Predictors of total morbidity burden on days 3, 5 and 8 after cardiac surgery.

BACKGROUND: Post-operative morbidity affects up to 36% of cardiac surgical patients. However, few countries reliably record morbidity outcome data, despite patients wanting to be informed of all the risks associated with surgery. The Cardiac Post-Operative Morbidity Score (C-POMS) is a new tool for describing and scoring (0-13) total morbidity burden after cardiac surgery, derived by noting the presence/absence of 13 morbidity domains on days 3, 5, 8 and 15. Identifying modifiable C-POMS risk factors may suggest targets for intervention to reduce morbidity and healthcare costs. Thus, we explored the association of C-POMS with previously identified predictors of post-operative morbidity. METHODS: A systematic literature review of pre-operative risk assessment models for post-operative morbidity was conducted to identify variables associated with post-operative morbidity. The association of those variables with C-POMS was explored in patients drawn from the original C-POMS study (n = 444). RESULTS: Seventy risk factors were identified, of which 56 were available in the study and 49 were suitable for analysis. Numbers were too few to analyse associations on D15. Thirty-three (67.3%) and 20 (40.8%) variables were associated with C-POMS on at least 1 or 2 days, respectively. Pre-operative albumin concentration, left ventricular ejection fraction and New York Heart Association functional class were associated with C-POMS on all days. Of the 16 independent risk factors, pre-operative albumin and haemoglobin concentrations and weight are potentially modifiable. CONCLUSIONS: Different risk factors are associated with total morbidity burden on different post-operative days. Pre-operative albumin and haemoglobin concentrations and weight were independently predictive of post-operative total morbidity burden suggesting therapeutic interventions aimed at these might reduce both post-operative morbidity risk and health-care costs in patients undergoing cardiac surgery

Synthesis and Antagonist Activity of Methyllycaconitine Analogues on Human α7 Nicotinic Acetylcholine Receptors

Methyllycaconitine (MLA), 1, is a naturally occurring norditerpenoid alkaloid that is a highly potent (IC50 = 2 nM) selective antagonist of α7 nicotinic acetylcholine receptors (nAChRs). Several structural factors affect its activity such as the neopentyl ester side-chain and the piperidine ring N-side-chain. The synthesis of simplified AE-bicyclic analogues 14-21 possessing different ester and nitrogen side-chains was achieved in three steps. The antagonist effects of synthetic analogues were examined on human α7 nAChRs and compared to that of MLA 1. The most efficacious analogue (16) reduced α7 nAChR agonist responses [1 nM acetylcholine (ACh)] to 53.2 ± 1.9% compared to 3.4 ± 0.2% for MLA 1. This demonstrates that simpler analogues of MLA 1 possess antagonist effects on human α7 nAChRs but also indicates that further optimization may be possible to achieve antagonist activity comparable to that of MLA 1

Approaches to analysis with infinitesimals following Robinson, Nelson, and others

This is a survey of several approaches to the framework for working with infinitesimals and infinite numbers, originally developed by Abraham Robinson in the 1960s, and their constructive engagement with the Cantor-Dedekind postulate and the Intended Interpretation hypothesis. We highlight some applications including (1) Loeb's approach to the Lebesgue measure, (2) a radically elementary approach to the vibrating string, (3) true infinitesimal differential geometry. We explore the relation of Robinson's and related frameworks to the multiverse view as developed by Hamkins. Keywords: axiomatisations, infinitesimal, nonstandard analysis, ultraproducts, superstructure, set-theoretic foundations, multiverse, naive integers, intuitionism, soritical properties, ideal elements, protozoa

