginine methyltransferase 5 (PRMT5) is pivotal in MYC-driven primary medulloblastoma tumors, suggesting PRMT5 as a potential therapeutic target. JNJ, a potent PRMT5 inhibitor currently in clinical trials, notably for non-Hodgkin lymphoma and lung cancer, was evaluated in this study. We report a validated LC–MS/MS bioanalytical method for quantifying JNJ in plasma and tissue matrices. The method demonstrated acceptable sensitivity, selectivity, and robustness in accordance with regulatory guidelines. The assay was linear over the range 0.2–500 ng mL⁻¹ (r² = 0.99), with plasma recovery exceeding 84% using only 100 µL of sample. Precision (%RSD < 15%) and accuracy (~91–108%) were within acceptable limits. JNJ showed >94% plasma protein binding and moderate Caco-2 permeability (3.4 ± 0.4 × 10⁻⁶ cm s⁻¹). Hepatic intrinsic clearance was higher in mouse liver microsomes than in human (41 ± 19 vs. 7 ± 0.6 mL min⁻¹ kg⁻¹). Following oral dosing in mice (10 mg kg⁻¹), T_max was 30 min with a C_max of 2781 ± 1033 ng mL⁻¹. Oral bioavailability was low (15%). The validated method was successfully applied to in vitro and in vivo studies and will guide dosing in animal models of medulloblastoma. Full article

Background/Objectives: Individuals with alcohol use disorder (AUD) and tobacco use disorder (TUD) are at increased risk for severe COVID-19 outcomes. However, real-world evidence on vaccine effectiveness (VE) in these populations remains limited, particularly in low- and middle-income countries. This study aimed to evaluate the effectiveness of three or more COVID-19 vaccine doses against mortality in hospitalized patients with AUD and TUD in Brazil. Methods: This retrospective cohort study used data from the SIVEP Gripe database, a national surveillance system of hospitalized COVID-19 cases in Brazil. The study included adults aged ≥18 years with confirmed SARS-CoV 2 infection between February 2020 and June 2025. The intervention was defined as receipt of three or more vaccine doses (fully vaccinated) versus no doses (unvaccinated). Propensity score matching was performed separately for AUD and TUD cohorts. Vaccine effectiveness was estimated using McNemar’s test for paired samples, and the average treatment effect (ATE) and number needed to vaccinate (NNV) were calculated. Results: Among 2,184,723 hospitalized patients, 12,115 had AUD and 45,679 had TUD. After matching, VE against mortality was 42% (95% CI: 27.5–53.5) in the AUD group and 52.6% (95% CI: 46.5–58.1) in the TUD group, compared to 58.5% and 58.9% in their respective non-exposed counterparts. The ATE was consistent across groups (approximately −0.12), and the NNV to prevent one death was 8 (95% CI: 6–15 for AUD; 7–12 for TUD). Conclusions: Although VE was attenuated in individuals with AUD and TUD compared to the general population, the absolute benefit of vaccination remained substantial. Full article

Copper (Cu) is an essential micronutrient, but poorly controlled inputs may increase phytotoxicity risks and alter soil–plant nutrient dynamics. Therefore, Cu formulations that regulate rhizosphere Cu availability are of agronomic interest. This study compared non-encapsulated Cu nanoparticles (CuNPs) and alginate-encapsulated Cu nanoparticles (eCuNPs) in a 42-day pot experiment with Lactuca sativa L. grown in two agricultural soils with different properties, applying 0, 10, 25, 50, and 100 mg of Cu kg⁻¹. Soil properties, Rhizzo-extractable Cu as a proxy of available Cu, plant biomass, Cu accumulation, and nutrient concentrations were evaluated. Rhizzo-extractable Cu increased with dose under CuNPs, particularly in the soil with lower organic matter and ECEC, whereas eCuNPs maintained values closer to the control levels. In the soil with higher organic matter and ECEC, CuNPs were associated with reduced shoot and root biomass at higher doses, while eCuNPs showed a more variable response and, in some cases, higher biomass values. In contrast, biomass remained low across all treatments in the more limiting soil. Cu accumulated mainly in roots, and foliar Cu (FW) remained low and close to typical values reported for lettuce in the USDA FoodData Central database. Alginate encapsulation may reduce short-term Cu mobilization in the rhizosphere and could represent a promising strategy to improve the safety of CuNP applications, particularly in soils with higher organic matter and ECEC. Full article

