| 1. |
- Witt, S. H., et al.
(author)
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Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia
- 2017
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7
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Journal article (peer-reviewed)abstract
- Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P = 4.42 x 10(-7)) and PKP4 (P = 8.67 x 10(-7)); and gene-set analysis yielded a significant finding for exocytosis (GO: 0006887, PFDR = 0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (r(g) = 0.28 [P = 2.99 x 10(-3)]), SCZ (r(g) = 0.34 [P = 4.37 x 10(-5)]) and MDD (r(g) = 0.57 [P = 1.04 x 10(-3)]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
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| 2. |
- de Jong, S, et al.
(author)
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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
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In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Journal article (peer-reviewed)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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| 3. |
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| 5. |
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| 6. |
- Jimenez, J. L., et al.
(author)
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Evolution of Organic Aerosols in the Atmosphere
- 2009
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 326:5959, s. 1525-1529
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Journal article (peer-reviewed)abstract
- Organic aerosol (OA) particles affect climate forcing and human health, but their sources and evolution remain poorly characterized. We present a unifying model framework describing the atmospheric evolution of OA that is constrained by high-time-resolution measurements of its composition, volatility, and oxidation state. OA and OA precursor gases evolve by becoming increasingly oxidized, less volatile, and more hygroscopic, leading to the formation of oxygenated organic aerosol (OOA), with concentrations comparable to those of sulfate aerosol throughout the Northern Hemisphere. Our model framework captures the dynamic aging behavior observed in both the atmosphere and laboratory: It can serve as a basis for improving parameterizations in regional and global models.
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| 7. |
- Poeschl, U., et al.
(author)
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Rainforest Aerosols as Biogenic Nuclei of Clouds and Precipitation in the Amazon
- 2010
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In: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 329:5998, s. 1513-1516
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Journal article (peer-reviewed)abstract
- The Amazon is one of the few continental regions where atmospheric aerosol particles and their effects on climate are not dominated by anthropogenic sources. During the wet season, the ambient conditions approach those of the pristine pre-industrial era. We show that the fine submicrometer particles accounting for most cloud condensation nuclei are predominantly composed of secondary organic material formed by oxidation of gaseous biogenic precursors. Supermicrometer particles, which are relevant as ice nuclei, consist mostly of primary biological material directly released from rainforest biota. The Amazon Basin appears to be a biogeochemical reactor, in which the biosphere and atmospheric photochemistry produce nuclei for clouds and precipitation sustaining the hydrological cycle. The prevailing regime of aerosol-cloud interactions in this natural environment is distinctly different from polluted regions.
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| 8. |
- Martin, S. T., et al.
(author)
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An overview of the Amazonian Aerosol Characterization Experiment 2008 (AMAZE-08)
- 2010
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In: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7324. ; 10:23, s. 11415-11438
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Journal article (peer-reviewed)abstract
- The Amazon Basin provides an excellent environment for studying the sources, transformations, and properties of natural aerosol particles and the resulting links between biological processes and climate. With this framework in mind, the Amazonian Aerosol Characterization Experiment (AMAZE-08), carried out from 7 February to 14 March 2008 during the wet season in the central Amazon Basin, sought to understand the formation, transformations, and cloud-forming properties of fine-and coarse-mode biogenic aerosol particles, especially as related to their effects on cloud activation and regional climate. Special foci included (1) the production mechanisms of secondary organic components at a pristine continental site, including the factors regulating their temporal variability, and (2) predicting and understanding the cloud-forming properties of biogenic particles at such a site. In this overview paper, the field site and the instrumentation employed during the campaign are introduced. Observations and findings are reported, including the large-scale context for the campaign, especially as provided by satellite observations. New findings presented include: (i) a particle number-diameter distribution from 10 nm to 10 mu m that is representative of the pristine tropical rain forest and recommended for model use; (ii) the absence of substantial quantities of primary biological particles in the submicron mode as evidenced by mass spectral characterization; (iii) the large-scale production of secondary organic material; (iv) insights into the chemical and physical properties of the particles as revealed by thermodenuder-induced changes in the particle number-diameter distributions and mass spectra; and (v) comparisons of ground-based predictions and satellite-based observations of hydrometeor phase in clouds. A main finding of AMAZE-08 is the dominance of secondary organic material as particle components. The results presented here provide mechanistic insight and quantitative parameters that can serve to increase the accuracy of models of the formation, transformations, and cloud-forming properties of biogenic natural aerosol particles, especially as related to their effects on cloud activation and regional climate.
