Global variation in prior exposure shapes antibody neutralization profiles of SARS-CoV-2 variants up to BA.2.86 (preprint)

The highly mutated SARS-CoV-2 variant, BA.2.86, and its descendants are now the most frequently sequenced variants of SARS-CoV-2. We analyze antibody neutralization data from eight laboratories from the UK, USA, Denmark, and China, including two datasets assessing the effect of XBB.1.5 vaccines, to determine the effect of infection and vaccination history on neutralization of variants up to and including BA.2.86, and produce antibody landscapes to describe these neutralization profiles. We find evidence for lower levels of immune imprinting on pre-Omicron variants in sera collected from Denmark and China, which may be explained by lower levels of circulation of the ancestral variant in these countries, and the use of an inactivated virus vaccine in China.

SARS-CoV-2 Omicron lineage XBB spike structures, conformations, antigenicity, and receptor recognition (preprint)

A recombinant lineage of the SARS-CoV-2 Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryo-EM structures of XBB.1.5, XBB.1.16 and EG.5 spike (S) ectodomains to reveal enhanced occupancy of the receptor inaccessible closed state. Interprotomer receptor binding domain (RBD) interactions previously observed in BA.1 and BA.2 were retained to reinforce the 3-RBD-down state. Improved stability of XBB.1.5 and XBB.1.16 RBD compensated for loss of stability caused by early Omicron mutations, while the F456L substitution reduced EG.5 RBD stability. Long-range impacts of S1 subunit mutations affected conformation and epitope presentation in the S2 subunit. Taken together, our results feature a theme of iterative optimization of S protein stability as Omicron continues to evolve, while maintaining high affinity receptor binding and bolstering immune evasion.

Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates (preprint)

Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs.

Evolutionary arms race between SARS-CoV-2 and interferon signaling via dynamic interaction with autophagy. (preprint)

SARS-CoV-2 emerged, and is evolving to efficiently infect humans worldwide. SARS-CoV-2 evades early innate recognition, interferon signaling activated only in bystander cells. This balance of innate activation and viral evasion has important consequences, but the pathways involved are incompletely understood. Here we find that autophagy genes regulate innate immune signaling, impacting the basal set point of interferons, and thus permissivity to infection. Mechanistically, autophagy genes negatively regulate MAVS, and this low basal level of MAVS is efficiently antagonized by SARS-CoV-2 ORF9b, blocking interferon activation in infected cells. However, upon loss of autophagy increased MAVS overcomes ORF9b-mediated antagonism suppressing infection. This has led to the evolution of SARS-CoV-2 variants to express higher levels of ORF9b, allowing SARS-CoV-2 to replicate under conditions of increased MAVS signaling. Altogether, we find a critical role of autophagy in the regulation of innate immunity and uncover an evolutionary trajectory of SARS-CoV-2 ORF9b to overcome host defenses.

Liver abnormalities following SARS-CoV-2 infection in children under 10 years of age (preprint)

ObjectiveBeginning in October 2021 in the US and elsewhere, cases of severe pediatric hepatitis of unknown etiology were identified in young children. While the adenovirus and adenovirus-associated virus have emerged as leading etiologic suspects, we attempted to investigate a potential role for SARS-CoV-2 in the development of subsequent liver abnormalities. DesignWe conducted a study utilizing retrospective cohorts of de-identified, aggregated data from the electronic health records of over 100 million patients contributed by US health care organizations. ResultsCompared to propensity-score-matched children with other respiratory infections, children aged 1-10 years with COVID-19 had a higher risk of elevated transaminases (Hazard ratio (HR) (95% Confidence interval (CI)) 2.16 (1.74-2.69)) or total bilirubin (HR (CI) 3.02 (1.91-4.78)), or new diagnoses of liver diseases (HR (CI) 1.67 (1.21-2.30)) from one to six months after infection. Patients with pre-existing liver abnormalities, liver abnormalities surrounding acute infection, younger age (1-4 years), or illness requiring hospitalization all had similarly elevated risk. Children who developed liver abnormalities following COVID-19 had more pre-existing conditions than those who developed abnormalities following other infections. ConclusionThese results indicate that SARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. While rare ([~]1 in 1,000), SARS-CoV-2 is a risk for subsequent abnormalities in liver function or the diagnosis of diseases of the liver. What is already known on this topicClusters of severe hepatitis in children in 2022 coincident with the increase in COVID-19 infections in children raised the question of the contribution of SARS-CoV-2 to the hepatitis outbreak, though it was soon determined that SARS-CoV-2 was not the primary etiologic agent. What this study addsSARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. How this study might affect research, practice or policyDespite the mild initial disease in children, there may be longer term consequences of COVID-19, such as liver abnormalities, that warrants further investigation.

Single cell susceptibility to SARS-CoV-2 infection is driven by variable cell states (preprint)

The ability of a virus to infect a cell type is at least in part determined by the presence of host factors required for the viral life cycle. However, even within cell types that express known factors needed for infection, not every cell is equally susceptible, suggesting that our knowledge of the full spectrum of factors that promote infection is incomplete. Profiling the most susceptible subsets of cells within a population may reveal additional factors that promote infection. However, because viral infection dramatically alters the state of the cell, new approaches are needed to reveal the state of these cells prior to infection with virus. Here, we used single-cell clone tracing to retrospectively identify and characterize lung epithelial cells that are highly susceptible to infection with SARS-CoV-2. The transcriptional state of these highly susceptible cells includes markers of retinoic acid signaling and epithelial differentiation. Loss of candidate factors identified by our approach revealed that many of these factors play roles in viral entry. Moreover, a subset of these factors exert control over the infectable cell state itself, regulating the expression of key factors associated with viral infection and entry. Analysis of patient samples revealed the heterogeneous expression of these factors across both cells and patients in vivo. Further, the expression of these factors is upregulated in particular inflammatory pathologies. Altogether, our results show that the variable expression of intrinsic cell states is a major determinant of whether a cell can be infected by SARS-CoV-2.

Prevalence of New-Onset Tinnitus after COVID-19 Vaccination with Comparison to Other Vaccinations.

OBJECTIVE: To investigate how often patients are diagnosed with new-onset tinnitus within 21 days after COVID-19 vaccination in comparison to after three other common vaccinations: influenza, Tdap (tetanus, diphtheria, and acellular pertussis), and polysaccharide pneumococcus. METHODS: The TriNetX Analytics Network, a federated health research network that aggregates the de-identified electronic health record (EHR) data of over 78 million patients, was queried for patients receiving each vaccination. Instances of new-onset tinnitus within 21 days of vaccination were recorded and reported. RESULTS: Out of 2,575,235 patients receiving a first dose of the mRNA COVID-19 vaccine without any prior tinnitus diagnosis, 0.038% (95% CI: 0.036%-0.041%) of patients had a new diagnosis of tinnitus within 21 days. There was a higher risk of a new tinnitus diagnosis after the influenza vaccine (RR: 1.95, 95% CI: 1.72-2.21), Tdap vaccine (RR: 2.36, 95% CI: 1.93-2.89), and pneumococcal vaccine (RR: 1.97, 95% CI: 1.48-2.64) than after the first dose of the COVID-19 vaccine. There was a lower risk of a new tinnitus diagnosis after the second dose of COVID-19 than after the first dose (RR: 0.80, 95% CI: 0.71-0.91). CONCLUSION: The rate of newly diagnosed tinnitus acutely after the first dose of the COVID-19 vaccine is very low. There was a higher risk of newly diagnosed tinnitus after influenza, Tdap, and pneumococcal vaccinations than after the COVID-19 vaccine. The present findings can help to address COVID-19 vaccine hesitancy during the ongoing pandemic. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 2022.

Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B-cell lymphoma.

Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response [CR]; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval [CI]: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Variants on Inpatient Clinical Outcome.

BACKGROUND: Prior observation has shown differences in COVID-19 hospitalization risk between SARS-CoV-2 variants, but limited information describes hospitalization outcomes. METHODS: Inpatients with COVID-19 at 5 hospitals in the eastern United States were included if they had hypoxia, tachypnea, tachycardia, or fever, and SARS-CoV-2 variant data, determined from whole-genome sequencing or local surveillance inference. Analyses were stratified by history of SARS-CoV-2 vaccination or infection. The average effect of SARS-CoV-2 variant on 28-day risk of severe disease, defined by advanced respiratory support needs, or death was evaluated using models weighted on propensity scores derived from baseline clinical features. RESULTS: Severe disease or death within 28 days occurred for 977 (29%) of 3369 unvaccinated patients and 269 (22%) of 1230 patients with history of vaccination or prior SARS-CoV-2 infection. Among unvaccinated patients, the relative risk of severe disease or death for Delta variant compared with ancestral lineages was 1.30 (95% confidence interval [CI]: 1.11-1.49). Compared with Delta, the risk for Omicron patients was .72 (95% CI: .59-.88) and compared with ancestral lineages was .94 (.78-1.1). Among Omicron and Delta infections, patients with history of vaccination or prior SARS-CoV-2 infection had half the risk of severe disease or death (adjusted hazard ratio: .40; 95% CI: .30-.54), but no significant outcome difference by variant. CONCLUSIONS: Although risk of severe disease or death for unvaccinated inpatients with Omicron was lower than with Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients, with no difference between Delta and Omicron infections.

