Christian Bime

Interests

Teaching

Pulmonary Physiology and PathophysiologyPrinciples of Acute Critical Care

Research

Genetics of Acute Respiratory Distress Syndrome (ARDS)Translational ARDS researchHealth Disparities in ARDSAsthma Clinical TrialsAsthma, Obesity, and Aerobic Exercise

Courses

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Scholarly Contributions

Books

• Bime, C., Gurguis, C. I., Hecker, L., Wang, T., Desai, A., & Garcia, J. G. (2016). MicroRNAs in inflammatory lung diseases. Translating MicroRNAs to the clinic. Elsevier.

Chapters

• Bime, C. (2023).

  Digital technologies and pulmonary medicine

  . In Comprehensive Precision Medicine. doi:10.1016/b978-0-12-824010-6.00071-x
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  Advances in technology, data science and medicine have ushered a new era of precision medicine with the hopes of streamlining investigations of novel therapies as well as innovative ways to deliver available therapies to the patients most likely to benefit and in a way that increases compliance. Chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD), asthma, interstitial lung diseases (ILD), cystic fibrosis (CF) are challenging due to lack of disease modifying therapies, heterogeneity among patients, and problems with patient compliance to available therapy. This chapter uses these chronic pulmonary conditions as examples to illustrate how current and future digital technologies could be leveraged to improve patient stratification for investigating novel therapies and to improve adherence to therapy. Finally, we review the challenges and opportunities of novel digital technologies in the context of chronic pulmonary diseases.
• Bime, C. (2022).

  Respiratory Health in Migrants and Refugees

  . In Encyclopedia of Respiratory Medicine (Second Edition). doi:10.1016/b978-0-08-102723-3.00063-9
• Celedon, J. C., & Bime, C. (2020). Respiratory Health in Migrants and Refugees. In Encyclopedia of Respiratory Medicine, 2nd Edition: Samuel Janes : CH 00063. Elsevier. doi:10.1016/B978-0-08-102723-3.00063-9
• Sears, S. P., Carr, G., & Bime, C. (2019). Acute and chronic respiratory failure in cancer patients. In Oncologic Critical Care. Springer International Publishing. doi:10.1007/978-3-319-74588-6_43
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  In 2016, there was an estimated 1.8 million new cases of cancer diagnosed in the United States. Remarkable advances have been made in cancer therapy and the 5-year survival has increased for most patients affected by malignancy. There are growing numbers of patients admitted to intensive care units (ICU) and up to 20% of all patients admitted to an ICU carry a diagnosis of malignancy. Respiratory failure remains the most common reason for ICU admission and remains the leading causes of death in oncology patients. There are many causes of respiratory failure in this population. Pneumonia is the most common cause of respiratory failure, yet there are many causes of respiratory insufficiency unique to the cancer patient. These causes are often a result of immunosuppression, chemotherapy, radiation treatment, or hematopoietic stem cell transplant (HCT). Treatment is focused on supportive care and specific therapy for the underlying cause of respiratory failure. Noninvasive modalities of respiratory support are available; however, careful patient selection is paramount as indiscriminate use of noninvasive positive pressure ventilation is associated with a higher mortality if mechanical ventilation is later required. Historically, respiratory failure in the cancer patient had a grim prognosis. Outcomes have improved over the past 20 years. Survivors are often left with significant disability.
• Bime, C., Gurguis, C. I., Hecker, L., Hecker, L., Wang, T., Wang, T., Garcia, J. G., Desai, A. A., Desai, A. B., & Desai, A. A. (2017). MicroRNAs in Inflammatory Lung Disease. In Translating MicroRNAs to the Clinic. Academic Press. doi:10.1016/B978-0-12-800553-8.00006-8
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  Inflammatory lung diseases include both acute inflammatory diseases such as acute respiratory distress syndrome (ARDS) and chronic inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis and sarcoidosis. Both acute and chronic inflammatory lung diseases are associated with airway inflammation and are influenced by a combination of environmental, genetic, and epigenetic components. Epigenetic regulation, including microRNA (miRNA), of gene expression contributes to inflammatory lung disease development and severity. With the advancement of “omics” technology, miRNA expression and function in inflammatory lung diseases have been well studied, leading to a clear conclusion that miRNAs are differentially expressed under inflammatory lung disease conditions and contribute to genomic dysregulation in these diseases. Here we summarized the most up-to-date findings of miRNA in the inflammatory lung diseases including asthma, ARDS, COPD, cystic fibrosis, and sarcoidosis, and clinical implications of miRNA in these diseases. miRNAs are valued to be served as biomarkers, diagnostic tools, as well as therapeutic targets of inflammatory lung diseases.
• Bime, C. (2016). Health Disparities in Asthma. In Health Disparities in Respiratory Medicine(pp 173-187). B. L. Gerald and E. C. Berry: Cham, Springer International Publishing.
• Bime, C., Gurguis, C. I., Hecker, L., Wang, T., Desai, A., & Garcia, J. G. (2016). MicroRNAs in inflammatory lung diseases.. In Translating MicroRNAs to the clinic(pp 135-177). Elsevier.
• Bime, C. (2019). Acute and Chronic Respiratory Failure. In Oncologic Critical Care(pp 1-31). Springer International Publishing.

Journals/Publications

• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Circulating endothelial signatures correlate with worse outcomes in COVID-19, respiratory failure and ARDS. Critical Care, 29(Issue 1). doi:10.1186/s13054-025-05596-0
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  Background: Elevated circulating endothelial cells (CECs), released from monolayers after insult, have been implicated in worse outcomes in ARDS and COVID-19, however there is no consensus proteomic phenotype that define CECs. We queried whether a transcriptomic approach would alternatively support the presence of endothelial cells in circulation and correlate with worsening respiratory failure. Methods: To test whether elevated endothelial cell signatures (ECS) in circulation plays a role in worse respiratory outcomes, we used unsupervised bulk-transcriptome deconvolution to quantify ECS% in two cohorts. Our pilot analysis included pediatric patients requiring invasive mechanical ventilation (CAF-PINT, NCT01892969). Our validation cohort included adult hospitalized patients with COVID-19 (IMPACC, NCT04378777), testing the association of ECS% to outcomes in patients at risk of acute respiratory failure/ARDS. Primary outcome was 28-day mortality. Results: In CAF-PINT, day 0 ECS% was higher in non-survivors compared to survivors of respiratory failure (2.8%, IQR 2.4–3.4% versus 2.6%, IQR 2.2–3.0% n = 244, p < 0.05, Wilcoxon rank-sum). In IMPACC, baseline ECS% (< 72 h of hospitalization) was higher in COVID-19 non-survivors versus survivors (2.9%, IQR 2.6–3.4%, versus 2.7%, IQR 2.3–3.1%, n = 932, p < 0.001, Wilcoxon rank-sum). Each 1% increase in baseline ECS% was significantly associated with mortality (adjusted OR 1.36, CI 1.03–1.79) by multivariable logistic regression. Increased baseline ECS% was associated with worse respiratory trajectories (2.5%, IQR 2.2–2.8% for trajectory with no oxygen requirements, 2.9%, IQR 2.6–3.4% for the trajectory with fatal outcome by day 28, n = 932, p < 0.001, one-way ANOVA). Conclusion: Quantifying ECS by deconvolution supports a transcriptomics-driven approach towards the non-invasive evaluation of endothelial damage in respiratory outcomes. This is a first step towards elucidating mechanistic components linking endothelial damage to ARDS utilizing non-invasive, circulating transcriptomic data by leveraging a novel deconvolution approach.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Host-microbe multiomic profiling identifies distinct COVID-19 immune dysregulation in solid organ transplant recipients. Nature Communications, 16(1). doi:10.1038/s41467-025-55823-z
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  Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant recipients, who have atypical but poorly characterized immune responses to infection. We aim to understand the host immunologic and microbial features of COVID-19 in transplant recipients by leveraging a prospective multicenter cohort of 86 transplant recipients age- and sex-matched with 172 non-transplant controls. We find that transplant recipients have higher nasal SARS-CoV-2 viral abundance and impaired viral clearance, and lower anti-spike IgG levels. In addition, transplant recipients exhibit decreased plasmablasts and transitional B cells, and increased senescent T cells. Blood and nasal transcriptional profiling demonstrate unexpected upregulation of innate immune signaling pathways and increased levels of several proinflammatory serum chemokines. Severe disease in transplant recipients, however, is characterized by a less robust induction of pro-inflammatory genes and chemokines. Together, our study reveals distinct immune features and altered viral dynamics in solid organ transplant recipients.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Type 2 immune responses are associated with less severe COVID-19 in a hospitalized cohort. Journal of Allergy and Clinical Immunology: Global, 4(Issue 4). doi:10.1016/j.jacig.2025.100515
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  Background: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly after its identification in December 2019 to cause a global pandemic. The respiratory tract is the primary site of infection, and there is a large range in the severity of respiratory illnesses caused by the virus. Defining molecular and cellular factors for protection from severe disease and death has been a goal to better understand and to predict and mitigate the effects of SARS-CoV-2 and future coronaviruses. Objective: Despite well-known susceptibilities to respiratory viral infections, respiratory allergy and allergic asthma have not been identified as risk factors for severe coronavirus disease 2019 (COVID-19) in most epidemiologic studies and may be protective. We sought to investigate associations between markers of type 2 (T2) immune responses with SARS-CoV-2 clinical outcomes and virus loads in a cohort of 1164 individuals hospitalized for COVID-19 from May 2020 to March 2021 as part of the IMPACC study. Methods: We characterized the clinical outcomes, as defined by severity trajectory groups reflecting the degree of respiratory support required, virus loads, and antibody titers of COVID-19 infections in IMPACC participants in relation to molecular and cellular markers of T2 immune responses through multiple assays, including, (1) IL-4, IL-5, and IL-13 levels in serum Olink data, (2) T2 cellular signatures in blood cytometry by time of flight data, (3) relative quantification of T2 signaling gene pathways in airway RNA sequencing data, and/or (4) T2 pathways in peripheral blood mononuclear cell RNA sequencing data. We also investigated the outcomes of individuals with self-reported asthma and evidence of T2 immune responses. Results: The diagnosis of asthma (odd ratio = 1.27), elevated serum T2 cytokine levels (median fold change = 1.06), and a higher frequency of TH2 cells (difference = +2%) were associated with less severe clinical disease during hospitalization. Distinct T2-related transcriptomic changes in nasal and blood samples were associated with reduced virus loads. This included the expression of T2-regulated genes implicated in T-/B-cell activation and apoptosis in nasal samples and the expression of T2-regulated genes implicated in myeloid differentiation and reactive oxygen species signaling in blood. Among these, several canonical T2-regulated genes that were increased in less severe disease were identified to have antiviral properties in large high-throughput screens. Conclusion: T2 immune responses were associated with lower virus loads and more favorable clinical outcomes, suggesting that T2 inflammation related to asthma and allergic diseases may have a direct protective effect against SARS-CoV-2.
• Casanova, N. G., Herazo-Maya, J. D., Kempf, C. L., Sun, B. L., Song, J. H., Hernandez, A., Galaviz, J. C., Sun, X., Camp, S. M., Ledford, J. G., Hellinger, R. D., Rodriguez, M., Zhao, A. Y., Unterman, A., Rosas, I., Duncan, S., Thannikal, V. J., Hufford, M. K., Ahmed, M., , Zaghloul, N., et al. (2025). eNAMPT Is a Novel DAMP and Therapeutic Target in Human and Murine Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology, 73(Issue 4). doi:10.1165/rcmb.2024-0342oc
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  Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder without curative therapies, underscoring the critical unmet need for identification of novel therapeutic strategies. eNAMPT (extracellular nicotinamide phosphoribosyltransferase) is a damage-associated molecular pattern protein (DAMP) and TLR4 (Toll-like receptor 4) ligand that contributes to the severity of radiation-induced lung fibrosis and nonalcoholic steatohepatitis–associated hepatic fibrosis. This study investigates eNAMPT as a druggable target in human and preclinical IPF using the eNAMPT-neutralizing ALT-100 monoclonal antibody (mAb). Blood, peripheral blood mononuclear cells (PBMCs), and lung tissues from patients with IPF and from an experimental bleomycin-induced lung fibrosis model in C57Bl6 mice were analyzed. Biochemical and histologic measurements, as well as gene expression through bulk and single-cell RNA sequencing of human PBMCs and murine lung tissues, were performed. Human studies revealed NAMPT expression to be significantly increased in plasma, lung tissues, and PBMCs from subjects with IPF, correlating with disease severity and inversely associated with IPF survival. Bleomycin-exposed mice exhibited increased inflammatory indices associated with lung fibrosis development (including NAMPT levels), as well as physiologic lung stiffening and TGF-b pathway–related protein and gene expression, with each index significantly mitigated in mice receiving ALT-100 mAb. Single-cell RNA sequencing studies demonstrated the ALT-100 mAb to reverse the bleomycin-induced dramatic expansion of alveolar type 2 epithelium and induction of endothelial cell– and epithelial cell–to–mesenchymal/myofibroblast transitions. These finding support the fundamental involvement of eNAMPT/ TLR4 signaling pathway in lung fibrosis pathobiology, with eNAMPT neutralization a viable therapeutic strategy to directly address the unmet need for novel IPF treatments.
• Gabernet, G., Maciuch, J., Gygi, J. P., Moore, J. F., Hoch, A., Syphurs, C., Chu, T., Doni Jayavelu, N., Corry, D. B., Kheradmand, F., Baden, L. R., Sekaly, R. P., McComsey, G. A., Haddad, E. K., Cairns, C. B., Rouphael, N., Fernandez-Sesma, A., Simon, V., Metcalf, J. P., , Agudelo Higuita, N. I., et al. (2025). A multiomics recovery factor predicts long COVID in the IMPACC study. The Journal of clinical investigation, 135(Issue 21). doi:10.1172/jci193698
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  BACKGROUNDFollowing SARS-CoV-2 infection, approximately 10%-35% of patients with COVID-19 experience long COVID (LC), in which debilitating symptoms persist for at least 3 months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities.METHODSWe utilized machine learning methods on biologic analytes provided over 12 months after hospital discharge from more than 500 patients with COVID-19 in the IMPACC cohort to identify a multiomics "recovery factor," trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood mass cytometry by time of flight (CyTOF) protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores.RESULTSParticipants with LC had lower recovery factor scores compared with recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC.CONCLUSIONThe multiomics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID), NIH (3U01AI167892-03S2, 3U01AI167892-01S2, 5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI057229-18, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07S1, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-1, 3U19AI1289130, U19AI128913-04S1, R01AI122220); NIH (UM1TR004528); and National Science Foundation (NSF) (DMS2310836).
• Hou, J., Haslund-Gourley, B., Diray-Arce, J., Hoch, A., Rouphael, N., Becker, P. M., Augustine, A. D., Ozonoff, A., Guan, L., Kleinstein, S. H., Peters, B., Reed, E., Altman, M., Langelier, C. R., Maecker, H., Kim, S., Montgomery, R. R., Krammer, F., Wilson, M., , Eckalbar, W., et al. (2025). Baseline predictors for 28-day COVID-19 severity and mortality among hospitalized patients: results from the IMPACC study. Frontiers in Medicine, 12(Issue). doi:10.3389/fmed.2025.1604388
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  Introduction: The coronavirus disease 2019 (COVID-19) pandemic threatened public health and placed a significant burden on medical resources. The Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study collected clinical, demographic, blood cytometry, serum receptor-binding domain (RBD) antibody titers, metabolomics, targeted proteomics, nasal metagenomics, Olink, nasal viral load, autoantibody, SARS-CoV-2 antibody titers, and nasal and peripheral blood mononuclear cell (PBMC) transcriptomics data from patients hospitalized with COVID-19. The aim of this study is to select baseline biomarkers and build predictive models for 28-day in-hospital COVID-19 severity and mortality with most predictive variables while prioritizing routinely collected variables. Methods: We analyzed 1102 hospitalized COVID-19 participants. We used the lasso and forward selection to select top predictors for severity and mortality, and built predictive models based on balanced training data. We then validated the models on testing data. Results: Severity was best predicted by the baseline SpO2/FiO2 ratio obtained from COVID-19 patients (test AUC: 0.874). Adding patient age, BMI, FGF23, IL-6, and LTA to the disease severity prediction model improves the test AUC by an additional 3%. The clinical mortality prediction model using SpO2/FiO2 ratio, age, and BMI resulted in a test AUC of 0.83. Adding laboratory results such as TNFRSF11B and plasma ribitol count increased the prediction model by 3.5%. The severity and mortality prediction models developed outperform the Sequential Organ Failure Assessment (SOFA) score among inpatients and perform similarly to the SOFA score among ICU patients. Conclusion: This study identifies clinical data and laboratory biomarkers of COVID-19 severity and mortality using machine learning models. The study identifies SpO2/FiO2 ratio to be the most important predictor for both severity and mortality. Several biomarkers were identified to modestly improve the predictions. The results also provide a baseline of SARS-CoV-2 infection during the early stages of the coronavirus emergence and can serve as a baseline for future studies that inform how the genetic evolution of the coronavirus affects the host response to new variants.
• Ignatenko, N. A., Trinh, H. T., Wagner, A. M., Gerner, E. W., Bime, C., Hsu, C. H., & Besselsen, D. G. (2025). Preclinical Evaluation of the Efficacy of α-Difluoromethylornithine and Sulindac Against SARS-CoV-2 Infection. Viruses, 17(Issue 10). doi:10.3390/v17101306
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  Despite numerous research efforts and several effective vaccines and therapies developed against coronavirus disease 2019 (COVID-19), drug repurposing remains an attractive alternative approach for treatment of SARS-CoV-2 variants and other viral infections that may emerge in the future. Cellular polyamines support viral propagation and tumor growth. Here we tested the antiviral activity of two polyamine metabolism-targeting drugs, an irreversible inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), and a non-steroidal anti-inflammatory drug (NSAID), Sulindac, which have been previously evaluated for colon cancer chemoprevention. The drugs were tested as single agents and in combination in the human Calu-3 lung adenocarcinoma and Caco-2 colon adenocarcinoma cell lines and the K18-hACE2 transgenic mouse model of severe COVID-19. In the infected human cell lines, the DFMO/Sulindac combination significantly suppressed SARS-CoV-2 N1 Nucleocapsid mRNA by interacting synergistically when cells were pretreated with drugs and additively when treatment was applied to the infected cells. The Sulindac alone and DFMO/Sulindac combination treatments also suppressed the expression of the viral Spike protein and the host angiotensin-converting enzyme 2 (ACE2). In K18-hACE2 mice, the antiviral activity of DFMO and Sulindac as single agents and in combination was tested as prophylaxis (drug supplementation started 7 days before infection) or as treatment (drug supplementation started 24 h post-infection) at the doses equivalent to patient chemoprevention trials (835 ppm DFMO and 167 ppm Sulindac). The drugs’ antiviral activity in vivo was evaluated by measuring the clinical (survival rates and clinical scores), viral (viral load and virus infectivity), and biochemical (plasma polyamine, Sulindac, and Sulindac metabolite levels) endpoints. Prophylaxis with DFMO and Sulindac as single agents significantly increased survival rates in the young male mice (p = 0.01 and p = 0.027, respectively), and the combination was effective in the aged male mice (p = 0.042). Young female mice benefited the most from the prophylaxis with Sulindac alone (p = 0.001) and the DFMO/Sulindac combination (p = 0.018), while aged female mice did not benefit significantly from any intervention. Treatment of SARS-CoV-2-infected animals with DFMO or/and Sulindac did not significantly improve their survival rates. Overall, our studies demonstrated that DFMO and Sulindac administration as the prophylaxis regimen provided strong protection against the lethal outcome of SARS-CoV-2 infection and that male mice benefited more from the polyamine-targeted antiviral treatment than female mice. Our findings underscore the importance of evaluation of the antiviral activity of the drugs in the context of sex and age.
• Pickering, H., Alipanah-Lechner, N., Chen, E., Duchen, D., Maecker, H. T., Kim-Schulze, S., Montgomery, R. R., Cotsapas, C., Steen, H., Krammer, F., Langelier, C. R., Levy, O., Baden, L. R., Melamed, E., Ehrlich, L. I., McComsey, G. A., Sekaly, R. P., Cairns, C. B., Haddad, E. K., , Shaw, A. C., et al. (2025). MICBG406A polymorphism reduces risk of mechanical ventilation and death during viral acute lung injury. JCI Insight, 10(Issue 15). doi:10.1172/jci.insight.191951
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  MHC class I polypeptide-related sequence B (MICB) is a ligand for NKG2D. We have shown NK cells are central to lung transplant acute lung injury (ALI) via NKG2D activation, and increased MICB in bronchoalveolar lavage predicts ALI severity. Separately, we found a MICB polymorphism (MICBG406A) is associated with decreased ALI risk. We hypothesized this polymorphism would protect against severe SARS-CoV-2 respiratory disease. We analyzed 1,036 patients hospitalized with SARS-CoV-2 infection from IMPACC. Associations between MICBG406A and outcomes were determined by linear regression or Cox proportional hazards models. We also measured immune profiles of peripheral blood and the upper and lower airway. We identified 560 major allele homozygous patients, and 426 and 50 with 1 or 2 copies of the variant allele, respectively. MICBG406A conferred reduced odds of severe COVID-19. MICBG406A homozygous participants demonstrated 34% reduced cumulative odds for mechanical ventilation or death and 43% reduced risk for mortality. Patients with MICBG406A variant alleles had reduced soluble inflammatory mediators and differential regulation of multiple immune pathways. These findings demonstrate a potentially novel association between increasing MICBG406A variant allele copies and reduced COVID-19 severity, independent of SARS-CoV-2 viral burden and humoral immunity, suggesting the NKG2D-ligand pathway as an intervention target.
• Qualls, A. E., Tsao, T., Lui, I., Lim, S. A., Su, Y., Chen, E., Duchen, D., Maecker, H. T., Kim-Schulze, S., Montgomery, R. R., Krammer, F., Langelier, C. R., Levy, O., Baden, L. R., Melamed, E., Ehrlich, L. I., McComsey, G. A., Sekaly, R. P., Cairns, C. B., , Haddad, E. K., et al. (2025). High-affinity CD16A polymorphism associated with reduced risk of severe COVID-19. JCI Insight, 10(Issue 13). doi:10.1172/jci.insight.191314
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  CD16A is an activating Fc receptor on NK cells that mediates antibody-dependent cellular cytotoxicity (ADCC), a key mechanism in antiviral immunity. However, the role of NK cell-mediated ADCC in SARS-CoV-2 infection remains unclear, particularly whether it limits viral spread and disease severity or contributes to the immunopathogenesis of COVID-19. We hypothesized that the high-affinity CD16AV176 polymorphism influences these outcomes. Using an in vitro reporter system, we demonstrated that CD16AV176 is a more potent and sensitive activator than the common CD16AF176 allele. To assess its clinical relevance, we analyzed 1, 027 patients hospitalized with COVID-19 from the Immunophenotyping Assessment in a COVID-19 cohort (IMPACC), a comprehensive longitudinal dataset with extensive transcriptomic, proteomic, and clinical data. The high-affinity CD16AV176 allele was associated with a significantly reduced risk of ICU admission, mechanical ventilation, and severe disease trajectories. Lower anti-SARS-CoV-2 IgG titers were correlated to CD16AV176; however, there was no difference in viral load across CD16A genotypes. Proteomic analysis revealed that participants homozygous for CD16AV176 had lower levels of inflammatory mediators. These findings suggest that CD16AV176 enhances early NK cell-mediated immune responses, limiting severe respiratory complications in COVID-19. This study identifies a protective genetic factor against severe COVID-19, informing future host-directed therapeutic strategies.
• Thota, L. N., Lopez Rosales, J. E., Isbatan, A., Bime, C., Carvalho-de-Souza, J. L., Dull, R. O., Black, S. M., & Chignalia, A. Z. (2025). Glypican 1 mechanosensing mediates eNOS uncoupling during hydrostatic pulmonary edema. Redox Biology, 87(Issue). doi:10.1016/j.redox.2025.103876
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  Hydrostatic pulmonary edema is a life-threatening condition caused by an acute increase in pulmonary capillary pressure. The molecular mechanisms whereby hydrostatic pulmonary edema develops are unresolved. The pulmonary endothelial glycocalyx is a mechano-sensitive signaling layer known to regulate lung endothelial permeability. Within the glycocalyx, membrane-bound heparan sulfate proteoglycans (HSPGs) are putative mechano-sensors. Herein, we investigated if the membrane-bound HSPG glypican 1 is a mechanosensor in the lung vasculature and its role in hydrostatic pulmonary edema progression. Using an isolated perfused lung system, we showed that glypican 1 knockout mice (Gpc1−/−) are protected from pressure-induced lung edema, a phenotype associated with impaired 70 KDa dextran transport and decreased reactive oxygen species (ROS) production. Using wild-type (WT) mouse lung endothelial cells (MLEC) and human lung microvascular endothelial cells (HLMEC), we show that high pressure induces the activation of Protein Kinase C-alpha (PKCα) at Y657, which phosphorylates endothelial nitric oxide synthase (eNOS) at T495. This is associated with increased ROS production by eNOS-dependent pathways. The inhibition of eNOS with ethyl thiourea (ETU) or N5-(1-iminoethyl)-L-ornithine (L-NIO) mitigates the effects of high pressure on ROS production, lung edema, and barrier stability. This pathologic signaling axis is not activated in Gpc1−/− MLEC exposed to high-pressure conditions. Notably, cells deficient in Glypican 1 show increased phosphorylation of PKCα at T638, a site associated with PKCα stability and inactivation. The protective signaling mechanisms observed in Gpc1−/− MLEC are replicated in HLMEC silenced for glypican 1, supporting a conserved role for glypican 1 in barrier function across species. In conclusion, we show that glypican 1 is a mechanosensor in the lung vasculature that mediates the effects of high pressure on barrier function by redox-sensitive pathways. This may be important for the progression of hydrostatic pulmonary edema in humans. Therapies targeting glypican 1 may be novel strategies to treat hydrostatic pulmonary edema.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2024). Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study. The Lancet Microbe, 5(6). doi:10.1016/S2666-5247(24)00015-6
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  Background: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes. Methods: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery. Findings: The study included 2149 participants. Participant median age was 57 years (IQR 46–68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319–559), CRP 174% higher (150–202), IL-6 173% higher (144–208), D-dimer 149% higher (134–165), and anti-nucleocapsid antibody 39% lower (60–18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29–6·15), CRP HR 3·37 (2·30–4·94), and IL-6 HR 5·67 (4·12–7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors. Interpretation: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment. Funding: US National Institutes of Health.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2024). Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study. Nature Communications, 15(1). doi:10.1038/s41467-023-44090-5
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  Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2024). IgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition. Nature Communications, 15(1). doi:10.1038/s41467-023-44211-0
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  The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients and modulated by exoglycosidase digestion. Taken together, this work links the IgM N-glycosylation with COVID-19 severity and highlights the need to understand IgM glycosylation and downstream immune function during human disease.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2024). Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study. Clinical Microbiology and Infection, 30(12). doi:10.1016/j.cmi.2024.09.001
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  Objectives: To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detection with postacute sequelae of COVID-19 (PASC) symptoms. Methods: Plasma and serum samples were collected from adults participating in four independent studies at different time points, ranging from several days up to 14 months post-SARS-CoV-2 infection. The primary outcome measure was to quantify SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid, in participant samples. The presence of 34 commonly reported PASC symptoms during the postacute period was determined from participant surveys or chart reviews of electronic health records. Results: Of the 1569 samples analysed from 706 individuals infected with SARS-CoV-2, 21% (95% CI, 18–24%) were positive for either S1, spike, or nucleocapsid. Spike was predominantly detected, and the highest proportion of samples was spike positive (20%; 95% CI, 18–22%) between 4 and 7 months postinfection. In total, 578 participants (82%) reported at least one of the 34 PASC symptoms included in our analysis ≥1 month postinfection. Cardiopulmonary, musculoskeletal, and neurologic symptoms had the highest reported prevalence in over half of all participants, and among those participants, 43% (95% CI, 40–45%) on average were antigen-positive. Among the participants who reported no ongoing symptoms (128, 18%), antigen was detected in 28 participants (21%). The presence of antigen was associated with the presence of one or more PASC symptoms, adjusting for sex, age, time postinfection, and cohort (OR, 1.8; 95% CI, 1.4–2.2). Discussion: The findings of this multicohort study indicate that SARS-CoV-2 antigens can be detected in the blood of a substantial proportion of individuals up to 14 months after infection. While approximately one in five asymptomatic individuals was antigen-positive, roughly half of all individuals reporting ongoing cardiopulmonary, musculoskeletal, and neurologic symptoms were antigen-positive.
• Bime, C. (2024). Circadian disruption dysregulates lung gene expression associated with inflammatory lung injury. Frontiers Immunology. doi:10.3389/fimmu.2024.1348181
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  Circadian systems drive the expression of multiple genes in nearly all cells and coordinate cellular-, tissue-, and system-level processes that are critical to innate immunity regulation.We examined the effects of circadian rhythm disorganization, produced by light shift exposure, on innate immunity-mediated inflammatory lung responses including vascular permeability and gene expression in a C57BL/6J murine model of inflammatory lung injury.A total of 32 C57BL/6J mice were assigned to circadian phase shifting (CPS) with intratracheal phosphate-buffered saline (PBS), CPS with intratracheal lipopolysaccharide (LPS), control (normal lighting) condition with intratracheal PBS, and control condition with intratracheal LPS. Bronchoalveolar lavage (BAL) protein, cell counts, tissue immunostaining, and differentially expressed genes (DEGs) were measured in lung tissues at 2 and 10 weeks.In mice exposed to both CPS and intratracheal LPS, both BAL protein and cell counts were increased at both 2 and 10 weeks compared to mice exposed to LPS alone. Multiple DEGs were identified in CPS-LPS-exposed lung tissues compared to LPS alone and were involved in transcriptional pathways associated with circadian rhythm disruption, regulation of lung permeability, inflammation with Rap1 signaling, and regulation of actin cytoskeleton. The most dysregulated pathways included myosin light chain kinase, MAP kinase, profilin 2, fibroblast growth factor receptor, integrin b4, and p21-activated kinase.Circadian rhythm disruption results in exacerbated immune response and dysregulated expression of cytoskeletal genes involved in the regulation of epithelial and vascular barrier integrity-the mechanistic underpinnings of acute lung injury. Further studies need to explore circadian disorganization as a druggable target.
• Casanova, N., De Armond, R., Sammani, S., Sun, X., Sun, B., Kempf, C., Bime, C., Garcia, J., & Parthasarathy, S. (2024). Circadian disruption dysregulates lung gene expression associated with inflammatory lung injury. Frontiers in Immunology, 15. doi:10.3389/fimmu.2024.1348181
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  Rationale: Circadian systems drive the expression of multiple genes in nearly all cells and coordinate cellular-, tissue-, and system-level processes that are critical to innate immunity regulation. Objective: We examined the effects of circadian rhythm disorganization, produced by light shift exposure, on innate immunity-mediated inflammatory lung responses including vascular permeability and gene expression in a C57BL/6J murine model of inflammatory lung injury. Methods: A total of 32 C57BL/6J mice were assigned to circadian phase shifting (CPS) with intratracheal phosphate-buffered saline (PBS), CPS with intratracheal lipopolysaccharide (LPS), control (normal lighting) condition with intratracheal PBS, and control condition with intratracheal LPS. Bronchoalveolar lavage (BAL) protein, cell counts, tissue immunostaining, and differentially expressed genes (DEGs) were measured in lung tissues at 2 and 10 weeks. Measurements and results: In mice exposed to both CPS and intratracheal LPS, both BAL protein and cell counts were increased at both 2 and 10 weeks compared to mice exposed to LPS alone. Multiple DEGs were identified in CPS–LPS-exposed lung tissues compared to LPS alone and were involved in transcriptional pathways associated with circadian rhythm disruption, regulation of lung permeability, inflammation with Rap1 signaling, and regulation of actin cytoskeleton. The most dysregulated pathways included myosin light chain kinase, MAP kinase, profilin 2, fibroblast growth factor receptor, integrin b4, and p21-activated kinase. Conclusion: Circadian rhythm disruption results in exacerbated immune response and dysregulated expression of cytoskeletal genes involved in the regulation of epithelial and vascular barrier integrity—the mechanistic underpinnings of acute lung injury. Further studies need to explore circadian disorganization as a druggable target.
• Covar, R., Covar, R., Lazarus, S., Lazarus, S., Krishnan, J., Krishnan, J., Blake, K., Blake, K., Sorkness, C., Sorkness, C., Dyer, A., Dyer, A., Lang, J., Lang, J., Lugogo, N., Lugogo, N., Mauger, D., Mauger, D., Wechsler, M., , Wechsler, M., et al. (2024). Association of Sputum Eosinophilia With Easily Measured Type-2 Inflammatory Biomarkers in Untreated Mild Persistent Asthma. Journal of Allergy and Clinical Immunology: In Practice, 12(4). doi:10.1016/j.jaip.2023.12.010
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  Background: A multicenter clinical trial in patients with mild persistent asthma indicated that response to inhaled corticosteroids (ICS) is limited to those with sputum eosinophilia. However, testing for sputum eosinophilia is impractical in most clinical settings. Objective: We examined associations between sputum eosinophilia and type 2 inflammatory biomarkers in untreated mild persistent asthma. Methods: Induced sputum, blood eosinophil count (BEC), fractional exhaled nitric oxide (FeNO), and serum periostin were obtained twice during the 6-week run-in period in a clinical trial that enrolled patients 12 years and older with symptomatic, mild persistent asthma without controller therapy. The optimal threshold for each biomarker was based on achieving 80% or greater sensitivity. Performance of biomarkers (area under the receiver operating characteristics curve [AUC], range 0.0–1.0) in predicting sputum eosinophilia 2% or greater was determined; AUCs of 0.8 to 0.9 and more than 0.9 define excellent and outstanding discrimination, respectively. Results: Of 564 participants, 27% were sputum eosinophilic, 83% were atopic, 70% had BEC of 200/uL or higher or FeNO of 25 ppb or greater; 64% of participants without sputum eosinophilia had elevated BEC or FeNO. The AUCs for BEC, FeNO, and both together in predicting sputum eosinophilia were all below the threshold for excellent discrimination (AUC 0.75, 0.78, and 0.79, respectively). Periostin (in adults) had poor discrimination (AUC 0.59; P =. 02). Conclusions: In untreated mild persistent asthma, there is substantial discordance between sputum eosinophilia, BEC, and FeNO. Until prospective trials test the ability of alternative biomarkers to predict ICS response, BEC or FeNO phenotyping may be an option to consider ICS through a shared decision-making process with consideration of other clinical features.
• Obaseki, D., Bime, C., & Awopeju, O. (2024). A look at spirometric PRISm in low-income and middle-income countries. The Lancet Global Health, 12(9). doi:10.1016/S2214-109X(24)00332-2
• Sun, X., Sun, B., Sammani, S., Dudek, S., Belvitch, P., Camp, S., Zhang, D., Bime, C., & Garcia, J. (2024). Genetic and epigenetic regulation of cortactin (CTTN) by inflammatory factors and mechanical stress in human lung endothelial cells. Bioscience Reports, 44(9). doi:10.1042/BSR20231934
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  Rationale: Cortactin, an actin-binding cytoskeletal protein, plays a crucial role in maintaining endothelial cell (EC) barrier integrity and regulating vascular permeability. The gene encoding cortactin, CTTN, is implicated in various lung inflammatory disorders. Despite this, the transcriptional regulation of CTTN by inflammatory stimuli and promoter SNPs remains unexplored. Methods: We transfected human lung ECs with a full-length CTTN promoters linked to a luciferase reporter to measure promoter activity. SNP-containing CTTN promoter was created via site-directed mutagenesis. Transfected ECs were exposed to LPS (PAMP), TNF-α (cytokine), cyclic stretch (CS), FG-4592 (HIF-inducer), NRF2 (anti-oxidant modulator), FTY-(S)-phosphate (endothelial barrier enhancer), and 5́-Aza (demethylation inducer). Immunohistochemistry was used to assess cortactin expression in mouse lungs exposed to LPS. Results: LPS, TNF-α, and 18%CS significantly increased CTTN promoter activities in a time-dependent manner (P
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2023). Relationship of Heterologous Virus Responses and Outcomes in Hospitalized COVID-19 Patients. Journal of Immunology, 211(8). doi:10.4049/jimmunol.2300391
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  The clinical trajectory of COVID-19 may be influenced by previous responses to heterologous viruses. We examined the relationship of Abs against different viruses to clinical trajectory groups from the National Institutes of Health IMPACC (Immunophenotyping Assessment in a COVID-19 Cohort) study of hospitalized COVID-19 patients. Whereas initial Ab titers to SARS-CoV-2 tended to be higher with increasing severity (excluding fatal disease), those to seasonal coronaviruses trended in the opposite direction. Initial Ab titers to influenza and parainfluenza viruses also tended to be lower with increasing severity. However, no significant relationship was observed for Abs to other viruses, including measles, CMV, EBV, and respiratory syncytial virus. We hypothesize that some individuals may produce lower or less durable Ab responses to respiratory viruses generally (reflected in lower baseline titers in our study), and that this may carry over into poorer outcomes for COVID-19 (despite high initial SARS-CoV-2 titers). We further looked at longitudinal changes in Ab responses to heterologous viruses, but found little change during the course of acute COVID-19 infection. We saw significant trends with age for Ab levels to many of these viruses, but no difference in longitudinal SARS-CoV-2 titers for those with high versus low seasonal coronavirus titers. We detected no difference in longitudinal SARS-CoV-2 titers for CMV seropositive versus seronegative patients, although there was an overrepresentation of CMV seropositives among the IMPACC cohort, compared with expected frequencies in the United States population. Our results both reinforce findings from other studies and suggest (to our knowledge) new relationships between the response to SARS-CoV-2 and Abs to heterologous viruses.
• Bime, C. (2023).

