Wellcome Open Research

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ISSN / EISSN : 2398502X / 2398502X
Current Publisher: F1000 Research, Ltd. (10.12688)
Total articles ≅ 824
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Published: 15 February 2020
Wellcome Open Research; doi:10.12688/wellcomeopenres

Agnes M. Mutua, Reagan M. Mogire, Alison M. Elliott, Thomas N. Williams, Emily L. Webb, Amina Abubakar, Sarah H. Atkinson
Published: 13 February 2020
Wellcome Open Research, Volume 5; doi:10.12688/wellcomeopenres.15730.1

Abstract:Introduction: Vitamin D plays an important role in brain development in experimental studies; however, the effect of vitamin D deficiency on child development remains inadequately characterized. We aimed to estimate the effects of vitamin D deficiency on neurobehavioural outcomes in children up to 18 years of age. Methods: We searched PubMed, EMBASE, PsycINFO, Scopus, Cochrane Library, Web of Science and Open Grey for published studies up to 10th January 2020. We included all studies that assessed the effects of maternal or child vitamin D status or vitamin D supplementation on neurobehavioural outcomes in children. Study findings were synthesized qualitatively as the high level of heterogeneity in study populations and methodologies precluded a quantitative meta-analysis. Results: Our search identified 5,633 studies, of which 32 studies with 31,445 participants from 18 countries were included in the systematic review. Of the studies identified, two were randomized controlled trials (RCTs) of vitamin D supplementation in children, while 30 were observational. One RCT (n=55) reported a beneficial effect of supplementation with lower doses compared to higher doses of vitamin D on motor development while the other RCT (n=70) found no beneficial effect of vitamin D supplementation on cognition in extremely preterm infants. Twelve mother-child studies (n=17,136) and five studies in children (n=1,091) reported an association between low maternal or child 25-hydroxyvitamin D levels and impaired neurobehavioural outcomes in children, while 15 mother-child studies (n=20,778) and eight studies in children (n=7,496) reported no association. Conclusions: Although animal studies point to an effect of vitamin D deficiency on brain development, there are few studies on the effects of vitamin D deficiency on neurobehavioural outcomes in children and their findings are inconsistent. There is a need for well-conducted, adequately powered studies to further determine these effects in children. Registration: PROSPERO ID CRD42018087619; registered on 15 February 2018.
Marina Mora-Ortiz, Hajir Ibraheim, Sherine Hermangild Kottoor, Ruth C. E. Bowyer, Sarah Metrustry, Jeremy Sanderson, Nicholas Powell, Tim D. Spector, Kerrin S. Small, Claire J. Steves
Published: 13 February 2020
Wellcome Open Research, Volume 5; doi:10.12688/wellcomeopenres.15632.1

Abstract:Background: The colon is populated by approximately 1012 microorganisms, but the relationships between this microbiome and the host health status are still not completely understood. Here, our objective is to present the cohort characteristics of ExHiBITT – Exploring Host microBIome inTeractions in Twins – including i) biomedical phenotypes, ii) environmental factors and ii) colonoscopic findings. Methods: Participants from the TwinsUK cohort were recruited to study the interactions between the microbiome and host adaptive immunity. In total, 205 monozygotic twins were recruited from the wider TwinsUK cohort. They completed health questionnaires, and provided saliva, blood, colon biopsies from three different locations, caecal fluid, and two faecal samples. Results: A significant proportion of this apparently normal cohort had colonic polyps (28%), which are of interest as potential precursors of colorectal cancer, and, as expected, the number of polyps found was significantly correlated with BMI and age. Hitherto undiagnosed diverticulosis was also not infrequently found during colonoscopy (26%) and was associated with changes in Hybrid Th1-17 cells in the colon. Twin proband co-occurrence rate for diverticulosis (82%) was much higher than for polyps (42%). Familial factors affecting morphology or tolerance may contribute to the ease of endoscopy, as both the time to reach the caecum and pain perceived were highly concordant (proband concordance: 85% and 56%, respectively). Conclusions: We found the expected positive relationship between BMI and colonoscopic anomalies such as diverticular disease and polyps in the whole population, but within twin pairs this association was reversed. This suggests that familial factors confound these associations. Host and microbial next generation sequencing and metabolomics of the samples collected are planned in this cohort.
Marwa El Zein, Chloe Seikus, Lee De-Wit, Bahador Bahrami
Published: 13 February 2020
Wellcome Open Research, Volume 4; doi:10.12688/wellcomeopenres.15474.2

