Limited sampling strategies for monitoring tacrolimus in paediatric liver transplant recipients

Ce travail de recherche a été réalisé dans le laboratoire de pharmacologie clinique, au Centre Hospitalier Universitaire Sainte-Justine, à Montréal. C'est une étude rétrospective basée sur le suivi thérapeutique du Tacrolimus prescrit chez les enfants après transplantation hépatique. Ce suivi est nécessaire car le Tacrolimus possède une importante variabilité pharmacocinétique inter et intra-individuelle ainsi qu'un index thérapeutique très étroit. Actuellement, l'individualisation des doses prescrites est basée sur la mesure de la concentration de base - du médicament dans le sang (C0), mais des études récentes montrent que cette mesure ne reflète pas précisément l'exposition du Tacrolimus dans l'organisme chez les enfants. Le meilleur reflet de cette exposition est la mesure de l'aire sous la courbe (AUC). Cependant, cette dernière implique la mesure de multiples concentrations tout au long de l'intervalle entre 2 doses de médicament (Tacrolimus: 12 heures) ce qui est long, cher et impraticable en ambulatoire. De nouvelles méthodes utilisant un nombre limité de prélèvements ont donc été développées pour prédire au mieux cette AUC. Ce sont les "Limited sampling strategies" ou LSS. La plupart de ces LSS pour le Tacrolimus ont été développées et validées chez des patients transplantés adultes et leur application directe chez les transplantés pédiatriques n'est pas possible en raison de différences importantes au niveau des paramètres pharmacocinétiques du médicament entre ces deux populations. Aussi, le but de ce travail était de développer et valider, pour la première fois, des LSS chez les enfants transplantés hépatiques. Pour cela, une analyse de 36 profils pharmacocinétiques de 28 patients transplantés hépatiques âgés de 0.4- 18.5 ans a été effectuée. Tous les profils ont été réalisés au Centre Hospitalier Universitaire Sainte-Justine entre janvier 2007 et janvier 2009. Les LSS comportant au maximum 4 mesures de concentration ont été développées en utilisant une analyse de régression multiple. Parmi tous les modèles obtenus, cinq ont été sélectionnés sur la base de critères précis puis validés selon la méthode décrite par Sheiner et Beal.¦Les résultats montrent que ces cinq modèles peuvent prédire l'AUC du Tacrolimus avec une précision cliniquement acceptable de ± 15% alors que la C0 présente la plus faible corrélation avec l'AUC.¦En conclusion, cette étude confirme que la C0 ne permet pas de prédire de manière efficace l'exposition du Tacrolimus dans l'organisme dans notre population de patients pédiatriques contrairement aux LSS analysées qui offrent une méthode pratique et fiable. Par ailleurs, en permettant d'obtenir une estimation précise et simplifiée de l'AUC complète du Tacrolimus chez les patients, ces LSS ouvrent la porte à de futures études prospectives visant à mieux définir l'AUC cible du médicament et à déterminer si le suivi basé sur la mesure de l'AUC est plus efficace et plus sûr que celui basé sur la mesure de la C0

Invasive candidiasis as a cause of sepsis in the critically ill patient.

Invasive fungal infections are an increasingly frequent etiology of sepsis in critically ill patients causing substantial morbidity and mortality. Candida species are by far the predominant agent of fungal sepsis accounting for 10% to 15% of health-care associated infections, about 5% of all cases of severe sepsis and septic shock and are the fourth most common bloodstream isolates in the United States. One-third of all episodes of candidemia occur in the intensive care setting. Early diagnosis of invasive candidiasis is critical in order to initiate antifungal agents promptly. Delay in the administration of appropriate therapy increases mortality. Unfortunately, risk factors, clinical and radiological manifestations are quite unspecific and conventional culture methods are suboptimal. Non-culture based methods (such as mannan, anti-mannan, β-d-glucan, and polymerase chain reaction) have emerged but remain investigational or require additional testing in the ICU setting. Few prophylactic or pre-emptive studies have been performed in critically ill patients. They tended to be underpowered and their clinical usefulness remains to be established under most circumstances. The antifungal armamentarium has expanded considerably with the advent of lipid formulations of amphotericin B, the newest triazoles and the echinocandins. Clinical trials have shown that the triazoles and echinocandins are efficacious and well tolerated antifungal therapies. Clinical practice guidelines for the management of invasive candidiasis have been published by the European Society for Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of North America

