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Immiscible sulphide liquids, preserved as magmatic sulphide droplets, are believed to strongly control the partitioning behaviour of chalcophile trace elements [1-2]. Hence, the chemical composition of sulphide droplets can be used to understand the fractionation processes of chalcophile elements in magmatic systems that reached sulphide saturation. We carried out LA-ICP-MS analysis of sulphide droplets from gabbros of the lower oceanic crust recovered by deep ocean drilling from mid-ocean ridge spreading centres in the Pacific (ODP147), Indian (ODP176, ODP179, IODP360) and the Atlantic (OPD209 and IODP305) Oceans. For comparison, sulphide droplets from mid-ocean ridge basalts from the East Pacific Rise, Mid-Atlantic Ridge and Southwest Indian Ridge were analysed. Our results show that most gabbros host abundant large magmatic sulphide droplets (mostly above 100 µm up to 1 mm) significantly exceeding those from the related lava units [2-4]. The droplets are commonly associated with or incorporated in olivine or clinopyroxene suggesting an early-stage sulphide saturation but are locally also incorporated in Fe-oxides indicating a later-stage formation during magma cooling [4-5]. The Ni contents of sulphide droplets hosted in gabbros from Hess Deep (Pacific Ocean) are highly variable ranging from ~10 µg/g to weight % levels. Nickel is also strongly controlled by olivine fractionation, and thus can be seen as a parameter indicating whether sulphide saturation was reached before or after the onset of olivine crystallisation. Due to the highly variable Ni contents and in combination with petrographic observations, we suggest that the magma reached early sulphide saturation at Hess Deep, as typically seen in mid-ocean ridge magmatic systems. However, the variable Ni contents in the sulphide droplets indicate that the magma was sulphide-saturated over a longer time span. Alternatively, the magma may frequently switch between being sulphide undersaturated and saturated, due to decreasing pressure during magma ascent accompanied by crystal fractionation at different levels in the crust. Generally, the trace element composition of the sulphide droplets hosted by gabbros from the different drill sites overlap. However, there are significant differences in the compositions of sulphide droplets from lava samples and from associated gabbroic xenoliths [4]. Thus, analysis of droplets from lavas alone provide an incomplete picture of the chalcophile element evolution of the magmatic system. We find no clear differences in sulphide composition with spreading rate or degree of melting as suggested for the silicate melt portion. Instead, the composition of sulphide droplets indicates that fractionation during magma ascent in the crust is the main driver that causes the observed chemical variations, which is part of ongoing investigations.[1] Wood, B. J. and Kiseeva, E. S. (2015), Earth and Planetary Science Letters, 424, 280-294. [2] Patten, C. et al. (2013), Chemical Geology, 358, 170–188. [3] Peach et al. (1990), Geochimica et Cosmochimica Acta, 12, 3379-3389. [4] Keith, M. et al. (2017), Chemical Geology, 451, 67–77. [5] Jenner, F. E. et al. (2010), Journal of Petrology, 51, 2445-2464.

This is the preprint of the accepted article: Klöcking, M., et. al. (2023). Community recommendations for geochemical data, services and analytical capabilities in the 21st century. In Geochimica et Cosmochimica Acta. Elsevier BV. https://doi.org/10.1016/j.gca.2023.04.024 Abstract The majority of geochemical and cosmochemical research is based upon observations and, in particular, upon the acquisition, processing and interpretation of analytical data from physical samples. The exponential increase in volumes and rates of data acquisition over the last century, combined with advances in instruments, analytical methods and an increasing variety of data types analysed, has necessitated the development of new ways of data curation, access and sharing. Together with novel data processing methods, these changes have enabled new scientific insights and are driving innovation in Earth and Planetary Science research. Yet, as approaches to data-intensive research develop and evolve, new challenges emerge. As large and often global data compilations increasingly form the basis for new research studies, institutional and methodological differences in data reporting are proving to be significant hurdles in synthesising data from multiple sources. Consistent data formats and descriptions as well as appropriate information on data quality are becoming crucial to enabling reproducibility and integration of results and fostering confidence for data reuse. Here, we explore the key challenges faced by the geo- and cosmochemistry community and, by drawing comparisons from other communities, recommend possible approaches to overcome them. The first challenge is bringing together the numerous sub-disciplines within our community. One key factor for this convergence will be gaining endorsement from the international geochemical, cosmochemical and analytical societies and associations, journals and institutions. Increased education and outreach, spearheaded by ambassadors recruited from leading scientists across disciplines, will further contribute to raising awareness, and to uniting and mobilising the community. Appropriate incentives, recognition and credit for good data management as well as an improved, user-oriented technical infrastructure will be essential for achieving a cultural change towards an environment in which the effective use and real-time interchange of large datasets is common-place. Finally, the development of best practices for standardised data reporting and exchange, driven by expert working groups, will be a crucial step towards making geo- and cosmochemical data more Findable, Accessible, Interoperable and Reusable by both humans and machines (FAIR).

