S-equol is an intestinal bacterial metabolite of soy isoflavones. S-equol-containing supplements have been demonstrated to alleviate menopausal symptoms, including hot flashes and joint pain, because of decreasing estrogen levels. Hence, some patients with hot flashes and joint pain induced by hormone therapy drugs are taking S-equol-containing supplements with expectation of reducing their symptoms. However, there is little information of pharmacokinetic interaction between S-equol and drugs. Therefore, we investigated the potential of S-equol to affect the pharmacokinetics of hormone therapy drugs. This open-label, crossover study was performed at a single center. Twenty-four healthy postmenopausal women were enrolled and divided into four groups containing six subjects (three equol-producers and three equol-nonproducers). Each group received either anastrozole, letrozole, exemestane, or tamoxifen at standard doses on days 1 and 15. All subjects received S-equol-containing supplement at a standard dose of 10mg on days 9-15. Blood samples for pharmacokinetic assessment were drawn at predefined time points. No significant differences were observed in the geometric mean area under the concentration-time curve from 0h to 24h of anastrozole (269.0 vs. 289.3 ng‧h/mL; P = 0.14), letrozole (496.5 vs. 523.5 ng‧h/mL; P = 0.07), exemestane (54.1 vs. 53.8 ng‧h/mL; P = 0.69), and tamoxifen (638.4 vs. 578.8 ng‧h/mL; P = 0.22) without and with S-equol-containing supplement on days 1 and 15. S-equol-containing supplement has no clinically significant effects on the exposure of oral hormone therapy drugs for breast cancer. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: jRCTs031200084, August 13th, 2020.

Abstract Background Anti-neuraminidase antibodies have been identified as a correlate of protection for influenza virus infection. We evaluated the immunogenicity of enhanced influenza vaccines versus standard-dose vaccine in inducing neuraminidase inhibition (NAI) antibodies in older adults in a 2-year randomized trial. Methods In 2017/2018, older adults aged 65-82 years in Hong Kong were randomly allocated to receive standard-dose quadrivalent (SD-IIV4), high-dose trivalent (HD-IIV3), MF59-adjuvanted trivalent (aIIV3), or recombinant quadrivalent (RIV4) influenza vaccines of 2017/2018 northern hemisphere formations; HD-IIV3, aIIV3 and RIV4 are enhanced vaccines. NAI antibodies to the 2017/2018 A(H1N1)pdm09 and A(H3N2) vaccine strains were determined from 400 recipients (100 per vaccine group). In 2018/2019, participants were re-randomized to receive the same or a different type of vaccine of northern hemisphere formations. NAI antibodies to the 2018/2019 A(H1N1)pdm09 and A(H3N2) vaccine strains were determined from SD-IIV4 (n=45), HD-IIV3 (n=64), aIIV3 (n=75), or RIV4 (n=29) recipients. NAI antibody titers on the day of vaccination and 30 days post-vaccination were used to compare the geometric mean titer-fold-rise (GMFR) and seroconversion rates of enhanced influenza vaccines versus SD-IIV4. Results SD-IIV4, HD-IIV3, and aIIV3 induced detectable NAI antibodies to both N1 and N2 antigens with GMFR significantly greater than 1. In both years, aIIV3 induced significantly higher GMFR and seroconversion rates to N1 and N2 antigens than SD-IIV4. Notably, individual baseline NAI antibody titers were inversely associated with the post-vaccination antibody titer-fold-rises in all vaccine groups. Conclusions MF-59 adjuvanted aIIV3 induced superior NAI antibody response in older adults than SD-IIV4 in a 2-year randomized trial.

Due to the difficulty of standardizing hammer mill machine settings due to the many design factors affecting their performance and the varying operating conditions, a factorial experiment was conducted using three factors: number of hammers (8 and 10), clearance (2.5 mm, 5 mm, and 7.5 mm), and screen opening (2.5 mm, 4 mm, and 8 mm). The aim was to evaluate the impact of the main factors and their interactions on some machine performance indicators (productivity, specific energy consumption rate, and the average geometric diameter of processed yellow maize grains), determine the percentage of importance of the factors, and determine the best combination of machine numbers before starting milling. The results showed that the number of hammers and clearance, along with their interaction with the sieve opening, had a slight effect on productivity, specific energy consumption, and geometric mean diameter compared to the sieve opening effect. The sieve opening effect was 100%, compared to 7% and 4% for clearance and number of hammers, respectively. A combination of 2.5 mm sieve opening with any of the two factors can be used for fine grinding, and 8 mm sieve opening with any of the two factors can be used for coarse grinding within the experimental limits

