The ProtekDuo in ECMO configuration for ARDS secondary to COVID-19 - a systematic review

Objectives: Assessment of the literature on the ProtekDuo cannula when used as venopulmonary (V-P) extracorporeal membrane oxygenation (ECMO) in ARDS secondary to COVID-19. Method(s): Systematic literature search in EMBASE, Medline (Pubmed) and NHS library using appropriate keywords as well as PICOS and PRISMA approach. Result(s): We found 285 publications, of which 5 publications met the search criteria and were included in this review. A total of 194 patients with COVID-19 related ARDS had a ProtekDuo placed to establish venovenous (V-V) ECMO and right ventricular (RV) support. Patients treated with the ProtekDuo cannula had survival rates between between the studies of 59 and 89%, with a significant survival compared to an invasive ventilation group or when compared to dual site V-V ECMO or other double lumen ECMO cannulas. One of the studies focused on extubation and early discontinuation of ventilator support, which the authors achieved in 100% of ProtekDuo patients. The incidence of acute kidney injury (AKI) and use of continuous renal replacement therapy (CRRT) was significantly reduced in the ProtekDuo versus other groups. Conclusion(s): The ProtekDuo displayed lower mortality rates, AKI occurrence and CRRT need as compared to other respiratory support modalities and has shown to be a game changer for ECMO support in patients suffering from COVID-19 ARDS. Many authors suggested the ProtekDuo for first line use in these patients.

Molecular Biology of SARS-CoV-2 and its Evolution within the Princeton University Campus Community

Background. SARS-CoV-2, a novel and highly pathogenic coronavirus, has caused unprecedented global disruption following its introduction into the human population. Beginning in January 2021, a NJ university invited all students to campus and initiated an asymptomatic testing protocol using weekly to twice-weekly PCR-based detection of human saliva samples. RNA extracted from PCR-positive human saliva samples was sequenced for surveillance purposes. Methods. Positive samples were submitted for RNA-Seq analysis (ARTIC amplicon sequencing protocol, Illumina MiSeq) and analyzed using Nextclade and USHER (comparison data from GISAID). Using sequencing data, the evolution, transmission, and emergence of SARS-CoV-2 variants were monitored over time in the campus community. Using sequencing data from NY, PA, and NJ in combination with University data, we performed an IQ-TREE based phylogenetic analysis. Results. Analyzing sequencing data of 1,011 University positive samples we demonstrate that SARS-CoV-2 variants Delta (B.1.617.2) and Omicron (BA.1 and BA.2) were first to emerge following widespread vaccination and, quickly, became predominant. These trends witnessed on campus preceded those same variants emerging in New Jersey, providing evidence of local campus spread distinct from the state-wide pandemic. The analysis of 2,359 total sequences from NY, PA, and NJ in combination with University data, provided evidence of the SARS-CoV-2 transmission chain on campus evolving from out-of-state (January 2021) to local (January 2022) spread over one year of the virus circulating within the community at large. Upon performing a Ct value analysis of 2,822 Princeton University sequences, no significant differences were discovered between N gene Ct values when grouped by age or vaccination status. However, there were significant differences in Ct values between strains. The Emergence of SARS-CoV-2 Variants at Princeton University This plot represents the emergence of SARS-CoV-2 clades at Princeton University, organized by Nextstrain clade and displayed as a proportion out of one. Dates of sample collection range from January 25, 2021, to March 1, 2022. X-axis represents SARS-CoV-2 sample test date (grouped by month);Y-axis represents the count per day organized by Nextstrain clade. Conclusion. Sequencing of positive SARS-CoV-2 samples from population screening of a highly vaccinated University campus community allowed the detection of emergence of new variants that became predominant on campus irrespective of the circulation of variants in the surrounding area.

Detection of SARS-CoV-2 Transmission on a College Campus using a Combined Contact Tracing and Molecular Strategy

