Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices.

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.

An Implementation of Real-time Activity Sensing using Wi-Fi: Identifying Optimal Machine Learning Techniques for Performance Evaluation

The elderly population is growing, and the health care system is experiencing a strain on services provided to the elderly. The recent COVID-19 pandemic has increased this strain and has resulted in an increased risk of exposure during visits to elderly homes. Increasing the desire to provide technological solutions to counteract this. Currently, there lack reliable real-time non-invasive sensing systems. This paper makes use of Radio Frequency sensing, where signal propagation is observed in Channel State Information (CSI) reports on Activities of Daily Living (ADLs). Real-time data has been collected for three classifications, “movement”, “empty room”, and “no activity”. A filter is applied to reduce the noise of the CSI data. Then the mean, max, min, kurtosis, skew and standard deviation features are extracted from the CSI data. A machine learning model provides classification for the real-time monitoring system allowing detection of abnormalities in the expected ADLs of the elderly. The timing of classifications gives insight into the real-time capabilities of the system. The Random Forest algorithm is chosen to create the machine learning model based on accuracy and timing capabilities. The model was able to achieve an accuracy of 100 % on new unseen testing data with an average classification time of 7.31 milliseconds. IEEE

IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques (preprint)

The pro- and anti-inflammatory pathways that determine the balance of inflammation and viral control during SARS-CoV-2 infection are not well understood. Here we examine the roles of IFN{gamma} and IL-10 in regulating inflammation, immune cell responses and viral replication during SARS-CoV-2 infection of rhesus macaques. IFN{gamma} blockade tended to decrease lung inflammation based on 18FDG-PET/CT imaging but had no major impact on innate lymphocytes, neutralizing antibodies, or antigen-specific T cells. In contrast, IL-10 blockade transiently increased lung inflammation and enhanced accumulation of virus-specific T cells in the lower airways. However, IL-10 blockade also inhibited the differentiation of virus-specific T cells into airway CD69+CD103+ TRM cells. While virus-specific T cells were undetectable in the nasal mucosa of all groups, IL-10 blockade similarly reduced the frequency of total TRM cells in the nasal mucosa. Neither cytokine blockade substantially affected viral load and infection ultimately resolved. Thus, in the macaque model of mild COVID-19, the pro- and anti-inflammatory effects of IFN{gamma} and IL-10 have no major role in control of viral replication. However, IL-10 has a key role in suppressing the accumulation of SARS-CoV-2-specific T cells in the lower airways, while also promoting TRM at respiratory mucosal surfaces.

A global perspective on the influence of the COVID-19 pandemic on freshwater fish biodiversity. (Special Issue: Conservation and ecological impacts of the COVID-19 pandemic.)

The COVID-19 global pandemic and resulting effects on the economy and society (e.g., sheltering-in-place, alterations in transportation, changes in consumer behaviour, loss of employment) have yielded some benefits and risks to biodiversity. Here, we considered the ways the COVID-19 pandemic has influenced (or may influence) freshwater fish biodiversity (e.g., richness, abundance). In many cases, we could only consider potential impacts using documented examples (often from the media) of likely changes, because anecdotal observations are still emerging and data-driven studies are yet to be completed or even undertaken. We evaluated the potential for the pandemic to either mitigate or amplify widely acknowledged, pre-existing threats to freshwater fish biodiversity (i.e., invasive species, pollution, fragmentation, flow alteration, habitat loss and alteration, climate change, exploitation). Indeed, we identified examples spanning the extremes of positive and negative outcomes for almost all known threats. We also considered the pandemic's impact on freshwater fisheries demand, assessment, research, compliance monitoring, and management interventions (e.g., restoration), with disruptions being experienced in all domains. Importantly, we provide a forward-looking synthesis that considers the potential mechanisms and pathways by which the consequences of the pandemic may positively and negatively impact freshwater fishes over the longer term. We conclude with a candid assessment of the current management and policy responses and the extent to which they ensure freshwater fish populations and biodiversity are conserved for human and aquatic ecosystem benefits in perpetuity.

Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues.

