Lag Time Parameter Research Articles

Extreme Rainfall-Runoff Events Modeling by HEC-HMS Model for Koudiet Rosfa Watershed, Algeria

Changing of precipitation regime and intensification of extreme storms in semi-arid regions because of climate change requires the use of numerical models to forecast the outlet hydrographs. In this paper, HEC-HMS software was applied using a loss method the curve number CN to estimate the precipitation excess and a parametric unit hydrograph model to compute the transformation of precipitation excess into direct runoff over the watershed. The Muskingum-Cunge routing model was used to simulate the propagation of direct runoff through the main streams of Koudiet Rosfa watershed. The curve number CN and lag time parameters were used to calibrate the model towards several storms. The Nash–Sutcliffe efficiency coefficient (NSE) was adopted to assess the performance of the model to reproduce the observed hydrographs. Volume of the storms, peak discharges, times of peak and times of center of mass between the simulated and observed discharges were used to validate the model. The simulated discharges reproduce the hydrological events. The calibrated model was used to simulate the different hypothetical storms that could occur in the future in order to ensure the safety of Koudiet Rosfa dam towards extreme rainfall-runoff events. Keywords:  HEC-HMS model; Hydrologic model; Rainfall-runoff; Semi-arid region.

Evolution of Platelet Function and Bleeding in Children and Adults with Chronic Immune Trombocytopenia on Romiplostim Treatment

INTRODUCTION. Platelets in immune thrombocytopenia (ITP) are not only reduced in quantity, but were also reported to have impaired function. There is evidence that this might be the mechanism behind the clinically established fact that severity of bleeding in ITP does not correllate well with the degree of thrombocytopenia. However, there are no established methods or guidelines to predict bleeding risks based on the platelet function tests, and little information about the effects of thrombopoietin mimetics on platelet function.MATERIALS. We studied evolution of platelet function and clinical bleeding symptoms in 32 adult and 44 pediatric patients with chronic ITP 32 over six months of romiplostim treatment using flow cytometry and thrombelastography (TEG). As controls, samples of 20 healthy donors were used. The median age of adult patients was 62 (19-80 years), that of pediatric patients was 10 (1-18 years). All had previous history of treatment (one to three lines of therapy). Platelet function was characterized by flow cytometry before and after activation with SFLLRN plus collagen-related peptide. Levels of CD42b, CD61, CD62P, PAC1, annexin V binding, and mepacrine uptake and release were evaluated. Bleeding score was determined using a standardized consensus-based ITP-specific bleeding assessment tool developed by the International Working Group on ITP. Thrombelastography (TEG) was employed to characterize integral hemostasis function. Investigations were performed in accordance with the Declaration of Helsinki under a protocol approved by the NSPC CHOI Ethical Committee, and written informed consent was obtained from all donors and patients. Comparisons between groups were performed using Mann-Whitney non-parametric test.RESULTS. Bleeding before the start of therapy was observed in 10 adults and 25 children. There was no significant difference in platelet count between the bleeding and non-bleeding adults (median 25 versus 23, respectively). For children, it was significantly (median 19 versus 83, p<0.05) lower for those with bleeding. Both adult's and children's platelets were significantly pre-activated by all parameters (PAC1, CD62p, annexin V) and increased in size (forward scatter, CD42b, CD61, mepacrine uptake) compared with normal ones. The TEG lag time parameters R and K were significantly increased in the ITP patients, while α angle and MA were decreased. Platelet pre-activation, size, and TEG parameter changes were significantly greater (by 50-100%) in the adult patients with bleeding phenotype compared with those who had no hemorrhage. Evaluation of their predictive capabilities with regard to bleeding risks using ROC analysis produced AUC values between 0.78 and 0.91, allowing design of a risk calculator. The results for children were similar when adjusted for the platelet count difference in the bleeding and non-bleeding groups. Romiplostim treatment led to a rapid (<1 month) decrease of procoagulant annexin V-positive platelets in the circulation to the normal level, followed by a more gradual normalization of platelet size and decrease of PAC1-positive platelets over several months. In some adult and pediatric patients, disappearance of clinical bleeding syndromes on romiplostim was associated with normalization of platelet function parameters in the absence of platelet count increase.CONCLUSIONS. Our data indicate that: a) platelets in chronic ITP are pre-activated, large and slowly reacting; b) these changes are associated with bleeding independently of platelet count, and can be used for risk stratification; c) romiplostim treatment decreases platelet size and pre-activation. DisclosuresPanteleev:Amgen: Research Funding.