  Delayed intubation associated with in-hospital mortality in patients with COVID-19 respiratory failure who fail heated and humified high flow nasal canula

  . BMC Anesthesiology. doi:10.1186/s12871-023-02198-7
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  Abstract Background Advanced respiratory support modalities such as non-invasive positive pressure ventilation (NiPPV) and heated and humidified high flow nasal canula (HFNC) served as useful alternatives to invasive mechanical ventilatory support for acute respiratory failure (ARF) during the peak of the SARS-CoV-2/COVID-19 pandemic. Unlike NiPPV, HFNC is a newer modality and its role in the treatment of patients with severe ARF is not yet clearly defined. Furthermore, the characteristics of responders versus non-responders to HFNC have not been determined. Although recent evidence indicates that many patients with ARF treated with HFNC survive without needing intubation, those who fail and are subsequently intubated have worse outcomes. Given that prolonged use of HFNC in patients with ARF might exacerbate patient self-inflicted lung injury, we hypothesized that among those patients with ARF due to COVID-19 pneumonia, prolonged HFNC beyond 24 h before intubation would be associated with increased in-hospital mortality. Methods This was a retrospective, multicenter, observational cohort study of 2720 patients treated for ARF secondary to SARS-CoV-2/COVID-19 pneumonia and initially managed with HFNC within the Banner Health system during the period from March 1 st , 2020, to July 31 st , 2021. In the subgroup of patients for went from HFNC to IMV, we assessed the effect of the duration of HFNC prior to intubation on mortality. Results 1392 (51%) were successfully treated with HFNC alone and 1328 (49%) failed HFNC and were intubated (HFNC to IMV). When adjusted for the covariates, HFNC duration less than 24 h prior to intubation was significantly associated with reduced mortality. Conclusions Among patients with ARF due to COVID-19 pneumonia who fail HFNC, delay of intubation beyond 24 h is associated with increased mortality
• Bime, C. (2023).

  Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection

  . JAMA Network. doi:10.1001/jama.2023.8823
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  SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.SARS-CoV-2 infection.PASC and 44 participant-reported symptoms (with severity thresholds).A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.
• Bime, C. (2023).

  Disparities in outcomes of COVID-19 hospitalizations in native American individuals

  . Frontiers Public Health. doi:10.3389/fpubh.2023.1220582
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  Objectives This study aimed to investigate COVID-19-related disparities in clinical presentation and patient outcomes in hospitalized Native American individuals. Methods The study was performed within 30 hospitals of the Banner Health system in the Southwest United States and included 8,083 adult patients who tested positive for SARS-CoV-2 infection and were hospitalized between 1 March 2020 and 4 September 2020. Bivariate and multivariate analyses were used to assess racial and ethnic differences in clinical presentation and patient outcomes. Results COVID-19-related hospitalizations in Native American individuals were over-represented compared with non-Hispanic white individuals. Native American individuals had fewer symptoms at admission; greater prevalence of chronic lung disease in the older adult; two times greater risk for ICU admission despite being younger; and 20 times more rapid clinical deterioration warranting ICU admission. Compared with non-Hispanic white individuals, Native American individuals had a greater prevalence of sepsis, were more likely to require invasive mechanical ventilation, had a longer length of stay, and had higher in-hospital mortality. Conclusion Native American individuals manifested greater case-fatality rates following hospitalization than other races/ethnicities. Atypical symptom presentation of COVID-19 included a greater prevalence of chronic lung disease and a more rapid clinical deterioration, which may be responsible for the observed higher hospital mortality, thereby underscoring the role of pulmonologists in addressing such disparities.
• Bime, C. (2023).

  Effect of Race and Ethnicity on Pulmonary Function Testing Interpretation

  . CHEST. doi:10.1016/j.chest.2023.03.026
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  Calls have been made to discontinue the routine use of race and ethnicity in medicine. Specific to respiratory medicine, the use of race- and ethnicity-specific reference equations for the interpretation of pulmonary function test (PFT) results has been questioned.Three key questions were addressed: (1) What is the current evidence supporting the use of race- and ethnicity-specific reference equations for the interpretation of PFTs? (2) What are the potential clinical implications of the use or nonuse of race and ethnicity in interpreting PFT results? and (3) What research gaps and questions must be addressed and answered to understand better the effect of race and ethnicity on PFT results interpretation and potential clinical and occupational health implications?A joint multisociety (American College of Chest Physicians, American Association for Respiratory Care, American Thoracic Society, and Canadian Thoracic Society) expert panel was formed to undertake a comprehensive evidence review and to develop a statement with recommendations to address the research questions.Several assumptions and gaps, both in the published literature and in our evolving understanding of lung health, were identified. It seems that many past perceptions and practices regarding the effect of race and ethnicity on PFT results interpretation are based on limited scientific evidence and measures that lack reliability.A need exists for more and better research that will inform our field about these many uncertainties and will serve as a foundation for future recommendations in this area. The identified shortcomings should not be discounted or dismissed because they may enable flawed conclusions, unintended consequences, or both. Addressing the identified research gaps and needs would allow a better-a more informed-understanding of the effects of race and ethnicity on PFT results interpretation.
• Bime, C. (2023).

  Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

  . eLife. doi:10.7554/elife.86014
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  With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis. In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients.
• Bime, C. (2023).

  Involvement of eNAMPT / TLR4 inflammatory signaling in progression of non‐alcoholic fatty liver disease, steatohepatitis, and fibrosis

  . The FASEB Journal, 37(3). doi:10.1096/fj.202201972rr
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  Although the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to steatohepatitis (NASH) and cirrhosis remains poorly understood, a critical role for dysregulated innate immunity has emerged. We examined the utility of ALT-100, a monoclonal antibody (mAb), in reducing NAFLD severity and progression to NASH/hepatic fibrosis. ALT-100 neutralizes eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel damage-associated molecular pattern protein (DAMP) and Toll-like receptor 4 (TLR4) ligand. Histologic and biochemical markers were measured in liver tissues and plasma from human NAFLD subjects and NAFLD mice (streptozotocin/high-fat diet-STZ/HFD, 12 weeks). Human NAFLD subjects (n = 5) exhibited significantly increased NAMPT hepatic expression and significantly elevated plasma levels of eNAMPT, IL-6, Ang-2, and IL-1RA compared to healthy controls, with IL-6 and Ang-2 levels significantly increased in NASH non-survivors. Untreated STZ/HFD-exposed mice displayed significant increases in NAFLD activity scores, liver triglycerides, NAMPT hepatic expression, plasma cytokine levels (eNAMPT, IL-6, and TNFα), and histologic evidence of hepatocyte ballooning and hepatic fibrosis. Mice receiving the eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg/week, IP, weeks 9 to 12) exhibited marked attenuation of each index of NASH progression/severity. Thus, activation of the eNAMPT/TLR4 inflammatory pathway contributes to NAFLD severity and NASH/hepatic fibrosis. ALT-100 is potentially an effective therapeutic approach to address this unmet NAFLD need.
• Bime, C. (2023).

  Linkage of NAMPT promoter variants to eNAMPT secretion, plasma eNAMPT levels, and ARDS severity

  . Therapeutic Advances in Respiratory Disease, 17. doi:10.1177/17534666231181262
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  eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel DAMP and TLR4 ligand, is a druggable ARDS therapeutic target with NAMPT promoter SNPs associated with ARDS severity. This study assesses the previously unknown influence of NAMPT promoter SNPs on NAMPT transcription, eNAMPT secretion, and ARDS severity.Human lung endothelial cells (ECs) transfected with NAMPT promoter luciferase reporters harboring SNPs G-1535A, A-1001 C, and C-948A, were exposed to LPS or LPS/18% cyclic stretch (CS) and NAMPT promoter activity, NAMPT protein expression, and secretion assessed. NAMPT genotypes and eNAMPT plasma measurements (Days 0/7) were assessed in two ARDS cohorts (DISCOVERY n = 428; ALVEOLI n = 103).Comparisons of minor allelic frequency (MAF) in both ARDS cohorts with the 1000 Human Genome Project revealed the G-1535A and C-948A SNPs to be significantly associated with ARDS in Blacks compared with controls and trended toward significance in non-Hispanic Whites. LPS-challenged and LPS/18% CS-challenged EC harboring the -1535G wild-type allele exhibited significantly increased NAMPT promoter activity (compared with -1535A) with the -1535G/-948A diplotype exhibiting significantly increased NAMPT promoter activity, NAMPT protein expression, and eNAMPT secretion compared with the -1535A/-948 C diplotype. Highly significant increases in Day 0 eNAMPT plasma values were observed in both DISCOVERY and ALVEOLI ARDS cohorts (compared with healthy controls). Among subjects surviving to Day 7, Day 7 eNAMPT values were significantly increased in Day 28 non-survivors versus survivors. The protective -1535A SNP allele drove -1535A/-1001A and -1535A/-948 C diplotypes that confer significantly reduced ARDS risk (compared with -1535G, -1535G/-1001 C, -1535G/-948A), particularly in Black ARDS subjects. NAMPT SNP comparisons within the two ARDS cohorts did not identify significant association with either APACHE III scores or plasma eNAMPT levels.NAMPT SNPs influence promoter activity, eNAMPT protein expression/secretion, plasma eNAMPT levels, and ARDS severity. NAMPT genotypes are a potential tool for stratification in eNAMPT-focused ARDS clinical trials.
• Bime, C. (2023).

