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1.
Article in English | MEDLINE | ID: mdl-35418750

ABSTRACT

Purpose: Inhaled triple therapy (TT) comprising a long-acting muscarinic antagonist, long-acting ß2 agonist, and inhaled corticosteroid is recommended for symptomatic chronic obstructive pulmonary disease (COPD) patients, or those at risk of exacerbation. However, it is not well understood which patient characteristics contribute most to future exacerbation risk. This study assessed patient predictors associated with future exacerbation time following initiation of TT. Patients and Methods: This retrospective cohort study used data from the Optum™ Clinformatics™ Data Mart, a large health claims database in the United States. COPD patients who initiated TT between January 2008 and March 2018 (index) were eligible. Patients were required to be aged ≥18 years at index and have continuous enrollment for the 12 months prior to index (baseline) and the 12 months following index (follow-up). Patients who had received TT during baseline were excluded. Data from eligible patients were analyzed using a reverse engineering forward simulation machine learning platform to predict future COPD exacerbation time. Results: Data from 73,625 patients were included. The model found that prior exacerbation was largely correlated with post-index exacerbation time; patients who had ≥4 exacerbation episodes during baseline had an average increase of 32.4 days post-index exacerbation, compared with patients with no exacerbations during baseline. Likewise, ≥2 inpatient visits (effect size 27.1 days), the use of xanthines (effect size 11.5 days), or rheumatoid arthritis (effect size 6.4 days) during baseline were associated with increased exacerbation time. Conversely, diagnosis of anemia (effect size -5.68 days), or oral corticosteroids in the past month (effect size -3.43 days) were associated with reduced exacerbation time. Conclusion: Frequent prior exacerbations, healthcare resource utilization, xanthine use, and rheumatoid arthritis were the strongest factors predicting the future increase of exacerbations. These results improve our understanding of exacerbation risk among COPD patients initiating triple therapy.


Subject(s)
Arthritis, Rheumatoid , Pulmonary Disease, Chronic Obstructive , Administration, Inhalation , Adolescent , Adrenal Cortex Hormones , Adrenergic beta-2 Receptor Agonists , Adult , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Bronchodilator Agents , Drug Therapy, Combination , Humans , Machine Learning , Muscarinic Antagonists , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/drug therapy , Retrospective Studies , United States
2.
J Virol ; 87(12): 6625-34, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23552423

ABSTRACT

The hepatitis C virus (HCV) genome contains numerous RNA elements that are required for its replication. Most of the identified RNA structures are located within the 5' and 3' untranslated regions (UTRs). One prominent RNA structure, termed the cis-acting replication element (CRE), is located within the NS5B coding region. Mutation of part of the CRE, the 5BSL3.2 stem-loop, impairs HCV RNA replication. This loop has been implicated in a kissing interaction with a complementary stem-loop structure in the 3' UTR. Although it is clear that this interaction is required for viral replication, the function of the interaction, and its regulation are unknown. In order to gain insight into the CRE function, we isolated cellular proteins that preferentially bind the CRE and identified them using mass spectrometry. This approach identified EWSR1 as a CRE-binding protein. Silencing EWSR1 expression impairs HCV replication and infectious virus production but not translation. While EWRS1 is a shuttling protein that is extensively nuclear in hepatocytes, substantial amounts of EWSR1 localize to the cytosol in HCV-infected cells and colocalize with sites of HCV replication. A subset of EWRS1 translocates into detergent-resistant membrane fractions, which contain the viral replicase proteins, in cells with replicating HCV. EWSR1 directly binds the CRE, and this is dependent on the intact CRE structure. Finally, EWSR1 preferentially interacts with the CRE in the absence of the kissing interaction. This study implicates EWSR1 as a novel modulator of CRE function in HCV replication.


Subject(s)
Calmodulin-Binding Proteins/metabolism , Enhancer Elements, Genetic/physiology , Gene Expression Regulation, Viral , Hepacivirus/physiology , RNA-Binding Proteins/metabolism , Viral Nonstructural Proteins/genetics , Virus Replication/genetics , Calmodulin-Binding Proteins/genetics , Cell Line, Tumor , HEK293 Cells , Hepacivirus/genetics , Hepacivirus/metabolism , Humans , RNA, Viral/genetics , RNA, Viral/metabolism , RNA-Binding Protein EWS , RNA-Binding Proteins/genetics , Viral Nonstructural Proteins/metabolism
3.
Proc Natl Acad Sci U S A ; 106(18): 7577-82, 2009 May 05.
Article in English | MEDLINE | ID: mdl-19376974

ABSTRACT

Hepatitis C virus (HCV) reorganizes cellular membranes to establish sites of replication. The required host pathways and the mechanism of cellular membrane reorganization are poorly characterized. Therefore, we interrogated a customized small interfering RNA (siRNA) library that targets 140 host membrane-trafficking genes to identify genes required for both HCV subgenomic replication and infectious virus production. We identified 7 host cofactors of viral replication, including Cdc42 and Rock2 (actin polymerization), EEA1 and Rab5A (early endosomes), Rab7L1, and PI3-kinase C2gamma and PI4-kinase IIIalpha (phospholipid metabolism). Studies of drug inhibitors indicate actin polymerization and phospholipid kinase activity are required for HCV replication. We found extensive co-localization of the HCV replicase markers NS5A and double-stranded RNA with Rab5A and partial co-localization with Rab7L1. PI4K-IIIalpha co-localized with NS5A and double-stranded RNA in addition to being present in detergent-resistant membranes containing NS5A. In a comparison of type II and type III PI4-kinases, PI4Ks were not required for HCV entry, and only PI4K-IIIalpha was required for HCV replication. Although PI4K-IIIalpha siRNAs decreased HCV replication and virus production by almost 100%, they had no effect on initial HCV RNA translation, suggesting that PI4K-IIIalpha functions at a posttranslational stage. Electron microscopy identified the presence of membranous webs, which are thought to be the site of HCV replication, in HCV-infected cells. Pretreatment with PI4K-IIIalpha siRNAs greatly reduced the accumulation of these membranous web structures in HCV-infected cells. We propose that PI4K-IIIalpha plays an essential role in membrane alterations leading to the formation of HCV replication complexes.


Subject(s)
Cell Membrane/virology , Endocytosis , Hepacivirus/physiology , Hepatitis C/enzymology , Phosphotransferases (Alcohol Group Acceptor)/physiology , Virus Replication , Cell Line , Endosomes/virology , Hepatitis C/genetics , Humans , Minor Histocompatibility Antigens , Phosphotransferases (Alcohol Group Acceptor)/genetics , RNA Interference , RNA-Dependent RNA Polymerase/physiology
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