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Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

Abstract Understanding the interplay between genetic drift, natural selection, gene flow, and demographic history in driving phenotypic and genomic differentiation of insular populations can help us gain insight into the speciation process. Comparing patterns across different insular taxa subjected to similar selective pressures upon colonizing oceanic islands provides the opportunity to study repeated evolution and identify shared patterns in their genomic landscapes of differentiation. We selected four species of passerine birds (Common Chaffinch Fringilla coelebs/canariensis, Red-billed Chough Pyrrhocorax pyrrhocorax, House Finch Haemorhous mexicanus and Dark-eyed/island Junco Junco hyemalis/insularis) that have both mainland and insular populations. Changes in body size between island and mainland populations were consistent with the island rule. For each species, we sequenced whole genomes from mainland and insular individuals to infer their demographic history, characterize their genomic differentiation, and identify the factors shaping them. We estimated the relative (F st ) and absolute (d xy ) differentiation, nucleotide diversity (π), Tajima’s D, gene density and recombination rate. We also searched for selective sweeps and chromosomal inversions along the genome. All species shared a marked reduction in effective population size (Ne) upon island colonization. We found diverse patterns of differentiated genomic regions relative to the genome average in all four species, suggesting the role of selection in island-mainland differentiation, yet the lack of congruence in the location of these regions indicates that each species evolved differently in insular environments. Our results suggest that the genomic mechanisms involved in the divergence upon island colonization—such as chromosomal inversions, and historical factors like recurrent selection—differ in each species, despite the highly conserved structure of avian genomes and the similar selective factors involved. These differences are likely influenced by factors such as genetic drift, the polygenic nature of fitness traits and the action of case-specific selective pressures.

OBJETIVO: Realizar a validação de conteúdo dos Critérios de Beers 2012 e STOPP 2006 para a obtenção de critérios nacionais de classificação de medicamentos potencialmente inapropriados (MPI) para idosos. MÉTODOS: A técnica Delphi modificada em duas etapas foi utilizada para o estabelecimento do Consenso Brasileiro de Medicamentos Potencialmente Inapropriados para Idosos, com base nos critérios de Beers 2012 e STOPP 2006. O painel de especialistas foi composto por dez indivíduos. Utilizou-se um questionário eletrônico em que cada especialista emitiu uma nota, por meio de uma escala de Likert de cinco pontos. Na primeira etapa Delphi, os participantes foram solicitados a avaliar a inadequação potencial de uma lista preliminar de medicamentos e propor sugestões. Posteriormente, calculou-se a média das notas e o respectivo IC de 95% para cada critério. Foram encaminhados para a segunda rodada os critérios com limite máximo de IC95% < 4,0. Todos os medicamentos contidos em critérios com um limite mínimo de IC95% ≥ 4,0 na segunda rodada foram classificados como potencialmente inapropriados. RESULTADOS: Os critérios que não obtiveram consenso foram: uso de aspirina para a prevenção primária de eventos cardiovasculares, prescrição de escala móvel de insulina, uso de alfa-bloqueadores, estrógenos orais ou transdérmicos para idosos com incontinência urinária e antidepressivos tricíclicos para aqueles com retenção urinária. Ao final, foram totalizados 118 critérios, sendo 43 independentes de condição clínica e 75 dependentes de condição clínica/doença dos idosos. CONCLUSÃO: Foi realizada a validação de conteúdo de critérios de medicamentos que devem ser evitados em idosos. Esses dados podem otimizar a prescrição de medicamentos nessa população.

