COVID-19 Immunologic Antiviral Therapy With Omalizumab (CIAO)-a Randomized Controlled Clinical Trial.

Background: Omalizumab is an anti-immunoglobulin E monoclonal antibody used to treat moderate to severe chronic idiopathic urticaria, asthma, and nasal polyps. Recent research suggested that omalizumab may enhance the innate antiviral response and have anti-inflammatory properties. Objective: We aimed to investigate the efficacy and safety of omalizumab in adults hospitalized for coronavirus disease 2019 (COVID-19) pneumonia. Methods: This was a phase II randomized, double blind, placebo-controlled trial comparing omalizumab with placebo (in addition to standard of care) in hospitalized patients with COVID-19. The primary endpoint was the composite of mechanical ventilation and/or death at day 14. Secondary endpoints included all-cause mortality at day 28, time to clinical improvement, and duration of hospitalization. Results: Of 41 patients recruited, 40 were randomized (20 received the study drug and 20 placebo). The median age of the patients was 74 years and 55.0% were male. Omalizumab was associated with a 92.6% posterior probability of a reduction in mechanical ventilation and death on day 14 with an adjusted odds ratio of 0.11 (95% credible interval 0.002-2.05). Omalizumab was also associated with a 75.9% posterior probability of reduced all-cause mortality on day 28 with an adjusted odds ratio of 0.49 (95% credible interval, 0.06-3.90). No statistically significant differences were found for the time to clinical improvement and duration of hospitalization. Numerically fewer adverse events were reported in the omalizumab group and there were no drug-related serious adverse events. Conclusions: These results suggest that omalizumab could prove protective against death and mechanical ventilation in hospitalized patients with COVID-19. This study could also support the development of a phase III trial program investigating the antiviral and anti-inflammatory effect of omalizumab for severe respiratory viral illnesses requiring hospital admission. ClinicalTrials.gov ID: NCT04720612.

Spatiotemporal coordination of Greatwall-Endos-PP2A promotes mitotic progression.

Mitotic entry involves inhibition of protein phosphatase 2A bound to its B55/Tws regulatory subunit (PP2A-B55/Tws), which dephosphorylates substrates of mitotic kinases. This inhibition is induced when Greatwall phosphorylates Endos, turning it into an inhibitor of PP2A-Tws. How this mechanism operates spatiotemporally in the cell is incompletely understood. We previously reported that the nuclear export of Greatwall in prophase promotes mitotic progression. Here, we examine the importance of the localized activities of PP2A-Tws and Endos for mitotic regulation. We find that Tws shuttles through the nucleus via a conserved nuclear localization signal (NLS), but expression of Tws in the cytoplasm and not in the nucleus rescues the development of tws mutants. Moreover, we show that Endos must be in the cytoplasm before nuclear envelope breakdown (NEBD) to be efficiently phosphorylated by Greatwall and to bind and inhibit PP2A-Tws. Disrupting the cytoplasmic function of Endos before NEBD results in subsequent mitotic defects. Evidence suggests that this spatiotemporal regulation is conserved in humans.

Proximate determinants of tuberculosis in Indigenous peoples worldwide: a systematic review.

BACKGROUND: Indigenous peoples worldwide carry a disproportionate tuberculosis burden. There is an increasing awareness of the effect of social determinants and proximate determinants such as alcohol use, overcrowding, type 1 and type 2 diabetes, substance misuse, HIV, food insecurity and malnutrition, and smoking on the burden of tuberculosis. We aimed to understand the potential contribution of such determinants to tuberculosis in Indigenous peoples and to document steps taken to address them. METHODS: We did a systematic review using seven databases (MEDLINE, Embase, CINAHL, Global Health, BIOSIS Previews, Web of Science, and the Cochrane Library). We identified English language articles published from Jan 1, 1980, to Dec 20, 2017, reporting the prevalence of proximate determinants of tuberculosis and preventive programmes targeting these determinants in Indigenous communities worldwide. We included any randomised controlled trials, controlled studies, cohort studies, cross-sectional studies, case reports, and qualitative research. Exclusion criteria were articles in languages other than English, full text not available, population was not Indigenous, focused exclusively on children or older people, and studies that focused on pharmacological interventions. FINDINGS: Of 34 255 articles identified, 475 were eligible for inclusion. Most studies confirmed a higher prevalence of proximate determinants in Indigenous communities than in the general population. Diabetes was more frequent in Indigenous communities within high-income countries versus in low-income countries. The prevalence of alcohol use was generally similar to that among non-Indigenous groups, although patterns of drinking often differed. Smoking prevalence and smokeless tobacco consumption were commonly higher in Indigenous groups than in non-Indigenous groups. Food insecurity was highly prevalent in most Indigenous communities evaluated. Substance use was more frequent in Indigenous inhabitants of high-income countries than of low-income countries, with wide variation across Indigenous communities. The literature pertaining to HIV, crowding, and housing conditions among Indigenous peoples was too scant to draw firm conclusions. Preventive programmes that are culturally appropriate targeting these determinants appear feasible, although their effectiveness is largely unproven. INTERPRETATION: Indigenous peoples were generally reported to have a higher prevalence of several proximate determinants of tuberculosis than non-Indigenous peoples, with wide variation across Indigenous communities. These findings emphasise the need for community-led, culturally appropriate strategies to address smoking, food insecurity, and diabetes in Indigenous populations as important public health goals in their own right, and also to reduce the burden of tuberculosis. FUNDING: Canadian Institutes of Health Research.