Development of an In Vitro System To Emulate an In Vivo Subcutaneous Environment: Small Molecule Drug Assessment

A reliable in vitro system can support and guide the development of subcutaneous (SC) drug products. Although several in vitro systems have been developed, they have some limitations, which may hinder them from getting more engaged in SC drug product development. This study sought to develop a novel in vitro system, namely, Emulator of SubCutaneous Absorption and Release (ESCAR), to better emulate the in vivo SC environment and predict the fate of drugs in SC delivery. ESCAR was designed using computer-aided design (CAD) software and fabricated using the three-dimensional (3D) printing technique. ESCAR has a design of two acceptor chambers representing the blood uptake pathway and the lymphatic uptake pathway, respectively, although only the blood uptake pathway was investigated for small molecules in this study. Via conducting a DoE factor screening study using acetaminophen solution, the relationship of the output (drug release from the “SC” chamber to the “blood circulation” chamber) and the input parameters could be modeled using a variety of methods, including polynomial equations, machine learning methods, and Monte Carlo simulation-based methods. The results suggested that the hyaluronic acid (HA) concentration was a critical parameter, whereas the influence of the injection volume and injection position was not substantial. An in vitro–in vivo correlation (IVIVC) study was developed using griseofulvin suspension to explore the feasibility of applying ESCAR in formulation development and bioequivalence studies. The developed LEVEL A IVIVC model demonstrated that the in vivo PK profile could be correlated with the in vitro release profile. Therefore, using this model, for new formulations, only in vitro studies need to be conducted in ESCAR, and in vivo studies might be waived. In conclusion, ESCAR had important implications for research and development and quality control of SC drug products. Future work would be focused on further optimizing ESCAR and expanding its applications via assessing more types of molecules and formulations

Fig 4 -

a) Average spectral amplitudes (mean± SEM) for cued location (blue), same-object location (yellow) and different-object location (red). b) Percentage of participants with significant amplitudes for cued location (blue), same- (yellow), and different-object location (red) at frequencies of 4–10 Hz.</p

Schematic diagram of one trial sequence for each of the three conditions.

Schematic diagram of one trial sequence for each of the three conditions.</p

Fig 3 -

Bootstrapped space- (a) and object-based effects (b) for individual participants. Black dots indicate cue-to-target intervals with significant bootstrapped effects. White dots indicate cue-to-target intervals with significant reversed object-based effects (different-object advantage). The color scale represents the size of the object-based effect in milliseconds (ms), spanning from -200 ms (negative effects) to +200 ms (positive effects). c) The percentage of participants with significant space- (green bars), object- (orange bars), and reversed object-based effects (white bars) in reaction times for each cue-to-target interval. The average percentage of space- (84%), object- (11%) and reversed object-based effects (2%) are indicated by a green/black line, an orange/black line, and a white/black line, respectively.</p

Fig 2 -

a) Mean RTs ± SEM (standard error from the mean) for valid (blue), invalid-same (yellow), and invalid-different trials (red) for all cue-to-target intervals. b) Space-based effects (green line) and object-based effects (orange line) for all cue-to-target intervals. Filled dots showed cue-to-target intervals with significant effects.</p

Additional analysis.

Our attention can be directed to specific locations in our visual field (space-based attention), or to specific objects (object-based attention). However, object-based attention tends to be less pronounced than space-based attention and can vary greatly between individuals. Here we investigated whether the low prevalence of object-based effects is related to variability in the temporal dynamics of attentional selection. We manipulated cue-to-target intervals from 50 to 600 ms in a two-rectangle discrimination task. Space- and object-based effects were measured at the group level and for individual participants. We used bootstrapping to highlight cue-to-target intervals with maximal space- and object-based effects, and fast Fourier transform (FFT) to investigate rhythmic sampling of locations within and between objects. Whereas overall, space-based effects were robust and stable across all cue-to-target intervals for most participants, object-based effects were small and were only found for a small subset of participants in the different cue-to-target intervals. In the frequency domain, only a small number of participants exhibited significant periodicities, prompting the need for further investigation and consideration. Overall, our study suggests variability in the temporal dynamics of object-based effects underlying their low prevalence, a finding that needs to be further investigated in future studies.</div

Molecular Dynamics Simulation of an Iron(III) Binding Site on the Fc Domain of IgG1 Relevant for Visible Light-Induced Protein Fragmentation

Molecular dynamics simulations were employed to investigate the interaction between Fe­(III) and an iron-binding site composed of THR259, ASP252, and GLU261 on the Fc domain of an IgG1. The goal was to provide microscopic mechanistic information for the photochemical, iron-dependent site-specific oxidative fragmentation of IgG1 at THR259 reported in our previous paper. The distance between Fe­(III) and residues of interest as well as the binding pocket size was examined for both protonated and deprotonated THR259. The Fe­(III) binding free energy (ΔG) was estimated by using an umbrella sampling approach. The pKa shift of the THR259 hydroxyl group caused by the presence of nearby Fe­(III) was estimated based on a thermodynamic cycle. The simulation results show that Fe­(III) resides inside the proposed binding pocket and profoundly changes the pocket configuration. The ΔG values indicate that the pocket possesses a strong binding affinity for Fe­(III). Furthermore, Fe­(III) profoundly lowers the pKa value of the THR259 hydroxyl group by 5.4 pKa units

Additional file 1 of Multidimensional self-rating biological rhythm disorder and its association with depression and anxiety symptoms among adolescents aged 11–23 years: a school-based cross-sectional study from China

Additional file 1: Fig. S1. Study participant flow diagram

Table_1_Trends of overweight and obesity prevalence in school-aged children among Henan Province from 2000 to 2019.DOCX

ObjectivesOverweight and obesity are harmful to human health. However, the latest trends of Chinese childhood overweight and obesity prevalence are not available. The aim of this study was to examine the trends from 2000 to 2019 among students in China.MethodsWe analyzed data of 66,072 students in the Chinese National Survey on Students' Constitution and Health from 2000 to 2019. Overweight and obesity were defined based on the standard formulated by the International Obesity Task Force (IOTF standard), the World Health Organization (WHO standard), and the Working Group on Obesity in China (WGOC standard), respectively. The χ2-test was used to test the trends of overweight and obesity prevalence and logistic regression was conducted to evaluate the prevalence odds ratios of boys vs. girls and urban vs. rural areas.ResultsThe prevalence of obesity/overweight and obesity combined was 6.03/23.58% (IOTF standard), 10.56/25.88% (WGOC standard) and 10.75/29.69% (WHO standard) in 2019. From 2000 to 2019, according to the WGOC standard, the prevalence increased from 2.51 to 10.56% for obesity and increased from 9.81 to 25.88% for overweight and obesity combined (P for trend ConclusionOverweight and obesity prevalence increased significantly in children and adolescents in China from 2000 to 2019. The prevalence of overweight and obesity in rural areas may contribute to a large percentage of children with overweight and obesity.</p

Additional file 2 of Multidimensional self-rating biological rhythm disorder and its association with depression and anxiety symptoms among adolescents aged 11–23 years: a school-based cross-sectional study from China

Additional file 2: Table S1. Sensitivity analysis. Table S2. The distribution of the score of the Self-Rating of Biological Rhythm Disorder for Adolescents (SBRDA). Table S3. Sample characteristics stratified by sleep rhythm disorder (N = 3693). Table S4. Sample characteristics stratified by activity rhythm disorder (N = 3693). Table S5. Sample characteristics stratified by eating habits rhythm disorder (N = 3693). Table S6. Sample characteristics stratified by digital media use (N = 3693). Table S7. Partial coefficients between self-rating biological rhythm disorders and Depression and anxiety symptoms. Table S8. Adjusted associations between self-rating biological rhythm disorders and depression symptoms. Table S9. Adjusted associations between self-rating biological rhythm disorders and anxiety symptoms