The association between prolonged SARS-CoV-2 symptoms and work outcomes (preprint)

While the early effects of the COVID-19 pandemic on the United States labor market are well-established, less is known about the long-term impact of SARS-CoV-2 infection and Long COVID on employment. To address this gap, we analyzed self-reported data from a prospective, national cohort study to estimate the effects of SARS-CoV-2 symptoms at three months post-infection on missed workdays and return to work. The analysis included 2,939 adults in the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) study who tested positive for their initial SARS-CoV-2 infection at the time of enrollment, were employed before the pandemic, and completed a baseline and three-month electronic survey. At three months post-infection, 40.8% of participants reported at least one SARS-CoV-2 symptom and 9.6% of participants reported five or more SARS-CoV-2 symptoms. When asked about missed work due to their SARS-CoV-2 infection at three months, 7.1% of participants reported missing >=10 workdays and 13.9% of participants reported not returning to work since their infection. At three months, participants with >=5 symptoms had a higher adjusted odds ratio (aOR) of missing >=10 workdays (2.96, 95% CI 1.81-4.83) and not returning to work (2.44, 95% CI 1.58-3.76) compared to those with no symptoms. Prolonged SARS-CoV-2 symptoms were common, affecting 4-in-10 participants at three-months post-infection, and were associated with increased odds of work loss, most pronounced among adults with >=5 symptoms at three months. Despite the end of the Federal COVID-19 Public Health Emergency and efforts to "return to normal", policymakers must consider the clinical and economic implications of the COVID-19 pandemic on peoples employment status and work absenteeism, particularly as data characterizing the numerous health and well-being impacts of Long COVID continue to emerge. Improved understanding of risk factors for lost work time may guide efforts to support people in returning to work.

Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico and cell-based approach (preprint)

The main protease (MPro) of SARS-CoV-2 plays a crucial role in viral replication and is a prime target for therapeutic interventions. Phytochemicals, known for their antiviral properties, have been previously identified as potential MPro inhibitors in several in silico studies. However, the efficacy of these remains in question owing to the inherent flexibility of the MPro binding site, posing challenges in selecting suitable protein structures for virtual screening. In this study, we conducted an extensive analysis of the MPro binding pocket, utilizing molecular dynamics (MD) simulations to explore its conformational diversity. Based on pocket volume and shape-based clustering, five representative protein conformations were selected for virtual screening. Virtual screening of a library of ~ 48,000 phytochemicals suggested 39 phytochemicals as potential MPro inhibitors. Based on subsequent MM-GBSA binding energy calculations and ADMET property predictions, five compounds were advanced to cell-based viral replication inhibition assays, with three compounds (demethoxycurcumin, shikonin, and withaferin A) exhibiting significant (EC50 < 10 uM) inhibition of SARS-CoV-2 replication. Our study provides an understanding of the binding interactions between these phytochemicals and MPro, contributing significantly to the identification of promising MPro inhibitors. Furthermore, beyond its impact on therapeutic development against SARS-CoV-2, this research highlights a crucial role of proper nutrition in the fight against viral infections.

Durable immunity to SARS-CoV-2 in both lower and upper airways achieved with a gorilla adenovirus (GRAd) S-2P vaccine in non-human primates (preprint)

SARS-CoV-2 continues to pose a global threat, and current vaccines, while effective against severe illness, fall short in preventing transmission. To address this challenge, theres a need for vaccines that induce mucosal immunity and can rapidly control the virus. In this study, we demonstrate that a single immunization with a novel gorilla adenovirus-based vaccine (GRAd) carrying the pre-fusion stabilized Spike protein (S-2P) in non-human primates provided protective immunity for over one year against the BA.5 variant of SARS-CoV-2. A prime-boost regimen using GRAd followed by adjuvanted S-2P (GRAd+S-2P) accelerated viral clearance in both the lower and upper airways. GRAd delivered via aerosol (GRAd(AE)+S-2P) modestly improved protection compared to its matched intramuscular regimen, but showed dramatically superior boosting by mRNA and, importantly, total virus clearance in the upper airway by day 4 post infection. GrAd vaccination regimens elicited robust and durable systemic and mucosal antibody responses to multiple SARS-CoV-2 variants, but only GRAd(AE)+S-2P generated long-lasting T cell responses in the lung. This research underscores the flexibility of the GRAd vaccine platform to provide durable immunity against SARS-CoV-2 in both the lower and upper airways.

Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates (preprint)

Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/565765v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@d49b9dorg.highwire.dtl.DTLVardef@347455org.highwire.dtl.DTLVardef@1c1a196org.highwire.dtl.DTLVardef@1579130_HPS_FORMAT_FIGEXP M_FIG C_FIG

Viral and host factors associated with SARS-CoV-2 disease severity in Georgia, USA (preprint)

While SARS-CoV-2 vaccines have shown strong efficacy, their suboptimal uptake combined with the continued emergence of new viral variants raises concerns about the ongoing and future public health impact of COVID-19. We investigated viral and host factors, including vaccination status, that were associated with SARS-CoV-2 disease severity in a setting with low vaccination rates. We analyzed clinical and demographic data from 1,957 individuals in the state of Georgia, USA, coupled with viral genome sequencing from 1,185 samples. We found no difference in disease severity between individuals infected with Delta and Omicron variants among the participants in this study, after controlling for other factors, and we found no specific mutations associated with disease severity. Compared to those who were unvaccinated, vaccinated individuals experienced less severe SARS-CoV-2 disease, and the effect was similar for both variants. Vaccination within 270 days before infection was associated with decreased odds of moderate and severe outcomes, with the strongest association observed at 91-270 days post-vaccination. Older age and underlying health conditions, especially immunosuppression and renal disease, were associated with increased disease severity. Overall, this study provides insights into the impact of vaccination status, variants/mutations, and clinical factors on disease severity in SARS-CoV-2 infection when vaccination rates are low. Understanding these associations will help refine and reinforce messaging around the crucial importance of vaccination in mitigating the severity of SARS-CoV-2 disease.

Interim Safety and Immunogenicity of COVID-19 Omicron-BA.1 Variant-Containing Vaccine in Children (preprint)

ObjectivesWe report interim safety and immunogenicity results from a phase 3 study of omicron-BA.1 variant-containing (mRNA-1273.214) primary vaccination series (Part 1) and booster dose (Part 2) in children aged 6 months to 5 years (NCT05436834). MethodsIn Part 1, SARS-CoV-2 unvaccinated participants, including participants who received placebo in the KidCOVE study (NCT04796896), received 2 doses of mRNA-1273.214 (25-g omicron-BA.1 and ancestral Wuhan-Hu-1 mRNA 1:1 co-formulation) primary series. In Part 2, participants who previously completed the mRNA-1273 (25-{micro}g) primary series in KidCOVE received a mRNA-1273.214 (10-g) booster dose. Primary objectives were safety, reactogenicity, and immunogenicity, including prespecified immune response success criteria. ResultsAt the data cutoff (December 5, 2022), 179 participants had received [≥]1 dose of mRNA-1273.214 primary series (Part 1) and 539 participants had received a mRNA-1273.214 booster dose (Part 2). The safety profile of mRNA-1273.214 primary series and booster dose was consistent with that of the mRNA-1273 primary series in this same age group, with no new safety concerns identified and no vaccine-related serious adverse events observed. Compared with neutralizing antibody responses induced by the mRNA-1273 primary series, both the mRNA-1273.214 primary series and booster elicited responses that were superior against omicron-BA.1 and non-inferior against ancestral Wuhan-Hu-1(D614G). ConclusionsmRNA-1273.214 was immunogenic against BA.1 and D614G in children aged 6 months to 5 years, with a comparable safety profile to mRNA-1273, when given as a 2-dose primary series or as a booster dose after the mRNA-1273 primary series. Clinical Trial RegistryNCT05436834

