Influence of Participant Perceptions of Adherence-Related Interactions with Study/Study Team on Drug Levels: HPTN069 Analysis of Self-Reported Adherence Experiences While on Study.

Adherence to HIV pre-exposure prophylaxis (PrEP) study drug is critical for safety, tolerability, and efficacy trials, and may be affected by how adherence is communicated by the study staff to trial participants. Increasingly, clinical trials investigating PrEP are creating and implementing 'participant-centered' approaches that discuss potential non-adherence neutrally (without negative judgement) and support efforts to adhere versus insisting on perfect adherence. In the HPTN069/ACTG A5305 study, we evaluated participant experiences of potentially negative adherence-related interactions with study teams using ten items to characterize the frequency of such experiences. We related these individual items and a combined set of seven negative experience items (total negative experience score) to drug concentrations (detectable or consistent with daily-dosing). The exploratory analyses used logistic regression for each experience item on the full sample and disaggregated by sex. Several experiences were related to drug detection and to daily-dosing, although more so for participants identifying as men than women. Total negative experience scores associated with not having detection drug concentrations for the full sample, and remained significant even when controlling for sex, age, and race. Daily dosing was associated with total negative experience score for men in the sample. Additional investigations into adherence-related interactions with study teams that are most problematic or helpful in general and uniquely for men and women are warranted.

Safety and pharmacokinetics of XOMA 3AB, a novel mixture of three monoclonal antibodies against botulinum toxin A.

Botulinum neurotoxin A is a category A bioterrorism agent. Current antitoxin therapies are scarce and produce adverse reactions. XOMA 3AB consists of 3 IgG1 monoclonal antibodies (MAbs), each with a distinct human or humanized variable region, which bind to distinct epitopes on botulinum neurotoxin serotype A. This first-in-human study evaluated the safety and pharmacokinetics (PK) of escalating doses of XOMA 3AB administered intravenously (i.v.) to healthy adults. In this double-blind placebo-controlled dose escalation study, 3 cohorts of 8 healthy subjects received a single intravenous dose of XOMA 3AB or placebo at a 3:1 ratio. Follow-up examinations included physical examinations, hematology and chemistry blood tests, electrocardiograms, and pharmacokinetics. Pharmacokinetic parameters were estimated using noncompartmental methods. There were no infusion discontinuations or hypersensitivity reactions. Two or more subjects experienced headache, hyperglycemia, or anemia; none was dose related. All adverse events (AEs) were mild to moderate except for an episode of exercise-induced elevation of a subject's creatine phosphokinase (CPK) level, unrelated to XOMA 3AB. Concentration-time plots demonstrated a peak in MAb concentrations 1 to 2 h after completion of the infusion, after which the levels declined in a biexponential decay pattern for all analytes. For each MAb, the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve from 0 to infinity (AUCinf) increased as the dose increased. Clearance of the humanized mouse MAb was more rapid than that of the two fully human MAbs, particularly at the lowest dose. None of the MAbs was immunogenic. At the doses administered, XOMA 3AB was well tolerated. These safety findings support further investigation of XOMA 3AB as a potential agent for botulism treatment and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01357213.).

Protein-free efavirenz concentrations in cerebrospinal fluid and blood plasma are equivalent: applying the law of mass action to predict protein-free drug concentration.