Left bundle branch block and coronary artery disease: Accuracy of dipyridamole thallium-201 single-photon emission computed tomography in patients with exercise anteroseptal perfusion defects

Background: Reduced septal or anteroseptal uptake of thallium-201 during exercise is frequently observed in patients with left bundle branch block (LBBB) even in the absence of left anterior descending (LAD) coronary artery disease. The purpose of this study was to evaluate prospectively the accuracy of dipyridamole201TI single-photon emission computed tomography (SPECT) in detecting LAD coronary artery disease in patients with LBBB and septal or anteroseptal perfusion defects on exercise201TI SPECT. Methods and Results: Twelve consecutive patients (10 men and two women) with complete LBBB and septal or anteroseptal perfusion defects on exercise201TI SPECT underwent dipyridamole201TI SPECT. The delay between dipyridamole and exercise was 2 to 30 days. Coronary angiography was performed during this period in all patients. Six (50%) of 12 patients with exercise perfusion defects showed normal perfusion after dipyridamole; all had normal coronary angiograms. The remaining six patients also had positive results of dipyridamole studies, two with moderate and four with severe septal or anteroseptal perfusion defects. Coronary angiography showed significant (>50%) LAD coronary artery stenosis in three patients; three patients with severe septal or anteroseptal perfusion defects after dipyridamole had normal coronary angiograms. Neither the evaluation of apical involvement nor the presence of dilated ventricles, decreased left ventricular ejection fraction, or wall motion abnormalities could help to identify (or explain) false-positive results. Conclusion: This study confirms that dipyridamole is more accurate than exercise in excluding LAD coronary artery disease. However, there are still false-positive results and the severity of the septal or anteroseptal perfusion defect does not add additional information to identify LAD coronary artery disease. Coronary angiography is thus necessary for positive dipyridamole study results to identify coronary artery disease as a major prognostic factor in patients with LBB

Direct comparison of a radioiodinated intact chimeric anti-CEA MAb with its F(ab')2 fragment in nude mice bearing different human colon cancer xenografts.

Tumour localisation and tumour to normal tissue ratios of a chimeric anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb), in intact form and as an F(ab')2 fragment labelled with 125I and 131I, were compared in groups of nude mice bearing four different colon cancer xenografts, T380, Co112 or LoVo, of human origin, or a rat colon cancer transfected with human CEA cDNA, called '3G7'. For each tumour, three to four mice per time point were analysed 6, 12, 24, 48 and 96 h after MAb injection. In the different tumours, maximal localisation of intact MAb was obtained at 24 to 48 h, and of F(ab')2 fragment 12 to 24 h after injection. Among the different tumours, localisation was highest with colon cancer T380, with 64% of the injected dose per gram (% ID/g) for the intact MAb and 57% for its F(ab')2 fragment, while in the three other tumours, maximal localisation ranged from 14 to 22% ID g-1 for the intact MAb and was about 11% for the F(ab')2. Tumour to normal tissue ratios of intact MAb increased rapidly until 24 h after injection and remained stable or showed only a minor increase thereafter. In contrast, for the F(ab')2 fragment, the tumour to normal tissue ratios increased steadily up to 4 days after injection reaching markedly higher values than those obtained with intact MAb. For the four different xenografts, tumour to blood ratios of F(ab')2 were about 2, 3 and 5 to 16 times higher than those of intact antibodies at 12, 24 and 96 h after injection, respectively

