A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density.

INTRODUCTION: Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density. METHODS: The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (P int) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density. RESULTS: No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5' of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02). CONCLUSIONS: The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-015-0625-

Genetic predisposition to ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. METHODS: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. RESULTS: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10(-8). CONCLUSION: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist

The culture variable vis-à-vis anti-bribery law: a grey area in transnational corporate criminal liability

Cross-border transactions are generating corresponding globalisation of law enforcement efforts. Culture has significantly influenced the legal analysis of anti-bribery law. With the increase of transnational bribery, benefits from globalisation will be undermined unless an effective legal regime can mitigate the harm of bribery. It is perceived that corruption in China is more prevalent than in the West given its embedded place in Chinese culture. It is further alleged that Chinese multinational companies (MNCs) are taking advantage of an unlevel playing field, as they are not subject to stringently-enforced anti-bribery laws. This hypothesis creates a myriad of anti-bribery problems in terms of legislation and enforcement, which particularly manifest in China’s perceived cultural toleration of bribery. Cultural assumptions undermine the global anti-bribery regime and compromise potential collaborative anti-bribery efforts across jurisdictions in a rapidly globalizing world. The Chinese culture does not necessarily impede China’s criminalisation of paying bribes to foreign officials. It is argued that the cultural role should not be overestimated, otherwise the hazard of the ethnocentric engagement with the Chinese culture would affect the ability of foreign MNCs to integrate their global compliance programmes. Multinationals can only mitigate their exposure to criminal liability globally, provided that they comply robustly with anti-bribery laws of both home and host jurisdictions

Lack of insurance coverage and urgent care use for asthma: A retrospective cohort study

BACKGROUND: Asthma is a common chronic disease with profound impacts upon individuals and the US health care system. Inadequate health care coverage has been associated with more frequent and severe exacerbations of the disease. We examined the relationship between adequacy of health care coverage and use of emergent care of adults with asthma. METHODS: The 2001 Behavioral Risk Factor Surveillance System was the source of data on adults with current asthma. Bivariate and multiple logistic regression analysis modeled identifiable factors in predicting urgent or emergent care. RESULTS: Key variables included demographics and information on self-reported gaps in health care coverage. The primary outcome was emergency room or urgent care visits for worsening of asthma symptoms. Of 16,234 subjects nationally with current asthma, 2,195 from eight states had valid responses to a supplemental module asking about emergency room use or urgent care visits because of asthma. Thirty four percent of these individuals required such care in the previous year. Having an interruption in health care coverage in the past year was associated with an increased risk of needed urgent or emergent care (crude Odds Ratio [OR] 1.48, 95% confidence intervals [CI]1.03, 2.1). The association was not statistically significant in the adjusted multivariate model including race/ethnicity, employment status, gender, age, education and the ability to identify a primary physician (adjusted OR 1.2, 95% CI 0.8, 1.8). CONCLUSION: This study provides population-level, generalizable evidence of increased risk of exacerbations of asthma in adults and (1) their demographic characteristics, and (2) continuous adequate health care coverage

Availability of substance abuse treatment services in Spanish: A GIS analysis of Latino communities in Los Angeles County, California

<p>Abstract</p> <p>Background</p> <p>The percentage of Latino clients entering outpatient substance abuse treatment (OSAT) in the United States has increased significantly in the past 10 years. Evidence suggests that a lack of services in Spanish is a significant barrier to treatment access among Latinos.</p> <p>Methods</p> <p>Using a geographic information system (GIS) approach, data from the U.S. Census Bureau and the National Survey of Substance Abuse Treatment Services (N-SSATS) were analyzed to determine the geographic distance between OSAT facilities with services in Spanish and Latino communities throughout Los Angeles County, CA. Data from N-SSATS were also analyzed using logistic regression models to examine organizational characteristics and their association with offering services in Spanish. Our GIS methods are tested in their ability to provide baseline measures to inform future analysis comparing changes in demography and service infrastructure.</p> <p>Results</p> <p>GIS analysis revealed cold spots representing high-density Latino communities with extensive travel distance to facilities offering services in Spanish. The average linear distance between Latino communities and facilities offering Spanish-language services ranged from 2 to 6 miles, while the location of the cold spots pointed to a need for services in Spanish in a particular subregion of the county. Further, secondary data analysis revealed that, on average, being privately owned (<it>OR </it>= .23, 95% CI = 0.06-0.90) was associated with a lower likelihood of providing services in Spanish compared to public facilities. Additionally, a facility with a state license (<it>OR </it>= 2.08, 95% CI = 1.12-3.88) or a higher number of Medicaid recipients (<it>OR </it>= 2.98, 95% CI = 1.76-5.05) was twice as likely to offer services in Spanish.</p> <p>Conclusion</p> <p>Despite the significant presence of Latinos in L.A. County in 2000, low capacity was found in discrete Latino communities in terms of offering OSAT services in Spanish. Funding and regulation play a significant role in facilities' capacity to offer these services. Future studies should build from our multi-method approach to compare changes in population demography and system infrastructure and inform health care policy that seeks to improve providers' capacity to provide linguistically competent care.</p

Mental health first aid for Indigenous Australians: using Delphi consensus studies to develop guidelines for culturally appropriate responses to mental health problems

<p>Abstract</p> <p>Background</p> <p>Ethnic minority groups are under-represented in mental health care services because of barriers such as poor mental health literacy. In 2007, the Mental Health First Aid (MHFA) program implemented a cultural adaptation of its first aid course to improve the capacity of Indigenous Australians to recognise and respond to mental health issues within their own communities. It became apparent that the content of this training would be improved by the development of best practice guidelines. This research aimed to develop culturally appropriate guidelines for providing first aid to an Australian Aboriginal or Torres Strait Islander person who is experiencing a mental health crisis or developing a mental illness.</p> <p>Methods</p> <p>A panel of Australian Aboriginal people who are experts in Aboriginal mental health, participated in six independent Delphi studies investigating depression, psychosis, suicidal thoughts and behaviours, deliberate self-injury, trauma and loss, and cultural considerations. The panel varied in size across the studies, from 20-24 participants. Panellists were presented with statements about possible first aid actions via online questionnaires and were encouraged to suggest additional actions not covered by the survey content. Statements were accepted for inclusion in a guideline if they were endorsed by ≥ 90% of panellists as <it>essential </it>or <it>important</it>. Each study developed one guideline from the outcomes of three Delphi questionnaire rounds. At the end of the six Delphi studies, participants were asked to give feedback on the value of the project and their participation experience.</p> <p>Results</p> <p>From a total of 1,016 statements shown to the panel of experts, 536 statements were endorsed (94 for depression, 151 for psychosis, 52 for suicidal thoughts and behaviours, 53 for deliberate self-injury, 155 for trauma and loss, and 31 for cultural considerations). The methodology and the guidelines themselves were found to be useful and appropriate by the panellists.</p> <p>Conclusion</p> <p>Aboriginal mental health experts were able to reach consensus about culturally appropriate first aid for mental illness. The Delphi consensus method could be useful more generally for consulting Indigenous peoples about culturally appropriate best practice in mental health services.</p

Germline Mutation in BRCA1 or BRCA2 and Ten-Year Survival for Women Diagnosed with Epithelial Ovarian Cancer

PurposeTo analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis.Experimental designWe used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model.ResultsThe combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality.ConclusionsBRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance