Naggie S.,Duke Clinical Research Institute |
Naggie S.,Durham Veterans Affairs Medical Center |
Sulkowski M.S.,Johns Hopkins University
Gastroenterology | Year: 2012
With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients. © 2012 AGA Institute.
Adam S.S.,Duke University |
Mcduffie J.R.,Durham Veterans Affairs Medical Center |
Lachiewicz P.F.,Durham Veterans Affairs Hospital |
Orte T.L.,Duke University |
Williams Jr. J.W.,Durham Veterans Affairs Medical Center
Annals of Internal Medicine | Year: 2013
Background: Pharmacologic thromboprophylaxis reduces the risk for venous thromboembolism after total hip replacement (THR) or total knee replacement (TKR). New oral anticoagulants (NOACs), including direct thrombin inhibitors and factor Xa inhibitors, are emerging options for thromboprophylaxis after these procedures. Purpose: To compare the benefits and risks of NOACs versus standard thromboprophylaxis for adults having THR or TKR. Data Sources: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2009 through March 2013. Study Selection: English-language systematic reviews. Data Extraction: Two independent reviewers abstracted data and rated study quality and strength of evidence. Data Synthesis: Six good-quality systematic reviews compared NOACs with low-molecular-weight heparin (LMWH) for thromboprophylaxis after THR or TKR. Risk for symptomatic deep venous thrombosis, but not risk for death or nonfatal pulmonary embolism, was reduced with factor Xa inhibitors compared with LMWH (4 fewer events per 1000 patients). Conversely, the risk for major bleeding increased (2 more events per 1000 patients). Outcomes of dabigatran did not significantly differ from those of LMWH. Indirect evaluation of NOACs by common comparison with LMWH showed nonsignificantly reduced risks for venous thromboembolism with rivaroxaban compared with dabigatran (risk ratio [RR], 0.68 [95% CI, 0.21 to 2.23]) and apixaban (RR, 0.59 [CI, 0.26 to 1.33]) but increased major bleeding. New oral anticoagulants have not been compared with warfarin, aspirin, or unfractionated heparin. Limitations: Head-to-head comparisons among NOACs were not available. Efficacy is uncertain in routine clinical practice. Conclusion: New oral anticoagulants are effective for thromboprophylaxis after THR and TKR. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding.
Luttrell L.M.,Medical University of South Carolina |
Luttrell L.M.,Ralph hnson Veterans Affairs Medical Center |
Gesty-Palmer D.,Duke University |
Gesty-Palmer D.,Durham Veterans Affairs Medical Center
Pharmacological Reviews | Year: 2010
Heptahelical G protein-coupled receptors are the most diverse and therapeutically important family of receptors in the human genome. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by arrestin binding, which uncouples the receptor and G protein and targets the receptor for internalization. It is clear, however, that heptahelical receptor signaling does not end with desensitization. Arrestins bind a host of catalytically active proteins and serve as ligand-regulated scaffolds that recruit protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into the receptor-arrestin complex. Although many of these arrestin-bound effectors serve to modulate G protein signaling, degrading second messengers and regulating endocytosis and trafficking, other signals seem to extend beyond the receptor-arrestin complex to regulate such processes as protein translation and gene transcription. Although these findings have led to a re-envisioning of heptahelical receptor signaling, little is known about the physiological roles of arrestin-dependent signaling. In vivo, the duality of arrestin function makes it difficult to dissociate the consequences of arrestin-dependent desensitization from those that might be ascribed to arrestin-mediated signaling. Nonetheless, recent evidence generated using arrestin knockouts, G protein-uncoupled receptor mutants, and arrestin pathway-selective "biased agonists" is beginning to reveal that arrestin signaling plays important roles in the retina, central nervous system, cardiovascular system, bone remodeling, immune system, and cancer. Understanding the signaling roles of arrestins may foster the development of pathway-selective drugs that exploit these pathways for therapeutic benefit.
Keating N.L.,Brigham and Women's Hospital |
Keating N.L.,Harvard University |
O'Malley A.J.,Harvard University |
Freedland S.J.,Durham Veterans Affairs Medical Center |
And 2 more authors.
European Urology | Year: 2013
Background: Androgen-deprivation therapy (ADT) for prostate cancer (PCa) may be associated with cardiovascular disease and diabetes. Some data suggest that men with certain conditions may be more susceptible to developing cardiovascular disease than others. Objective: To assess whether the risk of myocardial infarction (MI) or diabetes during ADT is modified by specific baseline comorbidities. Design, setting, and participants: We conducted a population-based observational study of 185 106 US men ≥66 yr of age diagnosed with local/regional PCa from 1992 to 2007. We assessed comorbidities monthly over the follow-up period. Outcome measurements and statistical analysis: Cox proportional hazards models with time-varying variables assessing incident diabetes or MI. Results and limitations: A total of 49.9% of the men received ADT during follow-up. Among men with no comorbidities, ADT was associated with an increase in the adjusted hazard of MI (adjusted hazard ratio [AHR]: 1.09; 95% confidence interval [CI], 1.02-1.16) and diabetes (AHR: 1.33; 95% CI, 1.27-1.39). Risks of MI and diabetes were similarly increased among men with and without specific comorbid illnesses (p > 0.10 for all interactions, with one exception). Previous MI, congestive heart failure, peripheral arterial disease, stroke, hypertension, chronic obstructive pulmonary disease, and renal disease were associated with new MI and diabetes, and obesity and rheumatologic disease were also associated with diabetes. Limitations include the observational study design, reliance on administrative data to ascertain outcomes, and lack of information on risk factors such as smoking and family history. Conclusions: Traditional risk factors for MI and diabetes were also associated with developing these conditions during ADT but did not significantly modify the risk attributable to ADT. Strategies to screen and prevent diabetes and cardiovascular disease in men with PCa should be similar to the strategies recommended for the general population. © 2012 European Association of Urology.
Wang S.,Duke University |
Wang S.,Durham Veterans Affairs Medical Center |
Blazer D.G.,Duke University
Annual Review of Clinical Psychology | Year: 2015
This review provides an overview of the relationship between depression and cognition in the elderly, with an emphasis on psychotherapies and nonpharmacologic approaches. We first review the clinical presentation of late-life depression and comorbid cognitive impairment, as well as the epidemiology and risk factors for cognitive impairment in late-life depression and the temporal relationship between depression and cognitive impairment. Next, we discuss the salient topic of elderly suicide and cognitive impairment. We then touch briefly on the neuropsychological deficits, biomarkers, and neuroimaging findings in late-life depression with comorbid cognitive impairment. We then focus most of this review on psychotherapies and nontraditional treatments for late-life depression with comorbid cognitive impairment and examine what evidence, if any, exists of the cognitive and functional benefits of these treatments. Finally, we examine the cognitive effects of pharmacologic treatments and brain stimulation therapies. © 2015 by Annual Reviews. All rights reserved.
Hoffman M.,Durham Veterans Affairs Medical Center |
Hoffman M.,Duke University
Seminars in Thrombosis and Hemostasis | Year: 2015
The liver plays a key role in hemostasis as the site of synthesis of many of the proteins involved in the coagulation, antithrombotic and fibrinolytic systems that interact to both establish hemostasis, and preventing thrombosis. The common laboratory tests, prothrombin time (PT) and activated partial thromboplastin time (aPTT), evolved from studies of plasma clotting in test tubes. Such studies laid the basis for the coagulation cascade model of hemostasis. However, thought has evolved to place a greater emphasis on the active roles of cells in localizing and regulating hemostasis. The PT and aPTT do not reflect the roles of cellular elements in hemostasis, nor do they reflect the crucial roles of antithrombotic and fibrinolytic systems. Thus, though the PT may indeed reflect the synthetic capacity of the liver, it does not accurately reflect the risk of bleeding or thrombosis in patients with liver failure. © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY.
