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.
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.
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.
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.
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).
Drug-induced tinnitus is a prevalent yet under-characterised adverse drug reaction. No prior study has systematically screened the FDA Adverse Event Reporting System (FAERS) for drug-tinnitus disproportionality signals using a rigorous, deduplication-validated framework. A case/non-case pharmacovigilance study was conducted using 53,243 tinnitus-associated individual case safety reports from the FAERS Public Dashboard (1983-2025). Following four-tier deduplication, the reporting odds ratio (ROR) was computed for 900 eligible active ingredients (N ≥ 10 ICSRs; signal criterion: ROR > 1, lower 95% CI > 1, Yates-corrected p < 0.05). Bayesian sensitivity analyses applied. Seventy-four. positive disproportionality signals were identified (8.2%; ROR 1.29-10.71). The strongest signal was diphenhydramine citrate/ibuprofen (ROR 10.71), followed by chloroquine phosphate (9.28). Signals spanned seven ATC Level-1 classes; the nervous system class contributed most signal drugs (n = 12). BCPNN positive 48/74 signals (64.9%; Spearman ρ = 0.997 vs ROR). Median reporting delay was 169 days (IQR 56-446). BH-FDR sensitivity analysis (q ≤ 0.05, m = 900) retained 60 signals, all BCPNN-corroborated. This 43-year analysis identifies 74 positive drug-associated tinnitus signals, including novel immunobiologic (guselkumab, lifitegrast) and cardiovascular (lovastatin, terazosin) associations without current audiological labelling warnings. The delayed onset profile implicates cumulative cochlear injury mechanisms. These findings provide an actionable basis for regulatory prioritisation and prospective audiological safety research for drug classes where audiological monitoring protocols are currently absent.
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.
Low energy availability (LEA) is a mismatch between dietary energy intake and training-related expenditure that can impair performance, recovery, endocrine function, bone health, and overall athlete well-being; it is most often expected in endurance, weight-category, and physique-sensitive sports but can occur across disciplines. In male athletes, LEA is under-recognized because symptoms are subtle and non-specific and are frequently attributed to training fatigue. Because abrupt workload fluctuations may further strain recovery, the acute to chronic workload ratio (ACWR) provides a practical field marker of recent load spikes and a rationale for examining workload alongside LEA screening. To determine the occurrence of LEA in young Indian athletes with the LEAM-Q questionnaire and determine the association with Acute on Chronic Workload Ratio (ACWR). This cross-sectional analysis included 30 male athletes (18-35 years) from boxing, judo, and weightlifting. LEAM-Q responses were screened using the validated sex drive criterion. ACWR was calculated as (7-day workload x weekly RPE)/([monthly workload/4] x monthly RPE). Descriptive statistics were reported as mean ± standard deviation or median (IQR), and between-group comparisons were performed using the chi-square test, Fisher's exact test, Mann-Whitney U test, and Spearman rank correlation as appropriate (p<0.05). Twelve athletes (40.0%) screened positive for LEA. Screen positivity differed significantly by sport: boxing 3/14 (21.4%), judo 3/8 (37.5%), and weightlifting 6/8 (75.0%) (chi-square=6.12, p=0.047; Cramer's V=0.45). Weightlifting athletes had higher odds of screening positive than non-weightlifters (Fisher's exact OR 8.0, p=0.034). The median sex-drive score was 3 (IQR 2-4). Median ACWR was 0.89 (IQR 0.75-1.00); 9 athletes (30.0%) were below the normal range, 19 (63.3%) were within the normal range (0.8-1.3), and 2 (6.7%) were above the high-risk threshold (>1.3). ACWR did not differ between LEA screen-positive and screen-negative athletes (median 0.89 vs. 0.89; p=0.966) and showed no correlation with LEAM-Q score (Spearman rho=0.05, p=0.805). LEAM-Q identified a substantial burden of low energy availability risk in this cohort of young Indian male athletes, with the strongest signal in weightlifting and the most consistent abnormalities in sex drive items. ACWR was largely within the normal range and did not differentiate screen-positive athletes in this sample. These findings support routine LEAM-Q-based screening in male athletes, especially in weight-sensitive sports, and reinforce the need for early nutritional and clinical evaluation when the screen is positive.