Radiation therapy is a central component of the definitive and postoperative management for head and neck cancers (HNC), with intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) now standard. Within these techniques, two principal boost strategies are used: simultaneous integrated boost (SIB) and sequential boost (SEQ). Although both are guideline-supported, they differ in planning logistics, treatment delivery, potential radiobiologic effects, adaptability to anatomic change, and potential toxicity profiles. In this narrative review, we summarize the key technical, dosimetric, and radiobiologic differences between SIB and SEQ and synthesize the available comparative clinical data, with a focus on their roles in contemporary dose de-escalation strategies. SIB allows for differential dosing within a single plan and potentially shorter overall treatment time but typically delivers higher biologically effective doses (BED) to elective nodal regions. SEQ requires two plans but offers greater flexibility for adaptive replanning, facilitates a lower BED to elective nodal volumes, and may allow for partial normal tissue recovery during the boost phase. Comparative studies, including retrospective series, randomized trials, and a meta-analysis, have not demonstrated consistent differences between SIB and SEQ in survival or local control, with mixed findings regarding toxicity. In the context of de-escalation, multiple prospective studies have successfully used SEQ to reduce elective nodal dose with low rates of elective nodal failure, while recent data suggest that SIB-based elective dose reduction may also be feasible in select settings. Overall, both SIB and SEQ are effective boost strategies in HNC radiotherapy. While practice is often driven by institutional workflow and clinician preference, emerging evidence suggests potential advantages of SEQ for elective nodal dose de-escalation. Further prospective studies are needed to better define the relative impacts of SIB and SEQ on toxicity and tumor control. Full article

Background/Objectives: This secondary and exploratory meta-analysis re-evaluated 30 randomized controlled trials on free and added sugars (FS) detailed in the European Food Safety Authority’s (EFSA) report on the tolerable upper intake level for dietary sugars, focusing on the influence of food source (beverages, foods, or mixed) on cardiometabolic and anthropometric health. Methods: The EFSA’s method of analyzing the relative FS intake (difference between treatment and comparator arms, Δ%E^fs) was used, with further adjustment for the reported intake of all sources of FS and energy. The EFSA’s “high vs. low” random-effects meta-analysis comparing groups with the highest and lowest FS intake was replicated, and additional exploratory dose–response meta-regressions (linear and non-linear) were performed, stratified by food source. Given the secondary and observational nature of the analysis, all source-stratified findings should be interpreted as hypothesis-generating, rather than causal. Results: There were no interactions between Δ%E^fs and food source for any outcome, and within a source there were linearly positive and statistically significant regressions for body weight (mixed), low-density lipoprotein cholesterol (LDL-C, foods), and uric acid (beverages). Across 13 outcomes, Δ%E^fs was positively and linearly related to greater fasting glucose, high-density lipoprotein cholesterol (HDL-C), and LDL-C, and non-linearly to body weight. However, the data were limited in their representation of FS intake at typical population levels, and there were insufficient data to investigate the effect of FS from foods on most anthropometric outcomes. Conclusions: Meta-regressive dose–responses revealed little relationship between Δ%E^fs from specific food sources and health outcomes, but such effects might be masked by confounding factors. Future trials that test realistic intakes of FS across diverse food matrices and account for dietary compensation would help to overcome limitations in the body of evidence. Full article

Vascularization remains a central challenge in thick tissue engineering. Building on our prior demonstration that carbonate buffer concentration governs multi-channel collagen gel (MCCG) architecture and perfusion culture performance, this study aimed to establish non-contact, orthogonal control of pore size and density in riboflavin-sensitized Type I collagen hydrogels via UV irradiation intensity and preparation temperature. UV intensity was modulated by varying the source-to-sample distance (25–52 mm); preparation temperature was set at 5, 25, or 40 °C; gelation kinetics were quantified using a vial-tilt assay. Pore area fraction ranged from 0.9% to 8.6% and Young’s modulus from 16 to 49 kPa depending on UV dose. Higher preparation temperatures accelerated gelation and produced smaller, more densely distributed pores, consistent with kinetically arrested phase separation. NIH/3T3 fibroblasts cultured on intermediate- and low-intensity UV scaffolds achieved >80% confluency by Day 7, with three-dimensional tissue-like organization and directionally aligned cellular bundles within large pores; cell metabolic activity, assessed by CCK-8 assay, remained consistently high throughout the culture period. These results demonstrate that UV irradiation intensity and preparation temperature are independently tunable, non-contact parameters for reproducible fabrication of collagen scaffolds with tunable vascular-like pore networks, complementing and extending the chemical (buffer concentration) design space of MCCG-based perfusion culture systems. Full article

