Simulation-based evaluation of the Pharmpy Automatic Model Development tool for population pharmacokinetic modeling in early clinical drug development.

The Pharmpy Automatic Model Development (AMD) tool automates the building of population pharmacokinetic (popPK) models by utilizing a systematic stepwise process. In this study, the performance of the AMD tool was assessed using simulated datasets. Ten true models mimicking classical popPK models were created. From each true model, dataset replicates were simulated assuming a typical phase I study design-single and multiple ascending doses with/without dichotomous food effect, with rich PK sampling. For every dataset replicate, the AMD tool automatically built an AMD model utilizing NONMEM for parameter estimation. The AMD models were compared to the true and reference models (true model fitted to simulated datasets) based on their model components, predicted population and individual secondary PK parameters (SP) (AUC0-24, cmax, ctrough), and model quality metrics (e.g., model convergence, parameter relative standard errors (RSEs), Bayesian Information Criterion (BIC)). The models selected by the AMD tool closely resembled the true models, particularly in terms of distribution and elimination, although differences were observed in absorption and inter-individual variability components. Bias associated with the derived SP was low. In general, discrepancies between AMD and true SP were also observed for reference models and therefore were attributed to the inherent stochasticity in simulations. In summary, the AMD tool was found to be a valuable asset in automating repetitive modeling tasks, yielding reliable PK models in the scenarios assessed. This tool has the potential to save time during early clinical drug development that can be invested in more complex modeling activities within model-informed drug development.

A fully automatic tool for development of population pharmacokinetic models.

Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi-step, challenging, and time-consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here. The AMD tool is implemented in Pharmpy, a versatile open-source library for pharmacometrics. It consists of different modules responsible for developing the different components of population PK models, including the structural model, the inter-individual variability (IIV) model, the inter-occasional variability (IOV) model, the residual unexplained variability (RUV) model, the covariate model, and the allometry model. The AMD tool was evaluated using 10 real PK datasets involving the structural, IIV, and RUV modules in three sequences. The different sequences yielded generally consistent structural models; however, there were variations in the results of the IIV and RUV models. The final models of the AMD tool showed lower Bayesian Information Criterion (BIC) values and similar visual predictive check plots compared with the available published models, indicating reasonable quality, in addition to reasonable run time. A similar conclusion was also drawn in a simulation study. The developed AMD tool serves as a promising tool for fast and fully automatic population PK model building with the potential to facilitate the use of modeling and simulation in drug development.

Gait Characteristics over the Six-minute Walk Test in Older Women of a Specific Portuguese Community: A Cross-Sectional Study.

INTRODUCTION AND OBJECTIVE: There is limited research on the changes that can occur in the gait biomechanical parameters of older adults over long-distance walking. Thus, this study aimed to evaluate the gait characteristics of older women of a specific Portuguese community over the six-minute walk test (6MWT) along with gait spatial and temporal parameters and angular kinematics of the lower limb joints. MATERIALS AND METHODS: Twenty-six older women voluntarily participated. Each woman performed the 6MWT, and during this, their spatial and temporal parameters were collected through plantar pressure data (100Hz) and angular kinematics through an inertial sensor system (100Hz). The 6MWT was divided into four intervals, and the Friedman test was used to compare them. The median age of the women was calculated, and the Mann-Whitney test was used to compare women above and below the median age value. RESULTS: An increase in gait speed, stance phase, and double stance phase along the intervals was observed, as well as larger angular displacements of the hip, knee, and ankle (p<0.05). Women below or above the median age value also yielded these behaviours. Gait speed, cadence, stride length, and step length were higher in women below the median age value, while stride and step duration were lower (p<0.05). CONCLUSION: Older women yielded changes in gait spatial and temporal parameters along the 6MWT, as well as larger angular displacements of the lower limb joints. Older women (compared to younger ones) yielded lower gait speed, cadence, stride length, and step length, higher stance and double stance phases, and shorter angular displacements of the lower limb joints.

Deep squat test - Functional movement Screen: Convergent validity and ability to discriminate subjects with different levels of joint mobility.

BACKGROUND: Functional Movement Screen (FMS) is an important tool in the assessment of exercise practice. Assuming FMS lacks precise validity for assessing postural deficits, further research is needed to assess whether it is a sufficiently precise tool for analysing joint mobility. Research aims were to evaluate: convergent validity of Deep Squat (DS) - one of FMS tests - regarding joint mobility, using data from a three-dimensional motion analysis as a comparable method; DS's ability to discriminate between subjects with different joint mobility levels. METHODS: Sixty subjects were selected (23.6 ± 3.8 years). DS was performed according to FMS guidelines. Subjects' performance in frontal and sagittal planes was recorded by two video cameras and subsequently scored by two FMS-certified evaluators. Three-dimensional motion analyses of DS were acquired by a Vicon Motion Capture System (200 Hz). Ten trials were acquired for each subject. Ankle, knee, hip, and shoulder angular positions in sagittal plane were determined from the FullBody PlugInGait model. Spearman's coefficient examined the correlation between angular positions and DS score. Kruskal-Wallis test was used to assess the DS ability to discriminate between subjects with different joint mobility levels by comparing different scores. RESULTS: Negligible to moderate correlations were found between DS score and angular positions (-0.5 < r < 0.5). Only shoulder angular positions showed differences between score "1" and "2" (p < 0.05). Shoulder and hip angular positions showed no differences between score "2" and "3" (p < 0.05). CONCLUSIONS: DS yielded low convergent validity regarding joint mobility and did not show the ability to discriminate between subjects with different joint mobility levels.

Proprioceptive and Strength Exercise Guidelines to Prevent Falls in the Elderly Related to Biomechanical Movement Characteristics.

Falls are a major concern in the elderly and walking is an important daily activity in which falls occur, with tripping and slipping being the most frequent causes. Gait biomechanical parameters have been related to the occurrence of falls in the elderly. Moreover, there is evidence that falls can be prevented through exercise programs, which have been shown to be also effective in improving gait biomechanical parameters. However, a question remains: "What types of exercises must be included in exercise programs to prevent falls?". The purpose of this manuscript was to present guidelines for a fall prevention exercise program for the elderly, which was created with the aim of improving the gait biomechanical parameters related to falls. The critical review performed during the preparation of this manuscript collected important evidence and knowledge in order to create a structural basis for the development of a fall prevention exercise program. This type of program should last 6 or more weeks and be prescribed based on four movement pillars (locomotion, level changes, pulling and pushing, and rotations); however, the locomotion pillar must be the focus of the program. Proprioceptive and functional strength exercises should be included in this program. Based on the theoretical rationale, a proposal for a fall prevention exercise program is presented.

Valorisation of Recycled Cement Paste: Feasibility of a Short-Duration Carbonation Process.

Cement paste powder (CPP) is a by-product of the recycling process of concrete with an elevated carbonation capability and potential to be recycled as a binding material in new concrete batches. The application of a carbonation treatment to CPP improves this potential even more, besides the evident gains in terms of CO2 net balance. However, the long duration usually adopted in this treatment, from 3 to 28 days, hampers the industrial viability of the process. We studied the feasibility of a short-duration carbonation process, with a duration of two hours, carrying out a comprehensive characterization of the material throughout the process. The test was performed on CPP with an average initial water content of 16.9%, exposed to a CO2 concentration of 80%. The results demonstrate two main carbonation rates: a rapid growth rate in the first 18 minutes of the process, involving all the calcium-bearing compounds in CPP, and a slow growth rate afterwards, where only C-S-H contributes to the carbonation reaction. During the 2 h carbonation process, the main CPP compounds, calcium silicate hydrate (C-S-H) and calcium hydroxide (CH), reached different carbonation degrees, 31% and 94%, with, however, close CO2 uptake values, 8% and 11%, respectively. Nevertheless, the total CO2 uptake for this process (≈19%) attained values not distant from the values usually obtained in a carbonation of 12 days or more (19-25%). Hence, these findings highlight the blocking role of C-S-H in the carbonation process, indicating that longer carbonation periods are only going to be useful if an effective carbonation of this compound is accomplished. In the present scenario, where CH is the main contributor to the reaction, the reduction in the process duration is feasible.

Biomechanical Performance Factors in the Track and Field Sprint Start: A Systematic Review.

In athletics sprint events, the block start performance can be fundamental to the outcome of a race. This Systematic Review aims to identify biomechanical factors of critical importance to the block start and subsequent first two steps performance. A systematic search of relevant English-language articles was performed on three scientific databases (PubMed, SPORTDiscus, and Web of Science) to identify peer-reviewed articles published until June 2021. The keywords "Block Start", "Track and Field", "Sprint Running", and "Kinetics and Kinematics" were paired with all possible combinations. Studies reporting biomechanical analysis of the block start and/or first two steps, with track and field sprinters and reporting PB100m were sought for inclusion and analysis. Thirty-six full-text articles were reviewed. Several biomechanical determinants of sprinters have been identified. In the "Set" position, an anthropometry-driven block setting facilitating the hip extension and a rear leg contribution should be encouraged. At the push-off, a rapid extension of both hips and greater force production seems to be important. After block exiting, shorter flight times and greater propulsive forces are the main features of best sprinters. This systematic review emphasizes important findings and recommendations that may be relevant for researchers and coaches. Future research should focus on upper limbs behavior and on the analysis of the training drills used to improve starting performance.

Fractal Brownian Motion Assessment of the Center of Pressure Excursion During Impulse Phase on Standard Vertical Jump.

This study presents and applies fractal Brownian motion assessment of the center of pressure (COP) excursion during feet ground contact on standard vertical jump impulse phase with long and short countermovement (CM) in relation with lower limb muscle stretch-shortening cycle (SSC) comparing it with no CM and SSC. Fifty-four tests were performed by a group of six healthy male students of sports and physical education degree without previous injury, specific training, or fitness ability. Three repetitions were performed by each subject of a squat jump (SJ) without CM and SSC, countermovement jump (CMJ) with long CM and SSC, as well as drop jump (DJ) with short CM and SSC after depth jump from a 40 cm step. During trial tests ground reaction force and force moments were acquired with force platform and impulse phases were segmented for COP coordinates computation. Fractal Brownian motion analysis of COP excursion during impulse phases conduced to detection of differences between critical time and displacement as well as short and long-term diffusion coefficient (Ds, Dl) and Hurst index scale exponent (Hs, Hl), with Ds, Dl presenting statistical significative correlations -0.491, -0.559 and Hs, Hl non statistical significative correlations 0.266 and -0.424 with MVJ height (ht) at 5% significance for explaining underlying mechanisms on CM and SSC at MVJ.Clinical Relevance- This work contributes with new method for the study expansion of the center of pressure excursion and stability during feet ground contact from orthostatic standing position to the impulse phase during standard maximum vertical jump as the most adequate method for assessment of lower limb muscle stretch-shortening cycle.

Equine Rehabilitation: A Scoping Review of the Literature.

Injuries to the locomotor system are a common problem in athletic horses. Veterinarians address these injuries using appropriate medical, surgical, and pharmacological treatments. During or after recovery from the initial injury, horses may be treated for functional locomotor deficits using specific rehabilitation techniques aimed at restoring full athletic performance. This study reviews the literature to identify which rehabilitative techniques have been used most frequently in horses over the past 20 years, the protocols that were used, and the outcomes of the treatments in naturally occurring injuries and diseases. Publications were identified using keyword selection (Equine Athlete OR Equine OR Horse) AND (Rehabilitation OR Physiotherapy OR Physical Therapy). After removing duplicates and screening papers for suitability, 49 manuscripts were included in the study. The majority of publications that met the inclusion criteria were narrative reviews (49%) in which the authors cited the relatively small number of published evidence-based studies supplemented by personal experience. Observational/descriptive studies were also popular (35%). Randomized control trials accounted for only 10%. The most frequently reported rehabilitation techniques were exercise, electrotherapy, and hydrotherapy. The findings highlight the need for further information regarding type of intervention, parameterization, and outcomes of equine rehabilitation in clinical practice.

Immediate effect of individual bars of insoles and their combination on gait parameters in asymptomatic healthy adults.

Objective: The way how individual bars of sensorimotor insoles influence the gait kinematics is not fully understood yet. Therefore, this study aimed to explore the effect of three sensorimotor orthotic conditions (the medial calcaneal and retrocapital lateral bars and their combination) on the gait parameters in healthy adults during the stance phase of gait cycle.Materials and methods: Twenty-six young adults performed 20 gait cycles in each condition using their self-selected cadence and provided standardised shoes with the base-sole and the three types of orthotics. A three-dimensional motion analysis system (8 cameras; 200 Hz) was used and a six-degrees of freedom model was applied. The cadence, the stride length, the first peaks of foot external rotation, eversion and dorsal flexion as well as the first peak of hip adduction were analysed.Results: Significant differences (p < 0.05) were found for all parameters between the orthotic conditions, except the cadence. Significant difference in the first peak of hip adduction (p = 0.008) was found between the dominant and non-dominant leg. There were no significant interactions between the factors of condition and leg dominance (p > 0.05).Conclusions: There seems to be overall tendencies in immediate changes in ankle joint kinematics caused by all three sensorimotor orthotic conditions and besides the mechanical principles, also 'proprioceptive mechanism' seems to play a role. However, maximum observed average angular change was 2° and some variability in reactions to each orthotic condition exists among the individuals. Therefore, clinical relevance of such changes remains unclear and careful analysis of expected outcomes should be the common part of every orthotic intervention.

Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients.

Pharmacokinetic-based prophylaxis of replacement factor VIII (FVIII) products has been encouraged in recent years, but the relationship between exposure (factor VIII activity) and response (bleeding frequency) remains unclear. The aim of this study was to characterize the relationship between FVIII dose, plasma FVIII activity, and bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled pharmacokinetic and bleeding data during prophylactic treatment with BAY 81-8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of FVIII activity and longitudinal bleeding frequency, as well as bleeding severity, were described using non-linear mixed effects modeling in NONMEM. In total, 183 patients [median age 22 years (range, 1-61); weight 60 kg (11-124)] contributed with 1,535 plasma FVIII activity observations, 633 bleeds and 11 patient/study characteristics [median observation period 12 months (3.1-13.1)]. A parametric repeated time-to-categorical bleed model, guided by plasma FVIII activity from a 2-compartment population pharmacokinetic model, described the time to the occurrence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability in the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research was based on a post-hoc analysis of the LEOPOLD studies registered at clinicaltrials.gov identifiers: 01029340, 01233258 and 01311648.

Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII.

Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic-repeated time-to-event model-based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65-0.69), 0.78 (95% CI, 0.76-0.80), and 0.79 (95% CI, 0.77-0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.

Postpartum ovarian vein thrombosis and venous anatomical variation.

A 34-year-old multipara presented 72 hours postpartum with acute right-sided abdominal pain. The investigation revealed mild leucocytosis with positive D-dimer and elevated C reactive protein. Abdominal ultrasound and abdominopelvic CT demonstrated an enlarged right ovarian vein with endoluminal thrombus, representing postpartum ovarian vein thrombosis. The patient became asymptomatic 48 hours after starting broad-spectrum antibiotic treatment and anticoagulant therapy. She completed the treatment in ambulatory regimen and control abdominopelvic CT imaging was performed and revealed a duplicated right ovarian vein and a small residual subacute thrombus in the lumen of the distal right ovarian vein. The patient remained asymptomatic in the clinical follow-up.

Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data.

AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example. METHODS: We assessed 5 model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error percentiles. RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the prediction error [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios. CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualization is to include IOV in the generation of the EBEs but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.

Novel sintering-free scaffolds obtained by additive manufacturing for concurrent bone regeneration and drug delivery: Proof of concept.

Advances on the fabrication of sintering-free biphasic calcium phosphate (BCP)/natural polymer composite scaffolds using robocasting as additive manufacturing technique are presented in the present work. Inks with high amounts of BCP powders (45 vol%) containing different HA/ß-TCP ratios, in presence of crosslinked polymer, were successfully fine-tuned for extrusion by robocasting. The non-existence of sintering step opened the possibility to obtain drug loaded scaffolds by adding levofloxacin to the extrudable inks. The drug presence induced slightly changes on the rheological behaviour of the inks, more emphasized for the BCP compositions with higher amounts of ß-TCP, and consequently, on the microstructure and on the mechanical properties of the final scaffolds. The strong interaction of ß-TCP with chitosan difficult the preparation of suitable rheological inks for printing. Drug delivery studies revealed a fast release of levofloxacin with a high burst of drug within the first 30 min. Levofloxacin loaded samples also presented bacteria growth inhibition ability, proving that antibiotic was not degraded during the fabrication process and its bactericidal efficacy was preserved. From the results obtained, the composite scaffolds containing higher amounts of HA (around 80% HA/20% ß-TCP) constitute a promising bi-functional synthetic bone substitute for simultaneous local bone regeneration and infection treatments.

Generalized Lower Limb Joint Angular Phase Space Analysis of Subject Specific Normal and Modified Gait.

