Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries

BACKGROUND: The synthesis of published research in systematic reviews is essential when providing evidence to inform clinical and health policy decision-making. However, the validity of systematic reviews is threatened if journal publications represent a biased selection of all studies that have been conducted (dissemination bias). To investigate the extent of dissemination bias we conducted a systematic review that determined the proportion of studies published as peer-reviewed journal articles and investigated factors associated with full publication in cohorts of studies (i) approved by research ethics committees (RECs) or (ii) included in trial registries. METHODS AND FINDINGS: Four bibliographic databases were searched for methodological research projects (MRPs) without limitations for publication year, language or study location. The searches were supplemented by handsearching the references of included MRPs. We estimated the proportion of studies published using prediction intervals (PI) and a random effects meta-analysis. Pooled odds ratios (OR) were used to express associations between study characteristics and journal publication. Seventeen MRPs (23 publications) evaluated cohorts of studies approved by RECs; the proportion of published studies had a PI between 22% and 72% and the weighted pooled proportion when combining estimates would be 46.2% (95% CI 40.2%-52.4%, I2 = 94.4%). Twenty-two MRPs (22 publications) evaluated cohorts of studies included in trial registries; the PI of the proportion published ranged from 13% to 90% and the weighted pooled proportion would be 54.2% (95% CI 42.0%-65.9%, I2 = 98.9%). REC-approved studies with statistically significant results (compared with those without statistically significant results) were more likely to be published (pooled OR 2.8; 95% CI 2.2-3.5). Phase-III trials were also more likely to be published than phase II trials (pooled OR 2.0; 95% CI 1.6-2.5). The probability of publication within two years after study completion ranged from 7% to 30%. CONCLUSIONS: A substantial part of the studies approved by RECs or included in trial registries remains unpublished. Due to the large heterogeneity a prediction of the publication probability for a future study is very uncertain. Non-publication of research is not a random process, e.g., it is associated with the direction of study findings. Our findings suggest that the dissemination of research findings is biased

Lipid Alterations in Experimental Murine Colitis: Role of Ceramide and Imipramine for Matrix Metalloproteinase-1 Expression

BACKGROUND:Dietary lipids or pharmacologic modulation of lipid metabolism are potential therapeutic strategies in inflammatory bowel disease (IBD). Therefore, we analysed alterations of bioactive lipids in experimental models of colitis and examined the functional consequence of the second messenger ceramide in inflammatory pathways leading to tissue destruction. METHODOLOGY/PRINCIPAL FINDINGS:Chronic colitis was induced by dextran-sulphate-sodium (DSS) or transfer of CD4(+)CD62L(+) cells into RAG1(-/-)-mice. Lipid content of isolated murine intestinal epithelial cells (IEC) was analysed by tandem mass spectrometry. Concentrations of MMP-1 in supernatants of Caco-2-IEC and human intestinal fibroblasts from patients with ulcerative colitis were determined by ELISA. Imipramine was used for pharmacologic inhibition of acid sphingomyelinase (ASM). Ceramide increased by 71% in chronic DSS-induced colitis and by 159% in the transfer model of colitis. Lysophosphatidylcholine (LPC) decreased by 22% in both models. No changes were detected for phosphatidylcholine. Generation of ceramide by exogenous SMase increased MMP-1-protein production of Caco-2-IEC up to 7-fold. Inhibition of ASM completely abolished the induction of MMP-1 by TNF or IL-1beta in Caco-2-IEC and human intestinal fibroblasts. CONCLUSIONS/SIGNIFICANCE:Mucosal inflammation leads to accumulation of ceramide and decrease of LPC in the intestinal epithelium. One aspect of ceramide generation is an increase of MMP-1. Induction of MMP-1 by TNF or IL-1beta is completely blocked by inhibition of ASM with imipramine. Therefore, inhibition of ASM may offer a treatment strategy to reduce MMP-1 expression and tissue destruction in inflammatory conditions

Planet Formation Imager (PFI): science vision and key requirements

The Planet Formation Imager (PFI) project aims to provide a strong scientific vision for ground-based optical astronomy beyond the upcoming generation of Extremely Large Telescopes. We make the case that a breakthrough in angular resolution imaging capabilities is required in order to unravel the processes involved in planet formation. PFI will be optimised to provide a complete census of the protoplanet population at all stellocentric radii and over the age range from 0.1 to ~100 Myr. Within this age period, planetary systems undergo dramatic changes and the final architecture of planetary systems is determined. Our goal is to study the planetary birth on the natural spatial scale where the material is assembled, which is the "Hill Sphere" of the forming planet, and to characterise the protoplanetary cores by measuring their masses and physical properties. Our science working group has investigated the observational characteristics of these young protoplanets as well as the migration mechanisms that might alter the system architecture. We simulated the imprints that the planets leave in the disk and study how PFI could revolutionise areas ranging from exoplanet to extragalactic science. In this contribution we outline the key science drivers of PFI and discuss the requirements that will guide the technology choices, the site selection, and potential science/technology tradeoffs.S.K. acknowledges support from an STFC Rutherford Fellowship (ST/J004030/1) and Philip Leverhulme Prize (PLP-2013-110). Part of this work was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration

On the use of titration calorimetry to study the association of surfactants in aqueous solutions

Isothermal titration calorimetry is increasingly becoming a common tool for the investigation of surfactant association processes. This can be associated with the development of new, sensitive and easy-to-operate commercial equipment, allied with the advantage of producing simultaneous information on the main thermodynamic parameters associated with the process under investigation. However, a significant fraction of users are still unfamiliar with many aspects related with the use of these calorimetric techniques. This review intends to discuss the design of experiments to investigate surfactant self-assembly in water and in the presence of polymers (charged and uncharged), as well as on how to derive the most relevant thermodynamic parameters from these calorimetric titration curves. Some literature examples are discussed to illustrate the use of these techniques for different systems

Ionization Constants pKa of Cardiolipin.

