| 1. |
- Munk, P., et al.
(författare)
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Genomic analysis of sewage from 101 countries reveals global landscape of antimicrobial resistance
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Antimicrobial resistance (AMR) is a major threat to global health. Understanding the emergence, evolution, and transmission of individual antibiotic resistance genes (ARGs) is essential to develop sustainable strategies combatting this threat. Here, we use metagenomic sequencing to analyse ARGs in 757 sewage samples from 243 cities in 101 countries, collected from 2016 to 2019. We find regional patterns in resistomes, and these differ between subsets corresponding to drug classes and are partly driven by taxonomic variation. The genetic environments of 49 common ARGs are highly diverse, with most common ARGs carried by multiple distinct genomic contexts globally and sometimes on plasmids. Analysis of flanking sequence revealed ARG-specific patterns of dispersal limitation and global transmission. Our data furthermore suggest certain geographies are more prone to transmission events and should receive additional attention.
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| 2. |
- Bar, N., et al.
(författare)
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A reference map of potential determinants for the human serum metabolome
- 2020
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Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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| 3. |
- Steinthorsdottir, V, et al.
(författare)
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Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 5976-
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Tidskriftsartikel (refereegranskat)abstract
- Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
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| 4. |
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| 5. |
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| 6. |
- Dareng, EO, et al.
(författare)
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Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- 2022
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 30:3, s. 349-362
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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| 7. |
- Hait, A. S., et al.
(författare)
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Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans
- 2020
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Ingår i: Science Immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 5:54
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Tidskriftsartikel (refereegranskat)abstract
- Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.
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| 8. |
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| 9. |
- Austin, CC, et al.
(författare)
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Fostering global data sharing: highlighting the recommendations of the Research Data Alliance COVID-19 working group
- 2020
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Ingår i: Wellcome open research. - : F1000 Research Ltd. - 2398-502X. ; 5, s. 267-
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Tidskriftsartikel (refereegranskat)abstract
- The systemic challenges of the COVID-19 pandemic require cross-disciplinary collaboration in a global and timely fashion. Such collaboration needs open research practices and the sharing of research outputs, such as data and code, thereby facilitating research and research reproducibility and timely collaboration beyond borders. The Research Data Alliance COVID-19 Working Group recently published a set of recommendations and guidelines on data sharing and related best practices for COVID-19 research. These guidelines include recommendations for clinicians, researchers, policy- and decision-makers, funders, publishers, public health experts, disaster preparedness and response experts, infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations), and other potential users. These guidelines include recommendations for researchers, policymakers, funders, publishers and infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations). Several overarching themes have emerged from this document such as the need to balance the creation of data adherent to FAIR principles (findable, accessible, interoperable and reusable), with the need for quick data release; the use of trustworthy research data repositories; the use of well-annotated data with meaningful metadata; and practices of documenting methods and software. The resulting document marks an unprecedented cross-disciplinary, cross-sectoral, and cross-jurisdictional effort authored by over 160 experts from around the globe. This letter summarises key points of the Recommendations and Guidelines, highlights the relevant findings, shines a spotlight on the process, and suggests how these developments can be leveraged by the wider scientific community.
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| 10. |
- Brogaard, K., et al.
