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TNX-1800 is a synthetically derived live chimeric Horsepox Virus (rcHPXV) vaccine expressing Wuhan SARS-CoV-2 spike (S) protein. The primary objective of this study was to evaluate the immunogenicity and efficacy of TNX-1800 in two nonhuman primate species challenged with USA-WA1/2020 SARS-CoV-2. TNX-1800 vaccination was well tolerated, as indicated by the lack of serious adverse events or significant changes in clinical parameters. A single dose of TNX-1800 generated robust humoral responses in African Green Monkeys and Cynomolgus Macaques, as measured by the total binding anti-SARS-CoV-2 S IgG and neutralizing antibody titers against the USA-WA1/2020 strain. In Cynomolgus Macaques, a single dose of TNX-1800 induced a strong interferon-gamma (IFN-{gamma}) mediated T cell response, promoting both pathogen clearance in the upper and lower airways and generation of systemic neutralizing antibody response against WA strain SARS-CoV-2. Future studies will assess the efficacy of TNX-1800 against newly emerging variants and demonstrate its safety in humans.
Subject(s)
Severe Acute Respiratory SyndromeABSTRACT
Background: Booster vaccinations are recommended to improve protection against severe disease from SARS-CoV-2 infection. With primary vaccinations involving various adenoviral vector and mRNA-based formulations, it remains unclear if these differentially affect the immune response to booster doses. We here examined the effects of homologous (mRNA/mRNA) and heterologous (adenoviral vector/mRNA) vaccination on antibody and memory B cell (Bmem) responses against ancestral and Omicron subvariants. Methods: Healthy adults who received primary BNT162b2 (mRNA) (n=18) or ChAdOx1 (vector) (n=25) vaccination were sampled 1-month and 6-months after their 2nd and 3rd dose (homologous or heterologous) vaccination. Recombinant spike receptor-binding domain (RBD) proteins from ancestral, Omicron BA.2 and BA.5 variants were produced for ELISA-based serology, and tetramerized for immunophenotyping of RBD-specific Bmem. Results: Dose 3 boosters significantly increased ancestral RBD-specific plasma IgG and Bmem in both cohorts. Up to 80% of ancestral RBD-specific Bmem expressed IgG1+. IgG4+ Bmem were detectable after primary mRNA vaccination, and expanded significantly to 5-20% after dose 3, whereas heterologous boosting did not elicit IgG4+ Bmem. Recognition of Omicron BA.2 and BA.5 by ancestral RBD-specific plasma IgG increased from 20% to 60% after the 3rd dose in both cohorts. Reactivity of ancestral RBD-specific Bmem to Omicron BA.2 and BA.5 increased following a homologous booster from 40% to 60%, but not after a heterologous booster. Conclusion: A 3rd mRNA dose generates similarly robust serological and Bmem responses in homologous and heterologous vaccination groups. The expansion of IgG4+ Bmem after mRNA priming might result from the unique vaccine formulation or dosing schedule affecting the Bmem response duration and antibody maturation.
Subject(s)
COVID-19ABSTRACT
TNX-1800 is a preclinical stage synthetic derived live chimeric horsepox virus vaccine that comprises an engineered SARS-CoV-2 spike (S) gene expression cassette. The objectives of this study were to assess the immunogenicity and tolerability of TNX-1800 administration in Syrian golden hamsters and New Zealand white rabbits. Animals were vaccinated via percutaneous inoculation and evaluated for dose tolerance and immunogenicity at three different dose levels. The 28-day study data showed that the single percutaneous administration of three TNX-1800 vaccine dose levels was well tolerated in both hamsters and rabbits. For all dose levels, rabbits had more dermal observations than hamsters at the same dose levels. Vaccine-induced viral load four weeks post-dosing was below the detection level for both species.
