US National Institutes of Health Prioritization of SARS-CoV-2 Variants.

Since late 2020, SARS-CoV-2 variants have regularly emerged with competitive and phenotypic differences from previously circulating strains, sometimes with the potential to escape from immunity produced by prior exposure and infection. The Early Detection group is one of the constituent groups of the US National Institutes of Health National Institute of Allergy and Infectious Diseases SARS-CoV-2 Assessment of Viral Evolution program. The group uses bioinformatic methods to monitor the emergence, spread, and potential phenotypic properties of emerging and circulating strains to identify the most relevant variants for experimental groups within the program to phenotypically characterize. Since April 2021, the group has prioritized variants monthly. Prioritization successes include rapidly identifying most major variants of SARS-CoV-2 and providing experimental groups within the National Institutes of Health program easy access to regularly updated information on the recent evolution and epidemiology of SARS-CoV-2 that can be used to guide phenotypic investigations.

Right dose, right now: bedside, real-time, data-driven, and personalised antibiotic dosing in critically ill patients with sepsis or septic shock-a two-centre randomised clinical trial.

BACKGROUND: Adequate antibiotic dosing may improve outcomes in critically ill patients but is challenging due to altered and variable pharmacokinetics. To address this challenge, AutoKinetics was developed, a decision support system for bedside, real-time, data-driven and personalised antibiotic dosing. This study evaluates the feasibility, safety and efficacy of its clinical implementation. METHODS: In this two-centre randomised clinical trial, critically ill patients with sepsis or septic shock were randomised to AutoKinetics dosing or standard dosing for four antibiotics: vancomycin, ciprofloxacin, meropenem, and ceftriaxone. Adult patients with a confirmed or suspected infection and either lactate > 2 mmol/L or vasopressor requirement were eligible for inclusion. The primary outcome was pharmacokinetic target attainment in the first 24 h after randomisation. Clinical endpoints included mortality, ICU length of stay and incidence of acute kidney injury. RESULTS: After inclusion of 252 patients, the study was stopped early due to the COVID-19 pandemic. In the ciprofloxacin intervention group, the primary outcome was obtained in 69% compared to 3% in the control group (OR 62.5, CI 11.4-1173.78, p < 0.001). Furthermore, target attainment was faster (26 h, CI 18-42 h, p < 0.001) and better (65% increase, CI 49-84%, p < 0.001). For the other antibiotics, AutoKinetics dosing did not improve target attainment. Clinical endpoints were not significantly different. Importantly, higher dosing did not lead to increased mortality or renal failure. CONCLUSIONS: In critically ill patients, personalised dosing was feasible, safe and significantly improved target attainment for ciprofloxacin. TRIAL REGISTRATION: The trial was prospectively registered at Netherlands Trial Register (NTR), NL6501/NTR6689 on 25 August 2017 and at the European Clinical Trials Database (EudraCT), 2017-002478-37 on 6 November 2017.

Pulmonary lesions following inoculation with the SARS-CoV-2 Omicron BA.1 (B.1.1.529) variant in Syrian golden hamsters.

The Omicron BA.1 (B.1.1.529) SARS-CoV-2 variant is characterized by a high number of mutations in the viral genome, associated with immune escape and increased viral spread. It remains unclear whether milder COVID-19 disease progression observed after infection with Omicron BA.1 in humans is due to reduced pathogenicity of the virus or due to pre-existing immunity from vaccination or previous infection. Here, we inoculated hamsters with Omicron BA.1 to evaluate pathogenicity and kinetics of viral shedding, compared to Delta (B.1.617.2) and to animals re-challenged with Omicron BA.1 after previous SARS-CoV-2 614G infection. Omicron BA.1 infected animals showed reduced clinical signs, pathological changes, and viral shedding, compared to Delta-infected animals, but still showed gross- and histopathological evidence of pneumonia. Pre-existing immunity reduced viral shedding and protected against pneumonia. Our data indicate that the observed decrease of disease severity is in part due to intrinsic properties of the Omicron BA.1 variant.

