XBB.1.5 monovalent booster improves antibody binding and neutralization against emerging SARS-CoV-2 Omicron variants (preprint)

The rapid emergence of divergent SARS-CoV-2 variants has led to an update of the COVID-19 booster vaccine to a monovalent version containing the XBB.1.5 spike. To determine the neutralization breadth following booster immunization, we collected blood samples from 24 individuals pre- and post-XBB.1.5 mRNA booster vaccination (~1 month). The XBB.1.5 booster improved both neutralizing activity against the ancestral SARS-CoV-2 strain (WA1) and the circulating Omicron variants, including EG.5.1, HK.3, HV.1, XBB.1.5 and JN.1. Relative to the pre-boost titers, the XBB.1.5 monovalent booster induced greater total IgG and IgG subclass binding, particular IgG4, to the XBB.1.5 spike as compared to the WA1 spike. We evaluated antigen-specific memory B cells (MBCs) using either spike or receptor binding domain (RBD) probes and found that the monovalent booster largely increases non-RBD cross-reactive MBCs. These data suggest that the XBB.1.5 monovalent booster induces cross-reactive antibodies that neutralize XBB.1.5 and related Omicron variants.

Immunological imprinting shapes the specificity of human antibody responses against SARS-CoV-2 variants (preprint)

The spike glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to accumulate substitutions, leading to breakthrough infections of vaccinated individuals and prompting the development of updated booster vaccines. Here, we determined the specificity and functionality of antibody and B cell responses following exposure to BA.5 and XBB variants in individuals who received ancestral SARS-CoV-2 mRNA vaccines. BA.5 exposures elicited antibody responses that primarily targeted epitopes conserved between the BA.5 and ancestral spike, with poor reactivity to the XBB.1.5 variant. XBB exposures also elicited antibody responses that targeted epitopes conserved between the XBB.1.5 and ancestral spike. However, unlike BA.5, a single XBB exposure elicited low levels of XBB.1.5-specific antibodies and B cells in some individuals. Pre-existing cross-reactive B cells and antibodies were correlated with stronger overall responses to XBB but weaker XBB-specific responses, suggesting that baseline immunity influences the activation of variant-specific SARS-CoV-2 responses. HighlightsO_LIVariant breakthrough infections boost ancestral cross-reactive antibodies and B cells C_LIO_LIFirst and second BA.5 exposures fail to elicit variant-specific antibodies and B cells C_LIO_LIXBB infections and monovalent vaccinations elicit XBB.1.5-specific responses in some individuals C_LIO_LIXBB.1.5-specific responses correlate with low levels of pre-existing humoral immunity C_LI

Characteristics and outcomes of patients treated with sotrovimab to prevent progression to severe COVID-19 in Belgium (preprint)

BackgroundSotrovimab, a dual-action, engineered human monoclonal antibody, has been demonstrated to significantly reduce the risk of hospitalization and death in high-risk patients with COVID-19. Here, we describe the real-world use of, and outcomes from, sotrovimab treatment in Belgium during the Delta and Omicron waves among patients with COVID-19 at high risk of developing severe disease. MethodsThis was a multicentric, single-arm observational cohort study of non-hospitalized patients receiving outpatient sotrovimab treatment between 1 November 2021 and 2 August 2022. We performed a retrospective analysis of hospital, pharmacy and administrative data from nine hospitals in Belgium. The primary outcomes were all-cause and COVID-19-related hospitalizations and all-cause deaths during the 29-day acute follow-up period from first administration of sotrovimab. ResultsA total of 634 patients were included in the analysis (63.4% aged <65 years; 50.3% male). A high proportion (67.7%; n = 429/634) of patients were immunocompromised, with 36.9% (n = 234/634) actively treated for malignancy. During the 29-day acute period, 12.5% (n = 79/634) of sotrovimab-treated patients were hospitalized due to any cause (median duration 4 days; median time to hospitalization 14 days) and 1.1% (n = 7/634) died due to any cause. In total, 0.8% (n = 5/634) of patients were admitted to an intensive care unit (ICU). COVID-19-related hospitalization was experienced by 2.5% (n = 16/634) of patients (median duration 10 days; median time to hospitalization 10.5 days), with 0.5% (n = 3/634) of patients admitted to an ICU. COVID-19-related hospitalization was experienced by 6.3% (n = 3/48) of patients during Delta predominance (04/11/2021-23/12/2021), 6.3% (n = 1/16) of patients during Delta/BA.1 codominance (24/12/2021-01/01/2022), 1.4% (n = 3/218) of patients during BA.1 predominance (02/01/2022-09/02/2022), 2.1% (n = 2/97) of patients during BA.1/BA.2 codominance (10/02/2022-07/03/2022) and 2.7% (n = 7/255) of patients during BA.2/BA.5 codominance (08/03/2022-02/08/2022). ConclusionsThis observational study demonstrated consistently low rates of COVID-19-related hospitalizations and all-cause deaths in sotrovimab-treated patients during the Omicron subvariant periods in Belgium, despite over two-thirds of the study population being immunocompromised. Comparative effectiveness studies are warranted to confirm sotrovimab effectiveness in highly immunocompromised patients with COVID-19.