IntroductionSafe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections.Methods and analysisBRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed.Ethics and disseminationThe study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals.Trial registration numberEUPAS30280.

AIM:To estimate the extent of off-label prescribing of antidepressants in older adults and to characterize patients with off-label vs on-label prescriptions of antidepressants using a large German health claims database. METHODS:Using data from the German Pharmacoepidemiological Research Database (GePaRD), we conducted a cross-sectional study in adults aged 65 years or older with a dispensation of an antidepressant between 1 January 2009 and 31 December 2015 after a period of 365 days without such a dispensation. We assessed the overall and annual proportion of off-label prescriptions of antidepressants by class and individual substance. RESULTS: Among 263 276 incident users of antidepressants, the proportion of off-label prescribing was 43.6% (95% CI 43.4-43.8%) with little variation between 2009 and 2015 (42.2-44.4%). The proportion of off-label use was higher in men (49%) than women (41%). While the proportion of off-label prescriptions was highest for tri- and tetracyclic antidepressants with 56.2% (amitriptyline 54.6%, maximum 65.9% for trimipramine), it amounted to 41.8% for selective serotonin reuptake inhibitors (citalopram 41.6%, maximum 46.0% for escitalopram) and was 51.2% for mirtazapine. Indicators of overall morbidity were similar in both groups, eg, pain was coded in 72% of off-label users vs 77% of on-label users (insomnia 20% vs 24%). CONCLUSION: Our study suggests a high prevalence of off-label antidepressant use among older adults in Germany, which was not restricted to certain classes of antidepressants or individual antidepressants. Given the unclear risk-benefit ratio, studies investigating the safety of off-label use among older adults for individual antidepressants are urgently needed.

INTRODUCTION: Studies have shown an increased risk of febrile convulsions (FC) after first immunization with the quadrivalent measles-mumps-rubella-varicella vaccine (MMRV) compared to a first dose of measles-mumps-rubella vaccine (MMR) only or in combination with separately administered varicella vaccine (MMR + V). Therefore, it is recommended to give MMR + V at first dose and MMRV or MMR + V at second dose. Little is known on the risk of FC after MMRV at second dose, especially whether the risk depends on age, sex, history of FC or type of first dose vaccine. METHODS: A retrospective cohort study using claims data from the German Pharmacoepidemiological Research database (GePaRD) was performed in children born between January 1st, 2004 and October 31st, 2015 who received two doses of MMRV, MMR + V or MMR. Cases were defined as hospitalization with a diagnosis of FC without neurological conditions coded as main discharge diagnosis. Unadjusted and adjusted odds ratios (OR) with 95% confidence intevals (CIs) were calculated to compare the risk of FC. Stratified analyses were performed to examine potential effect modification by age, sex, history of FC or type of first dose vaccine. RESULTS: In the first 30 days after second dose vaccination, 464 FCs were observed in a cohort of 528,639 children with a median age of 17 months. After adjustment for potential confounders, the adjusted OR for FC in the 30 days after vaccination was 1.25 (95% CI 0.67–2.30) for MMRV compared to MMR + V and 1.04 (0.82–1.32) for MMRV compared to MMR. History of FC was the most important risk factor with an OR of 36.26 (29.30–44.89). We found no effect modification by age, sex, history of FC, or type of first dose vaccine. CONCLUSION: Use of MMRV at second dose is not associated with an increased risk of FC compared to MMR + V or MMR, irrespective of age, sex, history of FC, or type of first dose vaccine.

