Publication bias in randomized controlled trials in dentistry. What factors affect statistical significance of outcomes?

OBJECTIVES To record the proportion of Randomized Controlled Trials (RCTs) reporting significant (versus non- significant) primary outcomes, published across 12 high impact journals in Dentistry, covering 6 specialty domains. Associations with certain journal, publication and outcome characteristics were examined. METHODS We identified and included all RCTs published from January 1st, 2017 to December 31st, 2021 in the two journals with the highest impact factors (Clarivate Analytics, 2020) from each of the following domains: Periodontology, Endodontics, Restorative Dentistry/ Prosthodontics, Orthodontics, Paediatric Dentistry, Oral and Maxillofacial Surgery. The primary outcome was the proportion of significant/ non- significant findings reported for the primary outcomes under study, while a range of characteristics such as: journal, year of publication, impact factor, funding, registration and others, were tested for associations. RESULTS A total of 474 RCTs were identified and included, with the majority reporting statistically significant outcomes (321/474; 67.7%). The multivariable model revealed significant effects of predictors related to specialty domain (p = 0.01), continent (p = 0.003) and registration (p = 0.004). Compared to Periodontology, RCTs published in Endodontics (OR= 0.40; 95%CIs: 0.22, 0.76) and Orthodontics (OR= 0.41; 95%CIs: 0.23, 0.74) were less likely to present statistically significant effects. There was strong evidence that registered trials presented lower odds of reporting statistically significant findings (OR= 0.52; 95%CIs: 0.34, 0.81). CONCLUSIONS The entirety of dentistry domains demonstrated preferential publication practices of outcomes considered as "successful" and statistically significant, with domains such as Orthodontics and Endodontics being more balanced. Trial non- registration is still prevalent and associated with reporting of statistically significant effects. CLINICAL SIGNIFICANCE The findings of this empirical report bring attention to the interpretation of Systematic Reviews (SRs) conclusions. These largely depend on the availability and nature of outcomes of randomized controlled trials (RCTs) on a topic, which may impact on the synthesized estimate of a pooled effect and its direction

Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth. However, tumor overproduction of pro-angiogenic ligands can overcome these therapies, hampering success of this approach. To circumvent this problem, we target the resynthesis of phosphoinositides consumed during intracellular transduction of pro-angiogenic signals in endothelial cells (EC), thus harnessing the tumors own production of excess stimulatory ligands to deplete adjacent ECs of the capacity to respond to these signals. Using zebrafish and human endothelial cells in vitro, we show ECs deficient in CDP-diacylglycerol synthase 2 are uniquely sensitive to increased vascular endothelial growth factor (VEGF) stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol-(4,5)-bisphosphate (PIP2), resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling. Using murine tumor allograft models, we show that systemic or EC specific suppression of phosphoinositide recycling results in reduced tumor growth and tumor angiogenesis. Our results suggest inhibition of phosphoinositide recycling provides a useful anti-angiogenic approach

Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration

Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and ανβ3 integrin. Screening for proteins that interact with RPTPβ/ζ and potentially regulate PTN signaling, through mass spectrometry analysis, identified cyclin-dependent kinase 5 (CDK5) activator p35 among the proteins displaying high sequence coverage. Interaction of p35 with the serine/threonine kinase CDK5 leads to CDK5 activation, known to be implicated in cell migration. Protein immunoprecipitation and proximity ligation assays verified p35-RPTPβ/ζ interaction and revealed the molecular association of CDK5 and RPTPβ/ζ. In endothelial cells, PTN activates CDK5 in an RPTPβ/ζ- and phosphoinositide 3-kinase (PI3K)-dependent manner. On the other hand, c-Src, ανβ3 and ERK1/2 do not mediate the PTN-induced CDK5 activation. Pharmacological and genetic inhibition of CDK5 abolished PTN-induced endothelial cell migration, suggesting that CDK5 mediates PTN stimulatory effect. A new pyrrolo[2,3-α]carbazole derivative previously identified as a CDK1 inhibitor, was found to suppress CDK5 activity and eliminate PTN stimulatory effect on cell migration, warranting its further evaluation as a new CDK5 inhibitor. Collectively, our data reveal that CDK5 is activated by PTN, in an RPTPβ/ζ-dependent manner, regulates PTN-induced cell migration and is an attractive target for the inhibition of PTN pro-angiogenic properties

