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Across four studies (N = 1544), we examined the relationship between individuals gender role mindsets, or beliefs about the malleability versus fixedness of traditional gender roles, and work-family conflict. We found that undergraduate women (but not men) business students holding a fixed, compared to growth, gender role mindset anticipated more work-family conflict. Next, we manipulated gender role mindset and demonstrated a causal link between womens growth mindsets (relative to fixed mindsets and control conditions) and reduced work-family conflict. We showed mechanistically that growth gender role mindsets unburden women from prescriptive gender roles, reducing work-family conflict. Finally, during COVID-19, we demonstrated a similar pattern among working women in high-achieving dual-career couples. We found an indirect effect of womens gender role mindset on job and relationship satisfaction, mediated through work-family conflict. Our preregistered studies suggest that holding the belief that gender roles can change mitigates womens work-family conflict.

In this study, we employed a pre-interview survey and conducted interviews with nursing home staff members and residents/family members to understand their perceptions of whether the COVID-19 restrictions fulfilled obligations to nursing home residents under various principles, including autonomy, beneficence, nonmaleficence, justice, and privacy. We conducted 20 semi-structured interviews with staff members from 14 facilities, and 20 with residents and/or family members from 13 facilities. We used a qualitative descriptive study design and thematic analysis methodology to analyze the interviews. Findings from the pre-interview survey indicated that, compared to nursing home staff, residents and their families perceived lower adherence to bioethics principles during the pandemic. Qualitative analysis themes included specific restrictions, challenges, facility notifications, consequences, communication, and relationships between staff and residents/family members. Our study exposes the struggle to balance infection control with respecting bioethical principles in nursing homes, suggesting avenues for improving processes and policies during public health emergencies.

The effects of the COVID-19 pandemic on comprehensive maternal deaths in Brazil have not been fully explored. Using publicly available data from the Brazilian Mortality Information (SIM) and Information System on Live Births (SINASC) databases, we used two complementary forecasting models to predict estimates of maternal mortality ratios using maternal deaths (MMR) and comprehensive maternal deaths (MMRc) in the years 2020 and 2021 based on data from 2008 to 2019. We calculated national and regional standardized mortality ratio estimates for maternal deaths (SMR) and comprehensive maternal deaths (SMRc) for 2020 and 2021. The observed MMRc in 2021 was more than double the predicted MMRc based on the Holt-Winters and autoregressive integrated moving average models (127.12 versus 60.89 and 59.12 per 100,000 live births, respectively). We found persisting sub-national variation in comprehensive maternal mortality: SMRc ranged from 1.74 (95% confidence interval [CI] 1.64, 1.86) in the Northeast to 2.70 (95% CI 2.45, 2.96) in the South in 2021. The observed national estimates for comprehensive maternal deaths in 2021 were the highest in Brazil in the past three decades. Increased resources for prenatal care, maternal health, and postpartum care may be needed to reverse the national trend in comprehensive maternal deaths.

We investigate the emergence, mutation profile, and dissemination of SARS-CoV-2 lineage B.1.214.2, first identified in Belgium in January 2021. This variant, featuring a 3-amino acid insertion in the spike protein similar to the Omicron variant, was speculated to enhance transmissibility or immune evasion. Initially detected in international travelers, it substantially transmitted in Central Africa, Belgium, Switzerland, and France, peaking in April 2021. Our travel-aware phylogeographic analysis, incorporating travel history, estimated the origin to the Republic of the Congo, with primary European entry through France and Belgium, and multiple smaller introductions during the epidemic. We correlate its spread with human travel patterns and air passenger data. Further, upon reviewing national reports of SARS-CoV-2 outbreaks in Belgian nursing homes, we found this strain caused moderately severe outcomes (8.7% case fatality ratio). A distinct nasopharyngeal immune response was observed in elderly patients, characterized by 80% unique signatures, higher B- and T-cell activation, increased type I IFN signaling, and reduced NK, Th17, and complement system activation, compared to similar outbreaks. This unique immune response may explain the variants epidemiological behavior and underscores the need for nasal vaccine strategies against emerging variants.

BackgroundCOVID-19 is associated with acute risk of major adverse cardiac events (MACE), including myocardial infarction, stroke, and mortality (all-cause). However, the duration and underlying determinants of heightened risk of cardiovascular disease and MACE post-COVID-19 are not known.MethodsData from the UK Biobank was used to identify COVID-19 cases (n=10 005) who were positive for polymerase chain reaction (PCR+)-based tests for SARS-CoV-2 infection (n=8062) or received hospital-based International Classification of Diseases version-10 (ICD-10) codes for COVID-19 (n=1943) between February 1, 2020 and December 31, 2020. Population controls (n=217 730) and propensity score-matched controls (n=38 860) were also drawn from the UK Biobank during the same period. Proportional hazard models were used to evaluate COVID-19 for association with long-term (>1000 days) risk of MACE and as a coronary artery disease risk equivalent. Additional analyses examined whether COVID-19 interacted with genetic determinants to affect the risk of MACE and its components.ResultsThe risk of MACE was elevated in COVID-19 cases at all levels of severity (HR, 2.09 [95% CI, 1.94-2.25]; P

Oral broad-spectrum antivirals are urgently needed for the treatment of many emerging and contemporary RNA viruses. We previously synthesized 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-RVn (ODBG-P-RVn, V2043), a phospholipid prodrug of GS-441524 (remdesivir nucleoside, RVn), and demonstrated its in vivo efficacy in a SARS-CoV-2 mouse model. Structure-activity relationship studies focusing on the prodrug scaffold identified two modifications, 3-fluoro-4-methoxy-benzyl (V2053) and 4-cyano-benzyl (V2067), that significantly enhanced the in vitro broad-spectrum antiviral activity against multiple RNA viruses when compared to V2043. Here, we demonstrate that V2043, V2053, and V2067 are all orally bioavailable, well-tolerated, and achieve high sustained plasma levels after single oral daily dosing. All three phospholipid prodrugs are significantly more active than RVn in vitro and significantly reduce SARS-CoV-2 lung titers in prophylaxis and treatment mouse models of SARS-CoV-2 B.1.351 infection. On a molar basis, V2043 and V2067 are substantially more active than obeldesivir/GS-5245 and molnupiravir in vivo. Together, these data support the continued development of phospholipid RVn prodrugs for the treatment of SARS-CoV-2 and other RNA viruses of clinical concern.