How to rapidly abolish knee extension deficit after injury or surgery: a practice-changing video pearl from the Scientific Anterior Cruciate Ligament Network International (SANTI) Study Group

Knee extension deficit is frequently observed after anterior cruciate ligament reconstruction or rupture and other acute knee injuries. Loss of terminal extension often occurs because of hamstring contracture and quadriceps inactivation rather than mechanical intra-articular pathology. Failure to regain full extension in the first few weeks after anterior cruciate ligament reconstruction is a recognized risk factor for adverse long-term outcomes, and therefore, it is important to try to address it. In this technical note, a simple, rapid, and effective technique to help regain full knee extension and abolish quadriceps activation failure is described

Isolated meniscotibial ligament rupture. The medial meniscus “belt lesion”

Ramp lesions play a major role in both anteroposterior and rotational instability following anterior cruciate ligament rupture. The meniscotibial ligament (MTL) is the most important structure to repair and is the primary stabilizer of the posterior horn of the medial meniscus. The posteroinferior insertion of the MTL on the posterior horn of the medial has been described, forming a posterior “belt.” Isolated MTL lesion diagnosis can be challenging, as the absence of a meniscocapsular ligament lesion prevents its correct visualization through transnotch vision. This article details a tech- nique to diagnose and repair the “belt lesion” of the medial meniscus

Anterolateral ligament reconstruction protects the repaired medial meniscus: a comparative study of 383 anterior cruciate ligament reconstructions from the SANTI study group with a minimum follow-up of 2 years

Background: The prevalence of osteoarthritis after successful meniscal repair is significantly less than that after failed meniscal repair. Study Design: Cohort study; Level of evidence, 3. Purpose: The aim of this study was to determine whether the addition of anterolateral ligament reconstruction (ALLR) confers a protective effect on medial meniscal repair performed at the time of anterior cruciate ligament reconstruction (ACLR). Methods: Retrospective analysis of prospectively collected data was performed to include all patients who had undergone primary ACLR with concomitant posterior horn medial meniscal repair through a posteromedial portal between January 2013 and August 2015. ACLR autograft choice was bone–patellar tendon–bone, hamstring tendons (or quadrupled hamstring tendons), or quadrupled semitendinosus tendon graft with or without ALLR. At the end of the study period, all patients were contacted to determine if they had undergone reoperation. A Kaplan-Meier survival curve was plotted, and a Cox proportional hazards regression model was used to perform multivariate analysis. Results: 383 patients (mean ± SD age, 27.4 ± 9.2 years) were included with a mean follow-up of 37.4 months (range, 24-54.9 months): 194 patients underwent an isolated ACLR, and 189 underwent a combined ACLR + ALLR. At final follow-up, there was no significant difference between groups in postoperative side-to-side laxity (isolated ACLR group, 0.9 ± 0.9 mm [min to max, –1 to 3]; ACLR + ALLR group, 0.8 ± 1.0 mm [min to max, –2 to 3]; P = .2120) or Lysholm score (isolated ACLR group, 93.0 [95% CI, 91.3-94.7]; ACLR + ALLR group, 93.7 [95% CI, 92.3-95.1]; P = .556). Forty-three patients (11.2%) underwent reoperation for failure of the medial meniscal repair or a new tear. The survival rates of meniscal repair at 36 months were 91.2% (95% CI, 85.4%-94.8) in the ACLR + ALLR group and 83.8% (95% CI, 77.1%-88.7%; P = .033) in the ACLR group. The probability of failure of medial meniscal repair was >2 times lower in patients with ACLR + ALLR as compared with patients with isolated ACLR (hazard ratio, 0.443; 95% CI, 0.218-0.866). No other prognosticators of meniscal repair failure were identified. Conclusion: Combined ACLR and ALLR is associated with a significantly lower rate of failure of medial meniscal repairs when compared with those performed at the time of isolated ACLR