(författare)
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Age and helium content of the open cluster NGC 6791 from multiple eclipsing binary members : III. Constraints from a subgiant
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 649
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Tidskriftsartikel (refereegranskat)abstract
- Context. Models of stellar structure and evolution can be constrained using accurate measurements of the parameters of eclipsing binary members of open clusters. Multiple binary stars provide the means to tighten the constraints and, in turn, to improve the precision and accuracy of the age estimate of the host cluster. In the previous two papers of this series, we have demonstrated the use of measurements of multiple eclipsing binaries in the old open cluster NGC 6791 to set tighter constraints on the properties of stellar models than was previously possible, thereby improving both the accuracy and precision of the cluster age. Aims. We identify and measure the properties of a non-eclipsing cluster member, V56, in NGC 6791 and demonstrate how this provides additional model constraints that support and strengthen our previous findings. Methods. We analyse multi-epoch spectra of V56 from FLAMES in conjunction with the existing photometry and measurements of eclipsing binaries in NGC6971. Results. The parameters of the V56 components are found to be Mp = 1.103 ± 0.008 Mpdbl and Ms = 0.974 ± 0.007 Mpdbl, Rp = 1.764 ± 0.099 Rpdbl and Rs = 1.045 ± 0.057 Rpdbl, Teff,p = 5447 ± 125 K and Teff,s = 5552 ± 125 K, and surface [Fe/H] = +0.29 ± 0.06 assuming that they have the same abundance. Conclusions. The derived properties strengthen our previous best estimate of the cluster age of 8.3 ± 0.3 Gyr and the mass of stars on the lower red giant branch (RGB), which is MRGB = 1.15 ± 0.02 Mpdbl for NGC 6791. These numbers therefore continue to serve as verification points for other methods of age and mass measures, such as asteroseismology.
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| 11. |
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| 12. |
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| 13. |
- Kamio, S., et al.
(författare)
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First experiments on plasma production using field-aligned ICRF fast wave antennas in the large helical device
- 2021
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Ingår i: Nuclear Fusion. - : Institute of Physics (IOP). - 0029-5515 .- 1741-4326. ; 61:11
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Tidskriftsartikel (refereegranskat)abstract
- The results of the first experimental series to produce a plasma using the ion cyclotron range of frequency (ICRF) in the large helical device (LHD) within the minority scenario developed at Uragan-2M (U-2M) are presented. The motivation of this study is to provide plasma creation in conditions when an electron cyclotron resonance heating start-up is not possible, and in this way widen the operational frame of helical machines. The major constraint of the experiments is the low RF power to reduce the possibility of arcing. No dangerous voltage increase at the radio-frequency (RF) system elements and no arcing has been detected. As a result, a low plasma density is obtained and the antenna-plasma coupling is not optimal. However, such plasmas are sufficient to be used as targets for further neutral beam injection (NBI) heating. This will open possibilities to explore new regimes of operation at LHD and Wendelstein 7-X (W7-X) stellarator. The successful RF plasma production in LHD in this experimental series stimulates the planning of further studies of ICRF plasma production aimed at increasing plasma density and temperature within the ICRF minority scenario as well as investigating the plasma prolongation by NBI heating.
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| 14. |
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| 15. |
- Vogel, N, et al.
(författare)
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Exposure to Phthalates in European Children, Adolescents and Adults since 2005: A Harmonized Approach Based on Existing HBM Data in the HBM4EU Initiative
- 2023
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Ingår i: Toxics. - : MDPI AG. - 2305-6304. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Phthalates are mainly used as plasticizers and are associated inter alia with adverse effects on reproductive functions. While more and more national programs in Europe have started monitoring internal exposure to phthalates and its substitute 1,2-Cyclohexanedicarboxylic acid (DINCH), the comparability of results from such existing human biomonitoring (HBM) studies across Europe is challenging. They differ widely in time periods, study samples, degree of geographical coverage, design, analytical methodology, biomarker selection, and analytical quality assurance level. The HBM4EU initiative has gathered existing HBM data of 29 studies from participating countries, covering all European regions and Israel. The data were prepared and aggregated by a harmonized procedure with the aim to describe—as comparably as possible—the EU-wide general population’s internal exposure to phthalates from the years 2005 to 2019. Most data were available from Northern (up to 6 studies and up to 13 time points), Western (11; 19), and Eastern Europe (9; 12), e.g., allowing for the investigation of time patterns. While the bandwidth of exposure was generally similar, we still observed regional differences for Butyl benzyl phthalate (BBzP), Di(2-ethylhexyl) phthalate (DEHP), Di-isononyl phthalate (DiNP), and Di-isobutyl phthalate (DiBP) with pronounced decreases over time in Northern and Western Europe, and to a lesser degree in Eastern Europe. Differences between age groups were visible for Di-n-butyl phthalate (DnBP), where children (3 to 5-year olds and 6 to 11-year olds) had lower urinary concentrations than adolescents (12 to 19-year-olds), who in turn had lower urinary concentrations than adults (20 to 39-year-olds). This study is a step towards making internal exposures to phthalates comparable across countries, although standardized data were not available, targeting European data sets harmonized with respect to data formatting and calculation of aggregated data (such as developed within HBM4EU), and highlights further suggestions for improved harmonization in future studies.
