Seasonal dynamics of seed dormancy and germination in the weed Diplachne fusca.

Background: Understanding the reproductive biology of weeds is crucial for managing them effectively. Diplachne fusca (Poaceae) is a widely distributed weed species that poses significant challenges to agricultural productivity. Nevertheless, it remains unclear how the soil seed bank of D. fusca responds to environmental shifts, and whether a dormancy cycle is present in this species. Methods: We investigated how seed dormancy in D. fusca is broken and how it responds to natural environmental changes. The impact of incubation temperature, light exposure, cold stratification at 4 °C, and gibberellic acid (GA3) on seed germination/dormancy-break was investigated, along with assessing seasonal changes in germinability through monthly excavation and laboratory incubation of buried seeds over 2 years. Results: Results indicated that newly ripened seeds of D. fusca were dormant, with germination facilitated by GA3, cold stratification, and after-ripening at ambient room conditions. Exposure to darkness inhibited germination. Seasonal patterns of germination were observed, with peak germination occurring in cooler months and a marked decline during the hot summer months. After 2 years of being buried, approximately 40% of the seeds remained viable. Conclusion: In summary, seeds of D. fusca exhibit non-deep physiological dormancy and maintain a persistent soil seed bank. Seeds buried in the soil undergo a yearly dormancy/non-dormancy cycle. This dormancy cycle prevents seed germination and seedling emergence in autumn, which boosts the survival of seedlings in less favorable seasons, yet it also makes it more challenging to eradicate this weed.

Causal association between blood leukocyte counts and vascular dementia: a two-sample bidirectional Mendelian randomization study.

While previous observational studies have suggested a link between leukocyte counts and vascular dementia (VD), the causal relationship between leukocyte counts and various subtypes of VD remains elusive. This study aimed to investigate the causal relationship between five types of leukocyte counts and VD, with the goal of improving prevention and treatment strategies. In this study, leukocyte counts were used as the exposure variable, with genome-wide association study (GWAS) data sourced from both the UK Biobank and the Blood Cell Consortium. Additionally, GWAS data for five subtypes of vascular dementia were obtained from the FinnGen database. We conducted rigorous statistical analysis and visualization using Mendelian randomization (MR) to elucidate the potential causal relationship between leukocyte counts and vascular dementia. This study, utilizing MR analysis with data from the UK Biobank and Blood Cell Consortium, identified significant causal associations between increased lymphocyte counts and VD. Specifically, lymphocyte counts were found to be causally related to multiple and mixed VD subtypes. Sensitivity analyses, including MR-Egger regression and MR-PRESSO tests, confirmed the robustness of these findings, with no evidence of reverse causality or significant horizontal pleiotropy detected. The results underscore a potential inflammatory or immunological mechanism in the pathogenesis of VD, highlighting lymphocytes as a key component in their etiology. This investigation establishes a robust association between elevated lymphocyte and leukocyte counts and an increased risk of VD, emphasizing the roles of inflammation, immune activation, and hematological factors in disease pathogenesis.

Screening of novel disease genes of sepsis-induced myocardial Disfunction by RNA sequencing and bioinformatics analysis.

BACKGROUND: There is still a lack of effective treatment for sepsis-induced myocardial dysfunction (SIMD), while the pathogenesis of SIMD still remains largely unexplained. METHODS: RNA sequencing results (GSE267388 and GSE79962) were used for cross-species integrative analysis. Bioinformatic analyses were used to delve into function, tissue- and cell- specificity, and interactions of genes. External datasets and qRT-PCR experiments were used for validation. L1000 FWD was used to predict targeted drugs, and 3D structure files were used for molecular docking. RESULTS: Based on bioinformatic analyses, ten differentially expressed genes were selected as genes of interest, seven of which were verified to be significantly differential expression. Bucladesine was considered as a potential targeted drug for SIMD, which banded to seven target proteins primarily by forming hydrogen bonds. CONCLUSION: It was considered that Cebpd, Timp1, Pnp, Osmr, Tgm2, Cp, and Asb2 were novel disease genes, while bucladesine was a potential therapeutic drug, of SIMD.

