Aerosolized Amiloride for the Treatment of Lung Disease in Cystic Fibrosis

To the Editor: The April 26 issue of the Journal presented encouraging results by Knowles et al. regarding the beneficial effects of aerosolized amiloride in the treatment of cystic fibrosis.1 The introduction and discussion sections of this article described the function of amiloride as an inhibitor of sodium transport in the airway epithelium, and the authors suggested that the beneficial effects observed were exerted “at least in part by increasing the clearance of secretions.” Although the results of this investigation were promising in terms of the improvement in the decline of forced vital capacity in patients with cystic fibrosis, this

Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications

Background Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection. Methods Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab. Findings AAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samples. Induction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection. Interpretation There is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy. Funding NIH Serological Sciences Network, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

A Pilot Study of Aerosolized Amiloride for the Treatment of Lung Disease in Cystic Fibrosis

Excessive active absorption of sodium is a unique abnormality of the airway epithelium in patients with cystic fibrosis. This defect is associated with thickened mucus and poor clearance of airway secretions and may contribute to the pulmonary disease in these patients. To study whether the inhibition of excessive absorption of sodium might affect the course of lung disease in cystic fibrosis, we performed a double-blind, crossover trial comparing aerosolized amiloride (5 mmol per liter; 3.5 ml four times daily), a sodium-channel blocker, with vehicle alone. Fourteen of the 18 adult patients initially enrolled in the study completed the one-year trial (25 weeks for each treatment). The mean (±SEM) loss of forced vital capacity (FVC) was reduced from 3.39±1.13 ml per day during treatment with vehicle alone to 1.44±0.67 ml per day during treatment with amiloride (P<0.04). A measured index of sputum viscosity and elasticity was abnormal during treatment with vehicle alone and improved during treatment with amiloride. Calculated indexes of mucociliary and cough clearance also improved during amiloride treatment. No systemic, respiratory, or subjective toxic effects of amiloride were noted. We conclude from this preliminary study that aerosolized amiloride can be safely administered to adults with cystic fibrosis. The slowing of the loss of FVC and the improvement in sputum viscosity and elasticity suggest a beneficial clinical effect. Aerosolized amiloride deserves further evaluation in the treatment of lung disease in patients with cystic fibrosis

Chewing substances with or without tobacco and risk of cardiovascular disease in Asia: a meta-analysis*

Objective: To assess whether people who ever use any form of chewing substance in Asia are at increased risk of cardiovascular disease (CVD). Methods: PubMed and ISI Web of Science were searched for relevant studies, with no limitation on language or study year. Studies were included if they provided quantitative estimate of the association between ever use of chewing substance and the occurrence of CVD. Two authors independently implemented inclusion criteria, abstracted study characteristics, and performed meta-analysis. Summary relative risks were estimated on the basis of a random effect model. We used Q statistic and Egger’s test to examine heterogeneity across studies and potential publication bias, respectively. Results: Eight eligible studies were included. The relative risk of CVD for ever using chewing substances with or without tobacco was 1.26 (95% confidence interval (CI) 1.12–1.40), which was unchanged when restricted to cohort studies [1.25 (1.08–1.42)] or cohort studies in Taiwan [1.31 (1.12–1.51)]. The summary relative risk for ischemic heart disease was 1.27 (1.02–1.52), and was lowered to 1.26 (0.85–1.67) after exclusion of a cross-sectional study. The overall relative risk for cerebrovascular disease was 1.32 (1.08–1.56). On the basis of the Taiwan data, the summary relative risk of CVD for betel (Areca catechu) chewing was 1.30 (1.17–1.44). Data on dose-response were limited to betel chewing in Taiwan, suggesting a relationship between risk of CVD and cumulative exposure. Two large cohorts in Taiwan reported a greater risk of CVD with betel chewing than with smoking. Conclusions: An association was detected between betel chewing with or without tobacco and the risk of CVD. Betel chewing may impose a greater CVD risk than smoking. More effort is needed in developing betel chewing cessation programmes. The relationship between betel chewing and subgroups of CVD requires further investigation