Abstract:Background: It has recently been proposed that a key motivation for joining groups is the protection from consequences of negative behaviours, such as norm violations. Here we empirically test this claim by investigating whether cooperative decisions and the punishment of associated fairness-based norm violations are different in individuals vs. collectives in economic games. Methods: In the ultimatum game, participants made or received offers that they could reject at a cost to their outcome, a form of social punishment. In the dictator game with third-party punishment, participants made offers to a receiver while being observed by a punisher, or could themselves punish unfair offers. Results: Participants made lower offers when making their decision as part of a group as compared to alone. This difference correlated with participants’ overall mean offers: those who were generally less generous were even less so in a group, suggesting that the collective structure was compatible with their intention. Participants were slower when punishing vs not punishing an unfair offer. Importantly here, they were slower when deciding whether to punish or not to punish groups as compared to individuals, only when the offer concerned them directly in second party punishment. Participants thus take more time to punish others, and to make their mind on whether to punish or not when facing a group of proposers. Conclusions: Together, these results show that people behave differently in a group, both in their willingness to share with others and in their punishment of norm violations. This could be explained by the fact that being in a collective structure allows to share responsibility with others, thereby protecting from negative consequences of norm violations.
Rebecca Lester, Hendran Maheswaran, Christopher P. Jewell, David G. Lalloo, Nicholas A. Feasey
Published: 13 February 2020
Wellcome Open Research, Volume 5; doi:10.12688/wellcomeopenres.15719.1

Abstract:Introduction: Antimicrobial resistance is a global public health concern, but the problems are context specific, with each county or setting facing differing challenges. In Africa, third-generation cephalosporin resistant Enterobacterales (3GCR-E) are of particular concern, given the widespread reliance on ceftriaxone for treatment of severe infection in this setting. In Malawi, despite the rising prevalence of 3GCR-E, the health impact of these infections has not been described. This study is designed to estimate attributable mortality, morbidity and economic cost of 3GC-R bloodstream infection (BSI) in a large, urban hospital. Methods: This study will investigate the burden of antimicrobial resistance by recruiting a a prospective longitudinal cohort of patients who have bloodstream infection with 3GCR-E, at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients whose blood culture is positive for either 3GC-S or 3GC-R Enterobacterales will be enrolled and provide clinical and healthcare economic data. Patients will be followed throughout their hospital stay and to 6-months post discharge. Mortality, direct and indirect costs and other health outcomes will be compared between patients with 3GC-R and comparable 3GC-sensitive BSI. Based on our observation that some patients with clinical suspicion of sepsis and 3GC-R BSI are surviving without an effective antibiotic, we review each patient prospectively and classify what role the isolated bacteria is playing in the patient’s clinical presentation. These classifications will then be incorporated into our analysis. Ethics and dissemination: The study protocol has been approved by the Malawi College of Medicine Research Ethics Committee and by the Liverpool School of Tropical Medicine Research Ethics committee. Written informed consent will be obtained from study participants or their parents/guardians. Results will be submitted to international peer-reviewed journals, presented at international conferences and shared with participating communities and collaborators.
Dan Mead, Kathryn Fingland, Rachel Cripps, Roberto Portela Miguez, Michelle Smith, Craig Corton, Karen Oliver, Jason Skelton, Emma Betteridge, Jale Doulcan, et al.
Published: 13 February 2020
Wellcome Open Research, Volume 5; doi:10.12688/wellcomeopenres.15721.1

