Over the past two decades, coronaviruses have caused three major public health crises, including the epidemics of SARS-CoV, MERS-CoV, and SARS-CoV-2. Following the outbreak of SARS-CoV-2, several antiviral drugs have been approved for the treatment of COVID-19. However, the high mutation rate of SARS-CoV-2 has led to the emergence of multiple variants, some of which can escape vaccine-induced immunity and develop resistance to virus-targeted drugs. Viruses rely on host cell mechanisms to complete replication and transmission. Host-directed therapy is an emerging strategy that inhibits infection by targeting host cell factors essential for pathogen replication. Interventions targeting host factors have been proven effective in limiting viral infections and have the potential to reduce the risk of drug resistance. Our previous study found that the sigma-1 receptor (σ1R) is involved in the autophagic process mediated by the SARS-CoV-2 non-structural protein NSP6, suggesting that σ1R may serve as a therapeutic target against SARS-CoV-2. In this study, we found that the σ1R antagonists BD-1047 and σ1RA1 inhibited SARS-CoV-2 and its variants in vitro and showed antiviral activity in vivo. At the cellular level, these compounds also inhibited porcine epidemic diarrhea virus (PEDV) and infectious bronchitis virus (IBV), indicating cross-model antiviral activity. BD-1047 further showed antiviral activity against HCoV-OC43 in both in vitro and in vivo models. In addition, Ocaperidone, identified through computer-aided screening, exhibited protective effects against SARS-CoV-2 and HCoV-OC43 in both cell-based and mouse models. Collectively, these findings support σ1R as a host-associated antiviral target candidate and provide several compounds for further optimization and mechanistic investigation.

Heparan sulfate (HS) is a key host-factor mediator of SARS-CoV-2 attachment and an attractive target for antiviral intervention, yet the synthesis of structurally defined HS oligosaccharides remains challenging. Here, we show that a defined HS hexasaccharide, heparin-dp6, efficiently inhibits RBD-ACE2 binding and exhibits superior antiviral activity compared with longer HS mimetics. Electronic-structure analyses suggest that the strong recognition capacity of HS arises from sulfate and carboxylate groups, which create highly negative electrostatic surfaces and serve as dominant hydrogen-bond acceptors, governing charge distribution and electronic properties along the glycan backbone to modulate binding specificity and affinity. Stepwise virtual screening of a comprehensive HS database further identified several high-affinity oligosaccharides, with top candidates displaying favorable RBD-binding properties. These findings indicate that HS activity is determined not only by chain length and sulfation pattern, but also by the spatial arrangement of charged functional groups, providing mechanistic insight into HS-RBD recognition and guiding the rational design of HS-based decoy inhibitors against SARS-CoV-2 entry.

Long COVID is a multi-system, heterogeneous condition that manifests as new or worsened symptoms lasting at least 3 months following acute SARS-CoV-2 infection, often despite normal results on routine diagnostic testing. Common manifestations include fatigue, post-exertional malaise, cognitive impairment, and orthostatic intolerance. Primary care clinicians are uniquely positioned to identify and manage Long COVID due to their longitudinal relationships with patients and holistic understanding of their patients' health. However, diagnostic uncertainty, time constraints, and limited access to specialty care present significant challenges, and sometimes hesitation, to addressing Long COVID in the primary care setting. This focused narrative review provides a pragmatic, primary care-focused approach for the evaluation and management of Long COVID. Using patient-centered vignettes, we first describe common clinical presentations. Next, we provide a framework for the pathophysiological mechanisms suspected to contribute to persistent symptoms after SARS-CoV-2 infection. We then present a simple approach to Long COVID diagnosis and management that leverages primary care clinicians' skillset and highlights unique aspects of Long COVID care (e.g., diagnostic workup to evaluate for competing or coexisting diagnoses; management strategies focused on validation and supportive care, including activity pacing, multidisciplinary rehabilitation, and consideration of symptom-based medication trials). We offer practical strategies to effectively, yet efficiently, address a possible Long COVID diagnosis within the context of brief primary care visits (e.g., prioritize the most bothersome or addressable symptom(s) first, focus on one or two symptoms each visit, leverage longitudinal follow-up). We conclude with evidence-based strategies for prevention counseling, including infection prevention and early outpatient treatment during acute infection. While we remain optimistic that reliable diagnostic biomarkers and curative treatments will one day be available, until then, this primer supports primary care clinicians in recognizing Long COVID and supporting their patients who are living with it, despite the constraints of our current healthcare environment.

This study investigates the FAIRness (Findability, Accessibility, Interoperability, and Reusability) of survey data collected during the COVID-19 pandemic in Germany. During the pandemic, surveys played a crucial role in capturing public attitudes and health-related behaviors, but researchers often faced a trade-off between rapid data collection and implementing high-quality survey designs. Using metadata from the "Survey Data Collection during the COVID-19 Pandemic" (SDCCP) project, which documents 717 surveys conducted in Germany, we assessed the FAIRness of surveys published with a persistent identifier or project website using the F-UJI assessment tool. Our results show substantial variation in FAIRness scores. Surveys can be divided into two groups, with one group achieving around 88.46% FAIRness and the other averaging around 65.38%. These differences are correlated with survey design. Surveys using fast and cost-efficient designs also exhibit lower FAIRness. The findings highlight that the trade-off between rapid data production and methodological rigor during the pandemic also affected the availability and reusability of survey data.

Previous studies investigated the effect of the COVID-19 pandemic on children's language development. This study explored the association between different COVID-19 infection statuses (children with no history of infection, children with a history of infection, and children with long COVID symptoms) and Hong Kong elementary children's Chinese and English reading performance. Participants were 195 dyads of parents and elementary children from Grades 1-6 (Mage = 8;8, SDage = 1;7, 89 boys and 106 girls) in 2022-2023. We adopted a 3 x 3 between-participant design. The two independent variables were COVID-19 status and grade levels. The dependent variables were parents' ratings of reading proficiencies, reading proficiencies in Chinese and English, and the differences between the parents' ratings and reading proficiencies. All measures (the language experience and proficiency questionnaire for parents' ratings, Chinese word reading battery, and the Wechsler Individual Achievement Test - Third Edition) were adapted from published works and showed high reliability in our sample. Using Multivariate Analysis of Covariates (MANCOVA) and Analyses of covariance (ANCOVA), we examined the links of infection with covariates, including parents' education level, number of children in the family, and monthly household income. We found that long COVID status was associated with lower parent-rated Chinese reading in the upper grades and lower Chinese spelling performance. Grade-specific differences in parent-performance discrepancy scores were also observed. These findings highlight the need for further longitudinal investigations and needs-based monitoring using both caregiver reports and performance-based assessments for children experiencing persistent health and learning difficulties.

A new series of thiazole-based carboxamide derivatives (5-12) was designed, synthesized with structural elucidation performed using standard spectroscopic techniques including NMR and HRMS. The synthesized compounds were evaluated for their inhibitory activity against SARS-CoV-2 papain-like protease (PL[pro]) and compared with the reference inhibitor GRL0617 (IC50 = 2.73 ± 2.20 µM). Among the tested compounds, compounds (8) (IC50 = 1.94 ± 1.50 µM) and (6) (IC50 = 2.53 ± 1.90 µM) exhibited the most potent inhibitory activity, outperforming or matching the reference inhibitor, while the remaining compounds showed moderate to good PLpro inhibition. Structure-activity relationship analysis was supported by molecular docking studies, which demonstrated that compound 8 possessed the strongest binding affinity (-7.875 kcal/mol), forming key hydrogen bonds with Gly163 and Gly271. Compound (6) also showed favorable binding (-7.426 kcal/mol), establishing similar hydrogen bonding interactions together with additional hydrophobic contacts within the active site. Density functional theory (DFT) calculations provided insights into the electronic properties underlying molecular reactivity and stability, whereas in silico ADME analysis predicted favorable pharmacokinetic characteristics and drug-likeness. Collectively, these experimental and computational findings identify thiazole-based carboxamide derivatives, particularly compounds (8) and (6), as promising candidates for the development of potent SARS-CoV-2 PL[pro] inhibitors.