The Rise of SARS-CoV-2 (COVID-19) Omicron Subvariant Pathogenicity.

During the COVID-19 pandemic, variants of the Betacoronavirus SARS-CoV-2, the etiologic agent of COVID-19 disease, progressively decreased in pathogenicity up to the Omicron strain. However, the case fatality rate has increased from Omicron through each major Omicron subvariant (BA.2/BA.4, BA.5, XBB.1.5) in the United States of America. World data also mirror this trend. We show that the rise of Omicron pathogenicity is exponential, and we have modeled the case fatality rate of the next major subvariant as 0.0413, 2.5 times that of the Alpha strain and 60% of the original Wuhan strain which caused the greatest morbidity and mortality during the pandemic. Small-molecule therapeutics have been developed, and some of these, such as chlorpheniramine maleate, may be useful in the event of an Omicron subvariant of higher risk.

Factors affecting the implementation of employee whole health in the veterans health administration: a qualitative evaluation.

BACKGROUND: There is increasing recognition of the need to focus on the health and well-being of healthcare employees given high rates of burnout and turnover. Employee wellness programs are effective at addressing these issues; however, participation in these programs is often a challenge and requires large scale organizational transformation. The Veterans Health Administration (VA) has begun to roll out their own employee wellness program-Employee Whole Health (EWH)-focused on the holistic needs of all employees. This evaluation's goal was to use the Lean Enterprise Transformation (LET) model for organizational transformation to identify key factors-facilitators and barriers-affecting the implementation of VA EWH. METHODS: This cross-sectional qualitative evaluation based on the action research model reflects on the organizational implementation of EWH. Semi-structured 60-minute phone interviews were conducted in February-April 2021 with 27 key informants (e.g., EWH coordinator, wellness/occupational health staff) knowledgeable about EWH implementation across 10 VA medical centers. Operational partner provided a list of potential participants, eligible because of their involvement in EWH implementation at their site. The interview guide was informed by the LET model. Interviews were recorded and professionally transcribed. Constant comparative review with a combination of a priori coding based on the model and emergent thematic analysis was used to identify themes from transcripts. Matrix analysis and rapid turnaround qualitative methods were used to identify cross-site factors to EWH implementation. RESULTS: Eight common factors in the conceptual model were found to facilitate and/or hinder EWH implementation efforts: [1] EWH initiatives, [2] multilevel leadership support, [3] alignment, [4] integration, [5] employee engagement, [6] communication, [7] staffing, and [8] culture. An emergent factor was [9] the impact of the COVID-19 pandemic on EWH implementation. CONCLUSIONS: As VA expands its EWH cultural transformation nationwide, evaluation findings can (a) enable existing programs to address known implementation barriers, and (b) inform new sites to capitalize on known facilitators, anticipate and address barriers, and leverage evaluation recommendations through concerted implementation at the organization, process, and employee levels to jump-start their EWH program implementation.

"It's Not a Sprint, It's a Marathon": Stages of Managing a Nursing Home Throughout the Pandemic.

