Astrocytic stress response is induced by exposure to astrocyte-binding antibodies expressed by plasmablasts from pediatric patients with acute transverse myelitis.

BACKGROUND: Pediatric acute transverse myelitis (ATM) accounts for 20-30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical presentation of a relapsing ADS such as multiple sclerosis (MS). B cells have been strongly implicated in the pathogenesis of adult MS. However, little is known about B cells in pediatric MS, and even less so in pediatric ATM. Our lab previously showed that plasmablasts (PB), the earliest B cell subtype producing antibody, are expanded in adult ATM, and that these PBs produce self-reactive antibodies that target neurons. The goal of this study was to examine PB frequency and phenotype, immunoglobulin selection, and B cell receptor reactivity in pediatric patients presenting with ATM to gain insight to B cell involvement in disease. METHODS: We compared the PB frequency and phenotype of 5 pediatric ATM patients and 10 pediatric healthy controls (HC) and compared them to previously reported adult ATM patients using cytometric data. We purified bulk IgG from the plasma samples and cloned 20 recombinant human antibodies (rhAbs) from individual PBs isolated from the blood. Plasma-derived IgG and rhAb autoreactivity was measured by mean fluorescence intensity (MFI) in neurons and astrocytes of murine brain or spinal cord and primary human astrocytes. We determined the potential impact of these rhAbs on astrocyte health by measuring stress and apoptotic response. RESULTS: We found that pediatric ATM patients had a reduced frequency of peripheral blood PB. Serum IgG autoreactivity to neurons in EAE spinal cord was similar in the pediatric ATM patients and HC. However, serum IgG autoreactivity to astrocytes in EAE spinal cord was reduced in pediatric ATM patients compared to pediatric HC. Astrocyte-binding strength of rhAbs cloned from PBs was dependent on somatic hypermutation accumulation in the pediatric ATM cohort, but not HC. A similar observation in predilection for astrocyte binding over neuron binding of individual antibodies cloned from PBs was made in EAE brain tissue. Finally, exposure of human primary astrocytes to these astrocyte-binding antibodies increased astrocytic stress but did not lead to apoptosis. CONCLUSIONS: Discordance in humoral immune responses to astrocytes may distinguish pediatric ATM from HC.

Association between SARS-CoV-2 infection and select symptoms and conditions 31 to 150 days after testing among children and adults.

BACKGROUND: An increasing number of studies have described new and persistent symptoms and conditions as potential post-acute sequelae of SARS-CoV-2 infection (PASC). However, it remains unclear whether certain symptoms or conditions occur more frequently among persons with SARS-CoV-2 infection compared with those never infected with SARS-CoV-2. We compared the occurrence of specific COVID-associated symptoms and conditions as potential PASC 31- to 150-day following a SARS-CoV-2 test among adults and children with positive and negative test results. METHODS: We conducted a retrospective cohort study using electronic health record (EHR) data from 43 PCORnet sites participating in a national COVID-19 surveillance program. This study included 3,091,580 adults (316,249 SARS-CoV-2 positive; 2,775,331 negative) and 675,643 children (62,131 positive; 613,512 negative) who had a SARS-CoV-2 laboratory test during March 1, 2020-May 31, 2021 documented in their EHR. We used logistic regression to calculate the odds of having a symptom and Cox models to calculate the risk of having a newly diagnosed condition associated with a SARS-CoV-2 positive test. RESULTS: After adjustment for baseline covariates, hospitalized adults and children with a positive test had increased odds of being diagnosed with ≥ 1 symptom (adults: adjusted odds ratio[aOR], 1.17[95% CI, 1.11-1.23]; children: aOR, 1.18[95% CI, 1.08-1.28]) or shortness of breath (adults: aOR, 1.50[95% CI, 1.38-1.63]; children: aOR, 1.40[95% CI, 1.15-1.70]) 31-150 days following a SARS-CoV-2 test compared with hospitalized individuals with a negative test. Hospitalized adults with a positive test also had increased odds of being diagnosed with ≥ 3 symptoms or fatigue compared with those testing negative. The risks of being newly diagnosed with type 1 or type 2 diabetes (adjusted hazard ratio[aHR], 1.25[95% CI, 1.17-1.33]), hematologic disorders (aHR, 1.19[95% CI, 1.11-1.28]), or respiratory disease (aHR, 1.44[95% CI, 1.30-1.60]) were higher among hospitalized adults with a positive test compared with those with a negative test. Non-hospitalized adults with a positive test also had higher odds or increased risk of being diagnosed with certain symptoms or conditions. CONCLUSIONS: Patients with SARS-CoV-2 infection, especially those who were hospitalized, were at higher risk of being diagnosed with certain symptoms and conditions after acute infection.