This study assessed the role that natural killer (NK) cells play in a murine model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike mRNA vaccination. Flow cytometric analyses revealed that mRNA vaccination results in recruitment and maturation of NK cells in the spleen. Primed (CD27+ CD11b+) NK cells increased from 0.35% of all CD45+ cells pre-vaccination to 2.44% at 4 d post-vaccination, while terminally mature (CD27- CD11b+) NK cells increased from 0.85% of all CD45+ cells pre-vaccination to 3.91% at 7 d post-vaccination. We next evaluated Spike mRNA and protein expression, circulating cytokines, and Spike-specific antibody and T cell responses in mice depleted of NK cells before primary or booster vaccination. Depleting NK cells prior to mRNA vaccination resulted in decreased serum levels of IL-1β and IL-6 at 6 and 24 h, respectively, after vaccination. NK depletion also caused a significant reduction in Spike mRNA expression in draining lymph nodes, with greater than 5-fold reductions in Spike mRNA copies/μL, as measured by digital droplet PCR. Three weeks post-vaccination with 1 μg mRNA LNP, Spike-specific CD25+ CD4 T cells were also significantly decreased. Despite these decreases in early pro-inflammatory cytokines, Spike mRNA expression, and Spike-specific CD4 T cells, NK depletion had little impact on Spike-specific antibody levels at 1 and 6 mo following single vaccination, as well as at 3 wk after booster vaccination. Together, these data suggest that NK cells contribute to early inflammatory responses induced by mRNA vaccination, yet their depletion does not impair the magnitude of long-term adaptive immune responses induced by this platform.

Synthetic messenger RNA (mRNA) formulated in lipid nanoparticles (LNPs) is increasingly used for vaccines and therapeutics, yet the consequences of high-dose systemic exposure for bone marrow hematopoiesis remain poorly defined. We previously reported that intramuscular mRNA/LNP administration transiently alters circulating reticulocytes and bone marrow erythroid cellularity in mice; here, we investigated the mechanistic basis and cross-species generalizability of this hematopoietic bias in murine and non-human primate models. Animals received intramuscular LNP-formulated mRNA encoding SARS-CoV-2 spike protein or firefly luciferase at deliberately supra-clinical, upper-bound doses, and type I interferon signaling was interrogated by interferon-α/β receptor blockade. Bone marrow was assessed by histopathology, bulk and single-cell RNA sequencing, and trajectory analysis. LNP-formulated mRNA induced reversible erythroid-lineage suppression with concomitant granulocytic expansion, irrespective of the encoded antigen. These effects were absent after naked mRNA and only modestly induced by LNP alone, indicating that formulation of synthetic mRNA within the LNP was required to elicit the full phenotype. Single-cell analysis showed biased hematopoietic stem and progenitor cell differentiation toward granulopoiesis with broad induction of interferon-stimulated genes, and the bias resolved within two weeks. Interferon-α/β receptor blockade mitigated both changes, demonstrating type I interferon dependence. High-dose LNP-formulated synthetic mRNA can therefore drive reversible, type I interferon-dependent hematopoietic lineage bias in preclinical animal models.