Universal Health Coverage and Social Health Protection: Policy relevance to health system financing reforms

Universal Health Coverage (UHC) and Social Health Protection (SHP) are key policy foci that cut across all dimensions of the 2030 Sustainable Development Goals agenda. Understanding of these two concepts, their fundamentals and relations would improve health policy development and implementation to attain UHC and effectively protect the health of people and save lives and livelihoods. The COVID-19 pandemic has provided useful lessons to improve multi-sector activities to strengthen and finance health and social protection systems. The aim of this article is to provide conceptual clarity on the contribution of the global frameworks on SHP to the policy goal of UHC. In doing so, the article contributes to health financing and social security related policy discussions and advocates for much needed integrated policy actions at global as well as country levels. It discusses the origins of the two concepts and the relevance of SHP to health systems financing for UHC. Although country situations differ, the main findings, especially for low- and middle-income countries, are highlighted and summarized.

Antigenic cartography of SARS-CoV-2 reveals that Omicron BA.1 and BA.2 are antigenically distinct.

The emergence and rapid spread of SARS-CoV-2 variants may affect vaccine efficacy substantially. The Omicron variant termed BA.2, which differs substantially from BA.1 based on genetic sequence, is currently replacing BA.1 in several countries, but its antigenic characteristics have not yet been assessed. Here, we used antigenic cartography to quantify and visualize antigenic differences between early SARS-CoV-2 variants (614G, Alpha, Beta, Gamma, Zeta, Delta, and Mu) using hamster antisera obtained after primary infection. We first verified that the choice of the cell line for the neutralization assay did not affect the topology of the map substantially. Antigenic maps generated using pseudo-typed SARS-CoV-2 on the widely used VeroE6 cell line and the human airway cell line Calu-3 generated similar maps. Maps made using authentic SARS-CoV-2 on Calu-3 cells also closely resembled those generated with pseudo-typed viruses. The antigenic maps revealed a central cluster of SARS-CoV-2 variants, which grouped on the basis of mutual spike mutations. Whereas these early variants are antigenically similar, clustering relatively close to each other in antigenic space, Omicron BA.1 and BA.2 have evolved as two distinct antigenic outliers. Our data show that BA.1 and BA.2 both escape vaccine-induced antibody responses as a result of different antigenic characteristics. Thus, antigenic cartography could be used to assess antigenic properties of future SARS-CoV-2 variants of concern that emerge and to decide on the composition of novel spike-based (booster) vaccines.

The novel P330L pathogenic variant of aromatic amino acid decarboxylase maps on the catalytic flexible loop underlying its crucial role.

Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease, often fatal in the first decade, causing severe intellectual disability, movement disorders and autonomic dysfunction. It is due to mutations in the gene coding for the AADC enzyme responsible for the synthesis of dopamine and serotonin. Using whole exome sequencing, we have identified a novel homozygous c.989C > T (p.Pro330Leu) variant of AADC causing AADC deficiency. Pro330 is part of an essential structural and functional element: the flexible catalytic loop suggested to cover the active site as a lid and properly position the catalytic residues. Our investigations provide evidence that Pro330 concurs in the achievement of an optimal catalytic competence. Through a combination of bioinformatic approaches, dynamic light scattering measurements, limited proteolysis experiments, spectroscopic and in solution analyses, we demonstrate that the substitution of Pro330 with Leu, although not determining gross conformational changes, results in an enzymatic species that is highly affected in catalysis with a decarboxylase catalytic efficiency decreased by 674- and 194-fold for the two aromatic substrates. This defect does not lead to active site structural disassembling, nor to the inability to bind the pyridoxal 5'-phosphate (PLP) cofactor. The molecular basis for the pathogenic effect of this variant is rather due to a mispositioning of the catalytically competent external aldimine intermediate, as corroborated by spectroscopic analyses and pH dependence of the kinetic parameters. Altogether, we determined the structural basis for the severity of the manifestation of AADC deficiency in this patient and discussed the rationale for a precision therapy.

Usefulness of telemedicine in paediatric emergency care during the COVID-19 pandemic

Introduction: our healthcare system has undergone an unprecedented reorganization, prioritizing the care of patients with COVID-19 symptoms. Telemedicine has emerged as a useful alternative in the post-COVID era. The aim of the study was to assess the usefulness of the Twitter® messaging service as a telemedicine tool for the screening of urgent pathology. Material and methods: cross-sectional, retrospective and descriptive study of a telemedicine programme developed by a team of specialists in paediatrics and its subspecialities during the state of alarm. We collected demographic data and the number and reasons for consultations based on the presenting signs and symptoms and how they were conveyed (text, photo and/or video). We analysed the number of resolved concerns, referrals and the degree of user satisfaction. Results: the service managed a total of 182 consultations, mostly made by women (71%) and during the first weeks of the survey (70%). All consultations included text, accompanied in almost 1/3 of the cases by audiovisual content (27.2% photo, 4.6% video). The average age of the managed patients was 2.72 ± 2.74 years and the main reasons for consultation were fever, exanthema and respiratory difficulty. Of all consultations, 18.13% were related to COVID-19, and only 8.24% led to referral. Conclusions: although telemedicine cannot replace face-to-face assessment and there are still technical and legal limitations, our results suggest that it could be a promising alternative to improve access, reduce triage times, coordinate available resources, and decrease the risk of contagion and the saturation of health care facilities. © 2022, Spanish Association of Primary Care Pediatrics. All rights reserved.

Defining the risk of SARS-CoV-2 variants on immune protection.

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures.

Occupational health information systems for health workers during the COVID-19 pandemic in South Africa

Introduction: Reliable health information systems (HIS) are crucial for sound decision-making for occupational health services (OHS). Strengthening OHS is essential for a healthy and safe healthcare workforce during the COVID-19 pandemic. This study aimed to assess the presence and utilization of OHS HIS in South African hospitals during the COVID-19 pandemic. Methods: A cross-sectional survey was utilized to assess OHS HIS use to inform the COVID-19 outbreak response to protect health workers (HWs) in four hospitals. A validated online questionnaire was administered among purposively selected hospital managers, trade unions and OHS teams. Data were then transferred to Stata for analysis. Results: Seventy-three HWs, representing a combined workforce of 14,743 HWs, participated. Fifty-five percent were female and 65% had an undergraduate qualification. OHS HIS reports were deemed poorly organized by 64%;31% indicated poor data collection;37% noted poor data storage, and ≥ 33% were unhappy or frustrated with the use of HIS for OHS planning. Over 67% felt OHS HIS needed reforms;≤ 14% reported access to IT developers, and 52% access to IT infrastructure. Only 33% knew the minimum set of OHS indicators, and 51% reported that there was demand for OHS information. None of the hospitals were utilizing electronic OHS HIS including for COVID-19. Conclusions: Overall there is poor knowledge and utilization of OHS HIS, despite the availability of an electronic system in two of the hospitals. It is essential, that all the hospitals are provided with access to OHS HIS, and training and awareness conducted to improve OHS management.

Mapping SARS-CoV-2 antigenic relationships and serological responses (preprint)

During the SARS-CoV-2 pandemic, multiple variants with differing amounts of escape from pre-existing immunity have emerged, causing concerns about continued protection. Here, we use antigenic cartography to quantify and visualize the antigenic relationships among 16 SARS-CoV-2 variants titrated against serum samples taken post-vaccination and post-infection with seven different variants. We find major antigenic differences caused by substitutions at positions 417, 452, 484, and possibly 501. B.1.1.529 (Omicron) showed the highest escape from all sera tested. Visualization of serological responses as antibody landscapes shows how reactivity clusters in different regions of antigenic space. We find changes in immunodominance of different spike regions depending on the variant an individual was exposed to, with implications for variant risk assessment and vaccine strain selection.

Cross-Reactivity Conferred by Homologous and Heterologous Prime-Boost A/H5 Influenza Vaccination Strategies in Humans: A Literature Review.