COVID presented an opportunity to revolutionize the traditional format of Medical Grand Rounds (MGR). In this Commentary, we explore the educational ramifications of shifting MGR virtually with a focus on COVID-related content and its long-term sustainability. This transformation offers an inclusive interdisciplinary approach to sustain learner interest and improve education.

BACKGROUND: While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID. METHODS: A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.). FINDINGS: Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events. INTERPRETATION: As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions. FUNDING: Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.

BACKGROUND: An association between driving pressure (∆P) and the outcomes of invasive mechanical ventilation (IMV) may exist. However, the effect of a sustained limitation of ∆P on mortality in patients with acute respiratory distress syndrome (ARDS), including patients with COVID-19 (COVID-19-related acute respiratory distress syndrome (C-ARDS)) undergoing IMV, has not been rigorously evaluated. The use of emulations of a target trial in intensive care unit research remains in its infancy. To inform future, large ARDS target trials, we explored using a target trial emulation approach to analyse data from a cohort of IMV adults with C-ARDS to determine whether maintaining daily ∆p24 hours of IMV were considered to be assigned to limited ∆P or LTVV. Lung mechanics were measured twice daily after ventilator setting adjustments were made. To evaluate the effect of each lung-protective ventilation (LPV) strategy on the 28-day mortality, we fit a stabilised inverse probability weighted marginal structural model that adjusted for baseline and time-varying confounders known to affect protection strategy use/adherence or survival. RESULTS: Among the 92 patients included, 27 (29.3%) followed limited ∆P ventilation, 23 (25.0%) the LTVV strategy and 42 (45.7%) received no LPV strategy. The adjusted estimated 28-day survival was 47.0% (95% CI 23%, 76%) in the limited ∆P group, 70.3% in the LTVV group (95% CI 37.6%, 100%) and 37.6% (95% CI 20.8%, 58.0%) in the no LPV strategy group. INTERPRETATION: Limiting ∆P may not provide additional survival benefits for patients with C-ARDS over LTVV. Our results help inform the development of future target trial emulations focused on evaluating LPV strategies, including reduced ∆P, in adults with ARDS.

INTRODUCTION: Expanding access to doula care is a key strategy for improving the perinatal experiences and health outcomes of birthing people of color in the U.S. This study investigates the future of maternal healthcare in the U.S. from the perspective of doulas and highlights emerging technology and other opportunities related to strengthening the doula workforce. METHODS: The study recruited community doulas from 12 unique U.S. states, ensuring at least half of the doulas predominantly served communities of color. Doulas (N = 26) participated in semi-structured, futures-oriented interviews that explored their experiences providing care during the COVID-19 pandemic and utilization of technology. A subset of doulas (n = 8) were engaged in interactive workshops where they envisioned alternative futures for doula care and childbirth. Interviews and workshops were analyzed using the Framework Method. RESULTS: The COVID-19 pandemic heightened technology use among doulas and increased client accessibility. Social media serves as a unique space for critical community building and client outreach. Doulas reported opportunities to strengthen and mobilize the future workforce: recognizing doula care as a reimbursable service by health insurers, utilizing doula collectives for community practice to decrease burnout, increasing emotional support for doulas, and instilling a chain of learning through mentorship. DISCUSSION: Futures thinking served as a valuable approach for doulas to illuminate the implications of present-day challenges and empowered doulas to design roadmaps toward better futures for doulas and maternal health. Doulas should be engaged as partners to hold a meaningful decision-making role when discussing policies, employment structures, emerging technology, and other aspects of doulas positioning within the healthcare system.

From single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST), one can extract high-dimensional gene expression patterns that can be described by intercellular communication networks or decoupled gene modules. These two descriptions of information flow are often assumed to occur independently. However, intercellular communication drives directed flows of information that are mediated by intracellular gene modules, in turn triggering outflows of other signals. Methodologies to describe such intercellular flows are lacking. We present FlowSig, a method that infers communication-driven intercellular flows from scRNA-seq or ST data using graphical causal modeling and conditional independence. We benchmark FlowSig using newly generated experimental cortical organoid data and synthetic data generated from mathematical modeling. We demonstrate FlowSig's utility by applying it to various studies, showing that FlowSig can capture stimulation-induced changes to paracrine signaling in pancreatic islets, demonstrate shifts in intercellular flows due to increasing COVID-19 severity and reconstruct morphogen-driven activator-inhibitor patterns in mouse embryogenesis.

BACKGROUND: This report summarizes the discussions and conclusions from the Correlates of Protection for Next Generation Influenza Vaccines: Lessons Learned from the COVID-19 Pandemic meeting, which took place in Seattle, USA, from March 1, 2023, to March 3, 2023. CONCLUSIONS: Discussions around influenza virus correlates of protection and their use continued from where the discussion had been left off in 2019. While there was not much progress in the influenza field itself, many lessons learned during the coronavirus disease 2019 (COVID-19) pandemic, especially the importance of mucosal immunity, were discussed and can directly be applied to influenza correlates of protection.

BackgroundBefore SARS-CoV-2 vaccination availability, medical center employees were at high risk of COVID-19. However, risk factors for SARS-CoV-2 infection in medical center employees, both healthcare and non-healthcare workers, are poorly understood.MethodsFrom September-December 2020, free IgG antibody testing was offered to all employees at a large urban medical center. Participants were asked to complete a questionnaire on work and non-work related risk factors for COVID-19 infection.ResultsSARS-CoV-2 seropositivity was found in 4.7%. Seropositivity was associated with close contact with COVID-19 cases with or without the use of adequate personal protective equipment (PPE), (OR 3.1 [95% CI 1.4-6.9] and OR 4.7 [95% CI 2.0-11.0] respectively), never wearing a mask outside of work (OR 10.1 [95% CI 1.9-57]), and Native Hawaiian/Pacific Islander race (OR 6.3 95% CI (1.6-25)].ConclusionsAmong workers in a large urban medical center, SARS-CoV-2 seropositivity was associated with work-related COVID-19 close contacts and low mask use outside of work, suggesting that non-workplace close contacts are also relevant routes of COVID-19 spread among healthcare workers.

