Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.

Polygenic risk scores for prediction of breast cancer risk in women of African ancestry: a cross-ancestry approach.

Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for the prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual-level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined (1) the PRSs built in the AA training dataset and (2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odds ratio per standard deviation of the joint PRS in the validation set was 1.34 [95% confidence interval (CI): 1.27-1.42] with the area under receiver operating characteristic curve (AUC) of 0.581. Compared with women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared with existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.

Outcomes of surgical treatments for acquired gynatresia in a tertiary institution in Ibadan, Nigeria.

A 16-year review of causes, clinical presentation and management outcomes of Acquired gynatresia (AG) at University College Hospital, Ibadan, Nigeria. Information was obtained using a proforma and data analysed using SPSS version 20.0. The mean age of the 31 women with AG was 35.6 ± 6.2 years. The majority (90.3%) were married and had a tertiary level of education. The mean parity was 0.74 ± 1.1 and 54.8% were nulliparous while 29.0% were primiparous women. The commonest cause of AG was the insertion of caustic substances into the vagina and this was mainly for the treatment of uterine fibroid (68.2%) and infertility (54.5%). Over three-quarters presented with dyspareunia while 54.8% had infertility. A majority (87.1%) had one-stage surgery with dissection/excision of fibrotic tissue being the commonest (45.2%) and sigmoid vaginoplasty the least performed. Postoperative complications were seen in 29.0% of cases. Acquired gynatresia remains a condition of public health interest despite an increase in female education and relatively improved health care in Nigeria.Impact statementWhat is already known on this subject? Acquired gynatresia (AG) could be of chemical and non-chemical origin and result from certain cultural beliefs and practices.What do the results of this study add? Irrespective of the women's level of education, there is inadequate awareness of the implications of inserting caustic materials into the vagina. However, there is a high success rate of treatment of AG.What the implications are of these findings for clinical practice and/or further research? There is a need to increase health education and awareness of the populace on the causes of AG and its associated complications.

Perceptions of male partners towards intimate partner violence in the Gambia: A qualitative study.

Intimate partner violence (IPV) is a form of Gender-based violence that is a public health problem. The health outcomes of IPV have cascading effects on the family's financial, emotional, sexual, and physical wellbeing. Sub-Saharan Africa carries a significant burden of IPV. In The Gambia, domestic is prevalent, with more than 80% of the women believing that it is justified for a man to beat his wife. Men are the predominant perpetrators of IPV in the Gambia. The study employed a cross-sectional design using a qualitative approach utilizing phenomenology focused on the participants lived experiences. The study was conducted in Basse in the Upper River Region in The Gambia. The study purposefully sampled 26 respondents, all of whom were married. Semi-Structured in-depth interviews were administered to the respondents in Mandinka, Wolof and Serahuli to collect the study data. Both deductive and inductive approaches were used to develop the codebook and themes relevant to the study data. The participants expressed various ideas regarding IPV, with the general perspectives suggesting the causes, effects, and ultimate probable solutions to the phenomenon. The respondents interviewed believed that both women and men bared the responsibility of IPV. Varying connotations were placed on the individual's responsibility towards perpetrating IPV with men seen as physically and financially violent compared to women. Solutions to the IPV problem were seen as both external and internal, with government intervention being offered up as a solution. The overall response in the study indicated that there was a general understanding of IPV and a need to educate both men and women of its dangers to the overall health. The finding of this study shows that further needed on a large scale to understand the dynamics of IPV in The Gambia. This will help in designing sustainable solutions to the IPV problem.

Household air pollution, ultrasound measurement, fetal biometric parameters and intrauterine growth restriction.

BACKGROUND: Low birthweight, intrauterine growth restriction (IUGR) and perinatal mortality have been associated with air pollution. However, intervention studies that use ultrasound measurements to assess the effects of household air pollution (HAP) on fetal biometric parameters (FBP) are rare. We investigated the effect of a cookstove intervention on FBP and IUGR in a randomized controlled trial (RCT) cohort of HAP-exposed pregnant Nigerian women. METHODS: We recruited 324 women early in the second trimester of pregnancy. Between 16 and 18 weeks, we randomized them to either continue cooking with firewood/kerosene (control group) or receive a CleanCook stove and ethanol fuel (intervention group). We measured fetal biparietal diameter (BPD), head circumference (HC), femur length (FL), abdominal circumference (AC) and ultrasound-estimated fetal weight (U-EFW) in the second and third trimesters. The women were clinically followed up at six regular time points during their pregnancies. Once during the women's second trimester and once during the third, we made 72-h continuous measurements of their personal exposures to particulate matter having aerodynamic diameter < 2.5 µm (PM2.5). We adopted a modified intent-to-treat approach for the analysis. Differences between the intervention and control groups on impact of HAP on fetal growth trajectories were analyzed using mixed effects regression models. RESULTS: There were no significant differences in fetal growth trajectories between the intervention and control groups. CONCLUSIONS: Larger studies in a setting of low ambient air pollution are required to further investigate the effect of transitioning to a cleaner fuel such as ethanol on intrauterine growth. TRIAL REGISTRATION: ClinicalTrials.gov NCT02394574 ; September 2012.

