Swiss School of Archaeology in Greece
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MR-link-2: pleiotropy robust cis Mendelian randomization validated in three independent reference datasets of causality
No full textMendelian randomization (MR) identifies causal relationships from observational data but has increased Type 1 error rates (T1E) when genetic instruments are limited to a single associated region, a typical scenario for molecular exposures. We developed MR-link-2, which leverages summary statistics and linkage disequilibrium (LD) to estimate causal effects and pleiotropy in a single region. We compare MR-link-2 to other cis MR methods: i) In simulations, MR-link-2 has calibrated T1E and high power. ii) We reidentify metabolic reactions from three metabolic pathway references using four independent metabolite quantitative trait locus studies. MR-link-2 often (76%) outperforms other methods in area under the receiver operator characteristic curve (AUC) (up to 0.80). iii) For canonical causal relationships between complex traits, MR-link-2 has lower per-locus T1E (0.096 vs. min. 0.142, at 5% level), identifying all but one of the true causal links, reducing cross-locus causal effect heterogeneity to almost half. iv) Testing causal direction between blood cell compositions and marker gene expression shows MR-link-2 has superior AUC (0.82 vs. 0.68). Finally, analyzing causality between metabolites not directly connected by canonical reactions, only MR-link-2 identifies the causal relationship between pyruvate and citrate ( α ̂ = 0.11, P = 7.2⋅10-7), a key citric acid cycle reaction. Overall, MR-link-2 identifies pleiotropy-robust causality from summary statistics in single associated regions, making it well suited for applications to molecular phenotypes.
© 2025. The Author(s)
The evolution of the international tax system: from State sovereignty to the emergence of global tax standards
No full textThe role of attachment anxiety and intolerance of uncertainty in gaming during adolescence: A two-wave longitudinal study
No full textAdolescents with attachment anxiety can compensate via gaming for their unmet needs of closeness, reassurance, and emotion regulation. However, individual factors linking attachment anxiety to compensation via gaming are still unclear. In this two-wave longitudinal study (Wave 1, W1 = baseline; Wave 2, W2 = 6 months later), we aimed to determine whether intolerance of uncertainty (IU) mediates the link between attachment anxiety and gaming behaviours (gaming compensation, gaming frequency, and problematic gaming). Online questionnaires were administered to Italian adolescent gamers (N = 570; Mage = 15.60; SDage = 1.56; 68.8 % males). First, via path analyses, we tested whether attachment anxiety towards mother and father (W1) and IU (W1) would predict gaming behaviours (W2). Second, we tested whether IU would mediate the link between attachment anxiety and gaming compensation specifically. Multigroup analysis was used to explore gender differences. We found that attachment anxiety towards the mother and father was positively associated with IU, whereas attachment anxiety towards only the mother predicted gaming compensation at W2 both directly and via IU. Moreover, IU positively predicted gaming compensation and problematic gaming at W2. Multigroup analysis further revealed that for females, attachment anxiety towards the mother positively predicted gaming compensation at W2. Findings revealed small/modest effect sizes. Overall, attachment anxiety and IU may boost individuals to compensate via gaming, increasing the risk of problematic gaming. These results hold implications for future prevention interventions, emphasizing the quality of the parent-child relationship and IU as potential targets to foster adaptive coping strategies in adolescence
The capsule and genetic background, rather than specific individual loci, strongly influence in vitro pneumococcal growth kinetics
No full textBacterial growth characteristics intrinsic to each strain can impact and influence gene expression, antibiotic susceptibility, and disease pathogenesis. However, little is known about specific genomic variations that influence these bacterial growth features. Here, we investigate the impact of Streptococcus pneumoniae genetics on its in vitro growth features to shed light on genes that may be important targets in the development of vaccines and therapeutics. We use statistical models to estimate growth features and demonstrate that they varied significantly across capsular serotypes and lineages, were strongly correlated with phylogeny, and showed high heritability, highlighting a strong genetic basis. Despite this, genome-wide association studies revealed no specific genomic loci statistically associated with the growth features independently of the genetic background, including those in the locus responsible for capsular polysaccharide synthesis. Our findings suggest that the serotype and lineage, as well as a combination of genomic loci, influence intrinsic pneumococcal growth kinetics, which may have implications for pneumococcal disease pathogenesis.
