Intersubject Coefficients Of Variation Research Articles

Pharmacokinetic evaluation and relative bioavailability pilot study of fidaxomicin in healthy Chinese subjects: An open, randomized, single-dose, cross-over study.

To compare the pharmacokinetic (PK) characteristics, investigate relative bioavailability, and provide data for potential additional bioequivalence trials between generic fidaxomicin (test (T) formulation) and the original brand (reference (R) formulation) in healthy Chinese subjects. An open, randomized, single-dose, cross-over study was conducted in 18 healthy Chinese subjects. The subjects randomly received T or R formulations and the alternative formulations were received after a 14-day wash-out period. Blood and fecal samples were collected and tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters were calculated using a non-compartmental model. Relative bioavailability considering commonly established bioequivalence criteria was assessed. Cmax were 3.58±2.74 ng/mL and 6.01±3.93 ng/mL, and AUC0-∞ were 35.71±18.68 h×ng/mL and 52.15±31.31 h×ng/mL for the T and R formulations, respectively. The tmax of both formulations was 5.00hours. The cumulative fecal excretion rate (Fe0-96h/F) of fidaxomicin and its main active metabolite OP-1118 were similar for both formulations. The geometric mean ratios and 90% confidence intervals (CI) of AUC0-t, AUC0-∞, and Cmax were not completely within the range of 80.00-125.00%. Significant within-subject and inter-subject coefficients of variation (> 30%) were found. Despite the differences in exposure, PK characteristics and fecal recovery of the two formulations were similar, suggesting that an effective concentration of the generic fidaxomicin could be achieved locally in the gastrointestinal tract. Fidaxomicin was a highly viable drug, thus providing reference for future clinical study design.

An Unsupervised Deep Learning Approach for Dynamic-Exponential Intravoxel Incoherent Motion MRI Modeling and Parameter Estimation in the Liver.

Dynamic-exponential intravoxel incoherent motion (IVIM) imaging is a potential technique for prediction, monitoring, and differential diagnosis of hepatic diseases, especially liver tumors. However, the use of such technique at voxel level is still limited. To develop an unsupervised deep learning approach for voxel-wise dynamic-exponential IVIM modeling and parameter estimation in the liver. Prospective. Ten healthy subjects (4 males; age 28 ± 6 years). Single-shot spin-echo echo planar imaging (SE-EPI) sequence with monopolar diffusion-encoding gradients (12 b-values, 0-800 seconds/mm2 ) at 3.0 T. The proposed deep neural network (DNN) was separately trained on simulated and in vivo hepatic IVIM datasets. The trained networks were compared to the approach combining least squares with Akaike information criterion (LSQ-AIC) in terms of dynamic-exponential modeling accuracy, inter-subject coefficients of variation (CVs), and fitting residuals on the simulated subsets and regions of interest (ROIs) in the left and right liver lobes. The ROIs were delineated by a radiologist (H.-X.Z.) with 7 years of experience in MRI reading. Comparisons between approaches were performed with a paired t-test (normality) or a Wilcoxon rank-sum test (nonnormality). P < 0.05 was considered statistically significant. In simulations, DNN gave significantly higher accuracy (91.6%-95.5%) for identification of bi-exponential decays with respect to LSQ-AIC (79.7%-86.8%). For tri-exponential identification, DNN was also superior to LSQ-AIC despite not reaching a significant level (P=0.08). Additionally, DNN always yielded comparatively low root-mean-square error for estimated parameters. For the in vivo IVIM measurements, inter-subject CVs (0.011-0.150) of DNN were significantly smaller than those (0.049-0.573) of LSQ-AIC. Concerning fitting residuals, there was no significant difference between the two approaches (P=0.56 and 0.76) in both the simulated and in vivo studies. The proposed DNN is recommended for accurate and robust dynamic-exponential modeling and parameter estimation in hepatic IVIM imaging. 2 TECHNICAL EFFICACY: Stage 1.

Inter-subject stability and regional concentration estimates of 3D-FID-MRSI in the human brain at 7 T.

