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Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8+ T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell RNA-sequencing data allows us to broadly infer the clonality of stromal cells and lineage-trace myeloid cell development. We report six conserved meta-programs that distinguish tumor cell function, and find an epithelial-mesenchymal transition meta-program highly enriched at the tumor-normal interface that co-localizes with IL1B-expressing macrophages, offering a potential therapeutic target.

Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.

Background: This case control study aimed to investigate whether symptoms of sexual dysfunction are more common in males from infertile couples than in the general population and to explore whether symptoms of sexual dysfunction are associated to hypogonadism. Objectives: Participants were 165 subfertile men in infertile heterosexual relationships, 18–50 years of age, with sperm concentrations < 15 × 106/mL. The controls were 199 men from a population-based group, matched for age. Material and methods: Logistic regression was applied in order to calculate odds ratios (ORs) for seven different symptoms of sexual dysfunction. In a multivariate model, we tested independent effects of infertility and primary as well as secondary hypogonadism. Results: Statistically significant association between subfertility and symptoms of sexual dysfunction was found for lack of ability to control ejaculation (OR 2.2, 95% CI: 1.2–4.2). For hypogonadism, statistical significance was seen both in relation to low sexual interest/desire for sex (OR 2.3, 95% CI: 1.0–5.5) and for being worried about the size or shape of the penis (OR 3.6, 95% CI: 1.3–9.5). These associations remained statistically significant in males with primary but not those with secondary hypogonadism. Discussion: Our study showed that men from infertile couples have an increased risk of symptoms of sexual dysfunction and this risk is linked to androgen deficiency. Conclusion: Assessment of reproductive hormone levels and sexual function should routinely be done in this group of males.

Background: This case control study aimed to investigate whether symptoms of sexual dysfunction are more common in males from infertile couples than in the general population and to explore whether symptoms of sexual dysfunction are associated to hypogonadism. Objectives: Participants were 165 subfertile men in infertile heterosexual relationships, 18–50 years of age, with sperm concentrations < 15 × 106/mL. The controls were 199 men from a population-based group, matched for age. Material and methods: Logistic regression was applied in order to calculate odds ratios (ORs) for seven different symptoms of sexual dysfunction. In a multivariate model, we tested independent effects of infertility and primary as well as secondary hypogonadism. Results: Statistically significant association between subfertility and symptoms of sexual dysfunction was found for lack of ability to control ejaculation (OR 2.2, 95% CI: 1.2–4.2). For hypogonadism, statistical significance was seen both in relation to low sexual interest/desire for sex (OR 2.3, 95% CI: 1.0–5.5) and for being worried about the size or shape of the penis (OR 3.6, 95% CI: 1.3–9.5). These associations remained statistically significant in males with primary but not those with secondary hypogonadism. Discussion: Our study showed that men from infertile couples have an increased risk of symptoms of sexual dysfunction and this risk is linked to androgen deficiency. Conclusion: Assessment of reproductive hormone levels and sexual function should routinely be done in this group of males.

Packed bed chromatography is an important unit operation for purification of product molecules in biopharmaceutical processes. Packed bed chromatographic processes are modeled as advection-diffusion-reaction partial differential equations. The advection term strongly dominates the diffusion term. Therefore, specialized numerical methods must be used for efficient simulation of packed bed chromatographic processes. In this paper, we use a discontinuous-Galerkin method on finite-elements for spatial discretization and low storage explicit Runge-Kutta (LSERK) methods for numerical solution of the resulting system of differential equations. We study the numerical solution of deterministic and stochastic models of packed bed chromatographic processes. The stochastic model and its corresponding numerical solution constitute the first step toward systematic monitoring, fault detection, and optimal predictive control of chromatographic processes. It is also an essential ingredient in uncertainty quantification for efficient and robust design and operation of chromatographic processes. (C) 2019, IFAC (International Federation of Automatic Control) Hosting by Elsevier Ltd. All rights reserved.