Protein tyrosine phosphatases in glioma biology

Gliomas are a diverse group of brain tumors of glial origin. Most are characterized by diffuse infiltrative growth in the surrounding brain. In combination with their refractive nature to chemotherapy this makes it almost impossible to cure patients using combinations of conventional therapeutic strategies. The drastically increased knowledge about the molecular underpinnings of gliomas during the last decade has elicited high expectations for a more rational and effective therapy for these tumors. Most studies on the molecular pathways involved in glioma biology thus far had a strong focus on growth factor receptor protein tyrosine kinase (PTK) and phosphatidylinositol phosphatase signaling pathways. Except for the tumor suppressor PTEN, much less attention has been paid to the PTK counterparts, the protein tyrosine phosphatase (PTP) superfamily, in gliomas. PTPs are instrumental in the reversible phosphorylation of tyrosine residues and have emerged as important regulators of signaling pathways that are linked to various developmental and disease-related processes. Here, we provide an overview of the current knowledge on PTP involvement in gliomagenesis. So far, the data point to the potential implication of receptor-type (RPTPδ, DEP1, RPTPμ, RPTPζ) and intracellular (PTP1B, TCPTP, SHP2, PTPN13) classical PTPs, dual-specific PTPs (MKP-1, VHP, PRL-3, KAP, PTEN) and the CDC25B and CDC25C PTPs in glioma biology. Like PTKs, these PTPs may represent promising targets for the development of novel diagnostic and therapeutic strategies in the treatment of high-grade gliomas

Genes Involved in Systemic and Arterial Bed Dependent Atherosclerosis - Tampere Vascular Study

BACKGROUND: Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the genes generally involved in human advanced atherosclerotic (AHA type V-VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25). CONCLUSIONS: This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds

Determination by potnetial flow analysis of the hydrodynamic coefficients for a body manoeuvering in restricted waters

SIGLEAvailable from British Library Document Supply Centre- DSC:D33358/80 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Is data missing? An assessment of publication bias in orthodontic systematic reviews from 2010 to 2021

AIM To assess the extent of publication bias assessment in systematic reviews (SRs) across the orthodontic literature over the last 12 years and to identify the appropriateness of assessment and association with publication characteristics, including year of publication, journal, searching practices within unpublished literature or attempts to contact primary study authors and others. MATERIALS AND METHODS We searched six journals and the Cochrane Database of Systematic Reviews for relevant articles, since January 2010, until November 2021. We recorded practices interrelated with publication bias assessment, at the SR and meta-analysis level. These pertained to reporting strategies for searching within unpublished literature, attempts to communicate with authors of primary studies and formal assessment of publication bias either graphically or statistically. Potential associations between publication bias assessment practices with variables such as journal, year, methodologist involvement, and others were sought at the meta-analysis level. RESULTS A sum of 289 SRs were ultimately included, with 139 of those incorporating at least one available mathematical synthesis. Efforts to search within unpublished literature were reported in 191 out of 289 Reviews (66.1%), while efforts to communicate with primary study authors were recorded for 150 of 289 of those (51.9%). An appropriate strategy plan to address issues of publication bias, conditional on the number of studies available and the methodology plan reported, was followed in 78 of the 139 meta-analyses (56.1%). Formal publication bias assessment was actually reported in 35 of 139 meta-analyses (25.2%), while only half of those (19/35; 54.3%) followed an appropriately established methodology. Ten of the latter 19 studies detected the presence of publication bias (52.6%). Predictor variables of appropriate publication bias assessment did not reveal any significant effects. CONCLUSIONS Appropriate methodology and rigorous practices for appraisal of publication bias are underreported in SRs within the orthodontic literature since 2010 and up-to-date, while other established methodologies including search strategies for unpublished data or communication with authors appear currently suboptimal

Is data missing? An assessment of publication bias in orthodontic systematic reviews from 2010 to 2021

Aim To assess the extent of publication bias assessment in systematic reviews (SRs) across the orthodontic literature over the last 12 years and to identify the appropriateness of assessment and association with publication characteristics, including year of publication, journal, searching practices within unpublished literature or attempts to contact primary study authors and others. Materials and Methods We searched six journals and the Cochrane Database of Systematic Reviews for relevant articles, since January 2010, until November 2021. We recorded practices interrelated with publication bias assessment, at the SR and meta-analysis level. These pertained to reporting strategies for searching within unpublished literature, attempts to communicate with authors of primary studies and formal assessment of publication bias either graphically or statistically. Potential associations between publication bias assessment practices with variables such as journal, year, methodologist involvement, and others were sought at the meta-analysis level. Results A sum of 289 SRs were ultimately included, with 139 of those incorporating at least one available mathematical synthesis. Efforts to search within unpublished literature were reported in 191 out of 289 Reviews (66.1%), while efforts to communicate with primary study authors were recorded for 150 of 289 of those (51.9%). An appropriate strategy plan to address issues of publication bias, conditional on the number of studies available and the methodology plan reported, was followed in 78 of the 139 meta-analyses (56.1%). Formal publication bias assessment was actually reported in 35 of 139 meta-analyses (25.2%), while only half of those (19/35; 54.3%) followed an appropriately established methodology. Ten of the latter 19 studies detected the presence of publication bias (52.6%). Predictor variables of appropriate publication bias assessment did not reveal any significant effects. Conclusions Appropriate methodology and rigorous practices for appraisal of publication bias are underreported in SRs within the orthodontic literature since 2010 and up-to-date, while other established methodologies including search strategies for unpublished data or communication with authors appear currently suboptimal