SARS-CoV-2 primarily replicates in mucosal sites, and more information is needed about immune responses in infected tissues. Here, we used rhesus macaques to model protective primary immune responses in tissues during mild COVID-19. Viral RNA levels were highest on days 1-2 post-infection and fell precipitously thereafter. 18F-fluorodeoxyglucose (FDG)-avid lung abnormalities and interferon (IFN)-activated monocytes and macrophages in the bronchoalveolar lavage (BAL) were found on days 3-4 post-infection. Virus-specific effector CD8+ and CD4+ T cells became detectable in the BAL and lung tissue on days 7-10, after viral RNA, radiologic evidence of lung inflammation, and IFN-activated myeloid cells had substantially declined. Notably, SARS-CoV-2-specific T cells were not detectable in the nasal turbinates, salivary glands, and tonsils on day 10 post-infection. Thus, SARS-CoV-2 replication wanes in the lungs of rhesus macaques prior to T cell responses, and in the nasal and oral mucosa despite the apparent lack of antigen-specific T cells, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19.

Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues (preprint)

SARS-CoV-2 primarily replicates in mucosal sites, and more information is needed about immune responses in infected tissues. We used rhesus macaques to model protective primary immune responses in tissues during mild COVID-19. Viral RNA levels were highest on days 1-2 post-infection and fell precipitously thereafter. 18F-fluorodeoxyglucose (FDG)-avid lung abnormalities and interferon (IFN)-activated myeloid cells in the bronchoalveolar lavage (BAL) were found on days ~3-4. Virus-specific effector CD8 and CD4 T cells were detectable in the BAL and lung tissue on days ~7-10, after viral RNA, lung inflammation, and IFN-activated myeloid cells had declined. Notably, SARS-CoV-2-specific T cells were not detectable in the nasal turbinates, salivary glands, and tonsils on day 10 post-infection. Thus, SARS-CoV-2 replication wanes in the lungs prior to T cell responses, and in the nasal and oral mucosa despite the apparent lack of Ag-specific T cells, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19.

Chloroquine/ hydroxychloroquine prevention of coronavirus disease (COVID-19) in the healthcare setting;protocol for a placebo-controlled prophylaxis study (COPCOV)

There is no proven preventative therapy or vaccine against COVID-19. Theinfection has spread rapidly and there has already been a substantial adverse impact on the global economy. Healthcare workers have been affected disproportionately in the continuing pandemic. Significant infection rates in this critical group have resulted in a breakdown of health services in some countries. Chloroquine, and the closely related hydroxychloroquine, are safe and well tolerated medications which can be given for years without adverse effects. Chloroquine and hydroxychloroquine have significant antiviral activity against SARS-CoV-2, and despite the lack of benefit of hydroxychloroquine treatment in patients hospitalised with severe COVID-19, these drugs could still work in prevention. The emerging infection paradigm of an early viral peak, and late inflammation where there is benefit from corticosteroids. If these direct actiing antivirals are to work, they have the best chance given either early in infection infection occurs. We describe the study protocol for multi-centre, multi-country randomised, double blind, placebo controlled trial to answer the question can chloroquine/ hydroxychloroquine prevent COVID-19. 40,000 participants working in healthcare facilities or involved in the management of COVID-19 will be randomised 1:1 to receive chloroquine/ hydroxychloroquine or matched placebo as daily prophylaxis for three months. The primary objective is the prevention of symptomatic, virological or serologically proven coronavirus disease (COVID-19). The study could detect a 23% reduction from an incidence of 3% in the placebo group for either drug with 80% power. Secondary objectives are to determine ifchloroquine/hydroxychloroquine prophylaxis attenuates severity, prevents asymptomaticCOVID-19 and symptomatic acute respiratory infections of another aetiology (non-SARS-CoV-2). © 2020. Schilling WH et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Social and technical readiness for a telehealth assessment service for adults with complex wheelchair and seating needs: A national survey of stakeholders

Wheelchairs can significantly improve quality of life for those who need them, yet access to physiotherapists or occupational therapists specialising in wheelchair and seating assessment can be difficult, especially for Mäori. This paper reports on a national online survey that was undertaken as phase 1 of a mixed methods study of key stakeholders of the perceived social and technical requirements of a telehealth wheelchair assessment service for people with complex mobility needs. Key stakeholders included wheelchair users and their families, specialist and non-specialist assessors, technicians, and service managers. Responses (n = 114) indicated perceived shortcomings with current in-person assessment. Telehealth assessment was anticipated to improve service quality, particularly the timeliness of services (52/92, 57%) and prioritisation of the urgency of assessment (71/92, 77%). Preferences were for use of existing software rather than bespoke systems. Training in conducting assessment via telehealth was considered essential by most assessors (29/41, 71%). Internet connectivity was in place for most wheelchair users (43/47, 92%) but was inadequate for 29% (14/49) of assessors (pre-COVID-19). Mäori wheelchair users largely had infrastructure in place for telehealth assessment (10/11, 91%) and held positive expectations of it. Telehealth wheelchair and seating assessment is anticipated to improve the quality of care for wheelchair users with complex needs. Upgraded technical capability of public health services and robust training in conducting assessment via telehealth will be critical to successful uptake of this service. Specific needs for Mäori wheelchair users warrant further investigation. © 2021, Physiotherapy New Zealand. All rights reserved.

