A New Look at Infant Problem-Solving: Using DeepLabCut to Investigate Exploratory Problem-Solving Approaches

When confronted with novel problems, problem-solvers must decide whether to copy a modeled solution or to explore their own unique solutions. While past work has established that infants can learn to solve problems both through their own exploration and through imitation, little work has explored the factors that influence which of these approaches infants select to solve a given problem. Moreover, past work has treated imitation and exploration as qualitatively distinct, although these two possibilities may exist along a continuum. Here, we apply a program novel to developmental psychology (DeepLabCut) to archival data (Lucca et al., 2020) to investigate the influence of the effort and success of an adult’s modeled solution, and infants’ firsthand experience with failure, on infants’ imitative versus exploratory problem-solving approaches. Our results reveal that tendencies toward exploration are relatively immune to the information from the adult model, but that exploration generally increased in response to firsthand experience with failure. In addition, we found that increases in maximum force and decreases in trying time were associated with greater exploration, and that exploration subsequently predicted problem-solving success on a new iteration of the task. Thus, our results demonstrate that infants increase exploration in response to failure and that exploration may operate in a larger motivational framework with force, trying time, and expectations of task success.

Development of A Physiological-Based Pharmacokinetic Model to Predict Bendamustine Exposure in Paediatric Patients

Background the study aimed to predict bendamustine pharmacokinetics in paediatric patients by employing physiological-based pharmacokinetic (PBPK) model that considers age-dependent physiological maturity. Methods Using PK-Sim, a paediatric PBPK model was constructed based on a validated PBPK adult model using the recommended paediatric dose at 120 mg/m2 bendamustine intravenous (IV) infusion for 60 minutes and age-dependent mechanistic scaling. Parameter optimisation was done based on model fitting to the observed in vivo population pharmacokinetic (PK) data using the visual predictive check. The final paediatric PBPK model was extrapolated to various paediatric age categories (term newborn, infant, toddler, preschool, school-age, adolescent) for PK estimate and comparisons. The PBPK paediatric model was compared with the adult model, and PK comparisons were made for different age categories with the reference paediatric model. Results The model estimated a bendamustine fraction unbound of 4% in a paediatric patient. Renal clearance, biliary clearance and total hepatic clearance in a typical child were 1.38 mL/min/kg, 0.02 mL/min/kg and 13.76 mL/min/kg respectively. The paediatric model was comparable to the adult model. Compared to a typical child, a term newborn has the highest estimated maximum plasma concentration (Cmax) and systemic exposure (AUC0-24h), which were 1.24-fold respectively. Clearance in term newborn and infant were 1.4-1.5-fold higher than a typical child. Conclusions We developed a bendamustine PBPK model for a paediatric patient with relapsed/refractory Acute Lymphocytic Leukaemia (ALL) and Acute Myeloid Leukaemia (AML). The current model may be useful to estimate systemic exposure in paediatric for various age categories in different settings. More in vivo studies are needed in paediatric patients to challenge the robustness of this model.

Internal Mechanics of a Subject-Specific Wrist in the Sagittal Versus Dart-Throwing Motion Plane in Adult and Elder Models: Finite Element Analyses

Introduction: Most of the wrist motions occur in a diagonal plane of motion, termed the dart-throwing motion (DTM) plane; it is thought to be more stable compared with movement in the sagittal plane. However, the effect of the altered carpus motion during DTM on the stress distribution at the radiocarpal joint has yet to be explored. Aim: To calculate and compare the stresses between the radius and two carpal bones (the scaphoid and the lunate) in two wrist positions, extension and radial extension (position in DTM), and between an adult and an elder model. Methods: A healthy wrist of a 40-year-old female was scanned using Magnetic Resonance Imaging in two wrist positions (extension, radial extension). The scans were transformed into three-dimensional models and meshed. Finite element (FE) analyses in each position of the wrist were conducted for both adult and elder models, which were differentiated by the mechanical properties of the ligaments. The distal surfaces of the carpal bones articulating with the metacarpals were loaded by physically accurate tendon forces for each wrist position. Results: The von Mises, shear stresses and contact stresses were higher in the extension model compared with the radial-extension model and were higher for the radius-scaphoid interface in the adult model compared with the elder model. In the radius-scaphoid interface, the stress differences between the two wrist positions were smaller in the elder model (11.5% to 22.5%) compared with the adult model (33.6–41.5%). During radial extension, the contact area at the radius-lunate interface was increased, more so in the adult model (222.2%) compared with the elder model (127.9%), while the contact area at the radius-scaphoid was not affected by the position of the wrist in the adult model (100.9%) but decreased in the elder model (50.2%) during radial extension. Conclusion: The reduced stresses during radial extension might provide an explanation to our frequent use of this movement pattern, as the reduced stresses decrease the risk of overuse injury. Our results suggest that this conclusion is relevant to both adults and elder individuals.

