83 research outputs found
Intravenous magnesium sulphate and sotalol for prevention of atrial fibrillation after coronary artery bypass surgery: a systematic review and economic evaluation
No full textObjectives: To assess the clinical and cost-effectiveness of magnesium sulphate compared with sotalol, and to assess the clinical effectiveness of magnesium sulphate compared with placebo in the prevention of atrial fibrillation (AF) in patients who have had a coronary artery bypass graft (CABG).Data sources: Major electronic databases were searched from December 2003 to May 2007.Review methods: Selected studies were assessed, subjected to data extraction using a standard template and quality assessment using published criteria. A simple short-term economic model was developed, informed by a systematic review of economic evaluations and populated with data from a review of costing/resource-use studies and other published studies. The cost-effectiveness of magnesium sulphate as prophylaxis was estimated for a set of base-case assumptions and the robustness of these results was assessed using deterministic and probabilistic sensitivity analysis.Results: Twenty-two papers met the inclusion criteria reporting 15 trials which all compared magnesium sulphate with placebo or control. They ranged in size from 15 to 176 patients randomised, and were conducted in Europe, the USA and Canada. The standard of reporting was generally poor, with details of key methodological attributes difficult to elucidate. No trials were identified that specifically aimed to compare magnesium sulphate with sotalol. Of 1070 patients in the pooled magnesium group, 230 (21%) developed postoperative AF, compared with 307 of 1031 (30%) patients in the placebo or (control) group. Meta-analysis using a fixed-effects model generated a pooled odds ratio (OR) that was significantly less than 1.0 [OR = 0.65, 95% confidence interval (CI) 0.53 to 0.79, test for overall effect p < 0.0001], but with statistically significant heterogeneity (I2 = 63.4%, p = 0.0005). Two randomised controlled trials (RCTs) were notable as they had relatively lower ORs in favour of magnesium sulphate. When these were removed from the analyses the pooled OR remained statistically significant, but heterogeneity no longer remained significant. These two studies tended to impart a highly significant reduction in the odds of AF to whichever subgroup they were analysed in. When studies were ordered by total duration of prophylaxis, an apparent relationship between duration and odds of AF was evident, with decreasing odds of AF as duration of prophylaxis increased. This was confirmed by linear regression analysis (R2 = 0.743, p < 0.001). When the data were grouped into three classes according to duration, a statistically significant intervention effect was only present for the longest duration (OR = 0.12, 95% CI 0.06 to 0.23, p = 0.00001). Statistically significant intervention effects were associated with the initiation of prophylaxis 12 hours or more before surgery (OR 0.26; 95% CI 0.16 to 0.44, test for overall effect p = 0.00001, fixed-effects model) and less than 12 hours before surgery or during the surgery itself (OR = 0.73, 95% CI 0.56 to 0.97, test for overall effect p = 0.03, fixed-effects model), but not when prophylaxis was initiated at the end of surgery or postsurgery (OR = 0.85, 95% CI 0.59, 1.22, p = 0.37, fixed-effects model). When studies were ordered by total dose of intravenous magnesium sulphate (<25 g), the odds of AF were independent of the dose. A notable exception was that for a total dose of 9 g magnesium sulphate; here the odds of AF were significantly reduced relative to the control group, although this may be explained by the fact that these studies had excluded patients who were on antiarrhythmic drugs and so may have been at higher risk of AF. Sixty-three potentially relevant references about cost-effectiveness were identified, but no economic evaluations of intravenous magnesium alone as prophylaxis against AF following CABG, compared with sotalol as prophylaxis or no prophylaxis, were identified. Studies reporting resource use by patients with AF following CABG suggest that while AF significantly increased inpatient stays, by up to 2.3 days in the intensive care unit (ICU) and 3.4 days on the ward, differences in length of stay and costs between patients receiving prophylaxis and those not receiving prophylaxis were not statistically significant. In the base-case analysis, magnesium sulphate prophylaxis resulted in 0.081 fewer cases of AF at an incremental cost of £2.55. The incremental cost-effectiveness ratio (ICER) was £32 per AF case avoided. The estimated difference in average length of stay between the prophylaxis and no-prophylaxis strategies was only 0.24 days, despite a large assumed difference of 3 days for patients experiencing AF in each group (1 extra day in the ICU and 2 extra days