Subject(s)
Severe Acute Respiratory SyndromeABSTRACT
Objective: Post-acute sequelae of COVID-19 (PASC, also referred as Long-COVID) sometimes follows COVID-19, a disease caused by SARS-CoV-2. While SARS-CoV-2 is well-known to promote a prothrombotic state, and especially to activate platelets acutely, less is known about the thrombosis risk in PASC. Approach and Results: PASC patients and age-matched healthy controls were enrolled in the study on average 15 months after documented SARS-CoV-2 infection. Platelet activation was evaluated by Light Transmission Aggregometry (LTA) and flow cytometry in response to platelet surface receptor agonists. Thrombosis in platelet-deplete plasma was evaluated by Factor Xa activity. A microfluidics system assessed thrombosis in whole blood under venous shear stress conditions. While only a mild increase in platelet aggregation in PASC patients through the thromboxane receptor was observed platelet activation through the glycoprotein VI (GPVI) receptor was markedly decreased in PASC patients compared to age- and sex-matched healthy controls. Thrombosis under venous shear conditions as well as Factor Xa activity were reduced in PASC patients. Plasma from PASC patients was an extremely potent activator of washed, healthy platelets - a phenomenon not observed using age- and sex-matched platelets from healthy individuals. Conclusions: PASC patients demonstrate dysregulated responses in platelets and coagulation in plasma, likely caused by a circulating plasma-derived molecule that promotes thrombosis. A hitherto undescribed protective response appears to exists in PASC patients to counterbalance ongoing thrombosis that is common to SARS-CoV-2 infection.
Subject(s)
Thrombosis , Blood Platelet Disorders , COVID-19ABSTRACT
Introduction: The clinical outcomes of COVID-19 infection in children with cancer have been variable worldwide. Therefore, we aimed to collect data from all regions in India through a national collaborative study and identify factors that cause mortality directly related to COVID-19 infection. Method(s): Data was collected prospectively on children across India on cancer therapy and diagnosed with COVID-19 infections from 47 centers from April 2020 to October 2021. Information was recorded on the demographics, the number of children that required intervention, and the outcome of the infection. In addition, we analyzed the impact of the delta variant in 2021. Result(s): A total of 659 children were studied, of whom 64% were male and 36% were female. The data from the eastern region was sparse, and this was a collection bias. COVID-19 infection was predominantly seen in children less than five years. The delta variant had a higher impact in the southern region, and this was statistically significant. Of the 659 children, 30 children died (4.5%), however only 7 of the deaths were directly attributed to COVID-19 infection (1%). Conclusion(s): The study reports the largest nationally representative cohort of children with cancer and COVID-19 to date in India. We identified demographic and clinical factors associated with increased all-cause mortality in patients with cancer. Complete characterization of the cohort has provided further insights into the effects of COVID-19 on cancer outcomes. The low mortality allows us to recommend that specific cancer treatments be continued without delays in therapy.Copyright © 2022
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BACKGROUND: Gender disparity in authorship broadly persists in medical literature, little is known about female authorship within pulmonary medicine. METHODS: A bibliometric analysis of publications from 2012 to 2021 in 12 journals with the highest impact in pulmonary medicine was conducted. Only original research and review articles were included. Names of the first and last authors were extracted and their genders were identified using the Gender-API web. Female authorship was described by overall distribution and distribution by country/region/continent and journal. We compared the article citations by gender combinations, evaluated the trend in female authorship, and forecasted when parity for first and last authorship would be reached. We also conducted a systematic review of female authorship in clinical medicine. RESULTS: 14,875 articles were included, and the overall percentage of female first authors was higher than last authors (37.0% vs 22.2%, p<0.001). Asia had the lowest percentage of female first (27.6%) and last (15.2%) authors. The percentages of female first and last authors increased slightly over time, except for a rapid increase in the COVID-19 pandemic periods. Parity was predicted in 2046 for the first authors and 2059 for the last authors. Articles with male authors were cited more than articles with female authors. However, male-male collaborations significantly decreased, whereas female-female collaborations significantly increased. CONCLUSIONS: Despite the slow improvement in female authorship over the past decade, there is still a substantial gender disparity in female first and last authorship in high-impact medical journals in pulmonary medicine.
