Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation, we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressing markers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non-HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder.cerebral cortex | developmental disorders D own syndrome (DS) is the most frequent single cause of human birth defects and intellectual disability (ID) (1). DS is caused by trisomy of chromosome 21 (Ts21) (2), resulting in the triplication of over 400 genes (3-5), which makes elucidation of the precise mechanisms underlying ID in DS a significant challenge. Confounding this difficulty is the relative inaccessibility of human tissue and incomplete human Ts21 in the context of mouse models. Despite these shortcomings, studies using mouse models containing trisomy of parts of syntenic chromosome 21 (HSA21) have put forth several critical hypotheses on the cellular and molecular mechanisms underlying DS features. It is essential, however, to test these hypotheses in human cells with full triplication of HSA21 in a context that allows for normal gene regulation. Here, we used Ts21-induced pluripotent stem cells (iPSCs) to test hypotheses of the underlying causes of ID in DS, with specific regard to neuropathophysiology. ResultsIsogenic Human Ts21 iPSCs. Fibroblasts from two individuals diagnosed with DS were reprogrammed to iPSCs. FISH for HSA21 in one fibroblast line showed mosaicism, where ∼90% of cells carried Ts21, whereas ∼10% were euploid (Fig. 1A). Reprogramming of the mosaic fibroblasts by retrovirus (6) resulted in three viable iPSC clones, two clones that carried Ts21 and one euploid (Fig. 1B). Mosaicism in DS individuals is rare, occurring in ∼1-3% of DS cases (7), but it can also emerge in vitro (8), potentially because of nondisjunction events during cell division.

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IMPORTANCE Patients with vascular malformations (VAMs) and vascular overgrowth syndromes have lower health-related quality of life (HRQoL) attributable to social stigmatization, poor mental health, severity, and pain. However, the factors that contribute to this decreased HRQoL are not clear.OBJECTIVE To perform a systematic review and meta-analysis of studies that used validated HRQoL instruments to compare the HRQoL of persons with VAMs with the US general population.DATA SOURCES A comprehensive search was performed in MEDLINE, Embase, PsycINFO, CINAHL, and Scopus from 1946 to March 31, 2017, with the consultation of an experienced librarian.STUDY SELECTION All VAM studies with validated HRQoL instruments published in the English language were included. Case reports, review articles, non-English-language publications, and studies about the development of new HRQoL instruments were not included.DATA EXTRACTION AND SYNTHESIS Two reviewers assessed studies' eligibility and the risk of bias and performed data extraction. The meta-analysis was performed using the random-effects model. Comparisons of means were performed using the unpaired, 2-sample t test. MAIN OUTCOMES AND MEASURESThe outcome was HRQoL.RESULTS Eleven studies met the inclusion criteria for a total of 692 patients with VAMs. Six studies (320 patients) were included in the meta-analysis, whereas 5 studies were included in the qualitative analysis (372 patients). Those with VAMs had lower 36-Item Short-Form Health Survey scores in bodily pain (mean difference, −11.87; 95% CI, −21.45 to −2.29; I 2 = 92%; P = .02) and mental health (mean difference, −6.04; 95% CI, −11.55 to −0.52; I 2 = 83%; P = .03) compared with the US general population. CONCLUSIONS AND RELEVANCEPatients with VAMs had increased pain and psychosocial distress compared with the US general population. Pain and psychological morbidity are associated with poorer HRQoL and may serve as indicators for quality of life.

In the anatomy laboratory, skill remains a critical component to unlocking the true value of learning from cadaveric dissection. However, there is little if any room for provision of instruction in proper dissection technique. We describe how near-peer instructors designed a supplemental learning activity to enhance the dissection experience for first-year medical students. This study aimed to evaluate the efficacy of this curriculum in improving participants' understanding of dissection technique and its impact on perceived challenges associated with the anatomy course. Curriculum was designed under faculty guidance and included didactic sessions, low-fidelity models, dissection, student presentations, and clinical correlations. Participants' (n = 13) knowledge of basic dissection techniques and concepts were assessed before the selective, and both participants' and nonparticipants' (n = 39) knowledge was assessed at the end of week one and week seven of the anatomy course. Scores were compared using repeated measures ANOVA followed by post hoc t-tests. Thirteen deidentified reflective essays were reviewed by four independent reviewers for themes that aligned with learning objectives. Participants in the selective course scored higher on assessment of dissection techniques and concepts one week after the selective compared to both nonparticipants and their own baseline scores before the selective. Analysis of student reflections resulted in four themes: confidence with dissection skill, sharing resources and transfer of knowledge, learning environment, and psychological impact of perceived challenges of the anatomy course. Near-peer driven supplemental exercises are effective in facilitating dissection skills. This dissection primer increases student confidence and alleviates apprehension associated with anatomy courses.