Long COVID is a chronic and often disabling illness with long-term consequences. Although progress has been made in the clinical characterization of long COVID, no approved treatments exist and disconnects between patients and researchers threaten to hinder future progress. Incorporating patients as active collaborators in long COVID research can bridge the gap and accelerate progress toward treatments and cures.

OBJECTIVE: To investigate Covid-19 vaccination as a potential secondary public health benefit of case management for Medicaid beneficiaries with health and social needs. DATA SOURCES AND STUDY SETTING: The CommunityConnect case management program for Medicaid beneficiaries is run by Contra Costa Health, a county safety net health system in California. Program enrollment data were merged with comprehensive county vaccination records. STUDY DESIGN: Individuals with elevated risk of hospital and emergency department use were randomized each month to a case management intervention or usual care. Interdisciplinary case managers offered coaching, community referrals, healthcare connections, and other support based on enrollee interest and need. Using survival analysis with intent-to-treat assignment, we assessed rates of first-dose Covid-19 vaccination from December 2020 to September 2021. In exploratory sub-analyses we also examined effect heterogeneity by gender, race/ethnicity, age, and primary language. DATA COLLECTION AND EXTRACTION METHODS: Data were extracted from county and program records as of September 2021, totaling 12,866 interventions and 25,761 control enrollments. PRINCIPAL FINDINGS: Approximately 58% of enrollees were female and 41% were under age 35. Enrollees were 23% White, 12% Asian/Pacific Islander, 20% Black/African American, and 36% Hispanic/Latino, and 10% other/unknown. Approximately 35% of the intervention group engaged with their case manager. Approximately 56% of all intervention and control enrollees were vaccinated after 9 months of analysis time. Intervention enrollees had a higher vaccination rate compared to control enrollees (adjusted hazard ratio [aHR]: 1.06; 95% confidence interval [CI]: 1.02-1.10). In sub-analyses, the intervention was associated with stronger likelihood of vaccination among males and individuals under age 35. CONCLUSIONS: Case management infrastructure modestly improved Covid-19 vaccine uptake in a population of Medicaid beneficiaries that over-represents social groups with barriers to early Covid-19 vaccination. Amidst mixed evidence on vaccination-specific incentives, leveraging trusted case managers and existing case management programs may be a valuable prevention strategy.

This study investigated posttraumatic stress disorder (PTSD) prevalence among a sample of intimate partner violence (IPV) survivors (n  =  77) who filed for restraining orders in rural Louisiana during the COVID-19 pandemic. IPV survivors were individually interviewed to assess their self-reported levels of perceived stress, resilience, potential PTSD, COVID-19-related experiences, and sociodemographic characteristics. Data were analyzed to differentiate group membership between two groups; non-PTSD and probable PTSD. Results suggest the probable PTSD group had lower levels of resilience and higher levels of perceived stress compared to the non-PTSD group. Findings suggest the importance of providing services during disaster to reduce PTSD for IPV survivors.

The COVID-19 pandemic has uniquely impacted people living with HIV (PLWH) worldwide. The negative impacts on PLWH's mental health from fear of COVID-19 are labeled as "a double stress." The association between fear of COVID-19 and HIV (internalized) stigma has been found among PLWH. Studies that explore the relationships between fear of COVID-19 and physical health outcomes are few, especially among PLWH. In this study, we explored the relationship between fear of COVID-19 and physical health among PLWH and the mediated effects of HIV stigma, social support, and substance use. A cross-sectional online survey of PLWH (n = 201) from November 2021 to May 2022 was carried out in Shanghai, China. The data on socio-demographics, fear of COVID-19, physical health, HIV-related perceived stigma, social support, and substance use were gathered and analyzed by structure equation modeling (SEM). In SEM analysis, fear of COVID-19 showed a significant and indirect effect on physical health (β=-0.085) which was primarily mediated by HIV stigma. In SEM analysis, the final model had a good fit. Fear of COVID-19 showed a significant effect on HIV stigma (β = 0.223) with the majority being direct effects (β = 0.262) and a small indirect effect via substance use (β=-0.039). Furthermore, HIV stigma showed a significant effect on physical health (β=-0.382), the majority of which was direct (β=-0.340), and a small indirect effect via social support (β=-0.042). This is one of the first studies to explore how fear of contracting COVID-19 can affect PLWH's coping behaviors (e.g., using substances and obtaining social support) used to combat HIV stigma as well as to achieve better physical health in China.

IntroductionThe COVID-19 pandemic raised significant concerns about fitness to dive due to potential damage to the pulmonary and cardiovascular systems. Our group previously published guidelines (original and revised) for assessment of these divers. Here, we report a prospective, observational study to evaluate the utility of these guidelines.MethodsRecreational, commercial, and scientific divers with a history of COVID-19 were consented and enrolled. Subjects were evaluated according to the aforementioned guidelines and followed for any additional complications or diving related injuries.ResultsOne-hundred and twelve divers (56 male, 56 female, ages 19-68) were enrolled: 59 commercial, 30 scientific, 20 recreational, two unknown (not documented), one military. Cases were categorised according to two previous guidelines ('original' n = 23 and 'revised' n = 89): category 0 (n = 6), category 0.5 (n = 64), category 1 (n = 38), category 2 (n = 2), category 3 (n = 1), uncategorisable due to persistent symptoms (n = 1). One hundred divers (89.3%) were cleared to return to diving, four (3.6%) were unable to return to diving, four (3.6%) were able to return to diving with restrictions, and four (3.6%) did not complete testing. Regarding diving related complications, one diver had an episode of immersion pulmonary oedema one year later and one diver presented with decompression sickness and tested positive for COVID-19.ConclusionsMost divers who presented for evaluation were able to return to diving safely. Abnormalities were detected in a small percentage of divers that precluded them from being cleared to dive. Guidelines were easily implemented by a variety of clinicians.

Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1-4. Despite the clinical evidence1,5-7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8-10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID.

BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo. METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels

Many patients infected with the SARS-CoV-2 virus (COVID-19) continue to experience symptoms for weeks to years as sequelae of the initial infection, referred to as Long COVID. Although many studies have described the incidence and symptomatology of Long COVID, there are little data reporting the potential burden of Long COVID on surgical departments. A previously constructed database of survey respondents who tested positive for COVID-19 was queried, identifying patients reporting experiencing symptoms consistent with Long COVID. Additional chart review determined whether respondents had a surgical or non-routine invasive procedure on or following the date of survey completion. Outcomes from surgeries on patients reporting Long COVID symptoms were compared to those from asymptomatic patients. A total of 17.4% of respondents had surgery or a non-routine invasive procedure in the study period. A total of 48.8% of these patients reported experiencing symptoms consistent with Long COVID. No statistically significant differences in surgical outcomes were found between groups. The results of this analysis demonstrate that Long COVID does not appear to have created a significant burden of surgical disease processes on the healthcare system despite the wide range of chronic symptoms and increased healthcare utilization by this population. This knowledge can help guide surgical operational resource allocation as a result of the pandemic and its longer-term sequelae.

BACKGROUND: Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. METHODS: We quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022, based on calendar-time proportional hazards models and matching approaches. RESULTS: We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR 1.66; 95% CI 1.07, 2.59; p = 0.02) after the first dose. CONCLUSIONS: Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

Phylogenetic and discrete-trait evolutionary inference depend heavily on an appropriate characterization of the underlying character substitution process. In this paper, we present random-effects substitution models that extend common continuous-time Markov chain models into a richer class of processes capable of capturing a wider variety of substitution dynamics. As these random-effects substitution models often require many more parameters than their usual counterparts, inference can be both statistically and computationally challenging. Thus, we also propose an efficient approach to compute an approximation to the gradient of the data likelihood with respect to all unknown substitution model parameters. We demonstrate that this approximate gradient enables scaling of sampling-based inference, namely Bayesian inference via Hamiltonian Monte Carlo, under random-effects substitution models across large trees and state-spaces. Applied to a dataset of 583 SARS-CoV-2 sequences, an HKY model with random-effects shows strong signals of nonreversibility in the substitution process, and posterior predictive model checks clearly show that it is a more adequate model than a reversible model. When analyzing the pattern of phylogeographic spread of 1441 influenza A virus (H3N2) sequences between 14 regions, a random-effects phylogeographic substitution model infers that air travel volume adequately predicts almost all dispersal rates. A random-effects state-dependent substitution model reveals no evidence for an effect of arboreality on the swimming mode in the tree frog subfamily Hylinae. Simulations reveal that random-effects substitution models can accommodate both negligible and radical departures from the underlying base substitution model. We show that our gradient-based inference approach is over an order of magnitude more time efficient than conventional approaches.

Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.

BACKGROUND: Co-administration of inactivated influenza vaccine (IIV) and SARS-CoV-2 vaccine may impact SARS-CoV-2 vaccine induced humoral immune responses. We aimed to compare IIV and SARS-CoV-2 vaccine induced cellular and humoral immune responses in those receiving concomitant vaccination to those receiving these vaccines separately. METHODS: We conducted a cohort study between 29th September 2021 and 5th August 2022 in healthcare workers who worked at the local NHS trust and in the surrounding area that were vaccinated with a mRNA SARS-CoV-2 booster and cell-based IIV. We measured haemagglutination inhibition assay (HAI) titres, SARS-CoV-2 anti-spike antibody and SARS-CoV-2 ELISpot count pre-vaccination, 1-month and 6-months post-vaccination and evaluated differences by vaccine strategy. FINDINGS: We recruited 420 participants, 234/420 (56%) were vaccinated concomitantly and 186/420 (44%) separately. The 1-month post-vaccination mean fold rise (MFR) in SARS-CoV-2 anti-spike antibodies was lower in those vaccinated concomitantly compared to separately (MFR [95% confidence interval (CI)] 9.7 [8.3, 11.4] vs 12.8 [10.3, 15.9], p = 0.04). After adjustment for age and sex, the adjusted geometric mean ratio (aGMR) remained lower for those vaccinated concomitantly compared to separately (aGMR [95% CI] 0.80 [0.70, 0.92], p = 0.001). At 6-months post-vaccination, we found no statistically significant difference in SARS-CoV-2 anti-spike antibody titres (aGMR [95% CI] 1.09 [0.87, 1.35], p = 0.45). We found no statistically significant correlation between vaccine strategy with SARS-CoV-2 ELISpot count and influenza HAI titres at 1-month and 6-months post-vaccination. INTERPRETATION: Our study found that concomitant vaccination with SARS-CoV-2 and IIV has no statistically significant impacts on long-term immunogenicity. Further research is required to understand the underlying mechanisms and assess the clinical significance of reduced anti-spike antibodies in those vaccinated concomitantly. FUNDING: Research and Innovation (UKRI) through the COVID-19 National Core Studies Immunity (NCSi) programme (MC_PC_20060).

BackgroundPublic health crises, such as the COVID-19 pandemic, have prompted a need for health agencies to improve their disease preparedness strategies, informing their communities of new information and promoting preventive behaviors to help curb the spread of the virus.MethodsWe ran unsupervised machine learning and emotion analysis, validated with manual coding, on posts of health agencies (N = 1588) and their associated public comments (N = 7813) during a crucial initial period of the COVID-19 pandemic (January 2020 to February 2021) among nine different counties with a higher proportion of vaccine-hesitant communities in Northern California. In addition, we explored differences in concerns and expressed emotions by two key group-level factors, county-level COVID-19 death rate and political party affiliation.ResultsWe consistently find that while health agencies primarily disseminated information about COVID-19 and the vaccine, they failed to address the concerns of their communities as expressed in public comment sections. Topics among public audiences focused on concerns with the COVID-19 vaccine safety and rollout, state mandates, flu vaccination, and frustration with politicians, and they expressed more positive and more negative emotions than health agencies. Further, there were several differences in primary topics and emotions expressed among public audiences by county-level COVID-19 death rate and political party affiliation.ConclusionWhile this research serves as a case study, findings indicate how local health agencies, and their audiences, discuss their perceptions and concerns regarding the COVID-19 pandemic and may inform health communication researchers and practitioners on how to prepare and manage for emerging health crises.

COVID-19 is associated with increased risk for cognitive decline but very little is known regarding the neural mechanisms of this risk. We enrolled 49 adults (55% female, mean age = 30.7 ± 8.7), 25 with and 24 without a history of COVID-19 infection. We administered standardized tests of cognitive function and acquired brain connectivity data using MRI. The COVID-19 group demonstrated significantly lower cognitive function (W = 475, p

There are two dominant approaches to implementing permanent supportive housing (PSH), namely place-based (PB) and scattered-site (SS). Formal guidance does not distinguish between these two models and only specifies that PSH should be reserved for those who are most vulnerable with complex health needs. To consider both system- and self-selection factors that may affect housing assignment, this study applied the Gelberg-Anderson behavioral model for vulnerable populations to compare predisposing, enabling, and need factors among people experiencing homelessness (PE) by whether they were assigned to PB-PSH (n = 272) or SS-PSH (n = 185) in Los Angeles County during the COVID-19 pandemic. This exploratory, observational study also included those who were approved but did not receive PSH (n = 94). Results show that there are notable differences between (a) those who received PSH versus those who did not, and (b) those in PB-PSH versus SS-PSH. Specifically, PEH who received PSH were more likely to be white, US-born, have any physical health condition, and have lower health activation scores. PEH who received PB- versus SS-PSH were more likely to be older, Black, have any alcohol use disorder, and have higher health activation scores. These findings suggest that homeless service systems may consider PB-PSH more appropriate for PEH with higher needs but also raises important questions about how race may be a factor in the type of PSH that PEH receive and whether PSH is received at all.

Background: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has posed a threat to society worldwide. The aim of the study was to analyze changes in the physical fitness of 11- to 15-year-olds during the COVID-19 pandemic. Methods: Cross-sectional research was conducted in randomly selected schools in Kraków (Poland) during the years 2020 and 2022. The study group included 1635 adolescents aged 11–15 years. The results of fitness tests such as flexibility, standing broad jump, handgrip strength, overhead medicine ball throw, shuttle run (10 × 5 m), and 30-second sit-ups were analyzed. Body height and weight measurements were also taken. The standing broad jump and handgrip strength were normalized. A statistical analysis was performed to compare the differences between groups using 2-way analysis of variance with the Tukey HSD post hoc test or Kruskal–Wallis test. Results: The test results revealed a deterioration decrease in sit-ups, standing broad jump, shuttle run, and normalized standing broad jump in both sexes. Furthermore, the test results among girls showed a decrease in overhead medicine ball throw and flexibility. An increase in test results of both sexes was noticed in handgrip strength of the right and left hand. Among boys in 2022, the results were better in the flexibility test and overhead medicine ball throw compared with their peers from 2020. Conclusion: This study indicates a decrease in overall physical fitness in adolescents. The observed results may be associated with a decrease in physical activity, changes in nutrition, and restrictions imposed during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Objectives: Autoimmune activation by COVID-19 infection/vaccination has been postulated to be responsible for initiating or reactivating multiple types of oral mucosal immune disorders. These include: oral lichen planus; oral pemphigoid; either bullous pemphigoid or mucous membrane pemphigoid with oral involvement; pemphigus vulgaris with oral involvement; and Sjögren disease. In addition, chronic conditions such as oral burning, xerostomia, or changes in taste and/or smell have also been linked to COVID-19 infection/vaccination. Data sources: Part 1 (mucosal conditions): an English-language literature review of Pubmed, Web of Science, Scopus, and Embase was performed searching cases of oral lichen planus, oral bullous pemphigoid, mucous membrane pemphigoid, pemphigus vulgaris, and COVID-19 infection/vaccination, with additional cases from the authors’ clinical practice presented. Part 2 (nonmucosal conditions): Cases of initiated or flared Sjögren disease, chronic oral burning, or xerostomia after COVID-19 infection/vaccination from the authors’ clinical practice were aggregated. Results: The literature review discovered 29 cases of oral lichen planus following COVID-19 infection/vaccination. For bullous pemphigoid, 10 cases were identified after infection/vaccination. The number of pemphigus vulgaris cases following infection/vaccination was 28. The majority of mucosal cases were reported after vaccination. Most reported initial disease, but a substantial amount included recurrences of existing diseases. Nonmucosal disease: Sjögren disease, chronic oral burning, or xerostomia after COVID-19 infection/vaccination cases totaled 12 cases identified from the authors’ clinical practice, with the majority occurring after infection. Conclusions: Chronic conditions after infection with COVID-19 or vaccination remain relatively rare and self-limited, yet reinforce the importance of comprehensive history taking involving COVID-19 to differentiate potential etiologic factors for these conditions. [ABSTRACT FROM AUTHOR]