A Slow-Rolling Disaster: Assessing the Impact of the Covid-19 Pandemic on Militant Violence

Despite alarming predications about the Covid 19 pandemic that appear to fit the literature on the impact of natural disasters on civil wars, there are reasons to be suspicious that a rise in militant violence would likely occur quickly or uniformly. Although the COVID-19 pandemic is most definitely a disaster that caught the world by surprise, this "slow-rolling” shock differs in important ways from the more commonly studied acute onset natural disasters such as earthquakes, hurricanes, and tsunamis that often increase violent competition among groups for scarce resources. Instead, the effects of slow-rolling disasters unfold in phases that, at least in the short run, are likely to encourage a period of relative decline in violence, as actors try and assess the effects of COVID-19 on their organization and their opponents. Both statistical and qualitative evidence from the initial months of the COVID-19 pandemic supports the initial phases of our theory. [ FROM AUTHOR] Copyright of Journal of Conflict Resolution is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

A microfluidic biosensor architecture for the rapid detection of COVID-19

The lack of enough diagnostic capacity to detect severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has been one of the major challenges in the control the 2019 COVID pandemic;this led to significant delay in prompt treatment of COVID-19 patients or accurately estimate disease situation. Current methods for the diagnosis of SARS-COV-2 infection on clinical specimens (e.g. nasal swabs) include polymerase chain reaction (PCR) based methods, such as real-time reverse transcription (rRT) PCR, real-time reverse transcription loop-mediated isothermal amplification (rRT-LAMP), and immunoassay based methods, such as rapid antigen test (RAT). These conventional PCR methods excel in sensitivity and specificity but require a laboratory setting and typically take up to six hours to obtain the results whereas RAT has a low sensitivity (typically at least 3000 TCID50/ml) although with the results with 15 mins. We have developed a robust micro-electro-mechanical system (MEMS) based impedance biosensor fit for rapid and accurate detection of SARS-COV-2 of clinical samples in the field with minimal training. The biosensor consisted of three regions that enabled concentrating, trapping, and sensing the virus present in low quantities with high selectivity and sensitivity in 40 minutes using an electrode coated with a specific SARS-COV-2 antibody cross-linker mixture. Changes in the impedance value due to the binding of the SARS-COV-2 antigen to the antibody will indicate positive or negative result. The testing results showed that the biosensor's limit of detection (LoD) for detection of inactivated SARS-COV-2 antigen in phosphate buffer saline (PBS) was as low as 50 TCID50/ml. The biosensor specificity was confirmed using the influenza virus while the selectivity was confirmed using influenza polyclonal sera. Overall, the results showed that the biosensor is able to detect SARS-COV-2 in clinical samples (swabs) in 40 min with a sensitivity of 26 TCID50/ml.

Accelerating Clinical Trial Design and Operations

Fully-integrated, component-based CDMS offers flexibility, customization, and efficiency Effective and efficient clinical data collection and management is one of the key factors affecting clinical trial success and is of heightened importance during the COVID-19 pandemic.1 Not only have the scope and complexity of clinical trials continued to increase over the past decade, but the volume and diversity of clinical study data grows ever larger. Researchers have accelerated the development of vaccines and therapeutics for COVID-19 as evidenced by the 4,846 trials found on clinicaltrials. gov.2 The COVID-19 pandemic presents a unique opportunity for understanding technologies that can enable trial data management and their effects on streamlining;and expediting clinical trial design and implementation. Specific measurements evaluated in this study were: database build efficiency, velocity of data collection, frequency of protocol amendments on the database, and the time impact of mid-study updates to the database. [...]the ability to execute mid-study updates or post-go live changes with minimal to no downtime (< one hour) allowed the users and sponsors to work in parallel rather than in serial fashion, speeding up trial start dates and implementation of protocol amendments, and accommodating adaptive COVID-19 trial design.

