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We present a direct criterion in the complex domain for analyzing the local exponential synchronization of complex networks of complex-valued systems. A standard procedure for analyzing synchronization involves splitting or transforming the complex-valued states into real and imaginary parts in the real domain, but this doubles the dimension of the system. However, this transformation obscures the richness of the complex system behavior. To address this, we propose a direct criterion in the complex domain Cn for network synchronization. This criterion preserves the system dimension, as well as its geometric and algebraic structure. Moreover, the criterion applies to both holomorphic and non-holomorphic systems, which means that it considers the effects of the complex conjugate states. The stability criterion can be viewed as a balance among three components: the local dissipation of the node dynamics, the destabilizing influence of the non-holomorphic part, which could induce instability, and the stabilizing effect of the diffusive coupling. We present two numerical examples to corroborate the criterion for exponential synchronization. One considers the synchronization of a network of Hamiltonian holomorphic oscillators, and the other presents the synchronization of a network of non-holomorphic Lorenz chaotic systems. The local direct synchronization criterion here presented is an alternative approach to studying synchronization of complex-valued systems, where the preservation of complex dynamic features is crucial.
One of the challenges in accessing cross-border clinical trials involving international participants in Europe is language diversity, with 32 official languages in the European continent. Some patients have reported being excluded from trials owing to their native language, and in certain studies, language has been used as an eligibility criterion for participation. Considering that pediatric studies in Europe are not conducted in all countries, cross-border access to clinical trials may represent the only therapeutic opportunity for children living with rare diseases for which no approved treatment exists. This study aimed to assess the use of language as an eligibility criterion in pediatric clinical trial protocols conducted in Europe (2007-2024) and published in the Clinicaltrials.gov database. It evaluated the frequency and context of language requirements and whether these were scientifically justified. The overall objective was to identify potential sources of language-based discrimination that may prevent cross-border access to pediatric clinical trials. The 32 official languages of the European continent were used as keywords to search the eligibility criteria of 1,754 pediatric clinical trial protocols for studies conducted in Europe between 2007 and 2024 and registered in the largest clinical trial registry, ClinicalTrials.gov, via an Application Programming Interface. Acceptable scientific justifications to use language as an eligibility criterion were defined as being (1) related to specific therapeutic areas that required language or cognitive assessments in communication with the health professionals, who do not speak the patient's language or (2) related to the use of patient- or caregiver-reported outcome measures that had only been validated in specific languages. The majority of the study protocols (95.2%) did not include any reference to European official languages in the eligibility criteria. Of the 85 study protocols that did include language requirements, only 23 (27.1%) had a scientific justification for the use of this criterion. The most frequent European languages required as eligibility criteria were English (20%) and French (16.5%). A minority of European paediatric studies (4.8%) included language in eligibility criteria in the study protocols, but of those that did, most offered no reasonable explanation for the restriction. To prevent language-based discrimination within the European regulatory framework, we recommend that ethics committees should require justification for any language-based eligibility criteria. Additionally, including dedicated sections on cross-border access in clinical trial protocols will help ensure the provision of appropriate resources such as translations, interpreters, travel, and accommodation when recruiting international participants. Pediatric clinical trials are needed to find safe and effective treatments for children. However, language requirements that are not scientifically necessary may prevent some children from taking part. In Europe, some families have reported that their child could not join a clinical trial because they did not speak a required language. This study examined 1,754 pediatric clinical trial studies conducted in Europe between 2007 and 2024, using data from a large database termed ClinicalTrials.gov. The researchers looked for any mention of language in the study entry rules (the criteria used to decide who can participate). They found that only a small number of trials (4.8%) mentioned language. However, when a language requirement was included, it was often not clearly justified. In only 27% of studies it was a scientific reason, for example, when tests required a specific language or relied on speech or understanding. English and French were the most commonly required languages. The study also identified other requirements that could limit participation, such as needing access to a mobile phone, Internet, or enrollment in a specific national health system. These factors may make it harder for international families or those with fewer resources to participate. The authors recommend that ethics committees carefully review language requirements and require a clear scientific reason before approving them. They also suggest that study plans include a section explaining how children from different language backgrounds and countries can be included.