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| 16. |
- Vogel, N, et al.
(författare)
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Exposure to Phthalates in European Children, Adolescents and Adults since 2005: A Harmonized Approach Based on Existing HBM Data in the HBM4EU Initiative
- 2023
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Ingår i: Toxics. - : MDPI AG. - 2305-6304. ; 11:3
-
Tidskriftsartikel (refereegranskat)abstract
- Phthalates are mainly used as plasticizers and are associated inter alia with adverse effects on reproductive functions. While more and more national programs in Europe have started monitoring internal exposure to phthalates and its substitute 1,2-Cyclohexanedicarboxylic acid (DINCH), the comparability of results from such existing human biomonitoring (HBM) studies across Europe is challenging. They differ widely in time periods, study samples, degree of geographical coverage, design, analytical methodology, biomarker selection, and analytical quality assurance level. The HBM4EU initiative has gathered existing HBM data of 29 studies from participating countries, covering all European regions and Israel. The data were prepared and aggregated by a harmonized procedure with the aim to describe—as comparably as possible—the EU-wide general population’s internal exposure to phthalates from the years 2005 to 2019. Most data were available from Northern (up to 6 studies and up to 13 time points), Western (11; 19), and Eastern Europe (9; 12), e.g., allowing for the investigation of time patterns. While the bandwidth of exposure was generally similar, we still observed regional differences for Butyl benzyl phthalate (BBzP), Di(2-ethylhexyl) phthalate (DEHP), Di-isononyl phthalate (DiNP), and Di-isobutyl phthalate (DiBP) with pronounced decreases over time in Northern and Western Europe, and to a lesser degree in Eastern Europe. Differences between age groups were visible for Di-n-butyl phthalate (DnBP), where children (3 to 5-year olds and 6 to 11-year olds) had lower urinary concentrations than adolescents (12 to 19-year-olds), who in turn had lower urinary concentrations than adults (20 to 39-year-olds). This study is a step towards making internal exposures to phthalates comparable across countries, although standardized data were not available, targeting European data sets harmonized with respect to data formatting and calculation of aggregated data (such as developed within HBM4EU), and highlights further suggestions for improved harmonization in future studies.
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| 17. |
- Duholm, C. S., et al.
(författare)
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Specific Contamination Symptoms are Associated with Experiencing a Limited Response of Cognitive-Behavioral Therapy in Pediatric Patients with OCD
- 2022
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Ingår i: Child Psychiatry & Human Development. - : Springer Science and Business Media LLC. - 0009-398X .- 1573-3327.
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Tidskriftsartikel (refereegranskat)abstract
- A recent study identified three distinct treatment-response trajectories in pediatric OCD where higher levels of contamination symptoms predicted a limited response to cognitive-behavioral therapy (CBT). This study extends these findings by examining which specific symptoms characterize limited CBT response from baseline to 3-year follow-up, with an emphasis on contamination symptoms. The study sample comprised 269 pediatric patients with OCD, all receiving stepped-care treatment with manualized CBT. Differences in single item-reporting between the three trajectory groups were examined using linear mixed-effect modeling. Limited responders displayed a higher symptom load across all OCD symptom categories at 3-year follow-up, dominated by contamination symptoms. Five of these (obsessions about dirt and germs, about bodily fluids, about the feeling of contamination and compulsions regarding handwashing and showering) showed persistence from baseline to 3-year follow-up. The results indicate that presence of specific contamination symptoms may influence long-term symptom severity trajectories in young patients with OCD.
