In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field.     

Increased activation of the fear neurocircuitry in children exposed to violence

Most studies investigating the effect of childhood trauma on the brain are retrospective and mainly focus on maltreatment, whereas different types of trauma exposure such as growing up in a violent neighborhood, as well as developmental stage, could have differential effects on brain structure and function. The current magnetic resonance imaging study assessed the effect of trauma exposure broadly and violence exposure more specifically, as well as developmental stage on the fear neurocircuitry in 8‐ to 14‐year‐old children and adolescents (N = 69). We observed reduced hippocampal and increased amygdala volume with increasing levels of trauma exposure. Second, higher levels of violence exposure were associated with increased activation in the amygdala, hippocampus, and ventromedial prefrontal cortex during emotional response inhibition. This association was specifically observed in children younger than 10 years. Finally, increased functional connectivity between the amygdala and brainstem was associated with higher levels of violence exposure. Based on the current findings, it could be hypothesized that trauma exposure during childhood results in structural changes that are associated with later risk for psychiatric disorders. At the same time, it could be postulated that growing up in an unsafe environment leads the brain to functionally adapt to this situation in a way that promotes survival, where the long‐term costs or consequences of these adaptations are largely unknown and an area for future investigations.     

Meta-analysis of the effects of transcranial direct current stimulation on inhibitory control

BackgroundInhibitory control refers to a central cognitive capacity involved in the interruption and correction of actions. Dysfunctions in these cognitive control processes have been identified as major maintaining mechanisms in a range of mental disorders such as ADHD, binge eating disorder, obesity, and addiction. Improving inhibitory control by transcranial direct current stimulation (tDCS) could ameliorate symptoms in a broad range of mental disorders.ObjectiveThe primary aim of this pre-registered meta-analysis was to investigate whether inhibitory control can be improved by tDCS in healthy and clinical samples. Additionally, several moderator variables were investigated.MethodsA comprehensive literature search was performed on PubMed/MEDLINE database, Web of Science, and Scopus. To achieve a homogenous sample, only studies that assessed inhibitory control in the go-/no-go (GNG) or stop-signal task (SST) were included, yielding a total of 75 effect sizes from 45 studies.ResultsResults of the meta-analysis indicate a small but significant overall effect of tDCS on inhibitory control (g = 0.21) which was moderated by target and return electrode placement as well as by the task. The small effect size was further reduced after correction for publication bias.ConclusionBased on the studies included, our meta-analytic approach substantiates previously observed differences between brain regions, i.e., involvement of the right inferior frontal gyrus (rIFG) vs. the right dorsolateral prefrontal cortex (rDLPFC) in inhibitory control. Results indicate a small moderating effect of tDCS on inhibitory control in single-session studies and highlight the relevance of technical and behavioral parameters.     

改良单图像法手工测量髌骨不稳患者胫骨结节-股骨滑车沟间距的可行性分析

目的 探讨改良单图像法手工测量髌骨不稳患者胫骨结节-股骨滑车沟（tibial tuberosity-trochlear groove，TT-TG）间距的可行性。 方法 选取髌骨不稳患者30例。高年资手术医师A、B，使用改良单图像法手工测量髌骨不稳患者TT-TG间距，对比高资年影像学医师C，使用双图法测量髌骨不稳患者TT-TG间距。应用Cronbach′s alpha系数评价结果的可信度。应用组内相关系数（intraclass correlation coefficient，ICC）评价结果的可重复性。使用Bland-Altman分析图评价结果的一致性。 结果 高年资手术医师A、B使用改良单图像法手工测量髌骨不稳患者TT-TG间距分别和高年资影像学医师C使用双图法测量髌骨不稳患者TT-TG间距比较，Cronbach′s alpha系数分别为0.913和0.959，组内相关系数分别为0.913和0.958。Bland-Altman分析图显示，TT-TG间距差值（mm）的均值为-0.276（95%CI：-3.526~2.974）和0.143（95%CI：-3.110~3.397）。A、B医师之间使用改良单图像法手工测量髌骨不稳患者TT-TG间距比较，Cronbach′s alpha系数为0.891，组内相关系数为0.891。Bland-Altman分析图显示TT-TG间距差值（mm）的均值为-0.276（95%CI：-3.526~2.974）。 结论 改良单图像法手工测量髌骨不稳患者TT-TG间距操作简单，可以准确测量出髌骨不稳患者的TT-TG间距，该方法和双图法可以相互替换使用。     

Immune checkpoint inhibitor-induced inflammatory arthritis: identification and management

ABSTRACT

Introduction

Immune checkpoint inhibitors (ICIs) have proved to be groundbreaking in the field of oncology. However, immune system overactivation from ICIs has introduced a novel medical entity known as immune-related adverse events (irAEs), that can affect any organ or tissue. ICI-induced inflammatory arthritis (ICI-IIA) is the most common musculoskeletal irAE and can lead to significant morbidity and limitation in anti-cancer therapy.     

Silicone-based simulation models for peripheral nerve microsurgery

Background

There is a need for a peripheral nerve model on which surgeons-in-training can simulate the repair of nerve injuries at their own pace. Although practicing on animal models/cadavers is considered the “gold standard” of microsurgical training, the proposed model aims to provide a platform for improving the technical skills of surgical trainees prior to their practice on cadaver/animal models. In addition, this model has the potential to serve as a standardized test medium for assessing the skill sets of surgeons.