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Background: COPD patients have high pulmonary and systemic oxidative stress that correlates with severity of disease. Sulforaphane has been shown to induce expression of antioxidant genes via activation of a transcription factor, nuclear factor erythroid-2 related factor 2 (Nrf2). Methods: This parallel, placebo-controlled, phase 2, randomized trial was conducted at three US academic medical centers. Patients who met GOLD criteria for COPD and were able to tolerate bronchoscopies were randomly assigned (1:1:1) to receive placebo, 25 μmoles, or 150 μmoles sulforaphane daily by mouth for four weeks. The primary outcomes were changes in Nrf2 target gene expression (NQ01, HO1, AKR1C1 and AKR1C3) in alveolar macrophages and bronchial epithelial cells. Secondary outcomes included measures of oxidative stress and airway inflammation, and pulmonary function tests. Results: Between July 2011 and May 2013, 89 patients were enrolled and randomized. Sulforaphane was absorbed in the patients as evident from their plasma metabolite levels. Changes in Nrf2 target gene expression relative to baseline ranged from 0.79 to 1.45 and there was no consistent pattern among the three groups; the changes were not statistically significantly different from baseline. Changes in measures of inflammation and pulmonary function tests were not different among the groups. Sulforaphane was well tolerated at both dose levels. Conclusion: Sulforaphane administered for four weeks at doses of 25 μmoles and 150 μmoles to patients with COPD did not stimulate the expression of Nrf2 target genes or have an effect on levels of other anti-oxidants or markers of inflammation. Trial Registration: Clinicaltrials.gov: . [ABSTRACT FROM AUTHOR]

Introduction Phase III/IV clinical trials are expensive and time consuming and often suffer from poor enrollment and retention rates. Pediatric trials are particularly difficult because scheduling around the parent, participant and potentially other sibling schedules can be burdensome. We are evaluating using the internet and mobile devices to conduct the consent process and study visits in a streamlined pediatric asthma trial. Our hypothesis is that these study processes will be non-inferior and will be less expensive compared to a traditional pediatric asthma trial. Materials/methods Parents and participants, aged 12 through 17 years, complete the informed consent process by viewing a multi-media website containing a consent video and study material in the streamlined trial. Participants are provided an iPad with WiFi and EasyOne spirometer for use during FaceTime visits and online twice daily symptom reporting during an 8-week run-in followed by a 12-week study period. Outcomes are compared with participants completing a similarly designed traditional trial comparing the same treatments within the same pediatric health-system. After 8 weeks of open-label Advair 250/50 twice daily, participants in both trial types are randomized to Advair 250/50, Flovent 250, or Advair 100/50 given 1 inhalation twice daily. Study staff track time spent to determine study costs. Results Participants have been enrolled in the streamlined and traditional trials and recruitment is ongoing. Conclusions This project will provide important information on both clinical and economic outcomes for a novel method of conducting clinical trials. The results will be broadly applicable to trials of other diseases. [ABSTRACT FROM AUTHOR]

Objective: To report the 2-year incidence of raised intraocular pressure (IOP) and glaucomatous optic nerve damage in patients with uveitis randomized to either fluocinolone acetonide (FA) implants or systemic therapy. Secondarily, we sought to explore patient and eye characteristics associated with IOP elevation or nerve damage. Design: A randomized, partially masked trial in which patients were randomized to either FA implants or systemic therapy. Participants: Patients aged ≥13 years with noninfectious intermediate, posterior, or panuveitis active within the prior 60 days for which systemic corticosteroids were indicated were eligible. Methods: Visual fields were obtained at baseline and every 12 months using the Humphrey 24-2 Swedish interactive threshold algorithm (SITA) fast protocol. Stereoscopic optic nerve photos were taken at baseline and at 3-, 6-, 12-, and 24-month follow-up visits. Masked examiners measured IOP at every study visit. Main Outcome Measures: Glaucoma was diagnosed based on an increase in optic nerve cup-to-disc ratio with visual field worsening or increased cup-to-disc ratio alone, for cases where visual field change was not evaluable, because of missing data or severe visual field loss at baseline. Results: Most patients were treated as assigned; among those evaluated for glaucoma, 97% and 10% of patients assigned to implant and systemic treatment, respectively, received implants. More patients (65%) assigned to implants experienced an IOP elevation of ≥10 mmHg versus 24% assigned to systemic treatment (P<0.001). Similarly, 69% of patients assigned to the implant required IOP-lowering therapy versus 26% in the systemic group (P<0.001). Glaucomatous optic nerve damage developed in 23% versus 6% (P<0.001) of implant and systemic patients, respectively. In addition to treatment assignment, black race, use of IOP-lowering medications, and uveitis activity at baseline were associated with incident glaucoma (P<0.05). Conclusions: Implant-assigned eyes had about a 4-fold risk of developing IOP elevation of ≥10 mmHg and incident glaucomatous optic neuropathy over the first 2 years compared with those assigned to systemic therapy. Central visual acuity was unaffected. Aggressive IOP monitoring with early treatment (often including early filtration surgery) is needed to avoid glaucoma when vision-threatening inflammation requires implant therapy. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

The article discusses a study on the effectiveness of the proton pump inhibitor (PPI) lansoprazole in asthmatic children without symptoms of gastroesophageal reflux (GER). The Study of Acid Reflux in Children With Asthma was a randomized placebo-controlled clinical trial in the U.S. that treated children with poor asthma control with either lansoprazole or placebo. More respiratory infections or adverse events were observed in children who received lansoprazole under the study. Children with poorly controlled asthma without GER symptoms and using inhaled corticosteriod showed no improvements in symptoms and lung function.

Purpose: To describe the prevalence and incidence of reduced visual acuity in eyes of patients with AIDS and without cytomegalovirus (CMV) retinitis at enrollment and estimate the proportion of incident vision loss attributable to new-onset CMV retinitis in this cohort. Design: Multicenter prospective observational study. Participants: Three thousand fourteen eyes of 1507 patients with AIDS and without CMV retinitis at enrollment. Methods: Medical history, ophthalmologic examination, and laboratory testing collected at enrollment and at follow-up visits every 6 months thereafter. Main Outcome Measures: Loss of visual acuity across the ≤20/50 and ≤20/200 thresholds and doubling of the visual angle; potential causes of this vision loss. Results: For eyes of patients without CMV retinitis at enrollment, the proportions with best-corrected visual acuity of ≤20/50 and of ≤20/200 were 3.9% and 1.8%, respectively. The incidence rates of vision loss to ≤20/50, ≤20/200, and to a doubling of the visual angle were 1.5/100 eye-year (EY), 0.8/100 EY, and 2.1/100 EY, respectively. Approximately 40% of the incident vision loss was attributable to CMV retinitis diagnosed during the follow-up period, and approximately 25% was attributable to cataract. Conclusions: Although the development of CMV retinitis was the most common reason for visual acuity loss in eyes of our patients with AIDS, it accounted for less than half of the vision loss in our population (∼40%). Newly diagnosed cataract during the follow-up period accounted for a substantial amount of incident vision loss as well. [Copyright &y& Elsevier]

Our goal was to explore associations between ß 2 adrenergic receptor polymorphisms and markers of asthma severity in African American and Caucasian patients with asthma. Polymorphisms at loci -1023, -654, -47, 46, 79, 491, and 523 were genotyped and haplotypes were imputed in 143 African Americans and 336 Caucasians. C523A genotype associated with percentage of African Americans (but not of Caucasians) having an asthma exacerbation: AA, AC, and CC genotypes were 17, 29, and 40%, respectively ( p = 0.018). Symptom scores, pulmonary function, and rescue inhaler use paralleled exacerbation prevalence. We conclude the 523 A allele modifies asthma severity in African Americans. [ABSTRACT FROM AUTHOR]

Objective: To evaluate risk factors for mortality among patients with AIDS in the era of highly active antiretroviral therapy (HAART), particularly the effect of cytomegalovirus (CMV). Design: Prospective cohort study of patients with AIDS, conducted from 1998 through 2003. Participants: One thousand five hundred eighty-three patients with AIDS, of whom 374 had CMV retinitis. Methods: Patients were contacted every 3 months, with examinations at least every 6 months, in which standardized data were collected on AIDS history and treatment, eye examinations, and hematologic, virologic, and immunologic laboratory data. Main Outcome Measure: Mortality. Results: The overall mortality rate was 0.07 deaths/person-year. In a multivariate analysis, the following baseline risk factors were associated with an increased mortality: higher human immunodeficiency virus (HIV) viral load (relative risk [RR] = 4.6 for HIV viral load >100000 copies/ml vs. &#60;400 copies/ml; P&#60;0.0001), lower CD4+ T-cell count at enrollment (RR = 3.8 for CD4+ T cell count 0–49 cells/μl vs. ≥200 cells/μl; P&#60;0.0001), CMV viral load ≥400 copies/ml (RR = 1.9; P = 0.002), lower hemoglobin (RR = 1.7 for hemoglobin &#60;10 g/dl; P = 0.009), a history of cryptococcal meningitis (RR = 1.7; P = 0.02), CMV retinitis (RR = 1.6; P = 0.0002), and Karnofsky score ≤80 (RR = 1.4; P = 0.008). Conclusions: In the era of HAART, CMV disease as manifested by CMV retinitis and a detectable CMV viral load were associated with an increased risk for mortality, even after adjusting for demographic, treatment, immunologic, and HIV virologic factors. [Copyright &y& Elsevier]

Purpose: To compare clinician and fundus photograph reading center assessments of the cytomegalovirus (CMV) retinitis area and change in the CMV retinitis area over time, and to investigate how these assessments correlate with the visual field (VF) of eyes with CMV retinitis. Design: Analysis of pooled data from 2 multicenter randomized clinical trials and 1 prospective multicenter epidemiologic study. Participants: Ninety-five eyes of 79 patients. At baseline, each eye had CMV retinitis restricted to zone 1 and/or zone 2 (approximately the photographable postequatorial retina), as assessed by the evaluating clinician. Methods: Comparison of CMV retinitis area, change in area over time as assessed by clinicians and a fundus photograph reading center, and correlation of these assessments with VF measurement. Main Outcome Measures: Cytomegalovirus retinitis area, change in CMV retinitis area over time, and VF score. Results: Baseline assessments of the mean retinitis area were, by clinicians, 12.8% of the total retinal area and, by the reading center, 6.3% of the total retinal area (P<0.001). There was a positive correlation between clinician and reading center assessments of retinitis area at baseline (ρ = 0.77 and P<0.0001 by Pearson correlation and ρ = 0.54 and P<0.001 by concordance). Both clinician and reading center size measures correlated negatively with VF (Spearman correlation ρs = −0.38 and −0.52, respectively; P<0.001 each). Mean changes in area over a 3-month interval were, by clinicians, +1.2% and, by the reading center, +1.1% (P = 0.68). Regression analysis showed a positive concordance (ρ = 0.42, P<0.001). Change in VF over a 3-month interval did not correlate with change in retinitis area as assessed by clinicians or the reading center. Conclusions: Awareness of the similarities and differences between clinician and reading center assessments of CMV retinitis area should permit clinicians to apply research data to clinical practice more effectively. Clinician assessment of retinitis area correlates negatively with VF, a clinically meaningful visual outcome in patients with CMV retinitis. [Copyright &y& Elsevier]

To determine if micronutrient intake is associated with asthma severity, we administered the Block food frequency questionnaire to participants in a randomized clinical trial of the safety of influenza vaccine for asthmatics. The nutrition substudy included 1033 participants, aged 12–75. Intake of antioxidant vitamins, soy isoflavones, total fruits and vegetables, fats, and fiber was compared with asthma severity at baseline[forced expiratory volume in 1 second(FEV1), peak expiratory flow rate(PEF), asthma symptoms] and the rate of asthma exacerbations during the 2 weeks following influenza vaccination. The only nutrient that had a consistent association with asthma severity was genistein, a soy isoflavone. None of the nutrients evaluated were related to asthma exacerbation rate when adjusted for known confounders. The FEV1 in genistein consumers of at least 250µg/1000 Kcal/day was 82.1% predicted, 79.9% predicted for those who consumed between 1 and 249µg/1000 kcal, and 76.2% predicted in genistein nonconsumers(p = 0.006); the PEF was 82.7% predicted, 80.8% predicted, and 78.3% predicted, respectively(p = 0.009). There were no differences in the Asthma Symptom Utility Index(ASUI). We could not account for these results based on differences in demographics, body mass index, or consumption of other nutrients. Thus, increasing consumption of genistein is associated with better lung function in patients with asthma. Further studies are needed to determine whether dietary supplementation with genistein can reduce asthma severity. [ABSTRACT FROM AUTHOR]

We report on two features of the early termination of the Studies of Ocular Complications of AIDS Monoclonal Antibody Cytomegalovirus Retinitis Trial: one related to the deliberative process of the treatment effects monitoring body (the policy and data monitoring board [PDMB]) and the other related to the relationships among the PDMB, the investigators, and the joint sponsors (the National Institutes of Health and a pharmaceutical company). The PDMB was challenged with reconciling internally inconsistent safety and mortality data and determining the weight to give mortality data from other concurrently running trials. The coordinating center faced a challenge in negotiating how to communicate results from a jointly sponsored trial. Early resolution of certain organizational and procedural issues, such as rules regarding absentee voting, to which body the monitoring committee should report officially, and the timing and general content of dissemination of different kinds of results, would make jointly sponsored trials more robust to difficulties at the final hour. [Copyright &y& Elsevier]

We report on the drug packaging, masking, and distribution procedures for a large double-masked, randomized, controlled, crossover trial. The Study of Inactivated Influenza Vaccine in Asthmatics was performed to evaluate whether influenza vaccination was safe for asthmatics. Nineteen clinical centers enrolled 2032 participants from 15 September to 30 November 2000. The participants were assigned individual kits with two syringes (placebo and vaccine); the order of injection was randomly assigned. All participants enrolled in the trial received the first injection and 2009 participants received the second injection. Five participants received their injections in the wrong order; we have no evidence that any participant received an injection from the wrong kit. Challenges faced by the trial were a manufacturing shortage of vaccine, the lack of a commercially available placebo, short time periods for planning and startup, and a diverse set of clinical centers. Utilizing individual syringe kits, using the same identification for patient, kit, and drug assignment, and dispensing drug from a central facility helped to successfully meet these challenges. [Copyright &y& Elsevier]

Background: Patients with chronic obstructive pulmonary disease (COPD) have high oxidative stress associated with the severity of the disease. Nuclear factor erythroid-2 related factor 2 (Nrf2)-directed stress response plays a critical role in the protection of lung cells to oxidative stress by upregulating antioxidant genes in response to tobacco smoke. There is a critical gap in our knowledge about Nrf-2 regulated genes in active smokers and former-smokers with COPD in different cell types from of lungs and surrogate peripheral tissues.Methods: We compared the expression of Nrf2 and six of its target genes in alveolar macrophages, nasal, and bronchial epithelium and peripheral blood mononuclear cells (PBMCs) in current and former smokers with COPD. We compared cell-type specific of Nrf2 and its target genes as well as markers of oxidative and inflammatory stress.Results: We enrolled 89 patients; expression all Nrf2 target gene measured were significantly higher in the bronchial epithelium from smokers compared to non-smokers. None were elevated in alveolar macrophages and only one was elevated in each of the other compartments.Conclusion: Bronchial epithelium is the most responsive tissue for transcriptional activation of Nrf2 target genes in active smokers compared to former-smokers with COPD that correlated with oxidative stress and inflammatory markers. There were no consistent trends in gene expression in other cell types tested.Trial Registration: Clinicaltrials.gov : NCT01335971. [ABSTRACT FROM AUTHOR]