Integrated Variational Approach to Conformational Dynamics: A Robust Strategy for Identifying Eigenfunctions of Dynamical Operators.

One approach to analyzing the dynamics of a physical system is to search for long-lived patterns in its motions. This approach has been particularly successful for molecular dynamics data, where slowly decorrelating patterns can indicate large-scale conformational changes. Detecting such patterns is the central objective of the variational approach to conformational dynamics (VAC), as well as the related methods of time-lagged independent component analysis and Markov state modeling. In VAC, the search for slowly decorrelating patterns is formalized as a variational problem solved by the eigenfunctions of the system's transition operator. VAC computes solutions to this variational problem by optimizing a linear or nonlinear model of the eigenfunctions using time series data. Here, we build on VAC's success by addressing two practical limitations. First, VAC can give poor eigenfunction estimates when the lag time parameter is chosen poorly. Second, VAC can overfit when using flexible parametrizations such as artificial neural networks with insufficient regularization. To address these issues, we propose an extension that we call integrated VAC (IVAC). IVAC integrates over multiple lag times before solving the variational problem, making its results more robust and reproducible than VAC's.

Model-dependent pharmacokinetic analysis of enalapril administered to healthy adult volunteers using orodispersible minitablets for use in pediatrics.

IntroductionComparative pharmacokinetic (PK) data analysis of drugs administered using developed child-appropriate and market authorized dosage formulation is sparse and is important in pediatric drug development.ObjectivesTo compare and evaluate any differences in PK of enalapril administered using two treatments of child-appropriate orodispersible minitablets (ODMTs) and market authorized reference tablet formulation (Renitec®) using PK compartment model and validated least square minimization method (LSMM) of parameter estimation.MethodsFull profile data sets were obtained from a phase I clinical trial, whereby three treatments of enalapril, ie, reference tablets with 240 mL water (treatment A), child-appropriate ODMTs with 240 mL (treatment B), and ODMTs dispersed in the mouth with 20 mL water (treatment C), were administered to 24 healthy adult volunteers. Virtual validation analysis was conducted using R program to select accurate and precise LSMM of parameter estimation. For the selection of PK model and estimation of parameters, enalapril data were fitted with one-and two-compartment models with first order of absorption and elimination, with and without incorporated lag time parameter (tlag). The log-transformed PK parameters were statistically compared by the two-sided paired t-test with the level of significance of P<0.05.ResultsOne-compartment model with first-order absorption and elimination and incorporated lag time adequately predicted concentrations of enalapril. Reciprocal of predicted concentration using iteratively reweighted LSMM was selected as the most appropriate method of parameter estimation. Comparison of PK parameters including rate constant of absorption and elimination, volume of distribution, and tlag between the three treatments showed significant difference (P=0.018) in tlag between treatments B and A only.ConclusionCompared with reference formulation, enalapril administered from child-appropriate ODMTs administered with 240 mL water appeared 4 minutes earlier in serum. No other differences were observed in absorption, elimination, and relative bioavailability of drug between the three treatment arms.

Effect-Site Target-Controlled Infusion in the Obese: Model Derivation and Performance Assessment.

The aim of this study is to derive a propofol pharmacokinetic (PK) pharmacodynamic (PD) model to perform effect-site target-controlled infusion (TCI) in obese patients, and to analyze its performance along with that of other available PK models. In the first step of the study, a 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (keo) was used to fit propofol concentration-bispectral index (BIS) data. Population modeling analysis was performed by nonlinear mixed effects regression in NONMEM (ICON, Dublin, Ireland). PK data from 3 previous studies in obese adult patients (n = 47), including PD (BIS) data from 1 of these studies (n = 20), were pooled and simultaneously analyzed. A decrease in NONMEM objective function (ΔOBJ) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. In the second step of the study, we analyzed the predictive performance (median predictive errors [MDPE] and median absolute predictive errors [MDAPE]) of the current model and of other available models using an independent data set (n = 14). Step 1: The selected PKPD model produced an adequate fit of the data. Total body weight resulted in the best size scalar for volumes and clearances (ΔOBJ, -18.173). Empirical allometric total body weight relationships did not improve model fit (ΔOBJ, 0.309). A lag time parameter for BIS response improved the fit (ΔOBJ, 89.593). No effect of age or gender was observed. Step 2: Current model MDPE and MDAPE were 11.5% (3.7-25.0) and 26.8% (20.7-32.6) in the PK part and 0.4% (-10.39 to 3.85) and 11.9% (20.7-32.6) in the PD part. The PK model developed by Eleveld et al resulted in the lowest PK predictive errors (MDPE = <10% and MDAPE = <25%). We derived and validated a propofol PKPD model to perform effect-site TCI in obese patients. This model, derived exclusively from obese patient's data, is not recommended for TCI in lean patients because it carries the risk of underdosing.

Abstract 2043: Effects of 24-h carboplatin pretreatment on olaparib clearance in women's cancers using noncompartmental and population pharmacokinetic analyses

Abstract Background: Olaparib (OLA) is a PARP inhibitor approved for use in deleterious germline BRCA mutated recurrent or refractory ovarian cancer. Combining OLA with carboplatin (CARBO) could have additive effects based on platinum-DNA adducts requiring PARP for DNA repair. Preclinical data suggest greater cytotoxicity when CARBO is given prior to OLA. However, the optimal treatment sequence of these agents has not been studied previously in patients. We therefore investigated: 1) the effects of CARBO treatment on the pharmacokinetics (PK) and pharmacodynamics (PD) of OLA; 2) in vitro mechanisms of the interaction between CARBO and OLA. Methods: Clinical PK and PD data of OLA were obtained from 58 patients with confirmed recurrent or refractory women's cancers participating in a two arm, parallel design, phase 1 trial (NCT01237067). In cycle 1 OLA tablets (200 mg BID) were given for 7 days either followed by CARBO (AUC 4) on day 8 (arm A) or after CARBO on day 1 (Arm B). In cycle 2 the arms received the reversed scheme. PK of OLA were assessed in both cycles by noncompartmental (NCA) and population pharmacokinetic (PPK) analyses. For PK/PD analyses, PAR levels were measured at baseline and 24 h after the first OLA dose. In vitro mechanistic studies were carried out by incubating whole human blood and avian DT40 PARP-1 KO cells with 10 μM CARBO for 24 h, followed by 1h-treatment of isolated PBMCs and PARP-1 KO cells with 10 μM OLA. Intracellular OLA concentrations were determined using UPLC-MS/MS. Results: Both NCA and PPK analyses showed a ∼50% increase in OLA clearance when CARBO was administered 24-h prior (P&amp;lt;0.02). The PPK model included a lag time parameter (P = 1.1E-18), a second absorption compartment (P = 7.7E-27), a single elimination compartment, and accounted for covariance among the clearance and volume parameters (P = 6.7E-7). Presence of CARBO was the only significant covariate affecting OLA clearance (P = 1.9E-13). Final estimates for clearance and volume of distribution were 6.8 L/h and 33 L, respectively, which were comparable with related reports. There were no trends between PK data and PAR levels, nor did the presence of CARBO affect PAR levels (P = 0.89). PBMC experiments showed that 24-h pretreatment with CARBO significantly increased intracellular OLA concentrations by more than 30% compared with control samples (P = 0.013). PARP-1 KO cells confirmed that intracellular PARP expression was not related to the increased OLA uptake. Possibly, CARBO affects other intracellular targets or transporters leading to increased intracellular uptake of OLA from the bloodstream. Conclusion: This is the first known PK analysis showing a significant increase in OLA clearance after pretreatment with CARBO, possibly leading to subtherapeutic plasma concentrations of OLA. Preclinical experiments are ongoing to reveal the exact pharmacological mechanisms of this interaction. Citation Format: Andrew K.L. Goey, Cody J. Peer, Tristan M. Sissung, Jeffrey Roth, Shandiz Shahbazi, Jeffers Nguyen, Christina M. Annunziata, Nicole Houston, Elise C. Kohn, Jung-Min Lee, William D. Figg. Effects of 24-h carboplatin pretreatment on olaparib clearance in women's cancers using noncompartmental and population pharmacokinetic analyses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2043.

Soil moisture‐based drought monitoring at different time scales: a case study for the U.S. Great Plains

AbstractShort‐term agricultural drought and longer term hydrological drought have important ecological and socioeconomic impacts. Soil moisture monitoring networks have potential to assist in the quantification of drought conditions because soil moisture changes are mostly due to precipitation and evapotranspiration, the two dominant water balance components in most areas. In this study, the Palmer approach to calculating a drought index was combined with a soil water content‐based moisture anomaly calculation. A drought lag time parameter was introduced to quantify the time between the start of a moisture anomaly and the onset of drought. The methodology was applied to four shortgrass prairie sites along a North‐South transect in the U.S. Great Plains with an 18‐year soil moisture record. Short time lags led to high periodicity of the resulting drought index, appropriate for assessing short‐term drought conditions at the field scale (agricultural drought). Conversely, long time lags led to low periodicity of the drought index, being more indicative of long‐term drought conditions at the watershed or basin scale (hydrological drought). The influence of daily, weekly, and monthly time steps on the drought index was examined and found to be marginal. The drought index calculated with a short drought lag time showed evidence of being normally distributed. A longer data record is needed to assess the statistical distribution of the drought index for longer drought lag times.

Multi-Site Calibration of Linear Reservoir Based Geomorphologic Rainfall-Runoff Models

Multi-site optimization of two adapted event-based geomorphologic rainfall-runoff models was presented using Non-dominated Sorting Genetic Algorithm (NSGA-II) method for the South Fork Eel River watershed, California. The first model was developed based on Unequal Cascade of Reservoirs (UECR) and the second model was presented as a modified version of Geomorphological Unit Hydrograph based on Nash’s model (GUHN). Two calibration strategies were considered as semi-lumped and semi-distributed for imposing (or unimposing) the geomorphology relations in the models. The results of models were compared with Nash’s model. Obtained results using the observed data of two stations in the multi-site optimization framework showed reasonable efficiency values in both the calibration and the verification steps. The outcomes also showed that semi-distributed calibration of the modified GUHN model slightly outperformed other models in both upstream and downstream stations during calibration. Both calibration strategies for the developed UECR model during the verification phase showed slightly better performance in the downstream station, but in the upstream station, the modified GUHN model in the semi-lumped strategy slightly outperformed the other models. The semi-lumped calibration strategy could lead to logical lag time parameters related to the basin geomorphology and may be more suitable for data-based statistical analyses of the rainfall-runoff process.

Performance of propofol target-controlled infusion models in the obese: pharmacokinetic and pharmacodynamic analysis.

Obesity is associated with important physiologic changes that can potentially affect the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anesthetic drugs. We designed this study to assess the predictive performance of 5 currently available propofol PK models in morbidly obese patients and to characterize the Bispectral Index (BIS) response in this population. Twenty obese patients (body mass index >35 kg/m), aged 20 to 60 years, scheduled for laparoscopic bariatric surgery, were studied. Anesthesia was administered using propofol by target-controlled infusion and remifentanil by manually controlled infusion. BIS data and propofol infusion schemes were recorded. Arterial blood samples to measure propofol were collected during induction, maintenance, and the first 2 postoperative hours. Median performance errors (MDPEs) and median absolute performance errors (MDAPEs) were calculated to measure model performance. A PKPD model was developed using NONMEM to characterize the propofol concentration-BIS dynamic relationship in the presence of remifentanil. We studied 20 obese adults (mean weight: 106 kg, range: 85-141 kg; mean age: 33.7 years, range: 21-53 years; mean body mass index: 41.4 kg/m, range: 35-52 kg/m). We obtained 294 arterial samples and analyzed 1431 measured BIS values. When total body weight (TBW) was used as input of patient weight, the Eleveld allometric model showed the best (P < 0.0001) performance with MDPE = 18.2% and MDAPE = 27.5%. The 5 tested PK models, however, showed a tendency to underestimate propofol concentrations. The use of an adjusted body weight with the Schnider and Marsh models improved the performance of both models achieving the lowest predictive errors (MDPE = <10% and MDAPE = <25%; all P < 0.0001). A 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (ke0) adequately described the propofol concentration-BIS data. A lag time parameter of 0.44 minutes (SE = 0.04 minutes) to account for the delay in BIS response improved the fit. A simulated effect-site target of 3.2 μg/mL (SE = 0.17 μg/mL) was estimated to obtain BIS of 50, in the presence of remifentanil, for a typical patient in our study. The Eleveld allometric PK model proved to be superior to all other tested models using TBW. All models, however, showed a trend to underestimate propofol concentrations. The use of adjusted body weight instead of TBW with the traditional Schnider and Marsh models markedly improved their performance achieving the lowest predictive errors of all tested models. Our results suggest no relevant effect of obesity on both the time profile of BIS response and the propofol concentration-BIS relationship.