BACKGROUNDThe Netherlands has experienced a decline in routine childhood vaccination uptake during and after the COVID-19 pandemic, with emerging evidence of reduced parental vaccine confidence.AIMTo evaluate the immediate and long-term impact of the COVID-19 pandemic on first-dose diphtheria-tetanus-pertussis-poliomyelitis (DTaP-IPV) vaccination uptake.METHODSWe conducted a retrospective nationwide cohort study including all children born in the Netherlands in 2016-2024. First-dose DTaP-IPV vaccination status by age 6 months was obtained from the national immunisation register. National trends in vaccination uptake across pre-pandemic, pandemic and post-pandemic periods were assessed using interrupted time series analyses (ITS). To further assess the independent effects of the pandemic, matched-sibling analysis compared vaccination uptake within families before, during and after the pandemic.RESULTSITS showed significant immediate decreases in vaccination uptake both at the start and end of the pandemic, accompanied by a continuing downward trend during the pandemic (OR: 0.984; 95% CI: 0.981-0.986) that further declined after its end (OR: 0.995; 95% CI: 0.993-0.998). In the matched-sibling analysis, children eligible during and after the pandemic had lower odds of being vaccinated (pandemic: OR: 0.66; 95% CI: 0.55-0.80; post-pandemic: OR: 0.20; 95% CI: 0.17-0.25) compared with their pre-pandemic siblings. Also, later birth order was associated with lower odds compared with first-born siblings (second-born: OR: 0.42; 95% CI: 0.37-0.48).CONCLUSIONSBoth analyses indicate a negative impact of the COVID-19 pandemic on childhood vaccination uptake, which may reflect lingering pandemic effects and/or new post-pandemic factors, highlighting the need for further research into the drivers of vaccination uptake changes in the post-pandemic era.

Background Repeated COVID-19 vaccination is widely used in long-term care facilities, yet SARS-CoV-2 infection and reinfection continue to occur in frail older populations. Resident-level longitudinal data linking vaccination records with first and recurrent infections remain limited in Japanese long-term care settings. Materials and methods We conducted a retrospective descriptive study in a 134-bed long-term care facility in Okinawa, Japan. We linked 976 valid, dated vaccination records for 232 residents from June 7, 2021, through January 16, 2026, to 136 infection episodes among 109 residents from May 22, 2023, through April 30, 2025, using de-identified resident identifiers. Because facility occupancy was dynamic and complete admission and discharge dates were unavailable, not all 232 residents were continuously at risk. Recurrent infection was operationally defined as a new symptomatic episode with a new positive antigen test at least 60 days after the preceding episode, following documented recovery and release from isolation. Analyses were descriptive; incidence rates, vaccine effectiveness, and inferential statistics were not estimated. Results Among 232 residents, 157/232 (67.7%) were female. The mean age at first recorded vaccination was 85.5 ± 8.3 years, and the median total number of documented doses was 4 (interquartile range [IQR], 2-7). Linkage was successful for 89 residents with 114 infection episodes; 20 residents with 22 episodes could not be linked. Linked documented infection occurred in 89/232 residents (38.4%; 95% confidence interval [CI], 32.3%-44.8%). Among these 89 residents, 65/89 (73.0%) had one episode, 23/89 (25.8%) had two, and 1/89 (1.1%) had three. Recurrent infection occurred in 24/89 residents (27.0%; 95% CI, 18.8%-37.0%). The median interval from the first to second episode was 364 days (IQR, 289.5-575; range, 286-599). Before first infection, the median number of documented doses was 5 (IQR, 2-6; range, 0-8). Among 84 residents with prior documented vaccination, the median interval from the most recent dose to first infection was 49 days (IQR, 14.5-131; range, 3-488). Eight aggregate hospitalizations were documented during infection surveillance but could not be linked to the vaccination roster; one resident died during hospitalization and seven returned to the facility. Conclusions Linking longitudinal vaccination and infection records was feasible and demonstrated a continuing burden of infection and reinfection. However, dynamic occupancy and incomplete time-at-risk data precluded incidence, person-time, dose-specific vaccine-effectiveness, or causal analyses. The dose distribution should not be interpreted as evidence that additional vaccination increased infection risk. Long-term care facilities require layered prevention combining vaccination with rapid testing, infection-control measures, and timely clinical management.