  Longitudinal Assessment of Mobility and Self-care Among Critically Ill Older Adults. An Age-Friendly Health Systems Initiative Quality Improvement Study.

  . Dimensions of Critical Care Nursing. doi:10.1097/dcc.0000000000000588
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  Early mobility in the intensive care unit (ICU) is vital to maintaining an older adult patient's performance of activities of daily living, functional mobility, and overall quality of life. Prior studies have shown reduced length of inpatient stay and onset of delirium in patients with early mobilization. Despite these benefits, many ICU patients are often labeled as too sick to participate in therapy and frequently do not receive physical (PT) or occupational therapy (OT) consults until they are considered floor status. This delay in therapy can negatively affect a patient's capacity to participate in his/her self-care, add to the burden on caregivers, and limit disposition options.Our goals were to perform a longitudinal assessment of mobility and self-care among older patients through their medical ICU (MICU) stays and to quantify visits by therapy services to identify areas for improvement in achieving early intervention in this at-risk population.This was a retrospective quality improvement analysis of a cohort of admissions to the MICU at a large tertiary academic medical center between November 2018 and May 2019. Admission information, PT and OT consult information, Perme Intensive Care Unit Mobility Score, and Modified Barthel Index scores were entered into a quality improvement registry. Inclusion criteria consisted of age older than 65 years and at least 2 distinct visits by PT and/or OT for evaluation. Patients without consults and patients with weekend-only MICU stays were not assessed.There were 302 MICU patients 65 years or older admitted during the study period. Forty-four percent (132) of these patients received PT/OT consults, and among these, 32% (42) had at least 2 visits to allow comparison of objective scores. Seventy-five percent of patients had improved Perme scores (median, 9.4%; interquartile range, 2.3%-15.6%), and 58% of patients had improved Modified Barthel Index scores (median, 3%; interquartile range, -2% to 13.5%). However, 17% of potential therapy days were missed because of inadequate staffing/time, and 14% were missed because of being sedated or unable to participate.In our cohort of patients older than 65 years, receipt of therapy in the MICU led to modest improvements in score-assessed mobility and self-care before transfer to floor. Staffing, time constraints, and patient sedation or encephalopathy appeared to interfere most with further potential benefits. In the next phase, we plan to implement strategies to increase PT/OT availability in the MICU and implement a protocol to increase identification and referral of candidates for whom early therapy can prevent loss of mobility and ability to perform self-care.
• Bime, C. (2023).

  Race and Ethnicity in Pulmonary Function Test Interpretation: An Official American Thoracic Society Statement

  . American Journal of Respiratory and Critical Care Medicine. doi:10.1164/rccm.202302-0310st
• Bime, C. (2023).

  Reply to Haynes and to Wang

  . American Journal of Respiratory and Critical Care Medicine. doi:10.1164/rccm.202308-1315le
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  "Reply to Haynes and to Wang." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
• Bime, C. (2023).

  Researching COVID to enhance recovery (RECOVER) adult study protocol: Rationale, objectives, and design

  . PLoS one. doi:10.1101/2023.05.26.23290475
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  Abstract Importance SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility– and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross– validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.
• Bime, C. (2023).

  T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults

  . GeroScience. doi:10.1007/s11357-022-00724-y
• Bime, C. (2023).

  Targeting SELPLG/ P‐selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter

  . Pulmonary Circulation, 13(1). doi:10.1002/pul2.12206
• Bime, C. (2023). Examination of eQTL Polymorphisms Associated with Increased Risk of Progressive Complicated Sarcoidosis in European and African Descent Subjects.. Eur J Res Med.
• Bime, C., & Casanova, N. (2022). Circulating eNAMPT as a Biomarker in the Critically Ill: Acute Pancreatitis, Sepsis, Trauma, and Acute Respiratory Distress Syndrome. BMC, anesthesiology.
• Diray-Arce, J., Fourati, S., Doni Jayavelu, N., Patel, R., Maguire, C., Chang, A., Dandekar, R., Qi, J., Lee, B., van Zalm, P., Schroeder, A., Chen, E., Konstorum, A., Brito, A., Gygi, J., Kho, A., Chen, J., Pawar, S., Gonzalez-Reiche, A., , Hoch, A., et al. (2023). Multi-omic longitudinal study reveals immune correlates of clinical course among hospitalized COVID-19 patients. Cell Reports Medicine, 4(6). doi:10.1016/j.xcrm.2023.101079
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  The IMPACC cohort, composed of >1,000 hospitalized COVID-19 participants, contains five illness trajectory groups (TGs) during acute infection (first 28 days), ranging from milder (TG1–3) to more severe disease course (TG4) and death (TG5). Here, we report deep immunophenotyping, profiling of >15,000 longitudinal blood and nasal samples from 540 participants of the IMPACC cohort, using 14 distinct assays. These unbiased analyses identify cellular and molecular signatures present within 72 h of hospital admission that distinguish moderate from severe and fatal COVID-19 disease. Importantly, cellular and molecular states also distinguish participants with more severe disease that recover or stabilize within 28 days from those that progress to fatal outcomes (TG4 vs. TG5). Furthermore, our longitudinal design reveals that these biologic states display distinct temporal patterns associated with clinical outcomes. Characterizing host immune responses in relation to heterogeneity in disease course may inform clinical prognosis and opportunities for intervention.
• Ozonoff, A., Schaenman, J., Jayavelu, N., Milliren, C., Calfee, C., Cairns, C., Kraft, M., Baden, L., Shaw, A., Krammer, F., van Bakel, H., Esserman, D., Liu, S., Sesma, A., Simon, V., Hafler, D., Montgomery, R., Kleinstein, S., Levy, O., , Bime, C., et al. (2023). Corrigendum to “Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: results from the IMPACC study” [eBioMedicine 83 (2022) 104208] (eBioMedicine (2022) 83, (S2352396422003905), (10.1016/j.ebiom.2022.104208)). eBioMedicine, 98. doi:10.1016/j.ebiom.2023.104860
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  As part of our internal review, we identified a point to be clarified in the methods. The omitted step involves the reclassification of all deaths to the most severe category of outcome trajectories (trajectory group 5), and corresponding reclassification of non-deaths in this category to the adjacent, less severe category (trajectory group 4). This is implied by our use of the descriptor ‘fatal’ for the most severe category, but our description of methods omits the step to reclassify participants. We have included the following in the Statistics paragraph of the online version: To ensure that the most severe group contained only deaths, a final step was to reclassify any participant that died within 28 days after enrollment in the most severe group, and to reclassify any non-deaths in this group to the adjacent, next-most-severe group. We have confirmed the following: • Although the description of methods can be clarified, the stated results, discussion, and conclusions from our study remain unchanged.• The publicly available data are accurate. The publicly available analysis code has been updated and replicates our published results.The authors would like to apologise for any inconvenience caused.
• Taleban, S., Bime, C., & Shrestha, M. (2018). Obesity is associated with increased risk of colectomy in inflammatory bowel disease patients hospitalized with Clostridium difficile infection.. Gastroenterology, 154, Supplement 1, S-411-412.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2022). Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: Results from the IMPACC study. eBioMedicine, 83(Issue). doi:10.1016/j.ebiom.2022.104208
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  Background: Better understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management. Methods: Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed. Findings: The median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age ≥ 65 years (odds ratio [OR], 2.01; 95% CI 1.28–3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13–2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63– 4.80) or troponin (OR 1.89; 95% 1.03–3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61–2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96–5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17–2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC. Interpretation: Integration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19. Funding: NIH.
• Abraham, I., Bime, C., Stocking, J. C., Drake, C., Aldrich, J. M., Ong, M. K., Amin, A., Marmor, R. A., Godat, L., Cannesson, M., Gropper, M., Romano, P. S., Sandrock, C. E., & Utter, G. (2022). Outcomes and Risk Factors for Delayed-Onset Postoperative Respiratory Failure: A Multi-Center Case-Control Study by the University of California Critical Care Research Collaborative (UC3RC). BMC Anestehsiology. doi:10.21203/rs.3.rs-824536/v1
• Belvitch, P., Casanova, N., Sun, X., Camp, S. M., Sammani, S., Brown, M. E., Mascarhenas, J., Lynn, H., Adyshev, D., Siegler, J., Desai, A., Seyed-Saadat, L., Rizzo, A., Bime, C., Shekhawat, G. S., Dravid, V. P., Reilly, J. P., Jones, T. K., Feng, R., , Letsiou, E., et al. (2022). A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subjects. Translational Research, 244(Issue). doi:10.1016/j.trsl.2022.02.002
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  The cortactin gene (CTTN), encoding an actin-binding protein critically involved in cytoskeletal dynamics and endothelial cell (EC) barrier integrity, contains single nucleotide polymorphisms (SNPs) associated with severe asthma in Black patients. As loss of lung EC integrity is a major driver of mortality in the Acute Respiratory Distress Syndrome (ARDS), sepsis, and the acute chest syndrome (ACS), we speculated CTTN SNPs that alter EC barrier function will associate with clinical outcomes from these types of conditions in Black patients. In case-control studies, evaluation of a nonsynonymous CTTN coding SNP Ser484Asn (rs56162978, G/A) in a severe sepsis cohort (725 Black subjects) revealed significant association with increased risk of sepsis mortality. In a separate cohort of sickle cell disease (SCD) subjects with and without ACS (177 SCD Black subjects), significantly increased risk of ACS and increased ACS severity (need for mechanical ventilation) was observed in carriers of the A allele. Human lung EC expressing the cortactin S484N transgene exhibited: (i) delayed EC barrier recovery following thrombin-induced permeability; (ii) reduced levels of critical Tyr486 cortactin phosphorylation; (iii) inhibited binding to the cytoskeletal regulator, nmMLCK; and (iv) attenuated EC barrier-promoting lamellipodia dynamics and biophysical responses. ARDS-challenged Cttn+/− heterozygous mice exhibited increased lung vascular permeability (compared to wild-type mice) which was significantly attenuated by IV delivery of liposomes encargoed with CTTN WT transgene but not by CTTN S484N transgene. In summary, these studies suggest that the CTTN S484N coding SNP contributes to severity of inflammatory injury in Black patients, potentially via delayed vascular barrier restoration.
• Belvitch, P., Casanova, N., Sun, X., Camp, S. M., Sammani, S., Brown, M. E., Mascarhenas, J., Lynn, H., Adyshev, D., Siegler, J., Desai, A., Seyed-Saadat, L., Rizzo, A., Bime, C., Shekhawat, G. S., Dravid, V. P., Reilly, J. P., Jones, T. K., Feng, R., , Letsiou, E., et al. (2022). A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subjects. Translational research : the journal of laboratory and clinical medicine, 244, 56-74.
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  The cortactin gene (CTTN), encoding an actin-binding protein critically involved in cytoskeletal dynamics and endothelial cell (EC) barrier integrity, contains single nucleotide polymorphisms (SNPs) associated with severe asthma in Black patients. As loss of lung EC integrity is a major driver of mortality in the Acute Respiratory Distress Syndrome (ARDS), sepsis, and the acute chest syndrome (ACS), we speculated CTTN SNPs that alter EC barrier function will associate with clinical outcomes from these types of conditions in Black patients. In case-control studies, evaluation of a nonsynonymous CTTN coding SNP Ser484Asn (rs56162978, G/A) in a severe sepsis cohort (725 Black subjects) revealed significant association with increased risk of sepsis mortality. In a separate cohort of sickle cell disease (SCD) subjects with and without ACS (177 SCD Black subjects), significantly increased risk of ACS and increased ACS severity (need for mechanical ventilation) was observed in carriers of the A allele. Human lung EC expressing the cortactin S484N transgene exhibited: (i) delayed EC barrier recovery following thrombin-induced permeability; (ii) reduced levels of critical Tyr486 cortactin phosphorylation; (iii) inhibited binding to the cytoskeletal regulator, nmMLCK; and (iv) attenuated EC barrier-promoting lamellipodia dynamics and biophysical responses. ARDS-challenged Cttn+/- heterozygous mice exhibited increased lung vascular permeability (compared to wild-type mice) which was significantly attenuated by IV delivery of liposomes encargoed with CTTN WT transgene but not by CTTN S484N transgene. In summary, these studies suggest that the CTTN S484N coding SNP contributes to severity of inflammatory injury in Black patients, potentially via delayed vascular barrier restoration.
• Bermudez, T., Sammani, S., Song, J. H., Hernon, V. R., Kempf, C. L., Garcia, A. N., Burt, J., Hufford, M., Camp, S. M., Cress, A. E., Desai, A. A., Natarajan, V., Jacobson, J. R., Dudek, S. M., Cancio, L. C., Alvarez, J., Rafikov, R., Li, Y., Zhang, D. D., , Casanova, N. G., et al. (2022). eNAMPT neutralization reduces preclinical ARDS severity via rectified NFkB and Akt/mTORC2 signaling. Scientific Reports, 12(Issue 1). doi:10.1038/s41598-021-04444-9
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  Despite encouraging preclinical data, therapies to reduce ARDS mortality remains a globally unmet need, including during the COVID-19 pandemic. We previously identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern protein (DAMP) via TLR4 ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to human ARDS by biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory lung injury with NFkB pathway activation and marked dysregulation of the Akt/mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum lactate, and plasma levels of eNAMPT, IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory lung injury and ARDS mortality.
• Bermudez, T., Sammani, S., Song, J. H., Hernon, V. R., Kempf, C. L., Garcia, A. N., Burt, J., Hufford, M., Camp, S. M., Cress, A. E., Desai, A. A., Natarajan, V., Jacobson, J. R., Dudek, S. M., Cancio, L. C., Alvarez, J., Rafikov, R., Li, Y., Zhang, D. D., , Casanova, N. G., et al. (2022). eNAMPT neutralization reduces preclinical ARDS severity via rectified NFkB and Akt/mTORC2 signaling. Scientific reports, 12(1), 696.
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  Despite encouraging preclinical data, therapies to reduce ARDS mortality remains a globally unmet need, including during the COVID-19 pandemic. We previously identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern protein (DAMP) via TLR4 ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to human ARDS by biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory lung injury with NFkB pathway activation and marked dysregulation of the Akt/mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum lactate, and plasma levels of eNAMPT, IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory lung injury and ARDS mortality.
• Bhakta, N. R., Kaminsky, D. A., Bime, C., Thakur, N., Hall, G. L., McCormack, M. C., & Stanojevic, S. (2022). Addressing Race in Pulmonary Function Testing by Aligning Intent and Evidence With Practice and Perception. Chest, 161(1), 288-297.
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  The practice of using race or ethnicity in medicine to explain differences between individuals is being called into question because it may contribute to biased medical care and research that perpetuates health disparities and structural racism. A commonly cited example is the use of race or ethnicity in the interpretation of pulmonary function test (PFT) results, yet the perspectives of practicing pulmonologists and physiologists are missing from this discussion. This discussion has global relevance for increasingly multicultural communities in which the range of values that represent normal lung function is uncertain. We review the underlying sources of differences in lung function, including those that may be captured by race or ethnicity, and demonstrate how the current practice of PFT measurement and interpretation is imperfect in its ability to describe accurately the relationship between function and health outcomes. We summarize the arguments against using race-specific equations as well as address concerns about removing race from the interpretation of PFT results. Further, we outline knowledge gaps and critical questions that need to be answered to change the current approach of including race or ethnicity in PFT results interpretation thoughtfully. Finally, we propose changes in interpretation strategies and future research to reduce health disparities.
• Bime, C., Casanova, N. G., Camp, S. M., Oita, R. C., Ndukum, J., Hernon, V. R., Oh, D. K., Li, Y., Greer, P. J., Whitcomb, D. C., Papachristou, G. I., & Garcia, J. G. (2022). Circulating eNAMPT as a biomarker in the critically ill: acute pancreatitis, sepsis, trauma, and acute respiratory distress syndrome. BMC Anesthesiology, 22(Issue 1). doi:10.1186/s12871-022-01718-1
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  Background: Nicotinamide phosphoribosyltransferase (NAMPT) exhibits dual functionality – as an intracellular enzyme regulating nicotinamide adenine dinucleotide metabolism and as an extracellular secreted protein (eNAMPT) to function as a cytokine regulator of innate immunity via binding to Toll-Like receptor 4 and NF-κB activation. In limited preclinical and clinical studies, eNAMPT was implicated in the pathobiology of acute respiratory distress syndrome (ARDS) suggesting that eNAMPT could potentially serve as a diagnostic and prognostic biomarker. We investigated the feasibility of circulating eNAMPT levels to serve as a biomarker in an expanded cohort of patients with ARDS and ARDS-predisposing conditions that included acute pancreatitis, sepsis, and trauma with comparisons to controls. Methods: A total of 671 patients and 179 healthy controls were included in two independent cohorts. Plasma and serum eNAMPT levels were quantified using one of two complementary Enzyme-linked Immunosorbent Assays. After log base 2 variance stabilizing transformation of plasma/serum eNAMPT measurements, differences between healthy controls and each disease cohort were compared using linear regression or a generalized estimating equation (GEE) model where applicable. Complementary analyses included sensitivity, specificity, positive predictive values, negative predictive values, and the area under the receiver operating curve. Results: Compared to controls, circulating eNAMPT levels were significantly elevated in subjects with acute pancreatitis, sepsis, trauma, and ARDS (all p < 0.01). In the acute pancreatitis cohort, circulating eNAMPT levels positively correlated with disease severity (p < 0.01). Conclusions: Circulating eNAMPT levels are novel biomarker in the critically ill with acute pancreatitis, sepsis, trauma, and/or ARDS with the potential to reflect disease severity.
• Bime, C., Casanova, N. G., Camp, S. M., Oita, R. C., Ndukum, J., Hernon, V. R., Oh, D. K., Li, Y., Greer, P. J., Whitcomb, D. C., Papachristou, G. I., & Garcia, J. G. (2022). Circulating eNAMPT as a biomarker in the critically ill: acute pancreatitis, sepsis, trauma, and acute respiratory distress syndrome. BMC anesthesiology, 22(1), 182.
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  Nicotinamide phosphoribosyltransferase (NAMPT) exhibits dual functionality - as an intracellular enzyme regulating nicotinamide adenine dinucleotide metabolism and as an extracellular secreted protein (eNAMPT) to function as a cytokine regulator of innate immunity via binding to Toll-Like receptor 4 and NF-κB activation. In limited preclinical and clinical studies, eNAMPT was implicated in the pathobiology of acute respiratory distress syndrome (ARDS) suggesting that eNAMPT could potentially serve as a diagnostic and prognostic biomarker. We investigated the feasibility of circulating eNAMPT levels to serve as a biomarker in an expanded cohort of patients with ARDS and ARDS-predisposing conditions that included acute pancreatitis, sepsis, and trauma with comparisons to controls.
