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1.	Forslund, Sofia K., et al. (author) Combinatorial, additive and dose-dependent drug–microbiome associations 2021 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7889, s. 500-505 Journal article (peer-reviewed)abstract During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1–5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
2.	Ilchen, Markus, et al. (author) Toward unifying chemical function with molecular structure using strong fields, x-rays, and electrons 2016 In: 2016 Conference On Lasers And Electro-Optics (CLEO). - 9781943580118 Conference paper (peer-reviewed)abstract Strong field molecular control can be used as a correlation parameter, allowing one to combine free electron laser based x-ray spectroscopy together with ultrafast electron diffraction. We will discuss this also in the light of emerging non-linear x-ray techniques.
3.	Amare, Azmeraw, et al. (author) Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder. 2023 In: Research square. - : Research Square Platform LLC. Journal article (peer-reviewed)abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<��.
4.	Amare, Azmeraw T, et al. (author) Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. 2023 In: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261 Journal article (peer-reviewed)abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
5.	Andrikopoulos, Petros, et al. (author) Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide 2023 In: Nature Communications. - 2041-1723 .- 2041-1723. ; 14:1 Journal article (peer-reviewed)abstract The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.
6.	Humborg, Christoph, et al. (author) Environmental Impacts - Freshwater Biogeochemistry 2015 In: Second Assessment of Climate Change for the Baltic Sea Basin. - Cham : Springer. - 9783319160054 - 9783319160061 ; , s. 307-336 Book chapter (peer-reviewed)abstract Climate change effects on freshwater biogeochemistry and riverine loads of biogenic elements to the Baltic Sea are not straight forward and are difficult to distinguish from other human drivers such as atmospheric deposition, forest and wetland management, eutrophication and hydrological alterations. Eutrophication is by far the most well-known factor affecting the biogeochemistry of the receiving waters in the various sub-basins of the Baltic Sea. However, the present literature review reveals that climate change is a compounding factor for all major drivers of freshwater biogeochemistry discussed here, although evidence is still often based on short-term and/or small-scale studies.
7.	Humborg, Christoph, et al. (author) Environmental Impacts—Freshwater Biogeochemistry 2015 In: Second Assessment of Climate Change for the Baltic Sea Basin. - Cham : Springer. - 9783319160054 - 9783319160061 ; , s. 307-336 Book chapter (other academic/artistic)
8.	Schmising, Clemens von Korff, et al. (author) Element-Specific Magnetization Dynamics of Complex Magnetic Systems Probed by Ultrafast Magneto-Optical Spectroscopy 2020 In: Applied Sciences. - : MDPI AG. - 2076-3417. ; 10:21 Journal article (peer-reviewed)abstract The vision to manipulate and control magnetism with light is driven on the one hand by fundamental questions of direct and indirect photon-spin interactions, and on the other hand by the necessity to cope with ever growing data volumes, requiring radically new approaches on how to write, read and process information. Here, we present two complementary experimental geometries to access the element-specific magnetization dynamics of complex magnetic systems via ultrafast magneto-optical spectroscopy in the extreme ultraviolet spectral range. First, we employ linearly polarized radiation of a free electron laser facility to demonstrate decoupled dynamics of the two sublattices of an FeGd alloy, a prerequisite for all-optical magnetization switching. Second, we use circularly polarized radiation generated in a laboratory-based high harmonic generation setup to show optical inter-site spin transfer in a CoPt alloy, a mechanism which only very recently has been predicted to mediate ultrafast metamagnetic phase transitions.
9.	Bedding, Timothy R., et al. (author) A multi-site campaign to measure solar-like oscillations in Procyon. II. mode frequencies 2010 In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 713:2, s. 935-949 Journal article (peer-reviewed)abstract We have analyzed data from a multi-site campaign to observe oscillations in the F5 star Procyon. The data consist of high-precision velocities that we obtained over more than three weeks with 11 telescopes. A new method for adjusting the data weights allows us to suppress the sidelobes in the power spectrum. Stacking the power spectrum in a so-called echelle diagram reveals two clear ridges, which we identify with even and odd values of the angular degree (l = 0 and 2, and l = 1 and 3, respectively). We interpret a strong, narrow peak at 446 mu Hz that lies close to the l = 1 ridge as a mode with mixed character. We show that the frequencies of the ridge centroids and their separations are useful diagnostics for asteroseismology. In particular, variations in the large separation appear to indicate a glitch in the sound-speed profile at an acoustic depth of similar to 1000 s. We list frequencies for 55 modes extracted from the data spanning 20 radial orders, a range comparable to the best solar data, which will provide valuable constraints for theoretical models. A preliminary comparison with published models shows that the offset between observed and calculated frequencies for the radial modes is very different for Procyon than for the Sun and other cool stars. We find the mean lifetime of the modes in Procyon to be 1.29(-0.49)(+0.55) days, which is significantly shorter than the 2-4 days seen in the Sun.
10.	Calogiuri, Tullia, et al. (author) Design and Construction of an Experimental Setup to Enhance Mineral Weathering through the Activity of Soil Organisms 2023 In: Journal of Visualized Experiments. - : Journal of Visualized Experiments. - 1940-087X. ; :201 Journal article (peer-reviewed)abstract Enhanced weathering (EW) is an emerging carbon dioxide (CO2) removal technology that can contribute to climate change mitigation. This technology relies on accelerating the natural process of mineral weathering in soils by manipulating the abiotic variables that govern this process, in particular mineral grain size and exposure to acids dissolved in water. EW mainly aims at reducing atmospheric CO2 concentrations by enhancing inorganic carbon sequestration. Until now, knowledge of EW has been mainly gained through experiments that focused on the abiotic variables known for stimulating mineral weathering, thereby neglecting the potential influence of biotic components. While bacteria, fungi, and earthworms are known to increase mineral weathering rates, the use of soil organisms in the context of EW remains underexplored. This protocol describes the design and construction of an experimental setup developed to enhance mineral weathering rates through soil organisms while concurrently controlling abiotic conditions. The setup is designed to maximize weathering rates while maintaining soil organisms' activity. It consists of a large number of columns filled with rock powder and organic material, located in a climate chamber and with water applied via a downflow irrigation system. Columns are placed above a fridge containing jerrycans to collect the leachate. Representative results demonstrate that this setup is suitable to ensure the activity of soil organisms and quantify their effect on inorganic carbon sequestration. Challenges remain in minimizing leachate losses, ensuring homogeneous ventilation through the climate chamber, and avoiding flooding of the columns. With this setup, an innovative and promising approach is proposed to enhance mineral weathering rates through the activity of soil biota and disentangle the effect of biotic and abiotic factors as drivers of EW.
11.	Corbett, Thomas, et al. (author) Organic carbon source controlled microbial olivine dissolution in small-scale flow-through bioreactors, for CO2 removal 2024 In: NPJ MATERIALS DEGRADATION. - : Nature Publishing Group. - 2397-2106. ; 8:1 Journal article (peer-reviewed)abstract The development of carbon dioxide removal methods, coupled with decreased CO2 emissions, is fundamental to achieving the targets outlined in the Paris Agreement limiting global warming to 1.5 degrees C. Here we are investigating the importance of the organic carbon feedstock to support silicate mineral weathering in small-scale flow through bioreactors and subsequent CO2 sequestration. Here, we combine two bacteria and two fungi, widely reported for their weathering potential, in simple flow through bioreactors (columns) consisting of forsterite and widely available, cheap organic carbon sources (wheat straw, bio-waste digestate of pig manure and biowaste, and manure compost), over six weeks. Compared to their corresponding abiotic controls, the inoculated straw and digestate columns release more total alkalinity (similar to 2 times more) and produce greater dissolved and solid inorganic carbon (29% for straw and 13% for digestate), suggesting an increase in CO2 sequestration because of bio-enhanced silicate weathering. Microbial biomass is higher in the straw columns compared to the digestate and manure compost columns, with a phospholipid fatty acid derived total microbial biomass 10 x greater than the other biotic columns. Scanning Electron Microscopy imaging shows the most extensive colonisation and biofilm formation on the mineral surfaces in the straw columns. The biotic straw and digestate columns sequester 50 and 14 mg C more than their abiotic controls respectively, while there is no difference in the manure columns. The selection of organic carbon sources to support microbial communities in the flow through bioreactors controlls the silicate weathering rates and CO2 sequestration.
12.	Fuchs, David, et al. (author) Scoring the Risk of Having Systemic Mastocytosis in Adult Patients with Mastocytosis in the Skin 2021 In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 2213-2198 .- 2213-2201. ; 9:4, s. 1705-1712.e4 Journal article (peer-reviewed)abstract BACKGROUND: Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a bone marrow biopsy is not performed, the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients. OBJECTIVE: To develop a risk score to predict SM in adults with MIS. METHODS: We examined 1145 patients with MIS from the European Competence Network on Mastocytosis Registry who underwent a bone marrow biopsy. A total of 944 patients had SM and 201 patients had cutaneous mastocytosis; 63.7% were female, and 36.3% were male. Median age was 44 +/- 13.3 years. The median serum tryptase level amounted to 29.3 +/- 81.9 ng/mL. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver-operating curves. RESULTS: In the multivariate model, the tryptase level (P < .001), constitutional/cardiovascular symptoms (P = .014), and bone symptoms/osteoporosis (P < .001) were independent predictors of SM (P < .001; sensitivity, 90.7%; specificity, 69.1%). A 6-point risk score was established (risk, 10.7%-98.0%) and validated. CONCLUSIONS: Using a large data set of the European Competence Network on Mastocytosis Registry, we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure cutaneous mastocytosis. (C) 2020 American Academy of Allergy, Asthma & Immunology
13.	Hans, Andreas, et al. (author) Suppression of X-ray-Induced Radiation Damage to Biomolecules in Aqueous Environments by Immediate Intermolecular Decay of Inner-Shell Vacancies 2021 In: The Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 12:30, s. 7146-7150 Journal article (peer-reviewed)abstract The predominant reason for the damaging power of high-energy radiation is multiple ionization of a molecule, either direct or via the decay of highly excited intermediates, as, e.g., in the case of X-ray irradiation. Consequently, the molecule is irreparably damaged by the subsequent fragmentation in a Coulomb explosion. In an aqueous environment, however, it has been observed that irradiated molecules may be saved from fragmentation presumably by charge and energy dissipation mechanisms. Here, we show that the protective effect of the environment sets in even earlier than hitherto expected, namely immediately after single inner-shell ionization. By combining coincidence measurements of the fragmentation of X-ray-irradiated microsolvated pyrimidine molecules with theoretical calculations, we identify direct intermolecular electronic decay as the protective mechanism, outrunning the usually dominant Auger decay. Our results demonstrate that such processes play a key role in charge delocalization and have to be considered in investigations and models on high-energy radiation damage in realistic environments.
14.	Hansen, Lea B.S., et al. (author) A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults 2018 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 9:1 Journal article (peer-reviewed)abstract © 2018, The Author(s). Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres.
15.	Kennedy, Vanessa E., et al. (author) Mast cell leukemia : clinical and molecular features and survival outcomes of patients in the ECNM Registry 2023 In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:9, s. 1713-1724 Journal article (peer-reviewed)abstract Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by >= 20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (>= 10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.
16.	Kluin-Nelemans, Hanneke C., et al. (author) Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis 2021 In: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 11:1, s. 292-303 Journal article (peer-reviewed)abstract In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXLI/RUNXI profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.
17.	Kluin-Nelemans, Hanneke C., et al. (author) Prognostic impact of eosinophils in mastocytosis : analysis of 2350 patients collected in the ECNM Registry 2020 In: Leukemia. - : Nature Publishing Group. - 0887-6924 .- 1476-5551. ; 34:4, s. 1090-1101 Journal article (peer-reviewed)abstract Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5-1.5x10(9)/l), and 3.1% hypereosinophilia (HE; >1.5x10(9)/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p<0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n=1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.
