Billie Bixby

Interests

Research

Thoracic oncology, early identification of lung cancer, advanced bronchoscopy, management of malignant and benign pleural disease.

Teaching

Pleural disease, thoracic oncology, complex airway disease, pulmonary procedures, bronchoscopy, critical care.

Courses

No activities entered.

Scholarly Contributions

Journals/Publications

• Khemasuwan, D., Wilshire, C., Reddy, C., Gilbert, C., Gorden, J., Balwan, A., Sanchez, T. M., Bixby, B., Sorensen, J. S., & Shojaee, S. (2025). Machine Learning Model Predictors of Intrapleural Tissue Plasminogen Activator and DNase Failure in Pleural Infection A Multicenter Study. Annals of the American Thoracic Society, 22(Issue 2). doi:10.1513/annalsats.202402-151oc
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  Rationale: Intrapleural enzyme therapy (IET) with tissue plasminogen activator (tPA) and DNase has been shown to reduce the need for surgical intervention for complicated parapneumonic effusion/empyema (CPPE/empyema). Failure of IET may lead to delayed care and increased length of stay. Objectives: The goal of this study was to identify risk factors for failure of IET. Methods: We performed a multicenter, retrospective study of patients who received IET for the treatment of CPPE/empyema. Clinical and radiological variables at the time of diagnosis were included. We compared four different machine learning classifiers (L1-penalized logistic regression, support vector machine [SVM], extreme gradient boosting [XGBoost], and light gradient-boosting machine [LightGBM]) by multiple bootstrap-validated metrics, including F-b, to demonstrate model performances. Results: A total of 466 participants who received IET for pleural infection were included from five institutions across the United States. Resolution of CPPE/empyema with IET was achieved in 78% (n = 365). SVM performed superiorly, with median F-b of 56%, followed by L1-penalized logistic regression, LightGBM, and XGBoost. Clinical and radiological variables were graded based on their ranked variable importance. The top two significant predictors of IET failure using SVM were the presence of an abscess/necrotizing pneumonia (17%) and pleural thickening (13%). Similarly, LightGBM identified abscess/necrotizing pneumonia (35%) and pleural thickening (26%) and XGBoost indicated pleural thickening (36%) and abscess/necrotizing pneumonia (17%) as the most significant predictors of treatment failure. Predictors identified by the L1-penalized logistic regression model were pleural thickening (18%) and pleural fluid lactate dehydrogenase (LDH) (9%). Conclusions: The presence of abscess/necrotizing pneumonia and pleural thickening consistently ranked among the strongest predictors of IET failure in all machine learning models. The difference in rankings between models may be a consequence of the different algorithms used by each model. These results indicate that the presence of abscess/necrotizing pneumonia and pleural thickening may predict IET failure. These results should be confirmed in larger studies.
• Khemasuwan, D., Wilshire, C., Reddy, C., Gilbert, C., Gorden, J., Balwan, A., Sanchez, T. M., Bixby, B., Sorensen, J. S., & Shojaee, S. (2025). Machine Learning Model Predictors of Intrapleural Tissue Plasminogen Activator and DNase Failure in Pleural Infection: A Multicenter Study. Annals of the American Thoracic Society, 22(2), 187-192.
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  Intrapleural enzyme therapy (IET) with tissue plasminogen activator (tPA) and DNase has been shown to reduce the need for surgical intervention for complicated parapneumonic effusion/empyema (CPPE/empyema). Failure of IET may lead to delayed care and increased length of stay. The goal of this study was to identify risk factors for failure of IET. We performed a multicenter, retrospective study of patients who received IET for the treatment of CPPE/empyema. Clinical and radiological variables at the time of diagnosis were included. We compared four different machine learning classifiers (L1-penalized logistic regression, support vector machine [SVM], extreme gradient boosting [XGBoost], and light gradient-boosting machine [LightGBM]) by multiple bootstrap-validated metrics, including F-β, to demonstrate model performances. A total of 466 participants who received IET for pleural infection were included from five institutions across the United States. Resolution of CPPE/empyema with IET was achieved in 78% ( = 365). SVM performed superiorly, with median F-β of 56%, followed by L1-penalized logistic regression, LightGBM, and XGBoost. Clinical and radiological variables were graded based on their ranked variable importance. The top two significant predictors of IET failure using SVM were the presence of an abscess/necrotizing pneumonia (17%) and pleural thickening (13%). Similarly, LightGBM identified abscess/necrotizing pneumonia (35%) and pleural thickening (26%) and XGBoost indicated pleural thickening (36%) and abscess/necrotizing pneumonia (17%) as the most significant predictors of treatment failure. Predictors identified by the L1-penalized logistic regression model were pleural thickening (18%) and pleural fluid lactate dehydrogenase (LDH) (9%). The presence of abscess/necrotizing pneumonia and pleural thickening consistently ranked among the strongest predictors of IET failure in all machine learning models. The difference in rankings between models may be a consequence of the different algorithms used by each model. These results indicate that the presence of abscess/necrotizing pneumonia and pleural thickening may predict IET failure. These results should be confirmed in larger studies.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., 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.