• Bohula, E., Berg, D., Lopes, M., Connors, J., Babar, I., Barnett, C., Chaudhry, S., Chopra, A., Ginete, W., Ieong, M., Katz, J., Kim, E., Kuder, J., Mazza, E., McLean, D., Mosier, J., Moskowitz, A., Murphy, S., O'Donoghue, M., , Park, J., et al. (2022). Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients With COVID-19: COVID-PACT. Circulation, 146(18). doi:10.1161/CIRCULATIONAHA.122.061533
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  Background: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain. Methods: COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit-level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit-level COVID-19 rates. Results: At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08-3.55]; P=0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32-0.99]; P=0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose (P=0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%; P=0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56-1.48]; P=0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy. Conclusions: In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04409834.
• Cai, H., Cress, A. E., Rappaport, J., Valera, D. G., Sun, X., Song, J. H., Sammani, S., Rogers, C., Oita, R. C., Moreno-vinasco, L., Menon, N., Kyubwa, E. M., Kempf, C. L., Hernon, V. R., Gregory, T., Garcia, J. G., Garcia, A. N., Casanova, N. G., Camp, S. M., , Bime, C., et al. (2022). eNAMPT is a Novel DAMP that Contributes to the Severity of Radiation-Induced Lung Fibrosis.. American journal of respiratory cell and molecular biology. doi:10.1165/rcmb.2021-0357oc
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  The paucity of therapeutic strategies to reduce the severity of radiation-induced lung fibrosis (RILF), a life-threatening complication of intended or accidental ionizing radia-tion exposure, is a serious unmet need. We evaluated the contribution of eNAMPT (ex-tracellular nicotinamide phosphoribosyltransferase), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, to the severity of whole thoracic lung irradiation (WTLI)-induced RILF. Wild type (WT) and Nampt+/- heterozygous C57BL6 mice and non-human primates (NHPs, Macaca Mulatta) were exposed to single WTLI dose (9.8 or 10.7 Gy-NHPs, 20 Gy-mice). WT mice received IgG1 (control) or a eNAMPT-neutralizing polyclonal (pAb) or monoclonal antibody (mAb) IP 4 hours post WTLI and weekly thereafter. At 8-12 weeks post WTLI), NAMPT expression was assessed by immunohistochemistry, biochemistry, and plasma biomarker studies. RILF severity was determined by BAL protein/cells, H&E and Trichrome blue staining and soluble collagen assays. RNA sequencing and bioinformatic analyses identified differentially-expressed lung tissue genes (DEGs)/pathways. NAMPT lung tissue expression was increased in both WTLI-exposed WT mice and NHPs. Nampt+/- mice and eNAMPT pAb/mAb-treated mice exhibited significantly attenuated WTLI-mediated lung fibrosis with reduced: i) NAMPT and Trichrome blue staining, ii) dysregulated lung tis-sue expression of smooth muscle actin, p-SMAD2/p-SMAD1/5/9, TGFβ, TSP-1, NOX4, IL-1β, NRF2; iii) plasma eNAMPT and IL-1β levels, and iv) soluble collagen. Multiple WTLI-induced dysregulated DEGs/pathways with known tissue fibrosis involvement were each rectified in mice receiving eNAMPT mAb.The eNAMPT/TLR4 inflammatory network is essentially involved in radiation pathobiology with eNAMPT neutralization an effective therapeutic strategy to reduce RILF severity.
• Casanova, N. G., Reyes-Hernon, V., Gregory, T., Sun, B., Bermudez, T., Hufford, M. K., Oita, R. C., Camp, S. M., Hernandez-Molina, G., Serrano, J. R., Sun, X., Fimbres, J., Mirsaeidi, M., Sammani, S., Bime, C., & Garcia, J. G. (2022). Biochemical and genomic identification of novel biomarkers in progressive sarcoidosis: HBEGF, eNAMPT, and ANG-2. Frontiers in Medicine, 9(Issue). doi:10.3389/fmed.2022.1012827
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  Background: Progressive pulmonary fibrosis is a serious complication in subjects with sarcoidosis. The absence of reliable, non-invasive biomarkers that detect early progression exacerbates the difficulty in predicting sarcoidosis severity. To potentially address this unmet need, we evaluated a panel of markers for an association with sarcoidosis progression (HBEGF, NAMPT, IL1-RA, IL-6, IL-8, ANG-2). This panel encompasses proteins related to inflammation, vascular injury, cell proliferation, and fibroblast mitogenesis processes. Methods: Plasma biomarker levels and biomarker protein expression in lung and lymph nodes tissues (immunohistochemical studies) from sarcoidosis subjects with limited disease and progressive (complicated) sarcoidosis were performed. Gene expression of the protein-coding genes included in this panel was analyzed using RNAseq in sarcoidosis granulomatous tissues from lung and lymph nodes. Results: Except for IL-8, plasma levels of each biomarker—eNAMPT, IL-1RA, IL-6, ANG-2, and HBEGF—were significantly elevated in sarcoidosis subjects compared to controls. In addition, plasma levels of HBEGF were elevated in complicated sarcoidosis, while eNAMPT and ANG-2 were observed to serve as markers of lung fibrosis in a subgroup of complicated sarcoidosis. Genomic studies corroborated HBEGF and NAMPT among the top dysregulated genes and identified cytokine-related and fibrotic pathways in lung granulomatous tissues from sarcoidosis. Conclusion: These findings suggest HBEGF, eNAMPT, and ANG-2 may serve as potential novel indicators of the clinical severity of sarcoidosis disease.
• Casanova, N. G., Reyes-Hernon, V., Gregory, T., Sun, B., Bermudez, T., Hufford, M. K., Oita, R. C., Camp, S. M., Hernandez-Molina, G., Serrano, J. R., Sun, X., Fimbres, J., Mirsaeidi, M., Sammani, S., Bime, C., & Garcia, J. G. (2022). Biochemical and genomic identification of novel biomarkers in progressive sarcoidosis: HBEGF, eNAMPT, and ANG-2. Frontiers in medicine, 9, 1012827.
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  Progressive pulmonary fibrosis is a serious complication in subjects with sarcoidosis. The absence of reliable, non-invasive biomarkers that detect early progression exacerbates the difficulty in predicting sarcoidosis severity. To potentially address this unmet need, we evaluated a panel of markers for an association with sarcoidosis progression (HBEGF, NAMPT, IL1-RA, IL-6, IL-8, ANG-2). This panel encompasses proteins related to inflammation, vascular injury, cell proliferation, and fibroblast mitogenesis processes.
• Garcia, A. N., Casanova, N. G., Kempf, C. L., Bermudez, T., Valera, D. G., Song, J. H., Sun, X., Cai, H., Moreno-Vinasco, L., Gregory, T., Oita, R. C., Hernon, V. R., Camp, S. M., Rogers, C., Kyubwa, E. M., Menon, N., Axtelle, J., Rappaport, J., Bime, C., , Sammani, S., et al. (2022). eNAMPT Is a Novel Damage-associated Molecular Pattern Protein That Contributes to the Severity of Radiation-induced Lung Fibrosis. American journal of respiratory cell and molecular biology, 66(5), 497-509.
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  The paucity of therapeutic strategies to reduce the severity of radiation-induced lung fibrosis (RILF), a life-threatening complication of intended or accidental ionizing radiation exposure, is a serious unmet need. We evaluated the contribution of eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a damage-associated molecular pattern (DAMP) protein and TLR4 (Toll-like receptor 4) ligand, to the severity of whole-thorax lung irradiation (WTLI)-induced RILF. Wild-type (WT) and heterozygous C57BL6 mice and nonhuman primates (NHPs, ) were exposed to a single WTLI dose (9.8 or 10.7 Gy for NHPs, 20 Gy for mice). WT mice received IgG (control) or an eNAMPT-neutralizing polyclonal or monoclonal antibody (mAb) intraperitoneally 4 hours after WTLI and weekly thereafter. At 8-12 weeks after WTLI, NAMPT expression was assessed by immunohistochemistry, biochemistry, and plasma biomarker studies. RILF severity was determined by BAL protein/cells, hematoxylin and eosin, and trichrome blue staining and soluble collagen assays. RNA sequencing and bioinformatic analyses identified differentially expressed lung tissue genes/pathways. NAMPT lung tissue expression was increased in both WTLI-exposed WT mice and NHPs. mice and eNAMPT polyclonal antibody/mAb-treated mice exhibited significantly attenuated WTLI-mediated lung fibrosis with reduced: ) NAMPT and trichrome blue staining; ) dysregulated lung tissue expression of smooth muscle actin, p-SMAD2/p-SMAD1/5/9, TGF-β, TSP1 (thrombospondin-1), NOX4, IL-1β, and NRF2; ) plasma eNAMPT and IL-1β concentrations; and ) soluble collagen. Multiple WTLI-induced dysregulated differentially expressed lung tissue genes/pathways with known tissue fibrosis involvement were each rectified in mice receiving eNAMPT mAbs.The eNAMPT/TLR4 inflammatory network is essentially involved in radiation pathobiology, with eNAMPT neutralization an effective therapeutic strategy to reduce RILF severity.
• Garcia, A. N., Casanova, N. G., Valera, D. G., Sun, X., Song, J. H., Kempf, C. L., Moreno-Vinasco, L., Burns, K., Bermudez, T., Valdez, M., Cuellar, G., Gregory, T., Oita, R. C., Hernon, V. R., Barber, C., Camp, S. M., Martin, D., Liu, Z., Bime, C., , Sammani, S., et al. (2022). Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis: protection by eNAMPT neutralization. Translational Research, 239(Issue). doi:10.1016/j.trsl.2021.06.002
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  Therapeutic strategies to prevent or reduce the severity of radiation pneumonitis are a serious unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Radiation-induced murine and human NAMPT expression was assessed in vitro, in tissues (IHC, biochemistry, imaging), and in plasma. Wild type C57Bl6 mice (WT) and Nampt+/− heterozygous mice were exposed to 20Gy whole thoracic lung irradiation (WTLI) with or without weekly IP injection of IgG1 (control) or an eNAMPT-neutralizing polyclonal (pAb) or monoclonal antibody (mAb). BAL protein/cells and H&E staining were used to generate a WTLI severity score. Differentially-expressed genes (DEGs)/pathways were identified by RNA sequencing and bioinformatic analyses. Radiation exposure increases in vitro NAMPT expression in lung epithelium (NAMPT promoter activity) and NAMPT lung tissue expression in WTLI-exposed mice. Nampt+/− mice and eNAMPT pAb/mAb-treated mice exhibited significant histologic attenuation of WTLI-mediated lung injury with reduced levels of BAL protein and cells, and plasma levels of eNAMPT, IL-6, and IL-1β. Genomic and biochemical studies from WTLI-exposed lung tissues highlighted dysregulation of NFkB/cytokine and MAP kinase signaling pathways which were rectified by eNAMPT mAb treatment. The eNAMPT/TLR4 pathway is essentially involved in radiation pathobiology with eNAMPT neutralization an effective therapeutic strategy to reduce the severity of radiation pneumonitis.
• Garcia, A. N., Casanova, N. G., Valera, D. G., Sun, X., Song, J. H., Kempf, C. L., Moreno-Vinasco, L., Burns, K., Bermudez, T., Valdez, M., Cuellar, G., Gregory, T., Oita, R. C., Hernon, V. R., Barber, C., Camp, S. M., Martin, D., Liu, Z., Bime, C., , Sammani, S., et al. (2022). Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis: protection by eNAMPT neutralization. Translational research : the journal of laboratory and clinical medicine, 239, 44-57.
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  Therapeutic strategies to prevent or reduce the severity of radiation pneumonitis are a serious unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Radiation-induced murine and human NAMPT expression was assessed in vitro, in tissues (IHC, biochemistry, imaging), and in plasma. Wild type C57Bl6 mice (WT) and Nampt heterozygous mice were exposed to 20Gy whole thoracic lung irradiation (WTLI) with or without weekly IP injection of IgG (control) or an eNAMPT-neutralizing polyclonal (pAb) or monoclonal antibody (mAb). BAL protein/cells and H&E staining were used to generate a WTLI severity score. Differentially-expressed genes (DEGs)/pathways were identified by RNA sequencing and bioinformatic analyses. Radiation exposure increases in vitro NAMPT expression in lung epithelium (NAMPT promoter activity) and NAMPT lung tissue expression in WTLI-exposed mice. Nampt mice and eNAMPT pAb/mAb-treated mice exhibited significant histologic attenuation of WTLI-mediated lung injury with reduced levels of BAL protein and cells, and plasma levels of eNAMPT, IL-6,  and IL-1β. Genomic and biochemical studies from WTLI-exposed lung tissues highlighted dysregulation of NFkB/cytokine and MAP kinase signaling pathways which were rectified by eNAMPT mAb treatment. The eNAMPT/TLR4 pathway is essentially involved in radiation pathobiology with eNAMPT neutralization an effective therapeutic strategy to reduce the severity of radiation pneumonitis.
• Jergović, M., Watanabe, M., Bhat, R., Coplen, C. P., Sonar, S. A., Wong, R., Castaneda, Y., Davidson, L., Kala, M., Wilson, R. C., Twigg, H. L., Knox, K., Erickson, H. E., Weinkauf, C. C., Bime, C., Bixby, B. A., Parthasarathy, S., Mosier, J. M., LaFleur, B. J., , Bhattacharya, D., et al. (2022). T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults. bioRxiv : the preprint server for biology.
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  In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18-39 years old. To understand age-specific immune pathobiology of COVID-19 we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naïve T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.
• Miller, D., Pu, J., Kukafka, D., & Bime, C. (2022). Failure of High Flow Nasal Cannula and Subsequent Intubation Is Associated With Increased Mortality as Compared to Failure of Non-Invasive Ventilation and Mechanical Ventilation Alone: A Real-World Retrospective Analysis. Journal of Intensive Care Medicine, 37(1). doi:10.1177/0885066620968041
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  Background: Despite the increasing use of high flow nasal cannula oxygenation systems (HFNC) in clinical practice, little is known about its role in all cause respiratory failure as compared to traditional non-invasive ventilation (BiPAP). Furthermore, the effect of HFNC on mortality is unknown. Methods: We conducted a retrospective analysis of 49,853 patients with respiratory failure treated with non-invasive respiratory support (HFNC or BiPAP) and/or invasive mechanical ventilation (IMV) between 2017 and 2018. Results: Patients initially treated with HFNC who underwent subsequent intubation and IMV had a higher mortality rate as compared to patients who were initially treated with BiPAP and underwent subsequent intubation and IMV (34.8% vs 26.3%, p < 0.0001, OR 1.49, 95% CI 1.26,1.76). Patients first treated with HFNC who underwent subsequent intubation and IMV had a significantly increased mortality compared to patients who underwent immediate intubation and IMV (34.8% vs. 21.5%, p ≤ 0.0001, OR 1.94, 95% CI 1.67, 2.27). Stratified based on ICD-10 diagnosis, patients with a diagnosis of COPD exacerbation or heart failure treated with HFNC and subsequent intubation and IMV had higher mortality as compared to those treated with immediate IMV alone. This trend did not hold true for patients with a diagnosis of pneumonia. Conclusion: In a real-world retrospective analysis, use of HFNC was associated with increased mortality as compared to BiPAP and IMV alone. Further study is needed to confirm these associations.
• Ozonoff, A., Schaenman, J., Jayavelu, N. D., Milliren, C. E., Calfee, C. S., Cairns, C. B., Kraft, M., Baden, L. R., Shaw, A. C., Krammer, F., van Bakel, H., Esserman, D. A., Liu, S., Sesma, A. F., Simon, V., Hafler, D. A., Montgomery, R. R., Kleinstein, S. H., Levy, O., , Bime, C., et al. (2022). Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: Results from the IMPACC study. EBioMedicine, 83, 104208.
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  Better understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management.
• Sammani, S., Bermudez, T., Kempf, C. L., Song, J. H., Fleming, J. C., Reyes Hernon, V., Hufford, M., Tang, L., Cai, H., Camp, S. M., Natarajan, V., Jacobson, J. R., Dudek, S. M., Martin, D. R., Karmonik, C., Sun, X., Sun, B., Casanova, N. G., Bime, C., & Garcia, J. G. (2022). eNAMPT Neutralization Preserves Lung Fluid Balance and Reduces Acute Renal Injury in Porcine Sepsis/VILI-Induced Inflammatory Lung Injury. Frontiers in Physiology, 13(Issue). doi:10.3389/fphys.2022.916159
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  Background: Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury. Methods/Results: Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS. Conclusions: These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality.
• Sammani, S., Bermudez, T., Kempf, C. L., Song, J. H., Fleming, J. C., Reyes Hernon, V., Hufford, M., Tang, L., Cai, H., Camp, S. M., Natarajan, V., Jacobson, J. R., Dudek, S. M., Martin, D. R., Karmonik, C., Sun, X., Sun, B., Casanova, N. G., Bime, C., & Garcia, J. G. (2022). eNAMPT Neutralization Preserves Lung Fluid Balance and Reduces Acute Renal Injury in Porcine Sepsis/VILI-Induced Inflammatory Lung Injury. Frontiers in physiology, 13, 916159.
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  Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury. Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS. These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality.
• Serrano, G. E., Walker, J. E., Tremblay, C., Piras, I. S., Huentelman, M. J., Belden, C. M., Goldfarb, D., Shprecher, D., Atri, A., Adler, C. H., Shill, H. A., Driver-Dunckley, E., Mehta, S. H., Caselli, R., Woodruff, B. K., Haarer, C. F., Ruhlen, T., Torres, M., Nguyen, S., , Schmitt, D., et al. (2022). SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19. Journal of Neuropathology and Experimental Neurology, 81(Issue 9). doi:10.1093/jnen/nlac056
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  Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.
• Serrano, G. E., Walker, J. E., Tremblay, C., Piras, I. S., Huentelman, M. J., Belden, C. M., Goldfarb, D., Shprecher, D., Atri, A., Adler, C. H., Shill, H. A., Driver-Dunckley, E., Mehta, S. H., Caselli, R., Woodruff, B. K., Haarer, C. F., Ruhlen, T., Torres, M., Nguyen, S., , Schmitt, D., et al. (2022). SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19. Journal of neuropathology and experimental neurology, 81(9), 666-695.
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  Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.
• Stocking, J. C., Drake, C., Aldrich, J. M., Ong, M. K., Amin, A., Marmor, R. A., Godat, L., Cannesson, M., Gropper, M. A., Romano, P. S., Sandrock, C., Bime, C., Abraham, I., & Utter, G. H. (2022). Outcomes and risk factors for delayed-onset postoperative respiratory failure: a multi-center case-control study by the University of California Critical Care Research Collaborative (UCRC). BMC anesthesiology, 22(1), 146.
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  Few interventions are known to reduce the incidence of respiratory failure that occurs following elective surgery (postoperative respiratory failure; PRF). We previously reported risk factors associated with PRF that occurs within the first 5 days after elective surgery (early PRF; E-PRF); however, PRF that occurs six or more days after elective surgery (late PRF; L-PRF) likely represents a different entity. We hypothesized that L-PRF would be associated with worse outcomes and different risk factors than E-PRF.
• Valley, T., Schutz, A., Peltan, I., Vranas, K., Mathews, K., Jolley, S., Palakshappa, J., Hough, C., Steingrub, J., Tidswell, M., Kozikowski, L., Kardos, C., DeSouza, L., Baron, R., Pinilla-Vera, M., Rubins, D., Arciniegas, A., Riker, R., Lord, C., , Elie, M., et al. (2022). Organization of Outpatient Care After COVID-19 Hospitalization. Chest, 161(6). doi:10.1016/j.chest.2022.01.034
• Altman, M. C., Atkinson, M. A., Augustine, A. D., Baden, L. R., Bakel, H. V., Becker, P. M., Bime, C., Bosinger, S. E., Brakenridge, S. C., Cairns, C. B., Calfee, C. S., Corry, D., Davis, M. M., Diray-arce, J., Eckalbar, W., Ehrlich, L. I., Erle, D. J., Fernandez-sesma, A., Guan, L., , Haddad, E. K., et al. (2021). Immunophenotyping assessment in a COVID-19 cohort (IMPACC): A prospective longitudinal study.. Science immunology, 6(62). doi:10.1126/sciimmunol.abf3733
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  The IMmunoPhenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective longitudinal study designed to enroll 1000 hospitalized patients with COVID-19 (NCT04378777). IMPACC collects detailed clinical, laboratory and radiographic data along with longitudinal biologic sampling of blood and respiratory secretions for in depth testing. Clinical and lab data are integrated to identify immunologic, virologic, proteomic, metabolomic and genomic features of COVID-19-related susceptibility, severity and disease progression. The goals of IMPACC are to better understand the contributions of pathogen dynamics and host immune responses to the severity and course of COVID-19 and to generate hypotheses for identification of biomarkers and effective therapeutics, including optimal timing of such interventions. In this report we summarize the IMPACC study design and protocols including clinical criteria and recruitment, multi-site standardized sample collection and processing, virologic and immunologic assays, harmonization of assay protocols, high-level analyses and the data sharing plans.
• Bime, C. (2021).

