Mark L Van Natta

Mount Sinai School of Medicine, Manhattan, NY, United States

Are you Mark L Van Natta?

Claim your profile

Publications (52)458.66 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Background. Unlike cytomegalovirus (CMV) infection and aging, HIV decreases the proportion of CD28-CD8+ T cells expressing CD57. Whether this abnormality predicts mortality in treated HIV infection and can be reversed by early antiretroviral therapy (ART) remains unknown.Methods. We sampled recently HIV-infected individuals (<6 months) and HIV-uninfected controls and compared longitudinal changes in the proportion of CD28-CD8+ T cells expressing CD57 between those who initiated ART early (<6 months) vs. later (>2 years). We also assessed the relationship between this phenotype and mortality in a nested case-control study of ART-suppressed chronically-infected individuals.Results. Compared to HIV-uninfected controls (n=15), recently HIV-infected individuals had lower proportions of CD28-CD8+ T cells expressing CD57 (P<0.001), and these proportions increased during ART. The early ART group (n=33) achieved normal levels, while the later ART group (n=30) continued to have lower levels than HIV-uninfected controls (P=0.02). Among 141 ART-suppressed participants in the SOCA study, those in the lowest quartile of CD28-CD8+ T cells expressing CD57 had five-fold higher odds of mortality than those in the highest quartile (95% CI: 1.6-15.9, P=0.007).Conclusions. Abnormally low proportions of CD28-CD8+ T cells expressing CD57 predict increased mortality during treated HIV infection, and may be reversed with early ART initiation.
    The Journal of Infectious Diseases 02/2014; · 5.85 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: IMPORTANCE Gastroparesis remains a challenging syndrome to manage, with few effective treatments and a lack of rigorously controlled trials. Tricyclic antidepressants are often used to treat refractory symptoms of nausea, vomiting, and abdominal pain. Evidence from well-designed studies for this use is lacking. OBJECTIVE To determine whether treatment with nortriptyline results in symptomatic improvement in patients with idiopathic gastroparesis. DESIGN, SETTING, AND PARTICIPANTS The NORIG (Nortriptyline for Idiopathic Gastroparesis) trial, a 15-week multicenter, parallel-group, placebo-controlled, double-masked, randomized clinical trial from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC), comparing nortriptyline with placebo for symptomatic relief in idiopathic gastroparesis. One hundred thirty patients with idiopathic gastroparesis were enrolled between March 2009 and June 2012 at 7 US academic medical centers. Patient follow-up was completed in October 2012. Inclusion criteria included delayed gastric emptying and moderate to severe symptom scores using the Gastroparesis Cardinal Symptom Index (GCSI). INTERVENTIONS Nortriptyline vs placebo. Study drug dose was increased at 3-week intervals (10, 25, 50, 75 mg) up to 75 mg at 12 weeks. MAIN OUTCOMES AND MEASURES The primary outcome measure of symptomatic improvement was a decrease from the patient's baseline GCSI score of at least 50% on 2 consecutive 3-week GCSI assessments during 15 weeks of treatment. RESULTS The primary symptomatic improvement outcome did not differ between 65 patients randomized to nortriptyline vs 65 patients randomized to placebo: 15 (23% [95% CI, 14%-35%]) in the nortriptyline group vs 14 (21% [95% CI, 12%-34%]) in the placebo group (P = .86). Treatment was stopped more often in the nortriptyline group (19 [29% {95% CI, 19%-42%}]) than in the placebo group (6 [9%] {95% CI, 3%-19%}]) (P = .007), but numbers of adverse events were not different (27 [95% CI, 18-39] vs 28 [95% CI, 19-40]) (P = .89). CONCLUSIONS AND RELEVANCE Among patients with idiopathic gastroparesis, the use of nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms. These findings do not support the use of nortriptyline for idiopathic gastroparesis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00765895.
