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HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Der Vorstand der Deutschen Gesellschaft für Epileptologie und die Kommission „Epilepsie und Synkopen“ der Deutschen Gesellschaft für Neurologie haben die aktuelle Datenlage zur Impfung zur Vorbeugung der Corona-Virus-Krankheit 2019 (COVID-19) sowie zur Impfpriorisierung bei Menschen mit Epilepsie gesichtet, diese zusammengefasst und geben die unten genannten Empfehlungen ab.
Recently, the potent antiandrogen 4-methyl-7-diethylaminocoumarin (C47) and its potential transformation products 4-methyl-7-ethylaminocoumarin (C47T1) and 4-methyl-7-aminocoumarin (C47T2) were identified as novel environmental contaminants. We assessed for the first time the sources, distribution, and fate of these compounds in aquatic systems using the Holtemme River (Saxony-Anhalt, Germany), which is a hotspot for these contaminants. To this end, wastewater-treatment plant (WWTP) influent and effluent samples, surface water samples over 3 years, and the longitudinal profiles in water, sediment, and gammarids were analyzed. From the longitudinal profile of the river stretch, the WWTP of Silstedt was identified as the sole point source for these compounds in the River Holtemme, and exposure concentrations in the low micrograms per liter range could be recorded continuously over 3 years. Analysis of WWTP influent and effluent showed a transformation of approximately half of the C47 into C47T1 and C47T2 but no complete removal. A further attenuation of the three coumarins after discharge into the river could be largely attributed to dilution, while transformation was only approximately 20%, thus suggesting a significant persistence in aquatic systems. Experimentally derived partitioning coefficients between water and sediment organic carbon exceeded those predicted using the OPERA quantitative structure–activity relationship tools and polyparameter linear free-energy relationships by up to 93-fold, suggesting cation binding as a significant factor for their sorption behavior. Near-equilibrium conditions between water and sediment were not observed close to the emitting WWTP but farther downstream in the river. Experimental and predicted bioaccumulation factors for gammarids were closely matching, and the concentrations in field-sampled gammarids were close to steady state with exposure concentrations in the water phase of the river. Environ Toxicol Chem 2021;40:3078–3091. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
Biogenic organic precursors play an important role in atmospheric new particle formation (NPF). One of the major precursor species is α-pinene, which upon oxidation can form a suite of products covering a wide range of volatilities. Highly oxygenated organic molecules (HOMs) comprise a fraction of the oxidation products formed. While it is known that HOMs contribute to secondary organic aerosol (SOA) formation, including NPF, they have not been well studied in newly formed particles due to their very low mass concentrations. Here we present gas- and particle-phase chemical composition data from experimental studies of α-pinene oxidation, including in the presence of isoprene, at temperatures (−50 and −30 ∘C) and relative humidities (20 % and 60 %) relevant in the upper free troposphere. The measurements took place at the CERN Cosmics Leaving Outdoor Droplets (CLOUD) chamber. The particle chemical composition was analyzed by a thermal desorption differential mobility analyzer (TD-DMA) coupled to a nitrate chemical ionization–atmospheric pressure interface–time-of-flight (CI-APi-TOF) mass spectrometer. CI-APi-TOF was used for particle- and gas-phase measurements, applying the same ionization and detection scheme. Our measurements revealed the presence of C8−10 monomers and C18−20 dimers as the major compounds in the particles (diameter up to ∼ 100 nm). Particularly, for the system with isoprene added, C5 (C5H10O5−7) and C15 compounds (C15H24O5−10) were detected. This observation is consistent with the previously observed formation of such compounds in the gas phase. However, although the C5 and C15 compounds do not easily nucleate, our measurements indicate that they can still contribute to the particle growth at free tropospheric conditions. For the experiments reported here, most likely isoprene oxidation products enhance the growth of particles larger than 15 nm. Additionally, we report on the nucleation rates measured at 1.7 nm (J1.7 nm) and compared with previous studies, we found lower J1.7 nm values, very likely due to the higher α-pinene and ozone mixing ratios used in the present study.