  Corrigendum: Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused

  . Frontiers in Medicine. doi:10.3389/fmed.2020.604640
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  Incorrect AffiliationIn the published article, there was an error in affiliation. Instead of “Sachin Chaudhary*, Bhupinder Natt, Christian Bime, Kenneth S. Knox, Marilyn K. Glassberg, Interstitial Lung Disease Program, University of Arizona Colleges of Medicine, Banner-University Medicine Division, Phoenix, AZ, United States”, it should be “Sachin Chaudhary 1*, Bhupinder Natt1, Christian Bime1, Interstitial Lung Disease Program, University of Arizona College of Medicine, Tucson, AZ, United States and Kenneth S. Knox2, Marilyn K Glassberg2, Immunologic Lung Disease Program, Banner-University Medical Center, Phoenix, AZ, United States.” The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
• Bose, S., Bime, C., Henderson, R. J., Blake, K. V., Castro, M., DiMango, E., Hanania, N. A., Holbrook, J. T., Irvin, C. G., Kraft, M., Peters, S. P., Reibman, J., Sugar, E. A., Sumino, K., Wise, R. A., Rogers, L., & , A. L. (2021). Biomarkers of Type 2 Airway Inflammation as Predictors of Loss of Asthma Control During Step-Down Therapy for Well-Controlled Disease: The Long-Acting Beta-Agonist Step-Down Study (LASST). The journal of allergy and clinical immunology. In practice, 8(10), 3474-3481.
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  Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking.
• Casanova, N. G., Bime, C., Lynn, H., Liao, S. Y., Garcia, J. G., Casanova, N. G., Camp, S. M., & Bime, C. (2021). Identification of early and intermediate biomarkers for ARDS mortality by multi-omic approaches.. Scientific reports, 11(1), 18874. doi:10.1038/s41598-021-98053-1
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  The lack of successful clinical trials in acute respiratory distress syndrome (ARDS) has highlighted the unmet need for biomarkers predicting ARDS mortality and for novel therapeutics to reduce ARDS mortality. We utilized a systems biology multi-"omics" approach to identify predictive biomarkers for ARDS mortality. Integrating analyses were designed to differentiate ARDS non-survivors and survivors (568 subjects, 27% overall 28-day mortality) using datasets derived from multiple 'omics' studies in a multi-institution ARDS cohort (54% European descent, 40% African descent). 'Omics' data was available for each subject and included genome-wide association studies (GWAS, n = 297), RNA sequencing (n = 93), DNA methylation data (n = 61), and selective proteomic network analysis (n = 240). Integration of available "omic" data identified a 9-gene set (TNPO1, NUP214, HDAC1, HNRNPA1, GATAD2A, FOSB, DDX17, PHF20, CREBBP) that differentiated ARDS survivors/non-survivors, results that were validated utilizing a longitudinal transcription dataset. Pathway analysis identified TP53-, HDAC1-, TGF-β-, and IL-6-signaling pathways to be associated with ARDS mortality. Predictive biomarker discovery identified transcription levels of the 9-gene set (AUC-0.83) and Day 7 angiopoietin 2 protein levels as potential candidate predictors of ARDS mortality (AUC-0.70). These results underscore the value of utilizing integrated "multi-omics" approaches in underpowered datasets from racially diverse ARDS subjects.
• Chaudhary, S., Natt, B., Bime, C., Knox, K., & Glassberg, M. (2021). Corrigendum: Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused (Front. Med., (2020), 7, (539), 10.3389/fmed.2020.00539). Frontiers in Medicine, 7. doi:10.3389/fmed.2020.604640
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  In the published article, there was an error in affiliations for Kenneth S. Knox. Instead of having affiliations 1 and 2, Kenneth S. Knox should only have affiliation 2. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
• Garcia, J. G., Casanova, N. G., Bime, C., Camp, S. M., Oita, R. C., Ndukum, J., Hernon, V. R., Oh, D. K., Li, Y., Greer, P. J., Whitcomb, D. C., & Papachristou, G. I. (2021). Circulating eNAMPT as a Diagnostic Biomarker in the Critically Ill: Acute Pancreatitis, Sepsis, Trauma, and Acute Respiratory Distress Syndrome. BMC Anesthesiology. doi:10.21203/rs.3.rs-847354/v1
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  Abstract Background: Nicotinamide phosphoribosyltransferase (NAMPT) is a protein that exhibits dual functionality – as an intracellular enzyme which regulates nicotinamide adenine dinucleotide metabolism and as an extracellular protein (eNAMPT) secreted into the blood and functions as a cytokine regulator of innate immunity by activating NF-κB via binding to Toll-Like receptor 4. In limited preclinical and clinical studies, eNAMPT was implicated in the pathobiology of acute respiratory distress syndrome (ARDS) suggesting that eNAMPT could be a potential diagnostic and prognostic biomarker. Our aim was to investigate the feasibility of circulating eNAMPT levels to serve as a biomarker in an expanded cohort of patients with ARDS and ARDS-predisposing conditions such as acute pancreatitis, sepsis, and trauma when compared to controls. Methods: 795 patients and 179 healthy controls were included in the discovery and validation cohorts. Plasma and serum eNAMPT levels were quantified using one of two complementary Enzyme-linked Immunosorbent Assays. After log base 2 variance stabilizing transformation of plasma/serum eNAMPT measurements, differences between healthy controls and each disease cohort were compared using linear regression or generalized estimating equation (GEE) model where applicable. Complementary analyses included sensitivity, specificity, positive predictive values, negative predictive values, and the area under the receiver operating curve. Results: Compared to controls, circulating eNAMPT levels were significantly higher in patients with acute pancreatitis, with sepsis, with trauma, and with ARDS (all p
• Harris, D. T., Badowski, M., Jernigan, B., Sprissler, R., Edwards, T., Cohen, R., Paul, S., Merchant, N., Weinkauf, C. C., Bime, C., Erickson, H. E., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., Campion, J., , Chopra, M., et al. (2021). SARS-CoV-2 Rapid Antigen Testing of Symptomatic and Asymptomatic Individuals on the University of Arizona Campus. Biomedicines, 9(5).
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  SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.
• Iii, A. G., Bime, C., Wisnivesky, J. P., Thakur, N., Shete, P., Sharma, S., Ruvalcaba, E., Roman, J., Riekert, K. A., Pakhale, S., Mageto, Y., Lovinsky-desir, S., Iii, A. G., Holguin, F., George, M., Ferreira, J., Celedon, J. C., Castro, L., Bime, C., & Appell, D. (2021). Enhancing Recruitment and Retention of Minority Populations for Clinical Research in Pulmonary, Critical Care, and Sleep Medicine: An Official American Thoracic Society Research Statement.. American journal of respiratory and critical care medicine, 204(3), e26-e50. doi:10.1164/rccm.202105-1210st
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  Background: Well-designed clinical research needs to obtain information that is applicable to the general population. However, most current studies fail to include substantial cohorts of racial/ethnic minority populations. Such underrepresentation may lead to delayed diagnosis or misdiagnosis of disease, wide application of approved interventions without appropriate knowledge of their usefulness in certain populations, and development of recommendations that are not broadly applicable.Goals: To develop best practices for recruitment and retention of racial/ethnic minorities for clinical research in pulmonary, critical care, and sleep medicine.Methods: The American Thoracic Society convened a workshop in May of 2019. This included an international interprofessional group from academia, industry, the NIH, and the U.S. Food and Drug Administration, with expertise ranging from clinical and biomedical research to community-based participatory research methods and patient advocacy. Workshop participants addressed historical and current mistrust of scientific research, systemic bias, and social and structural barriers to minority participation in clinical research. A literature search of PubMed and Google Scholar was performed to support conclusions. The search was not a systematic review of the literature.Results: Barriers at the individual, interpersonal, institutional, and federal/policy levels were identified as limiting to minority participation in clinical research. Through the use of a multilevel framework, workshop participants proposed evidence-based solutions to the identified barriers.Conclusions: To date, minority participation in clinical research is not representative of the U.S. and global populations. This American Thoracic Society research statement identifies potential evidence-based solutions by applying a multilevel framework that is anchored in community engagement methods and patient advocacy.
• Nikolich-zugich, J., Knox, K. S., Garcia, J. G., Casanova, N. G., Camp, S. M., Bime, C., Knox, K. S., Casanova, N. G., Nikolich-zugich, J., Knox, K. S., Garcia, J. G., Casanova, N. G., Camp, S. M., & Bime, C. (2021). Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury.. Translational research : the journal of laboratory and clinical medicine, 232, 37-48. doi:10.1016/j.trsl.2020.12.008
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  Approximately 15%-20% of patients infected with SARS-CoV-2 coronavirus (COVID-19) progress beyond mild and self-limited disease to require supplemental oxygen for severe pneumonia; 5% of COVID-19-infected patients further develop acute respiratory distress syndrome (ARDS) and multiorgan failure. Despite mortality rates surpassing 40%, key insights into COVID-19-induced ARDS pathology have not been fully elucidated and multiple unmet needs remain. This review focuses on the unmet need for effective therapies that target unchecked innate immunity-driven inflammation which drives unchecked vascular permeability, multiorgan dysfunction and ARDS mortality. Additional unmet needs including the lack of insights into factors predicting pathogenic hyperinflammatory viral host responses, limited approaches to address the vast disease heterogeneity in ARDS, and the absence of clinically-useful ARDS biomarkers. We review unmet needs persisting in COVID-19-induced ARDS in the context of the potential role for damage-associated molecular pattern proteins in lung and systemic hyperinflammatory host responses to SARS-CoV-2 infection that ultimately drive multiorgan dysfunction and ARDS mortality. Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies.
• Poeta, M. D., Lutrick, K., Hannun, Y. A., Bime, C., Zhang, H. H., Zec, M. M., You, J. K., Yao, G., Wang, X., Wang, Q., Sprissler, R., Snider, J. M., Snider, A. J., Sergeant, S., Seeds, M. C., Poeta, M. D., Parthasarathy, S., Mccall, C. E., Lutrick, K., , Luberto, C., et al. (2021). Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality.. The Journal of clinical investigation, 131(19). doi:10.1172/jci149236
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  There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
• Snider, J. M., You, J. K., Wang, X., Snider, A. J., Hallmark, B., Zec, M. M., Seeds, M. C., Sergeant, S., Johnstone, L., Wang, Q., Sprissler, R., Carr, T. F., Lutrick, K., Parthasarathy, S., Bime, C., Zhang, H. H., Luberto, C., Kew, R. R., Hannun, Y. A., , Guerra, S., et al. (2021). Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality. The Journal of clinical investigation, 131(19).
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  There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
• Sun, B., Sammani, S., Martin, D., Desai, A. A., Valera, D. G., Sun, X., Sun, B., Song, J. H., Sammani, S., Quijada, H., Oita, R. C., Natarajan, V., Moreno-vinasco, L., Mascarenhas, J. B., Martin, D. R., Liu, Z., Kempf, C. L., Jacobson, J. R., Hernon, V. R., , Garcia, J. G., et al. (2021). Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody.. The European respiratory journal, 57(5). doi:10.1183/13993003.02536-2020
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  The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target..Wild-type C57BL/6J or endothelial cell (EC)-cNAMPT -/- knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model. A NAMPT-specific monoclonal antibody (mAb) imaging probe (99mTc-ProNamptor) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were used in vitro and in vivo..Immunohistochemical, biochemical and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both pre-clinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb or mAb significantly attenuated inflammatory lung injury (haematoxylin and eosin staining, bronchoalveolar lavage (BAL) protein, BAL polymorphonuclear cells, plasma interleukin-6) in both pre-clinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild-type and EC-cNAMPT -/- mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both pre-clinical ARDS models..These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine.
• Sun, B., Song, J. H., Mascarenhas, J. B., Liu, Z., Garcia, J. G., Cress, A. E., Bime, C., Valera, D. G., Sun, X., Sun, B., Song, J. H., Sammani, S., Quijada, H., Oita, R. C., Natarajan, V., Moreno-vinasco, L., Mascarenhas, J. B., Martin, D., Liu, Z., , Kempf, C. L., et al. (2021). Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody.. The European respiratory journal, 57(5), 2002536. doi:10.1183/13993003.02536-2020
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  The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target..Wild-type C57BL/6J or endothelial cell (EC)-cNAMPT -/- knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model. A NAMPT-specific monoclonal antibody (mAb) imaging probe (99mTc-ProNamptor) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were used in vitro and in vivo..Immunohistochemical, biochemical and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both pre-clinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb or mAb significantly attenuated inflammatory lung injury (haematoxylin and eosin staining, bronchoalveolar lavage (BAL) protein, BAL polymorphonuclear cells, plasma interleukin-6) in both pre-clinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild-type and EC-cNAMPT -/- mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both pre-clinical ARDS models..These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine.
• Thakur, N., Lovinsky-Desir, S., Appell, D., Bime, C., Castro, L., Celedón, J. C., Ferreira, J., George, M., Mageto, Y., Mainous III, A. G., Pakhale, S., Riekert, K. A., Roman, J., Ruvalcaba, E., Sharma, S., Shete, P., Wisnivesky, J. P., & Holguin, F. (2021). Enhancing Recruitment and Retention of Minority Populations for Clinical Research in Pulmonary, Critical Care, and Sleep Medicine: An Official American Thoracic Society Research Statement. American journal of respiratory and critical care medicine, 204(3), e26-e50.
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  Well-designed clinical research needs to obtain information that is applicable to the general population. However, most current studies fail to include substantial cohorts of racial/ethnic minority populations. Such underrepresentation may lead to delayed diagnosis or misdiagnosis of disease, wide application of approved interventions without appropriate knowledge of their usefulness in certain populations, and development of recommendations that are not broadly applicable. To develop best practices for recruitment and retention of racial/ethnic minorities for clinical research in pulmonary, critical care, and sleep medicine. The American Thoracic Society convened a workshop in May of 2019. This included an international interprofessional group from academia, industry, the NIH, and the U.S. Food and Drug Administration, with expertise ranging from clinical and biomedical research to community-based participatory research methods and patient advocacy. Workshop participants addressed historical and current mistrust of scientific research, systemic bias, and social and structural barriers to minority participation in clinical research. A literature search of PubMed and Google Scholar was performed to support conclusions. The search was not a systematic review of the literature. Barriers at the individual, interpersonal, institutional, and federal/policy levels were identified as limiting to minority participation in clinical research. Through the use of a multilevel framework, workshop participants proposed evidence-based solutions to the identified barriers. To date, minority participation in clinical research is not representative of the U.S. and global populations. This American Thoracic Society research statement identifies potential evidence-based solutions by applying a multilevel framework that is anchored in community engagement methods and patient advocacy.
• Weinkauf, C. C., Sprissler, R., Spier, C. M., Sam, A., Rischard, F., Paul, S., Parthasarathy, S., Natt, B., Mosier, J., Merchant, N., Knox, K. S., Knepler, J. L., Jernigan, B., Insel, M., Harris, D. T., Erickson, H. E., Edwards, T., Dake, M. D., Cristan, E., , Cohen, R., et al. (2021). SARS-CoV-2 Rapid Antigen Testing of Symptomatic and Asymptomatic Individuals on the University of Arizona Campus.. Biomedicines, 9(5), 539. doi:10.3390/biomedicines9050539
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  SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.
• Weinkauf, C. C., Sprissler, R., Spier, C. M., Sam, A., Rischard, F., Paul, S., Parthasarathy, S., Natt, B., Mosier, J., Merchant, N., Knox, K. S., Knepler, J. L., Jernigan, B., Insel, M., Harris, D. T., Erickson, H. E., Edwards, T., Dake, M. D., Cristan, E., , Cohen, R., et al. (2021). SARS-CoV-2 Rapid Antigen Testing of Symptomatic and Asymptomatic Individuals on the University of Arizona Campus.. Biomedicines, 9(5). doi:10.3390/biomedicines9050539
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  SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.
• Witzl, A., Wilson, J., Wilson, C., Welsby, I., Vojnik, R., Tekin, A., Shaw, M., Sen, A., Rogers, A. J., Ribet, J., Reineck, L., Patel, R., Patel, N. M., Nicolau, L., Murray, R., Murray, J. E., Murphy, T., Mosier, J., Moran, K. M., , Matthay, M. A., et al. (2021). The ARREST Pneumonia Clinical Trial. Rationale and Design.. Annals of the American Thoracic Society, 18(4), 698-708. doi:10.1513/annalsats.202009-1115sd
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  Patients hospitalized for pneumonia are at high risk for mortality. Effective therapies are therefore needed. Recent randomized clinical trials suggest that systemic steroids can reduce the length of hospital stays among patients hospitalized for pneumonia. Furthermore, preliminary findings from a feasibility study demonstrated that early treatment with a combination of an inhaled corticosteroid and a bronchodilator can improve oxygenation and reduce risk of respiratory failure in patients at risk of acute respiratory distress syndrome. Whether such a combination administered early is effective in reducing acute respiratory failure (ARF) among patients hospitalized with pneumonia is unknown. Here we describe the ARREST Pneumonia (Arrest Respiratory Failure due to Pneumonia) trial designed to address this question. ARREST Pneumonia is a two-arm, randomized, double-blinded, placebo-controlled trial designed to test the efficacy of a combination of an inhaled corticosteroid and a β-agonist compared with placebo for the prevention of ARF in hospitalized participants with severe pneumonia. The primary outcome is ARF within 7 days of randomization, defined as a composite endpoint of intubation and mechanical ventilation; need for high-flow nasal cannula oxygen therapy or noninvasive ventilation for >36 hours (each alone or combined); or death within 36 hours of being placed on respiratory support. The planned enrollment is 600 adult participants at 10 academic medical centers. In addition, we will measure selected plasma biomarkers to better understand mechanisms of action. The trial is funded by the U.S. National Heart Lung and Blood Institute.Clinical trial registered with www.clinicaltrials.gov (NCT04193878).
• Bime, C. (2020).

  Biomarkers of Type 2 Airway Inflammation as Predictors of Loss of Asthma Control During Step-Down Therapy for Well-Controlled Disease: The Long-Acting Beta-Agonist Step-Down Study (LASST)