Integrative Metabolomics, Enzymatic Activity, and Gene Expression Analysis Provide Insights into the Metabolic Profile Differences between the Slow-Twitch Muscle and Fast-Twitch Muscle of Pseudocaranx dentex.

The skeletal muscles of teleost fish encompass heterogeneous muscle types, termed slow-twitch muscle (SM) and fast-twitch muscle (FM), characterized by distinct morphological, anatomical, histological, biochemical, and physiological attributes, driving different swimming behaviors. Despite the central role of metabolism in regulating skeletal muscle types and functions, comprehensive metabolomics investigations focusing on the metabolic differences between these muscle types are lacking. To reveal the differences in metabolic characteristics between the SM and FM of teleost, we conducted an untargeted metabolomics analysis using Pseudocaranx dentex as a representative model and identified 411 differential metabolites (DFMs), of which 345 exhibited higher contents in SM and 66 in FM. KEGG enrichment analysis showed that these DFMs were enriched in the metabolic processes of lipids, amino acids, carbohydrates, purines, and vitamins, suggesting that there were significant differences between the SM and FM in multiple metabolic pathways, especially in the metabolism of energy substances. Furthermore, an integrative analysis of metabolite contents, enzymatic activity assays, and gene expression levels involved in ATP-PCr phosphate, anaerobic glycolysis, and aerobic oxidative energy systems was performed to explore the potential regulatory mechanisms of energy metabolism differences. The results unveiled a set of differential metabolites, enzymes, and genes between the SM and FM, providing compelling molecular evidence of the FM achieving a higher anaerobic energy supply capacity through the ATP-PCr phosphate and glycolysis energy systems, while the SM obtains greater energy supply capacity via aerobic oxidation. These findings significantly advance our understanding of the metabolic profiles and related regulatory mechanisms of skeletal muscles, thereby expanding the knowledge of metabolic physiology and ecological adaptation in teleost fish.

Seasonality Affects Fluid Intake Behaviors among Young Adults in Hebei, China.

BACKGROUND: Evidence on the association between environmental factors and fluid intake behavior remains limited. The current study aims to explore seasonal variations in fluid intake behaviors among young adults in China. METHODS: A prospective cohort of 79 healthy young adults (43 males and 36 females) aged 19-21 in Hebei, China, was assessed for fluid intake behaviors for four seasons. For each assessment, the participants' anthropometric measurements were collected. Temperature and humidity on survey days were measured. Participants' total drinking fluid (TDF) was recorded using a self-administrative 7 d, 24 h fluid intake questionnaire. To calculate water from food (WFF), we weighed all foods consumed by participants. Duplicates of consumed food samples were collected to measure the water content via the drying method. RESULTS: The mean total water intake (TWI) was 2761 ± 881, 2551 ± 845, 2210 ± 551, and 1989 ± 579 for spring, summer, fall, and winter, respectively (F(2.37) = 42.29, p < 0.001). The volume and proportion of TWI from TDF and WFF varied across the four seasons. The volume of WFF in spring (1361 ± 281, F(2.61) = 17.21, p < 0.001) and TDF in summer (1218 ± 502, F(2.62) = 9.36, p < 0.001) was among the highest, while participants' fluid intake behaviors in spring and summer were less distinct than the other pairwise comparisons. A moderate association was found between outdoor temperature and TDF (r = 0.53, p < 0.01). Different general estimating equations suggested that gender, seasonality, outdoor temperature, differences in indoor and outdoor temperature, and mean temperature were independent factors of TDF. An interactive effect was found for gender and temperature, showing that the expected TDF of males may increase more as the temperature climbs. CONCLUSIONS: Gender, seasonality, and air temperature could significantly affect fluid intake behaviors, including the amount and type of fluid intake. However, the independent effect of BMI and humidity remains unclear.