BACKGROUND: Inflammation is a key feature of aging. We aimed to i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality, ii) develop a signature of 'inflammaging'. METHOD(S): Thirty-four blood markers relating to inflammation, B vitamin status and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age=59 years) and follow-up (median age=70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with two marker scores calculated across all markers associated with age and mortality, respectively. RESULT(S): The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, IL-6, TNF-alpha, several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5'-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, CRP, quinolinic acid, PAr index, and KTR. The inflammaging signature included ten markers and was strongly associated of mortality (HR per SD=1.40, 95%CI:1.24-1.57, P=2x10 -8), similar to scores based on all age-associated (HR=1.38, 95%CI:1.23-1.55, P=4x10 -8) and mortality-associated markers (HR=1.43, 95%CI:1.28-1.60, P=1x10 -10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study. CONCLUSION(S): Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on ten markers was strongly associated with

BACKGROUND: Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation. OBJECTIVE(S): We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality. METHOD(S): Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y). RESULT(S): The MDS, E-DII, and AHEI were associated (P < 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-gamma, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman rho: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns. CONCLUSION(S): Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E

Background: Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation. Objective(s): We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality. Method(s): Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y). Result(s): The MDS, E-DII, and AHEI were associated (P < 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-gamma, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman rho: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns. Conclusion(s): Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E

Malignant melanoma is one of the most dangerous tumor types due to its high metastasis rates and a steadily increasing incidence. During tumorigenesis, the molecular processes of embryonic development, exemplified by epithelial–mesenchymal transition (EMT), are often reactivated. For melanoma development, the exact molecular differences between melanoblasts, melanocytes, and melanoma cells are not completely understood. In this study, we aimed to identify microRNAs (miRNAs) that promote melanoma tumorigenesis and progression, based on an in vitro model of normal human epidermal melanocyte (NHEM) de-differentiation into melanoblast-like cells (MBrCs). Using miRNA-sequencing and differential expression analysis, we demonstrated in this study that a majority of miRNAs have an almost equal expression level in NHEMs and MBrCs but are significantly differentially regulated in primary tumor- and metastasis-derived melanoma cell lines. Further, a target gene analysis of strongly regulated but functionally unknown miRNAs yielded the implication of those miRNAs in many important cellular pathways driving malignancy. We hypothesize that many of the miRNAs discovered in our study are key drivers of melanoma development as they account for the tumorigenic potential that differentiates melanoma cells from proliferating or migrating embryonic cells.

BACKGROUND: Inflammation is a key feature of aging. We aimed to i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality, ii) develop a signature of 'inflammaging'. METHOD(S): Thirty-four blood markers relating to inflammation, B vitamin status and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age=59 years) and follow-up (median age=70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with two marker scores calculated across all markers associated with age and mortality, respectively. RESULT(S): The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, IL-6, TNF-alpha, several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5'-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, CRP, quinolinic acid, PAr index, and KTR. The inflammaging signature included ten markers and was strongly associated of mortality (HR per SD=1.40, 95%CI:1.24-1.57, P=2x10 -8), similar to scores based on all age-associated (HR=1.38, 95%CI:1.23-1.55, P=4x10 -8) and mortality-associated markers (HR=1.43, 95%CI:1.28-1.60, P=1x10 -10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study. CONCLUSION(S): Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on ten markers was strongly associated with

BACKGROUND: Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation. OBJECTIVE(S): We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality. METHOD(S): Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y). RESULT(S): The MDS, E-DII, and AHEI were associated (P < 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-gamma, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman rho: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns. CONCLUSION(S): Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E

Background: Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation. Objective(s): We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality. Method(s): Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y). Result(s): The MDS, E-DII, and AHEI were associated (P < 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-gamma, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman rho: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns. Conclusion(s): Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E

