The Costs, Benefits, and Cost-Effectiveness of Interventions to Reduce Maternal Morbidity and Mortality in Mexico

Background: In Mexico, the lifetime risk of dying from maternal causes is 1 in 370 compared to 1 in 2,500 in the U.S. Although national efforts have been made to improve maternal services in the last decade, it is unclear if Millennium Development Goal 5 - to reduce maternal mortality by three-quarters by 2015 - will be met. Methodology/Principal Findings: We developed an empirically calibrated model that simulates the natural history of pregnancy and pregnancy-related complications in a cohort of 15-year-old women followed over their lifetime. After synthesizing national and sub-national trends in maternal mortality, the model was calibrated to current intervention-specific coverage levels and validated by comparing model-projected life expectancy, total fertility rate, crude birth rate and maternal mortality ratio with Mexico-specific data. Using both published and primary data, we assessed the comparative health and economic outcomes of alternative strategies to reduce maternal morbidity and mortality. A dual approach that increased coverage of family planning by 15%, and assured access to safe abortion for all women desiring elective termination of pregnancy, reduced mortality by 43% and was cost saving compared to current practice. The most effective strategy added a third component, enhanced access to comprehensive emergency obstetric care for at least 90% of women requiring referral. At a national level, this strategy reduced mortality by 75%, cost less than current practice, and had an incremental cost-effectiveness ratio of $300 per DALY relative to the next best strategy. Analyses conducted at the state level yielded similar results. Conclusions/Significance: Increasing the provision of family planning and assuring access to safe abortion are feasible, complementary and cost-effective strategies that would provide the greatest benefit within a short-time frame. Incremental improvements in access to high-quality intrapartum and emergency obstetric care will further reduce maternal deaths and disability

Adherence to and appropriateness of anti-osteoporotic treatments in patients aged 50 and over in the Valencia Region (Spain). The ESOSVAL-AD Study

<p>Summary</p> <p>Background</p> <p>A study to evaluate the adherence to and appropriateness of anti-osteoporotic treatments in a cohort of men and women aged 50 and over participating in the ESOSVAL-R study.</p> <p>Methods/Design</p> <p><it>Design</it>: An observational, longitudinal, prospective cohort study; Study subjects: Men and women aged 50 and over living in the Valencia Region (Spain) who initiated treatment between June 15, 2009, and June 15, 2011, in primary healthcare centers with electronic medical records; <it>Data sources</it>: The main data source will be electronic medical records. <it>Measurement of results: </it>Degree of compliance with and persistence of anti-osteoporotic treatments, and the proportion of patients with appropriate anti-osteoporotic treatment in accordance with the most relevant and high impact recommendations with clearly defined treatment algorithms in Spain (the Spanish National Health System guide (2010), the General Practitioners' Society (2007) and the General Directorate for Pharmacy and Medical Products of Madrid (2007)), and with the National Osteoporosis Foundation (NOF, 2010), and the International Osteoporosis Foundation guidelines (IOF, 2008); <it>Analysis</it>: 1.) Descriptive analysis of patients undergoing treatment and the treatments prescribed; 2.) Descriptive analysis of compliance with and persistence of anti-osteoporotic treatments; 3.) Analysis of factors associated with compliance with and persistence of treatments by Cox proportional hazard regression models, 4.) Descriptive analysis of appropriateness of treatment; 5.) Analysis of factors associated with the appropriateness of treatment by multilevel models (4 levels: patient, doctor, Basic Healthcare Zone/Primary Healthcare Center, and Health Area variables).</p> <p>Discussion</p> <p>ESOSVAL-AD will provide information regarding adherence to osteoporosis treatments and the factors associated with a higher or lower adherence (including the appropriateness of the treatment) in the Spanish context. A better understanding of this phenomenon and the interventions needed to address it would contribute to the increased effectiveness of therapeutic measures, a reduction in morbidity and mortality, and a corresponding reduction in healthcare costs.</p

Brahma Is Required for Proper Expression of the Floral Repressor FLC in Arabidopsis

