Health worker education during the COVID-19 pandemic: global disruption, responses and lessons for the future-a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis identified early evidence quantifying the disruption to the education of health workers by the COVID-19 pandemic, ensuing policy responses and their outcomes. METHODS: Following a pre-registered protocol and PRISMA/AMSTAR-2 guidelines, we systematically screened MEDLINE, EMBASE, Web of Science, CENTRAL, clinicaltrials.gov and Google Scholar from January 2020 to July 2022. We pooled proportion estimates via random-effects meta-analyses and explored subgroup differences by gender, occupational group, training stage, WHO regions/continents, and study end-year. We assessed risk of bias (Newcastle-Ottawa scale for observational studies, RοB2 for randomized controlled trials [RCT]) and rated evidence certainty using GRADE. RESULTS: Of the 171 489 publications screened, 2 249 were eligible, incorporating 2 212 observational studies and 37 RCTs, representing feedback from 1 109 818 learners and 22 204 faculty. The sample mostly consisted of undergraduates, medical doctors, and studies from institutions in Asia. Perceived training disruption was estimated at 71.1% (95% confidence interval 67.9-74.2) and learner redeployment at 29.2% (25.3-33.2). About one in three learners screened positive for anxiety (32.3%, 28.5-36.2), depression (32.0%, 27.9-36.2), burnout (38.8%, 33.4-44.3) or insomnia (30.9%, 20.8-41.9). Policy responses included shifting to online learning, innovations in assessment, COVID-19-specific courses, volunteerism, and measures for learner safety. For outcomes of policy responses, most of the literature related to perceptions and preferences. More than two-thirds of learners (75.9%, 74.2-77.7) were satisfied with online learning (postgraduates more than undergraduates), while faculty satisfaction rate was slightly lower (71.8%, 66.7-76.7). Learners preferred an in-person component: blended learning 56.0% (51.2-60.7), face-to-face 48.8% (45.4-52.1), and online-only 32.0% (29.3-34.8). They supported continuation of the virtual format as part of a blended system (68.1%, 64.6-71.5). Subgroup differences provided valuable insights despite not resolving the considerable heterogeneity. All outcomes were assessed as very-low-certainty evidence. CONCLUSION: The COVID-19 pandemic has severely disrupted health worker education, inflicting a substantial mental health burden on learners. Its impacts on career choices, volunteerism, pedagogical approaches and mental health of learners have implications for educational design, measures to protect and support learners, faculty and health workers, and workforce planning. Online learning may achieve learner satisfaction as part of a short-term solution or integrated into a blended model in the post-pandemic future.

COVID-19 Inmate Risk Appraisal (CIRA): development and validation of a screening tool to assess COVID-19 vulnerability in prisons

OBJECTIVES: To develop and validate a screening tool designed to identify detained people at increased risk for COVID-19 mortality, the COVID-19 Inmate Risk Appraisal (CIRA). DESIGN: Cross-sectional study with a representative sample (development) and a case-control sample (validation). SETTING: The two largest Swiss prisons. PARTICIPANTS: (1) Development sample: all male persons detained in Poschwies, Zurich (n = 365);(2) Validation sample: case-control sample of male persons detained in Champ-Dollon, Geneva (n = 192, matching 1:3 for participants at risk for severe course of COVID-19 and participants without risk factors). MAIN OUTCOME MEASURES: The CIRA combined seven risk factors identified by the World Health Organization and the Swiss Federal Office of Public Health as predictive of severe COVID-19 to derive an absolute risk increase in mortality rate: Age >=60 years, cardiovascular disease, diabetes, hypertension, chronic respiratory disease, immunodeficiency and cancer. RESULT(S): Based on the development sample, we proposed a three-level classification: average (<3.7), elevated (3.7-5.7) and high (>5.7) risk. In the validation sample, the CIRA identified all individuals identified as vulnerable by national recommendations (having at least one risk factor). The category "elevated risk" maximised sensitivity (1) and specificity (0.97). The CIRA had even higher capacity in discriminating individuals vulnerable according to clinical evaluation (a four-level risk categorisation based on a consensus of medical staff). The category "elevated risk" maximised sensitivity and specificity (both 1). When considering the individuals classified as extremely high risk by medical staff, the category "high risk" had a high discriminatory capacity (sensitivity =0.89, specificity =0.97). CONCLUSION(S): The CIRA scores have a high discriminative ability and will be important in custodial settings to support decisions and prioritise actions using a standardised valid assessment method. However, as knowledge on risk factors for COVID-19 mortality is still limited, the CIRA may be considered preliminary. Underlying data will be updated regularly on the website (http://www.prison-research.com), where the CIRA algorithm is freely available. Copyright © 2021 EMH Swiss Medical Publishers Ltd.. All rights reserved.