    JAMA The Journal of the American Medical Association 12/2013; 310(24):2640-9. · 29.98 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Background. Both hepatitis C virus (HCV) and human immunodeficiency virus (HIV) penetrate the central nervous system. HIV-associated neuroretinal disorder (HIV-NRD), a visual impairment of reduced contrast sensitivity and reading ability, is associated with cytokine dysregulation and genetic polymorphisms in the anti-inflammatory interleukin 10 (IL-10) signaling pathway. We investigated associations between HCV and HIV-NRD and between HCV and single-nucleotide polymorphisms (SNPs) in the IL-10 receptor 1 (IL10R1) gene. Methods. Logistic and Cox regression analysis were used to analyze risk factors for HIV-NRD in 1576 HIV-positive patients who did not have an ocular opportunistic infection at enrollment. Median follow-up was 4.9 years (interquartile range, 2.4-8.8 years). Four IL10R1 SNPs were examined in a subset of 902 patients. Results. The group included 290 patients with chronic HCV infection, 74 with prior infection, and 1212 with no HCV markers. There were 244 prevalent cases of HIV-NRD and 263 incident cases (rate = 3.9/100 person-years). In models adjusted for demographics, HIV treatment and status, liver function, and immune status, both the prevalence and incidence of HIV-NRD were significantly higher in patients with chronic HCV infection (odds ratio = 1.54; 95% confidence interval [CI], 1.03-2.31 and hazard ratio = 1.62; 95% CI, 1.13-2.34, respectively), compared to patients with no HCV markers. Chronic HCV was associated with rs2228055 and 2 additional IL-10R1 SNPs expected to reduce IL-10 signaling. HIV-NRD was not significantly associated with these SNPs. Conclusions. HCV is a possible risk factor for HIV-NRD. Genetic analysis suggests that alterations in the IL-10 signaling pathway may increase susceptibility to HIV-NRD and HCV infection. Inflammation may link HCV and HIV-NRD.
    Clinical Infectious Diseases 09/2013; · 9.37 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: PURPOSE: To describe the outcomes of different treatment approaches for cytomegalovirus (CMV) retinitis in the era of highly active antiretroviral therapy (HAART). DESIGN: Prospective cohort study, the Longitudinal Study of the Ocular Complications of AIDS. PARTICIPANTS: A total of 250 patients with CMV retinitis and a CD4+ T-cell count <100 cells/μl (n = 221) at enrollment or incident retinitis (n = 29) during cohort follow-up. METHODS: The effects of systemic therapy (vs. intraocular therapy only) on systemic outcomes and the effect of intraocular therapies (ganciclovir implants, intravitreal injections) on ocular outcomes were evaluated. MAIN OUTCOME MEASURES: Mortality, CMV dissemination, retinitis progression, and treatment side effects. RESULTS: Regimens containing systemic anti-CMV therapy were associated with a 50% reduction in mortality (adjusted hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.3-0.7; P = 0.006), a 90% reduction in new visceral CMV disease (adjusted HR, 0.1; 95% CI, 0.04-0.4; P = 0.004), and among those with unilateral CMV retinitis at presentation, an 80% reduction in second eye disease (adjusted HR, 0.2; 95% CI, 0.1-0.5; P = 0.0005) when compared with those using only intraocular therapy (implants or injections). Compared with systemic treatment only, regimens containing intravitreal injections had greater rates of retinitis progression (adjusted HR, 3.4; P = 0.004) and greater visual field loss (for loss of one half of the normal field, adjusted HR, 5.5; P < 0.01). Intravitreal implants were not significantly better than systemic therapy (adjusted HR for progression, 0.5; P = 0.26; adjusted HR for loss of one half of the visual field, 0.5; P = 0.45), but the sample size was small. Hematologic and renal side effect rates were similar between those groups with and without systemic anti-CMV therapy. The rate of endophthalmitis was 0.017 per eye-year (EY) (95% CI, 0.006-0.05) among those treated with intravitreal injections and 0.01 per EY (95% CI, 0.002-0.04) among those treated with an implant. CONCLUSIONS: In the HAART era, systemic anti-CMV therapy, while there is immune compromise, seems to provide benefits in terms of longer survival and decreased CMV dissemination. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 02/2013; · 5.56 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height. We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry. Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P=0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P=0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P=0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants. The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.).