The existing research on the number of options in the Likert-type response format has focused primarily on reliability and descriptive statistics, often overlooking validity or examining it with limitations. This study addressed this gap through a within-subject experiment (N = 846, 69% women), manipulating response options (two, six, and 10) in two Likert-type scales: the Height Inventory and the autonomy subscale of the Basic Needs Satisfaction in General Scale. Two-point variants significantly differed in means and reliability compared to six- and 10-point versions. While the magnitudes of differences were small in Height Inventory, it did not follow for the autonomy subscale. On the other hand, validity (criterion, measurement model, and trait criterion validity) remained unaffected. Thus, the increased reliability may be spurious, stemming from systematic but construct-irrelevant variance related to response format (i.e., method variance). These findings suggest that response formats with fewer options can be viable, particularly in scales with more items. Future research should explore differences in cognitive processes across response formats.
Environmental pollution represents an important threat to women's health due to its potential effects on reproductive, maternal, hormonal, and general health outcomes. This study aimed to develop the Environmental Pollution Awareness Scale for Women's Health (EPAS-WH) and evaluate its psychometric properties. This methodological study was conducted with three independent samples consisting of a total of 760 women (Sample A: M age = 24.4 ± 7.8; Sample B: M age = 25.4 ± 8.7; Sample C: M age = 24.6 ± 8.2). The scale development process included item generation, expert evaluation, content validity analysis, exploratory factor analysis (EFA), confirmatory factor analysis (CFA), reliability analyses, test-retest reliability, and criterion-related validity assessment. Content validity was evaluated using the Lawshe technique. Internal consistency was assessed using Cronbach's alpha and McDonald's omega coefficients, while criterion-related validity was examined through correlations with the Eco-Anxiety Scale. Content validity analysis supported the relevance of the scale items (CVI = 0.889). EFA revealed a unidimensional structure consisting of 8 items, explaining 66.5% of the total variance. CFA confirmed the single-factor structure and demonstrated good model fit. The EPAS-WH showed excellent internal consistency (Cronbach's α = 0.940; McDonald's ω = 0.932), strong construct reliability (CR = 0.93), and adequate convergent validity (AVE = 0.63). Test-retest analysis demonstrated good temporal stability (ICC = 0.87). In addition, significant positive correlations between EPAS-WH and eco-anxiety scores supported criterion-related validity. The EPAS-WH is a valid, reliable, and psychometrically robust measurement instrument for assessing women's awareness of environmental pollution-related health risks. The scale may be used in research, public health practices, and educational interventions aimed at evaluating and improving environmental health awareness among women.
Medication reviews (MRs) are increasingly implemented to optimize medication use and address drug-related problems in patients with complex pharmacotherapy, with medication review type 2a (MR2a) representing an intermediate format involving a pharmacist-led structured assessment with patient interview, based on clinical and medication data, without direct prescriber interaction. Despite their widespread implementation, systematic and operational approaches to evaluate the quality of MRs remain limited. In Belgium, Medication Review type 2a (MR2a) has been implemented in routine practice of community pharmacies since 2023, yet no validated instruments exist to evaluate the quality of written MR2a reports. This study aimed to adapt the existing BRANT-MERQS framework for the quality evaluation of MR2a reports and to assess the usability, reproducibility and reliability of the resulting tool (BRANT-MERQS-2A). Relevant criteria were selected from the original BRANT-MERQS and expanded with criterion-specific instructions to form the BRANT-MERQS-2A. Initial testing involved two student assessors independently evaluating 98 MR2a reports, with interrater agreement (IRA) assessed using weighted Cohen's Kappa. In a subsequent extended testing phase, the same reports were assessed by 61 final-year pharmacy students, with three randomly selected students evaluating each MR2A report. Interrater reliability was evaluated using the Intraclass Correlation Coefficient (ICC) and Gwet's AC1. Assessment duration was recorded to evaluate feasibility. Initial testing demonstrated strong IRA between the two student assessors. In the extended student cohort, agreement at the criterion level ranged from poor to moderate, with an overall ICC of 0.62, indicating moderate reliability. Criteria differed in discriminatory capacity, with some showing high absolute agreement but limited variability. Assessment time decreased over successive rounds, reflecting a learning effect and improved efficiency. The BRANT-MERQS-2A provides a feasible and structured approach for assessing the quality of MR2a reports. While variability at criterion level reflects the inherent complexity of MR2a, the tool demonstrates potential for self-and peer-assessment and offers a valuable foundation for further refinement and integration into routine quality monitoring.
Pneumococcal disease (PD) causes significant illness and death, especially in young children, older adults, and individuals with chronic medical conditions. Due to increased risk, children with chronic conditions are often advised to receive additional pneumococcal vaccination beyond the routine primary series. This phase 3 study evaluated the safety and immunogenicity of V116, a 21-valent pneumococcal conjugate vaccine, compared to PPSV23 in children aged 2 to <18 y with certain medical conditions that increase risk of PD who had previously completed a primary pneumococcal vaccination regimen. Individuals with diabetes mellitus, chronic heart, chronic lung, chronic kidney, and/or chronic liver disease were randomized 3:2 to receive a single dose of either V116 (n = 531) or PPSV23 (n = 351). Immunogenicity was assessed at 30 d postvaccination comparing opsonophagocytic activity (OPA) geometric mean titers (GMTs) and immunoglobulin G (IgG) geometric mean concentrations (GMCs) between groups. Safety was evaluated by the proportion of participants with adverse events (AEs). The V116 group met the statistical noninferiority criterion for each of the 12 pneumococcal vaccine serotypes shared between V116 and PPSV23 and additionally met superiority criterion for each of the 9 serotypes unique to V116 based on OPA GMTs. IgG GMCs were consistent with the OPA results. The safety profile was generally comparable between groups. In children and adolescents aged 2 to <18 y with certain medical conditions, V116 is well tolerated and immunogenic. These findings support the use of V116 to broaden pneumococcal serotype coverage in populations at increased risk of pneumococcal disease.
To develop and validate a simple predictive model based on Day 3 embryo morphology to guide blastocyst culture strategy and optimize transfer outcomes for women of advanced maternal age (AMA). This retrospective study analyzed a total of 6840 cleavage-stage embryos from 1102 fresh oocyte retrieval cycles with subsequent blastocyst culture in AMA patients. Key parameters including the number of oocytes retrieved, Day 2 and Day 3 cell numbers, embryo fragmentation, embryo grade, and the number of high-quality Day 3 embryos were assessed. Their associations with the blastocyst formation rate (BR), high-quality blastocyst formation rate (HBR) and clinical outcomes were evaluated. Logistic regression identified the number of high-quality Day 3 embryos as a pivotal independent predictor. A threshold of ≥ 4 high-quality embryos was established. For cycles meeting this criterion, the risk of having no Day 5 transferable blastocyst was 19.30%. Within this group, Day 5 blastocyst transfer was associated with significantly higher clinical pregnancy and live birth rates, a lower multiple pregnancy rate, and improved neonatal outcomes (higher gestational age and birth weight) compared to Day 3 cleavage-stage transfer. The threshold showed good predictive performance in a temporally separated validation cohort (AUC 0.91). In AMA patients, a threshold of ≥ 4 high-quality Day 3 embryos may serve as a practical, low-cost criterion to guide blastocyst culture and elective single blastocyst transfer. The approach is associated with favorable clinical and neonatal outcomes but requires prospective validation in unselected populations.
Irisin is an exercise-induced myokine that has been proposed to exert beneficial effects on metabolic health. However, its response to different exercise training modalities in individuals with overweight or obesity remains inconsistent. This systematic review and meta-analysis primarily aimed to evaluate the effects of various exercise interventions on circulating irisin levels as the primary outcome in overweight and obese adults. Additionally, we assessed changes in other selected myokines and metabolic markers as secondary outcomes to provide a better understanding of exercise induced physiological adaptations. A systematic search was conducted in Web of Science, EMBASE, Cochrane Library, PubMed, SCOPUS, and Google Scholar (up to 22 April 2025) to identify randomized controlled trials (RCTs) evaluating the effects of different exercise training protocols (aerobic, resistance, concurrent, and high-intensity interval training) on circulating irisin levels in adults with overweight or obesity. The primary eligibility criterion to include studies was the measurement of circulating irisin. Within the RCTs meeting this criterion, we additionally extracted data on selected myokines (follistatin, myostatin, and FGF21) and metabolic markers (glycemic control and lipid profiles) when reported. These secondary outcomes were analyzed to contextualize irisin responses within broader metabolic adaptations, but no separate systematic search was performed for these variables. Pooled effect sizes were calculated using random-effects models and expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Using the median split technique, subgroup analyses were computed according to exercise training modality. A total of 50 studies comprising 1780 participants (1104 in exercise groups and 676 in passive control groups) were included. For the primary outcome, exercise training was associated with a significant increase in circulating irisin (SMD 0.62, 95% CI 0.39-0.85, p < 0.001, n = 76 arms, 1721 subjects) compared with passive controls. Among the secondary outcomes, training was also associated with increases in high-density lipoprotein cholesterol (SMD 0.25, 95% CI 0.03-0.47, p = 0.030], n = 18 arms, 420 subjects), follistatin (SMD 0.89, 95% CI 0.37-1.41, p = 0.008, n = 7 arms, 141 subjects), and fibroblast growth factor 21 (FGF-21; SMD 1.00, 95% CI 0.10-1.91, p = 0.003, n = 13 arms, 280 subjects). In contrast, exercise training did not significantly affect myostatin levels (SMD - 0.45, 95% CI - 1.07 to 0.18, p = 0.160, n = 11 arms, 283 subjects). Additionally, exercise training significantly reduced fasting blood glucose (SMD - 0.61, 95% CI - 0.89 to - 0.33, p < 0.001, n = 28 arms, 696 subjects), insulin (SMD - 0.80, 95% CI - 1.11 to - 0.50, p < 0.001, n = 24 arms, 566 subjects), homeostatic model assessment for insulin resistance (SMD - 0.75, 95% CI - 1.08 to - 0.43, p < 0.001, n = 28 arms, 609 subjects), hemoglobin A1C (HbA1C) (SMD - 0.96, 95% CI - 1.23 to - 0.70, p < 0.001, n = 12 arms, 275 subjects), and low-density lipoprotein cholesterol (SMD - 0.38, 95% CI - 0.74 to - 0.02, p = 0.040, n = 18 arms, 443 subjects). Exploratory subgroup analysis showed significant increases in irisin following resistance training (SMD 0.88 [95% CI, 0.44 to 1.33], [p = 0.001], n = 21 arms, 537 subjects, I2 = 79% [p = 0.001]), high-intensity interval training (SMD 0.61 [95% CI, 0.13 to 1.09], [p = 0.001], n = 17 arms, 346 subjects, I2 = 75% [p = 0.001]), and concurrent training (SMD 0.42 [95% CI, 0.16 to 0.68], [p = 0.002], n = 18 arms, 356 subjects, I2 = 21% [p = 0.20]). Although resistance training demonstrated numerically larger effects, differences between exercise modalities were not statistically significant (p > 0.05). Regular exercise is an effective intervention for increasing circulating irisin levels and favorably modulating other myokines such as follistatin and FGF-21 in adults with overweight or obesity. Resistance training showed larger numerical effects, but the differences between exercise types were not statistically significant. These adaptations, alongside improvements in metabolic markers, support the role of structured exercise as part of a comprehensive strategy for improving metabolic health in this population. PROSPERO CRD42025637476.
