The blueberry (Vaccinium corymbosum L.) is known for its high content of bioactive compounds, which are widely recognized for their health-promoting properties. This study aimed to characterize the fruit quality, total phenolic content (TPC), total monomeric anthocyanin content (TMA), anthocyanin profile and antioxidant activity of the nine Romanian V. corymbosum genotypes ('Augusta', 'Azur', 'Delicia', 'Lax', 'Pastel', 'Prod', 'Safir', 'Simultan', and 'Vital') over three consecutive harvest seasons (2023-2025). Significant genotype- and year-dependent variation was observed for all parameters. 'Lax' consistently accumulated the highest total anthocyanin content across all three seasons, while 'Simultan' exhibited the highest antioxidant activity and total monomeric anthocyanin content. 'Prod' consistently recorded the lowest phytochemical values despite achieving the highest firmness in 2025. UPLC analysis identified 10 anthocyanins, covering all five major anthocyanidin classes. Strong positive correlations were found between TPC, TMA, and antioxidant activity. These results confirm that genotype is the primary determinant of blueberry phytochemical composition, as indicated by the largest effect sizes in the two-way ANOVA, with harvest year and genotype × year interaction as statistically significant but secondary modulating factors, and identify 'Lax', 'Simultan', and 'Safir' as promising cultivars for nutraceutical and breeding applications.
Neutrophil Extracellular Traps (NETs) are web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils, which play a critical role in modulating neutrophil-mediated immune responses. Initially recognized for their role in host defense, NETs function as "molecular traps" that rapidly ensnare pathogens. They then achieve efficient clearance by directly degrading virulence factors through the action of associated antimicrobial proteins. However, the functions of NETs extend beyond immune defense. Dysregulation of NETs in pathological conditions can lead to detrimental effects. Recent studies have highlighted the importance of aberrant NET formation and impaired clearance in the pathogenesis of central nervous system (CNS) diseases, making them a field hotspot. In view of this, we discuss NETs, the structural characteristics and diverse generation patterns of NETs, and clarify how neutrophils cross the blood-brain barrier (BBB) to enter the CNS. We also explore triggers of NETosis within the brain, such as oxidative stress and inflammatory mediators. Furthermore, we analyze the pathological contributions of NETs to a range of CNS disorders, including stroke, traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), Alzheimer's disease (AD), multiple sclerosis (MS), etc. Finally, we summarize emerging neuroprotective strategies that target NETs, highlighting advances in interventions designed to inhibit NET formation or promote their degradation. By synthesizing current evidence, this review aims to uncover the mysterious veil of NETs in neurological diseases and to offer new insights for understanding disease mechanisms and developing targeted therapeutic approaches.
Child study satisfaction has rarely been assessed in longitudinal pediatric research. This study examined child and maternal study satisfaction among 10-15-year-old participants in The Environmental Determinants of Diabetes in the Young (TEDDY) study, an observational multinational (US, Finland, Germany, and Sweden) study of children at increased genetic risk for type 1 diabetes enrolled at birth. Child and maternal study satisfaction was measured by a 3-item annual questionnaire from child-age 10 years until the last visit at child-age 15. Generalized estimating equations identified sociodemographic and study-related variables associated with study satisfaction. Children and mothers exhibited high study satisfaction across all ages although their study satisfaction scores were weakly correlated (r ≥ 0.20, p < 0.001). Factors associated with higher study satisfaction were similar for children and mothers: living in the US compared to Finland (Finnish children: -0.78 95%CI -0.86, -0.69; Finnish mothers: -1.48 95%CI -1.61, -1.35; p < 0.001), older child age (15-year-old vs 10-year-old child: 0.09 95%CI 0.03,0.14; mother: 0.42 95%CI 0.37, 0.47; p < 0.001), and accurate perception about the child's type 1 diabetes risk (child: 0.20 95%CI 0.15,0.25; mothers: 0.20 95%CI 0.13, 0.22; p < 0.001). Additional factors associated with greater child study satisfaction included female sex (-0.29 95%CI -0.35, -0.24; p < 0.001), being multiple islet autoantibody positive (0.21 95%CI 0.11, 0.32; p < 0.001), lower child anxiety about type 1 diabetes risk (-0.01 95%CI -0.02, -0.01; p < 0.001), having a mother with higher study satisfaction (0.13 95%CI 0.12, 0.15; p < 0.001), and having read an age-appropriate book about the study, its purpose, and type 1 diabetes (0.19 95%CI 0.12, 0.25; p < 0.001). Study satisfaction was high among 10-15-year-old children at increased genetic risk for type 1 diabetes, and their mothers, who had participated in a longitudinal observational study since the child's birth. Factors associated with satisfaction were similar for children and their mothers. Potentially modifiable factors that could be targeted to improve study satisfaction include mother and child accuracy about the child's type 1 diabetes risk and for child study satisfaction in particular - the child's own anxiety about type 1 diabetes, the child's mother's satisfaction and having the child read high quality age-appropriate materials about the study. NCT00279318, 06/09/2004.