    New England Journal of Medicine 09/2012; 367(10):904-12. · 51.66 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Purpose: To evaluate morphology of the optic nerve head and visual field in AIDS patients without retinitis. Methods: One randomly selected eye from 246 patients with AIDS without retinitis was evaluated from prospective multicenter Longitudinal Studies of Ocular Complications of AIDS. Stereo fundus photographs of OHN and serial VF data over 5-years were analyzed. Main outcomes included vertical cup-to-disc ratio (CDR), mean deviation, and pattern standard deviation scores on VF testing. Results: The median CDR was 0.39 at enrollment and 0.40 at 5-year follow-up. An unadjusted linear regression model revealed a mean change in CDR of 0.004 after 5-years (P = 0.04). After adjustment for practice effect, there were no statistically significant changes in VF performance observed during the 5 years of follow-up. Conclusions: We detected clinically minimal, but statistically significant changes in ONH morphology and no change in VF performance among eyes of patients with AIDS and without retinitis.
    Ocular immunology and inflammation 06/2012; 20(5):342-8. · 0.72 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The adverse effects of corticosteroids on bone mineral accretion (BMA) have been well documented. Vitamin D insufficiency, a prevalent condition in the pediatric population, has also been associated with decreased bone mineral density (BMD). We sought to determine whether children with asthma who have lower vitamin D levels are more susceptible to the negative effects of corticosteroids on BMD over time. Children aged 5 to 12 years with mild-to-moderate asthma who participated in the Childhood Asthma Management Program were followed for a mean of 4.3 years. Total doses of inhaled corticosteroids and oral corticosteroids (OCSs) were recorded, serum 25-hydroxyvitamin D3 levels were measured at the beginning of the trial, and serial dual-energy x-ray absorptiometry scans of the lumbar spine were performed. Annual BMA rates were defined as follows: [(BMD at 4 years' follow-up - BMD at baseline)/4 years]. BMA was calculated for 780 subjects. In boys baseline vitamin D levels significantly modified the relationship between OCSs and BMA (vitamin D × OCS interaction, P= .023). Stratification by vitamin D levels showed a decrease in BMA with increased use of OCSs in vitamin D-insufficient boys only (P< .001). Compared with vitamin D-sufficient boys, vitamin D-insufficient boys exposed to more than 2 courses of OCSs per year had twice the decrease in BMA rate (relative to boys who were OCS unexposed). Vitamin D levels significantly modified the effect of OCSs on BMA in boys. Further research is needed to examine whether vitamin D supplementation in children with poorly controlled asthma might confer benefits to bone health.
    The Journal of allergy and clinical immunology 05/2012; 130(1):53-60.e4. · 12.05 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Before the introduction of combination antiretroviral therapy (cART), patients infected with the human immunodeficiency virus (HIV) rarely died of liver disease. In resource-rich countries, cART dramatically increased longevity. As patients survived longer, hepatitis C virus (HCV) infection became a leading cause of death; however, because patients with AIDS continue to have 5-fold greater mortality than non-AIDS patients, it is unclear whether HCV infection increases mortality in them. In this investigation, which is part of the Longitudinal Studies of the Ocular Complications of AIDS, plasma banked at enrollment from 2025 patients with AIDS as defined by the Centers for Disease Control and Prevention were tested for HCV RNA and antibodies. Three hundred thirty-seven patients had HCV RNA (chronic infection), 91 had HCV antibodies and no HCV RNA (cleared infection), and 1597 had no HCV markers. Median CD4(+) T-cell counts/µL were 200 (chronic), 193 (cleared), and 175 (no markers). There were 558 deaths. At a median follow-up of 6.1 years, patients with chronic HCV had a 50% increased risk of mortality compared with patients with no HCV markers (relative risk [RR], 1.5; 95% confidence interval [CI], 1.2-1.9; P = .001) in an adjusted model that included known risk factors. Mortality was not increased in patients with cleared infection (RR, 0.9; 95% CI, .6-1.5; P = .82). In patients with chronic HCV, 20.4% of deaths were liver related compared with 3.8% in patients without HCV. Chronic HCV infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS, despite competing risks. Effective HCV treatment may benefit HIV/HCV-coinfected patients with AIDS.
