The Ca and Mg isotope record of the Cryogenian Trezona carbon isotope excursion

This work was supported by a grant from the Simons Foundation (SCOL 611878, ASCA) and the Carlsberg Foundation to ASCA. ASCA and CJB also acknowledge support from the Danish National Research Foundation (Grant No. DNRF53). ACM and CVR acknowledge support from NSF (EAR-0842946) for funding fieldwork on the Trezona Formation in South Australia. JAH acknowledges support from NSF (IES-1410317) and from NSF OCE CAREER Grant (1654571).The Trezona carbon isotope excursion is recorded on five different continents in platform carbonates deposited prior to the end-Cryogenian Marinoan glaciation (>635 Ma) and represents a change in carbon isotope values of 16–18‰. Based on the spatial and temporal reproducibility, the excursion previously has been interpreted as tracking the carbon isotopic composition of dissolved inorganic carbon in the global ocean before the descent into a snowball Earth. However, in modern restricted shallow marine and freshwater settings, carbon isotope values have a similarly large range, which is mostly independent from open ocean chemistry and instead reflects local processes. In this study, we combine calcium, magnesium, and strontium isotope geochemistry with a numerical model of carbonate diagenesis to disentangle the degree to which the Trezona excursion reflects changes in global seawater chemistry versus local shallow-water platform environments. Our analysis demonstrates that the most extreme carbon isotope values (∼-10‰ versus +10‰) are preserved in former platform aragonite that was neomorphosed to calcite during sediment-buffered conditions and record the primary carbon isotope composition of platform-top surface waters. In contrast, the downturn and recovery of the Trezona excursion are recorded in carbonates that were altered during early fluid-buffered diagenesis and commonly are dolomitized. We also find that the nadir of the Trezona excursion is associated with a fractional increase in siliciclastic sediments, whereas the recovery from the excursion correlates with a relative increase in carbonate. This relationship suggests that the extreme negative isotopic shift in platform aragonite occurred in concert with periods of increased input of siliciclastic sediments, changes in water depth, and possibly nutrients to platform environments. Although the process for generating extremely negative carbon isotope values in Neoproterozoic platform carbonates remains enigmatic, we speculate that these excursions reflect kinetic isotope effects associated with CO2 invasion in platform waters during periods of intense primary productivity.Publisher PDFPeer reviewe

Complete response to anti-interleukin-5 biologics in a real-life setting:results from the nationwide Danish Severe Asthma Register

BACKGROUND: Phase III regulatory trials show that anti-interleukin (IL)-5 biologics efficiently reduce exacerbations and the use of maintenance oral corticosteroids (mOCS) in patients with severe eosinophilic asthma. However, patients eligible for these trials differ significantly compared with real-life severe asthma populations. Therefore, our aim was to explore efficacy in a real-life setting. The Danish Severe Asthma Register (DSAR) is a complete, nationwide register that comprises all Danish patients on biological therapy for severe asthma. METHODS: This prospective study identified patients in the DSAR who were complete responders to anti-IL-5 biologics after 1 year of treatment. A complete response was defined as resolution of the parameter setting the indication, i.e. recurrent exacerbations and/or use of mOCS. RESULTS: A total of 289 out of 502 (58%) patients were complete responders to anti-IL-5 biologics after 12 months. Complete responders had greater improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire (ACQ) score compared with noncomplete responders (Δ 210 versus 30 mL; p<0.0001 and Δ −1.04 versus −0.68; p=0.016, respectively). A complete response was predicted by age at onset, less severe disease at baseline (i.e. no mOCS and lower ACQ score) and higher blood eosinophils. CONCLUSIONS: More than half of Danish patients treated with anti-IL-5 biologics for severe asthma achieve a complete response to treatment, thereby becoming free from asthma exacerbations and the need for mOCS. Complete responders also achieved superior effects on lung function and symptoms compared with noncomplete responders

An early diagenetic deglacial origin for basal Ediacaran “cap dolostones”

ASCA acknowledges support from The Carlsberg Foundation. JAH acknowledges support from NSF grant no. IES1410317 and from National Science Foundation OCE CAREER Grant No. 1654571. ASA and CJB acknowledges support from the Danish National Research Foundation (Grant No. DNRF53).The beginning of the Ediacaran Period (∼635 Ma) is marked by conspicuous dolostone units that cap Marinoan glacial deposits worldwide. The extent and sedimentary characteristics of the cap dolostones indicate that anomalous carbonate over-saturation coincided with deglacial sea-level rise and ocean warming. However, the geochemical variability within cap dolostones, both between continents, across single continental margins, and within individual stratigraphic sections has been difficult to reconcile with depositional models. Using a compilation of new calcium and magnesium isotope measurements in Marinoan cap dolostone successions worldwide, we show that the geochemical variability can be explained by early diagenetic dolomitization of aragonite along a spectrum of fluid- and sediment-buffered conditions. Dolostones from the outer platform formed under fluid-buffered conditions, whereas dolostones on the inner platform and foreslope environment formed under sediment-buffered conditions. This spatial pattern of dolomitizing conditions is consistent with buoyant recirculation of glacial seawater within carbonate platforms driven by the deglacial sea-level rise and development of a meltwater surface ocean. Using a numerical diagenetic model to evaluate the geochemical differences between sediment- and fluid-buffered cap dolostone units, we constrain the chemical and isotopic composition of both the dolomitizing fluid (glacial seawater [δ13C∼ 0–2‰]), the meltwater lens (δ13C∼−11‰), and the primary aragonite sediment (δ13C∼−6 to −3‰). These model end-members do not imply that primary geochemical variability did not exist but demonstrates that it is not necessary to change the chemistry of seawater to explain the global stratigraphic variability in the geochemistry of basal Ediacaran cap dolostones. Our results provide a novel framework for understanding the geochemical variability of cap dolostone units, including large excursions in carbon isotopes, and how this variability is the product of local diagenetic processes expressed globally in continental margin environments following the last Snowball Earth.PostprintPeer reviewe