Coordinating virus research: The Virus Infectious Disease Ontology.

The COVID-19 pandemic prompted immense work on the investigation of the SARS-CoV-2 virus. Rapid, accurate, and consistent interpretation of generated data is thereby of fundamental concern. Ontologies-structured, controlled, vocabularies-are designed to support consistency of interpretation, and thereby to prevent the development of data silos. This paper describes how ontologies are serving this purpose in the COVID-19 research domain, by following principles of the Open Biological and Biomedical Ontology (OBO) Foundry and by reusing existing ontologies such as the Infectious Disease Ontology (IDO) Core, which provides terminological content common to investigations of all infectious diseases. We report here on the development of an IDO extension, the Virus Infectious Disease Ontology (VIDO), a reference ontology covering viral infectious diseases. We motivate term and definition choices, showcase reuse of terms from existing OBO ontologies, illustrate how ontological decisions were motivated by relevant life science research, and connect VIDO to the Coronavirus Infectious Disease Ontology (CIDO). We next use terms from these ontologies to annotate selections from life science research on SARS-CoV-2, highlighting how ontologies employing a common upper-level vocabulary may be seamlessly interwoven. Finally, we outline future work, including bacteria and fungus infectious disease reference ontologies currently under development, then cite uses of VIDO and CIDO in host-pathogen data analytics, electronic health record annotation, and ontology conflict-resolution projects.

Understanding Factors that Influence Prognosis and Response to Therapy in Clear Cell Renal Cell Carcinoma.

In this review, we highlight and contextualize emerging morphologic prognostic and predictive factors in renal cell carcinoma. We focus on clear cell renal cell carcinoma (ccRCC), the most common histologic subtype. Our understanding of the molecular characterization of ccRCC has dramatically improved in the last decade. Herein, we highlight how these discoveries have laid the foundation for new approaches to prognosis and therapeutic decision-making for patients with ccRCC. We explore the clinical relevance of common mutations, established gene expression signatures, intratumoral heterogeneity, sarcomatoid/rhabdoid morphology and PD-L1 expression, and discuss their impact on predicting response to therapy.

Vaccine Effectiveness Against Long COVID in Children.

OBJECTIVES: Vaccination reduces the risk of acute coronavirus disease 2019 (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 program for visits after vaccine availability. We examined both probable (symptom-based) and diagnosed long COVID after vaccination. RESULTS: The vaccination rate was 67% in the cohort of 1 037 936 children. The incidence of probable long COVID was 4.5% among patients with COVID-19, whereas diagnosed long COVID was 0.8%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5-44.7) against probable long COVID and 41.7% (15.0-60.0) against diagnosed long COVID. VE was higher for adolescents (50.3% [36.6-61.0]) than children aged 5 to 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% to 37.0%) at 18-months. CONCLUSIONS: This large retrospective study shows moderate protective effect of severe acute respiratory coronavirus 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 electronic health record sources and prospective data.

Vaccine Effectiveness Against Long COVID in Children: A Report from the RECOVER EHR Cohort.