• Aggarwal, N. R., Nordwall, J., Braun, D. L., Chung, L., Coslet, J., Der, T., Eriobu, N., Ginde, A. A., Hayanga, A. J., Highbarger, H., Holodniy, M., Horcajada, J. P., Jain, M. K., Kim, K., Laverdure, S., Lundgren, J., Natarajan, V., Nguyen, H. H., Pett, S. L., , Phillips, A., et al. (2024). Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 78(6), 1490-1503.
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  Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials.
• Ahmadian, D., Gleadhill, C. M., Wehbi, N., Bixby, B. A., & Yip, H. T. (2024). Predictors of response to endoscopic management of subglottic/tracheal stenosis in patients without tracheostomy. American Journal of Otolaryngology - Head and Neck Medicine and Surgery, 45(Issue 1). doi:10.1016/j.amjoto.2023.104055
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  Introduction: Subglottic and tracheal stenosis (SGTS) in adults is an acquired or idiopathic condition that can lead to dyspnea, and even life-threatening airway obstruction. Endoscopic techniques have advanced and largely eclipsed open surgery, with open surgery now reserved for refractory cases (Hseu et al., 2013; Feinstein et al., 2017). Currently, there is no accepted guideline for the endoscopic treatment of SGTS. Thus, the aim of the present study is to examine the impact of various clinical and pathological characteristics on outcomes to endoscopic treatment in a cohort of SGTS patients. Disclosure: None of the authors have any financial or personal relationship that could cause a conflict of interest regarding this article. Methods: Retrospective chart review was performed for 41 patients presenting with SGS without a tracheostomy over a 4-year-period (2018–2022), within a single tertiary care center. Quantitative outcomes including number of dilation procedures undergone and need for open procedures were examined. The qualitative variables included a history of pulmonary disease, prior tracheostomy/tracheal resection, presence of tracheomalacia, granulation tissue, excessive dynamic airway collapse (EDAC), and etiology of idiopathic subglottic stenosis. Results: The presence of granulation tissue seen on tracheoscopy was associated with a higher number (4+) of dilation procedures (p = 0.01). A history of pulmonary disease (p = 0.037), the presence of tracheomalacia (p = 0.039), and the presence of granulation tissue (0.003) were all associated with a need for open procedures. Conclusion: Patients with the presence of granulation tissue, tracheomalacia, and a history of pulmonary disease were more associated with more severe disease requiring either a higher number of endoscopic procedures or need for open procedures.
• Ahmadian, D., Gleadhill, C. M., Wehbi, N., Bixby, B. A., & Yip, H. T. (2024). Predictors of response to endoscopic management of subglottic/tracheal stenosis in patients without tracheostomy. American journal of otolaryngology, 45(1), 104055.
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  Subglottic and tracheal stenosis (SGTS) in adults is an acquired or idiopathic condition that can lead to dyspnea, and even life-threatening airway obstruction. Endoscopic techniques have advanced and largely eclipsed open surgery, with open surgery now reserved for refractory cases (Hseu et al., 2013; Feinstein et al., 2017). Currently, there is no accepted guideline for the endoscopic treatment of SGTS. Thus, the aim of the present study is to examine the impact of various clinical and pathological characteristics on outcomes to endoscopic treatment in a cohort of SGTS patients.
