Beyond denomination: The relationship between religion and family planning in rural Malawi

Despite the centrality of religion and fertility to life in rural Africa, the relationship between the two remains poorly understood. The study presented here uses unique integrated individual- and congregational-level data from rural Malawi to examine religious influences on contraceptive use. In this religiously diverse population, we find evidence that the particular characteristics of a congregation—leader’s positive attitudes toward family planning and discussion of sexual morality, which do not fall along broad denominational lines—are more relevant than denominational categories for predicting women’s contraceptive use. We further find evidence for a relationship between religious socialization and contraceptive behavior.family planning, fertility, religion, social interaction, Sub-Saharan Africa

Women's health decline following (some) unintended births: A prospective study

Background: As many as one in three unintended births occur in Africa. These births have the potential to adversely impact women's health, but data and design limitations have complicated efforts to understand their consequences. Moreover, there is growing evidence that women often feel happy about an unintended pregnancy, and this heterogeneity may be important for identifying the births that are - and those that are not - harmful to women's health. Objective: To assess whether having an unintended birth precipitates health declines for young women in a high-fertility, high-morbidity context and whether a woman's emotional reaction to a pregnancy foreshadows the consequences of the resulting birth. Methods: We use closely spaced panel data from 896 young women in Malawi that include prospective measures of fertility timing desires captured only months before conception and a contemporaneous measure of emotional reaction to the pregnancy. We run lagged dependent variable regression models of self-rated health that account for health and sociodemographic conditions prior to pregnancy and compare women with unintended births to women with intended births and to an alternative comparison group: women who avoid unintended births. We then disaggregate unintended births by women's emotional reactions after learning of the pregnancy. Results: Women who had an unintended birth but initially had a positive reaction to the pregnancy did not experience a decline in health after birth. Women who had a more negative reaction, however, experienced marked reductions in self-rated health, even years after the birth. Contribution: Our findings highlight meaningful heterogeneity in the consequences of unintended fertility for women's health and offer insights into the unintended births that put women at greatest risk of health decline

Factors associated with retention in Option B+ in Malawi: a case control study.

IntroductionThere are limited data on factors associated with retention in Option B+. We sought to explore the characteristics of women retained in Option B+ in Malawi, with a focus on the role of HIV disclosure, awareness of partner HIV status, and knowledge around the importance of Option B+ for maternal-child health. Methods We performed a case-control study of HIV-infected women in Malawi initiated on antiretroviral therapy (ART) under Option B+. Cases were enrolled if they met criteria for default from Option B+ (out of ART for >60 days), and controls were enrolled in approximately 3:1 ratio if they were retained in care for at least 12 months. We surveyed socio-demographic characteristics, HIV disclosure and awareness of partner HIV status, self-report about receiving pre-ART education, and knowledge of Option B+. Univariate logistic regression was performed to determine factors associated with retention. Multivariate logistic regression model was used to evaluate the relationship between HIV disclosure, Option B+ knowledge, and retention after adjusting for age, schooling, and travel time to clinic.ResultsWe enrolled 50 cases and 153 controls. Median age was 30 years (interquartile range (IQR) 25-34), and the majority (82%) initiated ART during pregnancy at a median gestational age of 24 weeks (IQR 16-28). Ninety-one per cent of the cases (39/43) who started ART during pregnancy defaulted by three months postpartum. HIV disclosure to the primary sex partner was more common among women retained in care (100% versus 78%, p < 0.001). Odds of retention were significantly higher among women with: age >25 years (odds ratio (OR) 2.44), completion of primary school (OR 3.06), awareness of partner HIV status (OR 5.20), pre-ART education (OR 6.17), higher number of correct answers to Option B+ knowledge questions (OR 1.82), and support while taking ART (OR 3.65). Pre-ART education and knowledge were significantly correlated (r = 0.43, p < 0.001). In multivariate analysis, awareness of partner HIV status (OR 4.07, 95% confidence interval (CI) 1.51-10.94, p = 0.02) and Option B+ knowledge (OR 1.60, 95% CI 1.15-2.23, p = 0.004) remained associated with retention.ConclusionsInterventions that address partner disclosure and strengthen pre-ART education around the benefits of ART for maternal and child health should be evaluated to improve retention in Malawi's Option B+ programme

Impact of ART on the fertility of HIV-positive women in sub-Saharan Africa.

OBJECTIVE: Understanding the fertility of HIV-positive women is critical to estimating HIV epidemic trends from surveillance data and to planning resource needs and coverage of prevention of mother-to-child transmission services in sub-Saharan Africa. In the light of the considerable scale-up in antiretroviral therapy (ART) coverage over the last decade, we conducted a systematic review of the impact of ART on the fertility outcomes of HIV-positive women. METHODS: We searched Medline, Embase, Popline, PubMed and African Index Medicus. Studies were included if they were conducted in sub-Saharan Africa and provided estimates of fertility outcomes (live births or pregnancies) among women on ART relative to a comparison group. RESULTS: Of 2070 unique references, 18 published papers met all eligibility criteria. Comparisons fell into four categories: fertility of HIV-positive women relative to HIV-negative women; fertility of HIV-positive women on ART compared to those not yet on ART; fertility differences by duration on ART; and temporal trends in fertility among HIV-positive women. Evidence indicates that fertility increases after approximately the first year on ART and that while the fertility deficit of HIV-positive women is shrinking, their fertility remains below that of HIV-negative women. These findings, however, were based on limited data mostly during the period 2005-2010 when ART scaled up. CONCLUSIONS: Existing data are insufficient to characterise how ART has affected the fertility of HIV-positive women in sub-Saharan Africa. Improving evidence about fertility among women on ART is an urgent priority for planning HIV resource needs and understanding HIV epidemic trends. Alternative data sources such as antenatal clinic data, general population cohorts and population-based surveys can be harnessed to understand the issue

Connectivity precedes function in the development of the visual word form area

What determines the cortical location at which a given functionally specific region will arise in development? We tested the hypothesis that functionally specific regions develop in their characteristic locations because of pre-existing differences in the extrinsic connectivity of that region to the rest of the brain. We exploited the visual word form area (VWFA) as a test case, scanning children with diffusion and functional imaging at age 5, before they learned to read, and at age 8, after they learned to read. We found the VWFA developed functionally in this interval and that its location in a particular child at age 8 could be predicted from that child's connectivity fingerprints (but not functional responses) at age 5. These results suggest that early connectivity instructs the functional development of the VWFA, possibly reflecting a general mechanism of cortical development.National Institutes of Health (U.S.) (Grant F32HD079169)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant F32HD079169)National Institutes of Health (U.S.) (Grant R01HD067312)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant R01HD067312

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of &lt;1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. </jats:sec

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre