Faculty Bibliography

Background. We and others have shown that primary hepatitis C (HCV) infection in men infected with human immunodeficiency virus (HIV) causes early-onset liver fibrosis; however, little is known about the long-term natural history of the liver disease in these HIV-infected men. Methods. We followed a cohort of HIV-infected men with primary HCV infection in New York City. Results. Four men who were not cured after their primary HCV infection developed decompensated cirrhosis within 17 months to 6 years after primary HCV infection. Three died within 8 years of primary HCV infection, and 1 survived after liver transplant done 2 years after primary HCV infection. Three of the 4 men had AIDS at the time of primary HCV infection, and the most rapid progression occurred in the 2 men with the lowest CD4 counts at the time of HCV infection. Liver histopathology was most consistent with HCV-induced damage even though some had exposures to other potential hepatotoxins. Conclusions. Primary HCV infection resulted in decompensated cirrhosis and death within 2-8 years in 4 HIV-infected men. The rapid onset of fibrosis due to primary HCV infection in HIV-infected men cannot therefore be considered benign. The rate of continued progression to liver failure may be proportional to the degree of underlying immunocompromise caused by HIV infection. More research is needed to better define the mechanisms behind accelerated liver damage.

BACKGROUND: This paper describes an innovative protocol for a type-II hybrid effectiveness-implementation trial that is evaluating a smoking cessation telephone care coordination program for Veterans Health Administration (VA) mental-health clinic patients. As a hybrid trial, the protocol combines implementation science and clinical trial methods and outcomes that can inform future cessation studies and the implementation of tobacco cessation programs into routine care. The primary objectives of the trial are (1) to evaluate the process of adapting, implementing, and sustaining a smoking cessation telephone care coordination program in VA mental health clinics, (2) to determine the effectiveness of the program in promoting long-term abstinence from smoking among mental health patients, and (3) to compare the effectiveness of telephone counseling delivered by VA staff with that delivered by state quitlines. METHODS/DESIGN: The care coordination program is being implemented at six VA facilities. VA mental health providers refer patients to the program via an electronic medical record consult. Program staff call referred patients to offer enrollment. All patients who enroll receive a self-help booklet, mailed smoking cessation medications, and proactive multi-call telephone counseling. Participants are randomized to receive this counseling from VA staff or their state's quitline. Four primary implementation strategies are being used to optimize program implementation and sustainability: blended facilitation, provider training, informatics support, and provider feedback. A three-phase formative evaluation is being conducted to identify barriers to, and facilitators for, program implementation and sustainability. A mixed-methods approach is being used to collect quantitative clinical effectiveness data (e.g., self-reported abstinence at six months) and both quantitative and qualitative implementation data (e.g., provider referral rates, coded interviews with providers). Summative data will be analyzed using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework. DISCUSSION: This paper describes the rationale and methods of a trial designed to simultaneously study the clinical effectiveness and implementation of a telephone smoking cessation program for smokers using VA mental health clinics. Such hybrid designs are an important methodological design that can shorten the time between the development of an intervention and its translation into routine clinical care. TRIAL REGISTRATION: ClinicalTrials.gov NCT00724308.

Past work has suggested a lasting impact of military service on the lives of veterans. By intervening at a critical stage in the lives of young men, service may open up opportunities for disadvantaged youth. In contrast, the negative consequences of exposure to combat may offset these presumed advantages. Induction into the military is also a nonrandom process that makes identifying the effects of service exceedingly difficult. In this study we use an instrumental variable (IV) approach to model the causal impact of Vietnam-era military service on two outcomes, marital stability and co-residence with adult offspring. We find limited evidence to suggest that military service may have a lasting effect on family life. In particular, we find that service reduces the probability of marital dissolution for white men. Service also significantly increases the probability of filial co-residence for men of other races.

OBJECTIVES/OBJECTIVE:Human papillomavirus (HPV) infection causes genital warts, penile cancer and cervical cancer. Africa has one of the highest rates of penile and cervical cancers, but there are little data on high-risk human papillomavirus (HR-HPV) prevalence in heterosexual men. Knowledge of HR-HPV prevalence, risk factors and genotype distribution among heterosexual men is important to establish risk-reduction prevention strategies. METHODS:1578 uncircumcised men aged 15-49 years who enrolled in male circumcision trials in Rakai, Uganda, were evaluated for HR-HPV from swabs of the coronal sulcus/glans using Roche HPV Linear Array. Adjusted prevalence risk ratios (adjPRRs) were estimated using modified Poisson multivariable regression. RESULTS:HPV prevalence (either high risk or low risk) was 90.7% (382/421) among HIV-positive men and 60.9% (596/978) among HIV-negative men (PRR 1.49, 95% CI 1.40 to 1.58). HIV-positive men had a significantly higher risk of infection with three or more HR-HPV genotypes (PRR=5.76, 95% CI 4.27 to 7.79). Among HIV-positive men, high-risk sexual behaviours were not associated with increased HR-HPV prevalence. Among HIV-negative men, HR-HPV prevalence was associated with self-reported genital warts (adjPRR 1.57, 95% CI 1.07 to 2.31). Among all men (both HIV negative and HIV positive), HR-HPV prevalence was associated with more than 10 lifetime sexual partners (adjPRR 1.30, 95% CI 1.01 to 1.66), consistent condom use (adjPRR 1.31, 95% CI 1.08 to 1.60) and HIV infection (adjPRR 1.80, 95% CI 1.60 to 2.02). HR-HPV prevalence was lower among men who reported no sexual partners during the past year (adjPRR 0.47, 95% CI 0.23 to 0.94). CONCLUSION/CONCLUSIONS:The burden of HR-HPV infection is high among heterosexual men in sub-Saharan Africa and most pronounced among the HIV-infected individuals.

Numerous studies report gene-environment interactions, suggesting that specific alleles have different effects on social outcomes depending on environment. In all these studies, however, environmental conditions are potentially endogenous to unmeasured genetic characteristics. That is, it could be that the observed interaction effects actually reflect underlying genetic tendencies that lead individuals into certain environments. What is critical to move this literature forward is random environmental variation that we know is not correlated with innate characteristics of subjects. We exploit a natural experiment that randomizes a particular stressor-birth weight discordance within twin pairs-to address this challenge and ask: Do random differences in early environment (prenatal nutrition) moderate genetic effects on depression, delinquency, or GPA? Using Add Health data, the only consistently significant allele-birth weight interaction we reveal works in the opposite direction of Caspi et al.'s classic finding regarding the interaction of maltreatment with genetic variation in the serotonin transporter promoter. Less robust interactions found for DRD2 and MAOA are consistent with this pattern that reverses prior findings. These results do not necessarily overturn existing research but support our methodological point that gene-environment research must address endogeneity.

BACKGROUND: : Patients with ulcerative colitis and Crohn's colitis have an increased risk of colon cancer influenced by the duration, extent, and severity of disease. Surveillance colonoscopy serves to detect cancer and precancerous dysplasia at the earliest possible time. Reduction of inflammation should theoretically reduce the development of cancer. Immunosuppressives should do so, but there is a fear that indeed the risk of cancer might be increased with their use. Our study was conducted to determine whether a relationship exists between receiving treatment with 6-MP for ulcerative and Crohn's colitis and increasing or decreasing the incidence of colorectal cancer (CRC). METHODS: : We conducted a single-center, retrospective cohort study of patients with long standing colitis (ulcerative and Crohn's) using the database of the senior investigator (B.I.K.). Two groups were matched based on their propensity to receive treatment with 6-MP; one group received 6-MP treatment, the other did not. Both groups were compared on the incidence of colon cancer. RESULTS: : No significant differences existed between the two cohorts with regard to type of disease, duration, extent, age, and sex. Six out of 27 patients not on 6-MP and seven out of 27 patients on 6-MP developed CRC (P= 1). CONCLUSIONS: : We conclude that there is neither sufficient evidence currently to state that 6-MP is associated with an increased development of CRC, nor that it has a chemopreventive effect.

Multiple myeloma (MM) is an ancient disease, but until the alkylating agent melphalan was found to have anti-myeloma properties in the 1950s there was virtually no effective therapy. By the late 1960s, extended dosing with melphalan and prednisone tripled survival from diagnosis and became the standard of care for newly diagnosed MM. "Maintenance therapy" to prolong survival through sustained disease control following induction chemotherapy was sought by 1970, but early strategies were ineffective and toxic. Subsequent applications of high-dose therapy (HDT)/autologous stem cell transplant (ASCT) changed the treatment paradigm for MM from extended dosing to an intensive strategy designed to eradicate the malignant cells in a single course of treatment. Although HDT-ASCT resulted in prolonged duration of remission and improved survival, the vast majority of patients still relapsed. Interferon (IFN) and glucocorticoid maintenance therapies demonstrated marginal improvements in outcomes but significant adverse effects. Novel agents introduced over the last decade have prolonged survival when given for maintenance following HDT-ASCT, but have also challenged the HDT-ASCT paradigm by achieving comparable remission rates when used alone as extended frontline therapy. This article reviews the evolution of therapeutic strategies for MM and discusses future questions facing MM investigators.

OBJECTIVE:A double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon β-1a (IFN) 30 μg intramuscularly weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis. METHODS:A total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics. RESULTS:Combination IFN+GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results. INTERPRETATION/CONCLUSIONS:Combining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences.

Most studies on Staphylococcus aureus have focused on the molecular epidemiology of methicillin-resistant S. aureus (MRSA) infections. In contrast, little information is available regarding the molecular epidemiology of currently circulating methicillin-susceptible S. aureus (MSSA) isolates in hospital settings, an epoch when the epidemiology of S. aureus has undergone significant changes. We conducted a cross-sectional study to compare the clinical, epidemiological, and genetic characteristics of MSSA and MRSA isolates at 3 tertiary-care hospitals in Medellin, Colombia, from February 2008 to June 2010. The infections were classified according to the Centers for Disease Control and Prevention (CDC) definitions. Genotypic analysis included spa typing, multilocus sequence typing (MLST) and staphylococcal cassette chromosome (mec) (SCCmec) typing. A total of 810 patients was enrolled. One hundred infections (12.3%) were classified as community-associated (31 CA-MSSA, 69 CA-MRSA), 379 (46.8%) as healthcare-associated community-onset (136 HACO-MSSA, 243 HACO-MRSA), and 331 (40.9%) as healthcare-associated hospital-onset (104 HAHO-MSSA, 227 HAHO-MRSA). Genotype analyses showed a higher diversity and a more varied spa type repertoire in MSSA than in MRSA strains. Most of the clinical-epidemiological characteristics and risk factors evaluated did not allow for discriminating MRSA- from MSSA-infected patients. The lack of equivalence among the genetic backgrounds of the major MSSA and MRSA clones would suggest that the MRSA clones are imported instead of arising from successful MSSA clones. This study emphasizes the importance of local surveillance to create public awareness on the changing S. aureus epidemiology.