18.	Lübke, Johannes, et al. (author) Prognostic Impact of Organomegaly in Mastocytosis : An Analysis of the European Competence Network on Mastocytosis 2023 In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 2213-2198 .- 2213-2201. ; 11:2, s. 581-590 Journal article (peer-reviewed)abstract BACKGROUND: Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM).OBJECTIVES: To investigate the prevalence and prognostic impact of 1 or more organomegalies on clinical course and survival in patients with CM/SM.METHODS: Therefore, 3155 patients with CM (n = 1002 [32%]) or SM (n = 2153 [68%]) enrolled within the registry of the European Competence Network on Mastocytosis were analyzed. RESULTS: Overall survival (OS) was adversely affected by the number of organomegalies (OS: #0 vs #1 hazard ratio [HR], 4.9; 95% CI, 3.4-7.1, P < .001; #1 vs #2 HR, 2.1, 95% CI, 1.4-3.1, P < .001; #2 vs #3 HR, 1.7, 95% CI, 1.2-2.5, P = .004). Lymphadenopathy was frequently detected in patients with smoldering SM (SSM, 18 of 60 [30%]) or advanced SM (AdvSM, 137 of 344 [40%]). Its presence confered an inferior outcome in patients with AdvSM compared with patients with AdvSM without lymphadenopathy (median OS, 3.8 vs 2.6 years; HR, 1.6; 95% CI, 1.2-2.2; P = .003). OS was not different between patients having organomegaly with either ISM or SSM (median, 25.5 years vs not reached; P = .435). At time of disease progression, a new occurrence of any organomegaly was observed in 17 of 40 (43%) patients with ISM, 4 of 10 (40%) patients with SSM, and 33 of 86 (38%) patients with AdvSM, respectively.CONCLUSIONS: Organomegalies including lymphadenopathy are often found in SSM and AdvSM. ISM with organomegaly has a similar course and prognosis compared with SSM. The number of organomegalies is adversely associated with OS. A new occurrence of organomegaly in all variants of SM may indicate disease progression.
19.	Lübke, Johannes, et al. (author) Serum chemistry profiling and prognostication in systemic mastocytosis : a registry-based study of the ECNM and GREM 2024 In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 8:11, s. 2890-2900 Journal article (peer-reviewed)abstract Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most speci fic serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, beta 2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥ 260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308 μg/L vs 146 μg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to β2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry pro filing is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.
20.	Menkveld, Albert J., et al. (author) Nonstandard Errors 2024 In: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390 Journal article (peer-reviewed)abstract In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
21.	Munch Roager, Henrik, et al. (author) Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: A randomised cross-over trial 2019 In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:1, s. 83-93 Journal article (peer-reviewed)abstract Objective T o investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality. Design 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of =6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed. Results 50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye. Conclusion C ompared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic lowgrade inflammation.
22.	Nolte, Annika, et al. (author) Disentangling coastal groundwater level dynamics in a global dataset 2024 In: Hydrology and Earth System Sciences. - 1027-5606. ; 28, s. 1215-1249 Journal article (peer-reviewed)abstract Groundwater level (GWL) dynamics result from a complex interplay between groundwater systems and the Earth system. This study aims to identify common hydrogeological patterns and to gain a deeper understanding of the underlying similarities and their link to physiographic, climatic, and anthropogenic controls of groundwater in coastal regions. The most striking aspects of GWL dynamics and their controls were identified through a combination of statistical metrics, calculated from about 8000 groundwater hydrographs, pattern recognition using clustering algorithms, classification using random forest, and SHapley Additive exPlanations (SHAPs). Hydrogeological similarity was defined by four clusters representing distinct patterns of GWL dynamics. These clusters can be observed globally across different continents and climate zones but simultaneously vary regionally and locally, suggesting a complicated interplay of controlling factors. The main controls differentiating GWL dynamics were identified, but we also provide evidence for the currently limited ability to explain GWL dynamics on large spatial scales, which we attribute mainly to uncertainties in the explanatory data. Finally, this study provides guidance for systematic and holistic groundwater monitoring and modeling and motivates a consideration of the different aspects of GWL dynamics, for example, when predicting climate-induced GWL changes, and the use of explainable machine learning techniques to deal with GWL complexity – especially when information on potential controls is limited or needs to be verified.
23.	Nolte, Annika, et al. (author) Disentangling coastal groundwater level dynamics on a global data set 2023 Journal article (other academic/artistic)abstract This study aims to identify common hydrogeological patterns and to gain a deeper understanding of the underlying similarities and their link to physiographic, climatic, and anthropogenic controls of coastal groundwater. The most striking aspects of GWL dynamics and their controls were identified through a combination of statistical metrics, calculated from about 8,000 groundwater hydrographs, and pattern recognition, classification, and explanation using machine learning techniques and SHapley Additive exPlanations (SHAP). Overall, four different GWL dynamics patterns emerge, independent of the different seasons, time series lengths, and periods. We show in this study that similar GWL dynamics can be observed around the world with different combinations of site characteristics, but also that the main factors differentiating these patterns can be identified. Three of the identified patterns exhibit high short-term and interannual variability and are most common in regions with low terrain elevation and shallow groundwater depth. Climate and soil characteristics are most important in differentiating these patterns. This study provides new insights into the hydrogeological behavior of groundwater in coastal regions and guides systematic and holistic groundwater monitoring and modelling, motivating to consider various aspects of GWL dynamics when, for example, estimating climate-driven GWL changes – especially when information on potential controls is limited.
