MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. Objective: MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. Methods and Findings: We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Conclusions: Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. Trial Registration: ClinicalTrials.gov NCT00592124

Reconstructing phylogenies from noisy quartets in polynomial time with a high success probability

<p>Abstract</p> <p>Background</p> <p>In recent years, quartet-based phylogeny reconstruction methods have received considerable attentions in the computational biology community. Traditionally, the accuracy of a phylogeny reconstruction method is measured by simulations on synthetic datasets with known "true" phylogenies, while little theoretical analysis has been done. In this paper, we present a new model-based approach to measuring the accuracy of a quartet-based phylogeny reconstruction method. Under this model, we propose three efficient algorithms to reconstruct the "true" phylogeny with a high success probability.</p> <p>Results</p> <p>The first algorithm can reconstruct the "true" phylogeny from the input quartet topology set without quartet errors in <it>O</it>(<it>n</it>²) time by querying at most (<it>n </it>- 4) log(<it>n </it>- 1) quartet topologies, where <it>n </it>is the number of the taxa. When the input quartet topology set contains errors, the second algorithm can reconstruct the "true" phylogeny with a probability approximately 1 - <it>p </it>in <it>O</it>(<it>n</it>⁴log <it>n</it>) time, where <it>p </it>is the probability for a quartet topology being an error. This probability is improved by the third algorithm to approximately <inline-formula><m:math name="1748-7188-3-1-i1" xmlns:m="http://www.w3.org/1998/Math/MathML"><m:semantics><m:mrow><m:mfrac><m:mn>1</m:mn><m:mrow><m:mn>1</m:mn><m:mo>+</m:mo><m:msup><m:mi>q</m:mi><m:mn>2</m:mn></m:msup><m:mo>+</m:mo><m:mfrac><m:mn>1</m:mn><m:mn>2</m:mn></m:mfrac><m:msup><m:mi>q</m:mi><m:mn>4</m:mn></m:msup><m:mo>+</m:mo><m:mfrac><m:mn>1</m:mn><m:mrow><m:mn>16</m:mn></m:mrow></m:mfrac><m:msup><m:mi>q</m:mi><m:mn>5</m:mn></m:msup></m:mrow></m:mfrac></m:mrow><m:annotation encoding="MathType-MTEF"> MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGacaGaaiaabeqaaeqabiWaaaGcbaqcfa4aaSaaaeaacqaIXaqmaeaacqaIXaqmcqGHRaWkcqWGXbqCdaahaaqabeaacqaIYaGmaaGaey4kaSYaaSaaaeaacqaIXaqmaeaacqaIYaGmaaGaemyCae3aaWbaaeqabaGaeGinaqdaaiabgUcaRmaalaaabaGaeGymaedabaGaeGymaeJaeGOnaydaaiabdghaXnaaCaaabeqaaiabiwda1aaaaaaaaa@3D5A@</m:annotation></m:semantics></m:math></inline-formula>, where <inline-formula><m:math name="1748-7188-3-1-i2" xmlns:m="http://www.w3.org/1998/Math/MathML"><m:semantics><m:mrow><m:mi>q</m:mi><m:mo>=</m:mo><m:mfrac><m:mi>p</m:mi><m:mrow><m:mn>1</m:mn><m:mo>−</m:mo><m:mi>p</m:mi></m:mrow></m:mfrac></m:mrow><m:annotation encoding="MathType-MTEF"> MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGacaGaaiaabeqaaeqabiWaaaGcbaGaemyCaeNaeyypa0tcfa4aaSaaaeaacqWGWbaCaeaacqaIXaqmcqGHsislcqWGWbaCaaaaaa@3391@</m:annotation></m:semantics></m:math></inline-formula>, with running time of <it>O</it>(<it>n</it>⁵), which is at least 0.984 when <it>p </it>< 0.05.</p> <p>Conclusion</p> <p>The three proposed algorithms are mathematically guaranteed to reconstruct the "true" phylogeny with a high success probability. The experimental results showed that the third algorithm produced phylogenies with a higher probability than its aforementioned theoretical lower bound and outperformed some existing phylogeny reconstruction methods in both speed and accuracy.</p

High blood pressure, antihypertensive medication and lung function in a general adult population

