Bone Marrow Stem Cell Treatment for Ischemic Heart Disease in Patients with No Option of Revascularization: A Systematic Review and Meta-Analysis

PMCID: PMC3686792This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Meta-analysis of continuous outcomes: using pseudo IPD created from aggregate data to adjust for baseline imbalance and assess treatment-by-baseline modification.

Meta-analysis of individual participant data (IPD) is considered the "gold-standard" for synthesizing clinical study evidence. However, gaining access to IPD can be a laborious task (if possible at all) and in practice only summary (aggregate) data are commonly available. In this work we focus on meta-analytic approaches of comparative studies where aggregate data are available for continuous outcomes measured at baseline (pre-treatment) and follow-up (post-treatment). We propose a method for constructing pseudo individual baselines and outcomes based on the aggregate data. These pseudo IPD can be subsequently analysed using standard analysis of covariance (ANCOVA) methods. Pseudo IPD for continuous outcomes reported at two timepoints can be generated using the sufficient statistics of an ANCOVA model i.e., the mean and standard deviation at baseline and follow-up per group, together with the correlation of the baseline and follow-up measurements. Applying the ANCOVA approach, which crucially adjusts for baseline imbalances and accounts for the correlation between baseline and change scores, to the pseudo IPD results in identical estimates to the ones obtained by an ANCOVA on the true IPD. In addition, an interaction term between baseline and treatment effect can be added. There are several modelling options available under this approach, which makes it very flexible. Methods are exemplified using reported data of a previously published IPD metaanalysis of 10 trials investigating the effect of antihypertensive treatments on systolic blood pressure, leading to identical results compared with the true IPD analysis and of a meta-analysis of fewer trials, where baseline imbalance occurred. This article is protected by copyright. All rights reserved

Heterologous effects of infant BCG vaccination: potential mechanisms of immunity

The current antituberculosis vaccine, BCG, was derived in the 1920s, yet the mechanisms of BCG-induced protective immunity and the variability of protective efficacy among populations are still not fully understood. BCG challenges the concept of vaccine specificity, as there is evidence that BCG may protect immunized infants from pathogens other than Mycobacterium tuberculosis – resulting in heterologous or nonspecific protection. This review summarizes the up-to-date evidence for this phenomenon, potential immunological mechanisms and implications for improved childhood vaccine design. BCG induces functional changes in infant innate and adaptive immune compartments, encouraging their collaboration in the first year of life. Understanding biological mechanisms beyond heterologous BCG effects is crucial to improve infant protection from infectious diseases.MRC; IMmunising PRegnant women and INfants neTwork (IMPRINT); GCRF Networks in Vaccines Research and Development; BBSRC; the National Vaccine Program Office (NVPO); Bill & Melinda Gates Foundation; Novavax, GSK; Janssen; European Commission; Horizon2020 TBVAC2020 (Grant No. H2020 PHC-643381); GCRF Networks in Vaccines Research and Development VALIDATE Network which was co-funded by the MRC and BBSRC (Grant No. MR/R005850/1)

Evidence for a core-shell structure of hydrothermal carbon

Hydrothermal carbonisation (HTC) has been demonstrated to be a sustainable thermochemical process, capable of producing functionalised carbon materials for a wide range of applications. In order to better apply such materials, the local chemistry and reaction pathways governing hydrothermal carbon growth must be understood. We report the use of scanning transmission X-ray microscopy (STXM) to observe chemical changes in the functionality of carbon between the interface and bulk regions of HTC. Spatially-resolved, element-specific X-ray photo-absorption spectra show the presence of differing local carbon chemistry between bulk “core” and interface “shell” regions of a glucose-derived hydrothermal carbon spherule. STXM provides direct evidence to suggest that mechanistic pathways differ between the core and shell of the hydrothermal carbon. In the shell region, at the water-carbon interface, more aldehyde and/or carboxylic species are suspected to provide a reactive interface for bridging reactions to occur with local furan-based monomers. In contrast, condensation reactions appear to dominate in the core, removing aryl-linking units between polyfuranic domains. The application of STXM to HTC presents opportunities for a more comprehensive understanding of the spatial distribution of carbon species within hydrothermal carbon, especially at the solvent-carbon interface

Subgroup effects despite homogeneous heterogeneity test results

Background. Statistical tests of heterogeneity are very popular in meta-analyses, as heterogeneity might indicate subgroup effects. Lack of demonstrable statistical heterogeneity, however, might obscure clinical heterogeneity, meaning clinically relevant subgroup effects. Methods. A qualitative, visual method to explore the potential for subgroup effects was provided by a modification of the forest plot, i.e., adding a vertical axis indicating the proportion of a subgroup variable in the individual trials. Such a plot was used to assess the potential for clinically relevant subgroup effects and was illustrated by a clinical example on the effects of antibiotics in children with acute otitis media. Results. Statistical tests did not indicate heterogeneity in the meta-analysis on the effects of amoxicillin on acute otitis media (Q = 3.29, p = 0.51; I2 = 0%; T2 = 0). Nevertheless, in a modified forest plot, in which the individual trials were ordered by the proportion of children with bilateral otitis, a clear relation between bilaterality and treatment effects was observed (which was also found in an individual patient data meta-analysis of the included trials: p-value for interaction 0.021). Conclusions. A modification of the forest plot, by including an additional (vertical) axis indicating the proportion of a certain subgroup variable, is a qualitative, visual, and easy-to-interpret method to explore potential subgroup effects in studies included in meta-analyse

Long-term interleukin-6 levels and subsequent risk of coronary heart disease: Two new prospective studies and a systematic review

Background The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context. Methods and Findings Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28-0.53, over 4 y, and 0.35, 95% CI 0.23-0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29-1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45-3.15) with long-term average ("usual'') IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42-1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45-4.56] per 2 SD increase in usual [long-term average] IL-6 levels). Conclusions Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6-mediated pathways to CH

Impact of inhaled corticosteroids on growth in children with asthma: systematic review and meta-analysis

Background: Long-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth. Methods: We initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic. Results: We found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65). Conclusion: Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users