Transcriptome landscape of high and low responders to an inactivated COVID-19 vaccine after 4 months using single-cell sequencing (preprint)

BackgroundVariability in antibody responses among individuals following vaccination is a universal phenomenon. Single-cell transcriptomics offers a potential avenue to understand the underlying mechanisms of these variations and improve our ability to evaluate and predict vaccine effectiveness. ObjectiveThis study aimed to explore the potential of single-cell transcriptomic data in understanding the variability of antibody responses post-vaccination and its correlation with transcriptomic changes. MethodsBlood samples were collected from 124 individuals on day 21 post COVID-19 vaccination. These samples were categorized based on antibody titers (high, medium, low). On day 135, PBMCs from 27 donors underwent single-cell RNA sequencing to depict the transcriptome atlas. ResultsDifferentially expressed genes (DEGs) affecting antibody expression in various cell types were identified. We found that innate immunity, B cell, and T cell population each had a small set of common DEGs (MT-CO1, HLA-DQA2, FOSB, TXNIP, and JUN), and Macrophages and Th1 cells exhibited the largest number of DEGs. Pathway analysis highlighted the dominant role of the innate immune cell population in antibody differences among populations, with a significant impact from the interferon pathway. Furthermore, protein complexes analysis revealed that alterations in the ribosome complex, primarily regulated by DC cells, may play a crucial role in regulating antibody differences. Combining these findings with previous research we proposed a potential regulatory mechanism model of DC cells on B cell antibody production. ConclusionWhile direct prediction of specific antibody levels using single-cell transcriptomic data remains technically and data-wise challenging, our study demonstrated the vast potential of single-cell transcriptomics in understanding the mechanisms underlying antibody responses induced by vaccines.

Racial/Ethnic Differences in Long-COVID-Associated Symptoms among Pediatrics Population: Findings from Difference-in-differences Analyses in RECOVER Program (preprint)

Racial/ethnic differences are associated with the potential symptoms and conditions of post-acute sequelae SARS-CoV-2 infection (PASC) in adults. These differences may exist among children and warrant further exploration. We conducted a retrospective cohort study for children and adolescents under the age of 21 from the thirteen institutions in the RECOVER Initiative. The cohort is 225,723 patients with SARS-CoV-2 infection or COVID-19 diagnosis and 677,448 patients without SARS-CoV-2 infection or COVID-19 diagnosis between March 2020 and October 2022. The study compared minor racial/ethnic groups to Non-Hispanic White (NHW) individuals, stratified by severity during the acute phase of COVID-19. Within the severe group, Asian American/Pacific Islanders (AAPI) had a higher prevalence of fever/chills and respiratory symptoms, Hispanic patients showed greater hair loss prevalence in severe COVID-19 cases, while Non-Hispanic Black (NHB) patients had fewer skin symptoms in comparison to NHW patients. Within the non-severe group, AAPI patients had increased POTS/dysautonomia and respiratory symptoms, and NHB patients showed more cognitive symptoms than NHW patients. In conclusion, racial/ethnic differences related to COVID-19 exist among specific PASC symptoms and conditions in pediatrics, and these differences are associated with the severity of illness during acute COVID-19.

Rates of Trauma Exposure, Posttraumatic Stress Disorder (PTSD), Depressive, and Anxiety Symptoms in Primary School Children: Findings Six Months before Covid-19 Pandemic (preprint)

