Publications

RATIONALE

Restoration of vitamin D sufficiency may reduce asthma exacerbations, events that are often associated with respiratory tract infections and cold symptoms.

OBJECTIVES

To determine whether vitamin D supplementation reduces cold symptom occurrence and severity in adults with mild to moderate asthma and vitamin D insufficiency.

METHODS

Colds were assessed in the AsthmaNet VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness) trial, in which 408 adult patients were randomized to receive placebo or cholecalciferol (100,000 IU load plus 4,000 IU/d) for 28 weeks as add-on therapy. The primary outcome was cold symptom severity, which was assessed using daily scores on the 21-item Wisconsin Upper Respiratory Symptom Survey.

MEASUREMENTS AND MAIN RESULTS

A total of 203 participants experienced at least one cold. Despite achieving 25-hydroxyvitamin D levels of 41.9 ng/ml (95% confidence interval [CI], 40.1-43.7 ng/ml) by 12 weeks, vitamin D supplementation had no effect on the primary outcome: the average peak WURSS-21 scores (62.0 [95% CI, 55.1-68.9; placebo] and 58.7 [95% CI, 52.4-65.0; vitamin D]; P = 0.39). The rate of colds did not differ between groups (rate ratio [RR], 1.2; 95% CI, 0.9-1.5); however, among African Americans, those receiving vitamin D versus placebo had an increased rate of colds (RR, 1.7; 95% CI, 1.1-2.7; P = 0.02). This was also observed in a responder analysis of all subjects achieving vitamin D sufficiency, regardless of treatment assignment (RR, 1.4; 95% CI, 1.1-1.7; P = 0.009).

CONCLUSIONS

Our findings in patients with mild to moderate asthma undergoing an inhaled corticosteroid dose reduction do not support the use of vitamin D supplementation for the purpose of reducing cold severity or frequency.

More than 15 years ago, mutations in the autoimmune regulator (AIRE) gene were identified as the cause of autoimmune polyglandular syndrome type 1 (APS1). It is now clear that this transcription factor has a crucial role in promoting self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery. In this Review, we highlight many of the recent advances in our understanding of the complex biology that is related to AIRE, with a particular focus on advances in genetics, molecular interactions and the effect of AIRE on thymic selection of regulatory T cells. Furthermore, we highlight new areas of biology that are potentially affected by this key regulator of immune tolerance.

OBJECTIVE

Coinfection with hepatitis C virus (HCV) is a major cause of morbidity and mortality among individuals with HIV. Our objective was to assess the prognostic performance of noninvasive measures of liver fibrosis in predicting all-cause mortality in women with HIV/HCV coinfection.

DESIGN

We studied HCV/HIV coinfected women enrolled in the prospective, multicenter Women's Interagency HIV Study. Aspartate aminotransferase to platelet ratio and FIB-4 were used to identify women without fibrosis at all visits and women who progressed to severe fibrosis.

METHODS

Enhanced liver fibrosis (ELF), which utilizes direct measures of fibrosis, hyaluronic acid, procollagen III aminoterminal peptide and tissue inhibitor of matrix metalloproteinase was performed.

RESULTS

Included were 381 women with 2296 ELF measurements, with mean follow-up 8.3 ± 3.3 years. There were 134 deaths (60% with severe liver fibrosis). Receiver operator characteristic curves at fixed time windows prior to death or at end of follow-up showed that ELF was best at predicting mortality when tested within a year of death (area under the curve for ELF 0.85 vs. APRI 0.69, P < 0.0001 and vs. FIB-4 0.75, P = 0.0036); and 1-3 years prior (ELF 0.71 vs. APRI 0.61, P = 0.005 and vs. FIB-4 0.65, P = 0.06). Use of all three measures did not improve on ELF alone. In multivariate logistic regression models controlling for CD4 cell count, HIV viral load, antiretroviral use and age, ELF continued to perform better than APRI and FIB-4.

CONCLUSION

ELF predicted all-cause mortality and was superior to APRI and FIB-4 in HIV/HCV coinfected women.

US EPA's Toxicity Forecaster (ToxCastTM) is a tool with potential use in evaluating safer consumer products, conducting chemical alternatives analyses, prioritizing chemicals for exposure monitoring, and ultimately performing screening-level risk assessments. As a case study exploring a potential use of ToxCast, we evaluated ToxCast results for ortho-phthalates focused on the well-established toxicological endpoints of some members of this class. We compared molecular perturbations measured in ToxCast assays with the known apical toxicity endpoints of o-phthalates reported in the open literature to broadly reflect on the predictive capability of the high-throughput screening (HTS) assays. We grouped the ToxCast assays into defined sets to examine o-phthalate activity and potency. This study revealed several links between key molecular events assayed in vitro and chemical-specific hazard traits. In general, parent o-phthalates are more active than their monoester metabolites. The medium-chain length o-phthalate group is also more active than other o-phthalate groups, as supported by Toxicological Priority Index ranking and statistical methods. Some HTS assay results correlated with in vivo findings, but others did not. For example, there was a notable lack of assay activity to explain the known male reproductive toxicity of these compounds. Ultimately, HTS data resources such as ToxCast may inform us of sensitive upstream toxicity endpoints and may assist in the rapid identification of environmental chemical hazards for screening and prioritization. However, this case study shows that the absence of positive results in ToxCast in vitro assays cannot be interpreted as absence of related in vivo toxicity, and limited biological coverage by the assays remains a concern.