Gestational weight gain (GWG), the maternal weight gained between pre-pregnancy and delivery, is an important risk factor for adverse maternal and infant health outcomes. In 1990, the National Academy of Medicine released GWG recommendations based on pre-pregnancy body mass index (BMI). These guidelines were revised in 2009, yet few studies have assessed temporal trends in GWG following the change. To evaluate temporal trends in total GWG within a large, ongoing pregnancy cohort. We used data from a prospective cohort in Boston, Massachusetts, of 3675 participants with deliveries between 2007 and 2019. Using 29,037 serial weight measures (median = 7/participant), we fit mixed-effect models to predict weight at delivery. Total GWG (kg) was defined as the difference between the model-predicted weight at delivery and self-reported pre-pregnancy weight. We categorised GWG as below, within or above the 2009 BMI-specific guidelines. We analysed proportional trends in GWG categories: (a) overall and (b) stratified by maternal characteristics (pre-pregnancy BMI, race/ethnicity, educational level and parity). We analysed trends in covariate-adjusted geometric mean (GMs) of GWG using multiple linear regression. The proportion of participants gaining weight within the GWG guidelines decreased from 46% in 2007-2008 to 24% in 2018-2019, which was driven by an increase in those gaining above the guidelines (40% to 73%). Across maternal characteristics, the largest increases of proportions above the guidelines were among those of normal pre-pregnancy BMI (19% to 62%) and of non-Hispanic Black (48% to 85%) or non-Hispanic White (37% to 74%) race/ethnicity. Consistently, GMs increased from 8.3 kg (95% confidence interval [CI] 6.3, 10.8) in 2007-2008 to 10.9 kg (95% CI 7.9, 14.9) in 2018-2019. Results from this large cohort study provide evidence that fewer women have been meeting the revised GWG guidelines and more have been gaining above the recommendations.

The rise of social media has democratized information sharing, allowing ordinary individuals to become influential voices in public discourse. However, traditional methods for identifying influential users rely primarily on network centrality measures that fail to capture the behavioral dynamics underlying actual influence capacity in digital environments. This study introduces the Social Influence Strength Index (SISI), a metric grounded in social impact theory that assesses influence through behavioral engagement indicators rather than network structure alone. The SISI combines three key elements: the average engagement rate, follower reach score, and mention prominence score, using a geometric mean to account for the multiplicative nature of social influence. This was developed and validated using a dataset of 1.2 million tweets from South African migration discussions, a context characterized by high emotional engagement and diverse participant types. SISI’s behavioral principles make it applicable for identifying influential voices across various social media contexts where authentic engagement matters. The results demonstrate substantial divergence between SISI and traditional centrality measures (Spearman ρ = 0.34, 95% CI: 0.32–0.36 with eigenvector centrality; top-10 user overlap Jaccard index = 0.20), with the SISI consistently recognizing behaviorally influential users that network-based approaches overlook. Validation analyses confirm the SISI’s predictive validity (high-SISI users maintain 3.5× higher engagement rates in subsequent periods, p < 0.001), discriminant validity (distinguishing content creators from amplifiers, Cohen’s d = 1.32), and convergent validity with expert assessments (Spearman ρ = 0.61 vs. ρ = 0.28 for eigenvector centrality). The research reveals that digital influence stems from genuine audience engagement and community recognition rather than structural network positioning. By integrating social science theory with computational methods, this work presents a theoretically grounded framework for measuring digital influence, with potential applications in understanding information credibility, audience mobilization, and the evolving dynamics of social media-driven public discourse across diverse domains including marketing, policy communication, and digital information ecosystems.

