Addressing the challenges of transforming laboratory advances into Alzheimer's Disease treatments

This essay addresses the challenges of clinical trials to develop treatments for Alzheimer’s Disease (AD). The issues covered are enrolling subjects, defining clinically meaningful endpoints, and making the claim that a drug slows the progression of the disease. The perspective to address these challenges is that dementia research should embrace a biopsychosocial model for drug development. In this model, the patient and caregiver are seen as interrelated subjects of both treatment and research and outcome measures reflect biomarkers of the disease, the functional morbidity of AD and the distress of caregiving.     

Minimizing Barriers in Learning for On-Call Radiology Residents—End-to-End Web-Based Resident Feedback System

Feedback is an essential part of medical training, where trainees are provided with information regarding their performance and further directions for improvement. In diagnostic radiology, feedback entails a detailed review of the differences between the residents’ preliminary interpretation and the attendings’ final interpretation of imaging studies. While the on-call experience of independently interpreting complex cases is important to resident education, the more traditional synchronous “read-out” or joint review is impossible due to multiple constraints. Without an efficient method to compare reports, grade discrepancies, convey salient teaching points, and view images, valuable lessons in image interpretation and report construction are lost. We developed a streamlined web-based system, including report comparison and image viewing, to minimize barriers in asynchronous communication between attending radiologists and on-call residents. Our system provides real-time, end-to-end delivery of case-specific and user-specific feedback in a streamlined, easy-to-view format. We assessed quality improvement subjectively through surveys and objectively through participation metrics. Our web-based feedback system improved user satisfaction for both attending and resident radiologists, and increased attending participation, particularly with regards to cases where substantive discrepancies were identified.     

Development and evolution of tooth renewal in neoselachian sharks as a model for transformation in chondrichthyan dentitions

A defining feature of dentitions in modern sharks and rays is the regulated pattern order that generates multiple replacement teeth. These are arranged in labio‐lingual files of replacement teeth that form in sequential time order both along the jaw and within successively initiated teeth in a deep dental lamina. Two distinct adult dentitions have been described: alternate, in which timing of new teeth alternates between two adjacent files, each erupting separately, and the other arranged as single files, where teeth of each file are timed to erupt together, in some taxa facilitating similarly timed teeth to join to form a cutting blade. Both are dependent on spatiotemporally regulated formation of new teeth. The adult Angel shark Squatina (Squalomorphii) exemplifies a single file dentition, but we obtained new data on the developmental order of teeth in the files of Squatina embryos, showing alternate timing of tooth initiation. This was based on micro‐CT scans revealing that the earliest mineralised teeth at the jaw margin and their replacements in file pairs (odd and even jaw positions) alternate in their initiation timing. Along with Squatina, new observations from other squalomorphs such as Hexanchus and Chlamydoselachus, together with representatives of the sister group Galeomorphii, have established that the alternate tooth pattern (initiation time and replacement order) characterises the embryonic dentition of extant sharks; however, this can change in adults. These character states were plotted onto a recent phylogeny, demonstrating that the Squalomorphii show considerable plasticity of dental development. We propose a developmental‐evolutionary model to allow change from the alternate to a single file alignment of replacement teeth. This establishes new dental morphologies in adult sharks from inherited alternate order.     

Stroma: the forgotten cells of innate immune memory

All organisms are exposed constantly to a variety of infectious and injurious stimuli. These induce inflammatory responses tailored to the threat posed. While the innate immune system is the front line of response to each stimulant, it has been considered traditionally to lack memory, acting in a generic fashion until the adaptive immune arm can take over. This outmoded simplification of the roles of innate and acquired arms of the immune system has been challenged by evidence of myeloid cells altering their response to subsequent encounters based on earlier exposure. This concept of ‘innate immune memory’ has been known for nearly a century, and is accepted among myeloid biologists. In recent years other innate immune cells, such as natural killer cells, have been shown to display memory, suggesting that innate immune memory is a trait common to several cell types. During the last 30 years, evidence has slowly accumulated in favour of not only haematopoietic cells, but also stromal cells, being imbued with memory following inflammatory episodes. A recent publication showing this also to be true in epithelial cells suggests innate immune memory to be widespread, if under‐appreciated, in non‐haematopoietic cells. In this review, we will examine the evidence supporting the existence of innate immune memory in stromal cells. We will also discuss the ramifications of memory in long‐lived tissue‐resident cells. Finally, we will pose questions we feel to be important in the understanding of these forgotten cells in the field of innate memory.     

On the Performance of Multiple Imputation Based on Chained Equations in Tackling Missing Data of the African α3.7‐Globin Deletion in a Malaria Association Study

Multiple imputation based on chained equations (MICE) is an alternative missing genotype method that can use genetic and nongenetic auxiliary data to inform the imputation process. Previously, MICE was successfully tested on strongly linked genetic data. We have now tested it on data of the HBA2 gene which, by the experimental design used in a malaria association study in Tanzania, shows a high missing data percentage and is weakly linked with the remaining genetic markers in the data set. We constructed different imputation models and studied their performance under different missing data conditions. Overall, MICE failed to accurately predict the true genotypes. However, using the best imputation model for the data, we obtained unbiased estimates for the genetic effects, and association signals of the HBA2 gene on malaria positivity. When the whole data set was analyzed with the same imputation model, the association signal increased from 0.80 to 2.70 before and after imputation, respectively. Conversely, postimputation estimates for the genetic effects remained the same in relation to the complete case analysis but showed increased precision. We argue that these postimputation estimates are reasonably unbiased, as a result of a good study design based on matching key socio‐environmental factors.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.