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 5-17 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 (5-11, 12-17) 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 probable 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. Article Summary: Vaccination against COVID-19 has a protective effect against long COVID in children and adolescents. The effect wanes over time but remains significant at 12 months. What's Known on This Subject: Vaccines reduce the risk and severity of COVID-19 in children. There is evidence for reduced long COVID risk in adults who are vaccinated, but little information about similar effects for children and adolescents, who have distinct forms of long COVID. What This Study Adds: Using electronic health records from US health systems, we examined large cohorts of vaccinated and unvaccinated patients <18 years old and show that vaccination against COVID-19 is associated with reduced risk of long COVID for at least 12 months. Contributors' Statement: Drs. Hanieh Razzaghi and Charles Bailey conceptualized and designed the study, supervised analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript.Drs. Christopher Forrest and Yong Chen designed the study and critically reviewed and revised the manuscript.Ms. Kathryn Hirabayashi, Ms. Andrea Allen, and Dr. Qiong Wu conducted analyses, and critically reviewed and revised the manuscript.Drs. Suchitra Rao, H Timothy Bunnell, Elizabeth A. Chrischilles, Lindsay G. Cowell, Mollie R. Cummins, David A. Hanauer, Benjamin D. Horne, Carol R. Horowitz, Ravi Jhaveri, Susan Kim, Aaron Mishkin, Jennifer A. Muszynski, Susanna Nagie, Nathan M. Pajor, Anuradha Paranjape, Hayden T. Schwenk, Marion R. Sills, Yacob G. Tedla, David A. Williams, and Ms. Miranda Higginbotham critically reviewed and revised the manuscript.All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Authorship statement: Authorship has been determined according to ICMJE recommendations.

VH2+ Antigen-Experienced B Cells in the Cerebrospinal Fluid Are Expanded and Enriched in Pediatric Anti-NMDA Receptor Encephalitis.

Pediatric and adult autoimmune encephalitis (AE) are often associated with Abs to the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Very little is known regarding the cerebrospinal fluid humoral immune profile and Ab genetics associated with pediatric anti-NMDAR-AE. Using a combination of cellular, molecular, and immunogenetics tools, we collected cerebrospinal fluid from pediatric subjects and generated 1) flow cytometry data to calculate the frequency of B cell subtypes in the cerebrospinal fluid of pediatric subjects with anti-NMDAR-AE and controls, 2) a panel of recombinant human Abs from a pediatric case of anti-NMDAR-AE that was refractory to treatment, and 3) a detailed analysis of the Ab genes that bound the NR1 subunit of the NMDAR. Ag-experienced B cells including memory cells, plasmablasts, and Ab-secreting cells were expanded in the pediatric anti-NMDAR-AE cohort, but not in the controls. These Ag-experienced B cells in the cerebrospinal fluid of a pediatric case of NMDAR-AE that was refractory to treatment had expanded use of variable H chain family 2 (VH2) genes with high somatic hypermutation that all bound to the NR1 subunit of the NMDAR. A CDR3 motif was identified in this refractory case that likely drove early stage activation and expansion of naive B cells to Ab-secreting cells, facilitating autoimmunity associated with pediatric anti-NMDAR-AE through the production of Abs that bind NR1. These features of humoral immune responses in the cerebrospinal fluid of pediatric anti-NMDAR-AE patients may be relevant for clinical diagnosis and treatment.

Neuron-binding antibody responses are associated with Black ethnicity in multiple sclerosis during natalizumab treatment.

Multiple sclerosis is an inflammatory degenerative condition of the central nervous system that may result in debilitating disability. Several studies over the past twenty years suggest that multiple sclerosis manifests with a rapid, more disabling disease course among individuals identifying with Black or Latin American ethnicity relative to those of White ethnicity. However, very little is known about immunologic underpinnings that may contribute to this ethnicity-associated discordant clinical severity. Given the importance of B cells to multiple sclerosis pathophysiology, and prior work showing increased antibody levels in the cerebrospinal fluid of Black-identifying, compared to White-identifying multiple sclerosis patients, we conducted a cohort study to determine B cell subset dynamics according to both self-reported ethnicity and genetic ancestry over time. Further, we determined relationships between ethnicity, ancestry, and neuron-binding IgG levels. We found significant associations between Black ethnicity and elevated frequencies of class-switched B cell subsets, including memory B cells; double negative two B cells; and antibody-secreting cells. The frequencies of these subsets positively correlated with West African genetic ancestry. We also observed significant associations between Black ethnicity and increased IgG binding to neurons. Our data suggests significantly heightened T cell-dependent B cell responses exhibiting increased titres of neuron-binding antibodies among individuals with multiple sclerosis identifying with the Black African diaspora. Factors driving this immunobiology may promote the greater demyelination, central nervous system atrophy and disability more often experienced by Black-, and Latin American-identifying individuals with multiple sclerosis.