Abstract:We present a genome assembly from an individual male Sciurus carolinensis (the eastern grey squirrel; Vertebrata; Mammalia; Eutheria; Rodentia; Sciuridae). The genome sequence is 2.82 gigabases in span. The majority of the assembly (92.3%) is scaffolded into 21 chromosomal-level scaffolds, with both X and Y sex chromosomes assembled.
Oonagh E. Keag, Lee Murphy, Aoibheann Bradley, Naomi Deakin, Sonia Whyte, Jane E. Norman, Sarah J. Stock
Published: 12 February 2020
Wellcome Open Research, Volume 5; doi:10.12688/wellcomeopenres.15207.1

Abstract:Background: Preterm birth (PTB) represents the leading cause of neonatal death. Large-scale genetic studies are necessary to determine genetic influences on PTB risk, but prospective cohort studies are expensive and time-consuming. We investigated the feasibility of retrospective recruitment of post-partum women for efficient collection of genetic samples, with self-collected saliva for DNA extraction from themselves and their babies, alongside self-recollection of pregnancy and birth details to phenotype PTB. Methods: 708 women who had participated in the OPPTIMUM trial (a randomised trial of progesterone pessaries to prevent PTB [ISRCTN14568373]) and consented to further contact were invited to provide self-collected saliva from themselves and their babies. DNA was extracted from Oragene OG-500 (adults) and OG-575 (babies) saliva kits and the yield measured by Qubit. Samples were analysed using a panel of Taqman single nucleotide polymorphism (SNP) assays. A questionnaire designed to meet the minimum data set required for phenotyping PTB was included. Questionnaire responses were transcribed and analysed for concordance with prospective trial data. Results: Recruitment rate was 162/708 (23%) for self-collected saliva samples and 157/708 (22%) for questionnaire responses. 161 samples from the mother provided DNA with median yield 59.0µg (0.4-148.9µg). 156 samples were successfully genotyped (96.9%). 136 baby samples had a median yield 11.5µg (0.1-102.7µg); two samples failed DNA extraction. 131 baby samples (96.3%) were successfully genotyped. Concordance between self-recalled birth details and prospective birth details ranged from 55 – 99%, median 86%. The highest rates of concordance were found for mode of birth (154/156 [99%]), smoking status (151/157 [96%]) and ethnicity (149/156 [96%]). Conclusion: This feasibility study demonstrates that self-collected DNA samples from mothers and babies were sufficient for genetic analysis but yields were variable. Self-recollection of pregnancy and birth details was inadequate for accurately phenotyping PTB, highlighting the need for alternative strategies for investigating genetic links with PTB.
Ben Morton, Sarah Burr, Kondwani Jambo, Jamie Rylance, Marc Y.R. Henrion, Ndaziona Peter Banda, Edna Nsomba, Blessings Kapumba, Lucinda Manda-Taylor, Clemens Masesa, et al.
Published: 11 February 2020
Wellcome Open Research, Volume 5; doi:10.12688/wellcomeopenres.15689.1

Abstract:Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement and demonstrate reduced effectiveness against mucosal colonisation. As asymptomatic colonisation of the human nasopharynx is a prerequisite for pneumococcal disease, this is proposed as a marker for novel vaccine efficacy. Our team established a safe and reproducible pneumococcal controlled human infection model at Liverpool School of Tropical Medicine (LSTM). This has been used to test vaccine induced protection against nasopharyngeal carriage for ten years in over 1000 participants. We will transfer established standardised operating procedures from LSTM to Malawi and test in up to 36 healthy participants. Primary endpoint: detection of the inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: confirmation of robust clinical and laboratory methods for sample capture and processing. Tertiary endpoints: participant acceptability of study and methods. We will test three doses of pneumococcal inoculation (20,000, 80,000 and 160,000 colony forming units [CFUs] per naris) using a parsimonious study design intended to reduce unnecessary exposure to participants. We hypothesise that 80,000 CFUs will induce nasal colonisation in approximately half of participants per established LSTM practice. The aims of the feasibility study are: 1) Establish Streptococcus pneumoniae experimental human pneumococcal carriage in Malawi; 2) Confirm optimal nasopharyngeal pneumococcal challenge dose; 3) Confirm safety and measure potential symptoms; 4) Confirm sampling protocols and laboratory assays; 5) Assess feasibility and acceptability of consent and study procedures. Confirmation of pneumococcal controlled human infection model feasibility in Malawi will enable us to target pneumococcal vaccine candidates for an at-risk population who stand the most to gain from new and improved vaccine strategies.
Zoe V.J. Woodhead, Holly A. Rutherford, Dorothy V.M. Bishop
Published: 11 February 2020
Wellcome Open Research, Volume 3; doi:10.12688/wellcomeopenres.14720.3