Background and objective: The reduction of forced expiratory volume in 1 s (FEV1) in response to methacholine challenge in asthma may reflect two components: airway narrowing, assessed by the change in FEV1/forced vital capacity (FVC), and airway closure, assessed by the change in FVC. The purpose of this study was to determine the degree and determinants of airway closure in response to methacholine in a large group of asthmatic patients participating in studies conducted by the American Lung Association‐Airways Clinical Research Centers (ALA‐ACRC). Methods: We used the methacholine challenge data from participants in five studies of the ALA‐ACRC to determine the closing index, defined as the contribution of airway closure to the decrease in FEV1, and calculated as %ΔFVC/%ΔFEV1. Results: There were a total of 936 participants with asthma, among whom the median closing index was 0.67 relative to that of a published healthy population of 0.54. A higher closing index was associated with increased age (10‐year increments) (0.04, 95% CI = 0.02, 0.05, P < 0.005) and obesity (0.07, 95% CI = 0.03, 0.10, P < 0.001). There was no association between the closing index and asthma control. Conclusion: Our findings confirm that airway closure in response to methacholine occurs in a large, diverse population of asthmatic participants, and that increased airway closure is associated with older age and obesity. These findings suggest that therapies targeting airway closure may be important in patients with a high closing index. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the comparative effectiveness of 3 regional corticosteroid injections for uveitic macular edema (ME): periocular triamcinolone acetonide (PTA), intravitreal triamcinolone acetonide (ITA), and the intravitreal dexamethasone implant (IDI). Design Multicenter, randomized clinical trial. Participants Patients with uveitic ME. Methods Patients were randomized 1:1:1 to receive 1 of the 3 therapies. Patients with bilateral ME were assigned the same treatment for both eyes. Main Outcome Measures The primary outcome was the proportion of baseline (PropBL) central subfield thickness (CST) at 8 weeks (CST at 8 weeks/CST at baseline) assessed with OCT by masked readers. Secondary outcomes included ≥20% improvement and resolution of ME, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) events over 24 weeks. Results All treatment groups demonstrated improved CST during follow-up. At 8 weeks, each group had clinically meaningful reductions in CST relative to baseline (PropBL: 0.77, 0.61, and 0.54, respectively, which translates to reductions of 23%, 39%, and 46% for PTA, ITA, and IDI, respectively). Intravitreal triamcinolone acetonide (PropBL ITA/PropBL PTA, hazard ratio [HR], 0.79; 99.87% confidence interval [CI], 0.65–0.96) and IDI (PropBL IDI/PropBL PTA, HR, 0.69; 99.87% CI, 0.56–0.86) had larger reductions in CST than PTA (P < 0.0001). Intravitreal dexamethasone implant was noninferior to ITA at 8 weeks (PropBL IDI/PropBL ITA, HR, 0.88; 99.87% CI, 0.71–1.08). Both ITA and IDI treatments also were superior to PTA treatment in improving and resolving uveitic ME. All treatment groups demonstrated BCVA improvement throughout follow-up. Both ITA and IDI groups had improvements in BCVA that was 5 letters greater than in the PTA group at 8 weeks (P < 0.004). The risk of having IOP ≥24 mmHg was higher in the intravitreal treatment groups compared with the periocular group (HR, 1.83; 95% CI, 0.91–3.65 and HR, 2.52; 95% CI, 1.29–4.91 for ITA and IDI, respectively); however, there was no significant difference between the 2 intravitreal treatment groups. Conclusions Intravitreal triamcinolone acetonide and the IDI were superior to PTA for treating uveitic ME with modest increases in the risk of IOP elevation. This risk did not differ significantly between intravitreal treatments. [ABSTRACT FROM AUTHOR]

To evaluate the effectiveness of 3 different intravitreal treatments for persistent or recurrent uveitic macular edema (ME): dexamethasone implant, methotrexate, and ranibizumab. Single-masked, randomized controlled clinical trial. Patients with minimally active or inactive uveitis and persistent or recurrent uveitic ME in one or both eyes. Patients at 33 centers were randomized 1:1:1 to receive 1 of the 3 therapies. Patients with bilateral ME received the same treatment in both eyes. The primary outcome, measured at 12 weeks, was reduction in central subfield thickness (CST) expressed as a proportion of baseline (CST per CST at baseline) assessed with spectral-domain OCT by readers masked to treatment assignment. Secondary outcomes included improvement and resolution of ME, change in best-corrected visual acuity (BCVA), and elevations in intraocular pressure (IOP). One hundred ninety-four participants (225 eligible eyes) were randomized to dexamethasone (n = 65 participants and 77 eyes), methotrexate (n = 65 participants and 79 eyes), or ranibizumab (n = 64 participants and 69 eyes). All received at least 1 injection of the assigned treatment. At the 12-week primary outcome point, each group showed significant reductions in CST relative to baseline: 35%, 11%, and 22% for dexamethasone, methotrexate, and ranibizumab, respectively. Reduction of ME was significantly greater in the dexamethasone group than for either methotrexate (P < 0.01) or ranibizumab (P = 0.018). Only the dexamethasone group showed a statistically significant improvement in BCVA during follow-up (4.86 letters; P < 0.001). Elevations of IOP by 10 mmHg, to 24 mmHg or more, or both were more common in the dexamethasone group; IOP spikes to 30 mmHg or more were uncommon overall and were not significantly different among groups. Reductions in BCVA of 15 letters or more were more common in the methotrexate group and typically were attributable to persistent ME. At 12 weeks, in eyes with minimally active or inactive uveitis, dexamethasone was significantly better at treating persistent or recurrent ME than methotrexate or ranibizumab. Risk of IOP elevation was greater with dexamethasone, but elevations to levels of 30 mmHg or more were infrequent. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Purpose To evaluate longitudinal vision-related quality of life (VRQoL) in patients with noninfectious uveitis. Design Cohort study using randomized controlled trial data. Participants Patients with active or recently active intermediate uveitis, posterior uveitis, or panuveitis enrolled in the Multicenter Steroid Treatment Trial and Follow-up Study. Methods Data from the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) for the first 3 years after randomization were evaluated semiannually. Analyses were stratified by assigned treatment (129 implants vs. 126 systemic therapies) because of substantial differences in the trajectories of VRQoL. The impact of baseline measurements of visual function (visual acuity and visual field), demographics, and disease characteristics was assessed using generalized estimating equations. Main Outcome Measures Primary outcome was the NEI-VFQ-25 composite score over 3 years after randomization. Results Individuals in both treatment groups showed similar improvement in NEI-VFQ-25 scores after 3 years of follow-up (implant: 11.9 points; 95% confidence interval [CI], 8.6–15.2; P < 0.001; systemic: 9.0 points; 95% CI, 5.6–12.3; P < 0.001; P = 0.21 for interaction). Individuals in the implant group showed a substantial improvement during the first 6 months followed by stable scores, whereas individuals in the systemic group showed a steady improvement over the course of follow-up. Worse initial visual acuity and visual fields were associated with lower initial NEI-VFQ-25 scores for both treatment groups. In the systemic group, these differences were maintained throughout follow-up. In the implant group, individuals with initial visual acuity worse than 20/40 showed additional improvement in NEI-VFQ-25 score to come within −7 points (95% CI, −15.0 to 0.9) of those with visual acuity 20/40 or better initially, a clinically meaningful but not statistically significant difference ( P = 0.081). Results based on sensitivity analyses showed similar patterns. Conclusions Both treatment groups demonstrated significant improvements in NEI-VFQ-25 scores; however, the improvement was immediate for the implant group as opposed to gradual for the systemic group. Poorer visual function was associated significantly with initial differences in NEI-VFQ-25 scores. However, only individuals in the implant group with poor visual acuity were able to overcome their initial deficits by the end of 3 years. [ABSTRACT FROM AUTHOR]

INTRODUCTION Acute exposure to e-cigarette aerosol has been shown to have potentially deleterious effects on the cardiovascular system. However, the cardiovascular effects of habitual e-cigarette use have not been fully elucidated. Therefore, we aimed to assess the association of habitual e-cigarette use with endothelial dysfunction and inflammation -- subclinical markers known to be associated with increased cardiovascular risk. METHODS In this cross-sectional study, we analyzed data from 46 participants (23 exclusive e-cigarette users; 23 non-users) enrolled in the VAPORS-Endothelial function study. E-cigarette users had used e-cigarettes for ≥6 consecutive months. Non-users had used e-cigarettes <5 times and had a negative urine cotinine test (<30 ng/mL). Flow-mediated dilation (FMD) and reactive hyperemia index (RHI) were used to assess endothelial dysfunction, and we assayed high-sensitivity C-reactive protein, interleukin-6, fibrinogen, p-selectin, and myeloperoxidase as serum measures of inflammation. We used multivariable linear regression to assess the association of e-cigarette use with the markers of endothelial dysfunction and inflammation. RESULTS Of the 46 participants with mean age of 24.3 ± 4.0 years, the majority were males (78%), non-Hispanic (89%), and White (59%). Among non-users, 6 had cotinine levels <10 ng/mL while 17 had levels 10-30 ng/mL. Conversely, among e-cigarette users, the majority (14 of 23) had cotinine ≥500 ng/mL. At baseline, the systolic blood pressure was higher among e-cigarette users than non-users (p=0.011). The mean FMD was slightly lower among e-cigarette users (6.32%) compared to non-users (6.53%). However, in the adjusted analysis, current e-cigarette users did not differ significantly from non-users in their mean FMD (Coefficient=2.05; 95% CI: -2.52-6.63) or RHI (Coefficient= -0.20; 95% CI: -0.88-0.49). Similarly, the levels of inflammatory markers were generally low and did not differ between e-cigarette users and non-users. CONCLUSIONS Our findings suggest that e-cigarette use may not be significantly associated with endothelial dysfunction and systemic inflammation in relatively young and healthy individuals. Longer term studies with larger sample sizes are needed to validate these findings. [ABSTRACT FROM AUTHOR]

