A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C>G SNP (odds ratio=8.6; P=0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5′-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C>G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Application of Bayesian Posterior Probabilistic Inference in Educational Trials

Educational researchers advocate the use of an effect size and its confidence interval to assess the effectiveness of interventions instead of relying on a p-value, which has been blamed for lack of reproducibility of research findings and the misuse of statistics. The aim of this study is to provide a framework, which can provide direct evidence of whether an intervention works for the study participants in an educational trial as the first step before generalizing evidence to the wider population. A hierarchical Bayesian model was applied to ten cluster and multisite educational trials funded by the Education Endowment Foundation in England, to estimate the effect size and associated credible intervals. The use of posterior probability is proposed as an alternative to p-values as a simple and easily interpretable metric of whether an intervention worked or not. The probability of at least one month’s progression or any other appropriate threshold is proposed to use in education outcomes instead of using a threshold of zero to determine a positive impact. The results show that the probability of at least one month’s progress ranges from 0.09 for one trial, GraphoGame Rime, to 0.94 for another, the Improving Numeracy and Literacy trial

Individual Participant Data Meta-analysis of the Impact of Educational Interventions on Pupils Eligible for Free School Meals

Meta-analysis is the synthesis of findings from research projects, which enables an estimate of the average or pooled effect across various studies. This study presents findings from the intention to treat analysis for a series of educational evaluations in England using a two stage meta-analysis with standardised outcome data and Individual Participant Data (IPD) meta-analyses. The research estimates the overall impact of educational trials on pupils eligible for Free School Meals (FSM) and the attainment gap in literacy and mathematics performance between FSM and non-FSM pupils based on analysis of 88 trials and data from over half a million pupils. For the meta-analyses, frequentist and Bayesian multilevel models were used to estimate the individual and pooled effect size across categories of explanatory variables such as age groups (key stages in England) and aspects of the type of interventions (one-to-one, small group, and whole class). Results indicated that the overall impact of interventions on the literacy outcomes of FSM pupils was positive with a pooled effect size of 0.06 (0.03, 0.08). However, for mathematics, no overall effect on FSM pupils was observed. Analysis of the attainment gap indicated that literacy outcomes for FSM pupils were improved by interventions marginally more than for non-FSM pupils (pooled attainment gap 0.01(-0.01, 0.04)). The risk of bias assessment showed that estimates were consistent across different methodological approaches. Overall, evidence from this study can be used to identify, test and scale educational interventions in schools to improve educational outcomes for disadvantaged pupils

Multisite educational trials: estimating the effect size and its confidence intervals

In education, multisite trials involve randomisation of pupils into intervention and comparison groups within schools. Most analytical models in multisite educational trials ignore that the impact of an intervention may be school dependent. This study investigates the impact of statistical models on the uncertainty associated with an effect size using comparable outcomes and covariates from ten multisite educational trials funded by the UK’s Education Endowment Foundation. Ordinary least squares (OLS) models often assume that the pupil’s outcomes within schools are independent, which is not always true. Multilevel models address this limitation by incorporating heterogeneity between schools to account for intra-school dependency. This inflates the confidence interval of an effect size obtained from the multilevel models than from an OLS model. For a multisite trial, the heterogeneity between schools also includes the differences in the expected impact of intervention between schools. Ignoring this additional school-by-intervention variation in a multisite trial could affect both its interpretation and conclusions. A robust approach to estimate the confidence intervals for effect size from multisite trials is by treating effect size as a parameter with its distribution. This paper is important for evaluating evidence from multisite trials by accounting for all sources of variability

Neuromuscular-blocking agents for tracheal intubation in pediatric patients (0-12 years): A systematic review and meta-analysis

Item does not contain fulltextBACKGROUND: The benefit of using neuromuscular-blocking agents to facilitate tracheal intubation in pediatric patients remains unclear due to variations in design, treatments, and results among trials. By combining the available evidence, we aimed to establish whether scientific findings are consistent and can be generalized across various populations, settings, and treatments. METHODS: A systematic search for randomized controlled trials, related to the use of neuromuscular-blocking agents for tracheal intubation in American Society of Anesthesiologists class I-II participants (0-12 years), was performed. We considered all randomized controlled trials that studied whether intubation conditions and hemodynamics obtained by using neuromuscular-blocking agents were equivalent to those that were achieved without neuromuscular-blocking agents. We combined the outcomes in Review Manager 5.3 (RevMan, The Cochrane Collaboration) by pairwise random-effects meta-analysis using a risk ratio (RR) for intubation conditions and mean difference for hemodynamic values (mean [95% Confidence Intervals]). Heterogeneity among trials was explored using sensitivity analyses. RESULTS: We identified 22 eligible randomized controlled trials with 1651 participants. Overall, the use of a neuromuscular-blocking agent was associated with a clinically important increase in the likelihood of both excellent (RR = 1.41 [1.19-1.68], I(2)  = 76%) and acceptable (RR = 1.13 [1.07-1.19], I(2)  = 68%) intubating conditions. There is strong evidence that both unacceptable intubation conditions (RR = 0.35 [0.22-0.46], I(2)  = 23%) and failed first intubation attempts (RR = 0.25 [0.14-0.42], I(2)  = 0%) were less likely to occur when a neuromuscular-blocking agent was used compared with when it was not. Higher systolic or mean arterial pressures (mean difference = 13.3 [9.1-17.5] mm Hg, I(2)  = 69%) and heart rates (mean difference = 15.9 [11.0-20.8] beats/min, I(2)  = 75%) as well as a lower incidence of arrhythmias were observed when tracheal intubation was facilitated by neuromuscular-blocking agents. CONCLUSION: The use of a neuromuscular-blocking agent during light-to-moderate depth of anesthesia can improve the quality as well as the success rate of tracheal intubation and is associated with better hemodynamic stability during induction of anesthesia