Little is known about the utilization of St. John’s wort (Hypericum perforatum L.) during pregnancy. In Germany, certain preparations of St. John’s wort can be reimbursed by statutory health insurances, facilitating to investigate exposure to St. John’s wort based on claims data. We therefore aimed to characterize pregnancies exposed to St. John’s wort and to explore potential malformations in the babies. Using claims data from the German Pharmacoepidemiological Research Database (GePaRD), pregnancies exposed to St. John’s wort during at least one trimester between 2006 and 2016 and the corresponding babies were identified. Exposure was identified via outpatient dispensations. Pregnancies were characterized regarding timing of exposure, use of other antidepressants, pregnancy outcomes and the occurrence of major malformations in the babies (not considering codes for musculoskeletal and other malformations due to low data quality in this regard). Out of 496 pregnancies with a dispensation of St. John’s wort during pregnancy, 420 (85 %) had a dispensation during the first trimester. There was a dispensation of other antidepressants before pregnancy in 21 % (during pregnancy: 12 %). Eleven percent of pregnancies ended in non-live births. In 312 babies linked to 305 pregnancies, major malformations were coded in 18 babies (5.8 %), of which 17 were exposed in the first trimester. The crude relative risk of major malformations for babies exposed during the first vs. the second or third trimester only was 3.56 (0.48–26.17). Our results suggest that only in a minority of pregnancies, St. John’s wort is used as an alternative to other antidepressants. Even though the relatively high rates of non-live births and major malformations after exposure to St. John’s wort during the first trimester need to be interpreted with caution, the findings are striking and generate hypotheses that merit further investigation.

BACKGROUND AND PURPOSE: Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed in the elderly due to a more favorable risk profile than other antidepressants (ADs). However, SSRIs are associated with an increased risk of gastrointestinal bleeding, while evidence on the risk of hemorrhagic stroke (HS) is limited. Therefore, we compared the risk of HS associated with the use of ADs in the elderly. METHODS: Based on data from the German Pharmacoepidemiological Research Database (GePaRD), a case–control study matched on age, sex, and health insurance provider, nested in a cohort of incident users of ADs ≥ 65 years of age was performed. Cases were identified from hospital discharge diagnoses, and exposure was identified from outpatient prescriptions. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Based on 4059 cases and 40,590 controls, an increased risk of HS was found in current use of SSRIs (OR 1.39, 95% CI 1.22–1.58), selective serotonin and noradrenaline reuptake inhibitors (1.69, 1.35–2.11), noradrenergic and specific serotonergic ADs (1.44, 1.22–1.69), and noradrenaline reuptake inhibitors (3.81, 1.54–9.43) compared with tri- and tetracyclic antidepressants. An increased risk of HS was seen in patients with a high baseline risk of bleeding and in patients with depression. The risk of HS varied between individual ADs. CONCLUSION: Our study shows that the use of medications inhibiting serotonin and/or noradrenaline reuptake increases the risk of HS in patients aged 65 years and older and that the risk varies across individual ADs.

INTRODUCTION: Given the sparsity of longitudinal studies on colonoscopy use, we quantified utilization of repeat colonoscopy within 10 years and the proportion of persons with polypectomies at first repeat colonoscopy using a large German claims database. METHODS: Based on the German Pharmacoepidemiological Research Database, we identified persons who underwent colonoscopy between 2006 and 2015 (index colonoscopy) and assessed colonoscopies and polypectomies during follow-up. We defined 3 subcohorts based on available procedure/diagnosis codes at index colonoscopy: persons with snare polypectomy, which is reimbursable for lesions ≥5 mm in size (cohort 1), with a forceps polypectomy (cohort 2), and without such procedures/diagnoses (cohort 3). We stratified all analyses by diagnostic vs screening index colonoscopy. RESULTS: Overall, we included 3,076,657 persons (cohort 1–3: 15%, 13%, 72%). Among persons with screening index colonoscopy (30%), the proportions with a repeat colonoscopy within 10 years in cohorts 1, 2, and 3 were 78%, 66%, and 43%, respectively, and a snare polypectomy at first repeat colonoscopy was performed in 27%, 17%, and 12%, respectively. In cohort 1, 32% of persons with a (first) repeat colonoscopy after 9 years had a snare polypectomy (after 3 years: 25%). Among persons with diagnostic index colonoscopies, 80%, 78%, and 65% had a repeat colonoscopy, and 27%, 17%, and 10% had a snare polypectomy at first repeat colonoscopy, respectively. DISCUSSION: Our study suggests substantial underuse of repeat colonoscopy among persons with previous snare polypectomy and overuse among lower risk groups. One-quarter of persons with a snare polypectomy at baseline had another snare polypectomy at first repeat colonoscopy.