16 October, 2023

Did long COVID increase road deaths in the U.S.? -

Objective To examine data on COVID-19 disease associated with a 10 percent increase in U.S. road deaths from 2020 to 2021 that raises the question of the potential effect of pandemic stress and neurological damage from COVID-19 disease. Methods Poisson regression was used to estimate the association of recent COVID-19 cases, accumulated cases, maximum temperatures, truck registrations, and gasoline prices with road deaths monthly among U.S. states in 2021. Using the regression coefficients, changes in each risk factor from 2020 to 2021 were used to calculate expected deaths in 2021 if each factor had remained the same as in 2020. Results Corrected for the other risk factors, road deaths were associated with accumulated COVID-19 cases but not cases in the previous month More than 20,700 road deaths were associated with the changes in accumulated COVID-19 cases but were substantially offset by about 19,100 less-than-expected deaths associated with increased gasoline prices. Conclusions While more research is needed, the data are sufficient to warn people with long COVID to minimize driving.

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Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction -

Viruses commonly interfere with the function of the eukaryotic translation initiation factor 4G1 (eIF4G1), a pivotal factor in the recruitment of the eIF3 complex and ribosome to the mRNA. This results in the inhibition of general host protein synthesis and redirecting ribosomes toward viral mRNAs. Certain viruses also selectively repress the translation of mRNAs involved in the host antiviral response. GIGYF2 and its interacting cap-binding protein 4EHP enable the transcript-specific repression of mRNA translation mediated by microRNAs and RNA-binding proteins (RBPs). RNA viruses, such as SARS-CoV-2, exploit the GIGYF2/4EHP complex to selectively repress the translation of transcripts such as Ifnb1 mRNA, which encodes the antiviral cytokine Interferon {beta} (IFN-{beta}). Herein, we reveal that GIGYF1, a paralogue of GIGYF2, robustly represses cellular mRNA translation through a distinct mechanism independent of 4EHP. Upon recruitment to a target mRNA by RBPs, the C-terminal region of GIGYF1 binds to subunits of eIF3 at the interaction interface of eIF3-eIF4G1. This disrupts the recruitment of eIF3 to the mRNA by eIF4G1, resulting in mRNA-specific translational repression. This mechanism exerts profound influences on the host cell's response to viral infection. Depletion of GIGYF1 induces a robust immune response by derepressing Ifnb1 mRNA translation. Overall, our study highlights a unique mechanism of translational regulation by GIGYF1 that involves sequestering eIF3 and abrogating its binding to eIF4G1. This mechanism can be utilized by RBPs that interact with GIGYF1 to specifically repress the translation of their target mRNAs, significantly affecting critical biological processes, including host-pathogen interactions.

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Inferring Viral Transmission Pathways from Within-Host Variation -

Genome sequencing can offer critical insight into pathogen spread in viral outbreaks, but existing transmission inference methods use simplistic evolutionary models and only incorporate a portion of available genetic data. Here, we develop a robust evolutionary model for transmission reconstruction that tracks the genetic composition of within-host viral populations over time and the lineages transmitted between hosts. We confirm that our model reliably describes within-host variant frequencies in a dataset of 134,682 SARS-CoV-2 deep-sequenced genomes from Massachusetts, USA. We then demonstrate that our reconstruction approach infers transmissions more accurately than two leading methods on synthetic data, as well as in a controlled outbreak of bovine respiratory syncytial virus and an epidemiologically-investigated SARS-CoV-2 outbreak in South Africa. Finally, we apply our transmission reconstruction tool to 5,692 outbreaks among the 134,682 Massachusetts genomes. Our methods and results demonstrate the utility of within-host variation for transmission inference of SARS-CoV-2 and other pathogens, and provide an adaptable mathematical framework for tracking within-host evolution.

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Evaluation of Stroke Risk Following COVID-19 mRNA Bivalent Vaccines Among U.S. Adults Aged ≥65 Years -

In January 2023, the United States Food and Drug Administration and the Centers for Disease Control and Prevention noted a safety concern for ischemic stroke in adults 65 years of age or older receiving the BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. This self-controlled case series analysis evaluated stroke risk among Medicare fee-for-service beneficiaries aged 65 years of age or older receiving: 1) a Pfizer-BioNTech (BNT162b2; WT OMI BA.4 and BA.5) or Moderna (mRNA 1273.222) COVID-19 bivalent vaccine, 2) high-dose/adjuvanted influenza vaccines, and 3) concomitant COVID-19 bivalent vaccines and influenza vaccines, from August 31 to November 6, 2022. The primary analysis did not find elevated stroke risk following COVID-19 bivalent vaccines. In the age subgroup analyses, only the 85+ year age group had a risk of NHS (Incident Rate Ratio (IRR)=1.36, 95% CI 1.09 to 1.69 [1 to 21 days]) and NHS/TIA (IRR=1.28, 95% CI 1.08 to 1.52 [1 to 21 days]) with BNT162b2 Bivalent WT OMI BA.4 and BA.5. Among beneficiaries receiving a concomitant COVID-19 bivalent vaccine and a high-dose/adjuvanted influenza vaccine, an increased risk was observed for NHS (IRR=1.20, 95% CI 1.01 to 1.42 [22 to 42 days]) with BNT162b2 Bivalent WT OMI BA.4 and BA.5 and for TIA (IRR=1.35, 95% CI 1.06 to 1.74 [1 to 21 days]) with mRNA 1273.222. Results of the secondary analyses showed a small increased risk of NHS following high-dose or adjuvanted influenza vaccines (IRR=1.09, 95% CI 1.02 to 1.17 [22 to 42 days]).

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Omicron COVID-19 Immune Correlates Analysis of a Third Dose of mRNA-1273 in the COVE Trial -

In the coronavirus efficacy (COVE) phase 3 efficacy trial of the mRNA-1273 vaccine, IgG binding antibody (bAb) concentration against Spike (BA.1 strain) and neutralizing antibody (nAb) titer against Spike (BA.1 strain) pseudovirus were assessed as correlates of risk of Omicron COVID-19 and as correlates of relative boost efficacy in per-protocol recipients of a third (booster) dose. Markers were measured on the day of the boost (BD1) and 28 days later (BD29). For SARS-CoV-2 naive individuals, BD29 Spike IgG-BA.1 strain bAbs and BD29 BA.1-strain nAbs inversely correlated with Omicron COVID-19: hazard ratio (HR) per 10-fold marker increase [95% confidence interval (CI)] = 0.16 (0.03, 0.79); P=0.024 and 0.31 (0.10, 0.96); P = 0.042, respectively. These markers also inversely correlated with Omicron COVID-19 in non-naive individuals: HR = 0.15 (0.04, 0.63); P = 0.009 and 0.28 (0.07, 1.08); P = 0.06, trend. Fold-rise in markers from BD1 to BD29 had similarly strong inverse correlations. For SARS-CoV-2 naive individuals, overall booster relative (three-dose vs two-dose) efficacy was 46% (95% CI: 20%, 64%) and correlated with BA.1 strain nAb titer at exposure. At 56, 251, and 891 arbitrary units (AU)/ml (10th, 50th, and 90th percentile), the booster relative efficacies were -8% (95% CI: -126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), respectively. Similar relationships were observed for Spike IgG-BA.1 strain bAbs and for the markers measured at BD29. The performance of bAb and nAb markers as correlates of protection against Omicron COVID-19 supports their continued use as surrogate endpoints for mRNA vaccination against Omicron COVID-19.

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IFIH1 loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases -

The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation linking it to weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss of this gene causes immunodeficiency. In this study, nine patients suffering from different cases of recurrent infections, inflammatory diseases, severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole exome sequencing. All patients revealed signs of lymphopenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin, and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19, or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2 related disorders.

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Surveillance and Stability of SARS-CoV-2 Wastewater Samples in Minnesota -

Wastewater-based epidemiology provides an approach for assessing the prevalence of pathogens such as COVID-19 in a sewer service area. In this study, SARS-CoV-2 RNA was measured serially in 44 wastewater treatment plants of varying service capacities comprising approximately 67% of the population of Minnesota, from September 2020 through December 2022. We employed linear regression models to establish a predictive relationship between the weekly SARS‐CoV‐2 RNA concentrations in wastewater and clinical case counts. Metrics were assessed under specified transformation and normalization methods which we confirmed by cross-validation averaged across the enrolled treatment plants. We report that the relationship between COVID-19 incidence and SARS-CoV-2 RNA in wastewater may be treatment plant-specific. Toward establishing guidelines for pathogen surveillance, we further studied storage and time-to-analysis for RNA wastewater data and observed large effects of storage temperature, indicating that collection methods may have an important effect on the utility and validity of wastewater data for infectious disease monitoring. Our findings are additive for any large-scale wastewater surveillance program.