• Ahmadian, D., Wehbi, N., Tseng, P. K., Bixby, B., & Yip, H. T. (2024). Assessing the interrater and intrarater reliability of subglottic stenosis grading systems. American Journal of Otolaryngology - Head and Neck Medicine and Surgery, 45(Issue 4). doi:10.1016/j.amjoto.2024.104323
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  Background: Subglottic stenosis (SGS) is a condition leading to narrowing of the upper airway which can lead to dyspnea and life-threatening airway obstruction. Although other proposed grading systems exist, the Cotton Myer (CM) and percent stenosis systems are the most widespread in clinical practice. Despite this, the CM system has not yet been validated for visual assessment of SGS. Objective: To determine the interrater and intrarater reliability of the CM grading system among a cohort of physicians who manage patients with SGS. Methods: An online survey created with videos of tracheoscopies from 20 adult patients with subglotticstenosis (SGS) was sent individually to 9 expert physicians from various medical specialties, all of whom managed patients with SGS. Physicians were asked to view the 20 tracheoscopy videos and assess both the percent stenosis and Cotton Myer (CM) grade of each patient. After a period of 4 weeks, the physicians were sent the same survey of the 20 tracheoscopy videos. The interrater and intrarater reliability was calculated using the intraclass correlation coefficient (ICC), a measurement used to evaluate the reliability (the extent to which a measurement can be replicated) of two or more raters measuring the same subject. Results: Overall, CM and percent stenosis systems were found to have an ICC of 0.94 and 0.90 within the domain of interrater reliability, respectively, and ICC of 0.71 and 0.81 within the domain of intrarater reliability, respectively. Conclusion: Our findings suggest that the CM and percent stenosis grading systems remain a valid clinical tool to measure and communicate the severity of airway obstruction in SGS.
• Ahmadian, D., Wehbi, N., Tseng, P., Bixby, B., & Yip, H. T. (2024). Assessing the interrater and intrarater reliability of subglottic stenosis grading systems. American journal of otolaryngology, 45(4), 104323.
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  Subglottic stenosis (SGS) is a condition leading to narrowing of the upper airway which can lead to dyspnea and life-threatening airway obstruction. Although other proposed grading systems exist, the Cotton Myer (CM) and percent stenosis systems are the most widespread in clinical practice. Despite this, the CM system has not yet been validated for visual assessment of SGS.
• Bixby, B., Vrba, L., Lenka, J., Oshiro, M. M., Watts, G. S., Hughes, T., Erickson, H., Chopra, M., Knepler, J. L., Knox, K. S., Jarnagin, L., Alalawi, R., Kala, M., Bernert, R., Routh, J., Roe, D. J., Garland, L. L., Futscher, B. W., & Nelson, M. A. (2024). Cell-free DNA methylation analysis as a marker of malignancy in pleural fluid. Scientific Reports, 14(Issue 1). doi:10.1038/s41598-024-53132-x
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  Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology for the diagnosis of malignant pleural effusion is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. This was a blind, prospective case–control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), indeterminate pleural effusion in subjects with known malignancy or IPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p < 0.0001) and the same tendency was observed relative to IPE (p = 0.004). We also noted that the methylation signal was significantly higher in IPE relative to BPE (p < 0.001). We also assessed the diagnostic efficiency of the Sentinel-MPE test by performing receiver operating characteristic analysis (ROC). For the ROC analysis we combined the malignant and indeterminate pleural effusion groups (n = 76) and compared against the benign group (n = 28). The detection sensitivity and specificity of the Sentinel-MPE test was high (AUC = 0.912). The Sentinel-MPE appears to have better performance characteristics than cytology analysis. However, combining Sentinel-MPE with cytology analysis could be an even more effective approach for the diagnosis of MPE. The Sentinel-MPE test can discriminate between BPE and MPE. The Sentinel-MPE liquid biopsy test can detect aberrant DNA in several different tumor types. The Sentinel-MPE test can be a complementary tool to cytology in the diagnosis of MPE.
• Bixby, B., Vrba, L., Lenka, J., Oshiro, M. M., Watts, G. S., Hughes, T., Erickson, H., Chopra, M., Knepler, J. L., Knox, K. S., Jarnagin, L., Alalawi, R., Kala, M., Bernert, R., Routh, J., Roe, D. J., Garland, L. L., Futscher, B. W., & Nelson, M. A. (2024). Cell-free DNA methylation analysis as a marker of malignancy in pleural fluid. Scientific reports, 14(1), 2939.