Studies on mental health rates among primary school children are still limited particularly related to psychological trauma and its relationship to other mental health challenges. This is the first cross-sectional study examining the rates of trauma exposure, posttraumatic stress disorder (PTSD), depressive, and anxiety symptoms in primary school children before covid-19 pandemic in Malaysia. Two hundred and twenty-one students participated in this study. They were recruited from four primary schools that volunteered to participate in the study. PTSD) Checklist for DSM-5 (PCL-5), Child PTSD Symptoms Scale-5 (CPSS-5), The Center for Epidemiologic Studies Depression Scale version (CESD) and the Spence Children's Anxiety Scale (SCAS) were used to survey psychological symptoms. Most of the students, or 54.3% of them, have experienced at least one traumatic event. Of 221 students, 39.4% reported having PTSD symptoms, 38% reported having depressive symptoms and 19% reported having anxiety symptoms. Female students were more likely to report PTSD symptoms compared to male students. The first regression analysis model showed that only depressive symptoms were significant predictors for PTSD. In the second model, religion, family income, anxiety and PTSD symptoms were significant predictors of depressive symptoms. In the third model, only depressive symptoms were significant predictors of anxiety. Findings, limitations, research future directions and recommendations were discussed.

Real-world Effectiveness and Causal Mediation Study of BNT162b2 on Long COVID Risks in Children and Adolescents (preprint)

BackgroundThe impact of pre-infection vaccination on the risk of long COVID remains unclear in the pediatric population. Further, it is unknown if such pre-infection vaccination can mitigate the risk of long COVID beyond its established protective benefits against SARS-CoV-2 infection. ObjectiveTo assess the effectiveness of BNT162b2 on long COVID risks with various strains of the SARS-CoV-2 virus in children and adolescents, using comparative effectiveness methods. To disentangle the overall effectiveness of the vaccine on long COVID outcomes into its independent impact and indirect impact via prevention of SARS-CoV-2 infections, using causal mediation analysis. DesignReal-world vaccine effectiveness study and mediation analysis in three independent cohorts: adolescents (12 to 20 years) during the Delta phase, children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. SettingTwenty health systems in the RECOVER PCORnet electronic health record (EHR) Program. Participants112,590 adolescents (88,811 vaccinated) in the Delta period, 188,894 children (101,277 vaccinated), and 84,735 adolescents (37,724 vaccinated) in the Omicron period. ExposuresFirst dose of the BNT162b2 vaccine vs. no receipt of COVID-19 vaccine. MeasurementsOutcomes of interest include conclusive or probable diagnosis of long COVID following a documented SARS-CoV-2 infection, and body-system-specific condition clusters of post-acute sequelae of SARS-CoV-2 infection (PASC), such as cardiac, gastrointestinal, musculoskeletal, respiratory, and syndromic categories. The effectiveness was reported as (1-relative risk)*100 and mediating effects were reported as relative risks. ResultsDuring the Delta period, the estimated effectiveness of the BNT162b2 vaccine against long COVID among adolescents was 95.4% (95% CI: 90.9% to 97.7%). During the Omicron phase, the estimated effectiveness against long COVID among children was 60.2% (95% CI: 40.3% to 73.5%) and 75.1% (95% CI: 50.4% to 87.5%) among adolescents. The direct effect of vaccination, defined as the effect beyond their impact on SARS-CoV-2 infections, was found to be statistically non-significant in all three study cohorts, with estimates of 1.08 (95% CI: 0.75 to 1.55) in the Delta study among adolescents, 1.24 (95% CI: 0.92 to 1.66) among children and 0.91 (95% CI: 0.69 to 1.19) among adolescents in the Omicron studies. Meanwhile, the estimated indirect effects, which are effects through protecting SARS-CoV-2 infections, were estimated as 0.04 (95% CI: 0.03 to 0.05) among adolescents during Delta phase, 0.31 (95% CI: 0.23 to 0.42) among children and 0.21 (95% CI: 0.16 to 0.27) among adolescents during the Omicron period. LimitationsObservational study design and potentially undocumented infection. ConclusionsOur study suggests that BNT162b2 was effective in reducing risk of long COVID outcomes in children and adolescents during the Delta and Omicron periods. The mediation analysis indicates the vaccines effectiveness is primarily derived from its role in reducing the risk of SARS-CoV-2 infection. Primary Funding SourceNational Institutes of Health.

