Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol

Severe acute respiratory syndrome coronavirus 2 (SARS- CoV- 2), the virus responsible for coronavirus disease 2019 (COVID- 19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin- converting enzyme 2 (ACE2), which facilitates SARS- CoV- 2 host cell entry, may be impacted by angiotensin- converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long- term outpatient ACEI or ARB upon hospitalization with COVID- 19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163400/2/jch14011_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163400/1/jch14011.pd

Effects of juvenile host density and food availability on adult immune response, parasite resistance and virulence in a Daphnia-parasite system

Host density can increase infection rates and reduce host fitness as increasing population density enhances the risk of becoming infected either through increased encounter rate or because host condition may decline. Conceivably, potential hosts could take high host density as a cue to up-regulate their defence systems. However, as host density usually covaries with food availability, it is difficult to examine the importance of host density in isolation. Thus, we performed two full-factorial experiments that varied juvenile densities of Daphnia magna (a freshwater crustacean) and food availability independently. We also included a simulated high-density treatment, where juvenile experimental animals were kept in filtered media that previously maintained Daphnia at high-density. Upon reaching adulthood, we exposed the Daphnia to their sterilizing bacterial parasite, Pasteuria ramosa, and examined how the juvenile treatments influenced the likelihood and severity of infection (Experiment I) and host immune investment (Experiment II). Neither juvenile density nor food treatments affected the likelihood of infection; however, well-fed hosts that were well-fed as juveniles produced more offspring prior to sterilization than their less well-fed counterparts. By contrast, parasite growth was independent of host juvenile resources or host density. Parasite-exposed hosts had a greater number of circulating haemocytes than controls (i.e., there was a cellular immune response), but the magnitude of immune response was not mediated by food availability or host density. These results suggest that density dependent effects on disease arise primarily through correlated changes in food availability: low food could limit parasitism and potentially curtail epidemics by reducing both the host's and parasite's reproduction as both depend on the same food

Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine .

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH

Local human pressures influence gene flow in a hybridizing Daphnia species complex

International audienceAnthropogenic environmental changes are considered critical drivers of the genetic structure of populations and communities through, for example, the facilitation of introgressive hybridization between syntopic species. However, the mechanisms by which environmental perturbations trigger changes in the genetic structure of populations and communities, such as the processes that determine the directionality of hybridization and patterns of mitochondrial introgression over many generations, remain largely unexplored. In this study, the changes in genetic structure of hybridizing members of the Daphnia longispina species complex were reconstructed over the last 100years for three large temperate lakes under strong anthropogenic pressures via palaeogenetic analyses of resting egg banks. Drastic changes in the genetic structure of the Daphnia community, associated with hybridization events between D.longispina and D.galeata and subsequent introgression, were detected in Lakes Geneva and Bourget. In Lake Bourget, these changes were induced by the successful establishment of D.galeata with rising phosphorus levels and reinforced by the sensitivity of D.longispina to fish predation pressure. In Lake Geneva, the pattern of hybridization during eutrophication is more likely a function of the original taxonomic composition of the species complex in this lake. Lakes seem to require at least a meso-oligotrophic status to allow D.galeata populations to establish and accordingly no D.galeata genotypes were found in the egg bank of oligotrophic Lake Annecy. In contrast to the generally assumed pattern of unidirectional hybridization in this species complex, bidirectional hybridization was recorded in Lakes Geneva and Bourget. Our results also demonstrate complex genetic trajectories within this species complex and highlight the irreversibility of changes in the genotypic architecture of populations driven by local human pressures. Finally, we show that extensive hybridization and introgression do not necessarily result in a large and homogenous hybrid swarm

Local human pressures influence gene flow in a hybridizing Daphnia species complex

International audienceAnthropogenic environmental changes are considered critical drivers of the genetic structure of populations and communities through, for example, the facilitation of introgressive hybridization between syntopic species. However, the mechanisms by which environmental perturbations trigger changes in the genetic structure of populations and communities, such as the processes that determine the directionality of hybridization and patterns of mitochondrial introgression over many generations, remain largely unexplored. In this study, the changes in genetic structure of hybridizing members of the Daphnia longispina species complex were reconstructed over the last 100years for three large temperate lakes under strong anthropogenic pressures via palaeogenetic analyses of resting egg banks. Drastic changes in the genetic structure of the Daphnia community, associated with hybridization events between D.longispina and D.galeata and subsequent introgression, were detected in Lakes Geneva and Bourget. In Lake Bourget, these changes were induced by the successful establishment of D.galeata with rising phosphorus levels and reinforced by the sensitivity of D.longispina to fish predation pressure. In Lake Geneva, the pattern of hybridization during eutrophication is more likely a function of the original taxonomic composition of the species complex in this lake. Lakes seem to require at least a meso-oligotrophic status to allow D.galeata populations to establish and accordingly no D.galeata genotypes were found in the egg bank of oligotrophic Lake Annecy. In contrast to the generally assumed pattern of unidirectional hybridization in this species complex, bidirectional hybridization was recorded in Lakes Geneva and Bourget. Our results also demonstrate complex genetic trajectories within this species complex and highlight the irreversibility of changes in the genotypic architecture of populations driven by local human pressures. Finally, we show that extensive hybridization and introgression do not necessarily result in a large and homogenous hybrid swarm

Mechanistic Toxicodynamic Model for Receptor-Mediated Toxicity of Diazoxon, the Active Metabolite of Diazinon, in Daphnia magna

The organothiophosphate diazinon inhibits the target site acetylcholinesterase only after activation to its metabolite diazoxon. Commonly, the toxicity of xenobiotics toward aquatic organisms is expressed as a function of the external concentration and the resulting effect on the individual level after fixed exposure times. This approach does not account for the time dependency of internal processes such as uptake, metabolism, and interaction of the toxicant with the target site. Here, we develop a mechanistic toxicodynamic model for Daphnia magna and diazoxon, which accounts for the inhibition of the internal target site acetylcholinesterase and its link to the observable effect, immobilization, and mortality. The model was parametrized by experiments performed in vitro with the active metabolite diazoxon on enzyme extracts and in vivo with the parent compound diazinon. The mechanism of acetylcholinesterase inhibition was shown to occur irreversibly in two steps via formation of a reversible enzyme inhibitor complex. The corresponding kinetic parameters revealed a very high sensitivity of acetylcholinesterase from D. magna toward diazoxon, which corresponds well with the high toxicity of diazinon toward this species. Recovery of enzyme activity but no recovery from immobilization was observed after in vivo exposure to diazinon. The toxicodynamic model combining all in vitro and in vivo parameters was successfully applied to describe the time course of immobilization in dependence of acetylcholinesterase activity during exposure to diazinon. The threshold value for enzyme activity below which immobilization set in amounted to 40% of the control activity. Furthermore, the model enabled the prediction of the time-dependent diazoxon concentration directly present at the target site

10 simple rules for a supportive lab environment

The transition to principal investigator (PI), or lab leader, can be challenging, partially due to the need to fulfil new managerial and leadership responsibilities. One key aspect of this role, which is often not explicitly discussed, is creating a supportive lab environment. Here, we present ten simple rules to guide the new PI in the development of their own positive and thriving lab atmosphere. These rules were written and voted on collaboratively, by the students and mentees of Professor Mark Stokes, who inspired this piec