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1.  Effects of Switching from Efavirenz to Raltegravir on Endothelial Function, Bone Mineral Metabolism, Inflammation, and Renal Function: A Randomized, Controlled Trial 
We performed a randomized, controlled trial in 30 HIV-infected participants to either continue tenofovir/emtricitabine/efavirenz (Continuation Group) or switch to tenofovir/emtricitabine/raltegravir (Switch Group) for 24 weeks. There were no significant differences in the changes in flow-mediated dilation, 25(OH)vitamin D, or parathyroid hormone levels. Total cholesterol, high sensitivity C-reactive protein, serum alkaline phosphatase, sCD14 levels, and renal function significantly declined in the Switch Group compared to the Continuation Group; however, sCD163 levels significantly increased in the Switch Group. These findings suggest that raltegravir is not inherently more beneficial to endothelial function compared to efavirenz but may impact renal function and monocyte activation.
PMCID: PMC4091630  PMID: 24278992
Efavirenz; raltegravir; endothelial function; vitamin D; monocyte activation; renal function
2.  Development of a web-based, work-related asthma educational tool for patients with asthma 
Asthma is a common chronic condition. Work-related asthma (WRA) has a large socioeconomic impact and is increasing in prevalence but remains under-recognized. Although international guidelines recommend patient education, no widely available educational tool exists.
To develop a WRA educational website for adults with asthma.
An evidence-based database for website content was developed, which applied evidence-based website design principles to create a website prototype. This was subsequently tested and serially revised according to patient feedback in three moderated phases (one focus group and two interview phases), followed by face validation by asthma educators.
Patients (n=10) were 20 to 28 years of age; seven (70%) were female, three (30%) were in university, two (20%) were in college and five (50%) were currently employed. Key format preferences included: well-spaced, bulleted text; movies (as opposed to animations); photos (as opposed to cartoons); an explicit listing of website aims on the home page; and an exploding tab structure. Participants disliked integrated games and knowledge quizzes. Desired informational content included a list of triggers, prevention/control methods, currently available tools and resources, a self-test for WRA, real-life scenario presentations, compensation information, information for colleagues on how to react during an asthma attack and a WRA discussion forum.
The website met the perceived needs of young asthmatic patients. This resource could be disseminated widely and should be tested for its effects on patient behaviour, including job choice, workplace irritant/allergen avoidance and/or protective equipment, asthma medication use and physician prompting for management of WRA symptoms.
PMCID: PMC3917815  PMID: 24137573
Asthma; Education; e-Health; Occupational asthma; Work-exacerbated asthma; Work-related asthma
3.  Substantial Effect of Efavirenz Monotherapy on Bilirubin Levels in Healthy Volunteers 
Efavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs.
To explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers.
Men and women (aged 18–49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported.
Data from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin.
Efavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its well-documented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. identifier: NCT00668395.
PMCID: PMC4209507  PMID: 25352936
anemia; bilirubin disposition; drug interactions; efavirenz; monotherapy; neutropenia
4.  The Role of 18 FDG PET-CT in Evaluation of Unknown Primary Tumours 
An unknown primary tumor (UPT) is defined as a biopsy-proven malignancy whose anatomic origin remains unidentified after diagnostic evaluation. The estimated incidence of unknown primary tumors is 2 %–7 % of all malignancies. In 15–25 % of cases, the primary site cannot be identified even on postmortem examination. The management of these patients remains a clinical challenge. The aim of this study was to determine the role of 18FDG-PET CT in evaluation of primary tumor and its influence on therapeutic management. Fifty patients with histologically-proven metastases of UPT were included. For all patients, the conventional diagnostic work-up was unsuccessful in localizing the primary site. Whole-body PET/CT images were obtained approximately 60 min after intravenous injection of 350–425 MBq of (18) F-FDG. PET/(CT) depicted histologically verified primary tumors in 21of 46 patients (P > .05), achieving detection rates of approx. 61 % in patients presenting with cervical lymph node metastases from unknown primary tumors, and 40 % in those with extra cervical disease presentation. A positive predictive value of 72 % to 92 % was seen for all patients, depending on category of clinical presentation. In this study, PET/CT detection of additional metastases in 14.2 % (3 cases out of 21 true positives) influenced change in management plan. Considering recent studies and the results of this study, whole body FDG-PET/CT has to be considered a useful tool in evaluating metastases from an UPT, allowing an identification of primary tumors in 42 %, and modifying the stage of the disease and oncological treatment in about 50 % of cases. These results suggest the use of PET/CT with FDG in an early phase of the diagnostic evaluation to optimize the management of these patients.