Real-world effectiveness of sotrovimab for the treatment of SARS-CoV-2 infection during Omicron BA.2 and BA.5 subvariant predominance: a systematic literature review (preprint)

Background: Emerging SARS-CoV-2 variants have impacted the in vitro activity of sotrovimab, with variable fold changes in neutralization potency reported for Omicron BA.2 and subsequent variants. We performed a systematic literature review (SLR) to evaluate clinical outcomes associated with sotrovimab use during Omicron BA.2 and BA.5 predominance. Methods: Electronic databases were searched for observational studies published in peer-reviewed journals, preprint articles and conference abstracts from January 1, 2022-February 27, 2023. Results: The 14 studies identified were heterogeneous in terms of study design, population, endpoints and definitions, and comprised >1.7 million high-risk patients with COVID-19, of whom approximately 41,000 received sotrovimab (range n=20-5979 during BA.2 and n=76-1383 during BA.5 predominance). Studies were from the US, UK, Italy, Denmark, France, Qatar, and Japan. Four studies compared the effectiveness of sotrovimab with untreated or no monoclonal antibody treatment controls, two compared sotrovimab with other treatments, and three single-arm studies compared outcomes during BA.2 and/or BA.5 versus BA.1. The remaining five studies descriptively reported rates of clinical outcomes in patients treated with sotrovimab. Rates of COVID-19-related hospitalization or mortality among sotrovimab-treated patients were consistently low (0.95% to 4.0% during BA.2; 0.5% to 2.0% during BA.5). All-cause hospitalization or mortality was also low (1.7% to 2.0% during BA.2; 3.4% during combined BA.2 and BA.5 periods). During BA.2, a lower risk of all-cause hospitalization or mortality was reported across studies with sotrovimab versus untreated cohorts. Compared with other treatments, sotrovimab was associated with a lower (molnupiravir) or similar (nirmatrelvir/ritonavir) risk of COVID-19-related hospitalization or mortality during BA.2 and BA.5. There was no significant difference in outcomes between the BA.1, BA.2 and BA.5 periods. Conclusions: The studies included in this SLR suggest continued effectiveness of sotrovimab in preventing severe clinical outcomes during BA.2 and BA.5 predominance, both against an active/untreated comparator and compared with BA.1 predominance.

Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates (preprint)

Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/565765v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@d49b9dorg.highwire.dtl.DTLVardef@347455org.highwire.dtl.DTLVardef@1c1a196org.highwire.dtl.DTLVardef@1579130_HPS_FORMAT_FIGEXP M_FIG C_FIG

Safety of Monovalent BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and NVX-CoV2373 (Novavax) COVID-19 Vaccines in US Children Aged 6 months to 17 years (preprint)