Background. SARS-CoV-2 has caused unprecedented global disruption following its introduction into the human population. Beginning in August 2021, a residential college initiated an asymptomatic testing protocol using PCR-based detection of human saliva samples (Thermofisher, TaqPath SARS-CoV-2 Assay;QuantStudio v1.3). In January 2021 all students were invited to campus and were required to test once or twice weekly in an effort to isolate those positive (cases) as early as possible and minimize transmission. Methods. Cases were contacted within 12 hours by trained clinical staff and interviewed with a standardized questionnaire to determine contacts and exposures. Positive samples were submitted for RNA-Seq analysis (ARTIC amplicon sequencing protocol, Illumina MiSeq) and analyzed using Nextclade and USHER (comparison data from GISAID). Using this sequence data, we monitored the evolution, transmission, and emergence of variants over time in the campus community. Results. In March 2022 a one-week break and the activities preceding it were followed by an outbreak of COVID among campus members. All cases were attributed to the Omicron variant. Based on traditional contact tracing 10 presumed clusters of transmission were identified (34 students). Sequence data from these 34 samples were assembled to identify phylogenetic and molecular patterns of similarity. Several molecular signatures were identified. In a group of 5 cases, all were Omicron BA.2.9;these individuals comprised a clinical cluster of students who had travelled together. Other lineages were BA.2 (N=26), BA.1(N=2), BA.2.12. (N=3), BA.2.3 (N=1) and an Omicron Clade 21M variant that appeared to be a BA.1/BA.2 recombinant (N=2). The BA.2.12 samples were contributed over 2 days;they were found in two different clusters (a social club and an artistic group), demonstrating likely transmission between members. The BA.2 samples were distributed across a wide number of student groups, and while not identical with one another, did not fall into the clusters identified by contact tracing, suggesting endemic transmission across our campus. Conclusion. This analysis demonstrates that molecular analysis of SARS-CoV-2 transmission can supplement and inform the data provided by clinical/epidemiological analysis of cases.

Mechanisms by which cystic fibrosis transmembrane conductance regulator may influence SARS-CoV-2 infection

Background: People with cystic fibrosis (PwCF) have chronic, pronounced respiratory damage and have been considered among those at highest risk for serious harm from SARS-CoV-2. Numerous clinical studies have reported that individuals with CF in North America and Europe, although highly susceptible to COVID-19, do not have mortality levels that exceed those of the general population. Method(s): To understand features that might influence lethality of COVID- 19 in PwCF, we tested potential relationships between CFTR and viral pathogenesis. As one approach to evaluate impact of CF transmembrane conductance regulator (CFTR) on COVID-19 severity, independent sets of blood samples fromvirally infected individualswere genotyped. Bloodwas obtained from 424 U.S. patients hospitalized with severe COVID-19 and a much larger European cohort of 7147 healthy individuals and 2587 individuals with severe COVID-19. Deoxyribonucleic acid in both studies was probed for the F508del variant. In other experiments, we investigated the possibility that lack of CFTR might alter viral binding and propagation. We used human bronchial epithelial cell (HBEC) monolayers from individuals without functional CFTR for this purpose. Finally, we examined effects of CF airway secretions and features such as viscosity, pH, and protease/anti-protease imbalance during SARS-CoV-2 infection. Result(s): We found no evidence of a relationship between deficient CFTR function (based on carrier status for the severe F508del defect) and clinical outcomes from COVID-19. In addition, viral propagation studies using airway epithelial monolayers (a model that reproduces many aspects of in vivo tissue biology) were not influenced by homozygous absence of CFTR. We show that levels of angiotensin converting enzyme-2 receptor messenger ribonucleic acid (mRNA) appear normal in CF primary epithelium, whereas transmembrane serine protease 2 mRNA is variable but lower ( p < 0.001) in a manner that correlates with viral infectivity (R2 = 0.76). Dependence of viral proliferation on features of CF mucosal fluid-including pH (viral replication optimum at pH 7-7.5), viscosity (diminished propagation in highly viscous apical media), and protease/ anti-protease imbalancewere identified as likely contributors to efficiency of SARS-CoV-2 replication and pathogenesis. Conclusion(s): These findings using patient data, CF and non-CF primary airway epithelia, and CF airway secretions fail to demonstrate a causal relationship between loss of CFTR and susceptibility to severe COVID-19. Notwithstanding the caveat that addition of virus in small buffer volumes disrupts airway surface liquid depth and composition, our findings also argue against a role for CFTR during acute infection of airway cells in vitro. On the other hand, chronic disruption of periciliary liquid, diminished pH, altered protease/anti-protease homeostasis, and increased fluid viscosity (sequelae that occur in CF lungs) were implicated as contributors to impaired SARS-CoV-2 propagation. Such studies provide a basis for future work to test relationships between CFTR and severity of COVID-19. Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