OBJECTIVES: To qualitatively examine the impact of COVID-19 on nursing homes over the course of the pandemic from the perspective of nursing home administrators. DESIGN: In-depth, semi-structured interviews with nursing home administrators, repeated 3 months apart for a total of 4 each from July 2020 through December 2021. SETTINGS AND PARTICIPANTS: Administrators from a total of 40 nursing homes from 8 health care markets across the United States. METHODS: Interviews were conducted virtually or via phone. The research team identified overarching themes using applied thematic analysis, and iteratively coded transcribed interviews. RESULTS: Nursing home administrators across the United States reported challenges of managing nursing homes during a pandemic. We found their experiences could generally be categorized into 4 stages, not necessarily coinciding with surge levels of the virus. The initial stage was characterized by fear and confusion. The second stage, by a "new normal," a term administrators used to report feeling better prepared for an outbreak and how residents, staff, and families began to adjust to life with COVID. Administrators started using the phrase "a light at the end of the tunnel" to describe the third stage, characterized by the hope associated with the availability of vaccinations. The fourth stage was marked by "caregiver fatigue" as nursing homes experienced numerous breakthrough cases. Some challenges, like staffing issues and uncertainty about the future, were reported throughout the pandemic, as was a continued mission to keep residents safe. CONCLUSIONS AND IMPLICATIONS: As the ability of nursing homes to provide safe, effective care faces unprecedented and continued challenges, the insights reported here from longitudinal perspectives of nursing home administrators may help policy makers develop solutions to encourage high-quality care. Knowing how the needs for resources and support vary across the progression of these stages has the potential to be helpful in addressing these challenges.

Prevalence and functional profile of SARS-CoV-2 T cells in asymptomatic Kenyan adults.

BackgroundSARS-CoV-2 infection in Africa has been characterized by a less severe disease profile than what has been observed elsewhere, but the profile of SARS-CoV-2-specific adaptive immunity in these mainly asymptomatic patients has not, to our knowledge, been analyzed.MethodsWe collected blood samples from residents of rural Kenya (n = 80), who had not experienced any respiratory symptoms or had contact with individuals with COVID-19 and had not received COVID-19 vaccines. We analyzed spike-specific antibodies and T cells specific for SARS-CoV-2 structural (membrane, nucleocapsid, and spike) and accessory (ORF3a, ORF7, ORF8) proteins. Pre-pandemic blood samples collected in Nairobi (n = 13) and blood samples from mild-to-moderately symptomatic COVID-19 convalescent patients (n = 36) living in the urban environment of Singapore were also studied.ResultsAmong asymptomatic Africans, we detected anti-spike antibodies in 41.0% of the samples and T cell responses against 2 or more SARS-CoV-2 proteins in 82.5% of samples examined. Such a pattern was absent in the pre-pandemic samples. Furthermore, distinct from cellular immunity in European and Asian COVID-19 convalescents, we observed strong T cell immunogenicity against viral accessory proteins (ORF3a, ORF8) but not structural proteins, as well as a higher IL-10/IFN-γ cytokine ratio profile.ConclusionsThe high incidence of T cell responses against different SARS-CoV-2 proteins in seronegative participants suggests that serosurveys underestimate SARS-CoV-2 prevalence in settings where asymptomatic infections prevail. The functional and antigen-specific profile of SARS-CoV-2-specific T cells in African individuals suggests that environmental factors can play a role in the development of protective antiviral immunity.FundingUS Centers for Disease Control and Prevention, Division of Global Health Protection; the Singapore Ministry of Health's National Medical Research Council (COVID19RF3-0060, COVID19RF-001, COVID19RF-008, MOH-StaR17Nov-0001).

Building an inpatient addiction medicine consult service in Sudbury, Canada: preliminary data and lessons learned in the era of COVID-19.

OBJECTIVE: The goal of this study was to (1) Describe the patient population of a newly implemented addiction medicine consult service (AMCS); (2) Evaluate referrals to community-based addiction support services and acute health service use, over time; (3) Provide lessons learned. METHODS: A retrospective observational analysis was conducted at Health Sciences North in Sudbury, Ontario, Canada, with a newly implemented AMCS from November 2018 and July 2021. Data were collected using the hospital's electronic medical records. The outcomes measured included the number of emergency department visits, inpatient admissions, and re-visits over time. An interrupted time-series analysis was performed to measure the effect of AMCS implementation on acute health service use at Health Sciences North. RESULTS: A total of 833 unique patients were assessed through the AMCS. A total of 1,294 referrals were made to community-based addiction support services, with the highest proportion of referrals between August and October 2020. The post-intervention trend for ED visits, ED re-visits, ED length of stay, inpatient visits, re-visits, and inpatient length of stay did not significantly differ from the pre-intervention period. CONCLUSION: Implementation of an AMCS provides a focused service for patients using with substance use disorders. The service resulted in a high referral rate to community-based addiction support services and limited changes in health service usage.

Conserved longitudinal alterations of anti-S-protein IgG subclasses in disease progression in initial ancestral Wuhan and vaccine breakthrough Delta infections.