24.	Raymond, Peter A., et al. (author) Global carbon dioxide emissions from inland waters 2013 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 503:7476, s. 355-359 Journal article (peer-reviewed)abstract Carbon dioxide (CO2) transfer from inland waters to the atmosphere, known as CO2 evasion, is a component of the global carbon cycle. Global estimates of CO2 evasion have been hampered, however, by the lack of a framework for estimating the inland water surface area and gas transfer velocity and by the absence of a global CO2 database. Here we report regional variations in global inland water surface area, dissolved CO2 and gas transfer velocity. We obtain global CO2 evasion rates of 1.8(-0.25)(+0.25) petagrams of carbon (Pg C) per year from streams and rivers and 0.32(-0.26)(+0.52) Pg C yr(-1) from lakes and reservoirs, where the upper and lower limits are respectively the 5th and 95th confidence interval percentiles. The resulting global evasion rate of 2.1 Pg C yr(-1) is higher than previous estimates owing to a larger stream and river evasion rate. Our analysis predicts global hotspots in stream and river evasion, with about 70 per cent of the flux occurring over just 20 per cent of the land surface. The source of inland water CO2 is still not known with certainty and new studies are needed to research the mechanisms controlling CO2 evasion globally.
25.	Sperr, Wolfgang R., et al. (author) International prognostic scoring system for mastocytosis (IPSM) : a retrospective cohort study 2019 In: The Lancet Haematology. - : ELSEVIER SCI LTD. - 2352-3026. ; 6:12, s. E638-E649 Journal article (peer-reviewed)abstract Background The WHO classification separates mastocytosis into distinct variants, but prognostication remains a clinical challenge. The aim of this study was to improve prognostication for patients with mastocytosis. Methods We analysed data of the registry of the European Competence Network on Mastocytosis including 1639 patients (age 17-90 years) diagnosed with mastocytosis according to WHO criteria between Jan 12, 1978, and March 16, 2017. Univariate and multivariate analyses with Cox regression were applied to identify prognostic variables predicting survival outcomes and to establish a prognostic score. We validated this International Prognostic Scoring System in Mastocytosis (IPSM) with data of 462 patients (age 17-79 years) from the Spanish network Red Espanola de Mastocitosis diagnosed between Jan 22, 1998, and Nov 2, 2017. Findings The prognostic value of the WHO classification was confirmed in our study (p<0.0001). For patients with non-advanced mastocytosis (n=1380), we identified age 60 years or older (HR 10.75, 95% CI 5.68-20.32) and a concentration of alkaline phosphatase 100 U/L or higher (2.91, 1.60-5.30) as additional independent prognostic variables for overall survival. The resulting scoring system divided patients with non-advanced mastocytosis into three groups: low (no risk factors), intermediate 1 (one risk factor), and intermediate 2 (two risk factors). Overall survival and progression-free survival differed significantly among these groups (p<0.0001). In patients with advanced mastocytosis (n=259), age 60 years or older (HR 2.14, 95% CI 1.42-3.22), a concentration of tryptase 125 ng/mL or higher (1.81, 1.20-2.75), a leukocyte count of 16 x 10(9) per L or higher (1.88, 1.27-2.79), haemoglobin of 11 g/dL or lower (1.71, 1.13-2.57), a platelet count of 100 x 10(9) per L or lower (1.63, 1.13-2.34), and skin involvement (0.46, 0.30-0.69) were prognostic variables. Based on these variables, a separate score for advanced mastocytosis with four risk categories was established, with significantly different outcomes for overall survival and progression-free survival (p<0.0001). The prognostic value of both scores was confirmed in 413 patients with non-advanced disease and 49 with advanced mastocytosis from the validation cohort. Interpretation The IPSM scores for patients with non-advanced and advanced mastocytosis can be used to predict survival outcomes and guide treatment decisions. However, the predictive value of the IPSM needs to be confirmed in forthcoming trials. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
26.	Trizuljak, Jakub, et al. (author) Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification 2020 In: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 75:8, s. 1927-1938 Journal article (peer-reviewed)abstract Background: In indolent systemic mastocytosis (ISM), several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM.Methods: We employed a dataset of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM.Results: We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM), and smoldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM, and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event-free survival (EFS) were found when comparing ISM, BMM, and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status, and organomegaly.Conclusion: Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.
