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1.  Fanconi Syndrome Accompanied by Renal Function Decline with Tenofovir Disoproxil Fumarate: A Prospective, Case-Control Study of Predictors and Resolution in HIV-Infected Patients 
PLoS ONE  2014;9(3):e92717.
The predictors of Fanconi syndrome (FS) accompanied by renal function decline with use of the antiretroviral tenofovir disoproxil fumarate (TDF) have not been assessed. In addition, the natural history of renal recovery from FS after TDF discontinuation is not well-described.
We prospectively enrolled HIV-infected patients receiving TDF with newly identified FS (defined as at least two markers of proximal tubulopathy and either a >25% decline in creatinine clearance (CrCl) from pre-TDF values or a CrCl <60 mL/min in those without a known pre-TDF CrCl) in a multicenter observational study. These case participants were matched 1∶2 to controls; characteristics between the two groups were compared. Case participants with known pre-TDF CrCl values were then followed over 48 weeks to assess renal recovery.
Nineteen cases and 37 controls were enrolled. In multivariable analysis, previous or concurrent use of lopinavir/ritonavir [OR 16.37, 95% CI (2.28, 117.68); P = 0.006] and reduced creatinine clearance prior to initiation of TDF [OR 1.44 for every 5 mL/min reduction, 95% CI (1.09, 1.92); P = 0.012; OR 19.77 for pre-TDF CrCl lower than 83 mL/min, 95% CI (2.24, 174.67); P = 0.007] were significantly associated with FS. Of the 14 cases followed for resolution, 7 (50%) achieved at least partial resolution (defined as recovering CrCl >70% of pre-TDF values) although most participants had full normalization of proximal tubulopathy markers within two months of TDF discontinuation.
FS, defined by specific CrCl decreases and markers of tubulopathy, is more likely in those who have received or are currently receiving concomitant lopinavir/ritonavir or who had lower CrCl prior to TDF initiation. Half of those with protocol-defined FS had CrCl recover to near pre-TDF values during the first year after TDF discontinuation.
PMCID: PMC3961428  PMID: 24651857
2.  Transfer of Intracellular HIV Nef to Endothelium Causes Endothelial Dysfunction 
PLoS ONE  2014;9(3):e91063.
With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef.GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.
PMCID: PMC3946685  PMID: 24608713
3.  Short- and long-term risk of colorectal adenoma recurrence among whites and blacks 
Gastrointestinal endoscopy  2013;77(3):447-454.
It is unclear if the higher burden from colorectal cancer among blacks is due to an increased biological susceptibility.
To determine whether non-Hispanic blacks (blacks) have a higher risk of adenoma recurrence than non-Hispanic whites (whites) after removal of colorectal adenomas.
Secondary analysis of the Polyp Prevention Trial (PPT) data
United States.
1,668 self-identified whites and 153 blacks who completed the 4-year trial. Of these, 688 whites and 55 blacks enrolled in a post-trial passive PPT Continued Follow-up Study (PPT-CFS) and underwent another colonoscopy.
Main outcome measurements
Recurrence and location of adenoma and advanced adenoma by race-ethnicity during the PPT and cumulative recurrence over a mean follow-up of 8.3 years (range 4.9–12.4 years) among PPT-CFS enrollees.
Blacks had a similar risk of any adenoma recurrence (39.2% versus 39.4%; incidence risk ratio (RR) =0.98; 95%CI: 0.80-1.20) and advanced adenoma (8.5% versus 6.4%; RR=1.18; 95%CI: 0.68-2.05) as whites at the end of the PPT. Recurrence risk did not differ by colon subsite.
Among PPT-CFS enrollees, the cumulative recurrence rate was similar for blacks and whites for any adenoma (67.3% versus 67.0%; RR=1.01; 95%CI: 0.84-1.21) and advanced adenoma (14.5% versus 16.9%; RR=1.03; 95%CI: 0.60-1.79).
There were few blacks in the long-term follow-up study
Adenoma and advanced adenoma recurrence did not differ by race. Our study does not support more frequent surveillance colonoscopies for blacks with a personal history of adenoma as an intervention to reduce colorectal cancer disparity.
PMCID: PMC3651852  PMID: 23337636
Adenomatous polyps; race-ethnicity; colonoscopy; health disparity
4.  HIV-1 Coinfection Profoundly Alters Intrahepatic Chemokine but Not Inflammatory Cytokine Profiles in HCV-Infected Subjects 
PLoS ONE  2014;9(2):e86964.
