Search

Abstract The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.

Abstract Background Motor vehicle crashes are the second leading cause of injury death among adults aged 65 and older in the U.S., second only to falls. A common state-level approach to mitigating older adult crash risk is the implementation of driver license renewal policies which vary largely between states and data on their effectiveness in preventing crashes and injuries are limited. To fill this gap, the aim of this study is to examine the association between state driver license renewal policies and older driver crash and injury rates. Methods Historical crash data, license renewal policy data, and other relevant policy and demographic data were gathered from 13 U.S. states (CO, IL, IA, KS, MN, MO, NE, ND, OH, SD, UT, WI, WY) for years 2000 through 2019, inclusive. Main exposures included six license renewal policies: renewal period, in-person renewal frequency, vision testing, knowledge testing, on-road drive testing, and mandatory physician reporting. The primary outcomes were crash and injury rates per 100,000 population. Results The study population included 19,010,179 crash-involved drivers aged 40 and older. State policies became less restrictive in many states over the study period, even for drivers aged 75 and older, resulting in longer times between renewals and fewer in-person renewal requirements. Loosening of in-person renewal from every time to less than every time was associated with increased crash rates, among drivers aged 65 to 74 (RRcrash = 1.08, 95% CI: 1.01–1.16). A longer duration between in-person renewals was associated with increased injury rates among drivers 75 and older (RRinjury = 1.18, 95% CI: 1.00–1.39). Conclusions Generally, state policies became less restrictive and resulted in longer required intervals between license renewal. Loosening of driver license renewal policies was associated with increased crash and injury rates. However, safety benefits of restrictive older driver licensing policies should be carefully weighed against costs to older adult well-being and quality of life following licensure loss. Additional methods to assess fitness to drive are necessary to identify the mechanisms behind the increased rates.

Here we describe a new specimen of Archaeopteryx sp. from the lower Tithonian Mörnsheim Formation in the Franconian Alb of Bavaria, Germany. This fossil is the third avialan specimen found in this formation. The skeleton comprises the right forelimb and shoulder as well as fragments of the left forelimb and both hind limbs. The lengths of the humerus and ulna are most similar to those of the Munich specimen of Archaeopteryx. Despite the specimen having been massively altered by late diagenesis, it can be referred to Archaeopteryx sp., based on the morphology of the furcula, coracoid, humerus and radius, as well as a manual ungual, which nests within the morphospace of Archaeopteryx rather than that of Anchiornis. Phylogenetic analyses also support the assignment of the new specimen to Archaeopteryx. Due to the fossil’s state of preservation, as well as the still-unresolved taxonomy of the genus Archaeopteryx on the species level, an identification beyond genus remains impossible.

Abstract Background Most transgender people face different conditions of health vulnerability on a daily basis. In the Brazilian context, no research review has been found on such situations in the light of the theoretical conceptualization of multidimensional vulnerability. This research aimed to identify and analyze components of social and/or programmatic vulnerability that interfere with access to health care for trans people in Brazil. Methods The scoping review followed the JBI Manual and the PRISMA-ScR list. Brazilian studies published in any language, in the period 2019-April 2023, in the NCBI/PubMed, Web of Science, EMBASE, Scopus, SciELO, and LILACS databases were selected. The inclusion criteria included: original research with a sample of transgender people aged 18 years and over; and research contemplating conditions of social and/or programmatic vulnerability. Three reviewers independently selected the articles. The extracted and mapped data included components of these dimensions, according to the theoretical framework, as well as characteristics of the studies, for the synthesis of the descriptive analysis. Results A total of 46 studies were included. Social and programmatic vulnerability components were present in 67% of the studies. Among the main findings, the social dimension included discrimination, situations of violence in different contexts and social exclusion; prejudice and school dropout, homelessness, informal work and precarious income; and harmful use of alcohol and/or other drugs. The programmatic dimension encompassed disrespect for the use of the social name and institutional discrimination; hormone therapy without professional monitoring and scarcity of specialized services; lack of integration between Primary Health Care (PHC) and specialized care and insufficient PHC involvement; distortions between what is contained in public health policies and the practice in the services. A higher percentage (61%) of studies with trans women and 7% with trans men were observed; inequalities in regional distribution; predominance of HIV and AIDS and mental health themes; and similar percentages in the various methodological approaches and publications in national and foreign journals. Conclusion The identified situations of vulnerability contribute mainly to supporting the formulation and implementation of new public policies in comprehensive health that are more comprehensive and inclusive, which mitigate the current social and health inequities.

Abstract Background The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Methods We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction. Results The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment. Conclusions Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.