Recently, a 3D-concentric ring trajectory (CRT)-based free induction decay (FID)-MRSI sequence was introduced for fast high-resolution metabolic imaging at 7 T. This technique provides metabolic ratio maps of almost the entire brain within clinically feasible scan times, but its robustness has not yet been thoroughly investigated. Therefore, we have assessed quantitative concentration estimates and their variability in healthy volunteers using this approach. We acquired whole-brain 3D-CRT-FID-MRSI at 7 T in 15 min with 3.4 mm nominal isometric resolution in 24 volunteers (12 male, 12 female, mean age 27 ± 6 years). Concentration estimate maps were calculated for 15 metabolites using internal water referencing and evaluated in 55 different regions of interest (ROIs) in the brain. Data quality, mean metabolite concentrations, and their inter-subject coefficients of variation (CVs) were compared for all ROIs. Of 24 datasets, one was excluded due to motion artifacts. The concentrations of total choline, total creatine, glutamate, myo-inositol, and N-acetylaspartate in 44 regions were estimated within quality thresholds. Inter-subject CVs (mean over 44 ROIs/minimum/maximum) were 9%/5%/19% for total choline, 10%/6%/20% for total creatine, 11%/7%/24% for glutamate, 10%/6%/19% for myo-inositol, and 9%/6%/19% for N-acetylaspartate. We defined the performance of 3D-CRT-based FID-MRSI for metabolite concentration estimate mapping, showing which metabolites could be robustly quantified in which ROIs with which inter-subject CVs expected. However, the basal brain regions and lesser-signal metabolites in particular remain as a challenge due susceptibility effects from the proximity to nasal and auditory cavities. Further improvement in quantification and the mitigation of B0 /B1 -field inhomogeneities will be necessary to achieve reliable whole-brain coverage.

An efficient R1ρ dispersion imaging method for human knee cartilage using constant magnetization prepared turbo-FLASH.

This work aimed to develop an efficient R1ρ dispersion imaging method for clinical studies of human knee cartilage at 3 T. Eight constant magnetizations (Mprep ) were prepared by tailoring both the duration and amplitude (ω1 ) of a fully refocused spin-lock preparation pulse. The limited Mprep dynamic range was expanded by the measure, equivalent to that with ω1 = ∞, from the magic angle location in the deep femoral cartilage. The developed protocol with Mprep = 60% was demonstrated on one subject's bilateral and two subjects' unilateral asymptomatic knees. The repeatability of the proposed protocol was estimated by two repeated scans with a three-month gap for the last two subjects. The synthetic R1ρ and R2 derived from R1ρ dispersions were compared with the published references using state-of-the-art R1ρ and R2 mapping (MAPSS). The proposed protocol demonstrated good (<5%) repeatability quantified by the intra- and intersubject coefficients of variation in the femoral and tibial cartilage. The synthetic R1ρ (1/s) and the references were comparable in the femoral (23.0 ± 5.3 versus 24.1 ± 3.8, P = 0.67) and the tibial (29.1 ± 8.8 versus 27.1 ± 5.1, P = 0.62), but not the patellar (16.5 ± 4.9 versus 22.7 ± 1.6, P < 0.01) cartilage. The same trends were also observed for the current and the previous R2 . In conclusion, the developed R1ρ dispersion imaging scheme has been revealed to be not only efficient but also robust for clinical studies of human knee cartilage at 3 T.

Simultaneous editing of GABA and GSH with Hadamard-encoded MR spectroscopic imaging.

To evaluate the feasibility of simultaneous MR spectroscopic imaging (MRSI) of gamma-aminobutyric acid (GABA) and glutathione (GSH) in the human brain using Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES). Point RESolved Spectroscopy (PRESS)-localized MRSI was performed in GABA and GSH phantoms and in the human brain (n = 3) using HERMES editing and compared to conventional MEGA editing of each metabolite. Multiplet patterns, signal intensities, and metabolite crosstalk were compared between methods. GABA+ and GSH levels were compared between methods for bias and variability. Linear regression of HERMES-MRSI GABA+/H2 O and GSH/H2 O versus gray matter (GM) fraction were performed to assess differences between GM and white matter (WM). Phantom HERMES-MRSI scans gave comparable GABA+ and GSH signals to MEGA-MRSI across the PRESS-localized volume. In vivo, HERMES-reconstructed GABA+ and GSH values had minimal measurement bias and variability relative to MEGA-MRSI. Intersubject coefficients of variation (CV) from two regions within the PRESS-localized volume for HERMES and MEGA were 6-12% for GABA+ and 6-19% for GSH. Interregion CVs were 5-15% for GABA+ and 3-17% for GSH. The GABA+/H2 O and GSH/H2 O ratios were ~1.8 times higher and ~1.9 times higher, respectively, in GM than in WM. HERMES-MRSI of GABA+ and GSH was found to be practical in the human brain with minimal measurement bias and comparable variability to separate MEGA-edited acquisitions of each metabolite performed in double the scan time. The HERMES-MRSI is a promising method for simultaneously mapping the distribution of multiple low-concentration metabolites.

Consistency of Multiple Renal Functional MRI Measurements Over 18 Months.

Identification of patients with progressive chronic kidney disease (CKD) and those likely to respond to candidate therapeutics is urgently needed. Functional MRI measurements have shown promise. However, knowledge about the consistency of the measurements is essential to conduct longitudinal studies. To investigate the consistency of repeated functional MRI measurements in healthy subjects. Prospective, longitudinal study. Seventeen healthy subjects were examined on two different occasions, 18 months apart. Multiple gradient-recalled-echo, 2D navigator-gated flow-sensitive alternating inversion recovery True-FISP and spin-echo planar diffusion-weighted sequences were used on a 3T scanner. Images were acquired on two different scanner configurations. Blood oxygenation level-dependent (BOLD) R2*, arterial spin labeling (ASL) perfusion-derived blood flow (BF) and apparent diffusion coefficient (ADC) maps were analyzed using a custom image processing toolbox. Regions of interest (ROIs) were placed on renal cortex, medulla, and whole kidney. Multiple researchers were involved in defining the ROIs. Intra- and intersubject coefficients of variation (CV) and Bland-Altman plots were used to measure consistency and evaluate bias in the measurements. A nonparametric Wilcoxon test was used to compare differences between two timepoints. The intrasubject CV for R2* and ADC were 6.8% and 5.3% with small (-3.8 and 5.3%) bias, respectively, comparing baseline and 18-month data. Intrasubject CV for renal cortex BF was higher (18.7%) compared to R2* and ADC, but comparable to prior literature values over shorter durations. It also exhibited a larger bias (-15.4%) between two timepoints and significantly lower values (P = 0.022) at 18-month data. All three MRI parameters over 18 months, even with a scanner upgrade and involving multiple observers, showed good consistency. These results are useful for the interpretation of longitudinal data and support the use of these methods to monitor progression in patients with CKD. 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:514-521.

Generalized Confidence Intervals for Intra- and Inter-subject Coefficients of Variation in Linear Mixed-effects Models.

Linear mixed-effects models are linear models with several variance components. Models with a single random-effects factor have two variance components: the random-effects variance, i. e., the inter-subject variance, and the residual error variance, i. e., the intra-subject variance. In many applications, it is practice to report variance components as coefficients of variation. The intra- and inter-subject coefficients of variation are the square roots of the corresponding variances divided by the mean. This article proposes methods for computing confidence intervals for intra- and inter-subject coefficients of variation using generalized pivotal quantities. The methods are illustrated through two examples. In the first example, precision is assessed within and between runs in a bioanalytical method validation. In the second example, variation is estimated within and between main plots in an agricultural split-plot experiment. Coverage of generalized confidence intervals is investigated through simulation and shown to be close to the nominal value.

Quantitative Analysis of Dynamic 123I-mIBG SPECT Imaging Data in Healthy Humans with a Population-Based Metabolite Correction Method.

Conventional 2-dimensional planar imaging of (123)I-metaiodobenzylguanidine ((123)I-mIBG) is not fully quantitative. To develop a more accurate quantitative imaging approach, we investigated dynamic SPECT imaging with kinetic modeling in healthy humans to obtain the myocardial volume of distribution (VT) for (123)I-mIBG. Twelve healthy humans underwent 5 serial 15-min SPECT scans at 0, 15, 90, 120, and 180 min after bolus injection of (123)I-mIBG on a hybrid cadmium zinc telluride SPECT/CT system. Serial venous blood samples were obtained for radioactivity measurement and radiometabolite analysis. List-mode data of all the scans were binned into frames and reconstructed with attenuation and scatter corrections. Myocardial and blood-pool volumes of interest were drawn on the reconstructed images to derive the myocardial time-activity curve and input function. A population-based blood-to-plasma ratio (BPR) curve was generated. Both the population-based metabolite correction (PBMC) and the individual metabolite correction (IMC) curves were generated for comparison. VT values were obtained from different compartment models, using different input functions with and without metabolite and BPR corrections. The BPR curve reached the peak value of 2.1 at 13 min after injection. Parent fraction was approximately 58% ± 13% at 15 min and stabilized at approximately 40% ± 5% by 180 min after injection. Two radiometabolite species were observed. When the reversible 2-tissue-compartment fit was used, the mean VT value was 29.0 ± 12.4 mL/cm(3) with BPR correction and PBMC, a 188% ± 32% increase compared with that without corrections. There was significant difference in VT with BPR correction (P = 2.3e-04) as well as with PBMC (P = 1.6e-05). The mean difference in VT between PBMC and IMC was -3% ± 8%, which was insignificant (P = 0.39). The intersubject coefficients of variation after PBMC (43%) and IMC (42%) were similar. The myocardial VT of (123)I-mIBG was established in healthy humans for the first time. Accurate kinetic modeling of (123)I-mIBG requires both BPR and metabolite corrections. Population-based BPR correction and metabolite correction curves were developed, allowing more convenient absolute quantification of dynamic (123)I-mIBG SPECT images.

Tissue‐ and column‐specific measurements from multi‐parameter mapping of the human cervical spinal cord at 3 T

The aim of this study was to quantify a range of MR parameters [apparent proton density, longitudinal relaxation time T1, magnetisation transfer (MT) ratio, MT saturation (which represents the additional percentage MT saturation of the longitudinal magnetisation caused by a single MT pulse) and apparent transverse relaxation rate R2*] in the white matter columns and grey matter of the healthy cervical spinal cord. The cervical cords of 13 healthy volunteers were scanned at 3 T using a protocol optimised for multi-parameter mapping. Intra-subject co-registration was performed using linear registration, and tissue- and column-specific parameter values were calculated. Cervical cord parameter values measured from levels C1–C5 in 13 subjects are: apparent proton density, 4822 ± 718 a.u.; MT ratio, 40.4 ± 1.53 p.u.; MT saturation, 1.40 ± 0.12 p.u.; T1 = 1848 ± 143 ms; R2* = 22.6 ± 1.53 s–1. Inter-subject coefficients of variation were low in both the cervical cord and tissue- and column-specific measurements, illustrating the potential of this method for the investigation of changes in these parameters caused by pathology. In summary, an optimised cervical cord multi-parameter mapping protocol was developed, enabling tissue- and column-specific measurements to be made. This technique has the potential to provide insight into the pathological processes occurring in the cervical cord affected by neurological disorders. © 2013 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.

Cognitive Diversity in Middle-Aged and Elderly Adults: The Role of Education

This study examines cognitive diversity through performance of four attentional tasks and a vocabulary measure in relation to age and level of education. Tasks were performed by 168 participants (aged between 45 and 91 years) who were grouped according to age and level of education. Multivariate analyses of variance were applied to Z scores calculated from intersubject coefficients of variation. When the variance associated with education was discounted prior to analysis, a disproportionate increase in cognitive diversity was observed in participants over 75 years of age. When cognitive diversity was analyzed in relation to age and education in the three youngest age groups, participants with a low level of education displayed higher diversity in most attentional tasks from 66 years of age. In participants with a high level of education, diversity was lower for all attentional tasks considered from 56 years of age. Vocabulary knowledge was the most sensitive to education-related cognitive diversity. The diversifying effect of the relationship between education and diversity on fluid cognitive performance appeared to reverse and become a homogenizing effect with increasing age.