27.	Valent, Peter, et al. (author) The Data Registry of the European Competence Network on Mastocytosis (ECNM) : Set Up, Projects, and Perspectives 2019 In: Journal of Allergy and Clinical Immunology. - : ELSEVIER SCIENCE BV. - 2213-2198 .- 2213-2201. ; 7:1, s. 81-87 Research review (peer-reviewed)abstract Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future. (C) 2019 American Academy of Allergy, Asthma & Immunology
28.	Vicca, Sara, et al. (author) Is the climate change mitigation effect of enhanced silicate weathering governed by biological processes? 2022 In: Global Change Biology. - : John Wiley & Sons. - 1354-1013 .- 1365-2486. ; 28:3, s. 711-726 Journal article (peer-reviewed)abstract A number of negative emission technologies (NETs) have been proposed to actively remove CO2 from the atmosphere, with enhanced silicate weathering (ESW) as a relatively new NET with considerable climate change mitigation potential. Models calibrated to ESW rates in lab experiments estimate the global potential for inorganic carbon sequestration by ESW at about 0.5-5 Gt CO2 year(-1), suggesting ESW could be an important component of the future NETs mix. In real soils, however, weathering rates may differ strongly from lab conditions. Research on natural weathering has shown that biota such as plants, microbes, and macro-invertebrates can strongly affect weathering rates, but biotic effects were excluded from most ESW lab assessments. Moreover, ESW may alter soil organic carbon sequestration and greenhouse gas emissions by influencing physicochemical and biological processes, which holds the potential to perpetuate even larger negative emissions. Here, we argue that it is likely that the climate change mitigation effect of ESW will be governed by biological processes, emphasizing the need to put these processes on the agenda of this emerging research field.
29.	Vieira-Silva, S., et al. (author) Statin therapy is associated with lower prevalence of gut microbiota dysbiosis 2020 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 581:7808, s. 310-315 Journal article (peer-reviewed)abstract Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n=888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n=2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
30.	Weyhenmeyer, Gesa A., et al. (author) Widespread diminishing anthropogenic effects on calcium in freshwaters 2019 In: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9 Journal article (peer-reviewed)abstract Calcium (Ca) is an essential element for almost all living organisms. Here, we examined global variation and controls of freshwater Ca concentrations, using 440 599 water samples from 43 184 inland water sites in 57 countries. We found that the global median Ca concentration was 4.0 mg L-1 with 20.7% of the water samples showing Ca concentrations <= 1.5 mg L-1, a threshold considered critical for the survival of many Ca-demanding organisms. Spatially, freshwater Ca concentrations were strongly and proportionally linked to carbonate alkalinity, with the highest Ca and carbonate alkalinity in waters with a pH around 8.0 and decreasing in concentrations towards lower pH. However, on a temporal scale, by analyzing decadal trends in > 200 water bodies since the 1980s, we observed a frequent decoupling between carbonate alkalinity and Ca concentrations, which we attributed mainly to the influence of anthropogenic acid deposition. As acid deposition has been ameliorated, in many freshwaters carbonate alkalinity concentrations have increased or remained constant, while Ca concentrations have rapidly declined towards or even below pre-industrial conditions as a consequence of recovery from anthropogenic acidification. Thus, a paradoxical outcome of the successful remediation of acid deposition is a globally widespread freshwater Ca concentration decline towards critically low levels for many aquatic organisms.
31.	Zanotti, Roberta, et al. (author) Refined diagnostic criteria for bone marrow mastocytosis : a proposal of the European competence network on mastocytosis 2022 In: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:2, s. 516-524 Journal article (peer-reviewed)abstract In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level >= 125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p < 0.05) and better overall survival (p < 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels <125 ng/mL.

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