Background: Hematological patients have a high risk of developing severe COVID-19 (37%). Most mRNA vaccine trials in hematological patients showed a low immunogenicity after two doses, while long-term data are scarce. Methods: In this monocentric retrospective observational study, we evaluated humoral and T cell-mediated immune responses in 230 hematological patients after three doses of the Pfizer-BioNTech mRNA COVID-19 vaccine. Patients were stratified by age, disease type/state, prior COVID-19 infection, and treatment status and regimens (anti-CD20 monoclonal antibodies, BTK and BCL-2 inhibitors, and treatment line). Antibody titer to SARS-CoV-2 was assessed by electrochemiluminescence immunoassay and T cell response by QuantiFERON interferon-γ release assay (IGRA). Data were analyzed using univariate (Fisher’s exact test) and Firth’s bias-reduced penalized-likelihood logistic regression. Results: A robust humoral response was observed with 91.55% of patients developing anti-spike antibodies (GMT 988.83 U/mL). Anti-CD20-bendamustine treatment was associated with a significantly lower antibody positivity compared to untreated subjects. Prior COVID-19 infection significantly boosted both antibody positivity (95.9% vs. 85.2%) and GMT (847.02 U/mL vs. 258.79 U/mL). Conversely, T cell response was suboptimal (36.1% positive), particularly in anti-CD20-bendamustine-treated and multi-treated patients (27.1%), but highest in those treated with BTK inhibitors (50%). Multivariable logistic regression analysis linked multiple treatments to lower T cell response. Following vaccination, 29.1% of patients contracted SARS-CoV-2, but only 0.89% developed severe COVID-19. Conclusions: Three doses of mRNA vaccine elicit a strong humoral but a low T cell response, as detected by IGRA, in hematological patients. These findings underscore the importance of completing vaccination before initiating immunosuppressive therapies. Full article

Background: Because of the increased awareness of the clinical importance of ILAs on chest CT, this study aims to determine the prevalence of ILAs in an Italian health cohort undergoing CT for a lung cancer screening (LCS) program and quantify ILA using both visual and deep learning-based analyses. Methods: In this observational, retrospective monocentric study, 500 participants (ITALUNG2, n = 100; RISP, n = 400) underwent low-dose CT (CTDI < 2mGy). Two radiologists retrospectively reviewed the images and determined the presence and extent of ILAs, classifying them as fibrotic or non-fibrotic, while a lung texture analysis was performed by using commercially available deep learning–based software. Results: ILAs were present in 34 patients (11 females and 23 males), with a prevalence of 6,8%, with similar rates across both screening cohorts taken individually. Interobserver agreement between radiologists was almost perfect, whereas concordance between visual and automated quantification was substantial. Visual assessment tended to yield higher estimates of ILA extent compared with software-based analysis. Conclusions: These findings confirm that ILAs are relatively common in LCS populations and highlight the importance of their detection and characterization, particularly for fibrotic patterns. Differences between visual and automated approaches underline the need for further refinement and validation of quantitative tools. Full article

Modern dentistry increasingly relies on light-curing units (LCUs) and lasers in essential clinical procedures such as composite resin polymerization, caries treatment, and periodontal therapy. This review aims to outline the evolution of light-emitting technologies and to assess their potential biological risks, with particular emphasis on effects on the visual system, oral tissues, and microbiome. The development of curing devices is presented chronologically, from the first-generation ultraviolet (UV-A) lamps introduced in the 1970s to current light-emitting diode (LED-LCU) systems and dental lasers (e.g., Er:YAG, Nd:YAG). The progressive increase in light intensity—now exceeding 3000 mW/cm²—has shortened curing times but simultaneously raised safety concerns. Major hazards include the so-called blue-light hazard, where exposure to high-energy visible (HEV) blue light may accelerate macular degeneration, and temperature elevations in the pulp chamber, which may damage the dentin–pulp complex. Laser radiation also exerts significant microbiological effects: Er:YAG and diode lasers demonstrate bactericidal activity against biofilms and oral pathogens (e.g., P. gingivalis), although therapeutic outcomes depend on wavelength, dose, and exposure time. Suboptimal parameters may lead to microbiome disturbances, whereas low-level laser therapy (LLLT; 600–1200 nm) supports tissue regeneration and helps restore microbial balance. The individualization of irradiation parameters, combined with thorough theoretical knowledge, operator expertise, and technical understanding of LCUs and lasers, is essential for maximizing clinical benefits while minimizing health risks and preserving oral microbiome homeostasis. Full article