Avian influenza viruses from the A/H5 A/goose/Guangdong/1/1996 (GsGd) lineage pose a continuing threat to animal and human health. Since their emergence in 1997, these viruses have spread across multiple continents and have become enzootic in poultry. Additionally, over 800 cases of human infection with A/H5 GsGd viruses have been reported to date, which raises concerns about the potential for a new influenza virus pandemic. The continuous circulation of A/H5 GsGd viruses for over 20 years has resulted in the genetic and antigenic diversification of their hemagglutinin (HA) surface glycoprotein, which poses a serious challenge to pandemic preparedness and vaccine design. In the present article, clinical studies on A/H5 influenza vaccination strategies were reviewed to evaluate the breadth of antibody responses induced upon homologous and heterologous prime-boost vaccination strategies. Clinical data on immunological endpoints were extracted from studies and compiled into a dataset, which was used for the visualization and analysis of the height and breadth of humoral immune responses. Several aspects leading to high immunogenicity and/or cross-reactivity were identified, although the analysis was limited by the heterogeneity in study design and vaccine type used in the included studies. Consequently, crucial questions remain to be addressed in future studies on A/H5 GsGd vaccination strategies.

A research program to provide a comparative contextualized analysis of occupational COVID-19 among health workers: Preliminary insights from a South African-Canadian collaboration

A research program to provide a comparative contextualized analysis of occupational COVID-19 among health workers: Preliminary insights from a South African-Canadian Collaboration. Objective The COVID-19 pandemic has demonstrated that healthcare workers (HCWs) in many settings are at high risk of occupational exposure to infectious diseases, especially where attention to occupational protection was lacking. In July 2020 our World Health Organization (WHO) collaborating centres in Canada and South Africa launched a joint Rapid Response Research program in partnership with local government health service delivery agencies in both countries to better understand how local contexts affect policies and practice;scrutinize their respective scientific and contextual rationales as well as outcome;grasp why and how these change over time;and understand organizational factors that enhance implementing resilient policies. Methods The collaboration includes cohort studies, in the Vancouver Coastal Health (VCH) region in Canada, and Gauteng province in South Africa respectively, to assess risk factors for SARS-CoV-2 infection among HCWs as well as evaluate the effectiveness of SARS-CoV-2 infection prevention and control measures. It also includes a cross-sectional study in Gauteng to explore mental health of HCWs during the pandemic and identify areas for intervention;a quasi-experimental study of the role of information systems in strengthening occupational health services for healthcare workers;and global policy analyses including an analysis of a global survey of HCWs from 161 countries. Results The global survey revealed considerable variations in the degree to which prevention and control measures were deemed adequate;the South African baseline audit of 42 hospitals also revealed considerable variations in implementing occupational health protection. We demonstrated the utility of information systems to assess risk by occupation and setting in VCH;preliminary results of the VCH case-control study demonstrated the feasibility of this design;and, importantly, we identified challenges in leveraging operational research to inform policy, practice and world-knowledge in both VCH and South Africa. Conclusion Our research activities showed the impact of vaccine roll-out and new variants on rates of COVID-19 among HCWs within different healthcare settings and occupational groups and how policies to protect HCWs have evolved (e.g., masking policies and vaccine protocols for HCWs). We conclude that lessons regarding procedural barriers to data acquisition and sharing must be addressed with an ethical framework in mind.

School Social Worker Voice during COVID-19 School Disruptions: A National Qualitative Analysis.

The novel coronavirus (COVID-19) pandemic has created unprecedented impacts on our schools and society, requiring school social workers (SSWs) to attend to layered and cascading effects for students and their families. This study presents rich qualitative data from a national survey of SSWs about their personal and professional roles supporting students, families, and staff members as schools shifted to remote instruction. Findings indicate that SSWs are highly concerned about a lack of basic needs resources, including food, housing, and mental health support for students and families. SSWs highlighted the unequal effects of school closures for families without technology and Internet access as well as the difficulties providing services during the pandemic. Recovery policies should target resources to schools with the highest needs while prioritizing food, housing, mental health, and access to tools for online learning. SSWs also need additional and refined professional support to overcome their isolated roles in schools and bolster their ability to deliver online services effectively.

Seasonal coronavirus–specific B cells with limited SARS-CoV-2 cross-reactivity dominate the IgG response in severe COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Little is known about the interplay between preexisting immunity to endemic seasonal coronaviruses and the development of a SARS-CoV-2-specific IgG response. We investigated the kinetics, breadth, magnitude, and level of cross-reactivity of IgG antibodies against SARS-CoV-2 and heterologous seasonal and epidemic coronaviruses at the clonal level in patients with mild or severe COVID-19 as well as in disease control patients. We assessed antibody reactivity to nucleocapsid and spike antigens and correlated this IgG response to SARS-CoV-2 neutralization. Patients with COVID-19 mounted a mostly type-specific SARS-CoV-2 response. Additionally, IgG clones directed against a seasonal coronavirus were boosted in patients with severe COVID-19. These boosted clones showed limited cross-reactivity and did not neutralize SARS-CoV-2. These findings indicate a boost of poorly protective CoV-specific antibodies in patients with COVID-19 that correlated with disease severity, revealing "original antigenic sin."