    Clinical Infectious Diseases 04/2012; 55(1):137-44. · 9.37 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To date, only mutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility. We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10(-5) in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent. After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: P(combined) = 7.76 × 10(-8). We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation.
    The Journal of Infectious Diseases 04/2012; 205(7):1155-62. · 5.85 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To evaluate relationships between retinal vessel caliber and tests of visual function among people with AIDS. Longitudinal, observational cohort study. We evaluated data for participants without ocular opportunistic infections at initial examination (baseline) in the Longitudinal Studies of the Ocular Complications of AIDS (1998-2008). Visual function was evaluated with best-corrected visual acuity, Goldmann perimetry, automated perimetry (Humphrey Field Analyzer), and contrast sensitivity (CS) testing. Semi-automated grading of fundus photographs (1 eye/participant) determined central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole-to-venule ratio (AVR) at baseline. Multiple linear regression models, using forward selection, sought independent relationships between indices and visual function variables. Included were 1250 participants. Smaller AVR was associated with reduced visual field by Goldmann perimetry (P = .003) and worse mean deviation (P = .02) on automated perimetry and possibly with worse pattern standard deviation (PSD) on automated perimetry (P = .06). There was a weak association between smaller AVR and worse CS (P = .07). Relationships were independent of antiretroviral therapy and level of immunodeficiency (CD4+ T lymphocyte count, human immunodeficiency virus [HIV] RNA blood level). On longitudinal analysis, retinal vascular indices at baseline did not predict changes in visual function. Variation in retinal vascular indices is associated with abnormal visual function in people with AIDS, manifested by visual field loss and possibly by reduced CS. Relationships are consistent with the hypothesis that HIV-related retinal vasculopathy is a contributing factor to vision dysfunction among HIV-infected individuals. Longitudinal studies are needed to determine whether changes in indices predict change in visual function.
    American Journal of Ophthalmology 03/2012; 153(3):428-433.e1. · 3.63 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To evaluate relationships between retinal vessel caliber, AIDS-related factors, and mortality. Longitudinal, observational cohort study. We evaluated data for participants without ocular opportunistic infections at initial examination (baseline) in the Longitudinal Studies of the Ocular Complications of AIDS (1998-2008). Semi-automated evaluation of fundus photographs (1 eye/participant) determined central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole-to-venule ratio (AVR) at baseline. Multiple linear regression models, using forward selection, identified independent relationships between indices and various host- and disease-related variables. Included were 1250 participants. Mean follow-up for determination of mortality was 6.1 years. Smaller CRAE was related to increased age (P < .001) and hypertension (P < .001); larger CRAE was related to lower hematocrit (P = .002). Larger CRAE and CRVE were associated with black race (P < .001). Larger CRVE was related to smoking (P = .004); smaller CRVE was related to age (P < .001) and higher mean corpuscular volume (P = .001). We observed the following relationships with AIDS-associated factors: smaller CRAE and larger CRVE with history of highly active antiretroviral therapy (HAART; P < .001); and larger CRAE with lower CD4+ T lymphocyte count (P = .04). We did not identify independent relationships with human immunodeficiency virus RNA blood levels. There was a 12% (95% CI, 2%-21%) increase in mortality risk per quartile of decreasing AVR (P = .02). Variations in retinal vascular caliber are associated with AIDS-specific factors and are markers for increased mortality risk. Relationships are consistent with the hypothesis that the vasculature is altered by known atherogenic effects of chronic HAART or the prolonged inflammatory state associated with AIDS.