Compared with adults who smoke cigarettes, adults who vape nicotine are exposed to similar levels of nicotine and significantly lower levels of tobacco-specific nitrosamines (TSNAs). Little research outside the USA has included youth who vape, particularly those using newer disposable vapes. We investigated exposure to nicotine and the TSNA NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) among youth in England who vape, smoke, do both (dual) or do neither. In 2023, youth aged 16-19 years from England completed a survey and provided a urine sample (n=201). Linear regressions examined associations of creatinine-normalised urinary concentrations of total nicotine equivalents (TNE-2) and NNAL (a metabolite of NNK) with past 7-day smoking/vaping status and self-reported recency of vaping. All analyses were adjusted for age, sex at birth, ethnicity and any past 7-day cannabis use. Over three-quarters (77%) of those vaping were using the newer disposable vapes. Urinary TNE-2 concentrations among those who exclusively vaped in the past 7 days (n=83, geometric mean (GM)=5.09 nmol/mg creatinine (95% CI 3.19 to 8.12)) did not differ significantly from those who smoked (n=9, GM=1.74 nmol/mg creatinine (95% CI 0.64 to 4.72), p=0.426) or those who dual used (n=55, GM=5.60 nmol/mg creatinine (95% CI 3.32 to 9.43), p=0.953). Levels of NNAL among those who exclusively vaped (GM=1.87 pg/mg creatinine (95% CI 1.62 to 2.17)) were significantly lower than those who smoked (GM=4.87 pg/mg creatinine (95% CI 2.45 to 9.68), p=0.001) or those who dual used (GM=3.67 pg/mg creatinine (95% CI 2.76 to 4.86), p<0.001) and not significantly different from youth who neither vaped nor smoked (GM=1.84 pg/mg creatinine (95% CI 1.52 to 2.24), p=0.887). Youth who vape are exposed to similar levels of nicotine as those who smoke or who dual use. NNAL exposure among youth who vape is much lower than among those who smoke and indistinguishable from youth who do not vape or smoke.

Infective endocarditis (IE) is a severe infection mainly caused by Staphylococcus aureus, Enterococcus faecalis and viridans streptococci. Coagulase-negative staphylococci (CoNS), especially methicillin-resistant Staphylococcus epidermidis (MRSE), are major pathogens in prosthetic valves and devices. Exebacase is a first-in-class, antistaphylococcal lysin with rapid bactericidal and antibiofilm activity. To assess the in vitro activity of exebacase and standard IE antibiotics against S. aureus and CoNS isolates from IE patients in a university hospital (2010-2020). A total of 211 consecutive strains were analysed: S. aureus [n = 103 (82 MSSA, 21 MRSA)], S. epidermidis [n = 76 (20 MSSE, 56 MRSE)] and other CoNS species (n = 32, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Staphylococcus hominis, Staphylococcus capitis, Staphylococcus schleiferi, Staphylococcus caprae, Staphylococcus pasteuri). Broth microdilution MICs were determined for exebacase and comparators (cloxacillin, ceftaroline, vancomycin, daptomycin, gentamicin, rifampicin). Exebacase inhibited all S. aureus at ≤1 mg/L. Geometric mean (GM) MICs were 0.56 mg/L for MSSA and 0.49 mg/L for MRSA, with MIC50/90 of 0.5/1 mg/L. For S. epidermidis, GM MICs were 3.03 mg/L (MSSE) and 3.40 mg/L (MRSE), with MIC50/90 of 4/16 and 4/8 mg/L, respectively. Other CoNS showed GM MICs ranging from 0.49 mg/L (S. capitis) to 2.59 mg/L (S. lugdunensis), with intermediate values for S. haemolyticus (1.15), S. hominis (1.0) and S. schleiferi (0.79). Exebacase activity was comparable to β-lactams, vancomycin and daptomycin and remained unaffected by resistance. Exebacase activity was independent of methicillin resistance and consistently higher against S. aureus than S. epidermidis. Further research is warranted to explore lysins in combination against staphylococcal infections.

ABSTRACT Certain attributes of large‐scale complex systems are often expressed through sets of indicators. For example, the sustainability of an entity, be it a nation, a city, an energy system, a corporation etc., can be effectively represented by indicators and corresponding data series. For such representations to be practical, aggregation methods should be devised that lead to concrete performance measures hierarchically. In this work a mathematical aggregation theory is presented for indicators regarding the behavior of complex systems. A set of relevant postulates leads to a simple model based on shifted geometric means combining values of basic indicators into an overall index. The model is augmented with a sensitivity analysis which pinpoints those indicators with the highest potential for improving performance, thus, providing decision‐makers with an important tool to compare alternative policies. An application is shown in detail regarding the sustainability of 161 countries and data up to 2024. We rank countries according to their sustainability standing and pinpoint those Sustainable Development Goals that are crucial in enhancing sustainability. European countries, Australia and Uruguay take the top 20 places, while most of the bottom places are taken by African states. Our analysis occasionally reveals surprising low rankings of some highly developed countries due to poor environmental performance. Plastics consumption, deforestation, renewable energy generation, and water stress are among the most frequent influential indicators for developed states. Low gross national income, corruption, plastics consumption, and deforestation are quite prevalent in developing and low‐income countries.