Adult horses are susceptible to equine coronavirus (ECoV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), although, only ECoV has been linked to clinical disease. Little information is available regarding the seroprevalence against ECoV and SARS-CoV-2 in adult healthy horses. The goal of the present study was to determine the seroprevalence against two coronaviruses known to infect horses using convenience samples collected from horses recently imported from Europe to the United States from 2019 to 2023. A total of 385 banked serum samples were tested against ECoV and SARS-CoV-2 using previously validated ELISA assays. Prevalence factors including date of arrival in the United States, signalment and country of origin were available for the majority of the horses. A total of 9/385 (2.3%) and 4/385 (1.0%) horses tested seropositive for ECoV and SARS-CoV-2, respectively. The ECoV seropositive horses were all mares, ages 4 to 26 years (median 9 years) and originated from Germany, the Netherlands, Ireland, Belgium and Italy. These mares were predominantly imported during the summer and fall months. All SARS-CoV-2 seropositive horses were mares ages 5 to 10 years (median 7.5 years) imported from the Netherlands and the United Kingdom. The majority of the SARS-CoV-2 seropositive horses were imported during the colder months of the year. The study results support the presence of ECoV in Europe and report on the first SARS-CoV-2 seropositive healthy adult horses outside the United States. Commingling for movements by air and close contact to humans may predispose transmission with ECoV and SARS-CoV-2, respectively.

IntroductionThe COVID-19 pandemic profoundly affected the health and well-being of people globally. Some studies suggest individuals with overweight or obesity may have been more adversely impacted by pandemic restrictions. Additionally, military personnel may have been more vulnerable to stress during the pandemic because of job demands (e.g., work in close quarters). Our research group was conducting a randomized clinical trial of a weight management intervention in active duty military personnel with overweight or obesity when the COVID-19 pandemic struck. Thus, we collected additional pandemic-related data from participants enrolled during the COVID-19 pandemic and conducted exploratory analyses to understand how the pandemic affected their stress levels and perceived abilities to engage in health behaviors like exercise and healthy eating. The aims of this exploratory study were to: (1) assess associations between pandemic-related stress and health behaviors with body fat percentage (BF%) and psychological and physical health, and (2) explore how pandemic-related stress and health behaviors affected BF% during and after the intervention.Materials and methodsA total of 29 active duty Navy personnel (55% female, 69% White) were enrolled after the onset of pandemic restrictions and completed measures assessing pandemic-related stress and health behaviors as well as measures of general psychological and physical health before the intervention. BF% was collected at 5 timepoints, including baseline, during, and following the intervention. Bivariate correlations assessed associations at baseline. Linearmixed-effects longitudinal models explored how pandemic-related stress and health behaviors affected BF%. Post-hoc analyses evaluated the effects of pandemic factors on BF% at each timepoint.ResultsMost participants perceived of the pandemic as increasing stress and detracting from their abilities to engage in health behaviors (i.e., exercise and healthy eating). Higher pandemic stress was significantly associated with reporting exercise and healthy eating as more difficult, worse overall health, and more anxiety and general stress. Reporting exercise as harder during the pandemic also was associated with more psychological distress at baseline. A linearmixed- effects model controlling for age, sex, and number of intervention sessions attended revealed endorsing "exercise as harder" was associated with higher BF%. Post-hoc regression analyses revealed rating "exercise as harder" significantly predicted higher BF% 3 months post-intervention (B = 0.65, P = .01), whereas pandemic stress was not significantly associated with higher BF% at 3 month (B =0.14, P = .08) or 6 month (B = 0.21, P = .09) follow-up.ConclusionsAs expected, most participants perceived of the pandemic as heightening stress and interfering with engagement in health behaviors. It is possible that pandemic-related stress may have exacerbated weight gain-promoting behaviors and/or interfered with achievement of desired weight management outcomes. Outside the context of the pandemic, it may be beneficial for healthcare providers to screen individuals for stress and perceptions of ease of engagement in health behaviors before enrollment in a weight management intervention. Further, tailoring interventions to mitigate stress and promote perceptions of ease in engaging in health behaviors may promote better weight management outcomes.

To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period. Compared to those who fully recovered, those reporting PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA and N-antigen, burden of RNA and infectious viral shedding, and lower Spike-specific IgG levels within 9 days post-illness onset. No significant differences were identified among a panel of host immune markers. Our results suggest early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC, highlighting the importance of understanding early biological markers in the natural history of PASC.

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimers opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.

As demonstrated by the SARS-CoV-2 pandemic, the emergence of novel viral strains with increased transmission rates poses a serious threat to global health. Statistical models of genome sequence evolution may provide a critical tool for early detection of these strains. Using a novel stochastic model that links transmission rates to the entire viral genome sequence, we study the utility of phylogenetic methods that use a phylogenetic tree relating viral samples versus count-based methods that use case counts of variants over time exclusively to detect increased transmission rates and identify candidate causative mutations. We find that phylogenies in particular can detect novel transmission-enhancing variants very soon after their origin and may facilitate the development of early detection systems for outbreak surveillance.

BACKGROUND: A concern before 2020, physician burnout worsened during the COVID-19 pandemic. Little empirical data are available on pandemic workplace support interventions or their influence on burnout. We surveyed a national sample of frontline physicians on burnout and workplace support during the pandemic. METHODS: We surveyed a stratified random sample of 12,833 US physicians most likely to care for adult COVID-19 patients from the comprehensive AMA Physician Professional Data ™ file. The sample included 6722 primary care physicians (3331 family physicians, 3391 internists), 880 hospitalists, 1783 critical care physicians (894 critical care physicians, 889 pulmonary intensivists), 2548 emergency medicine physicians, and 900 infectious disease physicians. The emailed survey elicited physicians perceptions of organizational interventions to provide workplace support and/or to address burnout. Burnout was assessed with the Professional Fulfillment Index Burnout Composite scale (PFI-BC). Proportional specialty representation and response bias were addressed by survey weighting. Logistic regression assessed the association of physician characteristics and workplace interventions with burnout. RESULTS: After weighting, respondents were representative of the total sample. Overall physician burnout was 45.4%, significantly higher than in our previous survey. Open-ended responses mentioned that staffing shortages (physician, nursing, and other staff) combined with the increased volume, complexity, and acuity of patients during the pandemic increased job demands. The most frequent workplace support interventions were direct pandemic control measures (increased access to personal protective equipment, 70.0%); improved telehealth functionality (43.4%); and individual resiliency tools (yoga, meditation, 30.7%). Respondents placed highest priority on workplace interventions to increase financial support and increase nursing and clinician staffing. Factors significantly associated with lower odds of burnout were practicing critical care (compared with emergency medicine) OR 0.33 (95% CI 0.12 - 0.93), improved telehealth functionality OR 0.47 (95% CI 0.23 - 0.97) and being in practice for 11 years or longer OR 0.44 (95% CI 0.19-0.99). CONCLUSIONS: Burnout across frontline specialties increased during the pandemic. Physician respondents focused on inadequate staffing in the context of caring for more and sicker patients, combined with the lack of administrative efforts to mitigate problems. Burnout mitigation requires system-level interventions beyond individual-focused stress reduction programs to improve staffing, increase compensation, and build effective teams.