Neuronal binding by antibodies can be influenced by low pH stress during the isolation procedure.

Low pH stress and its influence on antibody binding is a common consideration among chemists, but is only recently emerging as a consideration in Immunological studies. Antibody characterizations in Multiple Sclerosis (MS), an autoimmune disease of the Central Nervous System (CNS) has revealed that antibodies in the cerebrospinal fluid (CSF) of patients with Multiple Sclerosis bind to myelin-related and non-myelin antigen targets. Many laboratories have used molecular biology techniques to generate recombinant human antibodies (rhAbs) expressed by individual B cells from healthy donors and patients with systemic autoimmune disease to identify antigen targets. This approach has been adapted within the Neuroimmunology research community to investigate antigen targets of individual B cells in the CSF of MS patients. Our laboratory determines which antibodies to clone based on their immunogenetics and this method enriches for cloning of rhAbs that bind to neurons. However, newer technologies to assist in purification of these rhAbs from culture supernatants use an acidic elution buffer which may enhance low pH stress on the antibody structure. Our laboratory routinely uses a basic elution buffer to purify rhAbs from culture supernatants to avoid low pH stress to the antibody structure. Our goal was to investigate whether acidic elution of our rhAbs using Next Generation Chromatography would impact the rhAbs' ability to bind neurons. The limited data presented here for two neuron-binding rhAbs tested indicated that acidic elution buffers used during rhAb purification impacted the ability of rhAbs with low CDR3 charge to maintain binding to neuronal targets. Reproducibility in a larger panel of rhAbs and factors underlying these observations remain untested.

AIRR community curation and standardised representation for immunoglobulin and T cell receptor germline sets.

Analysis of an individual's immunoglobulin or T cell receptor gene repertoire can provide important insights into immune function. High-quality analysis of adaptive immune receptor repertoire sequencing data depends upon accurate and relatively complete germline sets, but current sets are known to be incomplete. Established processes for the review and systematic naming of receptor germline genes and alleles require specific evidence and data types, but the discovery landscape is rapidly changing. To exploit the potential of emerging data, and to provide the field with improved state-of-the-art germline sets, an intermediate approach is needed that will allow the rapid publication of consolidated sets derived from these emerging sources. These sets must use a consistent naming scheme and allow refinement and consolidation into genes as new information emerges. Name changes should be minimised, but, where changes occur, the naming history of a sequence must be traceable. Here we outline the current issues and opportunities for the curation of germline IG/TR genes and present a forward-looking data model for building out more robust germline sets that can dovetail with current established processes. We describe interoperability standards for germline sets, and an approach to transparency based on principles of findability, accessibility, interoperability, and reusability.

Factors Associated With Receipt of Molecular Testing and its Impact on Time to Initial Systemic Therapy in Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: Despite recommendations for molecular testing irrespective of patient characteristics, differences exist in receipt of molecular testing for oncogenic drivers amongst metastatic non-small cell lung cancer (mNSCLC) patients. Exploration into these differences and their effects on treatment is needed to identify opportunities for improvement. PATIENTS AND METHODS: We conducted a retrospective cohort study of adult patients diagnosed with mNSCLC between 2011 and 2018 using PCORnet's Rapid Cycle Research Project dataset (n = 3600). Log-binomial, Cox proportional hazards (PH), and time-varying Cox regression models were used to ascertain whether molecular testing was received, and time from diagnosis to molecular testing and/or initial systemic treatment in the context of patient age, sex, race/ethnicity, and multiple comorbidities status. RESULTS: The majority of patients in this cohort were ≤ 65 years of age (median [25th, 75th]: 64 [57, 71]), male (54.3%), non-Hispanic white individuals (81.6%), with > 2 comorbidities in addition to mNSCLC (54.1%). About half the cohort received molecular testing (49.9%). Patients who received molecular testing had a 59% higher probability of initial systemic treatment than patients who were yet to receive testing. Multiple comorbidity status was positively associated with receipt of molecular testing (RR, 1.27; 95% CI 1.08, 1.49). CONCLUSION: Receipt of molecular testing in academic centers was associated with earlier initiation of systemic treatment. This finding underscores the need to increase molecular testing rates amongst mNSCLC patients during a clinically relevant period. Further studies to validate these findings in community centers are warranted.