Abstract:Background: Relative blood flow in the two middle cerebral arteries can be measured using functional transcranial Doppler sonography (fTCD) to give an index of lateralisation as participants perform a specific task. Language laterality has mostly been studied with fTCD using a word generation task, but it is not clear whether this is optimal. Methods: Using fTCD, we evaluated a sentence generation task that has shown good reliability and strong left lateralisation in fMRI. We interleaved trials of word generation, sentence generation and list generation and assessed agreement of these tasks in 31 participants (29 right-handers). Results: Although word generation and sentence generation both gave robust left-lateralisation, lateralisation was significantly stronger for sentence generation. Bland-Altman analysis showed that these two methods were not equivalent. The comparison list generation task was not systematically lateralised, but nevertheless laterality indices (LIs) from this task were significantly correlated with the other two tasks. Subtracting list generation LI from sentence generation LI did not affect the strength of the laterality index. Conclusions: This was a pre-registered methodological study designed to explore novel approaches to optimising measurement of language lateralisation using fTCD. It confirmed that sentence generation gives robust left lateralisation in most people, but is not equivalent to the classic word generation task. Although list generation does not show left-lateralisation at the group level, the LI on this task was correlated with left-lateralised tasks. This suggests that word and sentence generation involve adding a constant directional bias to an underlying continuum of laterality that is reliable in individuals but not biased in either direction. In future research we suggest that consistency of laterality across tasks might have more functional significance than strength or direction of laterality on any one task.
Maria Lazo-Porras, Antonio Bernabe-Ortiz, Alvaro Taype-Rondan, Robert H. Gilman, German Malaga, Helard Manrique, Luis Neyra, Jorge Calderon, Miguel Pinto, David G. Armstrong, et al.
Published: 10 February 2020
Wellcome Open Research, Volume 5; doi:10.12688/wellcomeopenres.15531.1

Abstract:Background: Three previous clinical trials have found that thermometry use reduced diabetic foot ulcers (DFUs) incidence four- to ten-fold among individuals with diabetes at high-risk of developing a DFU. However, these benefits depend on patient adherence to self-assessment. Therefore, novel approaches to improve self-management thermometry adherence are needed. Our objective was to compare incidence of DFUs in the thermometry plus mobile health (mHealth) reminders intervention arm vs. thermometry-only control arm. Methods: We conducted a randomized trial, enrolling adults with type 2 diabetes mellitus at risk of foot ulcers (risk groups 2 or 3) but without foot ulcers at the time of recruitment and allocating them to control (instruction to use a liquid crystal-based foot thermometer daily) or intervention (same instruction supplemented with text and voice messages with reminders to use the device and messages to promote foot care) groups and followed for 18 months. The primary outcome was time to occurrence of DFU. A process evaluation was also conducted. Results: A total of 172 patients (63% women, mean age 61 years) were enrolled; 86 to each study group. More patients enrolled in the intervention arm had a history of DFU (66% vs. 48%). Follow-up for the primary endpoint was complete for 158 of 172 participants (92%). DFU cumulative incidence was 24% (19 of 79) in the intervention arm and 11% (9 of 79) in the control arm. After adjusting for history of foot ulceration and study site, the Hazard Ratio (HR) for DFU was 1.44 (95% CI 0.65, 3.22). Adherence to ≥80% of daily temperature measurements was 87% (103 of 118) among the study participants who returned the logbook, with no difference between the intervention and control arms. Conclusions: This trial contributes to the evidence about the value of mHealth in preventing diabetes foot ulcers. Trial registration: ClinicalTrials.gov NCT02373592 (27/02/2015)