Development and validation of a federated learning framework for detection of subphenotypes of multisystem inflammatory syndrome in children (preprint)

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe post-acute sequela of SARS-CoV-2 infection. The highly diverse clinical features of MIS-C necessities characterizing its features by subphenotypes for improved recognition and treatment. However, jointly identifying subphenotypes in multi-site settings can be challenging. We propose a distributed multi-site latent class analysis (dMLCA) approach to jointly learn MIS-C subphenotypes using data across multiple institutions. Methods We used data from the electronic health records (EHR) systems across nine U.S. childrens hospitals. Among the 3,549,894 patients, we extracted 864 patients < 21 years of age who had received a diagnosis of MIS-C during an inpatient stay or up to one day before admission. Using MIS-C conditions, laboratory results, and procedure information as input features for the patients, we applied our dMLCA algorithm and identified three MIS-C subphenotypes. As validation, we characterized and compared more granular features across subphenotypes. To evaluate the specificity of the identified subphenotypes, we further compared them with the general subphenotypes identified in the COVID-19 infected patients. Findings Subphenotype 1 (46.1%) represents patients with a mild manifestation of MIS-C not requiring intensive care, with minimal cardiac involvement. Subphenotype 2 (25.3%) is associated with a high risk of shock, cardiac and renal involvement, and an intermediate risk of respiratory symptoms. Subphenotype 3 (28.6%) represents patients requiring intensive care, with a high risk of shock and cardiac involvement, accompanied by a high risk of >4 organ system being impacted. Importantly, for hospital-specific clinical decision-making, our algorithm also revealed a substantial heterogeneity in relative proportions of these three subtypes across hospitals. Properly accounting for such heterogeneity can lead to accurate characterization of the subphenotypes at the patient-level. Interpretation Our identified three MIS-C subphenotypes have profound implications for personalized treatment strategies, potentially influencing clinical outcomes. Further, the proposed algorithm facilitates federated subphenotyping while accounting for the heterogeneity across hospitals.

Vaccine Effectiveness Against Long COVID in Children: A Report from the RECOVER EHR Cohort (preprint)

Objective Vaccination reduces the risk of acute COVID-19 in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5 to 17 years. Methods This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record (EHR) Program for visits between vaccine availability, and October 29, 2022. Conditional logistic regression was used to estimate VE against long COVID with matching on age group (5 to 11, 12 to 17) and time period and adjustment for sex, ethnicity, health system, comorbidity burden, and pre-exposure health care utilization. We examined both probable (symptom-based) and diagnosed long COVID in the year following vaccination. Results The vaccination rate was 56% in the cohort of 1,037,936 children. The incidence of probably long COVID was 4.5% among patients with COVID-19, while diagnosed long COVID was 0.7%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5 - 44.5) against probable long COVID and 41.7% (15.0- 60.0) against diagnosed long COVID. VE was higher for adolescents 50.3% [36.3 - 61.0]) than children aged 5-11 (23.8% [4.9 -39.0]). VE was higher at 6 months (61.4% [51.0 - 69.6]), but decreased to 10.6% (-26.8 - 37.0%) at 18 months. Discussion This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data. Discussion This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data.

Real-world Effectiveness of BNT162b2 in Children and Adolescents in Preventing Infection and Severe Diseases with SARS-CoV-2 During the Delta and Omicron Periods: Findings from Trial Emulation Using an EHR-based Cohort (preprint)