Complex febrile seizures (CFS) confer an elevated risk of epilepsy progression; however, the underlying genetic architecture remains insufficiently characterized in Chinese pediatric populations. This study aimed to delineate the mutational landscape and genotype-phenotype associations in a clinically stratified high-risk febrile seizure cohort. This retrospective, single-center study enrolled 233 children (aged 6 months-6 years) who were consecutively screened at the Wuhan Children's Hospital (July 2019-January 2025) and fulfilled ≥ 1 predefined high-risk criterion. Targeted epilepsy gene panel sequencing was performed, and variant pathogenicity was adjudicated according to ACMG/AMP guidelines. Between-group comparisons were made using the Mann-Whitney U test, Pearson's χ2 test with continuity correction, or Fisher's exact test; effect sizes are reported as odds ratios (OR) with 95% confidence intervals (CI). Sixty-seven patients (28.8%) harbored pathogenic/likely pathogenic (P/LP) variants in 18 genes. Voltage-gated sodium channel genes (SCN1A, SCN1B, SCN2A, SCN8A) accounted for 44.8% of positive cases, with SCN1A being most prevalent (25.4%). Patients fulfilling ≥ 2 high-risk criteria demonstrated a higher diagnostic yield than those with a single criterion (35.4% vs. 20.8%; OR = 2.10; 95% CI: 1.16-3.79; p = 0.020). P/LP-positive patients exhibited significantly elevated rates of status epilepticus (OR = 4.96), developmental delay (OR = 3.70), and abnormal interictal EEG (OR = 3.03). Among SCN1A-positive patients, 70.6% progressed to Dravet syndrome. Genetic findings modified antiseizure medication management in 62.7% of positive cases. Targeted genetic screening in high-risk CFS populations yields a clinically significant diagnostic rate dominated by ion channel genes, facilitating early epilepsy risk identification and precise therapeutic intervention.
Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8 + T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.
This study aimed to investigate the prognostic value of 4D Flow CMR-derived coronary sinus flow (CS Flow) and pressure gradients across the aortic valve in patients with acute myocardial infarction (AMI). We retrospectively enrolled 103 AMI patients who underwent CMR prior to PCI. CS Flow (normalized to left ventricular mass), supra- and sub-aortic valve peak pressure gradients (Supra-APGmax, Sub-APGmax) were quantified using 4D Flow CMR. The composite endpoint comprised all-cause death, unplanned revascularization, recurrent myocardial infarction, rehospitalization for heart failure, and stroke. After univariable screening, three stratified multivariate Cox regression models were constructed. Model performance was evaluated using the likelihood ratio test, Akaike Information Criterion (AIC), and Harrell's C-index. Kaplan-Meier curve analysis with the log-rank test was employed to evaluate survival estimates. Patients with events (n=21) showed lower standardized CS Flow and lower Supra-APGmax than event-free patients (all P < 0.001). Across the three stratified multivariate Cox regression models constructed, all models incorporating 4D Flow CMR-derived parameters consistently demonstrated that CS Flow and Supra-APGmax remained independent predictors (all P < 0.05). Kaplan-Meier curves demonstrated the poorest event-free survival when CS Flow < 0.59 mL/min/g and Supra-APGmax < 4.01 mmHg (log-rank P < 0.001). CS Flow and Supra-APGmax were independently associated with adverse cardiovascular outcomes after AMI. Their combined application demonstrated potential incremental prognostic information over conventional clinical markers and provided preliminary evidence for individualized risk assessment in patients with AMI.
β-Thalassemia is an inherited hemoglobin disorder caused by reduced or absent synthesis of the β-globin chain, leading to variable clinical severity and substantial lifelong health burden. Because prevention depends heavily on awareness, screening, and informed reproductive decision-making, understanding public knowledge, attitudes, and practices is essential for designing effective control strategies. An analytical cross-sectional study was conducted between November 2025 and January 2026 using a structured, self-administered Arabic questionnaire distributed online through Google Forms. The survey was adapted from a previously validated thalassemia KAP instrument and disseminated using snowball sampling through social media platforms. The minimum required sample size was 358, calculated using a single-proportion formula with an expected awareness proportion of 36.8% from a previous young-adult β-thalassemia KAP study, 95% confidence level, and 5% margin of error. A total of 424 Palestinian participants were included in the final analysis. Participants who had never heard of thalassemia were classified as unaware and excluded from domain-based KAP scoring analyses. Knowledge, attitude, and practice domains were scored using Bloom's 60% cut-off criterion. Descriptive statistics, chi-square tests, t-tests, ANOVA, correlation analyses, and multivariable logistic regression were used for data analysis. Overall, 87.0% of participants had heard of thalassemia. Among aware participants (n = 369), 46.1% demonstrated adequate knowledge, 73.7% had a positive attitude, and 82.7% had positive practice. Knowledge was stronger for hereditary concepts, carrier status, and the role of consanguinity, but weaker for disease treatability, clinical subtypes, and prevention policies. Females had significantly higher knowledge and practice scores than males, while positive attitude did not differ significantly by sex. Previous screening uptake was limited, but endorsement of premarital testing, prenatal diagnosis, and knowledge sharing was high. Knowledge score was positively correlated with practice score and independently predicted positive practice (aOR = 1.35, 95% CI: 1.15-1.57, p < 0.001). Female sex, increasing age, and higher education were independently associated with adequate knowledge. Although awareness of beta thalassemia among Palestinian young adults was high, important gaps remained in functionally relevant knowledge and in the translation of preventive intentions into actual screening behavior. The independent association between knowledge and positive practice suggests that strengthening practical genetic literacy may be a key pathway for improving prevention-oriented behavior. These findings support the need for culturally appropriate educational strategies, premarital counseling, and community-based initiatives to enhance informed decision-making and strengthen thalassemia prevention efforts in Palestine. Nurse-led health education, premarital counseling, and accessible community-based screening may help translate awareness into informed preventive action.
To determine a cutoff score for the Social Connectivity of Mothers with People in the Community Scale (SCMPCS) and revalidate the scale using additional psychosocial indicators. A cross-sectional analysis used baseline data from one arm of a randomized trial including 259 mothers with children under 3 years of age in Sapporo City, Japan. Reliability and structural validity were reassessed using Cronbach's alpha and confirmatory factor analysis. Parenting isolation was operationally defined as the absence of support from informal, community-based, and formal sources and used as the reference classification for ROC analysis. Predictive validity was examined using logistic regression adjusted for maternal age, educational attainment, daycare use, and perceived economic status. Criterion-related validity was evaluated using Mann-Whitney U tests. The SCMPCS showed good internal consistency (α = 0.85) and acceptable model fit (CFI = 0.90, RMSEA = 0.073). ROC analysis identified a cutoff of 30 or lower with moderate discriminatory ability (AUC = 0.73; sensitivity = 0.92; specificity = 0.50). Mothers at or below the cutoff had higher odds of meeting the operational reference classification of parenting isolation (OR = 11.94, 95% CI: 2.74-52.03) and reported lower self-efficacy and capacity to receive support, greater loneliness, and poorer well-being. The SCMPCS demonstrated stable psychometric performance, and the validated cutoff may support broad preventive screening to identify mothers who may need further assessment and early follow-up. Rather than serving as a diagnostic threshold, this cutoff may help maternal and child health services provide timely preventive support.
Research studies that include adults who smoke conventional combustible tobacco cigarettes (cigarettes) commonly use exhaled carbon monoxide (eCO) as a biomarker of cigarette usage. eCO is regularly used as an inclusion or exclusion criterion. Multiple studies have examined the time course of eCO levels after acute use of cigarettes. Published studies have verified the relationship between the reported number of cigarettes smoked per day (CPD) and eCO levels. One article suggested that collection time of day may induce variations in eCO elimination. Researchers can improve recruitment if there is confidence that collection time does not significantly affect eCO. We analyzed data from eight separate studies conducted between 2019 and 2024 that collected eCO levels from adults who were not abstinent from smoking, after they reported their usual consumption patterns of cigarettes, to determine whether collection time or CPD had a significant effect on eCO levels. Data analyzed included eCO levels, collection times of eCO levels, and reported CPD smoked. In the aggregate data, collection time did not result in significant changes in eCO levels (p = 0.87), as assessed throughout typical clinical hours (08:00 to 18:00). In contrast, and as expected, eCO levels were significantly impacted by CPD (p < 0.001). This finding verifies that screening eCO levels may be obtained throughout the day while minimally impacting eCO levels, allowing for greater flexibility in scheduling individuals for participation in research studies which require evaluation of smoking status.
Generalization is a fundamental criterion for evaluating learning effectiveness, a domain where biological intelligence excels yet artificial intelligence faces challenges. In biological learning and memory, the well-documented spacing effect shows that appropriately spaced intervals between learning trials significantly improve behavioral performance. While multiple theories have been proposed to explain its underlying mechanisms, one compelling hypothesis is that spaced training promotes integration of input and innate variations, thereby enhancing generalization to novel but related scenarios. Here, we examine this hypothesis by introducing a bio-inspired spacing effect into artificial neural networks, integrating input and innate variations across spaced intervals at neuronal, synaptic, and network levels. These spaced ensemble strategies yield significant performance gains across benchmark datasets and network architectures. Biological experiments on Drosophila further validate the complementary effect of appropriate variations and spaced intervals in improving generalization, which together reveal a convergent computational principle of biological learning and machine learning.