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| 18. |
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| 19. |
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| 20. |
- Jensen, S., et al.
(författare)
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Distinct trajectories of long-term symptom severity in pediatric obsessive-compulsive disorder during and after stepped-care treatment
- 2020
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Ingår i: Journal of Child Psychology and Psychiatry. - : Wiley. - 0021-9630 .- 1469-7610. ; 61:9, s. 969-978
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Tidskriftsartikel (refereegranskat)abstract
- Background First-line treatments for pediatric obsessive-compulsive disorder (OCD) include exposure-based cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs). No studies have thus far identified distinct classes and associated predictors of long-term symptom severity during and after treatment. Yet, these could form the basis for more personalized treatment in pediatric OCD. Method The study included 269 OCD patients aged 7-17 years from the Nordic Long-term OCD Treatment Study (NordLOTS). All participants received stepped-care treatment starting with 14 weekly sessions of manualized CBT. Nonresponders were randomized to either prolonged CBT or SSRIs. Symptom severity was assessed using the Children's Yale-Brown Obsessive-Compulsive Scale at seven time points from pre- to post-treatment and over a three-year follow-up. Latent class growth analysis (LCGA) was performed to identify latent classes of symptom severity trajectories. Univariate and multivariate analyses were used to detect differences between classes and identify predictors of trajectory class membership including several clinical and demographic variables. Trial registry: Nordic Long-term Obsessive-Compulsive Disorder (OCD) Treatment Study; ; ISRCTN66385119. Results Three LCGA classes were identified: (a) acute, sustained responders (54.6%); (b) slow, continued responders (23.4%); and (c) limited long-term responders (21.9%). Class membership was predicted by distinct baseline characteristics pertaining to age, gender, symptom presentation, insight, avoidance, and comorbidity. Conclusions The LCGA suggests three distinct trajectory classes of long-term symptom severity during and after treatment in pediatric OCD with different clinical profiles at pretreatment. The results point to required clinical attention for adolescent patients with contamination/cleaning symptoms and reduced insight who do not show convincing responses to first-line treatment even though they may have reached the established cutoff for treatment response.
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| 21. |
- Jensen, S., et al.
(författare)
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Quality of life in pediatric patients with obsessive-compulsive disorder during and 3 years after stepped-care treatment
- 2022
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Ingår i: European Child & Adolescent Psychiatry. - : Springer Science and Business Media LLC. - 1018-8827 .- 1435-165X. ; 31:9, s. 1377-1389
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Tidskriftsartikel (refereegranskat)abstract
- The present study aimed to investigate the long-term quality of life (QoL) in a large sample of pediatric obsessive-compulsive disorder (OCD) patients. The study included 220 pediatric OCD patients from the Nordic Long-term OCD Treatment Study (NordLOTS) who were evaluated at seven time points before, during, and after stepped-care treatment over a 3-year follow-up period. Data from three symptom severity trajectory classes formed the basis of the QoL evaluation: acute (n = 127, N = 147), slow (n = 46, N = 63), and limited responders (n = 47, N = 59). Patients' QoL was assessed using parent and child ratings of the revised Questionnaire for Measuring Health-related Quality of Life in Children and Adolescents (KINDL-R). QoL was analyzed by trajectory class using a random mixed effects model. The association between pre-treatment factors and long-term QoL was investigated across classes in a multivariate model. Three years after treatment, the acute responder class had reached QoL levels from a general population, whereas the limited responder class had not. The slow responder class reached norm levels for the child-rated QoL only. Higher levels of co-occurring externalizing symptoms before treatment were associated with lower parent-rated QoL during follow-up, while adolescence and higher levels of co-occurring internalizing symptoms were associated with lower child-rated QoL during follow-up. For some patients, residual OCD symptoms in the years after treatment, even at levels below assumed clinical significance, are associated with compromised QoL. Co-occurring symptoms could be part of the explanation. Assessing QoL after OCD treatment, beyond the clinician-rated symptom severity, could detect patients in need of further treatment and/or assessment. Trial registry: Nordic Long-term Obsessive-Compulsive Disorder (OCD) Treatment Study; ; ISRCTN66385119.
