Cognitive composites for genetic frontotemporal dementia: GENFI-Cog

Background: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. Methods: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be). Results: The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period. Discussion: We created gene-specific cognitive composite scores for C9orf72, GRN, and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration

The effect of educational expansion and family change on the sustainability of public and private transfers

This paper examines the impact of aging and related socio-economic trends (educational expansion and changes in family structure) on the sustainability of public and private transfers. For this purpose, recently available disaggregated National Transfer Accounts (NTA) are combined with dynamic microsimulation techniques to build the first dynamic microsimulation model that incorporates NTA accounting (microWELT) and is thus able to capture how agents rely on public and private transfers over their lifecycle. The model simulates the major lifetime transitions at the individual level, including education, emancipation, fertility, partnership formation and dissolution, and death. The analysis was conducted for four European countries, representative of four welfare models: Austria, Finland, Spain, and the UK. We compare sustainability indicators for the economy, the public sector, and families in the NTA tradition with enriched indicators that capture additional composition effects. When these additional composition effects are ignored, as in previous literature, we find that the Economic Support Ratio decreases more than the pure Demographic Support Ratio. In striking contrast, we show that composition effects due to educational expansion that interact with changes in family structures lead to the opposite result, alleviating the effects of demographic aging. Unlike public transfers, private transfers are only slightly affected by aging, as they are near zero for the elderl

Are there clinical, psychopathological and therapy outcomes correlates associated with self-exclusion from gambling?

Background and aims: Self-exclusion in gambling disorder (GD) is considered a measure to decrease the negative consequences of gambling behavior. Under a formal self-exclusion program, gamblers request to be banned from accessing to the gambling venues or online gambling. The aims of the present study are: 1) to determine sociodemographic characteristics of a clinical sample of seeking-treatment patients with GD who are self-excluded before arriving at the care unit; 2) to identify personality traits and general psychopathology of this clinical population; 3) to analyze the response to treatment, in terms of relapses and dropouts. Methods: 1,416 adults seeking treatment for GD, who are self-excluded completed screening tools to identify GD symptomatology, general psychopathology, and personality traits. The treatment outcome was measured by dropout and relapses. Results: Self-exclusion was significantly related to female sex and a high sociodemographic status. Also, it was associated with a preference for strategic and mixed gambling, longest duration and severity of the disorder, high rates of general psychopathology, more presence of illegal acts and high sensation seeking rates. In relation to treatment, self-exclusion was associated with low relapse rates. Conclusions: The patients who self-exclude before seeking treatment have a specific clinical profile, including high sociodemographic status, highest severity of GD, more years of evolution of the disorder and high emotional distress rates; however, these patients' presents better response to treatment. Clinically, it could be expected that this strategy could be used as a facilitating variable in the therapeutic process

Stabilization of metal and metalloids from contaminated soils using magnesia-based tundish deskulling waste from continuous steel casting

This study presents a groundbreaking exploration into the potential use of refractory tundish deskulling waste (TUN), a magnesium oxide-based by-product from continuous steel casting, as a stabilizing agent for remediating metal and metalloids contaminated soils. Up-flow column horizontal percolation tests were conducted to measure the concentrations of metals and metalloids, pH, and electrical conductivity (EC) in the leachates of two different combinations of contaminated soil and stabilizer (95-5 wt% and 90-10 wt%). The effectiveness of TUN as a soil-stabilizing agent for contaminated soils with metals and metalloids was evaluated by comparing its leachates with those obtained from a sample of a well-established low-grade magnesium oxide (LG-MgO) by-product, which underwent the same testing procedure. The findings revealed a significant correlation between the mobility of the examined metals and metalloids, and the water-soluble or acid phase of the contaminated soil, primarily governed by precipitation-solution reactions. While the stabilizing impact on non-pH-dependent metals, particularly redox-sensitive oxyanions, was less pronounced, both MgO-based stabilizers exhibited a favourable influence on soil pH-dependent metals and metalloids. They achieved this by establishing an optimal pH range of approximately 9.0-10.5, wherein the solubility of metal (hydr)oxides is minimized. Notably, metals like Zn and Cu, which have high leaching potential, experienced a remarkable reduction in leaching - Zn by over 99% and Cu by around 97% - regardless of the stabilizer content. In a broader context, this research champions the principles of the circular economy by offering a technical remedy for treating soils contaminated with pH-dependent metals and metalloids. The proposed solution harnesses industrial waste - currently relegated to landfills - as a resource, aligning with sustainable practices and environmental responsibility

Medidas procesales, concursales y organitzativas previstas para hacer frente al Covid-19 en el ámbito de la Administración de Justicia española.