Importance Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes that may not be identified in prelicensure trials. Objective To conduct near-real-time monitoring of health outcomes following COVID-19 vaccination in the United States (US) pediatric population aged 6 months to 17 years. Design We evaluated 21 pre-specified health outcomes; 15 were sequentially tested through near-real-time surveillance, and 6 were monitored descriptively within a cohort of vaccinated children. We tested for increased rate of each outcome following vaccination compared to a historical comparator cohort. Setting This population-based study was conducted under the US Food and Drug Administration public health surveillance mandate using three commercial claims databases. Participants Children aged 6 months to 17 years were included if they received a monovalent COVID-19 vaccine dose before early 2023 and had continuous enrollment in a medical health insurance plan from the start of an outcome-specific clean window to the COVID-19 vaccination dose. Exposure Exposure was defined as receipt of a monovalent BNT162b2, mRNA-1273, or NVX-CoV2373 COVID-19 vaccine dose. The primary analysis evaluated dose 1 and dose 2 combined, and secondary analyses evaluated each dose separately. Follow-up time was censored at death, disenrollment, end of risk window, end of study period, or a subsequent dose administration. Main Outcomes Twenty-one prespecified health outcomes. Results The study included 4,102,016 enrollees aged 6 months to17 years. Thirteen of 15 outcomes sequentially tested did not meet the threshold for a statistical signal. In the primary analysis, myocarditis or pericarditis signals were detected following BNT162b2 vaccine in children aged 12-17 years old and seizures/convulsions signals were detected following vaccination with BNT162b2 and mRNA-1273 in children aged 2-4/5 years. However, in a post-hoc sensitivity analysis, the seizures/convulsions signal was sensitive to background rates selection and was not observed when 2022 background rates were selected instead of 2020 rates. Conclusions and Relevance Of the two signaled outcomes, the myocarditis or pericarditis signals are consistent with previously published reports. The new signal detected for seizures/convulsions among younger children should be further investigated in a robust epidemiological study with better confounding adjustment.

Comparative effectiveness of sotrovimab versus no treatment in non-hospitalised high-risk patients with COVID-19 in North West London: aretrospective cohort study using the Discover dataset (preprint)

IntroductionThere is uncertainty regarding how in vitro antibody neutralisation activity translates to the clinical efficacy of sotrovimab against severe acute respiratory syndrome coronavirus 2, although real-world evidence has demonstrated continued effectiveness during both BA.2 and BA.5 predominance. We previously reported descriptive results from the Discover dataset for patients treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or patients at highest risk per National Health Service (NHS) criteria but who were untreated. This study sought to assess the effectiveness of sotrovimab compared with no early coronavirus disease 2019 (COVID-19) treatment in highest-risk patients with COVID-19. MethodsRetrospective cohort study using the Discover dataset in North West London. Patients had to be non-hospitalised at index, aged [≥]12 years old and meet [≥]1 of the NHS highest-risk criteria for receiving early COVID-19 treatment with sotrovimab. The primary objective was to assess the risk of COVID-19-related hospitalisation and/or COVID-19-related death within 28 days of the observed/imputed treatment date between patients treated with sotrovimab and highest-risk patients who received no early COVID-19 treatment. We also performed subgroup analyses for patients aged <65 and [≥]65 years, patients with renal dysfunction, and by Omicron subvariant prevalence period (BA.1/2 emergence: 1 December 2021-12 February 2022 [period 1]; BA.2 reaching and at its peak: 13 February-31 May 2022 [period 2]; BA.2 falling and BA.4/5 emergence: 1 June-31 July 2022 [period 3]). Inverse probability of treatment weighting based on propensity scores was used to adjust for measured known and likely confounders between the cohorts. Cox proportional hazards models with stabilised weights were performed to assess hazard ratios (HRs). ResultsA total of 599 highest-risk patients treated with sotrovimab and 5,191 untreated highest-risk patients were included. Compared with untreated patients, sotrovimab treatment reduced the risk of COVID-19 hospitalisation or death by 50% (HR=0.50; 95% confidence interval [CI] 0.24, 1.06); however, statistical significance was not reached (p=0.07). In addition, sotrovimab reduced the risk of COVID-19 hospitalisation by 57% (HR=0.43; 95% CI 0.18, 1.00) compared with the untreated group, although also not statistically significant (p=0.051). Among patients aged [≥]65 years and patients with renal disease, sotrovimab treatment was associated with a significantly reduced risk of COVID-19 hospitalisation, by 89% (HR=0.11; 95% CI 0.02, 0.82; p=0.03) and 82% (HR=0.18; 95% CI 0.05, 0.62; p=0.007), respectively. In period 1, sotrovimab treatment was associated with a 75% lower risk of COVID-19 hospitalisation or death compared with the untreated group (HR=0.25; 95% CI 0.07, 0.89; p=0.032). In periods 2 and 3, HRs of COVID-19 hospitalisation or death were 0.53 (95% CI 0.14, 2.00; p=0.35) and 0.78 (95% CI 0.23, 2.69; p=0.69), respectively, for the sotrovimab versus untreated groups, but differences were not statistically significant. ConclusionsSotrovimab treatment was associated with a significant reduction in risk of COVID-19 hospitalisation in patients aged [≥]65 years and those with renal disease compared with the untreated cohort. For the overall cohort, the risk of hospitalisation following sotrovimab treatment was also lower compared with the untreated group; however, this did not achieve statistical significance (p=0.051). The risk of hospitalisation and/or death was lower for the sotrovimab-treated cohort across all time periods but did not reach significance for periods 2 and 3.