Global environmental change is one of the most pressing issues facing future generations. Equipping schoolchildren with a clear understanding of physical geography is therefore a key educational priority. Effectively engaging schoolchildren with complex scientific ideas can be challenging, but with the appropriate tools, scientists can play a valuable role in developing meaningful science communication experiences. Climate Explorers addressed these issues by forging a collaboration between physical geography and social science academics, and 320 UK school students and their teachers in seven primary (elementary) schools. Using insights from co-production techniques and storytelling, the project aimed to 1) produce new open access, online climate science education resources, and 2) test co-production and storytelling approaches to physical geography science engagement. Our findings demonstrated that school children responded especially well to working with ‘real life’ scientists, where meaningful and memorable educational interactions were forged through the use of narratives, personal experiences and tailored language. Here we summarise our approach, and provide templates that can be readily applied by scientists working across the physical geography spectrum anywhere in the world. The flexibility of the templates means that they can be adapted and developed for a range of formats, from small-scale community workshops to national-scale educational initiatives, for delivery both in-person or online. We hope that our approach will provide a springboard to transform and enhance physical geography science communication more broadly.

QC 20211116

Malignant melanoma is one of the most dangerous tumor types due to its high metastasis rates and a steadily increasing incidence. During tumorigenesis, the molecular processes of embryonic development, exemplified by epithelial–mesenchymal transition (EMT), are often reactivated. For melanoma development, the exact molecular differences between melanoblasts, melanocytes, and melanoma cells are not completely understood. In this study, we aimed to identify microRNAs (miRNAs) that promote melanoma tumorigenesis and progression, based on an in vitro model of normal human epidermal melanocyte (NHEM) de-differentiation into melanoblast-like cells (MBrCs). Using miRNA-sequencing and differential expression analysis, we demonstrated in this study that a majority of miRNAs have an almost equal expression level in NHEMs and MBrCs but are significantly differentially regulated in primary tumor- and metastasis-derived melanoma cell lines. Further, a target gene analysis of strongly regulated but functionally unknown miRNAs yielded the implication of those miRNAs in many important cellular pathways driving malignancy. We hypothesize that many of the miRNAs discovered in our study are key drivers of melanoma development as they account for the tumorigenic potential that differentiates melanoma cells from proliferating or migrating embryonic cells.

Global environmental change is one of the most pressing issues facing future generations. Equipping schoolchildren with a clear understanding of physical geography is therefore a key educational priority. Effectively engaging schoolchildren with complex scientific ideas can be challenging, but with the appropriate tools, scientists can play a valuable role in developing meaningful science communication experiences. Climate Explorers addressed these issues by forging a collaboration between physical geography and social science academics, and 320 UK school students and their teachers in seven primary (elementary) schools. Using insights from co-production techniques and storytelling, the project aimed to 1) produce new open access, online climate science education resources, and 2) test co-production and storytelling approaches to physical geography science engagement. Our findings demonstrated that school children responded especially well to working with ‘real life’ scientists, where meaningful and memorable educational interactions were forged through the use of narratives, personal experiences and tailored language. Here we summarise our approach, and provide templates that can be readily applied by scientists working across the physical geography spectrum anywhere in the world. The flexibility of the templates means that they can be adapted and developed for a range of formats, from small-scale community workshops to national-scale educational initiatives, for delivery both in-person or online. We hope that our approach will provide a springboard to transform and enhance physical geography science communication more broadly.

Der Kommentar zur Schaffhauser Verwaltungsrechtspflege ist ein Gemeinschaftswerk von erfahrenen Juristinnen und Juristen aus Verwaltung, Justiz und Advokatur. Er stellt die aktuelle Praxis und Literatur zur Schaffhauser Verwaltungsrechtspflege übersichtlich und in gut verständlicher Sprache dar. Dieses Werk versteht sich in erster Linie als Arbeitsinstrument für Behörden und Anwaltschaft sowie als Orientierungshilfe für rechtsuchende Private. Es soll zu einer qualitativ hohen Rechtspflege und zu einem stärkeren Rechtsschutz der Bürgerinnen und Bürger beitragen. Die artikelweisen Kommentierungen behandeln das Verwaltungsrechtspflegegesetz wie auch diejenigen Bestimmungen des Justizgesetzes, die einen direkten Bezug zum Verwaltungsrecht aufweisen. Sie werden ergänzt durch zwei vertiefende Beiträge, die sich mit der Geschichte und den Perspektiven der Schaffhauser Verwaltungsrechtspflege auseinandersetzen. Angehängte Checklisten sowie ein Sachregister erhöhen den praktischen Nutzen des Kommentars.

We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org., QC 20200625

© The Authors 2020. Evidence linking fasting plasma total homocysteine (tHcy), methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype with hypertension is inconsistent. Differences in B vitamin status, other lifestyle factors, or their consideration in analyses, might explain this. We investigated these associations in the absence of mandatory fortification with folic acid and B vitamin supplement use. A cross-sectional was conducted in 788 adults, aged 18-75 years, randomly selected from 3 Catalonian town population registers. Fasting plasma folate, cobalamin, total homocysteine (tHcy), red blood cell folate, erythrocyte glutathione reductase activation coefficient (EGRAC, functional riboflavin status indicator; increasing EGRAC indicates worsening riboflavin status), MTHFR 677 C>T and solute carrier family 1 (SLC19A1) 80 G>A genotypes were determined. Medical history and lifestyle habits were recorded.Principal tHcy determinants differed between women (age, plasma folate, plasma cobalamin, cigarettes/day) and men (MTHFR 677TT genotype, plasma folate, plasma cobalamin and CT genotype). The MTHFR 677C>T polymorphism-tHcy association (β standardised regression coefficients) was stronger in male smokers (0.52, P < 0.001) compared to nonsmokers (0.21, P = 0.001) and weaker in participants >50 (0.19, P = 0.007) compared to ≤50 years (0.31, P < 0.001). Hypertension was more probable in the 3rd tHcy tertile compared to the other tertiles [OR 1.9 (1.2, 3.0)], and in participants ≤50 years, for the MTHFR 677TT genotype compared to the CC genotype [OR 4.1 (1.0, 16.9)]. EGRAC was associated with increased probability of hypertension in participants >50 years [OR 6.2 (1.0, 38.7)]. In conclusion, moderately elevated tHcy and the MTHFR 677CT genotype were associated with hypert

Deep rolling is a widely applied mechanical surface and subsurface treatment method. It is typically used after conventional machining to improve the roughness, increase the surface hardness and to induce compressive residual stresses. The main influence parameters on the surface topography are the applied deep rolling pressure, the ball diameter and the feed. In general, low feeds, larger ball diameters and higher pressures result in an even surface finish. However, an exact prediction of the roughness is not possible. Therefore, it is the aim of the presented research to find a generally applicable method for surface roughness prediction after deep rolling for a variety of steel and aluminum materials. It is shown that the surface topography can be predicted by an analytical model with high accuracy.

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.

Background This case control study aimed to investigate whether symptoms of sexual dysfunction are more common in males from infertile couples than in the general population and to explore whether symptoms of sexual dysfunction are associated to hypogonadism. Objectives Participants were 165 subfertile men in infertile heterosexual relationships, 18-50 years of age, with sperm concentrations < 15 x 10(6)/mL. The controls were 199 men from a population-based group, matched for age. Material and methods Logistic regression was applied in order to calculate odds ratios (ORs) for seven different symptoms of sexual dysfunction. In a multivariate model, we tested independent effects of infertility and primary as well as secondary hypogonadism. Results Statistically significant association between subfertility and symptoms of sexual dysfunction was found for lack of ability to control ejaculation (OR 2.2, 95% CI: 1.2-4.2). For hypogonadism, statistical significance was seen both in relation to low sexual interest/desire for sex (OR 2.3, 95% CI: 1.0-5.5) and for being worried about the size or shape of the penis (OR 3.6, 95% CI: 1.3-9.5). These associations remained statistically significant in males with primary but not those with secondary hypogonadism. Discussion Our study showed that men from infertile couples have an increased risk of symptoms of sexual dysfunction and this risk is linked to androgen deficiency. Conclusion Assessment of reproductive hormone levels and sexual function should routinely be done in this group of males.

