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1.
Heart ; 2022 Oct 24.
Article in English | MEDLINE | ID: covidwho-2088826

ABSTRACT

OBJECTIVE: To examine association of COVID-19 with incident cardiovascular events in 17 871 UK Biobank cases between March 2020 and 2021. METHODS: COVID-19 cases were defined using health record linkage. Each case was propensity score-matched to two uninfected controls on age, sex, deprivation, body mass index, ethnicity, diabetes, prevalent ischaemic heart disease (IHD), smoking, hypertension and high cholesterol. We included the following incident outcomes: myocardial infarction, stroke, heart failure, atrial fibrillation, venous thromboembolism (VTE), pericarditis, all-cause death, cardiovascular death, IHD death. Cox proportional hazards regression was used to estimate associations of COVID-19 with each outcome over an average of 141 days (range 32-395) of prospective follow-up. RESULTS: Non-hospitalised cases (n=14 304) had increased risk of incident VTE (HR 2.74 (95% CI 1.38 to 5.45), p=0.004) and death (HR 10.23 (95% CI 7.63 to 13.70), p<0.0001). Individuals with primary COVID-19 hospitalisation (n=2701) had increased risk of all outcomes considered. The largest effect sizes were with VTE (HR 27.6 (95% CI 14.5 to 52.3); p<0.0001), heart failure (HR 21.6 (95% CI 10.9 to 42.9); p<0.0001) and stroke (HR 17.5 (95% CI 5.26 to 57.9); p<0.0001). Those hospitalised with COVID-19 as a secondary diagnosis (n=866) had similarly increased cardiovascular risk. The associated risks were greatest in the first 30 days after infection but remained higher than controls even after this period. CONCLUSIONS: Individuals hospitalised with COVID-19 have increased risk of incident cardiovascular events across a range of disease and mortality outcomes. The risk of most events is highest in the early postinfection period. Individuals not requiring hospitalisation have increased risk of VTE, but not of other cardiovascular-specific outcomes.

2.
Cell Rep ; 41(7): 111650, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2086004

ABSTRACT

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concerns (VOCs) continue to emerge, cross-neutralizing antibody responses become key toward next-generation design of a more universal COVID-19 vaccine. By analyzing published data from the literature, we report here that the combination of germline genes IGHV2-5/IGLV2-14 represents a public antibody response to the receptor-binding domain (RBD) that potently cross-neutralizes a broad range of VOCs, including Omicron and its sub-lineages. Detailed molecular analysis shows that the complementarity-determining region H3 sequences of IGHV2-5/IGLV2-14-encoded RBD antibodies have a preferred length of 11 amino acids and a conserved HxIxxI motif. In addition, these antibodies have a strong allelic preference due to an allelic polymorphism at amino acid residue 54 of IGHV2-5, which is located at the paratope. These findings have important implications for understanding cross-neutralizing antibody responses to SARS-CoV-2 and its heterogenicity at the population level as well as the development of a universal COVID-19 vaccine.

3.
Preprint in English | bioRxiv | ID: ppbiorxiv-512324

ABSTRACT

Antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target multiple epitopes on different domains of the spike protein, and other SARS-CoV-2 proteins. We developed a SARS-CoV-2 multi-antigen protein microarray with the nucleocapsid, spike and its domains (S1, S2), and variants with single (D614G, E484K, N501Y) or double substitutions (N501Y/Deletion69/70), allowing a more detailed high-throughput analysis of the antibody repertoire following infection. The assay was demonstrated to be reliable and comparable to ELISA. We analyzed antibodies from 18 COVID-19 patients and 12 recovered convalescent donors. S IgG level was higher than N IgG in most of the COVID-19 patients, receptor-binding domain of S1 showed high reactivity, but no antibodies were detected against heptad repeat domain 2 of S2. Furthermore, antibodies were detected against S variants with single and double substitutions in COVID-19 patients who were infected with SARS-CoV-2 early in the pandemic. Here we demonstrated that SARS-CoV-2 multi-antigen protein microarray is a powerful tool for detailed characterization of antibody responses, with potential utility in understanding the disease progress and assessing current vaccines and therapies against evolving SARS-CoV-2.

