Three Preventative Interventions to Address the Fake News Phenomenon on Social Media

Fake news on social media undermines democracies and civil society. To date the research response has been message centric and reactive. This does not address the problem of fake news contaminating social media populations with disinformation, nor address the fake news producers and disseminators who are predominantly human social media users. Our research proposes three preventative interventions - two that empower social media users and one social media structural change to reduce the spread of fake news. Specifically, we investigate how i) psychological inoculation; ii) digital media literacy and iii) Transaction Cost Economy safeguarding through reputation ranking could elicit greater cognitive elaboration from social media users. Our research provides digital scalable preventative interventions to empower social media users with the aim to reduce the population size exposed to fake news

Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation

There is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available threedimensional techniques are time consuming and/or lack reproducibility; thus standardized and rapid protocols are urgently needed. To address this requirement, we have developed a versatile toolkit of reproducible three-dimensional tumor spheroid models for dynamic, automated, quantitative imaging and analysis that are compatible with routine high-throughput preclinical studies. Not only do these microplate methods measure three-dimensional tumor growth, but they have also been significantly enhanced to facilitate a range of functional assays exemplifying additional key hallmarks of cancer, namely cell motility and matrix invasion. Moreover, mutual tissue invasion and angiogenesis is accommodated by coculturing tumor spheroids with murine embryoid bodies within which angiogenic differentiation occurs. Highly malignant human tumor cells were selected to exemplify therapeutic effects of three specific molecularly-targeted agents: PI-103 (phosphatidylinositol-3-kinase (PI3K)- mammalian target of rapamycin (mTOR) inhibitor), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (heat shock protein 90 (HSP90) inhibitor) and CCT130234 (in-house phospholipase C (PLC)g inhibitor). Fully automated analysis using a Celigo cytometer was validated for tumor spheroid growth and invasion against standard image analysis techniques, with excellent reproducibility and significantly increased throughput. In addition, we discovered key differential sensitivities to targeted agents between two-dimensional and three-dimensional cultures, and also demonstrated enhanced potency of some agents against cell migration/invasion compared with proliferation, suggesting their preferential utility in metastatic disease.: We have established and validated a suite of highly reproducible tumor microplate threedimensional functional assays to enhance the biological relevance of early preclinical cancer studies. We believe these assays will increase the translational predictive value of in vitro drug evaluation studies and reduce the need for in vivo studies by more effective triaging of compounds.This work was funded by The National Centre for the Replacement, Refinement and Reduction of Animals in Research (G1000121 ID no. 94513), Cancer Research UK (grant number C309/A8274), and by Red Tematica de Investigación Cooperativa en Cancer (RD06/0020/1022). We acknowledge NHS funding to the NIHR Biomedical Research Centre. MM is supported by a postdoctoral research contract (FIS, Program ‘Sara Borrell’, Instituto de Salud Carlos III), Ministerio de Ciencia e Innovación, Spain

MinION Analysis and Reference Consortium: Phase 1 data release and analysis

The advent of a miniaturized DNA sequencing device with a high-throughput contextual sequencing capability embodies the next generation of large scale sequencing tools. The MinION™ Access Programme (MAP) was initiated by Oxford Nanopore Technologies™ in April 2014, giving public access to their USB-attached miniature sequencing device. The MinION Analysis and Reference Consortium (MARC) was formed by a subset of MAP participants, with the aim of evaluating and providing standard protocols and reference data to the community. Envisaged as a multi-phased project, this study provides the global community with the Phase 1 data from MARC, where the reproducibility of the performance of the MinION was evaluated at multiple sites. Five laboratories on two continents generated data using a control strain of Escherichia coli K-12, preparing and sequencing samples according to a revised ONT protocol. Here, we provide the details of the protocol used, along with a preliminary analysis of the characteristics of typical runs including the consistency, rate, volume and quality of data produced. Further analysis of the Phase 1 data presented here, and additional experiments in Phase 2 of E. coli from MARC are already underway to identify ways to improve and enhance MinION performance

\u27Mutiny on the Bounty\u27: the genetic history of Norfolk Island reveals extreme gender-biased admixture

Background The Pacific Oceania region was one of the last regions of the world to be settled via human migration. Here we outline a settlement of this region that has given rise to a uniquely admixed population. The current Norfolk Island population has arisen from a small number of founders with mixed Caucasian and Polynesian ancestry, descendants of a famous historical event. The ‘Mutiny on the Bounty’ has been told in history books, songs and the big screen, but recently this story can be portrayed through comprehensive molecular genetics. Written history details betrayal and murder leading to the founding of Pitcairn Island by European mutineers and the Polynesian women who left Tahiti with them. Investigation of detailed genealogical records supports historical accounts. Findings Using genetics, we show distinct maternal Polynesian mitochondrial lineages in the present day population, as well as a European centric Y-chromosome phylogeny. These results comprehensively characterise the unique gender-biased admixture of this genetic isolate and further support the historical records relating to Norfolk Island. Conclusions Our results significantly refine previous population genetic studies investigating Polynesian versus Caucasian diversity in the Norfolk Island population and add information that is beneficial to future disease and gene mapping studies

Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control.