In Japan, liver transplantation (LT) for hepatocellular carcinoma (HCC) is restricted to patients with decompensated cirrhosis. We investigated the clinical course, prognosis, and medical expenditure of patients with Child-Pugh class A (CP-A) HCC initially within the Japan criteria, including changes in oncological eligibility for LT during follow-up. We retrospectively analyzed patients with HCC treated at Kanazawa University Hospital between 2011 and 2021. After applying the age criterion (< 70 years), 134 patients with CP-A HCC, 45 with CP-B HCC, and 6 LT recipients were included. Survival and cumulative HCC-related medical expenditures were compared. A transplantable period was defined as the interval during which both hepatic reserve and tumor burden met LT eligibility. LT achieved the most favorable prognosis, with a 5-year overall survival rate of 83.3%. Among patients with CP-A HCC, progression beyond the Japan criteria was associated with markedly reduced survival, approaching that observed in CP-B disease. Of 53 patients who progressed beyond the Japan criteria, only 12 (22.6%) retained a transplantable period (median, 10.6 months). Early recurrence and a FIB-4 index > 5 were independently associated with poor prognosis. The cost per treatment life-year did not differ significantly between LT recipients and certain CP-A HCC subgroups. Many patients with CP-A HCC initially within the Japan criteria lost oncological eligibility for LT before hepatic decompensation. Further studies are warranted to determine whether a subset of patients with compensated cirrhosis may benefit from LT and to inform future discussions regarding the potential expansion of LT indications.
The development of valid and reliable health questionnaires relies on respondents' accurate comprehension of items. The thinking-aloud (TA) technique, where participants verbalize their thought processes while answering survey questions, offers a powerful means to explore cognitive mechanisms underlying response behaviour. Despite its wide use, there is no consensus on how TA protocols should be designed, conducted, and analysed. This scoping review aimed to map methodological approaches applied to TA in health-related questionnaire development and validation, describe their variability, and critically examine current methodological practices to inform future research. PubMed, Scopus, and Embase were searched on July 17, 2025, without time limits. Eligible studies were original articles in English applying TA for questionnaire validation, including assessment of content, face, construct validity, or comprehensibility. Two reviewers independently screened records and extracted data using a standardized charting form. An operational criterion was used to judge the completeness of methodological reporting. Data were synthesized narratively and tabulated to describe study purposes, TA typologies, analytical strategies, and theoretical frameworks. From 1,678 retrieved records, 210 studies met inclusion criteria, of which 84 provided complete methodological descriptions. Most of the 84 studies involved patients (48%) and used concurrent TA (48%), with frequent prompting (55%) and probing (48%). Sessions were mainly face-to-face (71%), audio recorded (64%), and transcribed verbatim. Thematic (38%) and content (26%) analyses predominated, often supported by NVivo. The Survey Response Model was the most cited theoretical framework (26%), though 22% of studies lacked any theoretical reference. Coding strategies were mixed (36%), and about half of the studies reported questionnaire revisions after analysis. TA remains a versatile but methodologically fragmented approach in questionnaire validation. The lack of standardization limits comparability and interpretability across studies. Greater transparency in reporting and explicit theoretical framing are recommended to improve methodological rigor. The review followed the PRISMA-ScR framework and was prospectively registered on OSF (DOI: https://doi.org/10.17605/OSF.IO/AZY3).
