Population Genetics Identifies Challenges in Analyzing Rare Variants

Geneticists have, for years, understood the nature of genome‐wide association studies using common genomic variants. Recently, however, focus has shifted to the analysis of rare variants. This presents potential problems for researchers, as rare variants do not always behave in the same way common variants do, sometimes rendering decades of solid intuition moot. In this paper, we present examples of the differences between common and rare variants. We show why one must be significantly more careful about the origin of rare variants, and how failing to do so can lead to highly inflated type I error. We then explain how to best avoid such concerns with careful understanding and study design. Additionally, we demonstrate that a seemingly low error rate in next‐generation sequencing can dramatically impact the false‐positive rate for rare variants. This is due to the fact that rare variants are, by definition, seen infrequently, making it hard to distinguish between errors and real variants. Compounding this problem is the fact that the proportion of errors is likely to get worse, not better, with increasing sample size. One cannot simply scale their way up in order to solve this problem. Understanding these potential pitfalls is a key step in successfully identifying true associations between rare variants and diseases.     

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.     

Caution! Overestimation of treatment effects of corticosteroid therapy for community-acquired pneumonia in a meta-analysis of randomized controlled trials

It is well known that a meta-analysis of randomized controlled trials aims to increase the power and precision of the estimated intervention effects. However, when a meta-analysis includes a limited number of patients and a small number of events, overestimation of intervention effect estimates may occur and could cause spurious results. Although many biases can cause the overestimation, random error may be the most common cause. Trial sequential analysis (TSA) can explore the independent effect of random error on intervention effect estimates in meta-analyses and protect meta-analyses against overestimation due to random error.     

Factors influencing development of residual stresses during crystallization firing in a novel lithium silicate glass-ceramic

ObjectiveDevelopment of residual stresses is a potential source of premature fractures in glassy materials, being of special interest in novel lithium silicate glass-ceramics that require a crystallization firing to achieve their final mechanical properties. The aim of this work was to assess the influence of various firing tray systems and the application of different cooling protocols on the development of residual stresses in Suprinity PC crowns. Their effect on the in vitro lifetime of the restorations was also studied.MethodsThirty crowns were milled out of Suprinity PC blocks and crystallized using one of five different commercial firing tray systems (n = 6). Samples in each group were cooled following a fast (FC = 5.5 °C/s), a slow (SC = 0.4 °C/s) or the manufacturer’s reference cooling (REF ). Obtained crowns were sagittally or transversally sectioned and the magnitude and distribution of residual stresses was determined using the light birefringence method. Extra crowns of three of the subgroups (n = 8) were produced and submitted to chewing simulation for 10⁶ cycles or until fracture ensued.ResultsAverage residual stresses ranged between 0 and 1.5 MPa (peaks of 5 MPa). Highest stress magnitudes were observed at the support areas of groups using firing pins, leading to thermal cracks in FC samples and premature failures in the REF subgroup. The use of fibrous pads and firing pastes limited the development of residual stresses, whereas application of SC regimes extended the lifetime of the restorations.SignificanceDevelopment of residual stresses during crystallization firing in lithium silicate glass-ceramics results critical for their mechanical performance and should be therefore avoided by ensuring a homogenous cooling of the structures.     

牙冠延长术在残根残冠修复中的临床疗效

目的评价牙冠延长术在牙体缺损达龈下的残根残冠修复中的临床疗效。方法自2004年5月至2005年6月,对32例患者的36颗牙体缺损达龈下的患牙,术前按断端位于龈下最深距离分为A组(20颗患牙,距离<3.0mm)和B组(16颗患牙,3.0mm≤距离≤4.0mm),均采用牙冠延长术暴露龈下牙体断面,术后6周行桩冠修复。分别记录和比较手术前、后牙周探诊深度(PD)、菌斑指数(PLI)、龈沟出血指数(SBI)和牙齿松动度,以观察临床疗效。结果术后随访患者6个月,两组病例术后6周牙体断端均暴露较好、龈缘颜色正常,术后修复效果有效率为100%,满意率为77.78%。A组术后无松动,修复效果满意;B组术后50.00%出现Ⅰ度松动,修复效果欠佳,两组修复效果比较差异有显著意义(P<0.05)。术后各阶段两组的PD、PLI、SBI均明显优于术前(P<0.05),但两组术后牙周指数比较差异无显著意义(P>0.05)。结论牙冠延长术有利于残根残冠的保存和修复,但要注意适应证的选择。