BACKGROUND The current understanding of the long-term effectiveness of the BNT162b2 vaccine for a range of outcomes across diverse U.S. pediatric populations is limited. In this study, we assessed the effectiveness of BNT162b2 against various strains of the SARS-CoV-2 virus using data from a national collaboration of pediatric health systems (PEDSnet). METHODS We emulated three target trials to assess the real-world effectiveness of BNT162b2: adolescents aged 12 to 20 years during the Delta variant period (Target trial 1), children aged 5 to 11 years (Target trial 2) and adolescents aged 12 to 20 years during the Omicron variant period (Target trial 3). The outcomes included documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and two cardiac-related outcomes, myocarditis and pericarditis. In the U.S., immunization records are often captured and stored across multiple disconnected sources, resulting in incomplete vaccination records in patients' electronic health records (EHR). We implemented a novel trial emulation pipeline accounting for possible misclassification bias in vaccine documentation in EHRs. The effectiveness of the BNT162b2 vaccine was estimated from the Poisson regression model with confounders balanced via propensity score stratification. RESULTS During the Delta period, the BNT162b2 vaccine demonstrated an overall effectiveness 98.4% (95% CI, 98.1 to 98.7) against documented infection among adolescents, with no significant waning after receipt of the first dose. During the Omicron period, the overall effectiveness was estimated to be 74.3% (95% CI, 72.2 to 76.2) in preventing documented infection among children, which was higher against moderate or severe COVID-19 (75.5%; 95% CI, 69.0 to 81.0) and ICU admission with COVID-19 (84.9%; 95% CI, 64.8 to 93.5). In the adolescent population, the overall effectiveness against documented Omicron infection was 85.5% (95% CI, 83.8 to 87.1), with effectiveness of 84.8% (95% CI, 77.3 to 89.9) against moderate or severe COVID-19, and 91.5% (95% CI, 69.5 to 97.6) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined after 4 months following the first dose and then stabilized with higher levels of uncertainty. Across all three cohorts, the risk of cardiac outcomes was approximately 65% to 85% lower in the vaccinated group than that of the unvaccinated group accounting for possible misclassification bias. CONCLUSIONS This study suggests BNT162b2 was effective among children and adolescents in Delta and Omicron periods for a range of COVID-19-related outcomes and is associated with a lower risk for cardiac complications. Waning effectiveness over time suggests that revaccination may be needed in the future.

Four new eudesmane-type and one new eremophilane-type sesquiterpenes from the whole plant of Carpesium abrotanoides L.

The extract of the whole plant of Carpesium abrotanoides L. yielded five new sesquiterpenes including four eudesmanes (1-4) and one eremophilane (5). The new compounds were characterized by spectroscopic analysis especially 1D and 2D NMR spectroscopy and HRESIMS data. Structurally, both compounds 1 and 2 were sesquiterpene epoxides and 2 owned an epoxy group at C-4/C-15 position to form a spiro skeleton. Compounds 4 and 5 were two sesquiterpenes without lactones and 5 possessed a carboxy group in the molecule. Additionally, all the isolated compounds were preliminarily evaluated for the inhibitory activity against SARS-CoV-2 main protease. As a result, compound 2 showed moderate activity with an IC50 value of 18.79 µM, while other compounds were devoid of noticeable activity (IC50 > 50 µM).

Addressing the COVID-19 Shock: The Potential Job Creation in China by the RCEP.

In 2020, coronavirus disease (COVID-19) left around 81% of the global workforce, nearly 2.7 billion workers, affected. Employment in China was the first to be hit by COVID-19. The Regional Comprehensive Economic Partnership (RCEP) is expected to bring dynamism to China's employment market in an era of long COVID-19. This study aims to examine the number of sectoral jobs that the RCEP will create in China, with the number of skilled or unskilled labour employed in each sector. The exogenous shocks to the RCEP can be reflected in the number of jobs created through multipliers based on a social accounting matrix compiled from China's input-output tables in 2017, combined with the employment satellite accounts compiled. The results show that the RCEP is expected to create over 17 million potential jobs in China, with unskilled labour accounting for 10.44 million and skilled labour for 6.77 million. It is even expected that there will be job losses in the metalworking machinery sector. The contribution of this paper can serve as a reference for policies to protect vulnerable sectors, further open up trade markets and strengthen cooperation among RCEP members as important measures to address the employment impact of long COVID-19.

Understanding pediatric long COVID using a tree-based scan statistic approach: An EHR-based cohort study from the RECOVER Program (preprint)

Objectives: Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect signals associated with PASC. Materials and Methods We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) (N=1250) to children with (N=6250) and without (N=6250) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. Results We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise. Discussion Our study addresses methodological limitations of prior studies that rely on pre-specified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes. Conclusion We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation.