We Are Living It

The Centers for Disease Control and Prevention (CDC) identified certain populations as being particularly vulnerable during the COVID-19 pandemic, including racial and ethnic minority populations, people living in rural or frontier areas, people experiencing homelessness, essential and frontline workers, people with disabilities, people with substance use disorders, people in incarcerated populations, and individuals born outside of the United States (CDC 2020). Because the pandemic is affecting people and communities disproportionately, we knew students needed to explore the social and historical dimensions of the pandemic that resulted from systemic inequalities. Throughout the unit, they work toward a better understanding of the following ideas: * How the COVID-19 virus is transmitted between individuals and within communities * How mitigation strategies lower the chance of transmitting the COVID-19 virus between individuals and across communities * An understanding that there are differences in how diseases spread across different communities that cannot be explained without taking social, historical, and economic factors into account and that understanding the larger social context, policies, and practices can help us understand disproportionate impacts within and between communities * How others are affected during a public health crisis and how empathizing with them can help us better protect ourselves and the people in our communities Our commitment to providing the information that young people need to understand COVID-19 and other pandemics led to an interesting discovery about the NGSS. Attempt to make sense of the phenomenon or problem Students share the patterns they observed from the data and create initial models to explain how and why communities were affected by COVID-19 differently (see Figure 1). [...]social awareness is defined as the ability to (1) take the perspective of and empathize with others, including those from diverse backgrounds and cultures;(2) understand social and ethical norms for behavior;and (3) recognize family, school, and community resources and supports.

An integrated cell atlas of the lung in health and disease.

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in Scotland (preprint)