In the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, epithelial populations in the distal lung expressing Angiotensin-converting enzyme 2 (ACE2) are infrequent, and therefore, the model of viral expansion and immune cell engagement remains incompletely understood. Using human lungs to investigate early host-viral pathogenesis, we found that SARS-CoV-2 had a rapid and specific tropism for myeloid populations. Human alveolar macrophages (AMs) reliably expressed ACE2 allowing both spike-ACE2-dependent viral entry and infection. In contrast to Influenza A virus, SARS-CoV-2 infection of AMs was productive, amplifying viral titers. While AMs generated new viruses, the interferon responses to SARS-CoV-2 were muted, hiding the viral dissemination from specific antiviral immune responses. The reliable and veiled viral depot in myeloid cells in the very early phases of SARS-CoV-2 infection of human lungs enables viral expansion in the distal lung and potentially licenses subsequent immune pathologies.

BACKGROUND AND OBJECTIVE: Congenital heart defects are known to be associated with increased odds of severe COVID-19. Congenital anomalies affecting other body systems may also be associated with poor outcomes. This study is an exhaustive assessment of congenital anomalies and odds of severe COVID-19 in pediatric patients. METHODS: Data were retrieved from the COVID-19 dataset of Cerner® Real-World Data for encounters from March 2020 to February 2022. Prior to matching, the data consisted of 664,523 patients less than 18 years old and 927,805 corresponding encounters with COVID-19 from 117 health systems across the United States. One-to-one propensity score matching was performed, and a cumulative link mixed-effects model with random intercepts for health system and patients was built to assess corresponding associations. RESULTS: All congenital anomalies were associated with worse COVID-19 outcomes, with the strongest association observed for cardiovascular anomalies (odds ratio [OR], 3.84; 95% CI, 3.63-4.06) and the weakest association observed for anomalies affecting the eye/ear/face/neck (OR, 1.16; 95% CI, 1.03-1.31). CONCLUSIONS AND RELEVANCE: Congenital anomalies are associated with greater odds of experiencing severe symptoms of COVID-19. In addition to congenital heart defects, all other birth defects may increase the odds for more severe COVID-19. IMPACT: All congenital anomalies are associated with increased odds of severe COVID-19. This study is the largest and among the first to investigate birth defects across all body systems. The multicenter large data and analysis demonstrate the increased odds of severe COVID19 in pediatric patients with congenital anomalies affecting any body system. These data demonstrate that all children with birth defects are at increased odds of more severe COVID-19, not only those with heart defects. This should be taken into consideration when optimizing prevention and intervention resources within a hospital.

With over 16 million submitted genomic sequences, the SARS-CoV-2 (SC2) virus, the cause of the most recent worldwide COVID-19 pandemic, has become the most sequenced genome of all known viruses, revealing, for example, a vast number of expanding viral lineages. Since the pandemic phase appears to be over, we performed a retrospective re-examination of the demographic grouping pattern and their genomic characteristics during the entire pandemic period up to the peak of the last pandemic wave. For our study, we extracted from the NCBI only unique viral sequences and converted each sequence data to a relational vector, indicating the presence/absence of each variational event compared to a reference sequence. Our study revealed several genomic features that are unexpected or different from those of previous studies. For example, approximately 44,000 variants with unique sequences emerged during the pandemic period; they group into only four major viral-genomic groups and each has a set of mostly unique highly-conserved variant-genotypes (HCVGs); and a small set from the first (ancestral) group was inherited by the three (descendant) groups, suggesting that HCVGs in the next group may be predictable from the current group(s). Such a concept may be potentially important in designing panvalent vaccines against the current and future waves of viral infections.

Effectively neutralizing inflammatory cytokines is crucial for managing a variety of inflammatory disorders. Current techniques that target only a subset of cytokines often fall short due to the intricate nature of redundant and compensatory cytokine networks. A promising solution to this challenge is using cell membrane-coated nanoparticles (CNPs). These nanoparticles replicate the complex interactions between cells and cytokines observed in disease pathology, providing a potential avenue for multiplex cytokine scavenging. While the development of CNPs using experimental animal models has shown great promise, their effectiveness in scavenging multiple cytokines in human diseases has yet to be demonstrated. To bridge this gap, this study selected macrophage membrane-coated CNPs (MФ-CNPs) and assessed their ability to scavenge inflammatory cytokines in serum samples from patients with COVID-19, sepsis, acute pancreatitis, or type-1 diabetes, along with synovial fluid samples from patients with rheumatoid arthritis. The results show that MФ-CNPs effectively scavenge critical inflammatory cytokines, including interleukin (IL)-6, IL-8, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, in a dose-dependent manner. Overall, this study demonstrates MФ-CNPs as a multiplex cytokine scavenging formulation with promising applications in clinical settings to treat a range of inflammatory disorders.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