Posterior ocular structural and vascular alterations in severe COVID-19 patients.

PURPOSE: This study aimed to evaluate posterior ocular structural and vascular changes in severe coronavirus disease 2019 (COVID-19) patients. METHODS: This was an observational, prospective, and controlled study including 106 eyes of 53 severe COVID-19 patients, compared to after recovery and 106 eyes of 53 age- and gender-matched healthy controls. All subjects were previously healthy adults and were assessed using spectral domain optical coherence tomography (SD-OCT) and ImageJ software. Subfoveal over a 1500-µm span and macular over a 6000-µm span cross-sectional areas of the vascular, stromal, and total choroid were measured. RESULTS: Of the 53 included patients, 28 (52.8%) were male, and 25 (47.2%) were female, with a mean age of 50.2 ± 7.4 years. In the active period of the disease, compared to after recovery and healthy controls, the outer plexiform layer thickness showed a significant increase (p = 0.004), and mean choroidal thickness was significantly higher (p < 0.0001); however, choroidal vascularity was significantly lower (p < 0.0001). The stromal area to vascular area (S/V) ratio of the choroid was significantly increased (p < 0.0001). All quadrants of the peripapillary retinal nerve fiber layer (RNFL) thicknesses were significantly increased (for all, p < 0.05). The reflectivity of OCT echo of the choroid and peripapillary RNFL was significantly higher (p = 0.023, p < 0.0001, respectively). CONCLUSION: This study detected significant posterior ocular structural and vascular alterations in patients with severe COVID-19 infections. These findings may be associated with direct host-virus interaction or linked to an autoimmune process, vasculopathy, or viral-mediated inflammation.

The next phase of SARS-CoV-2 surveillance: real-time molecular epidemiology.

The current coronavirus disease 2019 (COVID-19) pandemic is the first to apply whole-genome sequencing near to real time, with over 2 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whole-genome sequences generated and shared through the GISAID platform. This genomic resource informed public health decision-making throughout the pandemic; it also allowed detection of mutations that might affect virulence, pathogenesis, host range or immune escape as well as the effectiveness of SARS-CoV-2 diagnostics and therapeutics. However, genotype-to-phenotype predictions cannot be performed at the rapid pace of genomic sequencing. To prepare for the next phase of the pandemic, a systematic approach is needed to link global genomic surveillance and timely assessment of the phenotypic characteristics of novel variants, which will support the development and updating of diagnostics, vaccines, therapeutics and nonpharmaceutical interventions. This Review summarizes the current knowledge on key viral mutations and variants and looks to the next phase of surveillance of the evolving pandemic.

SARS-CoV and SARS-CoV-2 are transmitted through the air between ferrets over more than one meter distance.

SARS-CoV-2 emerged in late 2019 and caused a pandemic, whereas the closely related SARS-CoV was contained rapidly in 2003. Here, an experimental set-up is used to study transmission of SARS-CoV and SARS-CoV-2 through the air between ferrets over more than a meter distance. Both viruses cause a robust productive respiratory tract infection resulting in transmission of SARS-CoV-2 to two of four indirect recipient ferrets and SARS-CoV to all four. A control pandemic A/H1N1 influenza virus also transmits efficiently. Serological assays confirm all virus transmission events. Although the experiments do not discriminate between transmission via small aerosols, large droplets and fomites, these results demonstrate that SARS-CoV and SARS-CoV-2 can remain infectious while traveling through the air. Efficient virus transmission between ferrets is in agreement with frequent SARS-CoV-2 outbreaks in mink farms. Although the evidence for virus transmission via the air between humans under natural conditions is absent or weak for SARS-CoV and SARS-CoV-2, ferrets may represent a sensitive model to study interventions aimed at preventing virus transmission.