Service supply chain resilience: a social-ecological perspective on last-mile delivery operations

Purpose Considering the last-mile delivery service supply chain as a social-ecological system rather than just a firm-based service system, this research exploit the COVID-19 pandemic disruption to investigate how the supply chain develops resilience from a viewpoint that integrates a social-ecological perspective with the traditional engineering one. Design/methodology/approach This research adopt a multi-case study approach using qualitative data collected via semi-structured interviews with executive-level managers from nine leading UK last-mile delivery companies. Data analysis is guided by a research framework which is developed by combining the social-ecological perspective with the structure-conduct-performance paradigm. This framework aids the investigation of the impacts of external challenges on companies' resilience strategies and practices, as well as performance, in response to disruptions. Findings The research identifies three distinct pathways to resilience development: stabilization, focussing on bouncing back to the original normal;adaptation, involving evolutionary changes to a new normal;transformation, involving revolutionary changes in pursuit of a new normal-plus. Three strategic orientations are identified as operating across these pathways: people orientation, digital orientation, and learning orientation. Originality/value In contrast to the manufacturing supply chain focus of most current research, this research concentrates on the service supply chain, investigating its resilience with a social-ecological perspective alongside the traditional engineering one.

Impact of SARS-CoV-2 infection on disease trajectory in youth with T1D: An EHR-based cohort study from the RECOVER program (preprint)

Background: Post-acute sequelae of SARS-Co-V-2 infection (PASC) is associated with worsening diabetes trajectory. It is unknown whether PASC in children with type 1 diabetes (T1D) manifests as worsening diabetes trajectory. Objective: To explore the association between SARS-CoV-2 infection (COVID-19) and T1D-related healthcare utilization (for diabetic ketoacidosis [DKA] or severe hypoglycemia [SH]) or Hemoglobin (Hb) A1c trajectory. Methods: We included children <21 years with T1D and [≥]1 HbA1c prior to cohort entry, which was defined as COVID-19 (positive diagnostic test or diagnosis code for COVID-19, multisystem inflammatory syndrome in children, or PASC) or a randomly selected negative test for those who were negative throughout the study period (Broad Cohort). A subset with [≥]1 HbA1c value from 28-275 days after cohort entry (Narrow Cohort) was included in the trajectory analysis. Propensity score-based matched cohort design followed by weighted Cox regression was used to evaluate the association of COVID-19 with healthcare utilization >28 days after cohort entry. Generalized estimating equation models were used to measure change in HbA1c in the Narrow cohort. Results: From 03/01/2020-06/22/2022, 2,404 and 1,221 youth met entry criteria for the Broad and Narrow cohorts, respectively. The hazard ratio for utilization was (HR 1.45 [95%CI,0.97,2.16]). In the Narrow Cohort, the rate of change (slope) of HbA1c increased 91-180 days after cohort entry for those with COVID-19 (0.138 vs. -0.002, p=0.172). Beyond 180 days, greater declines in HbA1c were observed in the positive cohort (-0.104 vs. 0.008 per month, p=0.024). Conclusion: While a trend towards worse outcomes following COVID-19 in T1D patients was observed, these findings were not statistically significant. Continued clinical monitoring of youth with T1D following COVID-19 is warranted.

Clinical Subphenotypes of Multisystem Inflammatory Syndrome in Children: An EHR-based cohort study from the RECOVER program (preprint)