Impact of the Coronavirus (COVID-19) Pandemic on the Care of Pediatric Acute Appendicitis.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency in children. With the rise of the Coronavirus-19 pandemic, quarantine measures have been enforced to limit the viral transmission of this disease. The purpose of this study was to identify differences in the clinical presentation and outcomes of pediatric acute appendicitis during the Coronavirus-19 pandemic. METHODS: A single-institution retrospective assessment of all pediatric patients (<18 years old) with acute appendicitis from December 2019 to June 2020 was performed at a tertiary care children's hospital. Patients were divided into two groups: (1) the Pre-COVID group presented on or before March 15, 2020, and (2) the COVID group presented after March 15, 2020. Demographic, preoperative, and clinical outcomes data were analyzed. RESULTS: 45 patients were included with a median age of 13 years [IQR 9.9 - 16.2] and 35 males (78%). 28 patients were in the Pre-COVID group (62%) and 17 in the COVID group (38%). There were no differences in demographics or use of diagnostic imaging. The COVID group did have a significantly delayed presentation from symptom onset (36 vs 24 hours, P < .05), higher Pediatric Appendicitis Scores (8 vs 6, P = .003), and longer hospital stays (2.2 vs 1.3 days, P = .04). There were no significant differences for rates of re-admission, re-operation, surgical site infection, perforation, or abscess formation. CONCLUSION: During the Coronavirus-19 pandemic, the incidence of pediatric acute appendicitis was approximately 40% lower. These children presented in a delayed fashion with longer hospital stays. No differences were noted for postoperative complications.

Threshold conditions for curbing COVID-19 with a dynamic zero-case policy derived from 101 outbreaks in China.

By 31 May 2022, original/Alpha, Delta and Omicron strains induced 101 outbreaks of COVID-19 in mainland China. Most outbreaks were cleared by combining non-pharmaceutical interventions (NPIs) with vaccines, but continuous virus variations challenged the dynamic zero-case policy (DZCP), posing questions of what are the prerequisites and threshold levels for success? And what are the independent effects of vaccination in each outbreak? Using a modified classic infectious disease dynamic model and an iterative relationship for new infections per day, the effectiveness of vaccines and NPIs was deduced, from which the independent effectiveness of vaccines was derived. There was a negative correlation between vaccination coverage rates and virus transmission. For the Delta strain, a 61.8% increase in the vaccination rate (VR) reduced the control reproduction number (CRN) by about 27%. For the Omicron strain, a 20.43% increase in VR, including booster shots, reduced the CRN by 42.16%. The implementation speed of NPIs against the original/Alpha strain was faster than the virus's transmission speed, and vaccines significantly accelerated the DZCP against the Delta strain. The CRN ([Formula: see text]) during the exponential growth phase and the peak time and intensity of NPIs were key factors affecting a comprehensive theoretical threshold condition for DZCP success, illustrated by contour diagrams for the CRN under different conditions. The DZCP maintained the [Formula: see text] of 101 outbreaks below the safe threshold level, but the strength of NPIs was close to saturation especially for Omicron, and there was little room for improvement. Only by curbing the rise in the early stage and shortening the exponential growth period could clearing be achieved quickly. Strengthening China's vaccine immune barrier can improve China's ability to prevent and control epidemics and provide greater scope for the selection and adjustment of NPIs. Otherwise, there will be rapid rises in infection rates and an extremely high peak and huge pressure on the healthcare system, and a potential increase in excess mortality.

Remote administration of BICAMS measures and the Trail-Making Test to assess cognitive impairment in multiple sclerosis.

Reliable remote cognitive testing could provide a safer assessment of cognitive impairment in multiple sclerosis (MS) during the COVID-19 pandemic and thereafter. Here we aimed to investigate the reliability and feasibility of administering Brief International Cognitive Assessment for MS (BICAMS) and the Trail-Making Test (TMT) to people with MS online. Between-group differences on BICAMS and the TMT were examined in a sample of 68 participants. Group 1 (N = 34) was tested in-person pre-pandemic. Group 2 was tested remotely. Within-group differences for in-person and virtual administrations were examined for Group 1. No significant differences between virtual and in-person administrations of the CVLT-II and SDMT were detected. BVMT-R scores were significantly higher for virtual administrations (M = 20.59, SD = 6.65) compared to in-person administrations (M = 16.35, SD = 6.05), possibly indicating inter-rater differences. Strong positive correlations were found for in-person and virtual scores within Group 1 on the CVLT-II (r = .84), SDMT (r = .85), TMT-A (r = .88), TMT-B (r = .76) and BVMT-R (r = .72). No significant differences between in-person and remote administrations of CVLT-II and SDMT in people living with MS were detected. Recommendations for future studies employing the TMT and BVMT-R online are provided.

Intravenous heterologous prime-boost vaccination activates innate and adaptive immunity to promote tumor regression.

Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 T cells and tumor regression. ChAdOx1 administered intravenously (i.v.) had 4-fold higher antigen-specific CD8 T cell responses than mice boosted by the intramuscular (i.m.) route. In the therapeutic MC38 tumor model, i.v. heterologous prime-boost vaccination enhances regression compared with ChAdOx1 alone. Remarkably, i.v. boosting with a ChAdOx1 vector encoding an irrelevant antigen also mediates tumor regression, which is dependent on type I IFN signaling. Single-cell RNA sequencing of the tumor myeloid compartment shows that i.v. ChAdOx1 reduces the frequency of immunosuppressive Chil3 monocytes and activates cross-presenting type 1 conventional dendritic cells (cDC1s). The dual effect of i.v. ChAdOx1 vaccination enhancing CD8 T cells and modulating the TME represents a translatable paradigm for enhancing anti-tumor immunity in humans.

The Up-Side of the COVID-19 Pandemic: Are Core Belief Violation and Meaning Making Associated with Post-Traumatic Growth?

The negative impact of the COVID-19 pandemic on mental health has been extensively documented, while its possible positive impact on the individual, defined as Post-Traumatic Growth (PTG), has been much less investigated. The present study examines the association between PTG and socio-demographic aspects, pre-pandemic psychological adjustment, stressors directly linked to COVID-19 and four psychological factors theoretically implicated in the change processes (core belief violation, meaning-making, vulnerability and mortality perception). During the second wave of the pandemic 680 medical patients completed an online survey on direct and indirect COVID-19 stressors, health and demographic information, post-traumatic growth, core belief violation, meaning-making capacity, feelings of vulnerability and perceptions of personal mortality. Violation of core beliefs, feelings of vulnerability and mortality, and pre-pandemic mental illness positively correlated with post-traumatic growth. Moreover, the diagnosis of COVID-19, stronger violation of core beliefs, greater meaning-making ability, and lower pre-existing mental illness predicted greater PTG. Finally, a moderating effect of meaning-making ability was found. The clinical implications were discussed.

Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence.

Alpha-1-antitrypsin (AAT), a serine protease inhibitor (serpin), is increasingly recognized to inhibit SARS-CoV-2 infection and counter many of the pathogenic mechanisms of COVID-19. Herein, we reviewed the epidemiologic evidence, the molecular mechanisms, and the clinical evidence that support this paradigm. As background to our discussion, we first examined the basic mechanism of SARS-CoV-2 infection and contend that despite the availability of vaccines and anti-viral agents, COVID-19 remains problematic due to viral evolution. We next underscored that measures to prevent severe COVID-19 currently exists but teeters on a balance and that current treatment for severe COVID-19 remains grossly suboptimal. We then reviewed the epidemiologic and clinical evidence that AAT deficiency increases risk of COVID-19 infection and of more severe disease, and the experimental evidence that AAT inhibits cell surface transmembrane protease 2 (TMPRSS2) - a host serine protease required for SARS-CoV-2 entry into cells - and that this inhibition may be augmented by heparin. We also elaborated on the panoply of other activities of AAT (and heparin) that could mitigate severity of COVID-19. Finally, we evaluated the available clinical evidence for AAT treatment of COVID-19.