on the ward). In a deterministic sensitivity analysis the greatest variation in ICERs was observed for input parameters relating to the baseline risk of AF following CABG and the effectiveness of prophylaxis, cost of prophylaxis and the resource consequences of postoperative AF. The largest ICER (£2092) in the sensitivity analysis was associated with increasing the length of patients' preoperative stay. In the base case it was assumed that admission routines would be identical under both strategies. However, patients receiving prophylaxis by intravenous infusion may have longer preoperative stays. In a probabilistic analysis the majority of the simulations were associated with improved outcomes (in this case fewer cases of AF), but also higher costs. Prophylaxis was the dominant strategy (better outcome at lower cost) in about 41% of the simulations using the base-case assumptions. Under an alternative scenario where patients receiving prophylaxis are admitted for longer before their operation, to receive their initial infusion, the proportion of simulations where prophylaxis dominates fell to around 5%. The probability of being cost-effective was 99% at a willingness to pay (WTP) threshold of £2000 per AF case avoided and 100% at a WTP threshold of £5000 per AF case avoided under the base-case assumptions. Under the alternative scenario of longer preoperative stays the probability of being cost-effective at these two threshold values fell to 48% and 93%, respectively. It is unclear what the appropriate decision threshold should be, given that this model used intermediate rather than final outcomes.Conclusions: No RCTs were identified that specifically aimed to compare intravenous magnesium with sotalol as prophylaxis for AF in patients undergoing CABG. Intravenous magnesium, compared with placebo or control, is effective in preventing postoperative AF, as confirmed by a statistically significant intervention effect based on pooled analysis of 15 RCTs. It was also found that AF was less likely to occur when a longer duration of prophylaxis was used, and the earlier that prophylaxis is started; however, this finding was associated with two RCTs that had more favourable results than the other trials. No clear relationship between dose and AF was observed, although a lower constant dose rate was associated with the lowest odds of AF. Further research should investigate the relationship between dose, dose rate, duration of prophylaxis, timing of initiation of therapy and patient characteristics, such as degree of risk for AF. This will provide stronger evidence for the optimum delivery of intravenous magnesium in patients undergoing CABG. In the base-case analysis in the economic model, magnesium sulphate prophylaxis reduced the number of postoperative AF cases at a modest increase in cost. The results of the economic analysis are highly sensitive to variation in certain key parameters. Prophylaxis is less likely to be a cost-effective option if it requires changes in admission routines that result in longer preoperative stays than would be the case without prophylaxis
Two pathways for cysteine biosynthesis in Leishmania major
No full textGenome mining and biochemical analyses have shown that Leishmania major possesses two pathways for cysteine synthesis - the de novo biosynthesis pathway comprising SAT (serine acetyltransferase) and CS (cysteine synthase) and the RTS (reverse trans-sulfuration) pathway comprising CBS (cystathionine β-synthase) and CGL (cystathionine γ-lyase). The LmjCS (L. major CS) is similar to the type A CSs of bacteria and catalyses the synthesis of cysteine using O-acetylserine and sulfide with Kms of 17.5 and 0.13 mM respectively. LmjCS can use sulfide provided by the action of MST (mercaptopyruvate sulfurtransferase) on 3-MP (3-mercaptopyruvate). LmjCS forms a bi-enzyme complex with Leishmania SAT (and Arabidopsis SAT), with residues Lys222, His226 and Lys227 of LmjCS being involved in the complex formation. LmjCBS (L. major CBS) catalyses the synthesis of cystathionine from homocysteine, but, unlike mammalian CBS, also has high cysteine synthase activity (but with the Km for sulfide being 10.7 mM). In contrast, LmjCS does not have CBS activity. CS was up-regulated when promastigotes were grown in medium with limited availability of sulfur amino acids. Exogenous methionine stimulated growth under these conditions and also the levels of intracellular cysteine, glutathione and trypanothione, whereas cysteine had no effect on growth or the intracellular cysteine levels, correlating with the low rate of transport of cysteine into the cell. These results suggest that cysteine is generated endogenously by promastigotes of Leishmania. The absence of CS from mammals and the clear differences between CBS of mammals and Leishmania suggest that each of the parasite enzymes could be a viable drug target
Distinct roles in autophagy and importance in infectivity of the two ATG4 cysteine peptidases of leishmania major
No full textMacroautophagy in Leishmania, which is important for the cellular remodeling required during differentiation, relies upon the hydrolytic activity of two ATG4 cysteine peptidases (ATG4.1 and ATG4.2). We have investigated the individual contributions of each ATG4 to Leishmania major by generating individual gene deletion mutants (Δatg4.1 and Δatg4.2); double mutants could not be generated, indicating that ATG4 activity is required for parasite viability. Both mutants were viable as promastigotes and infected macrophages in vitro and mice, but Δatg4.2 survived poorly irrespective of infection with promastigotes or amastigotes, whereas this was the case only when promastigotes of Δatg4.1 were used. Promastigotes of Δatg4.2 but not Δatg4.1 were more susceptible than wild type promastigotes to starvation and oxidative stresses, which correlated with increased reactive oxygen species levels and oxidatively damaged proteins in the cells as well as impaired mitochondrial function. The antioxidant N-acetylcysteine reversed this phenotype, reducing both basal and induced autophagy and restoring mitochondrial function, indicating a relationship between reactive oxygen species levels and autophagy. Deletion of ATG4.2 had a more dramatic effect upon autophagy than did deletion of ATG4.1. This phenotype is consistent with a reduced efficiency in the autophagic process in Δatg4.2, possibly due to ATG4.2 having a key role in removal of ATG8 from mature autophagosomes and thus facilitating delivery to the lysosomal network. These findings show that there is a level of functional redundancy between the two ATG4s, and that ATG4.2 appears to be the more important. Moreover, the low infectivity of Δatg4.2 demonstrates that autophagy is important for the virulence of the parasite
A multi-paradigm, whole system view of health and social care for age-related macular degeneration
No full textAgainst the heads of words
No full textDans ce travail, il était question de vérifier si le mot a une tête morphologique. Suite aux faits de langues différentes, nous avons d´emontré la faiblesse de RHR infirmant le parallélisme entre morphologie et syntaxe. Nous constatons que le processus de la formation des mots dans les langues naturelle est très complexe et concluons que l’interaction entre la morphologie et les autres niveaux linguistiques peut aider à mieux comprendre ce processus.The question of derivation and the internal structure of words are the subject of this paper. we presented and discussed the Righthand Head Rule. Following several language facts, we concluded that RHR is not universal.We deduced also that word formation is closely related to interfaces and distributed [email protected]é Hassan II de CasablancaAckema P., 1999, Issues in Morphosyntax, Amsterdam, John Benjamins.Anderson S.R., 1982, «Where’s Morphology? », Linguistic Inquiry 13, pp. 571–612.Bauer L., 1990, « Be-heading the word », Journal of Linguistics 26, pp. 1–31.Carstairs Mc.C., 2012, « The evolutionary relevance of more and less complex forms of language », in : Tallerman M. et Gibson K. (éds.), Oxford Handbook of Language Evolution, Oxford, Oxford University Press, pp. 469–478.Ceccagno A. et Basciano B., 2007, « Compound Headedness in Chinese: An Analysis of neologisms », Morphology 17 : 2, pp. 207–231.Chomsky N., 1970, Remarks on nominalizations, Jacobs, Roderick/Rosenbaum.Chomsky N., 1995, The Minimalist Program, MIT Press, Cambridge Mass.Di Sciullo A.M., Williams E., 1987, On the Definition of Word, Cambridge, MIT Press.Halle M., Marantz A., 1993, « Distributed Morphology and the Pieces of Inflection», in : Halle M., Keyser S.J. (éds.), The View from Building 20: Essays in Honour of Sylvain Bromberger, Cambridge, MIT Press, pp. 111–176.Hoeksema J., 1992, « The Head Parameter in Morphology and Syntax », in : Gilbers D., Looyenga S. (éds.), Language and Cognition: Yearbook of the Research group for Linguistic Theory and Knowledge of the University of Groningen, Vol. II, Groningen, Universiteisdrukkerij Groningen, pp. 119–132.Jaeggli O.A., 1980, « Remarks on to contraction », Linguistic Inquiry Vol. 11, No 1, pp. 239–245.Lieber R., 1981, On the organization of the lexicon, Doctoral Dissertation, Massachusetts Institue of Technology.Scalise S., 1984, Generative morphology, Dordrecht, Foris.Selkirk E., 1982, The Syntax of Words, Cambridge, MIT Press.Williams E., 1981, « Argument Structure and Morphology », The Linguistic Review 1, pp. 81–114.1931932
Rooted in all its story, more is meant than meets the ear : a study of the relational and revelational nature of George MacDonald's mythopoeic art
No full textScholars and storytellers alike have deemed George MacDonald a great mythopoeic writer, an exemplar of the art. Examination of this accolade by those who first applied it to him proves it profoundly theological: for them a mythopoeic tale was a relational medium through which transformation might occur, transcending boundaries of time and space. The implications challenge much contemporary critical study of MacDonald, for they demand that his literary life and his theological life cannot be divorced if either is to be adequately assessed. Yet they prove consistent with the critical methodology MacDonald himself models and promotes. Utilizing MacDonald’s relational methodology evinces his intentional facilitating of Mythopoesis. It also reveals how oversights have impeded critical readings both of MacDonald’s writing and of his character. It evokes a redressing of MacDonald’s relationship with his Scottish cultural, theological, and familial environment – of how his writing is a response that rises out of these, rather than, as has so often been asserted, a mere reaction against them. Consequently it becomes evident that key relationships, both literary and personal, have been neglected in MacDonald scholarship – relationships that confirm MacDonald’s convictions and inform his writing, and the examination of which restores his identity as a literature scholar. Of particular relational import in this reassessment is A.J. Scott, a Scottish visionary intentionally chosen by MacDonald to mentor him in a holistic Weltanschauung. Little has been written on Scott, yet not only was he MacDonald’s prime influence in adulthood, but he forged the literary vocation that became MacDonald’s own. Previously unexamined personal and textual engagement with John Ruskin enables entirely new readings of standard MacDonald texts, as does the textual engagement with Matthew Arnold and F.D. Maurice. These close readings, informed by the established context, demonstrate MacDonald’s emergence, practice, and intent as a mythopoeic writer
The effect of feedback and information on children's pedometer step counts at school
No full textThis study examined whether feedback or feedback plus physical activity information could increase the number of pedometer steps taken during 1 school week. One hundred seventy-seven students (mean age 9.124 ± 1.11 years) in three elementary schools participated. Schools were randomly assigned to control (CON), feedback (FB), or feedback plus information (FB+I) groups. Children wore pedometers during school time for 5 consecutive weekdays. The total steps of the groups were recorded at the end of each school day, with students in the FB and FB+I groups free to view their step counts. In addition, the FB+I group received information and ideas about how they could increase their daily steps. The CON group received no step-count feedback or information. Students in the FB+I group achieved significantly more steps per minute (17.17 ± 4.87) than those in the FB (13.77 ± 4.06, p = 0.003) and CON (12.41 ± 3.12, p = 0.0001) groups. Information, as well as step-count feedback, increased elementary students’ school-based physical activity (number of steps) in the short term. A longer intervention period is necessary to assess the sustained impact of this type of approach
The Essence of Hospitality from the Texts of Classical Antiquity: The development of a hermeneutical helix to identify the origins and philosophy of the phenomenon of hospitality
No full textThe research project is an investigation into the origins and philosophy of the phenomenon of hospitality in order to identify the extent to which these are founded in ancient and classical history. The research focuses on Classical Antiquity and specifically investigates the origins of the history and philosophy of the phenomenon of hospitality within Greco-Roman texts and contemporaneous religious writings. In so doing it demonstrates how authoritative and disciplined research can make a significant contribution to the emergent research area of hospitality studies. The resulting thesis details a variety of outcomes and conclusions related to the phenomenon of hospitality, and also provides a basis for further enquiry. The research outcomes support the view that modern hospitality management literature has largely ignored this area of investigation. The principal methodological conclusion is that robust textual analysis can be undertaken within hermeneutical phenomenology and enhanced using a derived hermeneutical helix. The principal investigative outcome is that the hospitality phenomenon in its broadest sense has been recorded since the beginning of human history and it embraces a wide range of activities beyond the commercial provision of food, drink and accommodation. In particular, the essence of the hospitality phenomenon, within Classical Antiquity, is characterised by a reciprocally beneficial two-way process that takes place within three distinct and separate contexts: domestic, civil and commercial, which can also be summarised and represented by dynamic visual models
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