Background: Multi-system inflammatory syndrome in children (MIS-C) represents one of the most severe post-acute sequelae of SARS-CoV-2 infection in children, and there is a critical need to characterize its disease patterns for improved recognition and management. Our objective was to characterize subphenotypes of MIS-C based on presentation, demographics and laboratory parameters. Methods: We conducted a retrospective cohort study of children with MIS-C from March 1, 2020 - April 30, 2022 and cared for in 8 pediatric medical centers that participate in PEDSnet. We included demographics, symptoms, conditions, laboratory values, medications and outcomes (ICU admission, death), and grouped variables into eight categories according to organ system involvement. We used a heterogeneity-adaptive latent class analysis model to identify three clinically-relevant subphenotypes. We further characterized the sociodemographic and clinical characteristics of each subphenotype, and evaluated their temporal patterns. Findings: We identified 1186 children hospitalized with MIS-C. The highest proportion of children (44.4%) were aged between 5-11 years, with a male predominance (61.0%), and non-Hispanic white ethnicity (40.2%). Most (67.8%) children did not have a chronic condition. Class 1 represented children with a severe clinical phenotype, with 72.5% admitted to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 represented a mild presentation, with fewer organ systems involved, lower CRP, troponin values and less cardiac involvement. Class 1 initially represented 51.1% of children early in the pandemic, which decreased to 33.9% from the pre-delta period to the omicron period. Interpretation: MIS-C has a spectrum of clinical severity, with degree of laboratory abnormalities rather than the number of organ systems involved providing more useful indicators of severity. The proportion of severe/critical MIS-C decreased over time.

The role of interleukin-22 in lung health and its therapeutic potential for COVID-19

Although numerous clinical trials have been implemented, an absolutely effective treatment against coronavirus disease 2019 (COVID-19) is still elusive. Interleukin-22 (IL-22) has attracted great interest over recent years, making it one of the best-studied cytokines of the interleukin-10 (IL-10) family. Unlike most interleukins, the major impact of IL-22 is exclusively on fibroblasts and epithelial cells due to the restricted expression of receptor. Numerous studies have suggested that IL-22 plays a crucial role in anti-viral infections through significantly ameliorating the immune cell-mediated inflammatory responses, and reducing tissue injury as well as further promoting epithelial repair and regeneration. Herein, we pay special attention to the role of IL-22 in the lungs. We summarize the latest progress in our understanding of IL-22 in lung health and disease and further discuss maneuvering this cytokine as potential immunotherapeutic strategy for the effective manage of COVID-19.

Conservative Antibiotic Treatment of Pediatric Uncomplicated Appendicitis During Covid-19 Pandemic– a Case Control Study (preprint)

Background Our study aimed to compare the clinical outcomes and cost-efficiency of antibiotic management versus laparoscopic appendectomy for acute uncomplicated appendicitis (AUA) in children during the COVID-19 pandemic when resources were limited and transmission risks uncertain.Method In this prospective case-control study between Apr 2020 to Jan 2022, we analyzed the data of 139 children diagnosed with AUA meeting the following inclusion criteria: symptoms duration of ≤48 hours, appendix diameter ≤11 mm and no appendicolith. 78/139 cases were treated with antibiotics while 61 matched controls underwent upfront laparoscopic appendectomy. Antibiotic regimes were intravenous Ceftriaxone/Metronidazole or Amoxicillin/Clavulanic acid for 48 hours, followed by oral antibiotics to complete total 10-days course.Results 8/78 (10.3%) children had early failure (within 48hours) requiring appendectomy. 17/78 patients (21.8%) experienced late recurrence within mean follow-up time of 16.2±4.7 months. There were no statistical differences in peri-operative complications, negative appendicectomy rate, incidence of perforation and hospitalization duration between antibiotic and surgical treatment groups. Cost per patient in upfront surgical group was significantly higher ($6208.5±5284.0) than antibiotic group ($3588.6±3829.8; p = 0.001).Conclusion Despite 21.9% risk of recurrence of appendicitis in 16.2±4.7 months, antibiotic therapy for AUA appears to be a safe and cost-effective alternative to upfront appendectomy.