    American Journal of Ophthalmology 03/2012; 153(3):434-444.e1. · 3.63 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To evaluate United States Public Health Service (USPHS) guidelines for discontinuing anticytomegalovirus (CMV) therapy in patients with AIDS who have immune recovery and quiescent retinitis after initiating highly active antiretroviral therapy. Cohort study of patients with CMV retinitis (Longitudinal Study of Ocular Complications of AIDS). Participants had CMV retinitis and CD4+ T-cell counts of 50 cells/μL or fewer enrolled from 1998 through 2009 who demonstrated sustained immune recovery (2 consecutive CD4+ T-cell counts of 100 cells/μL or more at least 6 months apart) and inactive retinitis. Participants were classified into 2 groups according to anti-CMV treatment after immune recover: (1) continued anti-CMV therapy and (2) discontinued therapy. We evaluated survival, visual acuity, and CMV retinitis activity; we used propensity scores to adjust for confounding factors for these analyses. Of 152 participants reviewed, 71 demonstrated immune recovery, 37 of whom discontinued therapy and 34 of whom continued therapy. At immune recovery, participants continuing therapy tended to be older (44 vs 40 years; P = .09), have bilateral retinitis (53% vs 32%; P = .10), and have lower CD4+ T-cell counts (148 vs 207 cells/μL; P < .001). There were no statistical differences in any of the clinical outcomes (death, retinitis progress, visual acuity, or incidence of bilateral retinitis). Both groups lost visual acuity during follow-up, on average 1.2 letters per year (P < .01). Discontinuation of anti-CMV therapy after immune recovery did not increase the risk of poor outcomes. These results support the current guidelines for discontinuation of anti-CMV therapy after achievement of sustained immune recovery.
    American Journal of Ophthalmology 07/2011; 152(4):628-637.e1. · 3.63 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established. To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin. Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks. The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures. Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was -35.2 U/L (95% CI, -56.9 to -13.5) with placebo vs -48.3 U/L (95% CI, -66.8 to -29.8) with vitamin E (P = .07) and -41.7 U/L (95% CI, -62.9 to -20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, -0.2 to 0.3) vs -0.5 with vitamin E (95% CI, -0.8 to -0.3; P = .006) and -0.3 with metformin (95% CI, -0.6 to -0.0; P = .04); and in NAFLD activity score, -0.7 with placebo (95% CI, -1.3 to -0.2) vs -1.8 with vitamin E (95% CI, -2.4 to -1.2; P = .02) and -1.1 with metformin (95% CI, -1.7 to -0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features. Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. clinicaltrials.gov Identifier: NCT00063635.
    JAMA The Journal of the American Medical Association 04/2011; 305(16):1659-68. · 29.98 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To evaluate the effects of previously reported host genetics factors that influence cytomegalovirus (CMV) retinitis incidence, progression to acquired immune deficiency syndrome (AIDS), and efficacy of highly active antiretroviral therapy (HAART) for mortality, retinitis progression, and retinal detachment in patients with CMV retinitis and AIDS in the era of HAART. Prospective, multicenter, observational study. Cox proportional hazards model based genetic association tests examined the influence of IL-10R1_S420L, CCR5-Δ32, CCR2-V64I, CCR5 promoter, and SDF-3'A polymorphisms among patients with mortality, retinitis progression, and retinal detachment. Participants were 203 European-American and 117 African-American patients with AIDS and CMV retinitis. European-American patients with the CCR5 +.P1.+ promoter haplotype showed increased risk for mortality (hazard ratio [HR] = 1.83; 95% confidence interval [CI]: 1.00-3.40; P = .05). Although the same haplotype also trended for increased risk for mortality in African-American patients, the result was not significant (HR = 2.28; 95% CI: 0.93-5.60; P = .07). However, this haplotype was associated with faster retinitis progression in African Americans (HR = 5.22; 95% CI: 1.54-17.71; P = .007). Increased risk of retinitis progression was also evident for African-American patients with the SDF1-3'A variant (HR = 3.89; 95% CI: 1.42-10.60; P = .008). In addition, the SDF1-3'A variant increased the retinal detachment risk in this patient group (HR = 3.05; 95% CI: 1.01-9.16; P = .05). Besides overall immune health, host genetic factors influence mortality, retinitis progression, and retinal detachment in patients with AIDS and CMV retinitis that are receiving HAART.
