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Within a multistate viral genomic surveillance program, we evaluated whether proportions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections attributed to the JN.1 variant and to XBB-lineage variants (including HV.1 and EG.5) differed between inpatient and outpatient care settings during periods of cocirculation. Both JN.1 and HV.1 were less likely than EG.5 to account for infections among inpatients versus outpatients (adjusted odds ratio [aOR], 0.60 [95% confidence interval (CI), .43-.84; P = .003] and 0.35 [.21-.58; P < .001], respectively). JN.1 and HV.1 variants may be associated with a lower risk of severe illness. The severity of coronavirus disease 2019 may have attenuated as predominant circulating SARS-CoV-2 lineages shifted from EG.5 to HV.1 to JN.1., Competing Interests: Potential conflicts of interest . M. E. L., V. C., L. M. M., E. T. C., D. W., A. D. R., H. D., M. I., N. L. W., T. B., K. T., J. N., J. R., E. S., W. L., J. L., and S. L. are employees of Helix. M. E. L., E. T. C., D. W., M. I., J. L., and S. L. report support for attending meetings and/or travel from Helix. M. E. L., E. T. C., D. W., A. D. R., M. I., N. L. W., W. L., J. L., and S. L. report stock or stock options from Helix. M. E. L., M. I., W. L., and S. L. report contracted research from Pfizer. M. E. L., M. I., W. L., and S. L. report contracted research from the Centers for Disease Control and Prevention. M. E. L. reports contracted research and travel support from Novavax. R. E. D. reports consulting fees from Health Advances. P. R. H. reports contracted research from Seegene USA and Helix. J. D. G. reports contracted research from Helix, Gilead, Eli Lilly, and Regeneron; grants from Merck (BARDA) and Gilead; speaking honoraria and personal fees from Gilead Sciences and Eli Lilly; and collaborative services agreements with Adaptive Biotechnologies, Monogram Biosciences, and LabCorp; and service as a speaker or advisory board member for Gilead and Eli Lilly. C. A. S. reports giving educational lectures sponsored by Eli Lilly. M. I., N. L. W., and S. L. report patents pending or issued to Helix (M. I. and S. L.: US-11776694-B2 and US-20230178236-A1). P. A. P. reports no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Using a human factors engineering approach, the Johns Hopkins Personalized Pain Program adopted telemedicine for perioperative pain management in response to the COVID-19 pandemic. This study examines the impact of telemedicine adoption on the quality and outcomes of perioperative pain management., Methods: A mixed-methods study with a convergent parallel design was conducted. From June 2017 to December 2021, 902 patients participated in the Personalized Pain Program. Quantitative data on daily opioid consumption, pain severity and interference, physical and mental health status, and patient satisfaction and engagement were continuously collected with all patients using chart review and patient surveys. Beginning 23 March 2020, the Personalized Pain Program transitioned to telemedicine. A pre-post quasi-experimental design was used to examine the impact of telemedicine. In addition, qualitative interviews were conducted with 3 clinicians and 17 patients to explore their experience with telemedicine visits., Results: The monthly number of new patients seen in the Personalized Pain Program did not significantly change before and after telemedicine adoption. Compared to patients having in-person visits before the pandemic, patients having telemedicine visits during the pandemic achieved comparable improvements in daily opioid consumption, pain severity and interference, and physical health status. While telemedicine helped overcome many challenges faced by the patients, the limitations of telemedicine were also discussed., Conclusion: The COVID-19 pandemic stimulated the use of telemedicine. To facilitate telemedicine adoption beyond the pandemic, future research is needed to examine best practices for telemedicine adoption and provide additional evidence on the effectiveness of telemedicine., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

BACKGROUNDThere is uncertainty about the timing of booster vaccination against COVID-19 in highly vaccinated populations during the present endemic phase of COVID-19. Studies focused on primary vaccination have previously suggested improved immunity with a longer interval between the first and second vaccine doses.METHODSWe conducted a randomized, controlled trial (November 2022-August 2023) and assigned 52 fully vaccinated adults to an immediate or a 3-month delayed bivalent Spikevax mRNA booster vaccine. Follow-up visits were completed for 48 participants (n = 24 per arm), with collection of saliva and plasma samples following each visit.RESULTSThe rise in neutralizing antibody responses to ancestral and Omicron strains were almost identical between the immediate and delayed vaccination arms. Analyses of plasma and salivary antibody responses (IgG, IgA), plasma antibody-dependent phagocytic activity, and the decay kinetics of antibody responses were similar between the 2 arms. Symptomatic and asymptomatic SARS-CoV-2 infections occurred in 49% (21 of 49) participants over the median 11.5 months of follow-up and were also similar between the 2 arms.CONCLUSIONSOur data suggest that there was no benefit in delaying COVID-19 mRNA booster vaccination in preimmune populations during the present endemic phase of COVID-19.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry number 12622000411741 (https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12622000411741).FUNDINGNational Health and Medical Research Council, Australia (program grant App1149990) and Medical Research Future Fund (App2005544).

Behavioural science constructs can be incorporated into messaging strategies to enhance the effectiveness of public health campaigns by increasing the occurrence of desired behaviours. This study investigated the impact of behavioural science-informed text message strategies on COVID-19 vaccination rates in 18-39-year-olds in an area of low uptake in London during the first vaccination offer round in the United Kingdom. This three-armed randomised trial recruited unvaccinated residents of an urban Central London suburb being offered their first vaccination between May and June 2021. Participants were randomised to receive the control (current practice) text message or one of two different behavioural science-informed COVID-19 vaccine invitation strategies. Both intervention strategies contained the phrase "your vaccine is ready and waiting for you", aiming to evoke a sense of ownership, with one strategy also including a pre-alert message. The main outcome measures were vaccination rates at 3 and 8 weeks after message delivery. A total of 88,820 residents were randomly assigned to one of the three trial arms. Each arm had a vaccine uptake rate of 27.2 %, 27.4 % and 27.3 % respectively. The mean age of participants was 28.2 years (SD ± 5.7), the mean index of multiple deprivation was 4.3 (SD ± 2.0) and 50.4 % were women. Vaccine uptake varied by demographics, however there was no significant difference between trial arms (p = 0.872). Delivery was successful for 53.6 % of text messages. Our choice of behavioural science informed messaging strategies did not improve vaccination rates above the rate seen for the current practice message. This likely reflects the wide exposure to public health campaigns during the pandemic, as such text messages nudges were unlikely to alter existing informed decision-making processes. Text message delivery was relatively low, indicating a need for accurate mobile phone number records and multi-modal approaches to reach eligible patients for vaccination. The protocol was registered at clinicaltrials.gov (NCT04895683) on 20/05/2021., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ongoing COVID-19 pandemic necessitates cost-effective, high-throughput, and timely whole-genome sequencing (WGS) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses for outbreak investigations, identifying variants of concern (VoC), characterizing vaccine breakthrough infections, and public health surveillance. In addition, the enormous demand for WGS on supply chains and the resulting shortages of laboratory supplies necessitated the use of low-reagent and low-consumable methods. Here, we report an optimized library preparation method (the BCCDC cutdown method) that can be used in a high-throughput scenario, where one technologist can perform 576 library preparations (6 plates of 96 samples) over the course of one 8-hour shift. The same protocol can also be used in a rapid turnaround time scenario, from primary samples (up to 96 samples) to loading on a sequencer in an 8-hour shift. This new method uses Freed et al.'s 1,200 bp primer sets (Biol Methods Protoc 5:bpaa014, 2020, https://doi.org/10.1093/biomethods/bpaa014) and a modified and condensed Illumina DNA Prep workflow (Illumina, CA, USA). Compared to the original protocol, the application of this new method using hundreds of clinical specimens demonstrated equivalent results to the full-length DNA Prep workflow at 45% of the cost, 15% of consumables required (such as pipet tips), 25% of manual hands-on time, and 15% of on-instrument time if performing on a liquid handler, with no compromise in sequence quality. Results demonstrate that this new method is a rapid, simple, cost-effective, and high-quality SARS-CoV-2 WGS protocol., Importance: Sequencing has played an invaluable role in the response to the COVID-19 pandemic. Ongoing work in this area, however, demands optimization of laboratory workflow to increase sequencing capacity, improve turnaround time, and reduce cost without compromising sequence quality. This report describes an optimized DNA library preparation method for improved whole-genome sequencing of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen. The workflow advantages summarized here include significant time, cost, and consumable savings, which suggest that this new method is an efficient, scalable, and pragmatic alternative for SARS-CoV-2 whole-genome sequencing., Competing Interests: The authors declare no conflict of interest.

