RAG Represents a Widespread Threat to the Lymphocyte Genome.

The RAG1 endonuclease, together with its cofactor RAG2, is essential for V(D)J recombination but is a potent threat to genome stability. The sources of RAG1 mis-targeting and the mechanisms that have evolved to suppress it are poorly understood. Here, we report that RAG1 associates with chromatin at thousands of active promoters and enhancers in the genome of developing lymphocytes. The mouse and human genomes appear to have responded by reducing the abundance of "cryptic" recombination signals near RAG1 binding sites. This depletion operates specifically on the RSS heptamer, whereas nonamers are enriched at RAG1 binding sites. Reversing this RAG-driven depletion of cleavage sites by insertion of strong recombination signals creates an ectopic hub of RAG-mediated V(D)J recombination and chromosomal translocations. Our findings delineate rules governing RAG binding in the genome, identify areas at risk of RAG-mediated damage, and highlight the evolutionary struggle to accommodate programmed DNA damage in developing lymphocytes.

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.

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.

Differences in COVID-19 Outpatient Antiviral Treatment Among Adults Aged ≥65 Years by Age Group - National Patient-Centered Clinical Research Network, United States, April 2022-September 2023.

Adults aged ≥65 years experience the highest risk for COVID-19-related hospitalization and death, with risk increasing with increasing age; outpatient antiviral treatment reduces the risk for these severe outcomes. Despite the proven benefit of COVID-19 antiviral treatment, information on differences in use among older adults with COVID-19 by age group is limited. Nonhospitalized patients aged ≥65 years with COVID-19 during April 2022-September 2023 were identified from the National Patient-Centered Clinical Research Network. Differences in use of antiviral treatment among patients aged 65-74, 75-89, and ≥90 years were assessed. Multivariable logistic regression was used to estimate the association between age and nonreceipt of antiviral treatment. Among 393,390 persons aged ≥65 years, 45.9% received outpatient COVID-19 antivirals, including 48.4%, 43.5%, and 35.2% among those aged 65-75, 76-89, and ≥90 years, respectively. Patients aged 75-89 and ≥90 years had 1.17 (95% CI = 1.15-1.19) and 1.54 (95% CI = 1.49-1.61) times the adjusted odds of being untreated, respectively, compared with those aged 65-74 years. Among 12,543 patients with severe outcomes, 2,648 (21.1%) had received an outpatient COVID-19 antiviral medication, compared with 177,874 (46.7%) of 380,847 patients without severe outcomes. Antiviral use is underutilized among adults ≥65 years; the oldest adults are least likely to receive treatment. To prevent COVID-19-associated morbidity and mortality, increased use of COVID-19 antiviral medications among older adults is needed.

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.

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.

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.

iReceptor: A platform for querying and analyzing antibody/B-cell and T-cell receptor repertoire data across federated repositories.

Next-generation sequencing allows the characterization of the adaptive immune receptor repertoire (AIRR) in exquisite detail. These large-scale AIRR-seq data sets have rapidly become critical to vaccine development, understanding the immune response in autoimmune and infectious disease, and monitoring novel therapeutics against cancer. However, at present there is no easy way to compare these AIRR-seq data sets across studies and institutions. The ability to combine and compare information for different disease conditions will greatly enhance the value of AIRR-seq data for improving biomedical research and patient care. The iReceptor Data Integration Platform (gateway.ireceptor.org) provides one implementation of the AIRR Data Commons envisioned by the AIRR Community (airr-community.org), an initiative that is developing protocols to facilitate sharing and comparing AIRR-seq data. The iReceptor Scientific Gateway links distributed (federated) AIRR-seq repositories, allowing sequence searches or metadata queries across multiple studies at multiple institutions, returning sets of sequences fulfilling specific criteria. We present a review of the development of iReceptor, and how it fits in with the general trend toward sharing genomic and health data, and the development of standards for describing and reporting AIRR-seq data. Researchers interested in integrating their repositories of AIRR-seq data into the iReceptor Platform are invited to contact support@ireceptor.org.

Blood-based biomarkers of human papillomavirus-associated cancers: A systematic review and meta-analysis.

BACKGROUND: Despite the significant societal burden of human papillomavirus (HPV)-associated cancers, clinical screening interventions for HPV-associated noncervical cancers are not available. Blood-based biomarkers may help close this gap in care. METHODS: Five databases were searched, 5687 articles were identified, and 3631 unique candidate titles and abstracts were independently reviewed by 2 authors; 702 articles underwent a full-text review. Eligibility criteria included the assessment of a blood-based biomarker within a cohort or case-control study. RESULTS: One hundred thirty-seven studies were included. Among all biomarkers assessed, HPV-16 E seropositivity and circulating HPV DNA were most significantly correlated with HPV-associated cancers in comparison with cancer-free controls. In most scenarios, HPV-16 E6 seropositivity varied nonsignificantly according to tumor type, specimen collection timing, and anatomic site (crude odds ratio [cOR] for p16+ or HPV+ oropharyngeal cancer [OPC], 133.10; 95% confidence interval [CI], 59.40-298.21; cOR for HPV-unspecified OPC, 25.41; 95% CI, 8.71-74.06; cOR for prediagnostic HPV-unspecified OPC, 59.00; 95% CI, 15.39-226.25; cOR for HPV-unspecified cervical cancer, 12.05; 95% CI, 3.23-44.97; cOR for HPV-unspecified anal cancer, 73.60; 95% CI, 19.68-275.33; cOR for HPV-unspecified penile cancer, 16.25; 95% CI, 2.83-93.48). Circulating HPV-16 DNA was a valid biomarker for cervical cancer (cOR, 15.72; 95% CI, 3.41-72.57). In 3 cervical cancer case-control studies, cases exhibited unique microRNA expression profiles in comparison with controls. Other assessed biomarker candidates were not valid. CONCLUSIONS: HPV-16 E6 antibodies and circulating HPV-16 DNA are the most robustly analyzed and most promising blood-based biomarkers for HPV-associated cancers to date. Comparative validity analyses are warranted. Variations in tumor type-specific, high-risk HPV DNA prevalence according to anatomic site and world region highlight the need for biomarkers targeting more high-risk HPV types. Further investigation of blood-based microRNA expression profiling appears indicated.

Statistical classifiers for diagnosing disease from immune repertoires: a case study using multiple sclerosis.

BACKGROUND: Deep sequencing of lymphocyte receptor repertoires has made it possible to comprehensively profile the clonal composition of lymphocyte populations. This opens the door for novel approaches to diagnose and prognosticate diseases with a driving immune component by identifying repertoire sequence patterns associated with clinical phenotypes. Indeed, recent studies support the feasibility of this, demonstrating an association between repertoire-level summary statistics (e.g., diversity) and patient outcomes for several diseases. In our own prior work, we have shown that six codons in VH4-containing genes in B cells from the cerebrospinal fluid of patients with relapsing remitting multiple sclerosis (RRMS) have higher replacement mutation frequencies than observed in healthy controls or patients with other neurological diseases. However, prior methods to date have been limited to focusing on repertoire-level summary statistics, ignoring the vast amounts of information in the millions of individual immune receptors comprising a repertoire. We have developed a novel method that addresses this limitation by using innovative approaches for accommodating the extraordinary sequence diversity of immune receptors and widely used machine learning approaches. We applied our method to RRMS, an autoimmune disease that is notoriously difficult to diagnose. RESULTS: We use the biochemical features encoded by the complementarity determining region 3 of each B cell receptor heavy chain in every patient repertoire as input to a detector function, which is fit to give the correct diagnosis for each patient using maximum likelihood optimization methods. The resulting statistical classifier assigns patients to one of two diagnosis categories, RRMS or other neurological disease, with 87% accuracy by leave-one-out cross-validation on training data (N = 23) and 72% accuracy on unused data from a separate study (N = 102). CONCLUSIONS: Our method is the first to apply statistical learning to immune repertoires to aid disease diagnosis, learning repertoire-level labels from the set of individual immune repertoire sequences. This method produced a repertoire-based statistical classifier for diagnosing RRMS that provides a high degree of diagnostic capability, rivaling the accuracy of diagnosis by a clinical expert. Additionally, this method points to a diagnostic biochemical motif in the antibodies of RRMS patients, which may offer insight into the disease process.

VDJPipe: a pipelined tool for pre-processing immune repertoire sequencing data.

BACKGROUND: Pre-processing of high-throughput sequencing data for immune repertoire profiling is essential to insure high quality input for downstream analysis. VDJPipe is a flexible, high-performance tool that can perform multiple pre-processing tasks with just a single pass over the data files. RESULTS: Processing tasks provided by VDJPipe include base composition statistics calculation, read quality statistics calculation, quality filtering, homopolymer filtering, length and nucleotide filtering, paired-read merging, barcode demultiplexing, 5' and 3' PCR primer matching, and duplicate reads collapsing. VDJPipe utilizes a pipeline approach whereby multiple processing steps are performed in a sequential workflow, with the output of each step passed as input to the next step automatically. The workflow is flexible enough to handle the complex barcoding schemes used in many immunosequencing experiments. Because VDJPipe is designed for computational efficiency, we evaluated this by comparing execution times with those of pRESTO, a widely-used pre-processing tool for immune repertoire sequencing data. We found that VDJPipe requires <10% of the run time required by pRESTO. CONCLUSIONS: VDJPipe is a high-performance tool that is optimized for pre-processing large immune repertoire sequencing data sets.

Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients.

Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as a clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.

VDJML: a file format with tools for capturing the results of inferring immune receptor rearrangements.

BACKGROUND: The genes that produce antibodies and the immune receptors expressed on lymphocytes are not germline encoded; rather, they are somatically generated in each developing lymphocyte by a process called V(D)J recombination, which assembles specific, independent gene segments into mature composite genes. The full set of composite genes in an individual at a single point in time is referred to as the immune repertoire. V(D)J recombination is the distinguishing feature of adaptive immunity and enables effective immune responses against an essentially infinite array of antigens. Characterization of immune repertoires is critical in both basic research and clinical contexts. Recent technological advances in repertoire profiling via high-throughput sequencing have resulted in an explosion of research activity in the field. This has been accompanied by a proliferation of software tools for analysis of repertoire sequencing data. Despite the widespread use of immune repertoire profiling and analysis software, there is currently no standardized format for output files from V(D)J analysis. Researchers utilize software such as IgBLAST and IMGT/High V-QUEST to perform V(D)J analysis and infer the structure of germline rearrangements. However, each of these software tools produces results in a different file format, and can annotate the same result using different labels. These differences make it challenging for users to perform additional downstream analyses. RESULTS: To help address this problem, we propose a standardized file format for representing V(D)J analysis results. The proposed format, VDJML, provides a common standardized format for different V(D)J analysis applications to facilitate downstream processing of the results in an application-agnostic manner. The VDJML file format specification is accompanied by a support library, written in C++ and Python, for reading and writing the VDJML file format. CONCLUSIONS: The VDJML suite will allow users to streamline their V(D)J analysis and facilitate the sharing of scientific knowledge within the community. The VDJML suite and documentation are available from https://vdjserver.org/vdjml/ . We welcome participation from the community in developing the file format standard, as well as code contributions.

A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting.

BACKGROUND: Humans vary in their susceptibility to acquiring Staphylococcus aureus infection, and research suggests that there is a genetic basis for this variability. Several recent genome-wide association studies (GWAS) have identified variants that may affect susceptibility to infectious diseases, demonstrating the potential value of GWAS in this arena. METHODS: We conducted a GWAS to identify common variants associated with acquisition of S. aureus bacteremia (SAB) resulting from healthcare contact. We performed a logistic regression analysis to compare patients with healthcare contact who developed SAB (361 cases) to patients with healthcare contact in the same hospital who did not develop SAB (699 controls), testing 542,410 SNPs and adjusting for age (by decade), sex, and 6 significant principal components from our EIGENSTRAT analysis. Additionally, we evaluated the joint effect of the host and pathogen genomes in association with severity of SAB infection via logistic regression, including an interaction of host SNP with bacterial genotype, and adjusting for age (by decade), sex, the 6 significant principal components, and dialysis status. Bonferroni corrections were applied in both analyses to control for multiple comparisons. RESULTS: Ours is the first study that has attempted to evaluate the entire human genome for variants potentially involved in the acquisition or severity of SAB. Although this study identified no common variant of large effect size to have genome-wide significance for association with either the risk of acquiring SAB or severity of SAB, the variant (rs2043436) most significantly associated with severity of infection is located in a biologically plausible candidate gene (CDON, a member of the immunoglobulin family) and may warrant further study. CONCLUSIONS: The genetic architecture underlying SAB is likely to be complex. Future investigations using larger samples, narrowed phenotypes, and advances in both genotyping and analytical methodologies will be important tools for identifying causative variants for this common and serious cause of healthcare-associated 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.

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.

Pediatric Long COVID Subphenotypes: An EHR-based study from the RECOVER program.

Pediatric Long COVID has been associated with a wide variety of symptoms, conditions, and organ systems, but distinct clinical presentations, or subphenotypes, are still being elucidated. In this exploratory analysis, we identified a cohort of pediatric (age <21) patients with evidence of Long COVID and no pre-existing complex chronic conditions using electronic health record data from 38 institutions and used an unsupervised machine learning-based approach to identify subphenotypes. Our method, an extension of the Phe2Vec algorithm, uses tens of thousands of clinical concepts from multiple domains to represent patients' clinical histories to then identify groups of patients with similar presentations. The results indicate that cardiorespiratory presentations are most common (present in 54% of patients) followed by subphenotypes marked (in decreasing order of frequency) by musculoskeletal pain, neuropsychiatric conditions, gastrointestinal symptoms, headache, and fatigue.

Ontology for vector surveillance and management.

Ontologies, which are made up by standardized and defined controlled vocabulary terms and their interrelationships, are comprehensive and readily searchable repositories for knowledge in a given domain. The Open Biomedical Ontologies (OBO) Foundry was initiated in 2001 with the aims of becoming an "umbrella" for life-science ontologies and promoting the use of ontology development best practices. A software application (OBO-Edit; *.obo file format) was developed to facilitate ontology development and editing. The OBO Foundry now comprises over 100 ontologies and candidate ontologies, including the NCBI organismal classification ontology (NCBITaxon), the Mosquito Insecticide Resistance Ontology (MIRO), the Infectious Disease Ontology (IDO), the IDOMAL malaria ontology, and ontologies for mosquito gross anatomy and tick gross anatomy. We previously developed a disease data management system for dengue and malaria control programs, which incorporated a set of information trees built upon ontological principles, including a "term tree" to promote the use of standardized terms. In the course of doing so, we realized that there were substantial gaps in existing ontologies with regards to concepts, processes, and, especially, physical entities (e.g., vector species, pathogen species, and vector surveillance and management equipment) in the domain of surveillance and management of vectors and vector-borne pathogens. We therefore produced an ontology for vector surveillance and management, focusing on arthropod vectors and vector-borne pathogens with relevance to humans or domestic animals, and with special emphasis on content to support operational activities through inclusion in databases, data management systems, or decision support systems. The Vector Surveillance and Management Ontology (VSMO) includes >2,200 unique terms, of which the vast majority (>80%) were newly generated during the development of this ontology. One core feature of the VSMO is the linkage, through the has vector relation, of arthropod species to the pathogenic microorganisms for which they serve as biological vectors. We also recognized and addressed a potential roadblock for use of the VSMO by the vector-borne disease community: the difficulty in extracting information from OBO-Edit ontology files (*.obo files) and exporting the information to other file formats. A novel ontology explorer tool was developed to facilitate extraction and export of information from the VSMO*.obo file into lists of terms and their associated unique IDs in *.txt or *.csv file formats. These lists can then be imported into a database or data management system for use as select lists with predefined terms. This is an important step to ensure that the knowledge contained in our ontology can be put into practical use.

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.