Pharmacodynamic and Clinical Endpoints for Functional Colonic Disorders: Statistical Considerations

Intra- and inter-subject coefficients of variation (COV) of scintigraphic colonic transit (SCT) are well characterized. SCT response to therapy predicts clinical efficacy of experimental medications in lower functional gastrointestinal disorders (FGID). To compare COVs for bowel function with pharmacodynamic (PD) colonic transit geometric center (GC) as endpoints in lower FGID studies. We evaluated data from placebo arm of 9 phase IIA, parallel-group, clinical trials of PD effects of linaclotide, dexloxiglumide, renzapride, elobixibat, ROSE 010, and chenodeoxycholate in lower FGID with constipation, and pexacerafont, VSL#3, and colesevelam in lower FGID with diarrhea. Patients completed daily diaries for at least 7 days of stool frequency, consistency (7-point Bristol Stool Form Scale), and ease of passage (7-point scale from manual disimpaction to incontinence). Seventeen patients received placebo in 2 separate studies allowing assessment of intra-patient COVs. We calculated sample sizes required to demonstrate a 30 % effect size for colonic transit, stool frequency, consistency and ease of passage for patients with lower FGID with constipation and, separately, diarrhea. COV(inter) from 87 patients and COV(intra) from 17 patients are reported. Generally, COV(intra) is somewhat greater than COV(inter). The COVs for PD endpoints are lower than for clinical endpoints; however, clinically relevant effects can be identified with modest (~50 %) increases in the sample size using parallel-group design studies. Phase IIA studies that incorporate clinical and PD endpoints are feasible in lower FGID associated with constipation or diarrhea. Crossover design would require lower sample size for most endpoints compared to parallel-group studies.

Performance characteristics of scintigraphic measurement of gastric emptying of solids in healthy participants

Gastric emptying (GE) is measured in pharmacodynamic and diagnostic studies. Our aim was to assess inter- and intra-subject coefficients of variation (COV) of scintigraphic GE measurements in healthy subjects, and associations of GE with gender and body mass index (BMI). Data from participants with scintigraphic measurements of gastric emptying of solids were analyzed. Primary endpoints were gastric emptying T(1/2) (GE T(1/2) ) and GE at 1, 2, 3, and 4 h. The patient cohort consisted of 105 males and 214 females; at least two studies were performed in 47 subjects [16 males (M), 32 females (F)]. Inter-subject COV (COV(inter) ) for GE T(1/2) were similar in M and F: overall 24.5% (M 26.0%, F 22.5%); COV are predictably lowest for GE at 4 h (COV(inter) 9.6%). COV(intra) for T(1/2) and GE at 4 h were overall 23.8% and 12.6%, and were similar to COV(inter) values. Gender (but not age or BMI) was significantly associated with GE T1/2 [P < 0.001, F 127.6 ± 28.7 (SD) min; M 109.9 ± 28.6 min] and with GE at 1 h and 2 h. Repeat GE T(1/2) values in 47 participants were significantly correlated (r = 0.459, P < 0.001) with median difference of -6 min (mean -1.6, range -56 to 72 min). Bland-Altman plots showed Δ GE T(1/2) similarly distributed across mean GE T(1/2) 100-155 min, and across studies conducted 90-600 days apart. Inter-subject variations in scintigraphic GE results are only slightly higher than the intra-subject measurements, which are also reproducible over time in healthy volunteers. Gender, but not BMI, is significantly associated with GE results.

Variability comparison of simultaneous brain near-infrared spectroscopy and functional magnetic resonance imaging during visual stimulation

Brain near-infrared spectroscopy (NIRS) is emerging as a potential alternative to functional magnetic resonance imaging (fMRI). To date, no study has explicitly compared the two techniques in terms of measurement variability, a key parameter dictating attainable statistical power. Here, NIRS and fMRI were simultaneously recorded during event-related visual stimulation. Inter-subject coefficients of variation (CVs) for peak response amplitude were considerably larger for NIRS than fMRI, but inter-subject CVs for response latency and intra-subject CVs for response amplitude were overall comparable. Our results may represent an optimistic estimate of the CVs of NIRS measurements, as optode positioning was guided by structural MRI, which is normally unavailable. We concluded that fMRI may be preferable to NIRS for group comparisons, but NIRS is equally powerful when comparing conditions within participants. The discrepancy between inter- and intra-subject CVs is likely related to variability in head anatomy and tissue properties, which may be better accounted for by emerging NIRS technology.

Longitudinal inter‐ and intra‐individual human brain metabolic quantification over 3 years with proton MR spectroscopy at 3 T

The longitudinal repeatability of proton MR spectroscopy ((1) H-MRS) in the healthy human brain at high fields over long periods is not established. Therefore, we assessed the inter- and intra-subject repeatability of (1) H-MRS in an approach suited for diffuse pathologies in 10 individuals, at 3T, annually for 3 years. Spectra from 480 voxels over 360 cm(3) (∼30%) of the brain, were individually phased, frequency-aligned, and summed into one average spectrum. This dramatically increases metabolites' signal-to-noise-ratios while maintaining narrow linewidths that improve quantification precision. The resulting concentrations of the N-acetylaspartate, creatine, choline, and myo-inositol are: 8.9 ± 0.8, 5.9 ± 0.6, 1.4 ± 0.1, and 4.5 ± 0.5 mM (mean ± standard-deviation). the inter-subject coefficients of variation are 8.7%, 10.2%, 10.7%, and 11.8%; and the longitudinal (intra-subject) coefficients of variation are lower still: 6.6%, 6.8%, 6.8%, and 10%, much better than the 35%, 44%, 55%, and 62% intra-voxel coefficients of variation. The biological and nonbiological components of the summed spectra coefficients of variation had similar contributions to the overall variance.

Influence of the Numbers of Players in the Heart Rate Responses of Youth Soccer Players Within 2 vs. 2, 3 vs. 3 and 4 vs. 4 Small-sided Games

The purpose of this study was to compare heart rate (HR) responses within and between small-sided games (SSG) training methods in elite young soccer players. Twenty-seven youth soccer players (age: 16.5 ± 0.5 years, height: 174.5 ± 5.5 cm, weight: 62.9 ± 8.3, velocity at maximal aerobic speed (MAS): 15.9 ± 0.9 km.h−1) performed 3 different SSG (2 vs. 2, 3 vs. 3, 4 vs. 4 without goalkeeper). In each SSG, HR was continuously measured and expressed as a mean percentage of HR reserve (%HRreserve). The mean %HRreserve calculated during the SSG was significantly lower during 4 vs. 4 (70.6 ± 5.9 %) compared to 2 vs. 2 (80.1 ± 3.6 %, p<0.001) and 3 vs. 3 (81.5 ± 4.3 %, p<0.001) SSG. Regardless of the time spent above 60, 65, 70, 75, 80, 85 and 90 % of HRreserve, 4 vs. 4 solicited lower percentage of time than 3 vs. 3 and 2 vs. 2. Intersubject coefficients of variation were significantly higher during 4 vs. 4 compared to 2 vs.2 and 3 vs. 3. The %HRreserve after 30s of recovery was significantly higher for 3 vs. 3 (70.6 ± 5.3 %) compared to 2 vs. 2 (65.2 ± 4.8 %, p<0.05) and 4 vs. 4 (61.6 ± 9.3 %, p<0.05). In conclusion, this study demonstrates that the physiological demands is higher during 2 vs. 2 and 3 vs. 3 compared to 4 vs. 4 in youth soccer players. This difference could be due to that young soccer players do not have the same technical ability and experience as adult players and thus, their activity during the 2 vs. 2 and 3 vs. 3 induces a greater physical demand due to their lack of experience. The age of the players could be linked with the physical demands within small-sided games.

Sagittal and frontal lower limb joint moments during stair ascent and descent in young and older adults

Stair negotiation is an essential skill required for independent mobility, and is described by older adults as a challenging task that is associated with high fall risk. Little is known about the age-related changes in joint kinetics and the relative contribution of lower limb joint moments during stair negotiation. This study characterized lower extremity joint kinetics and their variability associated with stair ascent and descent in young and older adults. Twenty three young and 32 older adults (>55 years) participated. Three dimensional, bilateral gait analysis provided ankle, knee, and hip moment profiles, which in the sagittal plane were summed to provide the support moment. In addition, intra- and inter-subject coefficients of variation were calculated for ensemble averaged curves. Age-related differences were found in the magnitudes of the moment contributions during event transitions for stair ascent and descent. Within groups, the moment profiles were generally consistent. Ankle and knee moments predominantly contributed to extensor support in the sagittal plane. In the frontal plane, proximal joint abductor moments maintained lateral stability and were larger at the hip in older adults. Understanding age-related alterations in movement control during functional tasks can help inform the rehabilitation management and assessment of patient populations.

Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients

The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS, myfortic®) may have an impact on the variability of MPA trough (C0 h) levels. A randomized, two-period crossover study was performed in 24 maintenance renal transplants to evaluate the inter- and intrasubject variability of MPA predose levels from EC-MPS and mycophenolate mofetil (MMF, CellCept®), both in combination with cyclosporine. Patients received EC-MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at -1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1-80.3) and 54.4% (40.0-86.8) for EC-MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1-72.9) and 42.8% (37.9-49.2). High MPA C0 h levels>10 μg/mL were rarely observed with both EC-MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)0-3 h was comparable between treatments, while MPA C0 h was on average 46% higher with EC-MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC-MPS and MMF therapy given the large intrasubject variability in MPA C0 h levels with both treatments.

Reliability of Surface Electromyography During Maximal Voluntary Isometric Contractions, Jump Landings, and Cutting

The reliability of electromyographic (EMG) data has been examined for isometric and slow dynamic tasks, but little is known about the repeatability of this data for ballistic movements. The purpose of this study was to examine the within-session, trial-to-trial reliability of a variety of quadriceps and hamstrings muscles during isometric and ballistic activities. Data were analyzed by way of intraclass correlation coefficients (ICC), intersubject coefficients of variation (CVinter), and intrasubject coefficients of variation (CVintra). Twenty-four subjects performed 3 repetitions each of 2 randomly ordered test exercises, including landing from a depth jump (J) and cutting after a 10-m sprint (C). Data were acquired and processed with root mean square EMG for the muscles assessed, and data were analyzed for each exercise using a repeated measures analysis of variance. Results revealed that all ICC values were greater than 0.80, with most values greater than 0.90, CVinter values ranged from 5.4% to 148.7%, and CVintra values ranged from 11.5% to 49.3%. This study indicates that EMG is a reliable method for assessing the reproducibility of both the quadriceps and hamstrings muscle activation during either isometric or ballistic exercises.

Pharmacokinetics and variability of mycophenolic acid from enteric‐coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients

Sequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single-blind, randomized clinical trial comparing the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) in de novo heart transplant recipients. Patients were randomized to either EC-MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady-state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC-MPS and 15 on MMF). Dose-normalized peak (C(max,ss)) and area under the curve (AUC(tau,ss)) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC-MPS and MMF showed no statistically significant differences in MPA and MPAG AUC(tau,ss), C(max,ss), and trough (C(min,ss)) values (p-values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC-MPS, C(max,ss) occurred approximately one hour later compared with MMF. Inter-subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC-MPS and MMF were high (37-72% for AUC(tau,ss) at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra-subject %CVs for MPA AUC(tau,ss), C(max,ss), and C(min,ss) were 28%, 63%, and 34% with EC-MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC-MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetic parameters with both treatments.

Between session reproducibility and between subject variability of diffusion MR and tractography measures

As diffusion tractography is increasingly used to generate quantitative measures to address clinical questions, it is important to characterise the inter-session reproducibility and inter-subject variability of these measures. Here, we assess the reproducibility and variability of diffusion tractography measures using diffusion data from 8 subjects scanned 3 times. We used probabilistic tractography to define the cingulum bundle, pyramidal tracts, optic radiations and genu of the corpus callosum in each individual data set using three different methods of seed definition. Measures of mean fractional anisotropy (FA) and mean diffusivity (MD) along the tracts were more reproducible than measures of tract volume. Further, tracts defined using a two region of interest (ROI) approach were more reproducible than those defined using manually placed seed masks alone. For mean FA taken from tracts defined using the two ROI approach, inter-session coefficients of variation (CV) were all below 5% and inter-subject CVs were below 10%; for mean MD inter-session, CVs were all below 3% and inter-subject CVs were below 8%. We use the variability measures found here to calculate the sample sizes required to detect changes in FA, MD or tract volume of a given size, either between groups of subjects or within subjects over time. Finally, we compare tractography results using 60 diffusion encoding directions to those found using a subset of 12 directions; the number of diffusion directions did not have a significant effect on reproducibility, but tracts derived using fewer directions were consistently smaller than those derived using 60 direction data. We suggest that 12 direction data are sufficient for reproducibly defining the core of large bundles but may be less sensitive to smaller pathways.