Healthcare utilization following SARS-CoV-2 infection in children and adolescents with chronic conditions: An EHR-based Cohort Study from the RECOVER Program (preprint)

Background Chronic medical conditions are a risk factor for moderate or severe COVID-19 in children, but little is known about post-acute sequelae of SARS-CoV-2 infection (PASC) in children with chronic medical conditions (CMCs). To understand whether SARS-CoV-2 infection led to potential exacerbation of underlying chronic disease in children, we explored whether children with CMCs had increased healthcare utilization in the post-acute (28 days after infection) period compared to children with CMCs without SARS-CoV-2 infection. Methods We conducted a retrospective, matched-cohort study using electronic health record data collected from 8 pediatric health care systems participating in the PEDSnet network. We included children <21 years of age with a wide array of chronic conditions, defined by the presence of diagnostic codes, who were diagnosed with COVID-19 between March 1, 2020 and February 28, 2022. Cohort entry was defined by presence of a positive SARS-CoV-2 PCR test (polymerase chain reaction or antigen) or diagnostic codes for COVID-19, PASC or MIS-C. A comparison cohort of patients testing negative or without these conditions was matched using a stratified propensity score model and exact matching on age group, race/ethnicity, institution, test location, and month of cohort entry. A negative binomial model was used to examine our primary outcome: composite and setting-specific (inpatient, outpatient, ED) utilization rate ratios between the positive and comparison cohorts. Secondary outcomes included time to first utilization in the post-acute period, and utilization stratified by severity at cohort entry. Results We identified 748,692 patients with at least one chronic condition, 78,744 of whom met inclusion criteria for the COVID-19 cohort. 96% of patients from the positive cohort were matched. Cohorts were well-balanced for chronic condition clusters, total number of conditions, time since first diagnosis, baseline utilization, cohort entry period, age, sex, race/ethnicity and test location. We found that among children with chronic medical conditions, those with COVID-19 had higher healthcare utilization than those with no recorded COVID-19 diagnosis or positive test, with utilization rate ratio of 1.21 (95% CI: 1.18-1.24). The utilization was highest for inpatient care with utilization rate ratio of 2.03 (95% CI: 1.85-2.23) but the utilization was increased across all settings. Hazard ratios estimated in time-to-first-utilization analysis mirrored these results. Patients with severe or moderate acute COVID-19 illness had greater increases in utilization in all settings than those with mild or asymptomatic disease. Conclusions We found that care utilization in all settings was increased following COVID-19 in children with chronic medical conditions in the post-acute period, particularly in the inpatient setting. Increased utilization was correlated with more severe COVID-19. Additional research is needed to better understand the reasons for higher care utilization by studying condition-specific outcomes in children with chronic disease.

Identification of transcriptomics biomarker for the early prediction of critically ill COVID-19 patients (preprint)

Objective Identifying the biological subsets of severe COVID-19 could provide a basis for finding biomarkers for the early prediction of the prognosis of severe COVID-19 and poor prognosis, and may facilitate specific treatment for COVID-19.Methods In this study we downloaded microarray dataset GSE172114 from the Gene Expression Omnibus (GEO) database in NCBI, and screened differentially-expressed genes (DEGs) by using the limma package in R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, and the results were presented by volcano, Venn, heat, and enrichment pathway bubble maps in the R language package. Gene set enrichment analysis (GSEA) was used to explore and demonstrate the signal pathways related to severe COVID-19. Protein-Protein Interaction (PPI) Network analysis and visualization were performed by using STRING and Cytoscape. Seven key protein expression molecules were screened by the MOCDE plug-in. Then, the cytoHubba plug-in was used to screen 10 candidate genes with maximal clique centrality (MCC) algorithm as the standard, and the intersection with the Venn diagram was used to obtain seven Hub genes. Receiver operating characteristic (ROC) curves were drawn to determine the area under the curve (AUC), and the predictive value of the key genes was evaluated.Results A total of 210 DEGs were identified, including 186 upregulated genes as well as downregulated ones. GO enrichment and KEGG pathway analysis were used, and the results were presented by volcano, Venn, heat, and enrichment pathway bubble maps in the R language package. Gene set enrichment analysis (GSEA) was used to explore and demonstrate the signal pathways related to severe COVID-19. Protein interaction network (PPI) analysis and visualization were performed by using STRING and Cytoscape. Seven key protein expression molecules were screened by the MOCDE plug-in. Then, the cytoHubba plug-in was used to screen 10 candidate genes with maximal clique centrality (MCC) algorithm as the standard, and the intersection with the Venn diagram was used to obtain seven Hub genes. Receiver operating characteristic (ROC) curves were drawn to determine the area under the curve (AUC), and the predictive value of the key genes was evaluated. The AUC of the PLSCR1 gene was 0.879, which was the most significantly upregulated key gene in critically ill COVID-19 patients.Conclusions Based on bioinformatics analysis, we found that the screened candidate gene, PLSCR1, may be closely related to the occurrence of severe COVID-19, and can thus be used for the early prediction of patients with severe COVID-19, and may provide meaningful research direction for their treatment.