The pathogenesis of accelerated liver damage in subjects coinfected with hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) remains largely unknown. Recent studies suggest that ongoing chronic liver inflammation is responsible for the liver injury in HCV-infected patients. We aimed to determine whether HIV-1 coinfection altered intrahepatic inflammatory profiles in HCV infection, thereby hastening liver damage. We used a real-time RT-PCR-based array to comparatively analyze intrahepatic inflammation gene profiles in liver biopsy specimens from HCV-infected (n = 16), HCV/HIV-1-coinfected (n = 8) and uninfected (n = 8) individuals. We then used human hepatocytes to study the molecular mechanisms underlying alternations of the inflammatory profiles. Compared with uninfected individuals, HCV infection and HCV/HIV-1 coinfection markedly altered expression of 59.5% and 50.0% of 84 inflammation-related genes tested, respectively. Among these genes affected, HCV infection up-regulated the expression of 24 genes and down-regulated the expression of 26 genes, whereas HCV/HIV-1 coinfection up-regulated the expression of 21 genes and down-regulated the expression of 21 genes. Compared with HCV infection, HCV/HIV-1 coinfection did not dramatically affect intrahepatic gene expression profiles of cytokines and their receptors, but profoundly altered expression of several chemokine genes including up-regulation of the CXCR3-associated chemokines. Human hepatocytes produced these chemokines in response to virus-related microbial translocation, viral protein stimulation, and antiviral immune responses.
HIV-1 coinfection profoundly alters intrahepatic chemokine but not cytokine profiles in HCV-infected subjects. The altered chemokines may orchestrate the tissue-specific and cell-selective trafficking of immune cells and autoimmunity to accelerate liver disease in HCV/HIV-1 coinfection.
PMCID: PMC3916319  PMID: 24516541
5.  Measurement of colorectal cancer test use using medical claims data in a safety-net health system 
Optimizing colorectal cancer (CRC) screening requires identification of unscreened individuals, and tracking screening trends. A recent NIH State of the Science Conference, “Enhancing Use and Quality of CRC Screening,” cited a need for more population data sources for measurement of CRC screening, particularly for the medically underserved. Medical claims data (claims data) are created and maintained by many health systems to facilitate billing for services rendered, and may be an efficient resource for identifying unscreened individuals. The aim of our study, conducted at a safety-net health system, was to determine whether CRC test use measured by claims data matches medical chart documentation.
We randomly selected 400 patients from a universe of 20,000 patients previously included in an analysis of CRC test use based on claims data 2002–2006 in Tarrant Co, TX. Claims data were compared with medical chart documentation by estimation of agreement and examination of test use over-/under-documentation.
We found agreement on test use was very good for fecal occult blood testing (κ=0.83, 95% CI:0.75–0.90) and colonoscopy (κ=0.91, 95% CI:0.85–0.96), and fair for sigmoidoscopy (κ=0.39, 95% CI:0.28–0.49). Over- and under-documentation of the two most commonly used CRC tests―colonoscopy and FOBT―were rare.
Use of claims data by health systems to measure CRC test use is a promising alternative to measuring CRC test use with medical chart review, and may be used to identify unscreened patients for screening interventions, and track screening trends over time.
PMCID: PMC3479334  PMID: 22814361
Colorectal Neoplasms; Early Detection of Cancer; Reproducibility of Results; Mass Screening; Medically Underserved Area
6.  Polyps With Advanced Neoplasia Are Smaller in the Right Than in the Left Colon: Implications for Colorectal Cancer Screening 
Background & Aims
Colonoscopy is consistently associated with reduced left-sided, but not right-sided, colorectal cancer (CRC) incidence and mortality. This might be because polyps with advanced pathology are smaller and more easily missed in the right vs left colon. We explored this postulate by evaluating the relationship among size, location, and histology of polyps from a large nationwide sample.
We conducted a cross-sectional study of 233,414 polyps from 142,686 patients (47% women; mean age, 60 years), which were reviewed by Miraca Life Sciences in 2009. We assessed polyp histology, location, and size of largest fragment submitted. We compared size distribution of right vs left polyps with high-grade dysplasia (HGD) or adenocarcinoma as well as any advanced neoplasia.
The average size of right-sided polyps was smaller than that of left-sided polyps with HGD or adenocarcinoma (8.2 vs 12.4 mm, respectively); the same was true for polyps with advanced neoplasia (7.6 vs 11.1 mm, respectively) (P < .001). Most right-sided polyps with HGD, adenocarcinoma, or any advanced neoplasia were ≤9 mm, whereas most left-sided polyps with these findings were >9 mm. Polyps with advanced pathology were 5-fold more likely to be <6 mm in the right vs left colon: odds ratio, 5.27; 95% confidence interval, 4.06–6.82 for HGD or adenocarcinoma; odds ratio, 4.89; 95% confidence interval, 4.34–5.51 for advanced neoplasia.
