Wellcome Open Research

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ISSN / EISSN : 2398502X / 2398502X
Current Publisher: F1000 Research, Ltd. (10.12688)
Total articles ≅ 698
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Published: 14 October 2019
Wellcome Open Research; doi:10.12688/wellcomeopenres

Gkikas Magiorkinis, Philippa C. Matthews, Susan E. Wallace, Katie Jeffery, Kevin Dunbar, Richard Tedder, Jean L. Mbisa, Bernadette Hannigan, Effy Vayena, Peter Simmonds, et al.
Published: 14 October 2019
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15499.1

Abstract:The identification of microbiological infection is usually a diagnostic investigation, a complex process that is firstly initiated by clinical suspicion. With the emergence of high-throughput sequencing (HTS) technologies, metagenomic analysis has unveiled the power to identify microbial DNA/RNA from a diverse range of clinical samples (1). Metagenomic analysis of whole human genomes at the clinical/research interface bypasses the steps of clinical scrutiny and targeted testing and has the potential to generate unexpected findings relating to infectious and sometimes transmissible disease. There is no doubt that microbial findings that may have a significant impact on a patient’s treatment and their close contacts should be reported to those with clinical responsibility for the sample-donating patient. There are no clear recommendations on how such findings that are incidental, or outside the original investigation, should be handled. Here we aim to provide an informed protocol for the management of incidental microbial findings as part of the 100,000 Genomes Project which may have broader application in this emerging field. As with any other clinical information, we aim to prioritise the reporting of data that are most likely to be of benefit to the patient and their close contacts. We also set out to minimize risks, costs and potential anxiety associated with the reporting of results that are unlikely to be of clinical significance. Our recommendations aim to support the practice of microbial metagenomics by providing a simplified pathway that can be applied to reporting the identification of potential pathogens from metagenomic datasets. Given that the ambition for UK sequenced human genomes over the next 5 years has been set to reach 5 million and the field of metagenomics is rapidly evolving, the guidance will be regularly reviewed and will likely adapt over time as experience develops.
Li Yan, Ellison Carter, Yu Fu, Dongshuang Guo, Pinchun Huang, Gaoqiang Xie, Wuxiang Xie, Yidan Zhu, Frank Kelly, Paul Elliott, et al.
Published: 11 October 2019
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15470.1

Abstract:Background: Unfavourable blood pressure (BP) level is an established risk factor for cardiovascular diseases (CVD), while the exact underlying reasons for unfavourable BP are poorly understood. The INTERMAP China Prospective (ICP) Study is a prospective cohort to investigate the relationship of environmental and nutritional risk factors with key indicators of vascular function including BP, arterial stiffness, and carotid-intima media thickness. Methods: A total of 839 Chinese participants aged 40-59 years from three diverse regions of China were enrolled in INTERMAP in 1997/98; data collection included repeated BP measurements, 24-hour urine specimens, and 24-hour dietary recalls. In 2015/16, 574 of these 839 persons were re-enrolled along with 208 new participants aged 40-59 years that were randomly selected from the same study villages. Participant’s environmental and dietary exposures and health outcomes were assessed in this open cohort study, including BP, 24-hour dietary recalls, personal exposures to air pollution, grip strength, arterial stiffness, carotid-media thickness and plaques, cognitive function, and sleep patterns. Serum and plasma specimens were collected with 24-hour urine specimens. Discussion: Winter and summer assessments of a comprehensive set of vascular indicators and their environmental and nutritional risk factors were conducted with high precision. We will leverage advances in exposome research to identify biomarkers of exposure to environmental and nutritional risk factors and improve our understanding of the mechanisms and pathways of their hazardous cardiovascular effects. The ICP Study is observational by design, thus subject to several biases including selection bias (e.g., loss to follow-up), information bias (e.g., measurement error), and confounding that we sought to mitigate through our study design and measurements. However, extensive efforts will apply to minimize those limitations (continuous observer training, repeated measurements of BP, standardized methods in data collection and measurements, and on-going quality control).
Cyrille Ndo, Edmond Kopya, Helen Irving, Charles Wondji
Published: 11 October 2019
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15061.2

