Background: Numerous evidence-based guidelines (EBGs) pertaining to ventilator-associated pneumonia (VAP) have been published by domestic and international organizations, but their qualities have not been reported. Methods: A systematic search of the literature was performed up to July 2018 for relevant guidelines. Guidelines were eligible for inclusion if they incorporated recommendation statements for prevention and/ or management in adults or children with VAP and were developed on a systematic evidence-based method. Four reviewers evaluated each guideline using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument, which comprises 23 items organized into six domains in addition to two overall items. Results: Thirteen EBGs were identified for review. An overall high degree of agreement among reviewers was reached [intra-class correlation coefficient (ICC), 0.885; 95% CI, 0.862-0.905] during their review. The scores (mean, range) for the six AGREE domains were: scope and purpose (61%, 51-74%), stakeholder involvement (36%, 18-68%), rigor of development (41%, 22-59%), clarity and presentation (56%, 47-71%), applicability (38%, 21-59%) and editorial independence (50%, 0-77%). Only two EBGs (15.4%) were rated "recommended" for clinical practice. Approximately 86% of recommendations were based on moderate or low levels of evidence (levels B-D were 46.2%, 19.0%, and 21.2%, respectively). The recommendations for prevention and management of VAP were similar among the different EBGs. Conclusions: The overall quality of the identified EBGs pertaining to VAP was classified as moderate. The management of VAP varied by guideline. More high-quality evidence is needed to improve guideline recommendations.

Perturbations in transforming growth factor-β (TGF-β) signaling can lead to a plethora of diseases, including cancer. Mutations and posttranslational modi cations (PTMs) of the partner of Smad complexes contribute to the dysregulation of TGF-β signaling. Here, we reported a PTM of Smad4, R361 methylation, that was critical for Smad complexes formation and TGF-β signaling activation. Through mass spectrometric, co-immunoprecipitation (Co-IP) and immuno uorescent (IF) assays, we found that oncogene protein arginine methyltransferase 5 (PRMT5) interacted with Smad4 under TGF-β1 treatment.Mechanically, PRMT5 triggered Smad4 methylation at R361 and induced Smad complexes formation and nuclear import. Furthermore, we emphasized that PRMT5 interacting and methylating Smad4 was required for TGF-β1-induced epithelial-mesenchymal transition (EMT) and colorectal cancer (CRC) metastasis, and Smad4 R361 mutation diminished PRMT5 and TGF-β1-induced metastasis. In addition, highly expressed PRMT5 or high level of Smad4 R361 methylation indicated worse outcomes in clinical specimens analysis. Collectively, our study highlights the critical interaction of PRMT5 and Smad4 and the roles of Smad4 R361 methylation for controlling TGF-β signaling during metastasis. We provided a new insight for Smad4 activation. And this study indicated that blocking PRMT5-Smad4 signaling might be an effective targeting strategy in Smad4 wide type CRC.

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