Background: Electronic cigarettes (ECs) have been widely used by young individuals in the U.S. while being considered less harmful than conventional tobacco cigarettes. However, ECs have increasingly been regarded as a health risk, producing detrimental chemicals that may cause, combined with poor oral hygiene, substantial inflammation in gingival and subgingival sites. In this paper, we first report that EC smoking significantly increases the odds of gingival inflammation. Then, through mediation analysis, we seek to identify and explain the mechanism that underlies the relationship between EC smoking and gingival inflammation via the oral microbiome. Methods: We collected saliva and subgingival samples from 75 EC users and 75 non-users between 18 and 34 years in age and profiled their microbial compositions via 16S rRNA amplicon sequencing. We conducted raw sequence data processing, denoising and taxonomic annotations using QIIME2 based on the expanded human oral microbiome database (eHOMD). We then created functional annotations (i.e., KEGG pathways) using PICRUSt2. Results: We found significant increases in α-diversity for EC users and disparities in β-diversity between EC users and non-users. We also found significant disparities between EC users and non-users in the relative abundance of 36 microbial taxa in the saliva site and 71 microbial taxa in the subgingival site. Finally, we found that 1 microbial taxon in the saliva site and 18 microbial taxa in the subgingival site significantly mediated the effects of EC smoking on gingival inflammation. The mediators on the genus level, for example, include Actinomyces, Rothia, Neisseria, and Enterococcus in the subgingival site. In addition, we report significant disparities between EC users and non-users in the relative abundance of 71 KEGG pathways in the subgingival site. Conclusions: These findings reveal that continued EC use can further increase microbial dysbiosis that may lead to periodontal disease. Our findings also suggest that continued surveillance for the effect of ECs on the oral microbiome and its transmission to oral diseases is needed. [ABSTRACT FROM AUTHOR]

Purpose: 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. Design: Cohort study of patients with CMV retinitis (Longitudinal Study of Ocular Complications of AIDS). Methods: 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. Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate the risk factors for herpes zoster as well as the incidence and timing of this complication in patients who were treated with immunosuppression because of active Wegener’s granulomatosis. Subjects and methods: We studied the 180 Wegener’s granulomatosis patients in the Wegener’s Granulomatosis Etanercept Trial (WGET). Herpes zoster events during WGET were documented prospectively. Follow-up questionnaires were employed to describe the location, treatment, and complication(s) of herpes zoster and its therapy. Univariate and multivariate analyses were performed to evaluate risk factors, including history of herpes zoster, for the occurrence of herpes zoster during the trial. All analyses were based on the time to first occurrence of herpes zoster. Results: Eighteen patients (10% of the WGET cohort) suffered a total of 19 herpes zoster episodes over a mean follow-up period of 27 months. The annual incidence of herpes zoster in the WGET cohort was 45 cases/1000 patient-years (95% confidence interval [CI]: 27, 70). The median time from enrollment to the occurrence of herpes zoster in the subgroup of patients with that complication was 16.5 months (± 9.4). Fifteen of the 19 herpes zoster events (79%) occurred between months 6 and 36, many months after the period of most intensive immunosuppression. In univariate analyses, history of serum creatinine ≥1.5 mg/dL before enrollment was associated with a relative risk (RR) of 3.0 (95% CI: 1.1, 7.8) for herpes zoster during WGET (P =.03). In multivariate analyses, serum creatinine ≥1.5 mg/dL was associated with an RR of 6.3 (95% CI: 2.0, 19.8; P =.002), and female sex with an RR of 4.6 (95% CI: 1.6, 13.2; P =.004). Conclusion: Renal dysfunction and female sex were consistently strong risk factors for herpes zoster events in this population. Contrary to expectation, most herpes zoster events did not occur during periods of most intensive immunosuppression. These data may inform studies of interventions designed to prevent herpes zoster in patients on treatment for immune-mediated diseases. [Copyright &y& Elsevier]

Background: Research participants often misunderstand the required elements of informed consent information, whether provided in written or oral format. Informed consent instruments with embedded evidence-based learning theory principles administered in multimedia electronic formats may improve comprehension and retention. Objective: This study aims to determine whether study information comprehension and retention using an interactive multimedia video consent process was noninferior to comprehension and retention after an in-person face-to-face interaction with a conventional written consent document for caregivers and adolescents enrolled in a clinical trial. Methods: Participants were caregivers and children aged 12 to 17 years who were enrolled in a clinical trial of asthma treatment. Consent information was presented as a multimedia web-based video consent interaction or as a conventional written consent document with in-person interaction between the prospective participants and the study staff. The trial used a parallel nonrandomized noninferiority design that compared the 2 consent methods. Caregivers and adolescents completed a 17-item open-ended comprehension questionnaire (score range 17-51) at enrollment and at the end of the study 20 weeks later. Comprehension and retention were compared between the consent formats. Noninferiority was established if the 95% CI upper bound of the difference in scores (conventional format minus web-based) was less than the noninferiority margin of 2.4; superiority was established if the upper bound of the CI was <0. Results: In total, 54 caregiver and adolescent dyads completed the interactive multimedia web-based video consent, and 25 dyads completed the conventional consent. Overall, 33% (26/79) of all adolescents were Black, 57% (45/79) were male, and 61% (48/79) had a household income of

Background: Obese children for unknown reasons report greater asthma symptoms. Asthma and obesity both independently associate with gastro-oesophageal reflux symptoms (GORS). Determining if obesity affects the link between GORS and asthma will help elucidate the obese-asthma phenotype.Objective: Extend our previous work to determine the degree of associations between the GORS and asthma phenotype.Methods: We conducted a cross-sectional study of lean (20%-65% body mass index, BMI) and obese (≥95% BMI) children aged 10-17 years old with persistent, early-onset asthma. Participants contributed demographics, GORS and asthma questionnaires and lung function data. We determined associations between weight status, GORS and asthma outcomes using multivariable linear and logistic regression. Findings were replicated in a second well-characterised cohort of asthmatic children.Results: Obese children had seven times higher odds of reporting multiple GORS (OR=7.7, 95% CI 1.9 to 31.0, interaction p value=.004). Asthma symptoms were closely associated with GORS scores in obese patients (r=0.815, p<0.0001) but not in leans (r=0.291, p=0.200; interaction p value=0.003). Higher GORS scores associated with higher FEV1-per cent predicted (p=0.003), lower airway resistance (R10, p=0.025), improved airway reactance (X10, p=0.005) but significantly worse asthma control (Asthma Control Questionnaire, p=0.007). A significant but weaker association between GORS and asthma symptoms was seen in leans compared with obese in the replicate cohort.Conclusion: GORS are more likely to associate with asthma symptoms in obese children. Better lung function among children reporting gastro-oesophageal reflux and asthma symptoms suggests that misattribution of GORS to asthma may be a contributing mechanism to excess asthma symptoms in obese children. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma," from the March 18, 1999 issue.

Nonadherence to asthma medications is prevalent among adolescents and young adults (AYAs) with asthma, leading to worsened control of asthma symptoms and more frequent exacerbations. AYAs have unique developmental transitional challenges that may alter medication adherence. We aimed to use a socio-ecological framework to explore the effect of transitional challenges from adolescence to young adulthood on asthma controller medication adherence and to identify possible strategies to promote medication adherence. We conducted qualitative semi-structured interviews by phone with 7 adolescents (14 to 17 years), their respective caregivers, and 7 young adults (18 to 30 years). Participants were recruited from a respiratory clinical trial network and pulmonary clinics in 4 states at 6 different sites through convenience sampling. Interviews were audio recorded, transcribed and coded using thematic analyses. Participants identified personal challenges affecting adherence to asthma medications during the transition from adolescence to young adulthood including responsibility for asthma self-management, understanding of asthma condition and severity, embarrassment, and life demands. Health systems factors including medication cost, challenges with insurance, difficulties obtaining refills, and difficulty with access to medications at school also impacted asthma medication adherence. Participants recommended adherence strategies including improved access to inhalers, incorporating asthma medications into daily routines, and using reminders. Focusing on the transitional challenges of AYAs during the time period from adolescence to young adulthood is necessary for supporting their asthma medication adherence and creating future interventions. Socio-ecological and systems factors should also be targeted for improved asthma medication adherence. Supplemental data for this article can be accessed online at . [ABSTRACT FROM AUTHOR]

Objective: To compare the relative effectiveness of systemic corticosteroids plus immunosuppression when indicated (systemic therapy) versus fluocinolone acetonide implant (implant therapy) for noninfectious intermediate, posterior, or panuveitis (uveitis). Design: Randomized controlled parallel superiority trial. Participants: Patients with active or recently active uveitis. Methods: Participants were randomized (allocation ratio 1:1) to systemic or implant therapy at 23 centers (3 countries). Implant-assigned participants with bilateral uveitis were assigned to have each eye that warranted study treatment implanted. Treatment-outcome associations were analyzed by assigned treatment for all eyes with uveitis. Main Outcome Measures: Masked examiners measured the primary outcome: change in best-corrected visual acuity from baseline. Secondary outcomes included patient-reported quality of life, ophthalmologist-graded uveitis activity, and local and systemic complications of uveitis or therapy. Reading Center graders and glaucoma specialists assessing ocular complications were masked. Participants, ophthalmologists, and coordinators were unmasked. Results: On evaluation of changes from baseline to 24 months among 255 patients randomized to implant and systemic therapy (479 eyes with uveitis), the implant and systemic therapy groups had an improvement in visual acuity of +6.0 and +3.2 letters (P = 0.16, 95% confidence interval on difference in improvement between groups, −1.2 to +6.7 letters, positive values favoring implant), an improvement in vision-related quality of life of +11.4 and +6.8 units (P = 0.043), a change in EuroQol-EQ5D health utility of +0.02 and −0.02 (P = 0.060), and residual active uveitis in 12% and 29% (P=0.001), respectively. Over the 24 month period, implant-assigned eyes had a higher risk of cataract surgery (80%, hazard ratio [HR] = 3.3, P < 0.0001), treatment for elevated intraocular pressure (61%, HR=4.2, P < 0.0001), and glaucoma (17%, HR=4.2, P = 0.0008). Patients assigned to systemic therapy had more prescription-requiring infections than patients assigned to implant therapy (0.60 vs 0.36/person-year, P=0.034), without notable long-term consequences; systemic adverse outcomes otherwise were unusual in both groups, with minimal differences between groups. Conclusions: In each treatment group, mean visual acuity improved over 24 months, with neither approach superior to a degree detectable with the study''s power. Therefore, the specific advantages and disadvantages identified should dictate selection between the alternative treatments in consideration of individual patients'' particular circumstances. Systemic therapy with aggressive use of corticosteroid-sparing immunosuppression was well tolerated, suggesting that this approach is reasonably safe for local and systemic inflammatory disorders. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

Objective: To report the clinical features on eye examination of patients with AIDS in the era of highly active antiretroviral therapy (HAART). Design: Cohort study. Participants: Patients with AIDS, age ≥ 13 years. Methods: Ophthalmologic examination, contrast sensitivity, visual fields, and laboratory testing at enrollment. Main Outcome Measures: Eye examination findings at enrollment. Results: As of March 31, 2003, 1632 participants with AIDS were enrolled. Evidence of intraocular inflammation was substantially more common among patients with cytomegalovirus (CMV) retinitis or other major ocular complications than among those without, as were the complications of infection and inflammation, including cataracts, pseudophakia, macular edema, and epiretinal membrane. Among patients with CMV retinitis, macular edema and epiretinal membrane formation were most common among patients with long-standing retinitis and immune recovery. Patients with newly diagnosed retinitis had eye examination findings similar to those reported in the pre-HAART era. Visual impairment (<20/40) in the better-seeing eye was present in 9.2% of patients with CMV retinitis, 41.4% of patients with other major ocular complications (primarily ocular opportunistic infections), and only 0.6% of patients with no major ocular complication (P<.0001). Although patients without major ocular complications generally had good visual acuity, approximately 9.8% of eyes and 6.6% of participants had contrast sensitivity loss sufficient to impair reading speed. Conclusions: In the HAART era, CMV retinitis and other ocular opportunistic infections are associated with intraocular inflammation, structural ocular complications, and visual impairment. Patients with newly diagnosed CMV retinitis have eye examination findings similar to those seen in the pre-HAART era. [Copyright &y& Elsevier]

Objective: To report the prevalence of ocular complications of AIDS in the era of highly active antiretroviral therapy (HAART). Design: Cohort study. Participants: Patients with AIDS, 13 years or older. Methods: History, eye examination, and laboratory testing at enrollment. Main Outcome Measure: Frequency of ocular complications at enrollment. Results: As of March 31, 2003, 1632 participants with AIDS were enrolled. The cohort had a history of severe immune deficiency, as evidenced by a median nadir CD4+ T-cell count of 30 cells per microliter. At enrollment, the median CD4+ T-cell count was 164 cells per microliter. CD4+ T-cell counts were <50 in 24.1% but ≥100 in 63.6% and ≥200 in 43.0%. Cytomegalovirus (CMV) retinitis was present in 22.1%, whereas other ocular opportunistic infections each were present in ≤0.6%. The incidence of CMV retinitis estimated from retrospective data was 5.60/100 person-years. Of the 360 patients with CMV retinitis, 22.5% were newly diagnosed at enrollment, and the remainder had more long-standing CMV retinitis (median, 2.8 years). Conclusions: Although there is the possibility of oversampling patients with AIDS and ocular complications (as compared with a random sample), which would lead to increased estimates of prevalent and incident ocular morbidities, these data still suggest a substantial decline in the incidence of CMV retinitis from the pre-HAART era. Nevertheless, new cases of CMV retinitis continue to occur, and there is a population of patients with long-standing retinitis who will require management. [Copyright &y& Elsevier]

The article presents a study to determine the impact of self-reported rhinitis and sinusitis on lower airway disease of patients with well-characterized asthma. Results revealed that sinusitis and allergic rhinitis are more common on female patients especially those having gastroesophageal reflux disease and has white race. Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and in patients with poorly controlled asthma. Exacerbations found to be not associated with low lung function.

Background: Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known.Objective: To measure the incidence of VTEs in patients with Wegener granulomatosis.Design: Prospective, observational cohort study.Setting: A multicenter, randomized, double-blind, placebo-controlled treatment trial for Wegener granulomatosis.Patients: 180 patients with Wegener granulomatosis enrolled during periods of active disease.Measurements: Venous thrombotic events (deep venous thromboses or pulmonary emboli) were documented and confirmed prospectively. Incidence rates were calculated on the basis of time to first VTE.Results: Thirteen patients had VTEs before enrollment. During 228 person-years of prospective follow-up, 16 VTEs occurred in 167 patients with no history of VTE. Median time from enrollment to VTE for patients with an event was 2.1 months. The incidence of VTE among patients with Wegener granulomatosis was 7.0 per 100 person-years (95% CI, 4.0 to 11.4).Limitations: Although prospectively recorded, screening for VTEs did not occur.Conclusions: The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.*For a list of members of The Wegener's Granulomatosis Etanercept Trial Research Group, see the Appendix. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated visual acuity (VA) over 5 years in a subspecialty noninfectious uveitis population.Methods: Retrospective data from 5,530 noninfectious uveitis patients with anterior, intermediate, posterior or panuveitis were abstracted by expert reviewers. Mean VA was calculated using inverse probability of censoring weighting to account for losses to follow-up.Results: Patients were a median of 41 years old, 65% female, and 73% white. Initial mean VA was worse among panuveitis (20/84) than posterior (20/64), intermediate (20/47), and anterior (20/37) uveitides. On average, mean VA improved by 0.62, 0.51, 0.37, and 0.26 logMAR-equivalent lines over 2 years, respectively (each P < .001), then remained stable, except posterior uveitis mean VA worsened to initial levels.Conclusion: Mean VA of uveitic eyes improved and, typically, improvement was sustained under uveitis subspecialty care. Because VA tends to improve under tertiary care, mean VA change appears a better outcome for clinical studies than time-to-loss of VA. [ABSTRACT FROM AUTHOR]

Filgrastim, or granulocyte colony-stimulating factor, reverses neutropenia associated with human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) infections. During a trial of anti-CMV retinitis therapies coadministered with antiretroviral therapy, 2-4 plasma specimens of HIV-1 RNA were collected from 36 HIV-1-infected patients receiving filgrastim to prevent neutropenia and from 36 patients not receiving filgrastim. For both groups, the crude mean and mean rate of change of HIV-1 log(10) RNA levels were similar. Adjustment for covariates (CD4(+) T cell lymphocytes, virus load at enrollment, level of neutropenia and antiretroviral therapy [mainly non-highly active antiretroviral therapy], and anti-CMV therapy during follow-up) resulted in a mean log(10) HIV-1 RNA level for individuals receiving filgrastim versus those not receiving the drug of 5.11 versus 4.87 (P=.12) and respective log mean rates of change per month of -0.08 versus -0.21 (P=.08). This latter difference has borderline statistical significance, which suggests that filgrastim may reduce the decline of HIV-1 RNA loads. [ABSTRACT FROM AUTHOR]