Factors associated with induced abortion among women of reproductive age attending selected health facilities in Addis Ababa, Ethiopia: a case control study.

BACKGROUND: There has been a significant reduction of abortion rates in high-income countries, while the rates remain unchanged in low- and middle-income countries. In Ethiopia, for example, the number of women of reproductive age seeking an induced abortion is increasing. However, there is limited information concerning the reasons why the occurrence of this procedure is increasing. Thus, this study aimed to identify factors associated with having induced abortion in Addis Ababa, Ethiopia. METHODS: An unmatched case-control study was conducted using a semi-structured, interviewer-administered questionnaire from October to December 2017. The cases were 147 women of reproductive age who underwent abortion in a health facility or presented with complications due to induced abortion conducted outside the health facility. The controls were 295 women who came for antenatal care and who reported never having had an induced abortion. The cases were selected by consecutive sampling from nine health facilities, whereas the controls were selected by systematic sampling from the same health facilities. Bivariate and multivariate logistic regression models were employed using STATA version 14 to identify factors associated with induced abortion. RESULTS: The mean age of cases was 26.5 ± 5.7 years, while for the controls it was 28.1 ± 4.8 years. Being unmarried (AOR = 9.6; 95% CI: 1.5-61.7), having primary (AOR = 5.3; 95% CI: 1.5-18.3) and tertiary (AOR = 5.7; 95% CI: 1.6-21.1) education, earning monthly income 100-300 USD (AOR = 0.2; 95% CI: 0.1-0.4) and >  300 USD (AOR = 0.1; 95% CI: 0.0-0.2), initiating first intercourse between ages of 15 and 19 (AOR = 4.7; 95% CI: 1.4-15.6), marrying before the age of 18 (AOR = 2.9; 95% CI: 1.3-6.7), and having two children (AOR = 4.7; 95% CI: 1.8-12.7) were independent predictors of induced abortion. CONCLUSION: Family planning programs hoping to reduce the occurrence of induced abortion should specifically target unmarried women, low income, and those who have two children. The government should also work on preventing early marriage and providing sexual and reproductive health education to help adolescents delay age at first sexual experience.

Implementing oncology clinical trials in Nigeria: a model for capacity building.

BACKGROUND: There is both higher mortality and morbidity from cancer in low and medium income countries (LMICs) compared with high income countries (HICs). Clinical trial activities and development of more effective and less toxic therapies have led to significant improvements in morbidity and mortality from cancer in HICs. Unfortunately, clinical trials remain low in LMICs due to poor infrastructure and paucity of experienced personnel to execute clinical trials. There is an urgent need to build local capacity for evidence-based treatment for cancer patients in LMICs. METHODS: We conducted a survey at facilities in four Teaching Hospitals in South West Nigeria using a checklist of information on various aspects of clinical trial activities. The gaps identified were addressed using resources sourced in partnership with investigators at HIC institutions. RESULTS: Deficits in infrastructure were in areas of patient care such as availability of oncology pharmacists, standard laboratories and diagnostic facilities, clinical equipment maintenance and regular calibrations, trained personnel for clinical trial activities, investigational products handling and disposals and lack of standard operating procedures for clinical activities. There were two GCP trained personnel, two study coordinators and one research pharmacist across the four sites. Interventions were instituted to address the observed deficits in all four sites which are now well positioned to undertake clinical trials in oncology. Training on all aspects of clinical trial was also provided. CONCLUSIONS: Partnerships with institutions in HICs can successfully identify, address, and improve deficits in infrastructure for clinical trial in LMICs. The HICs should lead in providing funds, mentorship, and training for LMIC institutions to improve and expand clinical trials in LMIC countries.