Adam S.S.,Duke University |
McDuffie J.R.,Durham Veterans Affairs Medical Center |
Ortel T.L.,Duke University |
Williams Jr. J.W.,Durham Veterans Affairs Medical Center
Annals of Internal Medicine | Year: 2012
Background: New oral anticoagulants (NOACs), including direct thrombin inhibitors (DTIs) and factor Xa (FXa) inhibitors, are emerging alternatives for prophylaxis and treatment of atrial fibrillation (AF) and venous thromboembolism (VTE). Purpose: To compare the benefits and harms of NOACs versus warfarin for AF and VTE. Data Sources: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2001 through July 2012; U.S. Food and Drug Administration (FDA) database for adverse event reports. Study Selection: English-language, randomized, controlled trials (RCTs) comparing NOACs with warfarin for management of AF or VTE and observational studies and FDA reports on adverse effects. Data Extraction: Two independent reviewers abstracted data and rated study quality and strength of evidence. Data Synthesis: Six good-quality RCTs compared NOACs (2 DTI studies, 4 FXa inhibitor studies) with warfarin. In AF, NOACs decreased all-cause mortality (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]); in VTE, NOACs did not differ for mortality or VTE outcomes. Across indications, adverse effects of NOACs compared with warfarin were fatal bleeding (RR, 0.60 [CI, 0.46 to 0.77]), major bleeding (RR, 0.80 [CI, 0.63 to 1.01]), gastrointestinal bleeding (RR, 1.30 [CI, 0.97 to 1.73]), and discontinuation due to adverse events (RR, 1.23 [CI, 1.05 to 1.44]). Subgroup analyses suggest a higher risk for myocardial infarction with DTIs than with FXa inhibitors. Bleeding risk for NOACs may be increased in persons older than 75 years or those receiving warfarin who have good control. Limitation: There were no head-to-head comparisons of NOACs and limited data on harms. Conclusion: New oral anticoagulants are a viable option for patients receiving long-term anticoagulation. Treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment. © 2012 American College of Physicians.
Fox V.,Durham Veterans Affairs Medical Center
Occupational Therapy in Mental Health | Year: 2013
Major trends in the mental health field, including the transition toward deinstitutionalization and community-based care, the increased focus on cost-effectiveness and accountability, and the rise of consumer-based health care have had significant impacts on mental health practice. With the shift to community-based mental health, multidisciplinary teams and generic interventions have become the dominant means of providing client services. This shift to generic interventions has had detrimental effects on professional identity and self-efficacy, client care, and interdisciplinary team collaboration. © 2013 Copyright.
Williams C.D.,Durham Veterans Affairs Medical Center
Current Opinion in Gastroenterology | Year: 2013
Purpose of review: Gastrointestinal cancers account for 20% of all incident cancers in the United States. Much work has been done to understand the role dietary factors play in the prevention of gastrointestinal cancers, yet evidence regarding the potential preventive effect of antioxidants is conflicting. This review highlights the recent studies investigating the associations between dietary antioxidants and cancers of the gastrointestinal tract. RECENT FINDINGS: In-vitro and in-vivo studies in animals continue to support the hypothesis that antioxidants reduce the risk of gastrointestinal cancers. Results in human populations are not as supportive. Antioxidant nutrients and fruits and vegetables do not seem to confer protection against colorectal cancer, and certain antioxidants were found to increase the risk of distal colon cancer. Individual antioxidants also do not help prevent pancreatic cancer. Total antioxidant intake and plant-based foods seem promising for stomach cancer prevention, while vitamin C lowers the risk of esophageal cancer. Preventive effects for stomach and esophageal cancers were often limited to or stronger in smokers. Evidence is scarce regarding antioxidants and liver cancer. SUMMARY: Antioxidants do not aid in the prevention of gastrointestinal cancers in the general population; however, they may act as chemopreventive agents for stomach and esophageal cancers, especially in high-risk populations. Copyright © Lippincott Williams & Wilkins.
Jackson G.L.,Durham Veterans Affairs Medical Center
Journal of general internal medicine | Year: 2011
The Department of Veterans Affairs (VA) has been at the vanguard of information technology (IT) and use of comprehensive electronic health records. Despite the widespread use of health IT in the VA, there are still a variety of key questions that need to be answered in order to maximize the utility of IT to improve patient access to quality services. This paper summarizes the potential of IT to enhance healthcare access, key gaps in current evidence linking IT and access, and methodologic challenges for related research. We also highlight four key issues to be addressed when implementing and evaluating the impact of IT interventions on improving access to quality care: 1) Understanding broader needs/perceptions of the Veteran population and their caregivers regarding use of IT to access healthcare services and related information. 2) Understanding individual provider/clinician needs/perceptions regarding use of IT for patient access to healthcare. 3) System/Organizational issues within the VA and other organizations related to the use of IT to improve access. 4) IT integration and information flow with non-VA entities. While the VA is used as an example, the issues are salient for healthcare systems that are beginning to take advantage of IT solutions.