Kenneth S Knox

The University of Arizona, Tucson, Arizona, United States

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Publications (70)286.66 Total impact

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    ABSTRACT: Within a coccidioidal endemic region, pulmonary nodules due to coccidioidomycosis are common. Uptake of (18)fluorodeoxyglucose ((18)FDG) by positron emission tomography with computed axial tomography (PET/CT) has been used to assess whether pulmonary nodules are malignant but inflammatory lesions can be positive. The purpose of this study was to compare by PET/CT the (18)FDG uptake in pulmonary nodules likely due to coccidioidomycosis to that of nodules shown to be malignant among patients living in a coccidioidal endemic region. We retrospectively reviewed patients who underwent a PET/CT at the Southern Arizona Veterans Affairs Health Care System between January 2008 and March 2012 who were subsequently found on biopsy to have pulmonary nodules that were coccidioidal or granulomatous or were due to malignancy. Among 245 diagnostic biopsies where the subject had a previous PET/CT, 15 (6.1 %) were either coccidioidal (n = 12) or granulomatous without an identified organism (n = 3). The median maximum standard unit of uptake (SUVmax) on PET/CT of coccidioidal or granulomatous lesions was 2.0 compared to 9.8 for malignant lesions (P < 0.001). The maximum diameter of the coccidioidal or granulomatous nodules was 2.1 cm compared to 3.0 cm for the malignant lesions (P = 0.009). On multivariable analysis, an elevated SUVmax was the only distinguishing feature between the malignant and the granulomatous lesions (OR 1.28, 95 % CI 1.05-1.55; P = 0.013). Coccidioidal pulmonary nodules take up significantly less (18)FDG than those due to malignancies, but there is considerable overlap between granulomatous and malignant lesions at lower SUVmax.
    Beiträge zur Klinik der Tuberkulose 05/2014; · 2.06 Impact Factor
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    ABSTRACT: Coccidioidomycosis is a common cause of community-acquired pneumonia in the southwest United States, Mexico, and South America. The disease has seen a marked increase in incidence in the western United States in the last decade and can be acquired by individuals who travel even briefly through an endemic area, presenting a diagnostic dilemma for clinicians who are not familiar with the disease. The clinical and radiographic manifestations of pulmonary coccidioidomycosis often mimic those of other causes of pneumonia. However, because treatment recommendations and the potential for chronic sequelae of acute infection differ substantially from those for bacterial community-acquired pneumonia, accurate, timely diagnosis of coccidioidomycosis is paramount. A number of diagnostic tests are available with varying sensitivity and specificity, making the approach complex. Radiographic features, although nonspecific, sometimes demonstrate patterns more suggestive of coccidioidomycosis than bacterial community-acquired pneumonias. A routine blood count may reveal eosinophilia. Serologic testing is used most widely but may be negative early in the course of disease, potentially leading to misdiagnosis with subsequent inappropriate treatment and follow-up. The sensitivity of serologic testing is lower in immunocompromised patients, a population at the highest risk for developing severe disease. When clinically appropriate, other biologic specimens, such as sputum, bronchoalveolar lavage fluid, or lung biopsies, may allow for rapid, definitive diagnosis. In light of the significantly increased incidence and complexities in diagnosis of coccidioidomycosis, we examine the diagnostic approach and provide examples of classic clinical and radiographic presentations, discuss the utility of serologic testing, and suggest algorithms that may aid in the diagnosis.
    Annals of the American Thoracic Society. 02/2014; 11(2):243-53.
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    ABSTRACT: Rationale: The ability to determine the respiratory microbiome from bronchoalveolar lavage (BAL) is controversial due to oral contamination during bronchoscopy. To determine if processing BAL improved the ability to distinguish lung from oral wash microbiomes, we compared the oral and lung microbiome from whole and acellular BAL in 34 subjects. Methods: Oral wash samples and bronchoscopy with BAL were performed. After removing an aliquot of whole unprocessed BAL, the remaining was centrifuged at 1,500 rpm for 10 minutes and the supernatant harvested as acellular BAL. DNA was isolated from 2 ml of oral wash and 5 ml of acellular and whole BAL using the Qiagen DNeasy kit (Qiagen, Valencia, CA). DNA encoding 16s ribosomal RNA was amplified using NEB Phusion enzyme (NEB, Ipswich, MA) and degenerate of eubacterial primers that amplify the variable regions 1 through 3. DNA sequencing was performed using 454 sequencing. Results: The amount of genomic DNA isolated from whole BAL was 100-fold higher compared with acellular BAL. Despite this, the number of high-quality genera bacterial reads (RDP classifier > 90%) was identical between the two groups (whole BAL, 4,903 ± 3,209; acellular BAL, 4,245 ± 2,632). Bray-Curtis distances between oral wash and acellular BAL were significantly higher than the distance between whole BAL and oral wash (P = 0.000035), indicating acellular BAL was significantly more different from oral wash compared with whole BAL. Visually, the overlap between oral wash and whole BAL can be seen on the dendogram in Figure 1 (BA = acellular BAL; BW = whole BAL; OR = oral wash). [Figure: see text] Conclusions: The difference between acellular BAL and oral wash is significantly greater than the difference between whole BAL and oral wash. We suggest this represents greater contamination of whole BAL by upper airway organisms. We speculate acellular BAL provides a better representation of the true lower respiratory tract microbiome.
    Annals of the American Thoracic Society. 01/2014; 11(Supplement_1):S72-S73.
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    ABSTRACT: Background. The specific cellular immunological characteristics of bronchoalveolar lavage (BAL) fluid in acute pulmonary coccidioidomycosis have not been defined.Methods. BAL fluid results were compared among patients living in the coccidioidal endemic region undergoing bronchoscopy for pulmonary infiltrates. BAL fluid mononuclear cells and peripheral blood mononuclear cells (PBMC) were incubated with the coccidioidal antigen T27&emsp14;K in vitro and cellular immunological assays performed.Results. Forty-six patients were studied; 12 were diagnosed with acute pulmonary coccidioidomycosis; 17 had other diagnoses; and 17 had no diagnosis established. There was an increased proportion of polyfunctional CD8(+) T cells after antigen stimulation from subjects with coccidioidomycosis compared to those with another diagnosis (P=0.025). In cells collected from BAL and PBMC, the concentration of IFN-γ, TNF-α, and IL-17 were all significantly increased in samples from those with acute pulmonary coccidioidomycosis compared to the two other groups (for all, P<0.05).Conclusions. When incubated in vitro with a coccidioidal antigen preparation, cells from both the BAL and the peripheral blood compartment from patients with pulmonary coccidioidomycosis demonstrated specific cellular immune responses, including IL-17.
    The Journal of Infectious Diseases 06/2013; · 5.85 Impact Factor
  • Homer L Twigg, Kenneth S Knox
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    ABSTRACT: Human immunodeficiency virus (HIV) infection causes profound changes in the lung compartment characterized by macrophage and lymphocyte activation, secretion of proinflammatory cytokines and chemokines, and accumulation of CD8 T cells in the alveolar space, leading to lymphocytic alveolitis. Because many of the changes seen in the lung can be attributed to the direct effect of HIV on immune cells, therapy to reduce the HIV burden should have significant beneficial effects. Indeed, antiretroviral therapy rapidly reduces the viral burden in the lung, number of CD8 T cells in the alveolar space, and amount of proinflammatory cytokines and chemokines in bronchoalveolar lavage.
    Clinics in chest medicine 06/2013; 34(2):155-164. · 2.51 Impact Factor
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    ABSTRACT: RATIONALE: Lung infections caused by opportunistic or virulent pathogens are a principal cause of morbidity and mortality in HIV infection. It is unknown whether HIV infection leads to changes in basal lung microflora, which may contribute to chronic pulmonary complications that increasingly are being recognized in HIV-infected individuals. OBJECTIVES: To determine whether the immunodeficiency associated with HIV infection resulted in alteration of the lung microbiota. METHODS: We used 16S ribosomal RNA targeted pyrosequencing and shotgun metagenomic sequencing to analyze bacterial gene sequences in bronchoalveolar lavage and mouth of 82 HIV-positive and 77 HIV-negative subjects. MEASUREMENTS AND MAIN RESULTS: Sequences representing Tropheryma whipplei, the etiologic agent of Whipple's disease, were significantly more frequent in bronchoalveolar lavage of HIV-positive compared with HIV-negative individuals. T. whipplei dominated the community (>50% of sequence reads) in 11 HIV-positive subjects but only 1 HIV-negative individual (13.4% versus 1.3%; p = 0.0018). In 30 HIV-positive individuals sampled longitudinally, antiretroviral therapy resulted in a significantly reduced relative abundance of T. whipplei in the lung. Shotgun metagenomic sequencing was performed on 8 bronchoalveolar lavage samples dominated by T. whipplei 16S ribosomal RNA. Whole genome assembly of pooled reads showed that uncultured lung-derived T. whipplei had similar gene content to two isolates obtained from subjects with Whipple's disease. CONCLUSIONS: Asymptomatic subjects with HIV infection have unexpected colonization of the lung by T. whipplei, which is reduced by effective antiretroviral therapy and merits further study for a potential pathogenic role in chronic pulmonary complications of HIV infection.
    American Journal of Respiratory and Critical Care Medicine 02/2013; · 11.04 Impact Factor
  • Lancet Respir Med. 01/2013; 1:354-356.
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    ABSTRACT: Indoleamine 2,3 dioxygenase (IDO) plays an important role in immunoregulation as it is involved in downregulating immune responses to infections. We sought to characterize IDO activity in histoplasmosis and to do so, C57Bl6 mice were infected intranasally with Histoplasma capsulatum. After infection, lung and spleen IDO activity was assessed by HPLC and IDO expression by qRT-PCR. The distribution of IDO was determined by immunohistochemical staining. Cytokine levels were measured in lung and spleen homogenates using cytokine bead array. Fungal burden was quantified by culture. Subcutaneous pellets containing methyltryptophane (1-MT) were employed to inhibit IDO in vivo. Histoplasma infection strongly induced functional lung IDO, with activity at its highest at weeks 1 and 2 and then decreased thereafter as the mice cleared the infection. Lung IDO activity positively correlated with the fungal burden (Rho = 0.845), interferon-γ (Rho = 0.839) and tumor necrosis factor-α (Rho = 0.791) levels, P < 0.001. In contrast, spleen IDO activity was not induced despite high infection burden and cytokine levels. IDO expressing cells were predominately located at the ring edge of Histoplasma-induced granulomas. IDO inhibition prior to infection reduced fungal burdens and inflammation in lungs and spleen. Histoplasma preferentially induces lung IDO, as early as one week after infection. IDO appears to modulate the immune response to Histoplasma infection.
    Medical mycology: official publication of the International Society for Human and Animal Mycology 11/2012; · 2.13 Impact Factor
  • Chadi A Hage, Kenneth S Knox, Lawrence J Wheat
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    ABSTRACT: The endemic mycoses are important but often overlooked causes for community acquired pneumonia. Delays in recognition, diagnosis and proper treatment often lead to disastrous outcomes. This topic is not usually discussed in reviews and guidelines addressing the subject of community acquired pneumonia. In this review we discuss the three major endemic mycoses in North America that present as community acquired pneumonias; Coccidioidomycosis, Histoplasmosis and Blastomycosis. We discuss their epidemiology, clinical presentations, methods of diagnosis and current treatment strategies.
    Respiratory medicine 03/2012; 106(6):769-76. · 2.33 Impact Factor
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    ABSTRACT: Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ∼20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.
    PLoS ONE 01/2012; 7(9):e44818. · 3.53 Impact Factor
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    ABSTRACT: Background: Histoplasmosis is a cause of serious infection among patients receiving TNF blocker therapy. The safety of discontinuation of antifungal treatment after a favorable clinical response remains undetermined. Methods: We retrospectively reviewed records of patients diagnosed with histoplasmosis while receiving TNF blocker therapy in 18 centers. Cases had clinical signs and symptoms attributable to fungal infection and at least one of the following: growth of Histoplasma capsulatum from the affected site, histopathologic demonstration of morphologic forms consistent with H. capsulatum, and/or positive urine or serum Histoplasma antigen by means of an enzyme-linked immunoassay. Results: We identified 90 cases during the study period (2000-2010). Mean age was 46 years (range, 9 to 82). 58% were female. 67% were receiving infliximab, 23% adalimumab, and 10% etanercept. 53% had rheumatoid arthritis, 35% inflammatory bowel disease, and 7% psoriasis. Median duration of treatment with TNF blockers prior to diagnosis of histoplasmosis was 17 months. 80% had pulmonary involvement, and 76% disseminated disease. Disease was mild in 27% of cases, moderate in 50%, and severe in 18%. Urine Histoplasma antigen was positive in 88%. Two patients with severe disease died within 4 weeks after diagnosis. Among patients discontinuing biologic therapy, 14 were diagnosed with probable immune reconstitution inflammatory syndrome. Half of the patients received amphotericin B. All patients received azole treatment which was given for a median duration of 12 months. TNF blocker therapy was continued in 5 patients. One of them relapsed. Six patients had urine Histoplasma antigen levels >2 ng/mL at completion of antifungal treatment and none of them relapsed. Overall, relapse occurred in 6/90 (7%) cases. One was on antifungal treatment at the time of relapse. TNF blocker therapy was resumed in 23/85 (27%) cases at a median time of 12 months. For all surviving patients, histoplasmosis was in remission at last follow-up. Conclusion: Patients who develop histoplasmosis while receiving TNF blocker therapy commonly present with disseminated disease. Elevated Histoplasma antigen levels at completion of antifungal treatment do not necessarily portend relapse.
    Infectious Diseases Society of America 2011 Annual Meeting; 10/2011
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    ABSTRACT: The purpose of this review is to describe important findings published during the past 18 months using bronchoalveolar lavage (BAL) for diagnosis of pulmonary mycoses. Clinical studies and meta-analysis have established a high sensitivity and specificity for Aspergillus galactomannan testing of BAL specimens for diagnosis of invasive aspergillosis, superior to that observed with other diagnostic methods. Similar findings have been reported in histoplasmosis and blastomycosis. Fungal antigen testing of BAL specimens is recommended if bronchoscopy is performed for diagnosis of pulmonary infiltrates in patient groups at risk for aspergillosis or the endemic mycoses if the diagnosis cannot be established by evaluation of sputum specimens or detection of antigen in the urine or serum.
    Current opinion in pulmonary medicine 02/2011; 17(3):167-71. · 3.12 Impact Factor
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    ABSTRACT: With increasing numbers of immune-compromised patients with malignancy, hematologic disease, and HIV, as well as those receiving immunosupressive drug regimens for the management of organ transplantation or autoimmune inflammatory conditions, the incidence of fungal infections has dramatically increased over recent years. Definitive diagnosis of pulmonary fungal infections has also been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, polymerase chain reaction, serologies, computed tomography and positron emission tomography scans, bronchoscopy, mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has significantly broadened options available to physicians who treat these conditions. While traditionally antifungal therapy was limited to the use of amphotericin B, flucytosine, and a handful of clinically available azole agents, current pharmacologic treatment options include potent new azole compounds with extended antifungal activity, lipid forms of amphotericin B, and newer antifungal drugs, including the echinocandins. In view of the changing treatment of pulmonary fungal infections, the American Thoracic Society convened a working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections of special concern for immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections.
    American Journal of Respiratory and Critical Care Medicine 01/2011; 183(1):96-128. · 11.04 Impact Factor
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    ABSTRACT: The endemic region of blastomycosis historically has included the state of Indiana. However, few published reports of blastomycosis exist to substantiate this distinction. A surge of patients with blastomycosis in central Indiana (Indianapolis and surrounding counties) beginning in 2005 prompted us to review our local experience. We propose that this surge was related to major highway construction around Indianapolis. We reviewed all microbiologically confirmed cases from four hospitals serving central Indiana. Chart review was completed for adult patients, and data were collected on clinical presentations, methods of diagnosis, comorbidities, radiologic findings, treatment, and outcomes. We plotted patient residence addresses with sites of highway construction. Fifty-nine patients were identified from laboratory results and physician referral. Interestingly, a surge of blastomycosis incidence occurred in 34 patients between 2005 and 2008 during which time major highway projects were under way around the Indianapolis metropolitan area. The majority of these patients presented acutely and with pulmonary involvement. Fungal culture and antigen testing were the most sensitive means to diagnosis. Antifungal therapy was highly effective. This urban outbreak of blastomycosis in Indianapolis should prompt clinicians to consider blastomycosis in this highly endemic area of histoplasmosis.
    Chest 12/2010; 138(6):1377-82. · 7.13 Impact Factor
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    ABSTRACT: The massive depletion of gastrointestinal-tract CD4 T cells is a hallmark of the acute phase of HIV infection. In contrast, the depletion of the lower-respiratory-tract mucosal CD4 T cells as measured in bronchoalveolar lavage (BAL) fluid is more moderate and similar to the depletion of CD4 T cells observed in peripheral blood (PB). To understand better the dynamics of disease pathogenesis and the potential for the reconstitution of CD4 T cells in the lung and PB following the administration of effective antiretroviral therapy, we studied cell-associated viral loads, CD4 T-cell frequencies, and phenotypic and functional profiles of antigen-specific CD4 T cells from BAL fluid and blood before and after the initiation of highly active antiretroviral therapy (HAART). The major findings to emerge were the following: (i) BAL CD4 T cells are not massively depleted or preferentially infected by HIV compared to levels for PB; (ii) BAL CD4 T cells reconstitute after the initiation of HAART, and their infection frequencies decrease; (iii) BAL CD4 T-cell reconstitution appears to occur via the local proliferation of resident BAL CD4 T cells rather than redistribution; and (iv) BAL CD4 T cells are more polyfunctional than CD4 T cells in blood, and their functional profile is relatively unchanged after the initiation of HAART. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might aid in the reconstitution of mucosal CD4 T cells.