Age-Related Conservation in Plant-Soil Feedback Accompanied by Ectomycorrhizal Domination in Temperate Forests in Northeast China.

This study investigates the effects of forest aging on ectomycorrhizal (EcM) fungal community and foraging behavior and their interactions with plant-soil attributes. We explored EcM fungal communities and hyphal exploration types via rDNA sequencing and investigated their associations with plant-soil traits by comparing younger (~120 years) and older (~250 years) temperate forest stands in Northeast China. The results revealed increases in the EcM fungal richness and abundance with forest aging, paralleled by plant-soil feedback shifting from explorative to conservative nutrient use strategies. In the younger stands, Tomentella species were prevalent and showed positive correlations with nutrient availability in both the soil and leaves, alongside rapid increases in woody productivity. However, the older stands were marked by the dominance of the genera Inocybe, Hymenogaster, and Otidea which were significantly and positively correlated with soil nutrient contents and plant structural attributes such as the community-weighted mean height and standing biomass. Notably, the ratios of longer-to-shorter distance EcM fungal exploration types tended to decrease along with forest aging. Our findings underscore the integral role of EcM fungi in the aging processes of temperate forests, highlighting the EcM symbiont-mediated mechanisms adapting to nutrient scarcity and promoting sustainability in plant-soil consortia.

Translational two-pore PBPK model to characterize whole-body disposition of different-size endogenous and exogenous proteins.

Two-pore physiologically based pharmacokinetic (PBPK) modeling has demonstrated its potential in describing the pharmacokinetics (PK) of different-size proteins. However, all existing two-pore models lack either diverse proteins for validation or interspecies extrapolation. To fill the gap, here we have developed and optimized a translational two-pore PBPK model that can characterize plasma and tissue disposition of different-size proteins in mice, rats, monkeys, and humans. Datasets used for model development include more than 15 types of proteins: IgG (150 kDa), F(ab)2 (100 kDa), minibody (80 kDa), Fc-containing proteins (205, 200, 110, 105, 92, 84, 81, 65, or 60 kDa), albumin conjugate (85.7 kDa), albumin (67 kDa), Fab (50 kDa), diabody (50 kDa), scFv (27 kDa), dAb2 (23.5 kDa), proteins with an albumin-binding domain (26, 23.5, 22, 16, 14, or 13 kDa), nanobody (13 kDa), and other proteins (110, 65, or 60 kDa). The PBPK model incorporates: (i) molecular weight (MW)-dependent extravasation through large and small pores via diffusion and filtration, (ii) MW-dependent renal filtration, (iii) endosomal FcRn-mediated protection from catabolism for IgG and albumin-related modalities, and (iv) competition for FcRn binding from endogenous IgG and albumin. The finalized model can well characterize PK of most of these proteins, with area under the curve predicted within two-fold error. The model also provides insights into contribution of renal filtration and lysosomal degradation towards total elimination of proteins, and contribution of paracellular convection/diffusion and transcytosis towards extravasation. The PBPK model presented here represents a cross-modality, cross-species platform that can be used for development of novel biologics.

Development of a generalized pharmacokinetic model to characterize clinical pharmacokinetics of monomethyl auristatin E-based antibody-drug conjugates.

AIMS: This study aims to develop a generalized pharmacokinetic (PK) model for monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) that can simultaneously capture the PK of multiple ADC analytes commonly measured in the clinic. METHODS: A comprehensive literature review was conducted to collect PK data on MMAE-based ADCs from clinical trials. From each study, PK profiles of total antibody, the ADC, conjugated MMAE, and unconjugated MMAE, were extracted. These data were pooled and dose-normalized to evaluate the generalizability of PK across various ADCs and dose levels. Upon confirming PK generalizability, a generalized PK model for MMAE-based ADCs was developed using the entire dataset. Furthermore, exposure metrics ( C max and AUC) reported across the range of doses were combined to establish linear relationships between dose and exposure metrics for MMAE-based ADCs. RESULTS: A total of 109 PK profiles from 18 distinct MMAE-based ADCs were gathered. The dose-normalized PK profiles supported the generalizability of PK for MMAE-based ADCs. A generalized PK model was developed, which enabled capturing the PK data for 4 ADC analytes across all collected MMAE-based ADCs. A linear relationship between dose and PK exposure metrics was established, enabling the prediction of typical exposure values across different doses for MMAE-based ADCs. CONCLUSIONS: This study comprehensively analysed clinical PK data from different valine-citrulline (vc)-MMAE-based ADCs. The generalized PK model developed here serves as an important tool for a priori prediction of the PK for multiple ADC analytes in clinical settings and lays the foundation for establishing generalized exposure-response and exposure-toxicity correlations for MMAE-based ADCs.

Mixed Reality as a Digital Visualisation Solution for the Head and Neck Tumour Board: Application Creation and Implementation Study.

The preparation and implementation of interdisciplinary oncological case reviews are time-consuming and complex. The variety of clinical and radiological information must be presented in a clear and comprehensible manner. Only if all relevant patient-specific information is demonstrated in a short time frame can well-founded treatment decisions be made on this basis. Mixed reality (MR) technology as a multimodal interactive user interface could enhance understanding in multidisciplinary collaboration by visualising radiological or clinical data. The aim of the work was to develop an MR-based software prototype for a head and neck tumour board (HNTB) to support clinical decision-making. The article describes the development phases and workflows in the planning and creation of a MR-based software prototype that were required to meet the multidisciplinary characteristics of a HNTB.

An automated ICU agitation monitoring system for video streaming using deep learning classification.

OBJECTIVE: To address the challenge of assessing sedation status in critically ill patients in the intensive care unit (ICU), we aimed to develop a non-contact automatic classifier of agitation using artificial intelligence and deep learning. METHODS: We collected the video recordings of ICU patients and cut them into 30-second (30-s) and 2-second (2-s) segments. All of the segments were annotated with the status of agitation as "Attention" and "Non-attention". After transforming the video segments into movement quantification, we constructed the models of agitation classifiers with Threshold, Random Forest, and LSTM and evaluated their performances. RESULTS: The video recording segmentation yielded 427 30-s and 6405 2-s segments from 61 patients for model construction. The LSTM model achieved remarkable accuracy (ACC 0.92, AUC 0.91), outperforming other methods. CONCLUSION: Our study proposes an advanced monitoring system combining LSTM and image processing to ensure mild patient sedation in ICU care. LSTM proves to be the optimal choice for accurate monitoring. Future efforts should prioritize expanding data collection and enhancing system integration for practical application.

The association between hydration state and the metabolism of phospholipids and amino acids among young adults: a metabolomic analysis.

Background: Water is vital for humans' survival and general health, which is involved in various metabolic activities. Objectives: The aim of this study was to investigate the variation in urine metabolome and associated metabolic pathways among people with different hydration states. Methods: A metabolomic analysis was conducted using 24-h urine samples collected during a cross-sectional study on fluid intake behavior from December 9 to 11, 2021, in Hebei, China. Subjects were divided into the optimal hydration (OH, ≤500 mOsm/kg, n = 21), middle hydration (500-800 mOsm/kg, n = 33), and hypohydration groups (HH, >800 mOsm/kg, n = 13) based on the 3-d average 24-h urine osmolality. Collected 24-h urine samples from 67 subjects (43 males and 34 females) were analyzed for urine metabolome using liquid chromatography-MS. Results: The untargeted metabolomic analysis yielded 1055 metabolites by peak intensities. Integrating the results of the orthogonal projections to latent structures discriminant analysis and fold change test, 115 differential metabolites between the OH and HH groups, including phospholipids (PLs) and lysophospholipids, were identified. Among the 115 metabolites identified as differential metabolites, 85 were recorded by the Human Metabolome Database and uploaded to the Kyoto Encyclopedia of Genes and Genomes databases for pathway analysis. Twenty-one metabolic pathways were recognized. Phenylalanine metabolism (0.50, P = 0.007), phenylalanine, tyrosine, and tryptophan biosynthesis (0.50, P = 0.051), glycerophospholipid metabolism (0.31, P < 0.001), sphingolipid metabolism (0.27, P = 0.029), and cysteine and methionine metabolism (0.10, P = 0.066) had the leading pathway impacts. Conclusions: We found variations in the urinary PLs and amino acids among subjects with different hydration states. Pathways associated with these differential metabolites could further impact various physiologic and pathologic functions. A more comprehensive and in-depth investigation of the physiologic and pathologic impact of the hydration state and the underlying mechanisms to elucidate and advocate optimal fluid intake habits is needed.This trial was registered at Chinese Clinical Trial Registry as ChiCTR2100045268.

