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Background: Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, nearly all of these antibodies have been rendered obsolete by SARS-CoV-2 variants that evolved to resist similar, naturally occurring antibodies. Moreover, Most SARS-CoV-2 specific antibodies are inactive against divergent sarbecoviruses Methods: By immunizing mice that carry human immunoglobulin variable gene segments we generated a suite of fully human monoclonal antibodies that bind the human ACE2 receptor (hACE2) rather than the viral spike protein and were engineered to lack effector functions such as ADCC. Result(s): These ACE2 binding antibodies block infection by all hACE2 binding sarbecoviruses, including emergent SARS-CoV-2 variants, with a potency that of the most potent spike binding therapeutic antibodies. Structural and biochemical analyses revealed that the antibodies target an hACE2 epitope that engages SARS-CoV-2 spike. Importantly, the antibodies do not inhibit hACE2 enzymatic activity, nor do they induce ACE depletion from cell surfaces. The antibodies exhibit favorable pharmacology in human ACE2 knock in mice and provide near complete protection of hACE2 knock-in mice against SARS-CoV-2 infection. Conclusion(s): ACE2 binding antibodies should be useful prophylactic and treatment agents against any current and future SARS-CoV-2 variants, as well as hACE2-binding sarbecoviruses that might emerge as future pandemic threats.
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Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces lung pathology remains elusive. Here we describe a high-throughput platform to generate self-organizing and commensurate human lung buds derived from hESCs cultured on micropatterned substrates. Lung buds resemble human fetal lungs and display proximodistal patterning of alveolar and airway tissue directed by KGF. These lung buds are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-specific cytopathic effects in hundreds of lung buds in parallel. Transcriptomic comparisons of infected lung buds and postmortem tissue of COVID-19 patients identified an induction of BMP signaling pathway. BMP activity renders lung cells more susceptible to SARS-CoV-2 infection and its pharmacological inhibition impairs infection by this virus. These data highlight the rapid and scalable access to disease-relevant tissue using lung buds that recapitulate key features of human lung morphogenesis and viral infection biology.
Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Lung , Cells, CulturedABSTRACT
Objectives: Uterine cancer (UCa) is the most common gynecological cancer and 4th most common cancer in women. It has been well documented that the incidence rates of UCa are higher in older women, more socially deprived areas, and among women of Black ethnicity. The objective of our analysis was to describe changes in inequalities in UCa before and after COVID-19. Method(s): Using an England-wide reimbursement secondary care dataset we identified all women diagnosed with UCa. We used a binary classification of pre- (01 April 2018 to 31 March 2020) and post-COVID-19 pandemic (01 April 2020 to 31 March 2022) to group timing of diagnosis. We compared the age, ethnicity, and socioeconomic profile of the women diagnosed before and after COVID-19 using chi2 tests. Socioeconomic deprivation was derived from Indices of Multiple Deprivation (IMD) quintiles. Where there is no difference of effect, 20% of the given population should be observed in each quintile. Result(s): There were 11,231 women in England first diagnosed with UCa between April 2018 and March 2022;6,177 were diagnosed pre-COVID-19 pandemic and 5,054 post-COVID-19. There was no difference in the age breakdown of those diagnosed with uterine cancer pre- and post-COVID-19 (50-59 years 20.8% in both time periods. Pre-COVID-19, fewer women from the most deprived IMD quintile were diagnosed with UCa compared with the least deprived group (p-value 0.034). In the post-COVID-19 period, UCa diagnoses fell significantly among the least deprived compared with pre-COVID-19 (14.6%, vs 16.3% pre-COVID-19;p-value 0.04). Conclusion(s): Diagnosis of uterine cancer decreased after the onset of COVID-19, likely due to reduced non-COVID-19 healthcare interactions. Prior to COVID-19, there were fewer women from the most deprived areas of England with a Uca diagnosis, this reduced further after the onset of the pandemic. This finding warrants further investigation to ensure equal access to care. Copyright © 2022