Background: Post-COVID conditions encompass a range of long-term symptoms after SARS-CoV-2 infection. The potential clinical and economic burden in the United States is unclear. We evaluated diagnoses, medications, healthcare use, and medical costs before and after acute COVID-19 illness in US patients at high risk of severe COVID-19., Methods: Eligible adults were diagnosed with COVID-19 from April 1 to May 31, 2020, had ≥ 1 condition placing them at risk of severe COVID-19, and were enrolled in Optum's de-identified Clinformatics ® Data Mart Database for ≥ 12 months before and ≥ 13 months after COVID-19 diagnosis. Percentages of diagnoses, medications, resource use, and costs were calculated during baseline (12 months preceding diagnosis) and the post-acute phase (12 months after the 30-day acute phase of COVID-19). Data were stratified by age and COVID-19 severity., Results: The cohort included 19,558 patients (aged 18-64 y, n = 9381; aged ≥ 65 y, n = 10,177). Compared with baseline, patients during the post-acute phase had increased percentages of blood disorders (16.3%), nervous system disorders (11.1%), and mental and behavioral disorders (7.7%), along with increases in related prescriptions. Overall, there were substantial increases in inpatient and outpatient healthcare utilization, along with a 23.0% increase in medical costs. Changes were greatest among older patients and those admitted to the intensive care unit for acute COVID-19 but were also observed in younger patients and those who did not require COVID-19 hospitalization., Conclusions: There is a significant clinical and economic burden of post-COVID conditions among US individuals at high risk for severe COVID-19., (© 2024. The Author(s).)

The emergence of SARS-CoV-2 recombinants is of particular concern as they can result in a sudden increase in immune evasion due to antigenic shift. Recent recombinants XBB and XBB.1.5 have higher transmissibility than previous recombinants such as "Deltacron." We hypothesized that immunity to a SARS-CoV-2 recombinant depends on prior exposure to its parental strains. To test this hypothesis, we examined whether Delta or Omicron (BA.1 or BA.2) immunity conferred through infection, vaccination, or breakthrough infection could neutralize Deltacron and XBB/XBB.1.5 recombinants. We found that Delta, BA.1, or BA.2 breakthrough infections provided better immune protection against Deltacron and its parental strains than did the vaccine booster. None of the sera were effective at neutralizing the XBB lineage or its parent BA.2.75.2, except for the sera from the BA.2 breakthrough group. These results support our hypothesis. In turn, our findings underscore the importance of multivalent vaccines that correspond to the antigenic profile of circulating variants of concern and of variant-specific diagnostics that may guide public health and individual decisions in response to emerging SARS-CoV-2 recombinants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection of vaccinated individuals is increasingly common with the circulation of highly immune evasive and transmissible Omicron variants. Here, we report the dynamics and durability of recalled spike-specific humoral immunity following Omicron BA.1 or BA.2 breakthrough infection, with longitudinal sampling up to 8 months after infection. Both BA.1 and BA.2 infections robustly boosted neutralization activity against the infecting strain while expanding breadth against BA.4, although neutralization activity was substantially reduced for the more recent XBB and BQ.1.1 strains. Cross-reactive memory B cells against both ancestral and Omicron spike were predominantly expanded by infection, with limited recruitment of de novo Omicron-specific B cells or antibodies. Modeling of neutralization titers predicts that protection from symptomatic reinfection against antigenically similar strains will be durable but is undermined by new emerging strains with further neutralization escape.

Introduction: Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP)., Case Report: We report an unusual case of pneumonitis with atypical imaging in a patient who received pembrolizumab for metastatic p16-positive squamous cell carcinoma of the base of the tongue. We discuss the approach to the recognition and management of atypical CIP in patients on pembrolizumab with the intent to standardize workup and increase awareness among healthcare providers in the new era of immunotherapy., Management and Outcome: Serologic workup including laboratory studies for complete blood count (CBC), lactate, procalcitonin, SARS-CoV-2 (COVID-19), Legionella, Cytomegalovirus (CMV), Coccidioides, Coxiella, and viral respiratory panel were negative for infectious processes. Since CIP was suspected, the patient was started on steroid therapy. Interval computed tomography (CT) of the chest without contrast showed a resolution of pneumonitis., Discussion: In this case report, we discuss our workup of CIP and initial testing to rule out other possible causes of the patient's symptoms and radiographic findings, and management of the patient's diagnosis of atypical CIP which led to complete clinical recovery from CIP.

