Acute Thiopurine Overdose: Analysis of Reports to a National Poison Centre 1995-2013

Literature regarding acute human toxicity of thiopurines is limited to a handful of case reports. Our objectives were to describe all cases of overdose with thiopurines reported to the Swiss Toxicological Information Centre between 1995–2013. A retrospective analysis was performed to determine circumstances, magnitude, management and outcome of overdose with these substances. A total of 40 cases (14 paediatric) were reported (azathioprine, n = 35; 6-mercaptopurine, n = 5). Of these, 25 were with suicidal intent, 12 were accidental and 3 were iatrogenic errors. The magnitude of overdose ranged from 1.5 to 43 (median 8) times the usual dose in adults. Twelve cases (30%) had attributable symptoms. The majority of these were minor and included gastrointestinal complaints and liver function test and blood count abnormalities. Symptoms were experienced by patients who took at least 1.5-times their usual daily thiopurine dose. Overdoses over two or more consecutive days, even if of modest size, were less well tolerated. One case of azathioprine and allopurinol co-ingestion over consecutive days led to agranulocytosis. Decontamination measures were undertaken in 11 cases (10 activated charcoal, 1 gastric lavage) and these developed fewer symptoms than untreated patients. This study shows that acute overdoses with thiopurines have a favourable outcome in the majority of cases and provides preliminary evidence that gastrointestinal decontamination with activated charcoal may reduce symptom development after overdose of these substances if patients present to medical services soon after ingestion

Heart or heart-lung transplantation for patients with congenital heart disease in England

BACKGROUND: Increased longevity in patients with congenital heart disease (CHD) is associated with late complications, mainly heart failure, which may not be amenable to redo surgery and become refractory to medical therapy and so, trigger referral for transplantation. We assessed the current role and future prospects of heart and heart-lung transplantation for patients with CHD in England. METHODS: We performed a retrospective analysis of hospital episodes for England for 1997-2015, identifying patients with a CHD code (ICD-10 'Q2xx.x'), who underwent heart or heart-lung transplantation. RESULTS: In total, 469 transplants (82.2% heart and 17.8% heart-lung) were performed in 444 patients. Half of patients transplanted had mild or moderate CHD complexity, this percentage increased with time (p=0.001). While overall, more transplantations were performed over the years, the proportion of heart-lung transplants declined (p<0.0001), whereas the proportion of transplants performed in adults remained static. Mortality was high during the first year, especially after heart-lung transplantation, but remained relatively low thereafter. Older age and heart-lung transplantation were strong predictors of death. While an increase in CHD transplants is anticipated, actual numbers in England seem to lag behind the increase in CHD patients with advanced heart failure. CONCLUSIONS: The current and future predicted increase in the numbers of CHD transplants does not appear to parallel the expansion of the CHD population, especially in adults. Further investment and changes in policy should be made to enhance the number of donors and increase CHD transplant capacity to address the increasing numbers of potential CHD recipients and optimise transplantation outcomes in this growing population

Analyse multidimensionnelle interactive de résultats de simulation (aide à la décision dans le domaine de l'agroécologie)

Dans cette thèse, nous nous sommes intéressés à l'analyse des données de simulation issues du modèle agro-hydrologique TNT. Les objectifs consistaient à élaborer des méthodes d'analyse des résultats de simulation qui replacent l'utilisateur au coeur du processus décisionnel, et qui permettent d'analyser et d'interpréter de gros volumes de données de manière efficace. La démarche développée consiste à utiliser des méthodes d'analyse multidimensionnelle interactive. Tout d'abord, nous avons proposé une méthode d'archivage des résultats de simulation dans une base de données décisionnelle (i.e. entrepôt de données), adaptée au caractère spatio-temporel des données de simulation produites. Ensuite, nous avons suggéré d'analyser ces données de simulations avec des méthodes d'analyse en ligne (OLAP) afin de fournir aux acteurs des informations stratégiques pour améliorer le processus d'aide à la prise de décision. Enfin, nous avons proposé deux méthodes d'extraction de skyline dans le contexte des entrepôts de données afin de permettre aux acteurs de formuler de nouvelles questions en combinant des critères environnementaux contradictoires, et de trouver les solutions compromis associées à leurs attentes, puis d'exploiter les préférences des acteurs pour détecter et faire ressortir les données susceptibles de les intéresser. La première méthode EC2Sky, permet un calcul incrémental et efficace des skyline en présence de préférences utilisateurs dynamiques, et ce malgré de gros volumes de données. La deuxième méthode HSky, étend la recherche des points skyline aux dimensions hiérarchiques. Elle permet aux utilisateurs de naviguer le long des axes des dimensions hiérarchiques (i.e. spécialisation / généralisation) tout en assurant un calcul en ligne des points skyline correspondants. Ces contributions ont été motivées et expérimentées par l'application de gestion des pratiques agricoles pour l'amélioration de la qualité des eaux des bassins versants agricoles, et nous avons proposé un couplage entre le modèle d'entrepôt de données agro-hydrologiques construit et les méthodes d'extraction de skyline proposées.This thesis concerns the analysis of simulation data generated by the agrohydrological model TNT. Our objective is to develop analytical methods for massive simulation results. We want to place the user at the heart of the decision-making process, while letting him handle and analyze large amounts of data in a very efficient way. Our first contribution is an original approach N-Catch, relying on interactive multidimensional analysis methods for archiving simulation results in a decisional database (i.e. data warehouse) adapted to the spatio-temporal nature of the simulation data. In addition, we suggest to analyze the simulation data with online analytical methods (OLAP) to provide strategic information for stakeholders to improve the decision making process. Our second contribution concern two methods for computing skyline queries in the context of data warehouses. These methods enable stakeholders to formulate new questions by combining conflicting environmental criteria, to find compromise solutions associated with their expectations, and to exploit the stakeholder preferences to identify and highlight the data of potential interest. The first method EC2Sky, focuses on how to answer efficiently and progressively skyline queries in the presence of several dynamic user preferences despite of large volume of data. The second method HSky, extends the skyline computation to hierarchical dimensions. It allows the user to navigate along the dimensions hierarchies (i.e. specialize / generalize) while ensuring the online computation of associated skylines. Finally, we present the application of our proposals for managing agricultural practices to improve water quality in agricultural watersheds. We propose a coupling between the agro-hydrological data warehouse model N-Catch and the proposed skyline computation methods.RENNES1-Bibl. électronique (352382106) / SudocSudocFranceF

