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The objective of this population pharmacokinetic (PK) analysis was to characterize the concentration-time profile of brepocitinib plasma concentration after single- and multiple-oral administration in healthy volunteers (HVs) and patients with immuno-inflammatory diseases. Blood samples from phase I HV and phase II clinical studies of patients with alopecia areata, psoriasis, psoriatic arthritis, ulcerative colitis (UC), vitiligo, and hidradenitis suppurativa were analyzed using a nonlinear mixed-effects modeling approach. Effects of patients' characteristics on brepocitinib exposure were investigated. Overall, 8552 brepocitinib plasma concentrations from 775 individuals were included in the analysis. The PKs of brepocitinib were adequately described by a two-compartment model with first-order absorption and a lag time for tablet formulation, dose-dependent bioavailability, and Box-Cox transformed interindividual variabilities on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). For a typical 70-kg non-Asian female patient with baseline aspartate aminotransferase of 22 unit/liter, CL/F and Vc/F estimates were 17.5 L/h and 88.5 L, respectively. Asians had a higher exposure (independent of body weight), caused by a 10% lower CL/F when compared to other individuals. Independent of baseline body weight, the male population showed 13% higher Vc/F compared to the female population. Patients with UC were predicted to have 46% slower absorption rate compared to other individuals. The PKs of brepocitinib were well-characterized by a two-compartment model with first-order absorption and dose-dependent bioavailability. Several covariates, such as race and sex, were identified to have statistically significant, but not clinically meaningful, effects on the estimated PK parameters., (© 2024 Pfizer Inc and The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

In this work, a new equation consist of A⋅⋅⋅B, B⋅⋅⋅C, A⋅⋅⋅BC, and AB⋅⋅⋅C interactions is proposed for calculating the total interaction energy of noncyclic ABC triads. New equations are also proposed for calculating the changes in values of A⋅⋅⋅B and B⋅⋅⋅C interactions on the formation of triad from the corresponding dyads. The advantages of equations proposed here in comparison with many-body interaction energy approach are discussed. All proposed equations were tested in F 3 MLi⋅⋅⋅NCH⋅⋅⋅HLH and F 3 MLi⋅⋅⋅HLH⋅⋅⋅HCN (M = C, Si; L = Be, Mg) as well as H 3 N⋅⋅⋅XY⋅⋅⋅HF (X, Y = F, Cl, Br) noncyclic A⋅⋅⋅B⋅⋅⋅C triads. The data show that the total cooperativity of triad correlates well with the sum of the changes in values of A⋅⋅⋅B and B⋅⋅⋅C interactions calculated through new equations proposed here. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Purpose: To evaluate patterns of activation, convergence and divergence of three functional magnetic resonance imaging (fMRI) Working Memory (WM) tasks in two different age groups. We want to understand potential impact of task and subjects' age on WM activations as well as most important areas with regard to WM functions., Materials and Methods: Thirty-five healthy volunteers completed visual, verbal, and novel auditory WM tasks. The subjects were selected from age extremes to depict possible impact of normal aging. General Linear Model was used to report significant activations and the effect of group. One-to-one comparison of the tasks and Combined Task Analysis was also performed., Results: Most of the observed differences between the tasks were seen in areas that were responsible for feature processing. Frontal regions were mainstay activation areas, regardless of the utilized stimulus. We found an age-related reduction in activity of visual (in visually-presented tasks) and auditory (in auditory task) cortices but an age-related increase in prefrontal cortex for all tasks., Conclusion: Regardless of the type of the task stimuli, frontal regions are the most important activation areas in WM processing. These areas are also main targets of age-related changes with regard to activation patterns. Our results also indicate that prefrontal overactivity in working memory might be a compensatory effort to mask age-related decline in sensory processing.

Purpose: To evaluate patterns of activation, convergence and divergence of three functional magnetic resonance imaging (fMRI) Working Memory (WM) tasks in two different age groups. We want to understand potential impact of task and subjects' age on WM activations as well as most important areas with regard to WM functions., Materials and Methods: Thirty-five healthy volunteers completed visual, verbal, and novel auditory WM tasks. The subjects were selected from age extremes to depict possible impact of normal aging. The General Linear Model was used to report significant activations and the effect of age group. Contrasts revealed differences in activation between tasks, and Combined Task Analysis was performed to determine common regions of activation across tasks., Results: Most of the observed differences between the tasks were seen in areas that were responsible for feature processing. Frontal regions were mainstay activation areas, regardless of the utilized stimulus. We found an age-related reduction in activity of visual (in visually-presented tasks) and auditory (in auditory task) cortices but an age-related increase in prefrontal cortex for all tasks., Conclusion: Regardless of the type of the task stimuli, frontal regions are the most important activation areas in WM processing. These areas are also main targets of age-related changes with regard to activation patterns. Our results also indicate that prefrontal overactivity in working memory might be a compensatory effort to mask age-related decline in sensory processing.

During the formation of skeletal muscle, secondary fibres form, by cell fusion, on the surface of primary fibres. Three-dimensional reconstructions of primary fibres with the secondary fibres and cells on their surfaces were produced from spaced serial transmission electron micrographs. Reconstructions were made of fibres from embryonic day (E) 17, E19, and E21 of the Extensor Digitorum muscle of Balb/c mice. Cell distribution was analysed in two ways. Firstly, nearest neighbour analysis was used to see if cells were randomly arranged or clustered. Secondly, the association of cells and secondary fibres was tested by measuring the distances between cells and each secondary fibre. Cells were found to be randomly distributed on the surface of primaries at E17 but significantly clustered, and associated with smaller secondary fibres at E19 and E21. Cells were not associated with the ends of secondary fibres. Cells associated with secondary fibres lay in the groove formed by contact between adjacent primary and secondary fibres. This apparent response to the topography of the surface on which the cells are lying has previously been mimicked in vitro by growing cells on grooved surfaces. It is likely that cells associated with secondaries will fuse laterally with these fibres and their response to topography is part of the process of bringing them into correct alignment with the fibre before fusion.