Introduction: Severe acute respiratory syndrome coronavirus 2 is constantly evolving. The clinical benefit of coronavirus disease 2019 (COVID-19) treatments against new circulating variants remains unclear. We sought to describe the real-world use of, and clinical outcomes associated with, early COVID-19 treatments among non-hospitalised patients with COVID-19 at highest risk of developing severe disease in Scotland. Methods: Retrospective cohort study of non-hospitalised patients diagnosed with COVID-19 from 1 December 2021 to 25 October 2022, using administrative health data managed by Public Health Scotland and National Records of Scotland. Patients included in the study were aged [≥]18 years, met at least one of the National Health Service highest-risk conditions criteria for early COVID-19 treatment, and had received outpatient treatment with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or no early COVID-19 treatment. Index date was defined as the earliest of either COVID-19-positive diagnosis or early COVID-19 treatment during the study period. Baseline patient characteristics and acute clinical outcomes in the 28 days following the index date were reported. To protect patient confidentiality, values of [≤]5 were suppressed. Results: A total of 2548 patients were included (492: sotrovimab, 276: nirmatrelvir/ritonavir, 71: molnupiravir, and 1709 eligible highest-risk untreated). Patients aged [≥]75 years accounted for 6.9% (n=34/492) of the sotrovimab-treated group, 21.0% (n=58/276) of those treated with nirmatrelvir/ritonavir, 16.9% (n=12/71) of those treated with molnupiravir and 13.2% (n=225/1709) of untreated patients. Advanced renal disease was reported for 6.7% (n=33/492) of sotrovimab-treated and 4.7% (n=81/1709) of untreated patients, and five or fewer patients in the nirmatrelvir/ritonavir and molnupiravir cohorts. A high proportion of treated patients did not have a highest-risk condition reported in the database (71.7% for sotrovimab [n=353/492], 85.1% for nirmatrelvir/ritonavir [n=235/276], 85.9% for molnupiravir [n=61/71]). Five or fewer patients in each treated cohort experienced COVID-19-related hospitalisations during the 28-day acute period. For untreated patients, the percentage of COVID-19-related hospitalisations was 3.0% (n=48/1622). All-cause hospitalisations were experienced by 5.3% (n=25/476) of sotrovimab-treated patients, 6.9% (n=12/175) of nirmatrelvir/ritonavir-treated patients and 13.3% (n=216/1622) of untreated patients. Five or fewer patients in the molnupiravir cohort experienced all-cause hospitalisation. There were no deaths within 28 days of index for patients in the treated cohorts. Mortality was 4.3% (n=70/1622) in untreated patients (18.6% [n=13/70] had COVID-19 as the primary cause). In our analyses of outcomes for sotrovimab-treated and untreated patients during BA.1, BA.2 and BA.5 predominance, COVID-19-related hospitalisation rates were consistent, with n[≤]5 for sotrovimab-treated patients in each period. Conclusions: Our findings indicate that sotrovimab was often used amongst patients who were aged <75 years old and had advanced renal disease. Among patients who received early COVID-19 treatment, proportions of all-cause hospitalisation and death within 28 days of treatment were low.

RBD-based high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways (preprint)

SARS-CoV-2 has the capacity to evolve mutations to escape vaccine-and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool. Here, we challenged rhesus macaques with SARS-CoV-2 Delta and simultaneously treated them with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment gave equivalent protection in upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 did not block the development of memory responses to Delta and did not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

An evolutionarily conserved strategy for ribosome binding and inhibition by β-coronavirus non-structural protein 1 (preprint)

An important pathogenicity factor of SARS-CoV-2 and related coronaviruses is Nsp1, which suppresses host gene expression and stunts antiviral signaling. SARS-CoV-2 Nsp1 binds the ribosome to inhibit translation through mRNA displacement and induces degradation of host mRNAs through an unknown mechanism. Here we show that Nsp1-dependent host shutoff is conserved in diverse coronaviruses, but only Nsp1 from beta-CoV inhibits translation through ribosome binding. The C-terminal domain of all beta-CoV Nsp1s confers high-affinity ribosome-binding despite low sequence conservation. Modeling of interactions of four Nsp1s to the ribosome identified few absolutely conserved amino acids that, together with an overall conservation in surface charge, form the beta-CoV Nsp1 ribosome-binding domain. Contrary to previous models, the Nsp1 ribosome-binding domain is an inefficient translation inhibitor. Instead, the Nsp1-CTD likely functions by recruiting Nsp1's N-terminal effector domain. Finally, we show that a viral cis-acting RNA element has co-evolved to fine-tune SARS-CoV-2 Nsp1 function, but does not provide similar protection against Nsp1 from related viruses. Together, our work provides new insight into the diversity and conservation of ribosome-dependent host-shutoff functions of Nsp1, knowledge that could aide future efforts in pharmacological targeting of Nsp1 from SARS-CoV-2, but also related human-pathogenic beta-coronaviruses. Our study also exemplifies how comparing highly divergent Nsp1 variants can help to dissect the different modalities of this multi-functional viral protein.

Outcomes of SARS-CoV-2 infection in 126 children and adolescents with central nervous system tumors.