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| 22. |
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| 23. |
- Moiseyenko, Volodymyr, et al.
(författare)
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FUSION RESEARCH IN STELLARATOR DEPARTMENT OF IPP NSC KIPT
- 2022
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Ingår i: PROBLEMS OF ATOMIC SCIENCE AND TECHNOLOGY. - : Problems of Atomic Science and Technology. - 1562-6016. ; :6, s. 3-8, s. 3-8
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Tidskriftsartikel (refereegranskat)abstract
- This paper briefly describes intrinsic and collaborative scientific activities in the Stellarator Department of the Institute of Plasma Physics of the National Science Center "Kharkov Institute of Physics and Technology" in last two years. These activities include experiments on JET tokamak, stellarators Wendelstein 7-X and Uragan-2M, TOMAS toroidal device and theoretical studies related to modeling of radio-frequency fields in plasma and conceptual development of the stellarator-mirror fission-fusion hybrid.
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| 24. |
- Poteser, M, et al.
(författare)
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Time Trends of Acrylamide Exposure in Europe: Combined Analysis of Published Reports and Current HBM4EU Studies
- 2022
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Ingår i: Toxics. - : MDPI AG. - 2305-6304. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- More than 20 years ago, acrylamide was added to the list of potential carcinogens found in many common dietary products and tobacco smoke. Consequently, human biomonitoring studies investigating exposure to acrylamide in the form of adducts in blood and metabolites in urine have been performed to obtain data on the actual burden in different populations of the world and in Europe. Recognizing the related health risk, the European Commission responded with measures to curb the acrylamide content in food products. In 2017, a trans-European human biomonitoring project (HBM4EU) was started with the aim to investigate exposure to several chemicals, including acrylamide. Here we set out to provide a combined analysis of previous and current European acrylamide biomonitoring study results by harmonizing and integrating different data sources, including HBM4EU aligned studies, with the aim to resolve overall and current time trends of acrylamide exposure in Europe. Data from 10 European countries were included in the analysis, comprising more than 5500 individual samples (3214 children and teenagers, 2293 adults). We utilized linear models as well as a non-linear fit and breakpoint analysis to investigate trends in temporal acrylamide exposure as well as descriptive statistics and statistical tests to validate findings. Our results indicate an overall increase in acrylamide exposure between the years 2001 and 2017. Studies with samples collected after 2018 focusing on adults do not indicate increasing exposure but show declining values. Regional differences appear to affect absolute values, but not the overall time-trend of exposure. As benchmark levels for acrylamide content in food have been adopted in Europe in 2018, our results may imply the effects of these measures, but only indicated for adults, as corresponding data are still missing for children.
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| 25. |
- Poteser, M, et al.
(författare)
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Trends of Exposure to Acrylamide as Measured by Urinary Biomarkers Levels within the HBM4EU Biomonitoring Aligned Studies (2000-2021)
- 2022
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Ingår i: Toxics. - : MDPI AG. - 2305-6304. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Acrylamide, a substance potentially carcinogenic in humans, represents a very prevalent contaminant in food and is also contained in tobacco smoke. Occupational exposure to higher concentrations of acrylamide was shown to induce neurotoxicity in humans. To minimize related risks for public health, it is vital to obtain data on the actual level of exposure in differently affected segments of the population. To achieve this aim, acrylamide has been added to the list of substances of concern to be investigated in the HBM4EU project, a European initiative to obtain biomonitoring data for a number of pollutants highly relevant for public health. This report summarizes the results obtained for acrylamide, with a focus on time-trends and recent exposure levels, obtained by HBM4EU as well as by associated studies in a total of seven European countries. Mean biomarker levels were compared by sampling year and time-trends were analyzed using linear regression models and an adequate statistical test. An increasing trend of acrylamide biomarker concentrations was found in children for the years 2014–2017, while in adults an overall increase in exposure was found to be not significant for the time period of observation (2000–2021). For smokers, represented by two studies and sampling for, over a total three years, no clear tendency was observed. In conclusion, samples from European countries indicate that average acrylamide exposure still exceeds suggested benchmark levels and may be of specific concern in children. More research is required to confirm trends of declining values observed in most recent years.