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  Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology for the diagnosis of malignant pleural effusion is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), indeterminate pleural effusion in subjects with known malignancy or IPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p 
• Jensen, T. O., Grandits, G. A., Jain, M. K., Murray, T. A., Grund, B., Shaw-Saliba, K., Matthay, M. A., Abassi, M., Ardelt, M., Baker, J. V., Chen, P., Dewar, R. L., Goodman, A. L., Hatlen, T. J., Highbarger, H. C., Holodniy, M., Lallemand, P., Laverdure, S., Leshnower, B. G., , Looney, D., et al. (2024). Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19. The Journal of infectious diseases, 229(3), 671-679.
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  Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood.
• Jensen, T. O., Murray, T. A., Grandits, G. A., Jain, M. K., Grund, B., Shaw-Saliba, K., Matthay, M. A., Abassi, M., Ardelt, M., Baker, J. V., Chen, P., Dewar, R. L., Goodman, A. L., Hatlen, T. J., Highbarger, H. C., Holodniy, M., Lallemand, P., Laverdure, S., Leshnower, B. G., , Looney, D., 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), e559-e569.
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  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.
• Scott, A. M., Bixby, B., & Sam, A. (2024). A Rare Presentation of Disseminated Coccidioidomycosis Requiring Procedural Intervention. Journal of bronchology & interventional pulmonology, 31(1), 82-83.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2023). Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial. The Lancet Respiratory Medicine, 11(9). doi:10.1016/S2213-2600(23)00147-9
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  Background: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. Methods: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2–4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49–76 days, (3) at home and off oxygen for 1–48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. Findings: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46–66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80–1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77–1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94–2·08; p=0·10). Interpretation: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. Funding: National Institutes of Health.
• Bixby, B., Vrba, L., Lenka, J., Oshiro, M., Watts, G. S., Hughes, T., Erickson, H., Chopra, M., Knepler, J. L., Knox, K. S., Jarnagin, L., Alalawi, R., Kala, M., Bernert, R., Routh, J., Roe, D. J., Garland, L. L., Futscher, B. W., & Nelson, M. A. (2023). Cell-Free DNA Methylation Analysis as a Marker of Malignancy in Pleural Fluid. Research square.
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  Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology malignant pleural effusion diagnosis is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion.
• Highland, J., Torrecillas, V., Redding, T., Bixby, B., Iravani, A., Haller, T., Firpo, M., Nouraei, R., & Smith, M. (2023). Optimization of Subglottic View During Flexible Laryngoscopy With Patient Positioning. Otolaryngology - Head and Neck Surgery (United States), 169(Issue 6). doi:10.1002/ohn.419
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  Objective: Determine the ideal head position to optimize visualization of the subglottis using flexible laryngoscopy. Study Design: Prospective cohort study. Setting: Outpatient multidisciplinary airway clinic at a tertiary care center. Methods: Patients presenting to a multidisciplinary airway clinic undergoing nasoendoscopic airway examination were enrolled. Three head positions were utilized to examine the subglottis during laryngoscopy: “sniffing,” chin tuck, and stooping positions. In-office reviewers and blinded clinician participants evaluated views of the airway based on Cormack-Lehane (CL) scale, airway grade (AG), and visual analog scale (VAS). Demographic data were obtained. Statistical analysis compared head positions and demographic data using Student's t test, analysis of variance, and Tukey's post hoc analysis. Results: One hundred patients participated. No statistical differences existed among in-clinic or blinded reviewers for the CL score in any head position (p =.35,.5, respectively). For both AG and VAS, flexed and stooping positions were rated higher than the sniffing positions by both in-clinic and blinded reviewers (p
• Highland, J., Torrecillas, V., Redding, T., Bixby, B., Iravani, A., Haller, T., Firpo, M., Nouraei, R., & Smith, M. (2023). Optimization of Subglottic View During Flexible Laryngoscopy With Patient Positioning. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery, 169(6), 1556-1563.
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  Determine the ideal head position to optimize visualization of the subglottis using flexible laryngoscopy.
• 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. (2023). T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults. GeroScience, 45(3), 1713-1728.
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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.
• Kala, M., Weinkauf, C. C., Bixby, B. A., Nikolich-Žugich, J., Bhattacharya, D., LaFleur, B. J., Mosier, J. M., Parthasarathy, S., Bime, C., Erickson, H. E., Knox, K., Twigg, H. L., Wilson, R. C., Davidson, L., Castaneda, Y., Wong, R., Sonar, S. A., Coplen, C. P., Bhat, R., , Watanabe, M., et al. (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
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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.
• Scott, A. M., Bixby, B., & Sam, A. (2023). A Rare Presentation of Disseminated Coccidioidomycosis Requiring Procedural Intervention. Journal of Bronchology & Interventional Pulmonology, 31(1), 82-83. doi:10.1097/lbr.0000000000000940
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  *Department of Pulmonary and Critical Care Medicine, University of Arizona Tucson, AZ †Department of Pulmonary and Critical Care Medicine, City of Hope, Duarte, CA The patient provided signed consent for his case report and computed tomographic images to be published. Disclosure: There is no conflict of interest or other disclosures.
• 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.
• , A. L., Lundgren, J. D., Grund, B., Barkauskas, C. E., Holland, T. L., Gottlieb, R. L., Sandkovsky, U., Brown, S. M., Knowlton, K. U., Self, W. H., Files, D. C., Jain, M. K., Benfield, T., Bowdish, M. E., Leshnower, B. G., Baker, J. V., Jensen, J. U., Gardner, E. M., Ginde, A. A., , Harris, E. S., et al. (2021). A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. The New England journal of medicine, 384(10), 905-914.
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  LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.
• 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.
• 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(Issue 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.
• Balwan, A., Bixby, B., Grotepas, C., Witt, B. L., Iravani, A., Ansari, S., & Reddy, C. B. (2020). Core needle biopsy with endobronchial ultrasonography: single center experience with 100 cases. Journal of the American Society of Cytopathology, 9(Issue 4). doi:10.1016/j.jasc.2020.04.009
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  Introduction: Adequate sampling by endobronchial ultrasound (EBUS)-transbronchial needle aspiration to meet the demands of precision medicine or histologic evaluation is challenging. There is increasing demand for core biopsy specimens with advances in therapy. Franseen enodoscopic ultrasound needles have shown promising results in gastroenterology application for obtaining core biopsies and same design has recently been extended for pulmonary use. We evaluated Franseen needles with EBUS to assess its utility, safety and ability to provide core biopsy specimens. Materials and Methods: Retrospective analysis of our database at the University of Utah of patients undergoing EBUS with a Franseen needle was performed to ascertain the performance characteristics of this needle in the first 100 patients after its implementation. Medical records were also reviewed to identify any immediate procedure-related complications. Results: One hundred seventy locations were sampled in 100 patients. A total of 152 lymph nodes and 18 masses were sampled. Core biopsies, as per pathology report, were seen in 87% of patients. A clinically concordant pathological diagnosis was established in 97% of patients. Diagnostic yield for granulomatous lymphadenopathy was 95.6% (22 of 23). No patient-related adverse events were noted. Conclusion: The Franseen needle evaluated in this study can safely procure core tissue samples during EBUS bronchoscopy that are adequate for histopathological diagnosis in benign and malignant lesions. Its ability to provide adequate tissue in patients with granulomatous inflammation is encouraging.
• Bixby, B. (2020). Core needle biopsy with endobronchial ultrasonography: single center experience with 100 cases. Journal of the American Society of Cytopathology.
• Bixby, B., Maddock, S. D., Reddy, C., Iravani, A., & Ansari, S. (2020). Acquired esophago-respiratory fistulae in adults. Shangai Chest. doi:10.21037/shc.2019.11.06
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  Esophago-respiratory fistulae (ERF) are an uncommon group of abnormal connections between the esophagus and various locations in the respiratory tract. While rare, they confer significant morbidity and mortality, especially given that the majority of ERF in adults are acquired due to malignancy. As a result, management strategies are often complicated and should be undertaken with consultation between oncology, thoracic surgery, gastroenterology, and interventional pulmonary colleagues. In this review article we discuss the epidemiology, clinical presentations, etiologies, and diagnosis of ERF. We also discuss management strategies, complications related to management, and the differences in management between benign and malignant etiologies with a focus on bronchoscopic interventions.