Abstract High-grade serous ovarian carcinoma (HGSC) is a leading cause of gynecologic cancer death, driven by frequent recurrence and resistance to platinum therapies. Uncovering the mechanisms behind this process requires integrating genomic and transcriptional changes in space and time. Here, we present an evolutionary analysis combining multisite phylogenetic trees with transcriptomics, focusing on copy-number (CN) and structural variation (SV) to identify events that shape HGSC progression and treatment resistance. To address the changes during chemotherapy, we first reconstructed tumor phylogenies from 236 whole-genome–sequenced samples derived from 60 patients with relapsed HGSC using PyClone. Patients were stratified according to changes in mutational burden between diagnosis and relapse, as well as by clonal selection patterns, distinguishing cases of monoclonal versus multiclonal relapses. To extend the analysis beyond point mutations, CN and SV profiles were decomposed into clonal profiles within the phylogenetic framework, using a customized implementation of ALPACA. In parallel, matched bulk RNA-seq was integrated to connect relapse-specific genomic alterations with transcriptional changes and pathway deregulation, thereby uncovering pathways and processes underlying chemotherapy resistance. We observed that patients with a single dominant clone at relapse had significantly worse post-relapse survival compared with those exhibiting intra-sample clonal heterogeneity (p = 0.015). Across the cohort, clonal complexity, quantified as the geometric mean of within-sample subclonal heterogeneity per timepoint, showed a marked decline at relapse (p &amp;lt; 0.001). Since this cancer is driven by chromosomal instability, we next characterized CN segmentation and SV breakpoints, which were both significantly increased in relapse samples (p_CN = 0.004, p_SV = 0.006). Together, these results demonstrate structural remodeling rather than mutational burden as a defining feature of treatment resistance that underlies aggressive recurrences. Accordingly, we identified relapse-specific subclonal events as putative drivers of tumor progression during therapy, with impacts on pathways such as MAPK. Integration with matched transcriptomic samples enabled assessment of the functional impact of these events on gene expression and pathway activity. These findings show structural variation as a key driver of HGSC treatment resistance. By linking clonal genomic alterations with transcriptomic consequences, our approach uncovered relapse-specific drivers and opens new avenues for biomarker discovery and therapeutic targeting. Citation Format: Giulia Micoli, Jaana Oikkonen, Kari Lavikka, Déborah Boyenval, Johanna Hynninen, Sampsa Hautaniemi. Clonal evolution and structural variation drive chemotherapy resistance in ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B016.

Evidence regarding the optimal dose of paroxetine for lifelong premature ejaculation (LPE) with minimal adverse effects remains limited. This study evaluated the efficacy and safety of different paroxetine doses in patients with LPE. The study recruited 100 LPE patients. Group (A) included 50 randomized LPE patients who received 12.5mg paroxetine daily after breakfast for 3months. Group (B) included 50 randomized LPE patients who received 20mg paroxetine daily after breakfast for 3months. After a 2-week washout, a crossover was executed for 3months. Groups A and B demonstrated statistically significant increases in the scores of the Arabic index of premature ejaculation (AIPE) and the male sexual quality of life (QOL) throughout the follow-up period. Furthermore, upper and lower bounds of 95% confidence interval using estimates of fixed effects demonstrated significant changes in sequence in group A versus group B, treatment in group A versus group B and geometric mean intravaginal ejaculation latency time (IELT) in group A versus group B (- 4.13, - 0.26; - 4.16, - 0.27; - 8.02, - 4.15; p = 0.026 0.026, 0, respectively). Notably, upper and lower bounds of 95% confidence interval using estimates of fixed effects demonstrated significant changes in the occurrence of complications in group A versus group B (- 0.35, - 0.01, p = 0.041, respectively). 12.5mg paroxetine may be preferentially prescribed over 20mg as it shows a comparable efficacy with lower adverse events and subsequent better tolerability and male sexual QOL.

