Between-subject Coefficient Of Variation Research Articles

Radiologists' Rating for Comparative Qualitative Assessment of Intravoxel Incoherent Motion Using Novel Analysis Methods.

The objective was to assess qualitative interpretability and quantitative precision and reproducibility of intravoxel incoherent motion ( IVIM) parametric images evaluated using novel IVIM analysis methods for diagnostic accuracy. Intravoxel incoherent motion datasets of 55 patients (male/female = 41:14; age = 17.8 ± 5.5 years) with histopathology-proven osteosarcoma were analyzed. Intravoxel incoherent motion parameters-diffusion coefficient ( D ), perfusion fraction ( f ), and perfusion coefficient ( D* )-were estimated using 5 IVIM analysis methods-(i) biexponential (BE) model, (ii) BE-segmented fitting 2-parameter (BESeg-2), (iii) BE-segmented fitting 1-parameter (BESeg-1), (iv) BE model with total variation penalty function (BE + TV), and (v) BE model with Huber penalty function (BE + HPF). Qualitative scoring in a 5-point Likert scale (uninterpretable: 1; poor: 2; fair: 3; good: 4; excellent: 5) was performed by 2 radiologists for 4 criteria: (a) tumor shape and margin, (b) morphologic correlation, (c) noise suppression, and (d) overall interpretability. Interobserver agreement was evaluated using Spearman rank-order correlation ( rs ). Precision and reproducibility were evaluated using within-subject coefficient of variation (wCV) and between-subject coefficient of variation (bCV). BE + TV and BE + HPF produced significantly ( P < 10 -3 ) higher qualitative scores for D (fair-good [3.3-3.8]) than BE (poor [2.3]) and for D* (poor-fair [2.2-2.7]) and f (fair-good [3.2-3.8]) than BE, BESeg-2, and BESeg-1 ( D* : uninterpretable-poor [1.3-1.9] and f : poor-fair [1.5-3]). Interobserver agreement for qualitative scoring was rs = 0.48-0.59, P < 0.009. BE + TV and BE + HPF showed significantly ( P < 0.05) improved reproducibility in estimating D (wCV: 24%-31%, bCV: 21%-31% improvement) than the BE method and D* (wCV: 4%-19%, bCV: 5%-19% improvement) and f (wCV: 25%-49%, bCV: 25%-47% improvement) than BE, BESeg-2, and BESeg-1 methods. BE + TV and BE + HPF demonstrated qualitatively and quantitatively improved IVIM parameter estimation and may be considered for clinical use further.

Short-term biological variation study of plasma hemophilia and thrombophilia parameters in a population of apparently healthy Caucasian adults

Biological variation (BV) data obtained in a standardized way is valuable to assess the analytical requirements and the utility of a reference interval. Our study aimed to determine the short-term BV of thrombophilia (protein S, protein C, activated protein C resistance (APCR) and factor VIII) and hemophilia (factors VIII, IX and XI) parameters in plasma. Coagulation factors V and XII were also evaluated. Based on the obtained data, we assessed analytical performance specifications for the parameters. Finally, we intended to provide a robust tool for comparison of serial measurements of factors V, VIII, IX and XI. A blood draw was performed weekly in 19 apparently healthy Caucasian adults for five weeks at Saint-Luc University Hospital (Brussels, Belgium). Parameters were measured in duplicate. BV components were calculated with a nested analysis of variance after exclusion of outliers. The analytical coefficient of variation (CV) varied from 1.5 to 4.6%, the within-subject CV from 1.6 to 8.9% and the between-subject CV from 3.8 to 24.1%. All parameters showed high individuality. For most parameters, theanalytical goal was met with our assays. Reference changevalues (RCV) of-16.7% to +20.0%,-20.7% to +26.0%,-15.3% to +18.1% and-13.1% to +15.1% were obtained for factors V, VIII, IX and XI respectively. All studied parameters were highly individualized. The assessment of BV data can guide setting analytical goal specifications. Comparison of serial measurements in the follow-up of patients suffering from hepatic failure or mild hemophilia is facilitated by evaluation of the RCV.

Test-retest reliability of multi-parametric maps (MPM) of brain microstructure

Multiparameter mapping (MPM) is a quantitative MRI protocol that is promising for studying microstructural brain changes in vivo with high specificity. Reliability values are an important prior knowledge for efficient study design and facilitating replicable findings in development, aging and neuroplasticity research. To explore longitudinal reliability of MPM we acquired the protocol in 31 healthy young subjects twice over a rescan interval of 4 weeks. We assessed the within-subject coefficient of variation (WCV), the between-subject coefficient of variation (BCV), and the intraclass correlation coefficient (ICC). Using these metrics, we investigated the reliability of (semi-) quantitative magnetization transfer saturation (MTsat), proton density (PD), transversal relaxation (R2*) and longitudinal relaxation (R1). To increase relevance for explorative studies in development and training-induced plasticity, we assess reliability both on local voxel- as well as ROI-level. Finally, we disentangle contributions and interplay of within- and between-subject variability to ICC and assess the optimal degree of spatial smoothing applied to the data. We reveal evidence that voxelwise ICC reliability of MPMs is moderate to good with median values in cortex (subcortical GM): MT: 0.789 (0.447) PD: 0.553 (0.264) R1: 0.555 (0.369) R2*: 0.624 (0.477). The Gaussian smoothing kernel of 2 to 4 mm FWHM resulted in optimal reproducibility. We discuss these findings in the context of longitudinal intervention studies and the application to research designs in neuroimaging field.

Is Rating of Perceived Exertion a Valuable Tool for Monitoring Exercise Intensity During Steady-State Conditions in Elite Endurance Athletes?

Rating of perceived exertion (RPE) is a widely used tool to assess subjective perception of effort during exercise. The authors investigated between-subject variation and effect of exercise mode and sex on Borg RPE (6-20) in relation to heart rate (HR), oxygen uptake (VO2), and capillary blood lactate concentrations. A total of 160 elite endurance athletes performed a submaximal and maximal test protocol either during cycling (n = 84, 37 women) or running (n = 76, 32 women). The submaximal test consisted of 4 to 7 progressive 5-minute steps within ∼50% to 85% of maximal VO2. For each step, steady-state HR, VO2, and capillary blood lactate concentrations were assessed and RPE reported. An incremental protocol to exhaustion was used to determine maximal VO2 and peak HR to provide relative (%) HR and VO2 values at submaximal work rates. A strong relationship was found between RPE and %HR, %VO2, and capillary blood lactate concentrations (r = .80-.82, all Ps < .05). The between-subject coefficient of variation (SD/mean) for %HR and %VO2 decreased linearly with increased RPE, from ∼10% to 15% at RPE 8 to ∼5% at RPE 17. Compared with cycling, running induced a systematically higher %HR and %VO2 (∼2% and 5%, respectively, P < .05) with these differences being greater at lower intensities (RPE < 13). At the same RPE, women showed a trivial, but significantly higher %HR and %VO2 than men (<1%, P < .05). Among elite endurance athletes, exercise mode influenced RPE at a given %HR and %VO2, with greater differences at lower exercise intensities. Athletes should manage different tools to evaluate training based on intensity and duration of workouts.

In vivo spectral editing of phosphorylethanolamine.

To demonstrate J-difference editing of phosphorylethanolamine (PE) with chemical shifts at 3.22 (PE3.22 ) and 3.98 (PE3.98 ) ppm, and compare the merits of two editing strategies. Density-matrix simulations of MEGA-PRESS (Mescher-Garwood PRESS) for PE were performed at TEs ranging from 80 to 200 ms in steps of 2 ms, applying 20-ms editing pulses (ON/OFF) at (1) 3.98/7.5 ppm to detect PE3.22 and (2) 3.22/7.5 ppm to detect PE3.98 . Phantom experiments were performed using a PE phantom to validate simulation results. Ten subjects were scanned using a Philips 3T MRI scanner at TEs of 90 ms and 110 ms to edit PE3.22 and PE3.98 . Osprey was used for data processing, modeling, and quantification. Simulations show substantial TE modulation of the intensity and shape of the edited signals due to coupling evolution. Simulated and phantom integrals suggest that TEs of 110 ms and 90 ms were optimal for the edited detection of PE3.22 and PE3.98 , respectively. Phantom results indicated strong agreement with the simulated spectra and integrals. In vivo quantification of the PE3.22 /total creatine and PE3.98 /total creatine concentration ratio yielded values of 0.26 ± 0.04 (between-subject coefficient of variation [CV]: 15.4%) and 0.18 ± 0.04 (CV: 22.8%), respectively, at TE = 90 ms, and 0.24 ± 0.02 (CV: 8.2%) and 0.23 ± 0.04 (CV: 18.0%), respectively, at TE = 110 ms. Simulations and in vivo MEGA-PRESS of PE demonstrate that both PE3.22 and PE3.98 are potential candidates for editing, but PE3.22 at TE = 110 ms yields lower variation across TEs.

Serum symmetric dimethylarginine shows a relatively consistent long-term concentration in healthy dogs with a significant effect of increased body fat percentage.

Symmetric dimethylarginine (SDMA) is a promising renal marker that correlates well with the glomerular filtration rate and could allow earlier detection of impaired renal function. The main objectives of this study were to assess the long-term variability of SDMA in healthy dogs and examine the influence of an increased body fat percentage on the level of SDMA. Sixteen lean Beagles were randomly assigned to the control group or weight-change group in age- and gender-matched pairs. The energy intake of the control group (n = 8) was strictly regulated to maintain an ideal body weight for 83 weeks, while the weight-change group (n = 8) was fed to induce weight gain (week 0–47), to maintain stable excessive body weight (week 47–56) and to lose weight (week 56–83), consecutively. At 8 specified time points, the body condition score, body composition, glomerular filtration rate, serum concentration of SDMA and creatinine were analyzed. In the control group, the within-subject coefficient of variation, between-subject coefficient of variation, reference change value (type I error = 5%) and index of individuality were 0.16, 0.22, 0.43 and 0.73, respectively. The control group and weight-change group did not differ significantly in SDMA concentration. SDMA showed a significant negative association (coefficient = -0.07) with body fat percentage (p<0.01) in the weight-change group and a significant positive association (coefficient = 7.79) with serum creatinine (p<0.01) in the entire study population. In conclusion, SDMA concentration has high long-term stability in healthy adult dogs. For the evaluation of SDMA concentrations, subject-specific reference values are preferred over a population-based reference value seen their higher sensitivity. Moreover, an increased body fat percentage does seem to affect the serum SDMA concentration of otherwise healthy dogs, but its clinical relevance has to be clarified in further research.

Longitudinal Reproducibility of Neurite Orientation Dispersion and Density Imaging (NODDI) Derived Metrics in the White Matter

Diffusion-weighted magnetic resonance imaging (DWI) is undergoing constant evolution with the ambitious goal of developing in-vivo histology of the brain. A recent methodological advancement is Neurite Orientation Dispersion and Density Imaging (NODDI), a histologically validated multi-compartment model to yield microstructural features of brain tissue such as geometric complexity and neurite packing density, which are especially useful in imaging the white matter. Since NODDI is increasingly popular in clinical research and fields such as developmental neuroscience and neuroplasticity, it is of vast importance to characterize its reproducibility (or reliability). We acquired multi-shell DWI data in 29 healthy young subjects twice over a rescan interval of 4 weeks to assess the within-subject coefficient of variation (CVWS), between-subject coefficient of variation (CVBS) and the intraclass correlation coefficient (ICC), respectively. Using these metrics, we compared regional and voxel-by-voxel reproducibility of the most common image analysis approaches (tract-based spatial statistics [TBSS], voxel-based analysis with different extents of smoothing [“VBM-style”], ROI-based analysis). We observed high test–retest reproducibility for the orientation dispersion index (ODI) and slightly worse results for the neurite density index (NDI). Our findings also suggest that the choice of analysis approach might have significant consequences for the results of a study. Collectively, the voxel-based approach with Gaussian smoothing kernels of ≥4 mm FWHM and ROI-averaging yielded the highest reproducibility across NDI and ODI maps (CVWS mostly ≤3%, ICC mostly ≥0.8), respectively, whilst smaller kernels and TBSS performed consistently worse. Furthermore, we demonstrate that image quality (signal-to-noise ratio [SNR]) is an important determinant of NODDI metric reproducibility. We discuss the implications of these results for longitudinal and cross-sectional research designs commonly employed in the neuroimaging field.

Longitudinal Reproducibility of MR Perfusion Using 3D Pseudocontinuous Arterial Spin Labeling With Hadamard-Encoded Multiple Postlabeling Delays.

Arterial spin labeling (ASL) can be confounded by varying arterial transit times (ATT) across the brain and with disease. Hadamard encoding schemes can be applied to 3D pseudocontinuous ASL (pCASL) to acquire ASL data with multiple postlabeling delays (PLDs) to estimate ATT and then correct cerebral blood flow (CBF). To assess the longitudinal reproducibility of 3D pCASL with Hadamard-encoded multiple PLDs. Prospective, longitudinal. Fifty-two healthy, right-handed male subjects who underwent imaging at four timepoints over 45 days. A Hadamard-encoded 3D pCASL sequence was acquired at 3.0T with seven PLDs from 1.0-3.7 sec. ATT and corrected CBF (cCBF) were computed. Conventional uncorrected CBF (unCBF) was also estimated. Within- and between-subject coefficient of variation (wCV and bCV, respectively) and intraclass correlation coefficient (ICC) were evaluated across four time intervals: 7, 14, 30, and 45 days, in gray matter and 17 independent regions of interest (ROIs). A power analysis was also conducted. A repeated-measures analysis of variance (ANOVA) was used to compare ATT, cCBF, and unCBF across the four scan sessions. A paired two-sample t-test was used to compare cCBF and unCBF. Pearson's correlation was used to examine the relationship between the cCBF and unCBF difference and ATT. Power calculations were completed using both the cCBF and unCBF variances. ATT showed the lowest wCV and bCV (3.3-4.4% and 6.0-6.3%, respectively) compared to both cCBF (10.5-11.7% and 20.6-22.2%, respectively) and unCBF (12.0-13.6% and 22.7-23.7%, respectively). wCV and bCV were lower for cCBF vs. unCBF. A significant difference between cCBF and unCBF was found in most regions (P = 5.5 × 10-5 -3.8 × 10-4 in gray matter) that was highly correlated with ATT (R2 = 0.79-0.86). A power analysis yielded acceptable power at feasible sample sizes using cCBF. ATT and ATT-corrected CBF were longitudinally stable, indicating that ATT and CBF changes can be reliably evaluated with Hadamard-encoded 3D pCASL with multiple PLDs. 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1846-1853.

Organized Chaos in Late Specialization Team Sports: Weekly Training Loads of Elite Adolescent Rugby Union Players.

Phibbs, PJ, Jones, B, Roe, G, Read, DB, Darrall-Jones, J, Weakley, J, Rock, A, and Till, K. Organized chaos in late specialization team sports: weekly training loads of elite adolescent rugby union players. J Strength Cond Res 32(5): 1316-1323, 2018-The aim of this study was to quantify the mean weekly training load (TL) of elite adolescent rugby union players participating in multiple teams and examine the differences between playing positions. Twenty elite male adolescent rugby union players (17.4 ± 0.7 years) were recruited from a regional academy and categorized by playing position: forwards (n = 10) and backs (n = 10). Global positioning system and accelerometer microtechnology was used to quantify external TL, and session rating of perceived exertion (sRPE) was used to quantify internal TL during all sessions throughout a 10-week in-season period. A total of 97 complete observations (5 ± 3 weeks per participant) were analyzed, and differences between positions were assessed using Cohen's d effect sizes (ES) and magnitude-based inferences. Mean weekly sRPE was 1,217 ± 364 arbitrary units (AU) (between-subject coefficient of variation [CV] = 30%), with a total distance (TD) of 11,629 ± 3,445 m (CV = 30%), and PlayerLoad (PL) of 1,124 ± 330 AU (CV = 29%). Within-subject CV ranged between 5 and 78% for sRPE, 24 and 82% for TD, and 19 and 84% for PL. Mean TD (13,063 ± 3,933 vs. 10,195 ± 2,242 m) and PL (1,246 ± 345 vs. 1,002 ± 279 AU) were both likely greater for backs compared with forwards (moderate ES); however, differences in sRPE were unclear (small ES). Although mean internal TLs and volumes were low, external TLs were higher than previously reported during preseason and in-season periods in senior professional players. Additionally, the large between-subject and within-subject variation in weekly TL suggests that players participate in a chaotic training system.