Efavirenz (EFV) is one of the most commonly prescribed antiretroviral drugs (ARVs) for the treatment of HIV. Highly protein-bound drugs, like EFV, have limited central nervous system (CNS) penetration when measured using total drug concentration gradients between blood plasma (BP) and cerebrospinal fluid (CSF). However, the more relevant pharmacologically active protein-free drug concentrations are rarely assessed directly in clinical studies. Using paired BP and CSF samples obtained from 13 subjects on an EFV-containing regimen, both the protein-free and total concentrations of EFV were determined. Despite a median (interquartile range [IQR]) total EFV BP/CSF concentration ratio of 134 (116 to 198), the protein-free EFV BP/CSF concentration ratio was 1.20 (0.97 to 2.12). EFV median (IQR) protein binding was 99.78% (99.74 to 99.80%) in BP and 76.19% (74.47 to 77.15%) in CSF. In addition, using the law of mass action and an in vitro-derived EFV-human serum albumin dissociation constant, we have demonstrated that the predicted median (IQR) protein-free concentration in BP, 4.59 ng/ml (4.02 to 9.44 ng/ml), compared well to that observed in BP, 4.77 ng/ml (3.68 to 6.75 ng/ml). Similar results were also observed in CSF and seminal plasma. This method provides a useful predictive tool for estimating protein binding in varied anatomic compartments. Our results of equivalent protein-free EFV concentrations in BP and CSF do not support prior concerns of the CNS as a pharmacological sanctuary from EFV. As CSF penetration of ARVs may increase our understanding of HIV-associated neurological dysfunction and antiretroviral effect, assessment of protein-free CSF concentrations of other highly protein-bound ARVs is warranted.

The effects of creatine monohydrate loading on anaerobic performance and one-repetition maximum strength.

The purpose of this study was to examine the effects of 7 days of supplementation with 20 g·d⁻¹ of creatine monohydrate (CM) on mean power (MP) and peak power (PP) from the Wingate anaerobic test (WAnT), body weight (BW), 1-repetition maximum (1RM) bilateral leg extension (LE) strength, and 1RM bench press (BP) strength. This study used a randomized, double-blind, placebo-controlled design. Twenty-two men (mean ± SD: age = 22.1 ± 2.0 years; height = 178.0 ± 5.8 cm; body weight [BW] = 77.6 ± 7.6 kg) were randomly assigned to either a supplement (SUPP; n = 10) or placebo (PLAC; n = 12) group. The SUPP group ingested 20 g·d⁻¹ of CM powder for 7 days, whereas the PLAC ingested 20 g·d⁻¹ of maltodextrin powder. Measurements for the PLAC and SUPP groups included BW, PP, and MP from two 30-second WAnTs (separated by 7 minutes), and 1RM strength for LE and BP. Testing was conducted before (PRE) and after (POST) 7 days of ingesting either the supplement or placebo. The results of this study indicated that there was a significant (p ≤ 0.05) increase from PRE to POST testing in MP for the SUPP group (5.4%) but not for the PLAC group (-0.3%). There were no between-group differences, however, for 1RM LE and 1RM BP strength. Furthermore, there were no changes in PP or BW for either group. The findings of this study indicated that loading with 20 g·d⁻¹ of CM for 7 days increased MP (5.4% increase) from the WAnT, but it had no effect on strength (1RM LE and 1RM BP), PP, or BW.

Gender comparisons of anthropometric characteristics of young sprint swimmers.

The purpose of this study was to compare the body composition, body build, and anthropometric characteristics of boy and girl sprint swimmers. Two groups (boys, n = 38 and girls, n = 31) of sprint swimmers (mean age ± SD = 11.03 ± 2.29 and 10.45 ± 2.29 years, respectively) volunteered for this study. The subjects were members of local swimming clubs who competed in sprint swimming events (≤ 200 m). Gender comparisons were made for age, body weight (BW), height (HT), fat-free weight (FFW), percent body fat (%fat), endomorphic rating, mesomorphic rating, ectomorphic rating, sum of 12 diameters, sum of 11 circumferences, biacromial diameter/biiliac diameter, and FFW/HT. The results of the independent t-tests indicated that the only mean differences between the boy and girl sprint swimmers were for % fat (boys = 9.40 ± 5.35% fat; girls = 12.73 ± 6.19% fat) and endomorphic rating (boys = 2.87 ± 0.96; girls = 4.29 ± 1.22). For the current age group of sprint swimmers the only gender differences were for measures associated with body fatness, and there were no differences for body build measures associated with musculoskeletal size, muscularity, skeletal size, total body mass, or body breadth dimensions. These findings suggest that the swimming performance for girls may be improved through training programs designed to reduce body fatness.

Yearly changes in the anthropometric dimensions of female high school gymnasts.

The purpose of the present study was to compare the age-related patterns of anthropometric dimensions of female high school gymnasts to those of a national representative sample of teenage girls. One hundred and one female high school gymnasts (X ± SD age = 15.8 ± 1.1 year; height [HT] = 162.2 ± 5.7 cm; body weight [BW] = 54.1 ± 6.5 kg) volunteered as subjects in the present study. The sample was divided into 4 independent age groups: age group 14 (AG14) = 14.00 to 14.99 years (n = 26); AG15 = 15.00 to 15.99 years (n = 27); AG16 = 16.00 to 16.99 years (n = 29); and AG17 = 17.00 to 17.99 years (n = 19). Nine variables including BW; HT; body mass index (BMI); subscapular and triceps skinfolds; and waist, mid-arm, maximal calf, and mid-thigh circumferences were assessed on each subject. Independent t-tests indicated that for all age groups, the female high school gymnasts exhibited lower BW, BMI, circumferences (waist, mid-arm, maximal calf, and mid-thigh) and skinfolds (subscapular and triceps) than the national sample, except AG 17 for BW and maximal calf and mid-thigh circumferences. There were no significant differences in HT between samples for any of the age groups. Furthermore, there were no differences between the high school gymnasts and the national sample for the slope coefficients for the anthropometric dimensions vs. age relationships. These findings indicated that in females, participation in high school gymnastics does not adversely affect yearly changes in anthropometric dimensions.

A test for determining critical heart rate using the critical power model.

The purposes of this study were to (a) determine if the mathematical model that has previously been used to estimate the critical power (CP) was applicable to heart rate (HR) to estimate the critical heart rate (CHR), and (b) compare the CHR to the HR values at the CP (CP(HR)), ventilatory threshold (VT(HR)), and respiratory compensation point (RCP(HR)). Fifteen women (mean age ± SD = 21.7 ± 2.1 years) performed an incremental test to exhaustion to determine VO2peak, VT(HR), and RCP(HR). The subjects also performed 4 exhaustive workbouts at different power outputs for the determination of CP and CHR. For each power output, the total number of heart beats (HB(lim)) was calculated as the product of the average 5-second HR (bpm) and total time to exhaustion (T(lim) in minutes). The HB(lim) and total work (W(lim) in kilograms-meters) were plotted as a function of the T(lim) at each power output, and the slope coefficients of the regression lines between HB(lim) or W(lim) and T(lim) were defined as the CHR and CP, respectively. A 1-way repeated-measures analysis of variance (ANOVA) indicated that CHR (172 ± 11 bpm, 92.9 ± 2.7%HRmax) was similar to RCP(HR) (172 ± 9 bpm, 92.9 ± 2.2%HRmax) but was higher (p < 0.05) than CP(HR) (154 ± 10 bpm, 83.2 ± 4.0%HRmax) and VT(HR) (152 ± 12 bpm, 82.1 ± 4.3%HRmax). The relationship between HR and T(lim) from the CHR test can be described by the CP model. The CHR test may be a practical method for estimating RCP without the need to measure expired gas samples. Furthermore, like the RCP, the CHR test may be used to demarcate the heavy from severe exercise intensity domains, predict endurance exercise performance, and prescribe a training intensity for competitive cyclists.

An EMG frequency-based test for estimating the neuromuscular fatigue threshold during cycle ergometry.

The purposes of this investigation were twofold: (1) to determine if the model used for estimating the physical working capacity at the fatigue threshold (PWC(FT)) from electromyographic (EMG) amplitude data could be applied to the frequency domain of the signal to derive a new fatigue threshold for cycle ergometry called the mean power frequency fatigue threshold (MPF(FT)), and (2) to compare the power outputs associated with the PWC(FT), MPF(FT), ventilatory threshold (VT), and respiratory compensation point (RCP). Sixteen men [mean (SD) age = 23.4 (3.2) years] performed incremental cycle ergometer rides to exhaustion with bipolar surface EMG signals recorded from the vastus lateralis. There were significant (p < 0.05) mean differences for PWC(FT) [mean (SD) = 168 (36) W] versus MPF(FT) [208 (37) W] and VT [152 (33) W] versus RCP [205 (84) W], but no mean differences for PWC(FT) versus VT or MPF(FT) versus RCP. The mean difference between PWC(FT) and MPF(FT) may be due to the effects of specific metabolites that independently influence the time and frequency domains of the EMG signal. These findings indicated that the PWC(FT) model could be applied to the frequency domain of the EMG signal to estimate MPF(FT). Furthermore, the current findings suggested that the PWC(FT) may demarcate the moderate from heavy exercise domains, while the MPF(FT) demarcates heavy from severe exercise intensities.

A mechanomyographic fatigue threshold test for cycling.

The purposes of this study were twofold: 1) to derive the mechanomyographic mean power frequency fatigue threshold (MMG MPFFT) for submaximal cycle ergometry; and 2) to compare the power outputs associated to the MMG MPFFT to other neuromuscular and gas exchange fatigue thresholds. 9 adults (5 men and 4 women; mean+/-SD age=23.7+/-3.7 years; body weight=66.3+/-8.2 kg) performed an incremental cycle ergometry test to exhaustion while expired gas samples, electromyographic (EMG), and MMG signals were measured from the vastus lateralis muscle. The non-significant correlations (r=0.17 to 0.66; p>0.05) among the physical working capacity at the fatigue threshold (PWCFT), MMG MPFFT, and gas exchange threshold (GET) suggested that different physiological mechanisms may underlie these 3 fatigue thresholds. A significant correlation (r=0.83) for the MPFFT vs. respiratory compensation point (RCP) suggested that these fatigue thresholds may be mediated by a common physiological mechanism. In addition, the significantly lower mean values found for the PWCFT (mean+/-SD=163+/-43 W), MMG MPFFT (132+/-33 W), and GET (144+/-28 W) than MPFFT (196+/-53 W) and RCP (202+/-41 W) suggested that these gas exchange and neuromuscular fatigue thresholds may demarcate different exercise intensity domains.

Influences of body-size variables on age-related increases in isokinetic peak torque in young wrestlers.

The purposes of the present study were to determine the patterns of age-related changes in 1) height (HT), body weight (BW), fat-free weight (FFW), and absolute isokinetic peak torque (PT); and 2) isokinetic PT covaried separately for HT, BW, FFW, and HT and BW combined in young wrestlers. One hundred twenty-five male wrestlers (mean age +/- SD = 14.3 +/- 2.4 yr; range = 11.1-18.2 yr) volunteered to perform concentric, isokinetic leg extension and flexion at 180 degrees xs-1 on a Cybex II dynamometer to measure PT as well as underwater weighing to determine FFW. The polynomial regression analyses indicated there were significant quadratic increases across age for HT (R = 0.62), BW (R = 0.56), and FFW (R = 0.47). For leg extension, there were significant increases across age for absolute PT (quadratic, R = 0.66), PT covaried for HT (linear, r = 0.10), PT covaried for BW (linear, r = 0.12), PT covaried for FFW (quadratic, R = 0.32), and PT covaried for HT and BW combined (quadratic, R = 0.11). For leg flexion, there were significant increases across age for absolute PT (linear, r = 0.59), PT covaried for HT (linear, r = 0.07), PT covaried for BW (linear, r = 0.08), PT covaried for FFW (quadratic, R = 0.23), and PT covaried for BW and HT combined (linear, r = 0.03). The results of this study indicated that age-related increases in leg-extension and flexion PT for the current sample of young wrestlers could not be accounted for by changes in HT, BW, FFW, or HT and BW combined. These findings suggested that neural maturation may contribute to increases in leg strength across age in young wrestlers.