Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Women's place of delivery and experience of quality in delivery care: A quantitative and qualitative study in Nairobi's informal settlements

Background and objectives. A key indicator towards achieving the fifth Millennium Development Goal of reducing maternal mortality is the proportion of births in developing countries that occur with a skilled health professional. In urban slums of Africa, private health facilities may make up for the community's lack of access to or use of government health facilities. The dissertation research objectives are to first, to describe, and second, to determine the factors associated with women's place of delivery, their quality experience of delivery care, and their satisfaction with delivery care in two informal settlements of Nairobi, Kenya. Methods. A population-based, household survey and qualitative data are analyzed. The World Bank/APHRC Maternal Health Survey collected data from 1,926 mothers who delivered in 2004 and 2005 in two of Nairobi's informal settlements. Multivariate regression methods were used for statistical analyses. Exploratory and confirmatory factor analyses informed scale development. Focus group discussions and in-depth interviews were conducted with 58 women who delivered in health facilities. Results. Survey respondents were more likely to deliver in private facilities (45%) than in government facilities (22%) or at home/with a traditional birth attendant (33%). Private facilities located in the informal settlements were closer to women's homes and less expensive than government hospitals. Women's ethnicity and wealth level were associated with facility-based delivery, as were male partners' education and antenatal care characteristics. Women living in the slum further away from the city center had greater odds of delivery in private facilities compared to at home. More educated women, those who received higher quality antenatal care in government vs. private facilities, and those who had an obstetric complication had greater odds of delivery in government facilities vs. at home. Women's experience of quality in delivery care was more positive in private than in government facilities on 8 of 10 survey items. In multivariate analyses, quality scale scores were higher for older and wealthier women, women of certain ethnic groups, and were elated antenatal care characteristics. Women discussed how they appreciated continuous care from providers, being treated with respect and receiving medicines, food, tea and water for bathing after delivery. However, some women delivered unattended and others were insulted by providers. At government hospitals, women complained of high costs, being detained for unsettled bills, and a shortage of beds. Overall, 56% of the survey sample was "very satisfied" with delivery care. Satisfaction was strongly associated with providers' empathy towards women and whether the pregnancy was wanted or unwanted. Conclusion. Recommendations are made to address the fact that the private sector is widely relied upon for delivery care in the slums, and that the quality of care differs according to women's characteristics. Governmental efforts to improve access to maternity care that meets existing national standards should integrate the private sector. During antenatal care and community outreach, women from underrepresented groups should he encouraged to deliver in health facilities. Furthermore, health providers should he involved in strategies to reduce disparities in use of and quality of care, and increase empathy towards laboring women

“Practice so that the skill does not disappear”: mixed methods evaluation of simulator-based learning for midwives in Uganda

Abstract Background Postpartum hemorrhage and neonatal asphyxia are leading causes of maternal and neonatal mortality, respectively, that occur relatively rarely in low-volume health facilities in sub-Saharan Africa. Rare occurrence of cases may limit the readiness and skills that individual birth attendants have to address complications. Evidence suggests that simulator-based training and practice sessions can help birth attendants maintain these life-saving skills; one approach is called “low-dose, high-frequency” (LDHF). The objective of this evaluation is to determine the facilitating factors and barriers to participation in LDHF practice, using qualitative and quantitative information. Methods A trial in 125 facilities in Uganda compared three strategies of support for LDHF practice to improve retention of skills in prevention and treatment of postpartum hemorrhage and neonatal asphyxia. Birth attendants kept written logs of their simulator-based practice sessions, which were entered into a database, then analyzed using Stata to compare frequency of practice by the study arm. The evaluation also included 29 in-depth interviews and 19 focus group discussions with birth attendants and district trainers. Transcripts were entered in Atlas.ti software for coding, then analyzed using content analysis to identify factors that motivated or discouraged simulator-based practice. Results Practice log data indicated that simulator-based practice sessions occurred more frequently in facilities where one or two practice coordinators helped schedule and lead the practice sessions and in health centers compared to hospitals. The qualitative data suggest that birth attendants who practiced more were motivated by a desire to maintain skills and be prepared for emergencies, external recognition, and establishing a set schedule. Barriers to consistent practice included low staffing levels, heavy workloads, and a sense that competency can be maintained through routine clinical care alone. Some facilities described norms around continuing education and some did not. Conclusions Designating practice coordinators to lead their peers in simulator-based practice led to more consistent skills practice within frontline health facilities. Ongoing support, scheduling of practice sessions, and assessment and communication of motivation factors may help sustain LDHF practice and similar forms of continuing professional development. Trial registration Registered with clinicaltrials.gov #NCT03254628 on August 18, 2018 (registered retrospectively)

Use of a design challenge to develop postural support devices for intermediate wheelchair users

The provision of an appropriate wheelchair, one that provides proper fit and postural support, promotes wheelchair users’ physical health and quality of life. Many wheelchair users have postural difficulties, requiring supplemental postural support devices for added trunk support. However, in many low- and middle-income settings, postural support devices are inaccessible, inappropriate or unaffordable. This article describes the use of the design challenge model, informed by a design thinking approach, to catalyse the development of an affordable, simple and robust postural support device for low- and middle-income countries. The article also illustrates how not-for-profit organisations can utilise design thinking and, in particular, the design challenge model to successfully support the development of innovative solutions to product or process challenges

Wheelchair services and use outcomes: A cross-sectional survey in Kenya and the Philippines

Background: The World Health Organisation recommends that services accompany wheelchair distribution. This study examined the relationship of wheelchair service provision in Kenya and the Philippines and wheelchair-use–related outcomes. Method: We surveyed 852 adult basic manual wheelchair users. Participants who had received services and those who had not were sought in equal numbers from wheelchair-distribution entities. Outcomes assessed were daily wheelchair use, falls, unassisted outdoor use and performance of activities of daily living (ADL). Descriptive, bivariate and multivariable regression model results are presented. Results: Conditions that led to the need for a basic wheelchair were mainly spinal cord injury, polio/post-polio, and congenital conditions. Most Kenyans reported high daily wheelchair use (60%) and ADL performance (80%), while these practices were less frequent in the Philippine sample (42% and 74%, respectively). Having the wheelchair fit assessed while the user propelled the wheelchair was associated with greater odds of high ADL performance in Kenya (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.6, 5.1) and the Philippines (OR 2.8, 95% CI 1.8, 4.5). Wheelchair-related training was associated with high ADL performance in Kenya (OR 3.2, 95% CI 1.3, 8.4). In the Philippines, training was associated with greater odds of high versus no daily wheelchair use but also odds of serious versus no falls (OR 2.5, 95% CI 1.4, 4.5). Conclusion: Select services that were associated with some better wheelchair use outcomes and should be emphasised in service delivery. Service providers should be aware that increased mobility may lead to serious falls

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research