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Ischemic Stroke after Bivalent COVID-19 Vaccination: A Self-Controlled Case Series Study -

Introduction The potential association between bivalent COVID-19 vaccination and ischemic stroke remains uncertain, despite several studies conducted thus far. The purpose is to evaluate the risk of ischemic stroke following bivalent COVID-19 vaccination. Methods A self-controlled case series study was conducted among members aged 12 years and older who experienced ischemic stroke between September 1, 2022 and March 31, 2023 in a large California health care system. Ischemic strokes were identified using ICD-10 codes in Emergency Department and inpatient settings. Exposures were Pfizer-BioNTech or Moderna bivalent COVID-19 vaccination. Risk intervals were pre-specified as 1-21 days and 1-42 days after bivalent COVID-19 vaccination; all non-risk-interval person-time served as control interval. We conducted overall and subgroup analyses by age, history of SARS-CoV-2 infection, and co-administration of influenza vaccine. When an elevated risk was detected, we performed chart review of ischemic strokes, and re-evaluated the risk. RESULTS With 4933 cases, we found no increased risk within 21-day risk interval across vaccines and by subgroups. However, an elevated risk emerged within 42-day risk interval among individuals <65 years who received co-administration of Pfizer-BioNTech bivalent vaccine and influenza vaccine on the same day; relative incidence (RI) was 2.14 (95% CI, 1.02-4.49). Among those who also had history of SARS-CoV-2 infection, RI was 3.94 (95% CI, 1.10-14.16). After chart review, RIs were 2.35 (95% CI, 0.98-5.65) and 4.33 (95% CI, 0.98-19.11), respectively. Among individuals <65 years who received Moderna bivalent vaccine and had history of SARS-CoV-2 infection, RI was 2.62 (95% CI, 1.13-6.03) before chart review and 2.24 (95% CI, 0.78-6.47) after chart review. CONCLUSIONS The potential association between bivalent COVID-19 vaccination and ischemic stroke in the 1-42-day analysis warrants further investigation among individuals <65 years with influenza vaccine co-administration and prior SARS-CoV-2 infection.

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Longitudinal viscosity of blood plasma for rapid COVID-19 prognostics -

Blood Plasma Viscosity (PV) is an established biomarker for numerous diseases. While PV colloquially refers to the shear viscosity, there is a second viscosity component–the bulk viscosity–that describes the irreversible fluid compressibility on short time scales. The bulk viscosity is acutely sensitive to solid-like suspensions, and obtainable via the longitudinal viscosity from acoustic attenuation measurements. Whether it has diagnostic value remains unexplored yet may be pertinent given the association of diverse pathologies with the formation of plasma suspensions, such as fibrin-microstructures in COVID-19 and long-COVID. Here we show that the longitudinal PV measured using Brillouin Light Scattering (BLS) can serve as a proxy for the shear PV of blood plasma, and exhibits a temperature dependence consistent with increased suspension concentrations in severe COVID-patient plasma. Our results open a new avenue for PV diagnostics based on the longitudinal PV, and show that BLS can provide a means for its clinical implementation.

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Hyperglycemia-induced cathepsin L maturation: Implications for diabetic comorbidities and COVID-19 susceptibility -

Diabetes is the second most frequent chronic comorbidity for COVID-19 mortality, yet the underlying mechanism remains unclear. Previous studies suggest that Cathepsin L (CTSL) is implicated in diabetic complications such as nephropathy and retinopathy. Our previous research identified CTSL as a critical protease that promotes SARS-CoV-2 infection and a potential drug target. Here, we show that individuals with diabetes have elevated blood CTSL levels, which facilitates SARS-CoV-2 infection. Chronic hyperglycemia, as indicated by HbA1c levels, is positively correlated with CTSL concentration and activity in diabetic patients. Acute hyperglycemia induced by a hyperglycemic clamp in healthy individuals increases CTSL activity. In vitro, high glucose, but not high insulin, promotes SARS-CoV-2 infection in wild-type (WT) cells, while CTSL knockout (KO) cells show reduced susceptibility to high glucose-promoted effects. Using lung tissue samples from diabetic and non-diabetic patients, as well as db/db diabetic and control mice, our findings demonstrate that diabetic conditions increase CTSL activity in both humans and mice. Mechanistically, high glucose levels promote CTSL maturation and CTSL translocation from the endoplasmic reticulum (ER) to the lysosome via the ER-Golgi-lysosome axis. This study emphasizes the significance of hyperglycemia-induced cathepsin L maturation in the development of diabetic comorbidities and complications.

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Hidden evolutionary constraints dictate the retention of coronavirus accessory genes -

Genetic innovation is fundamental to the ability of viruses to adapt in the face of host immunity. Coronaviruses exhibit many mechanisms of innovation given flexibility in genomic composition relative to most RNA virus families (1-5). Examples include the acquisition of unique accessory genes that can originate by capture of cellular genes or through duplication and divergence of existing viral genes (6-8). Accessory genes may be influential in dictating viral host range and cellular tropism, but little is known about how selection acts on these variable regions of virus genomes. We used experimental evolution of mouse hepatitis virus (MHV) with an inactive native phosphodiesterase, NS2, that encodes a complementing cellular AKAP7 gene (9), to simulate the capture of a host gene and found hidden patterns of constraint that determine the fate of coronavirus accessory genes. After courses of serial infection, AKAP7 was retained under strong selection but rapidly lost under relaxed selection. In contrast, the gene encoding inactive NS2, ORF2, remained intact, suggesting it is under cryptic evolutionary constraint. Guided by the retention of ORF2 and hints of similar patterns in related betacoronaviruses, we analyzed the evolution of SARS-CoV-2 ORF8, which arose via gene duplication (6) and contains premature stop codons in several globally successful lineages. As with MHV ORF2, the coding-defective SARS-CoV-2 ORF8 gene remains largely intact, mirroring patterns observed during MHV experimental evolution and extending these findings to viruses currently adapting to humans. Retention of inactive genes challenges assumptions on the dynamics of gene loss in virus genomes and can help guide evolutionary analysis of emerging and pandemic coronaviruses.

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Antibodies utilizing VL6-57 light chains target a convergent cryptic epitope on SARS-CoV-2 spike protein driving the genesis of Omicron variants -

Continued evolution of SARS-CoV-2 generates variants to challenge antibody immunity established by infection and vaccination. A connection between population immunity and genesis of virus variants has long been suggested but its molecular basis remains poorly understood. Here, we identify a class of SARS-CoV-2 neutralising public antibodies defined by their shared usage of VL6-57 light chains. Although heavy chains of diverse genotypes are utilized, convergent HCDR3 rearrangements have been observed among these public antibodies to cooperate with germline VL6-57 LCDRs to target a convergent epitope defined by RBD residues S371-S373-S375. Antibody repertoire analysis identifies that this class of VL6-57 antibodies is present in SARS-CoV-2-naive individuals and is clonally expanded in most COVID-19 patients. We confirm that Omicron specific substitutions at S371, S373 and S375 mediate escape of antibodies of the VL6-57 class. These findings support that this class of public antibodies constitutes immune pressure promoting the introduction of S371L/F-S373P-S375F in Omicron variants. The results provide further molecular evidences to support that antigenic evolution of SARS-CoV-2 is driven by antibody mediated population immunity.

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Threat awareness and counter-terrorism preparedness of Dutch hospitals: a cross-sectional survey -

ABSTRACT Background Workplace violence, including violent extremism, is a growing concern in the healthcare environment. Furthermore, there has been a disproportionate rise in the rate of terrorist attacks on hospitals during the past two decades. Hospitals are vulnerable targets due to their easy accessibility and their high density of patients, staff and visitors. Nonetheless, little is known about the hospitals awareness of these risks, and to which extent these facilities protect themselves from violent extremism and terrorist attacks. Methods This was a cross-sectional survey study among emergency managers of acute care hospitals in the Netherlands. The questionnaire included 42 items across six themes: demographic (hospital) data; general and emergency department (ED) access control; ED security and preparedness; online security and offline transparency; violence, terrorism and warfare; and impact of the COVID-19 pandemic. Responses were collected and stored in a secured online database, and subsequently exported to an Excel spreadsheet for descriptive analysis. Continuous data were reported as means or as medians with interquartile ranges (IQR), using SPSS. Categorical data were reported as absolute numbers and as valid percentages. Results The questionnaire was completed on behalf of 33 out of 71 hospital organizations (46%), representing 38 out of 82 EDs (46%). Hospitals had broadly different policies with regards to patient and visitor registration, and the presence of security guards. Most hospitals had controlled vehicle access for the parking lot and ambulance bay, but this was not 24/7 in all hospitals. A paragraph on terrorist attacks was included in 34% of hospital disaster plans. Eighteen percent of hospitals had previous experience with acts of violent extremism and 55% of hospitals had sustained (attempted) cyberattacks. Whilst the likelihood of a physical terrorist attack was deemed low at 3.6 (median 4, IQR 2.6) on a 10-point Likert scale, the likelihood of a cyberattack was considered high at 7.3 (median 8, IQR 2.3). A significant proportion of emergency managers reported to experience an increased risk of violence since the onset of the COVID-19 pandemic. Conclusion Practice variation with regards to counter-terrorism defence measures in Dutch hospitals is high. The preparedness of hospitals for terrorist attacks or acts of violent extremism could be improved and may benefit from uniform, evidence based hospital security policies.

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Nanobodies against SARS-CoV-2 non-structural protein Nsp9 inhibit viral replication by targeting innate immunity -

Nanobodies are emerging as critical tools for drug design. Several have been recently created to serve as inhibitors of SARS-Cov-2 entry in the host cell by targeting surface-exposed Spike protein. However, due to the high frequency of mutations that affect Spike, these nanobodies may not target it to their full potential and as a consequence, inhibition of viral entry may not be efficient. Here we have established a pipeline that instead targets highly conserved viral proteins that are made only after viral entry into the host cell when the SARS-Cov-2 RNA-based genome is translated. As proof of principle, we designed nanobodies against the SARS-CoV-2 non-structural protein Nsp9, required for viral genome replication. To find out if this strategy efficiently blocks viral replication, one of these anti-Nsp9 nanobodies, 2NSP23, previously characterized using immunoassays and NMR spectroscopy for epitope mapping, was encapsulated into lipid nanoparticles (LNP) as mRNA. We show that this nanobody, hereby referred to as LNP-mRNA-2NSP23, is internalized and translated in HEK293 cells. We next infected HEK293-ACE2 cells with multiple SARS-CoV-2 variants and subjected them to LNP-mRNA-2NSP23 treatment. Analysis of total RNA isolated from infected cells treated or untreated with LNP-mRNA-2NSP23 using qPCR and RNA deep sequencing shows that the LNP-mRNA-2NSP23 nanobody protects HEK293-ACE2 cells and suppresses replication of several SARS-CoV-2 variants. These observations indicate that following translation, the nanobody 2NSP23 inhibits viral replication by targeting Nsp9 in living cells. We speculate that LNP-mRNA-2NSP23 may be translated into an innovative technology to generate novel antiviral drugs highly efficient across coronaviruses.

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Akaluc bioluminescence offers superior sensitivity to track in vivo dynamics of SARS-CoV-2 infection -

Monitoring in vivo viral dynamics can improve our understanding of pathogenicity and tissue tropism. For positive-sense, single-stranded RNA viruses, several studies have attempted to monitor viral kinetics in vivo using reporter genomes. The application of such recombinant viruses can be limited by challenges in accommodating bioluminescent reporter genes in the viral genome. Conventional luminescence also exhibits relatively low tissue permeability and thus less sensitivity for visualization in vivo. Here we show that unlike NanoLuc bioluminescence, the improved method, termed AkaBLI, allows visualization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Syrian hamsters. By successfully incorporating a codon-optimized Akaluc luciferase gene into the SARS-CoV-2 genome, we visualized in vivo infection, including the tissue-specific differences associated with particular variants. Additionally, we could evaluate the efficacy of neutralizing antibodies and mRNA vaccination by monitoring changes in Akaluc signals. Overall, AkaBLI is an effective technology for monitoring viral dynamics in live animals.

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