Cardiolipin is a phospholipid found in the inner mitochondrial membrane and in bacteria, and it is associated with many physiological functions. Cardiolipin has a dimeric structure consisting of two phosphatidyl residues connected by a glycerol bridge and four acyl chains, and therefore it can carry two negative charges. The pKa values of the phosphate groups have previously been reported to differ widely with pKa1 = 2.8 and pKa2 = 7.5-9.5. Still, there are several examples of experimental observations from cardiolipin-containing systems that do not fit with this dissociation behavior. Therefore, we have carried out pH-titration and titration calorimetric experiments on two synthetic cardiolipins, 1,1',2,2'-tetradecanoyl cardiolipin, CL (C14∶0), and 1,1',2,2'-tetraoctadecenoyl cardiolipin, CL (C18∶1). Our results show that both behave as strong dibasic acids with pKa1 about the same as the first pKa of phosphoric acid, 2.15, and pKa2 about one unit larger. The characterization of the acidic properties of cardiolipin is crucial for the understanding of the molecular organization in self-assembled systems that contain cardiolipin, and for their biological function

The Hydration of a DNA−Amphiphile Complex

We present measurements of isothermal DNA−hexadecyltrimethylammonium (DNACTA) complex and pure DNA hydration at 25 °C using a sorption microcalorimeter. This calorimeter provides simultaneous measurement of (i) water activity (sorption isotherms) and (ii) the partial molar enthalpy of water as a function of water uptake. For pure DNA, hydration is exothermic over the studied concentration range and we find an approximately linear relation between the partial molar enthalpy and the partial molar free energy. A kink in the isotherm appears at 20.0 ± 0.3 water molecules per base pair for a water activity of 0.80, consistent with A−B transition of the DNA. There is no detectable heat effect associated with this transition. At low water contents, the hydration of the DNACTA (1:1) complex is exothermic as for the pure DNA, but after incorporation of the first 7.0 ± 0.1 water molecules, the enthalpy changes sign. At 22 water molecules per base pair, the enthalpy levels off to 2.7 ± 0.2 kJ/mol. In a separate experiment, the swelling limit for the DNACTA complex was found to be 27 ± 1 waters per base pair. The DNACTA complex is arranged in a hexagonal structure. We propose a model for the DNACTA complex based on the packing of the components in an electroneutral way consisting of six DNA helices, presumably in an A configuration, placed around a central CTA+ cylinder. The hydration of the complex is seen as a balance between the attractive electrostatic interaction causing the formation of the complex and a repulsive component arising from a hexagonal deformation of CTA+ cylinders. An important contribution to the partial molar enthalpy of water comes, in this interpretation, from the release of conformational constraints of the CTA ion alkyl chains

Titration of fatty acids solubilized in cationic and anionic micelles. Calorimetry and thermodynamic modeling

The electrostatic properties of charged surfactant micelles are investigated through titrations of fatty acid probes solubilized in the micelles. The titration process is followed by means of calorimetric measurements and by determining the pH values as a function of added base. This approach yields a complete thermodynamic description of the titration process. In particular, we find that the process is endothermic at 298 K. This is contrary to the titration of carboxylic acids in water, where Delta H is approximately 0. To identify the main effect underlying the difference in Delta H between titration in a micelle and water, a thermodynamic model has been developed which focuses on the transfer properties of charged and uncharged species from bulk water to the surface of a micelle and which incorporates a dielectric discontinuity at the micellar surface. The model relies on the use of the Poisson-Boltzmann equation which is solved using a finite element method. Experimental results and the model calculations imply that the dielectric discontinuity at (or near) the micellar surface plays a major role and hence must be included when analyzing the titration behavior of an acid functionality at the surface of a charged micelle

Binding of hexadecyltrimethylammonium bromide to starch polysaccharides. Part II. Calorimetric study

Isothermal titration calorimetry was used to study the interaction between hexadecyltrimethylammonium bromide, CTAB, and three starch polysaccharides, amylose from potato, amylopectin from potato and amylopectin from barley. The enthalpy change for consecutive additions of CTAB to starch polysaccharide solutions were measured at 27degreesC. The starch-CTAB interaction enthalpies, DeltaH(f), were calculated by subtracting the enthalpy of micelle dissociation and dilution from the observed heat and relating the interaction enthalpy to the amount of interacting CTAB. The interaction was studied at three polysaccharide concentrations, 0.1, 0.25 and 0.5% w/w. The exothermic interaction enthalpy was constant and quite large in the main part of the concentration range studied for all three-starch polysaccharides. Amylose had an interaction enthalpy of -55 kJ/mol CTAB while the amylopectin samples had an interaction enthalpy of -40 kJ/mol CTAB. Amylopectin and amylose seemed to have a similar interaction with CTAB, the small differences were probably due to the differences in structure between the polysaccharides

Titration curves for CL (C14∶0).

<p>a) pH as a function of mole ratio <i>r</i>{H⁺/CL (C14∶0)²⁻} from titration of aqueous dispersion of CL (C14∶0) Na₂ with HCl, b) back titration with KOH of the resulting acidified CL (C14∶0) H₂; × and o in water (2 replicates); ⧫ in 0.05 mol l⁻¹ KCl.</p