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Background: Syncope and related disorders is an important area for training of all health professionals. During the COVID-19 pandemic, we adapted the delivery of our annual face-to-face certified program to a 9-month hybrid program. Here, we describe the development, delivery, and evaluation of such new program. Methods: A pre-existing curriculum was modified to incorporate online content, online lecture delivery and interactive group learning, in addition to individual practical placements in a syncope management unit, in line with government and hospital infection control guidance at the time. Monthly content included video consultant case presentations, ECG analysis and interpretation, and instructional videos of diagnostic testing and relevant technologies. A comprehensive online week-long lecture program was developed. Results: The lecture week included 30 clinical lectures, 10 clinical case presentations and 10 ‘how to’ practical videos for testing/monitoring procedures. Further learning over zoom incorporated learner case presentations in a small group format. At the completion of the course the leaners attended a final online half day of lectures and completed the multi choice question examination. Conclusion: “Thank you so much for putting together such a fantastic week of training.” “The quality and expertise of the speakers was outstanding.” “I have taken a huge amount away to incorporate into my practice and local unit.”The above learner feedback is consistent with our aim to deliver a high-quality specialist program for those interested in advancing the management of syncope and related disorders. Over time, this specialist training will aid the development of regional syncope management units across Ireland. The benefits of a hybrid learning model include multiple options to cater for all categories of learners, thus suggesting it is the cornerstone of future learning modalities.
ABSTRACT
The most recent coronavirus, SARS-CoV-2 and its subsequent coronavirus disease 2019 (COVID-19),1 has reached pandemic proportions requiring unprecedented actions. One established resource for national emergencies has been our nations military. The Department of Defense mobilized National Guard, Reserve, and Active Duty service members to support the COVID-19 response and thereby accessed the nations largest source for medical surge capacity. Our purpose for this commentary was to review over 80 years of publications in Military Medicine and identify a collection of relevant articles to the topic of COVID-19. These selected articles examine various aspects of infectious diseases, epidemics, and pandemics as analyzed through the lens of military medical experts. Our objective was to identify a selection of pertinent published military medical articles readily accessible with free access on the Military Medicine website.
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Background: The effects of MS disease modifying therapies (DMTs) on COVID-19 morbidity and mortality have been studied in clinician-reported registries, but the true prevalence of SARSCoV-2 infection and its outcomes in the MS population receiving DMTs are unknown. Objectives: To assess the prevalence of SARS-CoV-2 infection and its outcomes, and their association with individual DMTs among all MS patients receiving DMTs in England. Aims: To understand the magnitude of COVID-19's impact on a population of MS patients receiving DMTs. Methods: We analysed merged national databases to ascertain the rate of SARS-CoV-2 positive tests and COVID-19 in-hospital mortality among all MS patients receiving DMTs in England from 1/02/2020 to 27/03/2021. The National Health Service (NHS) England and NHS Improvement collect prescribing and dispensing data on all MS DMTs. Public Health England collects data on all SARS-CoV-2 tests and COVID-19 in-hospital deaths. Further clinical data collection on a random sample of patients who tested positive (cases) or were not tested (controls) for SARS-CoV-2 is ongoing in multiple centres to establish risk factors of adverse COVID-19 outcomes without selection bias. Results: A total of 35556 MS patients had received a DMT. Their mean (standard deviation) age was 44 (12) years. A total of 16,108 patients (45.3%) were tested for SARS-CoV-2, and 2000 (5.6%) tested positive with a mean age of 42 (12) years. Twentysix patients with a positive test (1.3%) died in hospital. Their mean age was 54 (16) years. The age-standardised mortality ratio (95% confidence interval) of the MS versus the general population was 1.2 (0.7-1.7). There was no clear difference between individual DMTs in their rates of positive tests or inhospital mortality. Detailed data on 79 randomly selected patients with a positive test has been collected at two centres so far. Their mean age is 44 (11) years and 55 (69.6%) are women. Five were hospitalised due to COVID-19 out of whom one was admitted to an intensive therapy unit and died. Data will be updated and reanalysed prior to ECTRIMS 2021. Conclusions: So far, COVID-19 does not appear to significantly increase the risk of mortality in MS patients on DMTs compared to the general population, in this large population study.