A Social Media-Based Support Group for Youth Living With HIV in Nigeria (SMART Connections): Randomized Controlled Trial.

BACKGROUND: Youth living with HIV (YLHIV) enrolled in HIV treatment experience higher loss to follow-up, suboptimal treatment adherence, and greater HIV-related mortality compared with younger children or adults. Despite poorer health outcomes, few interventions target youth specifically. Expanding access to mobile phone technology, in low- and middle-income countries (LMICs) in particular, has increased interest in using this technology to improve health outcomes. mHealth interventions may present innovative opportunities to improve adherence and retention among YLHIV in LMICs. OBJECTIVE: This study aimed to test the effectiveness of a structured support group intervention, Social Media to promote Adherence and Retention in Treatment (SMART) Connections, delivered through a social media platform, on HIV treatment retention among YLHIV aged 15 to 24 years and on secondary outcomes of antiretroviral therapy (ART) adherence, HIV knowledge, and social support. METHODS: We conducted a parallel, unblinded randomized controlled trial. YLHIV enrolled in HIV treatment for less than 12 months were randomized in a 1:1 ratio to receive SMART Connections (intervention) or standard of care alone (control). We collected data at baseline and endline through structured interviews and medical record extraction. We also conducted in-depth interviews with subsets of intervention group participants. The primary outcome was retention in HIV treatment. We conducted a time-to-event analysis examining time retained in treatment from study enrollment to the date the participant was no longer classified as active-on-treatment. RESULTS: A total of 349 YLHIV enrolled in the study and were randomly allocated to the intervention group (n=177) or control group (n=172). Our primary analysis included data from 324 participants at endline. The probability of being retained in treatment did not differ significantly between the 2 study arms during the study. Retention was high at endline, with 75.7% (112/163) of intervention group participants and 83.4% (126/161) of control group participants active on treatment. HIV-related knowledge was significantly better in the intervention group at endline, but no statistically significant differences were found for ART adherence or social support. Intervention group participants overwhelmingly reported that the intervention was useful, that they enjoyed taking part, and that they would recommend it to other YLHIV. CONCLUSIONS: Our findings of improved HIV knowledge and high acceptability are encouraging, despite a lack of measurable effect on retention. Retention was greater than anticipated in both groups, likely a result of external efforts that began partway through the study. Qualitative data indicate that the SMART Connections intervention may have contributed to retention, adherence, and social support in ways that were not captured quantitatively. Web-based delivery of support group interventions can permit people to access information and other group members privately, when convenient, and without travel. Such digital health interventions may help fill critical gaps in services available for YLHIV. TRIAL REGISTRATION: ClinicalTrials.gov NCT03516318; https://clinicaltrials.gov/ct2/show/NCT03516318.

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria.

Somatic mutation signatures may represent footprints of genetic and environmental exposures that cause different cancer. Few studies have comprehensively examined their association with germline variants, and none in an indigenous African population. SomaticSignatures was employed to extract mutation signatures based on whole-genome or whole-exome sequencing data from female patients with breast cancer (TCGA, training set, n = 1,011; Nigerian samples, validation set, n = 170), and to estimate contributions of signatures in each sample. Association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants were examined using linear regression. Nine stable signatures were inferred, and four signatures (APOBEC C>T, APOBEC C>G, aging and homologous recombination deficiency) were highly similar to known COSMIC signatures and explained the majority (60-85%) of signature contributions. There were significant heritable components associated with APOBEC C>T signature (h2 = 0.575, p = 0.010) and the combined APOBEC signatures (h2 = 0.432, p = 0.042). In TCGA dataset, seven common SNPs within or near GNB5 were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21-0.45) of APOBEC signature contribution at genome-wide significance, while rare germline mutations in MTCL1 was also significantly associated with a higher contribution of this signature (p = 6.1 × 10-6 ). This is the first study to identify associations between germline variants and mutational patterns in breast cancer across diverse populations and geography. The findings provide evidence to substantiate causal links between germline genetic risk variants and carcinogenesis.

Genetic variation in the vitamin D related pathway and breast cancer risk in women of African ancestry in the root consortium.

The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP-level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level p = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24-1.91, padj = 0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non-vitamin D relevant mechanism but further studies are needed.

Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer.

Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina's HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 − 8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 − 10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 − 8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.

Genetic variants demonstrating flip-flop phenomenon and breast cancer risk prediction among women of African ancestry.

BACKGROUND: Few studies have evaluated the performance of existing breast cancer risk prediction models among women of African ancestry. In replication studies of genetic variants, a change in direction of the risk association is a common phenomenon. Termed flip-flop, it means that a variant is risk factor in one population but protective in another, affecting the performance of risk prediction models. METHODS: We used data from the genome-wide association study (GWAS) of breast cancer in the African diaspora (The Root consortium), which included 3686 participants of African ancestry from Nigeria, USA, and Barbados. Polygenic risk scores (PRSs) were constructed from the published odds ratios (ORs) of four sets of susceptibility loci for breast cancer. Discrimination capacity was measured using the area under the receiver operating characteristic curve (AUC). RESULTS: Flip-flop phenomenon was observed among 30~40% of variants across studies. Using the 34 variants with consistent directionality among previous studies, we constructed a PRS with AUC of 0.531 (95% confidence interval [CI]: 0.512-0.550), which is similar to the PRS using 93 variants and ORs from European ancestry populations (AUC = 0.525, 95% CI: 0.506-0.544). Additionally, we found the 34-variant PRS has good discriminative accuracy in women with family history of breast cancer (AUC = 0.586, 95% CI: 0.532-0.640). CONCLUSIONS: We found that PRS based on variants identified from prior GWASs conducted in women of European and Asian ancestries did not provide a comparable degree of risk stratification for women of African ancestry. Further large-scale fine-mapping studies in African ancestry populations are desirable to discover population-specific genetic risk variants.

Genetic variation in the Hippo pathway and breast cancer risk in women of African ancestry.

Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r2 < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (Padj = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, Padj = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.

A longitudinal study of the prevalence and characteristics of breast disorders detected by clinical breast examination during pregnancy and six months postpartum in Ibadan, Southwestern Nigeria.

BACKGROUND: Breast disorders cause great anxiety for women especially when they occur in pregnancy because breast cancer is the most common cause of cancer related deaths in women. Majority of the disorders are Benign Breast Diseases (BBD) with various degrees of associated breast cancer risks. With increasing breast cancer awareness in Nigeria, we sought to determine the prevalence and characteristics of breast disorders among a cohort of pregnant women. METHODS: A longitudinal study of 1248 pregnant women recruited in their first trimester- till 26 weeks gestational age consecutively from selected antenatal clinics (ANCs), in Ibadan, Southwest Nigeria. A pretested interviewer- administered questionnaire was used to collect information at recruitment. Clinical Breast Examination (CBE) using MammaCare® technique was performed at recruitment and follow up visits at third trimester, six weeks postpartum and six months postpartum. Women with breast disorders were referred for Breast Ultrasound Scan (BUS) and those with Breast Imaging Reporting and Data System (BIRADS) ≥4 had ultrasound guided biopsy. Statistical analysis was performed using Stata version 14. RESULTS: Mean age of participants was 29.7 ± 5.2 years and mean gestational age at recruitment was 20.4 ± 4.4 weeks. Seventy-two participants (5.8%) had a past history of BBD and 345 (27.6%) were primigravidae. Overall, breast disorder was detected among 223 (17.9%) participants and 149 (11.9%) had it detected at baseline. Findings from the CBE showed that 208 (69.6%) of 299 breast disorders signs found were palpable lumps or thickenings in the breast, 28 (9.4%) were persistent pain, and 63 (21.1%) were abscesses, infection and mastitis. Twenty out of 127 (15.7%) participants who had BUS performed were classified as BIRADS ≥3. Lesions found by BUS were reactive lymph nodes (42.5%), prominent ducts (27.1%), fibroadenoma (9.6%), breast cysts (3.8%) and fibrocystic changes (2.5%). No malignant pathology was found on ultrasound guided biopsy. CONCLUSIONS: Breast lump is a major breast disorder among pregnant women attending antenatal clinics in Ibadan. Routine clinical breast examination and follow up of pregnant women found with breast disorders could facilitate early detection of pregnancy associated breast cancer in low resource settings.

Randomized Controlled Ethanol Cookstove Intervention and Blood Pressure in Pregnant Nigerian Women.

