Steven Grinspoon

Harvard University, Cambridge, Massachusetts, United States

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Publications (254)1836.93 Total impact

  • The Lancet HIV 02/2015; 2(2):e52-e63. DOI:10.1016/S2352-3018(14)00032-0
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    ABSTRACT: Some intestinal microbiota-generated metabolites of phosphatidylcholine are recognized to be proatherogenic. As the HIV population is vulnerable to cardiovascular disease and can develop intestinal dysbiosis associated with systemic inflammation, we investigated the novel relationship between microbiota-derived metabolites of phosphatidylcholine and coronary atherosclerosis in HIV. One hundred and fifty-five HIV-infected and 67 non-HIV-infected individuals without known history of cardiovascular disease were previously recruited to assess coronary plaque by computed tomography angiography. In the current study, we evaluate whether serum choline, trimethylamine (TMA), or trimethylamine-N-oxide (TMAO) levels are associated with plaque features. Young, asymptomatic HIV-infected patients (age 47 ± 7 years) demonstrated significantly higher prevalence of plaque (53 vs. 35%, P = 0.01) and number of total plaque segments (1.8 ± 2.5 vs. 1.2 ± 2.2, P = 0.03) when compared with well matched noninfected individuals with similar comorbidities. TMA was significantly associated with calcium score (r = 0.22, P = 0.006), number of total (r = 0.20, P = 0.02) and calcified (r = 0.18, P = 0.03) plaque segments, and calcium plaque volume (r = 0.19, P = 0.02) and mass (r = 0.22, P = 0.009) in the HIV cohort only. In multivariate modeling among HIV-infected patients, TMA remained significantly associated with calcium score (P = 0.008), number of total (P = 0.005) and calcified (P = 0.02) plaque segments, and calcium plaque volume (P = 0.01) and mass (P = 0.007), independent of Framingham risk score. In contrast, there was no association of TMAO to coronary plaque features in either cohort. A link between TMA and atherosclerosis has not previously been established. The current study suggests that TMA may be a nontraditional risk factor related to the number of plaque segments and severity of calcified plaque burden in HIV.
    AIDS (London, England) 01/2015; 29(4). DOI:10.1097/QAD.0000000000000565 · 6.56 Impact Factor
  • Ahmed Tawakol, Steven K Grinspoon
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    ABSTRACT: HIV disease, left inadequately treated, leads to an inexorable decline in immune function resulting in AIDS and ultimately in death from opportunistic infections. However, advances in treatment of HIV have resulted in a dramatic reduction in AIDS-related mortality.1 With the widespread use of highly active antiretroviral therapy (HAART), HIV infection has been transformed to a chronic disease associated with long-term viral suppression but at the cost of an increase in atherothrombotic diseases.2,3 Hence currently there is substantial interest in developing a better understanding of the mechanisms underlying the increased risk of atherothrombosis in HIV disease.While HIV infection is characterized by a decline of peripheral blood CD4+ T cells, a paradoxical chronic immune activation of T cells and monocytes is routinely seen in virally suppressed HIV disease.4-6 Multiple studies in HIV-infected individuals show that this persistently heightened state of immune activation likely contrib ...
    Journal of Nuclear Cardiology 12/2014; 22(2). DOI:10.1007/s12350-014-0044-9 · 2.65 Impact Factor
  • Takara L. Stanley, Steven K. Grinspoon
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    ABSTRACT: Increased visceral adipose tissue (VAT) is associated with reductions in endogenous GH secretion, possibly as a result of hyperinsulinemia, increased circulating free fatty acid, increased somatostatin tone, and reduced ghrelin. Reduced GH may, in turn, further exacerbate visceral fat accumulation because of decreased hormone sensitive lipolysis in this depot. Data from multiple populations demonstrate that both reduced GH and increased VAT appear to contribute independently to dyslipidemia, increased systemic inflammation, and increased cardiovascular risk. The reductions in GH in states of visceral adiposity are characterized by reduced basal and pulsatile GH secretion with intact pulse frequency. Treatment with GH releasing hormone (GHRH) provides a means to reverse these abnormalities, increasing endogenous basal and pulsatile GH secretion without altering pulse frequency. This review describes data from HIV-infected individuals and individuals with general obesity showing that treatment with GHRH significantly reduces visceral fat, ameliorates dyslipidemia, and reduces markers of cardiovascular risk. Further research is needed regarding long term efficacy and safety of this treatment modality.
