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.

Canadian Health Care Professionals' Familiarity with Chronic Cough Guidelines and Experiences with Diagnosis and Management: A Cross-Sectional Survey.

INTRODUCTION: Educational programs on chronic cough may improve patient care, but little is known about how Canadian physicians manage this common debilitating condition. We aimed to investigate Canadian physicians' perceptions, attitudes, and knowledge of chronic cough. METHODS: We administered a 10-min anonymous, online, cross-sectional survey to 3321 Canadian physicians in the Leger Opinion Panel who managed adult patients with chronic cough and had been in practice for > 2 years. RESULTS: Between July 30 and September 22, 2021, 179 physicians (101 general practitioners [GPs] and 78 specialists [25 allergists, 28 respirologists, and 25 ear/nose/throat specialists]) completed the survey (response rate: 5.4%). In a month, GPs saw a mean of 27 patients with chronic cough, whereas specialists saw 46. About one-third of physicians appropriately identified a duration of > 8 weeks as the definition for chronic cough. Many physicians reported not using international chronic cough management guidelines. Patient referrals and care pathways varied considerably, and patients frequently experienced lost to follow-up. While physicians endorsed nasal and inhaled corticosteroids as common treatments for chronic cough, they rarely used other guideline-recommended treatments. Both GPs and specialists expressed high interest in education on chronic cough. CONCLUSION: This survey of Canadian physicians demonstrates low uptake of recent advances in chronic cough diagnosis, disease categorization, and pharmacologic management. Canadian physicians also report unfamiliarity with guideline-recommended therapies, including centrally acting neuromodulators for refractory or unexplained chronic cough. This data highlights the need for educational programs and collaborative care models on chronic cough in primary and specialist care.

Exposure to silica and systemic sclerosis: A retrospective cohort study based on the Canadian Scleroderma Research Group.

Introduction: Systemic sclerosis (SSc) is thought to be induced by an environmental trigger in genetically predisposed individuals. This study assessed the demographic and clinical characteristics and disease severity of silica exposed SSc patients. Methods: Data was obtained from the Canadian Scleroderma Research Group (CSRG) cohort, containing 1,439 patients (2004-2019). Univariate and multivariate logistic regression analyses were performed, to determine the phenotype and severity of silica-exposed SSc patients. Mortality was assessed using Cox Survival Regression and Kaplan-Meier analyses. Results: Among 1,439 patients (86.7% females), 95 patients reported exposure to silica. Those exposed were younger, of male sex and with more severe disease. Sex differences were observed where male patients exposed to silica were more likely to be Caucasian and smokers whereas female patients were younger at SSc diagnosis compared to unexposed. Multivariate regression, controlled for multiple confounders, showed that silica exposure was associated with a younger age at diagnosis and worse disease severity and mortality. Conclusion: Exposure to silica was reported in ∼7% of CSRG cohort and ∼20% of male patients and was associated with a worse prognosis in terms of age of diagnosis, organ involvement and mortality. Hence, screening for silica exposure among higher risk individuals may be beneficial and these patients may require closer monitoring for systemic disease.

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.

Latent Tuberculosis in Pregnancy: A Systematic Review.

BACKGROUND: In countries with low tuberculosis (TB) incidence, immigrants from higher incidence countries represent the major pool of individuals with latent TB infection (LTBI). The antenatal period represents an opportunity for immigrant women to access the medical system, and hence for potential screening and treatment of LTBI. However, such screening and treatment during pregnancy remains controversial. OBJECTIVES: In order to further understand the prevalence, natural history, screening and management of LTBI in pregnancy, we conducted a systematic literature review addressing the screening and treatment of LTBI, in pregnant women without known HIV infection. METHODS: A systematic review of 4 databases (Embase, Embase Classic, Medline, Cochrane Library) covering articles published from January 1st 1980 to April 30th 2014. Articles in English, French or Spanish with relevant information on prevalence, natural history, screening tools, screening strategies and treatment of LTBI during pregnancy were eligible for inclusion. Articles were excluded if (1) Full text was not available (2) they were case series or case studies (3) they focused exclusively on prevalence, diagnosis and treatment of active TB (4) the study population was exclusively HIV-infected. RESULTS: Of 4,193 titles initially identified, 208 abstracts were eligible for review. Of these, 30 articles qualified for full text review and 22 were retained: 3 cohort studies, 2 case-control studies, and 17 cross-sectional studies. In the USA, the estimated prevalence of LTBI ranged from 14 to 48% in women tested, and tuberculin skin test (TST) positivity was associated with ethnicity. One study suggested that incidence of active TB was significantly increased during the 180 days postpartum (Incidence rate ratio, 1.95 (95% CI 1.24-3.07). There was a high level of adherence with both skin testing (between 90-100%) and chest radiography (93-100%.). In three studies from low incidence settings, concordance between TST and an interferon-gamma release assay was 77, 88 and 91% with kappa values ranging from 0.26 to 0.45. In low incidence settings, an IGRA may be more specific and less sensitive than TST, and results do not appear to be altered by pregnancy. The proportion of women who attended follow-up visits after positive tuberculin tests varied from 14 to 69%, while 5 to 42% of those who attended follow-up visits completed a minimum of 6 months of isoniazid treatment. One study raised the possibility of an association of pregnancy/post-partum state with INH hepatitis (risk ratio 2,5, 95% CI 0.8-8.2) and fatal hepatotoxicity (rate ratio 4.0, 95% CI 0.2-258). One study deemed INH safe during breastfeeding based on peak concentrations in plasma and breast milk after INH administration. CONCLUSION: Pregnancy is an opportunity to screen for LTBI. Interferon-gamma release assays are likely comparable to tuberculin skin tests and may be used during pregnancy. Efforts should be made to improve adherence with follow-up and treatment post-partum. Further data are needed with respect to safety and feasibility of antepartum INH therapy, and with respect to alternative treatment regimens.