Abstract Natural and artificial collectives exhibit heterogeneities across different dimensions, contributing to the complexity of their behavior. We investigate the effect of two such heterogeneities on collective opinion dynamics: heterogeneity of the quality of agents’ prior information and of degree centrality in the network. To study these heterogeneities, we introduce uncertainty as an additional dimension to the consensus opinion dynamics model, and consider a spectrum of heterogeneous networks with varying centrality. By quantifying and updating the uncertainty using Bayesian inference, we provide a mechanism for each agent to adaptively weigh their individual against social information. We observe that uncertainties develop throughout the interaction between agents, and capture information on heterogeneities. Therefore, we use uncertainty as an additional observable and show the bidirectional relation between centrality and information quality. In extensive simulations on heterogeneous opinion dynamics with Gaussian uncertainties, we demonstrate that uncertainty-driven adaptive weighting leads to increased accuracy and speed of consensus, especially with increasing heterogeneity. We also show the detrimental effect of overconfident central agents on consensus accuracy which can pose challenges in designing such systems. The opportunities for improved performance and observablility suggest the importance of considering uncertainty both for the study of natural and the design of artificial heterogeneous systems.

Surface albedo is an important parameter in radiative-transfer simulations of the Earth's system as it is fundamental for correctly calculating the energy budget of the planet. The Moderate Resolution Imaging Spectroradiometer (MODIS) instruments on NASA's Terra and Aqua satellites continuously monitor daily and yearly changes in reflection at the planetary surface. The MODIS Surface Reflectance Black-Sky Albedo dataset (version 6.1 of MCD43D) provides detailed albedo maps for seven spectral bands in the visible and near-infrared range. These albedo maps allow us to classify different Lambertian surface types and their seasonal and yearly variability and change, albeit only into seven spectral bands. However, a complete set of albedo maps covering the entire wavelength range is required to simulate radiance spectra and correctly retrieve atmospheric and cloud properties from remote sensing observations of the Earth. We use a principal component analysis (PCA) regression algorithm to generate hyperspectral albedo maps of the Earth. By combining different datasets containing laboratory measurements of hyperspectral reflectance for various dry soils, vegetation surfaces, and mixtures of both, we reconstruct albedo maps across the entire wavelength range from 400 to 2500 nm. The PCA method is trained with a 10-year average of MODIS data for each day of the year. We obtain hyperspectral albedo maps with a spatial resolution of 0.05° in latitude and longitude, a spectral resolution of 10 nm, and a temporal resolution of 1 d (day). Using the hyperspectral albedo maps, we estimate the spectral profiles of different land surfaces, such as forests, deserts, cities, and icy surfaces, and study their seasonal variability. These albedo maps will enable us to refine calculations of the Earth's energy budget and its seasonal variability and improve climate simulations.

This study examines whether racial/ethnic differences in personal dispositions, such as self-efficacy, cultural orientation, habitual explanations for good or poor academic outcomes, and age (as an index of life experience) exist among students enrolled in a general education course at a Hispanic-serving institution (HSI). Furthermore, the study examines the extent to which such dispositions may contribute differently to the academic success of students at such an institution depending on their race/ethnicity. Although the study uncovered only minor racial/ethnic differences in student dispositions, dissimilar patterns of contributions to course-specific performance and cumulative performance (as measured by grade point average) were observed for Latino/a/x/Hispanic and White students. Taken together, these findings suggest the importance of assessing the contribution of variables to academic success above and beyond the mere measurement of group differences. Applications of our findings to students at minority-serving institutions are discussed.

This study investigates the use of overt and null subjects in Bulgarian in child heritage speakers with L2 German. The alternation of overt and null pronominal subjects in null-subject languages like Bulgarian depends on grammatical and discourse conditions and contrasts with German. Oral narratives were elicited in Bulgarian, comparing the performance of the heritage children to that of monolingual children and adults. Overall 68 Bulgarian narratives of 39 speakers were analysed as to the use of overt and null pronominal subjects in topic-continuity and topic-shift contexts. The results reveal similar subject realisation for all speakers, supporting early acquisition of null-subject grammars. Analyses of topic-continuity and -shift contexts showed similar overall patterns in children's and adults' subject use, with children producing somewhat more overt subjects in topic-continuity and ambiguous overt pronouns in topic-shift contexts than adults. However, the bilinguals used significantly more ambiguous null subjects than monolinguals. These results suggest that fine-grained discourse constraints of null-subject grammars are more difficult for bilinguals to acquire and maintain. The near adult-like performance of the bilinguals in some contexts can be attributed to the fact that most of them were Bulgarian-dominant and received non-attrited parental input. Differences are also attributable to cross-linguistic influence.

RESUMO Estudos contemporâneos explicitam como a sexualidade é uma dimensão contextual e relacional da vida humana. Essa leitura de sexualidade tem colocado, paulatinamente, novos desafios às noções relativas à saúde, mas também, por extensão, tensionado o campo da garantia de direitos humanos fundamentais. Não por acaso, entidades internacionais e nacionais têm apontado a necessidade de intervenções psicossociais em contexto educativo, como espaço estratégico de garantia de direitos na interface com a sexualidade. Diante da necessidade, verificada na literatura internacional, de intervenções longitudinais, contextuais e não restritivas a uma leitura fisicalista de sexualidade, o presente estudo se propõe a apresentar a adaptação para o Brasil do protocolo de intervenção South Africa and Tanzania (SATZ). Tendo em vista adequações realizadas na presente adaptação, contemplando uma maior abertura para dissidências de gênero e sexualidade, maior ênfase em aspectos dialógicos e participação da comunidade escolar, a SATZ-BR se mostra em consonância com os direitos humanos, com a Agenda 2030 para o Desenvolvimento Sustentável e com as diretrizes do plano nacional curricular brasileiro.