Differential host responses in coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) remain poorly characterized. Here, we use next-generation sequencing to longitudinally analyze blood samples from pediatric patients with COVID-19 or MIS-C across three hospitals. Profiling of plasma cell-free nucleic acids uncovers distinct signatures of cell injury and death between COVID-19 and MIS-C, with increased multiorgan involvement in MIS-C encompassing diverse cell types, including endothelial and neuronal cells, and an enrichment of pyroptosis-related genes. Whole-blood RNA profiling reveals upregulation of similar pro-inflammatory pathways in COVID-19 and MIS-C but also MIS-C-specific downregulation of T cell-associated pathways. Profiling of plasma cell-free RNA and whole-blood RNA in paired samples yields different but complementary signatures for each disease state. Our work provides a systems-level view of immune responses and tissue damage in COVID-19 and MIS-C and informs future development of new disease biomarkers., Competing Interests: Declaration of interests I.D.V. is a member of the Scientific Advisory Board of Karius Inc., Kanvas Biosciences, and GenDX. C.Y.C. is a founder of Delve Bio and a member of the Scientific Advisory Boards of Delve Bio, Poppy Health, BiomeSense, and Mammoth Biosciences. A.P.C. is listed as an inventor on submitted patents pertaining to cfDNA (US patent applications 63/237,367, 63/056,249, 63/015,095, and 16/500,929) and receives consulting fees from Eurofins Viracor. C.A.R.’s institution has received funding to conduct clinical research unrelated to this manuscript from BioFire Inc., GSK, MedImmune, Micron, Merck, Novavax, PaxVax, Regeneron, Pfizer, and Sanofi-Pasteur. She is a co-inventor of patented RSV vaccine technology (International PCT Application No. PCT/US2016/058976, filed 12/28/2016 by Emory University), which has been licensed to Meissa Vaccines, Inc. with royalties received. Her institution has received funding from the NIH to conduct clinical trials of Moderna and Janssen COVID-19 vaccines. E.J.A has consulted for Pfizer, Sanofi Pasteur, GSK, Janssen, and Medscape, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Sanofi-Pasteur, Janssen, and Micron. He also serves on a safety monitoring board for Kentucky BioProcessing, Inc. and Sanofi Pasteur. He serves on a data adjudication board for WCG and ACI Clinical. His institution has also received funding from the NIH to conduct clinical trials of Moderna and Janssen COVID-19 vaccines. A.B. is a co-founder and consultant to Personalis and NuMedii; consultant to Mango Tree Corporation, and in the recent past, Samsung, 10× Genomics, Helix, Pathway Genomics, and Verinata (Illumina); has served on paid advisory panels or boards for Geisinger Health, Regenstrief Institute, Gerson Lehman Group, AlphaSights, Covance, Novartis, Genentech, Merck, and Roche; is a shareholder in Personalis and NuMedii; is a minor shareholder in Apple, Meta (Facebook), Alphabet (Google), Microsoft, Amazon, Snap, 10× Genomics, Illumina, Regeneron, Sanofi, Pfizer, Royalty Pharma, Moderna, Sutro, Doximity, BioNtech, Invitae, Pacific Biosciences, Editas Medicine, Nuna Health, Assay Depot, and Vet24seven, and several other non-health related companies and mutual funds; and has received honoraria and travel reimbursement for invited talks from Johnson and Johnson, Roche, Genentech, Pfizer, Merck, Lilly, Takeda, Varian, Mars, Siemens, Optum, Abbott, Celgene, AstraZeneca, AbbVie, Westat, and many academic institutions, medical or disease-specific foundations and associations, and health systems. A.B. receives royalty payments through Stanford University for several patents and other disclosures licensed to NuMedii and Personalis. A.B.’s research has been funded by the NIH, Peraton (as the prime on an NIH contract), Genentech, Johnson and Johnson, the FDA, the Robert Wood Johnson Foundation, the Leon Lowenstein Foundation, the Intervalien Foundation, Priscilla Chan and Mark Zuckerberg, the Barbara and Gerson Bakar Foundation, and in the recent past the March of Dimes, the Juvenile Diabetes Research Foundation, the California Governor’s Office of Planning and Research, the California Institute for Regenerative Medicine, L’Oréal, and Progenity. The authors have declared that none of these companies or competing interests had any role in this work or manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vascular activation is characterized by increased proinflammatory, pro thrombotic, and proadhesive signaling. Several chronic and acute conditions, including Bcr-abl-negative myeloproliferative neoplasms (MPNs), graft-vs-host disease, and COVID-19 have been noted to have increased activation of the janus kinase (JAK)-signal transducer and downstream activator of transcription (STAT) pathways. Two notable inhibitors of the JAK-STAT pathway are ruxolitinib (JAK1/2 inhibitor) and fedratinib (JAK2 inhibitor), which are currently used to treat MPN patients. However, in some conditions, it has been noted that JAK inhibitors can increase the risk of thromboembolic complications., Objectives: We sought to define the anti-inflammatory and antithrombotic effects of JAK-STAT inhibitors in vascular endothelial cells., Methods: We assessed endothelial activation in the presence or absence of ruxolitinib or fedratinib by using immunoblots, immunofluorescence, qRT-PCR, and function coagulation assays. Finally, we used endothelialized microfluidics perfused with blood from normal and JAK2 V617F+ individuals to evaluate whether ruxolitinib and fedratinib changed cell adhesion., Results: We found that both ruxolitinib and fedratinib reduced endothelial cell phospho-STAT1 and STAT3 signaling and attenuated nuclear phospho-NK-κB and phospho-c-Jun localization. JAK-STAT inhibition also limited secretion of proadhesive and procoagulant P-selectin and von Willebrand factor and proinflammatory IL-6. Likewise, we found that JAK-STAT inhibition reduced endothelial tissue factor and urokinase plasminogen activator expression and activity., Conclusions: By using endothelialized microfluidics perfused with whole blood samples, we demonstrated that endothelial treatment with JAK-STAT inhibitors prevented rolling of both healthy control and JAK2 V617F MPN leukocytes. Together, these findings demonstrate that JAK-STAT inhibitors reduce the upregulation of critical prothrombotic pathways and prevent increased leukocyte-endothelial adhesion., Competing Interests: Declaration of competing interests J.D.B. receives funds from Bayer independent from work herein. G.M.V. receives research funding from CSL Behring and Mitobridge (Astellas). C.B. has received reagents from CTI BioPharma for the conduct of clinical trial NCT 02891603 and a pending patent, WO2017058950A1, for methods of treating transplant rejection. B.C.B. holds patents related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD (WO2015120436A2); for the use of JAK inhibitors for rejection and GVHD prevention (WO2017058950A1); and for the use of CD83-targeted chimeric antigen receptor T cells in GVHD prevention, immune tolerance, autoimmunity, and acute myeloid leukemia therapy (WO2019165156). At this time, neither B.C.B. nor the University of Minnesota has received payment related to claims described in the patent. B.C.B. has received honoraria for participating in advisory board discussions for Incyte Corp and CTI BioPharma within the past 5 years. Remaining authors have no conflicts to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although the protective role of neutralizing antibodies against COVID-19 is well established, questions remain about the relative importance of cellular immunity. Using 6 pMHC multimers in a cohort with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4 + T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post symptom onset. Similarly, spike-specific CD8 + T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8 + T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates that a rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8 + T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections., Competing Interests: Declaration of interests M.K. has acted as a consultant for Sanofi group of companies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lipid encapsulated messenger RNA (LNP mRNA) has garnered a significant amount of interest from the pharmaceutical industry and general public alike. This attention has been catalyzed by the clinical success of LNP mRNA for SARS-CoV-2 vaccination as well as future promises that might be fulfilled by the biotechnology pipeline, such as the in vivo delivery of a CRISPR/Cas9 complex that can edit patient cells to reduce levels of low-density lipoprotein. LNP mRNAs are comprised of various chemically diverse molecules brought together in a sophisticated intermolecular complex. This can make it challenging to achieve thorough analytical characterization. Nevertheless, liquid chromatography is becoming an increasingly relied upon technique for LNP mRNA analyses. Although there have been significant advances in all types of LNP mRNA analyses, this review focuses on recent developments and the possibilities of applying anion exchange (AEX) and ion pairing reversed phase (IP-RP) liquid chromatography for intact mRNAs as well as techniques for oligo mapping analysis, 5' endcap testing and lipid compositional assays., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors are employed by Waters Corporation, a manufacturer of UHPLC systems and columns., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the COVID-19 vaccination rates of a severe mental illness (SMI) population in Western Australia (WA) in January to March 2022, and to evaluate an inpatient COVID-19 vaccination program available to this group., Method: A retrospective audit of the COVID-19 vaccination status of inpatients at the Mental Health Unit (MHU) at a tertiary hospital in WA was conducted and compared with the state average. Additionally, the medical records were interrogated to determine whether eligible inpatients were offered and received COVID-19 vaccination via the inpatient vaccination program., Results: Vaccination rates for the MHU population were substantially lower than those for the WA population, particularly earlier in 2022. During January, just 49.0% of admitted patients had received two doses of the vaccine, compared to 92.8% of WA. Over the three months, 67 (47.2%) of all admissions were eligible for vaccination during their admission and 19 of the eligible patients (28.4%) were successfully vaccinated., Conclusion: This audit has demonstrated a slow uptake of COVID-19 vaccinations in the SMI population, despite the wide availability for 12 months prior to this period. This indicates a significant potential for targeted, assertive programs to improve vaccination rates in this population group.

Aim: Respiratory testing with rapid antigen tests (RATs) in children under 5 years of age may be uncomfortable and presents specific challenges to testing due to compliance and procedural distress. The aim of this study was to investigate sensitivity and feasibility of self-collected nasal and saliva RAT tests compared with a combined nose and throat (CTN) swab PCR in children under 5., Methods: Children aged between 1 month and 5 years, with confirmed COVID-19 or who were a household contact within 7 days were included. A saliva RAT, nasal RAT and CTN swab were collected by the parent. SARS-CoV-2 cycle threshold (Ct) values for CTN tested by PCR were compared with saliva and nasal RAT results. Parent preference for method of sample was recorded., Results: Forty-one children were recruited with median age of 1.5 (interquartile range 0.7-4.0) years. Only 22/41 (54%) of parents were able to successfully collect a saliva RAT from their child. Sensitivity of the nasal RAT and saliva RAT was 0.889 (95% confidence interval (CI) 0.739-0.969) and 0.158 (95% CI 0.034-0.396), respectively. Upper limit of nasal RAT detection by CTN Ct value was higher than saliva (36.05 vs. 27.29). While saliva RAT was rated most comfortable, nasal RAT was rated the preferred specimen by parents for future testing, due to saliva collection difficulties and time taken., Conclusions: Rapid antigen testing with nasal RAT is a more feasible and sensitive method for SARS-CoV-2 detection in young children compared with saliva RAT., (© 2022 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Introduction: During the SARS-CoV-2 pandemic, Canadian postsecondary institutions were forced to rely on online teaching to comply with physical distancing recommendations. This sole reliance on virtual methods to deliver synchronous teaching sessions in medical education was novel. We found little empirical research examining pediatric educators' experiences. Hence, the objective of our study was to describe and gain a deeper understanding of pediatric educators' perspectives, focusing on the research question, "How is synchronous virtual teaching impacting and transforming teaching experiences of pediatricians during a pandemic?", Methods: A virtual ethnography was conducted guided by an online collaborative learning theory. This approach used both interviews and online field observations to obtain objective descriptions and subjective understandings of the participants' experiences while teaching virtually. Pediatric educators (clinical and academic faculty) from our institution were recruited using purposeful sampling and invited to participate in individual phone interviews and online teaching observations. Data were recorded and transcribed, and a thematic analysis was conducted., Results: Fifteen frontline pediatric teachers from our large Canadian research-intensive university were recruited. Four main themes, with subthemes, emerged: (1) the love/hate relationship with the virtual shift; (2) self-imposed pressure to increase virtual engagement; (3) looking back, moving forward; (4) accelerated adaptation and enhanced collaboration., Conclusion: Pediatricians adopted new delivery methods quickly and found many efficiencies and opportunities in this shift. Continued use of virtual teaching will lead to increased collaboration, enhanced student engagement strategies, and blending the advantages of virtual and face-to-face learning., Competing Interests: Disclosures: The authors declare no conflict of interest., (Copyright © 2022 The Alliance for Continuing Education in the Health Professions, the Association for Hospital Medical Education, and the Society for Academic Continuing Medical Education.)

Aims: To identify and synthesize evidence regarding how coronavirus disease 2019 (COVID-19) interventions, including vaccines and outpatient treatments, have impacted healthcare resource use (HCRU) and costs in the United States (US) during the Omicron era., Materials and Methods: A systematic literature review (SLR) was performed to identify articles published between 1 January 2021 and 10 March 2023 that assessed the impact of vaccination and outpatient treatment on costs and HCRU outcomes associated with COVID-19. Screening was performed by two independent researchers using predefined inclusion/exclusion criteria., Results: Fifty-eight unique studies were included in the SLR, of which all reported HCRU outcomes, and one reported costs. Overall, there was a significant reduction in the risk of COVID-19-related hospitalization for patients who received an original monovalent primary series vaccine plus booster dose vs. no vaccination. Moreover, receipt of a booster vaccine was associated with a lower risk of hospitalization vs. primary series vaccination. Evidence also indicated a significantly reduced risk of hospitalizations among recipients of nirmatrelvir/ritonavir (NMV/r), remdesivir, sotrovimab, and molnupiravir compared to non-recipients. Treated and/or vaccinated patients also experienced reductions in intensive care unit (ICU) admissions, length of stay, and emergency department (ED)/urgent care clinic encounters., Limitations: The identified studies may not represent unique patient populations as many utilized the same regional/national data sources. Synthesis of the evidence was also limited by differences in populations, outcome definitions, and varying duration of follow-up across studies. Additionally, significant gaps, including HCRU associated with long COVID and various high-risk populations and cost data, were observed., Conclusions: Despite evidence gaps, findings from the SLR highlight the significant positive impact that vaccination and outpatient treatment have had on HCRU in the US, including periods of Omicron predominance. Continued research is needed to inform clinical and policy decision-making in the US as COVID-19 continues to evolve as an endemic disease.

Background: Between November 2021 and February 2022, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron variants co-circulated in the United States, allowing for co-infections and possible recombination events., Methods: We sequenced 29,719 positive samples during this period and analyzed the presence and fraction of reads supporting mutations specific to either the Delta or Omicron variant., Findings: We identified 18 co-infections, one of which displayed evidence of a low Delta-Omicron recombinant viral population. We also identified two independent cases of infection by a Delta-Omicron recombinant virus, where 100% of the viral RNA came from one clonal recombinant. In the three cases, the 5' end of the viral genome was from the Delta genome and the 3' end from Omicron, including the majority of the spike protein gene, though the breakpoints were different., Conclusions: Delta-Omicron recombinant viruses were rare, and there is currently no evidence that Delta-Omicron recombinant viruses are more transmissible between hosts compared with the circulating Omicron lineages., Funding: This research was supported by the NIH RADx initiative and by the Centers for Disease Control Contract 75D30121C12730 (Helix)., Competing Interests: Declarations of interests A.B., T.B., S.W., A.D.R., D.W., H.D., J.T.M., E.K., T.C., K.T., J.N., J.R., S.C., E.T.C., K.S.B., N.L.W., P.B.-F., S.J., E.S., D.B., J.T.L., M.I., W.L., and S.L. are all employees of Helix., (Copyright © 2022 Elsevier Inc. All rights reserved.)

There is limited understanding of antibody responses in children across different SARS-CoV-2 variants. As part of an ongoing household cohort study, we assessed the antibody response among unvaccinated children infected with Wuhan, Delta, or Omicron variants, as well as vaccinated children with breakthrough Omicron infection, using a SARS-CoV-2 S1-specific IgG assay and surrogate virus neutralization test (% inhibition). Most children infected with Delta (100%, 35/35) or Omicron (81.3%, 13/16) variants seroconverted by one month following infection. In contrast, 37.5% (21/56) children infected with Wuhan seroconverted, as previously reported. However, Omicron-infected children (geometric mean concentration 46.4 binding antibody units/ml; % inhibition = 16.3%) mounted a significantly lower antibody response than Delta (435.5 binding antibody untis/mL, % inhibition = 76.9%) or Wuhan (359.0 binding antibody units/mL, % inhibition = 74.0%). Vaccinated children with breakthrough Omicron infection mounted the highest antibody response (2856 binding antibody units/mL, % inhibition = 96.5%). Our findings suggest that despite a high seropositivity rate, Omicron infection in children results in lower antibody levels and function compared with Wuhan or Delta infection or with vaccinated children with breakthrough Omicron infection. Our data have important implications for public health measures and vaccination strategies to protect children., (© 2022. The Author(s).)

Multiple sclerosis (MS) is an incurable autoimmune disease known to cause widespread demyelinating lesions in the central nervous system (CNS) and a host of debilitating symptoms in patients. The development of MS is believed to be driven by the breakdown of the blood brain barrier, subsequent infiltration by CD4 + and CD8 + T cells, and widespread CNS inflammation and demyelination. Disease modifying therapies (DMTs) profoundly disrupt these processes and therefore compose an essential component of disease management. However, the effects of these therapeutic agents on vaccine safety and immunogenicity in individuals with MS are not yet fully understood. As such, the primary objective of this review article was to summarize the findings of recently conducted studies on vaccine safety and immunogenicity in MS patients treated with DMTs, particularly in the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Discussed in this review are vaccinations against influenza, yellow fever, human papillomavirus, measles, mumps, rubella, Streptococcus pneumoniae, hepatitis B, and COVID-19. This article additionally reviews our current understanding of COVID-19 severity and incidence in this patient population, the risks and benefits of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and vaccination guidelines set forth by MS societies and organizations., Competing Interests: Declaration of Interest The authors have no conflicts of interest to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Background: The UK COVID-19 vaccination programme began in December, 2020. By February, 2021, eight North West London Clinical Commissioning Groups (CCGs) had the lowest vaccination rates nationally. This study evaluated the impact of behavioural science-informed (BI) letters on vaccination uptake., Methods: Unvaccinated residents of the Central London CCG who were deemed uncontactable (through text messaging and phone calls) were identified with the whole systems integrated care database. BI letters were sent to residents in the intervention CCG between May and June, 2021. Three neighbouring CCGs in London with similar non-responder data were used as control groups. A linear difference-in-difference analysis was undertaken to assess change in vaccine uptake rate across all four CCGs. Percentage point change was adjusted for selected covariates including ethnicity, age, gender, and index of multiple deprivation (IMD) quintiles. Approval was obtained from the quality improvement and audit office of Imperial College Healthcare NHS Trust (London, UK)., Findings: Within the intervention Central London CCG, 10 161 residents received the BI letter. The control CCGs contained 27 383 uncontactable residents. All CCGs showed an increase in vaccination rates in this population. The linear difference-in-difference analysis showed an increase in vaccination uptake in the intervention CCG (relative change 31·9% (95% CI 30·5-33·3; p<0·0001). Residents in IMD quintile 5 (least deprived) showed the largest rate of change (4·1%; p<0·0001). Residents with a mixed or multiple ethnic background were less likely to receive a COVID-19 vaccine (-4·1%, p<0·0001)., Interpretation: BI letters improved the rate of vaccine uptake. The percentage point increase of 31·9% equates to 436 additional previously uncontactable residents being vaccinated. Our data highlighted differences in the effect of BI-informed interventions in population subgroups. BI letters are a cost-effective and trusted communication tool, effectively engaging residents where other communication strategies did not work., Funding: None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In response to COVID-19, mental health clinics transitioned to telehealth to maintain psychotherapy delivery. Community mental health (CMH) settings, which are often under-resourced, likely experienced many barriers. This study examined CMH clinicians' experiences transitioning to telehealth. Data came from a state-funded initiative training CMH clinicians in cognitive behavioral therapy. Participants (N = 197) completed pre-training and post-consultation surveys which included questions about their experiences with telehealth. Most clinicians found telehealth beneficial and effective. Clinicians strongly endorsed wanting telehealth as an option even after in-person services resume. CMH clinicians rated "engaging younger children" as the most significant barrier to telehealth. Despite some telehealth barriers, clinicians generally viewed telehealth favorably and prefer having it as a long-term option. Future work should continue to understand when telehealth may be advantageous and for whom in order to improve the accessibility and quality of behavioral health services., (© 2022. National Council for Mental Wellbeing.)

Risks of intimate partner violence (IPV) escalated during the COVID-19 pandemic given mitigation measures, socioeconomic hardships, and isolation concerns. The objective of this study was to explore the impact of COVID-19 on the incidence of IPV. We conducted an interrupted time series analysis for IPV incidence at a single level 1 trauma center located in the United States. IPV cases were identified by triangulation of institutional data sources. There were 4,624 traumatic injuries of which 292 (6.3%) were due to IPV. IPV-related injury admissions increased 17% in the weeks following the COVID lockdown (RR = 1.17; 95% CI: 1.16, 1.19). Over a quarter of victims (27.4%) were male. Compared to before COVID, victims of IPV during the pandemic were younger (p = .04); no difference in mechanism or severity of injury was found. Our results suggest an ongoing need for universal IPV screening during health emergencies to avoid missed opportunities for IPV detection and referral to support services.

SARS-CoV-2 Delta and Omicron are globally relevant variants of concern. Although individuals infected with Delta are at risk of developing severe lung disease, infection with Omicron often causes milder symptoms, especially in vaccinated individuals 1,2 . The question arises of whether widespread Omicron infections could lead to future cross-variant protection, accelerating the end of the pandemic. Here we show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. Sera from mice overexpressing the human ACE2 receptor and infected with Omicron neutralize only Omicron, but not other variants of concern, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced expression of pro-inflammatory cytokines and diminished activation of lung-resident T cells. Sera from individuals who were unvaccinated and infected with Omicron show the same limited neutralization of only Omicron itself. By contrast, Omicron breakthrough infections induce overall higher neutralization titres against all variants of concern. Our results demonstrate that Omicron infection enhances pre-existing immunity elicited by vaccines but, on its own, may not confer broad protection against non-Omicron variants in unvaccinated individuals., (© 2022. The Author(s).)

Background: This study investigated the impact of COVID-19 infection on hospitalized trauma patients., Methods: A retrospective review of hospitalized trauma patients at a level I trauma center was performed from March-December 2020. Data pertaining to patient demographics, presentation and hospital course was compared between COVID positive and negative trauma patients., Results: There were 4,912 patients and 179 (3.64%) were COVID-19 positive. Demographics and clinical presentation did not differ significantly between those with and without concomitant COVID-19. However, COVID positive trauma patients had higher rates of acute kidney injury (p = 0.016), sepsis (p = 0.016), unplanned intubation (p = 0.002) and unplanned return to the ICU (p = 0.01). The COVID positive cohort also had longer hospital stays (p < 0.01) with no significant difference in mortality., Conclusions: In the setting of an ongoing pandemic, awareness of the complications COVID positive trauma patients are predisposed to is important for providers., (Copyright © 2022. Published by Elsevier Inc.)