Characterization of patients in the International Severe Asthma Registry with high steroid exposure who did or did not initiate biologic therapy

Peer reviewedPostprin

Association between T2-related co-morbidities and effectiveness of biologics in severe asthma

Acknowledgments The authors thank Mr. Joash Tan (BSc, Hons), of the Observational and Pragmatic Research Institute (OPRI), and Ms Andrea Lim (BSc, Hons) of the Observational Pragmatic Research Institute (OPRI) for their editorial and formatting assistance that supported the development of this publication. Funding statement: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. AstraZeneca UK LimitedPeer reviewe

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy

Background: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. Objective: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. Methods: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non-oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. Results: For non-OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. Conclusions: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction

Distributed practice. The more the merrier? A randomised bronchoscopy simulation study

Introduction: The distribution of practice affects the acquisition of skills. Distributed practice has shown to be more effective for skills acquisition than massed training. However, it remains unknown as to which is the most effective distributed practice schedule for learning bronchoscopy skills through simulation training. This study compares two distributed practice schedules: One-day distributed practice and weekly distributed practice. Method: Twenty physicians in training were randomly assigned to one-day distributed or weekly distributed bronchoscopy simulation practice. Performance was assessed with a pre-test, a post-test after each practice session, and a 4-week retention test using previously validated simulator measures. Data were analysed with repeated measures ANOVA. Results: No interaction was found between group and test (F(4,72) <1.68, p>0.16), except for the measure ‘percent-segments-entered’, and no main effect of group was found for any of the measures (F(1,72)< 0.87, p>0.36), which indicates that there was no difference between the learning curves of the one-day distributed practice schedule and the weekly distributed practice schedule. Discussion: We found no difference in effectiveness of bronchoscopy skills acquisition between the one-day distributed practice and the weekly distributed practice. This finding suggests that the choice of bronchoscopy training practice may be guided by what best suits the clinical practice

Disentangling the record of diagenesis, local redox conditions, and global seawater chemistry during the latest Ordovician glaciation

The Late Ordovician stratigraphic record integrates glacio-eustatic processes, water-column redox conditions and carbon cycle dynamics. This complex stratigraphic record, however, is dominated by deposits from epeiric seas that are susceptible to local physical and chemical processes decoupled from the open ocean. This study contributes a unique deep water basinal perspective to the Late Ordovician (Hirnantian) glacial record and the perturbations in seawater chemistry that may have contributed to the Hirnantian mass extinction event. We analyze recently drilled cores and outcrop samples from the upper Vinini Formation in central Nevada and report combined trace- and major element geochemistry, Fe speciation (FePy/FeHR and FeHR/FeT), and stable isotope chemostratigraphy (δ13COrg and δ34SPy). Measurements of paired samples from outcrop and core reveal that reactive Fe is preserved mainly as pyrite in core samples, while outcrop samples have been significantly altered as pyrite has been oxidized and remobilized by modern weathering processes. Fe speciation in the more pristine core samples indicates persistent deep water anoxia, at least locally through the Late Ordovician, in contrast to the prevailing interpretation of increased Hirnantian water column oxygenation in shallower environments. Deep water redox conditions were likely decoupled from shallower environments by a basinal shift in organic matter export driven by decreasing rates of organic matter degradation and decreasing shelf areas. The variable magnitude in the record of the Hirnantian carbon isotope excursion may be explained by this increased storage of isotopically light carbon in the deep ocean which, in combination with increased glacio-eustatic restriction, would strengthen lateral- and vertical gradients in seawater chemistry. We adopt multivariate statistical methods to deconstruct the spatial and temporal re-organization of seawater chemistry during the Hirnantian glaciation and attempt to isolate the latent magnitude and global perturbation in the carbon cycle. We speculate, using a two component mixing model and residual estimates from principal component analysis, that the secular open ocean Hirnantian C isotope excursion possibly amounts to only ∼ +1.5‰. Such an increase could be mechanistically driven by the combination of sea-level fall, persistent deep water anoxia, and cooler glacial temperatures that increased the organic carbon burial efficiency in the deeper basins