Invasive alien species are an important component of global change, threatening biodiversity, ecosystem functioning, economy, and human health. The number of alien species that attain the invasive status has experienced an exponential increase in recent years, leading some government agencies and stakeholders to allocate substantial resources to early detection, control, mitigation, and eradication programs. To develop effective nature conservation strategies, it is crucial to understand the invasive status of alien species and to identify priority species for management at spatial scales with a biogeographical basis. Despite significant progress in producing lists of alien species at the country level, a standard methodology for species assessment within ecological regions (i.e., regions with similar environmental or biogeographical characteristics) is still lacking. Here, we develop a systematic approach to determine invasion status and to prioritize invasive alien plant species within an ecoregion. We apply this approach in the Cantabrian Mixed Forests ecoregion, which encompasses biogeographically related areas from N Portugal, NW Spain, and SW France, and is strongly affected by plant invasions. By combining scientific evidence with expert opinion on the ecological characteristics of alien plants, we identified 175 invasive plant species in the study ecoregion, of which 37 cause massive environmental and/or socio-economic impacts. For each species, we provide comprehensive information and recommendations for scientists, land managers, policy makers, and other stakeholders under a biogeographical basis. This information includes species characteristics, invasion status/level, population trends, geographic locations and range size, local abundance, environmental and socio-economic impacts, and invaded habitats. We also accounted for administrative divisions within the ecoregion to facilitate the use of such evaluations in local-scale management and conservation plans. Our framework may be applied to any ecoregion worldwide, enhancing the assessment and management of invasive species pools within biogeographically meaningful regions.

En su reflexión acerca de la política, Hannah Arendt se vio obligada de dar cuenta de la importancia de la filosofía hegeliana para la moderna concepción de los asuntos humanos. El objeto de este artículo reside en el análisis de la naturaleza ambivalente, con respecto a lo político, que Arendt localiza en el pensamiento de Hegel. De acuerdo con Arendt, en Hegel se da, por un lado, una rehabilitación de la política, dado que el pensador alemán deshecha definitivamente la convicción metafísica de que a la esfera de la acción no pertenece verdad ninguna; no obstante, y al mismo tiempo, se alcanzan ciertos resultados que tendieron a fijarse en un concepto anti-político de los asuntos humanos, ajustado a ciertos derroteros dominantes en la Modernidad. En Hegel, en suma, se presentan, en un mismo gesto, las promesas modernas de la política, pero también sus riesgos, paradojas y callejones ciegos.

Abstract As robust cellular responses are important for protection against dengue, this phase 2 study evaluated the kinetics and phenotype of T cell responses induced by TAK-003, a live-attenuated tetravalent dengue vaccine, in 4–16-year-old living in dengue-endemic countries (NCT02948829). Two hundred participants received TAK-003 on Days 1 and 90. Interferon-gamma (IFN-γ) enzyme-linked immunospot assay [ELISPOT] and intracellular cytokine staining were used to analyze T cell response and functionality, using peptide pools representing non-structural (NS) proteins NS3 and NS5 matching DENV-1, -2, -3, and -4 and DENV-2 NS1. One month after the second TAK-003 dose (Day 120), IFN-γ ELISPOT T cell response rates against any peptide pool were 97.1% (95% CI: 93.4% to 99.1%), and similar for baseline dengue seropositive (96.0%) and seronegative (98.6%) participants. IFN-γ ELISPOT T cell response rates at Day 120 were 79.8%, 90.2%, 77.3%, and 74.0%, against DENV-1, -2, -3, and -4, respectively, and remained elevated through 3 years post-vaccination. Multifunctional CD4 and CD8 T cell responses against DENV-2 NS peptides were observed, independent of baseline serostatus: CD8 T cells typically secreted IFN-γ and TNF-α whereas CD4 T cells secreted ≥ 2 of IFN-γ, IL-2 and TNF-α cytokines. NAb titers and seropositivity rates remained substantially elevated through 3 years post-vaccination. Overall, TAK-003 was well tolerated and elicited durable T cell responses against all four DENV serotypes irrespective of baseline serostatus in children and adolescents aged 4–16 years living in dengue-endemic countries. TAK-003-elicited CD4 and CD8 T cells were multifunctional and persisted up to 3 years post-vaccination.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, characterized by late diagnosis and poor treatment response. Surgery is the only curative approach, only available to early‐diagnosed patients. Current therapies have limited effects, cause severe toxicities, and minimally improve overall survival. Understanding of splicing machinery alterations in PDAC remains incomplete. Here, we comprehensively examined 59 splicing machinery components, uncovering dysregulation in pre‐mRNA processing factor 8 (PRPF8) and RNA‐binding motif protein X‐linked (RBMX). Their downregulated expression was linked to poor prognosis and malignancy features, including tumor stage, invasion and metastasis, and associated with poorer survival and the mutation of key PDAC genes. Experimental modulation of these splicing factors in pancreatic cancer cell lines reverted their expression to non‐tumor levels and resulted in decreased key tumor‐related features. These results provide evidence that the splicing machinery is altered in PDAC, wherein PRPF8 and RBMX emerge as candidate actionable therapeutic targets.