© 2025, Chaguza et al
Outcomes in Older Patients After Switching to a Newer Anticoagulant or Remaining on Warfarin: The COMBINE-AF Substudy.
No full textWhether frail, elderly patients with atrial fibrillation (AF) on a vitamin K antagonist (VKA) should switch to a direct-acting oral anticoagulant (DOAC) was studied in the FRAIL-AF trial and remains controversial.The purpose of this study was to evaluate, in the COMBINE-AF data set, the impact on clinical outcomes of switching frail, elderly AF patients from VKA to DOAC.COMBINE-AF consists of individual patient-level data from 71,683 patients with AF in 4 randomized clinical trials comparing DOAC vs warfarin. Frailty was evaluated using a frailty index derived from a modified Rockwood's Accumulation Model including 18 age-related conditions. Patients with a frailty index score above the median were considered frail. Prespecified outcomes were stroke or systemic embolic events, bleeding events, death, and a net clinical outcome combining these events.We identified 5,913 patients who were frail, elderly (age ≥75 years), and VKA-experienced and 52,721 patients who did not meet all 3 of these criteria. Patients were randomized to a standard-dose (SD) DOAC or warfarin. After 27 months median follow-up, there was no heterogeneity in treatment effect with SD-DOAC vs warfarin among those who met all 3 criteria vs those who did not for the endpoints of stroke or systemic embolic events (HR: 0.83 vs 0.81; Pint = 0.75) or for death (HR: 0.95 vs 0.91; Pint = 0.54). Major bleeding was similar with SD-DOAC vs warfarin in frail, elderly, VKA-experienced patients (HR: 1.06 [95% CI: 0.90-1.25]), while it was significantly reduced with SD-DOAC in patients without all 3 criteria (HR: 0.82 [95% CI: 0.76-0.89]; Pint = 0.007). Likewise, the net clinical outcome was similar in the frail, elderly, VKA-experienced patients with SD-DOAC vs warfarin (HR: 1.01 [95% CI: 0.91-1.13]), while significantly reduced with SD-DOAC patients without all 3 criteria (HR: 0.89 [95% CI: 0.85-0.93]; Pint = 0.028). Fatal and intracranial bleeding were significantly reduced with SD-DOAC in both subgroups to a similar degree (both Pint > 0.05), while gastrointestinal bleeding with SD-DOAC was increased to a greater degree in frail, elderly, VKA-experienced patients (HR: 1.83 [95% CI: 1.42-2.36]) compared with those without all 3 criteria (HR: 1.23 [95% CI: 1.09-1.39]; Pint = 0.006).Frail, elderly, VKA-experienced patients with AF switched to SD-DOAC experienced significant reductions in stroke or systemic embolism, fatal and intracranial bleeding, and death. Gastrointestinal bleeding was increased with SD-DOAC, while major bleeding and the primary net clinical outcome were similar. Based on these findings, SD-DOAC is a reasonable choice for frail, elderly, VKA-experienced patients to reduce stroke and systemic embolism, death, and the most serious types of bleeding.Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved
Unsuspected diversity and multiple origins of the frog legs imported to Switzerland for human consumption, as determined by DNA barcoding and morphology.
No full textThe frog leg industry relies on a global, largely underregulated market with potentially important ecological impact such as the uncontrolled harvest of declining wild populations and the introduction of invasive species. Here, we inferred the taxonomic nature and geographic origins of frog legs imported to Switzerland by DNA barcoding. Out of 34 samples, we retrieved eight distinct lineages attributed to five species from four genera, namely Hoplobatrachus rugulosus from Vietnam, Fejervarya cancrivora from Indonesia (invasive on several Pacific islands), two phylogeographic lineages of Limnonectes macrodon from Western and Central Java, L. kadarsani from eastern Indonesia, and three phylogeographic lineages of Pelophylax ridibundus from northern and central southern Turkey (invasive in Western Europe). Only the first two species were correctly declared, which is particularly problematic to track down harvests of the declining and geographically restricted Limnonectes taxa. In this respect, we show that the three Asian genera can be reliably distinguished by basic measurements of the frog legs, which could be used in future forensic controls. Our study calls for more stringent international regulations of the frog trade, including shipment monitoring to document the relative abundance of harvested species and ensure the sustainability of their wild populations