4.
J Pediatr ; 2022 Aug 06.
Article in English | MEDLINE | ID: covidwho-2031478

ABSTRACT

In this retrospective single-institution cohort study of 113 hospitalized pediatric patients with respiratory coronavirus disease 2019, those admitted to the intensive care unit or requiring mechanical ventilation had significantly higher immature platelet fractions than those who did not require intensive care unit-level care or ventilation. Immature platelet fraction may be an accessible biomarker for disease severity in pediatric respiratory coronavirus disease 2019.

5.
Preprint in English | bioRxiv | ID: ppbiorxiv-509341

ABSTRACT

Designing prefusion-stabilized SARS-CoV-2 spike is critical for the effectiveness of COVID-19 vaccines. All COVID-19 vaccines in the US encode spike with K986P/V987P mutations to stabilize its prefusion conformation. However, contemporary methods on engineering prefusion-stabilized spike immunogens involve tedious experimental work and heavily rely on structural information. Here, we established a systematic and unbiased method of identifying mutations that concomitantly improve expression and stabilize the prefusion conformation of the SARS-CoV-2 spike. Our method integrated a fluorescence-based fusion assay, mammalian cell display technology, and deep mutational scanning. As a proof-of-concept, this method was applied to a region in the S2 domain that includes the first heptad repeat and central helix. Our results revealed that besides K986P and V987P, several mutations simultaneously improved expression and significantly lowered the fusogenicity of the spike. As prefusion stabilization is a common challenge for viral immunogen design, this work will help accelerate vaccine development against different viruses.

6.
Sci Transl Med ; 14(662): eabq1945, 2022 09 14.
Article in English | MEDLINE | ID: covidwho-2029465

ABSTRACT

Emergence of SARS-CoV-2 variants of concern (VOCs), including the highly transmissible Omicron and Delta strains, has posed constant challenges to the current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified messenger RNA (mRNA) vaccine that expresses the more conserved viral nucleoprotein (mRNA-N) and show that mRNA-N vaccination alone can induce modest control of SARS-CoV-2. Critically, combining mRNA-N with the clinically proven S-expressing mRNA vaccine (mRNA-S+N) induced robust protection against both Delta and Omicron variants. In the hamster models of SARS-CoV-2 VOC challenge, we demonstrated that, compared to mRNA-S alone, combination mRNA-S+N vaccination not only induced more robust control of the Delta and Omicron variants in the lungs but also provided enhanced protection in the upper respiratory tract. In vivo CD8+ T cell depletion suggested a potential role for CD8+ T cells in protection conferred by mRNA-S+N vaccination. Antigen-specific immune analyses indicated that N-specific immunity, as well as augmented S-specific immunity, was associated with enhanced protection elicited by the combination mRNA vaccination. Our findings suggest that combined mRNA-S+N vaccination is an effective approach for promoting broad protection against SARS-CoV-2 variants.


Subject(s)
COVID-19 , Viral Vaccines , Animals , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , COVID-19 Vaccines , Cricetinae , Humans , Nucleocapsid , RNA, Messenger/genetics , SARS-CoV-2 , Vaccination , Vaccines, Synthetic , Viral Proteins , mRNA Vaccines
7.
Clin Infect Dis ; 2021 Oct 26.
Article in English | MEDLINE | ID: covidwho-2017772

ABSTRACT

BACKGROUND: Phase III trials have estimated COVID-19 vaccine efficacy (VE) against symptomatic and asymptomatic infection. We explore the direction and magnitude of potential biases in these estimates and their implications for vaccine protection against infection and against disease in breakthrough infections. METHODS: We developed a mathematical model that accounts for natural and vaccine-induced immunity, changes in serostatus and imperfect sensitivity and specificity of tests for infection and antibodies. We estimated expected biases in VE against symptomatic, asymptomatic and any SARS͏CoV2 infections and against disease following infection for a range of vaccine characteristics and measurement approaches, and the likely overall biases for published trial results that included asymptomatic infections. RESULTS: VE against asymptomatic infection measured by PCR or serology is expected to be low or negative for vaccines that prevent disease but not infection. VE against any infection is overestimated when asymptomatic infections are less likely to be detected than symptomatic infections and the vaccine protects against symptom development. A competing bias towards underestimation arises for estimates based on tests with imperfect specificity, especially when testing is performed frequently. Our model indicates considerable uncertainty in Oxford-AstraZeneca ChAdOx1 and Janssen Ad26.COV2.S VE against any infection, with slightly higher than published, bias-adjusted values of 59.0% (95% uncertainty interval [UI] 38.4 to 77.1) and 70.9% (95% UI 49.8 to 80.7) respectively. CONCLUSIONS: Multiple biases are likely to influence COVID-19 VE estimates, potentially explaining the observed difference between ChAdOx1 and Ad26.COV2.S vaccines. These biases should be considered when interpreting both efficacy and effectiveness study results.