DNA barcoding, identification, and validation of the pufferfish (Order: Tetraodontiformes) in China coastal waters.

The order Tetraodontiformes are one of the most unique groups of teleostean fish, exhibiting highly derived and greatly diversified phenotypes. It is a difficult task for both professionals and nonprofessionals to accurately identify these species only according to morphological characteristics. DNA barcoding can identify species at the molecular level to overcome the limitations of morphological classification. In this study, we collected 616 specimens of pufferfish from the coastal waters of China. According to the morphological characteristics, they were preliminarily identified as 50 species. Further analysis using DNA barcodes identified these specimens as 46 species, belonging to 23 genera, 6 families. According to the species classification results of DNA barcoding, the three species identified by morphology as Takifugu pseudommus, Takifugu chinensis, and Takifugu rubripes should be the same species. Similarly, Lagocephalus wheeleri is the synonym of Lagocephalus spadiceus. Another important discovery of DNA barcoding analysis is that there are closer interspecific genetic distances within the genus Takifugu. If T. rubripes, T. pseudommus, and T. chinensis are taken as one species, the average interspecific to intraspecific genetic distance ratio of Takifugu is only 6.21 times, which does not reach the DNA barcoding threshold of more than 10 times proposed previously. Although the interspecific genetic distance in the genus Takifugu is relatively small, each species can be clustered into independent clades in the NJ tree. In conclusion, this study not only found that there are synonymous phenomena in the order Tetraodontiformes but also provided molecular evidence for the valid species names of Takifugu rubripes and Lagocephalus Spadiceus. The results can provide reliable DNA barcoding information for the identification of pufferfish species, help solve the problem of classification confusion in this order, and provide technical support for the identification of the original components of related commodities on the aquatic product market.

A basket trial design based on constrained hierarchical Bayesian model for latent subgroups.

It is well known a basket trial consisting of multiple cancer types has the potential of borrowing strength across the baskets defined by the cancer types, leading to an efficient design in terms of sample size and trial duration. The treatment effects in those baskets are often heterogeneous and categorized by the cancer types being sensitive or insensitive to the treatment. Hence, the assumption of exchangeability in many existing basket trials may be violated, and there is a need to design trials without this assumption. In this paper, we simplify the constrained hierarchical Bayesian model for latent subgroups (CHBM-LS) for two classifiers to deal with the potential heterogeneity of treatment effects due to the single classifier of the cancer type. Different baskets are aggregated into subgroups using a latent subgroup modeling approach. The treatment effects are similar and exchangeable to facilitate information borrowing within each latent subgroup. Applying the simplified CHBM-LS approach to the real basket trials where baskets defined by only cancer types shows better performance than other available approaches. Further simulation study also demonstrates this CHBM-LS approach outperforms other approaches with higher statistical power and better-controlled type I error rates under various scenarios.

Mitochondrial Homeostasis Regulating Mitochondrial Number and Morphology Is a Distinguishing Feature of Skeletal Muscle Fiber Types in Marine Teleosts.

