Publications

BACKGROUND

There are many occupational health hazards associated with long hours of air travel, including cosmic radiation exposure, circadian rhythm disruptions, prior and secondhand smoke exposure, for flight attendants who flew before smoking bans were initiated in the 1990s. Previous studies in flight attendants have found increased incidence of breast cancer and melanoma. However, there is little information on the relationship of airline travel and reproductive health in flight attendants. Secondhand smoke exposure has numerous negative health effects, such as increased cardiac events and respiratory infections, but its effect on reproductive health is not known. This study seeks to examine the role of secondhand smoke exposure on the miscarriage rate in flight attendants who flew before the smoking ban.

METHODS

Flight attendants who flew before the smoking ban and participating in a study of health effects of secondhand smoke were asked to complete a reproductive health survey. We compared miscarriage rates of flight attendants to the general population using 2010 data from the Centers for Disease Control and Prevention.

RESULTS

In our cohort of 145 female flight attendants exposed to secondhand smoke, there were 45 miscarriages (26%), compared with a 17.1% rate in the Centers for Disease Control and Prevention report (P = .002). There was no difference in secondhand smoke exposure between the flight attendants with miscarriage and the group without miscarriage (P = .93).

CONCLUSIONS

This study found an increased incidence of miscarriage in flight attendants, which was unrelated to secondhand smoke exposure. Other factors, such as circadian rhythm disruption and radiation, may be related to these reproductive health findings and require further investigation.

Background.

Treatment with latency reversing agents (LRAs) enhances human immunodeficiency virus type 1 (HIV-1) transcription in vivo but leads to only modest reductions in the size of the reservoir, possibly due to insufficient immune-mediated elimination of infected cells. We hypothesized that a single drug molecule-a novel Toll-like receptor 9 (TLR9) agonist, MGN1703-could function as an enhancer of innate immunity and an LRA in vivo.

Methods.

We conducted a single-arm, open-label study in which 15 virologically suppressed HIV-1-infected individuals on antiretroviral therapy received 60 mg MGN1703 subcutaneously twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, natural killer (NK), and T-cell activation using flow cytometry on baseline and after 4 weeks of treatment. HIV-1 transcription was quantified by measuring plasma HIV-1 RNA during MGN1703 administration.

Results.

In accordance with the cell type-specific expression of TLR9, MGN1703 treatment led to pronounced activation of plasmacytoid dendritic cells and substantial increases in plasma interferon-α2 levels (P < .0001). Consistently, transcription of interferon-stimulated genes (eg, OAS1, ISG15, Mx1; each P < .0001) were upregulated in CD4+ T cells as demonstrated by RNA sequencing. Further, proportions of activated cytotoxic NK cells and CD8+ T cells increased significantly during MGN1703 dosing, suggesting an enhancement of cellular immune responses. In 6 of 15 participants, plasma HIV-1 RNA increased from <20 copies/mL to >1500 copies/mL (range, 21-1571 copies/mL) during treatment.

Conclusions.

TLR9 agonist treatment in HIV infection has a dual potential by increasing HIV-1 transcription and enhancing cytotoxic NK cell activation, both of which are key outcomes in HIV-1 eradication therapy.

Clinical Trials Registration.

NCT02443935.

The treatment of advanced prostate cancer has changed significantly in the last decade, as a result of the introduction of multiple new systemic therapies that have had a positive impact on treatment outcomes. The increasing number of therapies, along with new insights into the biological underpinnings of prostate cancer, have led to a growing appreciation for the heterogeneity of the disease and an awareness of emerging subcategories that have direct therapeutic implications for the practicing clinician. In the metastatic hormone-naive setting, the extent of metastatic disease visible on scans can serve as a useful measure to guide treatment decisions; the addition of docetaxel chemotherapy to hormonal therapy has significant benefit in patients whose scans show more extensive disease. In the castration-resistant setting, abiraterone and enzalutamide have both had a transformative impact; however, the emergence of resistance to these therapies often heralds a more aggressive phenotype. Emerging clinically relevant subcategories include disease that demonstrates treatment-emergent neuroendocrine differentiation, as well as tumors with somatic and/or germline alterations in the DNA repair pathway. Identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors, and likely further therapies as new therapeutic targets are identified in these groups.

BACKGROUND

The use of inflammatory biomarkers to delineate the type of lung inflammation present in asthmatic subjects is increasingly common. However, the effect of obesity on these markers is unknown.

OBJECTIVES

We aimed to determine the effect of obesity on conventional markers of inflammation in asthmatic subjects.

METHODS

We performed secondary analysis of data from 652 subjects previously enrolled in 2 Asthma Clinical Research Network trials. We performed linear correlations between biomarkers and logistic regression analysis to determine the predictive value of IgE levels, blood eosinophil counts, and fraction of exhaled nitric oxide values in relationship to sputum eosinophil counts (>2%), as well as to determine whether cut points existed that would maximize the sensitivity and specificity for predicting sputum eosinophilia in the 3 weight groups.