Pre-operative anaemia is associated with total morbidity burden on days 3 and 5 after cardiac surgery: a cohort study.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: Pre-operative anaemia is associated with mortality and red blood cell (RBC) transfusion requirement after cardiac surgery. However, the effect on post-operative total morbidity burden (TMB) is unknown. We explored the effect of pre-operative anaemia on post-operative TMB. METHODS: Data were drawn from the Cardiac Post-Operative Morbidity Score (C-POMS) development study (n = 442). C-POMS describes and quantifies (0-13) TMB after cardiac surgery by noting the presence/absence of 13 morbidity domains on days 3 (D3), 5 (D5), 8 (D8) and 15 (D15). Anaemia was defined as a haemoglobin concentration below 130 g/l for men and 120 g/l for women. RESULTS: Most patients were White British (86.1%) and male (79.2%) and underwent coronary artery bypass surgery (67.4%). Participants with pre-operative anaemia (n = 137, 31.5%) were over three times more likely to receive RBC transfusion (OR 3.08, 95%CI 1.88-5.06, p < 0.001), had greater D3 and D5 TMB (5 vs 3, p < 0.0001; 3 vs 2, p < 0.0001, respectively) and remained in hospital 2 days longer (8 vs 6 days, p < 0.0001) than non-anaemic patients. Transfused patients remained in hospital 5 days longer than non-transfused patients (p < 0.0001), had higher TMB on all days (all p < 0.001) and suffered greater pulmonary, renal, GI, neurological, endocrine and ambulation morbidities (p 0.026 to <0.001). Pre-operative anaemia and RBC transfusion were independently associated with increased C-POMS score. CONCLUSIONS: Pre-operative anaemia and RBC transfusion are independently associated with increased post-operative TMB. Understanding TMB may assist in post-operative patient management to reduce morbidity. We recommend the use of the C-POMS tool as a standard outcome tool in further studies.Professors Hugh Montgomery and Michael Mythen were supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centr

From DNA sequence to application: possibilities and complications

The development of sophisticated genetic tools during the past 15 years have facilitated a tremendous increase of fundamental and application-oriented knowledge of lactic acid bacteria (LAB) and their bacteriophages. This knowledge relates both to the assignments of open reading frames (ORF’s) and the function of non-coding DNA sequences. Comparison of the complete nucleotide sequences of several LAB bacteriophages has revealed that their chromosomes have a fixed, modular structure, each module having a set of genes involved in a specific phase of the bacteriophage life cycle. LAB bacteriophage genes and DNA sequences have been used for the construction of temperature-inducible gene expression systems, gene-integration systems, and bacteriophage defence systems. The function of several LAB open reading frames and transcriptional units have been identified and characterized in detail. Many of these could find practical applications, such as induced lysis of LAB to enhance cheese ripening and re-routing of carbon fluxes for the production of a specific amino acid enantiomer. More knowledge has also become available concerning the function and structure of non-coding DNA positioned at or in the vicinity of promoters. In several cases the mRNA produced from this DNA contains a transcriptional terminator-antiterminator pair, in which the antiterminator can be stabilized either by uncharged tRNA or by interaction with a regulatory protein, thus preventing formation of the terminator so that mRNA elongation can proceed. Evidence has accumulated showing that also in LAB carbon catabolite repression in LAB is mediated by specific DNA elements in the vicinity of promoters governing the transcription of catabolic operons. Although some biological barriers have yet to be solved, the vast body of scientific information presently available allows the construction of tailor-made genetically modified LAB. Today, it appears that societal constraints rather than biological hurdles impede the use of genetically modified LAB.

The dusty SF history of high-z galaxies, modelling tools and future prospects

We summarize recent advances in the determination of the cosmic history of star formation and other properties of high-z galaxies, and the relevance of this information in our understanding of the formation of structures. We emphasize the importance of dust reprocessing in the high--z universe, as demonstrated in particular by IR and sub-mm data. This demand a panchromatic approach to observations and suitable modelling tools. We spend also some words on expectations from future instruments

Ram pressure feeding super-massive black holes

When supermassive black holes at the center of galaxies accrete matter (usually gas), they give rise to highly energetic phenomena named Active Galactic Nuclei (AGN). A number of physical processes have been proposed to account for the funneling of gas towards the galaxy centers to feed the AGN. There are also several physical processes that can strip gas from a galaxy, and one of them is ram pressure stripping in galaxy clusters due to the hot and dense gas filling the space between galaxies. We report the discovery of a strong connection between severe ram pressure stripping and the presence of AGN activity. Searching in galaxy clusters at low redshift, we have selected the most extreme examples of jellyfish galaxies, which are galaxies with long tentacles of material extending for dozens of kpc beyond the galaxy disk. Using the MUSE spectrograph on the ESO Very Large Telescope, we find that 6 out of the 7 galaxies of this sample host a central AGN, and two of them also have galactic-scale AGN ionization cones. The high incidence of AGN among the most striking jellyfishes may be due to ram pressure causing gas to flow towards the center and triggering the AGN activity, or to an enhancement of the stripping caused by AGN energy injection, or both. Our analysis of the galaxy position and velocity relative to the cluster strongly supports the first hypothesis, and puts forward ram pressure as another, yet unforeseen, possible mechanism for feeding the central supermassive black hole with gas.Comment: published in Nature, Vol.548, Number 7667, pag.30

Non-classical ProIL-1beta activation during mammary gland infection is pathogen-dependent but caspase-1 independent

Infection of the mammary gland with live bacteria elicits a pathogen-specific host inflammatory response. To study these host-pathogen interactions wild type mice, NF-kappaB reporter mice as well as caspase-1 and IL-1beta knockout mice were intramammarily challenged with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The murine mastitis model allowed to compare the kinetics of the induced cytokine protein profiles and their underlying pathways. In vivo and ex vivo imaging showed that E. coli rapidly induced NF-kappaB inflammatory signaling concomitant with high mammary levels of TNF-alpha, IL-1 alpha and MCP-1 as determined by multiplex analysis. In contrast, an equal number of S. aureus bacteria induced a low NF-kappaB activity concomitant with high mammary levels of the classical IL-1beta fragment. These quantitative and qualitative differences in local inflammatory mediators resulted in an earlier neutrophil influx and in a more extensive alveolar damage post-infection with E. coli compared to S. aureus. Western blot analysis revealed that the inactive proIL-1beta precursor was processed into pathogen-specific IL-1beta fragmentation patterns as confirmed with IL-1beta knockout animals. Additionally, caspase-1 knockout animals allowed to investigate whether IL-1beta maturation depended on the conventional inflammasome pathway. The lack of caspase-1 did not prevent extensive proIL-1beta fragmentation by either of S. aureus or E. coli. These non-classical IL-1beta patterns were likely caused by different proteases and suggest a sentinel function of IL-1beta during mammary gland infection. Thus, a key signaling nodule can be defined in the differential host innate immune defense upon E. coli versus S. aureus mammary gland infection, which is independent of caspase-1

Modeling the Structural Consequences of \u3cem\u3eBEST1\u3c/em\u3e Missense Mutations

Mutations in the bestrophin-1 gene (BEST1) are an important cause of inherited retinal disorders. Hitherto, over 100 unique allelic variants have been linked to the human BEST1 (hBEST1), and associated with disease phenotypes, broadly termed as bestrophinopathies. A spontaneous animal model recapitulating BEST1-related phenotypes, canine multifocal retinopathy (cmr), is caused by mutations in the canine gene ortholog (cBEST1). We have recently characterized molecular consequences of cmr, demonstrating defective protein trafficking as a result of G161D (cmr2) mutation. To further investigate the pathological effects of BEST1 missense mutations, canine and human peptide fragments derived from the protein sequence have been studied in silico as models for early events in the protein folding. The results showed that G161D as well as I201T substitutions cause severe conformational changes in the structure of bestrophin-1, suggesting protein misfolding as an underlying disease mechanism. The comparative modeling studies expand our insights into BEST1 pathogenesis

Fermentation performance and nutritional assessment of physically processed lentil and green pea flour

BACKGROUND A significant amount of nutrients, including dietary fibers, proteins, minerals, and vitamins are present in legumes, but the presence of anti‐nutritional factors (ANFs) like phytic acid, tannins, and enzyme inhibitors impact the consumption of legume and nutrient availability. In this research, the effect of a physical process (sonication or precooking) and fermentation with Lactobacillus plantarum and Pediococcus acidilactici on ANFs of some legumes was evaluated. RESULTS Total phenolic contents were significantly (p\u3c0.05) reduced for modified and fermented substrates compared to non‐fermented controls. Trypsin inhibitory activity (TIA) was reduced significantly for all substrates except for unsonicated soybean and lentil fermented with L. plantarum and P. acidilactici. When physical processing was done, there was a decrease in TIA for all the substrate. Phytic acid content decreased for physically modified soybean and lentil but not significantly for green pea. Even though there was a decrease in ANFs, there was no significant change in in vitro protein digestibility for all substrates except for unsonicated L. plantarum fermented soybean flour and precooked L. plantarum fermented lentil. Similarly, there was change in amino acid content when physically modified and fermented. CONCLUSION Both modified and unmodified soybean flour, green pea flour, and lentil flour supported the growth of L. plantarum and P. acidilactici. The fermentation of this physically processed legume and pulse flours influenced the non‐nutritive compounds, thereby potentially improving nutritional quality and usage