Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Little is known about the pharmacokinetics of potassium canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS • A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received potassium canrenoate as part of their therapy in the intensive care unit. AIMS To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients. METHODS Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16–28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTS A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h−1) = 11.4 × (WT/70.0)0.75 and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h−1 and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h. CONCLUSIONS The range of estimated CL/F in the study population was 0.67–7.38 l h−1. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.

Real-time biosensor for the assessment of nanotoxicity and cancer electrotherapy

Knowledge of cell electronics has led to their integration to medicine either by physically interfacing electronic devices with biological systems or by using electronics for both detection and characterization of biological materials. In this dissertation, an electrical impedance sensor (EIS) was used to measure the electrode surface impedance changes from cell samples of human and environmental toxicity of nanoscale materials in 2D and 3D cell culture models. The impedimetric response of human lung fibroblasts and rainbow trout gill epithelial cells when exposed to various nanomaterials was tested to determine their kinetic effects towards the cells and to demonstrate the biosensor's ability to monitor nanotoxicity in real-time. Further, the EIS allowed rapid, real-time and multi-sample analysis creating a versatile, noninvasive tool that is able to provide quantitative information with respect to alteration in cellular function. We then extended the application of the unique capabilities of the EIS to do real-time analysis of cancer cell response to externally applied alternating electric fields at different intermediate frequencies and low-intensity. Decreases in the growth profiles of the ovarian and breast cancer cells were observed with the application of 200 and 100 kHz, respectively, indicating specific inhibitory effects on dividing cells in culture in contrast to the non-cancerous HUVECs and mammary epithelial cells. We then sought to enhance the effects of the electric field by altering the cancer cell's electronegative membrane properties with HER2 antibody functionalized nanoparticles. An Annexin V/EthD-III assay and zeta potential were performed to determine the cell death mechanism indicating apoptosis and a decrease in zeta potential with the incorporation of the nanoparticles. With more negatively charged HER2-AuNPs attached to the cancer cell membrane, the decrease in membrane potential would thus leave the cells more vulnerable to the detrimental effects of the applied electric field due to the decrease in surface charge. Therefore, by altering the cell membrane potential, one could possibly control the fate of the cell. This whole cell-based biosensor will enhance our understanding of the responsiveness of cancer cells to electric field therapy and demonstrate potential therapeutic opportunities for electric field therapy in the treatment of cancer.

Using geophysical surveys to test tracer-based storage estimates in headwater catchments

Acknowledgements The authors are grateful to Stian Bradford, Chris Gabrielli, and Julie Timms for practical and logistical assistance. The provision of transport by Iain Malcolm and Ross Glover of Marine Scotland Science was greatly appreciated. We also thank the European Research Council ERC (project GA 335910 VEWA) for funding through the VeWa project and the Leverhulme Trust for funding through PLATO (RPG-2014-016).

Arquitetura para o desenvolvimento de unidades de medição fasorial sincronizada no monitoramento a nível de distribuição

This work presents a low cost architecture for development of synchronized phasor measurement units (PMU). The device is intended to be connected in the low voltage grid, which allows the monitoring of transmission and distribution networks. Developments of this project include a complete PMU, with instrumentation module for use in low voltage network, GPS module to provide the sync signal and time stamp for the measures, processing unit with the acquisition system, phasor estimation and formatting data according to the standard and finally, communication module for data transmission. For the development and evaluation of the performance of this PMU, it was developed a set of applications in LabVIEW environment with specific features that let analyze the behavior of the measures and identify the sources of error of the PMU, as well as to apply all the tests proposed by the standard. The first application, useful for the development of instrumentation, consists of a function generator integrated with an oscilloscope, which allows the generation and acquisition of signals synchronously, in addition to the handling of samples. The second and main, is the test platform, with capabality of generating all tests provided by the synchronized phasor measurement standard IEEE C37.118.1, allowing store data or make the analysis of the measurements in real time. Finally, a third application was developed to evaluate the results of the tests and generate calibration curves to adjust the PMU. The results include all the tests proposed by synchrophasors standard and an additional test that evaluates the impact of noise. Moreover, through two prototypes connected to the electrical installation of consumers in same distribution circuit, it was obtained monitoring records that allowed the identification of loads in consumer and power quality analysis, beyond the event detection at the distribution and transmission levels.

