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1.  Expression of the potential therapeutic target CXXC5 in primary acute myeloid leukemia cells - high expression is associated with adverse prognosis as well as altered intracellular signaling and transcriptional regulation 
Oncotarget  2014;6(5):2794-2811.
The CXXC5 gene encodes a transcriptional activator with a zinc-finger domain, and high expression in human acute myeloid leukemia (AML) cells is associated with adverse prognosis. We now characterized the biological context of CXXC5 expression in primary human AML cells. The global gene expression profile of AML cells derived from 48 consecutive patients was analyzed; cells with high and low CXXC5 expression then showed major differences with regard to extracellular communication and intracellular signaling. We observed significant differences in the phosphorylation status of several intracellular signaling mediators (CREB, PDK1, SRC, STAT1, p38, STAT3, rpS6) that are important for PI3K-Akt-mTOR signaling and/or transcriptional regulation. High CXXC5 expression was also associated with high mRNA expression of several stem cell-associated transcriptional regulators, the strongest associations being with WT1, GATA2, RUNX1, LYL1, DNMT3, SPI1, and MYB. Finally, CXXC5 knockdown in human AML cell lines caused significantly increased expression of the potential tumor suppressor gene TSC22 and genes encoding the growth factor receptor KIT, the cytokine Angiopoietin 1 and the selenium-containing glycoprotein Selenoprotein P. Thus, high CXXC5 expression seems to affect several steps in human leukemogenesis, including intracellular events as well as extracellular communication.
PMCID: PMC4413618  PMID: 25605239
Acute myeloid leukemia; CXXC5; transcription; cytokines; all-trans retinoic acid
2.  Central Implementation Strategies Outperform Local Ones in Improving HIV Testing in Veterans Healthcare Administration Facilities 
Journal of General Internal Medicine  2013;28(10):1311-1317.
Pilot data suggest that a multifaceted approach may increase HIV testing rates, but the scalability of this approach and the level of support needed for successful implementation remain unknown.
To evaluate the effectiveness of a scaled-up multi-component intervention in increasing the rate of risk-based and routine HIV diagnostic testing in primary care clinics and the impact of differing levels of program support.
Three arm, quasi-experimental implementation research study.
Veterans Health Administration (VHA) facilities.
Persons receiving primary care between June 2009 and September 2011
A multimodal program, including a real-time electronic clinical reminder to facilitate HIV testing, provider feedback reports and provider education, was implemented in Central and Local Arm Sites; sites in the Central Arm also received ongoing programmatic support. Control Arm sites had no intervention
Frequency of performing HIV testing during the 6 months before and after implementation of a risk-based clinical reminder (phase I) or routine clinical reminder (phase II).
The adjusted rate of risk-based testing increased by 0.4 %, 5.6 % and 10.1 % in the Control, Local and Central Arms, respectively (all comparisons, p < 0.01). During phase II, the adjusted rate of routine testing increased by 1.1 %, 6.3 % and 9.2 % in the Control, Local and Central Arms, respectively (all comparisons, p < 0.01). At study end, 70–80 % of patients had been offered an HIV test.
Use of clinical reminders, provider feedback, education and social marketing significantly increased the frequency at which HIV testing is offered and performed in VHA facilities. These findings support a multimodal approach toward achieving the goal of having every American know their HIV status as a matter of routine clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-013-2420-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3785651  PMID: 23605307
HIV/AIDS; implementation research; quality improvement; diagnosis
3.  A novel GATA6 mutation in a child with congenital heart malformation and neonatal diabetes 
Clinical Case Reports  2013;1(2):86-90.
Key Clinical Message
Diabetes in neonates is a monogenetic disease and genetic analysis is warranted to allow best treatment, prognosis, and genetic counseling. Transcription factor mutations may have a variable expression and different organs may be involved.
PMCID: PMC4184756  PMID: 25356219
Exocrine pancreas dysfunction; GATA6; heart malformation; intrauterine growth retardation; neonatal diabetes; transcription factor mutation
4.  In Vivo Detection of Oxidation-Specific Epitopes in Atherosclerotic Lesions Using Bio-Compatible Mn(II) Molecular Magnetic Imaging Probes 
To evaluate the in vivo magnetic resonance (MR) imaging efficacy of manganese (Mn(II)) molecular imaging probes targeted to oxidation-specific epitopes (OSE).