Fishes' skeletal muscles are crucial for swimming and are differentiated into slow-twitch muscles (SM) and fast-twitch muscles (FM) based on physiological and metabolic properties. Consequently, mitochondrial characteristics (number and morphology) adapt to each fiber type's specific functional needs. However, the mechanisms governing mitochondrial adaptation to the specific bioenergetic requirements of each fiber type in teleosts remain unclear. To address this knowledge gap, we investigated the mitochondrial differences and mitochondrial homeostasis status (including biogenesis, autophagy, fission, and fusion) between SM and FM in teleosts using Takifugu rubripes as a representative model. Our findings reveal that SM mitochondria are more numerous and larger compared to FM. To adapt to the increased mitochondrial number and size, SM exhibit elevated mitochondrial biogenesis and dynamics (fission/fusion), yet show no differences in mitochondrial autophagy. Our study provides insights into the adaptive mechanisms shaping mitochondrial characteristics in teleost muscles. The abundance and elongation of mitochondria in SM are maintained through elevated mitochondrial biogenesis, fusion, and fission, suggesting an adaptive response to fulfill the bioenergetic demands of SM that rely extensively on OXPHOS in teleosts. Our findings enhance our understanding of mitochondrial adaptations in diverse muscle types among teleosts and shed light on the evolutionary strategies of bioenergetics in fishes.

Combined use of 3D printing and mixed reality technology for neurosurgical training: getting ready for brain surgery.

OBJECTIVE: Learning surgical skills is an essential part of neurosurgical training. Ideally, these skills are acquired to a sufficient extent in an ex vivo setting. The authors previously described an in vitro brain tumor model, consisting of a cadaveric animal brain injected with fluorescent agar-agar, for acquiring a wide range of basic neuro-oncological skills. This model focused on haptic skills such as safe tissue ablation technique and the training of fluorescence-based resection. As important didactical technologies such as mixed reality and 3D printing become more readily available, the authors developed a readily available training model that integrates the haptic aspects into a mixed reality setup. METHODS: The anatomical structures of a brain tumor patient were segmented from medical imaging data to create a digital twin of the case. Bony structures were 3D printed and combined with the in vitro brain tumor model. The segmented structures were visualized in mixed reality headsets, and the congruence of the printed and the virtual objects allowed them to be spatially superimposed. In this way, users of the system were able to train on the entire treatment process from surgery planning to instrument preparation and execution of the surgery. RESULTS: Mixed reality visualization in the joint model facilitated model (patient) positioning as well as craniotomy and the extent of resection planning respecting case-dependent specifications. The advanced physical model allowed brain tumor surgery training including skin incision; craniotomy; dural opening; fluorescence-guided tumor resection; and dura, bone, and skin closure. CONCLUSIONS: Combining mixed reality visualization with the corresponding 3D printed physical hands-on model allowed advanced training of sequential brain tumor resection skills. Three-dimensional printing technology facilitates the production of a precise, reproducible, and worldwide accessible brain tumor surgery model. The described model for brain tumor resection advanced regarding important aspects of skills training for neurosurgical residents (e.g., locating the lesion, head position planning, skull trepanation, dura opening, tissue ablation techniques, fluorescence-guided resection, and closure). Mixed reality enriches the model with important structures that are difficult to model (e.g., vessels and fiber tracts) and advanced interaction concepts (e.g., craniotomy simulations). Finally, this concept demonstrates a bridging technology toward intraoperative application of mixed reality.

Pharmacokinetics of AAV9 Mediated Trastuzumab Expression in Rat Brain Following Systemic and Local Administration.

