Mammalian Target of Rapamycin Complex 1 Activation in Macrophages Contributes to Persistent Lung Inflammation following Respiratory Tract Viral Infection.

Respiratory tract virus infections cause millions of hospitalizations worldwide each year. Severe infections lead to lung damage that coincides with persistent inflammation and a lengthy repair period. Vaccination and antiviral therapy help to mitigate severe infections before or during the acute stage of disease, but there are currently limited specific treatment options available to individuals experiencing the long-term sequelae of respiratory viral infection. Herein, C57BL/6 mice were infected with influenza A/PR/8/34 as a model for severe viral lung infection and allowed to recover for 21 days. Mice were treated with rapamycin, a well-characterized mammalian target of rapamycin complex 1 (mTORC1) inhibitor, on days 12 to 20 after infection, a time period after viral clearance. Persistent inflammation following severe influenza infection in mice was primarily driven by macrophages and T cells. Uniform manifold approximation and projection analysis of flow cytometry data revealed that lung macrophages had high activation of mTORC1, an energy-sensing kinase involved in inflammatory immune cell effector functions. Rapamycin treatment reduced lung inflammation and the frequency of exudate macrophages, T cells, and B cells in the lung, while not impacting epithelial progenitor cells or adaptive immune memory. These data highlight mTORC1's role in sustaining persistent inflammation following clearance of a viral respiratory pathogen and suggest a possible intervention for post-viral chronic lung inflammation.

Sex-based differences in persistent lung inflammation following influenza infection of juvenile outbred mice.

Children are susceptible to influenza infections and can experience severe disease presentation due to a lack of or limited pre-existing immunity. Despite the disproportionate impact influenza has on this population, there is a lack of focus on pediatric influenza research, particularly when it comes to identifying the pathogenesis of long-term outcomes that persist beyond the point of viral clearance. In this study, juvenile outbred male and female mice were infected with influenza and analyzed following viral clearance to determine how sex impacts the persistent inflammatory responses to influenza. It was found that females maintained a broader cytokine response in the lung following clearance of influenza, with innate, type I and type II cytokine signatures in almost all mice. Males, on the other hand, had higher levels of IL-6 and other macrophage-related cytokines, but no evidence of a type I or type II response. The immune landscape was similar in the lungs between males and females postinfection, but males had a higher regulatory T cell to TH1 ratio compared with female mice. Cytokine production positively correlated with the frequency of TH1 cells and exudate macrophages, as well as the number of cells in the bronchoalveolar lavage fluid. Furthermore, female lungs were enriched for metabolites involved in the glycolytic pathway, suggesting glycolysis is higher in female lungs compared with males after viral clearance. These data suggest juvenile female mice have persistent and excessive lung inflammation beyond the point of viral clearance, whereas juvenile males had a more immunosuppressive phenotype.NEW & NOTEWORTHY This study identifies sex-based differences in persistent lung inflammation following influenza infection in an outbred, juvenile animal model of pediatric infection. These findings indicate the importance of considering sex and age as variable in infectious disease research.

From "glycosyltransferase" to "congenital muscular dystrophy": integrating knowledge from NCBI Entrez Gene and the Gene Ontology.

Entrez Gene (EG), Online Mendelian Inheritance in Man (OMIM) and the Gene Ontology (GO) are three complementary knowledge resources that can be used to correlate genomic data with disease information. However, bridging between genotype and phenotype through these resources currently requires manual effort or the development of customized software. In this paper, we argue that integrating EG and GO provides a robust and flexible solution to this problem. We demonstrate how the Resource Description Framework (RDF) developed for the Semantic Web can be used to represent and integrate these resources and enable seamless access to them as a unified resource. We illustrate the effectiveness of our approach by answering a real-world biomedical query linking a specific molecular function, glycosyltransferase, to the disorder congenital muscular dystrophy.

Building a standards-based and collaborative e-prescribing tool: MyRxPad.

MyRxPad (rxp.nlm.nih.gov) is a prototype application intended to enable a practitioner-patient collaborative approach towards e-prescribing: patients play an active role by maintaining up-to-date and accurate medication lists. Prescribers make well-informed and safe prescribing decisions based on personal medication records contributed by patients. MyRxPad is thus the vehicle for collaborations with patients using MyMedicationList (MML). Integration with personal medication records in the context of e-prescribing is thus enabled. We present our experience in applying RxNorm in an e-prescribing setting: using standard names and codes to capture prescribed medication as well as extracting information from RxNorm to support medication-related clinical decision.

Normalized names for clinical drugs: RxNorm at 6 years.

OBJECTIVE: In the 6 years since the National Library of Medicine began monthly releases of RxNorm, RxNorm has become a central resource for communicating about clinical drugs and supporting interoperation between drug vocabularies. MATERIALS AND METHODS: Built on the idea of a normalized name for a medication at a given level of abstraction, RxNorm provides a set of names and relationships based on 11 different external source vocabularies. The standard model enables decision support to take place for a variety of uses at the appropriate level of abstraction. With the incorporation of National Drug File Reference Terminology (NDF-RT) from the Veterans Administration, even more sophisticated decision support has become possible. DISCUSSION: While related products such as RxTerms, RxNav, MyMedicationList, and MyRxPad have been recognized as helpful for various uses, tasks such as identifying exactly what is and is not on the market remain a challenge.

Design and implementation of a personal medication record-MyMedicationList.

A record of current medications as well as prior medication history is useful if not vital information to an individual. Such information needs to be easily accessible, yet adequately protected. MyMedicationList is a prototype application developed at the National Library of Medicine that helps users manage their medication lists and make the records readily available when needed. This personal medication list can be printed out and serve as a reminder to the individual for taking medications, or as reference information to support continuity of care at doctors offices or hospitals. This paper presents the design and implementation of MyMedicationList. As the personal medication record is considered a specialized Personal Health Record (PHR), the experience may be applied to general PHR design and implementation. An early version of MyMedicationList is available at http://mml.nlm.nih.gov/.

MyMedicationList: integrating personal medication records with resources.

A record of current medications as well as prior medication history is useful information to an individual. MyMedicationList is a prototype application developed at the National Library of Medicine that helps users manage their medication lists and make the records readily available when needed. This personal medication list can be printed out and serve as a reminder to the individual for taking medications, or as reference information to support continuity of care at doctor's offices or hospitals. We present functionalities and features of MyMedicationList: adding, deleting, updating entries from the list; creating, saving, viewing the list; and storing the list in a standard format. In particular, we demonstrate the integration of personal medication records with a variety of resources. MyMedicationList is currently being tested with user groups. An early version of MyMedicationList is publicly available at http://mml.nlm.nih.gov/.

Besides precision & recall: exploring alternative approaches to evaluating an automatic indexing tool for MEDLINE.

OBJECTIVE: This paper explores alternative approaches for the evaluation of an automatic indexing tool for MEDLINE, complementing the traditional precision and recall method. MATERIALS AND METHODS: The performance of MTI, the Medical Text Indexer used at NLM to produce MeSH recommendations for biomedical journal articles is evaluated on a random set of MEDLINE citations. The evaluation examines semantic similarity at the term level (indexing terms). In addition, the documents retrieved by queries resulting from MTI index terms for a given document are compared to the PubMed related citations for this document. RESULTS: Semantic similarity scores between sets of index terms are higher than the corresponding Dice similarity scores. Overall, 75% of the original documents and 58% of the top ten related citations are retrieved by queries based on the automatic indexing. CONCLUSIONS: The alternative measures studied in this paper confirm previous findings and may be used to select particular documents from the test set for a more thorough analysis.