The plasma diagnostic and control (D&C) system for a future tokamak demonstration fusion reactor (DEMO) will have to provide reliable operation near technical and physics limits, while its front-end components will be subject to strong adverse effects within the nuclear and high temperature plasma environment. The ongoing developments for the ITER D&C system represent an important starting point for progressing towards DEMO. Requirements for detailed exploration of physics are however pushing the ITER diagnostic design towards using sophisticated methods and aiming for large spatial coverage and high signal intensities, so that many front-end components have to be mounted in forward positions. In many cases this results in a rapid aging of diagnostic components, so that additional measures like protection shutters, plasma based mirror cleaning or modular approaches for frequent maintenance and exchange are being developed. Under the even stronger fluences of plasma particles, neutron/gamma and radiation loads on DEMO, durable and reliable signals for plasma control can only be obtained by selecting diagnostic methods with regard to their robustness, and retracting vulnerable front-end components into protected locations. Based on this approach, an initial DEMO D&C concept is presented, which covers all major control issues by signals to be derived from at least two different diagnostic methods (risk mitigation).

The plasma diagnostic and control (D&C) system for a future tokamak demonstration fusion reactor (DEMO) will have to provide reliable operation near technical and physics limits, while its front-end components will be subject to strong adverse effects within the nuclear and high temperature plasma environment. The ongoing developments for the ITER D&C system represent an important starting point for progressing towards DEMO. Requirements for detailed exploration of physics are however pushing the ITER diagnostic design towards using sophisticated methods and aiming for large spatial coverage and high signal intensities, so that many front-end components have to be mounted in forward positions. In many cases this results in a rapid aging of diagnostic components, so that additional measures like protection shutters, plasma based mirror cleaning or modular approaches for frequent maintenance and exchange are being developed. Under the even stronger fluences of plasma particles, neutron/gamma and radiation loads on DEMO, durable and reliable signals for plasma control can only be obtained by selecting diagnostic methods with regard to their robustness, and retracting vulnerable front-end components into protected locations. Based on this approach, an initial DEMO D&C concept is presented, which covers all major control issues by signals to be derived from at least two different diagnostic methods (risk mitigation).

The plasma diagnostic and control (D&C) system for a future tokamak demonstration fusion reactor (DEMO) will have to provide reliable operation near technical and physics limits, while its front-end components will be subject to strong adverse effects within the nuclear and high temperature plasma environment. The ongoing developments for the ITER D&C system represent an important starting point for progressing towards DEMO. Requirements for detailed exploration of physics are however pushing the ITER diagnostic design towards using sophisticated methods and aiming for large spatial coverage and high signal intensities, so that many front-end components have to be mounted in forward positions. In many cases this results in a rapid aging of diagnostic components, so that additional measures like protection shutters, plasma based mirror cleaning or modular approaches for frequent maintenance and exchange are being developed. Under the even stronger fluences of plasma particles, neutron/gamma and radiation loads on DEMO, durable and reliable signals for plasma control can only be obtained by selecting diagnostic methods with regard to their robustness, and retracting vulnerable front-end components into protected locations. Based on this approach, an initial DEMO D&C concept is presented, which covers all major control issues by signals to be derived from at least two different diagnostic methods (risk mitigation).

The plasma diagnostic and control (D&C) system for a future tokamak demonstration fusion reactor (DEMO) will have to provide reliable operation near technical and physics limits, while its front-end components will be subject to strong adverse effects within the nuclear and high temperature plasma environment. The ongoing developments for the ITER D&C system represent an important starting point for progressing towards DEMO. Requirements for detailed exploration of physics are however pushing the ITER diagnostic design towards using sophisticated methods and aiming for large spatial coverage and high signal intensities, so that many front-end components have to be mounted in forward positions. In many cases this results in a rapid aging of diagnostic components, so that additional measures like protection shutters, plasma based mirror cleaning or modular approaches for frequent maintenance and exchange are being developed. Under the even stronger fluences of plasma particles, neutron/gamma and radiation loads on DEMO, durable and reliable signals for plasma control can only be obtained by selecting diagnostic methods with regard to their robustness, and retracting vulnerable front-end components into protected locations. Based on this approach, an initial DEMO D&C concept is presented, which covers all major control issues by signals to be derived from at least two different diagnostic methods (risk mitigation).