8.
Value Health ; 2022 Aug 10.
Article in English | MEDLINE | ID: covidwho-1983584

ABSTRACT

OBJECTIVES: A significant indirect impact of COVID-19 has been the increasing elective waiting times observed in many countries. In England's National Health Service, the waiting list has grown from 4.4 million in February 2020 to 5.7 million by August 2021. The objective of this study was to estimate the trajectory of future waiting list size and waiting times up to December 2025. METHODS: A scenario analysis was performed using computer simulation and publicly available data as of November 2021. Future demand assumed a phased return of various proportions (0%, 25%, 50%, and 75%) of the estimated 7.1 million referrals "missed" during the pandemic. Future capacity assumed 90%, 100%, and 110% of that provided in the 12 months immediately before the pandemic. RESULTS: As a worst-case scenario, the waiting list would reach 13.6 million (95% confidence interval 12.4-15.6 million) by Autumn 2022, if 75% of missed referrals returned and only 90% of prepandemic capacity could be achieved. The proportion of patients waiting under 18 weeks would reduce from 67.6% in August 2021 to 42.2% (37.4%-46.2%) with the number waiting over 52 weeks reaching 1.6 million (0.8-3.1 million) by Summer 2023. At this time, 29.0% (21.3%-36.8%) of patients would be leaving the waiting list before treatment. Waiting lists would remain pressured under even the most optimistic of scenarios considered, with 18-week performance struggling to maintain 60%. CONCLUSIONS: This study reveals the long-term challenge for the National Health Service in recovering elective waiting lists and potential implications for patient outcomes and experience.

9.
Preprint in English | bioRxiv | ID: ppbiorxiv-502301

ABSTRACT

The strength of binding between human angiotensin converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of viral spike protein plays a role in the transmissibility of the SARS-CoV-2 virus. In this study we focus on a subset of RBD mutations that have been frequently observed in infected individuals and probe binding affinity changes to ACE2 using surface plasmon resonance (SPR) measurements and free energy perturbation (FEP) calculations. Our SPR results are largely in accord with previous studies but discrepancies do arise due to differences in experimental methods and to protocol differences even when a single method is used. Overall, we find that FEP performance is superior to that of other computational approaches examined as determined by agreement with experiment and, in particular, by its ability to identify stabilizing mutations. Moreover, the calculations successfully predict the observed cooperative stabilization of binding by the Q498R N501Y double mutant present in Omicron variants and offer a physical explanation for the underlying mechanism. Overall, our results suggest that despite the significant computational cost, FEP calculations may offer an effective strategy to understand the effects of interfacial mutations on protein-protein binding affinities and in practical applications such as the optimization of neutralizing antibodies.

10.
Viruses ; 14(7)2022 Jun 24.
Article in English | MEDLINE | ID: covidwho-1911652

ABSTRACT

Antigenic imprinting, which describes the bias of the antibody response due to previous immune history, can influence vaccine effectiveness. While this phenomenon has been reported for viruses such as influenza, there is little understanding of how prior immune history affects the antibody response to SARS-CoV-2. This study provides evidence for antigenic imprinting through immunization with two Sarbecoviruses, the subgenus that includes SARS-CoV-2. Mice were immunized subsequently with two antigenically distinct Sarbecovirus strains, namely SARS-CoV-1 and SARS-CoV-2. We found that sequential heterologous immunization induced cross-reactive binding antibodies for both viruses and delayed the emergence of neutralizing antibody responses against the booster strain. Our results provide fundamental knowledge about the immune response to Sarbecovirus and important insights into the development of pan-sarbecovirus vaccines and guiding therapeutic interventions.


Subject(s)
Antibodies, Neutralizing , COVID-19 , Animals , Antibodies, Viral , Antibody Formation , COVID-19/prevention & control , Immunization , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
11.
Antimicrob Agents Chemother ; 66(7): e0019822, 2022 07 19.
Article in English | MEDLINE | ID: covidwho-1901915

ABSTRACT

In vitro selection of remdesivir-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed the emergence of a V166L substitution, located outside of the polymerase active site of the Nsp12 protein, after 9 passages of a single lineage. V166L remained the only Nsp12 substitution after 17 passages (10 µM remdesivir), conferring a 2.3-fold increase in 50% effective concentration (EC50). When V166L was introduced into a recombinant SARS-CoV-2 virus, a 1.5-fold increase in EC50 was observed, indicating a high in vitro barrier to remdesivir resistance.


Subject(s)
COVID-19 , SARS-CoV-2 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Alanine/analogs & derivatives , Alanine/metabolism , Antiviral Agents/chemistry , COVID-19/drug therapy , Humans
12.
Immunity ; 55(6): 1105-1117.e4, 2022 06 14.
Article in English | MEDLINE | ID: covidwho-1889505

ABSTRACT

Global research to combat the COVID-19 pandemic has led to the isolation and characterization of thousands of human antibodies to the SARS-CoV-2 spike protein, providing an unprecedented opportunity to study the antibody response to a single antigen. Using the information derived from 88 research publications and 13 patents, we assembled a dataset of ∼8,000 human antibodies to the SARS-CoV-2 spike protein from >200 donors. By analyzing immunoglobulin V and D gene usages, complementarity-determining region H3 sequences, and somatic hypermutations, we demonstrated that the common (public) responses to different domains of the spike protein were quite different. We further used these sequences to train a deep-learning model to accurately distinguish between the human antibodies to SARS-CoV-2 spike protein and those to influenza hemagglutinin protein. Overall, this study provides an informative resource for antibody research and enhances our molecular understanding of public antibody responses.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Antibody Formation , Humans , Pandemics , Spike Glycoprotein, Coronavirus
13.
Interv Neuroradiol ; : 15910199221104616, 2022 Jun 01.
Article in English | MEDLINE | ID: covidwho-1886889

ABSTRACT

INTRODUCTION: As we emerge from the current pandemic, hospitals, staff, and resources will need to continue to adjust to meet ongoing healthcare demands. Lessons learned during past shortages can be used to optimize peri-procedural protocols to safely improve the utilization of hospital resources. METHODS: Retrospective review of patients who underwent elective endovascular intracranial aneurysm treatment was performed. Multivariable logistic regression was used to identify factors associated with patients who were able to be discharged within 24 h of elective procedures. Rates of complications (particularly readmission) were determined. RESULTS: 330 patients underwent elective endovascular aneurysm treatment with 86 (26.1%) discharged within 24 h. Factors associated with earlier discharge included procedure years (2019-2021) and male sex. Patients were more likely to be discharged later (after 24 h) if they underwent stent-coil embolization or flow-diversion. There was no association between discharge timing and likelihood of readmission. DISCUSSION: Our review highlights the safety of earlier discharge and allowed us to prepare a fast-track protocol for same-day discharge in these patients. This protocol will be studied prospectively in the next phase of this study. As we gain more comfort with emerging, minimally invasive endovascular therapies, we hope to safely achieve same-day discharge on a protocolized and routine basis, reducing the demand of elective aneurysm treatments on our healthcare system. CONCLUSION: We retrospectively demonstrate that early discharge following elective aneurysm treatment is safe in our cohort and provide a fast-track pathway based on these findings for other centers developing similar protocols.

14.
Preprint in English | bioRxiv | ID: ppbiorxiv-496903

ABSTRACT

Increasing the expression level of the SARS-CoV-2 spike (S) protein has been critical for COVID-19 vaccine development. While previous efforts largely focused on engineering the receptor-binding domain (RBD) and the S2 subunit, the N-terminal domain (NTD) has been long overlooked due to the limited understanding of its biophysical constraints. In this study, the effects of thousands of NTD single mutations on S protein expression were quantified by deep mutational scanning. Our results revealed that in terms of S protein expression, the mutational tolerability of NTD residues was inversely correlated with their proximity to the RBD and S2. We also identified NTD mutations at the interdomain interface that increased S protein expression without altering its antigenicity. Overall, this study not only advances the understanding of the biophysical constraints of the NTD, but also provides invaluable insights into S-based immunogen design.