NRAS VIRTUAL GROUPS

Background/Aims NRAS Groups have long provided an opportunity for those with RA to meet others in a similar situation for mutual benefit. Attendees have told us how they enjoy meeting in a non-clinical environment to learn more about the condition and receive encouragement from others. When COVID-19 hit and NRAS groups were unable to meet in person and most people living with RA had to shield this intensified the feelings of isolation. NRAS responded to this need by establishing online regional groups and JoinTogether virtual groups. Methods 1. NRAS offered training and support to facilitate online group meetings to its regional groups' leaders. Volunteers were provided with a dedicated NRAS email address, access to an Office 365 portal and Zoom account and GDPR training. NRAS colleagues attended introductory meetings to support the Group Leaders and continue to provide technical support, promotion via website and social media as well as general advice. 2. Recognising a need to reach a wider audience who were not accessing the regional groups - i.e. younger and perhaps 'time poor' due to working etc. - NRAS took advantage of the move to online engagement and also initiated the exclusively online JoinTogether topic-based groups, using a Volunteer Lead model. Results Regional Groups: Almost half of the regional groups signed up to the online training. Many found that the online meetings brought very positive benefits e.g. they were able to reach a wider audience as attendees were not put off by having to travel and could still attend if they were feeling fatigued. Many reported it was easier to attract NHS rheumatology health professionals to give talks as they did not have to travel and could even join meetings from home in the evenings. Some groups in adjoining areas joined forces so they could expand their offerings. JoinTogether Groups: Volunteer Lead, with NRAS support, has now set up 5 topic-based groups, each led by two co-ordinators. Topics are: Exercise and Back to Sport;Parenting With Inflammatory Arthritis;18-35 year olds with RA or JIA: Working with Inflammatory Arthritis and Parents with children with JIA. These groups are thriving and attracting new audiences. They are very much volunteer led and attendees play a key role in directing the development of the JoinTogether groups to suit their needs. Conclusion NRAS virtual groups have allowed those living with RA or JIA to maintain contact with a community, with shared experiences, throughout the pandemic. They have also been instrumental in attracting attendees from audiences NRAS had traditionally found harder to access. The Volunteer Lead model that has been successfully implemented for the JoinTogether groups can now be expanded to other areas, enabling NRAS to increase capacity for delivering vital services.

Inflammasome activation in infected macrophages drives COVID-19 pathology.

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA and a sustained interferon (IFN) response, all of which are recapitulated and required for pathology in the SARS-CoV-2-infected MISTRG6-hACE2 humanized mouse model of COVID-19, which has a human immune system1-20. Blocking either viral replication with remdesivir21-23 or the downstream IFN-stimulated cascade with anti-IFNAR2 antibodies in vivo in the chronic stages of disease attenuates the overactive immune inflammatory response, especially inflammatory macrophages. Here we show that SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release interleukin 1 (IL-1) and IL-18, and undergo pyroptosis, thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and the accompanying inflammatory response are necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Notably, this blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 through the production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.

COVID-19 At-Home Capillary Blood Specimen Collection Pilot - Gaining Insight into Independent Self- Collection of Blood Specimens and COVID-19 Within the Veteran Population

Background. The VA Million Veteran Program (MVP) studies what factors influence Veteran health. Current procedures involve collection of venous blood at MVP enrollment sites. To examine home specimen collection options, MVP performed a pilot study comparing two blood specimen collection devices and evaluated SARSCoV-2 antibody assays to determine known COVID-19 infection or vaccination. Methods. A sub-sample of MVP Veteran participants were asked to self-collect a capillary blood specimen using the Neoteryx Mitra Clamshell (up to 120uL dried blood) or Tasso-SST (up to 200uL liquid blood) per the vendor instructions. Veterans were randomly assigned to a device prior to consent. Eligibility included 30% of Veterans with known COVID-19 diagnosis or vaccination and sampling time was variable from these events. Veterans rated their device experience and shipped collected specimens directly to an MVP laboratory. Mitra tip (4) blood was eluted in 1 mL of 0.9% normal saline for 1 hour at room temperature shaking at 300 rpm. Tasso tubes were centrifuged per vendor instructions. All samples were stored at -80°C until tested with SARS-Cov-2 antibody (Ab) assays (InBios Spike IgG, BioRad Nucleocapsid (NC) Total Ab, Abbott NC IgG, and Abbott Spike IgG II) per vendor instructions. Results. 312 MVP participants consented to the pilot (52%) of which 136 (43.6%) were sent Mitra and 176 (56.4%) were sent Tasso-SST (Table 1). Participants rated the Mitra Tasso-SST equally on average as 4.4 on a 0-5 usability scale. The Abbott IgG II assay had the highest sensitivity across both devices (87% Mitra and 98% Tasso-SST) for detecting known COVID infection and/or vaccination. The InBios IgG assay with the Tasso-SST had the best sensitivity (97%) and specificity (80%) for detecting known COVID-19 infection and/or vaccination (Table 2). Conclusion. Veterans successfully collected their own specimens and had no strong preference for either device. The Tasso-SST combined with the InBios Spike IgG assay provided the highest combination of sensitivity and specificity. Limitations included one collection device per subject, varied timing of testing, unknown infection or vaccination status among some, and Tasso collection volume and Mitra whole blood dilution may have affected comparison across assays or performance.