Solitary intradural plasmacytomas are extremely rare. We present a case of a patient with headache and diagnosis of meningiomatosis. Onset symptoms were abrupt neurological deterioration and paraparesis. The patient underwent surgery by craniotomy and tumor resection, with final pathological findings of solitary extramedullary plasmacytoma without evidence of multiple myeloma. Of note is the great similarity of this infrequent pathology with meningiomas and the need to differentiate it from the dural involvement of multiple myeloma. Treatment always includes tumor resection surgery and postoperative radiotherapy.

The Lean Management had its origin in the 50s in the Japanese automobile industry, and is currently used in different production processes, included those related to pharmaceutical production, for which has raised its application in the manufacture of loperamide HCl-orodispersible tablets (HCl-ODT) under the coordination of the Pharmaceutical Quality System (PQS). A theoretical proposal for process reengineering has been carried out both incorporating and applying the different Lean tools in the industrial manufacturing process of HCl-ODT, and their subsequent integration into the PQS, through each one of the processes stages, such as: weighing, screening, mixing, compression, and packaging, under the compliance of the current legislation of the pharmaceutical industry and in compatibility with what is established in the ICHs within the Quality System, in order to increase the effectiveness and efficiency of the process and its profitability. Lean Management under the coordination of the Pharmaceutical Quality System (PQS), is an excellent strategy for manufacturing loperamide HCl-orodispersible tablets since it improves its Quality System, as well as facilitates compliance with the national and international guides, standards and legislation that are suitable to it.

Abstract Sensory processing sensitivity (SPS), linked to processing external and internal stimuli, has drawn attention to its associations with clinical factors, particularly with health-related quality of life (HRQOL) variables. This study examined the relationships among SPS, stress, sleep quality, and HRQOL, establishing an explanation model. Eight hundred adults (M = 26.66 years, SD = 12.24; range age: 18–85 years) completed self-administered questionnaires on SPS, stress, sleep quality, and HRQOL. Correlation analysis and structural equation modeling (SEM) were used to analyze HRQOL pathways. Stress positively correlated with sleep quality disturbances (r = 0.442, p

Abstract Background A third of children born in England have at least one parent born outside the United Kingdom (UK), yet family migration history is infrequently studied as a social determinant of child health. We describe rates of hospital admissions in children aged up to 5 years by parental migration and socioeconomic group. Methods Birth registrations linked to Hospital Episode Statistics were used to derive a cohort of 4,174,596 children born in state-funded hospitals in England between 2008 and 2014, with follow-up until age 5 years. We looked at eight maternal regions of birth, maternal country of birth for the 6 most populous groups and parental migration status for the mother and second parent (UK-born/non-UK-born). We used Index of Multiple Deprivation (IMD) quintiles to indicate socioeconomic deprivation. We fitted negative binomial/Poisson regression models to model associations between parental migration groups and the risk of hospital admissions, including interactions with IMD group. Results Overall, children whose parents were both born abroad had lower emergency admission rates than children with parents both born in the UK. Children of UK-born (73.6% of the cohort) mothers had the highest rates of emergency admissions (171.6 per 1000 child-years, 95% confidence interval (CI) 171.4–171.9), followed by South Asia-born mothers (155.9 per 1000, 95% CI 155.1–156.7). The high rates estimated in the South Asia group were driven by children of women born in Pakistan (186.8 per 1000, 95% CI 185.4–188.2). A socioeconomic gradient in emergency admissions was present across all maternal regions of birth groups, but most pronounced among children of UK-born mothers (incidence rate ratio 1.43, 95% CI 1.42–1.44, high vs. low IMD group). Patterns of planned admissions followed a similar socioeconomic gradient and were highest among children with mothers born in Middle East and North Africa, and South Asia. Conclusions Overall, we found the highest emergency admission rates among children of UK-born parents from the most deprived backgrounds. However, patterns differed when decomposing maternal place of birth and admission reason, highlighting the importance of a nuanced approach to research on migration and health.