15.
Paideusis ; 29(1):5, 2022.
Article in English | ProQuest Central | ID: covidwho-1848420

ABSTRACT

We are witnessing what can only be called an anti-critical thinking trend in contemporary society. In this brief essay I want to describe how and why critical thinking is in crisis, and what that means for reconsidering the promotion of critical thinking as an educational aim. Several of my examples show how this crisis has distorted the public debate over COVID.

17.
Preprint in English | bioRxiv | ID: ppbiorxiv-492220

ABSTRACT

As SARS-CoV-2 variants of concerns (VOCs) continue to emerge, cross-neutralizing antibody responses become key towards next-generation design of a more universal COVID-19 vaccine. By analyzing published data from the literature, we report here that the combination of germline genes IGHV2-5/IGLV2-14 represents a public antibody response to the receptor-binding domain (RBD) that potently cross-neutralizes all VOCs to date, including Omicron and its sub-lineages. Detailed molecular analysis shows that the complementarity-determining region H3 sequences of IGHV2-5/IGLV2-14-encoded RBD antibodies have a preferred length of 11 amino acids and a conserved HxIxxI motif. In addition, these antibodies have a strong allelic preference due to an allelic polymorphism at amino-acid residue 54 of IGHV2-5, which locates at the paratope. These findings have important implications for understanding cross-neutralizing antibody responses to SARS-CoV-2 and its heterogenicity at the population level as well as the development of a universal COVID-19 vaccine.

18.
J Am Acad Orthop Surg ; 30(14): 648-657, 2022 Jul 15.
Article in English | MEDLINE | ID: covidwho-1811110

ABSTRACT

INTRODUCTION: The COVID-19 pandemic created unprecedented challenges to residency recruitment. With in-person away rotations prohibited and interviews held virtually, orthopaedic residency programs turned to social media. Studies document the exponential growth of residency program Instagram accounts after March 2020, but few analyze the content of their posts. This study provides an updated assessment of such Instagram accounts including a detailed analysis of their content and a discussion of potentially concerning posts. METHODS: Orthopaedic surgery residency programs participating in the National Resident Matching Program and any Instagram accounts associated with these programs were identified. Instagram accounts were analyzed, and the 25 most recent posts and all highlighted stories for each account were coded for content based on a predetermined list of categories. Specific attention was given to content that may raise legal, ethical, or professionalism concerns. The primary outcome was the most common content code among posts. The secondary outcomes were the number of posts identified as potentially concerning and the types of concerns represented. RESULTS: Overall, 138 of 193 residency programs (72%) had an Instagram account at the time of cross-sectional analysis, 65% of which were created between April and December 2020. All accounts were public. Profiles had on average 1,156 ± 750 followers and 59 ± 75 posts. Of the 3,348 posts analyzed, the most common coded themes were resident introductions (33%), camaraderie (27%), and social life and hobbies (26%). There were 81 concerning posts from 52 separate accounts. Seventy-five of the concerning posts (93%) depicted residents scrubbed alone. CONCLUSION: Orthopaedic residency Instagram accounts are potential tools for residency recruitment and can depict a program's culture through posts over time. However, public accounts are open to scrutiny by other viewers, including patients and their families. Care must be taken to consider multiple perspectives of post content, so as to bolster, not damage, the residency program's reputation.


Subject(s)
COVID-19 , Internship and Residency , Orthopedic Procedures , Cross-Sectional Studies , Humans , Pandemics
19.
Sci Transl Med ; 14(646): eabn6859, 2022 05 25.
Article in English | MEDLINE | ID: covidwho-1794534

ABSTRACT

The devastation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus, we identified a human monoclonal antibody, 10-40, that neutralized or bound all sarbecoviruses tested in vitro and protected against SARS-CoV-2 and SARS-CoV in vivo. Comparative studies with other receptor-binding domain (RBD)-directed antibodies showed 10-40 to have the greatest breadth against sarbecoviruses, suggesting that 10-40 is a promising agent for pandemic preparedness. Moreover, structural analyses on 10-40 and similar antibodies not only defined an epitope cluster in the inner face of the RBD that is well conserved among sarbecoviruses but also uncovered a distinct antibody class with a common CDRH3 motif. Our analyses also suggested that elicitation of this class of antibodies may not be overly difficult, an observation that bodes well for the development of a pan-sarbecovirus vaccine.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Humans , Immunoglobulin Isotypes , Spike Glycoprotein, Coronavirus
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