Objective The study aimed to investigate the seroprevalence and geometric mean concentrations (GMCs) of Anti- Mycoplasma pneumoniae immunoglobulin G (Anti-MP-IgG) among children aged 0–6 years in October-December 2023 in Huzhou City, China, and explore the influence of age and gender on seropositivity. Design Anti-MP-IgG levels were categorized into negative (&amp;lt;24 AU/mL), borderline (≥24 AU/mL and &amp;lt;36 AU/mL), and positive (≥36 AU/mL) groups. The GMCs and prevalence rates were analyzed according to age and gender. Linear regression and logistic regression analyses were performed to assess trends and associations. Results A total of 526 participants were enrolled in the study. The overall GMC of Anti-MP-IgG was 6.21 AU/mL (95% CI: 5.39–7.15). While there was no significant difference in GMCs between genders ( P = 0.862), a significant increasing trend in GMCs was observed with age ( F = 16.649, P &amp;lt; 0.001). The proportion of positive Anti-MP-IgG levels increased significantly with age, from 10.20% in 0-year group to 32.50% in 6-years group ( P &amp;lt; 0.001). Logistic regression revealed that age was significantly associated with Anti-MP-IgG positivity (OR: 1.37, 95% CI: 1.21–1.56, P &amp;lt; 0.001), while gender was not. Conclusions The seroprevalence and GMCs of Anti-MP-IgG showed a clear age-related increasing trend, indicating age as a significant factor for seropositivity in children aged 0–6 years. Further studies are needed to explore underlying mechanisms and the implications for public health strategies.

BackgroundC3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis (MPGN) generally result in glomerular C3 deposition and irreversible kidney damage. The efficacy and safety of pegcetacoplan, a C3 and C3b inhibitor, in persons with C3 glomerulopathy or primary immune-complex MPGN are unclear.MethodsWe conducted a phase 3, double-blind, placebo-controlled trial involving adolescents and adults with C3 glomerulopathy or primary immune-complex MPGN, including those with native kidney disease and those with disease recurrence after transplantation. Patients were randomly assigned in a 1:1 ratio to receive pegcetacoplan or placebo. The primary end point was the log-transformed ratio of the urinary protein-to-creatinine ratio at week 26 as compared with baseline.ResultsA total of 124 patients underwent randomization. The change in proteinuria (as measured by the log-transformed ratio to baseline in the urinary protein-to-creatinine ratio) was significantly greater with pegcetacoplan than with placebo (geometric mean of the urinary protein-to-creatinine ratio, −67.2% [95% confidence interval {CI}, −74.9 to −57.2] vs. 2.9% [95% CI, −8.6 to 15.9]). The difference represents a relative reduction of 68.1% (95% CI, 57.3 to 76.2) as compared with placebo. In hierarchical testing of five secondary end points, significantly higher percentages of patients in the pegcetacoplan group than in the placebo group met the composite renal end-point criteria (stabilization of estimated glomerular filtration rate [eGFR] and ≥50% reduction in urinary protein-to-creatinine ratio) (49% vs. 3%) and had at least a 50% reduction in the protein-to-creatinine ratio (60% vs. 5%). Among 69 patients with evaluable kidney-biopsy samples, the change in the activity score of the C3 glomerulopathy histologic index did not differ significantly between the two groups; subsequent end points (decrease in C3 staining and change in eGFR) were not formally tested. Pegcetacoplan was not associated with more adverse events than placebo. No serious infections from encapsulated bacteria occurred; 1 patient receiving pegcetacoplan died from coronavirus disease 2019 pneumonia. No allograft rejection or loss occurred.ConclusionsPegcetacoplan resulted in a significantly greater reduction in proteinuria than placebo among patients with C3 glomerulopathy or primary immune-complex MPGN. (Funded by Apellis Pharmaceuticals and Sobi [Swedish Orphan Biovitrum]; VALIANT ClinicalTrials.gov number, NCT05067127.)