Introduction: COVID-19 has a wide disease spectrum ranging from asymptomatic to severe. While humoral immune responses are critical in preventing infection, the immune mechanisms leading to severe disease, and the identification of biomarkers of disease progression and/or resolution of the infection remains to be determined. Methods: Plasma samples were obtained from infections during the initial wave of ancestral wildtype SARS-CoV-2 and from vaccine breakthrough infections during the wave of Delta variant, up to six months post infection. The spike-specific antibody profiles were compared across different severity groups and timepoints. Results: We found an association between spike-specific IgM, IgA and IgG and disease severity in unvaccinated infected individuals. In addition to strong IgG1 and IgG3 response, patients with severe disease develop a robust IgG2 and IgG4 response. A comparison of the ratio of IgG1 and IgG3 to IgG2 and IgG4 showed that disease progression is associated with a smaller ratio in both the initial wave of WT and the vaccine breakthrough Delta infections. Time-course analysis revealed that smaller (IgG1 and IgG3)/(IgG2 and IgG4) ratio is associated with disease progression, while the reverse associates with clinical recovery. Discussion: While each IgG subclass is associated with disease severity, the balance within the four IgG subclasses may affect disease outcome. Acute disease progression or infection resolution is associated with a specific immunological phenotype that is conserved in both the initial wave of WT and the vaccine breakthrough Delta infections.

Prolonged inflammation in patients hospitalized for coronavirus disease 2019 (COVID-19) resolves 2 years after infection.

Long-term complications from coronavirus disease 2019 (COVID-19) are concerning, as survivors can develop subclinical multiorgan dysfunction. It is unknown if such complications are due to prolonged inflammation, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination may reduce sequela. We conducted a prospective longitudinal study on hospitalized patients over 24 months. Clinical symptoms were collected by self-reporting during follow-up, along with blood samples for quantification of inflammatory markers and immune cell frequencies. All patients were given one dose of mRNA vaccine at 12-16 months. Their immune profiles at 12 and 24 months were compared. Approximately 37% and 39% of our patients reported post-COVID-19 symptoms at 12 and 24 months, respectively. The proportion of symptomatic patients with more than one symptom decreased from 69% at 12 months to 56% at 24 months. Longitudinal cytokine profiling revealed a cluster of individuals with persistently high inflammatory cytokine levels 12 months after infection. Patients with prolonged inflammation showed elevated terminally differentiated memory T cells in their blood; 54% had symptoms at 12 months. The majority of inflammatory markers and dysregulated immune cells in vaccinated patients recovered to a healthy baseline at 24 months, even though symptoms persisted. Post-COVID-19 symptoms can linger for 2 years after the initial infection and are associated with prolonged inflammation. Prolonged inflammation in hospitalized patients resolves after 2 years. We define a set of analytes associated with persistent inflammation and presence of symptoms, which could be useful biomarkers for identifying and monitoring high-risk survivors.

Nursing home infection control strategies during the COVID-19 pandemic.

BACKGROUND: The American Rescue Plan Act of 2021 awarded $500 million toward scaling "strike teams" to mitigate the impact of Coronavirus Disease 2019 (COVID-19) within nursing homes. The Massachusetts Nursing Facility Accountability and Support Package (NFASP) piloted one such model during the first weeks of the pandemic, providing nursing homes financial, administrative, and educational support. For a subset of nursing homes deemed high-risk, the state offered supplemental, in-person technical infection control support. METHODS: Using state death certificate data and federal nursing home occupancy data, we examined longitudinal all-cause mortality per 100,000 residents and changes in occupancy across NFASP participants and subgroups that varied in their receipt of the supplemental intervention. RESULTS: Nursing home mortality peaked in the weeks preceding the NFASP, with a steeper increase among those receiving the supplemental intervention. There were contemporaneous declines in weekly occupancy. The potential for temporal confounding and differential selection across NFASP subgroups precluded estimation of causal effects of the intervention on mortality. CONCLUSIONS: We offer policy and design suggestions for future strike team iterations that could inform the allocation of state and federal funding. We recommend expanded data collection infrastructure and, ideally, randomized assignment to intervention subgroups to support causal inference as strike team models are scaled under the direction of state and federal agencies.

Baricitinib Treatment of Coronavirus Disease 2019 Is Associated With a Reduction in Secondary Infections.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.