Although a wide range of molecular and histopathological biomarkers has been explored for oral squamous cell carcinoma (OSCC), few have reached the level of validation needed for routine clinical application. Updates to the TNM staging system and accumulating evidence for emerging histopathological parameters may enhance prognostic accuracy, but robust prospective studies are still required. Progress in genomics, transcriptomics, proteomics, and liquid biopsy technologies has identified several promising candidates, however methodological variations and the limited number of validation studies continue to slow their clinical adoption. Current OSCC treatment remains centered on surgery, radiotherapy, and chemotherapy, with targeted therapies and immunotherapy drugs offering only modest benefits. Emerging precision oncology strategies and patient-derived drug testing platforms hold potential, though technical and biological barriers still limit their widespread application. In this expert perspective, the discussion highlights advances in emerging biomarkers, evaluates their readiness for clinical application, and examines evolving treatment strategies. It also outlines key translational challenges and future directions that may support the development of more personalized OSCC management.
Dostarlimab+carboplatin-paclitaxel followed by dostarlimab maintenance demonstrated statistically significant and clinically meaningful benefits in progression-free and overall survival in the overall population of primary advanced/recurrent endometrial cancer versus chemotherapy alone in Part 1 of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial (NCT03981796). Part 2 evaluated the efficacy and safety of the addition of the poly(adenosine diphosphate-ribose) polymerase inhibitor niraparib to dostarlimab maintenance following dostarlimab+chemotherapy versus placebo maintenance following placebo+chemotherapy in primary advanced/recurrent endometrial cancer. Patients were randomized 2:1 to dostarlimab+chemotherapy followed by niraparib+dostarlimab maintenance (niraparib+dostarlimab arm) or placebo+chemotherapy followed by placebo maintenance (control arm). Primary endpoint was progression-free survival in the overall and mismatch repair-proficient/micro-satellite stable populations. Overall survival (key secondary endpoint) and safety were assessed. In total, 291 patients were randomized (192 to niraparib+dostarlimab; 99 to control). With approximately 22 months of follow-up, the risk of progression or death was significantly reduced by 40% (hazard ratio 0.60, 95% confidence interval 0.43 to 0.82, p <.001) and 37% (hazard ratio 0.63, 95% confidence interval 0.44 to 0.91, p =.006) with niraparib+dostarlimab versus the control in the overall and mismatch repair-proficient/micro-satellite stable populations, respectively. At 36.2 months of follow-up, no overall survival benefit was observed with niraparib+dostarlimab versus the control (hazard ratio 1.2, 95% confidence interval 0.81 to 1.78). Grade ≥3 treatment-related adverse events occurred in 70.7% of patients in the niraparib+dostarlimab arm and 37.5% in the control arm; serious treatment-related adverse events occurred in 24.6% and 9.4%, respectively. Discontinuations due to adverse events occurred in 38.7% of patients in the niraparib+dostarlimab arm and 11.5% in the control arm. While the addition of niraparib to dostarlimab maintenance showed a significant improvement in progression-free survival, there was no observed overall survival benefit. Dostarlimab+carboplatin-paclitaxel followed by dostarlimab maintenance remains the only regimen to demonstrate significant overall survival benefit versus carboplatin-paclitaxel alone in primary advanced/recurrent endometrial cancer.
Family caregivers of patients with lung cancer experience high levels of unmet needs, burden, and distress, yet systematic processes to identify and connect caregivers with resources are lacking in community oncology. The Caregiver Oncology Needs Evaluation Tool (CONNECT) is a hybrid intervention delivered through a combination of web-based components and telephone-based navigation to inform caregivers about resources, assess their needs, and connect them to tailored supportive care services. Initial pilot testing at a single academic center demonstrated feasibility and acceptability, but feasibility in community settings remains untested. In this study, we aim to assess the multi-site feasibility of CONNECT. This multi-site, randomized controlled pilot trial (WF-2301CD) is conducted through the Wake Forest National Cancer Institute Community Oncology Research Program (NCORP) Research Base. Lung cancer caregiver-patient dyads (N = 120) are recruited from 12 community oncology practices and randomized to: CONNECT, generic resource list, or usual care. The primary objective is to assess multi-site feasibility, measured by caregiver retention at 12-weeks. Secondary objectives include evaluating caregiver accrual, participation, retention at 24-weeks, and acceptability, as well as process metrics. Exploratory objectives assess patient accrual, participation and retention. Data are collected via surveys at baseline, 12-, and 24-weeks, with additional process tracking by site staff and navigators. This trial will provide critical data on the multi-site feasibility of implementing CONNECT in community oncology practices to inform protocol and design refinements for a future efficacy trial. If feasible, future efficacy testing will focus on the impact of CONNECT on caregiver burden and distress.NCT06383988.
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Establishing the Korean Pediatric and Congenital Heart Surgery Database (KPCHSD) and linking it to the World Database for Pediatric and Congenital Heart Surgery (WDPCHS) is an important step toward creating a global network for quality care. Worldwide outcomes data are needed to support quality assurance and advocacy for necessary resources for pediatric and congenital cardiac care. The Korean Society for Thoracic and Cardiovascular Surgery collaborated with the World Society for Pediatric and Congenital Heart Surgery (WSPCHS) to develop and implement the KPCHSD. Variables selected for collection met the specific needs of Korean congenital heart surgery practice and were harmonized with the WDPCHS. Software was developed to link the databases in a secure environment, transfer data from KPCHSD to the WDPCHS, and produce outcomes reports. The initial data upload from the KPCHSD to the WDPCHS was successfully completed in 2023. Over 2,500 operations from a 2-year period were transferred from the KPCHSD into the WDPCHS. Comparisons of individual center data will be made with both national and international aggregates. These comparisons will be available to individual centers via a password-protected cloud-based dashboard. Working in collaboration with our Korean colleagues, the WSPCHS has taken the next step toward developing a global network to share knowledge and expertise and to promote quality improvement in the treatment of congenital heart disease. Using this platform, countries perform data validation and completeness checks while maintaining control over their data. This aggregated data can support quality assessment and help secure the necessary resources for all countries, regardless of economic status.
Ischemic stroke is associated with increased risk of subsequent cardiac ischemic events, yet mechanisms linking cerebral ischemia to coronary dysfunction remain unclear. We hypothesized that ischemic stroke directly impairs coronary microvascular function through circulating factors released after cerebral ischemia. We found that the vasodilator function of coronary arterioles (CA) was reduced in patients with prior ischemic stroke. In rats, transient middle cerebral artery occlusion impaired CA vasodilator function. Extracellular vesicles (EVs) isolated after cerebral ischemia and delivered into the rat CA lumen also impaired vasodilation. Moreover, we found that luminal delivery of RGD peptide attenuated flow-induced vasodilation in rat CA, an effect that was prevented by BQ-123, an endothelin ETA receptor antagonist. We propose that ischemic stroke directly induces coronary microvascular dysfunction via circulating EV-mediated, RGD-motif-dependent activation of endothelin signaling. This brain-heart vascular axis provides a mechanistic basis for increased post-stroke coronary risk and identifies EV-mediated pathways as potential therapeutic targets.