    Growth Hormone & IGF Research 12/2014; 25(2). DOI:10.1016/j.ghir.2014.12.005 · 1.33 Impact Factor
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    ABSTRACT: Human immunodeficiency virus (HIV) infection is associated with increased risk of myocardial infarction (MI). The use of aspirin for primary and secondary MI prevention in HIV infection has not been extensively studied. We performed a cross-sectional study of 4037 patients infected with HIV and 36 338 demographics-matched control patients in the Partners HealthCare System HIV cohort. We developed an algorithm to ascertain rates of nonepisodic acetylsalicylic acid (ASA) use using medication and electronic health record free text data. We assessed rates of ASA use among HIV-infected and HIV-uninfected (negative) patients with and without coronary heart disease (CHD). Rates of ASA use were lower among HIV-infected compared with HIV-uninfected patients (12.4% vs 15.3%, P < .001), with a relatively greater difference among patients with ≥2 CHD risk factors (22.1% vs 42.4%, P < .001). This finding was present among men and among patients in the 30-39 and 40-49 age groups. Among patients with prevalent CHD using ASA for secondary prevention, rates of ASA use were also lower among HIV-infected patients compared with HIV-uninfected patients (51.6% vs 65.4%, P < .001). Rates of ASA use were lower among HIV-infected patients compared with controls, with a greater relative difference among those with elevated CHD risk and those with known CHD. Further studies are needed to investigate the optimal strategies for ASA use among patients infected with HIV.
    12/2014; 1(3):ofu076. DOI:10.1093/ofid/ofu076
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    ABSTRACT: Individuals infected with human immunodeficiency virus (HIV) have decreased high-density lipoprotein (HDL)-cholesterol and increased cardiovascular disease (CVD). Reverse cholesterol transport from macrophages may be inhibited by HIV and contribute to increased CVD. Human studies have not investigated longitudinal effects of HIV and antiretroviral therapy (ART) on cholesterol efflux. Subjects with acute HIV infection were randomized to ART or not. Cholesterol efflux capacity was determined ex vivo after exposure of murine macrophages to apolipoprotein B-depleted patient sera obtained at baseline and after 12 weeks. After 12 weeks, HIV RNA decreased most in subjects randomized to ART. Available data on cholesterol demonstrated that efflux capacity from Abca1(+/+) macrophages was increased most by sera obtained from ART-treated subjects (20.5% ± 5.0% to 24.3 % ± 6.9%, baseline to 12 weeks, P = .007; ART group [n = 6] vs 18.0 % ± 3.9% to 19.1 % ± 2.9%, baseline to 12 weeks, P = .30; untreated group [n = 6] [P = .04 ART vs untreated group]). Change in HIV RNA was negatively associated with change in Abca1(+/+) macrophage cholesterol efflux (r = - 0.62, P = .03), and this finding remained significant (P = .03) after controlling for changes in HDL-cholesterol, CD4(+) cells, and markers of monocyte or macrophage activation. In subjects acutely infected with HIV, ATP-binding cassette transporter A1-mediated cholesterol efflux was stimulated to a greater degree over time by apolipoprotein B-depleted serum from subjects randomized to ART. The improvement in cholesterol efflux capacity is independently related to reduction in viral load.
    12/2014; 1(3):ofu108. DOI:10.1093/ofid/ofu108
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    ABSTRACT: The lives of individuals infected with HIV who have access to combination antiretroviral therapy (cART) are substantially prolonged, which increases the risk of developing non-AIDS comorbidities, including coronary heart disease (CHD). In Europe and the USA, individuals with HIV infection have a ∼1.5-fold increased risk of myocardial infarction relative to uninfected individuals. In Africa, the relative risk of myocardial infarction is unknown, but broadened access to life-extending cART suggests that rates of CHD will rise in this and other resource-constrained regions. Atherogenesis in HIV is affected by complex interactions between traditional and immune risk factors. cART has varied, regimen-specific effects on metabolic risk factors. Overall, cART seems to lessen proatherogenic immune activation, but does not eliminate it even in patients in whom viraemia is suppressed. Current strategies to decrease the risk of CHD in individuals infected with HIV include early initiation of cART regimens with the fewest metabolic adverse effects, and careful management of traditional CHD risk factors throughout treatment. Future strategies to prevent CHD in patients with HIV infection might involve the use of HIV-tailored CHD risk-prediction paradigms and the administration of therapies alongside cART that will further decrease proatherogenic HIV-specific immune activation.
    Nature Reviews Cardiology 10/2014; DOI:10.1038/nrcardio.2014.167 · 10.15 Impact Factor
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    ABSTRACT: To compare rates of intracerebral hemorrhage (ICH) in HIV-infected and uninfected individuals in a large clinical care cohort and to assess risk factors associated with ICH.
    Neurology 10/2014; 83(19). DOI:10.1212/WNL.0000000000000958 · 8.30 Impact Factor
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    ABSTRACT: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines are being applied to HIV-infected patients but have not been validated in this at-risk population, which is known to have a high prevalence of subclinical high-risk morphology (HRM) coronary atherosclerotic plaque.
    AIDS (London, England) 09/2014; 28(14):2061-2070. DOI:10.1097/QAD.0000000000000360 · 6.56 Impact Factor
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    ABSTRACT: Telomere length (TL) and immune activation markers were measured in a cohort of HIV-infected (n=102) and age-matched non-HIV-infected (n=41) men. TL was significantly shorter in HIV-infected compared to non-HIV-infected subjects (P = 0.04). Univariate analysis revealed a strong inverse relationship of TL to sCD163, and thus, monocyte/macrophage activation, among the HIV group (ρ = -0.30, P = 0.003). In multivariate modeling among the whole group, HIV positive serostatus (P = 0.06) and sCD163 (P = 0.05) were independent predictors of TL controlling for age and smoking status. Our data demonstrate that increased immune activation relates to shorter TL in HIV.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 09/2014; DOI:10.1097/QAI.0000000000000329 · 4.39 Impact Factor
  • Steven K Grinspoon
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    ABSTRACT: A new paradigm for atherogenesis in HIV infection is emerging, in which viral replication and microbial translocation result in ongoing T-cell and monocyte activation, with persistent inflammation leading to the development of atypical, high-risk morphology plaques. These plaques, characterized by low attenuation and positive remodeling, can be found even among HIV-infected patients who are at low risk for cardiovascular disease based on traditional risk factors. Prevention of cardiovascular events in HIV infection requires modulation of traditional risk factors and is also likely to require effective antiinflammatory treatment strategies. Statins, which are traditionally used to treat dyslipidemia, have also been shown to exert antiinflammatory effects associated with clinical benefit and may be useful to treat and prevent cardiovascular disease in HIV-infected patients. However, large-scale studies of statins in the context of HIV infection must be conducted. This article summarizes a presentation by Steven K. Grinspoon, MD, at the IAS-USA continuing education program held in Chicago, Illinois, in May 2014.
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    ABSTRACT: Objective Few studies have investigated irisin and FGF21 to elucidate the role of these hormones to regulate “beiging” in HIV-infected patients.Design50 HIV-infected subjects with the metabolic syndrome were previously recruited and randomized to receive lifestyle modification(LSM) and/or metformin over 12 months. In the current study, we assessed FGF21 and irisin at baseline and after intervention. In addition, we assessed circulating FGF21 and irisin in relationship to brown adipose tissue(BAT) gene expression in dorsocervical subcutaneous fat biopsies from 13 HIV-infected subjects.ResultsAt baseline, prior to intervention, HIV-infected subjects demonstrated increased log FGF21 (2.13±0.06 vs. 1.98±0.05 pg/mL, P=0.05) and log irisin (0.33±0.02 vs. 0.17±0.04 μg/mL, P=0.003) compared to healthy controls well-matched based on waist circumference. After 12 months, HIV-infected subjects randomized to LSM demonstrated a relative reduction in FGF21 compared to those not randomized to LSM (-10[-35,22]) vs. 40[0,94] %change, P=0.01). Changes in FGF21 were inversely associated with improved parameters of energy homeostasis, including increased REE (ρ=-0.34, P=0.046) and max VO2 (ρ=-0.38, P=0.02), and reduced RQ (ρ=0.40, P=0.02) among all HIV-infected subjects. Increased UCP-1 (r=0.75, P=0.003), DIO2 (r=0.58, P=0.04), and CideA(r=0.73, P=0.01) gene expression in dorsocervical fat was significantly associated with FGF21 in HIV-infected subjects.ConclusionHIV-infected subjects with metabolic complications demonstrate increases in FGF21 in relationship to BAT gene expression. Relative reductions in FGF21 in those receiving long-term LSM relate to overall improvements in energy expenditure parameters. In contrast, irisin levels are elevated in HIV-infected subjects, but are not influenced by LSM nor associated with BAT gene expression.This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 08/2014; 82(5). DOI:10.1111/cen.12582 · 3.35 Impact Factor
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    ABSTRACT: Among patients infected with human immunodeficiency virus (HIV), visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analog, specifically targets visceral fat reduction but its effects on liver fat are unknown.
    JAMA The Journal of the American Medical Association 07/2014; 312(4):380-9. DOI:10.1001/jama.2014.8334 · 30.39 Impact Factor
  • Steven Grinspoon
    AIDS (London, England) 07/2014; 28(11):1679-1681. DOI:10.1097/QAD.0000000000000117 · 6.56 Impact Factor
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    ABSTRACT: miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and "whitening" of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte-like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.
    Journal of Clinical Investigation 07/2014; 124(8). DOI:10.1172/JCI73468 · 13.77 Impact Factor
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    ABSTRACT: Mechanisms predisposing HIV-infected patients to increased cardiovascular disease (CVD) risk remain unclear. To determine the interrelationship between arterial inflammation and high-risk coronary plaque morphology in HIV-infected patients with subclinical coronary atherosclerosis. Forty-one HIV-infected patients on stable antiretroviral therapy without known CVD but with atherosclerotic plaque on coronary CT angiography were evaluated with F-FDG-PET. Patients were stratified into 2 groups based on relative degree of arterial inflammation [aortic target-to-background ratio (TBR)]. High-risk coronary atherosclerotic plaque morphology features were compared between groups. HIV-infected patients with higher and lower TBRs were similar with respect to traditional CVD risk parameters. Among HIV-infected patients with higher TBR, an increased percentage of patients demonstrated at least 1 low-attenuation coronary atherosclerotic plaque (40% vs. 10%, P = 0.02) and at least 1 coronary atherosclerotic plaque with both low attenuation and positive remodeling (35% vs. 10%, P = 0.04). Moreover, in the higher TBR group, both the number of low-attenuation plaques per patient (P = 0.02) and the number of vulnerability features in the most vulnerable plaque (P = 0.02) were increased. TBR grouping remained significantly related to the number of low-attenuation plaques/subject (β = 0.35, P = 0.004), controlling for age, gender, low-density lipoprotein, duration of HIV, and CD4. These data demonstrate a relationship between arterial inflammation on F-FDG-PET and high-risk coronary atherosclerotic plaque features among HIV-infected patients with subclinical coronary atherosclerosis. Further studies are needed to determine whether arterial inflammation and related high-risk coronary morphology increase the risk of clinical CVD events in the HIV population.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 06/2014; 66(2):164-71. DOI:10.1097/QAI.0000000000000138 · 4.39 Impact Factor
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    ABSTRACT: HIV is associated with atherosclerosis and low HDL. With inflammation, HDL becomes dysfunctional. We previously showed that pro-inflammatory HDL has high HDL redox activity (HRA). In this study, we: 1) compare HRA in HIV-infected versus non-HIV-infected subjects and 2) relate HRA to indices of macrophage activation and cardiovascular disease risk. 102 HIV-infected subjects and 41 matched non-HIV controls without clinical cardiovascular disease underwent coronary CT angiography (CTA) and testing for immune/inflammatory biomarkers. The effect of purified HDL from each study subject on the oxidation rate of dihydrorhodamine-123(DOR) was normalized to the DOR of pooled HDL from healthy subjects. The normalized ratio DORsubject/DORpooled (nHRA) was used as a measure of HRA, with higher HRA suggesting dysfunctional HDL. HRA was higher in HIV-infected versus non-HIV subjects (1.4±0.01 versus 1.3±0.01, p=0.03). In multivariate modeling for HRA among all subjects, HIV status remained positively related to HRA (p=0.02), even after controlling for traditional cardiovascular risk factors, comorbid conditions, and immune activation. Among HIV-infected subjects, HRA correlated inversely with HDL (rho=-0.32, p=0.002) and log adiponectin (r=-0.28, p=0.006) and correlated positively with log sCD163 (r=0.24, p=0.02) - a monocyte/macrophage activation marker - and with percent non-calcified coronary atherosclerotic plaque (r=0.29, p=0.03). sCD163 remained significantly associated with HRA in multivariate modeling among HIV-infected subjects (p=0.03). These data demonstrate increased HRA among HIV-infected subjects versus matched non-HIV subjects with comparable HDL levels. In HIV-infected subjects, HRA relates to macrophage activation and to non-calcified coronary atherosclerotic plaque, which may be rupture prone. Further studies are needed in HIV-infected patients to elucidate the interplay between immune activation, HDL function, and CVD risk.