PMCID: PMC3771057  PMID: 24426729
Unknown primary tumour; PET/CT
6.  Introducing the Canadian Thoracic Society Framework for Guideline Dissemination and Implementation, with Concurrent Evaluation 
The Canadian Thoracic Society (CTS) is leveraging its strengths in guideline production to enable respiratory guideline implementation in Canada. The authors describe the new CTS Framework for Guideline Dissemination and Implementation, with Concurrent Evaluation, which has three spheres of action: guideline production, implementation infrastructure and knowledge translation (KT) methodological support. The Canadian Institutes of Health Research ‘Knowledge-to-Action’ process was adopted as the model of choice for conceptualizing KT interventions. Within the framework, new evidence for formatting guideline recommendations to enhance the intrinsic implementability of future guidelines were applied. Clinical assemblies will consider implementability early in the guideline production cycle when selecting clinical questions, and new practice guidelines will include a section dedicated to KT. The framework describes the development of a web-based repository and communication forum to inventory existing KT resources and to facilitate collaboration and communication among implementation stakeholders through an online discussion board. A national forum for presentation and peer-review of proposed KT projects is described. The framework outlines expert methodological support for KT planning, development and evaluation including a practical guide for implementers and a novel ‘Clinical Assembly – KT Action Team’, and in-kind logistical support and assistance in securing peer-reviewed funding.
PMCID: PMC3956335  PMID: 23936883
Implementation; Guidelines; Knowledge translation
7.  Major care gaps in asthma, sleep and chronic obstructive pulmonary disease: A road map for knowledge translation 
Large gaps between best evidence-based care and actual clinical practice exist in respiratory medicine, and carry a significant health burden. The authors reviewed two key care gaps in each of asthma, chronic obstructive pulmonary disease and obstructive sleep apnea. Using the ‘Knowledge-to-Action Framework’, the nature of each gap, its magnitude, the barriers that cause and perpetuate it, and past and future strategies that might address the problem were considered. In asthma: disease control is ascertained inadequately, leading to a prevalence of poor asthma control of approximately 50%; and asthma action plans, a key component of asthma management, are provided by only 22% of physicians. In obstructive sleep apnea: disease is under-recognized, with sleep histories ascertained in only 10% of patients; and Canadian polysomnography wait times remain longer than recommended, leading to unnecessary morbidity and societal cost. In chronic obstructive pulmonary disease: a large proportion of patients seen in primary care remain undiagnosed, mainly due to underuse of spirometry; and <10% of patients are referred for pulmonary rehabilitation, despite strong evidence demonstrating its cost effectiveness. Given the prevalence of these chronic conditions and the size and nature of these gaps, the latter exact an important toll on patients, the health care system and society. In turn, complex barriers at the patient, provider and health care system levels contribute to each gap. There have been few previous attempts to bridge these gaps. Innovative and multifaceted implementation approaches are needed and have the potential to make a large impact on Canadian respiratory health.
PMCID: PMC3956336  PMID: 23936884
Asthma; Chronic obstructive lung disease; Guidelines; Implementation; Knowledge translation; Obstructive sleep apnea
8.  Asthma and chronic obstructive pulmonary disease guideline implementation: Lessons learned on recruitment of primary care physicians to a knowledge translation study 
Implementation of current clinical practice guidelines in asthma and chronic obstructive pulmonary disease (COPD) is suboptimal. New implementation strategies should be developed and evaluated.
The authors report the rationale and planned methods of a project that sought to use a multifaceted knowledge translation intervention consisting of interactive education, mentorship through quality circles and practice-based tools in primary care to address key asthma and COPD care gaps. The present study was aborted due to inadequate primary care physician recruitment. Accordingly, the authors provide a critical review of their recruitment strategies and discuss alternative approaches and examples based on previous literature.
These practical lessons and discussion seek to inform researchers involved in designing and recruiting for future knowledge translation studies addressing chronic disease management in primary care.
PMCID: PMC3956338  PMID: 23936886
Asthma; COPD; Guidelines implementation; Knowledge transfer; Knowledge translation; Medical education; Mentorship; Quality circles
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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