BACKGROUND: Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed. METHODS: Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms. RESULTS: No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms. CONCLUSIONS: Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status

Variant connective tissue (joint hypermobility) and its relevance to depression and anxiety in adolescents: a cohort-based case-control study

Objective: To test whether variant connective tissue structure, as indicated by the presence of joint hypermobility, poses a developmental risk for mood disorders in adolescence. Design: Cohort-based case-control study. Setting: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were interrogated. Participants: 6105 children of the ALSPAC cohort at age 14 years old, of whom 3803 also were assessed when aged 18 years. Main outcome measures: In a risk analysis, we examined the relationship between generalised joint hypermobility (GJH) at age 14 years with psychiatric symptoms at age 18 years. In an association analysis, we examined the relationship between presence of symptomatic joint hypermobility syndrome (JHS) and International Classification of Diseases (ICD-10) indication of depression and anxiety (Clinical Interview Schedule Revised [CIS-R], Anxiety Sensitivity Index [ASI]) at age 18 years. Results: GJH was more common in females (n=856, 28%) compared to males (n=319, 11%; OR 3.20 (95% CI 2.78 to 3.68); P<0.001). In males only, GJH at age 14 years was associated with depression at 18 years (OR 2.10 (95%CI 1.17 to 3.76); P=0.013). An index of basal physiological arousal, elevated resting heart rate, mediated this effect. Across genders, the diagnosis of JHS at age 18 years was associated with the presence of depressive disorder (adjusted OR 3.53 (95%CI 1.67 to 7.40); P=0.001), anxiety disorder (adjusted OR 3.14 (95% CI 1.52 to 6.46); P=0.002), level of anxiety (B=8.08, t(3278)=3.95; P<0.001), and degree of psychiatric symptomatology (B=5.89, t(3441)=0.093; p<0.001). Conclusions: Variant collagen, indexed by joint hypermobility, is linked to the emergence of depression and anxiety in adolescence, an effect mediated by autonomic factors in males. Recognition of this association may motivate further evaluation, screening, and interventions to mitigate development of psychiatric disorders and improve health outcomes

A pragmatic cluster randomised controlled trial of a Diabetes REcall And Management system: the DREAM trial

BACKGROUND: Following the introduction of a computerised diabetes register in part of the northeast of England, care initially improved but then plateaued. We therefore enhanced the existing diabetes register to address these problems. The aim of the trial was to evaluate the effectiveness and efficiency of an area wide 'extended,' computerised diabetes register incorporating a full structured recall and management system, including individualised patient management prompts to primary care clinicians based on locally-adapted, evidence-based guidelines. METHODS: The study design was a pragmatic, cluster randomised controlled trial, with the general practice as the unit of randomisation. Set in 58 general practices in three Primary Care Trusts in the northeast of England, the study outcomes were the clinical process and outcome variables held on the diabetes register, patient-reported outcomes, and service and patient costs. The effect of the intervention was estimated using generalised linear models with an appropriate error structure. To allow for the clustering of patients within practices, population averaged models were estimated using generalized estimating equations. RESULTS: Patients in intervention practices were more likely to have at least one diabetes appointment recorded (OR 2.00, 95% CI 1.02, 3.91), to have a recording of a foot check (OR 1.87, 95% CI 1.09, 3.21), have a recording of receiving dietary advice (OR 2.77, 95% CI 1.22, 6.29), and have a recording of blood pressure (BP) (OR 2.14, 95% CI 1.06, 4.36). There was no difference in mean HbA1c or BP levels, but the mean cholesterol level in patients from intervention practices was significantly lower (-0.15 mmol/l, 95% CI -0.25, -0.06). There were no differences in patient-reported outcomes or in patient-reported use of drugs, or uptake of health services. The average cost per patient was not significantly different between the intervention and control groups. Costs incurred in administering the system at the register and in general practice were in addition to these. CONCLUSION: This study has shown benefits from an area-wide, computerised diabetes register incorporating a full structured recall and individualised patient management system. However, these benefits were achieved at a cost. In future, these costs may fall as electronic data exchange becomes a reliable reality. Trial registration: International Standard Randomised Controlled Trial Number (ISRCTN) Register, ISRCTN32042030

Personalised asthma action plans for adults with asthma

BACKGROUND: A key aim of asthma care is to empower each person to take control of his or her own condition. A personalised asthma action plan (PAAP), also known as a written action plan, an individualised action plan, or a self-management action plan, contributes to this endeavour. A PAAP includes individualised self-management instructions devised collaboratively with the patient to help maintain asthma control and regain control in the event of an exacerbation. A PAAP includes baseline characteristics (such as lung function), maintenance medication and instructions on how to respond to increasing symptoms and when to seek medical help. OBJECTIVES: To evaluate the effectiveness of PAAPs used alone or in combination with education, for patient-reported outcomes, resource use and safety among adults with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials, clinical trial registers, reference lists of included studies and review articles, and relevant manufacturers' websites up to 14 September 2016. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs), both blinded and unblinded, that evaluated written PAAPs in adults with asthma. Included studies compared PAAP alone versus no PAAP, and/or PAAP plus education versus education alone. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study characteristics and outcome data and assessed risk of bias for each included study. Primary outcomes were number of participants reporting at least one exacerbation requiring an emergency department (ED) visit or hospitalisation, asthma symptom scores on a validated scale and adverse events (all causes). Secondary outcomes were quality of life measured on a validated scale, number of participants reporting at least one exacerbation requiring systemic corticosteroids, respiratory function and days lost from work or study. We used a random-effects model for all analyses and standard Cochrane methods throughout. MAIN RESULTS: We identified 15 studies described in 27 articles that met our inclusion criteria. These 15 included studies randomised a total of 3062 participants (PAAP vs no PAAP: 2602 participants; PAAP plus education vs education alone: 460 participants). Ten studies (eight PAAP vs no PAAP; two PAAP plus education vs education alone) provided outcome data that contributed to quantitative analyses. The overall quality of evidence was rated as low or very low.Fourteen studies lasted six months or longer, and the remaining study lasted for 14 weeks. When reported, mean age ranged from 22 to 49 years and asthma severity ranged from mild to severe/high risk. PAAP alone compared with no PAAPResults showed no clear benefit or harm associated with PAAPs in terms of the number of participants requiring an ED visit or hospitalisation for an exacerbation (odds ratio (OR) 0.75, 95% confidence interval (CI) 0.45 to 1.24; 1385 participants; five studies; low-quality evidence), change from baseline in asthma symptoms (mean difference (MD) -0.16, 95% CI -0.25 to - 0.07; 141 participants; one study; low-quality evidence) or the number of serious adverse events, including death (OR 3.26, 95% CI 0.33 to 32.21; 125 participants; one study; very low-quality evidence). Data revealed a statistically significant improvement in quality of life scores for those receiving PAAP compared with no PAAP (MD 0.18, 95% CI 0.05 to 0.30; 441 participants; three studies; low-quality evidence), but this was below the threshold for a minimum clinically important difference (MCID). Results also showed no clear benefit or harm associated with PAAPs on the number of participants reporting at least one exacerbation requiring oral corticosteroids (OR 1.45, 95% CI 0.84 to 2.48; 1136 participants; three studies; very low-quality evidence) nor on respiratory function (change from baseline forced expiratory volume in one second (FEV1): MD -0.04 L, 95% CI -0.25L to 0.17 L; 392 participants; three studies; low-quality evidence). In one study, PAAPs were associated with significantly fewer days lost from work or study (MD -6.20, 95% CI -7.32 to - 5.08; 74 participants; low-quality evidence). PAAP plus education compared with education aloneResults showed no clear benefit or harm associated with adding a PAAP to education in terms of the number of participants requiring an ED visit or hospitalisation for an exacerbation (OR 1.08, 95% CI 0.27 to 4.32; 70 participants; one study; very low-quality evidence), change from baseline in asthma symptoms (MD -0.10, 95% CI -0.54 to 0.34; 70 participants; one study; low-quality evidence), change in quality of life scores from baseline (MD 0.13, 95% CI -0.13 to 0.39; 174 participants; one study; low-quality evidence) and number of participants requiring oral corticosteroids for an exacerbation (OR 0.28, 95% CI 0.07 to 1.12; 70 participants; one study; very low-quality evidence). No studies reported serious adverse events, respiratory function or days lost from work or study. AUTHORS' CONCLUSIONS: Analysis of available studies was limited by variable reporting of primary and secondary outcomes; therefore, it is difficult to draw firm conclusions related to the effectiveness of PAAPs in the management of adult asthma. We found no evidence from randomised controlled trials of additional benefit or harm associated with use of PAAP versus no PAAP, or PAAP plus education versus education alone, but we considered the quality of the evidence to be low or very low, meaning that we cannot be confident in the magnitude or direction of reported treatment effects. In the context of this caveat, we found no observable effect on the primary outcomes of hospital attendance with an asthma exacerbation, asthma symptom scores or adverse events. We recommend further research with a particular focus on key patient-relevant outcomes, including exacerbation frequency and quality of life, in a broad spectrum of adults, including those over 60 years of age

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis