Intersubject Coefficient Of Variation Research Articles

Reliability of quantitative magnetic susceptibility imaging metrics for cerebral cortex and major subcortical structures.

Susceptibility estimates derived from quantitative susceptibility mapping (QSM) images for the cerebral cortex and major subcortical structures are variably reported in brain magnetic resonance imaging (MRI) studies, as average of all ( ), absolute ( ), or positive- ( ) and negative-only ( ) susceptibility values using a region of interest (ROI) approach. This pilot study presents a reliability analysis of currently used ROI-QSM metrics and an alternative ROI-based approach to obtain voxel-weighted ROI-QSM metrics ( and ). Ten healthy subjects underwent repeated (test-retest) 3-dimensional multi-echo gradient-echo (3DMEGE) 3 Tesla MRI measurements. Complex-valued 3DMEGE images were acquired and reconstructed with slice thicknesses of 1 and 2mm (3DMEGE1, 3DMEGE2) along with 3DT1-weighted isometric (voxel 1 mm3) images for independent registration and ROI segmentation. Agreement, consistency, and reproducibility of ROI-QSM metrics were assessed through Bland-Altman analysis, intraclass correlation coefficient, and interscan and intersubject coefficient of variation (CoV). All ROI-QSM metrics exhibited good to excellent consistency and test-retest agreement with no proportional bias. Interscan CoV was higher for in comparison to the other metrics where it was below 15%, in both 3DMEGE1 and 3DMEGE2 datasets. Intersubject CoV for and exceeded 50% in all ROIs. Among the evaluated ROI-QSM metrics, and estimates were less reliable, whereas separating positive and negative values (using ) improved the reproducibility within, and the comparability between, subjects, even when reducing the slice thickness. These preliminary findings may offer valuable insights toward standardizing ROI-QSM metrics across different patient cohorts and imaging settings in future clinical MRI studies.

CEST and nuclear Overhauser enhancement imaging withdeep learning-extrapolated semisolid magnetization transfer reference: Scan-rescan reproducibility andreliability studies.

To develop a novel MR physics-driven, deep-learning, extrapolated semisolid magnetization transfer reference (DeepEMR) framework to provide fast, reliable magnetization transfer contrast (MTC) and CEST signal estimations, and to determine the reproducibility and reliability of the estimates from the DeepEMR. A neural network was designed to predict a direct water saturation and MTC-dominated signal at a certain CEST frequency offset using a few high-frequency offset features in the Z-spectrum. The accuracy, scan-rescan reproducibility, and reliability of MTC, CEST, and relayed nuclear Overhauser enhancement (rNOE) signals estimated from the DeepEMR were evaluated on numerical phantoms and in heathy volunteers at 3 T. In addition, we applied the DeepEMR method to brain tumor patients and compared tissue contrast with other CEST calculation metrics. The DeepEMR method demonstrated a high degree of accuracy in the estimation of reference MTC signals at ±3.5 ppm for APT and rNOE imaging, and computational efficiency (˜190-fold) compared with a conventional fitting approach. In addition, the DeepEMR method achieved high reproducibility and reliability (intraclass correlation coefficient = 0.97, intersubject coefficient of variation = 3.5%, and intrasubject coefficient of variation = 1.3%) of the estimation of MTC signals at ±3.5 ppm. In tumor patients, DeepEMR-based amide proton transfer images provided higher tumor contrast than a conventional MT ratio asymmetry image, particularly at higher B1 strengths (>1.5 μT), with a distinct delineation of the tumor core from normal tissue or peritumoral edema. The DeepEMR approach is feasible for measuring clean APT and rNOE effects in longitudinal and cross-sectional studies with low scan-rescan variability.

7 tricks for 7 T CEST: Improving the reproducibility of multipool evaluation provides insights into the effects of age and the early stages of Parkinson's disease.

The objective of the current study was to optimize the postprocessing pipeline of 7 T chemical exchange saturation transfer (CEST) imaging for reproducibility and to prove this optimization for the detection of age differences and differences between patients with Parkinson's disease versus normal subjects. The following 7 T CEST MRI experiments were analyzed: repeated measurements of a healthy subject, subjects of two age cohorts (14 older, seven younger subjects), and measurements of 12 patients with Parkinson's disease. A slab-selective, -homogeneous parallel transmit protocol was used. The postprocessing, consisting of motion correction, smoothing, -correction, normalization, denoising, -correction and Lorentzian fitting, was optimized regarding the intrasubject and intersubject coefficient of variation (CoV) of the amplitudes of the amide pool and the aliphatic relayed nuclear Overhauser effect (rNOE) pool within the brain. Seven "tricks" for postprocessing accomplished an improvement of the mean voxel CoV of the amide pool and the aliphatic rNOE pool amplitudes of less than 5% and 3%, respectively. These postprocessing steps are: motion correction with interpolation of the motion of low-signal offsets (1) using the amide pool frequency offset image as reference (2), normalization of the Z-spectrum using the outermost saturated measurements (3), correction of the Z-spectrum with moderate spline smoothing (4), denoising using principal component analysis preserving the 11 highest intensity components (5), correction using a linear fit (6) and Lorentzian fitting using the five-pool fit model (7). With the optimized postprocessing pipeline, a significant age effect in the amide pool can be detected. Additionally, for the first time, an aliphatic rNOE contrast between subjects with Parkinson's disease and age-matched healthy controls in the substantia nigra is detected. We propose an optimized postprocessing pipeline for CEST multipool evaluation. It is shown that by the use of these seven "tricks", the reproducibility and, thus, the statistical power of a CEST measurement, can be greatly improved and subtle changes can be detected.

Radiofrequency Bias Correction of Magnetization Prepared Rapid Gradient Echo MRI at 7.0 Tesla Using an External Reference in a Sequential Protocol.

At field strengths of 7 T and above, T1-weighted imaging of human brain suffers increasingly from radiofrequency (RF) B1 inhomogeneities. The well-known MP2RAGE (magnetization prepared two rapid acquisition gradient echoes) sequence provides a solution but may not be readily available for all MR systems. Here, we describe the implementation and evaluation of a sequential protocol to obtain normalized magnetization prepared rapid gradient echo (MPRAGE) images at 0.7, 0.8, or 0.9-mm isotropic spatial resolution. Optimization focused on the reference gradient-recalled echo (GRE) that was used for normalization of the MPRAGE. A good compromise between white-gray matter contrast and the signal-to-noise ratio (SNR) was reached at a flip angle of 3° and total scan time was reduced by increasing the reference voxel size by a factor of 8 relative to the MPRAGE resolution. The average intra-subject coefficient-of-variation (CV) in segmented white matter (WM) was 7.9 ± 3.3% after normalization, compared to 20 ± 8.4% before. The corresponding inter-subject average CV in WM was 7.6 ± 7.6% and 13 ± 7.8%. Maps of T1 derived from forward signal modelling showed no obvious bias after correction by a separately acquired flip angle map. To conclude, a non-interleaved acquisition for normalization of MPRAGE offers a simple alternative to MP2RAGE to obtain semi-quantitative purely T1-weighted images. These images can be converted to T1 maps, analogously to the established MP2RAGE approach. Scan time can be reduced by increasing the reference voxel size which has only a miniscule effect on image quality.

Quantitative Multi-Parameter Mapping Optimized for the Clinical Routine.

Using quantitative multi-parameter mapping (MPM), studies can investigate clinically relevant microstructural changes with high reliability over time and across subjects and sites. However, long acquisition times (20 min for the standard 1-mm isotropic protocol) limit its translational potential. This study aimed to evaluate the sensitivity gain of a fast 1.6-mm isotropic MPM protocol including post-processing optimized for longitudinal clinical studies. 6 healthy volunteers (35±7 years old; 3 female) were scanned at 3T to acquire the following whole-brain MPM maps with 1.6 mm isotropic resolution: proton density (PD), magnetization transfer saturation (MT), longitudinal relaxation rate (R1), and transverse relaxation rate (R2*). MPM maps were generated using two RF transmit field (B1+) correction methods: (1) using an acquired B1+ map and (2) using a data-driven approach. Maps were generated with and without Gibb's ringing correction. The intra-/inter-subject coefficient of variation (CoV) of all maps in the gray and white matter, as well as in all anatomical regions of a fine-grained brain atlas, were compared between the different post-processing methods using Student's t-test. The intra-subject stability of the 1.6-mm MPM protocol is 2–3 times higher than for the standard 1-mm sequence and can be achieved in less than half the scan duration. Intra-subject variability for all four maps in white matter ranged from 1.2–5.3% and in gray matter from 1.8 to 9.2%. Bias-field correction using an acquired B1+ map significantly improved intra-subject variability of PD and R1 in the gray (42%) and white matter (54%) and correcting the raw images for the effect of Gibb's ringing further improved intra-subject variability in all maps in the gray (11%) and white matter (10%). Combining Gibb's ringing correction and bias field correction using acquired B1+ maps provides excellent stability of the 7-min MPM sequence with 1.6 mm resolution suitable for the clinical routine.

On the reproducibility of hippocampal MEGA-sLASER GABA MRS at 7T using an optimized analysis pipeline

ObjectivesGABA is the most important inhibitory neurotransmitter. Thus, variation in its concentration is connected to a wide variety of diseases. However, the low concentration and the overlap of more prominent resonances hamper GABA quantification using MR spectroscopy. The hippocampus plays a pivotal role in neurodegeneration. Susceptibility discontinuities in the vicinity of the hippocampus cause strong B0 inhomogeneities, impeding GABA spectroscopy. The aim of this work is to improve the reproducibility of hippocampal GABA+ MRS.MethodsThe GABA+/total creatine ratio in the hippocampus was measured using a MEGA-sLASER sequence at 7 Tesla. 10 young healthy volunteers participated in the study. A dedicated pre-processing approach was established. Spectral quantification was performed with Tarquin. The quantification parameters were carefully adjusted to ensure optimal quantification.ResultsAn inter-subject coefficient of variation of the GABA+/total creatine of below 15% was achieved. Additional to spectral registration, which is essential to obtain reproducible GABA measures, eddy current compensation and additional difference artifact suppression improved the reproducibility. The mean FWHM was 23.1 Hz (0.078 ppm).ConclusionThe increased spectral dispersion of ultra-high-field spectroscopy allows for reproducible spectral quantification, despite a very broad line width. The achieved reproducibility enables the routine use of hippocampal GABA spectroscopy at 7 Tesla.

Cerebral oxygenation and blood flow in normal term infants at rest measured by a hybrid near-infrared device (BabyLux).

The BabyLux device is a prototype optical neuro-monitor of cerebral oxygenation and blood flow for neonatology integrating time-resolved reflectance spectroscopy and diffuse correlation spectroscopy. Here we report the variability of six consecutive 30 s measurements performed in 27 healthy term infants at rest. Poor data quality excluded four infants. Mean cerebral oxygenation was 59.6 ± 8.0%, with intra-subject standard deviation of 3.4%, that is, coefficient of variation (CV) of 5.7%. The inter-subject CV was 13.5%. Mean blood flow index was 2.7 × 10-8 ± 1.56 × 10-8 (cm2/s), with intra-subject CV of 27% and inter-subject CV of 56%. The variability in blood flow index was not reduced by the use of individual measures of tissue scattering, nor accompanied by a parallel variability in cerebral oxygenation. The intra-subject variability for cerebral oxygenation variability was improved compared to spatially resolved spectroscopy devices, while for the blood flow index it was comparable to that of other modalities for estimating cerebral blood flow in newborn infants. Most importantly, the simultaneous measurement of oxygenation and flow allows for interpretation of the high inter-subject variability of cerebral blood flow as being due to error of measurement rather than to physiological instability.

3D gradient echo snapshot CEST MRI with low power saturation for human studies at 3T.

PurposeFor clinical implementation, a chemical exchange saturation transfer (CEST) imaging sequence must be fast, with high signal‐to‐noise ratio (SNR), 3D coverage, and produce robust contrast. However, spectrally selective CEST contrast requires dense sampling of the Z‐spectrum, which increases scan duration. This article proposes a compromise: using a 3D snapshot gradient echo (GRE) readout with optimized CEST presaturation, sampling, and postprocessing, highly resolved Z‐spectroscopy at 3T is made possible with 3D coverage at almost no extra time cost.MethodsA 3D snapshot CEST sequence was optimized for low‐power CEST MRI at 3T. Pulsed saturation was optimized for saturation power and saturation duration. Spectral sampling and postprocessing (B0 correction, denoising) was optimized for spectrally selective Lorentzian CEST effect extraction. Reproducibility was demonstrated in 3 healthy volunteers and feasibility was shown in 1 tumor patient.ResultsLow‐power saturation was achieved by a train of 80 pulses of duration tp = 20 ms (total saturation time tsat = 3.2 seconds at 50% duty cycle) with B1 = 0.6 μT at 54 irradiation frequency offsets. With the 3D snapshot CEST sequence, a 180 × 220 × 54 mm field of view was acquired in 7 seconds per offset. Spectrally selective CEST effects at +3.5 and –3.5 ppm were quantified using multi‐Lorentzian fitting. Reproducibility was high with an intersubject coefficient of variation below 10% in CEST contrasts. Amide and nuclear overhauser effect CEST effects showed similar correlations in tumor and necrosis as show in previous ultra‐high field work.ConclusionA sophisticated CEST tool ready for clinical application was developed and tested for feasibility.

Energy Expenditure in Playground Games in Primary School Children Measured by Accelerometer and Heart Rate Monitors.

The aim of this study was to examine the energy expenditure (EE) measured using indirect calorimetry (IC) during playground games and to assess the validity of heart rate (HR) and accelerometry counts as indirect indicators of EE in children´s physical activity games. 32 primary school children (9.9 ± 0.6 years old, 19.8 ± 4.9 kg · m-2 BMI and 37.6 ± 7.2 ml · kg-1 · min-1 VO2max). Indirect calorimetry (IC), accelerometry and HR data were simultaneously collected for each child during a 90 min session of 30 playground games. Thirty-eight sessions were recorded in 32 different children. Each game was recorded at least in three occasions in other three children. The intersubject coefficient of variation within a game was 27% for IC, 37% for accelerometry and 13% for HR. The overall mean EE in the games was 4.2 ± 1.4 kcals · min-1 per game, totaling to 375 ± 122 kcals/per 90 min/session. The correlation coefficient between indirect calorimetry and accelerometer counts was 0.48 (p = .026) for endurance games and 0.21 (p = .574) for strength games. The correlation coefficient between indirect calorimetry and HR was 0.71 (p = .032) for endurance games and 0.48 (p = .026) for strength games. Our data indicate that both accelerometer and HR monitors are useful devices for estimating EE during endurance games, but only HR monitors estimates are accurate for endurance games.

Uncertainty assessment of gamma-aminobutyric acid concentration of different brain regions in individual and group using residual bootstrap analysis.

The aim of this work is to quantify individual and regional differences in the relative concentration of gamma-aminobutyric acid (GABA) in human brain with in vivo magnetic resonance spectroscopy. Spectral editing Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) sequence and GABA analysis toolkit (Gannet) were used to detect and quantify GABA in anterior cingulate cortex (ACC) and occipital cortex (OCC) of healthy volunteers. Residual bootstrap, a model-based statistical analysis technique, was applied to resample the fitting residuals of GABA from the Gaussian fitting model (referred to as GABA+ thereafter) in both individual and group data of ACC and OCC. The inter-subject coefficient of variation (CV) of GABA+ in OCC (20.66%) and ACC (12.55%) with residual bootstrap was lower than that of a standard Gaussian model analysis (21.58% and 16.73% for OCC and ACC, respectively). The intra-subject uncertainty and CV of OCC were lower than that of ACC in both analyses. The residual bootstrap analysis thus provides a more robust uncertainty estimation of individual and group GABA+ detection in different brain regions, which may be useful in our understanding of GABA biochemistry in brain and its use for the diagnosis of related neuropsychiatric diseases.

Reproducibility of hypocapnic cerebrovascular reactivity measurements using BOLD fMRI in combination with a paced deep breathing task

It has recently been proposed that hypocapnic cerebrovascular reactivity (CVR) can be assessed by measuring the blood oxygenation level dependent (BOLD) response to paced deep breathing (PDB) tasks inducing mild hypocapnia and vasoconstriction. In this work, we aim to assess the test–retest reproducibility and inter-subject variability of BOLD CVR measurements obtained using a PDB task and different methods to analyse the associated BOLD signal. The respiratory protocol consisted of alternating 40s of PDB with normal free breathing; expired CO2 pressure levels (PETCO2) were continuously monitored. CVR was quantified using either a timecourse curve analysis (TCA) approach, where the magnitude of response peaks is emphasized, or general linear modelling (GLM) including optimisation of the BOLD response latencies. The GLM fit was carried out using two types of response regressors: one that was computed as the convolution of PETCO2 traces with a gamma function and another that consisted of the convolution of PDB paradigm blocks with a physiological model of the respiratory response. Haemodynamic response latencies were optimised either on a voxel basis or for the whole imaging region. We found that the GLM method based on PDB task or PETCO2 traces and voxelwise optimisation of response latencies provided the most reproducible measures of CVR. For the average grey matter CVR, the inter-subject coefficient of variation (CVinter) / intra-subject coefficient of variation (CVintra) / intra-class correlation coefficient (ICC) were 20%/8%/0.8 and 27%/8%/0.9, using the task and PETCO2 timecourses, respectively. In terms of the spatial reproducibility, the group mean (±standard deviation) of the spatial ICC (ICCspatial) was 1.04±0.23 and 1.02±0.26, for the task and PETCO2 timecourses, respectively. These results indicate generally good reproducibility of the hypocapnic CVR maps obtained using the proposed PDB task and analysis methodology. This suggests that such protocol may therefore offer a promising alternative to conventional vasoactive challenges, which avoids their discomfort and difficulty.

INTEROCULAR SYMMETRY OF PARAFOVEAL PHOTORECEPTOR CONE DENSITY DISTRIBUTION

To investigate the variation and symmetry of cone density distribution along the nasal and temporal retina of fellow eyes. An adaptive optics retinal camera (rtx1; Imagine Eyes) was used to obtain images of the parafoveal cone mosaic in 20 healthy subjects. Cone density was estimated at 250, 420, 760, and 1,300 μm eccentricity from the fovea along the nasal and temporal retina of both eyes in each subject. The coefficient of variation and the intraclass correlation coefficient were used to calculate the variation and absolute agreement of cone density between the same retinal eccentricity locations of fellow eyes, respectively. A considerable variation of cone density between subjects was found at all eccentricities along the nasal and temporal retina (intersubject coefficient of variation ≥ 11%, P < 0.001). The intrasubject variation of cone density was, however, moderate (coefficient of variation ≤ 13% in 95% of the subjects); a high agreement was, on average, found between the cone density estimates at the same eccentricity along the nasal and temporal retina of fellow eyes (intraclass correlation coefficient ≥ 0.86, P < 0.001). Cone density follows a symmetrical distribution between fellow eyes. A systematic distribution of parafoveal cones between fellow eyes may provide an anatomical basis for the involvement of the photoreceptor layer in the first step of binocular spatial sampling.

Cerebellar transcranial direct current stimulation does not alter motor surround inhibition

Motor surround inhibition (mSI) is one mechanism by which the central nervous system individuates finger movements, and yet the neuroanatomical substrate of this phenomenon is currently unknown. In this study, we examined the role of the cerebellum in the generation of mSI, using transcranial direct current stimulation of the cerebellum (cDC). We also examined intrasubject and intersubject variability of mSI. Twelve subjects completed a three session cross over study in which mSI was measured before and after (0 and 20 minutes) sham, anodal and cathodal cDC. mSI of the surround muscle (adductor digiti minimi) at the onset of flexion of the index finger was consistently observed. Anodal and cathodal cDC did not modulate the magnitude of mSI. For individual subjects (across the three sessions), the intrasubject coefficient of variation was 27%. Between subjects, the intersubject coefficient of variation was 47%. mSI was a stable effect in individual subjects across multiple sessions. This is an important observation and contrasts with other neurophysiological paradigms such as paired associative stimulation response, which exhibit great variability. In addition, we have quantified intrasubject variability of mSI, which will allow future therapeutic studies that attempt to modulate mSI to be adequately powered. We have not found evidence that the cerebellum contributes to the neuroanatomical network needed for the generation of mSI. Understanding the mechanisms of mSI remains a challenge but is important for disorders in which it is deficient such as Parkinson's disease and focal hand dystonia.