This is an open-access article distributed under the terms of the Creative Commons Attribution License.[Background]: BRAHMA (BRM) is a member of a family of ATPases of the SWI/SNF chromatin remodeling complexes from Arabidopsis. BRM has been previously shown to be crucial for vegetative and reproductive development. [Methodology/Principal Findings]: Here we carry out a detailed analysis of the flowering phenotype of brm mutant plants which reveals that, in addition to repressing the flowering promoting genes CONSTANS (CO), FLOWERING LOCUS T (FT) and SUPPRESSOR OF OVEREXPRESSION OF CO1 (SOC1), BRM also represses expression of the general flowering repressor FLOWERING LOCUS C (FLC). Thus, in brm mutant plants FLC expression is elevated, and FLC chromatin exhibits increased levels of histone H3 lysine 4 tri-methylation and decreased levels of H3 lysine 27 tri-methylation, indicating that BRM imposes a repressive chromatin configuration at the FLC locus. However, brm mutants display a normal vernalization response, indicating that BRM is not involved in vernalization-mediated FLC repression. Analysis of double mutants suggests that BRM is partially redundant with the autonomous pathway. Analysis of genetic interactions between BRM and the histone H2A.Z deposition machinery demonstrates that brm mutations overcome a requirement of H2A.Z for FLC activation suggesting that in the absence of BRM, a constitutively open chromatin conformation renders H2A.Z dispensable. [Conclusions/Significance]: BRM is critical for phase transition in Arabidopsis. Thus, BRM represses expression of the flowering promoting genes CO, FT and SOC1 and of the flowering repressor FLC. Our results indicate that BRM controls expression of FLC by creating a repressive chromatin configuration of the locus.This work was supported by Ministerio de Educacin y Ciencia (BFU2008-00238, CSD2006-00049), and by Junta de Andaluca (P06-CVI-01400) to J.C.R. and by the National Institutes of Health (grant no. 1R01GM079525), and the National Science Foundation (grant no. 0446440) to R.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Poverty related risk for potentially preventable hospitalisations among children in Taiwan

<p>Abstract</p> <p>Background</p> <p>This study investigated the incidence of potentially preventable hospitalisations in the first two years of life among children in the National Health Insurance (NHI) system of Taiwan. It also examined income disparities in potentially preventable hospitalisations across four economic categories: below a government-established poverty line and low-, middle-, and upper-income. Five major diseases causing potentially preventable hospitalisations were investigated: gastroenteritis and dehydration, asthma and chronic bronchitis, acute upper respiratory infections, lower respiratory infections, and acute injuries and poisonings.</p> <p>Methods</p> <p>NHI data on enrolee registrations and use of ambulatory and hospital care by all children born between July 1, 2003 and June 30, 2004 (n = 218,158) was used for the study. The negative binomial regression method was used to identify factors associated with total inpatient care and the severity level for various types of potentially preventable hospitalisations during the first two years of life.</p> <p>Results</p> <p>This study found high inpatient expenses for lower respiratory infections for children in all income categories. Furthermore, results from the multivariate analysis indicate that children in the lowest economic category used inpatient care to a much greater extent than better-off children for problems considered potentially avoidable through primary prevention or through timely outpatient care. This was especially true for acute injuries and poisonings and for lower respiratory infections. On average, and controlling for other variables, a child in poverty spent 6.1 times more days in inpatient care for acute injuries and poisonings (p < 0.01) and 2.7 times more days for lower respiratory infections (p < 0.01) before age two, compared with a similarly-aged high-income child. The results also suggest a connection between economic status and the severity of a condition causing a potentially avoidable hospital admission. On average, length of stay for each admission for gastroenteritis and dehydration for children in poverty was 1.3 times that for high-income children (p < 0.01). Both the ratios for lower respiratory infections and for acute upper respiratory infections were 1.2 (p < 0.01 for both).</p> <p>Conclusions</p> <p>There were high hospital admission rates and lengths of stays for lower respiratory infections among young children in all income categories. Hospital care use of young children in the poorest category was significantly higher for acute injuries and poisonings as well as for lower respiratory infections, compared with those of better-off children. The findings suggest the need for increased attention to these two disease types. It particularly calls for more research on the causes of high hospital care use for lower respiratory infections and on the reasons for large economic disparities in hospital care use for acute injuries and poisonings.</p

Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer

Background:Breast cancer anti-oestrogen resistance 4 (BCAR4) was identified in a search for genes involved in anti-oestrogen resistance in breast cancer. We explored whether BCAR4 is predictive for tamoxifen resistance and prognostic for tumour aggressiveness, and studied its function.Methods:BCAR4 mRNA levels were measured in primary breast tumours, and evaluated for association with progression-free survival (PFS) and clinical benefit in patients with oestrogen receptor (ERα)-positive tumours receiving tamoxifen as first-line monotherapy for advanced disease. In a separate cohort of patients with lymph node-negative, ERα-positive cancer, and not receiving systemic adjuvant therapy, BCAR4 levels were evaluated for association with distant metastasis-free survival (MFS). The function of BCAR4 was studied with immunoblotting and RNA interference in a cell model.Results:Multivariate analyses established high BCAR4 mRNA levels as an independent predictive factor for poor PFS after start of tamoxifen therapy for recurrent disease. High BCAR4 mRNA levels were associated with poor MFS and overall survival, reflecting tumour aggressiveness. In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased. Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance.Conclusion:BCAR4 may have clinical relevance for tumour aggressiveness and tamoxifen resistance. Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling. Patients with such tumours may benefit from ERBB-targeted therapy

Recombinant Lysyl Oxidase Propeptide Protein Inhibits Growth and Promotes Apoptosis of Pre-Existing Murine Breast Cancer Xenografts