OSE are critical in the initiation, progression and de-stabilization of atherosclerotic plaques. Gadolinium (Gd(III)) based MR imaging agents can be associated with systemic toxicity. Mn is an endogenous, bio-compatible, paramagnetic metal ion that has poor MR efficacy when chelated, but strong efficacy when released within cells.
Multimodal Mn-micelles were generated to contain rhodamine for confocal microscopy and conjugated with either the murine monoclonal IgG antibody MDA2 targeted to malondialdehyde (MDA)-lysine epitopes or the human single-chain Fv antibody fragment IK17 targeted to MDA-like epitopes (‘targeted micelles”). Micelle formulations were characterized in vitro and in vivo and their MR efficacy (9.4 Tesla) evaluated in apoE−/− and LDLR−/− mice (0.05 mmol Mn/Kg dose) (total of 120 mice for all experiments). In vivo competitive inhibition studies were performed to evaluate target specificity. Untargeted, MDA2-Gd and IK17-Gd micelles (0.075 mmol Gd/Kg) were included as controls.
In vitro studies demonstrated that targeted Mn-micelles accumulate in macrophages when pre-exposed to MDA-LDL with ~10X increase in longitudinal relativity. Following intravenous injection, strong MR signal enhancement was observed 48–72 hours after administration of targeted Mn-micelles, with co-localization within intraplaque macrophages. Co-injection of free MDA2 with the MDA2-Mn micelles resulted in full suppression of MR signal in the arterial wall confirming target specificity. Similar MR efficacy was noted in apoE−/− and LDLR−/− mice with aortic atherosclerosis. No significant differences in MR efficacy were noted between targeted Mn and Gd micelles.
This study demonstrates that bio-compatible multimodal Mn-based molecular imaging probes detect OSE within atherosclerotic plaques and may facilitate clinical translation of non-invasive imaging of human atherosclerosis.
PMCID: PMC3333483  PMID: 22300697
Atherosclerosis; MRI; oxidation; molecular imaging; inflammation
5.  Increasing Prevalence of HCC and Cirrhosis in Patients with Chronic Hepatitis C Virus Infection 
Gastroenterology  2010;140(4):1182-1188.e1.
Background & Aims
Patients with hepatitis C virus (HCV) infection are at risk for developing additional liver disorders that are costly to treat and have high rates of morbidity, although the actual prevalence of these diseases is not known. We examined time trends in the prevalence of cirrhosis and its related complications, such as hepatic decompensation and hepatocellular cancer (HCC).
We calculated the annual prevalence of cirrhosis, decompensated cirrhosis, and HCC in a national sample of veterans diagnosed with HCV between 1996 and 2006. Patients with HCV who had at least 1 physician visit in a given calendar year were included in the analysis of prevalence for that year. We used direct standardization to adjust the prevalence of cirrhosis and related complications for increasing age of the cohort, as well as sex and changes in clinical characteristics.
In this cohort, the number of individuals with HCV increased from 17,261 in 1996 to 106,242 in 2006. The prevalence of cirrhosis increased from 9% in 1996 to 18.5% in 2006. Similarly, the prevalence of patients with decompensated cirrhosis doubled, from 5% in 1996 to 11% in 2006, whereas the prevalence of HCC increased approximately 20-fold (0.07% in 1996 to 1.3% in 2006). After adjustment, the time trend in the prevalence of cirrhosis (and its complications) was lower than the crude trend, although it still increased significantly.
The prevalence of cirrhosis and HCC in HCV-infected patients has increased significantly over the past 10 years, and could increase further. An aging cohort of HCV patients could partly explain our findings. Clinicians and healthcare systems should develop strategies to provide timely and effective care to this high-risk population of patients.
PMCID: PMC3073667  PMID: 21184757
liver cancer; epidemiology; virology
6.  The Impact of Integrated HIV Care on Patient Health Outcomes 
Medical care  2009;47(5):560-567.
Control of viral replication through combination antiretroviral therapy (cART) improves patient health outcomes. Yet many HIV-infected patients have co-morbidities that pose social and clinical barriers to achieving viral suppression. Integration of subspecialty services into HIV primary care may overcome such barriers.
Evaluate effect of Integrated HIV Care on suppression of HIV replication.
Research Design
A retrospective cohort study of HIV patients from five Veterans Affairs healthcare facilities 2000–2006.
Patients with >3 months of follow-up, sufficient baseline HIV severity, on cART.
We measured and ranked Integrated Care at the facilities. These rankings were applied to patient visits to form an index of Integrated HIV Care utilization. We evaluated effect of Integrated HIV Care utilization on likelihood of achieving viral suppression while on cART, controlling for demographic and clinical factors using survival analysis.
The 1,018 HIV-infected patients eligible for analysis had substantial barriers to responding to cART: 93% had co-morbidities with mean 3.2 co-morbidities per patient (S.D.=2.0); 52% achieved viral suppression in median 231 days (S.D.=411.6). Patients visiting clinics which offered hepatitis, psychiatric, psychological and social services in addition to HIV primary care were 3.1 times more likely to achieve viral suppression than patients visiting clinics which offered only HIV primary care (Hazard ratio=3.1, p<.001).
Patients who visited Integrated HIV Care clinics were more likely to achieve viral suppression while on cART. Future research should investigate which elements of Integrated Care are most associated with viral control and what role provider experience plays in this association.
PMCID: PMC3108041  PMID: 19318998
7.  Switch from Stress Response to Homeobox Transcription Factors in Adipose Tissue After Profound Fat Loss 
PLoS ONE  2010;5(6):e11033.
In obesity, impaired adipose tissue function may promote secondary disease through ectopic lipid accumulation and excess release of adipokines, resulting in systemic low-grade inflammation, insulin resistance and organ dysfunction. However, several of the genes regulating adipose tissue function in obesity are yet to be identified.
Methodology/Principal Findings
In order to identify novel candidate genes that may regulate adipose tissue function, we analyzed global gene expression in abdominal subcutaneous adipose tissue before and one year after bariatric surgery (biliopancreatic diversion with duodenal switch, BPD/DS) (n = 16). Adipose tissue from lean healthy individuals was also analyzed (n = 13). Two different microarray platforms (AB 1700 and Illumina) were used to measure the differential gene expression, and the results were further validated by qPCR. Surgery reduced BMI from 53.3 to 33.1 kg/m2. The majority of differentially expressed genes were down-regulated after profound fat loss, including transcription factors involved in stress response, inflammation, and immune cell function (e.g., FOS, JUN, ETS, C/EBPB, C/EBPD). Interestingly, a distinct set of genes was up-regulated after fat loss, including homeobox transcription factors (IRX3, IRX5, HOXA5, HOXA9, HOXB5, HOXC6, EMX2, PRRX1) and extracellular matrix structural proteins (COL1A1, COL1A2, COL3A1, COL5A1, COL6A3).
The data demonstrate a marked switch of transcription factors in adipose tissue after profound fat loss, providing new molecular insight into a dichotomy between stress response and metabolically favorable tissue development. Our findings implicate homeobox transcription factors as important regulators of adipose tissue function.
PMCID: PMC2882947  PMID: 20543949
8.  Cost-Effectiveness of Strategies to Improve HIV Testing and Receipt of Results: Economic Analysis of a Randomized Controlled Trial 
The CDC recommends routine voluntary HIV testing of all patients 13-64 years of age. Despite this recommendation, HIV testing rates are low even among those at identifiable risk, and many patients do not return to receive their results.
To examine the costs and benefits of strategies to improve HIV testing and receipt of results.
Cost-effectiveness analysis based on a Markov model. Acceptance of testing, return rates, and related costs were derived from a randomized trial of 251 patients; long-term costs and health outcomes were derived from the literature.
Setting/target population
Primary-care patients with unknown HIV status.
Comparison of three intervention models for HIV counseling and testing: Model A = traditional HIV counseling and testing; Model B = nurse-initiated routine screening with traditional HIV testing and counseling; Model C = nurse-initiated routine screening with rapid HIV testing and streamlined counseling.
Main measures
Life-years, quality-adjusted life-years (QALYs), costs and incremental cost-effectiveness.
Key results
Without consideration of the benefit from reduced HIV transmission, Model A resulted in per-patient lifetime discounted costs of $48,650 and benefits of 16.271 QALYs. Model B increased lifetime costs by $53 and benefits by 0.0013 QALYs (corresponding to 0.48 quality-adjusted life days). Model C cost $66 more than Model A with an increase of 0.0018 QALYs (0.66 quality-adjusted life days) and an incremental cost-effectiveness of $36,390/QALY. When we included the benefit from reduced HIV transmission, Model C cost $10,660/QALY relative to Model A. The cost-effectiveness of Model C was robust in sensitivity analyses.
In a primary-care population, nurse-initiated routine screening with rapid HIV testing and streamlined counseling increased rates of testing and receipt of test results and was cost-effective compared with traditional HIV testing strategies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-010-1265-5) contains supplementary material, which is available to authorized users.
PMCID: PMC2869414  PMID: 20204538
HIV; cost-benefit analysis; highly active antiretroviral therapy; transmission; nurse-initiated HIV screening; HIV rapid testing; Streamlined counseling
9.  Evaluation of the Sustainability of an Intervention to Increase HIV Testing 
Journal of General Internal Medicine  2009;24(12):1275-1280.
Sustainability—the routinization and institutionalization of processes that improve the quality of healthcare—is difficult to achieve and not often studied.
To evaluate the sustainability of increased rates of HIV testing after implementation of a multi-component intervention in two Veterans Health Administration healthcare systems.
Quasi-experimental implementation study in which the effect of transferring responsibility to conduct the provider education component of the intervention from research to operational staff was assessed.
Persons receiving healthcare between 2005 and 2006 (intervention year) and 2006 and 2007 (sustainability year).
Monthly HIV testing rate, stratified by frequency of clinic visits.
The monthly adjusted testing rate increased from 2% at baseline to 6% at the end intervention year and then declined reaching 4% at the end of the sustainability year. However, the stratified, visit-specific testing rate for persons newly exposed to the intervention (i.e., having their first through third visits during the study period) increased throughout the intervention and sustainability years. Increases in the proportion of visits by patients who remained untested despite multiple, prior exposures to the intervention accounted for the aggregate attenuation of testing during the sustainability year. Overall, the percentage of patients who received an HIV test in the sustainability year was 11.6%, in the intervention year 11.1%, and in the pre-intervention year 5.0%
Provider education combined with informatics and organizational support had a sustainable effect on HIV testing rates. The effect was most pronounced during patients’ early contacts with the healthcare system.
PMCID: PMC2787938  PMID: 19798538
HIV testing; provider education; sustainability; VA hospitals
10.  A System-wide Intervention to Improve HIV Testing in the Veterans Health Administration 
Journal of General Internal Medicine  2008;23(8):1200-1207.
Although the benefits of identifying and treating asymptomatic HIV-infected individuals are firmly established, health care providers often miss opportunities to offer HIV-testing.
To evaluate whether a multi-component intervention increases the rate of HIV diagnostic testing.
Pre- to post-quasi-experiment in 5 Veterans Health Administration facilities. Two facilities received the intervention; the other three facilities were controls. The intervention included a real-time electronic clinical reminder that encourages HIV testing, and feedback reports and a provider activation program.
Persons receiving health care between August 2004 and September 2006 who were at risk but had not been previously tested for HIV infection
Pre- to post-changes in the rates of HIV testing at the intervention and control facilities
At the two intervention sites, the adjusted rate of testing increased from 4.8% to 10.8% and from 5.5% to 12.8% (both comparisons, p < .001). In addition, there were 15 new diagnoses of HIV in the pre-intervention year (0.46% of all tests) versus 30 new diagnoses in the post-intervention year (0.45% of all tests). No changes were observed at the control facilities.
Use of clinical reminders and provider feedback, activation, and social marketing increased the frequency of HIV testing and the number of new HIV diagnoses. These findings support a multimodal approach toward achieving the Centers for Disease Control and Prevention’s goal of having every American know their HIV status as a matter of routine clinical practice.
PMCID: PMC2517965  PMID: 18452045
diagnosis; HIV testing; quality improvement
11.  Improving HIV Screening and Receipt of Results by Nurse-Initiated Streamlined Counseling and Rapid Testing 
HIV testing is cost-effective in unselected general medical populations, yet testing rates among those at risk remain low, even among those with regular primary care. HIV rapid testing is effective in many healthcare settings, but scant research has been done within primary care settings or within the US Department of Veteran’s Affairs Healthcare System.
We evaluated three methods proven effective in other diseases/settings: nurse standing orders for testing, streamlined counseling, and HIV rapid testing.
Randomized, controlled trial with three intervention models: model A (traditional counseling/testing); model B (nurse-initiated screening, traditional counseling/testing); model C (nurse-initiated screening, streamlined counseling/rapid testing).
Two hundred fifty-one patients with primary/urgent care appointments in two VA clinics in the same city (one large urban hospital, one freestanding outpatient clinic in a high HIV prevalence area).
Rates of HIV testing and receipt of results; sexual risk reduction; HIV knowledge improvement.
Testing rates were 40.2% (model A), 84.5% (model B), and 89.3% (model C; p = <.01). Test result receipt rates were 14.6% (model A), 31.0% (model B), 79.8% (model C; all p = <.01). Sexual risk reduction and knowledge improvement did not differ significantly between counseling methods.
Streamlined counseling with rapid testing significantly increased testing and receipt rates over current practice without changes in risk behavior or posttest knowledge. Increased testing and receipt of results could lead to earlier disease identification, increased treatment, and reduced morbidity/mortality. Policymakers should consider streamlined counseling/rapid testing when implementing routine HIV testing into primary/urgent care.
PMCID: PMC2517869  PMID: 18421508
nurse-initiated HIV screening; HIV rapid testing; streamlined counseling
12.  Implementing and evaluating a regional strategy to improve testing rates in VA patients at risk for HIV, utilizing the QUERI process as a guiding framework: QUERI Series 
We describe how we used the framework of the U.S. Department of Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) to develop a program to improve rates of diagnostic testing for the Human Immunodeficiency Virus (HIV). This venture was prompted by the observation by the CDC that 25% of HIV-infected patients do not know their diagnosis – a point of substantial importance to the VA, which is the largest provider of HIV care in the United States.
Following the QUERI steps (or process), we evaluated: 1) whether undiagnosed HIV infection is a high-risk, high-volume clinical issue within the VA, 2) whether there are evidence-based recommendations for HIV testing, 3) whether there are gaps in the performance of VA HIV testing, and 4) the barriers and facilitators to improving current practice in the VA.
Based on our findings, we developed and initiated a QUERI step 4/phase 1 pilot project using the precepts of the Chronic Care Model. Our improvement strategy relies upon electronic clinical reminders to provide decision support; audit/feedback as a clinical information system, and appropriate changes in delivery system design. These activities are complemented by academic detailing and social marketing interventions to achieve provider activation.
Our preliminary formative evaluation indicates the need to ensure leadership and team buy-in, address facility-specific barriers, refine the reminder, and address factors that contribute to inter-clinic variances in HIV testing rates. Preliminary unadjusted data from the first seven months of our program show 3–5 fold increases in the proportion of at-risk patients who are offered HIV testing at the VA sites (stations) where the pilot project has been undertaken; no change was seen at control stations.
This project demonstrates the early success of the application of the QUERI process to the development of a program to improve HIV testing rates. Preliminary unadjusted results show that the coordinated use of audit/feedback, provider activation, and organizational change can increase HIV testing rates for at-risk patients. We are refining our program prior to extending our work to a small-scale, multi-site evaluation (QUERI step 4/phase 2). We also plan to evaluate the durability/sustainability of the intervention effect, the costs of HIV testing, and the number of newly identified HIV-infected patients. Ultimately, we will evaluate this program in other geographically dispersed stations (QUERI step 4/phases 3 and 4).
PMCID: PMC2335105  PMID: 18353185

Results 1-12 (12)