Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies

The design of randomised controlled trials (RCTs) should incorporate characteristics (such as concealment of randomised allocation and blinding of participants and personnel) that avoid biases resulting from lack of comparability of the intervention and control groups. Empirical evidence suggests that the absence of such characteristics leads to biased intervention effect estimates, but the findings of different studies are not consistent.

Engineering Tocopherol Selectivity in alpha-TTP: A Combined In Vitro/In Silico Study

"We present a combined in vitro/in silico study to determine the molecular origin of the selectivity of a-tocopherol transfer" "protein (a-TTP) towards a-tocopherol. Molecular dynamics simulations combined to free energy perturbation calculations predict a binding free energy for a-tocopherol to a-TTP 8.26+2.13 kcal mol{1 lower than that of c-tocopherol. Our calculations show that c-tocopherol binds to a-TTP in a significantly distorted geometry as compared to that of the natural ligand. Variations in the hydration of the binding pocket and in the protein structure are found as well. We propose a mutation, A156L, which significantly modifies the selectivity properties of a-TTP towards the two tocopherols. In particular, our simulations predict that A156L binds preferentially to c-tocopherol, with striking structural similarities to the wild-type- a-tocopherol complex. The affinity properties are confirmed by differential scanning fluorimetry as well as in vitro competitive binding assays. Our data indicate that residue A156 is at a critical position for determination of the selectivity of a-TTP. The engineering of TTP mutants with modulating binding properties can have potential impact at industrial level for easier purification of single tocopherols from vitamin E mixtures coming from natural oils or synthetic processes. Moreover," "the identification of a c-tocopherol selective TTP offers the possibility to challenge the hypotheses for the evolutionary development of a mechanism for a-tocopherol selection in omnivorous animals."

Combined use of transcranial magnetic stimulation and metal electrode implants: a theoretical assessment of safety considerations

This paper provides a theoretical assessment of the safety considerations encountered in the simultaneous use of transcranial magnetic stimulation (TMS) and neurological interventions involving implanted metallic electrodes, such as electrocorticography. Metal implants are subject to magnetic forces due to fast alternating magnetic fields produced by the TMS coil. The question of whether the mechanical movement of the implants leads to irreversible damage of brain tissue is addressed by an electromagnetic simulation which quantifies the magnitude of imposed magnetic forces. The assessment is followed by a careful mechanical analysis determining the maximum tolerable force which does not cause irreversible tissue damage. Results of this investigation provide useful information on the range of TMS stimulator output powers which can be safely used in patients having metallic implants. It is shown that conventional TMS applications can be considered safe when applied on patients with typical electrode implants as the induced stress in the brain tissue remains well below the limit of tissue damage.

Combined anatomical and clinical factors for the long-term risk stratification of patients undergoing percutaneous coronary intervention: the Logistic Clinical SYNTAX score

The SYNTAX score (SXscore), an anatomical-based scoring tool reflecting the complexity of coronary anatomy, has established itself as an important long-term prognostic factor in patients undergoing percutaneous coronary intervention (PCI). The incorporation of clinical factors may further augment the utility of the SXscore to longer-term risk stratify the individual patient for clinical outcomes.

Comparison of dual-energy subtraction and electronic bone suppression combined with computer-aided detection on chest radiographs: effect on human observers' performance in nodule detection

The objective of our study was to compare the effect of dual-energy subtraction and bone suppression software alone and in combination with computer-aided detection (CAD) on the performance of human observers in lung nodule detection.

Combined effect of 25-OH vitamin D plasma levels and genetic vitamin D receptor (NR 1I1) variants on fibrosis progression rate in HCV patients

Decreased vitamin D levels have been described in various forms of chronic liver disease and associated with advanced fibrosis. Whether this association is a cause or consequence of advanced fibrosis remains unclear to date.

Outcome of combined stenotic and regurgitant aortic valve disease

This study sought to describe the natural history of combined stenotic and regurgitant aortic valve disease.

Detecting subarachnoid hemorrhage: Comparison of combined FLAIR/SWI versus CT

OBJECTIVES: Aim of this study was to compare the utility of susceptibility weighted imaging (SWI) with the established diagnostic techniques CT and fluid attenuated inversion recovery (FLAIR) in their detecting capacity of subarachnoid hemorrhage (SAH), and further to compare the combined SWI/FLAIR MRI data with CT to evaluate whether MRI is more accurate than CT. METHODS: Twenty-five patients with acute SAH underwent CT and MRI within 6 days after symptom onset. Underlying pathology for SAH was head trauma (n=9), ruptured aneurysm (n=6), ruptured arteriovenous malformation (n=2), and spontaneous bleeding (n=8). SWI, FLAIR, and CT data were analyzed. The anatomical distribution of SAH was subdivided into 8 subarachnoid regions with three peripheral cisterns (frontal-parietal, temporal-occipital, sylvian), two central cisterns and spaces (interhemispheric, intraventricular), and the perimesencephalic, posterior fossa, superior cerebellar cisterns. RESULTS: SAH was detected in a total of 146 subarachnoid regions. CT identified 110 (75.3%), FLAIR 127 (87%), and SWI 129 (88.4%) involved regions. Combined FLAIR and SWI identified all 146 detectable regions (100%). FLAIR was sensitive for frontal-parietal, temporal-occipital and Sylvian cistern SAH, while SWI was particularly sensitive for interhemispheric and intraventricular hemorrhage. CONCLUSIONS: By combining SWI and FLAIR, MRI yields a distinctly higher detection rate for SAH than CT alone, particularly due to their complementary detection characteristics in different anatomical regions. Detection strength of SWI is high in central areas, whereas FLAIR shows a better detection rate in peripheral areas.

Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria

The Krebs cycle is of fundamental importance for the generation of the energetic and molecular needs of both prokaryotic and eukaryotic cells. Both enantiomers of metabolite 2-hydroxyglutarate are directly linked to this pivotal biochemical pathway and are found elevated not only in several cancers, but also in different variants of the neurometabolic disease 2-hydroxyglutaric aciduria. Recently we showed that cancer-associated IDH2 germline mutations cause one variant of 2-hydroxyglutaric aciduria. Complementary to these findings, we now report recessive mutations in SLC25A1, the mitochondrial citrate carrier, in 12 out of 12 individuals with combined D-2- and L-2-hydroxyglutaric aciduria. Impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling experiments and the absence of SLC25A1 in fibroblasts harboring certain mutations, suggest that SLC25A1 deficiency is pathogenic. Our results identify defects in SLC25A1 as a cause of combined D-2- and L-2-hydroxyglutaric aciduria.