Dynamic kernel matching for non-conforming data: A case study of T cell receptor datasets.

Most statistical classifiers are designed to find patterns in data where numbers fit into rows and columns, like in a spreadsheet, but many kinds of data do not conform to this structure. To uncover patterns in non-conforming data, we describe an approach for modifying established statistical classifiers to handle non-conforming data, which we call dynamic kernel matching (DKM). As examples of non-conforming data, we consider (i) a dataset of T-cell receptor (TCR) sequences labelled by disease antigen and (ii) a dataset of sequenced TCR repertoires labelled by patient cytomegalovirus (CMV) serostatus, anticipating that both datasets contain signatures for diagnosing disease. We successfully fit statistical classifiers augmented with DKM to both datasets and report the performance on holdout data using standard metrics and metrics allowing for indeterminant diagnoses. Finally, we identify the patterns used by our statistical classifiers to generate predictions and show that these patterns agree with observations from experimental studies.

Therapeutic Vaccination for HPV-Mediated Cancers.

Purpose of Review: The goal of this narrative review is to educate clinicians regarding the foundational concepts, efficacy, and future directions of therapeutic vaccines for human papillomavirus (HPV)-mediated cancers. Recent Findings: Therapeutic HPV vaccines deliver tumor antigens to stimulate an immune response to eliminate tumor cells. Vaccine antigen delivery platforms are diverse and include DNA, RNA, peptides, proteins, viral vectors, microbial vectors, and antigen-presenting cells. Randomized, controlled trials have demonstrated that therapeutic HPV vaccines are efficacious in patients with cervical intraepithelial neoplasia. In patients with HPV-mediated malignancies, evidence of efficacy is limited. However, numerous ongoing studies evaluating updated therapeutic HPV vaccines in combination with immune checkpoint inhibition and other therapies exhibit significant promise. Summary: Therapeutic vaccines for HPV-mediated malignancies retain a strong biological rationale, despite their limited efficacy to date. Investigators anticipate they will be most effectively used in combination with other regimens, such as immune checkpoint inhibition.

Immune Repertoire Analysis on High-Performance Computing Using VDJServer V1: A Method by the AIRR Community.

AIRR-seq data sets are usually large and require specialized analysis methods and software tools. A typical Illumina MiSeq sequencing run generates 20-30 million 2 × 300 bp paired-end sequence reads, which roughly corresponds to 15 GB of sequence data to be processed. Other platforms like NextSeq, which is useful in projects where the full V gene is not needed, create about 400 million 2 × 150 bp paired-end reads. Because of the size of the data sets, the analysis can be computationally expensive, particularly the early analysis steps like preprocessing and gene annotation that process the majority of the sequence data. A standard desktop PC may take 3-5 days of constant processing for a single MiSeq run, so dedicated high-performance computational resources may be required.VDJServer provides free access to high-performance computing (HPC) at the Texas Advanced Computing Center (TACC) through a graphical user interface (Christley et al. Front Immunol 9:976, 2018). VDJServer is a cloud-based analysis portal for immune repertoire sequence data that provides access to a suite of tools for a complete analysis workflow, including modules for preprocessing and quality control of sequence reads, V(D)J gene assignment, repertoire characterization, and repertoire comparison. Furthermore, VDJServer has parallelized execution for tools such as IgBLAST, so more compute resources are utilized as the size of the input data grows. Analysis that takes days on a desktop PC might take only a few hours on VDJServer. VDJServer is a free, publicly available, and open-source licensed resource. Here, we describe the workflow for performing immune repertoire analysis on VDJServer's high-performance computing.

Data Sharing and Reuse: A Method by the AIRR Community.

