Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes.

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting ß2-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ≥60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting ß2-agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.

Collaborative faculty professional development: Bringing the classroom to the screen

When the higher education practice of face-to-face instruction was disrupted by the COVID pandemic, faculty unaccustomed to and/or uncomfortable with online teaching needed to adapt quickly to serve their students. Fortunately, there are faculty and institutions with long histories of online teaching with much to share about the why and how of offering high-quality, deeply engaging digital learning experiences to support the success of higher education students. The paper explores the collaboration of two universities to create professional development delivered through a virtual workshop series to support faculty needs and encourage an emerging community of practice related to online teaching and learning, jointly envisioned and delivered with pilot funding from the Bill and Melinda Gates Foundation. Four key issues conclude the paper: (1) how can success be measured and supported, (2) how can emerging practices be disseminated beyond workshop participants, (3) how can we respond to the need for changes in how we recognize, incentivize, and reward good teaching, and (4) how do we move forward from here?. © 2021, North American Business Press. All rights reserved.

A preliminary study on the impact of pandemic anthropause on wildlife activities of smooth-coated otters (Lutrogale perspicillata) at Abbas beach, Pulau Pinang and the initiation of citizen science in Malaysia

The Coronavirus 19 (SARS-CoV-2) protracted health crisis has led to the restrictions of human mobility around the world, which ultimately created rare sightings of wildlife activities in public areas. In this paper, we reveal the occurrences of an otter family on the shores of Abbas beach, located in Tanjung Bungah at the north of Pulau Pinang, Malaysia. Observations were conducted for a duration of ten months, unscheduled, during the Malaysian government's full and partial Movement Control Order (MCO). We deduced that the events leading up to the appearances of this particular group of otters could be due to the lack of human presence at the shores, or anthropause, as previous sightings before MCO were not indicated. Also, our findings are significant in regards to explaining that the presence of otters is an important indicator of healthy and balanced eco-faunas where they occurred naturally, followed by the existence of undisturbed quality of water bodies. We identified the otter family as belonging to the smooth-coated otter (Lutrogale perspicillata). Together with this discovery, we diligently emphasise on having proper conservation efforts through the establishment of citizen science among Malaysians, to which the knowledge obtained will enable proactive actions from communities in ensuring harmonious human-wildlife coexistence. © 2021 Malaysian Nature Society. All rights reserved.

The impact of the COVID-19 pandemic on mental health of nurses in British Columbia, Canada using trends analysis across three time points.

PURPOSE: This study examined trends over time in the prevalence of anxiety and depression among Canadian nurses: 6 months before, 1-month after, and 3 months after COVID-19 was declared a pandemic. METHODS: This study adopted a repeated cross-sectional design and surveyed unionized nurses in British Columbia (BC), Canada on three occasions: September 2019 (Time 1, prepandemic), April 2020 (Time 2, early-pandemic) and June 2020 (Time 3). RESULTS: A total of 10,117 responses were collected across three timepoints. This study found a significant increase of 10% to 15% in anxiety and depression between Time 1 and 2, and relative stability between Time 2 and 3, with Time 3 levels still higher than Time 1 levels. Cross-sector analyses showed similar patterns of findings for acute care and community nurses. Long-term care nurses showed a two-fold increase in the prevalence of anxiety early pandemic, followed by a sharper decline mid pandemic. CONCLUSIONS: COVID-19 has had short- and mid-term mental health implications for BC nurses particularly among those in the long-term care sector. Future research should evaluate the impact of COVID-19 on the mental health of health workers in different contexts, such as jurisdictional analyses, and better understand the long-term health and labor market consequences of elevated mental health symptoms over an extended time period.

Effect of ACE1 polymorphism rs1799752 on protein levels of ACE2, the SARS-CoV-2 entry receptor, in alveolar lung epithelium.

Increased protein levels of ACE2 in alveolar epithelium of subjects who are homozygous for the ACE1 insertion of rs1799752 might facilitate host cell entry of #SARSCoV2 and explain the higher prevalence of #COVID19 in certain regions https://bit.ly/3k6aAE8.

The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-related CoVs encode 3 tandem macrodomains within nonstructural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated antiviral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here, we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) Mac1 domains exhibit similar structural folds, and all 3 proteins bound to ADP-ribose with affinities in the low micromolar range. Importantly, using ADP-ribose-detecting binding reagents in both a gel-based assay and novel enzyme-linked immunosorbent assays (ELISAs), we demonstrated de-MARylating activity for all 3 CoV Mac1 proteins, with the SARS-CoV-2 Mac1 protein leading to a more rapid loss of substrate than the others. In addition, none of these enzymes could hydrolyze poly-ADP-ribose. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are MAR-hydrolases with similar functions, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity.IMPORTANCE SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused more than 1.2 million deaths worldwide. With no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic posttranslational process that is increasingly being recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here, we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose and describe its ADP-ribose binding and hydrolysis activities in direct comparison to those of SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.

Expression of ACE2, the SARS-CoV-2 Receptor, in Lung Tissue of Patients With Type 2 Diabetes.

Increased expression of pulmonary ACE2, the SARS-CoV-2 receptor, could contribute to increased infectivity of COVID-19 in patients with diabetes, but ACE2 expression has not been studied in lung tissue of subjects with diabetes. We therefore studied ACE2 mRNA and protein expression in lung tissue samples of subjects with and without diabetes that were collected between 2002 and 2020 from patients undergoing lobectomy for lung tumors. For RT-PCR analyses, samples from 15 subjects with diabetes were compared with 91 randomly chosen control samples. For immunohistochemical staining, samples from 26 subjects with diabetes were compared with 66 randomly chosen control samples. mRNA expression of ACE2 was measured by quantitative RT-PCR. Protein levels of ACE2 were visualized by immunohistochemistry on paraffin-embedded lung tissue samples and quantified in alveolar and bronchial epithelium. Pulmonary ACE2 mRNA expression was not different between subjects with or without diabetes. In contrast, protein levels of ACE2 were significantly increased in both alveolar tissue and bronchial epithelium of patients with diabetes compared with control subjects, independent of smoking, chronic obstructive pulmonary disease, BMI, renin-angiotensin-aldosterone system inhibitor use, and other potential confounders. To conclude, we show increased bronchial and alveolar ACE2 protein expression in patients with diabetes. Further research is needed to elucidate whether upregulation of ACE2 expression in airways and lungs has consequences on infectivity and clinical outcomes of COVID-19.

Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects (preprint)

Rationale: Smokers and patients with chronic obstructive pulmonary disease (COPD) are at increased risk for severe Coronavirus Disease 2019 (COVID-19). Objectives: We investigated the expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor ACE2 and the protease TMPRSS2 in lung tissue from never smokers and smokers with and without COPD. Methods: In a cross-sectional, observational study we measured mRNA expression of ACE2 and TMPRSS2 by RT-PCR in lung tissue samples from 120 well phenotyped subjects. Next, protein levels of ACE2 were visualized by immunohistochemistry on paraffin sections from 87 subjects and quantified in alveolar and bronchial epithelium. Finally, primary human bronchial epithelial cells (HBECs) were cultured at air liquid interface and exposed to air or cigarette smoke. Results: ACE2 mRNA expression was significantly higher in lung tissue from current smokers and subjects with moderate to very severe COPD and correlated with physiological parameters of airway obstruction and emphysema. Pulmonary expression levels of TMPRSS2 were significantly higher in patients with (very) severe COPD and correlated significantly with ACE2 expression. Importantly, protein levels of ACE2 were elevated in both alveolar and bronchial epithelium of current smokers and subjects with moderate to very severe COPD. Finally, TMPRSS2 mRNA expression increased in in vitro cultured HBECs upon acute exposure to cigarette smoke. Conclusions: We demonstrate increased expression of ACE2 in lungs of smokers and COPD subjects, which might facilitate host cell entry of SARS-CoV-2. These findings help identifying populations at risk for severe COVID-19.

The SARS-CoV-2 conserved macrodomain is a highly efficient ADP-ribosylhydrolase enzyme (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like-CoVs encode 3 tandem macrodomains within non-structural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs, and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated anti-viral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV and MERS-CoV Mac1 exhibit similar structural folds and all 3 proteins bound to ADP-ribose with low M affinities. Importantly, using ADP-ribose detecting binding reagents in both a gel-based assay and novel ELISA assays, we demonstrated de-MARylating activity for all 3 CoV Mac1 proteins, with the SARS-CoV-2 Mac1 protein leading to a more rapid loss of substrate compared to the others. In addition, none of these enzymes could hydrolyze poly-ADP-ribose. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are MAR-hydrolases with similar functions, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity. IMPORTANCESARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused greater than 900 thousand deaths worldwide. With, no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode for a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic post-translational process increasingly recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose, and describe its ADP-ribose binding and hydrolysis activities in direct comparison to SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.