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The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.

Abstract Background Migrants experience substantial changes in their neighborhood physical and social environments along their migration journeys, but little is known about how perceived changes in their neighborhood environment pre- and post-migration correlate with their mental health. Our aim was to examine the associations between recalled changes in the perceived neighborhood physical and social environments and migrants’ mental health in the host city. Methods We used cross-sectional data on 591 migrants in Shenzhen, China. We assessed their risk of mental illness using the General Health Questionnaire (GHQ). Neighborhood perceptions were collected retrospectively pre- and post-migration. We used random forests to analyze possibly non-linear associations between GHQ scores and changes in the neighborhood environment, variable importance, and for exploratory analysis of variable interactions. Results Perceived changes in neighborhood aesthetics, safety, and green space were non-linearly associated with migrants’ mental health: A decline in these characteristics was associated with poor mental health, while improvements in them were unrelated to mental health benefits. Variable importance showed that change in safety was the most influential neighborhood characteristic, although individual-level characteristics—such as self-reported physical health, personal income, and hukou (i.e., the Chinese household registration system)—appeared to be more important to explain GHQ scores and also strongly interacted with other variables. For physical health, we found different associations between changes in the neighborhood provoked by migration and mental health. Conclusion Our findings suggest that perceived degradations in the physical environment are related to poorer post-migration mental health. In addition, it seems that perceived changes in the neighborhood environment play a minor role compared to individual-level characteristics, in particular migrants’ physical health condition. Replication of our findings in longitudinal settings is needed to exclude reverse causality.

Abstract The aim of this study was to explore the association between genetically predicted circulating levels of immunity and inflammation, and the risk of Alzheimer’s disease (AD) and hippocampal volume, by conducting a two-sample Mendelian Randomization Study. We identified 12 markers of immune cells and derived ratios (platelet count, eosinophil count, neutrophil count, basophil count, monocyte count, lymphocyte count, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, CD4 count, CD8 count, CD4-to-CD8 ratio, and CD56) and 5 signaling molecules (IL-6, fibrinogen, CRP, and Lp-PLA2 activity and mass) as primary exposures of interest. Other genetically available immune biomarkers with a weaker a priori link to AD were considered secondary exposures. Associations with AD were evaluated in The International Genomics of Alzheimer’s Project (IGAP) GWAS dataset (21,982 cases; 41,944 controls of European ancestry). For hippocampal volume, we extracted data from a GWAS meta-analysis on 33,536 participants of European ancestry. None of the primary or secondary exposures showed statistically significant associations with AD or with hippocampal volume following P-value correction for multiple comparisons using false discovery rate 0.05). There was evidence for heterogeneity in the MR inverse variance-weighted meta-analyses as measured by Cochran Q, and weighted median and weighted mode for multiple exposures. Further cluster analyses did not reveal clusters of variants that could influence the risk factor in distinct ways. This study suggests that genetically predicted circulating biomarkers of immunity and inflammation are not associated with AD risk or hippocampal volume. Future studies should assess competing risk, explore in more depth the role of adaptive immunity in AD, in particular T cells and the CD4 subtype, and confirm these findings in other ethnicities.

Abstract The early identification of asymptomatic yet infectious cases is vital to curb the 2019 coronavirus (COVID-19) pandemic and to control the disease in the post-pandemic era. In this paper, we propose a fast, inexpensive and high-throughput approach using painless nasal-swab self-collection followed by direct RT-qPCR for the sensitive PCR detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This approach was validated in a large prospective cohort study of 1038 subjects, analysed simultaneously using (1) nasopharyngeal swabs obtained with the assistance of healthcare personnel and analysed by classic two-step RT-qPCR on RNA isolates and (2) nasal swabs obtained by self-collection and analysed with direct RT-qPCR. Of these subjects, 28.6% tested positive for SARS-CoV-2 using nasopharyngeal swab sampling. Our direct RT-qPCR approach for self-collected nasal swabs performed well with results similar to those of the two-step RT-qPCR on RNA isolates, achieving 0.99 positive and 0.98 negative predictive values (cycle threshold [Ct]

En este articulo se describe el proyecto de publicacion que el arquitecto argentino Amancio Williams teni para su obra, asi como la publicacion que hicieron en 1990 Claudio Williams (uno de sus hijos, arquitecto y curador del archivo Williams) y Claudio Vekstein (ultimo colaborador y continuador de su obra). Se abordan los temas de la re-edicion “seriada” y la transcripcion – traduccion de formatos. Se analizan otros niveles de lo publico: la importancia que Amancio le daba al registro fotografico de sus obras y el tra- bajo que se tomaba incluso para las fotos familiares (escenas domesticas de alcance publico). Finalmente, se aborda la re-construccion de sus paragutas como otro trabajo de traduccion – transcripcion.

Cementitious materials are frequently applied in environments in which they are exposed to acid attack, e.g., in sewer systems, biogas plants, and agricultural/food-related industries. Alkali-activated materials (AAMs) have repeatedly been shown to exhibit a remarkably high resistance against attack by organic and inorganic acids and, thus, are promising candidates for the construction and the repair of acid-exposed structures. However, the reaction mechanisms and processes affecting the acid resistance of AAMs have just recently begun to be understood in more detail. The present contribution synthesises these advances and outlines potentially fruitful avenues of research. The interaction between AAMs and acids proceeds in a multistep process wherein different aspects of deterioration extend to different depths, complicating the overall determination of acid resistance. Partly due to this indistinct definition of the ‘depth of corrosion’, the effects of the composition of AAMs on their acid resistance cannot be unambiguously identified to date. Important parallels exist between the deterioration of low-Ca AAMs and the weathering/corrosion of minerals and glasses (dissolution-reprecipitation mechanism). Additional research requirements relate to the deterioration mechanism of high-Ca AAMs; how the character of the corroded layer influences the rate of deterioration; the effects of shrinkage and the bond between AAMs and substrates.