Characteristics of a diverse cohort of stroke patients with sars-cov-2 and outcome by sex

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is associated with stroke. The role of sex on stroke outcome has not been investigated. We describe the characteristics of a diverse cohort of acute stroke patients with COVID-19 disease, and investigate the role of sex on outcome. Methods: This is a retrospective study of patients with acute stroke and SARS-CoV-2 infection admitted between March 15 to May 15, 2020 to one of the six participating comprehensive stroke centers from Chicago metropolitan area. Baseline characteristics, stroke subtype, workup, treatment and outcome are presented as total number and percentage. Outcome at discharge was determined by the modified Rankin Scale Score (mRS). Variables and outcomes were compared for males and females using univariate and multivariate analysis. Results: The study included 83 patients. Median age was 64 years and the majority were Blacks (47%) followed by Hispanics (28%) and whites (16%). Approximately 89% had at least one preexisting vascular risk factor (VRF). The most common complications were respiratory failure (59%) and septic shock (34%). Higher proportions of male experienced severe SARS-CoV-2 symptoms requiring ICU hospitalization (73% vs. 49%;p=0.04). When divided by stroke subtype, there were 77% ischemic, 19% intracerebral hemorrhage and 3% subarachnoid hemorrhage. The most common ischemic stroke etiologies were cryptogenic (39%) and cardioembolic (27%).Compared to female, males had higher mortality (38% vs. 13%;p=0.02) and were less likely to bedischarged home (12% vs. 33%;p=0.04). After adjustment for age, race/ethnicity, and number ofVRFs, mRS was higher in males than in females (OR=1.47, 95% CI=1.03-2.09) Conclusion: In this cohort of SARS-CoV-2 stroke patients, most had clinical evidence ofcoronavirus infection on admission and preexisting VRFs. Severe in-hospital complications andworse outcomes after ischemic strokes were higher in males, than females.

Characteristics of a Diverse Cohort of Stroke Patients with SARS-CoV-2 and Outcome by Sex.

BACKGROUND AND PURPOSE: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is associated with stroke. The role of sex on stroke outcome has not been investigated. To objective of this paper is to describe the characteristics of a diverse cohort of acute stroke patients with COVID-19 disease and determine the role of sex on outcome. METHODS: This is a retrospective study of patients with acute stroke and SARS-CoV-2 infection admitted between March 15 to May 15, 2020 to one of the six participating comprehensive stroke centers. Baseline characteristics, stroke subtype, workup, treatment and outcome are presented as total number and percentage or median and interquartile range. Outcome at discharge was determined by the modified Rankin Scale Score (mRS). Variables and outcomes were compared for males and females using univariate and multivariate analysis. RESULTS: The study included 83 patients, 47% of which were Black, 28% Hispanics/Latinos, and 16% whites. Median age was 64 years. Approximately 89% had at least one preexisting vascular risk factor (VRF). The most common complications were respiratory failure (59%) and septic shock (34%). Compared with females, a higher proportion of males experienced severe SARS-CoV-2 symptoms requiring ICU hospitalization (73% vs. 49%; p = 0.04). When divided by stroke subtype, there were 77% ischemic, 19% intracerebral hemorrhage and 3% subarachnoid hemorrhage. The most common ischemic stroke etiologies were cryptogenic (39%) and cardioembolic (27%). Compared with females, males had higher mortality (38% vs. 13%; p = 0.02) and were less likely to be discharged home (12% vs. 33%; p = 0.04). After adjustment for age, race/ethnicity, and number of VRFs, mRS was higher in males than in females (OR = 1.47, 95% CI = 1.03-2.09). CONCLUSION: In this cohort of SARS-CoV-2 stroke patients, most had clinical evidence of coronavirus infection on admission and preexisting VRFs. Severe in-hospital complications and worse outcomes after ischemic strokes were higher in males, than females.

SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.