ABSTRACT Drought‐adapted new‐generation wheat genotypes enhance production and productivity in water‐limited agroecologies, including South Africa. Therefore, drought‐tolerant wheat ideotypes need to be bred and deployed using economic traits and tolerance indices. The aim of this study was to evaluate genetically diverse wheat genotypes and select drought‐adapted lines based on yield response, tolerance indices and genetic groups using biplot analyses for breeding and production. Ninety‐eight wheat genotypes were assessed in five environments, that is, two seasons and three sites under drought‐stressed (DS) and non‐stressed (NS) growing conditions using an alpha lattice design with two replications. Grain yield (GY) was recorded, and yield‐based 10 drought‐tolerance indices were computed for genotype selection and comparison of test environments using the genotype plus genotype by environment interaction (GGE) biplot model. The mean GY values of the test genotypes in descending order across the five environments (E) were 1.59 t ha −1 (Bethlehem site in 2022, designated as BHM‐E2), 1.57 t ha −1 (Kransfontein in 2021, KRANS‐E4), 1.03 t ha −1 (Ficksburg in 2021, FICKS‐E3), 0.63 t ha −1 (Bethlehemin 2021, BHM‐E1) and 0.58 t ha −1 (Kransfontein in 2022, KRANS‐E5). The following genotypes were the best yielders: LM29, LM9 and at BHM‐E1, BHM‐E2, FICKS‐E3 and KRANS‐E4; LM59, LM63, LM66 and LM67 at BHM‐E2, FICKS‐E3 and KRANS‐E4; and LM83 at BHM‐E1, BHM‐E2 and FICKS‐E3. The genotypes LM59, LM25, LM84, LM96, LM23 and LM39 exhibited low tolerance (TOL), susceptibility index (SSI) and high mean productivity (MP), geometric mean productivity (GMP), drought index (DI), yield index (YI), yield stability index (YSI) and relative drought index (RDI) values in a desirable trend. Correlation analysis revealed a strong association ( p &lt; 0.001) between mean GY in non‐stressed conditions ( Y p ) and drought tolerance indices such as TOL ( r = 0.87), MP ( r = 0.77), SSI ( r = 0.72), SDI ( r = 0.72), GMP ( r = 0.65) and STI ( r = 0.54). In contrast, the mean GY in stressed conditions ( Y s ) positively and significantly ( p &lt; 0.001) correlated with YI ( r = 1.00), DI ( r = 0.97), RDI ( r = 0.73), YSI ( r = 0.73), GMP ( r = 0.51) and MP ( r = 0.41). The indices were invaluable in identifying relatively high‐yielding and drought‐tolerant wheat genotypes, and their combined use could be effective for screening drought tolerance in wheat breeding programmes. Based on GGE biplot analysis, genotypes LM6, LM9, LM30, LM64, LM83 and LM95 were discerned to be stable and high‐yielding in the test environments. Developing new breeding populations is recommended using the above complementary selections through combining ability tests and progeny selection for yield and agronomic traits performance for variety registration and release.

ABSTRACTRivaroxaban is an oral anticoagulant that requires food intake at high doses (15 and 20 mg) due to a pronounced food effect. AD‐109 is a novel formulation of rivaroxaban 18 mg, designed to enhance oral bioavailability and mitigate the food effect. This study aimed to evaluate the pharmacokinetics (PKs) of AD‐109 compared to the conventional formulation, Xarelto (Xarelto, rivaroxaban 20 mg) and the effect of food on the PK of AD‐109. Two open‐label, single‐dose, two‐period, two‐sequence crossover studies were conducted. In Study 1, participants received a single dose of AD‐109 and Xarelto under fed state, while in Study 2, participants received a single dose of AD‐109 under fed and fasted state. Serial blood samples were collected up to 34 h post‐dose and PK parameters were calculated by non‐compartmental method. In both studies, 33 out of 36 volunteers completed the study. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for the maximum plasma concentration (Cmax) and area under the curve until the last measurable concentration (AUC0‐last) of rivaroxaban for AD‐109 to Xarelto were 1.0466 (0.9961–1.0996) and 0.9450 (0.9094–0.9819), falling within the bioequivalence range of 0.8–1.25. The corresponding values of AD‐109 in the fed to fasted state were 1.0475 (0.9789–1.1209) and 0.9795 (0.9371–1.0238), suggesting the systemic exposure was not substantially influenced by food intake. AD‐109 (rivaroxaban 18 mg) demonstrated a PK profile comparable to that of Xarelto (rivaroxaban 20 mg) and effectively minimized the food effect on drug exposure.

Severe cutaneous adverse reactions (SCARs) are rare but potentially life-threatening. Children and adolescents are especially vulnerable due to developmental pharmacology, immature immune systems, and limited premarketing safety data. However, large-scale evidence of drug-specific SCAR patterns in pediatric populations remains limited. To investigate the epidemiology, clinical features, drug associations, and safety signals of SCARs in children and adolescents using the FDA Adverse Event Reporting System (FAERS). Reports of SCARs in patients aged ≤18years were retrieved from FAERS from Q1 2004 to Q2 2024 and identified using narrow-scope Standardised MedDRA Queries (SMQs). Data cleaning followed the FDA-recommended procedures. Disproportionality analysis was performed using four methods: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN; yielding Information Component, IC), Multi-item Gamma Poisson Shrinker (MGPS), and empirical Bayes geometric mean (EBGM). Drug-label reviews were used to compare the signal detection results with existing safety warnings. A total of 7183 pediatric SCAR reports were included. The number of reports has increased over time, with adolescents (13-17years) and school-aged children (7-12years) accounting for 68% of cases. The most frequently reported Preferred Terms were drug reaction with eosinophilia and systemic symptoms (DRESS; 32.5%), Stevens-Johnson syndrome (SJS; 27.9%), and toxic epidermal necrolysis (TEN; 19.0%). Hospitalization occurred in 64.5% of cases, and 6.3% were fatal. Among the 2005 cases with available onset time, 82.7% developed within 30days of drug exposure. Thirty-eight drugs showed positive signals, including lamotrigine, phenytoin, sulfamethoxazole, and phenobarbital. Four drugs, ranitidine, anakinra, clonazepam, and rifampin, showed signals without corresponding warnings in the FDA pediatric labeling. SCARs in children and adolescents show distinct patterns, high hospitalization and mortality, and strong links with antiepileptics and anti-infectives. Strengthening pediatric pharmacovigilance, implementing risk-alert systems, and promoting genotype-guided prescribing may help prevent these severe reactions.