    Journal of Virology 09/2010; 84(18):9010-8. · 5.08 Impact Factor
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    Oluwole Onadeko, Kenneth S Knox
    Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine 06/2010; 6(3):297-8. · 2.93 Impact Factor
  • Kenneth S Knox, Chadi A Hage
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    ABSTRACT: Histoplasmosis is the most prevalent endemic fungal infection in North America. The clinical spectrum ranges from asymptomatic, self-limited illness to a life-threatening progressive disseminated disease. Chronic manifestations of healed infection can also be problematic. Clinical presentation depends on the infectious load, underlying immune status, and lung function. The preferred diagnostic methods and treatment options vary with clinical scenario and severity of illness. New diagnostic tools and treatment options are now available in clinical practice. We present an overview of this important endemic mycosis with emphasis on diagnosis and treatment recommendations for the different clinical syndromes of histoplasmosis.
    Proceedings of the American Thoracic Society 05/2010; 7(3):169-72.
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    ABSTRACT: Detection of antigen in BAL is useful for diagnosis of histoplasmosis. The MVista Histoplasma antigen enzyme immunoassay has been modified to permit quantification. The purpose of this study is to compare the sensitivity of the quantitative antigen detection assay with cytopathology and culture of BAL specimens. BAL from patients with histoplasmosis who were evaluated at the Indiana University Medical Center and controls without histoplasmosis were studied. BAL fluid was tested in the quantitative Histoplasma antigen assay. Antigen was detected in the BAL in 93.5% of patients with histoplasmosis, 80% with blastomycosis, and 0% of controls with nonfungal infections. Antigen was detected in the urine of 79% and serum in 65% of patients with histoplasmosis. Cytopathology was positive in 48% and culture in 48% of patients with histoplasmosis, and 40% and 60% of patients with blastomycosis, respectively. Serology was positive in 65%. Combining BAL antigen detection and BAL cytopathology, both methods for rapid diagnosis, the sensitivity was 96.8% in histoplasmosis and 80% in blastomycosis. Detection of antigen in BAL complements antigen detection in serum and urine as an objective diagnostic test for histoplasmosis.
    Chest 10/2009; 137(3):623-8. · 7.13 Impact Factor
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    ABSTRACT: Histoplasmosis may result in a spectrum of complications that require thoracic surgical intervention. We reviewed our 17-year experience in the management of histoplasmosis to determine outcomes as well as gain insight into the distribution of complications requiring surgical intervention. The hospital records of patients who underwent surgical treatment for complications related to histoplasmosis from 1991 to 2008 were reviewed. Based on the predominant presentation, patients were categorized with complications secondary to broncholithiasis, granulomatous disease, or fibrosing mediastinitis. Patients who underwent diagnostic surgery and were found to have histoplasmosis were excluded. Of the 49 patients who underwent surgery for histoplasmosis-related complications, 27 (55%) had granulomatous disease, 13 (27%) had broncholithiasis, and 9 (18%) had fibrosing mediastinitis. The most common clinical presentations were recurrent pneumonia (n = 16) and hemoptysis (n = 13); less common presentations included dysphagia (n = 3) and superior vena cava syndrome (n = 1). Two patients required cardiopulmonary bypass for resection; 1 of these died postoperatively (series mortality 2%). Seven patients (14%) had complications. Relief of symptoms was achieved in all surviving patients. Complications of histoplasmosis requiring thoracic surgical intervention are diverse with pulmonary complications predominating. Although surgically challenging, excellent short- and long-term outcomes may be expected.
    The Annals of thoracic surgery 09/2009; 88(2):399-403. · 3.45 Impact Factor
  • Kenneth S Knox, George A Sarosi
    Clinics in chest medicine 07/2009; 30(2):xi-xii. · 2.51 Impact Factor

Publication Stats

1k Citations
286.66 Total Impact Points

Institutions

  • 2009–2013
    • The University of Arizona
      Tucson, Arizona, United States
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States
  • 2000–2013
    • Indiana University-Purdue University Indianapolis
      • Department of Medicine
      Indianapolis, IN, United States
  • 2006–2010
    • Richard L. Roudebush VA Medical Center
      Indianapolis, Indiana, United States