Caffeine labelling requirements in the Republic of Korea were revised in 2024, with expanded provisions for guarana-containing solid foods implemented on 1 January 2026. This study quantified caffeine concentrations in 61 guarana-containing solid and semi-solid products purchased in Korea (2020-2021), prior to the enforcement of the revised requirements, using HPLC with diode-array detection (HPLC-DAD). Single-serving caffeine intake was estimated based on labelled serving sizes and compared against established safety benchmarks. For powdered products, caffeine concentrations ranged from 0.2 to 30.2 mg/g, yielding up to 218.7 mg per maximum labelled serving. Single-serving exposure peaked at 4.4 mg/kg body weight (bw) for a 50 kg adolescent, exceeding the conservative daily intake screening value of 2.5 mg/kg bw/day, applied under a one-serving-per-day worst-case assumption. This exposure also accounted for approximately 109% of the 200-mg single-dose reference and 55% of the 400-mg/day guidance level for adults. Eight powdered products exceeded a hazard quotient (HQ) of 1 for adolescents under a conservative one-serving-per-day screening scenario. The HQ framework was used solely as a screening tool to identify products requiring further scrutiny; HQ values > 1 should not be interpreted as evidence of adverse health effects. Applying Korea's current high-caffeine criterion for guarana-containing solid foods (≥ 0.15 mg/g), 59 of 61 products (96.7%) would require mandatory quantitative disclosure; however, only 14 of 61 (23.0%) provided such information at the time of purchase. These findings establish a pre-implementation baseline for post-2026 market monitoring.
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.
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.
Colorectal neuroendocrine neoplasms (CR-NENs) are traditionally classified into midgut and hindgut derivatives, a binary classification that potentially oversimplifies the underlying developmental continuum. We investigated whether CR-NEN phenotype and prognosis follow a continuous proximal-to-distal gradient to identify the optimal stratification strategy. We analyzed 1,158 patients from the RGETNE registry. Anatomical location was modeled as a continuous variable using restricted cubic splines to dissect spatial trends in proliferation (Ki-67), differentiation, and survival. Prognostic performance of the continuous spatial model was formally compared with categorical approaches (right/left/rectum and midgut/hindgut) using the Akaike Information Criterion (AIC). A distinct proximal-to-distal gradient was observed. The continuous spline-based model provided the superior fit for Ki-67 (R2=0.494), outperforming categorical approaches. Anatomical position was an independent prognostic factor, with risk increasing distally in localized disease (HR 1.79; 95% CI 1.31-2.45 for rectum vs. cecum) and significant mortality differences in metastatic disease (p<0.001). Adjuvant benefit was also heterogeneously distributed, being concentrated in distal segments. Despite the biological continuum, the embryological midgut-hindgut dichotomy yielded the most efficient statistical fit (lowest AIC) for predicting clinical recurrence. CR-NENs exhibit a topographical biological continuum. Continuous modeling is optimal for molecular research and characterizing tumor aggressiveness. However, for clinical risk stratification and trial design, the traditional discrete classifications (midgut-hindgut or anatomical segments) remain the most robust, parsimonious, and practically applicable surrogates.
The number of sunspots is a key indicator of solar magnetic activity and strongly influences space weather, affecting technological systems and Earth's environment. This study develops a long-memory statistical framework based on the Auto-Regressive Fractionally Integrated Moving Average (ARFIMA) model to forecast monthly mean sunspot numbers ([Formula: see text]) for Solar Cycles 25 and 26 using historical data from January 1749 to October 2025. The model parameters are selected using the Bayesian Information Criterion (BIC), and the fractional integration parameter d is estimated via maximum likelihood ([Formula: see text]), indicating significant long-memory behavior in the series. The selected ARFIMA (3,d,2) model captures the persistent dynamics of solar activity and provides accurate in-sample fitting, with a high correlation coefficient (0.989) between observed and fitted values. Forecast results predict a maximum [Formula: see text] of 224.7 for Solar Cycle 25 (observed peak: approximately 216 in August 2024) and 179.3 for Solar Cycle 26 around March 2035, suggesting a slightly weaker upcoming cycle. Model performance is evaluated using standard accuracy measures, including RMSE, MAE, and relative error metrics, computed against observed data within a validation framework. The proposed model achieves an RMSE of 3.37 and a SMAPE of 9.25%, indicating improved forecasting accuracy.
We compared real-world outcomes among patients with ulcerative colitis (UC) prescribed second-line tumour necrosis factor inhibitor (TNFi) versus non-TNFi therapy after a first-line TNFi. We included adults with ≥ 2 claims for UC and ≥ 1 medical or pharmacy claim for a UC-approved TNFi as first-line therapy between 1 January 2015 and 30 June 2022 from the Healthcare Integrated Research Database. Second-line therapy was identified by one or more claims for a different TNFi or non-TNFi. The primary outcome was inadequate response, a composite of at least one of switch/add alternative advanced therapy, augment with conventional therapy, dose escalation, glucocorticoid intensification, UC-related hospitalisation, or UC-related surgery. We used multivariable logistic regression with trimmed inverse probability treatment weighting (IPTW) to calculate adjusted odds of inadequate response with second-line TNFi versus non-TNFi. Among 921 IPTW-weighted patients (second-line TNFi, n = 281; non-TNFi, n = 640), 62% of the TNFi cohort versus 49% non-TNFi had inadequate response (chi-square p = 0.001; odds ratio [95% CI], 1.76 [1.31-2.37], p < 0.001). Mean/median time to inadequate response among patients with inadequate response within 1 year was 139/125 days (TNFi) and 150/130 days (non-TNFi). The most common criterion for inadequate response was addition of new conventional therapy (35% second-line TNFi vs. 25% non-TNFi, p < 0.01); switch to or addition of alternative advanced therapy (30% vs. 15%, p < 0.01), and dose increase of oral glucocorticoids (14% vs. 9%, p < 0.05) were also significantly more common among patients in the TNFi cohort than the non-TNFi cohort. Total healthcare costs were modestly higher in the TNFi cohort. These results suggest that patients with UC have higher odds of inadequate response with a second TNFi versus non-TNFi after a first TNFi failure. Switching to an alternate mechanism of action for second-line therapy yielded better clinical outcomes.
While the Postnatal Growth and Retinopathy of Prematurity (G-ROP) screening criteria have undergone retrospective validation across various populations, prospective validation is essential before these criteria can be recommended for clinical use and wider adoption. We conducted a prospective study to validate the generalizability of G-ROP screening criteria in a new cohort of Taiwanese preterm newborns. This prospective study included 114 premature infants who were admitted to the neonatal intensive care unit between December 2019 and August 2024. The diagnostic performance of the G-ROP criteria for ROP detection were assessed. Using the G-ROP criteria, 89 of 89 (specificity 100%) infants without ROP were accurately excluded, while a sensitivity of 88.0%, a positive predictive value (PPV) of 100.0% and a negative predictive value (NPV) of 96.7% for any ROP were identified. This criterion exhibited a sensitivity of 87.5%, a specificity of 100.0%, a PPV of 100.0% and a NPV of 100.0% for identifying type 1 ROP; a sensitivity of 100.0%, a specificity of 100.0%, a PPV of 100% and a NPV of 98.9% for identifying type 2 ROP; and a sensitivity of 0%, a specificity of 100.0%, a PPV of 0% and a NPV of 97.8% for identifying A-ROP. Compared to the screening criteria of currently recommended body weight and gestational age, G-ROP criteria reduced unnecessary examinations in 26 infants (23%) without any ROP. This prospective study demonstrated that G-ROP criteria are generalizable and may reduce lower-risk infants (who did not develop treatment-requiring ROP during follow-up) receiving examination, exhibiting higher sensitivity, specificity, PPV and NPV for ROP detection than currently recommended guideline.
Background Bipedalism, defined as locomotion using only two feet, is a distinctive trait that sets humans apart from most other creatures. This study explores the significance of the obturator externus groove (OEG) as a marker for bipedalism. This topic is important due to its implications in evolutionary history. Previous studies have identified various anatomical features indicative of bipedalism, including an S-shaped spine, a centrally positioned foramen magnum, and unique pelvic and femoral structures. Among these, the morphology of the femur, particularly the presence of the OEG, has been proposed as a potential marker of habitual bipedalism. Material and methods This study examined the presence and dimensions of the OEG in both dry bone and cadaveric specimens. The dry bone study included 18 femur specimens from 14 individuals, analyzed by trained anatomists for the presence, visibility, and dimensions of the OEG. A cadaveric study was conducted on 28 formalin-fixed embalmed cadavers, utilizing precise dissection techniques to examine the relationship between the obturator externus tendon (OET) and the neck of the femur, and to identify and describe the OEG. Results In the dry bone study, 36% of individuals exhibited the OEG, while the cadaveric study found grooves in 21% of individuals. The OEG in this study was seen in 11 out of all 42 study subjects (dry bones and cadaveric), resulting in an incidence of about 26%. The groove's depth varied, with shallow grooves measuring less than 1 mm and deeper grooves measuring more than 1 mm. Additionally, the study identified the obturator externus notch and a soft tissue bed cushioning the OET, providing new anatomical insights. Conclusions The findings revealed that the OEG is uncommon and typically observed unilaterally. The presence of the groove may result from biomechanical factors, such as activities requiring strong hip extension, rather than bipedal locomotion alone. The cadaveric dissection approach allowed for direct observation and measurement of the groove to minimize user interpretation bias, providing more accurate findings. The OEG was an infrequent finding, indicating that it should not be used as a criterion for determining bipedalism in fossils.