An Automated Phenotype-Driven Approach (GeneForce) for Refining Metabolic and Regulatory Models

Integrated constraint-based metabolic and regulatory models can accurately predict cellular growth phenotypes arising from genetic and environmental perturbations. Challenges in constructing such models involve the limited availability of information about transcription factor—gene target interactions and computational methods to quickly refine models based on additional datasets. In this study, we developed an algorithm, GeneForce, to identify incorrect regulatory rules and gene-protein-reaction associations in integrated metabolic and regulatory models. We applied the algorithm to refine integrated models of Escherichia coli and Salmonella typhimurium, and experimentally validated some of the algorithm's suggested refinements. The adjusted E. coli model showed improved accuracy (∼80.0%) for predicting growth phenotypes for 50,557 cases (knockout mutants tested for growth in different environmental conditions). In addition to identifying needed model corrections, the algorithm was used to identify native E. coli genes that, if over-expressed, would allow E. coli to grow in new environments. We envision that this approach will enable the rapid development and assessment of genome-scale metabolic and regulatory network models for less characterized organisms, as such models can be constructed from genome annotations and cis-regulatory network predictions

Protocol for assessing feasibility, acceptability and fidelity of screening for antenatal depression (FAFSAD) by midwives in Blantyre District, Malawi

Depression is often underdiagnosed by treating health professionals. This is a situation in Malawi where there is no routine screening of depression at antenatal clinics. Recently, a Screening Protocol for Antenatal Depression (SPADe) that can be used by midwives to screen for antenatal depression was developed in Blantyre District. SPADe proposes multistage screening of antenatal depression by midwives which may enable early detection and treatment of pregnant women with depression. Proper treatment of antenatal depression can assist in achieving Sustainable Development Goals (SDGs). However, utilisation of SPADe in clinical practice to screening for depression in antenatal clinics has not been established yet. Therefore, the primary aim of this study is to assess feasibility of screening for depression by midwives using SPADe in antenatal clinics in Blantyre District. The secondary aim was to assess acceptability and fidelity of screening for depression by midwives using SPADe in antenatal clinics in Blantyre District

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

The feasibility of a role for community health workers in integrated mental health care for perinatal depression: a qualitative study from Surabaya, Indonesia.

BACKGROUND: Indonesian maternal health policies state that community health workers (CHWs) are responsible for detection and referral of pregnant women and postpartum mothers who might suffer from mental health problems (task-sharing). The documents have been published for a while, however reports on the implementation are hardly found which possibly resulted from feasibility issue within the health system. AIMS: To examine the feasibility of task-sharing in integrated mental health care to identify perinatal depression in Surabaya, Indonesia. METHODS: Semi-structured interviews were conducted with 62 participants representing four stakeholder groups in primary health care: program managers from the health office and the community, health workers and CHWs, mental health specialists, and service users. Questions on the feasibility were supported by vignettes about perinatal depression. WHO's health systems framework was applied to analyse the data using framework analysis. RESULTS: Findings indicated the policy initiative is feasible to the district health system. A strong basis within the health system for task-sharing in maternal mental health rests on health leadership and governance that open an opportunity for training and supervision, financing, and intersectoral collaboration. The infrastructure and resources in the city provide potential for a continuity of care. Nevertheless, feasibility is challenged by gaps between policy and practices, inadequate support system in technologies and information system, assigning the workforce and strategies to be applied, and the lack of practical guidelines to guide the implementation. CONCLUSION: The health system and resources in Surabaya provide opportunities for task-sharing to detect and refer cases of perinatal depression in an integrated mental health care system. Participation of informal workforce might facilitate in closing the gap in the provision of information on perinatal mental health

Review: Strategies to engage clinical staff in subject recruitment

As a Research Ethics Committee (REC) Chair in the National Health Service (NHS), one of the commonest amendments submitted for consideration by RECs relates to the need to manage poor participant recruitment and the failure to meet recruitment targets. This usually involves either extending the duration of the research, which can have significant cost implications, or introducing other strategies that will, if successful, increase recruitment. It is unfortunate that more researchers do not give sufficient consideration to recruitment enhancement strategies during the planning stages of their research