Opioids are essential for cancer pain; however, regional and hospital prescribing variations in Japan remain poorly understood. This study aimed to investigate the regional and hospital functional differences in opioid prescribing among terminally ill patients with cancer in Japan using nationwide claims data. We analysed anonymized claims data from the DeSC database, focusing on patients who died of cancer in hospitals (2018-2022). We calculated opioid prescription prevalence and mean daily doses (converted to oral morphine equivalents) in the last 30days of life. Outcomes were compared across regions and hospital functions using multivariate logistic and linear regression models adjusted for age, sex, and cancer type. We analysed 119 850 decedents. Oxycodone injection use was highest in Tokai (16.4%) and South Kanto (15.7%), approximately four times that in Shikoku (4.0%). Transdermal fentanyl use ranged from 51.5% in Kyushu/Okinawa to 25.4% in South Kanto. Oxycodone injections increased with hospital functionality (4.1% in non-acute care vs. 20.4% in university hospitals), whereas transdermal fentanyl use declined (56.7%-13.1%). Compared to South Kanto, adjusted odds ratios (ORs) for opioid prescribing were higher in Kyushu/Okinawa (1.29) and lower in Kinki (0.68). For dose, no region exceeded South Kanto, and the lowest geometric mean ratio (GMR) was observed in Shikoku (0.87). No significant differences in adjusted ORs or GMRs were observed across hospital categories. Opioid prescribing patterns varied across regions and hospital functions, with significant differences in both prevalence and dosing. These findings may contribute to advancing the uniform implementation of palliative care.

The coronavirus disease 2019 (COVID-19) has considerably changed the game in the field of hygiene. The aim of the study was to compare microbiological colonization present on the emergency physicians' stethoscopes and smartphones before and after the outbreak of COVID-19. This was a prospective cohort study in 1 academic hospitals' emergency department. A microbiological analysis was conducted on the emergency doctors' stethoscopes and smartphones for a month in 2018 and 2021. Analysis concerned stethoscopes diaphragms and the most used surface of the cellphones screen around to the main button. The authors used a solid growth medium irradiated Count-Tact® 3P agar (CT3P) (BioMerieux, Lyon, France) for collecting samples. Results were obtained after 5 days of growth at 30°C to collect all the saprophytes environmental flora. A total of 27 doctors were included in 2018 and 30 doctors in 2021. Stethoscope diaphragm contamination was very high in both period with a geometric mean (GM) without difference before and after COVID respectively, GM = 68 colony-forming unit (cfu) per 25 cm² (95% CI: 50-94 cfu/25 cm²) vs. 68 cfu/25 cm² (95% CI: 44-105 cfu/25 cm²), p > 0.05. Smartphones were cleaner than stethoscopes with a GM <50 cfu/25 cm² without significant difference between 2 periods, respectively GM = 45 cfu/25 cm² (95% CI: 34-59 cfu/25 cm²) vs. 31 cfu/25 cm² (95% CI: 20-48 cfu/25 cm²), p > 0.05. The study shows an urgent need to regularly inform of the hygiene of the medical tools and COVID-19 does not really bring improvements in the matter. Particularly in emergency department, where physicians examine several patients per day and can possibly transmit pathogens. Int J Occup Med Environ Health. 2025;38(6).

