Forced sexual experiences as risk factor for self-reported HIV infection among southern African lesbian and bisexual women

Even though women who have sex with women are usually understood to be at no or very low risk for HIV infection, we explored whether lesbian and bisexual women in a geographical area with high HIV prevalence (Southern Africa) get tested for HIV and whether, among those women who get tested, there are women who live with HIV/AIDS. The study was conducted in collaboration with community-based organizations in Botswana, Namibia, South Africa and Zimbabwe. Data were collected via written surveys of women who in the preceding year had had sex with a woman (18 years and older; N = 591). Most participating women identified as lesbian and black. Almost half of the women (47.2%) reported ever having had consensual heterosexual sex. Engagement in transactional sex (lifetime) was reported by 18.6% of all women. Forced sex by men or women was reported by 31.1% of all women. A large proportion of the women reported to ever have been tested for HIV (78.3%); number of lifetime female and male partners was independently associated with having been tested; women who had engaged in transactional sex with women only or with women and men were less likely to have been tested. Self-reported HIV prevalence among tested women who knew their serostatus was 9.6%. Besides age, the sole independent predictor of a positive serostatus was having experienced forced sex by men, by women, or by both men and women. Study findings indicate that despite the image of invulnerability, HIV/AIDS is a reality for lesbian and bisexual women in Southern Africa. Surprisingly, it is not sex with men per se, but rather forced sex that is the important risk factor for self-reported HIV infection among the participating women. HIV/AIDS policy should also address the needs of lesbian, bisexual and other women who have sex with women

COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration

published_or_final_versio

Rapid and Accurate Assessment of GPCR-Ligand Interactions Using the Fragment Molecular Orbital-Based Density-Functional Tight-Binding Method

The reliable and precise evaluation of receptor–ligand interactions and pair-interaction energy is an essential element of rational drug design. While quantum mechanical (QM) methods have been a promising means by which to achieve this, traditional QM is not applicable for large biological systems due to its high computational cost. Here, the fragment molecular orbital (FMO) method has been used to accelerate QM calculations, and by combining FMO with the density-functional tight-binding (DFTB) method we are able to decrease computational cost 1000 times, achieving results in seconds, instead of hours. We have applied FMO-DFTB to three different GPCR–ligand systems. Our results correlate well with site directed mutagenesis data and findings presented in the published literature, demonstrating that FMO-DFTB is a rapid and accurate means of GPCR–ligand interactions

Characterising Inter-helical Interactions of G Protein-Coupled Receptors with the Fragment Molecular Orbital Method

G-protein coupled receptors (GPCRs) are the largest superfamily of membrane proteins, regulating almost every aspect of cellular activity and serving as key targets for drug discovery. We have identified an accurate and reliable computational method to characterise the strength and chemical nature of the inter-helical interactions between the residues of transmembrane (TM) domains during different receptor activation states, something that cannot be characterised solely by visual inspection of structural information. Using the fragment molecular orbital (FMO) quantum mechanics method to analyse 35 crystal structures representing different branches of the class A GPCR family, we have identified 69 topologically-equivalent TM residues that form a consensus network of 51 inter-TM interactions, providing novel results that are consistent with and help to rationalise experimental data. This discovery establishes a comprehensive picture of how defined molecular forces govern specific inter-helical interactions which, in turn, support the structural stability, ligand binding and activation of GPCRs

Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age

BACKGROUND: BRCA1 and BRCA2 mutations are found in a proportion of families with multiple early-onset breast cancers. There are a large number of different deleterious mutations in both genes, none of which would be detectable using standard genetic association studies. Single common variants and haplotypes of common variants may capture groups of deleterious mutations since some low prevalence haplotypes of common variants occur more frequently among chromosomes that carry rare, deleterious mutations than chromosomes that do not. METHODS: DNA sequence data for BRCA1 and BRCA2 was obtained from 571 participants from the Australian Breast Cancer Family Study. Genetic variants were classified as either deleterious mutations or common genetic variants. Variants tagging common polymorphisms were selected and haplotypes resolved using Haploview. Their frequency was compared to those with and without deleterious mutations using a permutation test. RESULTS: A common genetic variant in BRCA1 (3232A > G) was found to be over-represented in deleterious mutation carriers (p = 0.05), whereas a common genetic variant in BRCA2 (1342A > C) occurred less frequently in deleterious mutation carriers (p = 0.04). All four of the common BRCA1 variants used to form haplotypes occurred more frequently in the deleterious mutation carriers when compared to the non-carriers, but there was no evidence of a difference in the distributions between the two groups (p = 0.34). In BRCA2, all four common variants were found to occur less frequently in the deleterious mutation carriers when compared to non-carriers, but the evidence for difference in the distribution between the two groups was weak (p = 0.16). Several less common haplotypes of common BRCA1 variants were found to be over-represented among deleterious mutation carriers but there was no evidence for this at the population level. In BRCA2, only the most common haplotype was found to occur more frequently in deleterious mutation carriers, with again no evidence at the population level. CONCLUSIONS: We observed differences in the frequency of common genetic variants of the BRCA1 and BRCA2 and their haplotypes between early-onset breast cancer cases who did and did not carry deleterious mutations in these genes. Although our data provide only weak evidence for a difference in frequencies at the population level, the number of deleterious mutation carriers was low and the results may yet be substantiated in a larger study using pooled data

HIV and sexually transmitted infection knowledge among women who have sex with women in four Southern African countries

Women who have sex with women in Southern Africa, where HIV prevalence is high, are often presumed to have minimal risk for sexually transmitted infections (STI) and HIV despite research documenting female-to-female transmission. This study examined the demographic and social factors contributing to female-to-female STI/HIV transmission knowledge among Southern African women who have sex with women using an integrated model of health literacy. In collaboration with community-based organisations in Botswana, Namibia, South Africa and Zimbabwe, data were collected through anonymous surveys (N = 591). Multivariable stepwise forward logistic regression assessed independent associations between participant characteristics and high vs. low knowledge using five items. Overall, 64.4% (n = 362) of women had high knowledge; 35.6% (n = 200) had low knowledge. Higher education (adjusted odds ratio [aOR]: 2.24, 95% confidence interval [CI]: 1.48, 3.40), regular income (aOR: 2.14, 95% CI: 1.43, 3.21), residence in Botswana (aOR: 3.12, 95% CI: 1.15, 8.48) and having ever received tailored STI/HIV information (aOR: 2.17, 95% CI: 1.41, 3.32) predicted significantly higher odds of high knowledge in the final multivariable model. Results suggest opportunities for peer-led sexual health programming and expanded HIV prevention campaigns addressing women who have sex with women.The Open Society Initiative for Southern Africa (PI: Vasu Reddy), with additional support from the United Nations Development Programme and the Open Society Foundations who also participated in the study. Margaret Paschen-Wolff was supported by a training grant (T32 MH019139; PI: Theodorus Sandfort) from the US National Institute of Mental Health at the HIV Center for Clinical and Behavioral Studies at the NY State Psychiatric Institute and Columbia University (P30-MH43520; PI: Robert Remien).http://www.tandfonline.com/loi/tchs202020-07-26hj2019Psycholog

Southern African lesbian and bisexual women responses to symptoms of sexually transmitted infections

Sexually transmitted infections (STI) in lesbian and bisexual women is a relatively unexplored topic, particularly for women from low and middle-income countries. Despite perceptions that women who have sex with women (WSW) are at negligible risk for contracting STI, existing research demonstrates that WSW do become infected with STI. Given the opposition between assumptions of invulnerability and the observed risks, we explored how WSW would respond to symptoms of STI (i.e., wait until symptoms passed, see a medical doctor, and inform sexual partners). We used data collected as part of a collaboration between academic researchers and community-based LGBTQ organizations in Botswana, Namibia, South Africa, and Zimbabwe. Chi-square tests were used to test whether participants’ responses to hypothetical STI symptoms varied in relation to several intrapersonal, interpersonal, and structural factors. Multivariable logistic regression (backward) was used to assess whether these variables were independently associated with women’s responses. Most women would be proactive in response to potential STI symptoms and would see a medical doctor. However, most women would not inform their sexual partner of symptoms of STI. Findings demonstrate several intrapersonal, interpersonal, and structural factors that influence WSW’s health agency, and show a clustering of high-risk factors among women who would not be proactive about their health. Our findings suggest the need for improved health and health care of WSW in Southern Africa.The Open Society Initiative for Southern Africa (PI: Vasu Reddy, Ph.D.), with additional support from the United Nations Development Programme, and Open Society Foundations; these organizations also participated in the study. Additional support came from a NIMH-center grant (P30-MH43520; PI: Robert Remien, Ph.D.) and a NIMH-training grant (T32-MH19139; PI: Theo Sandfort, Ph.D.).http://link.springer.com/journal/105082020-10-12hj2019Psycholog

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

Adenocarcinomas of the colon and rectum are graded using a 2-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas. We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female; mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with low-grade tumors (20% versus 6%; P < .001). Using Cox regression models, adjusting for sex and age at diagnosis and stratifying by the American Joint Committee on Cancer stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of all-cause and colorectal cancer specific mortality: hazard ratio 2.09 (95% confidence interval [CI], 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P < .001. A new grading system separating adenocarcinoma into low grade (all histologic low grade and MSI high grade) and high grade (MSS histologic high grade) gave a lower Akaike information criterion value when compared with the current grading system and thus represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor. (C) 2014 Elsevier Inc. All rights reserved

Epigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking

Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case–control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients