Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

The marine macroalga Ulva mutabilis (Chlorophyta) develops into callus-like colonies consisting of undifferentiated cells and abnormal cell walls under axenic conditions. Ulva mutabilis is routinely cultured with two bacteria, the Roseovarius sp. MS2 strain and the Maribacter sp. MS6 strain, which release morphogenetic compounds and ensure proper algal morphogenesis. Using this tripartite community as an emerging model system, we tested the hypothesis that the bacterial-algal interactions evolved as a result of mutually taking advantage of signals in the environment. Our study aimed to determine whether cross-kingdom crosstalk is mediated by the attraction of bacteria through algal chemotactic signals. Roseovarius sp. MS2 senses the known osmolyte dimethylsulfoniopropionate (DMSP) released by Ulva into the growth medium. Roseovarius sp. is attracted by DMSP and takes it up rapidly such that DMSP can only be determined in axenic growth media. As DMSP did not promote bacterial growth under the tested conditions, Roseovarius benefited solely from glycerol as the carbon source provided by Ulva. Roseovarius quickly catabolized DMSP into methanethiol (MeSH) and dimethylsulphide (DMS). We conclude that many bacteria can use DMSP as a reliable signal indicating a food source and promote the subsequent development and morphogenesis in Ulva.

Background The spatial and temporal dynamics of SARS-CoV-2 have been described in case series and retrospective studies. In this study, we provide a coherent overview of the duration of viral detection and viral RNA load in COVID-19 patients, stratified by specimen type, clinical severity, and age. Method We systematically searched PubMed/MEDLINE and Cochrane review database for studies published between 1.11.2019 and 23.04.2020. We pooled the data of selected studies (22/7226 (650 patients) for meta-analysis) to estimate duration of viral detection and visualized viral load over time. Findings Our analysis showed consistent viral detection from specimen from the upper respiratory tract (URT), the lower respiratory tract (LRT), and faeces, irrespective of the clinical severity of COVID-19. Our analysis suggests that SARS-CoV-2 persists for a longer duration in the LRT compared to the URT in adult patients (5•7 days in mild; 5•9 days in moderate-severe patients). The differences in the duration of viral detection between mild and moderate-severe patients is limited in the LRT, but an indication of longer duration of viral detection for moderate-severe patients was observed in feces (15 days in mild vs. 21 days in moderate-severe patients) and the URT (12 days in mild vs. 16 days in moderate-severe patients). Further, viral load was demonstrated to peak in earlier stages of infection in the URT compared to LRT. Interpretation This review may aid mathematical modelling and help in defining appropriate endpoints for clinical trails with antivirals in COVID-19. Funding The project has received funding support from Innovation Fund Denmark.

Macroalgal microbiomes have core functions related to biofilm formation, growth, and morphogenesis of seaweeds. In particular, the growth and development of the sea lettuce Ulva spp. (Chlorophyta) depend on bacteria releasing morphogenetic compounds. Under axenic conditions, the macroalga Ulva mutabilis develops a callus-like phenotype with cell wall protrusions. However, co-culturing with Roseovarius sp. (MS2) and Maribacter sp. (MS6), which produce various stimulatory chemical mediators, completely recovers morphogenesis. This ecological reconstruction forms a tripartite community which can be further studied for its role in cross-kingdom interactions. Hence, our study sought to identify algal growth- and morphogenesis-promoting factors (AGMPFs) capable of phenocopying the activity of Maribacter spp. We performed bioassay-guided solid-phase extraction in water samples collected from U. mutabilis aquaculture systems. We uncovered novel ecophysiological functions of thallusin, a sesquiterpenoid morphogen, identified for the first time in algal aquaculture. Thallusin, released by Maribacter sp., induced rhizoid and cell wall formation at a concentration of 11 pmol l−1. We demonstrated that gametes acquired the iron complex of thallusin, thereby linking morphogenetic processes with intracellular iron homeostasis. Understanding macroalgae–bacteria interactions permits further elucidation of the evolution of multicellularity and cellular differentiation, and development of new applications in microbiome-mediated aquaculture systems.

Background Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed. Methods We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1–4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined. Findings The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration. Interpretation UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials. Funding The study was funded by Innovationsfonden Denmark and UNION therapeutics.