In agricultural landscapes, forest herbs live in small, spatially isolated forest patches. For their long-term survival, their populations depend on animals as genetic linkers that provide pollen- or seed-mediated gene flow among different forest patches. However, whether insect pollinators serve as genetic linkers among spatially isolated forest herb populations in agricultural landscapes remains to be shown. Here, we used population genetic methods to analyze: (A) the genetic diversity and genetic differentiation of populations of two common, slow-colonizing temperate forest herb species [Polygonatum multiflorum (L.) All. and Anemone nemorosa L.] in spatially isolated populations within three agricultural landscapes in Germany and Sweden and (B) the movement activity of their most relevant associated pollinator species, i.e., the bumblebee Bombus pascuorum (Scopoli, 1,763) and the hoverfly Melanostoma scalare (Fabricus, 1,794), respectively, which differ in their mobility. We tested whether the indicated pollinator movement activity affected the genetic diversity and genetic differentiation of the forest herb populations. Bumblebee movement indicators that solely indicated movement activity between the forest patches affected both genetic diversity and genetic differentiation of the associated forest herb P. multiflorum in a way that can be explained by pollen-mediated gene flow among the forest herb populations. In contrast, movement indicators reflecting the total movement activity at a forest patch (including within-forest patch movement activity) showed unexpected effects for both plant-pollinator pairs that might be explained by accelerated genetic drift due to enhanced sexual reproduction. Our integrated approach revealed that bumblebees serve as genetic linkers of associated forest herb populations, even if they are more than 2 km apart from each other. No such evidence was found for the forest associated hoverfly species which showed significant genetic differentiation among forest patches itself. Our approach also indicated that a higher within-forest patch movement activity of both pollinator species might enhance sexual recruitment and thus diminishes the temporal buffer that clonal growth provides against habitat fragmentation effects.

Abstract Although X‐ray contrast agents offer specific characteristics in terms of targeting and attenuation, their accumulation in the tissue on a cellular level is usually not known and difficult to access, as it requires high resolution and sensitivity. Here, quantitative near‐field ptychographic X‐ray computed tomography is demonstrated to assess the location of X‐ray stains at a resolution sufficient to identify intracellular structures by means of a basis material decomposition. On the example of two different X‐ray stains, the nonspecific iodine potassium iodide, and eosin Y, which mostly interacts with proteins and peptides in the cell cytoplasm, the distribution of the stains within the cells in murine kidney samples is assessed and compared to unstained samples with similar structural features. Quantitative nanoscopic stain concentrations are in good agreement with dual‐energy micro computed tomography measurements, the state‐of‐the‐art modality for material‐selective imaging. The presented approach can be applied to a variety of X‐ray stains advancing the development of X‐ray contrast agents.

Purpose: Successful completion of higher education is a significant factor of both individual and national development. Self-esteem has been neglected in previous empirical research as a constraint in course completion. We investigate this factor as a basis to develop suitable interventions. Method: We use secondary, administrative data of course completion from fully accredited Bachelor- and Master-courses at an Austrian higher education institution. Findings: Self-Esteem, using measures of social comparison and gender as proxies, lead to reductions of successful completion of higher education. Practical implications: National and educational institutions aiming at supporting students should focus on emotional support programs alongside professional support programs. Value: We offer tentative first evidence of a novel theory on the impact of fragile self-esteem on intertemporal choices, applied to the context of higher education. Future research: An empirical analysis of higher education performance based on a model unifying both ability and self-esteem constraints would provide an ambitious, but interesting avenue for further research. JEL Сlassіfіcatіon: A20, D01, D15

Summary: Background: IgE-mediated hypersensitivity is becoming increasingly prevalent and activation of mast cells and basophils represent key events in the pathophysiology of allergy. We have previously reported that the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCsec) exerts beneficial anti-inflammatory effects. Yet, its ability to alleviate allergic symptoms has not been investigated so far. Methods: Several experimental in vitro and in vivo models have been used in this basic research study. A murine ear swelling model was used to study the effects of PBMCsec on 48/80-induced mast cell degranulation in vivo. The transcriptional profile of murine mast cells was analysed by single cell RNA sequencing (scRNAseq). Mast cell activation was studied in vitro using primary skin mast cells. Basophils from individuals allergic to birch pollens were used to investigate basophile activation by allergens. Transcriptomic and lipidomic analyses were used to identify mRNA expression and lipid species present in PBMCsec, respectively. Findings: Topical application of PBMCsec on mouse ears (C57BL/6) significantly reduced tissue swelling following intradermal injection of compound 48/80, an inducer of mast cell degranulation. Single cell RNA sequencing of PBMCsec-treated murine dermal mast cells (Balb/c) revealed a downregulation of genes involved in immune cell degranulation and Fc-receptor signalling. In addition, treatment of primary human dermal mast cells with PBMCsec strongly inhibited compound 48/80- and α-IgE-induced mediator release in vitro. Furthermore, PBMCsec remarkably attenuated allergen driven activation of basophils from allergic individuals. Transcriptomic analysis of these basophils showed that PBMCsec downregulated a distinct gene battery involved in immune cell degranulation and Fc-receptor signalling, corroborating results obtained from dermal mast cells. Finally, we identified the lipid fraction of PBMCsec as the major active ingredient involved in effector cell inhibition. Interpretation: Collectively, our data demonstrate that PBMCsec is able to reduce activation of mast cells and basophils, encouraging further studies on the potential use of PBMCsec for treating allergy. Funding: Austrian Research Promotion Agency (852748 and 862068, 2015-2019), Vienna Business Agency (2343727, 2018-2020), Aposcience AG, Austrian Federal Ministry of Education, Science and Research (SPA06/055), Danube Allergy Research Cluster, Austrian Science Fund (I4437 and P32953).