Depression experienced by older adults is proving an increasing global health burden, with rates generally 7% and as high as 27% in the USA. This is likely to significantly increase in coming years as the number and proportion of older adults in the population rises all around the world. Therefore, it is imperative that the effectiveness of approaches to the prevention and treatment of depression are understood. Creative arts interventions, including art, dance movement, drama, and music modalities, are utilized internationally to target depression and depressive symptoms in older adults. This includes interventions led by trained arts therapists as well as other health and arts professionals. However, to date there has not been a systematic review that reports effects and examines the processes (why) and mechanisms (how) of creative arts interventions are used to address depression in this older age group. This systematic review of studies on creative arts interventions for older adults experiencing depression examined: outcomes of four creative arts modalities (art, dance movement, drama, and music); with particular attention paid to processes documented as contributing to change in each modality; and mechanisms considered to result from these processes. Our analysis of 75 articles (17 art, 13 dance, 4 drama, and 41 music) indicates mostly significant quantitative or positive qualitative findings, particularly for interventions led by creative arts therapists. Mechanisms of change gleaned from the studies that were common across modalities include physical (e.g., increased muscle strength; neurochemical effects, such as endorphin release), intra-personal (e.g., enhanced self-concept, strengthened agency and mastery; processing and communication of emotions), cultural (e.g., creative expression, aesthetic pleasure), cognitive (e.g., stimulation of memory), and social (e.g., increased social skills and connection), that were all considered to contribute to reduced d

The plasma diagnostic and control (D&C) system for a future tokamak demonstration fusion reactor (DEMO) will have to provide reliable operation near technical and physics limits, while its front-end components will be subject to strong adverse effects within the nuclear and high temperature plasma environment. The ongoing developments for the ITER D&C system represent an important starting point for progressing towards DEMO. Requirements for detailed exploration of physics are however pushing the ITER diagnostic design towards using sophisticated methods and aiming for large spatial coverage and high signal intensities, so that many front-end components have to be mounted in forward positions. In many cases this results in a rapid aging of diagnostic components, so that additional measures like protection shutters, plasma based mirror cleaning or modular approaches for frequent maintenance and exchange are being developed. Under the even stronger fluences of plasma particles, neutron/gamma and radiation loads on DEMO, durable and reliable signals for plasma control can only be obtained by selecting diagnostic methods with regard to their robustness, and retracting vulnerable front-end components into protected locations. Based on this approach, an initial DEMO D&C concept is presented, which covers all major control issues by signals to be derived from at least two different diagnostic methods (risk mitigation).

The plasma diagnostic and control (D&C) system for a future tokamak demonstration fusion reactor (DEMO) will have to provide reliable operation near technical and physics limits, while its front-end components will be subject to strong adverse effects within the nuclear and high temperature plasma environment. The ongoing developments for the ITER D&C system represent an important starting point for progressing towards DEMO. Requirements for detailed exploration of physics are however pushing the ITER diagnostic design towards using sophisticated methods and aiming for large spatial coverage and high signal intensities, so that many front-end components have to be mounted in forward positions. In many cases this results in a rapid aging of diagnostic components, so that additional measures like protection shutters, plasma based mirror cleaning or modular approaches for frequent maintenance and exchange are being developed. Under the even stronger fluences of plasma particles, neutron/gamma and radiation loads on DEMO, durable and reliable signals for plasma control can only be obtained by selecting diagnostic methods with regard to their robustness, and retracting vulnerable front-end components into protected locations. Based on this approach, an initial DEMO D&C concept is presented, which covers all major control issues by signals to be derived from at least two different diagnostic methods (risk mitigation).