Lysyl oxidase propeptide (LOX-PP) ectopic overexpression inhibits the growth of cancer xenografts. Here the ability and mode of action of purified recombinant LOX-PP (rLOX-PP) protein to inhibit the growth of pre-existing xenografts was determined. Experimental approaches employed were direct intratumoral injection (i.t.) of rLOX-PP protein into murine breast cancer NF639 xenografts, and application of a slow release formulation of rLOX-PP implanted adjacent to tumors in NCR nu/nu mice (n = 10). Tumors were monitored for growth, and after sacrifice were subjected to immunohistochemical and Western blot analyses for several markers of proliferation, apoptosis, and for rLOX-PP itself. Direct i.t. injection of rLOX-PP significantly reduced tumor volume on days 20, 22 and 25 and tumor weight at harvest on day 25 by 30% compared to control. Implantation of beads preloaded with 35 micrograms rLOX-PP (n = 10) in vivo reduced tumor volume and weight at sacrifice when compared to empty beads (p<0.05). A 30% reduction of tumor volume on days 22 and 25 (p<0.05) and final tumor weight on day 25 (p<0.05) were observed with a reduced tumor growth rate of 60% after implantation. rLOX-PP significantly reduced the expression of proliferation markers and Erk1/2 MAP kinase activation, while prominent increases in apoptosis markers were observed. rLOX-PP was detected by immunohistochemistry in harvested rLOX-PP tumors, but not in controls. Data provide pre-clinical findings that support proof of principle for the therapeutic anti-cancer potential of rLOX-PP protein formulations

Estrogen Receptor Silencing Induces Epithelial to Mesenchymal Transition in Human Breast Cancer Cells

We propose the hypothesis that loss of estrogen receptor function which leads to endocrine resistance in breast cancer, also results in trans-differentiation from an epithelial to a mesenchymal phenotype that is responsible for increased aggressiveness and metastatic propensity. siRNA mediated silencing of the estrogen receptor in MCF7 breast cancer cells resulted in estrogen/tamoxifen resistant cells (pII) with altered morphology, increased motility with rearrangement and switch from a keratin/actin to a vimentin based cytoskeleton, and ability to invade simulated components of the extracellular matrix. Phenotypic profiling using an Affymetrix Human Genome U133 plus 2.0 GeneChip indicated geometric fold changes ≥3 in approximately 2500 identifiable unique sequences, with about 1270 of these being up-regulated in pII cells. Changes were associated with genes whose products are involved in cell motility, loss of cellular adhesion and interaction with the extracellular matrix. Selective analysis of the data also showed a shift from luminal to basal cell markers and increased expression of a wide spectrum of genes normally associated with mesenchymal characteristics, with consequent loss of epithelial specific markers. Over-expression of several peptide growth factors and their receptors are indicative of an increased contribution to the higher proliferative rates of pII cells as well as aiding their potential for metastatic activity. Signalling molecules that have been identified as key transcriptional drivers of epithelial to mesenchymal transition were also found to be elevated in pII cells. These data support our hypothesis that induced loss of estrogen receptor in previously estrogen/antiestrogen sensitive cells is a trigger for the concomitant loss of endocrine dependence and onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type. Inhibition of this transition through targeting of specific mediators may offer a useful supplementary strategy to circumvent the effects of loss of endocrine sensitivity

CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer

Background:Endocrine therapies of breast cancer are effective but ultimately fail because of the development of treatment resistance. We have previously revealed several genes leading to tamoxifen resistance in vitro by retroviral insertion mutagenesis. To understand the manner in which these genes yield tamoxifen resistance, their effects on global gene expression were studied and those genes resulting in a distinct gene expression profile were further investigated for their clinical relevance.Methods:Gene expression profiles of 69 human breast cancer cell lines that were made tamoxifen resistant through retroviral insertion mutagenesis were obtained using oligonucleotide arrays and analysed with bioinformatic tools. mRNA levels of NCOR2 and CITED2 in oestrogen receptor-positive breast tumours were determined by quantitative RT-PCR. mRNA levels were evaluated for association with metastasis-free survival (MFS) in 620 patients with lymph node-negative primary breast cancer who did not receive systemic adjuvant therapy, and with clinical benefit in 296 patients receiving tamoxifen therapy for recurrent breast cancer.Results:mRNA expression profiles of most tamoxifen-resistant cell lines were strikingly similar, except for the subgroups of cell lines in which NCOR2 or CITED2 were targeted by the retrovirus. Both NCOR2 and CITED2 mRNA levels were associated with MFS, that is, tumour aggressiveness, independently of traditional prognostic factors. In addition, high CITED2 mRNA levels were predictive for a clinical benefit from first-line tamoxifen treatment in patients with advanced disease.Conclusions: Most retrovirally targeted genes yielding tamoxifen resistance in our cell lines do not impose a distinctive expressi

Alternative Strategies to Reduce Maternal Mortality in India: A Cost-Effectiveness Analysis

A cost-effectiveness study by Sue Goldie and colleagues finds that better family planning, provision of safe abortion, and improved intrapartum and emergency obstetrical care could reduce maternal mortality in India by 75% in 5 years