  . The Journal of Allergy and Immunology: In Practice. doi:10.1016/j.jaip.2020.06.067
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  Background Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking. Objective To evaluate whether baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (Feno) predict loss of asthma control as therapy is stepped down. Methods In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase, or baseline or serial Feno measurements during follow-up predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the 3 treatment groups (continuation of stable dose of combination inhaled corticosteroid-long-acting beta-agonist, step-down of inhaled corticosteroid, or discontinuation of long-acting bronchodilator). Results Four hundred forty-seven of the 553 Long-Acting Beta-Agonist Step-Down Study participants who were randomized to 1 of 3 treatment arms and had at least 1 biomarker measurement were included in this analysis. At baseline, higher levels of Feno were significantly associated with greater levels of multiallergen IgE levels (P < .001), but not with serum eosinophil peroxidase (P = .742). Among all participants as a group, elevations in baseline biomarkers were not predictive of a higher risk of treatment failure. In addition, Feno levels measured serially at 6-week intervals demonstrated that compared with participants with low levels (50 parts per billion) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios, 1.03 [95% CI, 0.59-1.78] and 1.29 [95% CI, 0.65-2.54], respectively). There were no significant interactions of treatment group and baseline biomarkers. Conclusions In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of Feno are strong predictors of treatment failure. Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking. To evaluate whether baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (Feno) predict loss of asthma control as therapy is stepped down. In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase, or baseline or serial Feno measurements during follow-up predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the 3 treatment groups (continuation of stable dose of combination inhaled corticosteroid-long-acting beta-agonist, step-down of inhaled corticosteroid, or discontinuation of long-acting bronchodilator). Four hundred forty-seven of the 553 Long-Acting Beta-Agonist Step-Down Study participants who were randomized to 1 of 3 treatment arms and had at least 1 biomarker measurement were included in this analysis. At baseline, higher levels of Feno were significantly associated with greater levels of multiallergen IgE levels (P < .001), but not with serum eosinophil peroxidase (P = .742). Among all participants as a group, elevations in baseline biomarkers were not predictive of a higher risk of treatment failure. In addition, Feno levels measured serially at 6-week intervals demonstrated that compared with participants with low levels (50 parts per billion) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios, 1.03 [95% CI, 0.59-1.78] and 1.29 [95% CI, 0.65-2.54], respectively). There were no significant interactions of treatment group and baseline biomarkers. In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of Feno are strong predictors of treatment failure.
• Bime, C., Camp, S. M., Casanova, N., Oita, R. C., Ndukum, J., Lynn, H., & Garcia, J. G. (2020). The acute respiratory distress syndrome biomarker pipeline: crippling gaps between discovery and clinical utility. Translational research : the journal of laboratory and clinical medicine, 226, 105-115.
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  Recent innovations in translational research have ushered an exponential increase in the discovery of novel biomarkers, thereby elevating the hope for deeper insights into "personalized" medicine approaches to disease phenotyping and care. However, a critical gap exists between the fast pace of biomarker discovery and the successful translation to clinical use. This gap underscores the fundamental biomarker conundrum across various acute and chronic disorders: how does a biomarker address a specific unmet need? Additionally, the gap highlights the need to shift the paradigm from a focus on biomarker discovery to greater translational impact and the need for a more streamlined drug approval process. The unmet need for biomarkers in acute respiratory distress syndrome (ARDS) is for reliable and validated biomarkers that minimize heterogeneity and allow for stratification of subject selection for enrollment in clinical trials of tailored therapies. This unmet need is particularly highlighted by the ongoing SARS-CoV-2/COVID-19 pandemic. The unprecedented numbers of COVID-19-induced ARDS cases has strained health care systems across the world and exposed the need for biomarkers that would accelerate drug development and the successful phenotyping of COVID-19-infected patients at risk for development of ARDS and ARDS mortality. Accordingly, this review discusses the current state of ARDS biomarkers in the context of the drug development pipeline and highlight gaps between biomarker discovery and clinical implementation while proposing potential paths forward. We discuss potential ARDS biomarkers by category and by context of use, highlighting progress in the development continuum. We conclude by discussing challenges to successful translation of biomarker candidates to clinical impact and proposing possible novel strategies.
• Bime, C., Casanova, N. G., Nikolich-Zugich, J., Knox, K. S., Camp, S. M., & Garcia, J. G. (2020). Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury. Translational research : the journal of laboratory and clinical medicine.
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  Approximately 15%-20% of patients infected with SARS-CoV-2 coronavirus (COVID-19) progress beyond mild and self-limited disease to require supplemental oxygen for severe pneumonia; 5% of COVID-19-infected patients further develop acute respiratory distress syndrome (ARDS) and multiorgan failure. Despite mortality rates surpassing 40%, key insights into COVID-19-induced ARDS pathology have not been fully elucidated and multiple unmet needs remain. This review focuses on the unmet need for effective therapies that target unchecked innate immunity-driven inflammation which drives unchecked vascular permeability, multiorgan dysfunction and ARDS mortality. Additional unmet needs including the lack of insights into factors predicting pathogenic hyperinflammatory viral host responses, limited approaches to address the vast disease heterogeneity in ARDS, and the absence of clinically-useful ARDS biomarkers. We review unmet needs persisting in COVID-19-induced ARDS in the context of the potential role for damage-associated molecular pattern proteins in lung and systemic hyperinflammatory host responses to SARS-CoV-2 infection that ultimately drive multiorgan dysfunction and ARDS mortality. Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies.
• Bime, C., Perkins, B., Huckleberry, Y., Bogdanich, I., Leelathanalerk, A., Huckleberry, A., Konecnik, M., Miller, D. C., & Bailey, M. (2020). Evaluation of Inpatient Opioid Prescribing Resulting in Outpatient Opioid Prescriptions for Previously Opioid-Naive Internal Medicine Patients. Journal of Pharmacy Practice, 35(2), 179-183. doi:10.1177/0897190020961290
• Bime, C., Thakur, N., Lovinsky-Desir, S., Wisnivesky, J. P., & Celedón, J. C. (2020). The Structural and Social Determinants of the Racial/Ethnic Disparities in the U.S. COVID-19 Pandemic. What’s Our Role?. American Journal of Respiratory and Critical Care Medicine, 202(7), 943-949. doi:10.1164/rccm.202005-1523pp
• Casanova, N. G., Gonzalez-Garay, M. L., Sun, B., Bime, C., Sun, X., Knox, K. S., Crouser, E. D., Sammani, N., Gonzales, T., Natt, B., Chaudhary, S., Lussier, Y., & Garcia, J. G. (2020). Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas. Respiratory research, 21(1), 321.
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  Despite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures.
• Chaudhary, S., Natt, B., Bime, C., Knox, K. S., & Glassberg, M. K. (2020). Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused. Frontiers in Medicine, 7(Issue). doi:10.3389/fmed.2020.00539
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  After decades of research, two therapies for chronic fibrotic lung disease are now approved by the FDA, with dozens more anti-fibrotic therapies in the pipeline. A great deal of enthusiasm has been generated for the use of these drugs, which are by no means curative but clearly have a favorable impact on lung function decline over time. Amidst a flurry of newly developed and repurposed drugs to treat the coronavirus disease 2019 (COVID-19) and its accompanying acute respiratory distress syndrome (ARDS), few have emerged as effective. Historically, survivors of severe viral pneumonia and related acute lung injury with ARDS often have near full recovery of lung function. While the pathological findings of the lungs of patients with COVID-19 can be diverse, current reports have shown significant lung fibrosis predominantly in autopsy studies. There is growing enthusiasm to study anti-fibrotic therapy for inevitable lung fibrosis, and clinical trials are underway using currently FDA-approved anti-fibrotic therapies. Given the relatively favorable outcomes of survivors of virus-mediated ARDS and the low prevalence of clinically meaningful lung fibrosis in survivors, this perspective examines if there is a rationale for testing these repurposed antifibrotic agents in COVID-19-associated lung disease.
• Chaudhary, S., Natt, B., Bime, C., Knox, K. S., & Glassberg, M. K. (2020). Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused. Frontiers in medicine, 7, 539.
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  After decades of research, two therapies for chronic fibrotic lung disease are now approved by the FDA, with dozens more anti-fibrotic therapies in the pipeline. A great deal of enthusiasm has been generated for the use of these drugs, which are by no means curative but clearly have a favorable impact on lung function decline over time. Amidst a flurry of newly developed and repurposed drugs to treat the coronavirus disease 2019 (COVID-19) and its accompanying acute respiratory distress syndrome (ARDS), few have emerged as effective. Historically, survivors of severe viral pneumonia and related acute lung injury with ARDS often have near full recovery of lung function. While the pathological findings of the lungs of patients with COVID-19 can be diverse, current reports have shown significant lung fibrosis predominantly in autopsy studies. There is growing enthusiasm to study anti-fibrotic therapy for inevitable lung fibrosis, and clinical trials are underway using currently FDA-approved anti-fibrotic therapies. Given the relatively favorable outcomes of survivors of virus-mediated ARDS and the low prevalence of clinically meaningful lung fibrosis in survivors, this perspective examines if there is a rationale for testing these repurposed antifibrotic agents in COVID-19-associated lung disease.
• Chaudhary, S., Natt, B., Bime, C., Knox, K. S., & Glassberg, M. K. (2020). Corrigendum: Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused. Frontiers in medicine, 7, 604640.
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  [This corrects the article DOI: 10.3389/fmed.2020.00539.].
• Garcia, J. G., Lussier, Y., Natt, B., Sun, X., Knox, K. S., Bime, C., Sun, B., Gonzalez-Garay, M. L., Casanova, N. G., Crouser, E., Sammani, N., Gregory, T., & Chaudhary, S. (2020). Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas. Respiratory Research. doi:10.21203/rs.3.rs-29265/v3
• Miller, D. C., Bime, C., Partharsarathy, S., & Mosier, J. M. (2020). High-Flow Oxygen Therapy Concepts: Time to Standardize Nomenclature and Avoid Confusion. Journal of Intensive Care Medicine, 35(Issue 5). doi:10.1177/0885066620908243
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  High-flow nasal oxygen systems are rapidly being adopted as an initial noninvasive treatment for acute respiratory failure. However, the term “high-flow nasal cannula” is nonspecific and leads to imprecise communication between physicians, respiratory therapists, and nurses with the potential for patient harm. In this viewpoint and a brief review of the technology, we argue for a change in nomenclature in order to reduce the chance for future clinical, administrative, and research misunderstanding surrounding high-flow nasal oxygen systems.
• Miller, D. C., Bime, C., Partharsarathy, S., & Mosier, J. M. (2020). High-Flow Oxygen Therapy Concepts: Time to Standardize Nomenclature and Avoid Confusion. Journal of intensive care medicine, 35(5), 519-523.
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  High-flow nasal oxygen systems are rapidly being adopted as an initial noninvasive treatment for acute respiratory failure. However, the term "high-flow nasal cannula" is nonspecific and leads to imprecise communication between physicians, respiratory therapists, and nurses with the potential for patient harm. In this viewpoint and a brief review of the technology, we argue for a change in nomenclature in order to reduce the chance for future clinical, administrative, and research misunderstanding surrounding high-flow nasal oxygen systems.
• Miller, D. C., Pu, J., Kukafka, D., & Bime, C. (2020). Failure of High Flow Nasal Cannula and Subsequent Intubation Is Associated With Increased Mortality as Compared to Failure of Non-Invasive Ventilation and Mechanical Ventilation Alone: A Real-World Retrospective Analysis. Journal of intensive care medicine, 885066620968041.
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  Despite the increasing use of high flow nasal cannula oxygenation systems (HFNC) in clinical practice, little is known about its role in all cause respiratory failure as compared to traditional non-invasive ventilation (BiPAP). Furthermore, the effect of HFNC on mortality is unknown.
• Perkins, B., Huckleberry, Y., Bogdanich, I., Leelathanalerk, A., Huckleberry, A., Konecnik, M., Miller, D. C., Bailey, M., & Bime, C. (2020). Evaluation of Inpatient Opioid Prescribing Resulting in Outpatient Opioid Prescriptions for Previously Opioid-Naive Internal Medicine Patients. Journal of pharmacy practice, 897190020961290.
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  Little data exist regarding inpatient opioid prescriptions as a potential contribution to the current opioid crisis. While pain management is essential to inpatient care, the ease of which opioids may be prescribed for all levels of pain may contribute to unnecessary inpatient exposure and new outpatient prescriptions. The aim of this study was to observe patterns of opioid prescribing potentially leading to new opioid prescriptions at hospital discharge for previously opioid-naive patients.
• Quijada, H., Bermudez, T., Kempf, C. L., Valera, D. G., Garcia, A. N., Camp, S. M., Song, J. H., Franco, E., Burt, J. K., Sun, B., Mascarenhas, J. B., Burns, K., Gaber, A., Oita, R. C., Reyes Hernon, V., Barber, C., Moreno-Vinasco, L., Sun, X., Cress, A. E., , Martin, D., et al. (2020). Endothelial eNAMPT Amplifies Preclinical Acute Lung Injury: Efficacy of an eNAMPT-Neutralising mAb. The European respiratory journal.
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  The SARS-CoV-2/COVID-19 pandemic has highlighted the serious unmet need for effective therapies that reduce ARDS mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor 4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target.
• Rajagopal, K., Keller, S. P., Akkanti, B., Bime, C., Loyalka, P., Cheema, F. H., Zwischenberger, J. B., El Banayosy, A., Pappalardo, F., Slaughter, M. S., & Slepian, M. J. (2020). Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations From ASAIO-A "Living Working Document". ASAIO journal (American Society for Artificial Internal Organs : 1992), 66(6), 588-598.
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  The severe acute respiratory syndrome (SARS)-CoV-2 is an emerging viral pathogen responsible for the global coronavirus disease 2019 (COVID)-19 pandemic resulting in significant human morbidity and mortality. Based on preliminary clinical reports, hypoxic respiratory failure complicated by acute respiratory distress syndrome is the leading cause of death. Further, septic shock, late-onset cardiac dysfunction, and multiorgan system failure are also described as contributors to overall mortality. Although extracorporeal membrane oxygenation and other modalities of mechanical cardiopulmonary support are increasingly being utilized in the treatment of respiratory and circulatory failure refractory to conventional management, their role and efficacy as support modalities in the present pandemic are unclear. We review the rapidly changing epidemiology, pathophysiology, emerging therapy, and clinical outcomes of COVID-19; and based on these data and previous experience with artificial cardiopulmonary support strategies, particularly in the setting of infectious diseases, provide consensus recommendations from ASAIO. Of note, this is a "living document," which will be updated periodically, as additional information and understanding emerges.
• Rajagopal, K., Keller, S. P., Akkanti, B., Bime, C., Loyalka, P., Cheema, F. H., Zwischenberger, J. B., El Banayosy, A., Pappalardo, F., Slaughter, M. S., & Slepian, M. J. (2020). Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations From ASAIOa Living Working Document. Circulation. Heart failure, 13(5), e007175.
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  The severe acute respiratory syndrome-CoV-2 is an emerging viral pathogen responsible for the global coronavirus disease 2019 pandemic resulting in significant human morbidity and mortality. Based on preliminary clinical reports, hypoxic respiratory failure complicated by acute respiratory distress syndrome is the leading cause of death. Further, septic shock, late-onset cardiac dysfunction, and multiorgan system failure are also described as contributors to overall mortality. Although extracorporeal membrane oxygenation and other modalities of mechanical cardiopulmonary support are increasingly being utilized in the treatment of respiratory and circulatory failure refractory to conventional management, their role and efficacy as support modalities in the present pandemic are unclear. We review the rapidly changing epidemiology, pathophysiology, emerging therapy, and clinical outcomes of coronavirus disease 2019; and based on these data and previous experience with artificial cardiopulmonary support strategies, particularly in the setting of infectious diseases, provide consensus recommendations from American Society for Artificial Internal Organs. Of note, this is a living document, which will be updated periodically, as additional information and understanding emerges.
• Rajagopal, K., Keller, S. P., Akkanti, B., Bime, C., Loyalka, P., Cheema, F. H., Zwischenberger, J. B., El Banayosy, A., Pappalardo, F., Slaughter, M. S., & Slepian, M. J. (2020). Advanced pulmonary and cardiac support of COVID-19 Patients: Emerging recommendations from ASAIO - A "living working document". ASAIO Journal, 66(Issue 6). doi:10.1097/mat.0000000000001180
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  The severe acute respiratory syndrome (SARS)-CoV-2 is an emerging viral pathogen responsible for the global coronavirus disease 2019 (COVID)-19 pandemic resulting in significant human morbidity and mortality. Based on preliminary clinical reports, hypoxic respiratory failure complicated by acute respiratory distress syndrome is the leading cause of death. Further, septic shock, late-onset cardiac dysfunction, and multiorgan system failure are also described as contributors to overall mortality. Although extracorporeal membrane oxygenation and other modalities of mechanical cardiopulmonary support are increasingly being utilized in the treatment of respiratory and circulatory failure refractory to conventional management, their role and efficacy as support modalities in the present pandemic are unclear. We review the rapidly changing epidemiology, pathophysiology, emerging therapy, and clinical outcomes of COVID-19; and based on these data and previous experience with artificial cardiopulmonary support strategies, particularly in the setting of infectious diseases, provide consensus recommendations from ASAIO. Of note, this is a "living document," which will be updated periodically, as additional information and understanding emerges.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., Aini, T. E., Rischard, F., , Campion, J., et al. (2020). Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure. medRxiv : the preprint server for health sciences.
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  We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., , Campion, J., et al. (2020). Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity. Immunity, 53(5), 925-933.e4.
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  We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., , Campion, J., et al. (2020). Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity. Immunity, 53(Issue 5). doi:10.1016/j.immuni.2020.10.004
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  We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5–7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5–7 months after SARS-CoV-2 infection. Serological assays for SARS-CoV-2 exposures are challenging due to poor positive predictive values. Ripperger et al. show that the combinatorial use of spike receptor binding domain and S2 eliminates almost all false positives. This serological assay is used to show durable antibody production for at least 5–7 months after infection.
• Slepian, M. J., Slaughter, M. S., Bime, C., Keller, S. P., Rajagopal, K., Akkanti, B., Loyalka, P., Cheema, F. H., Zwischenberger, J. B., El Banayosy, A., & Pappalardo, F. (2020). Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations From ASAIO — a Living Working Document. Circulation: Heart Failure, 13(5). doi:10.1161/circheartfailure.120.007175
• Thakur, N., Lovinsky-Desir, S., Bime, C., Wisnivesky, J. P., & Celedón, J. C. (2020). The Structural and Social Determinants of the Racial/Ethnic Disparities in the U.S. COVID-19 Pandemic. What's Our Role?. American journal of respiratory and critical care medicine, 202(7), 943-949.
• Bime, C., Casanova, N., Oita, R. C., Ndukum, J., Lynn, H., Camp, S. M., Lussier, Y., Abraham, I., Carter, D., Miller, E. J., Mekontso-Dessap, A., Downs, C. A., & Garcia, J. G. (2019). Development of a biomarker mortality risk model in acute respiratory distress syndrome. Critical Care, 23(Issue 1). doi:10.1186/s13054-019-2697-x
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  Background: There is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome. Methods: This is a secondary analysis using a cohort of 252 mechanically ventilated subjects with the diagnosis of acute respiratory distress syndrome. Survival to day 7 with both day 0 (first day of presentation) and day 7 sample availability was required. Blood was collected for biomarker measurements at first presentation to the intensive care unit and on the seventh day. Biomarkers included cytokine-chemokines, dual-functioning cytozymes, and vascular injury markers. Logistic regression, latent class analysis, and classification and regression tree analysis were used to identify the plasma biomarkers most predictive of 28-day ARDS mortality. Results: From eight biologically relevant biomarker candidates, six demonstrated an enhanced capacity to predict mortality at day 0. Latent-class analysis identified two biomarker-based phenotypes. Phenotype A exhibited significantly higher plasma levels of angiopoietin-2, macrophage migration inhibitory factor, interleukin-8, interleukin-1 receptor antagonist, interleukin-6, and extracellular nicotinamide phosphoribosyltransferase (eNAMPT) compared to phenotype B. Mortality at 28 days was significantly higher for phenotype A compared to phenotype B (32% vs 19%, p = 0.04). Conclusions: An adult biomarker-based risk model reliably identifies ARDS subjects at risk of death within 28 days of hospitalization.
• Bime, C., Casanova, N., Oita, R. C., Ndukum, J., Lynn, H., Camp, S. M., Lussier, Y., Abraham, I., Carter, D., Miller, E. J., Mekontso-Dessap, A., Downs, C. A., & Garcia, J. G. (2019). Development of a biomarker mortality risk model in acute respiratory distress syndrome. Critical care (London, England), 23(1), 410.
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  There is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome.
• Goel, K., Bailey, M., Borgstrom, M., Parthasarathy, S., Natt, B., Berry, C., & Bime, C. (2019). Trends in Chronic Obstructive Pulmonary Disease Hospitalization and In-Hospital Deaths in the United States by Sex: 2005 to 2014. Annals of the American Thoracic Society, 16(3), 391-393.
• Insel, M., Natt, B., Mosier, J., Malo, J., & Bime, C. (2019). The Association of Non-Cardiac ECMO With Influenza Incidence: A Time Series Analysis. Respiratory care, 64(3), 279-284.
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  The 2009 H1N1 influenza epidemic saw a rise in the use of extracorporeal membrane oxygenation (ECMO) as a supportive therapy for refractory ARDS. We sought to determine whether ECMO utilization follows a seasonal pattern that matches the influenza season, and whether it can further be explained by the incidence of each influenza subtype.
• Insel, M., Natt, B., Mosier, J., Malo, J., & Bime, C. (2019). The association of non-cardiac ECMO with influenza incidence: A time series analysis. Respiratory Care, 64(Issue 3). doi:10.4187/respcare.06145
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  BACKGROUND: The 2009 H1N1 influenza epidemic saw a rise in the use of extracorporeal membrane oxygenation (ECMO) as a supportive therapy for refractory ARDS. We sought to determine whether ECMO utilization follows a seasonal pattern that matches the influenza season, and whether it can further be explained by the incidence of each influenza subtype. METHODS: We performed a longitudinal analysis of non-cardiac and cardiac-associated ECMO cases from the National In-patient Sample from 2005 to 2014, using overdispersed Poisson regression to evaluate associations with influenza incidence categorized by influenza-like illness and total positive influenza tests divided by subtype from the Centers for Disease Control and Prevention. RESULTS: Non-cardiac ECMO use was positively associated with influenza-like illness incidence in the current month (incidence risk ratio [IRR] 1.11, 95% confidence interval [CI] 1.07–1.15, P < .001) and with influenza-like illness in the previous month (IRR 1.09, 95% CI 1.05–1.14, P < .001). The 2009 H1N1 subtype had the strongest association with non-cardiac ECMO (IRR 1.19, 95% CI 1.09–1.31, P < .001). Cardiac ECMO was also positively associated with the incidence of influenza-like illness (IRR 1.05, 95% CI 1.01–1.09, P = .02). CONCLUSION: Non-cardiac and cardiac ECMO use in the United States were significantly associated with influenza incidence. The influenza A, H1N1 2009, subtype had the strongest association.
• Lynn, H., Sun, X., Casanova, N., Gonzales-Garay, M., Bime, C., & Garcia, J. G. (2019). Genomic and Genetic Approaches to Deciphering Acute Respiratory Distress Syndrome Risk and Mortality. Antioxidants & redox signaling, 31(14), 1027-1052.
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  Acute respiratory distress syndrome (ARDS) is a severe, highly heterogeneous critical illness with staggering mortality that is influenced by environmental factors, such as mechanical ventilation, and genetic factors. Significant unmet needs in ARDS are addressing the paucity of validated predictive biomarkers for ARDS risk and susceptibility that hamper the conduct of successful clinical trials in ARDS and the complete absence of novel disease-modifying therapeutic strategies. The current ARDS definition relies on clinical characteristics that fail to capture the diversity of disease pathology, severity, and mortality risk. We undertook a comprehensive survey of the available ARDS literature to identify genes and genetic variants (candidate gene and limited genome-wide association study approaches) implicated in susceptibility to developing ARDS in hopes of uncovering novel biomarkers for ARDS risk and mortality and potentially novel therapeutic targets in ARDS. We further attempted to address the well-known health disparities that exist in susceptibility to and mortality from ARDS. Bioinformatic analyses identified 201 ARDS candidate genes with pathway analysis indicating a strong predominance in key evolutionarily conserved inflammatory pathways, including reactive oxygen species, innate immunity-related inflammation, and endothelial vascular signaling pathways. Future studies employing a system biology approach that combines clinical characteristics, genomics, transcriptomics, and proteomics may allow for a better definition of biologically relevant pathways and genotype-phenotype connections and result in improved strategies for the sub-phenotyping of diverse ARDS patients molecular signatures. These efforts should facilitate the potential for successful clinical trials in ARDS and yield a better fundamental understanding of ARDS pathobiology.
• Bime, C., Berry, C., Goel, K., Bailey, M., Borgstrom, M., Parthasarathy, S., & Natt, B. (2018). Trends in COPD Hospitalization and In-Hospital Deaths in the United States by Sex: 2005-2014. Annals of the American Thoracic Society. doi:10.1513/annalsats.201807-488rl
• Bime, C., Malo, J., Mosier, J. M., Natt, B., & Insel, M. (2018). The Association of Non-Cardiac ECMO With Influenza Incidence: A Time Series Analysis.. Respiratory Care.
• Bime, C., Pouladi, N., Sammani, S., Batai, K., Casanova, N., Zhou, T., Kempf, C. L., Sun, X., Camp, S. M., Wang, T., Kittles, R. A., Lussier, Y. A., Jones, T. K., Reilly, J. P., Meyer, N. J., Christie, J. D., Karnes, J. H., Gonzalez-Garay, M., Christiani, D. C., , Yates, C. R., et al. (2018). Genome-Wide Association Study in African Americans with Acute Respiratory Distress Syndrome Identifies the Selectin P Ligand Gene as a Risk Factor. American journal of respiratory and critical care medicine, 197(11), 1421-1432.
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  Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches.
• Bime, C., Pouladi, N., Sammani, S., Batai, K., Casanova, N., Zhou, T., Kempf, C. L., Sun, X., Camp, S. M., Wang, T., Kittles, R. A., Lussier, Y. A., Jones, T. K., Reilly, J. P., Meyer, N. J., Christie, J. D., Karnes, J. H., Gonzalez-Garay, M., Christiani, D. C., , Yates, C. R., et al. (2018). Genome-wide association study in African Americans with acute respiratory distress syndrome identifies the selectin P ligand gene as a risk factor. American Journal of Respiratory and Critical Care Medicine, 197(Issue 11). doi:10.1164/rccm.201705-0961oc
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  Rationale: Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches. Objectives: To identify genetic susceptibility targets for ARDS. Methods: A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort. Measurements and Main Results: Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg2/2 mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation. Conclusions: These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.
• Dill, J., Bixby, B., Ateeli, H., Sarsah, B., Goel, K., Buckley, R., Finkelshteyn, I., Thajudeen, B., Kadambi, P. V., & Bime, C. (2018). Renal replacement therapy in patients with acute respiratory distress syndrome: A single-center retrospective study. International Journal of Nephrology and Renovascular Disease, 11. doi:10.2147/ijnrd.s164628
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  Background: Patients with acute respiratory distress syndrome (ARDS) who develop acute kidney injury have increased mortality and frequently require renal replacement therapy (RRT). The optimal timing for initiation of RRT after onset of ARDS to improve survival is not known. Methods: We retrospectively reviewed clinical data on patients admitted to our health system over a 2-year period. Individual charts were carefully reviewed to ascertain that patients met the Berlin criteria for ARDS and to categorize RRT utilization. The Kaplan–Meier analysis was conducted to compare early (£48 hours postintubation) versus late (>48 hours postintubation) initiation of RRT. Associations between RRT initiation and mortality were evaluated using Cox proportional hazards regression. Results: A total of 75 patients were identified with ARDS, 95% of whom received RRT. Mortality of patients who required RRT was 56%. The main indications for RRT initiation were fluid overload (75%), metabolic acidosis (64%), and hyperkalemia (33%). The Kaplan–Meier analysis comparing early initiation of RRT to late initiation of RRT showed no survival benefit. Cox proportional hazard models testing the association between timing of RRT initiation with survival and adjusting for sex, race, ethnicity, and Acute Physiology and Chronic Health Evaluation II score did not reach statistical significance (HR=0.94, 95% CI=0.48–1.86). Conclusion: Timing of RRT initiation was not associated with a survival benefit. Prospective study in the utilization and outcomes of RRT in ARDS could assist in optimizing its usage in this population.
• Dill, J., Bixby, B., Ateeli, H., Sarsah, B., Goel, K., Buckley, R., Finkelshteyn, I., Thajudeen, B., Kadambi, P. V., & Bime, C. (2018). Renal replacement therapy in patients with acute respiratory distress syndrome: a single-center retrospective study. International journal of nephrology and renovascular disease, 11, 249-257.
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  Patients with acute respiratory distress syndrome (ARDS) who develop acute kidney injury have increased mortality and frequently require renal replacement therapy (RRT). The optimal timing for initiation of RRT after onset of ARDS to improve survival is not known.
• Gaefke, C. L., Carr, T. F., Borgstrom, M., & Bime, C. (2018). Disparities in Risk of Hospitalization for Food Anaphylaxis in the United States. The Journal of Allergy and Clinical Immunology, 141(2), AB89. doi:10.1016/j.jaci.2017.12.285
• Kempf, C., Zhou, T., Casanova, N., Batai, K., Sammani, S., Pouladi, N., Bime, C., Bime, C., Pouladi, N., Sammani, S., Batai, K., Casanova, N., Zhou, T., & Kempf, C. (2018). GWAS in African Americans identifies the Selectin P Ligand gene, SELPLG, as an ARDS risk gene. American J Respiratory Critical Care Medicine.
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  Rationale: Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches.Objectives: To identify genetic susceptibility targets for ARDS.Methods: A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort.Measurements and Main Results: Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg−/− mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation.Conclusions: These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.
• Roman, J., Viegi, G., Schenker, M., Ojeda, V. D., Pérez-Stable, E. J., Nemery, B., Annesi-Maesano, I., Patel, S. R., La Grutta, S., Holguin, F., Moughrabieh, A., Bime, C., Lindberg, A., Migliori, G. B., de Vries, G., Ramírez, J., Aliberti, S., Feldman, C., & Celedón, J. C. (2018). Research Needs on Respiratory Health in Migrant and Refugee Populations. An Official American Thoracic Society and European Respiratory Society Workshop Report. Annals of the American Thoracic Society, 15(11), 1247-1255.
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  Migrants represent a diverse population comprising workers, students, undocumented individuals, and refugees. Worldwide, approximately 1 billion people were considered migrants in 2016. Notably, about 65 million of these migrants were forcibly displaced from their homes, and 20 million were considered refugees. While the geopolitical consequences of such migration continue to be considered, less is known about the impact of these events on the respiratory health of migrants and refugees. In recognition of this knowledge gap, the American Thoracic Society and the European Respiratory Society brought together investigators with diverse and relevant expertise to participate in a workshop and develop a consensus on research needs on the respiratory health of migrants and refugees. The workshop focused on environmental and occupational hazards, chronic noninfectious diseases, and respiratory infectious diseases, which were presented by experts in three distinct sessions, each culminating with panel discussions. A writing committee collected summaries prepared by speakers and other participants, and the information was collated into a single document. Recommendations were formulated, and differences were resolved by discussion and consensus. The group identified important areas of research need, while emphasizing that reducing the burden of pulmonary, critical care, and sleep disorders in migrants and refugees will require a concerted effort by all stakeholders. Using best research practices, considering how research impacts policies affecting migrant and refugee populations, and developing new approaches to engage and fund trainees, clinical investigators, and public health practitioners to conduct high-quality research on respiratory health of migrants and refugees is essential.
• Shrestha, M. P., Bime, C., & Taleban, S. (2018). Decreasing Clostridium difficile-Associated Fatality Rates Among Hospitalized Patients in the United States: 2004-2014. The American journal of medicine, 131(1), 90-96.
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  Clostridium difficile infection has emerged as a major public health problem in the United States over the last 2 decades. We examined the trends in the C. difficile-associated fatality rate, hospital length of stay, and hospital charges over the last decade.
• Shrestha, M. P., Bime, C., & Taleban, S. (2018). Decreasing Clostridium difficile–Associated Fatality Rates Among Hospitalized Patients in the United States: 2004-2014. American Journal of Medicine, 131(Issue 1). doi:10.1016/j.amjmed.2017.07.022
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  Background Clostridium difficile infection has emerged as a major public health problem in the United States over the last 2 decades. We examined the trends in the C. difficile–associated fatality rate, hospital length of stay, and hospital charges over the last decade. Methods We used data from the National Inpatient Sample to identify patients with a principal diagnosis of C. difficile infection from 2004 to 2014. Outcomes included in-hospital fatality rate, hospital length of stay, and hospital charges. For each outcome, trends were also stratified by age categories because the risk of infection and associated mortality increases with age. Results Clostridium difficile infection discharges increased from 19.9 per 100,000 persons in 2004 to 33.8 per 100,000 persons in 2014. Clostridium difficile–associated fatality decreased from 3.6% in 2004 to 1.6% in 2014 (P
• Bime, C. (2017).