RESULTS

Overall, statistically significant but relatively weak correlations were observed among all 4 markers of inflammation. Within obese subjects, the only significant correlation found was between IgE levels and blood eosinophil counts (r = 0.33, P < .001); furthermore, all other correlations between inflammatory markers were approximately 0, including correlations with sputum eosinophil counts. In addition, the predictive value of each biomarker alone or in combination was poor in obese subjects. In fact, in obese subjects none of the biomarkers of inflammation significantly predicted the presence of high sputum eosinophil counts. Obese asthmatic subjects have lower cut points for IgE levels (268 IU), fraction of exhaled nitric oxide values (14.5 ppb), and blood eosinophil counts (96 cells/μL) than all other groups.

CONCLUSIONS

In obese asthmatic subjects conventional biomarkers of inflammation are poorly predictive of eosinophilic airway inflammation. As such, biomarkers currently used to delineate eosinophilic inflammation in asthmatic subjects should be approached with caution in these subjects.

Despite the refinements in molecular methods for the detection of cytomegalovirus (CMV) and the advent of highly effective preemptive strategies, CMV remains a leading cause of morbidity and mortality in hematopoietic cell transplant (HCT) recipients. CMV can cause tissue-invasive disease including pneumonia, hepatitis, colitis, retinitis, and encephalitis. Mortality in HCT recipients with CMV disease can be as high as 60%. CMV infection has been associated with increased risk of secondary bacterial and fungal infections, increased risk of graft-versus-host disease, and high rates of non-relapse mortality following HCT. The risk of CMV is highly dependent on the donor (D) and the recipient (R) serostatus (D/R>D/R>D/R>D/R). Among allogeneic HCT recipients, high-dose corticosteroids, T-cell depletion, graft-versus-host disease, and mismatched or unrelated donors constitute the main predisposing factors. However, not all seropositive individuals with these risk factors develop CMV, which strongly suggests that host factors, such as those regulating CMV-specific T-cell responses, play a major role in predisposition to CMV in HCT recipients. Here, we discuss emerging concepts in CMV infection in HCT with emphasis on immunological factors that govern CMV reactivation and the applicability of immune monitoring to understand correlates of pathogenesis and its potential to guide clinical decision making.

Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG. In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicates that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in normal and in cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumour growth, and ERF loss rescues TMPRSS2-ERG-positive prostate cancer cells from ERG dependency. Collectively, these data provide evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF and they raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors.

Mesenchymal stem/stromal cells (MSCs) play crucial roles in maintaining tissue homeostasis during physiological turnovers and injuries. Very little is known about the phenotype, distribution and molecular nature of MSCs in freshly isolated human salivary glands (SGs) as most reports have focused on the analysis of cultured MSCs. Our results demonstrate that the cell adhesion molecule CD34 was widely expressed by the MSCs of human major SGs, namely parotid (PAG), sublingual (SLG) and submandibular (SMG) glands. Further, gene expression analysis of CD34 cells derived from fetal SMGs showed significant upregulation of genes involved in cellular adhesion, proliferation, branching, extracellular matrix remodeling and organ development. Moreover, CD34 SMG cells exhibited elevated expression of genes encoding extracellular matrix, basement membrane proteins, and members of ERK, FGF and PDGF signaling pathways, which play key roles in glandular development, branching and homeostasis. In vitro CD34 cell derived SG-MSCs revealed multilineage differentiation potential. Intraglandular transplantation of cultured MSCs in immunodeficient mice led to their engraftment in the injected and uninjected contralateral and ipsilateral glands. Engrafted cells could be localized to the stroma surrounding acini and ducts. In summary, our data show that CD34 derived SG-MSCs could be a promising cell source for adoptive cell-based SG therapies, and bioengineering of artificial SGs.

OBJECTIVES

To examine how dual coverage for nonelderly, low-income veterans by Veterans Affairs (VA) and Medicaid affects their demand for care.

DATA SOURCES

Veterans Affairs utilization data and Medicaid Analytic Extract Files.

STUDY DESIGN

A retrospective, longitudinal study of VA users prior to and following enrollment in Medicaid 2006-2010.

DATA COLLECTION/EXTRACTION METHODS

Veterans Affairs reliance, or proportion of care provided by VA, was estimated with beta-binomial models, adjusting for patient and state Medicaid program factors.

PRINCIPAL FINDINGS

In a cohort of 19,890 nonelderly veterans, VA utilization levels were similar before and after enrolling in Medicaid. VA outpatient reliance was 0.65, and VA inpatient reliance was 0.53 after Medicaid enrollment. Factors significantly associated with greater VA reliance included sociodemographic factors, having a service-connected disability, comorbidity, and higher state Medicaid reimbursement. Factors significantly associated with less VA reliance included months enrolled in Medicaid, managed care enrollment, Medicaid eligibility type, longer drive time to VA care, greater Medicaid eligibility generosity, and better Medicaid quality.

CONCLUSION

Veterans Affairs utilization following new Medicaid enrollment remained relatively unchanged, and the VA continued to provide the large majority of care for dually enrolled veterans. There was variation among patients as Medicaid eligibility and other program factors influenced their use of Medicaid services.