Evaluation of between-, within- and day-to-day variation of coagulation measured by rotational thrombelastometry (ROTEM)

Background and aims: The aim of this study was to assess the circadian variation and the between- and within-subject variation in 10 healthy subjects over a period of 8 weeks by ROTEM®. We further evaluated the influence of elevated body mass index and the effect of low molecular weight heparin and antithrombin on clot formation.Methods: Citrated blood samples were analysed in the NATEM® test system. The clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF) and the maximum lysis (ML) were assessed.Results: Duplicate measurements showed that 23% of the CT and 31% of the CFT measurements had a coefficient of variation (CV) greater than 10%. The within-subject CV was 16% for the CT and 30% for the CFT. The MCF was fairly constant (6%), whereas ML showed more variation (18%). The between-subject CV was 6% for the CT and 20% for the CFT. Analytical variability was improved by summing up CT and CFT. Compared to morning values, CT, CFT and the sum of CT + CFT were shortened in the afternoon. High body mass index was associated with faster clotting. High concentrations of antithrombin had similar effects on clot formation as 0.2 IU/ml of enoxaparin.Conclusions: To overcome the influence of diurnal variation, we recommend obtaining blood samples at specified times in the morning. The within-subject variation should be taken into account, when serial measurements of drug effects are required.

Test-retest reproducibility of quantitative binding measures of [11C]Ro15-4513, a PET ligand for GABAA receptors containing alpha5 subunits

IntroductionAlteration of γ-aminobutyric acid “A” (GABAA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. [11C]Ro15-4513 is a PET ligand with high affinity for α5-subunit-containing GABAA receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of [11C]Ro15-4513 binding derived from six different quantification methods (12 variants). MethodsFive healthy males (median age 40 years, range 38–49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11–30 days), after injection of a median dose of 441 MegaBequerels of [11C]Ro15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans.We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs – regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan’s graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs – voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997).To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus. ResultsTwo of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8–11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75–0.90) for voxelwise SA, 0.71 (0.64–0.84) for regional SRTM-cerebellum and 0.83 (0.70–0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum. ConclusionQuantification of [11C]Ro15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the α5 subunit-rich hippocampus is particularly reliable. The very low expression of the α5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial α1 subunit density in this region may hamper the application of reference tissue methods.

Reproducibility of diffusion tensor imaging in normal subjects: an evaluation of different gradient sampling schemes and registration algorithm

Diffusion tensor imaging (DTI) is very useful for investigating white matter integrity in ageing and neurological disorders; thus, evaluating its reproducibility under different acquisition protocols and analysis methods may assist in the design of clinical studies. To measure the reproducibility of DTI in normal subjects, this study include (1) depicting the reproducibility of DTI measurements in commonly used regions-of-interest analysis by intraclass correlation coefficient (ICC) and coefficient of variation (CV), (2) evaluating and comparing inter and intrasession test-retest reproducibility, and (3) illustrating the effect of the number of diffusion-encoding directions (NDED) and registration algorithms on measurement reproducibility. DTI measurements exhibit high reproducibility, with overall (430/480) ICC ≥ 0.70, (478/480) within-subject CV (CVws) ≤10.00 % and between-subject CV (CVbs) ranging from 1.32 to 13.63 %. Repeated measures ANOVAs and paired t tests were conducted to compare inter and intrasession reproducibility with different diffusion sampling schemes and registration algorithms. Our results also confirmed that increasing the NDED could improve the accuracy and reproducibility of DTI measurements. In addition, we compared reproducibility indices that were derived using different registration algorithms, and a tensor-based deformable registration yielded the most reproducible results. Finally, we found that increasing the NDED could reduce the difference between the reproducibility of measurement derived using different registration algorithms and between the reproducibility of intersession and intrasession. Our results suggest that the choice of DTI acquisition protocol and post-processing methods can influence the accurate estimation and reproducibility of DTI measurements and should be considered carefully for clinical applications.

Population pharmacokinetic analysis of abiraterone acetate in healthy volunteers and chemotherapy-naive and chemotherapy-pretreated metastatic castration-resistant prostate cancer patients.

58 Background: Abiraterone acetate (AA) is an effective therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). AA is metabolized to abiraterone, an androgen biosynthesis inhibitor. We performed population pharmacokinetic (PK) analyses to estimate PK parameters after a 1,000 mg/d oral dose of AA in patients with mCRPC with and without prior chemotherapy and after a one-time 1,000 mg dose in healthy volunteers, to determine consistency between groups. Methods: Studies included in analysis: COU-AA-302 (pre-chemotherapy mCRPC); COU-AA-301 and COU-AA-006 (post-docetaxel mCRPC); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 360 subjects were analyzed using nonlinear mixed-effects modeling. Results: A two-compartment model with three-transit compartments following sequential zero-first order kinetics was used to characterize the systemic absorption of abiraterone. Absorption-related parameters were affected by food intake. Abiraterone PK was characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1505 L/h) compared with healthy subjects (2240 L/h), and by large apparent central (5630 L) and peripheral volumes of distribution (17,400 L). PK of abiraterone was similar in chemotherapy-naïve and chemotherapy-pretreated patients and was characterized by a relatively high between- and within-subject variability (eg, between-subject coefficient of variation [CV%] for relative bioavailability in the clinical studies was 61.1% and the CV% for within-subject variability was 71.3%). No factors other than food intake and patient-healthy volunteer status impacted PK. Conclusions: Based on this population PK model, the recommended 1,000 mg/d dose of AA results in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy status. The food effect on absorption-related parameters in this analysis confirms current dosing instructions for AA. Clinical trial information: NCT00638690, NCT00887198.

Cardiac Repolarization With Gabapentin Enacarbil in a Randomized, Double-Blind, Placebo- and Active-Controlled, Crossover Thorough QT/QTc Study in Healthy Adults

BackgroundGabapentin enacarbil (GEn) is a prodrug of gabapentin and is approved in the United States in adults for the management of postherpetic neuralgia and in the United States and Japan for the treatment of moderate-to-severe primary restless legs syndrome. ObjectiveThis study examined the lack of effect of GEn on cardiac repolarization in accordance with International Conference on Harmonisation E14 guidance. MethodsThis was a randomized, double-blind, double-dummy, placebo- and active- controlled, crossover study in healthy adults (age range, 18–50 years). Study participants received the following in randomized order with a minimum 7-day washout period between treatments: placebo at 0 hours and GEn 1200 mg at 2 hours (GEn 1200 mg group), placebo at 0 hours and GEn 6000 mg at 2 hours (GEn 6000 mg group), placebo at 0 and 2 hours (placebo group), moxifloxacin 400 mg (active control group) at 0 hours, and placebo at 2 hours (moxifloxacin group). Dose offsetting permitted moxifloxacin to be administered in the fasted state and GEn to be administered in the fed state. Assessments included continuous ECG monitoring, pharmacokinetic parameters, and safety and tolerability profiles. The primary end point was the change from baseline in the Fridericia corrected QT interval, at each time point, for the GEn 6000 mg and placebo groups. ResultsOf 52 adults enrolled (mean [SD] age, 30.8 [8.55] years; 50% women), 44 adults (85%) completed the study. Forty-nine adults received GEn 1200 mg, 47 received GEn 6000 mg, 48 received placebo, and 47 received moxifloxacin. The highest estimated (upper limit of the 95% CI) model-adjusted difference in mean change from baseline in the Fridericia corrected QT interval between GEn and placebo was 3.55 (5.66) msec for 1200 mg and 1.20 (3.32) msec for 6000 mg. Assay sensitivity was confirmed with moxifloxacin 400 mg. The geometric mean (%CV) Cmax (between-subject coefficient of variation) was 7.49 (21.2) μg/mL for GEn 1200 mg, 32.46 (23.9) μg/mL for GEn 6000 mg, and 2.08 (24.5) μg/mL for moxifloxacin 400 mg. The most frequently reported adverse events with GEn 6000 mg were dizziness (30%), feeling drunk (26%), nausea (15%), headache (13%), and vomiting (13%). ConclusionSingle doses of GEn, up to 6000 mg, had no effect on cardiac repolarization in this thorough-QT study and are unlikely to cause clinically relevant QT prolongation in clinical use. Assay sensitivity was confirmed with moxifloxacin as an active control. ClinicalTrials.gov identifier: NCT01516372.

Resting metabolic rate in old-old women with and without frailty: variability and estimation of energy requirements.

To measure resting metabolic rate (RMR) in old-old adults living in the community and examine the association between measured RMR and frailty status and compare it with expected RMR generated by a predictive equation. Physiological substudy conducted as a home visit within an observational cohort study. Baltimore City and County, Maryland. Seventy-seven women aged 83 to 93 enrolled in the Women's Health and Aging Study II. Resting metabolic rate with indirect calorimetry, frailty status, fat-free mass, ambient and body temperature, expected RMR according to the Mifflin-St. Jeor equation. Average RMR was 1,119 ± 205 kcal/d (range 595-1,560 kcal/d). Agreement between observed and expected RMR was biased and poor (between-subject coefficient of variation 38.0%, 95% confidence interval = 35.1-40.8). Variability of RMR was greater in frail individuals (heteroscedasticity F-test P = .02). Low and high RMR were associated with being frail (odds ratio 5.4, P = .04) and slower self-selected walking speed (P < .001) after adjustment for covariates. Equations to predict RMR that are not validated in old-old adults appear to correlate poorly with measured RMR. RMR is highly variable in old-old women, with deviations from the mean predicting clinical frailty. These exploratory findings suggest a pathway to clinical frailty through high or low RMR.

Reproducibility and seasonal variation of ambulatory short-term heart rate variability in healthy subjects during a self-selected rest period and during sleep

Although ambulatory measurements of heart rate variability (HRV) are widely used, the reproducibility and seasonal variation of ambulatory sampled short-term HRV measurements in healthy participants has not been investigated before. In the present study we collected ambulatory ECGs from 19 healthy participants monthly for 12 months, and for a sub-group of 12 participants weekly for one month. Frequency-domain HRV-metrics were calculated for 5 min ECG segments during (i) a 15-min self-selected rest period (awake period), and (ii) a 30-min sleep period starting 45 min after estimated sleep onset. Total, within- and between-subject coefficient of variation (CV) and seasonal variation were estimated for ln (TP), ln (LFP), ln (HFP), ln (LF/HF), LFnu, HFnu, the mean heart period and the ECG derived respiratory frequency. The within- and between-subject CV varied considerably between different variables, from < 10% for ln (TP) and ln (LFP) to >100% for ln (LF/HF). Within- and between-subject CV of ln (HFP), LFnu and HFnu were 10-40%. A weak, but significant, seasonal variation was found for ln (TP) (p = 0.05), ln (LFP) (p<0.05) and the respiratory frequency (p<0.01), but the seasonal variation did not affect the within-subject CV. Furthermore, sample size calculations demonstrated that the reproducibility was sufficient for ambulatory HRV measurements to be used to study autonomic cardiac regulation in healthy populations.

Test–retest stability of cerebral A1 adenosine receptor quantification using [18F]CPFPX and PET

The goal of the present study was to evaluate the reproducibility of cerebral A1 adenosine receptor (A1AR) quantification using [18F]CPFPX and PET in a test-retest design. Eleven healthy volunteers were studied twice. Eight brain regions ranging from high to low receptor binding were examined. [18F]CPFPX was injected as a bolus with subsequent infusion over 120 min. Various outcome parameters were compared based on either metabolite-corrected venous blood sampling [e.g. apparent equilibrium total distribution volume (DVt')] or a reference region [ratio of specific to non-specific distribution volume (BP2)]. Test-retest variability was low in the outcome measure BP2 (on average 5.9%) and moderate in DVt' (on average 13.2%). Regarding reproducibility, the outcome parameter BP2 showed an intra-class correlation coefficient (ICC) of 0.94 +/- 0.1. For DVt' the between-subject coefficient of variation (%CV) was similar to the within-subject %CV (around 10%), resulting in a poor ICC of 0.06 +/- 0.2. Our results suggest that quantification of [18F]CPFPX imaging is reproducible and reliable for PET studies of the cerebral A1AR. Among the outcome parameters the non-invasive measures were of superior test-retest stability over the invasive.

Pharmacokinetic–pharmacodynamic modelling of QT interval prolongation following citalopram overdoses

To develop a pharmacokinetic-pharmacodynamic model describing the time-course of QT interval prolongation after citalopram overdose and to evaluate the effect of charcoal on the relative risk of developing abnormal QT and heart-rate combinations. Plasma concentrations and electrocardiograph (ECG) data from 52 patients after 62 citalopram overdose events were analysed in WinBUGS using a Bayesian approach. The reported doses ranged from 20 to 1700 mg and on 17 of the events a single dose of activated charcoal was administered. The developed pharmacokinetic-pharmacodynamic model was used for predicting the probability of having abnormal combinations of QT-RR, which was assumed to be related to an increased risk for torsade de pointes (TdP). The absolute QT interval was related to the observed heart rate with an estimated individual heart-rate correction factor [alpha = 0.36, between-subject coefficient of variation (CV) = 29%]. The heart-rate corrected QT interval was linearly dependent on the predicted citalopram concentration (slope = 40 ms l mg(-1), between-subject CV = 70%) in a hypothetical effect-compartment (half-life of effect-delay = 1.4 h). The heart-rate corrected QT was predicted to be higher in women than in men and to increase with age. Administration of activated charcoal resulted in a pronounced reduction of the QT prolongation and was shown to reduce the risk of having abnormal combinations of QT-RR by approximately 60% for citalopram doses above 600 mg. Citalopram caused a delayed lengthening of the QT interval. Administration of activated charcoal was shown to reduce the risk that the QT interval exceeds a previously defined threshold and therefore is expected to reduce the risk of TdP.

Bicompartmental kinetics of tobramycin analysed with a wide range of covariates

The pharmacokinetics of tobramycin was studied in adult patients ( N = 151) admitted either for initial suspicion of Gram-negative infection or for prophylaxis. In addition to age, weight, height and creatinine clearance (CrCL), a range of other covariates were also analysed, including type of pathology, co-medication, fever, sex and ethnicity (Basque or not). All patients received 100 mg tobramycin every 8 h and samples were collected at three time points after the first dose and at two time points after the fourth dose and assayed with a fluorescence polarisation immunoassay. The population mixed effects bicompartmental parameters were obtained from 725 concentration measurements using NONMEM, FOCE method, and were: systemic clearance, CL = 6.03 L/h (between-subject coefficient of variation (CV) %, 29.4%); volume of distribution, V = 15.04 L (7.3%); and intercompartmental constants, k 12 = 0.192 h −1 (56%) and k 21 = 0.55 h −1 (no CV% determined). Covariate modelling was performed within NONMEM. Two alternative significant covariate models (Models 1 and 2) are proposed, with functions of CrCL and/or sex (Model 2). However, for clinical purposes, differentiation by sex is insignificant. Model 1 is for CL = 3.1 + 0.05·CrCL L/h (17.3%); V = 14.6 L (12%); k 12 = 0.224 h −1 (63%) and k 21 = 0.468 h −1. Stochastic simulation was used to predict the expected concentration 95th percentiles after the recommended 7 mg/kg dose and for minimum inhibitory concentration (MIC) = 1 mg/L, as well as alternative once-daily dosing regimens for MIC = 2 mg/L. It is seen that once-daily high-dose tobramycin is an appropriate strategy with respect to pharmacodynamic indices, C peak/MIC or AUC/MIC (where C peak is the peak plasma concentration and AUC is the area under the concentration–time curve).

A survey to determine the blood concentration of cyclosporine 2 hours postdose in stable renal transplant patients

The current method for monitoring cyclosporine measures predose concentrations (C 0). A better method has been developed, namely, measurement of the blood cyclosporine concentration at 2 hours postdose (C 2). The aim of this survey was to determine the variability of C 0 and C 2 concentrations among stable renal transplant patients. One hundred two stable renal transplant patients who were at least 6 months posttransplant were recruited from the renal transplant outpatient clinic. The cyclosporine dose was between 100 and 500 mg daily; all patients had been monitored using C 0 concentrations. Blood samples for cyclosporine concentration measurements were taken at both C 0 and C 2 at two consecutive clinic visits. The within- and between-patient variabilities were calculated using nested analysis of variance. The mean age was 50 years (21 to 81); the mean weight was 75 kg. The mean cyclosporine dose was 3.18 mg/kg/d (1.2 to 8.8). The average serum creatinine was 174 μmol/L (77 to 626) and the average cholesterol was 5 μmol/L (3 to 9). The mean (±SD) C 0 concentration was 150 (47.31) μg/L and C 2 = 895 (239) μg/L. The C 0 concentration varied over 16-fold between patients compared to a sevenfold variation in C 2. The between-subject coefficient of variation (CV) was 35% for C 0 and 30% for C 2 and the within subject CV was 23% for C 0 and 20% for C 2. The results suggest that cyclosporine concentrations at C 0 are slightly more variable than those at C 2. Whether this modest reduction in variability results in better patient outcomes is the subject of the next phase of this study.