To evaluate the long-term outcomes of uveitic macular edema (ME). Longitudinal follow-up of a cohort of participants in a randomized clinical trial. A total of 248 eyes of 177 participants with uveitic ME enrolled in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study. OCT measurements, taken at baseline and annually, were graded by reading center graders masked to clinical data. Macular edema was defined as a center macular thickness (CMT) ≥240 μm on time-domain OCT or time-domain OCT equivalent. Resolution of ME was defined as normalization of macular thickness on OCT. Relapse of ME was defined as increase in macular thickness to ≥240 μm in an eye that previously had resolution. Visual acuity was measured at each visit with logarithmic visual acuity charts. Resolution and relapse of ME. Visual acuity. Among 227 eyes with ME followed ≥1 year, the cumulative percent of eyes with ME resolving at any point during 7 years was 94% (95% confidence interval [CI], 89–97). Epiretinal membranes on OCT were associated with a lower likelihood of ME resolution (hazard ratio [HR], 0.74; 95% CI, 0.55–1.01; P = 0.05). Among 177 eyes with resolved ME, the cumulative percent with relapse within 7 years was 43% (95% CI, 32–51). Eyes in which ME resolved gained a mean of 6.24 letters (95% CI, 4.40–8.09; P < 0.001) compared with eyes that remained free from ME during the 1-year follow-up intervals, whereas eyes in which ME did not resolve experienced no gain in vision (mean change −1.30 letters; 95% CI, −2.70 to 0.09; P = 0.065), and eyes that developed ME during the year (incident or relapsed) experienced a mean loss of −8.65 letters (95% CI, −11.5 to −5.84, P < 0.001). Given sufficient time and treatment, nearly all uveitic ME resolves, but episodes of relapse were common. Visual acuity results were better among eyes with resolved ME, suggesting that control of inflammation and resolution of ME might be visually relevant treatment targets. [ABSTRACT FROM AUTHOR]

To evaluate the responsiveness of quality of life (QoL) metrics to ocular and systemic events in patients with noninfectious uveitis. Cohort study using randomized controlled trial data. Patients with active or recently active intermediate, posterior, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study. Data on the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), EuroQol Questionnaire (EQ-5D), and Short Form Survey Instrument (SF-36) were evaluated semiannually during the first 3 years after randomization. The impact of ocular (e.g., changes in visual acuity [VA], activity status, cataract surgery) and systemic events (e.g., infections requiring treatment) on the 6-month changes in QoL was assessed for each metric using generalized estimating equations. The primary outcomes were the 6-month changes in vision-related (NEI-VFQ-25) and general health-related (EQ-5D index, SF-36 physical component summary [PCS]) QoL. Changes in VA (adjusted change [aΔ]: 2.70 units per 5 letter change, P < 0.001), implant placement in at least 1 eye (aΔ: 5.50, P < 0.001), cataract surgery (aΔ: 3.01, P = 0.017), and quieting of all eyes active at the beginning of the interval (aΔ: 2.20, P < 0.010) were associated with improvements in the NEI-VFQ-25. Reductions in VA (aΔ: −0.014 per 5 letter decline, P = 0.003), infections requiring a prescription (aΔ: −0.024, P = 0.021), and incident uveitis activity in at least 1 eye (aΔ: −0.023, P = 0.031) were associated with declines in the EQ-5D index. Hospitalization (aΔ: −2.24, P = 0.019), infections requiring a prescription (aΔ: −1.00, P = 0.024), and vitreous hemorrhage in at least 1 eye (aΔ: −1.92, P = 0.021) were associated with declines in the SF-36 PCS. Declines in VA, initiation in IOP medication, and age were associated with changes in SF-36 PCS; however, the magnitude of the change was less than a single point. The NEI-VFQ-25 was more sensitive to ocular changes than the general QoL metrics but less sensitive to acute systemic events. When performing QoL or cost-effectiveness analyses, it is important to consider the expected outcomes (e.g., ocular vs. systemic) to ensure that the selected measurement is sensitive enough to detect clinically important changes in disease status or effects of treatment. [ABSTRACT FROM AUTHOR]

A reply is presented by Drs. Stephen P. Peters, Mario Castro and Janet T. Holbrook to letters to the editor about their article "Randomized comparison of strategies for reducing treatment in mild persistent asthma," which appeared in the May 17, 2007 issue.

Objective: To characterize a cohort of children with airflow limitation resistant to bronchodilator (BD) therapy. Methods: Pulmonary function tests performed in children 6–17 years of age at 15 centers in a clinical research consortium were screened for resistant airflow limitation, defined as a post-BD FEV1 and/or an FEV1/FVC less than the lower limits of normal. Demographic and clinical data were analyzed for associations with pulmonary function. Results: 582 children were identified. Median age was 13 years (IQR: 11, 16), 60% were males; 62% were Caucasian, 28% were African-American; 19% were obese; 32% were born prematurely and 21% exposed to second hand smoke. Pulmonary diagnoses included asthma (93%), prior significant pneumonia (28%), and bronchiectasis (5%). 65% reported allergic rhinitis, and 11% chronic sinusitis. Subjects without a history of asthma had significantly lower post-BD FEV1% predicted (p = 0.008). Subjects without allergic rhinitis had lower post-BD FEV1% predicted (p = 0.003). Children with allergic rhinitis, male sex, obesity and Black race had better pulmonary function post-BD. There was lower pulmonary function in children after age 11 years without a history of allergic rhinitis, as compared to those with a history of allergic rhinitis. Conclusions: The most prevalent diagnosis in children with BD-resistant airflow limitation is asthma. Allergic rhinitis and premature birth are common co-morbidities. Children without a history of asthma, as well as those with asthma but no allergic rhinitis, had lower pulmonary function. Children with BD-resistant airflow limitation may represent a sub-group of children with persistent obstruction and high risk for life-long airway disease. [ABSTRACT FROM AUTHOR]

Background: The use of electronic cigarettes (EC) has risen exponentially over the past decade, including among never smokers, and ECs are now the most popular tobacco product among teenagers in the US. While, EC manufacturers utilize numerous marketing strategies to target both smokers and non-smokers, it is unclear how perceptions and behaviors differ between these two groups.Methods: We conducted a survey of 320 adults either via online surveys or in Baltimore vape shops to determine demographics, behaviors, perceptions, and motivations underlying use of ECs.Results: Our survey respondents were predominantly young, Caucasian males, 74% of whom identified themselves as former smokers, while 20% identified as current smokers and 6% were never smokers. Former smokers reported a longer history of EC use and higher nicotine concentrations than current smokers. For former and current smokers, the primary motivation for EC use was assistance to quit smoking, and nearly half indicated that they plan to reduce their nicotine concentration and eventually quit using ECs. Among former smokers, self-reports on use and measures of dependence were consistent with nicotine replacement as their primary motivation. The majority of former and current smokers also reported that their respiratory health had improved as a result of EC use, although this effect was stronger for former smokers. Never smokers reported less frequent EC use and dependence compared to former and current smokers. Their motivations for use were more commonly for enjoyment and popularity, and they displayed a reduced desire to eventually quit using ECs.Conclusions: These responses provide insight into the underlying thoughts and behaviors of smoking and non-smoking EC users and also suggest that never smoking EC users are an emerging demographic with different motivations and perceptions than those of current and former smokers. [ABSTRACT FROM AUTHOR]

