Population pharmacokinetic study of gentamicin: A retrospective analysis in a large cohort of neonate patients

Objectives: Gentamicin is one of the most commonly prescribed antibiotics for suspected or proven infection in newborns. Because of age-associated (pre- and post- natal) changes in body composition and organ function, large interindividual variability in gentamicin drug levels exists, thus requiring a close monitoring of this drug due to its narrow therapeutic index. We aimed to investigate clinical and demographic factors influencing gentamicin pharmacokinetics (PK) in a large cohort of unselected newborns and to explore optimal regimen based on simulation. Methods: All gentamicin concentration data from newborns treated at the University Hospital Center of Lausanne between December 2006 and October 2011 were retrieved. Gentamicin concentrations were measured within the frame of a routine therapeutic drug monitoring program, in which 2 concentrations (at 1h and 12h) are systematically collected after the first administered dose, and a few additional concentrations are sampled along the treatment course. A population PK analysis was performed by comparing various structural models, and the effect of clinical and demographic factors on gentamicin disposition was explored using NONMEM®. Results: A total of 3039 concentrations collected in 994 preterm (median gestational age 32.3 weeks, range 24.2-36.5 weeks) and 455 term newborns were used in the analysis. Most of the data (86%) were sampled after the first dose (C1 h and C12 h). A two-compartment model best characterized gentamicin PK. Average clearance (CL) was 0.044 L/h/kg (CV 25%), central volume of distribution (Vc) 0.442 L/kg (CV 18%), intercompartmental clearance (Q) 0.040 L/h/kg and peripheral volume of distribution (Vp) 0.122 L/kg. Body weight, gestational age and postnatal age positively influenced CL. The use of both gestational age and postnatal age better predicted CL than postmenstrual age alone. CL was affected by dopamine and furosemide administration and non-significantly by indometacin. Body weight, gestational age and dopamine coadminstration significantly influenced Vc. Model based simulation confirms that preterm infants need higher dose, superior to 4 mg/kg, and extended interval dosage regimen to achieve adequate concentration. Conclusions: This study, performed on a very large cohort of neonates, identified important factors influencing gentamicin PK. The model will serve to elaborate a Bayesian tool for dosage individualization based on a single measurement.

Ambulatory blood pressure monitoring in the elderly

The incidence of hypertension is high in the elderly and is present in 2/3 of the patients older than 65 years. Prevalence can reach 90% in patients older than 80 years. The presence of isolated systolic hypertension (ISH) is characteristic of this population. However, the prevalence of hypertension by ambulatory blood pressure monitoring (ABPM) is not well known. In this study, we analyzed the special characteristics of hypertension in this population, giving special emphasis on ABPM readings

Biology, diversity and strategies for the monitoring and control of triatomines - Chagas disease vectors

Despite the relevant achievements in the control of the main Chagas disease vectors Triatoma infestans and Rhodnius prolixus, several factors still promote the risk of infection. The disease is a real threat to the poor rural regions of several countries in Latin America. The current situation in Brazil requires renewed attention due to its high diversity of triatomine species and to the rapid and drastic environmental changes that are occurring. Using the biology, behaviour and diversity of triatomines as a basis for new strategies for monitoring and controlling the vectorial transmission are discussed here. The importance of ongoing long-term monitoring activities for house infestations by T. infestans, Triatoma brasiliensis, Panstrongylus megistus, Triatoma rubrovaria and R. prolixus is also stressed, as well as understanding the invasion by sylvatic species. Moreover, the insecticide resistance is analysed. Strong efforts to sustain and improve surveillance procedures are crucial, especially when the vectorial transmission is considered interrupted in many endemic areas.

Polymerase chain reaction of peripheral blood as a tool for the diagnosis of visceral leishmaniasis in children

The diagnosis of visceral leishmaniasis (VL) generally requires the use of invasive tests for the collection of infected tissue (aspirates of bone marrow, spleen, liver or lymph nodes). This difficulty has led to the search for safer and less painful techniques to confirm the occurrence of the disease in children. Polymerase chain reaction (PCR) is a method that is advantageous in that it allows the use of peripheral blood samples for diagnosis. This paper reports the utilisation of PCR on peripheral blood samples to diagnose VL in 45 children in Mato Grosso do Sul, Brazil. This technique is compared with methods carried out using tissue collected by invasive procedures, including direct microscopy, culture and detection of Leishmania DNA by PCR in bone marrow aspirates. The results show that PCR of peripheral blood provides great sensitivity (95.6%) that is similar to that from the PCR of bone marrow aspirates (91.1%) and higher than that achieved with microscopy (80%) or culture (26.7%) methods. PCR of peripheral blood proved to be a suitable tool for the diagnosis of VL in children because it is highly sensitive and safe, with tissue collection being less invasive than in traditional tests.

Lightweight monitoring of label switched paths for bandwidth management

The purpose of resource management is the efficient and effective use of network resources, for instance bandwidth. In this article, a connection oriented network scenario is considered, where a certain amount of bandwidth is reserved for each label switch path (LSP), which is a logical path, in a MPLS or GMPLS environment. Assuming there is also some kind of admission control (explicit or implicit), these environments typically provide quality of service (QoS) guarantees. It could happen that some LSPs become busy, thus rejecting connections, while other LSPs may be under-utilised. We propose a distributed lightweight monitoring technique, based on threshold values, the objective of which is to detect congestion when it occurs in an LSP and activate the corresponding alarm which will trigger a dynamic bandwidth reallocation mechanism

Brachial artery peak velocity variation to predict fluid responsiveness in mechanically ventilated patients

INTRODUCTION Although several parameters have been proposed to predict the hemodynamic response to fluid expansion in critically ill patients, most of them are invasive or require the use of special monitoring devices. The aim of this study is to determine whether noninvasive evaluation of respiratory variation of brachial artery peak velocity flow measured using Doppler ultrasound could predict fluid responsiveness in mechanically ventilated patients. METHODS We conducted a prospective clinical research in a 17-bed multidisciplinary ICU and included 38 mechanically ventilated patients for whom fluid administration was planned due to the presence of acute circulatory failure. Volume expansion (VE) was performed with 500 mL of a synthetic colloid. Patients were classified as responders if stroke volume index (SVi) increased >or= 15% after VE. The respiratory variation in Vpeakbrach (DeltaVpeakbrach) was calculated as the difference between maximum and minimum values of Vpeakbrach over a single respiratory cycle, divided by the mean of the two values and expressed as a percentage. Radial arterial pressure variation (DeltaPPrad) and stroke volume variation measured using the FloTrac/Vigileo system (DeltaSVVigileo), were also calculated. RESULTS VE increased SVi by >or= 15% in 19 patients (responders). At baseline, DeltaVpeakbrach, DeltaPPrad and DeltaSVVigileo were significantly higher in responder than nonresponder patients [14 vs 8%; 18 vs. 5%; 13 vs 8%; P < 0.0001, respectively). A DeltaVpeakbrach value >10% predicted fluid responsiveness with a sensitivity of 74% and a specificity of 95%. A DeltaPPrad value >10% and a DeltaSVVigileo >11% predicted volume responsiveness with a sensitivity of 95% and 79%, and a specificity of 95% and 89%, respectively. CONCLUSIONS Respiratory variations in brachial artery peak velocity could be a feasible tool for the noninvasive assessment of fluid responsiveness in patients with mechanical ventilatory support and acute circulatory failure. TRIAL REGISTRATION ClinicalTrials.gov ID: NCT00890071.

Improvement in secondary hyperparathyroidism due to drug adherence monitoring in dialysis patients.

BACKGROUND: Poor medication adherence is a frequent cause of treatment failure but is difficult to diagnose. In this study we have evaluated the impact of measuring adherence to cinacalcet-HCl and phosphate binders in dialysis patients with uncontrolled secondary hyperparathyroidism. METHODS: 7 chronic dialysis patients with iPTH-levels >= 300 pg/ml despite treatment with >= 60 mg cinacalcet-HCl were included. Medication adherence was measured using the "Medication Events Monitoring System" during 3 months, followed by another 3-month period without monitoring. The adherence results were monthly discussed with the patients, as well as strategies to improve them. RESULTS: During monitoring, the percentage of prescribed doses taken was higher for cinacalcet-HCl (87.4%) and sevelamer (86.3%) than for calcium acetate (76.1%), as was the taking adherence (81.9% vs. 57.3% vs. 49.1%) but not the percentage of drug holidays (12.3% vs. 4.5% vs. 3.6%). Mean PO4 levels (from 2.24 +/- 0.6 mmol/l to 1.73 +/- 0.41 mmol/l; p = 0.14) and Ca++ x PO4 product (4.73 +/- 1.43 to 3.41 +/- 1.04 mmol2/l2; p = 0.12) improved and iPTH-level improved significantly from 916 +/- 618 pg/ml to 442 +/- 326 pg/ml (p = 0.04), without any change in medication. However, as drug monitoring was interrupted, all laboratory parameters worsened again. CONCLUSIONS: Assessment of drug adherence helped to document episodes of non-compliance and helped to avoid seemingly necessary dose increases.

Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0.

Metabolic problems lead to numerous failures during clinical trials, and much effort is now devoted to developing in silico models predicting metabolic stability and metabolites. Such models are well known for cytochromes P450 and some transferases, whereas less has been done to predict the activity of human hydrolases. The present study was undertaken to develop a computational approach able to predict the hydrolysis of novel esters by human carboxylesterase hCES2. The study involved first a homology modeling of the hCES2 protein based on the model of hCES1 since the two proteins share a high degree of homology (congruent with 73%). A set of 40 known substrates of hCES2 was taken from the literature; the ligands were docked in both their neutral and ionized forms using GriDock, a parallel tool based on the AutoDock4.0 engine which can perform efficient and easy virtual screening analyses of large molecular databases exploiting multi-core architectures. Useful statistical models (e.g., r (2) = 0.91 for substrates in their unprotonated state) were calculated by correlating experimental pK(m) values with distance between the carbon atom of the substrate's ester group and the hydroxy function of Ser228. Additional parameters in the equations accounted for hydrophobic and electrostatic interactions between substrates and contributing residues. The negatively charged residues in the hCES2 cavity explained the preference of the enzyme for neutral substrates and, more generally, suggested that ligands which interact too strongly by ionic bonds (e.g., ACE inhibitors) cannot be good CES2 substrates because they are trapped in the cavity in unproductive modes and behave as inhibitors. The effects of protonation on substrate recognition and the contrasting behavior of substrates and products were finally investigated by MD simulations of some CES2 complexes.

A teaching/learning support tool for introductory programming courses

In This work we present a Web-based tool developed with the aim of reinforcing teaching and learning of introductory programming courses. This tool provides support for teaching and learning. From the teacher's perspective the system introduces important gains with respect to the classical teaching methodology. It reinforces lecture and laboratory sessions, makes it possible to give personalized attention to the student, assesses the degree of participation of the students and most importantly, performs a continuous assessment of the student's progress. From the student's perspective it provides a learning framework, consisting in a help environment and a correction environment, which facilitates their personal work. With this tool students are more motivated to do programming

An automatic correction tool for relational database schemas

A Web-based tool developed to automatically correct relational database schemas is presented. This tool has been integrated into a more general e-learning platform and is used to reinforce teaching and learning on database courses. This platform assigns to each student a set of database problems selected from a common repository. The student has to design a relational database schema and enter it into the system through a user friendly interface specifically designed for it. The correction tool corrects the design and shows detected errors. The student has the chance to correct them and send a new solution. These steps can be repeated as many times as required until a correct solution is obtained. Currently, this system is being used in different introductory database courses at the University of Girona with very promising results

Evaluation of a mixed approach combining stationary and wearable systems to monitor gait over long distance.

Thanks to decades of research, gait analysis has become an efficient tool. However, mainly due to the price of the motion capture systems, standard gait laboratories have the capability to measure only a few consecutive steps of ground walking. Recently, wearable systems were proposed to measure human motion without volume limitation. Although accurate, these systems are incompatible with most of existing calibration procedures and several years of research will be necessary for their validation. A new approach consisting of using a stationary system with a small capture volume for the calibration procedure and then to measure gait using a wearable system could be very advantageous. It could benefit from the knowledge related to stationary systems, allow long distance monitoring and provide new descriptive parameters. The aim of this study was to demonstrate the potential of this approach. Thus, a combined system was proposed to measure the 3D lower body joints angles and segmental angular velocities. It was then assessed in terms of reliability towards the calibration procedure, repeatability and concurrent validity. The dispersion of the joint angles across calibrations was comparable to those of stationary systems and good reliability was obtained for the angular velocities. The repeatability results confirmed that mean cycle kinematics of long distance walks could be used for subjects' comparison and pointed out an interest for the variability between cycles. Finally, kinematics differences were observed between participants with different ankle conditions. In conclusion, this study demonstrated the potential of a mixed approach for human movement analysis.