Forecasting exchange rates with linear and nonlinear models

In this paper the exchange rate forecasting performance of neural network models are evaluated against random walk and a range of time series models. There are no guidelines available that can be used to choose the parameters of neural network models and therefore the parameters are chosen according to what the researcher considers to be the best. Such an approach, however, implies that the risk of making bad decisions is extremely high which could explain why in many studies neural network models do not consistently perform better than their time series counterparts. In this paper through extensive experimentation the level of subjectivity in building neural network models is considerably reduced and therefore giving them a better chance of performing well. Our results show that in general neural network models perform better than traditionally used time series models in forecasting exchange rates.

Population pharmacokinetics of single-dose intravenous paracetamol in children

Background To determine the pharmacokinetics (PK) of a new i.v. formulation of paracetamol (Perfalgan) in children ≤15 yr of age. Methods After obtaining written informed consent, children under 16 yr of age were recruited to this study. Blood samples were obtained at 0, 15, 30 min, 1, 2, 4, 6, and 8 h after administration of a weight-dependent dose of i.v. paracetamol. Paracetamol concentration was measured using a validated high-performance liquid chromatographic assay with ultraviolet detection method, with a lower limit of quantification (LLOQ) of 900 pg on column and an intra-day coefficient of variation of 14.3% at the LLOQ. Population PK analysis was performed by non-linear mixed-effect modelling using NONMEM. Results One hundred and fifty-nine blood samples from 33 children aged 1.8–15 yr, weight 13.7–56 kg, were analysed. Data were best described by a two-compartment model. Only body weight as a covariate significantly improved the goodness of fit of the model. The final population models for paracetamol clearance (CL), V1 (central volume of distribution), Q (inter-compartmental clearance), and V2 (peripheral volume of distribution) were: 16.51×(WT/70)0.75, 28.4×(WT/70), 11.32×(WT/70)0.75, and 13.26×(WT/70), respectively (CL, Q in litres per hour, WT in kilograms, and V1 and V2 in litres). Conclusions In children aged 1.8–15 yr, the PK parameters for i.v. paracetamol were not influenced directly by age but were by total body weight and, using allometric size scaling, significantly affected the clearances (CL, Q) and volumes of distribution (V1, V2).

An Interactive Method of Linear Mixed Integer Multicriteria Optimization

The paper describes a learning-oriented interactive method for solving linear mixed integer problems of multicriteria optimization. The method increases the possibilities of the decision maker (DM) to describe his/her local preferences and at the same time it overcomes some computational difficulties, especially in problems of large dimension. The method is realized in an experimental decision support system for finding the solution of linear mixed integer multicriteria optimization problems.

The enantioselective population pharmacokinetics of intravenous ketorolac in children using a stereoselective assay suitable for microanalysis

Objective: To describe the effect of age and body size on enantiomer selective pharmacokinetic (PK) of intravenous ketorolac in children using a microanalytical assay. Methods: Blood samples were obtained at 0, 15 and 30 min and at 1, 2, 4, 6, 8 and 12 h after a weight-dependent dose of ketorolac. Enantiomer concentration was measured using a liquid chromatography tandem mass spectrometry method. Non-linear mixed-effect modelling was used to assess PK parameters. Key findings: Data from 11 children (1.7–15.6 years, weight 10.7–67.4 kg) were best described by a two-compartment model for R(+), S(−) and racemic ketorolac. Only weight (WT) significantly improved the goodness of fit. The final population models were CL = 1.5 × (WT/46)0.75, V1 = 8.2 × (WT/46), Q = 3.4 × (WT/46)0.75, V2 = 7.9 × (WT/46), CL = 2.98 × (WT/46), V1 = 13.2 × (WT/46), Q = 2.8 × (WT/46)0.75, V2 = 51.5 × (WT/46), and CL = 1.1 × (WT/46)0.75, V1 = 4.9 × (WT/46), Q = 1.7 × (WT/46)0.75 and V2 = 6.3 × (WT/46)for R(+), S(−) and racemic ketorolac. Conclusions: Only body weight influenced the PK parameters for R(+) and S(−) ketorolac. Using allometric size scaling significantly affected the clearances (CL, Q) and volumes of distribution (V1, V2).