This study presents and applies generalized angular phase space analysis to lower limb joint angles of specific subject during normal and modified gait for discrimination of gait and joint angular movements. Case study of an adult healthy male in-vivo and noninvasive kinematic assessment of skin surface adhesive markers at lower limb was performed at human movement lab during normal gait, stiff knee gait and slow running. Musculoskeletal modeling was performed using AnyGait v.0.92 morphing Twente Lower Extremity Model (TLEM) to match the size and joint morphology of the stick-figure model. Inverse kinematics was performed obtaining hip, knee and ankle joint flexion-extension angular displacements, velocities and accelerations. Generalized phase space analysis was applied to lower limb joint angular displacements, velocities and accelerations. Directional statistics was applied to generalized phase planes with mean direction, resultant length and circular standard deviation assessment. Rayleigh test was employed for directional concentration and coordination assessment, and Watson's $\mathrm{U^{2$ goodness of fit test applied to the von Mises distribution. Results point for the importance of subject specific study, generalized joint angular phase space analysis, comparing results with other normalization methods and validation of applied methods with qualitative clinical analysis.

Differences in foot contact times between obese and non-obese postmenopausal women when crossing obstacles.

OBJECTIVE: This study aimed to investigate the foot contact time differences between obese and non-obese subjects during walking when crossing obstacles. METHODS: Ninety-eight postmenopausal women were assigned to four groups, and their plantar pressure temporal data were collected using a two-step protocol during walking when crossing an obstacle set at 30% height of lower limb length of each subject. The initial, final, and duration of contact of 10 foot areas were measured. RESULTS: Leading limb: (1) the heel groups initiated foot contact using the heel, and the non-heel groups initiated contact using the metatarsals; (2) heel obese subjects showed an earlier initial contact and a longer contact duration of metatarsals 2-3; (3) non-heel obese subjects showed an earlier midfoot initial contact. Regarding the trailing limb: (4) heel obese subjects showed an earlier midfoot initial contact and a longer contact duration of metatarsal 5; (5) non-heel obese subjects showed an earlier initial contact and a longer contact duration of metatarsals 4-5. CONCLUSIONS: (1) The non-heel groups' foot rollover pattern may result from an attempt of rapidly restoring stability; (2) the heel obese subjects seem to regulate their plantar foot muscles to overcome their overweight; (3) the overweight of the non-heel obese subjects leads to a quicker backward foot roll-over from the metatarsals to the heel; (4) the overweight of the heel obese subjects can distort their footprints and/or their higher inertia may precipitate an anticipation of the midfoot contact, which can also explain the result observed for 5.

Influência da intensidade de precipitação na geração de escoamento em telhados cerâmicos: experimentos em laboratório sob chuva simulada / Influence of rainfall intensity on the production of runoff on ceramic tile roofs: laboratory experiments under simulated rainfall

RESUMO Os sistemas de aproveitamento de água de chuva baseiam-se na coleta do escoamento de superfícies pouco permeáveis, como telhados e ruas. Esses sistemas são projetados, muitas vezes, com dados de pluviômetros, e não de pluviógrafos, e podem desconsiderar informações importantes da quantidade precipitada disponível para aproveitamento. Neste trabalho foram realizados experimentos em laboratório com simulação de chuvas de baixa, moderada e forte intensidades sobre um telhado cerâmico. As análises indicam que chuvas com intensidade entre 12,8 e 61,6 mm h-1 (moderada a forte) resultam em coeficiente de escoamento superior a 0,9, enquanto em chuvas com baixa intensidade (inferior a 1,2 mm h-1), o coeficiente de escoamento diminui drasticamente, aproximando-se a 0 para intensidades próximas a 0,25 mm h-1. Conclui-se que, para as condições dos experimentos realizados, a absorção de telhas cerâmicas influencia mais na redução do escoamento superficial para chuvas de baixa intensidade do que para chuvas de intensidade moderada ou forte.

ABSTRACT Rainwater harvesting consists on the collection of runoff from low permeable surfaces, as roofs and streets. Designing these systems is often based on pluviometer data and not on pluviograph data, therefore they do not consider crucial data on the amount of rainwater available to harvesting. Laboratory experiments were conducted by simulating low, moderate and high intensity rainfall on a ceramic tile roof. Results shown that rainfall intensities between 12.8 and 61.6 mm h-1 (moderate to high intensity) lead to runoff coefficients greater than 0.9, while for rainfall low intensities (lower than 1.2 mm h-1), the runoff coefficient drastically decreased, reaching values of zero for rainfall intensities lower than 0.25 mm h-1. In conclusion, for the simulated experimental conditions, water absorption of the ceramic tiles is more significant on the runoff for very low rainfall intensities than the strong or moderate rainfall intensities.