High-throughput sequencing of adaptive immune receptor repertoires (AIRR, i.e., IG and TR ) has revolutionized the ability to study the adaptive immune response via large-scale experiments. Since 2009, AIRR sequencing (AIRR-seq) has been widely applied to survey the immune state of individuals (see "The AIRR Community Guide to Repertoire Analysis" chapter for details). One of the goals of the AIRR Community is to make the resulting AIRR-seq data FAIR (Findable, Accessible, Interoperable, and Reusable) (Wilkinson et al. Sci Data 3:1-9, 2016), with a primary goal of making it easy for the research community to reuse AIRR-seq data (Breden et al. Front Immunol 8:1418, 2017; Scott and Breden. Curr Opin Syst Biol 24:71-77, 2020). The basis for this is the MiAIRR data standard (Rubelt et al. Nat Immunol 18:1274-1278, 2017). For long-term preservation, it is recommended that researchers store their sequence read data in an INSDC repository. At the same time, the AIRR Community has established the AIRR Data Commons (Christley et al. Front Big Data 3:22, 2020), a distributed set of AIRR-compliant repositories that store the critically important annotated AIRR-seq data based on the MiAIRR standard, making the data findable, interoperable, and, because the data are annotated, more valuable in its reuse. Here, we build on the other AIRR Community chapters and illustrate how these principles and standards can be incorporated into AIRR-seq data analysis workflows. We discuss the importance of careful curation of metadata to ensure reproducibility and facilitate data sharing and reuse, and we illustrate how data can be shared via the AIRR Data Commons.

Cardiac Complications After SARS-CoV-2 Infection and mRNA COVID-19 Vaccination - PCORnet, United States, January 2021-January 2022.

Cardiac complications, particularly myocarditis and pericarditis, have been associated with SARS-CoV-2 (the virus that causes COVID-19) infection (1-3) and mRNA COVID-19 vaccination (2-5). Multisystem inflammatory syndrome (MIS) is a rare but serious complication of SARS-CoV-2 infection with frequent cardiac involvement (6). Using electronic health record (EHR) data from 40 U.S. health care systems during January 1, 2021-January 31, 2022, investigators calculated incidences of cardiac outcomes (myocarditis; myocarditis or pericarditis; and myocarditis, pericarditis, or MIS) among persons aged ≥5 years who had SARS-CoV-2 infection, stratified by sex (male or female) and age group (5-11, 12-17, 18-29, and ≥30 years). Incidences of myocarditis and myocarditis or pericarditis were calculated after first, second, unspecified, or any (first, second, or unspecified) dose of mRNA COVID-19 (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) vaccines, stratified by sex and age group. Risk ratios (RR) were calculated to compare risk for cardiac outcomes after SARS-CoV-2 infection to that after mRNA COVID-19 vaccination. The incidence of cardiac outcomes after mRNA COVID-19 vaccination was highest for males aged 12-17 years after the second vaccine dose; however, within this demographic group, the risk for cardiac outcomes was 1.8-5.6 times as high after SARS-CoV-2 infection than after the second vaccine dose. The risk for cardiac outcomes was likewise significantly higher after SARS-CoV-2 infection than after first, second, or unspecified dose of mRNA COVID-19 vaccination for all other groups by sex and age (RR 2.2-115.2). These findings support continued use of mRNA COVID-19 vaccines among all eligible persons aged ≥5 years.

Prevalence of Select New Symptoms and Conditions Among Persons Aged Younger Than 20 Years and 20 Years or Older at 31 to 150 Days After Testing Positive or Negative for SARS-CoV-2.