    American journal of ophthalmology 03/2011; 151(6):999-1006.e4. · 3.83 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Patient-reported outcomes are measured in many epidemiologic studies using self- or interviewer-administered questionnaires. While in some studies differences between these administration formats were observed, other studies did not show statistically significant differences important to patients. Since the evidence about the effect of administration format is inconsistent and mainly available from cross-sectional studies our aim was to assess the effects of different administration formats on repeated measurements of patient-reported outcomes in participants with AIDS enrolled in the Longitudinal Study of Ocular Complications of AIDS. We included participants enrolled in the Longitudinal Study of Ocular Complications in AIDS (LSOCA) who completed the Medical Outcome Study [MOS] -HIV questionnaire, the EuroQol, the Feeling Thermometer and the Visual Function Questionnaire (VFQ) 25 every six months thereafter using self- or interviewer-administration. A large print questionnaire was available for participants with visual impairment. Considering all measurements over time and adjusting for patient and study site characteristics we used linear models to compare HRQL scores (all scores from 0-100) between administration formats. We defined adjusted differences of ≥0.2 standard deviations [SD]) to be quantitatively meaningful. We included 2,261 participants (80.6% males) with a median of 43.1 years of age at enrollment who provided data on 23,420 study visits. The self-administered MOS-HIV, Feeling Thermometer and EuroQol were used in 70% of all visits and the VFQ-25 in 80%. For eight domains of the MOS-HIV differences between the interviewer- and self- administered format were < 0.1 SD. Differences in scores were highest for the social and role function domains but the adjusted differences were still < 0.2 SD. There was no quantitatively meaningful difference between administration formats for EuroQol, Feeling Thermometer and VFQ-25 domain scores. For ocular pain (VFQ-25), we found a statistically significant difference of 3.5 (95% CI 0.2, 6.8), which did, however, not exceed 0.2 SD. For all instruments scores were similar for the large and standard print formats with all adjusted differences < 0.2 SD. Our large study provides evidence that administration formats do not have a meaningful effect on repeated measurements of patient-reported outcomes. As a consequence, longitudinal studies may not need to consider the effect of different administration formats in their analyses.
    Health and Quality of Life Outcomes 01/2011; 9:30. · 2.27 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The recently developed histologic scoring system for nonalcoholic fatty liver disease (NAFLD) by the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) is becoming increasingly popular. However, its generalizability to a community setting has not been evaluated. We conducted a study to compare a community general pathologist to an expert hepatopathologist in assessing NAFLD using the NASH CRN scoring system. Forty-eight consecutive patients with suspected NAFLD underwent liver biopsy. Histologic features of interest such as steatosis, lobular inflammation, balloon degeneration, fibrosis, NAFLD Activity Score (NAS), and the presence of NASH were scored in a blinded fashion by the 2 pathologists on 2 separate occasions 3 months apart. The mean (± SD) length of the liver biopsy samples was 25 ± 5 mm. Interobserver agreement (κ) between 2 pathologists was 0.62 (0.45-0.80) for steatosis, 0.44 (0.23-0.65) for lobular inflammation, 0.25 (0.11-0.38) for ballooning, 0.40 for NAS (0.28-0.52), and 0.35 (0.19-0.52) for fibrosis. The 2 pathologists diagnosed "definite NASH" in a similar proportion of patients (56% vs. 57%), but their interobserver agreement was only 0.46 (0.24-0.67) as they both diagnosed different levels of NASH (borderline vs. definite) in different subjects. Intraobserver agreement was generally comparable for steatosis, lobular inflammation, NAS, and diagnosis of NASH, but not for fibrosis. Clinically important differences exist between community general pathologist and expert hepatopathologist in assessing NAFLD using the NASH CRN scoring system. More studies are needed to investigate its suitability for community-based clinical practice.