Abstract:Background: Malaria control heavily relies on insecticide-based interventions against mosquito vectors. However, the increasing spread of insecticide resistance is a major threat. The extent to which such resistance, notably metabolic resistance, influences the development of the Plasmodium parasite and its impact on overall malaria transmission remains poorly characterized. Here, we investigated whether glutathione S-transferase-based resistance could influence Plasmodium falciparum development in Anopheles funestus. Methods: Anopheles funestus females were infected with P. falciparum gametocytes and midguts were dissected at day 7 post infection for detection/quantification of oocysts. Infection parameters were compared between individuals with different L119F-GSTe2 genotypes, and the polymorphism of the GSTe2 gene was analyzed in infected and uninfected mosquito groups. Results: Overall, 403 An. funestus mosquitoes were dissected and genotyped. The frequency of the L119F-GSTe2 resistance allele was significantly higher in non-infected (55.88%) compared to infected (40.99%) mosquitoes (Fisher's exact test, P Conclusion: Altogether, these results suggest that GSTe2-based metabolic resistance may affect the vectorial competence of resistant An. funestus mosquitoes to P. falciparum infection, by possibly increasing its permissiveness to Plasmodium infection.
Blanche Oguti, Malick Gibani, Christopher Darlow, Claire S Waddington, Celina Jin, Emma Plested, Danielle Campbell, Claire Jones, Tom C Darton, Andrew J Pollard
Published: 11 October 2019
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15469.1

Abstract:Background: Enteric fever is an acute febrile-illness caused by infection with the human-restricted Salmonella serovars Typhi and Paratyphi. Controlled human infection models (CHIM) of S. Typhi and Paratyphi infection are used to accelerate vaccine development and to better understand host-pathogen interactions. The primary motivations for participants to take part in these studies are unknown. We studied participant motivations, attitudes and the factors influencing CHIM study participation. Methods: Participant surveys were nested in six enteric fever CHIM studies conducted at a single centre in Oxford, UK, between 2011 and 2017. All eligible participants received one invitation to complete an anonymous, self-administered paper or online survey on either day 28 or 60 after challenge. A descriptive analysis was performed on these pooled data. All studies were included, to minimize selection bias. Results: Survey response rates varied from 33.0%-86.1%, yielding 201 participants. In the cohort, 113/198(57.0%) were educated to bachelor’s level, 61.6% were employed, 30.3% were students and 4.6% were unemployed. The most commonly cited motivations for CHIM study participation were a desire to contribute to the progression of medicine (170/201; 84.6%); the prospect of financial reimbursement (166/201; 82.6%) and curiosity about clinical trials (117/201; 57.2%). The majority of respondents (139/197; 70.6%) reported that most people advised them against participation. Conclusion: Motivation to participate in a CHIM study was multi-factorial and heavily influenced by internal drivers beyond monetary reimbursement alone. High educational attainment and employment may be protective factors against financial inducement; however, further research is needed, particularly with CHIM studies expanding to low-income and middle-income countries.
Michele Tinti, Maria Lucia S. Güther, Thomas W. M. Crozier, Angus I. Lamond, Michael A. J. Ferguson
Published: 9 October 2019
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15421.1

Abstract:Background: Cellular proteins vary significantly in both abundance and turnover rates. These parameters depend upon their rates of synthesis and degradation and it is useful to have access to data on protein turnover rates when, for example, designing genetic knock-down experiments or assessing the potential usefulness of covalent enzyme inhibitors. Little is known about the nature and regulation of protein turnover in Trypanosoma brucei, the etiological agent of human and animal African trypanosomiasis. Methods: To establish baseline data on T. brucei proteome turnover, a Stable Isotope Labelling with Amino acids in Cell culture (SILAC)-based mass spectrometry analysis was performed to reveal the synthesis and degradation profiles for thousands of proteins in the bloodstream and procyclic forms of this parasite. Results: This analysis revealed a slower average turnover rate of the procyclic form proteome relative to the bloodstream proteome. As expected, many of the proteins with the fastest turnover rates have functions in the cell cycle and in the regulation of cytokinesis in both bloodstream and procyclic forms. Moreover, the cellular localization of T. brucei proteins correlates with their turnover, with mitochondrial and glycosomal proteins exhibiting slower than average turnover rates. Conclusions: The intention of this study is to provide the trypanosome research community with a resource for protein turnover data for any protein or group of proteins. To this end, bioinformatic analyses of these data are made available via an open-access web resource with data visualization functions.
Sean Tomlinson, Andy South, Joshua Longbottom
Published: 9 October 2019
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15495.1

Abstract:Preventable diseases still cause huge mortality in low- and middle-income countries. Research in spatial epidemiology and earth observation is helping academics to understand and prioritise how mortality could be reduced and generates spatial data that are used at a global and national level, to inform disease control policy. These data could also inform operational decision making at a more local level, for example to help officials target efforts at a local/regional level. To be usable for local decision-making, data needs to be presented in a way that is relevant to and understandable by local decision makers. We demonstrate an approach and prototype web application to make spatial outputs from disease modelling more useful for local decision making. Key to our approach is: (1) we focus on a handful of important data layers to maintain simplicity; (2) data are summarised at scales relevant to decision making (administrative units); (3) the application has the ability to rank and compare administrative units; (4) open-source code that can be modified and re-used by others, to target specific user-needs. Our prototype application allows visualisation of a handful of key layers from the Malaria Atlas Project. Data can be summarised by administrative unit for any malaria endemic African country, ranked and compared; e.g. to answer questions such as, ‘does the district with the highest malaria prevalence also have the lowest coverage of insecticide treated nets?’. The application is developed in R and the code is open-source. It would be relatively easy for others to change the source code to incorporate different data layers, administrative boundaries or other data visualisations. We suggest such open-source web application development can facilitate the use of data for public health decision making in low resource settings.
Antje K. Grotz, Fernando Abaitua, Elena Navarro-Guerrero, Benoit Hastoy, Daniel Ebner, Anna L. Gloyn
Published: 8 October 2019
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15447.1

Abstract:Type 2 diabetes (T2D) is a global pandemic with a strong genetic component, but most causal genes influencing the disease risk remain unknown. It is clear, however, that the pancreatic beta cell is central to T2D pathogenesis. In vitro gene-knockout (KO) models to study T2D risk genes have so far focused on rodent beta cells. However, there are important structural and functional differences between rodent and human beta cell lines. With that in mind, we have developed a robust pipeline to create a stable CRISPR/Cas9 KO in an authentic human beta cell line (EndoC-βH1). The KO pipeline consists of a dual lentiviral sgRNA strategy and we targeted three genes (INS, IDE, PAM) as a proof of concept. We achieved a significant reduction in mRNA levels and complete protein depletion of all target genes. Using this dual sgRNA strategy, up to 94 kb DNA were cut out of the target genes and the editing efficiency of each sgRNA exceeded >87.5%. Sequencing of off-targets showed no unspecific editing. Most importantly, the pipeline did not affect the glucose-responsive insulin secretion of the cells. Interestingly, comparison of KO cell lines for NEUROD1 and SLC30A8 with siRNA-mediated knockdown (KD) approaches demonstrate phenotypic differences. NEUROD1-KO cells were not viable and displayed elevated markers for ER stress and apoptosis. NEUROD1-KD, however, only had a modest elevation, by 34%, in the pro-apoptotic transcription factor CHOP and a gene expression profile indicative of chronic ER stress without evidence of elevated cell death. On the other hand, SLC30A8-KO cells demonstrated no reduction in KATP channel gene expression in contrast to siRNA silencing. Overall, this strategy to efficiently create stable KO in the human beta cell line EndoC-βH1 will allow for a better understanding of genes involved in beta cell dysfunction, their underlying functional mechanisms and T2D pathogenesis.
Indraneel Banerjee, Senthil Senniappan, Thomas W. Laver, Richard Caswell, Martin Zenker, Klaus Mohnike, Tim Cheetham, Matthew N. Wakeling, Dunia Ismail, Belinda Lennerz, et al.
Published: 8 October 2019
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15465.1

Abstract:Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.
Luke Bratton, Rachel C. Adams, Aimée Challenger, Jacky Boivin, Lewis Bott, Christopher D. Chambers, Petroc Sumner
Published: 7 October 2019
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15486.1

Abstract:Background: Exaggerations in health news were previously found to strongly associate with similar exaggerations in press releases. Moreover, such press release exaggerations did not appear to attract more news. Methods: Here we tested the replicability of these findings in a new cohort of news and press releases based on research in UK universities in 2014 and 2015. Press releases and news were compared to their associated peer-reviewed articles to define exaggeration in advice, causal claims and human inference from non-human studies. Results: We found that the association between news and press releases did not replicate for advice exaggeration, while this association did replicate for causal claims and human inference from non-human studies. There was no evidence for higher news uptake for exaggerated press releases, consistent with previous results. Base exaggeration rates were lower for human inference from non-human studies, possibly reflecting the Concordat on Openness on Animal Research in the UK. Conclusions: Overall, the picture remains that the strength of news statements is normally associated with the strength of press release statements, and without evidence that exaggerated statements get significantly more news.