RATIONALE: Hypertension during pregnancy is a leading cause of maternal mortality. Exposure to household air pollution elevates blood pressure (BP). OBJECTIVES: To investigate the ability of a clean cookstove intervention to lower BP during pregnancy. METHODS: We conducted a randomized controlled trial in Nigeria. Pregnant women cooking with kerosene or firewood were randomly assigned to an ethanol arm (n = 162) or a control arm (n = 162). BP measurements were taken during six antenatal visits. In the primary analysis, we compared ethanol users with control subjects. In subgroup analyses, we compared baseline kerosene users assigned to the intervention with kerosene control subjects and compared baseline firewood users assigned to ethanol with firewood control subjects. MEASUREMENTS AND MAIN RESULTS: The change in diastolic blood pressure (DBP) over time was significantly different between ethanol users and control subjects (P = 0.040); systolic blood pressure (SBP) did not differ (P = 0.86). In subgroup analyses, there was no significant intervention effect for SBP; a significant difference for DBP (P = 0.031) existed among preintervention kerosene users. At the last visit, mean DBP was 2.8 mm Hg higher in control subjects than in ethanol users (3.6 mm Hg greater in control subjects than in ethanol users among preintervention kerosene users), and 6.4% of control subjects were hypertensive (SBP ≥140 and/or DBP ≥90 mm Hg) versus 1.9% of ethanol users (P = 0.051). Among preintervention kerosene users, 8.8% of control subjects were hypertensive compared with 1.8% of ethanol users (P = 0.029). CONCLUSIONS: To our knowledge, this is the first cookstove randomized controlled trial examining prenatal BP. Ethanol cookstoves have potential to reduce DBP and hypertension during pregnancy. Accordingly, clean cooking fuels may reduce adverse health impacts associated with household air pollution. Clinical trial registered with www.clinicaltrials.gov (NCT02394574).

Association of breast cancer risk and the mTOR pathway in women of African ancestry in 'The Root' Consortium.

Functional studies have elucidated the role of the mammalian target of rapamycin (mTOR) pathway in breast carcinogenesis, but to date, there is a paucity of data on its contribution to breast cancer risk in women of African ancestry. We examined 47628 SNPs in 61 mTOR pathway genes in the genome wide association study of breast cancer in the African Diaspora study (The Root consortium), which included 3686 participants (1657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10994 SNPs that were not highly correlated (r2 < 0.8). Odds ratio (OR) and 95% confidence interval (CI) were estimated with logistic regression for each single-nucleotide polymorphism. The mTOR pathway was significantly associated with overall and estrogen receptor-negative (ER-) breast cancer risk (P = 0.003 and 0.03, respectively). PRKAG3 (Padj = 0.0018) and RPS6KA3 (Padj = 0.061) were the leading genes for the associations with overall breast cancer risk and ER- breast cancer risk, respectively. rs190843378 in PRKAG3 was statistically significant after gene-level adjustment for multiple comparisons (OR = 0.50 for each T allele, 95% CI = 0.38-0.66, Padj = 3.6E-05), with a statistical power of 0.914. These results provide new insights on the biological relevance of the mTOR pathway in breast cancer progression and underscore the need for more genetic epidemiology studies of breast cancer in the African Diaspora.

Genetic variants in microRNA and microRNA biogenesis pathway genes and breast cancer risk among women of African ancestry.

MicroRNAs (miRNA) regulate breast biology by binding to specific RNA sequences, leading to RNA degradation and inhibition of translation of their target genes. While germline genetic variations may disrupt some of these interactions between miRNAs and their targets, studies assessing the relationship between genetic variations in the miRNA network and breast cancer risk are still limited, particularly among women of African ancestry. We systematically put together a list of 822 and 10,468 genetic variants among primary miRNA sequences and 38 genes in the miRNA biogenesis pathway, respectively; and examined their association with breast cancer risk in the ROOT consortium which includes women of African ancestry. Findings were replicated in an independent consortium. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). For overall breast cancer risk, three single-nucleotide polymorphisms (SNPs) in miRNA biogenesis genes DROSHA rs78393591 (OR = 0.69, 95 % CI: 0.55-0.88, P = 0.003), ESR1 rs523736 (OR = 0.88, 95 % CI: 0.82-0.95, P = 3.99 × 10(-4)), and ZCCHC11 rs114101502 (OR = 1.33, 95 % CI: 1.11-1.59, P = 0.002), and one SNP in primary miRNA sequence (rs116159732 in miR-6826, OR = 0.74, 95 % CI: 0.63-0.89, P = 0.001) were found to have significant associations in both discovery and validation phases. In a subgroup analysis, two SNPs were associated with risk of estrogen receptor (ER)-negative breast cancer, and three SNPs were associated with risk of ER-positive breast cancer. Several variants in miRNA and miRNA biogenesis pathway genes were associated with breast cancer risk. Risk associations varied by ER status, suggesting potential new mechanisms in etiology.