    Journal of clinical gastroenterology 01/2011; 45(1):55-8. · 2.21 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To describe visual field (VF) loss among patients with cytomegalovirus (CMV) retinitis and the risk factors for such loss. Multicenter, prospective, observational study. A total of 476 patients with AIDS and CMV retinitis, and VF data. Follow-up every 3 months with medical history, ophthalmologic examination, Goldmann visual fields, and laboratory testing. Incidence of VF loss in eyes affected with CMV retinitis and characteristics associated with such VF loss. Over a median follow-up of 4 years (range, 0.5-9 years), the incidence rates of VF loss to 75% and 50% of normal were 0.22/eye-year (EY, 95% confidence interval [CI], 0.20-0.25) and 0.08/EY (95% CI, 0.06-0.10), respectively. The observed rates were 6- to 7-fold less than those observed rates of VF loss in the era before highly active antiretroviral therapy (HAART). Decreased CD4+ T-cell count, whether measured at enrollment or over follow-up time, was associated with increased rates of VF loss for all VF outcomes in a dose-dependent fashion. Risk factors for VF loss included lower CD4+ T-cell count, CMV lesion size >25% of the total retinal area, and active CMV retinitis after controlling for potential confounding. Highly active antiretroviral therapy use and immune recovery (CD4+ T-cell count >100 cells/μL) were associated with reduced risk of VF loss in multiple regression models. Immune recovery was statistically significantly associated with a lower risk of VF loss to 75% of normal (relative risk [RR] = 0.63; 95% CI, 0.49-0.86; P = 0.003) and to 50% of normal (RR = 0.60; 95% CI, 0.44-0.82; P = 0.001) after controlling for demographic characteristics, HIV viral load, HAART use, CMV lesion location and size, and retinitis activity. Cytomegalovirus retinitis was associated with a substantial risk of incident VF loss, but the incidence is approximately 6-fold lower than that observed in the pre-HAART era. Those who have HAART-induced immune recovery have approximately 40% lower risk of VF loss for both outcomes after controlling for confounding.
    Ophthalmology 12/2010; 118(5):895-901. · 5.56 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To describe the 5-year outcomes of patients with cytomegalovirus (CMV) retinitis and AIDS in the era of highly active antiretroviral therapy (HAART). Prospective, multicenter, observational study. A total of 503 patients with AIDS and CMV retinitis. Follow-up every 3 months with medical history, ophthalmologic examination, laboratory testing, and retinal photographs. Participants were classified as having previously diagnosed CMV retinitis and immune recovery (CD4+ T cells ≥ 100 cells/μl), previously diagnosed retinitis and immune compromise, and newly diagnosed CMV retinitis (diagnosis <45 days before enrollment). Mortality, retinitis progression (movement of the border of a CMV lesion ≥ ½ disc diameter or occurrence of a new lesion), retinal detachment, immune recovery uveitis (IRU), and visual loss (< 20/40 and ≥ 20/200). Overall mortality was 9.8 deaths/100 person-years (PY). Rates varied by group at enrollment from 3.0/100 PY for those with previously diagnosed retinitis and immune recovery to 26.1/100 PY for those with newly diagnosed retinitis. The rate of retinitis progression was 7.0/100 PY and varied from 1.4/100 PY for those with previously diagnosed retinitis and immune recovery to 28.0/100 PY for those with newly diagnosed retinitis. The rate of retinal detachment was 2.3/100 eye-years (EY) and varied from 1.2/100 EY for those with previously diagnosed retinitis and immune recovery to 4.9/100 EY for those with newly diagnosed retinitis. The rate of IRU was 1.7/100 PY and varied from 1.3/100 PY for those with previously diagnosed retinitis and immune recovery at enrollment to 3.6/100 PY for those with newly diagnosed retinitis who subsequently experienced immune recovery. The rates of visual loss to < 20/40 and to ≤ 20/200 were 7.9/100 EY and 3.4/100 EY, respectively; they varied from 6.1/100 EY and 2.7/100 EY for those with previously diagnosed retinitis and immune recovery to 11.8/100 EY and 5.1/100 EY for those with newly diagnosed retinitis. Although the event rates tended to decline with time, in general, at no time did they reach zero. Despite the availability of HAART, patients with AIDS and CMV retinitis remain at increased risk for mortality, retinitis progression, complications of the retinitis, and visual loss over a 5-year period. Proprietary or commercial disclosure may be found after the references.