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| 26. |
- Ren, Fanghui, et al.
(författare)
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ER stress induces caspase-2-tBID-GSDMEdependent cell death in neurons lytically infected with herpes simplex virus type 2
- 2023
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Ingår i: EMBO JOURNAL. - 0261-4189 .- 1460-2075. ; 42:19
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Tidskriftsartikel (refereegranskat)abstract
- Neurotropic viruses, including herpes simplex virus (HSV) types 1 and 2, have the capacity to infect neurons and can cause severe diseases. This is associated with neuronal cell death, which may contribute to morbidity or even mortality if the infection is not controlled. However, the mechanistic details of HSV-induced neuronal cell death remain enigmatic. Here, we report that lytic HSV-2 infection of human neuron-like SH-SY5Y cells and primary human and murine brain cells leads to cell death mediated by gasdermin E (GSDME). HSV-2-induced GSDME-mediated cell death occurs downstream of replication-induced endoplasmic reticulum stress driven by inositol-requiring kinase 1 alpha (IRE1 alpha), leading to activation of caspase-2, cleavage of the pro-apoptotic protein BH3interacting domain death agonist (BID), and mitochondriadependent activation of caspase-3. Finally, necrotic neurons released alarmins, which activated inflammatory responses in human iPSC-derived microglia. In conclusion, lytic HSV infection in neurons activates an ER stress-driven pathway to execute GSDMEmediated cell death and promote inflammation.
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| 27. |
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| 28. |
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| 29. |
- Allesøe, Rosa Lundbye, et al.
(författare)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 30. |
- Bizzotto, Roberto, et al.
(författare)
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Processes Underlying Glycemic Deterioration in Type 2 Diabetes : An IMI DIRECT Study
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44:2, s. 511-518
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
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| 31. |
- Bobbio, Emanuele, et al.
(författare)
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Clinical Diagnosis and Subtyping of Cardiac Amyloidosis by Mass Spectrometry.
- 2020
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Ingår i: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. - : Elsevier BV. - 1557-3117. ; 39:4S
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Tidskriftsartikel (refereegranskat)abstract
- Medical treatment for cardiac amyloidosis (CA) is evolving rapidly. Heart transplantation can be a valid option when followed by transplantation of bone marrow or liver, dependent on the type and origin of the amyloid protein. Thus, accurate typing of amyloidosis has implications for treatment, prognosis, and genetic counseling. Although non-invasive diagnostic techniques can type CA, endomyocardial biopsy (EMB) may be needed in the case of equivocal imaging findings or discordant data. We aimed to define the role of mass spectrometry (MS) for diagnosis and subtyping of CA.Nineteen previously diagnosed CA cases, who underwent EMB at Sahlgrenska University Hospital (SU), Gothenburg, between the beginning 1990s and 2016, were selected. MS analysis, modified from was conducted on duplicate samples from myocardial tissue for each case included.1 Clinical features and diagnoses were used as gold standard and compared to the MS findings.Clinical diagnosis and the MS analysis agreed in 14 cases (73.7 %); in 3/19 (15.8 %) diagnosis was unclear or discordant (Fig.1). MS analysis revealed that transthyretin (TTR) amyloidosis was the most abundant amyloid protein in the samples examined (9/19; 47.3 %), whereas the AA subtype only occurred in 1 case (5.2 %). The AL κ type amyloidosis occurred in 3 cases (15.8 %), and AL λ type in six cases (31.6 %). These results strongly correlated with the clinical features in all patients. Clinical diagnosis could not be retrieved from the medical records in 2 cases (10.4 %). Additional 20 patients with clinical CA are presently under study.MS analysis of a small amount of endomyocardial tissue can be used to subtype CA with a high diagnostic validity. The method differentiated between TTR, SAA and Ig light chain amyloidosis. AL κ and AL λ identities correlated to those found in serum and urine electrophoreses. MS can therefore be of use to subtype CA for cases in which clinical findings are inconclusive. 1) Brambilla F et al. Blood. 2012 Feb 23;119(8):1844-7.
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| 32. |
- Gudmundsdottir, Valborg, et al.
(författare)
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Whole blood co-expression modules associate with metabolic traits and type 2 diabetes : an IMI-DIRECT study
- 2020
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Ingår i: Genome Medicine. - : BioMed Central. - 1756-994X. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D.Methods: Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts.Results: We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling.Conclusions: Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.
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| 33. |
- Jensen, S., et al.
(författare)
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Long- term remission status in pediatric obsessive-compulsive disorder: Evaluating the predictive value of symptom severity after treatment
- 2022
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Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781. ; 317
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Tidskriftsartikel (refereegranskat)abstract
- It is unknown if long-term remission for pediatric obsessive-compulsive disorder (OCD) patients is associated with post-treatment OCD symptom severity. The aim of the present study was to evaluate if post-treatment symptom severity cut-offs can discriminate remitters from non-remitters in pediatric OCD patients during three years of follow-up. All participants (N = 269) from the Nordic Long-term OCD Treatment Study (Nor-dLOTS) undergoing stepped-care treatment were included. Patients were rated with the Clinical Global Impression - Severity Scale (CGI-S) one (n = 186), two (n = 167), and three years (n = 166) after first-line cognitive-behavioral therapy. Post-treatment symptom severity scores as well as percentage reductions during treatment evaluated with the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) were analyzed using receiver operating characteristics according to the CGI-S remission scores (< 2) at follow-up. Post-treatment CY-BOCS severity scores acceptably discriminated remitters from non-remitters at one-year follow-up, but poorly for the two-and three-year follow-up. Severity percentage reduction during treatment did not discriminate remis-sion status acceptably at any follow-up point. Post-treatment OCD symptom severity status seems to have little discriminative value for long-term remission status in pediatric patients. Further research is warranted to detect post-treatment factors of prognostic value.
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| 34. |
- Skarphedinsson, G., et al.
(författare)
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Family Accommodation in Pediatric Obsessive-Compulsive Disorder: Investigating Prevalence and Clinical Correlates in the NordLOTS Study
- 2023
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Ingår i: Child Psychiatry & Human Development. - 0009-398X.
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Tidskriftsartikel (refereegranskat)abstract
- Family accommodation (FA) involves the actions taken by family members, particularly parents, to accommodate a child & PRIME;s obsessive-compulsive disorder (OCD) symptoms, reducing distress or impairment. This behavior may maintain compulsive and avoidant behavior, preventing corrective learning or habituation. This study aims to investigate the prevalence and factors influencing FA in a large Scandinavian sample of children with OCD. We assessed 238 children using standardized diagnostic interviews, OCD symptom severity assessments and questionnaires evaluating functional impairment and internalizing and externalizing symptoms. FA was measured using the Family Accommodation Scale, a 12-item clinician-rated interview. Our results confirmed a high frequency of accommodation, with approximately 70% of primary caregivers reporting some accommodation daily and 98% at least once per week. FA was associated with increased OCD symptom severity, contamination/cleaning symptoms, internalizing and externalizing behavior, and functional impairment. Linear regression analysis showed that high levels of FA are specifically associated with lower age, higher OCD symptom severity, parent-reported impairment, internalizing, and externalizing symptoms. A path analysis revealed that FA partially mediated the relationship between OCD severity, externalizing symptoms, and child's age, highlighting the role of FA in the progression of OCD and related symptoms. The findings emphasize the importance of evaluating FA before initiating treatment and specifically addressing it during the therapeutic process.
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