BACKGROUND: The Global Registry of COVID-19 in Childhood Cancer (GRCCC) seeks to describe the natural history of SARS-CoV-2 in children with cancer across the world. Here, we report the disease course and management of coronavirus disease 2019 (COVID-19) infection in the subset of children and adolescents with central nervous system (CNS) tumors who were included in the GRCCC until February 2021, the first data freeze. PROCEDURE: The GRCCC is a deidentified web-based registry of patients less than 19 years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30 and 60 days post infection. RESULTS: The GRCCC included 1500 cases from 45 countries, including 126 children with CNS tumors (8.4%). Sixty percent of the cases were from middle-income countries, while no cases were reported from low-income countries. Low-grade gliomas, high-grade gliomas, and CNS embryonal tumors were the most common CNS cancer diagnoses (67%, 84/126). Follow-up at 30 days was available for 107 (85%) patients. Based on the composite measure of severity, 53.3% (57/107) of reported SARS-CoV-2 infections were asymptomatic, 39.3% (42/107) were mild/moderate, and 6.5% (7/107) were severe or critical. One patient died from SARS-CoV-2 infection. There was a significant association between infection severity and absolute neutrophil count less than 500 (p = .04). Of 107 patients with follow-up available, 40 patients (37.4%) were not receiving cancer-directed therapy. Thirty-four patients (50.7%) had a modification to their treatment due to withholding of chemotherapy or delays in radiotherapy or surgery. CONCLUSION: In this cohort of patients with CNS tumors and COVID-19, the frequency of severe infection appears to be low, although severe disease and death do occur. We found that greater severity was seen in patients with severe neutropenia, although treatment modifications were not associated with infection severity or cytopenias. Additional analyses are needed to further describe this unique group of patients.

Safety of the BNT162b2 COVID-19 Vaccine in Children Aged 5 to 17 Years.

Importance: Active monitoring of health outcomes after COVID-19 vaccination offers early detection of rare outcomes that may not be identified in prelicensure trials. Objective: To conduct near-real-time monitoring of health outcomes following BNT162b2 COVID-19 vaccination in the US pediatric population aged 5 to 17 years. Design, Setting, and Participants: This population-based study was conducted under a public health surveillance mandate from the US Food and Drug Administration. Participants aged 5 to 17 years were included if they received BNT162b2 COVID-19 vaccination through mid 2022 and had continuous enrollment in a medical health insurance plan from the start of an outcome-specific clean window until the COVID-19 vaccination. Surveillance of 20 prespecified health outcomes was conducted in near real time within a cohort of vaccinated individuals from the earliest Emergency Use Authorization date for the BNT162b2 vaccination (December 11, 2020) and was expanded as more pediatric age groups received authorization through May and June 2022. All 20 health outcomes were monitored descriptively, 13 of which additionally underwent sequential testing. For these 13 health outcomes, the increased risk of each outcome after vaccination was compared with a historical baseline with adjustments for repeated looks at the data as well as a claims processing delay. A sequential testing approach was used, which declared a safety signal when the log likelihood ratio comparing the observed rate ratio against the null hypothesis exceeded a critical value. Exposure: Exposure was defined as receipt of a BNT162b2 COVID-19 vaccine dose. The primary analysis assessed primary series doses together (dose 1 + dose 2), and dose-specific secondary analyses were conducted. Follow-up time was censored for death, disenrollment, end of the outcome-specific risk window, end of the study period, or a receipt of a subsequent vaccine dose. Main Outcomes: Twenty prespecified health outcomes: 13 were assessed using sequential testing and 7 were monitored descriptively because of a lack of historical comparator data. Results: This study included 3 017 352 enrollees aged 5 to 17 years. Of the enrollees across all 3 databases, 1 510 817 (50.1%) were males, 1 506 499 (49.9%) were females, and 2 867 436 (95.0%) lived in an urban area. In the primary sequential analyses, a safety signal was observed only for myocarditis or pericarditis after primary series vaccination with BNT162b2 in the age group 12 to 17 years across all 3 databases. No safety signals were observed for the 12 other outcomes assessed using sequential testing. Conclusions and Relevance: Among 20 health outcomes that were monitored in near real time, a safety signal was identified for only myocarditis or pericarditis. Consistent with other published reports, these results provide additional evidence that COVID-19 vaccines are safe in children.