Autopsy findings from patients diagnosed with COVID-19 demonstrate unique morphological patterns in bone marrow and lymph node.

AIMS: The identification of haemophagocytosis in bone marrow (BM) is recurrently identified in patients with severe COVID-19. These initial COVID-19 autopsy studies have afforded valuable insight into the pathophysiology of this disease; however, only a limited number of case series have focused on lymphoid or haematopoietic tissues. METHODS: BM and lymph node (LN) specimens were obtained from adult autopsies performed between 1 April 2020 and 1 June 2020, for which the decedent had tested positive for SARS-CoV-2. Tissue sections (H&E, CD3, CD20, CD21, CD138, CD163, MUM1, kappa/lambda light chains in situ hybridisation) were examined by two haematopathologists, who recorded morphological features in a blinded fashion. Haemophagocytic lymphohistiocytosis (HLH) was assessed based on HLH 2004 criteria. RESULTS: The BM demonstrated a haemophagocytic pattern in 9 out of 25 patients (36%). The HLH pattern was associated with longer hospitalisation, BM plasmacytosis, LN follicular hyperplasia and lower aspartate aminotransferase (AST), as well as ferritin at demise. LN examination showed increased plasmacytoid cells in 20 of 25 patients (80%). This pattern was associated with a low absolute monocyte count at diagnosis, lower white cell count and lower absolute neutrophil count at demise, and lower ferritin and AST at demise. CONCLUSIONS: Autopsy results demonstrate distinct morphological patterns in BM, with or without haemophagocytic macrophages, and in LN, with or without increased plasmacytoid cells. Since only a minority of patients met diagnostic criteria for HLH, the observed BM haemophagocytic macrophages may be more indicative of an overall inflammatory state.

Renin-Angiotensin System Components and Arachidonic Acid Metabolites as Biomarkers of COVID-19 (preprint)

Through the ACE2, a main enzyme of the renin-angiotensin system (RAS), the SARS-CoV2 gains access into the cell, resulting in different complications which may extend beyond the RAS and impact the Arachidonic Acid (ArA) pathway. The contribution of the RAS through ArA pathways metabolites in the pathogenesis of COVID-19 is unknown. We investigated whether RAS components and ArA metabolites can be considered biomarkers of COVID-19. We measured the plasma levels of RAS and ArA metabolites using an LC-MS/MS. Results indicate that Ang1-7 levels were significantly lower, whereas Ang II levels were higher in the COVID-19 patients than healthy control individuals. The ratio of Ang1-7/Ang II as an indicator of the RAS classical and protective arms balance was dramatically lower in COVID-19 patients. There was no significant increase in inflammatory 19-HETE and 20-HETE lev-els. The concentration of EETs was significantly increased in COVID-19 patients, whereas the DHETs concentration was repressed. Their plasma levels were correlated with Ang II concentration in COVID-19 patients. In conclusion, evaluating the RAS and ArA pathway biomarkers could provide helpful information for the early detection of high-risk groups, avoid delayed medical attention, facilitate resource allocation and improve patient clinical outcomes to prevent long COVID incidence.

RBD-based high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways (preprint)

SARS-CoV-2 has the capacity to evolve mutations to escape vaccine-and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool. Here, we challenged rhesus macaques with SARS-CoV-2 Delta and simultaneously treated them with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment gave equivalent protection in upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 did not block the development of memory responses to Delta and did not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Symptom Burden, Coagulopathy and Heart Disease after Acute SARS- CoV-2 Infection in Primary Practice - Results from the Study of HEarT DiseAse and ImmuNiTy After COVID-19 in Ireland (SETANTA) (preprint)

Purpose: The aim of SETANTA (Study of HEarT DiseAse and ImmuNiTy After COVID-19 in Ireland) study was to investigate symptom burden and incidence of cardiac abnormalities after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 and correlate these results with immunological response and biomarkers of coagulation.  Methods: SETANTA was a prospective, single-arm observational cross-sectional study in a primary practice setting, prospectively registered with ClinicalTrials.gov identifier: NCT04823182. Patients with recent COVID-19 infection ≥6 weeks and ≤12 months before enrolment were enrolled. Primary outcomes of interest were markers of cardiac injury detected by cardiac magnetic resonance imaging (MRI), including left ventricular ejection fraction, late gadolinium enhancement and pericardial abnormalities, and serum biomarker levels. Results: 100 patients (n= 129 approached) were included, 64% were female. Mean age was 45.2 years. The median (interquartile range) time interval between COVID-19 infection and enrolment was 189 [125, 246] days. 83% had at least one persistent symptom. 96% had positive serology for prior SARS-CoV-2 infection. Late gadolinium enhancement, pericardial effusion, was present in 2.2% and 8.3% respectively; left ventricular ejection fraction was below the normal reference limit in 17.4% of patients. Von Willebrand factor antigen was elevated in 32.7% of patients. Fibrinogen and D-Dimer levels were raised in 10.2% and 11.1% of patients, respectively.  Conclusion: In a cohort of primary practice patients recently recovered from SARS-CoV-2 infection, prevalence of persistent symptoms and markers of abnormal coagulation were high, despite a lower frequency of abnormalities on cardiac MRI compared with prior reports of patients assessed in a hospital setting.  Trial Registration: Clinicaltrials.gov, NCT04823182 (prospectively registered on 30th March 2021)

Anti-Viral and Anti-Inflammatory Therapeutic Effect of RAGE-Ig Protein Against Multiple SARS-CoV-2 Variants of Concern Demonstrated in K18-hACE2 Mouse and Syrian Golden Hamster Models (preprint)

Significance: SARS-CoV-2 Variants of Concern (VOCs) continue to evolve and re-emerge with chronic inflammatory long-COVID sequelae necessitating the development of anti-inflammatory therapeutic molecules. Therapeutic effects of the Receptor for Advanced Glycation End products (RAGE) were reported in many inflammatory diseases. However, a therapeutic effect of the RAGE in COVID-19 has not been reported. In the present study, we investigated whether and how the RAGE-Ig fusion protein would have an anti-viral and anti-inflammatory therapeutic effect in the COVID-19 system. Methods: The protective therapeutic effect of RAGE-Ig was determined in vitro in K18-hACE2 transgenic mice and Syrian golden hamsters infected with six various VOCs of SARS-CoV-2. The underlying anti-viral mechanism of RAGE-Ig was determined in vitro in SARS-CoV-2-infected human lung epithelial cells (BEAS-2B). Results: Following treatment of K18-hACE2 mice and hamsters infected with various SARS-CoV-2 VOCs with RAGE-Ig, we demonstrated: (i) significant dose-dependent protection (i.e. greater survival, less weight loss, lower virus replication in the lungs); (ii) a reduction of inflammatory macrophages (F4/80+/Ly6C+) and neutrophils (CD11b+/Ly6G+) infiltrating the infected lungs; (iii) a RAGE-Ig dose-dependent increase in the expression of type I interferons (IFN-alpha;, and IFN-beta) and type III interferon (IFN lambda2) and a decrease in the inflammatory cytokines (IL-6 and IL-8) in SARS-CoV-2-infected human lung epithelial cells; and (iv) a dose-dependent decrease in the expression of CD64 (FcgR1) on monocytes and lung epithelial cells from symptomatic COVID-19 patients. Conclusion: Our pre-clinical findings revealed type I and III interferons-mediated anti-viral and anti-inflammatory therapeutic effects of RAGE-Ig protein against COVID-19 caused by multiple SARS-CoV-2 VOCs.