• 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.
• Bixby, B., Ansari, S., Stringham, J. C., Lee, J., Iravani, A., & Reddy, C. R. (2019). A LIFE-THREATENING PRESENTATION OF A BENIGN ENTITY. Chest. doi:10.1016/j.chest.2019.08.147
• Bixby, B. (2018). Renal replacement therapy in patients with acute respiratory distress syndrome: a single-center retrospective study. International Journal of Nephrology and Renovascular Disease.
• Bixby, B., & Knepler, J. (2018). Medical image of the week: post pneumonectomy syndrome. Southwest Journal of Pulmonary and Critical Care, 16(6), 332-333. doi:10.13175/swjpcc071-18
• Bixby, B., & Knepler, J. L. (2018). Medical Image of the week: postpneumonectomy syndrome.. Southwest Journal of Pulmonary & Critical Care. 2018;16(6): p. 332-3., 16(6), 332-3.. doi:https://doi.org/10.13175/swjpcc071-18
• 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(Issue). 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.
• Peltier, A., Gordon, A. S., Russell, J. W., Sheikh, K., Bixby, B., Howard, J., Goldstein, J., Song, Y., Wang, L., Feldman, E. L., & Robinson, J. S. (2009). Reliability of quantitative sudomotor axon reflex testing and quantitative sensory testing in neuropathy of impaired glucose regulation. Muscle and Nerve, 39(Issue 4). doi:10.1002/mus.21210
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  Reproducible neurophysiologic testing paradigms are critical for multicenter studies of neuropathy associated with impaired glucose regulation (IGR), yet the best methodologies and endpoints remain to be established. This study evaluates the reproducibility of neurophysiologic tests within a multicenter research setting. Twenty-three participants with neuropathy and IGR were recruited from two study sites. The reproducibility of quantitative sudomotor axon reflex test (QSART) and quantitative sensory test (QST) (using the CASE IV system) was determined in a subset of patients at two sessions, and it was calculated from intraclass correlation coefficients (ICCs). QST (cold detection threshold: ICC = 0.80; vibration detection threshold: ICC = 0.75) was more reproducible than QSART (ICC foot = 0.52). The performance of multiple tests in one setting did not improve reproducibility of QST. QST reproducibility in our IGR patients was similar to reports of other studies. QSART reproducibility was significantly lower than QST. In this group of patients, the reproducibility of QSART was unacceptable for use as a secondary endpoint measure in clinical research trials. © 2009 Wiley Periodicals, Inc.
• Singleton, J. R., Bixby, B., Russell, J. W., Feldman, E. L., Peltier, A., Goldstein, J., Howard, J., & Smith, A. G. (2008). The Utah Early Neuropathy Scale: A sensitive clinical scale for early sensory predominant neuropathy. Journal of the Peripheral Nervous System, 13(Issue 3). doi:10.1111/j.1529-8027.2008.00180.x
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  Early neuropathy is often sensory predominant and prominently involves small-diameter nerve fibers. Established neuropathy examination scales such as the Michigan Diabetic Neuropathy Scale (MDNS) and the Neuropathy Impairment Score-Lower Leg (NIS-LL) focus primarily on large-fiber sensory and motor function. Here, we validate the Utah Early Neuropathy Scale (UENS), a physical examination scale specific to early sensory predominant polyneuropathy. Compared with other scales, the UENS emphasizes severity and spatial distribution of pin (sharp) sensation loss in the foot and leg and focuses less on motor weakness. UENS, MDNS, and NIS-LL were compared in 215 diabetic or prediabetic subjects, with (129) or without neuropathy (86), and repeated in 114 neuropathy subjects after 1 year of follow-up. Neuropathy severity was also evaluated with nerve conduction studies, quantitative sensory testing, quantitative sudomotor axonal reflex testing, and intraepidermal nerve fiber density determination. The UENS had a high degree of interrater reliability (interclass correlation of 94%). UENS correlated significantly to MDNS and NIS-LL (p < 0.01), and more significantly than MDNS or NIS-LL to confirmatory tests. In this cohort, UENS had a superior profile to receiver operating characteristic analysis across a range of scores, with a sensitivity (92%) higher than MDNS (67%) or NIS-LL (81%), without sacrificing specificity. UENS more closely correlated with change in ancillary and small-fiber neuropathy measures over 1 year follow-up than did MDNS or NIS-LL. UENS is a sensitive and reproducible clinical measure of sensory and small-fiber nerve injury and may be useful in trials of early neuropathy. © 2008 Peripheral Nerve Society.