Nucleocapsid antibody assays can be used to estimate SARS-CoV-2 infection prevalence in regions implementing spike-based COVID-19 vaccines. However, poor sensitivity of nucleocapsid antibody assays in detecting infection after vaccination has been reported. We derived a lower cutoff for identifying previous infections in a large blood donor cohort (N = 142,599) by using the Ortho VITROS Anti-SARS-CoV-2 Total-N Antibody assay, improving sensitivity while maintaining specificity >98%. We validated sensitivity in samples donated after self-reported swab-confirmed infections diagnoses. Sensitivity for first infections in unvaccinated donors was 98.1% (95% CI 98.0-98.2) and for infection after vaccination was 95.6% (95% CI 95.6-95.7) based on the standard cutoff. Regression analysis showed sensitivity was reduced in the Delta compared with Omicron period, in older donors, in asymptomatic infections,

Humanized mice are limited in terms of modeling human immunity, particularly with regards to antibody responses. Here we constructed a humanized (THX) mouse by grafting non-γ-irradiated, genetically myeloablated KitW-41J mutant immunodeficient pups with human cord blood CD34+ cells, followed by 17β-estradiol conditioning to promote immune cell differentiation. THX mice reconstitute a human lymphoid and myeloid immune system, including marginal zone B cells, germinal center B cells, follicular helper T cells and neutrophils, and develop well-formed lymph nodes and intestinal lymphoid tissue, including Peyers patches, and human thymic epithelial cells. These mice have diverse human B cell and T cell antigen receptor repertoires and can mount mature T cell-dependent and T cell-independent antibody responses, entailing somatic hypermutation, class-switch recombination, and plasma cell and memory B cell differentiation. Upon flagellin or a Pfizer-BioNTech coronavirus disease 2019 (COVID-19) mRNA vaccination, THX mice mount neutralizing antibody responses to Salmonella or severe acute respiratory syndrome coronavirus 2 Spike S1 receptor-binding domain, with blood incretion of human cytokines, including APRIL, BAFF, TGF-β, IL-4 and IFN-γ, all at physiological levels. These mice can also develop lupus autoimmunity after pristane injection. By leveraging estrogen activity to support human immune cell differentiation and maturation of antibody responses, THX mice provide a platform to study the human immune system and to develop human vaccines and therapeutics.

Science is humanity's best insurance against threats from nature, but it is a fragile enterprise that must be nourished and protected. The preponderance of scientific evidence indicates a natural origin for SARS-CoV-2. Yet, the theory that SARS-CoV-2 was engineered in and escaped from a lab dominates media attention, even in the absence of strong evidence. We discuss how the resulting anti-science movement puts the research community, scientific research, and pandemic preparedness at risk.

The prevalence of "long COVID" is just one of the conundrums highlighting how little we know about the lung's response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical "backdoor" route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell-intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic.

Recent emerging zoonotic disease outbreaks, such as that of SARS-CoV-2, have demonstrated the need for wider companion animal disease surveillance. We tested 1000 dogs and cats belonging to employees of a US veterinary hospital network that were exposed to human COVID-19 cases in the household between 1 January 2020 and 10 March 2022 for SARS-CoV-2 and surveyed their owners about clinical signs and risk factors. The seropositivity was 33% for 747 dogs and 27% for 253 cats. Pet seropositivity correlated with the US human case rates over time, exhibiting peaks corresponding with the major COVID-19 surges. Antibodies persisted longer than previously documented (828 days in dogs; 650 days in cats). Increasing age and duration of proximity to infected people were associated with increased seropositivity in dogs but not cats. Cats were more likely to have clinical signs, but an association between seropositivity and the presence of clinical signs was not found in either species.

The coronavirus disease 2019 (COVID-19) pandemic and respective shutdowns dramatically altered human activities, potentially changing human pressures on urban-dwelling animals. Here, we use such COVID-19-induced variation in human presence to evaluate, across multiple temporal scales, how urban birds from five countries changed their tolerance towards humans, measured as escape distance. We collected 6369 escape responses for 147 species and found that human numbers in parks at a given hour, day, week or year (before and during shutdowns) had a little effect on birds escape distances. All effects centered around zero, except for the actual human numbers during escape trial (hourly scale) that correlated negatively, albeit weakly, with escape distance. The results were similar across countries and most species. Our results highlight the resilience of birds to changes in human numbers on multiple temporal scales, the complexities of linking animal fear responses to human behavior, and the challenge of quantifying both simultaneously in situ.

The mechanisms of postacute medical conditions and unexplained symptoms after SARS-CoV-2 infection [Long Covid (LC)] are incompletely understood. There is growing evidence that viral persistence, immune dysregulation, and T cell dysfunction may play major roles. We performed whole-body positron emission tomography imaging in a well-characterized cohort of 24 participants at time points ranging from 27 to 910 days after acute SARS-CoV-2 infection using the radiopharmaceutical agent [18F]F-AraG, a selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the postacute COVID-19 group, which included those with and without continuing symptoms, was higher compared with prepandemic controls in many regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. T cell activation in the spinal cord and gut wall was associated with the presence of LC symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms specifically. Increased T cell activation in these tissues was also observed in many individuals without LC. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization of SARS-CoV-2 RNA and immunohistochemical studies in a subset of five participants with LC symptoms. We identified intracellular SARS-CoV-2 single-stranded spike protein-encoding RNA in rectosigmoid lamina propria tissue in all five participants and double-stranded spike protein-encoding RNA in three participants up to 676 days after initial COVID-19, suggesting that tissue viral persistence could be associated with long-term immunologic perturbations.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

BACKGROUND: Infectious conjunctivitis is common in Nepal. MATERIALS AND METHODS: This prospective study recruited 60 patients with presumed acute infectious conjunctivitis from the B.P. Koirala Lions Center for Ophthalmic Studies in Kathmandu, Nepal. Swabs from the conjunctiva and anterior nares were processed for metagenomic RNA deep sequencing (RNA-seq). RESULTS: Pathogens were identified in 55% of cases. RNA viruses were the most common pathogen class identified. Severe acute respiratory syndrome coronavirus 2 was the most common RNA virus identified. CONCLUSIONS: Acute infectious conjunctivitis varies by location. Contrary to expectations, RNA viruses predominated. Repeat surveillance may be useful and RNA-seq allows for detection of the unexpected pathogen including RNA viruses.