Clinical features and burden of post-acute sequelae of SARS-CoV-2 infection in children and adolescents: an exploratory EHR-based cohort study from the RECOVER program (preprint)

Importance The post-acute sequelae of SARS-CoV-2 (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. Objective To identify diagnosed symptoms, diagnosed health conditions and medications associated with PASC in children. Design, Setting and Participants Retrospective cohort study using electronic health records from 9 US children’s hospitals for individuals <21 years-old who underwent reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020 – October 31, 2021 and had at least 1 encounter in the 3 years before testing. Exposure SARS-CoV-2 PCR positivity. Main Outcomes and Measures We identified syndromic (symptoms), systemic (conditions), and medication PASC features in the 28-179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting PCR-positive with PCR-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race/ethnicity, and time-period of cohort entrance. We estimated the incidence proportion for any syndromic, systemic or medication PASC feature in the two groups to obtain a burden of PASC estimate. Results Among 659,286 children in the study sample, 59,893 (9.1%) tested positive by PCR for SARS-CoV-2. Most were tested in outpatient testing facility (50.3%) or office (24.6%) settings. The most common syndromic, systemic, and medication features were loss of taste or smell (aHR 1.96 [95% CI 1.16-3.32), myocarditis (aHR 3.10 [95% CI 1.94-4.96]), and cough and cold preparations (aHR 1.52 [95% CI 1.18-1.96]). The incidence of at least one systemic/syndromic/medication feature of PASC was 41.9% among PCR-positive children versus 38.2% among PCR-negative children, with an incidence proportion difference of 3.7% (95% CI 3.2-4.2%). A higher strength of association for PASC was identified in those cared for in the ICU during the acute illness phase, children less than 5 years-old, and individuals with complex chronic conditions. Conclusions and Relevance In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC. Key Points Question What are the incidence and clinical features of post-acute sequelae of SARS-CoV-2 infection (PASC) in children? Findings In this retrospective cohort study of 659,286 children tested for SARS-CoV-2 by polymerase chain reaction (PCR), the symptom, condition and medication with the strongest associations with SARS-CoV-2 infection were loss of taste/smell, myocarditis, and cough and cold preparations. The incidence proportion of non-MIS-C related PASC in the PCR-positive group exceeded the PCR-negative group by 3.7% (95% CI 3.2-4.2), with increased rates associated with acute illness severity, young age, and medical complexity. Meaning PASC in children appears to be uncommon, with features that differ from adults.

In situ architecture and membrane fusion of SARS-CoV-2 Delta variant (preprint)

Among the current five Variants of Concern, infections caused by the SARS-CoV-2 B.1.617.2 (Delta) variant are often associated with the greatest severity. Despite recent advances on the molecular basis of elevated pathogenicity using recombinant proteins, architecture of intact Delta virions remains veiled. Moreover, the detailed mechanism of S-mediated membrane fusion remains elusive. Here we report the molecular assembly and fusion snapshots of the authentic Delta variant. Envelope invagination and fusion events were frequently observed. Native structures of pre- and postfusion S were determined up to 4.1-A resolution. Site-specific glycan analysis revealed increased oligomannose-type glycosylation of native Delta S over that of the Wuhan-Hu-1 S. Based on these findings, we proposed a model for S-mediated membrane fusion and a model for the invagination formation.