El carácter estructural que tiene la violencia hacia las mujeres y, en particular, el femicidio en América Latina ha sido demostrado por los estudios de género, los estudios sociales de la violencia y diversas ramas de la criminología, entre otras áreas de conocimiento. No obstante, las perspectivas y visiones del mundo de quienes ejercen la violencia han sido ejes comparativamente poco explorados, más aún cuando se trata de femicidios. En este artículo nos preguntamos —en el marco de un estudio cualitativo biográfico con enfoque socio-narrativo y hermenéutico— por los modos en los que los varones que han cometido femicidio íntimo en Buenos Aires (Argentina) hablan y se refieren a las mujeres en sus narrativas. Para ello analizamos 19 entrevistas narrativas hechas a varones condenados por femicidio en el Área Metropolitana de Buenos Aires y realizamos un análisis intertestimonial a partir de un proceso inductivo de codificación temática. Las narrativas acerca de las mujeres se organizaron en torno a tres grandes temas: la amenaza, el control y el contexto. La recurrencia de estos temas, su función estructurante de los relatos y el alcance que tienen en las racionalizaciones indican su centralidad para comprender el proceso de legitimación y neutralización de la violencia. En las narrativas las referencias a una amenaza colectiva contra el yo de los entrevistados y el uso discursivo del contexto sociopolítico son ejes salientes para pensar la interfaz entre masculinidad, violencia y cambio social. Destacamos que el cambio social en torno al estatus de las mujeres es utilizado por los varones como factor explicativo y legitimador de la violencia, lo cual es un resultado poco explorado en la literatura especializada. Discutimos la importancia de indagar en las perspectivas de los perpetradores y la centralidad de analizar la interacción entre sus narraciones y los discursos prevalentes en la sociedad.

Abstract The tissue microenvironment in chronic lymphocytic leukaemia (CLL) plays a key role in the pathogenesis of CLL, but the complex blood microenvironment in CLL has not yet been fully characterised. Therefore, immunophenotyping of circulating immune cells in 244 CLL patients and 52 healthy controls was performed using flow cytometry and analysed by multivariate Patient Similarity Networks (PSNs). Our study revealed high inter-individual heterogeneity in the distribution and activation of bystander immune cells in CLL, depending on the bulk of the CLL cells. High CLL counts were associated with low activation on circulating monocytes and T cells and vice versa. The highest activation of immune cells, particularly of intermediate and non-classical monocytes, was evident in patients treated with novel agents. PSNs revealed a low activation of immune cells in CLL progression, irrespective of IgHV status, Binet stage and TP53 disruption. Patients with high intermediate monocytes (> 5.4%) with low activation were 2.5 times more likely (95% confidence interval 1.421–4.403, P = 0.002) to had shorter time-to-treatment than those with low monocyte counts. Our study demonstrated the association between the activation of circulating immune cells and the bulk of CLL cells. The highest activation of bystander immune cells was detected in patients with slow disease course and in those treated with novel agents. The subset of intermediate monocytes showed predictive value for time-to-treatment in CLL.

The development of specific anti-cytokine/chemokine therapeutic strategies for atherosclerotic disease is challenging. Here, the authors have designed a peptide-based ectodomain mimic of the chemokine receptor CXCR4 that selectively targets MIF but not CXCL12 and blocks experimental atherosclerosis in vivo.

Palaeo-environmental conditions can be recorded in low-temperature continental archives, according to geochemical and isotopic analyses of dolomitic fracture infills at Erzberg, Austria

Abstract Background The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. Methods We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer’s disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Results Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen’s f 2 = 0.137) and memory decline (p = 0.006, Cohen’s f 2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen’s f 2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1–42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. Conclusion Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.

Abstract Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult‐to‐treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.

Abstract The purpose of this study was to provide an overview of entry screening measures applied at airports in response to the COVID-19 epidemic worldwide. Between 24 January and 17 February 2020, 5.2% (95% CI 3.1–8.5) of the 271 total imported COVID-19 cases worldwide (excluding imported cases arriving in China, Macao, and Hong Kong) with known detection location were captured through airport entry screening. The majority of imported COVID-19 cases (210) were identified by the health care system (77.5%). Efforts should focus on health care system preparedness for early case detection, since according to our and previous studies health care facilities are the actual point of entry of imported cases.

Abstract Background Current guidelines recommend measurement of troponin in acute ischemic stroke (AIS) patients. In AIS patients, troponin elevation is associated with increased mortality and worse outcome. However, uncertainty remains regarding the underlying pathophysiology of troponin elevation after stroke, particularly regarding diagnostic and therapeutic consequences. Troponin elevation may be caused by coronary artery disease (CAD) and more precisely acute coronary syndrome (ACS). Both have a high prevalence in stroke patients and contribute to poor outcome. Therefore, better diagnostic algorithms are needed to identify those AIS patients likely to have ACS or other manifestations of CAD. Methods/design The primary goal of the “PRediction of Acute coronary syndrome in acute Ischemic StrokE” (PRAISE) study is to develop a diagnostic algorithm for prediction of ACS in AIS patients. The primary hypothesis will test whether dynamic high-sensitivity troponin levels determined by repeat measurements (i.e., “rise or fall-pattern”) indicate presence of ACS when compared to stable (chronic) troponin elevation. PRAISE is a prospective, multicenter, observational trial with central reading and predefined endpoints guided by a steering committee. Clinical symptoms, troponin levels as well as findings on electrocardiogram, echocardiogram, and coronary angiogram will be recorded and assessed by central academic core laboratories. Diagnosis of ACS will be made by an endpoint adjudication committee. Severe adverse events will be evaluated by a critical event committee. Safety will be judged by a data and safety monitoring board. Follow-up will be conducted at three and twelve months and will record new vascular events (i.e., stroke and myocardial infarction) as well as death, functional and cognitive status. According to sample size calculation, 251 patients have to be included. Discussion PRAISE will prospectively determine the frequency of ACS and characterize cardiac and coronary pathologies in a large, multicenter cohort of AIS patients with troponin elevation. The findings will elucidate the origin of troponin elevation, shed light on its impact on necessary diagnostic procedures and provide data on the safety and diagnostic yield of coronary angiography early after stroke. Thereby, PRAISE will help to refine algorithms and develop guidelines for the cardiac workup in AIS. Trial registration NCT03609385 registered 1st August 2018.