Biogenic organic precursors play an important role in atmospheric new particle formation (NPF). One of the major precursor species is α-pinene, which upon oxidation can form a suite of products covering a wide range of volatilities. Highly oxygenated organic molecules (HOMs) comprise a fraction of the oxidation products formed. While it is known that HOMs contribute to secondary organic aerosol (SOA) formation, including NPF, they have not been well studied in newly formed particles due to their very low mass concentrations. Here we present gas- and particle-phase chemical composition data from experimental studies of α-pinene oxidation, including in the presence of isoprene, at temperatures (−50 and −30 ∘C) and relative humidities (20 % and 60 %) relevant in the upper free troposphere. The measurements took place at the CERN Cosmics Leaving Outdoor Droplets (CLOUD) chamber. The particle chemical composition was analyzed by a thermal desorption differential mobility analyzer (TD-DMA) coupled to a nitrate chemical ionization–atmospheric pressure interface–time-of-flight (CI-APi-TOF) mass spectrometer. CI-APi-TOF was used for particle- and gas-phase measurements, applying the same ionization and detection scheme. Our measurements revealed the presence of C8−10 monomers and C18−20 dimers as the major compounds in the particles (diameter up to ∼ 100 nm). Particularly, for the system with isoprene added, C5 (C5H10O5−7) and C15 compounds (C15H24O5−10) were detected. This observation is consistent with the previously observed formation of such compounds in the gas phase. However, although the C5 and C15 compounds do not easily nucleate, our measurements indicate that they can still contribute to the particle growth at free tropospheric conditions. For the experiments reported here, most likely isoprene oxidation products enhance the growth of particles larger than 15 nm. Additionally, we report on the nucleation rates measured at 1.7 nm (J1.7 nm) and compared with previous studies, we found lower J1.7 nm values, very likely due to the higher α-pinene and ozone mixing ratios used in the present study.
Tiotropium as an add-on treatment option for severe uncontrolled asthma in preschool patients
(2021)
Background: Toddlers with asthma suffer disproportionally more than school-aged children from exacerbations with emergency visits and hospital admissions despite inhaled corticosteroid (ICS) treatment. A recent trial for children ≤ 5 years showed tolerability of tiotropium and potential to reduce asthma-related events.
Methods: We conducted a retrospective analysis of electronic outpatient records (2017‒2019) of children < 6 years treated with ICS plus long-acting β2-agonists (LABAs) plus tiotropium as an add-on for uncontrolled severe asthma. The primary endpoint was a comparison of systemic corticosteroid (SCS) prescriptions 6 months before and after ICS/LABA/tiotropium start. Secondary endpoints included physician visits, hospitalisations and antibiotic prescriptions. We compared outcomes with children without asthma matched for age, sex, season and screening date.
Results: Compared with a mean 2.42 (95% CI: 1.75, 3.36) SCS courses per patient within 6 months prior to ICS/LABA/tiotropium, 0.74 (95% CI: 0.25, 1.08) SCS courses per patient were prescribed within 6 months after starting ICS/LABA/tiotropium (P< 0.001). Physician visits dropped from 9.23 (95% CI: 7.15, 12.72) to 5.76 (95% CI: 3.10, 7.70) per patient (P< 0.01). Nineteen hospitalisations were recorded 6 months before ICS/LABA/tiotropium compared with one hospitalisation after (P< 0.01). A mean 1.79 antibiotic courses (95% CI: 1.22, 2.23) per patient were prescribed before ICS/LABA/tiotropium compared with 0.74 (95% CI: 0.22, 1.00) after ICS/LABA/tiotropium (P< 0.001). Hospitalisation rates for patients at observation end were not statistically different from healthy controls before/after matching.
Interpretation: Our retrospective study showed that adding tiotropium to ICS/LABA is a new treatment option for patients with severe preschool asthma; however, larger confirmatory studies are needed.
Qualitätsstandards (QS) sind messbare Konstrukte, die helfen sollen, Versorgungslücken quantitativ zu erfassen, um langfristig die Versorgungsqualität zu verbessern. Die Assessment of SpondyloArthritis International Society (ASAS) hat kürzlich erstmals internationale QS für das Management von Patient*innen mit axialer Spondyloarthritis (axSpA) konsentiert und veröffentlicht. Die Deutsche Gesellschaft für Rheumatologie (DGRh) hat daraufhin beschlossen, diese Standards durch eine Gruppe von Expert*innen aus unterschiedlichen Versorgungsbereichen zu übersetzen, zu prüfen und ggf. zu übernehmen. Vor diesem Hintergrund wurden erstmals nationale QS für das Management von Patient*innen mit axSpA für Deutschland entwickelt. Hierbei wurde v. a. auf Machbarkeit und Praxisrelevanz geachtet. Letztlich wurden 9 QS definiert, mit denen die Qualität der Versorgung in Deutschland gemessen und verbessert werden kann bzw. soll.