Objective: This study aimed to determine independent community pharmacist preparedness for coronavirus disease 2019 (COVID-19) vaccination and to identify strategies for COVID-19 pandemic vaccination implementation in Pennsylvania., Methods: This study used a complementary mixed-methods approach to recruit independent community pharmacists to participate in an electronic survey and 2 virtually conducted focus groups before the availability of the first COVID-19 vaccine. Information was gathered and compiled into 5 topic areas: (1) workflow, (2) resources, (3) staff and patient safety, (4) communication, and (5) documentation and training. Data collection occurred between October and December 2020. Survey data were analyzed using descriptive statistics. Focus group discussions were audiorecorded and transcribed. A directed, content analysis was conducted to identify strategies for each topic area, and supporting quotes were selected., Results: A total of 88 and 11 independent community pharmacists participated in the survey and focus groups, respectively. Because of the small size of most independent pharmacies, participants recommended working with community partners to support off-site mass vaccination clinics. Leveraging partnerships with community organizations and universities could be used to support staffing for vaccination efforts. Using an appointment-based immunization model was identified as one tool to optimize patient and staff safety during the pandemic. Pharmacists suggested using existing scheduling tools and text messaging and automated phone calls for second-dose reminders. Finally, independent pharmacists recommended further training and process improvements to support vaccine documentation and transmission to the Pennsylvania Statewide Immunization Information System., Conclusion: Recommendations from this study were used to support planning and preparation for COVID-19 vaccinations across Pennsylvania. Incorporation of pharmacists' ideas and recommendations on pandemic vaccination implementation is an important strategy to efficiently expand vaccination administration during pandemics., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Household studies are crucial for understanding the transmission of SARS-CoV-2 infection, which may be underestimated from PCR testing of respiratory samples alone. We aim to combine the assessment of household mitigation measures; nasopharyngeal, saliva, and stool PCR testing; along with mucosal and systemic SARS-CoV-2-specific antibodies, to comprehensively characterize SARS-CoV-2 infection and transmission in households., Methods: Between March and September 2020, we obtained samples from 92 participants in 26 households in Melbourne, Australia, in a 4-week period following the onset of infection with ancestral SARS-CoV-2 variants., Results: The secondary attack rate was 36% (24/66) when using nasopharyngeal swab (NPS) PCR positivity alone. However, when respiratory and nonrespiratory samples were combined with antibody responses in blood and saliva, the secondary attack rate was 76% (50/66). SARS-CoV-2 viral load of the index case and household isolation measures were key factors that determine secondary transmission. In 27% (7/26) of households, all family members tested positive by NPS for SARS-CoV-2 and were characterized by lower respiratory Ct values than low transmission families (Median 22.62 vs. 32.91; IQR 17.06-28.67 vs. 30.37-34.24). High transmission families were associated with enhanced plasma antibody responses to multiple SARS-CoV-2 antigens and the presence of neutralizing antibodies. Three distinguishing saliva SARS-CoV-2 antibody features were identified according to age (IgA1 to Spike 1, IgA1 to nucleocapsid protein (NP)), suggesting that adults and children generate distinct mucosal antibody responses during the acute phase of infection., Conclusion: Utilizing respiratory and nonrespiratory PCR testing, along with the measurement of SARS-CoV-2-specific local and systemic antibodies, provides a more accurate assessment of infection within households and highlights some of the immunological differences in response between children and adults., (© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background:  The impact of the coronavirus disease 2019 (COVID-19) outbreak shut down most conferences. To minimalize the influence, virtual meetings sprang up subsequently. International Microsurgery Club (IMC), as one of the largest professionals-only online microsurgery education groups worldwide, began to host regular weekend webinars during the pandemic to fill the knowledge gap. This study aims to discuss how webinars have fundamentally changed the way knowledge is delivered and exchanged., Methods:  From February 29, 2020 to March 14, 2021, 103 IMC webinars were reviewed and analyzed in detail to determine the use, benefit, and effect. A comparison between webinars hosted by the different societies was made as well. A questionnaire survey focusing on attendees' behavior, attitude, and using habit about webinars was also made., Results:  As for the 103 IMC webinar events, the peak participants were 112.3 people in average. The members requesting to join IMC abruptly increased during the pandemic, and the group activity increased dramatically. From the questionnaire ( n  = 68), the satisfaction level was high (8.88 ± 1.18/10). The respondents were most satisfied with the good quality of the speakers (73.5%). Not only hosts our webinar series but IMC also serves as the platform that welcomes webinars from other societies to share their information. In September 2020, International Microsurgery Webinar League was established via the significant webinar hosts, with more than 300 recorded webinar talks connected successfully., Conclusion:  As the knowledge revolution driven by COVID-19 will continue, IMC will keep playing an essential role in exploring new and emerging opportunities to improve knowledge dissemination worldwide beyond the space-time boundary., Competing Interests: None declared., (Thieme. All rights reserved.)

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared with uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared with Omicron (p = 0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared with moderate to severe infections (p = 0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants., Competing Interests: Declaration of interests C.Y.C. is the director of the UCSF-Abbott Viral Diagnostics and Discovery and receives research support for SARS-CoV-2 studies from Abbott Laboratories. The other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: COH04S1, a synthetic attenuated modified vaccinia virus Ankara vector co-expressing SARS-CoV-2 spike and nucleocapsid antigens, was tested for safety and immunogenicity in healthy adults., Methods: This combined open-label and randomised, phase 1 trial was done at the City of Hope Comprehensive Cancer Center (Duarte, CA, USA). We included participants aged 18-54 years with a negative SARS-CoV-2 antibody and PCR test, normal haematology and chemistry panels, a normal electrocardiogram and troponin concentration, negative pregnancy test if female, body-mass index of 30 kg/m 2 or less, and no modified vaccinia virus Ankara or poxvirus vaccine in the past 12 months. In the open-label cohort, 1·0 × 10 7 plaque-forming units (PFU; low dose), 1·0 × 10 8 PFU (medium dose), and 2·5 × 10 8 PFU (high dose) of COH04S1 were administered by intramuscular injection on day 0 and 28 to sentinel participants using a queue-based statistical design to limit risk. In a randomised dose expansion cohort, additional participants were randomly assigned (3:3:1), using block size of seven, to receive two placebo vaccines (placebo group), one low-dose COH04S1 and one placebo vaccine (low-dose COH04S1 plus placebo group), or two low-dose COH04S1 vaccines (low-dose COH04S1 group). The primary outcome was safety and tolerability, with secondary objectives assessing vaccine-specific immunogenicity. The primary immunological outcome was a four times increase (seroconversion) from baseline in spike-specific or nucleocapsid-specific IgG titres within 28 days of the last injection, and seroconversion rates were compared with participants who received placebo using Fisher's exact test. Additional secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ClinicalTrials.gov, NCT046339466., Findings: Between Dec 13, 2020, and May 24, 2021, 56 participants initiated vaccination. On day 0 and 28, 17 participants received low-dose COH04S1, eight received medium-dose COH04S1, nine received high-dose COH04S1, five received placebo, 13 received low-dose COH04S1 followed by placebo, and four discontinued early. Grade 3 fever was observed in one participant who received low-dose COH04S1 and placebo, and grade 2 anxiety or fatigue was seen in one participant who received medium-dose COH04S1. No severe adverse events were reported. Seroconversion was observed in all 34 participants for spike protein and 32 (94%) for nucleocapsid protein (p<0·0001 vs placebo for each comparison). Four times or more increase in SARS-CoV-2 neutralising antibodies within 56 days was measured in nine of 17 participants in the low-dose COH04S1 group, all eight participants in the medium-dose COH04S1 group, and eight of nine participants in the high-dose COH04S1 group (p=0·0035 combined dose levels vs placebo). Post-prime and post-boost four times increase in spike-specific or nucleocapsid-specific T cells secreting interferon-γ was measured in 48 (98%; 95% CI 89-100) of 49 participants who received at least one dose of COH04S1 and provided a sample for immunological analysis., Interpretation: COH04S1 was well tolerated and induced spike-specific and nucleocapsid-specific antibody and T-cell responses. Future evaluation of this COVID-19 vaccine candidate as a primary or boost vaccination is warranted., Funding: The Carol Moss Foundation and City of Hope Integrated Drug Development Venture programme., Competing Interests: DJD and FW are co-inventors on a patent application covering the design and construction of the synthetic modified vaccinia Ankara platform (PCT/US2021/016247). DJD, FW, and FC are co-inventors on a patent application covering the development of a COVID-19 vaccine (PCT/US2021/032821). FC, JAZ, PHF, RS, JD, BW, AMA, KFr, RAT, JKD, SD, AGP, DDN, PA, YC, HC, CLR, KT, YP, JM, AI, QZ, VK, DJ, KFa, TK, JN, MK, VHN, SOF, AW, FW, and DJD are employees of City of Hope National Medical Center (Duarte, CA, USA), which developed the vaccine and funded the trial. AS is a consultant for Gritstone, Flow Pharma, Merck, Epitogenesis, Gilead, and Avalia. La Jolla Institute for Immunology has filed for patent protection for various aspects of T-cell epitope and vaccine design work. All other authors declare no competing interests., (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