Failure Mode and Effects Analysis (FMEA) is a systematic risk assessment tool that effectively evaluates the safety and reliability of products prior to their deployment. However, traditional FMEA fails to consider and leverage inherent system-specific information during risk assessment, while also neglecting the weights of risk factors (RFs) when processing data related to the Risk Priority Number (RPN). This leads to significant subjectivity in the final risk ranking of failure modes. To overcome these drawbacks, this study proposes an improved FMEA risk assessment method based on load sharing, aiming to develop an improved FMEA method that addresses the critical limitations of traditional approaches by integrating load sharing principles and systematic weight determination, thereby enhancing risk assessment objectivity and accuracy in complex multi-component systems. First, probabilistic linguistic terms are adopted to quantify experts’ risk assessment information, and the geometric mean method is then used to aggregate assessments from multiple experts. Second, the Fuzzy Best–Worst Method (FBWM) is employed to determine the relative weights of the three RPN factors (Occurrence, Severity, and Detection). Additionally, partial system structural data are obtained through load sharing, and these data—combined with the calculated factor weights—are integrated into the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) to generate the final risk ranking of failure modes. Finally, a case study of a magnetic crane is conducted to verify the feasibility and effectiveness of the proposed method, supplemented by comparative experiments to demonstrate its superiority.

Abstract. The contribution of natural aerosol particles from boreal forests to total aerosol loadings may increase with reduction in anthropogenic emissions. Aitken and accumulation mode particles in boreal regions differ significantly in hygroscopicity, and ignoring this size dependence can cause large uncertainty in Cloud Condensation Nuclei (CCN) prediction. We applied κ-Köhler theory to a multi-year dataset (2016–2020) from Hyytiälä, Finland, to evaluate different representations of aerosol chemical composition for CCN prediction. Overpredictions by forward closures using either bulk chemical composition from an Aerosol Chemical Speciation Monitor (ACSM) or a constant κ= 0.18 were mitigated to a great extent by optimizing size-resolved composition using two inverse modeling approaches: (1) Nelder–Mead method with the size distribution fixed to its median during each 2 h CCN measurement cycle, and (2) MCMC (Markov Chain Monte Carlo) accounting also for the variability in the size distribution during each cycle. Both methods improved closure at SS = 0.2 %–1.0 % (with Geometric Mean Bias GMB values 1.12–1.20 and 0.95–1.05, respectively), with moderate improvement at 0.1 % (GMBs of 1.53 and 1.32, respectively). The Aitken mode was enriched in organics in 77 % of cases using method (1) and 46 % using method (2) – with typical κ values of ∼ 0.1 for Aitken and ∼ 0.3 for accumulation modes. The results generally align with known size-dependent chemical composition in Hyytiälä and indicate that variability in CCN hygroscopicity is largely driven by Aitken mode composition. Our results demonstrate the potential of inverse CCN closure methods for obtaining valuable information of the size-dependent chemical composition.

Rifampicin reduces plasma tenofovir and intracellular tenofovir diphosphate (TFV-DP) concentrations when co-administered with tenofovir alafenamide fumarate (TAF). Standard-dose TAF with rifampicin still provided higher TFV-DP concentrations than tenofovir disoproxil fumarate (TDF) in a healthy volunteer study, but this interaction has not been assessed in people with HIV-associated tuberculosis. Open label, three-period pharmacokinetic study in participants with HIV-1 on tenofovir based ART (plus emtricitabine and efavirenz) in the maintenance phase of weight-based tuberculosis therapy. Concentrations of intracellular peripheral blood mononuclear cell TFV-DP and plasma tenofovir were measured during three treatment periods: 1) TDF 300 mg daily and rifampicin (TDF + RIF), 2) TAF 25 mg daily and rifampicin (TAF + RIF), and 3) TDF without rifampicin post-completion of tuberculosis therapy (TDF-NoRIF). Twenty-four hour area under the concentration-time curves (AUC0-24h) were estimated, and geometric mean ratios (GMR) with 95% confidence intervals were calculated to compare concentrations. Eighteen participants were enrolled: median age of 42 years; 56% male. The TFV-DP AUC0-24h GMRs comparing the TAF + RIF treatment period with the TDF + RIF and TDF-NoRIF periods were 5.46 (4.26 to 7.00) and 5.23 (3.71 to 7.37), respectively. Plasma tenofovir AUC0-24h GMR was 0.08 (0.06 to 0.09) and 0.07 (0.06 to 0.09) when comparing TAF + RIF with the TDF + RIF and TDF-NoRIF periods, respectively. When combined with rifampicin, ART containing standard-dose TAF resulted in higher TFV-DP concentrations than TDF-based ART in participants with HIV-associated tuberculosis, supporting its use with rifampicin-containing tuberculosis therapy.