Changes in income-related inequalities in cervical cancer screening during the Spanish economic crisis: a decomposition analysis.

BACKGROUND: Cervical cancer is one of the most prevalent cancers, but it may be prevented by early detection. Social inequalities in the use of cytology testing have been identified in the literature. However, the degree of income-related inequality has not been quantified and determinants of inequality changes during the economic crisis remain unknown. METHODS: Using the Spanish National Health Surveys (2006-07 / 2011-12), we analyzed how income-related inequalities in the use of cervical cancer screening for women aged 25-64 changed across the economic crisis. We used corrected concentration indices (CCI) which were further decomposed in order to compute the contribution of the explanatory variables. An Oaxaca-type approach was employed to investigate the origin of changes over time. RESULTS: Our final sample consisted of 10,743 observations in 2006-07 and 6587 in 2011-12. Despite the higher prevalence of screening over time (from 73.9 to 77.9%), pro-rich inequality significantly increased (from CCI = 0.1726 to CCI = 0.1880, p < 0.001). Income was the main determinant of inequality in cervical screening, although its contribution decreased over time, as well as the contribution of the type of health insurance, mainly due to changes in elasticity. Other factors, such as nationality or the educational level, seem to have played an important role in the increase of pro-rich inequality of cytology testing. CONCLUSIONS: Reducing cervical screening inequalities would require actions focused on most vulnerable groups such as migrants, low income and low educated population. The implementation of population-based screening programs would also help to cope with income-related inequalities in cytology testing.

Assessing adherence to inhaled medication in asthma: Impact of once-daily versus twice-daily dosing frequency. The ATAUD study.

INTRODUCTION: This study was aimed at evaluating whether once-daily regimens (od-r) show benefits in adherence when compared to twice-daily (td-r). METHODS: Prospective, multicenter, 6-month follow-up study with two visits. The main objective was to compare adherence assessed by the electronic prescription refill rate (EPRR) and by the 10-item Test of Adherence to Inhalers (TAI) in patients with od-r and td-r. Suboptimal adherence was defined as TAI < 50 or EPRR ≤ 80%. The effect of suboptimal adherence on meaningful clinical outcomes and the concordance between EPRR and TAI were also examined. RESULTS: One hundred and ninety-seven patients (47.3 ± 15.9 years, 65% women) were included and 180 completed the study. TAI score was <50 in 29.8% od-r patients and 46.9% in td-r (p = 0.01) and EPRR was ≤80% in 22.6% and 37.5% respectively (p = 0.02). The correlation between the two methods was moderate (rho = 0.548; p < 0.001). There were no significant differences in FEV1 (%), symptoms or exacerbations between patients with optimal and suboptimal adherence. During follow-up, five patients (6%) with o-dr and 17 patients (17.7%) with t-dr suffered an exacerbation (p = 0.013). At visit two, 13.1% of the patients with o-dr and 31.3% with t-dr had uncontrolled asthma (p = 0.003), although more patients with o-dr were receiving inhaled corticosteroids in the high-dose stratum (25.8% vs. 11.5%; p = 0.001). CONCLUSION: Mean adherence rates were greater with od-r than with td-r, but we did not observe an effect on clinical outcomes.

Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV-1 vector.

BACKGROUND: Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disease caused by mutations in the frataxin gene (FXN), which lead to reduced levels of the essential mitochondrial protein frataxin. Currently, there is no effective cure. METHODS: With the aim of developing a gene therapy for FA neuropathology, we describe the construction and preliminary characterization of a high-capacity nonreplicative genomic herpes simplex virus type 1 vector (H24B-FXNlac vector) carrying a reduced version of the human FXN genomic locus, comprising the 5-kb promoter and the FXN cDNA with the inclusion of intron 1. RESULTS: We show that the transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression. Transduction of cultured fetal rat dorsal root ganglia neurons with the H24B-FXNlac vector results in sustained expression of human FXN transcripts and frataxin protein. Rat footpad inoculation with the H24B-FXNlac vector results in human FXN transgene delivery to the dorsal root ganglia, with expression persisting for at least 1 month. CONCLUSIONS: The results of the present study support the feasibility of using this vector for sustained neuronal expression of human frataxin for FA gene therapy.

G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy.

Mutant isocitrate-dehydrogenase 1 (mIDH1) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells' transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells' compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the mIDH1 TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. Blocking G-CSF in mIDH1 glioma­bearing mice restores the inhibitory potential of the tumor-infiltrating myeloid cells, accelerating tumor progression. We demonstrate that G-CSF reprograms bone marrow granulopoiesis, resulting in noninhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy.

Fyn tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates antiglioma immune responses.