Origins of intersubject variability of blood oxygenation level dependent and arterial spin labeling fMRI: implications for quantification of brain activity

Accurate localization of brain activity using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been challenged because of the large BOLD signal within distal veins. Arterial spin labeling (ASL) techniques offer greater sensitivity to the microvasculature but possess low temporal resolution and limited brain coverage. In this study, we show that the physiological origins of BOLD and ASL depend on whether percent change or statistical significance is being considered. For BOLD and ASL fMRI data collected during a simple unilateral hand movement task, we found that in the area of the contralateral motor cortex the centre of gravity (CoG) of the intersubject coefficient of variation (CV) of BOLD fMRI was near the brain surface for percent change in signal, whereas the CoG of the intersubject CV for Z-score was in close proximity of sites of brain activity for both BOLD and ASL. These findings suggest that intersubject variability of BOLD percent change is vascular in origin, whereas the origin of inter-subject variability of Z-score is neuronal for both BOLD and ASL. For longer duration tasks (12 s or greater), however, there was a significant correlation between BOLD and ASL percent change, which was not evident for short duration tasks (6 s). These findings suggest that analyses directly comparing percent change in BOLD signal between pre-defined regions of interest using short duration stimuli, as for example in event-related designs, may be heavily weighted by large-vessel responses rather than neuronal responses.

Reproducibility of Tumor Motion Probability Distribution Function in Stereotactic Body Radiation Therapy of Lung Cancer

To evaluate the reproducibility of tumor motion probability distribution function (PDF) in stereotactic body radiation therapy (SBRT) of lung cancer using cine megavoltage (MV) images. Cine MV images of 20 patients acquired during three-dimensional conformal (6-11 beams) SBRT treatments were retrospectively analyzed to extract tumor motion trajectories. For each patient, tumor motion PDFs were generated per fraction (PDF(n)) using three selected "usable" beams. Patients without at least three usable beams were excluded from the study. Fractional PDF reproducibility (R(n)) was calculated as the Dice similarity coefficient between PDF(n) to a "ground-truth" PDF (PDF(g)), which was generated using the selected beams of all fractions. The mean of R(n), labeled as R(m), was calculated for each patient and correlated to the patient's mean tumor motion rang (A(m)). Change of R(m) during the course of SBRT treatments was also evaluated. Intra- and intersubject coefficient of variation (CV) of R(m) and A(m) were determined. Thirteen patients had at least three usable beams and were analyzed. The mean of R(m) was 0.87 (range, 0.84-0.95). The mean of A(m) was 3.18 mm (range, 0.46-7.80 mm). R(m) was found to decrease as A(m) increases following an equation of R(m) = 0.17e(-0.9Am) + 0.84. R(m) also decreased slightly throughout the course of treatments. Intersubject CV of R(m) (0.05) was comparable to intrasubject CV of R(m) (range, 0.02-0.09); intersubject CV of A(m) (0.73) was significantly greater than intrasubject CV of A(m) (range, 0.09-0.24). Tumor motion PDF can be determined using cine MV images acquired during the treatments. The reproducibility of lung tumor motion PDF decreased exponentially as the tumor motion range increased and decreased slightly throughout the course of the treatments.

Serum albumin-bound proteomic signature for early detection and staging of hepatocarcinoma: sample variability and data classification

Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) proteomic signature might be of interest for the early detection and staging of hepatocellular carcinoma (HCC). However, published procedures have been criticized for the lack of data about analytical reproducibility, and the use of inadequate data processing. MALDI-TOF profiling of peptides bound to serum albumin ("albuminome") was performed using 90 μL of serum from 45 study subjects (HCV-related cirrhosis, small, unifocal HCCs and advanced HCCs). To overcome the large intra-sample variability, a Quality Assurance protocol was implemented, and 4-8 samples for each subject were processed and analyzed. Overall, 522 subject samples and 299 quality-control spectra were analyzed. A machine-learning approach (Random Forest) was applied to analyze the data sets. Mean intra-sample coefficient of variation (CV) of the analytical procedure was 17.6%-30.0%; inter-subject CV was in the range 48.8%-71.3% among the three study groups. The Random Forest procedure correctly classified 433/522 "patient samples" and 295/299 "reference samples"; 43/45 patients were correctly classified following this approach. Our data suggest that, notwithstanding the large analytical variability found, multiple proteomic profiles obtained from each subject can differentiate cirrhosis with and without HCC, and HCCs with and without vascular invasion, warranting further investigation in a prospective setting.