The Staphylococcus aureus Response to Unsaturated Long Chain Free Fatty Acids: Survival Mechanisms and Virulence Implications

Staphylococcus aureus is an important human commensal and opportunistic pathogen responsible for a wide range of infections. Long chain unsaturated free fatty acids represent a barrier to colonisation and infection by S. aureus and act as an antimicrobial component of the innate immune system where they are found on epithelial surfaces and in abscesses. Despite many contradictory reports, the precise anti-staphylococcal mode of action of free fatty acids remains undetermined. In this study, transcriptional (microarrays and qRT-PCR) and translational (proteomics) analyses were applied to ascertain the response of S. aureus to a range of free fatty acids. An increase in expression of the σB and CtsR stress response regulons was observed. This included increased expression of genes associated with staphyloxanthin synthesis, which has been linked to membrane stabilisation. Similarly, up-regulation of genes involved in capsule formation was recorded as were significant changes in the expression of genes associated with peptidoglycan synthesis and regulation. Overall, alterations were recorded predominantly in pathways involved in cellular energetics. In addition, sensitivity to linoleic acid of a range of defined (sigB, arcA, sasF, sarA, agr, crtM) and transposon-derived mutants (vraE, SAR2632) was determined. Taken together, these data indicate a common mode of action for long chain unsaturated fatty acids that involves disruption of the cell membrane, leading to interference with energy production within the bacterial cell. Contrary to data reported for other strains, the clinically important EMRSA-16 strain MRSA252 used in this study showed an increase in expression of the important virulence regulator RNAIII following all of the treatment conditions tested. An adaptive response by S. aureus of reducing cell surface hydrophobicity was also observed. Two fatty acid sensitive mutants created during this study were also shown to diplay altered pathogenesis as assessed by a murine arthritis model. Differences in the prevalence and clinical importance of S. aureus strains might partly be explained by their responses to antimicrobial fatty acids

Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop

<p>Abstract</p> <p>Background</p> <p>Envenomation by crotaline snakes (rattlesnake, cottonmouth, copperhead) is a complex, potentially lethal condition affecting thousands of people in the United States each year. Treatment of crotaline envenomation is not standardized, and significant variation in practice exists.</p> <p>Methods</p> <p>A geographically diverse panel of experts was convened for the purpose of deriving an evidence-informed unified treatment algorithm. Research staff analyzed the extant medical literature and performed targeted analyses of existing databases to inform specific clinical decisions. A trained external facilitator used modified Delphi and structured consensus methodology to achieve consensus on the final treatment algorithm.</p> <p>Results</p> <p>A unified treatment algorithm was produced and endorsed by all nine expert panel members. This algorithm provides guidance about clinical and laboratory observations, indications for and dosing of antivenom, adjunctive therapies, post-stabilization care, and management of complications from envenomation and therapy.</p> <p>Conclusions</p> <p>Clinical manifestations and ideal treatment of crotaline snakebite differ greatly, and can result in severe complications. Using a modified Delphi method, we provide evidence-informed treatment guidelines in an attempt to reduce variation in care and possibly improve clinical outcomes.</p

Acute heart failure and cardiogenic shock.

Acute heart failure and cardiogenic shock are medical emergencies requiring urgent medical intervention. This article defines each syndrome and reviews the latest evidence regarding their clinical presentation, management and prognosis