Importance: New symptoms and conditions can develop following SARS-CoV-2 infection. Whether they occur more frequently among persons with SARS-CoV-2 infection compared with those without is unclear. Objective: To compare the prevalence of new diagnoses of select symptoms and conditions between 31 and 150 days after testing among persons who tested positive vs negative for SARS-CoV-2. Design, Setting, and Participants: This cohort study analyzed aggregated electronic health record data from 40 health care systems, including 338 024 persons younger than 20 years and 1 790 886 persons aged 20 years or older who were tested for SARS-CoV-2 during March to December 2020 and who had medical encounters between 31 and 150 days after testing. Main Outcomes and Measures: International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes were used to capture new symptoms and conditions that were recorded 31 to 150 days after a SARS-CoV-2 test but absent in the 18 months to 7 days prior to testing. The prevalence of new symptoms and conditions was compared between persons with positive and negative SARS-CoV-2 tests stratified by age (20 years or older and young than 20 years) and care setting (nonhospitalized, hospitalized, or hospitalized and ventilated). Results: A total of 168 701 persons aged 20 years or older and 26 665 younger than 20 years tested positive for SARS-CoV-2, and 1 622 185 persons aged 20 years or older and 311 359 younger than 20 years tested negative. Shortness of breath was more common among persons with a positive vs negative test result among hospitalized patients (≥20 years: prevalence ratio [PR], 1.89 [99% CI, 1.79-2.01]; <20 years: PR, 1.72 [99% CI, 1.17-2.51]). Shortness of breath was also more common among nonhospitalized patients aged 20 years or older with a positive vs negative test result (PR, 1.09 [99% CI, 1.05-1.13]). Among hospitalized persons aged 20 years or older, the prevalence of new fatigue (PR, 1.35 [99% CI, 1.27-1.44]) and type 2 diabetes (PR, 2.03 [99% CI, 1.87-2.19]) was higher among those with a positive vs a negative test result. Among hospitalized persons younger than 20 years, the prevalence of type 2 diabetes (PR, 2.14 [99% CI, 1.13-4.06]) was higher among those with a positive vs a negative test result; however, the prevalence difference was less than 1%. Conclusions and Relevance: In this cohort study, among persons hospitalized after a positive SARS-CoV-2 test result, diagnoses of certain symptoms and conditions were higher than among those with a negative test result. Health care professionals should be aware of symptoms and conditions that may develop after SARS-CoV-2 infection, particularly among those hospitalized after diagnosis.

CSF-Derived CD4+ T-Cell Diversity Is Reduced in Patients With Alzheimer Clinical Syndrome.

BACKGROUND AND OBJECTIVES: Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4+ T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia. METHODS: Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4+ and CD8+ T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort. RESULTS: Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4+ T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs. DISCUSSION: Examination of CSF indicates that CD4+ T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.

Burden of Renal Cysts Imaging: A Survey of Patients among the Greater Plains Collaborative.

PURPOSE: Renal cysts are a frequent incidental finding on cross-sectional radiographic imaging. While most cysts are indolent, individuals with such cysts are frequently monitored for interval growth and potential malignant transformation, which is ultimately rare. In this study, we aimed to assess patients' values and preferences (believes and attitudes) about renal cysts. METHODS: We deployed a cross-sectional survey to a random sample of patients with a diagnosis of renal cysts who were identified by billing code and self-identification. We collected data about demographics, insurance status, family history and overall health, and characteristics of patients with renal cysts. We performed a binary regression analysis (adjusted for age, gender, family history of cancer and kidney disease, and treatment plan for renal cysts) to determine anxiety predictors in patients with renal cysts. RESULTS: We included 301 respondents in whom billing code and self-identification corresponded; of these, 138 had renal cysts and 163 did not. In an adjusted regression analysis, there was a suggestion that a clear management plan (OR = 0.49, 95% CI [0.22-1.11]) (p value 0.08) may be associated with less anxiety and a family history of renal disease may be associated with more anxiety (OR = 1.94 [0.76-4.94]) (p value 0.17). Family history of cancer also did not significantly predict anxiety (OR = 0.54 [0.24-1.19]) (p value 0.13). All these results were not statistically significant and had wide confidence intervals of the effect estimates make the results imprecise. CONCLUSION: Findings of this pilot study suggest a clear management plan for the renal cyst(s) management may be associated with a lower level of anxiety, thereby by emphasizing the importance of good communication, patient engagement and evidence-based guidance. More definitive, adequately powered studies are needed to evaluate this finding further. In addition, further studies exploring differences in imaging practices, patient symptomatology and patient engagement by different provider types would be insightful. Ultimately, tools to improve shared decision-making are needed to provide more patient-centered care.