    Antiviral therapy 02/2014; 19(8). DOI:10.3851/IMP2756 · 3.14 Impact Factor
  • Suman Srinivasa, Steven Grinspoon
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    ABSTRACT: In the absence of a cure, HIV-infected patients are being successfully treated with antiretroviral therapies (ART) and living longer. Indeed, an increasing number of HIV-infected patients are living beyond the age of 50, and in that regard, the use of ART has transformed HIV to a chronic medical condition. As more HIV-infected patients are virologically controlled and living longer, the trajectory of disease morbidity has shifted, however, primarily from opportunistic infections and immune dysfunction to metabolic complications. Evidence suggests that HIV-infected patients acquire significant metabolic risks, including lipodystrophic changes, subclinical atherosclerosis, and insulin resistance. The etiology of these metabolic complications specifically in HIV-infected patients is not entirely clear, but may be related to a complex interaction between long term consequences of infection and HIV itself, chronic use of antiretrovirals, and underlying inflammatory processes. Previous classes of ART, such as protease inhibitors and reverse transcriptase inhibitors, have been implicated in altering fat redistribution and lipid and glucose homeostasis. Advances in drug development have introduced newer ART with strategies to target novel mechanisms of action and improve patient adherence with multi-class drug combinations. In this review, we will focus on these newer classes of ART, including selected entry inhibitors, integrase inhibitors, and multi-class drug combinations, and two newer protease inhibitors, and the potential of these newer agents to cause metabolic complications in HIV-infected patients. Taken together, further reduction of morbidity in HIV-infected patients will require increasing awareness of the deleterious metabolic complications of ART with subsequent management to mitigate these risks.
    European Journal of Endocrinology 02/2014; DOI:10.1530/EJE-13-0967 · 3.69 Impact Factor
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    ABSTRACT: Background. Human immunodeficiency virus (HIV)-1 elite controllers (ECs) represent an ideal population to study the effects of HIV persistence on chronic inflammation in the absence of antiretroviral therapy (ART). Methods. Twenty inflammatory markers measured in cohorts of ECs, HIV suppressed noncontrollers, and HIV-uninfected controls were compared using rank-based tests and partial least squares discriminant analysis (PLSDA). Spearman correlations were determined among the inflammatory markers, residual viremia by the single-copy assay, and CD4(+) T cell slope. Results. Significant differences were seen between cohorts in 15 of the soluble inflammatory markers. Human immunodeficiency virus-1 ECs were found to have the highest levels for all of the markers with the exception of RANTES. In particular, median levels of 7 inflammatory markers (soluble CD14 [sCD14], interferon [IFN]-γ, IFN-γ-inducible protein [IP]-10, interleukin [IL]-4, IL-10, sCD40L, and granulocyte-macrophage colony-stimulating factor) were twice as high in the HIV-1 ECs compared with either of the HIV-suppressed or uninfected groups. Multivariate PLSDA analysis of inflammatory markers improved differentiation between the patient cohorts, discerning gender differences in inflammatory profile amongst individuals on suppressive ART. Soluble markers of inflammation in ECs were not associated with either levels of residual HIV-1 viremia or CD4(+) T cell decline. Conclusions. Despite maintaining relatively low levels of viremia, HIV-1 ECs had elevated levels of a set of key inflammatory markers. Additional studies are needed to determine whether ECs may benefit from ART and to further evaluate the observed gender differences.
    01/2014; 2(1):ofu117-ofu117. DOI:10.1093/ofid/ofu117

Publication Stats

12k Citations
1,836.93 Total Impact Points

Institutions

  • 1995–2014
    • Harvard University
      Cambridge, Massachusetts, United States
    • Massachusetts General Hospital
      • • Division of Infectious Diseases
      • • Neuroendocrine Unit
      Boston, Massachusetts, United States
  • 1970–2014
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Radiology
      Boston, Massachusetts, United States
  • 2002–2013
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
    • University of Massachusetts Medical School
      • Department of Pediatrics
      Worcester, MA, United States
  • 2011
    • Chestnut Hill College
      Boston, Massachusetts, United States
  • 1992–2008
    • Columbia University
      • • Department of Epidemiology
      • • Department of Medicine
      New York City, NY, United States
  • 2007
    • McGill University Health Centre
      Montréal, Quebec, Canada
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
    • Indiana University-Purdue University Indianapolis
      • Division of Infectious Diseases
      Indianapolis, IN, United States
  • 2006
    • Emory University
      Atlanta, Georgia, United States
  • 2005
    • U.S. Food and Drug Administration
      Washington, Washington, D.C., United States
  • 1996–2005
    • Boston University
      Boston, Massachusetts, United States
    • Eli Lilly
      Indianapolis, Indiana, United States
  • 2004
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 2003
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, California, United States