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| 9. |
- von Hobe, M, et al.
(author)
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Reconciliation of essential process parameters for an enhanced predictability of Arctic stratospheric ozone loss and its climate interactions (RECONCILE): activities and results
- 2013
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In: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 13:18, s. 9233-9268
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Journal article (peer-reviewed)abstract
- The international research project RECONCILE has addressed central questions regarding polar ozone depletion, with the objective to quantify some of the most relevant yet still uncertain physical and chemical processes and thereby improve prognostic modelling capabilities to realistically predict the response of the ozone layer to climate change. This overview paper outlines the scope and the general approach of RECONCILE, and it provides a summary of observations and modelling in 2010 and 2011 that have generated an in many respects unprecedented dataset to study processes in the Arctic winter stratosphere. Principally, it summarises important outcomes of RECONCILE including (i) better constraints and enhanced consistency on the set of parameters governing catalytic ozone destruction cycles, (ii) a better understanding of the role of cold binary aerosols in heterogeneous chlorine activation, (iii) an improved scheme of polar stratospheric cloud (PSC) processes that includes heterogeneous nucleation of nitric acid trihydrate (NAT) and ice on non-volatile background aerosol leading to better model parameterisations with respect to denitrification, and (iv) long transient simulations with a chemistryclimate model (CCM) updated based on the results of RECONCILE that better reproduce past ozone trends in Antarctica and are deemed to produce more reliable predictions of future ozone trends. The process studies and the global simulations conducted in RECONCILE show that in the Arctic, ozone depletion uncertainties in the chemical and microphysical processes are now clearly smaller than the sensitivity to dynamic variability.
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| 11. |
- Kloprogge, F., et al.
(author)
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Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis
- 2018
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In: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 15:6
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Journal article (peer-reviewed)abstract
- Background The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. A search in PubMed, Embase, ClinicalTrials. gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing < 15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.
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| 12. |
- Venkatesan, M, et al.
(author)
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Erratum
- 2019
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In: The American journal of tropical medicine and hygiene. - : American Society of Tropical Medicine and Hygiene. - 1476-1645 .- 0002-9637. ; 100:3, s. 766-766
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Journal article (peer-reviewed)
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| 13. |
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| 14. |
- Adjuik, Martin A., et al.
(author)
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The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria : a meta-analysis of individual patient data
- 2015
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In: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 13
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Journal article (peer-reviewed)abstract
- Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
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| 15. |
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| 19. |
- Drewnick, Frank, et al.
(author)
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Measurement of ambient, interstitial, and residual aerosol particles on a mountaintop site in central Sweden using an aerosol mass spectrometer and a CVI
- 2007
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In: Journal of Atmospheric Chemistry. - : Springer Science and Business Media LLC. - 0167-7764 .- 1573-0662. ; 56:1, s. 1-20
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Journal article (peer-reviewed)abstract
- The Aerodyne aerosol mass spectrometer (Q-AMS) was coupled with a counterflow virtual impactor (CVI) for the first time to measure cloud droplet residuals of warm tropospheric clouds on Mt. Areskutan in central Sweden in July 2003. Operating the CVI in different operational modes generated mass concentration and species-resolved mass distribution data for non-refractory species of the ambient, interstitial, and residual aerosol. The ambient aerosol measurements revealed that the aerosol at the site was mainly influenced by long-range transport and regional photochemical generation of nitrate and organic aerosol components. Four different major air masses were identified for the time interval of the experiment. While two air masses that approached the site from northeastern Europe via Finland showed very similar aerosol composition, the other two air masses from polar regions and the British Islands had a significantly different composition. During cloud events the larger aerosol particles were found to be activated into cloud droplets. On a mass basis the activation cut-off diameter was approximately 150 nm for nitrate and organics dominated particles and 200 nm for sulfate dominated particles. Generally nitrate and organics were found to be activated into cloud droplets with higher efficiency than sulfate. While a significant fraction of the nitrate in ambient particles was organic nitrates or nitrogen-containing organic species, the nitrate found in the cloud droplet residuals was mainly ammonium nitrate. After passage of clouds the ambient aerosol size distribution had shifted to smaller particle sizes due to the predominantly activation of larger aerosol particles without a significant change in the relative composition of the ambient aerosol.
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| 20. |
- Dusek, Ulrike, et al.
(author)
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Enhanced organic mass fraction and decreased hygroscopicity of cloud condensation nuclei (CCN) during new particle formation events
- 2010
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In: Geophysical Research Letters. - 1944-8007. ; 37
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Journal article (peer-reviewed)abstract
- In a forested near-urban location in central Germany, the CCN efficiency of particles smaller than 100 nm decreases significantly during periods of new particle formation. This results in an increase of average activation diameters, ranging from 5 to 8% at supersaturations of 0.33% and 0.74%, respectively. At the same time, the organic mass fraction in the sub-100-nm size range increases from approximately 2/3 to 3/4. This provides evidence that secondary organic aerosol (SOA) components are involved in the growth of new particles to larger sizes, and that the reduced CCN efficiency of small particles is caused by the low hygroscopicity of the condensing material. The observed dependence of particle hygroscopicity (k) on chemical composition can be parameterized as a function of organic and inorganic mass fractions (forg, finorg) determined by aerosol mass spectrometry: k = korg forg + kinorg finorg. The obtained value of korg ~ 0.1 is characteristic for SOA, and kinorg ~ 0.7 is consistent with the observed mix of ammonium, sulfate and nitrate ions.
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| 21. |
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| 22. |
- Krieger, Jonas A., et al.
(author)
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Weyl spin-momentum locking in a chiral topological semimetal
- 2024
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In: Nature Communications. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- Spin-orbit coupling in noncentrosymmetric crystals leads to spin-momentum locking – a directional relationship between an electron’s spin angular momentum and its linear momentum. Isotropic orthogonal Rashba spin-momentum locking has been studied for decades, while its counterpart, isotropic parallel Weyl spin-momentum locking has remained elusive in experiments. Theory predicts that Weyl spin-momentum locking can only be realized in structurally chiral cubic crystals in the vicinity of Kramers-Weyl or multifold fermions. Here, we use spin- and angle-resolved photoemission spectroscopy to evidence Weyl spin-momentum locking of multifold fermions in the chiral topological semimetal PtGa. We find that the electron spin of the Fermi arc surface states is orthogonal to their Fermi surface contour for momenta close to the projection of the bulk multifold fermion at the Γ point, which is consistent with Weyl spin-momentum locking of the latter. The direct measurement of the bulk spin texture of the multifold fermion at the R point also displays Weyl spin-momentum locking. The discovery of Weyl spin-momentum locking may lead to energy-efficient memory devices and Josephson diodes based on chiral topological semimetals.
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| 23. |
- Raty, S., et al.
(author)
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Non-invasive electrical brain stimulation for vision restoration after stroke: An exploratory randomized trial (REVIS)
- 2021
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In: Restorative Neurology and Neuroscience. - : IOS Press. - 0922-6028 .- 1878-3627. ; 39:3, s. 221-235
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Journal article (peer-reviewed)abstract
- Background: Occipital strokes often cause permanent homonymous hemianopia leading to significant disability. In previous studies, non-invasive electrical brain stimulation (NIBS) has improved vision after optic nerve damage and in combination with training after stroke. Objective: We explored different NIBS modalities for rehabilitation of hemianopia after chronic stroke. Methods: In a randomized, double-blinded, sham-controlled, three-armed trial, altogether 56 patients with homonymous hemianopia were recruited. The three experiments were: i) repetitive transorbital alternating current stimulation (rtACS, n=8) vs. rtACS with prior cathodal transcranial direct current stimulation over the intact visual cortex (tDCS/rtACS, n=8) vs. sham (n = 8); ii) rtACS (n = 9) vs. sham (n = 9); and iii) tDCS of the visual cortex (n = 7) vs. sham (n = 7). Visual functions were evaluated before and after the intervention, and after eight weeks follow-up. The primary outcome was change in visual field assessed by high-resolution and standard perimetries. The individual modalities were compared within each experimental arm. Results: Primary outcomes in Experiments 1 and 2 were negative. Only significant between-group change was observed in Experiment 3, where tDCS increased visual field of the contralesional eye compared to sham. tDCS/rtACS improved dynamic vision, reading, and visual field of the contralesional eye, but was not superior to other groups. rtACS alone increased foveal sensitivity, but was otherwise ineffective. All trial-related procedures were tolerated well. Conclusions: This exploratory trial showed safety but no main effect of NIBS on vision restoration after stroke. However, tDCS and combined tDCS/rtACS induced improvements in visually guided performance that need to be confirmed in larger-sample trials.
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