Importance: A randomized clinical trial comparing fluocinolone acetonide implant vs systemic corticosteroids and immunosuppression for treatment of severe noninfectious intermediate, posterior, and panuveitides did not result in a significant difference in visual acuity at 2 and 4.5 years; longer-term outcomes are not known.Objective: To compare the association between intravitreous fluocinolone acetonide implant vs systemic therapy and long-term visual and other outcomes in patients with uveitis.Design, Setting, and Participants: Nonprespecified 7-year observational follow-up of the Multicenter Uveitis Steroid Treatment (MUST) randomized clinical trial comparing the alternative treatments. Follow-up was conducted in tertiary uveitis subspecialty practices in the United States (21), the United Kingdom (1), and Australia (1). Of 255 patients 13 years or older with intermediate, posterior, or panuveitis (active within ≤60 days) enrolled in the MUST trial between December 6, 2005, and December 9, 2008, 215 consented to ongoing follow-up through at least 7 years postrandomization (last visit, February 10, 2016).Interventions: Participants had been randomized to receive a surgically placed intravitreous fluocinolone acetonide implant or systemic corticosteroids supplemented by immunosuppression. When both eyes required treatment, both eyes were treated.Main Outcomes and Measures: Primary outcome was change from baseline in best-corrected visual acuity in uveitic eyes (5 letters = 1 visual acuity chart line; potential range of change in letters read, -121 to +101; minimal clinically important difference, 7 letters), analyzed by treatment assignment accounting for nonindependence of eyes when patients had 2 uveitic eyes. Secondary outcomes included potential systemic toxicities of corticosteroid and immunosuppressive therapy and death.Results: Seven-year data were obtained for 161 uveitic eyes (70% of 90 patients assigned to implant) and 167 uveitic eyes (71% of 90 patients assigned to systemic therapy) (77% female; median age at enrollment, 48 [interquartile range, 36-56] years). Change in mean visual acuity from baseline (implant, 61.7; systemic therapy, 65.0) through 7 years (implant, 55.8; systemic therapy, 66.2) favored systemic therapy by 7.2 (95% CI, 2.1-12) letters. Among protocol-specified, prospectively collected systemic adverse outcomes, the cumulative 7-year incidence in the implant and systemic therapy groups, respectively, was less than 10%, with the exceptions of hyperlipidemia (6.1% vs 11.2%), hypertension (9.8% vs 18.4%), osteopenia (41.5% vs 43.1%), fractures (11.3% vs 18.6%), hospitalization (47.6% vs 42.3%), and antibiotic-treated infection (57.4% vs 72.3%).Conclusions and Relevance: In 7-year extended follow-up of a randomized trial of patients with severe intermediate, posterior, or panuveitis, those randomized to receive systemic therapy had better visual acuity than those randomized to receive intravitreous fluocinolone acetonide implants. Study interpretation is limited by loss to follow-up.Trial Registration: clinicaltrials.gov Identifier: NCT00132691. [ABSTRACT FROM AUTHOR]

Purpose To assess the visual outcomes of cataract surgery in eyes that received fluocinolone acetonide implant or systemic therapy with oral corticosteroids and immunosuppression during the Multicenter Uveitis Steroid Treatment (MUST) Trial. Design Nested prospective cohort study of patients enrolled in a randomized clinical trial. Participants Patients that underwent cataract surgery during the first 2 years of follow-up in the MUST Trial. Methods Visual outcomes of cataract surgery were evaluated 3, 6, and 9 months after surgery using logarithmic visual acuity charts. Change in visual acuity over time was assessed using a mixed-effects model. Main Outcome Measures Best-corrected visual acuity. Results After excluding eyes that underwent cataract surgery simultaneously with implant surgery, among the 479 eyes in the MUST Trial, 117 eyes (28 eyes in the systemic, 89 in the implant group) in 82 patients underwent cataract surgery during the first 2 years of follow-up. Overall, visual acuity increased by 23 letters from the preoperative visit to the 3-month visit (95% confidence interval [CI], 17–29 letters; P < 0.001) and was stable through 9 months of follow-up. Eyes presumed to have a more severe cataract, as measured by inability to grade vitreous haze, gained an additional 42 letters (95% CI, 34–56 letters; P < 0.001) beyond the 13-letter gain in eyes that had gradable vitreous haze before surgery (95% CI, 9–18 letters; P < 0.001) 3 months after surgery, making up for an initial difference of −45 letters at the preoperative visit (95% CI, −56 to −34 letters; P < 0.001). Black race, longer time from uveitis onset, and hypotony were associated with worse preoperative visual acuity ( P < 0.05), but did not affect postsurgical recovery ( P > 0.05, test of interaction). After adjusting for other risk factors, there was no significant difference in the improvement in visual acuity between the 2 treatment groups (implant vs. systemic therapy, 2 letters; 95% CI, −10 to 15 letters; P = 0.70). Conclusions Cataract surgery resulted in substantial, sustained, and similar visual acuity improvement in the eyes of patients with uveitis treated with the fluocinolone acetonide implant or standard systemic therapy. [ABSTRACT FROM AUTHOR]

IMPORTANCE Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. objective To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. INTERVENTIONS Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. MAIN OUTCOMES AND MEASURES The primary outcome measure was change in forced expiratory volume in the first second (FEV,) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. RESULTS Mean changes in prebronchodilator FEV, over 24 weeks were 0.03 L (95% Cl, -0.01 to 0.08 L) in the placebo group and 0.01 L (95% Cl, -0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% Cl, 1.42-2.54] vs soy isoflavones, 2.20 [95% Cl, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% Cl, 2.7-4.1] vs soy isoflavones, 3.0 [95% Cl, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, -3.48 ppb [95% Cl, -5.99 to -0.97 ppb] vs soy isoflavones, 1.39 ppb [95% Cl, -1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement. CONCLUSIONS AND RELEVANCE Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. [ABSTRACT FROM AUTHOR]

Purpose: To describe the evaluation of optical coherence tomography (OCT) scans in the Muliticenter Uveitis Steroid Treatment (MUST) trial and report baseline OCT features of enrolled participants. Methods: Time-domain OCTs acquired by certified photographers using a standardized scan protocol were evaluated at a reading center. Accuracy of retinal thickness data was confirmed with quality evaluation, and caliper measurement of centerpoint thickness (CPT) was performed when retinal thickness data were unreliable. Morphological evaluation included cysts, subretinal fluid, epiretinal membranes (ERMs), and vitreomacular traction. Results: Of the 453 OCTs evaluated, automated retinal thickness was accurate in 69.5% of scans, caliper measurement was performed in 26%, and 4% were ungradable. Intraclass correlation was.98 for reproducibility of caliper measurement. Macular edema (centerpoint thickness ≥ 240 μm) was present in 36%. Cysts were present in 36.6% of scans and ERMs in 27.8%, predominantly central. Intergrader agreement ranged from 78 to 82% for morphological features. Conclusion: Retinal thickness data can be retrieved in a majority of OCT scans in clinical trial submissions for uveitis studies. Small cysts and ERMs involving the center are common in intermediate and posterior/panuveitis requiring systemic corticosteroid therapy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact of macular edema on visual acuity and visual field sensitivity in uveitis. Design: This study utilized baseline data from the Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized, parallel treatment clinical trial comparing alternative treatments for intermediate, posterior and panuveitis. Patients & Methods: 255 patients (481 eyes with uveitis) recruited at 23 subspecialty centers. Visual acuity, optical coherence tomography and Humphrey 24-2 visual field testing. Results: Macular edema was associated with impaired visual acuity ( p < 0.01). Different phenotypes of macular edema were associated with different degrees of visual impairment: cystoid changes without retinal thickening were associated with moderately impaired visual acuity (-5 ETDRS letters), but visual acuity was worse in eyes with retinal thickening (-13 letters) and with both cysts and thickening (-19 letters). Uveitis sufficient to satisfy the study's inclusion criteria was associated with impaired visual field sensitivity, but eyes with macular edema had even worse visual field sensitivity ( p < 0.01). Conclusions: The observation that macular edema substantially reduces visual function suggests macular edema itself is an important endpoint to study in the treatment of uveitis. As uveitis and macular edema both impair visual field sensitivity as measured by Humphrey 24-2 perimetry, both should be considered when evaluating patients with uveitis and raised intraocular pressure for glaucoma. [ABSTRACT FROM AUTHOR]