    Ophthalmology 11/2010; 117(11):2152-61.e1-2. · 5.56 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Excess mortality has decreased among human immunodeficiency virus (HIV)-infected patients but without evidence of a decrease among patients with AIDS. We assessed temporal changes in excess mortality and elucidated risk factors for excess mortality in patients with AIDS diagnosed in the era of highly active antiretroviral therapy (HAART). We included 1188 patients of the Longitudinal Study of Ocular Complications in AIDS who were aged 25-64 years at enrollment and who received a diagnosis of AIDS after 1995. We calculated excess mortality as the age-, year-, and sex-adjusted difference in mortality rates between patients with AIDS and persons in the US general population during the period 1999-2007. We used a relative survival model to identify risk factors for excess mortality. There were a mean of 50 excess deaths per 1000 person-years (95% confidence interval [CI], 44-57 excess deaths per 1000 person-years) during 1999-2007. Excess mortality almost halved, with an annual decrease of 8.0% per year (95% CI, 3.0%-12.7%; P = .002) but remained high at 36 excess deaths per 1000 person-years in 2007. Viral load >400 copies/mL (compared with <or= 400 copies/mL; risk ratio, 3.4; 95% CI, 2.3-5.0), CD4(+) count <200 cells/μL (compared with >or= 200 cells/μL; risk ratio, 2.7; 95% CI, 1.9-3.9), and cytomegalovirus retinitis (risk ratio, 1.6; 95% CI, 1.2-2.1) were the strongest risk factors for excess mortality. Excess mortality among patients with AIDS was nearly halved in the HAART era and most strongly linked to stage of HIV disease. These results reflect the continuing improvements in AIDS management but also highlight that excess mortality remains ∼5 times higher in patients with AIDS than in HIV-infected patients without AIDS.
    Clinical Infectious Diseases 10/2010; 51(8):947-56. · 9.37 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was formed to conduct multicenter studies on the etiology, contributing factors, natural history, and treatment of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine the associations of readily available demographic, clinical, and laboratory variables with the diagnosis of NASH and its key histological features, and determine the ability of these variables to predict the severity of nonalcoholic fatty liver disease (NAFLD). A total of 1266 adults were enrolled in NASH CRN studies between October 2004 and February 2008, of whom 1101 had available liver histology. The median age was 50 years; 82% were white and 12% Hispanic. The median body mass index was 33 kg/m(2); 49% had hypertension and 31% had type 2 diabetes. On liver biopsy, 57% were judged to have definite NASH and 31% bridging fibrosis or cirrhosis. Using data from the 698 patients with liver biopsies within 6 months of clinical data, patients with definite NASH were more likely to be female and have diabetes, higher levels of aspartate and alanine aminotransferases, alkaline phosphatase, gamma glutamyl transpeptidase, and homeostasis model assessment of insulin resistance (HOMA-IR). Progressive models for predicting histological diagnoses performed modestly for predicting steatohepatitis or ballooning (area under receiver operating characteristic curves [AUROC] ranged from 0.70-0.79), and better for advanced fibrosis (AUROC 0.73-0.85). CONCLUSION: Readily available clinical and laboratory variables can predict advanced fibrosis in adults with NAFLD, but additional information is needed to reliably predict the presence and severity of NASH. Prospective studies of this well-characterized population and associated tissue bank samples offer a unique opportunity to better understand the cause and natural history of NAFLD and develop more precise means for noninvasive diagnosis.
    Hepatology 09/2010; 52(3):913-24. · 12.00 Impact Factor

Publication Stats

2k Citations
1k Downloads
3k Views
458.66 Total Impact Points

Institutions

  • 2012–2013
    • Mount Sinai School of Medicine
      • Division of Liver Diseases
      Manhattan, NY, United States
    • University of Wisconsin, Madison
      • Department of Ophthalmology and Visual Sciences
      Madison, MS, United States
  • 2010–2012
    • Jules Stein Eye Institute
      Maryland, United States
  • 2008–2012
    • University of New Mexico
      • Department of Pediatrics
      Albuquerque, New Mexico, United States
    • National University (California)
      San Diego, California, United States
    • University of Washington Seattle
      • Department of Pediatrics
      Seattle, WA, United States
  • 2005–2012
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, Maryland, United States
  • 2002–2012
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, Maryland, United States
  • 1990–2012
    • Johns Hopkins University
      • Department of Epidemiology
      Baltimore, Maryland, United States
  • 2010–2011
    • National Cancer Institute (USA)
      Maryland, United States