• Smith, A. G., Russell, J., Feldman, E. L., Goldstein, J., Peltier, A., Smith, S., Hamwi, J., Pollari, D., Bixby, B., Howard, J., & Singleton, J. R. (2006). Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care, 29(Issue 6). doi:10.2337/dc06-0224
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  OBJECTIVE - The purpose of this study was to evaluate intraepidermal nerve fiber density (IENFD) as a sensitive measure of neuropathy change in patients with neuropathy associated with impaired glucose tolerance (IGT) receiving lifestyle intervention based on that used in the Diabetes Prevention Program. RESEARCH DESIGN AND METHODS - We performed 3-mm skin biopsies with measurement of IENFD at the distal leg and proximal thigh at baseline and after 1 year in 32subjects with IGT. Each received individualized diet and exercise counseling as a standard of care. Nerve conduction studies, quantitative sensory testing, quantitative sudomotor axon reflex testing, and the Michigan Diabetic Neuropathy score were performed, and a visual analog pain scale was completed. Two-hour oral glucose tolerance tests (OGTTs) following the American Diabetes Association guidelines were performed, and serum lipid levels were measured at baseline and 1 year later. RESULTS - Baseline distal IENFD was 0.9 ± 1.2 fibers/mm and proximal IENFD was 4.8 ± 2.3 fibers/mm. Baseline distal IENFD correlated with fasting glucose (P < 0.001) and OGTT (P < 0.01). After 1 year of treatment, there was a 0.3 ± 1.1-fiber/mm improvement in distal IENFD and a 1.4 ± 2.3-fiber/mm improvement in proximal IENFD (P < 0.004). The change in proximal IENFD correlated with decreased neuropathic pain (P < 0.05) and a change in sural sensory amplitude (P < 0.03). CONCLUSIONS - These findings indicate that diet and exercise counseling for IGT results in cutaneous reinnervation and improved pain. Skin biopsy was the most sensitive measure of neuropathy change over 1 year. IENFD should be included as an end point in future neuropathy trials. © 2006 by the American Diabetes Association.

Proceedings Publications

• Jothi, S., Albasha, W., Sarazen, M., Collura, B., & Bixby, B. (2023). A Novel Case of Spontaneous Pulmonary Hematoma and Hemothorax in a Patient With Glanzmann Thrombasthenia. In ATS.
• Kumar, S., & Bixby, B. (2023). When Mold Masks Mesothelioma. In ATS.
• Kumar, S., Aboul-Nasr, A., Williamson, P., & Bixby, B. (2023). Protein in the Alveoli Leads to Mold in the Lung. In ATS.
• Lenka, J., Sharma, N., & Bixby, B. (2023). Pulmonary Lymphomatoid Granulomatosis vs Diffuse Large B-cell Lymphoma (DLBCL): A Diagnostic and Management Dilemma. In ATS.
• Bixby, B., & Upson, S. (2022). The Endobronchial Enigma. In American Thoracic Society.
• Bixby, B., & Upson, S. (2022). The Silent Solitary Fibrous Tumor. In American Thoracic Society.
• Bixby, B., Bixby, B., Sam, A., Sam, A., Scott, A., & Scott, A. (2022). A Rare Presentation of Disseminated Coccidioidomycosis Requiring Mechanical Intervention. In American Thoracic Society.
• Bixby, B., Khemasuwan, D., Shojaee, S., Balwan, A., Sanchez, T., Sorensen, J., & Reddy, C. (2021). Machine Learning Model to Predict Failure of Intrapleural tPA/DNase in Patients with Complicated Parapneumonic Effusions/Empyema: A Multicenter Study. In American Thoracic Society.