Neuronal networks with gap junctions: A study of piece-wise linear planar neuron models

The presence of gap junction coupling among neurons of the central nervous systems has been appreciated for some time now. In recent years there has been an upsurge of interest from the mathematical community in understanding the contribution of these direct electrical connections between cells to large-scale brain rhythms. Here we analyze a class of exactly soluble single neuron models, capable of producing realistic action potential shapes, that can be used as the basis for understanding dynamics at the network level. This work focuses on planar piece-wise linear models that can mimic the firing response of several different cell types. Under constant current injection the periodic response and phase response curve (PRC) is calculated in closed form. A simple formula for the stability of a periodic orbit is found using Floquet theory. From the calculated PRC and the periodic orbit a phase interaction function is constructed that allows the investigation of phase-locked network states using the theory of weakly coupled oscillators. For large networks with global gap junction connectivity we develop a theory of strong coupling instabilities of the homogeneous, synchronous and splay state. For a piece-wise linear caricature of the Morris-Lecar model, with oscillations arising from a homoclinic bifurcation, we show that large amplitude oscillations in the mean membrane potential are organized around such unstable orbits.

Relationship between median nerve somatosensory evoked potentials and spinal cord injury levels in patients with quadriplegia

Study design: Cross-sectional study. Objectives: To observe if there is a relationship between the level of injury by the American Spinal Cord Injury Association (ASIA) and cortical somatosensory evoked potential (SSEP) recordings of the median nerve in patients with quadriplegia. Setting: Rehabilitation Outpatient Clinic at the university hospital in Brazil. Methods: Fourteen individuals with quadriplegia and 8 healthy individuals were evaluated. Electrophysiological assessment of the median nerve was performed by evoked potential equipment. The injury level was obtained by ASIA. N(9), N(13) and N(20) were analyzed based on the presence or absence of responses. The parameters used for analyzing these responses were the latency and the amplitude. Data were analyzed using mixed-effect models. Results: N(9) responses were found in all patients with quadriplegia with a similar latency and amplitude observed in healthy individuals; N(13) responses were not found in any patients with quadriplegia. N(20) responses were not found in C5 patients with quadriplegia but it was present in C6 and C7 patients. Their latencies were similar to healthy individuals (P > 0.05) but the amplitudes were decreased (P < 0.05). Conclusion: This study suggests that the SSEP responses depend on the injury level, considering that the individuals with C6 and C7 injury levels, both complete and incomplete, presented SSEP recordings in the cortical area. It also showed a relationship between the level of spinal cord injury assessed by ASIA and the median nerve SSEP responses, through the latency and amplitude recordings. Spinal Cord (2009) 47, 372-378; doi:10.1038/sc.2008.147; published online 20 January 2009

CO2 Concentration in Day Care Centres is Related to Wheezing in Attending Children

Poor ventilation at day care centres (DCCs) was already reported, although its effects on attending children are not clear. This study aimed to evaluate the association between wheezing in children and indoor CO2 (a ventilation surrogate marker) in DCC and to identify behaviours and building characteristics potentially related to CO2. In phase I, 45 DCCs from Lisbon and Oporto (Portugal) were selected through a proportional stratified random sampling. In phase II, 3 months later, 19 DCCs were further reassessed after cluster analysis for the greatest difference comparison. In both phases, children’s respiratory health was assessed by ISAAC-derived questionnaires. Indoor CO2 concentrations and building characteristics of the DCC were evaluated in both phases, using complementary methods. Mixed effect models were used to analyze the data. In phase I, which included 3,186 children (mean age 3.1±1.5 years), indoor CO2 concentration in the DCC rooms was associated with reported wheezing in the past 12months (27.5 %) (adjusted odds ratio (OR) for each increase of 200 ppm 1.04, 95 % CI 1:01 to 1:07). In phase II, the association in the subsample of 1,196 children seen in 19 out of the initial 45 DCCs was not significant (adjusted OR 1.02, 95 % CI 0.96 to 1.08). Indoor CO2 concentration was inversely associated with the practices of opening Windows and internal doors and with higher wind velocity. A positive trend was observed between CO2 and prevalence of reported asthma (4.7 %). Conclusion: Improved ventilation is needed to achieve a healthier indoor environment in DCC.

Blood Pressure Variation Throughout Pregnancy According to Early Gestational BMI: A Brazilian Cohort

Background: The maternal cardiovascular system undergoes progressive adaptations throughout pregnancy, causing blood pressure fluctuations. However, no consensus has been established on its normal variation in uncomplicated pregnancies. Objective: To describe the variation in systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels during pregnancy according to early pregnancy body mass index (BMI). Methods: SBP and DBP were measured during the first, second and third trimesters and at 30-45 days postpartum in a prospective cohort of 189 women aged 20-40 years. BMI (kg/m2) was measured up to the 13th gestational week and classified as normal-weight (<25.0) or excessive weight (≥25.0). Longitudinal linear mixed-effects models were used for statistical analysis. Results: A decrease in SBP and DBP was observed from the first to the second trimester (βSBP=-0.394; 95%CI: -0.600- -0.188 and βDBP=-0.617; 95%CI: -0.780- -0.454), as was an increase in SBP and DBP up to 30-45 postpartum days (βSBP=0.010; 95%CI: 0.006-0.014 and βDBP=0.015; 95%CI: 0.012-0.018). Women with excessive weight at early pregnancy showed higher mean SBP in all gestational trimesters, and higher mean DBP in the first and third trimesters. Excessive early pregnancy BMI was positively associated with prospective changes in SBP (βSBP=7.055; 95%CI: 4.499-9.610) and in DBP (βDBP=3.201; 95%CI: 1.136-5.266). Conclusion: SBP and DBP decreased from the first to the second trimester and then increased up to the postpartum period. Women with excessive early pregnancy BMI had higher SBP and DBP than their normal-weight counterparts throughout pregnancy, but not in the postpartum period.

Ganciclovir Exposure under a 450 mg Daily Dosage of Valganciclovir for the Prevention of Cytomegalovirus Disease in Kidney Transplant Recipients.

Background: It is suggested that a low dose of valganciclovir can be equally effective than a standard dose for cytomegalovirus (CMV) prophylaxis after kidney transplantation. The aim of our study was to determine the ganciclovir exposure observed under a routine daily dosage of 450 mg valganciclovir in kidney transplant recipients with a wide range of renal function. Methods: In this prospective study, kidney transplant recipients with a GFR MDRD above 25 mL/min at risk for CMV (donor or recipient seropositive for CMV) received a dose of valganciclovir (450 mg daily) prophylaxis for 3 months. Ganciclovir levels at trough (Ctrough) and at peak (C3h) were measured monthly. Ganciclovir exposure (AUC0-24) was estimated using Bayesian non-linear mixed-effect modelling (NONMEM) and compared between 3 groups of patients according to their kidney function: GFRMDRD 26-39 mL/min (Group 1), GFRMDRD 40-59 mL/min (Group 2) and GFRMDRD 60-90 mL/min (Group 3). CMV DNAemia was assessed during and after prophylaxis using PCR. Results: Thirty-six patients received 450 mg daily of valganciclovir for 3 months. Median ganciclovir C3h was 3.9 mg/L (range: 1.3-7.1) and Ctrough was 0.4 mg/L (range 0.1-2.7). Median (range) AUC0-24 of ganciclovir was 59.3 mg.h/L (39.0-85.3) in Group 1 patients, 35.8 mg.h/L (24.9-55.8) in Group 2 patients and 29.6 mg.h/L (22.0- 43.2) in Group 3 patients (p<0.001). Anemia was more common in Group 1 patients compared to patients on the other groups (p=0.01). No differences in other adverse events according to ganciclovir exposure were observed. CMV DNAemia was not detected during prophylaxis. After discontinuing prophylaxis, CMV DNAemia was seen in 8/34 patients (23.5%) and 4/36 patients (11%) developed CMV disease. Conclusion: A routine dosage of valganciclovir achieved plasma levels of ganciclovir in patients with GFR>60 mL/min similar to those previously reported using oral ganciclovir. A daily dose of 450 mg valganciclovir appears to be acceptable for CMV prophylaxis in most kidney transplant recipients.

Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST). However, the treatment must be taken indefinitely and is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occurs in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene), and is also bound to the alpha1-acid glycoprotein (AAG) in plasma. Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations were measured in 59 patients receiving Glivec® at diverse dosage regimens, using a validated chromatographic method developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one-compartment model with first-order absorption described the data appropriately, with an average apparent clearance of 12.4 l/h, a volume of distribution of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T and the AAG phenotype appears to modulate the disposition of imatinib. Large inter-individual variability (CV %) remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen. This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help in individualising the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Ganciclovir exposure under a 450mg daily dosage of valganciclovir for cytomegalovirus prevention in kidney transplantation: a prospective study.

Manuel O, Pascual M, Perrottet N, Lamoth F, Venetz J-P, Decosterd LA, Buclin T, Meylan PR. Ganciclovir exposure under a 450 mg daily dosage of valganciclovir for cytomegalovirus prevention in kidney transplantation: a prospective study. 
Clin Transplant 2010: 24: 794-800. Abstract:  This prospective study aimed at determining the ganciclovir exposure observed under a daily dosage of 450 mg valganciclovir routinely applied to kidney transplant recipients with a GFR above 25 mL/min at risk for cytomegalovirus (CMV) disease. Ganciclovir levels at trough (C(trough) ) and at peak (C(3 h) ) were measured monthly. Ganciclovir exposure (area under the curve [AUC(0-24) ]) was estimated using Bayesian non-linear mixed-effect modeling (NONMEM). Thirty-six patients received 450 mg of valganciclovir daily for three months. Median ganciclovir C(3 h) was 3.9 mg/L (range: 1.3-7.1), and C(trough) was 0.4 mg/L (range 0.1-2.7). Median AUC(0-24) of ganciclovir was 59.3 mg h/L (39.0-85.3) in patients with GFR(MDRD) 26-39 mL/min, 35.8 mg h/L (24.9-55.8) in patients with GFR(MDRD) 40-59 mL/min, and 29.6 mg h/L (22.0-43.2) in patients with GFR(MDRD)  ≥ 60 mL/min. No major differences in adverse events according to ganciclovir exposure were observed. CMV viremia was not detected during prophylaxis. After discontinuing prophylaxis, CMV viremia was seen in 8/36 patients (22%), and 4/36 patients (11%) developed CMV disease. Ganciclovir exposure after administration of valganciclovir 450 mg daily in recipients with GFR ≥60 mL/min was comparable to those previously reported with oral ganciclovir. A routine daily dose of 450 mg valganciclovir appears to be acceptable for CMV prophylaxis in most kidney transplant recipients.

Imatinib plasma concentrations variability in oncologic patients

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occurs in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P-glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualization. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after the latest dose, were measured in 59 patients receiving Glivec at diverse regimens, using a validated HPLC-UV method developed for this study. The results were analyzed by non-linear mixed effect modeling (NONMEM). A one-compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. At present, only the MDR1 polymorphism has been assessed and seems to affect the pharmacokinetic parameters of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40 %) and distribution volume (71 %). Together with intra-patient variability (34 %), this translates into an 8-fold width of the 90 %-prediction interval of plasma concentrations expected under a fixed dosing regimen. This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring program for imatinib. It may help to individualize the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumour (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occur in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after latest dose, were measured in 59 patients receiving Glivec® at diverse regimens, using a validated chromatographic method (HPLC-UV) developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one- compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T appears to affect the disposition of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen ! This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help to individualise the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

The impact of fasting on the interpretation of triglyceride levels for predicting myocardial infarction risk in HIV-positive individuals: the D:A:D study.

We assessed whether fasting modifies the prognostic value of these measurements for the risk of myocardial infarction (MI). Analyses used mixed effect models and Poisson regression. After confounders were controlled for, fasting triglyceride levels were, on average, 0.122 mmol/L lower than nonfasting levels. Each 2-fold increase in the latest triglyceride level was associated with a 38% increase in MI risk (relative rate, 1.38; 95% confidence interval, 1.26-1.51); fasting status did not modify this association. Our results suggest that it may not be necessary to restrict analyses to fasting measurements when considering MI risk.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.