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Vaccines against SARS-CoV-2 have alleviated infection rates, hospitalization and deaths associated with COVID-19. In order to monitor humoral immunity, several serology tests have been developed, but the recent emergence of variants of concern has revealed the need for assays that predict the neutralizing capacity of antibodies in a fast and adaptable manner. Sensitive and fast neutralization assays would allow a timely evaluation of immunity against emerging variants and support drug and vaccine discovery efforts. Here we describe a simple, fast, and cell-free multiplexed flow cytometry assay to interrogate the ability of antibodies to prevent the interaction of Angiotensin-converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of the original Wuhan-1 SARS-CoV-2 strain and emerging variants simultaneously, as a surrogate neutralization assay. Using this method, we demonstrate that serum antibodies collected from representative individuals at different time-points during the pandemic present variable neutralizing activity against emerging variants, such as Omicron BA.1 and South African B.1.351. Importantly, antibodies present in samples collected during 2021, before the third dose of the vaccine was administered, do not confer complete neutralization against Omicron BA.1, as opposed to samples collected in 2022 which show significant neutralizing activity. The proposed approach has a comparable performance to other established surrogate methods such as cell-based assays using pseudotyped lentiviral particles expressing the spike of SARS-CoV-2, as demonstrated by the assessment of the blocking activity of therapeutic antibodies (i.e. Imdevimab) and serum samples. This method offers a scalable, cost effective and adaptable platform for the dynamic evaluation of antibody protection in affected populations against variants of SARS-CoV-2.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antibodies, Blocking , Flow Cytometry , COVID-19 VaccinesABSTRACT
Introduction/Aim: The interferon gamma release assay (IGRA), used in diagnosing latent tuberculosis infections (LTBI), relies on the release of interferon gamma from T-cells exposed to M. tuberculosis specific peptides. An 'indeterminate' IGRA result is most commonly due an inadequate control (or 'mitogen') response, which may reflect underlying T-cell dysfunction, that is potentially associated with markers of severity in patients with COVID-19. The aim of this study was to determine associations and predictors of an indeterminate IGRA in hospitalised patients with COVID-19. Method(s): We performed a single centre, retrospective study on COVID-19 patients admitted to a tertiary referral hospital who had IGRA testing performed over a 5 months period. Demographics, markers of COVID-19 severity and other parameters were recorded, along with outcomes of COVID-19 infection. The primary outcomes included predictors of indeterminate IGRA results and associations with COVID-19 outcomes (severity, length of stay and mortality). Result(s): A total of 181 patients were included for analysis. Outcomes of IGRA testing included negative (n = 117) and indeterminate (n = 60) results. Patients with a positive IGRA (n = 4) were excluded from analysis. The odds of an indeterminate IGRA were increased with a higher severity grade of COVID-19 (OR 2.5;95% CI 1.3-4.9), immunosuppression at baseline (OR 2.3;95% CI 1.1-4.7) and when IGRA testing was done after immunosuppression for COVID-19 was commenced (OR 1.4;95% CI 1.1-1.8). A longer length of stay was more likely with an indeterminate IGRA compared to a negative result (OR 1.08;95% CI 1.03-1.14), No difference in mortality between the two IGRA subgroups was found. Conclusion(s): Our study demonstrates an indeterminate IGRA was associated with markers of disease severity and immunosuppression. In this cohort an indeterminate result was also associated with worse COVID-19 outcomes in hospitalised patients. This result could potentially be used as a prognostic marker for patients admitted with COVID-19.
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COVID-19 has become the first modern-day pandemic of historic proportion, affecting >600 million individuals worldwide and causing >6.5 million deaths. While acute infection has had devastating consequences, postacute sequelae of SARS-CoV-2 infection appears to be a pandemic of its own, impacting up to one-third of survivors and often causing symptoms suggestive of cardiovascular phenomena. This review will highlight the suspected pathophysiology of postacute sequelae of SARS-CoV-2, its influence on the cardiovascular system, and potential treatment strategies.