Polyps with features of HGD, adenocarcinoma, or advanced neoplasia were significantly smaller in the right vs left colon. Strategies to prevent right-sided CRC require more accurate detection of small, advanced polyps.
PMCID: PMC3595198  PMID: 22835574
Colorectal Neoplasms; Epidemiology; Colon Cancer Screening; Early Detection
7.  The effect of patient care order sets on medical resident education: a prospective before-after study 
BMC Medical Education  2013;13:146.
Patient care order sets are increasingly being used to optimize care. While studies have evaluated the impact of order sets on provider performance and patient outcomes, their impact on postgraduate medical trainee knowledge remains unknown. We sought to evaluate the impact of order sets on respirology knowledge, order-writing skills, and self-reported learning.
We conducted a prospective before-after study. Postgraduate trainees completing a Respirology rotation at a quaternary-care hospital 6 months before (no order set period) and 12 months after (order set period) order set introduction. Guideline-based admission order sets with educational prompts detailing recommended management of cystic fibrosis and chronic obstructive pulmonary disease were implemented on the respirology ward. Each resident completed a test before and after the rotation assessing knowledge and order-writing. Residents in the order set period additionally completed a questionnaire regarding the impact of order set use on their learning. Analysis: The primary outcome, the difference between pre and post rotation scores was compared between residents in the no order set period and residents in the order set period, using univariate linear regression. Test validity was assessed with a 2-sample t-test, analysis of variance and Pearson’s correlation coefficient. Self-reported impact of order set use were descriptively analyzed, and written responses were collated and coded.
Investigators consecutively recruited 11 subjects before and 28 subjects after order set implementation. Residents in the order set period had a greater improvement in post-rotation test scores than residents in the no order set period (p = 0.04); after adjustment for baseline scores, this was not significant (p = 0.3). The questionnaire demonstrated excellent convergent, discriminant and construct validity. Residents reported that order sets improved their knowledge and skills and provided a systematic approach to care.
Order sets do not appear to impair resident education, and may impart a benefit. This will require validation in larger studies and across diseases.
PMCID: PMC3829666  PMID: 24195667
Clinical decision support systems; Medical order entry systems; Internship and residency; Medical education; Guideline adherence; Hospital information systems; Patient admission; Clinical competence
8.  Pentoxifylline Reduces Tumor Necrosis Factor-α and HIV-Induced Vascular Endothelial Activation 
AIDS Research and Human Retroviruses  2012;28(10):1207-1215.
Untreated HIV infection is associated with endothelial dysfunction and subsequent cardiovascular disease, likely due to both direct effects of the virus and to indirect effects of systemic inflammation on the vasculature. We have recently shown that treatment with the antiinflammatory agent pentoxifylline (PTX) improved in vivo endothelial function and reduced circulating levels of the inflammatory markers vascular cell adhesion molecule-1 (VCAM-1) and interferon-gamma-induced protein (IP-10) in HIV-infected patients. To delineate the mechanisms underlying this therapeutic effect, we tested whether clinically relevant concentrations of PTX suppress VCAM-1 or IP-10 release in cultivated human lung microvascular endothelial cells. Indeed, we found that tumor necrosis factor (TNF)-α-induced VCAM-1 was reduced with concentrations of PTX in the low nanomolar range, comparable to plasma levels in PTX-treated groups. We also investigated the effect of HIV proteins and found that HIV transactivator of transcription (HIV-Tat) and HIV-envelope-derived recombinant gp120 enhanced TNF-α-induced VCAM-1 gene expression in lung microvascular and coronary macrovascular endothelial cells, respectively. In addition, PTX and a NF-κB-specific inhibitor reduced this enhanced VCAM-1 gene induction in microvascular and macrovascular endothelial cells. These results provide novel insights in how the antiinflammatory agent PTX can directly reduce HIV-associated proinflammatory endothelial activation, which may underlie vascular dysfunction and coronary vascular diseases.
PMCID: PMC3448099  PMID: 22463742
9.  Failure Rates in the Hepatocellular Carcinoma Surveillance Process 
Hepatocellular carcinoma (HCC) surveillance is underutilized among patients with cirrhosis. Understanding which steps in the surveillance process are not being performed is essential for designing effective interventions to improve surveillance rates. Our study's aim was to characterize reasons for failure in the HCC surveillance process among a cohort of cirrhotic patients with HCC. We conducted a retrospective cohort study of cirrhotic patients diagnosed with HCC at a large urban safety-net hospital between 2005–2011. Patients were characterized by receipt of HCC surveillance over a two-year period prior to HCC diagnosis. Among patients without HCC surveillance, we classified reasons for failure into four categories: failure to recognize liver disease, failure to recognize cirrhosis, failure to order surveillance, and failure to complete surveillance despite orders. Univariate and multivariate analyses were performed to identify predictors of failures. We identified 178 patients with HCC, of whom 20% had undergone surveillance. There were multiple points of failure- 20% had unrecognized liver disease, 19% had unrecognized cirrhosis, 38% lacked surveillance orders, and 3% failed to complete surveillance despite orders. Surveillance was more likely among patients seen by hepatologists (OR 6.11, 95%CI 2.5–14.8) and less likely in those with alcohol abuse (OR 0.14, 95%CI 0.03–0.65). Although a retrospective analysis in a safety-net hospital, our data suggest only one in five patients received surveillance prior to HCC diagnosis. There are multiple points of failure in the surveillance process, with the most common being failure to order surveillance in patients with known cirrhosis. Future interventions must target multiple failure points in the surveillance process to be highly effective.
PMCID: PMC3435471  PMID: 22846843
Screening; underutilization; quality of care; liver cancer; cirrhosis
10.  Modestly Increased Use of Colonoscopy When Copayments Are Waived 
Colorectal cancer (CRC) screening with colonoscopy often requires expensive copayments from patients. The 2010 Patient Protection and Affordable Care Act mandated elimination of copayments for CRC screening, including colonoscopy, but little is known about the effects of copayment elimination on use. The University of Texas employee, retiree, and dependent health plan instituted and promoted a waiver of copayments for screening colonoscopies in fiscal year (FY) 2009; we examined the effects of removing cost sharing on colonoscopy use.
We conducted a retrospective cohort study of 59,855 beneficiaries of the University of Texas employee, retiree, and dependent health plan, associated with 16 University of Texas health and nonhealth campuses, ages 50 – 64 years at any point in FYs 2002–2009 (267,191 person-years of follow-up evaluation). The primary outcome was colonoscopy incidence among individuals with no prior colonoscopy. We compared the age- and sex-standardized incidence ratios for colonoscopy in FY 2009 (after the copayment waiver) with the expected incidence for FY 2009, based on secular trends from years before the waiver.
The annual incidence of colonoscopy increased to 9.5% after the copayment was waived, compared with an expected incidence of 8.0% (standardized incidence ratio, 1.18; 95% confidence interval, 1.14 –1.23; P < .001). After adjusting for age, sex, and beneficiary status, the copayment waiver remained significantly associated with greater use of colonoscopy, with an adjusted hazard ratio of 1.19 (95% confidence interval, 1.12–1.26).
Waiving copayments for colonoscopy screening results in a statistically significant, but modest (1.5%), increase in use. Additional strategies beyond removing financial disincentives are needed to increase use of CRC screening.
PMCID: PMC3595312  PMID: 22401903
Colorectal Neoplasm; Cost Sharing; Early Detection; Colon Cancer
11.  Pentoxifylline, Inflammation, and Endothelial Function in HIV-Infected Persons: A Randomized, Placebo-Controlled Trial 
PLoS ONE  2013;8(4):e60852.
Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy.
We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed.
The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [−1.06 (1.45)%] and PTX [−1.93 (3.03)%] groups was not significant (P = 0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [−83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated.
PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population.
Trial Registration NCT00796822
PMCID: PMC3621886  PMID: 23593327
12.  Continuous Furosemide Infusion in the Management of Ascites 
Journal of Investigative Medicine  2012;60(4):671-675.
The current therapy for patients hospitalized with ascites requires titration of oral diuretics and often needs several days. A faster method for predicting the response to a given dose of diuretic may allow this process to be completed more rapidly.
Describe the short-term safety and efficacy of a diuretic infusion to predict net sodium excretion in patients with cirrhosis, ascites and edema using a fractional excretion of sodium (FENa) of ≥1% as the target.
We conducted a retrospective case series of patients admitted for management of ascites who received intravenous furosemide by continuous infusion in ascites management. Patients were stratified depending on whether they had edema, received an intravenous bolus of furosemide or a large-volume paracentesis. The primary outcome was the proportion of patients achieving a FENa of ≥1% during the infusion. Secondary outcomes included development of electrolyte abnormalities or acute kidney injury (AKI) during or immediately following the infusion and natriuresis on titrated oral furosemide.
47 patients meeting criteria were identified from 721 patients seen in consultation. 10 of the patients had edema and received neither bolus intravenous diuretic therapy nor therapeutic paracentesis; all ten achieved a FENa ≥1%. One patient had transient hypokalemia. Of 37 patients who either had no edema or received additional treatment options, all but six patients achieved a FENa of ≥1%. Transient complications in the 31/37 patients with natriuresis included hyponatremia (n = 1), hypokalemia (n = 5) and AKI (n = 3). 24 hour urine sodium averaged > 4 g/d on the titrated oral furosemide regimen in 19 patients completing the collection.
Use of a short continuous furosemide infusion can achieve a FENa ≥ 1% in patients with cirrhotic ascites and may be safe and efficacious for diuresis, meriting further study.
PMCID: PMC3310244  PMID: 22373660
13.  Suppression of HIV-1 replication by antiretroviral therapy improves renal function in persons with low CD4 cell counts and chronic kidney disease 
AIDS (London, England)  2008;22(4):481-487.
To examine the association between changes in glomerular filtration rates (GFR) and antiretroviral therapy (ART)-mediated suppression of plasma HIV-1 viremia.
Observational, prospective, multicenter cohort study.
ART regimens or treatment strategies in HIV-1-infected subjects were implemented through randomized clinical trials; 1776 ambulatory subjects from these trials also enrolled in this cohort study.
The association between suppression of viremia and GFR changes from baseline was examined using the abbreviated Modification of Diet and Renal Disease equation in mixed effects linear models.
GFR improvement was associated with ART-mediated suppression of plasma viremia in subjects with both chronic kidney disease stage ≥2 and low baseline CD4 cell counts (< 200 cells/µl). In this subset, viral suppression (by > 1.0 log10 copies/ml or to < 400 copies/ml) was associated with an average increase in GFR of 9.2 ml/min per 1.73 m2 from baseline (95% confidence interval, 1.6–16.8; P = 0.02) over a median follow-up of 160 weeks. The magnitude of this association increased in subjects who had greater baseline impairment of renal function, and it did not depend on race or sex.
Viral suppression was associated with GFR improvements in those with both low CD4 cell counts and impaired baseline renal function, supporting an independent contribution of HIV-1 replication to chronic renal dysfunction in advanced HIV disease. GFR improvement not associated with viral suppression also was observed in subjects with higher CD4 cell counts.
PMCID: PMC3529361  PMID: 18301060
antiretroviral therapy; chronic kidney disease; HIV-1 viremia; HIV-associated nephropathy
14.  Neither Proteinuria Nor Albuminuria Is Associated With Endothelial Dysfunction in HIV-Infected Patients Without Diabetes or Hypertension 
The Journal of Infectious Diseases  2011;204(12):1946-1950.
It is unknown whether systemic endothelial dysfunction underlies the association between nephropathy and cardiovascular disease (CVD) in persons infected with human immunodeficiency virus (HIV). Spot urine protein to creatinine ratio, spot urine albumin to creatinine ratio, creatinine clearance, estimated glomerular filtration rate, and flow-mediated dilation (FMD) of the brachial artery were evaluated in 123 study participants infected with HIV (58 receiving antiretroviral therapy [ART] and 65 not receiving ART) with no history of diabetes or hypertension. None of the renal markers, modeled as either continuous or categorical variables, correlated with FMD. Contrary to expectations, endothelial dysfunction may not be the link between nephropathy and CVD in HIV.
PMCID: PMC3209818  PMID: 22013226
15.  Novel Approaches to Surfactant Administration 
Surfactant replacement therapy has been the mainstay of treatment for preterm infants with respiratory distress syndrome for more than twenty years. For the most part, surfactant is administered intratracheally, followed by mechanical ventilation. In recent years, the growing interest in noninvasive ventilation has led to novel approaches of administration. This paper will review these techniques and the associated clinical evidence.
PMCID: PMC3518953  PMID: 23243504
16.  Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks 
AIDS Research and Human Retroviruses  2012;28(10):1184-1195.
We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4+ cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, –0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.
PMCID: PMC3448095  PMID: 22352336
17.  Worsening Endothelial Function with Efavirenz Compared to Protease Inhibitors: A 12-Month Prospective Study 
PLoS ONE  2012;7(9):e45716.
Changes in endothelial function, measured as flow-mediated dilation (FMD) of the brachial artery, has not been systematically assessed beyond 6 months of initiation of antiretroviral therapy (ART) when drug-related effects might offset initial improvements with virologic control.
We assessed 6 and 12 month changes in FMD [presented as median (quartile 1, quartile 3)] and circulating HIV and cardiovascular biomarkers in 23 subjects initiating ART.
There were no significant changes in FMD at 6 or 12 months overall despite significant increases in CD4 cell count and HDL-C and reductions in HIV RNA level, MCP-1, IP-10, sVCAM-1, sTNFR2, and sCD14. However, there were significant differences (P = 0.04) in the changes in FMD between those receiving efavirenz [N = 12; −3.50% (−4.90%, 0.68%)] vs. protease inhibitors at 12 months [N = 11; 1.50% (−0.86%, 4.56%)]. The differences in changes in FMD between those receiving and not receiving emtricitabine/tenofovir/efavirenz were more pronounced and were significantly different at both 6 and 12 months (P<0.02 for both). Additional studies showed no significant differences in changes in 25-(OH)-vitamin D, PTH, FGF-23, of F2-isoprostane levels between efavirenz and PI use or between those receiving and not receiving emtricitabine/tenofovir/efavirenz.
Efavirenz use was associated with reduced FMD at 12 months compared to PI-based regimens while emtricitabine/tenofovir/efavirenz was associated with reduced FMD at both 6 and 12 months compared to those not receiving this combination. Long-term effects of antiretrovirals on endothelial function may play an important role in the risk of cardiovascular disease in HIV-infected patients.
PMCID: PMC3447812  PMID: 23029197
18.  Relationship between Microbial Translocation and Endothelial Function in HIV Infected Patients 
PLoS ONE  2012;7(8):e42624.
Circulating levels of microbial products are increased in HIV infection, and provoke endothelial dysfunction in other disease settings.
Methodology/Principal Findings
We examined data from a cross-sectional single site study at Indiana University (Indiana, N = 85) and a 24- week multicenter prospective study of antiretroviral therapy (ART) initiation (ACTG 5152s, N = 75). Brachial artery flow-mediated dilation (FMD) was measured by ultrasound. Plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels were measured from stored specimens and correlated with FMD values using Pearson correlations. The Indiana subjects were 63% male with a mean age of 39 years and a median CD4 count of 406 cells/mm3 (388 not on ART, 464 on ART). The 5152s subjects were 92% were male with a mean age of 35 years and a median CD4 count of 251 cells/mm3 at entry which increased to 396 cells/mm3 on ART. When analyzing the two cohorts individually or in combination neither sCD14 nor LPS correlated significantly with FMD. In a pre-specified subgroup analysis of the Indiana subjects receiving ART (N = 46, mean ART duration 40 months) LPS was inversely correlated with FMD (r = −0.33, p = 0.02), but not sCD14 (r = −0.01, p = 0.9). Multivariate analysis confirmed LPS as an independent predictor of FMD in this subgroup (p = 0.02).
In HIV- infected individuals on prolonged ART, higher LPS levels are associated with worse endothelial function but not in untreated subjects or at 24 weeks after ART initiation. Persistent microbial translocation may contribute to arterial dysfunction and the increased cardiovascular disease risk observed in individuals on long-term ART.
PMCID: PMC3431387  PMID: 22952600
19.  Endothelial, Inflammatory, Coagulation, Metabolic Effects and Safety of Etravirine in HIV-Uninfected Volunteers 
AIDS Patient Care and STDs  2011;25(6):327-331.
The innate proatherosclerotic properties of non-nucleoside reverse transcriptase inhibitors have not previously been examined. Therefore, we performed a pilot study of etravirine (ETR) in healthy volunteers over 28 days. This investigation also allowed us to evaluate the safety of ETR over a period commonly used for HIV postexposure prophylaxis. ETR 200 mg twice daily was given to 28 healthy HIV-uninfected volunteers over 28 days. Flow-mediated dilation (FMD) of the brachial artery and circulating markers of inflammation, coagulation, and metabolism were measured at entry and at day 28. These circulating markers were also measured at day 35. Of the initial 28 subjects, 23 completed both entry and day 28 procedures. Two subjects were discontinued due to development of rash. No other major toxicities developed. The change in FMD over 28 days was minimal and not significant (0.03 [−3.21, 0.97] %; p=0.36). The post hoc estimated detectable absolute change in FMD with the 23 subjects in our study was 2.26%, which is an effect size that has been associated with future cardiovascular event rates in the general population; thus our study had sufficient power to find clinically relevant changes in FMD. In addition, there were no significant changes in any of the circulating markers from entry to day 28 or from day 28 to day 35. ETR did not demonstrate any innate proatherosclerotic properties over 28 days in these HIV-uninfected volunteers. ETR was generally well tolerated. Larger studies are warranted to confirm that ETR can be used safely as part of HIV postexposure prophylaxis regimens.
PMCID: PMC3143389  PMID: 21470045
20.  Rare diseases: Canada’s “research orphans” 
Open Medicine  2012;6(1):e24-e27.
PMCID: PMC3329116  PMID: 22567079
21.  WikiBuild: A New Application to Support Patient and Health Care Professional Involvement in the Development of Patient Support Tools 
Active patient and public involvement as partners in their own health care and in the development of health services is key to achieving a health care system that is responsive to patients’ needs and values. It promotes better use of the health care system, and improves health outcomes, quality of life and patient satisfaction. By involving patients and health care professionals as partners in the creation and updating of patient health support tools, wikis—highly accessible, interactive vehicles of communication—have the potential to empower users to implement these support tools in daily life. Acknowledging the potential of wikis, and recognizing that they capitalize on the free and open access to information, scientists, opinion leaders and patient advocates have suggested that wikis could help decision-making constituencies improve the delivery of health care. They might also decrease its cost and improve access to knowledge within developing countries. However, little is known about the efficacy of wikis in helping to attain these goals. There is also a need to know more about the intention of patients and health care workers to use wikis, in what circumstances and what factors will influence their use of wikis. In this issue of the Journal of Medical Internet Research, Gupta et al describe how they developed and tested a new wiki-inspired application to improve asthma care. The researchers involved patients with asthma, primary care physicians, pulmonologists and certified asthma educators in the construction of an asthma action plan. Their paper—entitled “WikiBuild: a new online collaboration process for multistakeholder tool development and consensus building”—is the first description of a wiki-inspired technology built to involve patients and health care professionals in the development of a patient support tool. This innovative study has made important contributions toward how wikis could be generalized to involve multiple stakeholders in the development of other knowledge translation tools such as clinical practice guidelines or decision aids. More specifically, Gupta et al have uncovered potential action mechanisms toward increasing usage of these tools by patients and health care professionals. These are decreasing hierarchical influences, increasing usability and adapting a tool to local context. More research is now needed to determine if the use of the resulting wiki-developed plan will actually be higher than a plan developed using other methods. Furthermore, there is also a need to assess the intention of participants to continue using wiki-based processes on an ongoing basis. It is in this dynamic and continuous retroaction loop that the support tool users—both patients and health care professionals—can adapt and improve the product after its real-life shortcomings are revealed and as new evidence becomes available. As such, a wiki would be more than a simple patient support development tool, but could also become a dynamic and interactive repository and delivery tool that would facilitate ongoing and sustainable patient and professional engagement.
PMCID: PMC3278100  PMID: 22155746
Medical informatics; patient-centered care; wikis; collaborative writing applications; knowledge translation; patient and public involvement
22.  WikiBuild: A New Online Collaboration Process For Multistakeholder Tool Development and Consensus Building 
Production of media such as patient education tools requires methods that can integrate multiple stakeholder perspectives. Existing consensus techniques are poorly suited to design of visual media, can be expensive and logistically demanding, and are subject to caveats arising from group dynamics such as participant hierarchies.
Our objective was to develop a method that enables multistakeholder tool building while averting these difficulties.
We developed a wiki-inspired method and tested this through the collaborative design of an asthma action plan (AAP). In the development stage, we developed the Web-based tool by (1) establishing AAP content and format options, (2) building a Web-based application capable of representing each content and format permutation, (3) testing this tool among stakeholders, and (4) revising this tool based on stakeholder feedback. In the wiki stage, groups of participants used the revised tool in three separate 1-week “wiki” periods during which each group collaboratively authored an AAP by making multiple online selections.
In the development stage, we recruited 16 participants (9/16 male) (4 pulmonologists, 4 primary care physicians, 3 certified asthma educators, and 5 patients) for system testing. The mean System Usability Scale (SUS) score for the tool used in testing was 72.2 (SD 10.2). In the wiki stage, we recruited 41 participants (15/41 male) (9 pulmonologists, 6 primary care physicians, 5 certified asthma educators, and 21 patients) from diverse locations. The mean SUS score for the revised tool was 75.9 (SD 19.6). Users made 872, 466, and 599 successful changes to the AAP in weeks 1, 2, and 3, respectively. The site was used actively for a mean of 32.0 hours per week, of which 3.1 hours per week (9.7%) constituted synchronous multiuser use (2–4 users at the same time). Participants averaged 23 (SD 33) minutes of login time and made 7.7 (SD 15) changes to the AAP per day. Among participants, 28/35 (80%) were satisfied with the final AAP, and only 3/34 (9%) perceived interstakeholder group hierarchies.
Use of a wiki-inspired method allowed for effective collaborative design of content and format aspects of an AAP while minimizing logistical requirements, maximizing geographical representation, and mitigating hierarchical group dynamics. Our method faced unique software and hardware challenges, and raises certain questions regarding its effect on group functioning. Potential uses of our method are broad, and further studies are required.
PMCID: PMC3278094  PMID: 22155694
Consensus; focus groups; user-computer interface; Web 2.0; asthma; self-care
23.  Microsatellite instability among individuals of Hispanic origin with colorectal cancer 
Cancer  2010;116(21):4965-4972.
Though the presence of microsatellite instability (MSI) in patients with colorectal cancer (CRC) may have implications for prognosis, therapy, and family counseling, MSI prevalence is not well described among individuals of Hispanic origin in the United States (US) with CRC.
We conducted a retrospective cohort study employing a hospital-based tumor registry to identify individuals of Hispanic origin diagnosed with CRC. Clinical data and tumor samples were retrieved. Molecular analyses included testing for MSI using a panel of 5 mononucleotide markers (BAT25, BAT26, NR21, NR24 and NR27) in a pentaplex polymerase chain reaction assay, as well as immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMHS2 on representative tissue.
111 individuals of Hispanic origin with CRC were identified. 41.1% were women, median age was 57 years (IQR:47.1–63.5). 11 (9.8%, 95%CI:4.2–15.6) had MSI CRC, while 14 (14.6%, 95%CI:7.3–21.8) had CRC with≥1 MMR protein abnormality. 10 of 11 individuals with MSI had clinical or molecular characteristics suspicious for Lynch syndrome such as abnormal expression of MSH2 and/or MSH6 (n=7) or age<50 at diagnosis (n=7).
The prevalence of MSI CRC among Hispanic individuals may be similar to other races and ethnicities, but clinical-pathological characteristics, including age at diagnosis and pattern of abnormal MMR protein expression, suggests that sporadic MSI CRC may be less common in individuals of Hispanic origin, and that much MSI observed in this situation may be attributable to Lynch syndrome. Further exploration of the causes of disparate presentations of CRC by ethnicity and race is warranted.
PMCID: PMC2963686  PMID: 20665498
colorectal neoplasms; Hispanic Americans; genomic instability; microsatellite instability; DNA mismatch repair
24.  Relationship of Body Composition, Metabolic Status, Antiretroviral Use, and HIV Disease Factors to Endothelial Dysfunction in HIV-Infected Subjects 
Vascular endothelial dysfunction may contribute to the increase in cardiovascular events during HIV-1 infection and its treatment. Antiretroviral therapy (ART), metabolic factors, lipodystrophy, and HIV infection itself may be involved. Ninety-six HIV-infected subjects were evaluated for endothelial function by measurement of brachial artery flow-mediated dilation (FMD) by ultrasound, single-slice CT of the abdomen and mid-thigh, whole-body dual x-ray absorptiomety (DXA) scans, and metabolic evaluations in a cross-sectional study. The median age was 40 years; 28% were female, 38% black, 3% Hispanic, and 59% white. Forty-nine (51%) were receiving ART, which included a PI in 28 (57%) and was non-PI based in 21 (43%). FMD (±SD) in subjects not on ART was 5.5 ± 4.3%, PI-ART 5.3 ± 3.6%, and non-PI-ART 5.5 ± 4.1% (p = 0.9). Age, race, CD4 cell count, and HIV RNA did not correlate significantly with FMD. Among ART-treated subjects in the lowest tertile of thigh subcutaneous fat area (range 3–31 cm2), FMD was 4.4 ± 3.5% and in the highest tertile (range 67–237 cm2) FMD was 6.8 ± 3.6% (p = 0.07, t-test). However, in multivariate analyses, no body composition measure showed a significant association with FMD for either the group as a whole or in ART-treated subjects. ART use, PI use, CD4 cell count, and HIV RNA levels were not associated with endothelial dysfunction by brachial FMD. A definitive association with measures of adiposity was not detected in multivariate analysis, suggesting that lipoatrophy may not be an important contributor to endothelial dysfunction in HIV-infected individuals on ART.
PMCID: PMC2957631  PMID: 20673142
25.  A Pilot Study to Determine the Impact on Dyslipidemia of Adding Tenofovir to Stable Background Antiretroviral Therapy: ACTG 5206 
AIDS (London, England)  2010;24(11):1781-1784.
Several studies have reported improvements in lipids after antiretroviral therapy (ART) switches to tenofovir disoproxil fumarate (TDF)-containing regimens. We assessed lipid-lowering effects of TDF by adding it to a stable ART regimen in this double-blind, placebo-controlled crossover study. We demonstrated that non-HDL-C, LDL-C and TC improved significantly over TDF vs. placebo treatment in HIV-infected individuals with dyslipidemia. Adding TDF to stable, virologically-suppressive ART regimens improved lipid parameters, supporting a lipid-lowering effect of TDF.
PMCID: PMC2913151  PMID: 20495438
Dyslipidemia; Tenofovir; Complications of Antiretroviral therapy

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