INTRODUCTION: Recombinant adeno-associated viruses(rAAVs) are an attractive tool to ensure long-term expression monoclonal antibody(mAb) in the central nervous system(CNS). It is still unclear whether systemic injection or local CNS administration of AAV9 is more beneficial for the exposure of the expressed mAb in the brain. Hence, we compared the biodistribution and transgene expression following AAV9-Trastuzumab administration through different routes. METHODS AND RESULT: In-house generated AAV9-Trastuzumab vectors were administered at 5E+11 Vgs/rat through intravenous(IV), intracerebroventricular(ICV), intra-cisterna magna(ICM) and intrastriatal(IST) routes. Vector and trastuzumab blood/plasma concentrations were assessed at different time points up to the terminal time point of 21 days. Different brain regions in addition to the spinal cord, cerebrospinal fluid(CSF) and interstitial fluid(ISF), were also analyzed at the terminal time point. Our results show that vector biodistribution and Trastuzumab expression in the brain could the ranked as follows: IST>ICM>ICV>IV. Rapid clearance of vector was observed after administration via the ICM and ICV routes. The ICV route produced similar expression levels across different brain regions, while the ICM route had better expression in the hindbrain and spinal cord region. The IST route had higher expression in the forebrain region compared to the hindbrain region. A sharp decline in trastuzumab plasma concentration was observed across all routes of administration due to anti-trastuzumab antibody response. CONCLUSION: In this study we have characterized vector biodistribution and transgene mAb expression after AAV9 vector administration through different routes in rats. IST and ICM represent the best administration routes to deliver antibody genes to the brain.

Whole-Body Disposition and Physiologically Based Pharmacokinetic Modeling of Adeno-Associated Viruses and the Transgene Product.

To facilitate model-informed drug development (MIDD) of adeno-associated virus (AAV) therapy, here we have developed a physiologically based pharmacokinetic (PBPK) model for AAVs following preclinical investigation in mice. After 2E11 Vg/mouse dose of AAV8 and AAV9 encoding a monoclonal antibody (mAb) gene, whole-body disposition of both the vector and the transgene mAb was evaluated over 3 weeks. At steady-state, the following tissue-to-blood (T/B) concentration ratios were found for AAV8/9: ∼50 for liver; ∼10 for heart and muscle; ∼2 for brain, lung, kidney, adipose, and spleen; ≤1 for bone, skin, and pancreas. T/B values for mAb were compared with the antibody biodistribution coefficients, and five different clusters of organs were identified based on their transgene expression profile. All the biodistribution data were used to develop a novel AAV PBPK model that incorporates: (i) whole-body distribution of the vector; (ii) binding, internalization, and intracellular processing of the vector; (iii) transgene expression and secretion; and (iv) whole-body disposition of the secreted transgene product. The model was able to capture systemic and tissue PK of the vector and the transgene-produced mAb reasonably well. Pathway analysis of the PBPK model suggested that liver, muscle, and heart are the main contributors for the secreted transgene mAb. Unprecedented PK data and the novel PBPK model developed here provide the foundation for quantitative systems pharmacology (QSP) investigations of AAV-mediated gene therapies. The PBPK model can also serve as a quantitative tool for preclinical study design and preclinical-to-clinical translation of AAV-based gene therapies.

A New Approach to Virtual Occlusion in Orthognathic Surgery Planning Using Mixed Reality-A Technical Note and Review of the Literature.

Orthognathic surgery plays a vital role in correcting various skeletal discrepancies of the maxillofacial region. Achieving optimal occlusion is a fundamental aspect of orthognathic surgery planning, as it directly influences postoperative outcomes and patient satisfaction. Traditional methods for setting final occlusion involve the use of dental casts which are time-consuming, prone to errors and cannot be easily shared among collaborating specialties. In recent years, advancements in digital technology have introduced innovative approaches, such as virtual occlusion, which may offer enhanced accuracy and efficiency in orthognathic surgery planning. Furthermore, the emergence of mixed reality devices and their 3D visualization capabilities have brought about novel benefits in the medical field, particularly in computer-assisted planning. This paper presents for the first time a prototype tool for setting virtual occlusion during orthognathic surgery planning using mixed reality technology. A complete walkthrough of the workflow is presented including an explanation of the implicit advantages of this novel tool. The new approach to defining virtual occlusion is set into context with other published methods of virtual occlusion setting, discussing advantages and limitations as well as concepts of surgical occlusion for orthognathic surgery.