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COVID-19 , Cardiovascular System , Humans , SARS-CoV-2 , Pandemics , Lung , Disease ProgressionABSTRACT
BACKGROUND: While prior work has revealed conditions that foster policymakers' use of research evidence, few studies have rigorously investigated the effectiveness of theory-based practices. Specifically, policymakers are most apt to use research evidence when it is timely, relevant, brief, and messaged appropriately, as well as when it facilitates interactive engagement. This study sought to experimentally evaluate an enhanced research dissemination intervention, known as the SciComm Optimizer for Policy Engagement (SCOPE), implemented during the COVID-19 pandemic among US state legislators. METHODS: State legislators assigned to health committees and their staff were randomized to receive the SCOPE intervention. This involved providing academic researchers with a pathway for translating and disseminating research relevant to current legislative priorities via fact sheets emailed directly to officials. The intervention occurred April 2020-March 2021. Research language was measured in state legislators' social media posts. RESULTS: Legislators randomized to receive the intervention, relative to the control group, produced 24% more social media posts containing research language related to COVID-19. Secondary analyses revealed that these findings were driven by two different types of research language. Intervention officials produced 67% more COVID-related social media posts referencing technical language (e.g., statistical methods), as well as 28% more posts that referenced research-based concepts. However, they produced 31% fewer posts that referenced creating or disseminating new knowledge. CONCLUSIONS: This study suggests that strategic, targeted science communication efforts may have the potential to change state legislators' public discourse and use of evidence. Strategic science communication efforts are particularly needed in light of the role government officials have played in communicating about the pandemic to the general public.
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COVID-19 , Humans , Pandemics , Communication , Policy , ResearchABSTRACT
Keeping up with the latest developments in the point-of-care ultrasound (POCUS) literature is challenging, as with any area of medicine. Our group of POCUS experts has selected 10 influential papers from the past 12 months and provided a short summary of each. We hope to provide emergency physicians, intensivists, and other acute care providers with a succinct update concerning some key areas of ultrasound interest.
Subject(s)
Point-of-Care Systems , Point-of-Care Testing , Humans , UltrasonographyABSTRACT
Large spatial datasets with many spatial covariates have become ubiquitous in many fields in recent years. A question of interest is to identify which covariates are likely to influence a spatial response, and whether and how the effects of these covariates vary across space, including potential abrupt changes from region to region. To solve this question, a new efficient regularized spatially clustered coefficient (RSCC) regression approach is proposed, which could achieve variable selection and identify latent spatially heterogeneous covariate effects with clustered patterns simultaneously. By carefully designing the regularization term of RSCC as a chain graph guided fusion penalty plus a group lasso penalty, the RSCC model is computationally efficient for large spatial datasets while still achieving the theoretical guarantees for estimation. RSCC also adopts the idea of adaptive learning to allow for adaptive weights and adaptive graphs in its regularization terms and further improves the estimation performance. RSCC is applied to study the acceptance of COVID-19 vaccines using county-level data in the United States and discover the determinants of vaccination acceptance with varying effects across counties, revealing important within-state and across-state spatially clustered patterns of covariates effects.
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The current study investigated the assessment of depression, anxiety, and stress during normal and COVID-19 pandemic conditions. Generalisability theory (G-theory) was applied to examine stable and dynamic aspects of psychological distress and the overall reliability of the Depression, Anxiety and Stress Scales (DASS-21), using data from two independent samples collected on three occasions with 2- to 4-week intervals. The US data (n = 115) was collected before the COVID-19 pandemic, and the New Zealand (NZ) data (n = 114) was obtained during the pandemic. The total DASS-21 demonstrated excellent reliability in measuring enduring symptoms of psychological distress (G = .94-.96) across both samples. While all DASS-21 subscales demonstrated good reliability with the pre-pandemic US sample, the subscales' reliability was below an acceptable level for the NZ sample. Findings from this study indicate that the overall psychological distress is enduring and can be reliably measured by the DASS-21 across different conditions and populations, while shifts across depression, anxiety and stress levels are likely during emergency and uncertainty, as seen in the COVID-19 pandemic.
Subject(s)
COVID-19 , Depression , Humans , Depression/diagnosis , Depression/epidemiology , Depression/psychology , COVID-19/epidemiology , Pandemics , Reproducibility of Results , Stress, Psychological/psychology , Psychometrics , Anxiety/diagnosis , Anxiety/epidemiology , Anxiety/psychologyABSTRACT
BACKGROUND: Long-COVID (LC) encompasses diverse symptoms lasting months after the initial SARS-CoV-2 infection. Symptoms can be debilitating and affect the quality of life of individuals with LC and their families. Although the symptoms of LC are well described, the aetiology of LC remains unclear, and consequently, patients may be underdiagnosed. Identification of LC specific biomarkers is therefore paramount for the diagnosis and clinical management of the syndrome. This scoping review describes the molecular and cellular biomarkers that have been identified to date with potential use for diagnosis or prediction of LC. METHODS: This review was conducted using the Joanna Briggs Institute (JBI) Methodology for Scoping Reviews. A search was executed in the MEDLINE and EMBASE databases, as well as in the grey literature for original studies, published until October 5th, 2022, reporting biomarkers identified in participants with LC symptoms (from all ages, ethnicities, and sex), with a previous infection of SARS-CoV-2. Non-English studies, cross-sectional studies, studies without a control group, and pre-prints were excluded. Two reviewers independently evaluated the studies, extracted population data and associated biomarkers. FINDINGS: 23 cohort studies were identified, involving 2163 LC patients [median age 51.8 years, predominantly female sex (61.10%), white (75%), and non-vaccinated (99%)]. A total of 239 candidate biomarkers were identified, consisting mainly of immune cells, immunoglobulins, cytokines, and other plasma proteins. 19 of the 239 candidate biomarkers identified were evaluated by the authors, by means of receiver operating characteristic (ROC) curves. INTERPRETATION: Diverse cellular and molecular biomarkers for LC have been proposed. Validation of candidate biomarkers in independent samples should be prioritized. Modest reported performance (particularly in larger studies) suggests LC may encompass many distinct aetiologies, which should be explored e.g., by stratifying by symptom clusters and/or sex. FUNDING: Dr. Tebbutt has received funding from the Canadian Institutes of Health Research (177747) to conduct this work. The funding source was not involved in this scoping review, or in the decision to submit this manuscript for publication.
Subject(s)
COVID-19 , Humans , Female , Middle Aged , Male , COVID-19/diagnosis , COVID-19/epidemiology , SARS-CoV-2 , Post-Acute COVID-19 Syndrome , Cross-Sectional Studies , Quality of Life , Canada , BiomarkersABSTRACT
Background Most of the studies that have informed the public health response to the COVID-19 pandemic in Kenya have relied on samples that are not representative of the general population. We conducted population-based serosurveys at three Health and Demographic Surveillance Systems (HDSSs) to determine the cumulative incidence of infection with SARS-CoV-2. Methods We selected random age-stratified population-based samples at HDSSs in Kisumu, Nairobi and Kilifi, in Kenya. Blood samples were collected from participants between 01 Dec 2020 and 27 May 2021. No participant had received a COVID-19 vaccine. We tested for IgG antibodies to SARS-CoV-2 spike protein using ELISA. Locally-validated assay sensitivity and specificity were 93% (95% CI 88–96%) and 99% (95% CI 98–99.5%), respectively. We adjusted prevalence estimates using classical methods and Bayesian modelling to account for the sampling scheme and assay performance. Results We recruited 2,559 individuals from the three HDSS sites, median age (IQR) 27 (10–78) years and 52% were female. Seroprevalence at all three sites rose steadily during the study period. In Kisumu, Nairobi and Kilifi, seroprevalences (95% CI) at the beginning of the study were 36.0% (28.2–44.4%), 32.4% (23.1–42.4%), and 14.5% (9.1–21%), and respectively;at the end they were 42.0% (34.7–50.0%), 50.2% (39.7–61.1%), and 24.7% (17.5–32.6%), respectively. Seroprevalence was substantially lower among children (<16 years) than among adults at all three sites (p≤0.001). Conclusion By May 2021 in three broadly representative populations of unvaccinated individuals in Kenya, seroprevalence of anti-SARS-CoV-2 IgG was 25–50%. There was wide variation in cumulative incidence by location and age.