The marine green macroalga Ulva (Chlorophyta) lives in a mutualistic symbiosis with bacteria that influence growth, development, and morphogenesis. We surveyed changes in Ulva’s chemosphere, which was defined as a space where organisms interact with each other via compounds, such as infochemicals, nutrients, morphogens, and defense compounds. Thereby, Ulva mutabilis cooperates with bacteria, in particular, Roseovarius sp. strain MS2 and Maribacter sp. strain MS6 (formerly identified as Roseobacter sp. strain MS2 and Cytophaga sp. strain MS6). Without this accompanying microbial flora, U. mutabilis forms only callus-like colonies. However, upon addition of the two bacteria species, in effect forming a tripartite community, morphogenesis can be completely restored. Under this strictly standardized condition, bioactive and eco-physiologically-relevant marine natural products can be discovered. Solid phase extracted waterborne metabolites were analyzed using a metabolomics platform, facilitating gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) analysis, combined with the necessary acquisition of biological metadata. Multivariate statistics of the GC-MS and LC-MS data revealed strong differences between Ulva’s growth phases, as well as between the axenic Ulva cultures and the tripartite community. Waterborne biomarkers, including glycerol, were identified as potential indicators for algal carbon source and bacterial-algal interactions. Furthermore, it was demonstrated that U. mutabilis releases glycerol that can be utilized for growth by Roseovarius sp. MS2.

Growth and morphogenesis of the sea lettuce Ulva (Chlorophyta) depends on the combination of regulative morphogenetic compounds released by specific associated bacteria. Axenic Ulva gametes develop parthenogenetically into callus-like colonies consisting of undifferentiated cells without normal cell walls. In Ulva mutabilis Føyn, two bacterial strains, Maribacter sp. strain MS6 and Roseovarius strain MS2, can restore the complete algal morphogenesis forming a tripartite symbiotic community. Morphogenetic compounds ( = morphogens) released by the MS6-strain induce rhizoid formation and cell wall development in U. mutabilis, while several bacteria of the Roseobacter clade, including the MS2-strain, promote blade cell division and thallus elongation. In this study, 12 type strains of the Flavobacteriaceae family, including six Maribacter strains, were examined for their morphogenetic activity in comparison to the original MS6-strain isolated from U. mutabilis. The bioassay is based on the functional complementation of the tested Flavobacteriaceae strain with the Roseovarius MS2-strain. If the test-strain possesses morphogenetic activity complementary to the factor of the MS2-strain, the complete morphogenesis of U. mutabilis can be restored. This bioassay revealed not only the stand-alone activity of certain bacteria, but also their essential capability to take part in the orchestrated bacteria-induced morphogenesis of U. mutabilis. All Maribacter type strains isolated from Ulva could phenocopy the MS6-strain, whereas some distantly related Flavobacteriaceae and a Maribacter strain isolated from a red alga did not possess any activity.

Although a reduction in hospital admissions of acute coronary syndromes (ACS) patients has been observed globally during the coronavirus disease 2019 (COVID-19) pandemic, clinical features of those patients have not been fully investigated. The aim of the present analysis is to investigate the incidence, clinical presentation, and outcomes of patients with ACS during the COVID-19 pandemic. We performed a retrospective analysis of consecutive patients who were admitted for ACS at our institution between March 1 and April 20, 2020 and compared with the equivalent period in 2019. Admissions for acute myocardial infarction (AMI) reduced by 39.5% in 2020 compared with the equivalent period in 2019. Owing to the emergency medical services (EMS) of our region, all time components of ST-elevated myocardial infarction care were similar during the COVID-19 outbreak as compared with the previous year’s dataset. Among the 106 ACS patients in 2020, 7 patients tested positive for COVID-19. Higher incidence of type 2 myocardial infarction (29% vs. 4%, p = 0.0497) and elevated D-dimer levels (5650 μg/l [interquartile range (IQR) 1905–13,625 μg/l] vs. 400 μg/l [IQR 270–1050 μg/l], p = 0.02) were observed in COVID-19 patients. In sum, a significant reduction in admission for AMI was observed during the COVID-19 pandemic. COVID-19 patients were characterized by elevated D-dimer levels on admission, reflecting enhanced COVID-19 related thrombogenicity. The prehospital evaluation by EMS may have played an important role for the timely revascularization for STEMI patients. Electronic supplementary material The online version of this article (10.1007/s11239-020-02340-z) contains supplementary material, which is available to authorized users.