  Decreased In-Hospital Mortality after Lobectomy Using Video-assisted Thoracoscopic Surgery Compared with Open Thoracotomy

  . Annals American Thoracic Soceity. doi:10.1513/annalsats.201606-429oc
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  Rationale: There is a paucity of data regarding the optimal surgical approach for lung lobectomy. Lobectomy performed by video-assisted thoracoscopic surgery (VATS) has been associated with lower morbidity as compared with lobectomy performed by thoracotomy. However, no multicenter studies have shown improved mortality with VATS lobectomy compared with open surgical lobectomy.Objectives: We used data from the United States Healthcare Cost and Utilization Project Nationwide Inpatient Sample database from 2009 to 2012 to compare VATS with open lobectomy for in-hospital mortality and other short-term outcomes.Methods: We used International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes to identify the patients undergoing lobectomy. We used 1:1 ratio propensity matching with the nearest neighbor method without replacement to generate matched pairs.Measurements and Main Results: Over the 4-year period, 27,451 patients underwent lobectomy. The majority of these procedures were performed by thoracotomy (65%) as compared with VATS (35%). A total of 9,393 matched pairs were created. VATS lobectomy was associated with significantly lower in-hospital mortality when compared with thoracotomy (1.3% vs. 2.5%, P < 0.001). A shorter length of hospital stay was observed for those undergoing VATS lobectomy (6.21 vs. 8.75 d, P < 0.001). The overall rate of perioperative complications was low, with those undergoing VATS being less likely to have any perioperative morbidity.Conclusions: In recent years, the use of VATS for lobectomy has increased relative to thoracotomy. This trend has coincided with increased survival and shorter length of stay for VATS lobectomy compared with thoracotomy. Further studies are needed to identify comorbidities that identify ideal candidates for VATS lobectomy.
• Bime, C., Fiero, M., Lu, Z., Oren, E., Berry, C. E., Parthasarathy, S., & Garcia, J. G. (2017). High Positive End-Expiratory Pressure Is Associated with Improved Survival in Obese Patients with Acute Respiratory Distress Syndrome. American Journal of Medicine, 130(Issue 2). doi:10.1016/j.amjmed.2016.09.029
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  Background In acute respiratory distress syndrome, minimizing lung injury from repeated collapse and reopening of alveoli by applying a high positive end-expiratory pressure improves oxygenation without influencing mortality. Obesity causes alveolar atelectasis, thus suggesting that a higher positive end-expiratory pressure might be more protective among the obese. We hypothesized that the effect of applying a high positive end-expiratory pressure on mortality from acute respiratory distress syndrome would differ by obesity status. Methods This was a retrospective analysis of 505 patients from the Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury Trial, a multicenter randomized trial that compared a higher vs a lower positive end-expiratory pressure ventilatory strategy in acute respiratory distress syndrome. We examined the relationship between positive end-expiratory pressure strategy and 60-day mortality stratified by obesity status. Results Among obese patients with acute respiratory distress syndrome, those assigned to a high positive end-expiratory pressure strategy experienced lower mortality compared with those assigned to a low strategy (18% vs 32%; P =.04). Among the nonobese, those assigned to high positive end-expiratory pressure strategy experienced similar mortality with those assigned to low strategy (34% vs 23%; P = .13). Multivariate analysis demonstrated an interaction between obesity status and the effect of positive end-expiratory pressure strategy on mortality (P
• Bime, C., Fiero, M., Lu, Z., Oren, E., Berry, C. E., Parthasarathy, S., & Garcia, J. G. (2017). High Positive End-Expiratory Pressure Is Associated with Improved Survival in Obese Patients with Acute Respiratory Distress Syndrome. The American journal of medicine, 130(2), 207-213.
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  In acute respiratory distress syndrome, minimizing lung injury from repeated collapse and reopening of alveoli by applying a high positive end-expiratory pressure improves oxygenation without influencing mortality. Obesity causes alveolar atelectasis, thus suggesting that a higher positive end-expiratory pressure might be more protective among the obese. We hypothesized that the effect of applying a high positive end-expiratory pressure on mortality from acute respiratory distress syndrome would differ by obesity status.
• Bime, C., Natt, B., Desai, H., Poongkunran, C., & Borgstrom, M. (2017). Reply. Annals of the American Thoracic Society, 14(Issue 2).
• Bime, C., Poongkunran, C., Natt, B., Natt, B., Desai, H., Bime, C., Poongkunran, C., Desai, H., Borgstrom, M., & Borgstrom, M. (2017). Reply: Racial Disparities in Acute Respiratory Distress Syndrome Mortality. Annals of the American Thoracic Society, 14(2), 300-301.
• Dalen, J. E., Alpert, J. S., Dill, J., Desai, H., Dalen, J. E., Bime, C., Bhupinder, N., & Alpert, J. S. (2017). Pulmonary Embolism With Right Ventricular Dysfunction: Who Should Receive Thrombolytic Agents?. Journal of vascular surgery. Venous and lymphatic disorders, 5(2), 298. doi:10.1016/j.jvsv.2017.01.009
• Natt, B., Dalen, J. E., Alpert, J. S., Natt, B., Dill, J., Desai, H., Dalen, J. E., Bime, C., & Alpert, J. S. (2017). Pulmonary Embolism with Right Ventricular Dysfunction: Who Should Receive Thrombolytic Agents?. The American journal of medicine, 130(1), 93.e29-93.e32. doi:10.1016/j.amjmed.2016.07.023
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  Appropriate management of pulmonary embolism patients with right ventricular dysfunction is uncertain. Recent guidelines have stressed the need for more data on the use of thrombolytic agents in the stable pulmonary embolism patient with right ventricular dysfunction. The objective of this study is to investigate the hypothesis that thrombolytic therapy in hemodynamically stable pulmonary embolism patients with right ventricular dysfunction is not associated with improved mortality..We did a retrospective analysis using multi-institutional observational data from the Nationwide Inpatient Sample database. International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes were used to identify the patients with pulmonary embolism and right ventricular dysfunction. In-hospital mortality was defined as the primary outcome of interest..Over the 4 years of the study period, 3668 patients with right ventricular dysfunction and pulmonary embolism were found, of which 3253 patients were identified as having hemodynamically stable right-sided heart failure with pulmonary embolism. There was no significant difference in mortality between hemodynamically stable pulmonary embolism patients with right ventricular dysfunction who received thrombolytic agents compared with those who did not. When outcomes were assessed for patients with right ventricular dysfunction and hemodynamic instability, a significant improvement in mortality was noted for patients with right ventricular dysfunction who received thrombolytic agents, which confirmed previous reports that thrombolytic therapy decreases mortality in pulmonary embolism patients who are hemodynamically unstable..Our data support the use of less aggressive treatment for stable pulmonary embolism patients with right ventricular dysfunction. These results argue against the reflexive use of thrombolytic agents in stable pulmonary embolism patients with right ventricular dysfunction.
• Natt, B., Desai, H., Bime, C., Dill, J., Dalen, J. E., & Alpert, J. S. (2017). The Reply. American Journal of Medicine, 130(Issue 4). doi:10.1016/j.amjmed.2016.11.007
• Natt, B., Desai, H., Bime, C., Dill, J., Dalen, J. E., & Alpert, J. S. (2017). The Reply. The American journal of medicine, 130(4), e165.
• Shrestha, M. P., Bime, C., & Taleban, S. (2017). Decreasing Clostridium difficile-Associated Fatality Rates Among Hospitalized Patients in the United States: 2004-2014. Am J Med. doi:10.1016/j.amjmed.2017.07.022
• Toosizadeh, N., Berry, C., Bime, C., Najafi, B., Kraft, M., & Mohler, J. (2017). Assessing upper-extremity motion: An innovative method to quantify functional capacity in patients with chronic obstructive pulmonary disease. PLoS ONE, 12(Issue 2). doi:10.1371/journal.pone.0172766
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  Background Assessment of functional capacity is important in directing chronic obstructive pulmonary disease (COPD) care (e.g., rehabilitation and discharge readiness), and in predicting outcomes (e.g., exacerbation, hospitalization, and mortality). The 6-minute walk distance (6MWD) test for functional capacity assessment, may be time-consuming and burdensome. Objective The purpose of the current study was to evaluate an upper-extremity function (UEF) test for assessing functional capacity in older adults with COPD. Methods In this cross-sectional study, 49 older adults (≥55 years) with diagnosed COPD were recruited, and pulmonary function measures and 6MWD were obtained. Participants wore wireless sensors on forearm and upper-arm and performed rapid elbow flexion for 20 seconds (the UEF test). Slowness was assessed by measuring elbow speed, and acceleration and weakness (muscle strength) were assessed by measuring power of movement and elbow moment. Results Speed, power, and moment UEF parameters were independently associated with 6MWD, when controlling for age, gender, and body mass index (BMI) (r = 0.78, p < .001). Elbow moment showed significant Pearson correlations with all pulmonary function measures and maximal inspiratory/expiratory pressure measures (r = 0.35-0.69, p
• Toosizadeh, N., Berry, C., Bime, C., Najafi, B., Kraft, M., & Mohler, J. (2017). Assessing upper-extremity motion: An innovative method to quantify functional capacity in patients with chronic obstructive pulmonary disease. PloS one, 12(2), e0172766.
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  Assessment of functional capacity is important in directing chronic obstructive pulmonary disease (COPD) care (e.g., rehabilitation and discharge readiness), and in predicting outcomes (e.g., exacerbation, hospitalization, and mortality). The 6-minute walk distance (6MWD) test for functional capacity assessment, may be time-consuming and burdensome.
• Bime, C. (2016).

  Inhaler device preferences in older adults with chronic lung disease

  . Southwest Journal of Pulmonary Critical Care and Sleep. doi:10.13175/swjpcc097-16
• Bime, C. (2016).

  Tucson critical care journal club: albumin use in the critical care unit

  . Southwest Journal of Pulmonary, Critical Care and Sleep. doi:10.13175/swjpcc116-16
• Bime, C., Gerald, J. K., Wei, C. Y., Holbrook, J. T., Teague, W. G., Wise, R. A., & Gerald, L. B. (2016). Measurement characteristics of the childhood Asthma-Control Test and a shortened, child-only version. NPJ primary care respiratory medicine, 26, 16075.
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  The childhood Asthma-Control Test (C-ACT) is validated for assessing asthma control in paediatric asthma. Among children aged 4-11 years, the C-ACT requires the simultaneous presence of both parent and child. There is an unmet need for a tool that can be used to assess asthma control in children when parents or caregivers are not present such as in the school setting. We assessed the psychometric properties and estimated the minimally important difference (MID) of the C-ACT and a modified version, comprising only the child responses (C-ACTc). Asthma patients aged 6-11 years (n=161) from a previously completed multicenter randomised trial were included. Demographic information, spirometry and questionnaire scores were obtained at baseline and during follow-up. Participants or their guardians kept a daily asthma diary. Internal consistency reliabilities of the C-ACT and C-ACTc were 0.76 and 0.67 (Cronbach's α), respectively. Test-retest reliabilities of the C-ACT and C-ACTc were 0.72 and 0.66 (intra-class correlation), respectively. Significant correlations were noted between C-ACT scores and ACQ scores (Spearman's correlation r=-0.56, 95% CI (-0.66, -0.44), P
• Bime, C., Gerald, J. K., Wei, C. Y., Holbrook, J. T., Teague, W. G., Wise, R. A., & Gerald, L. B. (2016). Measurement characteristics of the childhood Asthma-Control Test and a shortened, child-only version. npj Primary Care Respiratory Medicine, 26(Issue). doi:10.1038/npjpcrm.2016.75
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  The childhood Asthma-Control Test (C-ACT) is validated for assessing asthma control in paediatric asthma. Among children aged 4-11 years, the C-ACT requires the simultaneous presence of both parent and child. There is an unmet need for a tool that can be used to assess asthma control in children when parents or caregivers are not present such as in the school setting. We assessed the psychometric properties and estimated the minimally important difference (MID) of the C-ACT and a modified version, comprising only the child responses (C-ACTc). Asthma patients aged 6-11 years (n=161) from a previously completed multicenter randomised trial were included. Demographic information, spirometry and questionnaire scores were obtained at baseline and during follow-up. Participants or their guardians kept a daily asthma diary. Internal consistency reliabilities of the C-ACT and C-ACTc were 0.76 and 0.67 (Cronbach's α), respectively. Test-retest reliabilities of the C-ACT and C-ACTc were 0.72 and 0.66 (intra-class correlation), respectively. Significant correlations were noted between C-ACT scores and ACQ scores (Spearman's correlation r=-0.56, 95% CI (-0.66,-0.44), P
• Bime, C., Poongkunran, C., Borgstrom, M., Natt, B., Desai, H., Parthasarathy, S., & Garcia, J. G. (2016). Racial Differences in Mortality from Severe Acute Respiratory Failure in the United States, 2008-2012. Annals of the American Thoracic Society, 13(12), 2184-2189.
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  Racial disparities in health and healthcare in the United States are well documented and are increasingly recognized in acute critical illnesses such as sepsis and acute respiratory failure.
• Bime, C., Zhou, T., Wang, T., Slepian, M. J., Garcia, J. G., & Hecker, L. (2016). Reactive oxygen species-associated molecular signature predicts survival in patients with sepsis. Pulmonary Circulation, 6(Issue 2). doi:10.1086/685547
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  Sepsis-related multiple organ dysfunction syndrome is a leading cause of death in intensive care units. There is overwhelming evidence that oxidative stress plays a significant role in the pathogenesis of sepsis-associated multiple organ failure; however, reactive oxygen species (ROS)-associated biomarkers and/or diagnostics that define mortality or predict survival in sepsis are lacking. Lung or peripheral blood gene expression analysis has gained increasing recognition as a potential prognostic and/or diagnostic tool. The objective of this study was to identify ROS-associated biomarkers predictive of survival in patients with sepsis. In-silico analyses of expression profiles allowed the identification of a 21-gene ROS-associated molecular signature that predicts survival in sepsis patients. Importantly, this signature performed well in a validation cohort consisting of sepsis patients aggregated from distinct patient populations recruited from different sites. Our signature outperforms randomly generated signatures of the same signature gene size. Our findings further validate the critical role of ROSs in the pathogenesis of sepsis and provide a novel gene signature that predicts survival in sepsis patients. These results also highlight the utility of peripheral blood molecular signatures as biomarkers for predicting mortality risk in patients with sepsis, which could facilitate the development of personalized therapies.
• Bime, C., Zhou, T., Wang, T., Slepian, M. J., Garcia, J. G., & Hecker, L. (2016). Reactive oxygen species-associated molecular signature predicts survival in patients with sepsis. Pulmonary circulation, 6(2), 196-201.
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  Sepsis-related multiple organ dysfunction syndrome is a leading cause of death in intensive care units. There is overwhelming evidence that oxidative stress plays a significant role in the pathogenesis of sepsis-associated multiple organ failure; however, reactive oxygen species (ROS)-associated biomarkers and/or diagnostics that define mortality or predict survival in sepsis are lacking. Lung or peripheral blood gene expression analysis has gained increasing recognition as a potential prognostic and/or diagnostic tool. The objective of this study was to identify ROS-associated biomarkers predictive of survival in patients with sepsis. In-silico analyses of expression profiles allowed the identification of a 21-gene ROS-associated molecular signature that predicts survival in sepsis patients. Importantly, this signature performed well in a validation cohort consisting of sepsis patients aggregated from distinct patient populations recruited from different sites. Our signature outperforms randomly generated signatures of the same signature gene size. Our findings further validate the critical role of ROSs in the pathogenesis of sepsis and provide a novel gene signature that predicts survival in sepsis patients. These results also highlight the utility of peripheral blood molecular signatures as biomarkers for predicting mortality risk in patients with sepsis, which could facilitate the development of personalized therapies.
• Desai, H., Natt, B., Bime, C., Dill, J., Dalen, J. E., & Alpert, J. S. (2016). Pulmonary Embolism with Right Ventricular Dysfunction: Who Should Receive Thrombolytic Agents?. The American journal of medicine.
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  Appropriate management of pulmonary embolism patients with right ventricular dysfunction is uncertain. Recent guidelines have stressed the need for more data on the use of thrombolytic agents in the stable pulmonary embolism patient with right ventricular dysfunction. The objective of this study is to investigate the hypothesis that thrombolytic therapy in hemodynamically stable pulmonary embolism patients with right ventricular dysfunction is not associated with improved mortality.
• Desai, H., Natt, B., Kim, S. S., & Bime, C. (2016). Decreased In-hospital Mortality after Lobectomy Using Video-Assisted Thoracoscopic Surgery Compared to Open Thoracotomy.. Annals of American Thoracic Society.
• Desai, H., Natt, B., Kim, S., & Bime, C. (2016). Decreased In-hospital Mortality after Lobectomy Using Video-Assisted Thoracoscopic Surgery Compared to Open Thoracotomy. Annals of the American Thoracic Society.
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  There is a paucity of data regarding the optimal surgical approach for lung lobectomy. Lobectomy performed by video-assisted thoracoscopic surgery (VATS) has been associated with lower morbidity as compared to thoracotomy. However, no multicenter studies have shown improved mortality with VATS lobectomy compared to open surgical lobectomy.
• Garcia, J. G., Natt, B., Bime, C., Poongkunran, C., Borgstrom, M., Desai, H., & Parthasarathy, S. (2016). Racial Differences in Mortality from Severe Acute Respiratory Failure in the United States, 2008–2012. Annals of the American Thoracic Society, 13(12), 2184-2189. doi:10.1513/annalsats.201605-359oc
• Ghazala, L., Bime, C., Cortopassi, F., Golden, T., & Berry, C. E. (2016). Inhaler preferences in older adults with chronic lung disease. Southwest Journal of Pulmonary and Critical Care Medicine, 13, 225-234.
• Huthayfa, A., Bime, C., & Gerald, J. K. (2016). Tucson Critical Care Journal Club: Albumin Use in the Critical Care Unit. Southwest J Pulm Crit Care.
• Natt, B. S., Desai, H., Singh, N., Poongkunran, C., Parthasarathy, S., & Bime, C. (2016). Extracorporeal Membrane Oxygenation for ARDS: National Trends in the United States 2008-2012. Respiratory care, 61(10), 1293-8.
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  Recent advances in technology and protocols have made the use of extracorporeal membrane oxygenation (ECMO) a viable rescue therapy for patients with ARDS who present with refractory hypoxemia. Despite the lack of strong evidence supporting the use of ECMO in ARDS, its use seems to be increasing. We sought to determine recent trends in the use of ECMO for ARDS. We also assessed trends in mortality among patients with ARDS in whom ECMO was used.
• Natt, B. S., Desai, H., Singh, N., Poongkunran, C., Parthasarathy, S., & Bime, C. (2016). Extracorporeal membrane oxygenation for ARDS: National trends in the United States 2008–2012. Respiratory Care, 61(Issue 10). doi:10.4187/respcare.04760
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  INTRODUCTION: Recent advances in technology and protocols have made the use of extracorporeal membrane oxygenation (ECMO) a viable rescue therapy for patients with ARDS who present with refractory hypoxemia. Despite the lack of strong evidence supporting the use of ECMO in ARDS, its use seems to be increasing. We sought to determine recent trends in the use of ECMO for ARDS. We also assessed trends in mortality among patients with ARDS in whom ECMO was used. METHODS: We performed a retrospective analysis using the largest all-payer in-patient healthcare database in the United States, the Healthcare Cost and Utilization project, the National In-patient Sample database from 2008 to 2012. Subjects with ARDS were identified using carefully chosen International Classification of Diseases, Ninth Revision codes. RESULTS: We found that in 2008, about 1 in 1,000 subjects with ARDS underwent ECMO. Over the subsequent 4-y time period, there was a 0.19% absolute increase and 70% relative increase in the use of ECMO for ARDS. The mortality rate among subjects with ARDS in whom ECMO was used declined from 78% in 2008 to 64% in 2012. We also found a trend toward a reduction in hospital stay among survivors. CONCLUSION: In the United States, between 2008 and 2012, there was an increasing trend toward the use of ECMO in patients with ARDS that coincided with a slight increase in survival among these patients.
• Natt, B., Natt, B., Desai, H., & Bime, C. (2016). Outcome of Patients With Pulmonary Hypertension Undergoing Elective, Non-Cardiac Surgery: A Propensity-Matched Study. Chest, 150(4), 37A. doi:10.1016/j.chest.2016.08.044
• Pouladi, N., Bime, C., Garcia, J. G., & Lussier, Y. A. (2016). Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing. Translational research : the journal of laboratory and clinical medicine, 168, 22-39.
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  The advent of high-throughput technologies has provided exceptional assistance for lung scientists to discover novel genetic variants underlying the development and progression of complex lung diseases. However, the discovered variants thus far do not explain much of the estimated heritability of complex lung diseases. Here, we review the literature of successfully used genome-wide association studies (GWASs) and identified the polymorphisms that reproducibly underpin the susceptibility to various noncancerous complex lung diseases or affect therapeutic responses. We also discuss the inherent limitations of GWAS approaches and how the use of next-generation sequencing technologies has furthered our understanding about the genetic determinants of these diseases. Next, we describe the contribution of the metagenomics to understand the interactions of the airways microbiome with lung diseases. We then highlight the urgent need for new integrative genomics-phenomics methods to more effectively interrogate and understand multiple downstream "omics" (eg, chromatin modification patterns). Finally, we address the scarcity of genetic studies addressing under-represented populations such as African Americans and Hispanics.
• Bime, C. (2015).

  A Meta-analysis of Sleep-promoting Interventions During Critical Illness

  . American Journal oF Medicine. doi:10.1016/j.amjmed.2015.05.026
• Bime, C. (2015).

  February 2015 Tucson pulmonary journal club: fibrinolysis for PE

  . Southwest Journal of Pulmonary, Critical Care, and Sleep. doi:10.13175/swjpcc028-15
• Dill, J., Gerald, J. K., Bime, C., & Knepler, J. L. (2015). September 2015 Tucson pulmonary journal club: genomic classifier for lung cancer. .. Southwest J Pulm Crit Care. doi:doi: http://dx.doi.org/10.13175/swjpcc125-15 PDF
• Dill, J., Gerald, J. K., Bime, C., & Knepler, J. L. (2015). Tucson pulmonary journal club: genomic classifier for lung cancer.. Southwest J Pulm Crit Care.
• Dill, J., Gerald, J., & Knepler, J. (2015). A bronchial genomic classifier for the diagnostic evaluation of lung cancer.. Southwest Journal of Pulmonary & Critical Care, 11(3), 119-20.
• Ganesh, A., Bime, C., & Gerald, J. (2015). Fibrinolysis for patients with intermediate-risk pulmonary embolism. Southwest Journal of Pulmonary & Critical Care, 10(2), 97-8.
• Ganesh, A., Bime, C., & Gerald, J. K. (2015). Tucson pulmonary journal club: fibrinolysis for Pulmonary Embolus. Southwest J Pulm Crit Care.
• Gordon, J. S., Berry, C. E., Sekhon, K., Gordon, J. S., Golden, T., Ghazala, L., Gerald, L. B., Bime, C., & Berry, C. E. (2015). Cross Sectional Survey of Electronic Cigarettes Use Among Ambulatory COPD Patients. Chest, 148(4), 1076A. doi:10.1378/chest.2256166
• Hecker, L., Bime, C., Zhou, T., Wang, T., Slepian, M., & Garcia, G. (2015). Reactive oxygen species-associated molecular signature predicts survival in patients with sepsis. Pulmonary Circulation, 0(0).
• Malaisamy, S., Dalal, B., Bimenyuy, C., & Soubani, A. O. (2015). The clinical and radiologic features of nodular pulmonary sarcoidosis. Lung, 187(1), 9-15.
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  Nodular sarcoidosis is an uncommon presentation of sarcoidosis. Our objective was to describe the clinical characteristics of a large cohort of patients with nodular sarcoidosis.
• Natt, B., Poongkunran, C., Singh, N., Poongkunran, C., Natt, B., Desai, H., & Bime, C. (2015). ARDS Prevalence and Survival Trends in the United States; 2008-2012. Chest, 148(4), 1-7. doi:10.1378/chest.2278583
• Natt, B., Poongkunran, C., Singh, N., Raz, Y., Poongkunran, C., Natt, B., Desai, H., & Bime, C. (2015). Extracorporeal Membrane Oxygenator Use in ARDS; Trends From 2008-2012. Chest, 148(4), 292A. doi:10.1378/chest.2278195
• Poongkunran, C., John, S. G., Kannan, A. S., Shetty, S., Bime, C., & Parthasarathy, S. (2015). A meta-analysis of sleep-promoting interventions during critical illness. The American journal of medicine, 128(10), 1126-1137.e1.
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  Sleep quality and quantity are severely reduced in critically ill patients receiving mechanical ventilation with a potential for adverse consequences. Our objective was to synthesize the randomized controlled trials (RCTs) that measured the efficacy of sleep-promoting interventions on sleep quality and quantity in critically ill patients.
• Poongkunran, C., Natt, B., Singh, N., Poongkunran, C., Natt, B., Desai, H., Borgstrom, M., & Bime, C. (2015). 679: INCREASED MORTALITY IN ARDS PATIENTS REQUIRING CONTINUOUS RENAL REPLACEMENT THERAPY. Critical Care Medicine, 43, 171. doi:10.1097/01.ccm.0000474507.38895.79
• Soler, X., Searing, D. A., Santiago, M. T., Morgan, W. J., Knox, K. S., Goodwin, J. L., Ezmigna, D. R., Daines, M. O., Berry, C. E., Zheng, G., Zagaja, V., Yasin, R., Xu, B., Wu, N., Wu, E. Y., Wolf, D., Wise, R. A., Williams, J., Wences, J. A., , Welter, J., et al. (2015). Effect of a soy isoflavone supplement on lung function and clinical outcomes in patients with poorly controlled asthma: a randomized clinical trial.. JAMA, 313(20), 2033-43. doi:10.1001/jama.2015.5024
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  Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control..To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease..Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24..Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks..The primary outcome measure was change in forced expiratory volume in the first second (FEV1) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation..Mean changes in prebronchodilator FEV1 over 24 weeks were 0.03 L (95% CI, -0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, -0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, -3.48 ppb [95% CI, -5.99 to -0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, -1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement..Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma..clinicaltrials.gov Identifier: NCT01052116.
• Bime, C. (2014).

  April 2014 Tucson critical care journal club: early goal-directed therapy

  . Southwest Journal oF Pulmonary, Critical Care, and Sleep. doi:10.13175/swjpcc058-14
• Bime, C. (2014).

  January 2014 Tucson critical care journal club: esmolol in septic shock

  . Southwest Journal of Pulmonary Critical Care and Sleep. doi:10.13175/swjpcc016-14
• Bime, C., Sun, K., Ulliman, E., & Hypes, C. (2014). Medical image of the week: secondary pneumonia presenting as hemoptysis. Southwest J Pulm Crit Care.
• Natt, B., Berry, C. E., Bime, C., & Gerald, J. K. (2014). Tucson critical care journal club: early goal-directed therapy. Southwest J Pulm Crit Care.
• Natt, B., Berry, C. E., Bime, C., & Gerald, J. K. (2014). Tucson critical care journal club: early goal-directed therapy. Southwest Journal of Pulmonary and Critical Care.
• Strawter, C., Berry, C. E., Bime, C., & Gerald, J. K. (2014). Tucson critical care journal club: esmolol in septic shock. Southwest J Pulm Crit Care.
• Bime, C. (2012).

  Asthma Symptom Utility Index: Reliability, validity, responsiveness, and the minimal important difference in adult asthmatic patients

  . Journal oF Allergy and CLinical Immunology. doi:10.1016/j.jaci.2012.07.058
  More info

  BackgroundThe evaluation of asthma symptoms is a core outcome measure in asthma clinical research. The Asthma Symptom Utility Index (ASUI) was developed to assess the frequency and severity of asthma symptoms. The psychometric properties of the ASUI are not well characterized, and a minimal important difference (MID) is not established.ObjectivesWe assessed the reliability, validity, and responsiveness to change of the ASUI in a population of adult asthmatic patients. We also sought to determine the MID for the ASUI.MethodsAdult asthmatic patients (n = 1648) from 2 previously completed multicenter randomized trials were included. Demographic information, spirometric results, ASUI scores, and other asthma questionnaire scores were obtained at baseline and during follow-up visits. Participants also kept a daily asthma diary.ResultsThe internal consistency reliability of the ASUI was 0.74 (Cronbach α). Test-retest reliability was 0.76 (intraclass correlation). Construct validity was demonstrated by significant correlations between ASUI scores and Asthma Control Questionnaire scores (Spearman correlation r = −0.79; 95% CI, −0.85 to −0.75; P < .001) and Mini Asthma Quality of Life Questionnaire scores (r = 0.59; 95% CI, 0.51-0.61; P < .001). Responsiveness to change was demonstrated, with significant differences between mean changes in ASUI scores across groups of participants differing by 10% in percent predicted FEV1 (P < .001) and by 0.5 points in Asthma Control Questionnaire scores (P < .001). Anchor-based and statistical methods support an MID for the ASUI of 0.09 points.ConclusionsThe ASUI is reliable, valid, and responsive to changes in asthma control over time. The MID of the ASUI (range of scores, 0-1) is 0.09. The evaluation of asthma symptoms is a core outcome measure in asthma clinical research. The Asthma Symptom Utility Index (ASUI) was developed to assess the frequency and severity of asthma symptoms. The psychometric properties of the ASUI are not well characterized, and a minimal important difference (MID) is not established. We assessed the reliability, validity, and responsiveness to change of the ASUI in a population of adult asthmatic patients. We also sought to determine the MID for the ASUI. Adult asthmatic patients (n = 1648) from 2 previously completed multicenter randomized trials were included. Demographic information, spirometric results, ASUI scores, and other asthma questionnaire scores were obtained at baseline and during follow-up visits. Participants also kept a daily asthma diary. The internal consistency reliability of the ASUI was 0.74 (Cronbach α). Test-retest reliability was 0.76 (intraclass correlation). Construct validity was demonstrated by significant correlations between ASUI scores and Asthma Control Questionnaire scores (Spearman correlation r = −0.79; 95% CI, −0.85 to −0.75; P < .001) and Mini Asthma Quality of Life Questionnaire scores (r = 0.59; 95% CI, 0.51-0.61; P < .001). Responsiveness to change was demonstrated, with significant differences between mean changes in ASUI scores across groups of participants differing by 10% in percent predicted FEV1 (P < .001) and by 0.5 points in Asthma Control Questionnaire scores (P < .001). Anchor-based and statistical methods support an MID for the ASUI of 0.09 points. The ASUI is reliable, valid, and responsive to changes in asthma control over time. The MID of the ASUI (range of scores, 0-1) is 0.09.
• Bime, C., Nguyen, J., & Wise, R. A. (2012). Measures of asthma control. Current opinion in pulmonary medicine, 18(1), 48-56.
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  Over the past decade, the concept of asthma control as distinct from asthma severity has been clearly defined. Well controlled asthma is the goal of therapy in all asthma patients. This review is a comprehensive description of the tools currently available for a methodical assessment of different aspects of asthma control in clinical practice and research.
• Bime, C., Wei, C. Y., Holbrook, J. T., Sockrider, M. M., Revicki, D. A., & Wise, R. A. (2012). Asthma symptom utility index: reliability, validity, responsiveness, and the minimal important difference in adult asthmatic patients. The Journal of allergy and clinical immunology, 130(5), 1078-84.
  More info

  The evaluation of asthma symptoms is a core outcome measure in asthma clinical research. The Asthma Symptom Utility Index (ASUI) was developed to assess the frequency and severity of asthma symptoms. The psychometric properties of the ASUI are not well characterized, and a minimal important difference (MID) is not established.
• Bime, C., Wei, C. Y., Holbrook, J., Smith, L. J., & Wise, R. A. (2012). Association of dietary soy genistein intake with lung function and asthma control: A post-hoc analysis of patients enrolled in a prospective multicentre clinical trial. Primary Care Respiratory Journal, 21(Issue 4). doi:10.4104/pcrj.2012.00073
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  Background: Broad dietary patterns have been linked to asthma but the relative contribution of specific nutrients is unclear. Soy genistein has important anti-inflammatory and other biological effects that might be beneficial in asthma. A positive association was previously reported between soy genistein intake and lung function but not with asthma exacerbations. Aims: To conduct a post-hoc analysis of patients with inadequately controlled asthma enrolled in a prospective multicentre clinical trial to replicate this association. Methods: A total of 300 study participants were included in the analysis. Dietary soy genistein intake was measured using the Block Soy Foods Screener. The level of soy genistein intake (little or no intake, moderate intake, or high intake) was compared with baseline lung function (pre-bronchodilator forced expiratory volume in 1 second (FEV1)) and asthma control (proportion of participants with an episode of poor asthma control (EPAC) and annualised rates of EPACs over a 6-month follow-up period. Results: Participants with little or no genistein intake had a lower baseline FEV1 than those with a moderate or high intake (2.26L vs. 2.53L and 2.47L, respectively; p=0.01). EPACs were more common among those with no genistein intake than in those with a moderate or high intake (54% vs. 35% vs. 40%, respectively; p
• Bime, C., Wei, C. Y., Holbrook, J., Smith, L. J., & Wise, R. A. (2012). Association of dietary soy genistein intake with lung function and asthma control: a post-hoc analysis of patients enrolled in a prospective multicentre clinical trial. Primary care respiratory journal : journal of the General Practice Airways Group, 21(4), 398-404.
  More info

  Broad dietary patterns have been linked to asthma but the relative contribution of specific nutrients is unclear. Soy genistein has important anti-inflammatory and other biological effects that might be beneficial in asthma. A positive association was previously reported between soy genistein intake and lung function but not with asthma exacerbations.
• Wise, R. A., Teague, W. G., Nguyen, J. M., Holbrook, J. T., & Bime, C. (2012). Reliability, Validity, and Responsiveness of the Asthma Control Questionnaire among Pediatric Patients. The Journal of Allergy and Clinical Immunology, 129(2), AB206. doi:10.1016/j.jaci.2011.12.194
• Hammad, H., Bimenyuy, C., Rau, S., & Siddiqui, F. (2006). Upper Extremity Venous Thrombosis after Infliximab Therapy. American Journal of Gastroenterology.

Proceedings Publications

• Bime, C. (2023).

  A Confusing Case of Bloody Cough: Not Everything is TB

  . In American Thoracic SOceity International Conference.
• Bime, C. (2023).

  A Confusing Case of Bloody Cough: Not Everything is TB

  . In American Thoracic Soceity International Conference.
• Bime, C. (2023).

  A LASSO-DERIVED PREDICTIVE MODEL FOR POSTOPERATIVE RESPIRATORY FAILURE IN A HETEROGENEOUS ADULT ELECTIVE SURGERY PATIENT POPULATION

  . In ACCP-CHEST.
• Bime, C. (2023).

  A LASSO-derived predictive model for postoperative respiratory failure in a heterogeneous adult elective surgery patient population

  . In ACCP - CHEST.
• Bime, C. (2023).

  BEYOND THE MUDPILES OF METABOLIC ACIDOSIS

  . In ACCP-CHEST.
• Bime, C. (2023).

  Inclusion of Racial and Ethnic Minority Populations in SARS-CoV-2 Vaccine Clinical Trials

  . In American Thoracic Society International Conference.
• Bime, C. (2023).

  Presence of Heart Failure With Preserved Ejection Fraction Is Associated With Increased Rates of Failure of High Flow Nasal Cannula in Patients Presenting With Acute Hypoxemic Respiratory Failure

  . In American Thoracic Soceity International Conference.
• Bime, C. (2023).

  Trend of ROX Index Predicts Failure of High Flow Nasal Cannula

  . In American Thoracic Soceity International Conference.
• Garcia, J., Bime, C., Letsiou, E., Bandela, M., Meliton, L., Epshtein, Y., Kumar, P., Ramchandran, R., Natarajan, V., & Dudek, S. (2021). PSGL1 and P-Selectin Mediate Inflammatory Responses in Lung Endothelium. In American Thoracic Society Conference.
• Bime, C. (2020).

  Inhaled Epoprostenol Versus Inhaled Nitric Oxide for Refractory Hypoxemia in Acute Respiratory Distress Syndrome

  . In American Thoracic Soceity International Conference.
• Bime, C. (2020).

  Quantification of Early Physical and Occupational Therapy in a Medical ICU- An Age Friendly Health Systems Initiative

  . In American Thoracic Society International Conference.
• Lynn, H., Liao, S. Y., Garcia, J. G., Casanova, N. G., & Bime, C. (2020). Longitudinal and Multi-Omics Analysis Identified Gene Sets Associated with Acute Respiratory Distress Syndrome Mortality. In C59. DISSECTING ACUTE LUNG INJURY AND ARDS.
• Oita, R. C., Ndukum, J., Miller, E. J., Lynn, H., Lussier, Y. A., Garcia, J. G., Downs, C. A., Dessap, A. M., Casanova, N. G., Carter, D., Camp, S. M., Bime, C., & Abraham, I. (2020). A Prognostic Biomarker-Based Panel for Patient Stratification in Adults with Acute Respiratory Distress Syndrome. In A104. LUNGS, BUGS, AND THE DIAPHRAGM: TRANSLATIONAL STUDIES IN THE ICU.
• Pu, J., Miller, D. C., Kukafka, D., & Bime, C. (2020). Patients with Acute Respiratory Failure Who Fail High Flow Nasal Cannula Before Intubation Have a Higher Mortality Compared to Invasive Mechanical Ventilation Alone. In A40. CRITICAL CARE: FROM HFNC TO ECMO.
• Sammani, S., Oita, R. C., Kempf, C. L., Garcia, J. G., Casanova, N. G., Camp, S. M., & Bime, C. (2020). Selectin P Ligand Gene Knockout Mice (Selplg-/-) Exhibit Attenuated LPS-Induced Lung Injury and Increased Selectin P (Selp) Expression. In A104. LUNGS, BUGS, AND THE DIAPHRAGM: TRANSLATIONAL STUDIES IN THE ICU.
• Bime, C. (2019).

  Trends and Outcomes in Surgical Management of Pleural Space Infections in the Era of TPA and DNase: Analysis Using Nationwide Data from 2005-2014

  . In American Thoracic Soceity International Conference.
• Casanova, N. G., Sun, X., Lynn, H., Garcia, J. G., Ganay, M. G., Coletta, D., Casanova, N. G., & Bime, C. (2019). The mTOR Pathway Genes Are Differentially Methylated in African- and Hispanic- Americans Who Fail to Survive Acute Respiratory Distress Syndrome (ARDS). In C59. GENETIC AND EPIGENETIC MECHANISMS IN PULMONARY FIBROSIS.
• Miller, D., Johnston, C. B., Insel, M., Fain, M., & Bime, C. (2019). Regional Differences in Do Not Resuscitate Status and Inpatient Mortality Among Patients in US Hospitals: Analysis Using Nationwide Data from 2014. In A22. FACILITATING PALLIATIVE AND END-OF-LIFE CARE.
• Bime, C. (2018).

  Sa1830 - Obesity is Associated with Increased Risk of Colectomy in Inflammatory Bowel Disease Patients Hospitalized with Clostridium Difficile Infection

  . In American Gastroenterological Association Conference.
• Roman, J., Viegi, G., Schenker, M., Ojeda, V., Nemery, B., Annesi-Maesano, I., Patel, S., La Grutta, S., Holguin, F., Moughrabieh, A., Bime, C., Lindberg, A., Migliori, G., De Vries, G., Aliberti, S., Feldman, C., Celedón, J., Pérez-Stable, E., & Ramírez, J. (2018). American thoracic society documents: Research needs on respiratory health in migrant and refugee populations An Official American Thoracic Society and European Respiratory Society Workshop Report. In ATS International Conference.
  More info

  Migrants represent a diverse population comprising workers, students, undocumented individuals, and refugees. Worldwide, approximately 1 billion people were considered migrants in 2016. Notably, about 65 million of these migrants were forcibly displaced from their homes, and 20 million were considered refugees. While the geopolitical consequences of such migration continue to be considered, less is known about the impact of these events on the respiratory health of migrants and refugees. In recognition of this knowledge gap, the American Thoracic Society and the European Respiratory Society brought together investigators with diverse and relevant expertise to participate in a workshop and develop a consensus on research needs on the respiratory health of migrants and refugees. The workshop focused on environmental and occupational hazards, chronic noninfectious diseases, and respiratory infectious diseases, which were presented by experts in three distinct sessions, each culminating with panel discussions. A writing committee collected summaries prepared by speakers and other participants, and the information was collated into a single document. Recommendations were formulated, and differences were resolved by discussion and consensus. The group identified important areas of research need, while emphasizing that reducing the burden of pulmonary, critical care, and sleep disorders in migrants and refugees will require a concerted effort by all stakeholders. Using best research practices, considering how research impacts policies affecting migrant and refugee populations, and developing new approaches to engage and fund trainees, clinical investigators, and public health practitioners to conduct high-quality research on respiratory health of migrants and refugees is essential.
• Bime, C. (2017).

  Decreasing Clostridium difficile-associated Mortality Rates Among Hospitalized Patients in the United States: 2004-2014: 2017 Category Award (Practice Management): 2017 Presidential Poster Award

  . In American College of Gastroenterology.
  More info

  Introduction:Clostridium difficile infection (CDI) has emerged as a major public health problem in the United States over the last two decades. Several strategies have been implemented at the hospital, community, state and national levels to combat this infection. We sought to examine the trends in the CDI-associated mortality rate, hospital length of stay and hospital charges over the last decade. Methods: We used data from the National Inpatient Sample (NIS) to identify patients with a principal diagnosis of CDI from 2004-2014. Outcomes included in-hospital mortality, hospital length of stay and hospital charges. For each outcome, trends were also stratified by age categories. Results: The CDI discharges increased from 19.9/100,000 persons in 2004 to 33.8/100,000 persons in 2014. CDI-associated mortality decreased from 3.6% in 2004 to 1.6% in 2014 (linear trend P < 0.001). Among patients aged 45-64 years with CDI, mortality decreased from 1.2% in 2004 to 0.7% in 2014 (linear trend P < 0.001). Among patients aged 65-84 years with CDI, mortality decreased from 4.3% in 2004 to 2.0% in 2014 (linear trend P < 0.001). Among patients aged ≥85 years with CDI, mortality decreased from 6.9% in 2004 to 3.6% in 2014 (linear trend P < 0.001). The mean length of hospital stay for CDI patients decreased from 6.9 days in 2004 to 5.8 days in 2014 (P < 0.001). The mean hospital charges for CDI patients increased from 2004 ($24,535) to 2014 ($35,898) (P < 0.001).Figure: In-hospital mortality rate. In-hospital mortality rate decreased for all patients with Clostridium difficile infection (CDI) from 2004 to 2014. The in-hospital mortality rate of decline was faster in older patients (aged 65-84 and 85+) than in younger patients aged 45-64. The decline in mortality rate was faster in patients with CDI than in patients with any diagnosis (all discharges).Conclusion: In-hospital mortality associated with CDI in the United States has decreased over two fold in the last decade despite increasing CDI rates. Despite decreasing length of stay, the hospital charges of CDI are increasing.
• Wise, R. A., Wei, C. Y., Sockrider, M., Nguyen, J., Holbrook, J. T., & Bime, C. (2012). Asthma Symptom Utility Index: Reliability, Validity, Responsiveness And The Minimally Important Clinical Difference In Adult Asthma Patients. In D41. DEVELOPING AND IMPROVING MEASURES TO ASSESS AND CHANGE BELIEFS, SKILLS, BEHAVIORS AND OUTCOMES.
• Wise, R. A., Wei, C. Y., Sugar, E. A., & Bime, C. (2012). Repeatability Of Fractional Concentration Of Exhaled Nitric Oxide (FeNO) Using The NIOX MINO And The Agreement Between Two NIOX MINO Machines. In D39. EVALUATION AND MONITORING OF ASTHMA AND COPD.
• Wise, R. A., Wei, C. Y., Smith, L. J., Holbrook, J. T., & Bime, C. (2011). Dietary Intake Of Soy Genistein Is Associated With Asthma Control And Lung Function In Asthma Patients. In C33. CLINICAL PROFILES AND SEVERITY OF ASTHMA.

Presentations

• Bime, C., Gerald, L. B., Stern, D., Garcia, D. L., & Lowe, A. (2018, May). Home based exercise intervention versus remote asthma care guidance via telephone/text message in obese asthmatics. American Thoracic Society International Conference. San Diego, CA: American Thoracic Society.
• Lowe, A., Garcia, D. L., Stern, D., Gerald, L. B., & Bime, C. (2018, May). Feasibility of home based exercise intervention with remote guidance for obese asthmatics. American Thoracic Society International Conference. San Diego, CA: American Thoracic Society.

Poster Presentations

• Shrestha, M., Shrestha, M., Shrestha, M., Bime, C., Bime, C., Bime, C., Taleban, S., Taleban, S., & Taleban, S. (2018, 06/2018). Obesity is associated with increased risk of colectomy in inflammatory bowel disease patients hospitalized with Clostridium difficile infection.. DDW Annual Meeting. Washington, DC: DDW.
• Desai, H., Natt, B., & Bime, C. (2016, May/Spring). Decreased in-hospital mortality after lobectomy using video-assisted thoracoscopic surgery compared to open thoracotomy. ATS International Conference. San Francisco, CA.
• Berry, C. E., Ghazala, L., Mohler, M. J., Bime, C., Berry, C. E., Ghazala, L., Mohler, M. J., & Bime, C. (2015, June). Frailty features are common in ambulatory patients with COPD and may be associated with respiratory muscle weakness. COPD9USA. Chicago, IL.
• Ghazala*, L., Gordon, J. S., Berry, C. E., Bime, C., Gerald, L. B., Golden*, T., Sekhon*, K., Ghazala*, L., Gordon, J. S., Berry, C. E., Bime, C., Gerald, L. B., Golden*, T., Sekhon*, K., Ghazala*, L., Gordon, J. S., Berry, C. E., Bime, C., Gerald, L. B., , Golden*, T., et al. (2015, October). Cross-section survey of electronic cigarette use among ambulatory COPD patients. CHEST.
• Ghazala, L., Bime, C., Cortopassi, F., Baalachandran, R., Oren, E., Berry, C. E., Ghazala, L., Bime, C., Cortopassi, F., Baalachandran, R., Oren, E., & Berry, C. E. (2015, May). Inhaler Device Preferences In Older Adults With Chronic Lung Disease. American Thoracic Society. Denver, CO.
• Natt, B., Desai, H., Poongkunran, C., & Bime, C. (2015, October/Fall). Extracorporeal Membrane Oxygenator Use in ARDS. CHEST Annual Meeting. Montreal, Québec, Canada.
• Natt, B., Desai, H., Singh, N., Poongkunran, C., & Bime, C. (2015, October/Fall). ARDS Prevalence and Survival Trends in the United States; 2008-2012. CHEST Annual Meeting. Montreal, Québec, Canada.
• Shrestha, M. P., Bime, C., & Taleban, S. (2017, Oct/ Fall). Decreasing Clostridium difficile-Associated Mortality Rates Among Hospitalized Patients in the Unites States: 2004-2014. WCOG. Orlando: ACG.
• Toosizahdeh, N., Berry, C. E., Bime, C., Najafi, B., Mohler, M. J., Toosizahdeh, N., Berry, C. E., Bime, C., Najafi, B., & Mohler, M. J. (2015, May). An Association between Frailty and Pulmonary Function in Patients with Chronic Obstructive Pulmonary Disease (COPD) – Application of a Routine Frailty Assessment Approach using Wearable Technology. American Aging Association. Marina del Rey, CA.

Others

• Bime, C., Bhupinder, N., Singh, N., Desai, H., Poongkunran, C., Parthasarathy, S., & Garcia, G. (2015, Jan). Racial and ethnic differences in Acute Respiratory Distress Syndrome mortality in the United States.
• Bime, C., Oren, E., Fierro, M., Berry, C., Parthasarathy, S., & Garcia, G. (2015, Jan). Obesity, Positive End-Expiratory Pressure, and Acute Respiratory Distress Syndrome Survival - Submitted to Journal of Critical Care Medicine. Journal of Critical Care Medicine.
• Bime, C., Oren, E., Fierro, M., Berry, C., Parthasarathy, S., & Garcia, G. (2015, March). High versus low PEEP and ARDS survival: Effect modification by BMI. ATS 2015 Denver, CO.
• Bime, C., Wei, R., & Gerald, J. (2015, Jan). Measurement characteristics of the Childhood Asthma Control Test (C-ACT) and a shortened, child-only version (C-ACTc).. Nature Publication Journals Primary Care Respiratory Medicine.
• Chazala, L., Bime, C., Baalachandran, R., Cortopassi, F., Oren, E., Golden, T., & Berry, C. (2015, March). Inhaler Device Preferences in Older Adults with Chronic Lung Disease. ATS, Denver, CO.
• Desai, H., Poongkunran, C., Singh, N., & Bime, C. (2016, February). ARDS Prevalence and Survival Trends in the United States; 2008-2012. ACCP 2015 Montreal, Canada.
• H, D., N, B., & N, S. (2015, October). Extracorporeal Membrane Oxygenator use in ARDS; trends from 2008-2012. ACCP 2015 Montreal, Canada.
• Natt, B., Singh, N., Desai, H., Poongkunran, C., Parthasarathy, S., & Bime, C. (2015, Jan). Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: National Trends in the United States 2008-2012. Respiratory Care Journal.
• Toosizahdeh, N., Berry, C., Bime, C., Najafi, B., & Mohler, J. (2015, Jan). An Association between Frailty and Pulmonary Function in Patients with Chronic Obstructive Pulmonary Disease (COPD) – Application of a Routine Frailty Assessment Approach using Wearable Technology. Journal of COPD.
• Bimenyuy, C., & Kuaban, C. (2001, 2001). The correlation between radiographic aspects of pulmonary tuberculosis and degree of HIV associated immune-suppression. MD. Thesis Presentation FMSB.