Utility of physiologically based pharmacokinetic modeling to predict inter-antibody variability in monoclonal antibody pharmacokinetics in mice.

In this investigation, we tested the hypothesis that a physiologically based pharmacokinetic (PBPK) model incorporating measured in vitro metrics of off-target binding can largely explain the inter-antibody variability in monoclonal antibody (mAb) pharmacokinetics (PK). A diverse panel of 83 mAbs was evaluated for PK in wild-type mice and subjected to 10 in vitro assays to measure major physiochemical attributes. After excluding for target-mediated elimination and immunogenicity, 56 of the remaining mAbs with an eight-fold variability in the area under the curve (AUC0-672h: 1.74 × 106 -1.38 × 107 ng∙h/mL) and 10-fold difference in clearance (2.55-26.4 mL/day/kg) formed the training set for this investigation. Using a PBPK framework, mAb-dependent coefficients F1 and F2 modulating pinocytosis rate and convective transport, respectively, were estimated for each mAb with mostly good precision (coefficient of variation (CV%) <30%). F1 was estimated to be the mean and standard deviation of 0.961 ± 0.593, and F2 was estimated to be 2.13 ± 2.62. Using principal component analysis to correlate the regressed values of F1/F2 versus the multidimensional dataset composed of our panel of in vitro assays, we found that heparin chromatography retention time emerged as the predictive covariate to the mAb-specific F1, whereas F2 variability cannot be well explained by these assays. A sigmoidal relationship between F1 and the identified covariate was incorporated within the PBPK framework. A sensitivity analysis suggested plasma concentrations to be most sensitive to F1 when F1 > 1. The predictive utility of the developed PBPK model was evaluated against a separate panel of 14 mAbs biased toward high clearance, among which area under the curve of PK data of 12 mAbs was predicted within 2.5-fold error, and the positive and negative predictive values for clearance prediction were 85% and 100%, respectively. MAb heparin chromatography assay output allowed a priori identification of mAb candidates with unfavorable PK.

Diagnosis and management of Neuro-Behçet disease with isolated intracranial hypertension: a case report and literature review.

BACKGROUND: Neuro-Behçet's disease (NBD), characterized by isolated intracranial hypertension, is a rarely encountered condition, especially in children. In this study, we describe the treatment of a pediatric patient with NBD, who exhibited isolated intracranial pressure elevation as indicated by the initial manifestation of diplopia and physical examination finding of papilledema. CASE PRESENTATION: An 8-year-old boy was admitted to the hospital with a confirmed diagnosis of Behçet's disease (BD) over eight months. The patient also presented with the symptom of diplopia for three days. The evaluation of the patient's nervous system did not reveal any apparent abnormalities. The measurement of cerebrospinal fluid pressure yielded a reading of 470 mm H2O. The examination of the fundus indicated papilledema, and imaging scans revealed evidence of focal demyelination. The symptoms of the child showed alleviation after the administration of mannitol, methylprednisolone, and azathioprine. Furthermore, this study involved a comprehensive analysis of 18 cases of NBD with isolated intracranial hypertension, comprising one case reported herein and 17 cases from the literature review. Three cases were children, and an equal distribution of males and females 9:9 was noted. The average age at the onset of symptoms was 24.7 years (8-38 years). Headache (90%) was the most commonly reported clinical manifestation, followed by blurred vision or diplopia (80%). The ocular manifestations included papilledema (100%), abducent nerve paralysis (20%) and local eye hemorrhages in the retina (30%). Notably, 88.9% of these ocular manifestations were relieved or cured after treatment. CONCLUSION: This study presents the first reported case of NBD with isolated intracranial hypertension in the pediatric population of China. In a child with Bechet's disease presenting with features of raised intracranial pressure, it is important to be aware of neuro Bechet's presenting with intracranial hypertension without other neurological abnormalities. This will help make early diagnosis, institute treatment and prevent sequelae resulting from untreated raised intracranial pressure.