Context: Asymptomatic gastroesophageal reflux (GER) is prevalent in children with asthma. Untreated GER has been postulated to be a cause of inadequate asthma control in children despite inhaled corticosteroid treatment, but it is not known whether treatment with proton pump inhibitors improves asthma control.Objective: To determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER.Design, Setting, and Participants: The Study of Acid Reflux in Children With Asthma, a randomized, masked, placebo-controlled, parallel clinical trial that compared lansoprazole with placebo in children with poor asthma control who were receiving inhaled corticosteroid treatment. Three hundred six participants enrolled from April 2007 to September 2010 at 19 US academic clinical centers were followed up for 24 weeks. A subgroup had an esophageal pH study before randomization.Intervention: Participating children were randomly assigned to receive either lansoprazole, 15 mg/d if weighing less than 30 kg or 30 mg/d if weighing 30 kg or more (n = 149), or placebo (n = 157).Main Outcome Measures: The primary outcome measure was change in Asthma Control Questionnaire (ACQ) score (range, 0-6; a 0.5-unit change is considered clinically meaningful). Secondary outcome measures included lung function measures, asthma-related quality of life, and episodes of poor asthma control.Results: The mean age was 11 years (SD, 3 years). The mean difference in change (lansoprazole minus placebo) in the ACQ score was 0.2 units (95% CI, 0.0-0.3 units). There were no statistically significant differences in the mean difference in change for the secondary outcomes of forced expiratory volume in the first second (0.0 L; 95% CI, -0.1 to 0.1 L), asthma-related quality of life (-0.1; 95% CI, -0.3 to 0.1), or rate of episodes of poor asthma control (relative risk, 1.2; 95% CI, 0.9-1.5). Among the 115 children with esophageal pH studies, the prevalence of GER was 43%. In the subgroup with a positive pH study, no treatment effect for lansoprazole vs placebo was observed for any asthma outcome. Children treated with lansoprazole reported more respiratory infections (relative risk, 1.3 [95% CI, 1.1-1.6]).Conclusion: In this trial of children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole, compared with placebo, improved neither symptoms nor lung function but was associated with increased adverse events.Trial Registration: clinicaltrials.gov Identifier: NCT00442013. [ABSTRACT FROM AUTHOR]

Background. Leukotriene receptor antagonists including montelukast are an option for step-down therapy for mild asthmatics controlled on low-dose inhaled corticosteroids (ICS). Because some patients fail montelukast step-down therapy, it would be helpful for clinicians to be able to predict the risk of treatment failure. Objectives. To determine patient characteristics associated with montelukast treatment failure and develop a clinical index to predict the risk of montelukast treatment failure. Methods. Using the 165 participants in the Leukotriene or Corticosteroid or Corticosteroid-Salmeterol Study (LOCCS) trial who were stepped down from low-dose ICS to montelukast, we determined associations between enrollment variables and treatment failure. We constructed a montelukast failure index to predict the risk of montelukast treatment failure during step-down. To assess its specificity for montelukast, index performance was evaluated in the other LOCCS treatment groups. Results. Characteristics independently associated with montelukast treatment failure included age of asthma onset <10 years old (OR = 2.39; 95% CI = 1.17-5.02; p = .018), need for steroid burst in the last year (OR = 2.39; 95% CI = 1.13-5.09; p = .022), and pre-bronchodilator forced expiratory volume in 1 s (FEV1) (OR = 1.44 per 10% lower % predicted; 95% CI = 1.07-1.97; p = .016). A montelukast failure index was generated from these three variables (range: ?5 to 7 points). Scores <0 predicted low risk (<0.20) of treatment failure, whereas scores >5 predicted high risk (>0.60) of treatment failure. Conclusion. Early asthma onset, worse asthma control in the last year, and lower pre-bronchodilator FEV1 are associated with montelukast treatment failure. A montelukast failure index is proposed to quantify the risk of failure prior to treatment initiation. [ABSTRACT FROM AUTHOR]

Background: Treatment guidelines recommend the use of inhaled corticosteroids in patients with asthma who have persistent symptoms and the "stepping down" of therapy to the minimum needed to maintain control of asthma. Whether patients with asthma that is well controlled with the use of inhaled corticosteroids twice daily can receive a step-down treatment with once-daily montelukast (our primary hypothesis) or once-daily fluticasone propionate plus salmeterol (our secondary hypothesis) has not yet been determined.Methods: We randomly assigned 500 patients with asthma that was well controlled by inhaled fluticasone (100 microg twice daily) to receive continued fluticasone (100 microg twice daily) (169 patients), montelukast (5 or 10 mg each night) (166 patients), or fluticasone (100 microg) plus salmeterol (50 microg) each night (165 patients). Treatment was administered for 16 weeks in a double-blind manner. The primary outcome was the time to treatment failure.Results: Approximately 20% of patients assigned to receive continued fluticasone or switched to treatment with fluticasone plus salmeterol had treatment failure, as compared with 30.3% of subjects switched to montelukast. The hazard ratio for both comparisons was 1.6 (95% confidence interval, 1.1 to 2.6; P=0.03). The percentage of days on which patients were free of asthma symptoms (78.7 to 85.8%) was similar across the three groups.Conclusions: Patients with asthma that is well controlled with the use of twice-daily inhaled fluticasone can be switched to once-daily fluticasone plus salmeterol without increased rates of treatment failure. A switch to montelukast results in an increased rate of treatment failure and decreased asthma control; however, patients taking montelukast remained free of symptoms on 78.7% of treatment days. (ClinicalTrials.gov number, NCT00156819 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people. [ABSTRACT FROM AUTHOR]

Purpose: To quantitate the frequencies of the common causes of visual acuity loss for patients with AIDS and cytomegalovirus (CMV) retinitis in the era of highly active antiretroviral therapy (HAART). Design: Multicenter prospective observational study. Participants: Three hundred seventy-nine patients (494 eyes) with CMV retinitis. Methods: Follow-up every 3 months with medical history, ophthalmologic examination, and laboratory testing. Main Outcome Measures: Loss of visual acuity across the 20/50 or worse and 20/200 or worse thresholds and doubling of the visual angle; frequencies of causes of such vision loss. Results: Overall, involvement of the posterior pole with CMV retinitis (zone 1 retinitis) accounted for approximately one half of incident visual acuity loss of 20/50 or worse, 20/200 or worse, and of doubling of the visual angle. Cataract and retinitis-related retinal detachment were the second and third most common causes of vision loss, accounting for 22% to 33% and 13% to 20% of vision loss for the 3 outcomes, respectively. In subset analysis, cataract and cystoid macular edema (CME) accounted for approximately 50% of incident vision loss in eyes of patients with longstanding CMV retinitis and immune recovery at baseline, but these complications accounted for <10% of incident vision loss in eyes of patients with newly diagnosed CMV retinitis at baseline. Of eyes that had a vision-threatening complication of CMV retinitis, eyes that developed retinal detachment had the highest risk of vision loss, with 100% of eyes developing visual impairment (20/50 or worse vision) and 42% of eyes developing legal blindness (20/200 or worse vision) at 12 months after diagnosis of the retinal detachment. Conclusions: In the HAART era, zone 1 involvement and retinal detachment remain the most common causes of visual acuity loss among patients with CMV retinitis. Cataract and CME also are common causes of loss of visual acuity, primarily in those patients with HAART-induced immune recovery. [Copyright &y& Elsevier]

Purpose: To describe the incidence of and risk factors for visual acuity loss among patients with AIDS and cytomegalovirus (CMV) retinitis in the era of highly active antiretroviral therapy (HAART). Design: Multicenter prospective observational study. Participants: Three hundred seventy-nine patients with AIDS and CMV retinitis (494 eyes). Methods: Follow-up every 3 months with medical history, ophthalmologic examination, and laboratory testing. Main Outcome Measures: Incidence of visual acuity loss to 20/50 or worse, to 20/200 or worse, and of doubling of the visual angle in eyes affected with CMV retinitis. Results: Among the 494 eyes with CMV retinitis, the baseline frequencies of visual acuity loss to 20/50 or worse and to 20/200 or worse were 29% and 15%, respectively. Over a median follow-up period of 3.1 years, the incidences of visual acuity loss to 20/50 or worse, to 20/200 or worse, and of doubling of the visual angle were 0.10/eye-year (EY), 0.06/EY, and 0.13/EY, respectively. Immune recovery was associated with a 42% reduction in vision loss to 20/50 or worse and with a 61% reduction in vision loss to 20/200 or worse after adjusting for confounding. Of the patients with immune recovery at baseline, 17% had immune recovery uveitis (IRU). In these patients, the incidence rate of 20/50 or worse vision was similar to that observed in patients without immune recovery (0.17/EY vs. 0.16/EY), but the incidence of 20/200 or worse vision was similar to that observed among patients with immune recovery (0.04/EY vs. 0.04/EY). Conclusions: Cytomegalovirus retinitis is associated with a substantial risk of incident vision loss in the era of HAART. Those who have HAART-induced immune recovery have approximately 50% lower risk of visual acuity loss. Presence of IRU at baseline attenuated the protective effect of immune recovery for moderate vision loss but not for blindness. [Copyright &y& Elsevier]

After publication of the article [1], it has been brought to our attention that there is a funding acknowledgement missing. The authors would also like to include "Dr. Michael Joseph Blaha is funded by the American Heart Association Tobacco Regulatory Center, funding number: 1P50HL120163". [ABSTRACT FROM AUTHOR]