Background: Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study. Methods: Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24. Findings: Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation

To secure the sustainable use of nature, governments track nature's health and develop regulations and policies. Although there is a seeming abundance in observation-recordings, decision- and policy-makers are constrained by the lack of data and indicators, mostly as a result of barriers preventing existing data from being found, accessed, made suitable for (automated) processing and reused, but also due to missing visualisations targeted at answering questions asked by policy makers. This paper explores the process and principles for developing a biodiversity web-platform that informs policy and management on the state and trends of nature, based on experiences with the Dutch Caribbean Biodiversity Database (DCBD). The DCBD supports the assessment of the state of nature and guarantees long-term data availability in an environment that experiences a high turnover in project funds and personnel. Three principles made DCBD's uptake and growth possible: The platform is funded, promoted and used by national and regional policy makers, it simplifies tasks of local management and rapporteurs, and it is continuously being adapted to changing needs and insights. Stronger dissemination of DCBD's narratives in social arenas (e.g. newspapers, social media) may make Caribbean nature and biodiversity more politically and societally relevant.

It is desirable to use computational fluid dynamics for optimization of the in-cylinder processes in low-speed two-stroke uniflow-scavenged marine diesel engines. However, the complex nature of the turbulent swirling in-cylinder flow necessitates experimental data for validation of the used turbulence models. In the present work, the flow in a dynamic scale model of a uniflow-scavenged cylinder is investigated experimentally. The model has a transparent cylinder and a moving piston driven by a linear motor. The flow is investigated using phase-locked stereoscopic particle image velocimetry (PIV) and time-resolved laser Doppler anemometry (LDA). Radial profiles of the phase-locked mean and rms velocities are computed from the velocity fields recorded with PIV, and the accuracy of the obtained profiles is demonstrated by comparison with reference LDA measurements. Measurements are carried out at five axial positions for 15 different times during the engine cycle and show the temporal and spatial development of the swirling in-cylinder flow. The tangential velocity profiles in the bottom of the cylinder near the end of the scavenge process are characterized by a concentrated swirl resulting in wake-like axial velocity profiles and the occurrence of a vortex breakdown. After scavenge port closing, the axial velocity profiles indicate that large transient swirl-induced structures exist in the cylinder. Comparison with profiles obtained under steady-flow conditions shows that the scavenge flow cannot be assumed to be quasi-steady. The temporal development of the swirl strength is investigated by computing the angular momentum. The swirl strength shows an exponential decay from scavenge port closing to scavenge port opening corresponding to a reduction of 34%, which is in good agreement with theoretical predictions.

Background: In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Results: Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition shows that we can reduce the potential artifacts introduced by technical differences in generating microbiota data. We are now in the process of benchmarking the association tests and performing meta-analyses of genome-wide associations. All pipeline and summary statistics results will be shared using public data repositories. Conclusion: We present the largest consortium to date devoted to microbiota-GWAS. We have adapted our analytical pipelines to suit multi-cohort analyses and expect to gain insight into host-microbiota cross-talk at the genome-wide level. And, as an open consortium, we invite more cohorts to join us (by contacting one of the corresponding authors) and to follow the analytical pipeline we have developed.

Bei der Fusariumtrockenfäule der Kartoffel handelt es sich um eine verbreitete Lagerkrankheit. Zur Abschätzung eines möglichen Gesundheitsrisikos für den Verbraucher wurden verschiedene Kartoffelsorten und -produkte auf 18 relevante Typ A und B Trichothecene sowie Zearalenon untersucht. Dabei wurden in 30,6 % der Proben Toxine mit maximalen Konzentrationen bis zu 254 µg/kg nachgewiesen. In einzelnen Kartoffelknollen wurde zudem eine Diffusion von Fusarientoxinen aus der Faulstelle in angrenzendes Knollengewebe beobachtet. Auf Grundlage der erhobenen Daten ist nicht von einer besonderen Gesundheitsgefährdung des Verbrauchers durch Kartoffeln und Kartoffelprodukte auszugehen. Durch den Metabolismus der Kartoffelzellkulturen wurden die Typ A Trichothecene T-2 Toxin und Diacetoxyscirpenol in fünf glucosidierte Toxinmetaboliten umgewandelt. Einige dieser Konjugate sowie Deoxynivalenol-Glucosid konnten in Kartoffeln und -produkten nachgewiesen werden., Fusarium dry rot of potato is a common storage disease. To estimate a possible health risk of the consumers different potato varieties and potato based products were examined for 18 relevant type A and B trichothecenes and zearalenone. In 30.6 % of all samples those toxins could be detected with maximum concentrations up to 254 µg/kg. Additionally, toxin diffusion from the rotted part of the tuber into adjacent tissue was observed in several potatoes. On the basis of this data no hazards for human health as a consequence of Fusarium toxins should be expected after consuming potatoes and potato products. The metabolism of potato cell cultures transformed the type A trichothecenes T-2 toxin and diacetoxyscirpenol into five glucosylated toxin metabolites. Some of those conjugates as well as deoxynivalenol-glucoside could also be detected in potatoes and potato based products.

Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4thvs.1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.

Deep rolling is often used as a finishing step after cutting because of its beneficial influence on surface and subsurface properties, which lead to an increase in performance and lifecycle behavior. This manufacturing process is suitable to reduce roughness and to induce compressive residual stresses. As thermal effects only play a minor role in the deep rolling process, it is possible to link the resulting residual stresses to the analytically determined internal process loads. The boundaries of these relationships are investigated on hardened AISI 4140 using different mechanical loads and overlap factors.

Aims/hypothesis: A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes. Methods: A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes. Results: Analysis in FINRISK 2002 showed that the Cer(d18:1/18:0)/Cer(d18:1/16:0) ceramide ratio was predictive of incident diabetes (HR per SD 2.23, 95% CI 2.05, 2.42), and remained significant after adjustment for several risk factors, including BMI, fasting glucose and HbA1c (HR 1.34, 95% CI 1.14, 1.57). The finding was validated in the WECAC study (unadjusted HR 1.81, 95% CI 1.53, 2.14; adjusted HR 1.39, 95% CI 1.16, 1.66). In the intervention trial, the ceramide ratio and diabetes risk scores significantly decreased in individuals

Bei der Fusariumtrockenfäule der Kartoffel handelt es sich um eine verbreitete Lagerkrankheit. Zur Abschätzung eines möglichen Gesundheitsrisikos für den Verbraucher wurden verschiedene Kartoffelsorten und -produkte auf 18 relevante Typ A und B Trichothecene sowie Zearalenon untersucht. Dabei wurden in 30,6 % der Proben Toxine mit maximalen Konzentrationen bis zu 254 µg/kg nachgewiesen. In einzelnen Kartoffelknollen wurde zudem eine Diffusion von Fusarientoxinen aus der Faulstelle in angrenzendes Knollengewebe beobachtet. Auf Grundlage der erhobenen Daten ist nicht von einer besonderen Gesundheitsgefährdung des Verbrauchers durch Kartoffeln und Kartoffelprodukte auszugehen. Durch den Metabolismus der Kartoffelzellkulturen wurden die Typ A Trichothecene T-2 Toxin und Diacetoxyscirpenol in fünf glucosidierte Toxinmetaboliten umgewandelt. Einige dieser Konjugate sowie Deoxynivalenol-Glucosid konnten in Kartoffeln und -produkten nachgewiesen werden., Fusarium dry rot of potato is a common storage disease. To estimate a possible health risk of the consumers different potato varieties and potato based products were examined for 18 relevant type A and B trichothecenes and zearalenone. In 30.6 % of all samples those toxins could be detected with maximum concentrations up to 254 µg/kg. Additionally, toxin diffusion from the rotted part of the tuber into adjacent tissue was observed in several potatoes. On the basis of this data no hazards for human health as a consequence of Fusarium toxins should be expected after consuming potatoes and potato products. The metabolism of potato cell cultures transformed the type A trichothecenes T-2 toxin and diacetoxyscirpenol into five glucosylated toxin metabolites. Some of those conjugates as well as deoxynivalenol-glucoside could also be detected in potatoes and potato based products.

IMPORTANCE Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. OBJECTIVE To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC 50% and 90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [DLCO] 25% and 90% predicted; and distance of 150 m on the 6-minute walk test). Study period was August 2015-May 2017. INTERVENTIONS Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. MAIN OUTCOMES AND MEASURES The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). RESULTS Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quan