Dose selection for fremanezumab (AJOVY) phase 3 pediatric migraine studies using pharmacokinetic data from a pediatric phase 1 study and a population pharmacokinetic modeling and simulation approach

Background Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study’s results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies. Methods Initial application of the adult model suggested that a 75 mg dose in pediatric patients would match exposures determined safe and efficacious in adults; thus, in the phase 1 study, 15 patients, aged 6–11 years and weighing 17–45 kg received a single subcutaneous 75 mg fremanezumab dose. The sparse pharmacokinetic data collected were used to refine the adult model and simulate concentration-time profiles for monthly subcutaneous doses (60 to 225 mg) in a virtual pediatric population. Results In the phase 1 pediatric study, the safety profile was similar to that of adults. A two-compartment model with first-order absorption and elimination and body weight effects on clearance and central volume was found to adequately describe the pediatric pharmacokinetic data. Conclusions Using exposure matching to the effective adult fremanezumab dose (225 mg subcutaneous monthly), modeling and simulations predict recommended dose of 120 mg in pediatric patients weighing < 45 kg. Registration: The phase 1 study of this report is registered at EudraCT with the identifier 2018-000734-35.

Global analysis of a juvenile-adult model for cannibalistic species

Cannibalism is a life trait occurring in a wide variety of species. To describe the population dynamics of cannibalistic species, we develop a stage-structured population model in which adults prey on juveniles with a Holling type I functional response. We make a rigorous analysis of the global dynamics in the model. The results of theoretical analysis show that the model has no boundary equilibrium other than the extinction one since juveniles and adults are cooperative (adults reproduce juveniles and juveniles grow into adults). Under certain conditions, the model has multiple interior equilibria and exhibits several types of bistable dynamics, in which different initial densities of juveniles and adults produce different long-term outcomes.

Fetuin-A is a HIF target that safeguards tissue integrity during hypoxic stress

Intrauterine growth restriction (IUGR) is associated with reduced kidney size at birth, accelerated renal function decline, and increased risk for chronic kidney and cardiovascular diseases in adults. Precise mechanisms underlying fetal programming of adult diseases remain largely elusive and warrant extensive investigation. Setting up a mouse model of hypoxia-induced IUGR, fetal adaptations at mRNA, protein and cellular levels, and their long-term functional consequences are characterized, using the kidney as a readout. Here, we identify fetuin-A as an evolutionary conserved HIF target gene, and further investigate its role using fetuin-A KO animals and an adult model of ischemia-reperfusion injury. Beyond its role as systemic calcification inhibitor, fetuin-A emerges as a multifaceted protective factor that locally counteracts calcification, modulates macrophage polarization, and attenuates inflammation and fibrosis, thus preserving kidney function. Our study paves the way to therapeutic approaches mitigating mineral stress-induced inflammation and damage, principally applicable to all soft tissues.

Supporting family as a form of family support

The aim of the article is to analyse the functioning of supporting families. They play an important role in the process of supporting the natural family experiencing difficulties in caring for and bringing up children. In their work with the family, they carry out tasks related to the care and education of children, running a household, shaping and fulfilling social roles. Supporting families are appointed and function on behalf of the commune pursuant to the Act of 9 June 2011 on supporting the family and the foster care system. The article presents legal aspects and figures on the performance of supporting families. The legal aspect includes the performance rules, the recruitment scheme, taking into account a number of requirements and the scope of tasks performed by supporting families. The statistical data presents an analysis of the trends of changes regarding the number of functioning families, the time spent by children in the care of supporting families and the number of supported families. Supporting families become each time more popular form of support for a natural family experiencing caring and upbringing difficulties. By embracing a family with support, members of the supporting family play the role of the authority of behaviour for parents and the role of a “positive adult” model for children. The supporting family is a model of parenting, an authority in fulfilling social roles, a guide for the change made and a teacher of everyday family life. By implementing the entrusted tasks resulting from the Act and the contract concluded with the head of the commune, the supporting family supervises the overall development of the family as a system and its individual members.

Pharmacological Considerations When Transitioning the Care of Epilepsy Patients from Pediatric to Adult Epilepsy Centers

There is scarce evidence in review of the available literature to support a clear and superior model for the transition of care for epilepsy patients from pediatric to adult centers. Anecdotally, there is a common perception that families are reluctant to make this change and that the successful transition of care for epilepsy can be a challenge for patients, families, and physicians. As part of the effort to prepare the patient and family for the adult model of care, several treatment issues should be addressed. In this article, we discuss the specific challenges for physicians in transition of care for epilepsy patients from a pharmacological standpoint, which include differences in metabolism and pharmacodynamics that can impact tolerability or efficacy of antiepileptic medications, lifestyle changes affecting medication compliance and seizure control, acquired adult health conditions necessitating new medications that may result in adverse drug interactions, and adult neurologists' potential lack of familiarity with certain medications typically used in the pediatric epilepsy population. We offer this as a guide to avoid one of the many possible pitfalls when epilepsy patients transition to adult care.