Abstract The standard method for identifying active Brown Adipose Tissue (BAT) is [18F]-Fluorodeoxyglucose ([18F]-FDG) PET/CT imaging, which is costly and exposes patients to radiation, making it impractical for population studies. These issues can be addressed with computational methods that predict [18F]-FDG uptake by BAT from CT; earlier population studies pave the way for developing such methods by showing some correlation between the Hounsfield Unit (HU) of BAT in CT and the corresponding [18F]-FDG uptake in PET. In this study, we propose training convolutional neural networks (CNNs) to predict [18F]-FDG uptake by BAT from unenhanced CT scans in the restricted regions that are likely to contain BAT. Using the Attention U-Net architecture, we perform experiments on datasets from four different cohorts, the largest study to date. We segment BAT regions using predicted [18F]-FDG uptake values, achieving 23% to 40% better accuracy than conventional CT thresholding. Additionally, BAT volumes computed from the segmentations distinguish the subjects with and without active BAT with an AUC of 0.8, compared to 0.6 for CT thresholding. These findings suggest CNNs can facilitate large-scale imaging studies more efficiently and cost-effectively using only CT.

Abstract Background Depression is a chronic psychiatric disease of multifactorial etiology, and its pathophysiology is not fully understood. Stress and other chronic inflammatory pathologies are shared risk factors for psychiatric diseases, and comorbidities are features of major depression. Epidemiological evidence suggests that periodontitis, as a source of low-grade chronic systemic inflammation, may be associated with depression, but the underlying mechanisms are not well understood. Methods Periodontitis (P) was induced in Wistar: Han rats through oral gavage with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. The following four groups were established (n = 12 rats/group): periodontitis and CMS (P + CMS+), periodontitis without CMS, CMS without periodontitis, and control. The morphology and inflammatory phenotype of microglia in the frontal cortex (FC) were studied using immunofluorescence and bioinformatics tools. The endocannabinoid (EC) signaling and proteins related to synaptic plasticity were analyzed in FC samples using biochemical and immunohistochemical techniques. Results Ultrastructural and fractal analyses of FC revealed a significant increase in the complexity and heterogeneity of Iba1 + parenchymal microglia in the combined experimental model (P + CMS+) and increased expression of the proinflammatory marker inducible nitric oxide synthase (iNOS), while there were no changes in the expression of cannabinoid receptor 2 (CB2). In the FC protein extracts of the P + CMS + animals, there was a decrease in the levels of the EC metabolic enzymes N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), and monoacylglycerol lipase (MAGL) compared to those in the controls, which extended to protein expression in neurons and in FC extracts of cannabinoid receptor 1 (CB1) and to the intracellular signaling molecules phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). The protein levels of brain-derived neurotrophic factor (BDNF) and synaptophysin were also lower in P + CMS + animals than in controls. Conclusions The combined effects on microglial morphology and inflammatory phenotype, the EC signaling, and proteins related to synaptic plasticity in P + CMS + animals may represent relevant mechanisms explaining the association between periodontitis and depression. These findings highlight potential therapeutic targets that warrant further investigation. Graphical Abstract

In a classroom environment where students are encouraged to talk and share their thinking about mathematics, it comes as no surprise to find an abundance of ideas flooding the room. Yet, what does one do with all these ideas? How do teachers and students use these ideas as they learn in the classroom? Moreover, how do teachers and students manage these conversations in a linguistically diverse classroom? These complex questions are major points of discussion for educators (Adams Corral & Sayer, 2023). In this article, the authors (a teacher educator, a multilingual learner-teacher, and an artist) initiate a dialogue about the intersection of planning and spontaneity in classroom instruction. Often perceived as opposites, the authors assert that they can be complementary. They begin by presenting an example from a linguistically diverse classroom to illustrate the origin of an idea, how the three authors navigated it with students, and how it enriched the learning experience of the classroom. They then delve into two additional examples of how spontaneous student ideas were included within the planned mathematics lessons.

