Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult outpatients: CONTAIN phase II randomised controlled trial.

OBJECTIVE: To determine if inhaled and intranasal ciclesonide are superior to placebo at decreasing respiratory symptoms in adult outpatients with covid-19. DESIGN: Randomised, double blind, placebo controlled trial. SETTING: Three Canadian provinces (Quebec, Ontario, and British Columbia). PARTICIPANTS: 203 adults aged 18 years and older with polymerase chain reaction confirmed covid-19, presenting with fever, cough, or dyspnoea. INTERVENTION: Participants were randomised to receive either inhaled ciclesonide (600 µg twice daily) and intranasal ciclesonide (200 µg daily) or metered dose inhaler and nasal saline placebos for 14 days. MAIN OUTCOME MEASURES: The primary outcome was symptom resolution at day 7. Analyses were conducted on the modified intention-to-treat population (participants who took at least one dose of study drug and completed one follow-up survey) and adjusted for stratified randomisation by sex. RESULTS: The modified intention-to-treat population included 203 participants: 105 were randomly assigned to ciclesonide (excluding two dropouts and one loss to follow-up) and 98 to placebo (excluding three dropouts and six losses to follow-up). The median age was 35 years (interquartile range 27-47 years) and 54% were women. The proportion of participants with resolution of symptoms by day 7 did not differ significantly between the intervention group (42/105, 40%) and control group (34/98, 35%); absolute adjusted risk difference 5.5% (95% confidence interval -7.8% to 18.8%). Results might be limited to the population studied, which mainly included younger adults without comorbidities. The trial was stopped early, therefore could have been underpowered. CONCLUSION: Compared with placebo, the combination of inhaled and intranasal ciclesonide did not show a statistically significant increase in resolution of symptoms among healthier young adults with covid-19 presenting with prominent respiratory symptoms. As evidence is insufficient to determine the benefit of inhaled and intranasal corticosteroids in the treatment of covid-19, further research is needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT04435795.

Regulation of cortical stability by RhoGEF3 in mitotic Sensory Organ Precursor cells in Drosophila.

In epithelia, mitotic cells round up and push against their neighbors to divide. Mitotic rounding results from increased assembly of F-actin and cortical recruitment of Myosin II, leading to increased cortical stability. Whether this process is developmentally regulated is not well known. Here, we examined the regulation of cortical stability in Sensory Organ Precursor cells (SOPs) in the Drosophila pupal notum. SOPs differed in apical shape and actomyosin dynamics from their epidermal neighbors prior to division, and appeared to have a more rigid cortex at mitosis. We identified RhoGEF3 as an actin regulator expressed at higher levels in SOPs, and showed that RhoGEF3 had in vitro GTPase Exchange Factor (GEF) activity for Cdc42. Additionally, RhoGEF3 genetically interacted with both Cdc42 and Rac1 when overexpressed in the fly eye. Using a null RhoGEF3 mutation generated by CRISPR-mediated homologous recombination, we showed using live imaging that the RhoGEF3 gene, despite being dispensable for normal development, contributed to cortical stability in dividing SOPs. We therefore suggest that cortical stability is developmentally regulated in dividing SOPs of the fly notum.

Planar Cell Polarity Breaks the Symmetry of PAR Protein Distribution prior to Mitosis in Drosophila Sensory Organ Precursor Cells.

During development, cell-fate diversity can result from the unequal segregation of fate determinants at mitosis. Polarization of the mother cell is essential for asymmetric cell division (ACD). It often involves the formation of a cortical domain containing the PAR complex proteins Par3, Par6, and atypical protein kinase C (aPKC). In the fly notum, sensory organ precursor cells (SOPs) divide asymmetrically within the plane of the epithelium and along the body axis to generate two distinct cells. Fate asymmetry depends on the asymmetric localization of the PAR complex. In the absence of planar cell polarity (PCP), SOPs divide with a random planar orientation but still asymmetrically, showing that PCP is dispensable for PAR asymmetry at mitosis. To study when and how the PAR complex localizes asymmetrically, we have used a quantitative imaging approach to measure the planar polarization of the proteins Bazooka (Baz, fly Par3), Par6, and aPKC in living pupae. By using imaging of functional GFP-tagged proteins with image processing and computational modeling, we find that Baz, Par6, and aPKC become planar polarized prior to mitosis in a manner independent of the AuroraA kinase and that PCP is required for the planar polarization of Baz, Par6, and aPKC during interphase. This indicates that a "mitosis rescue" mechanism establishes asymmetry at mitosis in PCP mutants. This study therefore identifies PCP as the initial symmetry-breaking signal for the planar polarization of PAR proteins in asymmetrically dividing SOPs.