Breast cancer risk after full-term pregnancies among African women from Nigeria, Cameroon, and Uganda.

BACKGROUND: The breast cancer (BC) risk profiles of African women differ significantly from those of women of European ancestry. African women are younger at the age of onset and tend to have high parity. The purpose of this study was to examine the relationship between full-term pregnancy (FTP) and the risk of BC. METHODS: A case-control study was conducted among 1995 women with invasive BC and 2631 controls in Nigeria, Cameroon, and Uganda. Odds ratios (ORs) for individual ages at FTP according to the time since delivery were calculated and adjusted for confounders. A fitted spline model was used to assess the impact of the number of pregnancies on BC risk. RESULTS: In comparison with a nulliparous woman, a parous woman with her first FTP at 20 years showed an OR of 0.76 (95% confidence interval [CI], 0.57-0.99) for developing BC in the following 5 years. Ten years later, this risk was 0.76 (95% CI, 0.58-0.99) and 0.76 (95% CI, 0.58-0.98) for women aged 25 and 30 years, respectively. Similarly, a parous woman with 1 pregnancy had an OR of 0.69 (95% CI, 0.49-0.96), whereas the OR was 0.66 (95% CI, 0.48-0.91) with 2 or 5 pregnancies and 0.67 (95% CI, 0.47-0.94) with 6 pregnancies in comparison with nulliparous women. CONCLUSIONS: In contrast to studies in women of European ancestry, this study showed no transient increase in the risk of developing BC after FTP among African women. Further studies are needed to examine the impact of reproductive factors on early-onset BC in African women.

Disposition of amodiaquine and desethylamodiaquine in HIV-infected Nigerian subjects on nevirapine-containing antiretroviral therapy.

OBJECTIVES: Artesunate plus amodiaquine is used for malaria treatment in regions with overlapping HIV endemicity. Co-administration of artesunate/amodiaquine with antiretroviral therapy (ART) may result in drug-drug interactions, but minimal data exist. This study evaluated the impact of nevirapine-based ART, containing a backbone of zidovudine and lamivudine, on the disposition of amodiaquine and its active metabolite, desethylamodiaquine (DEAQ). METHODS: This was an open-label, parallel-group pharmacokinetic comparison between HIV-infected, adult subjects receiving steady-state nevirapine-based ART (n = 10) and ART-naive subjects (control group, n = 11). All subjects received a loose formulation of artesunate/amodiaquine (200/600 mg) daily for 3 days, with serial pharmacokinetic sampling over 96 h following the final dose of artesunate/amodiaquine. Amodiaquine and DEAQ were quantified using a validated HPLC method with UV detection. Pharmacokinetic parameters were determined using standard non-compartmental methods. RESULTS: Exposures to both amodiaquine and DEAQ were significantly lower in the nevirapine-based ART group compared with the control group (amodiaquine AUC0₋24 145 versus 204 ng·h/mL, P = 0.02; DEAQ AUC0₋96 14,571 versus 21,648 ng·h/mL, P < 0.01). The AUCDEAQ/AUC(amodiaquine) ratio was not different between groups (ART group 116 versus control group 102, P = 0.67). CONCLUSIONS: Subjects on nevirapine-based ART had lower exposure to both amodiaquine and DEAQ (28.9% and 32.7%, respectively). Consequently, this may negatively impact the effectiveness of artesunate/amodiaquine in HIV-infected individuals on this ART combination.

Group psychological therapy in obstetric fistula care: a complementary recipe for the accompanying mental ill health morbidities?

The objective of this study is to determine the impact of group psychological therapy (GPT) on the mental health of obstetric fistula patients. It was a comparative pre and post intervention design. All patients had GPT prior to surgery and mental health assessment conducted before and after surgical repair. There was a significant reduction in proportion of those with severe mental health status after surgery. Specifically, the proportion of those with depression score of 4 and above reduced from 71.7% to 43.4%, and those with score of less than 4 increased from 28.3 to 56.6 percent. There was a significant reduction in those with very low self-esteem from 65.0% to 18.3%. Suicidal ideation reduced generally; severe (15.0 to 0%), moderate (16.7 to 5.0%) and mild (25.0 to 21.7%) and those without increased (43.3 to 73.3%). In conclusion, GPT is a useful adjunct to OF care as it improves their overall mental health status.