Online mining abnormal period patterns from multiple medical sensor data streams

With the advanced technology of medical devices and sensors, an abundance of medical data streams are available. However, data analysis techniques are very limited, especially for processing massive multiple physiological streams that may only be understood by medical experts. The state-of-the-art techniques only allow multiple medical devices to independently monitor different physiological parameters for the patient's status, thus they signal too many false alarms, creating unnecessary noise, especially in the Intensive Care Unit (ICU). An effective solution which has been recently studied is to integrate information from multiple physiologic parameters to reduce alarms. But it is a challenge to detect abnormalities from high frequently changed physiological streams data, since abnormalities occur gradually due to the complex situation of patients. An analysis of ICU physiological data streams shows that many vital physiological parameters are changed periodically (such as heart rate, arterial pressure, and respiratory impedance) and thus abnormalities are generally abnormal period patterns. In this paper, we develop a Mining Abnormal Period Patterns from Multiple Physiological Streams (MAPPMPS) method to detect and rank abnormalities in medical sensor streams. The efficiency and effectiveness of the MAPPMPS method is demonstrated by a real-world massive database of multiple physiological streams sampled in ICU, comprising 250 patients' streams (each stream involving over 1.3 million data points) with a total size of 28 GB data.

Multi-task transfer learning for in hospital-death prediction for ICU patients

Multi-Task Transfer Learning (MTTL) is an efficient approach for learning from inter-related tasks with small sample size and imbalanced class distribution. Since the intensive care unit (ICU) data set (publicly available in Physionet) has subjects from four different ICU types, we hypothesizethat there is an underlying relatedness amongst various ICU types. Therefore, this study aims to explore MTTL model for in-hospital mortality prediction of ICU patients. We used singletask learning (STL) approach on the augmented data as well as individual ICU data and compared the performance with the proposed MTTL model. As a performance measurement metrics, we used sensitivity (Sens), positive predictivity (+Pred), and Score. MTTL with class balancing showed the best performance with score of 0.78, 0.73, o.52 and 0.63 for ICU type 1(Coronary care unit), 2 (Cardiac surgery unit), 3 (Medical ICU) and 4 (Surgical ICU) respectively. In contrast the maximum score obtained using STL approach was 0.40 for ICU type 1 & 2. These results indicates that the performance of in-hospital mortality can be improved using ICU type information and by balancing the ’non-survivor’ class. The findings of the study may be useful for quantifying the quality of ICU care, managing ICU resources and selecting appropriate interventions.

Real-time Biosensor for the Assessment of Nanotoxicity and Cancer Electrotherapy

Knowledge of cell electronics has led to their integration to medicine either by physically interfacing electronic devices with biological systems or by using electronics for both detection and characterization of biological materials. In this dissertation, an electrical impedance sensor (EIS) was used to measure the electrode surface impedance changes from cell samples of human and environmental toxicity of nanoscale materials in 2D and 3D cell culture models. The impedimetric response of human lung fibroblasts and rainbow trout gill epithelial cells when exposed to various nanomaterials was tested to determine their kinetic effects towards the cells and to demonstrate the biosensor’s ability to monitor nanotoxicity in real-time. Further, the EIS allowed rapid, real-time and multi-sample analysis creating a versatile, noninvasive tool that is able to provide quantitative information with respect to alteration in cellular function. We then extended the application of the unique capabilities of the EIS to do real-time analysis of cancer cell response to externally applied alternating electric fields at different intermediate frequencies and low-intensity. Decreases in the growth profiles of the ovarian and breast cancer cells were observed with the application of 200 and 100 kHz, respectively, indicating specific inhibitory effects on dividing cells in culture in contrast to the non-cancerous HUVECs and mammary epithelial cells. We then sought to enhance the effects of the electric field by altering the cancer cell’s electronegative membrane properties with HER2 antibody functionalized nanoparticles. An Annexin V/EthD-III assay and zeta potential were performed to determine the cell death mechanism indicating apoptosis and a decrease in zeta potential with the incorporation of the nanoparticles. With more negatively charged HER2-AuNPs attached to the cancer cell membrane, the decrease in membrane potential would thus leave the cells more vulnerable to the detrimental effects of the applied electric field due to the decrease in surface charge. Therefore, by altering the cell membrane potential, one could possibly control the fate of the cell. This whole cell-based biosensor will enhance our understanding of the responsiveness of cancer cells to electric field therapy and demonstrate potential therapeutic opportunities for electric field therapy in the treatment of cancer.

Treatment trials for neonatal seizures: the effect of design on sample size

Neonatal seizures are common in the neonatal intensive care unit. Clinicians treat these seizures with several anti-epileptic drugs (AEDs) to reduce seizures in a neonate. Current AEDs exhibit sub-optimal efficacy and several randomized control trials (RCT) of novel AEDs are planned. The aim of this study was to measure the influence of trial design on the required sample size of a RCT. We used seizure time courses from 41 term neonates with hypoxic ischaemic encephalopathy to build seizure treatment trial simulations. We used five outcome measures, three AED protocols, eight treatment delays from seizure onset (Td) and four levels of trial AED efficacy to simulate different RCTs. We performed power calculations for each RCT design and analysed the resultant sample size. We also assessed the rate of false positives, or placebo effect, in typical uncontrolled studies. We found that the false positive rate ranged from 5 to 85% of patients depending on RCT design. For controlled trials, the choice of outcome measure had the largest effect on sample size with median differences of 30.7 fold (IQR: 13.7–40.0) across a range of AED protocols, Td and trial AED efficacy (p<0.001). RCTs that compared the trial AED with positive controls required sample sizes with a median fold increase of 3.2 (IQR: 1.9–11.9; p<0.001). Delays in AED administration from seizure onset also increased the required sample size 2.1 fold (IQR: 1.7–2.9; p<0.001). Subgroup analysis showed that RCTs in neonates treated with hypothermia required a median fold increase in sample size of 2.6 (IQR: 2.4–3.0) compared to trials in normothermic neonates (p<0.001). These results show that RCT design has a profound influence on the required sample size. Trials that use a control group, appropriate outcome measure, and control for differences in Td between groups in analysis will be valid and minimise sample size.

FAST-E en Pacientes con Trauma Abdominal Cerrado Estable, en un Departamento de Urgencias en Colombia

El impacto que ha generado el trauma en Colombia a lo largo de la historia, nos ha obligado a mejorar y adaptar diferentes tipos de sistemas de atención en trauma, basados en los lineamientos internacionales, los cuales buscan evitar el significativo aumento en las tasas de mortalidad y discapacidad que se obtienen de este, especialmente en los servicios de Emergencias en los cuales se reciben el 100% de estos pacientes con traumatismo múltiple o politraumatismo. Dentro de este grupo de pacientes hay un subgrupo que son las pacientes con trauma de abdomen que cursan con estabilidad hemodinámica y además son clasificados de bajo riesgo, ya sea por índices de trauma o por otros métodos como la medición sérica de lactato, los cuales tienen un papel poco despreciable al momento de ver mortalidad y discapacidad por trauma, ya sea penetrante o cerrado; en este trabajo específicamente nos centramos en las personas que consultan al servicio de Emergencias con trauma cerrado de abdomen los cuales son considerados de bajo riesgo, siendo este subgrupo de pacientes uno de los más difíciles de abordar y enfocar al momento de la valoración inicial, ya que se debe tener la seguridad de que no hay lesiones que comprometen la vida y por consiguiente estos pacientes puedan ser dados de alta.