IntroductionRemyelination of demyelinated axons can occur as an endogenous repair mechanism in multiple sclerosis (MS), but its efficacy varies between both MS individuals and lesions. The molecular and cellular mechanisms that drive remyelination remain poorly understood. Here, we studied the relation between microglia activation and remyelination activity in MS.MethodsWe correlated regenerative (CD163+) and inflammatory (iNOS+) microglia with BCAS1+ oligodendrocytes, subdivided into early-stage (

This investigation showcases the viability of producing SixGe1−x bulk single crystals via the Czochralski technique. A high Si content in Ge-rich SiGe wafers is highly desirable for various applications in quantum technology, particularly as strain-relaxed buffers for the realization of hole spin qubits in strained Ge quantum well heterostructures. The focus lies on the bulk crystal growth of such materials and their chemical and structural quality. For this, the Czochralski process, starting from a highly pure Ge seed and melt, utilizing continuous feeding by dissolution of Si rods was performed.Si0.16Ge0.86 wafers with a diameter of up to 15 mm obtained from the bulk crystal exhibited homogeneous structural quality in contrast to the conventionally used epitaxial strain-relaxed SiGe buffers. The compositional fluctuations of Si measured throughout the wafer were below 0.4 at. % in addition to a dislocation density below 3 × 106 dislocations/cm2. Interestingly, the central region of the wafer displayed no measurable compositional fluctuations and contained less than 105 dislocations/cm2. Furthermore, the difficulties and limits of growing such SiGe crystals are discussed, such as the continuous dissolution of Si during growth and the formation of oxides in the melt during growth. The current observations indicate significant potential for further enhancement of the crystal quality and to realize higher Si concentrations using the Czochralski technique. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) is the main driver in the development of castration‐resistant prostate cancer, where the emergence of AR splice variants leads to treatment‐resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs. MA suppressed the full‐length AR (AR‐FL), its spliced variant AR‐V7, and the AR‐regulated prostate‐specific antigen (PSA; also known as KLK3) and human kallikrein 2 (hK2; also known as KLK2) genes. RNA sequencing (RNA‐seq) analysis and protein modeling studies revealed E2F8 interactions with DNA as a potential novel target of MA, suppressing AR transcription and its synthesis. This novel mechanism of blocking AR biogenesis via E2F8 may provide an opportunity to control therapy‐resistant prostate cancer over the currently used AR antagonists designed to target different parts of the AR gene.

Coastal areas provide essential habitats for marine turtle nesting and hatching, but they are under increasing threat due to climate change and other anthropogenic impacts. Very little is known about the nesting habitat characteristics of flatback Natator depressus, green Chelonia mydas and loggerhead Caretta caretta turtles in eastern Queensland, which limits our ability to evaluate which nesting beaches are at risk due to anthropogenic and environmental disturbances and prioritise conservation and monitoring actions. Here, we used generalised linear models to investigate the relationship between the presence/absence of flatback, green and loggerhead turtle nests and environmental and topographic characteristics of 237 potential nesting sites along the central and southern coasts of Queensland. The presence of nesting flatback turtles was strongly correlated with the mainland and non-coral cay islands with decreasing latitude, as there is an interaction between site type and latitude. In contrast, green turtles preferred to nest on coral cays rather than mainland and island beaches. Loggerhead turtles were more likely to nest on coral cays, the mainland, then islands, with presence increasing with latitude. Among these site types and higher latitudes, presence was stronger on sheltered than on semi-exposed beaches. Identifying environmental and topographical features influencing the presence of nesting flatback, green and loggerhead turtles is an important first step to improve the conservation of these species by prioritising sites for monitoring and managing threats to important beaches.

Abstract SuperWIMPs are extremely weakly interacting massive particles that inherit their relic abundance from late decays of frozen-out parent particles. Within supersymmetric models, gravitinos and axinos represent two of the most well motivated superWIMPs. In this paper we revisit constraints on these scenarios from a variety of cosmological observations that probe their production mechanisms as well as the superWIMP kinematic properties in the early Universe. We consider in particular observables of Big Bang Nucleosynthesis and the Cosmic Microwave Background (spectral distortion and anisotropies), which limit the fractional energy injection from the late decays, as well as warm and mixed dark matter constraints derived from the Lyman- $$\alpha $$ α forest and other small-scale structure observables. We discuss complementary constraints from collider experiments, and argue that cosmological considerations rule out a significant part of the gravitino and the axino superWIMP parameter space.