Exercise offers many benefits, but its role in ketone body (KB) metabolism is unclear in children. Aerobic exercise enhances KB uptake into muscle and improves mitochondrial function. Reduced ketone body concentration may indicate improved mitochondrial function. We hypothesized that physical activity would reduce circulating ketone levels in children. Healthy young Black girls (n = 201) were randomized to a control condition or a daily, after-school exercise intervention. Participants (n = 53) with missing blood samples at baseline or follow up were excluded, 148 (75 intervention and 73 control) participants analyzed. The intervention entailed 30 min of homework time and 80 min of physical activity, including 35 min of moderate to vigorous physical activity over 10 months. Circulating ketone concentration was measured using nuclear magnetic resonance spectroscopy (NMR) and maximal oxygen consumption (VO2 max) assessed oxidative capacity. Participants had a mean age of 9.5 years and BMI percentile of 69.9 at baseline. After adjusting for age, BMI percentile and breast development, decreased circulating ketone levels (mean = 248-170 μM, 31.3% change, Cohen's D = 0.402, p = 0.017) were observed in the treatment group. Exercise reduces KB levels in young girls, highlighting metabolic adaptation to physical activity programming in children consistent with improved mitochondrial function. Existing literature does not consider the effects of long-term exercise on basal ketone concentration. Exercise intervention decreased serum ketone body concentration in girls. This is evidence for changes in nutrient utilization with exercise in active children. Puberty does not impact basal ketone utilization This change could serve as indication of changes in mitochondrial function.
The renin-angiotensin-aldosterone system (RAAS) is essential in controlling fluid balance and blood pressure. In salt-sensitive (SS) hypertension, circulating RAAS is overactive, and the renin response to changes in sodium intake is bidirectionally blunted. Here, we used wild-type Dahl SS rats and renin knockout rats on the Dahl SS background (SSren-/-) to understand the role of renin in blood pressure regulation under salt-deficient (SD; 0.01% NaCl) and high-salt (HS; 4% NaCl) diets. We hypothesized that, compared to SSWT rats, SSren-/- rats would have lower blood pressure on the SD diet due to underdeveloped medulla and would return to normal blood pressure on the HS diet. First, we examined circulating RAAS responses after 10 days of SD and HS diets in SSWT rats. A 10-day SD diet robustly activated all parts of the circulating RAAS in Dahl SS rats, while a 10-day HS diet significantly decreased the aldosterone-to-Ang II ratio. Additionally, we measured mean arterial blood pressure, glomerular filtration rate, urine output, and blood and urine electrolyte levels in SSren-/- rats and SSWT rats (littermates) under normal salt (NS; 0.4% NaCl) and after 10 days of SD or HS diets. SD feeding significantly reduced the blood pressure, plasma Na+, and Cl- of SSren-/- rats. HS diet caused a rapid rise in blood pressure, with 100% mortality in SSren-/- rats. In summary, these findings demonstrate that loss of renin impairs adaptive responses to dietary salt, and proper RAAS function is vital for maintaining blood pressure in salt-sensitive hypertension.
Ozone therapy, a clinical application of various ozone forms that is used for its antiseptic techniques, has sparked interest in recent years over its unique antimicrobial and anti-inflammatory properties in the body. Moreover, its ability to work as an antiseptic while avoiding antimicrobial resistance has sparked interest in the dental field as no other antiseptic agent is able to do so. As a triatomic molecule of oxygen (O₃), ozone functions through oxidative mechanisms that disrupt microbial cell walls, inhibit biofilm formation, and modulate host immune responses without contributing to antimicrobial resistance. Types of study reviewed: Peer-reviewed articles published in English, including systematic reviews, meta-analyses, observational studies, narrative reviews, case series, and case reports were included in the article. This narrative review synthesizes current evidence on the mechanisms of ozone as well as the therapeutic efficacy of ozone in clinical applications across multiple dental specialties. Three main delivery modalities (gaseous ozone, ozonated water, and ozonated oils) demonstrate diverse clinical benefits and are discussed in the review. Comparative studies indicate that for some dental applications ozone achieves antimicrobial efficacy comparable to conventional agents such as chlorhexidine gluconate (CHX) while exhibiting reduced cytotoxicity.
Two principal strategies have gained prominence among currently recognised approaches to anti-ageing: systemic interventions that modulate the circulatory environment and cellular interventions that reset epigenetic information. Systemic approaches, beginning with experimental heterochronic parabiosis models that are not applicable to humans and extending to clinically applicable therapeutic plasma exchange, test the hypothesis that ageing is promoted by the accumulation of inhibitory blood-borne factors. Cellular reprogramming, particularly partial reprogramming through transient expression of Yamanaka factors, tests the alternative hypothesis that ageing is primarily a cell-intrinsic process associated with loss of epigenetic information. This perspective critically evaluates these two modalities. The dilution hypothesis is examined together with its limitations and the unresolved complexities of systemic interventions. The challenge of cell-autonomous ageing is also considered, particularly the persistence of cell populations that remain refractory to systemic rejuvenation. A conceptual framework integrating these two axes of ageing is then presented. This framework suggests that combined systemic recalibration and targeted partial reprogramming warrant further investigation as a multimodal approach to ageing intervention. Future research priorities include mechanistic clarification of this systemic-cellular interaction and development of robust biomarkers to evaluate multimodal interventions.
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To study the associations of dietary intake of A and E vitamins, as well as plasma retinols, carotenoids, and tocopherols in relation to development of islet autoimmunity and progression to T1D. The Environmental Determinants of Diabetes in the Young (TEDDY) Study followed 7659 newborns with genetic susceptibility to T1D for 6 years in the USA, Finland, Germany, and Sweden. Dietary vitamin intake was assessed repeatedly with 3-day food-records in full cohort at ages 6 months to 6 years. Plasma retinols, carotenoids, and tocopherols were analysed in a nested case-control setting with 359 children with islet autoimmunity and 1033 matched controls. In the full cohort analyses, dietary intake of retinol, β-carotene, and vitamin E was not associated with the risk of islet autoimmunity or progression to T1D. Further, none of the plasma retinol, carotenoid, and tocopherol biomarkers were associated with islet autoimmunity or T1D in the full nested case-control analyses. We observed effect modification by country, breastfeeding, sex, and follow-up time for both intake and biomarkers of vitamins on the risk of islet autoimmunity or T1D, and some subgroup associations. Finally, a plasma carotenoid metabolite (likely zeinoxanthin) (OR 0.61, 95% CI 0.39, 0.95, p = 0.03) and γ-carotene at 6 months (OR 0.65, 95% CI 0.45, 0.94, p = 0.02) were inversely associated with the odds of developing GADA-first. Retinol, carotenoids and tocopherols were not consistently associated with islet autoimmunity. This study adds to the understanding of factors and their interactions related to T1D development.
Insomnia is common in the clinical course of schizophrenia, including in individuals at clinical high risk for psychosis (CHR-P). We previously found associations between insomnia and psychosis-risk symptoms in CHR-P. We attempted to replicate findings in an independent cohort. We explored associations between insomnia and psychosis-risk symptoms in CHR-P individuals in the Accelerating Medicines Partnership Schizophrenia (AMP SCZ) program (n = 269). We investigated relationships between insomnia and psychosis-risk symptoms (Brief Psychiatric Rating Scale [BPRS]). The prevalence of any terminal and initial insomnia at AMP SCZ baseline was 28% and 38%, respectively. After controlling for potential confounders, insomnia was a significant indicator of higher BPRS total (β = 0.33) and positive (β = 0.22), affect (β = 0.34), and activation (β = 0.13) subscale scores. Insomnia is prevalent and associated with psychosis-risk symptoms in CHR-P individuals. Findings are clinically relevant and highlight the need for more rigorous assessment and treatment of insomnia in this population.
This cohort study examines patterns of bone-modifying agent use from 2013 to 2024 among men with metastatic castration-resistant prostate cancer.
It remains unclear whether radiation exposure to bronchoscopists and staff differs between conventional and robotic bronchoscopy (RAB). Does the radiation dose received by the bronchoscopist and team members differ between fluoroscopically guided conventional bronchoscopy and RAB? This prospective study evaluated radiation exposure during conventional and RAB with fluoroscopy. Radiation dose was measured per the International Commission on Radiological Protection (ICRP) and National Council on Radiation Protection and Measurements (NCRP) guidelines. Over a 10-month period, 54 fluoroscopy-guided bronchoscopies were analyzed: 15 conventional and 39 RABs. Among the RABs, 27 used C-arm-based tomosynthesis (CABT) and 12 used standard C-arm fluoroscopy (CF). The median total radiation exposure per case was highest for RAB using CABT (0.237 mSv vs 0.065 mSv vs 0.02 mSv) compared with conventional and RAB with CF, respectively (p=0.025). The comparison of radiation exposure per case between conventional bronchoscopy and RAB with CF showed no difference (p=0.33). RAB with CABT resulted in significantly higher radiation exposure to the operator's skin underneath the thyroid collar (median 0.0022 mSv/min, p=0.007), while both conventional and RAB with CF had negligible exposure at this site (0 mSv/min, p=0.18). Radiation dose to staff (nurses, bronchoscopy technicians, pathologists, and anesthesiologists) was minimal across all procedure types. Patients with BMI >35 had significantly higher Dose-Area Product (DAP) /min (5.1 Gy·cm2, p=0.0067), with no differences observed based on nodule size, CT pattern, or location. In this prospective study applying a rigorous methodology to measure and compare radiation doses, we did not find an overall reduction in operator radiation exposure with RAB when only conventional fluoroscopy was used. The addition of CABT was associated with significantly increased radiation dose. The maximum number of RABs using these external imaging modalities performed per year should align with the current regulatory authorities' recommendations.
Phenotypic modulation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular remodeling and cardiovascular disease. Recent lineage-tracing and single-cell transcriptomic studies have identified secreted phosphoprotein 1 (SPP1) as a prominent marker associated with disease-associated VSMC states, particularly those linked to fibrotic remodeling and vascular calcification. However, the cellular origins and fate of SPP1-associated VSMC populations remain incompletely understood. We generated a novel Spp1-rSTOPr-Cre (Spp1Cre) knock-in mouse line in which Cre recombinase is expressed from the endogenous Spp1 locus following Dre-mediated excision of a rox-flanked transcriptional STOP cassette. Correct targeting of the knock-in allele was validated by internal, 5' junction, 3' junction, and long-range PCR analyses, as well as Sanger sequencing. To establish an intersectional lineage-tracing strategy, Spp1Cre mice were crossed with Myh11DreERT2 and Rosa26-RSR-LSL-tdTomato-LSL-eGFP reporter mice, enabling permanent labeling of VSMC-derived populations following activation of the endogenous Spp1 locus. Under physiological conditions, GFP-positive cells were detected at low frequency within the vascular wall and were predominantly negative for the contractile markers ACTA2 and MYH11. As a proof-of-principle application, GFP-positive cells markedly expanded within atherosclerotic lesions induced by PCSK9-AAV and high-fat diet feeding. These lineage-traced cells remained largely ACTA2- and MYH11-negative, consistent with a modulated phenotype. Notably, only a minority of GFP-positive cells expressed SPP1 or fibronectin at the time of analysis, demonstrating the utility of permanent lineage tracing for tracking cells with a history of endogenous Spp1 activation during vascular remodeling. We report the generation and validation of a novel Myh11Dre-Spp1Cre intersectional mouse model for lineage tracing of VSMC-derived populations that have activated the endogenous Spp1 locus. This genetic resource provides a valuable platform for investigating the origin, fate, and phenotypic evolution of Spp1-associated VSMC populations during vascular remodeling and cardiovascular disease.