We report on the sequencing of 74,348 SARS-CoV-2 positive samples collected across the United States and show that the Delta variant, first detected in the United States in March 2021, made up the majority of SARS-CoV-2 infections by July 1, 2021 and accounted for >99.9% of the infections by September 2021. Not only did Delta displace variant Alpha, which was the dominant variant at the time, it also displaced the Gamma, Iota, and Mu variants. Through an analysis of quantification cycle (Cq) values, we demonstrate that Delta infections tend to have a 1.7× higher viral load compared to Alpha infections (a decrease of 0.8 Cq) on average. Our results are consistent with the hypothesis that the increased transmissibility of the Delta variant could be due to the ability of the Delta variant to establish a higher viral load earlier in the infection as compared to the Alpha variant., Competing Interests: A.B., S.L., E.T.C., S.W., D. Wyman, A.D.R., H.M., T.C., S.J., K.M.S.B., F.T., K.T., J.N., J.M.R., E.S., X.W., D. Wong, D.B., M.L., J.T.L., M.I., N.L.W., and W.L. are employees of Helix., (© 2022 The Author(s).)

Importance: The immune response in children with SARS-CoV-2 infection is not well understood., Objective: To compare seroconversion in nonhospitalized children and adults with mild SARS-CoV-2 infection and identify factors that are associated with seroconversion., Design, Setting, and Participants: This household cohort study of SARS-CoV-2 infection collected weekly nasopharyngeal and throat swabs and blood samples during the acute (median, 7 days for children and 12 days for adults [IQR, 4-13] days) and convalescent (median, 41 [IQR, 31-49] days) periods after polymerase chain reaction (PCR) diagnosis for analysis. Participants were recruited at The Royal Children's Hospital, Melbourne, Australia, from May 10 to October 28, 2020. Participants included patients who had a SARS-CoV-2-positive nasopharyngeal or oropharyngeal swab specimen using PCR analysis., Main Outcomes and Measures: SARS-CoV-2 immunoglobulin G (IgG) and cellular (T cell and B cell) responses in children and adults. Seroconversion was defined by seropositivity in all 3 (an in-house enzyme-linked immunosorbent assay [ELISA] and 2 commercial assays: a SARS-CoV-2 S1/S2 IgG assay and a SARS-CoV-2 antibody ELISA) serological assays., Results: Among 108 participants with SARS-CoV-2-positive PCR findings, 57 were children (35 boys [61.4%]; median age, 4 [IQR, 2-10] years) and 51 were adults (28 women [54.9%]; median age, 37 [IQR, 34-45] years). Using the 3 established serological assays, a lower proportion of children had seroconversion to IgG compared with adults (20 of 54 [37.0%] vs 32 of 42 [76.2%]; P < .001). This result was not associated with viral load, which was similar in children and adults (mean [SD] cycle threshold [Ct] value, 28.58 [6.83] vs 24.14 [8.47]; P = .09). In addition, age and sex were not associated with seroconversion within children (median age, 4 [IQR, 2-14] years for both seropositive and seronegative groups; seroconversion by sex, 10 of 21 girls [47.6%] vs 10 of 33 boys [30.3%]) or adults (median ages, 37 years for seropositive and 40 years for seronegative adults [IQR, 34-39 years]; seroconversion by sex, 18 of 24 women [75.0%] vs 14 of 18 men [77.8%]) (P > .05 for all comparisons between seronegative and seropositive groups). Symptomatic adults had 3-fold higher SARS-CoV-2 IgG levels than asymptomatic adults (median, 227.5 [IQR, 133.7-521.6] vs 75.3 [IQR, 36.9-113.6] IU/mL), whereas no differences were observed in children regardless of symptoms. Moreover, differences in cellular immune responses were observed in adults compared with children with seroconversion., Conclusions and Relevance: The findings of this cohort study suggest that among patients with mild COVID-19, children may be less likely to have seroconversion than adults despite similar viral loads. This finding has implications for future protection after SARS-CoV-2 infection in children and for interpretation of serosurveys that involve children. Further research to understand why seroconversion and development of symptoms are potentially less likely in children after SARS-CoV-2 infection and to compare vaccine responses may be of clinical and scientific importance.