<p>Abstract</p> <p>Background</p> <p>Several studies showed that blood pressure and lung function are associated. Additionally, a potential effect of antihypertensive medication, especially beta-blockers, on lung function has been discussed. However, side effects of beta-blockers have been investigated mainly in patients with already reduced lung function. Thus, aim of this analysis is to determine whether hypertension and antihypertensive medication have an adverse effect on lung function in a general adult population.</p> <p>Methods</p> <p>Within the population-based KORA F4 study 1319 adults aged 40-65 years performed lung function tests and blood pressure measurements. Additionally, information on anthropometric measurements, medical history and use of antihypertensive medication was available. Multivariable regression models were applied to study the association between blood pressure, antihypertensive medication and lung function.</p> <p>Results</p> <p>High blood pressure as well as antihypertensive medication were associated with lower forced expiratory volume in one second (p = 0.02 respectively p = 0.05; R²: 0.65) and forced vital capacity values (p = 0.01 respectively p = 0.05, R²: 0.73). Furthermore, a detailed analysis of antihypertensive medication pointed out that only the use of beta-blockers was associated with reduced lung function, whereas other antihypertensive medication had no effect on lung function. The adverse effect of beta-blockers was significant for forced vital capacity (p = 0.04; R²: 0.65), while the association with forced expiratory volume in one second showed a trend toward significance (p = 0.07; R²: 0.73). In the same model high blood pressure was associated with reduced forced vital capacity (p = 0.01) and forced expiratory volume in one second (p = 0.03) values, too.</p> <p>Conclusion</p> <p>Our analysis indicates that both high blood pressure and the use of beta-blockers, but not the use of other antihypertensive medication, are associated with reduced lung function in a general adult population.</p

Visual, Motor and Attentional Influences on Proprioceptive Contributions to Perception of Hand Path Rectilinearity during Reaching

We examined how proprioceptive contributions to perception of hand path straightness are influenced by visual, motor and attentional sources of performance variability during horizontal planar reaching. Subjects held the handle of a robot that constrained goal-directed movements of the hand to the paths of controlled curvature. Subjects attempted to detect the presence of hand path curvature during both active (subject driven) and passive (robot driven) movements that either required active muscle force production or not. Subjects were less able to discriminate curved from straight paths when actively reaching for a target versus when the robot moved their hand through the same curved paths. This effect was especially evident during robot-driven movements requiring concurrent activation of lengthening but not shortening muscles. Subjects were less likely to report curvature and were more variable in reporting when movements appeared straight in a novel “visual channel” condition previously shown to block adaptive updating of motor commands in response to deviations from a straight-line hand path. Similarly, compromised performance was obtained when subjects simultaneously performed a distracting secondary task (key pressing with the contralateral hand). The effects compounded when these last two treatments were combined. It is concluded that environmental, intrinsic and attentional factors all impact the ability to detect deviations from a rectilinear hand path during goal-directed movement by decreasing proprioceptive contributions to limb state estimation. In contrast, response variability increased only in experimental conditions thought to impose additional attentional demands on the observer. Implications of these results for perception and other sensorimotor behaviors are discussed

Use of Self-Selected Postures to Regulate Multi-Joint Stiffness During Unconstrained Tasks

The human motor system is highly redundant, having more kinematic degrees of freedom than necessary to complete a given task. Understanding how kinematic redundancies are utilized in different tasks remains a fundamental question in motor control. One possibility is that they can be used to tune the mechanical properties of a limb to the specific requirements of a task. For example, many tasks such as tool usage compromise arm stability along specific directions. These tasks only can be completed if the nervous system adapts the mechanical properties of the arm such that the arm, coupled to the tool, remains stable. The purpose of this study was to determine if posture selection is a critical component of endpoint stiffness regulation during unconstrained tasks.Three-dimensional (3D) estimates of endpoint stiffness were used to quantify limb mechanics. Most previous studies examining endpoint stiffness adaptation were completed in 2D using constrained postures to maintain a non-redundant mapping between joint angles and hand location. Our hypothesis was that during unconstrained conditions, subjects would select arm postures that matched endpoint stiffness to the functional requirements of the task. The hypothesis was tested during endpoint tracking tasks in which subjects interacted with unstable haptic environments, simulated using a 3D robotic manipulator. We found that arm posture had a significant effect on endpoint tracking accuracy and that subjects selected postures that improved tracking performance. For environments in which arm posture had a large effect on tracking accuracy, the self-selected postures oriented the direction of maximal endpoint stiffness towards the direction of the unstable haptic environment.These results demonstrate how changes in arm posture can have a dramatic effect on task performance and suggest that postural selection is a fundamental mechanism by which kinematic redundancies can be exploited to regulate arm stiffness in unconstrained tasks

In Vivo Dynamics of the Musculoskeletal System Cannot Be Adequately Described Using a Stiffness-Damping-Inertia Model

Background: Visco-elastic properties of the (neuro-)musculoskeletal system play a fundamental role in the control of posture and movement. Often, these properties are described and identified using stiffness-damping-inertia (KBI) models. In such an approach, perturbations are applied to the (neuro-)musculoskeletal system and subsequently KBI-model parameters are optimized to obtain a best fit between simulated and experimentally observed responses. Problems with this approach may arise because a KBI-model neglects critical aspects of the real musculoskeletal system. Methodology/Principal Findings: The purpose of this study was to analyze the relation between the musculoskeletal properties and the stiffness and damping estimated using a KBI-model, to analyze how this relation is affected by the nature of the perturbation and to assess the sensitivity of the estimated stiffness and damping to measurement errors. Our analyses show that the estimated stiffness and damping using KBI-models do not resemble any of the dynamical parameters of the underlying system, not even when the responses are very accurately fitted by the KBI-model. Furthermore, the stiffness and damping depend non-linearly on all the dynamical parameters of the underlying system, influenced by the nature of the perturbation and the time interval over which the KBI-model is optimized. Moreover, our analyses predict a very high sensitivity of estimated parameters to measurement errors. Conclusions/Significance: The results of this study suggest that the usage of stiffness-damping-inertia models t

Equilibrium of Global Amphibian Species Distributions with Climate

A common assumption in bioclimatic envelope modeling is that species distributions are in equilibrium with contemporary climate. A number of studies have measured departures from equilibrium in species distributions in particular regions, but such investigations were never carried out for a complete lineage across its entire distribution. We measure departures of equilibrium with contemporary climate for the distributions of the world amphibian species. Specifically, we fitted bioclimatic envelopes for 5544 species using three presence-only models. We then measured the proportion of the modeled envelope that is currently occupied by the species, as a metric of equilibrium of species distributions with climate. The assumption was that the greater the difference between modeled bioclimatic envelope and the occupied distribution, the greater the likelihood that species distribution would not be at equilibrium with contemporary climate. On average, amphibians occupied 30% to 57% of their potential distributions. Although patterns differed across regions, there were no significant differences among lineages. Species in the Neotropic, Afrotropics, Indo-Malay, and Palaearctic occupied a smaller proportion of their potential distributions than species in the Nearctic, Madagascar, and Australasia. We acknowledge that our models underestimate non equilibrium, and discuss potential reasons for the observed patterns. From a modeling perspective our results support the view that at global scale bioclimatic envelope models might perform similarly across lineages but differently across regions

Long-term social skills group training for children and adolescents with autism spectrum disorder: a randomized controlled trial

Social skills group training (SSGT) is widely used for intellectually able children and adolescents with autism spectrum disorder (ASD). Previous studies indicate small to moderate effects on social communication capacities. The duration of most available programs is relatively short, and extended training might lead to further improvement. This randomized controlled trial compared an extended 24-week version of the SSGT program KONTAKT with standard care. The weekly sessions gradually shifted in content from acquisition of new skills to real-world application of the acquired skills. A total of 50 participants with ASD (15 females; 35 males) aged 8–17 years were included. The study was conducted at two child and adolescent psychiatry outpatient units in Sweden. The primary outcome was the Social Responsiveness Scale–Second Edition (SRS-2) rated by parents and blinded teachers. Secondary outcomes included parent- and teacher-rated adaptive behaviors, trainer-rated global functioning and clinical severity, and self-reported child and caregiver stress. Assessments were made at baseline, posttreatment, and at 3-months follow-up. Parent-rated SRS-2 scores indicated large effects posttreatment [- 19.2; 95% CI - 29.9 to - 8.5; p &lt; .001, effect size (ES) = 0.76], which were maintained at follow-up (- 20.7; 95% CI - 31.7 to - 9.7; p &lt; .0001, ES = 0.82). These estimates indicate substantially larger improvement than previously reported for shorter SSGT. However, the effects on teacher-rated SRS-2 and most secondary outcomes did not reach statistical significance. Our results suggest added benefits of extended SSGT training, implying that service providers might reach better results by optimizing the delivery of SSGT

The relation between neuromechanical parameters and Ashworth score in stroke patients

Quantifying increased joint resistance into its contributing factors i.e. stiffness and viscosity ("hypertonia") and stretch reflexes ("hyperreflexia") is important in stroke rehabilitation. Existing clinical tests, such as the Ashworth Score, do not permit discrimination between underlying tissue and reflexive (neural) properties. We propose an instrumented identification paradigm for early and tailor made interventions.BioMechanical EngineeringMechanical, Maritime and Materials Engineerin