In semiarid and subhumid environments, plant growth promoting microorganisms mitigate abiotic stresses that frequently limit the grain production of winter cereals. Our objective was to quantify the field evolution of the shoot dry matter production of barley (Hordeum vulgare L.) cover crops inoculated with Azospirillum brasilense combined with two levels of fertilization. Four treatments combining a seed treatment with Azospirillum brasilense and nitrogen and phosphorus fertilization at sowing were placed in two sites from the semiarid and subhumid pampas region under contrasting initial water conditions. During the growing season, the water availability (rainfalls and water table contribution) was adequate for achieving normal growth of the crops. The fertilization and the inoculation treatments showed independent effects on the shoot biomass production with 23% mean response to inoculation and 44% mean response to fertilization. In the inoculated treatments, the greater shoot growth rate was observed between tillering and stem elongation anticipating the moment for maximum dry matter production compared with the treatments without inoculation. The inoculation of barley seeds with Azospirillum brasilense is a recommended management practice in dryland agricultural systems in the semiarid and subhumid pampas integrated with the production of annual summer crops.

Abstract Microglia activation is the brain's major immune response to amyloid plaques in Alzheimer's disease (AD). Both cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2), a biomarker of microglia activation, and microglia PET are increased in AD; however, whether an increase in these biomarkers is associated with reduced amyloid‐beta (Aβ) accumulation remains unclear. To address this question, we pursued a two‐pronged translational approach. Firstly, in non‐demented and demented individuals, we tested CSF sTREM2 at baseline to predict (i) amyloid PET changes over ∼2 years and (ii) tau PET cross‐sectionally assessed in a subset of patients. We found higher CSF sTREM2 associated with attenuated amyloid PET increase and lower tau PET. Secondly, in the AppNL‐G-F mouse model of amyloidosis, we studied baseline 18F‐GE180 microglia PET and longitudinal amyloid PET to test the microglia vs. Aβ association, without any confounding co‐pathologies often present in AD patients. Higher microglia PET at age 5 months was associated with a slower amyloid PET increase between ages 5‐to‐10 months. In conclusion, higher microglia activation as determined by CSF sTREM2 or microglia PET shows protective effects on subsequent amyloid accumulation.

We report the annotated draft genome sequence of Enterococcus durans EDD2 strain isolated from freshly collected pollen granules derived from three different beehives. This isolate showed strong inhibitory activity in vitro against Paenibacillus larvae ATCC 9545; thus the genome sequence presented here will contribute to a better understanding of its protective potential against bacterial pathogen invasion, as well as to the assessment of its beneficial potential for the bee colonies.

Abstract dialectical frameworks (ADFs) are generalizations of Dung argumentation frameworks where arbitrary relationships among arguments can be formalized. This additional expressibility comes with the price of higher computational complexity, thus an understanding of potentially easier subclasses is essential. Compared to Dung argumentation frameworks, where several subclasses such as acyclic and symmetric frameworks are well understood, there has been no in-depth analysis for ADFs in such direction yet (with the notable exception of bipolar ADFs). In this work, we introduce certain subclasses of ADFs and investigate their properties. In particular, we show that for acyclic ADFs, the different semantics coincide. On the other hand, we show that the concept of symmetry is less powerful for ADFs and further restrictions are required to achieve results that are similar to the known ones for Dung’s frameworks. A particular such subclass (support-free symmetric ADFs) turns out to be closely related to argumentation frameworks with collective attacks (SETAFs); we investigate this relation in detail and obtain as a by-product that even for SETAFs symmetry is less powerful than for AFs. We also discuss the role of odd-length cycles in the subclasses we have introduced. Finally, we analyse the expressiveness of the ADF subclasses we introduce in terms of signatures.

AimEvidence on the association between natural-built environments and depression is largely derived from the general population and prone to residential self-selection bias because of the nature of cross-sectional research design. Despite emerging adulthood, which includes the university years, is a critical stage for forming life-long health habits, studies on this topic focusing on undergraduate students are limited. The current study aims to illustrate the underlying mechanisms for how the campus-based environments affect depression in undergraduate students.MethodsBased on a nationwide representative analytical sample of 22,009 Chinese undergraduates in 2018, we examined participants' reports of depression and campus-centered natural/built environments within multiple buffer sizes including 0.5, 1.0, and 2.5 km. After disentangling residential self-selection, we explored the moderating role of the socioeconomic attributes of undergraduates. The depression outcome was measured by the nine-item Patient Health Questionnaire (PHQ9). Indicators of exposure to green and blue space, transportation infrastructure, and food environments were objectively assessed using different circular buffers around each campus address.ResultsModeling results indicated that campus neighborhoods with more scattered trees (0.5 km), water (0.5, 1.0, and 2.5 km), and street intersections (1.0 and 2.5 km) were protective against depression. In contrast, those living near denser distributions of outlets serving take-away sweets and fast food (0.5, 1.0, and 2.5 km) were susceptible to depression. These associations were modified by undergraduates' socioeconomic attributes (e.g., grade, Hukou status, and ethnicity) and varied according to geographical scales and exposure metrics.ConclusionTo deliver effective environmental interventions to curb the prevalence of depression among undergraduate students, further planning policies should focus on the careful conception of the campus-based environment, especially regarding different spatial scales.

BackgroundChildren born to parents with severe mental illness have gained more attention during the last decades because of increasing evidence documenting that these children constitute a population with an increased risk of developing mental illness and other negative life outcomes. Because of high-quality research with cohorts of offspring with familial risk and increased knowledge about gene–environment interactions, early interventions and preventive strategies are now being developed all over the world. Adolescence is a period characterized by massive changes, both in terms of physical, neurologic, psychological, social, and behavioral aspects. It is also the period of life with the highest risk of experiencing onset of a mental disorder. Therefore, investigating the impact of various risk and resilience factors in adolescence is important.MethodsThe Danish High-Risk and Resilience Study started data collection in 2012, where 522 7-year-old children were enrolled in the first wave of the study, the VIA 7 study. The cohort was identified through Danish registers based on diagnoses of the parents. A total of 202 children had a parent diagnosed with schizophrenia, 120 children had a parent diagnosed with bipolar disorder, and 200 children had parents without these diagnoses. At age 11 years, all children were assessed for the second time in the VIA 11 study, with a follow-up retention rate of 89%. A comprehensive assessment battery covering domains of psychopathology, neurocognition, social cognition and behavior, motor development and physical health, genetic analyses, attachment, stress, parental functioning, and home environment was carried out at each wave. Magnetic resonance imaging scans of the brain and electroencephalograms were included from age 11 years. This study protocol describes the third wave of assessment, the VIA 15 study, participants being 15 years of age and the full, 3-day-long assessment battery this time including also risk behavior, magnetoencephalography, sleep, and a white noise paradigm. Data collection started on May 1, 2021.DiscussionWe will discuss the importance of longitudinal studies and cross-sectional data collection and how studies like this may inform us about unmet needs and windows of opportunity for future preventive interventions, early illness identification, and treatment in the future.

ObjectivesThis study examined the gender and cross-country differences in the relationship between working hours and self-assessed health among working men and women in Europe, and further explored the moderating role of sleep disturbance in the relationship.MethodsWe used cross-sectional data from the 6th European Working Condition Survey on 14,603 men and 15,486 women across 30 countries in Europe. A multivariate logistic regression was applied to evaluate the relationship between working hours, sleep disturbance, and self- assessed health. In addition, we employed a two-stage multilevel logistic regression to assess the cross-country variations in the relationship between working hours and self-assessed health.ResultsThe study showed a slightly U-shaped relationship between working hours and less-than-good self-assessed health among working adults in Europe (

A bainite dual-phase (FB) steel containing polygonal ferrite and granular bainite is thermo-mechanically rolled, followed by an accelerated cooling. Two different cooling rates are applied to obtain two different materials. The aim of the study is to explore the reasons for the differences in the mechanical response experimentally observed for these two materials which are modeled by means of high-resolution crystal plasticity simulations with a phenomenological constitutive description. First, the CP parameters of the individual constituents are determined. Second, different three-dimensional (3D) representative volume elements (RVEs)—one of which includes the substructure of bainite—are used to study the mechanical properties of both FB microstructures. It is shown that, in contrast to the macroscopic response, the microscopic response differs among the RVEs. Third, a comparison of both materials is performed by analyzing their stress–strain response. The onset of plasticity in granular bainite is found to be different for both materials in addition to the strain partitioning, although they both obeyed the iso-work assumption. Finally, a parameter study is carried out in order to investigate the correlation between different microstructures and damage initiation that can be seen experimentally in this steel. It is shown that the difference in ultimate elongation may depend on whether the first voids appear within polygonal ferrite or at the phase boundary.

BackgroundStroke in UK Biobank (UKB) is ascertained via linkages to coded administrative datasets and self-report. We studied the accuracy of these codes using genetic validation.MethodsWe compiled stroke-specific and broad cerebrovascular disease (CVD) code lists (Read V2/V3, ICD-9/-10) for medical settings (hospital, death record, primary care) and self-report. Among 408,210 UKB participants, we identified all with a relevant code, creating 12 stroke definitions based on the code type and source. We performed genome-wide association studies (GWASs) for each definition, comparing summary results against the largest published stroke GWAS (MEGASTROKE), assessing genetic correlations, and replicating 32 stroke-associated loci.ResultsThe stroke case numbers identified varied widely from 3,976 (primary care stroke-specific codes) to 19,449 (all codes, all sources). All 12 UKB stroke definitions were significantly correlated with the MEGASTROKE summary GWAS results (rg.81-1) and each other (rg.4-1). However, Bonferroni-corrected confidence intervals were wide, suggesting limited precision of some results. Six previously reported stroke-associated loci were replicated using ≥1 UKB stroke definition.ConclusionsStroke case numbers in UKB depend on the code source and type used, with a 5-fold difference in the maximum case-sample size. All stroke definitions are significantly genetically correlated with the largest stroke GWAS to date.

Objective: This article investigates whether within-domain and cross-domain buffering by family and work resources can help mitigate the negative mental health effects of work-to-family conflicts (WFC) and family-to-work conflicts (FWC). Background: Most literature on the work–life interface stresses the need to maintain employees’ health and well-being by preventing the emergence of work–family conflicts. Since such conflicts tend to be an unavoidable concomitant of role expansion, we aim to put forward the debate on the conditions that might prevent their negative health consequences instead. Method: Fixed-effects linear regression analyses were applied to a sample of 4,920 employees in a three-wave employer–employee panel study in Germany. Using interaction analyses, we tested within-domain and cross-domain buffering of family (social support and relative bargaining power within partnerships) and work (job resources, support from direct supervisors or co-workers, formal and informal organizational support) resources in the relationship between strain-based and time-based WFC and FWC and mental health (SF-12). Results: Family resources and work resources somewhat mitigated the health risks of WFC and FWC. Overall, within-domain resources were more effective than cross-domain ones. Conclusion: It is important to consider resources in both the family and the work domains to determine the most effective ways of preventing the negative mental health consequences of work–family conflicts.

Array

The COVID-19 pandemic has dramatically affected everyone’s daily life in one way or another, requiring a re-negotiation of existing strategies for work–life integration, not only for individuals but also within families and partnerships. To contribute to existing knowledge on work-life integration during COVID-19 in Germany, we look at gender and parenthood differences in the experiences of work-to-family (WFC) and family-to-work (FWC) conflicts. By accounting for employees’ previous conflict experiences, we were able to reveal the extent to which the current conditions contributed to differences in these conflicts. Moreover, we explored the relevance of demands and resources in the family and work spheres as a way to explain different levels of WFC and FWC across gender and parenthood. Our analyses are based on a sample of 660 employees from a German linked employer–employee panel study and a COVID-19 follow-up survey conducted in late 2020. Results revealed that work–family conflict experiences before the pandemic play an important role in current conflict perceptions. Whereas WFC were more likely to be accentuated during the pandemic, prior FWC experiences may have helped to mitigate conflicts under these new conditions. Work–family conflicts in general have increased during the COVID-19 pandemic, but this finding applied only to conflicts in the family-to-work direction. Although such increases were not limited to parents, they were particularly high in this group. Overall, gender differences in work–family conflicts were absent, but differences were found between mothers and fathers. The need to compensate for a lack of external childcare, as well as having to work from home, increased FWC, especially among fathers. This study suggests that FWC in particular became more important during the pandemic; however, parents were not the only ones who were disadvantaged when it came to work–life integration; childless individuals likewise struggled to balance the demands of work and private life.

Background: DTI is sensitive to white matter (WM) microstructural damage and has been suggested as a surrogate marker for phase 2 clinical trials in cerebral small vessel disease (SVD). The study’s objective is to establish the best way to analyse the diffusion-weighted imaging data in SVD for this purpose. The ideal method would be sensitive to change and predict dementia conversion, but also straightforward to implement and ideally automated. As part of the OPTIMAL collaboration, we evaluated five different DTI analysis strategies across six different cohorts with differing SVD severity. Methods: Those 5 strategies were: (1) conventional mean diffusivity WM histogram measure (MD median), (2) a principal component-derived measure based on conventional WM histogram measures (PC1), (3) peak width skeletonized mean diffusivity (PSMD), (4) diffusion tensor image segmentation θ (DSEG θ) and (5) a WM measure of global network efficiency (Geff). The association between each measure and cognitive function was tested using a linear regression model adjusted by clinical markers. Changes in the imaging measures over time were determined. In three cohort studies, repeated imaging data together with data on incident dementia were available. The association between the baseline measure, change measure and incident dementia conversion was examined using Cox proportional-hazard regression or logistic regression models. Sample size estimates for a hypothetical clinical trial were furthermore computed for each DTI analysis strategy. Results: There was a consistent cross-sectional association between the imaging measures and impaired cognitive function across all cohorts. All baseline measures predicted dementia conversion in severe SVD. In mild SVD, PC1, PSMD and Geff predicted dementia conversion. In MCI, all markers except Geff predicted dementia conversion. Baseline DTI was significantly different in patients converting to vascular dementia than to Alzheimer’ s disease. Significant change in all measures was associated with dementia conversion in severe but not in mild SVD. The automatic and semi-automatic measures PSMD and DSEG θ required the lowest minimum sample sizes for a hypothetical clinical trial in single-centre sporadic SVD cohorts. Conclusion: DTI parameters obtained from all analysis methods predicted dementia, and there was no clear winner amongst the different analysis strategies. The fully automated analysis provided by PSMD offers advantages particularly for large datasets.

Background Although trials suggest that anti‐inflammatory approaches targeting interleukin (IL)‐6 signaling can reduce cardiovascular risk, it remains unknown whether targeting IL‐6 signaling could reduce risk additively to low‐density lipoprotein cholesterol (LDL‐C) lowering. Here, we assess interactions in associations of genetic downregulation of IL‐6 signaling and LDL‐C lowering with lifetime cardiovascular disease risk. Methods and Results Genetic scores for IL‐6 signaling downregulation and LDL‐C lowering were used to divide 408 225 White British individuals in UK Biobank into groups of lifelong exposure to downregulated IL‐6 signaling, lower LDL‐C, or both. Associations with risk of cardiovascular disease (coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, vascular death) were explored in factorial Mendelian randomization. Compared with individuals with genetic IL‐6 and LDL‐C scores above the median, individuals with LDL‐C scores lower than the median but IL‐6 scores above the median had an odds ratio (OR) of 0.96 (95% CI, 0.93–0.98) for cardiovascular disease. A similar OR (0.96; 95% CI, 0.93–0.98) was estimated for individuals with genetic IL‐6 scores below the median but LDL‐C scores above the median. Individuals with both genetic scores lower than the median were at lower odds of cardiovascular disease (OR, 0.92; 95% CI, 0.90–0.95). There was no interaction between the 2 scores (relative excess risk attributed to interaction index, 0; synergy index, 1; P for multiplicative interaction=0.51). Genetic IL‐6 score below the median was associated with lower cardiovascular disease risk across measured LDL‐C strata (

The major aim of the German TwinLife study is the investigation of gene-environment interplay driving educational and other inequalities across developmental trajectories from childhood to early adulthood. TwinLife encompasses an 8-year longitudinal, cross-sequential extended twin family design with data from same-sex twins of four age cohorts (5, 11, 17, and 23 years) and their parents, as well as their non-twin siblings, partners, and children, if available, altogether containing N = 4,096 families. As such, TwinLife includes unique and openly accessible data that allows, but is not limited to, genetically informative and environmentally sensitive research on sources of inequalities regarding educational attainment, school achievement, and skill development.

Hypertrophic scars can cause pain, movement restrictions, and reduction in the quality of life. Despite numerous options to treat hypertrophic scarring, efficient therapies are still scarce, and cellular mechanisms are not well understood. Factors secreted by peripheral blood mononuclear cells (PBMCsec) have been previously described for their beneficial effects on tissue regeneration. In this study, we investigated the effects of PBMCsec on skin scarring in mouse models and human scar explant cultures at single-cell resolution (scRNAseq). Mouse wounds and scars, and human mature scars were treated with PBMCsec intradermally and topically. The topical and intradermal application of PBMCsec regulated the expression of various genes involved in pro-fibrotic processes and tissue remodeling. We identified elastin as a common linchpin of anti-fibrotic action in both mouse and human scars. In vitro, we found that PBMCsec prevents TGFβ-mediated myofibroblast differentiation and attenuates abundant elastin expression with non-canonical signaling inhibition. Furthermore, the TGFβ-induced breakdown of elastic fibers was strongly inhibited by the addition of PBMCsec. In conclusion, we conducted an extensive study with multiple experimental approaches and ample scRNAseq data demonstrating the anti-fibrotic effect of PBMCsec on cutaneous scars in mouse and human experimental settings. These findings point at PBMCsec as a novel therapeutic option to treat skin scarring.

The COVID-19 pandemic burdened the working and living conditions of seafaring personnel with particular challenges. The present study investigated the health and occupational burden of 301 multinational seafarers from merchant ships using self-administered questionnaires. The survey was carried out between September and November 2021 on the occasion of SARS-CoV-2 vaccinations at the Port of Hamburg, Germany. Participants generally reported good physical and mental health status while general burden perception increased compared to pre-pandemic levels. Three-quarters of seafarers reported experiencing shore-leave denial at least once throughout the pandemic. In summary, the study reveals the substantial impact of the COVID-19 pandemic on the perceived occupational burden of seafaring personnel.

Background: Antithymocyte globulins (ATG) are T cell-depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with a high risk of graft rejection. Previously described effects besides the depletion of T cells have suggested additional modes of action and identified further cellular targets. Methods: We examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG at the single-cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. Findings: Analysis of the paracrine factors present in the plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines, including interferon-γ (IFN-γ). Furthermore, we identified an increase in the surface expression of the programmed death ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we showed that this induction is dependent on the activation of JAK/STAT signaling via the binding of IFN-γ to interferon-γ receptor 1 (IFN-γR1). Lastly, we demonstrated that the modulation of the immune regulatory axis of programmed cell death protein 1 (PD1) on activated CD8+ T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including the proliferation and granzyme B release of activated T cells. Interpretation: Together, our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects.

The aim of this study was to develop a physical activity advisory system supporting the correct implementation of sport exercises using inertial sensors and machine learning algorithms. Specifically, three mobile sensors (tags), six stationary anchors and a system-controlling server (gateway) were employed for 15 scenarios of the series of subsequent activities, namely squats, pull-ups and dips. The proposed solution consists of two modules: an activity recognition module (ARM) and a repetition-counting module (RCM). The former is responsible for extracting the series of subsequent activities (so-called scenario), and the latter determines the number of repetitions of a given activity in a single series. Data used in this study contained 488 three defined sport activity occurrences. Data processing was conducted to enhance performance, including an overlapping and non-overlapping window, raw and normalized data, a convolutional neural network (CNN) with an additional post-processing block (PPB) and repetition counting. The developed system achieved satisfactory accuracy: CNN + PPB: non-overlapping window and raw data, 0.88; non-overlapping window and normalized data, 0.78; overlapping window and raw data, 0.92; overlapping window and normalized data, 0.87. For repetition counting, the achieved accuracies were 0.93 and 0.97 within an error of ±1 and ±2 repetitions, respectively. The archived results indicate that the proposed system could be a helpful tool to support the correct implementation of sport exercises and could be successfully implemented in further work in the form of web application detecting the user’s sport activity.

Consolidation of MgO castables by organic acids is a common technique for various applications, but the distinct hardening mechanisms of caste stone formation are still poorly constrained. In this study, the individual hardening behavior was experimentally investigated by intermixing of (i) active fine-grained magnesia (MgO_A), (ii) dead-burned coarse magnesia (MgO_D) or inert quartz sand aggregates, (iii) citric acid, malic acid or acetic acid, and (iv) water. The effects of MgO purity, MgO reactivity and the type of organic additive on the evolution of hardening, Mg-organo salt formation, mineralogy and microstructure of the MgO intermixes were assessed by sound velocity measurements, XRD, FTIR spectroscopy, and electron microscopy. The reactivity of MgO_A controls the overall hardening behavior of the MgO intermixes but is strongly affected by the type and spatial distribution of the solid Mg-organo binder. MgO intermixes prepared with citric and malic acid result in stronger hardening compared to those based on acetic acid, which is caused by the interconnecting Mg-Hcitrate and Mg-malate binders vs spatially restricted and compact Mg-acetate encapsulation in micropores. MgO_D with low purity degree yields in stronger hardening, which is due to the high reactivity of accessory solid phases, such as merwinite, magnesioferrite and larnite, forming additional Ca-Fe-Mg-organo binder phases. Systematics in the above MgO-H2O-organo systems are discussed in the scope of hardening reaction mechanisms of castables inferred by type and compositions of distinct MgO and carboxylic acids.

Objective: The loss of forkhead box protein O1 (FoxO1) signaling in response to metabolic stress contributes to the etiology of type II diabetes, causing the dedifferentiation of pancreatic beta cells to a cell type reminiscent of endocrine progenitors. Lack of methods to easily model this process in vitro, however, have hindered progress into the identification of key downstream targets and potential inhibitors. We therefore aimed to establish such an in vitro cellular dedifferentiation model and apply it to identify novel agents involved in the maintenance of beta-cell identity. Methods: The murine beta-cell line, Min6, was used for primary experiments and high-content screening. Screens encompassed a library of small-molecule drugs representing the chemical and target space of all FDA-approved small molecules with an automated immunofluorescence readout. Validation experiments were performed in a murine alpha-cell line as well as in primary murine and human diabetic islets. Developmental effects were studied in zebrafish and C. elegans models, while diabetic db/db mouse models were used to elucidate global glucose metabolism outcomes. Results: We show that short-term pharmacological FoxO1 inhibition can model beta-cell dedifferentiation by downregulating beta-cell-specific transcription factors, resulting in the aberrant expression of progenitor genes and the alpha-cell marker glucagon. From a high-content screen, we identified loperamide as a small molecule that can prevent FoxO inhibitor-induced glucagon expression and further stimulate insulin protein processing and secretion by altering calcium levels, intracellular pH, and FoxO1 localization. Conclusions: Our study provides novel models, molecular targets, and drug candidates for studying and preventing beta-cell dedifferentiation.

Este artículo tiene como objetivo analizar la efectividad del sistema de inteligencia ecuatoriano, institución que brinda información al presidente de la República sobre las amenazas que pueden afectar al país. Para ello, se estudió la evolución del concepto de seguridad en Ecuador, ya que de este concepto depende la actuación de su sistema de inteligencia, teniendo en cuenta que en el escenario mundial actual las amenazas no son ya las mismas, y que deben enfrentarse de manera integral. El trabajo utiliza un marco conceptual enfocado en las definiciones de inteligencia como comunidad de inteligencia y ciclo de inteligencia, entre otros. También se examinan documentos oficiales ecuatorianos, para comprender la definición de seguridad integral y su evolución. Para lograr el objetivo propuesto, primero se explica lo que significa la inteligencia en términos de seguridad y defensa, para luego pasar a conocer la evolución histórica que ha tenido el concepto de seguridad integral en Ecuador. Posteriormente se explica el funcionamiento de la comunidad de inteligencia de Ecuador. Después se aplicará el ciclo de inteligencia en dos casos particulares, para analizar la efectividad del sistema de inteligencia ecuatoriano. Finalmente, se presentan las conclusiones y algunas recomendaciones. Se concluye que el sistema de inteligencia ecuatoriano evidencia posibilidades de mejora, debido a la confusión en cuanto al concepto de seguridad integral y la falta de funcionamiento de su comunidad de inteligencia.

The Australian Community Climate and Earth System Simulator (ACCESS) has been extended to include land and ocean carbon cycle components to form an Earth System Model (ESM). The current version, ACCESS-ESM1.5, has been mainly developed to enable Australia to participate in the Coupled Model Intercomparison Project Phase 6 (CMIP6) with an ESM version. Here we describe the model components and changes to the previous version, ACCESS-ESM1. We use the 500-year pre-industrial control run to highlight the stability of the physical climate and the carbon cycle. The long spin-up, negligible drift in temperature and small pre-industrial net carbon fluxes (0.02 and 0.08 PgC year−1 for land and ocean respectively) highlight the suitability of ACCESS-ESM1.5 to explore modes of variability in the climate system and coupling to the carbon cycle. The physical climate and carbon cycle for the present day have been evaluated using the CMIP6 historical simulation by comparing against observations and ACCESS-ESM1. Although there is generally little change in the climate simulation from the earlier model, many aspects of the carbon simulation are improved. An assessment of the climate response to CO2 forcing indicates that ACCESS-ESM1.5 has an equilibrium climate sensitivity of 3.87°C.

A new version of the Australian Community Climate and Earth System Simulator coupled model, ACCESS-CM2, has been developed for a wide range of climate modelling research and applications. In particular, ACCESS-CM2 is one of Australia's contributions to the World Climate Research Programme's Coupled Model Intercomparison Project Phase 6 (CMIP6). Compared with the ACCESS1.3 model used for our CMIP5 submission, all model components have been upgraded as well as the coupling framework (OASIS3-MCT) and experiment control system (Rose/Cylc). The component models are: UM10.6 GA7.1 for the atmosphere, CABLE2.5 for the land surface, MOM5 for the ocean, and CICE5.1.2 for the sea ice. This paper describes the model configuration of ACCESS-CM2, documents the experimental set up, and assesses the model performance for the preindustrial spin-up simulation in comparison against (reconstructed) observations and ACCESS1.3 results. While the performance of the two generations of the ACCESS coupled model is largely comparable, ACCESS-CM2 shows better global hydrological balance, more realistic ocean water properties (in terms of spatial distribution) and meridional overturning circulation in the Southern Ocean but a poorer simulation of the Antarctic sea ice and a larger energy imbalance at the top of atmosphere. This energy imbalance reflects a noticeable warming trend of the global ocean over the spin-up period.