Flowchart.

<p>Flowchart showing the screening and inclusion process for randomised controlled trials, which were included or excluded in the current study.</p

Adherence of RCTs to CONSORT checklist.

<p>Kernel density estimation showing the percentage of the 37 respective 36 (in case of not applicability of item 11b) possible CONSORT items that were reported in 119 randomised controlled trials.</p

Correlation of RCT adherence to CONSORT checklist and citation frequency.

<p>Correlation of citation frequency from 01.01.2012–31.12.2014 and fulfilled CONSORT items of each RCT.</p

Journals’ information.

<p>List of included journals, journals´ s impact factor, number of published RCTs in each journal and total number of citations assessed form 01.01.2012–31.12.2014 of the analysed RCTs per journal.</p><p>Journals’ information.</p

Overview of journals`adherence to CONSORT checklist items.

<p>Shown are three categories of adherence to the 37 respective 36 (in case of not applicability of item 11b) CONSORT checklist items: below 50%, between 50% and 80%, above 80%. Results are shown in percent per journal and of all assessed journals (total).</p

Animals receiving the combined ibuprofen-Pep19-2.5 treatment have low serum levels of both TNFα and PGE 2h after LPS administration.

<p>Plasma TNFα (pg/ml) (A) and PGE Metabolites (pg/ml) (B) levels in groups of mice (at least n = 6) intraperitoneally inoculated with LPS from <i>S</i>. <i>enterica</i> Serovar Minnesota R60 (400 μg/mouse). Groups received the same treatments as detailed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133291#pone.0133291.g002" target="_blank">Fig 2</a>. Negative control group (n = 3) received neither LPS nor treatment. Statistical differences were analysed using ANOVA followed by DMS (parametrical, A) and Thamhane (no parametrical, B as there was heterogeneity of variances) post hoc tests (*, <i>P <</i> 0.05; **, <i>P <</i> 0.01; *** p<0.001). Very significant statistical differences (p<0.01 for PGE2 or p<0.001 for TNFα) were found between the negative control group (labelled with the symbol #) and the rest of the groups.</p

Administration of Ibuprofen to mice before or after LPS challenge has no protective effect.

<p>Kinetics of mortality of groups of mice (n = 6) intraperitoneally challenged with LPS from <i>S</i>. <i>enterica</i> Serovar Minnesota R60 (400 μg/mouse) and treated with (40 μg/mouse) of ibuprofen at different time points with respect to LPS inoculation (30 minutes before or immediately afterwards or 1 h subsequent to challenge). A control group (labeled as “LPS”) received only 400 μg/mouse of LPS. The Kaplan Meier test was used for statistical analysis.</p

The cellular response to LPS of monocytes is influenced by different combinations of anti-inflammatory drugs.

<p>Results from Gene Ontology analysis of data set retrieved from 1W-ANOVA. (A) List of genes belonging to GO term “Cellular Response to LPS” displayed as heatmap of hierarchical clustering (Pearson Centered distance matrix; Ward`s linkage rule) according to their relative expression. (B) Selected single genes from (A) displayed with their relative, quantile-normalized expression.</p

Pep19-2.5 acts in synergy with ibuprofen and protects mice against lethal endotoxemia.

<p>Kinetics of mortality of groups of mice (n = 6) intraperitoneally inoculated with LPS from <i>S</i>. <i>enterica</i> Serovar Minnesota R60 (400 μg/mouse) and treated 1 h later with either ibuprofen (40 μg/mouse), or Pep19-2.5 (400 μg/mouse) or a combination of both treatments. A control group (labelled as “LPS”) received only 400 μg/mouse of LPS. The Kaplan Meier test was used for statistical analysis.</p

The combination of ibuprofen and Pep19.2–5 alleviates the transcriptional LPS-response of human monocytes.

<p>Gene expression analysis of human monocytes stimulated with LPS, ibuprofen, Pep and combinations of both after 4 h of stimulation. Samples from 3 biological replicates of different donors were analysed by 1W-ANOVA with Tukey HSD post hoc testing for detection of differential expressed genes between parameters with a Benjamini-Hochberg multiple testing correction (cut-off ≤0.05). A: Variance in gene expression as indicated by the mean value of gene expression as well as its range with regard to LPS, LPS+Ibu, LPS+Pep and LPS+Ibu+Pep stimulation. The variance in gene expression upon LPS-stimulation is reduced by treatment with anti-inflammatory drugs ibuprofen, Pep or both. B: Pearson correlation analysis of significantly regulated genes from 1W-ANOVA analysis with subsequent hierarchical clustering (squared Euclidian distance; Ward`s linkage rule) on experimental conditions ordered the samples according to their similarity. Correlation coefficients are colour coded and exact numbers provided inside the boxes. C: Hierarchical clustering of significantly regulated genes from those genes that were found to be significantly regulated by LPS were subjected to Hierarchical Clustering (Pearson Centered distance matrix, Wards Linkage Rule) and relative gene expression is displayed for all experimental parameters as a heatmap.</p