To compare the efficacy and safety of gonadotropin-releasing hormone agonist combined with an aromatase inhibitor versus oral progestins as fertility-sparing treatment in patients with endometrial carcinoma or atypical endometrial hyperplasia. This prospective, open-label, randomized non-inferiority trial (March 2023-March 2025) allocated patients 1:1 to gonadotropin-releasing hormone agonist plus letrozole (Arm A) or oral progestins (Arm B). A pre-specified interim analysis was conducted with a data cutoff date of March 17, 2025. The primary endpoint was the 24-week complete response rate. At this interim analysis, a total of 131 patients who completed the 24-week assessment were analyzed (Arm A: n = 67; Arm B: n = 64). At 24 weeks, the per-protocol complete response rate was significantly higher in Arm A than in Arm B (98.5% vs 68.8%; odds ratio 30.00, 95% confidence interval 3.88 to 231.71, p <.001), with a shorter mean time to response (127.48 vs 185.30 days; mean difference = 57.8 days, 95% confidence interval 32.97 to 82.66, p <.001). Pregnancy (53.1% vs 35.7%, p =.14) and recurrence rates (6.1% vs 12.3%, p =.19) showed no significant differences between groups. Multi-variate analysis confirmed the gonadotropin-releasing hormone agonist-based regimen as an independent predictor of complete response (adjusted odds ratio 31.07, 95% confidence interval 4.00 to 241.26, p =.001), with no significant influence from histology or body mass index. Patients in Arm A experienced significantly less weight gain than those in Arm B (21.9% vs 43.9%, p =.012), although menopausal symptom scores were higher in Arm A. This pre-specified interim analysis demonstrates that the gonadotropin-releasing hormone agonist-based regimen met the criterion for non-inferiority compared with oral progestins and was associated with higher complete response rates and a more favorable metabolic profile (less weight gain). These exploratory findings support continued investigation, but final conclusions await trial completion.
Ultrathin copper (Cu) films are indispensable in micro- and nano-electronic devices but suffer from severe environmental oxidation due to their high surface-to-volume ratio. Here, we report a plasma-induced pre-oxidation strategy that enhances the environmental stability of Cu nanofilms using an ultrathin aluminum (Al) layer with a critical thickness as low as ∼3 nm. Al layers were physically vapor deposited onto Cu surfaces (Cu@Al) and subsequently exposed to low-power plasma treatment (Cu@Al-P), enabling controlled in situ formation of a compact and structurally uniform Al2O3 barrier. Electrical measurements under ambient air, high temperature and high-temperature & high-humidity conditions show that the Cu@Al-P films with 3 nm Al exhibit significantly improved oxidation resistance. Under these conditions, the resistance variation of Cu@Al-P is ∼2.9 times, ∼9.34 times, and ∼5.75 times lower than that of Cu@Al, respectively. Compared to bare Cu, the improvements are even more significant, with Cu@Al-P exhibiting resistance variations that are ∼5.84 times, ∼27.19 times and ∼23.93 times lower. X-ray photoelectron spectroscopy, scanning Kelvin probe microscopy characterization and parallel resistance model calculation confirm that plasma treatment enables the rapid formation of a more uniform and stable Al2O3 barrier, which effectively suppresses oxygen diffusion and stabilizes the electrical properties of the Cu films. This work establishes a critical thickness criterion for ultrathin barrier design and provides a simple, scalable and fabrication-compatible strategy to enhance the environmental stability of copper-based nanoscale electronic systems and other ultrathin metallic nanostructures.
Emotion regulation significantly influences emotional experiences. While research has extensively explored the overall effects of regulation strategies, little attention has been paid to their item-level impacts. This study addresses this gap by employing a complex systems approach to examine the intricate dynamics and interdependencies among individual regulation items, using network analysis to reveal how these strategies collectively shape emotional outcomes. This cross-sectional study, conducted in Tehran, Iran in 2023, recruited 528 participants (396 females, 132 males; mean age: 25.9 years) via online platforms. Using R for data analysis, a regularized Gaussian graphical model was estimated utilizing glasso in combination with the extended Bayesian information criterion model. The centrality of nodes in the network was calculated using measures of betweenness, closeness, and strength. The findings revealed significant connections among various emotion regulation strategies, with the highest edge weights observed between ERQ7 __ ERQ8 (0.371), ERQ2 __ ERQ6 (0.289), ERQ2 __ ERQ4 (0.275), and ERQ6 __ ERQ9 (0.278). Additionally, the analysis demonstrated that ERQ6, ERQ10, and ERQ7 emerged as the most central nodes in the emotion regulation network, indicating their influential role in controlling and transforming emotions. The findings of this study are expected to advance our theoretical understanding of emotion regulation and offer practical implications for clinical interventions and interventions aimed at enhancing emotional well-being.