BACKGROUND: High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. Fyn tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinase pathway and is overexpressed in human gliomas. Fyn's role in vivo in glioma growth remains unknown. We investigated whether Fyn regulates glioma initiation, growth and invasion. METHODS: We evaluated the role of Fyn using genetically engineered mouse glioma models (GEMMs). We also generated Fyn knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (nonobese diabetic severe combined immunodeficient gamma mice [NSG], CD8-/-, CD4-/-). We analyzed molecular mechanism by RNA sequencing and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the Fyn knockdown glioma TME. RESULTS: We demonstrate that Fyn knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontology (GO) analysis of differentially expressed genes in wild-type versus Fyn knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG and CD8-/- and CD4-/- immune-deficient mice, Fyn knockdown gliomas failed to show differences in survival. These data suggest that the expression of Fyn in glioma cells reduces antiglioma immune activation. Examination of glioma immune infiltrates by flow cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells in the Fyn glioma TME. CONCLUSIONS: Gliomas employ Fyn mediated mechanisms to enhance immune suppression and promote tumor progression. We propose that Fyn inhibition within glioma cells could improve the efficacy of antiglioma immunotherapies.

Immunotherapy for gliomas: shedding light on progress in preclinical and clinical development.

INTRODUCTION: Gliomas are infiltrating brain tumors associated with high morbidity and mortality. Current standard of care includes radiation, chemotherapy, and surgical resection. Today, survival rates for malignant glioma patients remain dismal and unchanged for decades. The glioma microenvironment is highly immunosuppressive and consequently this has motivated the development of immunotherapies for counteracting this condition, enabling the immune cells within the tumor microenvironment to react against this tumor. AREAS COVERED: The authors discuss immunotherapeutic strategies for glioma in phase-I/II clinical trials and illuminate their mechanisms of action, limitations, and key challenges. They also examine promising approaches under preclinical development. EXPERT OPINION: In the last decade there has been an expansion in immune-mediated anti-cancer therapies. In the glioma field, sophisticated strategies have been successfully implemented in preclinical models. Unfortunately, clinical trials have not yet yielded consistent results for glioma patients. This could be attributed to our limited understanding of the complex immune cell infiltration and its interaction with the tumor cells, the selected time for treatment, the combination with other therapies and the route of administration of the agent. Applying these modalities to treat malignant glioma is challenging, but many new alternatives are emerging to by-pass these hurdles.

Disentangling effects of socioeconomic status on obesity: A cross-sectional study of the Spanish adult population.

This paper complements previous estimations regarding socioeconomic inequalities in obesity for Spanish adults, and provides new evidence about the mechanisms through which socioeconomic status (SES) affects obesity. Microdata from the Spanish National Health Survey (SNHS) 2011-2012 are analysed. Corrected concentration indices (CCI) are calculated to measure inequality. Path analysis is employed to disentangle direct and indirect effects of SES on obesity, where dietary patterns, physical activity and sleep habits act as mediator variables. Multivariate logistic models are used to select those exogenous variables to be included in the path diagram. Men and women are analysed separately. Our results show significant pro-rich inequality in the distribution of obesity (the poorer the more obese), particularly for women (CCI=-0.070 for men, CCI=-0.079 for women). The indirect effects of SES on obesity (those transmitted via mediator variables) are quite modest (3.3% for males, 2.4% for females) due to three reasons. Firstly, dietary habits do not show a significant mediating effect. Secondly, the mediating effect of physical activity in leisure time, although significant (14% for males, 11.1% for females), is offset by that related to main activity. Finally, sleep habits contribution to total effect of SES on obesity is statistically significant but small (roughly 1%). Our results indicate that promoting physical activity in leisure time for those with a low SES, particularly for men, would contribute to prevent obesity and to reduce health inequalities. Promotion of adequate sleep habits for women with a low SES might have a similar effect. However, interventions aimed to reduce sedentarism related to main activity, although useful to prevent obesity, would amplify the obesity socioeconomic gradient. Since effects of SES are different for men and women, socioeconomic health inequalities should be addressed also from a gender perspective.

Biosafety of gene therapy vectors derived from herpes simplex virus type 1.

The majority of humans have been infected with Herpes Simplex Virus Type 1 (HSV-1) and harbor its viral DNA in the latent form within neurons for lifetime. This, combined with the absence of serious adverse effects due to HSV-1 derived vectors in clinical trials so far, highlight the potential to use this virus to develop neuronal gene transfer vectors which are transparent to the host, allowing the effects of the transgene to act without interference from the transfer system eg., for functional genomics in basic neuroscience or gene therapy of neurological disorders. On the other hand, other HSV-1 derived vectors which also have a promising perspective in the clinic, are designed to have enhanced cytotoxicity in certain cell types, as in the case of oncolytic vectors. Understanding virus-host interactions is fundamental not only to the success of these gene therapy vectors but also with respect to identifying and minimizing biohazards associated with their use. In this review we discuss characteristics of HSV-1 and gene therapy vectors derived from this virus which are useful to consider in the context of biosafety risk assessment and risk management.