Background and Objective: In silico methods have become the key for efficiently testing and qualifying drug properties. Due to the complexity of the LADME processes and drug characteristics associated to oral drug absorption , there is a growing demand in the development of Physiologically-based Pharmacokinetic (PBPK) software with greater flexibility. Thus, the aims of this work are (i) to develop a mechanistic-based modeling framework of dissolution, transit and absorption (Phys-DAT) processes in the PhysPK platform and (ii) to assess the predictive power of the acausal MOOM methodology embedded in Phys-DAT versus reference ODE-based PBPK software. Methods: A PBPK model was developed including unreleased, undissolved and dissolved thermodynamic states of the drug. The gastrointestinal tract (GI) was represented by nine compartments and first-order transit kinetics was assumed for the drug fractions. Dissolution processes were described using solubility-independent or solubility-dependent mechanisms and pH effects. Linear transit and linear absorption mechanisms including gradual decrease absorption rate were considered to represent the passive diffusion process. Internal validation of the Phys-DAT model was performed through simulation-based analysis, considering different theoretical scenarios. External validation was carried out using in silico and in vivo data of GI segments and plasma concentrations. Both BCS I and II class drugs were included. Results: The model predicts plasma-concentration profiles of each compartment for undissolved, dissolved, and absorbed fractions using PhysPK® v.2.4.1. Internal and external validations demonstrate that the model aligned with the theoretical assumptions and accurately predicted C max , T max , and AUC 0-t for both BCS I and II drugs. Average Fold Error (AFE), Absolute Average Fold Error (AAFE), and Percent Prediction Error (PPE) calculations indicate good predictive performance, with predicted/observed ratios falling within the acceptable range. Conclusions: Phys-DAT represents a mechanistic model for predicting oral absorption, including the dissolution, pH effect, transit, and absorption processes. PhysPK has shown to be a tool with strong prediction accuracy, similar to the obtained by ODE-based PBPK reference software, and the results obtained with the Phys-DAT model for oral administered drugs showed predictive reliability in healthy volunteers, setting the basis to determine the interchangeability of the acausal MOOM methodology with other modeling approaches.
Aims The aim of this study was to determine the global incidence of type 1 diabetes mellitus (T1DM) in children and adolescents under 20 years of age from 2000 to 2022. Materials and Methods Two reviewers searched three electronic databases (PubMed, Web of Science, and CINAHL) for studies published between January 2000 and November 2022. Pooled estimates of T1DM incidence with a 95% confidence interval (CI) per 100,000 person‐years were calculated by country/region, sex, age, and COVID‐19 pandemic period (pre‐COVID‐19 and pandemic). Results The study included 126 studies from 55 countries and 18 regions. The incidence rate (IR) of T1DM from 2000 to 2022 was 14.07 (95%CI, 12.15–16.29) per 100,000 person‐years. Finland and high‐income North America had the highest IR, with 56.81 (95%CI, 55.91–57.73) and 28.77 (95%CI, 26.59–31.13) per 100,000 person‐years, respectively. The IR was 13.37 (95%CI, 10.60–16.88) per 100,000 person‐years in boys and 13.87 (95%CI, 11.51–16.70) per 100,000 person‐years in girls. There were statistically significant differences among different age ranges: 0–4 versus 5–9 and 10–14 years old ( p < 0.001); 5–9 versus 15–19 ( p < 0.001) and 10–14 versus 15–19 years old ( p = 0.003). Finally, during the pandemic period (2020–2022), the IR was 24.84 (95%CI, 17.16–35.96) per 100,000 person‐years, which was higher but not significant compared with the prepandemic period (2017–2019) of 13.56 (95%CI, 7.49–24.56) per 100,000 person‐years ( p = 0.090). Conclusions The IR of T1DM in children and adolescents under 20 years of age is substantial, especially during the pandemic period, although it varies across regions. More reliable data from additional countries are needed to determine the worldwide incidence of T1DM.
A wide variety of insect-specific non-retroviral RNA viruses specifically infect insects. During viral infection, fragments of viral sequences can integrate into the host genomes creating non-retroviral endogenous viral elements (nrEVEs). Although the exact function of nrEVEs is so far unknown, some studies suggest that nrEVEs may interfere with virus replication by producing PIWI-interacting RNAs (piRNAs) that recognize and degrade viral RNAs through sequence complementarity. In this article, we identified the nrEVEs repertoire of ten species within the dipteran family Tephritidae (true fruit flies), which are considered a major threat to agriculture worldwide. Our results suggest that each of these species contains nrEVEs, although in limited numbers, and that nrEVE integration may have occurred both before and after speciation. Furthermore, the majority of nrEVEs originated from viruses with negative single-stranded RNA genomes and represent structural viral functions. Notably, these nrEVEs exhibit low similarity to currently known circulating viruses. To explore the potential role of nrEVEs, we investigated their transcription pattern and the production of piRNAs in different tissues of Ceratitis capitata. We successfully identified piRNAs that are complementary to the sequence of one nrEVE in C. capitata, thereby highlighting a potential link between nrEVEs and the piRNA pathway. Overall, our results provide valuable insights into the comparative landscape of nrEVEs in true fruit flies, contributing to the understanding of the intimate relation between fruit flies and their past and present viral pathogens.
Plant sterols are minor bioactive components of food lipids, which are often used for the formulation of functional foods due to their cholesterol-lowering properties. However, they have low solubility and tend to crystallize, which may affect their biological effects, the sensory profile of the sterol-enriched food, and its consumer acceptability. Moreover, due to the unsaturated structure of sterols, they are susceptible to oxidation, so different encapsulation systems have been developed to improve their dispersibility/solubility, stability, delivery, and bioaccessibility. This chapter provides an overview of the main encapsulation systems currently used for plant sterols and their application in model and food systems, with a particular focus on their efficiency and impact on sterol bioaccessibility.
The Mesolithic technology in Western Europe depicts the last cultural expressions and adaptations of hunter-gatherers before the adoption of Neolithic agro-pastoral practices. Many questions arise when investigating the timing, nature, and historical significance of the Mesolithic. The development of the Mesolithic culture is usually associated with the onset of milder environmental conditions at the beginning of the Holocene. Hunter-gatherer societies would have adopted new subsistence and territorial strategies in response to environmental changes, which would have consecutively impacted their technological system. This assertion considers the Mesolithic in South-western Europe as one homogeneous phenomenon and eludes the putative role that early Holocene climatic fluctuations may have played in hunter-gatherer organizations. In this study, we aimed at questioning the archaeological variability of the first Mesolithic by taking benefit from new data provided by recent excavations at La Baume de Monthiver (Comps-sur-Artuby, France). La Baume de Monthiver is a small rock shelter located along the Jabron Valley in the southern French pre-Alps. The rock shelter records several Mesolithic occupations documenting Sauveterrian technological traditions. By studying the Baume de Monthiver, we take the opportunity to explore the Sauveterrian in its longue durée and address the question of its diachronic variability. In this study, we investigated the M-B′ archaeological assemblage and question its homogeneity at the transition of the 10th- and 9th-millennium cal. BP. Our results document stable technological and subsistence practices before and after the climatic fluctuations at the end of the 10th-millennium cal. BP, supporting the hypothesis of well-adapted Mesolithic societies to the climatic “instability” characterizing the early Holocene.
The advent of twist engineering in two-dimensional crystals enables the design of van der Waals heterostructures with emergent properties. In the case of magnets, this approach can afford artificial antiferromagnets with tailored spin arrangements. Here we fabricate an orthogonally twisted bilayer by twisting two CrSBr ferromagnetic monolayers with an easy-axis in-plane spin anisotropy by 90°. The magnetotransport properties reveal multistep magnetization switching with a magnetic hysteresis opening, which is absent in the pristine case. By tuning the magnetic field, we modulate the remanent state and coercivity and select between hysteretic and non-hysteretic magnetoresistance scenarios. This complexity pinpoints spin anisotropy as a key aspect in twisted magnetic superlattices. Our results highlight control over the magnetic properties in van der Waals heterostructures, leading to a variety of field-induced phenomena and opening a fruitful playground for creating desired magnetic symmetries and manipulating non-collinear magnetic configurations.
Although weekend recovery sleep is common, the physiological responses to weekend recovery sleep are not fully elucidated. Identifying molecular biomarkers that represent adequate versus insufficient sleep could help advance our understanding of weekend recovery sleep. Here, we identified potential molecular biomarkers of insufficient sleep and defined the impact of weekend recovery sleep on these biomarkers using metabolomics in a randomized controlled trial. Healthy adults (n = 34) were randomized into three groups: control (CON: 9-h sleep opportunities); sleep restriction (SR: 5-h sleep opportunities); or weekend recovery (WR: simulated workweek of 5-h sleep opportunities followed by ad libitum weekend recovery sleep and then 2 days with 5-h sleep opportunities). Blood for metabolomics was collected on the simulated Monday immediately following the weekend. Nine machine learning models, including a machine learning ensemble, were built to classify samples from SR versus CON. Notably, SR showed decreased glycerophospholipids and sphingolipids versus CON. The machine learning ensemble showed the highest G-mean performance and classified 50% of the WR samples as insufficient sleep. Our findings show insufficient sleep and recovery sleep influence the plasma metabolome and suggest more than one weekend of recovery sleep may be necessary for the identified biomarkers to return to healthy adequate sleep levels.
Integration of video games in classroom instruction poses challenges for teachers, including the need for technical and financial resources, support from parents and administrators, concerns about toxic gaming culture, and uncertainty in teaching and evaluating using video games. These barriers hinder teachers’ progress, diminish their motivation, and impede the transition toward game-based teaching. This article explores the valid barriers faced by teachers during video game integration into their classrooms and explores the application of the Solution-Focused Approach (SFA) instruments, namely SFA questions, as a possible means to address these barriers. The SFA questions facilitate a shift in focus from deficiencies to existing strengths and from an ineffective Problem Talk to an effective Solution Talk. Various SFA questions are provided to guide teachers toward fostering a healthier and more productive dialogue with themselves and others, allowing concentration on desired outcomes. Promising results of the SFA-based Education Professional Development Programme for Teachers are presented, and future directions are proposed to explore SFA application in this area.
1. Introduction: a message from the Editors Unlike most special issues that put a theory, concept, or method central, we are paying tribute to a person. At the beginning of what now has been a very long pandemic, our Prof. Paul Benneworth, unexpectedly passed away leaving behind not just an exciting and inspirational academic and professional career but also a personal legacy that combined a wicked sense of humour with the type of honest and personalized academic support that has fostered the careers of many of the contributors contained herein. Indeed, the fact that more than 3 years after his death, Paul’s research still lives on in the pieces contained herein, is a testament to the extent that he was engaged in important topics in the field. More importantly however, for each piece contained within this Special Edition, Paul’s legacy is shown through the way that he contributed value to projects and ideas, and also how he contributed to the personal and professional development of individuals.
Inspired by macroeconomic scenarios, we aim to experimentally investigate the evolution of short- and long-run expectations under different specifications of the fundamentals. We collect individual predictions for future prices in a series of Learning to Forecast Experiments with a time-varying fundamental value. In particular, we observe how expectations evolve in markets where the fundamental value follows either a V-shaped or an inverse V-shaped pattern. These conditions are compared with markets characterized by a constant and a slightly linear increasing fundamental value. We assess whether minor but systematic variations in the fundamentals affect individual short- and long-run expectations by considering positive and negative feedback-expectation systems. Compared to a setting with constant fundamentals, the slowly varying fundamentals have a limited impact on how subjects form their expectations in positive feedback markets, whereas in negative feedback markets we observe notable changes.
This work focuses on the examination of a regular black hole within Verlinde's emergent gravity, specifically investigating the Hayward-like (modified) solution. The study reveals the existence of three horizons under certain conditions, i.e., an event horizon and two Couchy horizons. Our results indicate regions which phase transitions occur based on the analysis of heat capacity and Hawking temperature. To compute the latter quantity, we utilize three distinct methods: the surface gravity approach, Hawking radiation, and the application of the first law of thermodynamics. In the case of the latter approach, it is imperative to introduce a correction to ensure the preservation of the Bekenstein-Hawking area law. Geodesic trajectories and critical orbits (photon spheres) are calculated, highlighting the presence of three light rings. Additionally, we investigate the black hole shadows. Furthermore, the quasinormal modes are explored using third-and sixth-order WKB approximations. In particular, we observe stable and unstable oscillations for certain frequencies. Finally, in order to comprehend the phenomena of time-dependent scattering in this scenario, we provide an investigation of the time-domain solution. * Electronic address: email@example.com
Background This study aimed to evaluate the effects of a 15‐week telerehabilitation program and a detraining period on cardiorespiratory fitness and mechanical efficiency in patients with post‐COVID‐19 sequelae. Methods 131 patients with post‐COVID‐19 sequelae were randomly assigned to one of two groups: patients who carried out the supervised telerehabilitation program (TRG, n = 66) and a control group (CG, n = 65). An incremental cardiopulmonary exercise testing (CPET) was performed on cycle ergometer to compare cardioventilatory responses between experimental groups. Results A significant increase in the CPET duration, peak power output, and mechanical efficiency was observed in TRG compared to CG after the telerehabilitation program (p ≤ 0.001). A significant increase in the CPET duration, peak power output, and mechanical efficiency was verified at 3 months compared to the pretest and after detraining in TRG (p < 0.001). A significant increase in peak oxygen uptake (V̇O2peak) was identified after the intervention and in the detraining period compared to the pretest in both experimental groups (p < 0.001). A higher ventilatory efficiency was observed after the telerehabilitation program (p = 0.021) than in pretest only in TRG. Conclusions A 15‐week supervised home telerehabilitation program improved exercise capacity, power output, and mechanical efficiency in TRG compared to a CG. The telerehabilitation program was not more effective in improving V̇O2peak than the activities of the CG. However, ventilatory efficiency was improved only after the telerehabilitation program. The reported results after the detraining period highlight the need to maintain the rehabilitation program over time.
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