Mutations in emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages can interfere with laboratory methods used to generate viral genome sequences for public health surveillance. We identified 20 mutations that are widespread in variant of concern lineages and affect widely used sequencing protocols by the ARTIC network and Freed et al. Three of these mutations disrupted sequencing of P.1 lineage specimens during a recent outbreak in British Columbia, Canada. We provide laboratory validation of protocol modifications that restored sequencing performance. The study findings indicate that genomic sequencing protocols require immediate updating to address emerging mutations. This work also suggests that routine monitoring and protocol updates will be necessary as SARS-CoV-2 continues to evolve. The bioinformatic and laboratory approaches used here provide guidance for this kind of assay maintenance., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The COVID-19 pandemic has highlighted the need for generic reagents and flexible systems in diagnostic testing. Magnetic bead-based nucleic acid extraction protocols using 96-well plates on open liquid handlers are readily amenable to meet this need. Here, one such approach is rigorously optimized to minimize cross-well contamination while maintaining sensitivity., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Many public institutions and settings have taken action to limit exposure to and slow the spread of the novel coronavirus (COVID-19). We sought to characterize the impact of stay-at-home orders on our study of cerebral autoregulation and its association with developmental delays in infants with congenital heart disease compared with healthy controls., Design and Methods: We calculated the number of participants recruited (i.e., not enrolled in the study) and assessed (i.e., currently enrolled) before March 2020 (pre-COVID-19) and the number of participants that we could not recruit or assess between March and July 2020 (missed due to COVID-19), separately for congenital heart disease and healthy control infants, in reference to the impacts of COVID-19. We used negative binomial regressions to determine incidence rate ratios which compared participants recruited and assessed pre-COVID-19 and missed due to COVID-19., Results: Recruitment and assessments significantly decreased following the pandemic, i.e., participants were more likely to be recruited or be assessed pre-COVID-19 compared to during the pandemic. Study participants were 3.3 times as likely to have assessments performed pre-COVID-19 compared to during the COVID-19 pandemic (p < 0.001)., Clinical Implications: Clinical research teams may consider making protocol modifications such as virtual visits or video recordings explaining the study, for example, to adjust to the restrictions caused by COVID-19., Conclusion: The COVID-19 pandemic drastically reduced recruitment and assessments completed in our study. Study teams will need to continue to modify procedures for recruitment and assessments that align with COVID-19 regulations to facilitate research progress during the pandemic., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Children have reduced severity of COVID-19 compared to adults and typically have mild or asymptomatic disease. The immunological mechanisms underlying these age-related differences in clinical outcomes remain unexplained. Here, we quantify 23 immune cell populations in 141 samples from children and adults with mild COVID-19 and their PCR-negative close household contacts at acute and convalescent time points. Children with COVID-19 displayed marked reductions in myeloid cells during infection, most prominent in children under the age of five. Recovery from infection in both children and adults was characterised by the generation of CD8 T CM and CD4 T CM up to 9 weeks post infection. SARS-CoV-2-exposed close contacts also had immunological changes over time despite no evidence of confirmed SARS-CoV-2 infection on PCR testing. This included an increase in low-density neutrophils during convalescence in both exposed children and adults, as well as increases in CD8 T CM and CD4 T CM in exposed adults. In comparison to children with other common respiratory viral infections, those with COVID-19 had a greater change in innate and T cell-mediated immune responses over time. These findings provide new mechanistic insights into the immune response during and after recovery from COVID-19 in both children and adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Neeland, Bannister, Clifford, Nguyen, Dohle, Overmars, Toh, Anderson, Donato, Sarkar, Do, McCafferty, Licciardi, Ignjatovic, Monagle, Bines, Mulholland, Curtis, McNab, Steer, Burgner, Saffery, Tosif and Crawford.)

Background: Emergency medicine (EM) physicians have been on the front line of the COVID-19 pandemic. This study aims to determine the impact of COVID-19 pandemic and other related factors such as resource availability and institutional support on well-being, burnout and job-satisfaction of EM physicians in the United States., Methods: A cross-sectional survey study of EM physicians was conducted through the Emergency Medicine Practice Research Network of the ACEP. The survey focused on resource adequacy, institutional support, well-being, and burnout. A total of 890 EM physicians were invited to participate. Both descriptive and risk adjusted, and multivariate regressions were performed with a statistical significance defined as p < 0.05., Results: EM physicians' response rate was 18.7% (166) from 39 states. Burnout was reported by 74.7% (124) since the start of the pandemic. Factors contributing included work-related emotional strain and anxiety, isolation from family and friends, and increased workload. Those reporting inadequate resources felt ignored by their institutions (p < 0.0001). Physicians who felt there was inadequate institutional support, were also dissatisfied with patient care resources (p = 0.001). Physicians expressing job dissatisfaction were more likely to report feelings of burnout (p = 0.001)., Conclusion: EM physicians face greater burnout in the COVID-19 pandemic. This may be compounded by resource scarcity, psychological stress, isolation, and job dissatisfaction. Many of the survey respondents reported inadequate mental health services and resources. The findings of this study may help identify solutions to mitigate these issues., Competing Interests: Declaration of Competing Interest Authors disclose no competing interest., (Copyright © 2021. Published by Elsevier Inc.)

Venous thromboembolic complications have emerged as serious sequelae in COVID-19 infections. This article summarizes the most current information regarding pathophysiology, risk factors and hematologic markers, incidence and timing of events, atypical venous thromboembolic complications, prophylaxis recommendations, and therapeutic recommendations. Data will likely to continue to rapidly evolve as more knowledge is gained regarding venous events in COVID-19 patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Information on bronchoalveolar lavage (BAL) in patients with COVID-19 is limited, and clinical correlation has not been reported. This study investigated the key features of BAL fluids from COVID-19 patients and assessed their clinical significance. A total of 320 BAL samples from 83 COVID-19 patients and 70 non-COVID-19 patients (27 patients with other respiratory viral infections) were evaluated, including cell count/differential, morphology, flow cytometric immunophenotyping, and immunohistochemistry. The findings were correlated with clinical outcomes. Compared to non-COVID-19 patients, BAL from COVID-19 patients was characterized by significant lymphocytosis (p < 0.001), in contrast to peripheral blood lymphopenia commonly observed in COVID-19 patients and the presence of atypical lymphocytes with plasmacytoid/plasmablastic features (p < 0.001). Flow cytometry and immunohistochemistry demonstrated that BAL lymphocytes, including plasmacytoid and plasmablastic cells, were composed predominantly of T cells with a mixture of CD4+ and CD8+ cells. Both populations had increased expression of T-cell activation markers, suggesting important roles of helper and cytotoxic T-cells in the immune response to SARS-CoV-2 infection in the lung. More importantly, BAL lymphocytosis was significantly associated with longer hospital stay (p < 0.05) and longer requirement for mechanical ventilation (p < 0.05), whereas the median atypical (activated) lymphocyte count was associated with shorter hospital stay (p < 0.05), shorter time on mechanical ventilation (p < 0.05) and improved survival. Our results indicate that BAL cellular analysis and morphologic findings provide additional important information for diagnostic and prognostic work-up, and potential new therapeutic strategies for patients with severe COVID-19., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Otolaryngologists in Texas have been greatly affected by the coronavirus disease 2019 (COVID-19) pandemic. Executive orders and professional recommendations have changed the way otolaryngologists practice. The objective of the study was to determine the effect of COVID-19 on otolaryngologists in the state of Texas., Methods: We surveyed the Texas Association of Otolaryngology to evaluate burnout, research output, and ability to respond to the pandemic. We also looked at the effect of Texas governmental executive orders GA-09 and GA-15 on work hours and patient load., Results: Our survey showed no significant difference in personnel contracting COVID-19 with perception of adequate personal protective equipment ( P = 0.203), population density ( P = 0.445), or type of practice ( P = 0.763). The phenomenon of "pandemic burnout" was prevalent, with prolonged uncertainty the primary contributing factor for burnout caused by the pandemic., Conclusions: The response to COVID-19 and the course of the pandemic are continuing to evolve and may play a significant role in how otolaryngologists practice and on their well-being during the pandemic.

The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality., Competing Interests: Declaration of interests N.L.W., A.B., E.T.C., K.M.S.B., S.W., C.R.-G., E. Sandoval, T.C., X.W., J.N., J.M.R., G.L., D.W., D.B., M.L., M.I., S.J., J.T.L., and W.L. are employees of Helix. K. Gietzen, B.S., J.A., K.H., J.L., E.d.F., and P.G.F. are employees of Illumina. J.N., C.R.-G., and M.L. own stock in ILMN. K.G.A. has received consulting fees for advising on SARS-CoV-2, variants, and the COVID-19 pandemic., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression., Methods: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants., Results: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections., Conclusions: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

The duration of the humoral immune response in children infected with severe acute respiratory syndrome coronavirus 2 is unknown. We detected specific IgG 6 months after infection in children who were asymptomatic or had mild symptoms of coronavirus disease. These findings will inform vaccination strategies and other prevention measures.