Benefits of ICU admission in critically ill patients: Whether instrumental variable methods or propensity scores should be used

<p>Abstract</p> <p>Background</p> <p>The assessment of the causal effect of Intensive Care Unit (ICU) admission generally involves usual observational designs and thus requires controlling for confounding variables. Instrumental variable analysis is an econometric technique that allows causal inferences of the effectiveness of some treatments during situations to be made when a randomized trial has not been or cannot be conducted. This technique relies on the existence of one variable or "instrument" that is supposed to achieve similar observations with a different treatment for "arbitrary" reasons, thus inducing substantial variation in the treatment decision with no direct effect on the outcome. The objective of the study was to assess the benefit in terms of hospital mortality of ICU admission in a cohort of patients proposed for ICU admission (ELDICUS cohort).</p> <p>Methods</p> <p>Using this cohort of 8,201 patients triaged for ICU (including 6,752 (82.3%) patients admitted), the benefit of ICU admission was evaluated using 3 different approaches: instrumental variables, standard regression and propensity score matched analyses. We further evaluated the results obtained using different instrumental variable methods that have been proposed for dichotomous outcomes.</p> <p>Results</p> <p>The physician's main specialization was found to be the best instrument. All instrumental variable models adequately reduced baseline imbalances, but failed to show a significant effect of ICU admission on hospital mortality, with confidence intervals far higher than those obtained in standard or propensity-based analyses.</p> <p>Conclusions</p> <p>Instrumental variable methods offer an appealing alternative to handle the selection bias related to nonrandomized designs, especially when the presence of significant unmeasured confounding is suspected. Applied to the ELDICUS database, this analysis failed to show any significant beneficial effect of ICU admission on hospital mortality. This result could be due to the lack of statistical power of these methods.</p

Regulation of Epithelial Cell Morphology and Functions Approaching To More In Vivo-Like by Modifying Polyethylene Glycol on Polysulfone Membranes

Cytocompatibility is critically important in design of biomaterials for application in tissue engineering. However, the currently well-accepted “cytocompatible" biomaterials are those which promote cells to sustain good attachment/spreading. The cells on such materials usually lack the self-assembled cell morphology and high cell functions as in vivo. In our view, biomaterials that can promote the ability of cells to self-assemble and demonstrate cell-specific functions would be cytocompatible. This paper examined the interaction of polyethylene glycol (PEG) modified polysulfone (PSf) membranes with four epithelial cell types (primary liver cells, a liver tumor cell line, and two renal tubular cell lines). Our results show that PSf membranes modified with proper PEG promoted the aggregation of both liver and renal cells, but the liver cells more easily formed aggregates than the renal tubular cells. The culture on PEG-modified PSf membranes also enhanced cell-specific functions. In particular, the cells cultured on F127 membranes with the proper PEG content mimicked the in vivo ultrastructure of liver cells or renal tubules cells and displayed the highest cell functions. Gene expression data for adhesion proteins suggest that the PEG modification impaired cell-membrane interactions and increased cell-cell interactions, thus facilitating cell self-assembly. In conclusion, PEG-modified membrane could be a cytocompatible material which regulates the morphology and functions of epithelial cells in mimicking cell performance in vivo

Does the history of food energy units suggest a solution to "Calorie confusion"?

The Calorie (kcal) of present U.S. food labels is similar to the original French definition of 1825. The original published source (now available on the internet) defined the Calorie as the quantity of heat needed to raise the temperature of 1 kg of water from 0 to 1°C. The Calorie originated in studies concerning fuel efficiency for the steam engine and had entered dictionaries by 1840. It was the only energy unit in English dictionaries available to W.O. Atwater in 1887 for his popular articles on food and tables of food composition. Therefore, the Calorie became the preferred unit of potential energy in nutrition science and dietetics, but was displaced when the joule, g-calorie and kcal were introduced. This article will explain the context in which Nicolas Clément-Desormes defined the original Calorie and the depth of his collaboration with Sadi Carnot. It will review the history of other energy units and show how the original Calorie was usurped during the period of international standardization. As a result, no form of the Calorie is recognized as an SI unit. It is untenable to continue to use the same word for different thermal units (g-calorie and kg-calorie) and to use different words for the same unit (Calorie and kcal). The only valid use of the Calorie is in common speech and public nutrition education. To avoid ongoing confusion, scientists should complete the transition to the joule and cease using kcal in any context

A Comprehensive Genome-Wide Map of Autonomously Replicating Sequences in a Naive Genome

Eukaryotic chromosomes initiate DNA synthesis from multiple replication origins. The machinery that initiates DNA synthesis is highly conserved, but the sites where the replication initiation proteins bind have diverged significantly. Functional comparative genomics is an obvious approach to study the evolution of replication origins. However, to date, the Saccharomyces cerevisiae replication origin map is the only genome map available. Using an iterative approach that combines computational prediction and functional validation, we have generated a high-resolution genome-wide map of DNA replication origins in Kluyveromyces lactis. Unlike other yeasts or metazoans, K. lactis autonomously replicating sequences (KlARSs) contain a 50 bp consensus motif suggestive of a dimeric structure. This motif is necessary and largely sufficient for initiation and was used to dependably identify 145 of the up to 156 non-repetitive intergenic ARSs projected for the K. lactis genome. Though similar in genome sizes, K. lactis has half as many ARSs as its distant relative S. cerevisiae. Comparative genomic analysis shows that ARSs in K. lactis and S. cerevisiae preferentially localize to non-syntenic intergenic regions, linking ARSs with loci of accelerated evolutionary change

Repeated evolution of self-compatibility for reproductive assurance

Sexual reproduction in eukaryotes requires the fusion of two compatible gametes of opposite sexes or mating types. To meet the challenge of finding a mating partner with compatible gametes evolutionary mechanisms such as hermaphroditism and self-fertilisation have repeatedly evolved. Combining insight from comparative genomics, computer simulations and experimental evolution in fission yeast, we shed light on the conditions promoting separate mating types or self-compatibility by mating-type switching. Analogous to multiple independent transitions between switchers and non-switchers in natural populations mediated by structural genomic changes, novel switching genotypes were readily evolving under selection in experimental populations. Detailed fitness measurements accompanied by computer simulations show the benefits and costs of switching during sexual and asexual reproduction governing the occurrence of both strategies in nature. Our findings illuminate the trade-off between the benefits of reproductive assurance and its fitness costs under benign conditions governing the evolution of self-compatibility

Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms

The propensity of segmental duplications (SDs) to promote genomic instability is of increasing interest since their involvement in numerous human genomic diseases and cancers was revealed. However, the mechanism(s) responsible for their appearance remain mostly speculative. Here, we show that in budding yeast, replication accidents, which are most likely transformed into broken forks, play a causal role in the formation of SDs. The Pol32 subunit of the major replicative polymerase Polδ is required for all SD formation, demonstrating that SDs result from untimely DNA synthesis rather than from unequal crossing-over. Although Pol32 is known to be required for classical (Rad52-dependant) break-induced replication, only half of the SDs can be attributed to this mechanism. The remaining SDs are generated through a Rad52-independent mechanism of template switching between microsatellites or microhomologous sequences. This new mechanism, named microhomology/microsatellite-induced replication (MMIR), differs from all known DNA double-strand break repair pathways, as MMIR-mediated duplications still occur in the combined absence of homologous recombination, microhomology-mediated, and nonhomologous end joining machineries. The interplay between these two replication-based pathways explains important features of higher eukaryotic genomes, such as the strong, but not strict, association between SDs and transposable elements, as well as the frequent formation of oncogenic fusion genes generating protein innovations at SD junctions