A ‘bottom‐up’ approach for endo‐PK/PD analysis

A 'bottom-up' PK/PD analysis approach employing system analysis principles of convolution/deconvolution and special nonparametric estimation procedures is presented to resolve the complex 'endo-PK/PD' of the endogenous form of recombinant drugs using erythropoietin (EPO) as an example. A novel cellular deconvolution algorithm is presented that facilitates the identification of the functional relationship between the variables involved in EPO's complex PK/PD. Five sheep each underwent two phlebotomies spaced 4-6 weeks apart when their hemoglobin levels were reduced from 12 g/dl to 3-4 g/dl. EPO levels and reticulocyte counts were frequently sampled. The data were analysed using end-constrained cubic splines. The rate of reticulocyte production was determined using the novel deconvolution methodology. The erythroid progenitor cells activation rate by EPO was estimated from the reticulocyte production rate using a lag-time parameter which determines the delay in the reticulocyte appearance in the blood relative to the activation of erythroid progenitors. Hysteresis minimization combined with cellular deconvolution was employed to determine the population PK/PD transduction function relating the progenitor activation rate to EPO concentrations in a nonparametric manner without assuming a specific structure. The proposed approach provides a rational informative starting point for developing parametric PK/PD models to resolve the complex endo-PK/PD of recombinant drugs.

Predicting the growth of Salmonella typhimurium on beef by using the temperature function integration technique.

Lag and generation times for the growth of Salmonella typhimurium on sterile lean beef were modeled as functions of cooling time under various carcass-chilling scenarios. Gompertz growth models were fit to the log10 colony counts over time at each of six temperatures in the range of 15 to 40 degrees C. Lag and generation times were defined as the points at which the second and first derivatives, respectively, of each growth curve attained a maximum. Generation time and lag time parameters were modeled as functions of temperature by use of exponential-decay models. The models were applied to typical beef carcass-cooling scenarios to predict the potential growth of S. typhimurium during the cooling of beef. Validation studies indicated no significant difference between the observed and predicted bacterial populations on inoculated lean and fatty beef tissues cooled at either 6 or 9 degrees C/h.

In vivo and in vitro dermal penetration of 2,4,5,2′,4′,5′-Hexachlorobiphenyl in young and adult rats

Penetration of 2,4,5,2',4',5'-[14C]hexachlorobiphenyl (HCB) through skin of young (33 days) and adult (82 days) female Fischer 344 rats was determined in vivo and by two in vitro methods. In vivo dermal penetration at 120 hr was 45% in young and 43% in adults. At 72 hr in vivo dermal penetration was 35% in young and 26% in adults compared to 1.5% for young and 1.0% for adult as measured with a continuous flow in vitro system and 2.9% for young and 1.9% for adults as measured with a static in vitro system. Most of the dermally absorbed HCB remained in the body as only 4.9 and 2.6% of that absorbed was excreted by young and adult rats, respectively, at the end of 120 hr. Significant differences in dermal penetration and kinetics of HCB between young and adult female rats were observed. The elimination of HCB-derived material was approximately six times higher in feces than in urine. A physiological pharmacokinetic model was fitted to the organ and tissue radioactivity distribution data. Parameters in the model determined from dermal dosing of female Fischer 344 rats were in reasonable agreement with those reported in the literature for adult male Sprague-Dawley rats (iv dose). The rat constant for dermal penetration was 0.83 x 10(-4) min-1 for adults and 0.96 x 10(-4)min-1 for young. The delay or lag time parameter for dermal penetration was 4.4 hr in adults and 1.1 hr in young.

Resolution in seismic trace inversion by parameter estimation

An alternative to the conventional time series approach to single‐trace modeling and inversion by convolution and inverse filtering is a parametric approach. To obtain insight into the potential of the parametric approach, the solution of the single‐trace forward problem is formulated in matrix terms. For the nonlinear reflector lag time parameters this is achieved by linearization, which is shown to be a valid approximation over a sufficiently large region. The matrix forward operators are analyzed by means of the singular value decomposition (SVD). The SVD can be considered a generalization of the Fourier transform of convolution operators. On the basis of the SVD analysis, inverse operators are designed which combine stability with high resolving power. A method to determine the resolving power of the parametric inverse operators is presented. Several examples show how wavelet bandwidth, data noise level, and model complexity influence the resolving power of the data for the reflection coefficient and the lag‐time parameters. The most important result is that the resolution obtained in parametric inversion is, in most cases, superior to and, at worst, equal to the resolution obtained with wavelet inverse filtering. The explanation is that in parametric inversion a different representation of the reflectivity function is used which, in practical situations, involves fewer unknowns. In wavelet inverse filtering the reflectivity function is represented as a regularly sampled function where every sample point represents an unknown. In practical applications of parametric inversion the reflectivity function is represented as a model with a limited number of reflectors as unknowns. To formulate parametric models, a priori information is required. The effort of collecting sufficient a priori information is the cost of increasing resolution beyond the resolution offered by wavelet inverse filtering.