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Introduction: The global coronavirus disease 2019 (COVID-19) pandemic has made the provision of cancer care services a challenging task all over the world, even in developed countries. Multiple studies have already reported increased rate of diagnostic delays, interruptions in radiotherapy and chemotherapy administration, and shortage of health care personnel to deliver these services. Background: The aim of this study was to analyze the impact of strategies used to deliver uninterrupted childhood cancer services at our center during the COVID-19 pandemic. Materials and Methods: This is a cross-sectional study of the children less than 18 years of age admitted at our center between March 2020 and September 2021 to assess the effect of strategies adopted to provide uninterrupted cancer services during the COVID-19 pandemic. All the children with cancer who were managed during the study period were included in the study. The children who had treatment interruptions/lost to follow-up prior to onset of COVID-19 were excluded from the study. The primary outcome was to measure the effect of COVID-19 on delivery of cancer care services. The secondary outcome was to assess whether the strategies followed at our center helped to reduce diagnostic delays or loss to follow-up during the COVID-19 pandemic. Results: Out of total 1,490 admissions, 199 children were managed during the study period. Among the 199 children managed, 124 of them were newly diagnosed, 75 had ongoing treatment, 16 children relapsed, 13 children received palliative care, and 6 families were lost to follow-up. Out of 1,471 tests done, only 16 children and 6 caregivers tested COVID-19 positive during routine screening. Thirty-five underwent surgery and 23 received radiotherapy during this period. Among 199 children, 143 (71.8%) received financial support for hospital expenses, 23 (11.5%) received travel support, 20 (10%) were provided free accommodation, and 15 (7.5%) received home delivery of oral chemotherapy and pain medications. A total of $86,989.05 was supported for diagnostic investigations, COVID-19 testing, chemotherapy, and supportive care;$1,144.90 for travel support;and $17,010.94 was waived off by hospital administration to support the poor families. Conclusion: The shared care model, support from nongovernmental organizations and hospital administration, and utilization of local resources productively and effectively helped to avoid diagnostic delays and treatment interruptions, and provide uninterrupted pediatric cancer care services at our center.
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INTRODUCTION: Since 2009, the Military Health System (MHS) has represented its mission as that of attaining the Quadruple Aim (QUAD AIM): increased readiness, better health, better care, and low per capita costs. The journey to reach the four goals is challenging and ongoing. Leaders in the MHS's Central Texas Market (CTM) sought to understand and overcome the root-cause obstacles that interfered with achieving the QUAD AIM. This process required a self-critical and thoroughly objective review of the behavioral economics of the system. We hypothesized that two corporate behaviors fed upon each other to create a vicious downward spiral. First, as a socialized (salary-based) system, the enterprise has a built-in incentive that covertly competes with the attainment of the QUAD AIM. Because additional work does not result in any material gain for its workers, the system regulates to a comfortable flow. Second, centralized leaders defer important management controls to tactical teammates due to their special medical expertise. This corporate behavior makes overcoming the first one challenging-keeping realization of the QUAD AIM elusive. METHODS: Beginning in July of 2019, CTM leaders strove to replace the two identified corporate behaviors with more productive ones. First, in place of regulating to comfort, we directed teammates to focus wholly on achieving the QUAD AIM. Second, we exerted leadership from the top down to attain the QUAD AIM's four goals. Because the vicious cycle manifested itself differently in the realms of primary, inpatient, and specialty care, we adapted the application of our virtuous behaviors to match the problem set in each realm. In primary care, we replaced fee-for-service incentives with value-based ones. In inpatient care, we eliminated hidden incentives that resulted in inappropriate and unnecessary transfers. In specialty care, we consolidated the management of referrals, templating, and scheduling-taking central control of system productivity. The interventions in each realm required the introduction of new workflows, policies, and dashboards to ensure change. RESULTS: Over a 2-year period, the CTM made a quantum to leap toward attaining the QUAD AIM. In our community based primary care homes, we significantly improved our operations as quantified by the value-based metrics of patient satisfaction, Healthcare Effectiveness Data and Information Set (HEDIS) quality metrics, access to care, and leakage. In the inpatient realm, we decreased monthly transfers by 73% (110 s to 30 s) resulting in higher bed censuses and multiple downstream positive impacts. In specialty care, we demonstrated our ability to return our specialty service lines quickly to high levels of production in the coronavirus disease-2019 crisis. Each of these interventions demonstrated large-scale movement toward the QUAD AIM. CONCLUSIONS: The CTM's actions demonstrate that the QUAD AIM can be attained in military medicine. Doing so requires the recognition of two destructive corporate behaviors. Through decades of hardening, these corporate behaviors have been imprinted upon the MHS, making them practically invisible as guiding currents in economic behavior. Counteracting them with persistent regulation to the QUAD AIM facilitated by proactive top-down leadership offers a solution.