The Effects of COVID-19 on Orthopaedic Surgery Training Programs in the United States.

INTRODUCTION: This study investigates the effects of the COVID-19 pandemic on medical education, research opportunities, and mental health in orthopaedic surgical training programs. METHODS: A survey was sent to the 177 Electronic Residency Application Service-participating orthopaedic surgery training programs. The survey contained 26 questions covering demographics, examinations, research, academic activities, work settings, mental health, and educational communication. Participants were asked to assess their difficulty in performing activities relative to COVID-19. RESULTS: One hundred twenty-two responses were used for data analysis. Difficulties were experienced in collaborating with others (49%), learning through online web platforms (49%), maintaining the attention span of others through online web platforms (75%), and in gaining knowledge as a presenter or participating through online web platforms (56%). Eighty percent reported that managing time to study was the same or easier. There was no reported change in difficulty for performing activities in the clinic, emergency department, or operating room. Most respondents reported greater difficulty in socializing with others (74%), participating in social activities with coresidents (82%), and seeing their family (66%). Coronavirus disease 2019 has had a significant effect on the socialization of orthopaedic surgery trainees. DISCUSSION: Clinical exposure and engagement were marginally affected for most respondents, whereas academic and research activities were more greatly affected by the transition from in-person to online web platforms. These conclusions merit investigation of support systems for trainees and evaluating best practices moving forward.

Assessment of Infectious Diseases Risks From Dental Aerosols in Real-World Settings.

Background: Infectious diseases physicians are leaders in assessing the health risks in a variety of community settings. An understudied area with substantial controversy is the safety of dental aerosols. Previous studies have used in vitro experimental designs and/or indirect measures to evaluate bacteria and viruses from dental surfaces. However, these findings may overestimate the occupational risks of dental aerosols. The purpose of this study was to directly measure dental aerosol composition to assess the health risks for dental healthcare personnel and patients. Methods: We used a variety of aerosol instruments to capture and measure the bacterial, viral, and inorganic composition of aerosols during a variety of common dental procedures and in a variety of dental office layouts. Equipment was placed in close proximity to dentists during each procedure to best approximate the health risk hazards from the perspective of dental healthcare personnel. Devices used to capture aerosols were set at physiologic respiration rates. Oral suction devices were per the discretion of the dentist. Results: We detected very few bacteria and no viruses in dental aerosols-regardless of office layout. The bacteria identified were most consistent with either environmental or oral microbiota, suggesting a low risk of transmission of viable pathogens from patients to dental healthcare personnel. When analyzing restorative procedures involving amalgam removal, we detected inorganic elements consistent with amalgam fillings. Conclusions: Aerosols generating from dental procedures pose a low health risk for bacterial and likely viral pathogens when common aerosol mitigation interventions, such as suction devices, are employed.

Communication transforms the impact of the COVID-19 pandemic on children with cancer and their families.

BACKGROUND: The COVID-19 pandemic altered healthcare systems globally, causing delays in care delivery and increased anxiety among patients and families. This study examined how hospital stakeholders and clinicians perceived the global impact of the COVID-19 pandemic on children with cancer and their families. METHODS: This secondary analysis examined data from a qualitative study consisting of 19 focus groups conducted in 8 languages throughout 16 countries. A codebook was developed with novel codes derived inductively from transcript review. In-depth analysis focused on the impact of the COVID-19 pandemic on children with cancer and their families. RESULTS: Eight themes describing the impact of the pandemic on patients and their families were identified and classified into three domains: contributing factors (COVID-19 Policies, Cancer Treatment Modifications, COVID-19 Symptoms, Beliefs), patient-related impacts (Quality of Care, Psychosocial impacts, Treatment Reluctance), and the central transformer (Communication). Participants described the ability of communication to transform the effect of contributing factors on patient-related impacts. The valence of impacts depended on the quality and quantity of communication among clinicians and between clinicians and patients and families. CONCLUSIONS: Communication served as the central factor impacting whether the COVID-19 pandemic positively or negatively affected children with cancer and families. These findings emphasize the key role communication plays in delivering patient-centered care and can guide future development of communication-centered interventions globally.