Aims: To determine the effect of a 16-week fitness program (strength vs. aerobic) on different indicators of body composition and components of health-related physical fitness in youths with Down syndrome. Methods and procedures outcomes: Fifty adolescents (19 girls and 31 boys; average age, 18.33 ± 1.42 years) with Down syndrome were recruited and randomized to two groups (strength group vs. aerobic group). Adolescents allocated in the aerobic group carried out a physical activity program three times a week for 16 weeks meanwhile adolescents allocated in the strength group performed a fitness program three times a week for 16 weeks. Results: The exercise group had significant improvements in all health-related physical fitness variables (p < 0.05) but not on body composition. Conclusions and implications: A sixteen week fitness program consisting of three sessions of 60 min is able to increase levels of health-related physical fitness but not on body composition in youths with Down syndrome. The aerobic program does not seem to show significant differences.

Genito-Pelvic Pain/Penetration Disorder is a common sexual disorder that affects an individual's sexual health and overall well-being. Education is a therapeutic resource that presents several advantages, and it can potentially generate improvements both in pain and sexual functioning-related outcomes in patients suffering from this affliction. The objective of this study was to assess if a therapeutic educational program produced improvements in the different domains of the Female Sexual Function Index in participants suffering from Genito-Pelvic Pain Penetration Disorder. Participants were randomized into a group that received a face-to-face therapeutic educational program, a group that received the same program but online, or a control group. The Female Sexual Function Index was assessed, and analysis of the change in the domains for every group was performed using multiple t-tests. Improvements were found in the face-to-face intervention group, but only the "Pain" domain showed significant improvements (-1.1 points, p < 0.05). Improvements were also found in the online group, but they were only significant in the "Pain" and "Satisfaction" domains (-0.8 points, p < 0.05 for both). A therapeutic educational program improves pain-related outcomes, and it shows a positive tendency to also improve sexual functioning-related outcomes in patients suffering from Genito-Pelvic Pain/Penetration Disorder. Registration: Clinical Trials (NCT05114473).

While social media is evolving rapidly, understanding its underlying and persistent features with the potential to support high-quality learning would provide opportunities to enhance competence acquisition and collaborative work in higher education. Moreover, the adoption of tools that students already use in their everyday lives facilitates the integration of new forms of learning. In this context, we have developed an initiative to disseminate content through TikTok in three modules of the Bachelor's Degree in Nursing course, with the aim of promoting quality learning through these microlearning environments. To this end, we have implemented these learning environments and evaluated the users' perceptions, as well as their level of acceptance of the technology according to the Technology Acceptance Model. Overall, our results show high levels of satisfaction with regard to engagement and the content generated, as well as in terms of the acceptance of the technology. Our results do not show gender-specific variations, but we did detect slight variations depending on the subject in which the microlearning tool was deployed. Although for the most part these variations do not change the participants' assessment of their experience, it will be necessary in the future to determine the underlying reasons for these variations. In addition, our results suggest that it is possible to design a content creation system to promote quality learning through microlearning that can be transferred to other subjects, at least in the Bachelor's Degree in Nursing.

OBJECTIVE: Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs), including autism (ASD) and schizophrenia. Little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, the authors investigated gross volume, vertex-level thickness, and surface maps of subcortical structures in 11 CNVs and six NPDs. METHODS: Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (CNVs at 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2; age range, 6-80 years; 340 males) and 782 control subjects (age range, 6-80 years; 387 males) as well as ENIGMA summary statistics for ASD, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, bipolar disorder, and major depression. RESULTS: All CNVs showed alterations in at least one subcortical measure. Each structure was affected by at least two CNVs, and the hippocampus and amygdala were affected by five. Shape analyses detected subregional alterations that were averaged out in volume analyses. A common latent dimension was identified, characterized by opposing effects on the hippocampus/amygdala and putamen/pallidum, across CNVs and across NPDs. Effect sizes of CNVs on subcortical volume, thickness, and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and schizophrenia. CONCLUSIONS: The findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions, as well distinct effects, with some CNVs clustering with adult-onset conditions and others with ASD. These findings provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD and why a single CNV increases the risk for a diverse set of NPDs.