El presente artículo se centra en el análisis de la medidas procesales, concursales y organizativas previstas en el RDL 16/2020, de 28 de abril, para hacer frente al Covid-19 en el ámbito de la Administración de Justicia española. Este estudio cualitativo, basado en la práctica jurídica y el conocimiento legal presta atención, entre otras cuestiones, a la habilitación parcial del mes de agosto, el reinicio del cómputo de los plazos procesales, la incorporación de un procedimiento especial en el ámbito del derecho de familia orientado a reequilibrar las pensiones de alimentos y el régimen de visitas o custodia compartida, diferentes aspectos concursales relacionados con la renegociación de la deuda y la segunda oportunidad, y la potenciación de las actuaciones telemáticas en el ámbito de la Administración de Justicia, así como de las tecnologías de la información y comunicación. La principal contribución de esta investigación estriba en ofrecer a los abogados una visión teórico-práctica acerca de las novedades legislativas, de urgencia, con las que en los próximos meses, quizás años, deberán enfrentar el seguimiento de diferentes procesos que traen causa de la crisis sanitaria, pero también social y económica, derivada del coronavirus. Cabe concluir que muchas de estas medidas, aun siendo bienintencionadas, no tendrán fácil aplicación en la realidad actual de los Juzgados y Tribunales españole

TFAW survey - I. Wavelet-based denoising of K2 light curves. Discovery and validation of two new Earth-sized planets in K2 campaign 1

The wavelet-based detrending and denoising method TFAW is applied for the first time to EVEREST 2.0-corrected light curves to further improve the photometric precision of almost all K2 observing campaigns (C1-C8, C12-C18). The performance of both methods is evaluated in terms of 6 h combined differential photometric precision (CDPP), simulated transit detection efficiency, and planet characterization in different SNR regimes. On average, TFAW median 6 h CDPP is ∼30percent better than the one achieved by EVEREST 2.0 for all observing campaigns. Using the TRANSIT LEAST-SQUARES (TLS) algorithm, we show that the transit detection efficiency for simulated Earth-Sun-like systems is ∼8.5× higher for TFAW-corrected light curves than that for EVEREST 2.0 ones. Using the light curves of two confirmed exoplanets, K2-44 b (high SNR) and K2-298 b (low SNR), we show that TFAW yields better Markov chain Monte Carlo posterior distributions, transit parameters compatible with the catalogued ones but with smaller uncertainties, and narrows the credibility intervals. We use the combination of TFAW's improved photometric precision and TLS enhancement of the signal detection efficiency for weak signals to search for new transit candidates in K2 observing campaign 1. We report the discovery of two new K2-C1 Earth-sized planets statistically validated, using the VESPA software: EPIC 201170410.02, with a radius of 1.047+0.276−0.257R⊕ planet orbiting an M-type star, and EPIC 201757695.02, with a radius of 0.908+0.059−0.064R⊕ planet orbiting a K-type star. EPIC 201757695.02 is the 9th smallest planet ever discovered in K2-C1, and the 39th smallest in all K2 campaigns

"El archivo al cuadrado de Marta Aponte: cómo friccionar la tradición en la muerte feliz de WCW o cuando la madre es la última frontera"

El presente artículo pretende demostrar cómo La muerte feliz de William Carlos Williams propone una reescritura de lo materno como una forma de recrear la identidad archipelágica que fricciona diversas tradiciones. Se entiende como fricción aquello que incorpora la ficción y la no ficción de un modo natural, a la vez que desdibuja esos límites que el mercado editorial ha intentado anteponer a fin de catalogar claramente sus productos

Biological basis of extensive pleiotropy between blood traits and cancer risk

Background: The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. Methods: Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. Results: The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood-cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15-TERT and 6p21-HLA. Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. Conclusions: This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk

Palamedes a l'<em>Eneida</em>

The mythical character of Palamedes, absent from the Homeric tradition, is retrieved by Virgil in his Aeneid, as he is referred to by Sinon when he aims to persuade Trojans, who inevitably fall into his trap. The character of Sinon, a sort of double agent, who, after all, accomplishes the great betrayal that ruined Troy pretending he was betraying his own fellows, presents an interesting set of crossed-roles with the gorgianic tradition of Palamedes' defence, in which Palamedes strives to get rid of the accusation of betrayal against the Greeks in favour of the Trojans. Keywords: Palamedes, Sinon, betrayal, Aeneid, myth

Groundwater discharge as a driver of methane emissions from Arctic lakes

Lateral CH4 inputs to Arctic lakes through groundwater discharge could be substantial and constitute an important pathway that links CH4 production in thawing permafrost to atmospheric emissions via lakes. Yet, groundwater CH4 inputs and associated drivers are hitherto poorly constrained because their dynamics and spatial variability are largely unknown. Here, we unravel the important role and drivers of groundwater discharge for CH4 emissions from Arctic lakes. Spatial patterns across lakes suggest groundwater inflows are primarily related to lake depth and wetland cover. Groundwater CH4 inputs to lakes are higher in summer than in autumn and are influenced by hydrological (groundwater recharge) and biological drivers (CH4 production). This information on the spatial and temporal patterns on groundwater discharge at high northern latitudes is critical for predicting lake CH4 emissions in the warming Arctic, as rising temperatures, increasing precipitation, and permafrost thawing may further exacerbate groundwater CH4 inputs to lakes