Characterization of BNT162b2 mRNA to Evaluate Risk of Off-Target Antigen Translation.

mRNA vaccines have been established as a safe and effective modality, thanks in large part to the expedited development and approval of COVID-19 vaccines. In addition to the active, full-length mRNA transcript, mRNA fragment species can be present as a byproduct of the cell-free transcription manufacturing process or due to mRNA hydrolysis. In the current study, mRNA fragment species from BNT162b2 mRNA were isolated and characterized. The translational viability of intact and fragmented mRNA species was further explored using orthogonal expression systems to understand the risk of truncated spike protein or off-target antigen translation. The study demonstrates that mRNA fragments are primarily derived from premature transcriptional termination during manufacturing, and only full-length mRNA transcripts are viable for expression of the SARS-CoV-2 spike protein antigen.

Contribution of PEPFAR-Supported HIV and TB Molecular Diagnostic Networks to COVID-19 Testing Preparedness in 16 Countries.

The US President's Emergency Plan for AIDS Relief (PEPFAR) supports molecular HIV and tuberculosis diagnostic networks and information management systems in low- and middle-income countries. We describe how national programs leveraged these PEPFAR-supported laboratory resources for SARS-CoV-2 testing during the COVID-19 pandemic. We sent a spreadsheet template consisting of 46 indicators for assessing the use of PEPFAR-supported diagnostic networks for COVID-19 pandemic response activities during April 1, 2020, to March 31, 2021, to 27 PEPFAR-supported countries or regions. A total of 109 PEPFAR-supported centralized HIV viral load and early infant diagnosis laboratories and 138 decentralized HIV and TB sites reported performing SARS-CoV-2 testing in 16 countries. Together, these sites contributed to >3.4 million SARS-CoV-2 tests during the 1-year period. Our findings illustrate that PEPFAR-supported diagnostic networks provided a wide range of resources to respond to emergency COVID-19 diagnostic testing in 16 low- and middle-income countries.

T Cell Response After SARS-CoV-2 Vaccination in Immunocompromised Patients with Inflammatory Bowel Disease.

BACKGROUND: Vaccination is a promising strategy to protect vulnerable groups like immunocompromised inflammatory bowel disease [IBD] patients from an infection with SARS-CoV-2. These patients may have lower immune responses. Little is known about the cellular and humoral immune response after a SARS-CoV-2 vaccination in IBD patients. METHODS: Totals of 28 patients with IBD and 27 age- and sex-matched healthy controls were recruited at Jena University Hospital. Blood samples were taken before, after the first, and in a subgroup of 11 patients after second dose of a SARS-CoV-2 vaccination. Cellular immune response, including IFN-γ and TNF-α response and antibody titres, were analysed. RESULTS: Overall, 71.4% of the IBD patients and 85.2% of the controls showed levels of anti-SARS-CoV-2 antibodies above the cutoff of 33.8 BAU/ml [p = 0.329] after the first dose. Even in the absence of SARS-CoV-2 antibodies, IBD patients showed significant T cell responses after first SARS-CoV-2 vaccination compared with healthy controls, which was not influenced by different immunosuppressive regimens. Associated with the vaccination, we could also detect a slight increase of the TNF production among SARS-CoV-2-reactive TH cells in healthy donorsn [HD] and IBD patients. After the second dose of vaccination, in IBD patients a further increase of humoral immune response in all but one patient was observed. CONCLUSIONS: Already after the first dose of a SARS-CoV-2 vaccination, cellular immune response in IBD patients is comparable to controls, indicating a similar efficacy. However, close monitoring of long-term immunity in these patients should be considered.

A Perspective of International Collaboration Through Web-Based Telecommunication-Inspired by COVID-19 Crisis.

The tsunami effect of the COVID-19 pandemic is affecting many aspects of scientific activities. Multidisciplinary experimental studies with international collaborators are hindered by the closing of the national borders, logistic issues due to lockdown, quarantine restrictions, and social distancing requirements. The full impact of this crisis on science is not clear yet, but the above-mentioned issues have most certainly restrained academic research activities. Sharing innovative solutions between researchers is in high demand in this situation. The aim of this paper is to share our successful practice of using web-based communication and remote control software for real-time long-distance control of brain stimulation. This solution may guide and encourage researchers to cope with restrictions and has the potential to help expanding international collaborations by lowering travel time and costs.

Profound Treg perturbations correlate with COVID-19 severity (preprint)

The hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We explored the hypothesis that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in both Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, which correlated with poor outcomes. Accordingly, these Tregs over-expressed a range of suppressive effectors, but also pro-inflammatory molecules like IL32. Most strikingly, they acquired similarity to tumor-infiltrating Tregs, known to suppress local anti-tumor responses. These traits were most marked in acute patients with severe disease, but persisted somewhat in convalescent patients. These results suggest that Tregs may play nefarious roles in COVID-19, via suppressing anti-viral T cell responses during the severe phase of the disease, and/or via a direct pro-inflammatory role.

Oligonucleotide Capture Sequencing of the SARS-CoV-2 Genome and Subgenomic Fragments from COVID-19 Individuals (preprint)

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity and provided evidence of expression of ORF10. Heterogeneous allelic frequencies along the 20kb ORF1ab gene suggested the presence of a defective interfering viral RNA species subpopulation in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.

BNT162b vaccines are immunogenic and protect non-human primates against SARS-CoV-2 (preprint)

A safe and effective vaccine against COVID-19 is urgently needed in quantities sufficient to immunise large populations. We report the preclinical development of two BNT162b vaccine candidates, which contain lipid-nanoparticle (LNP) formulated nucleoside-modified mRNA encoding SARS-CoV-2 spike glycoprotein-derived immunogens. BNT162b1 encodes a soluble, secreted, trimerised receptor-binding domain (RBD-foldon). BNT162b2 encodes the full-length transmembrane spike glycoprotein, locked in its prefusion conformation (P2 S). The flexibly tethered RBDs of the RBD-foldon bind ACE2 with high avidity. Approximately 20% of the P 2S trimers are in the two-RBD down, one-RBD up state. In mice, one intramuscular dose of either candidate elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong TH1 CD4+ and IFN{gamma}+ CD8+ T-cell responses. Prime/boost vaccination of rhesus macaques with BNT162b candidates elicits SARS-CoV-2 neutralising geometric mean titres 8.2 to 18.2 times that of a SARS-CoV-2 convalescent human serum panel. The vaccine candidates protect macaques from SARS-CoV-2 challenge, with BNT162b2 protecting the lower respiratory tract from the presence of viral RNA and with no evidence of disease enhancement. Both candidates are being evaluated in phase 1 trials in Germany and the United States. BNT162b2 is being evaluated in an ongoing global, pivotal Phase 2/3 trial (NCT04380701, NCT04368728).

Identification of eight SARS-CoV-2 ORF7a deletion variants in 2,726 clinical specimens (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF7a, the ortholog of SARS-CoV ORF7a, is a type I transmembrane protein and plays an important role in virus-host interactions. Deletion variants in ORF7a may influence virulence, but only a few such isolates have been reported. Here, we report 8 unique ORF7a deletion variants of 6 to 96 nucleotides in length identified from 2,726 clinical specimens collected in March of 2020.