Pharmacokinetic and Pharmacodynamic Modeling of a Copper‐Selective Chelator (TETA) in Healthy Adults

The population pharmacokinetics (PK) and pharmacodynamics (PD) of triethylenetetramine (TETA) dihydrochloride (trientine, GC811007) administered orally as 100-, 300-, 600-, or 1800-mg twice-daily doses were assessed in healthy adult male and female volunteers. This study was a randomized, double-blind, placebo-controlled, group-sequential, dose-escalating design. Forty participants, 10 per dose level (8 receiving TETA, 2 receiving placebo), received twice-daily doses for 14 consecutive days. A 2-compartment model for the PK and a linear direct effect model for drug-induced copper excretion (PD) were employed. The population PK/PD model was applied using the NONMEM software. Covariates tested were glomerular filtration rate (GFR), body weight, and gender. Multiple daily doses of TETA were safe and generally well tolerated. The linear 2-compartment model with first-order absorption well characterized the serum concentration data. Although its role was small, GFR had a statistically significant (P < .05) influence on systemic clearance (CL/F). The augmentation of copper excretion was well described by a direct linear model in which the slope was related to GFR and gender (P < .001). The intersubject coefficient of variation was 22.2% for slope (SL) and 82.5% for intercept (ER0). TETA has consistent single/multiple-dose pharmacokinetics and dose-proportional and serum concentration-proportional effects on enhancing copper excretion.

Reproducibility of 31P cardiac magnetic resonance spectroscopy at 3 T

The purpose of this work was to take advantage of the new clinical field strength of 3 T to implement and optimize a chemical shift imaging (CSI) acquisition protocol to produce spectra of high quality with high specificity to the myocardium within a clinically feasible scan time. Further, an analysis method was implemented dependent purely on anatomical location of spectra, and as such free from any potential user bias caused by inference from spectral information. Twenty healthy male subjects were scanned on two separate occasions using the optimized CSI protocol at 3 T. Data were analyzed for intra- and inter-subject variability, as well as intra- and inter-observer variability. The average phosphocreatine (PCr)/adenosine triphosphate (ATP) value for scan 1 was 2.07 +/- 0.38 and for scan 2 was 2.14 +/- 0.46, showing no significant difference between scans. Intra-subject variability was 0.43 +/- 0.35 (percentage difference 20%) and the inter-subject coefficient of variation was 18%. The intra-observer variability, assessed as the absolute difference between analyses of the data by a single observer, was 0.14 +/- 0.24 with no significant difference between analyses. The inter-observer variability showed no significant differences between the PCr/ATP value measured by four different observers as demonstrated by an intra-class correlation coefficient of 0.763. The increased signal available at 3 T has improved spatial resolution and thereby increased myocardial specificity without any significant decrease in reproducibility over previous studies at 1.5 T. We present an acquisition protocol that routinely provides high quality spectra and a robust analysis method that is free from potential user bias.

A signalling role for muscle glycogen in the regulation of pace during prolonged exercise

Introduction: In this study we examined the pacing strategy and the end muscle glycogen contents in eight cyclists, once when they were carbohydrate loaded and once when they were non-loaded....

A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe

Background: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, is in clinical development for the treatment of hypercholesterolemia. It is rapidly absorbed and glucuronidated in the intestine. The parent compound and its conjugated metabolite undergo enterohepatic recirculation, resulting in multiple peaks in the plasma concentration-time profile. Objective: The purpose of this study was to develop a population pharmacokinetic (PPK) model for ezetimibe that incorporates enterohepatic recirculation. Methods: A population compartment model incorporating input from the gallbladder, consistent with food intake, was developed to account for enterohepatic recirculation. The amount recycled was allowed to vary within a subject and between subjects, accommodating variability in bile secretion. The data used consisted of 90 profiles from healthy subjects who received single or multiple doses of ezetimibe 10 or 20 mg. Modeling was carried out using a nonlinear mixed-effect function in the S-PLUS ® statistical program. Results: The amount of ezetimibe recycled into the central compartment was estimated to be ∼17% to 20% of the total amount absorbed, independent of the volume of distribution. The intersubject coefficient of variation was 46% to 80% in the absorption rate constant, 27% in the distribution phase, and ∼50% in the volume of distribution. Conclusions: PPK models adapted for enterohepatic recirculation allowed a formal assessment of the magnitude and frequency of the enterohepatic recirculation process, and the associated intersubject and intrasubject variability in healthy subjects. The PPK approach also helped to assess the correlation between the observed maximum or minimum (24 hours postdose) concentration with the model-based area under the curve, confirming the appropriateness of the former measures as a surrogate of drug exposure for a possible correlation with pharmacodynamics.