Bleach Emissions Interact Substantially with Surgical and KN95 Mask Surfaces.

Mask wearing and bleach disinfectants became commonplace during the COVID-19 pandemic. Bleach generates toxic species including hypochlorous acid (HOCl), chlorine (Cl2), and chloramines. Their reaction with organic species can generate additional toxic compounds. To understand interactions between masks and bleach disinfection, bleach was injected into a ventilated chamber containing a manikin with a breathing system and wearing a surgical or KN95 mask. Concentrations inside the chamber and behind the mask were measured by a chemical ionization mass spectrometer (CIMS) and a Vocus proton transfer reaction mass spectrometer (Vocus PTRMS). HOCl, Cl2, and chloramines were observed during disinfection and concentrations inside the chamber are 2-20 times greater than those behind the mask, driven by losses to the mask surface. After bleach injection, many species decay more slowly behind the mask by a factor of 0.5-0.7 as they desorb or form on the mask. Mass transfer modeling confirms the transition of the mask from a sink during disinfection to a source persisting >4 h after disinfection. Humidifying the mask increases reactive formation of chloramines, likely related to uptake of ammonia and HOCl. These experiments indicate that masks are a source of chemical exposure after cleaning events occur.

A Delayed Presentation of Bilateral Adrenal Hemorrhage Secondary to COVID-19

Background/Objective Bilateral adrenal hemorrhage is a rare cause of adrenal insufficiency. Cases have been reported of acute adrenal crisis with bilateral adrenal hemorrhage during acute COVID-19. Our objective is to report a delayed presentation of acute adrenal crisis with bilateral adrenal hemorrhage two months following COVID-19 disease. Case Report An 89-year-old male, with a hospitalization for COVID-19 pneumonia two months prior, presented with lethargy. He was disorientated and hypotensive to 70/50 mm/hg, without improvement with intravenous fluids. According to family, since his previous hospitalization for COVID-19, his mental status continued to deteriorate and was no longer able to perform activities of daily living. A CT scan of the abdomen revealed bilateral heterogeneous enlargement of the adrenal glands (figure 1). Labs were significant for an AM cortisol of 8.42 mcg/dL, sodium of 134 mEq/L, and bicarbonate of 17 mEq/L. He was treated with hydrocortisone 100 mg IV with rapid improvement. Discussion It has been shown that infection with COVID-19 may cause an increased risk of bleeding or thromboembolism. The exact frequency of bilateral adrenal hemorrhage secondary to COVID-19 is unknown. Although there are a handful of cases reported, there are none to our knowledge with a delayed presentation as exhibited in our patient. Conclusion The patient's presentation was consistent with acute adrenal crisis due to bilateral adrenal hemorrhage from prior COVID-19 infection. We aim to highlight the importance for clinicians to be aware of adrenal hemorrhage and adrenal insufficiency as a possible delayed consequence in patients with a history of COVID-19.

From a genome-wide screen of RNAi molecules against SARS-CoV-2 to a validated broad-spectrum and potent prophylaxis.

Expanding the arsenal of prophylactic approaches against SARS-CoV-2 is of utmost importance, specifically those strategies that are resistant to antigenic drift in Spike. Here, we conducted a screen of over 16,000 RNAi triggers against the SARS-CoV-2 genome, using a massively parallel assay to identify hyper-potent siRNAs. We selected Ten candidates for in vitro validation and found five siRNAs that exhibited hyper-potent activity (IC50 < 20 pM) and strong blockade of infectivity in live-virus experiments. We further enhanced this activity by combinatorial pairing of the siRNA candidates and identified cocktails that were active against multiple types of variants of concern (VOC). We then examined over 2,000 possible mutations in the siRNA target sites by using saturation mutagenesis and confirmed broad protection of the leading cocktail against future variants. Finally, we demonstrated that intranasal administration of this siRNA cocktail effectively attenuates clinical signs and viral measures of disease in the gold-standard Syrian hamster model. Our results pave the way for the development of an additional layer of antiviral prophylaxis that is orthogonal to vaccines and monoclonal antibodies.